University of Adelaide€¦ · IV Acknowledgements First, I would like to thank my supervisor Dr. Jonathan George for his guidance during my PhD. I remember when I first joined the

Biomimetic Total Synthesis of Natural

Products

Thesis submitted for the degree of Doctor of Philosophy

Hiu Chun Lam

Bsc (Hons.) Chemistry

Department of Chemistry

University of Adelaide

Aug, 2017

II

To my family

III

Declaration

I certify that this work contains no material which has been accepted for the award of any

other degree or diploma in my name, in any university or other tertiary institution and, to the

best of my knowledge and belief, contains no material previously published or written by

another person, except where due reference has been made in the text. In addition, I certify

that no part of this work will, in the future, be used in a submission in my name, for any other

degree or diploma in any university or other tertiary institution without the prior approval of

the University of Adelaide and where applicable, any partner institution responsible for the

joint-award of this degree.

I give consent to this copy of my thesis, when deposited in the University Library, being

made available for loan and photocopying, subject to the provisions of the Copyright Act

1968.

I also give permission for the digital version of my thesis to be made available on the web,

via the University’s digital research repository, the Library Search and also through web

search engines, unless permission has been granted by the University to restrict access for a

period of time.

I acknowledge the support I have received for my research through the provision of an

Australian Government Research Training Program Scholarship

Hiu Chun Lam Date

IV

Acknowledgements

First, I would like to thank my supervisor Dr. Jonathan George for his guidance during my

PhD. I remember when I first joined the George group during my 2nd year of undergraduate

studies, Jonathan personally trained me in the laboratory. His passion and enthusiasm in

organic chemistry has influenced me greatly during my research studies, and his constant

presence in the laboratory has motivated me to work hard. In addition, Jonathan is

extraordinarily generous to send me to conferences in Europe and Australia, where I could

present my work and learn chemistry. For all the reasons above, my PhD experience has been

superb and it is my pleasure to work with Jonathan.

Next, I would like to thank the George group, for being supportive throughout my PhD. The

regular Wednesday group lunch and Friday drinking sessions have always been enjoyable. To

Kevin, thank you for being my mentor. To Justin, thanks for your help with the hyperjapone

project. To Henry, thank you for helping me with the verrubenzospirolactone project. I would

also like to thank Aaron where we worked on the rhodonoid project together. To all the new

additions of the George group (Aaron, Lauren, Stefania and Laura), I wish you all the best in

your PhD. To the prodigy JP, I also wish you good luck in your future postgraduate studies. I

would like to specifically thank Kevin and Justin, for their company on my roller coaster

research journey. Their encouragement has always been helpful. I will cherish the good times

we had inside and outside of the laboratory.

I would like to thank Professor Andrew Abell to allow me to use his group’s HPLC and

polarimeter. To Professor Chris Sumby, thank you for running all the single crystal X-ray

crystallography. To the Sumby/Doonan group (particular Michael, Alex, Natasha and Rob),

thanks for examining the crystals after we have recrystallized them in the laboratory. I would

like to thank eResearch SA to grant my access to the supercomputer Tizard and the database

for theoretical calculations. To Professor Greg Metha and Dr. David Huang and their groups,

thank you for teaching me to perform the theoretical calculations. To Phil, thank you for

running the NMR machines and mass spectrometers. To Dr. Justin Chalker from Flinders

University, thank you for giving us chemicals for my research project. I would like to thank

the University of Adelaide, it is my privilege to study for a PhD here.

At the end, I would like to thank my family for their support, specifically my parents Kent

and Daisy, my sister Elva for their unconditional love.

V

Abstract

This thesis describes several syntheses of natural products. The overall synthetic approach is

to mimic how these secondary metabolites could be derived in Nature, where we aim to gain

insights into the biosynthesis of these natural products from the syntheses.

The first synthesis of hyperjapones A-I was achieved by an oxidative hetero-Diels-Alder

reaction. The transformation of hyperjapone A to hyperajaponols A and C was achieved via

an epoxidation and an acid-catalysed rearrangement cascade reaction, forming 4 stereocenters

and 2 rings in 1 step.

The first synthesis of verrubenzospirolactone was achieved from a Diels-Alder reaction of the

polyene in water. Capillobenzopyranol, the proposed biosynthetic precursor of

verrubenzospirolactone was also synthesized and converted into verrubenzospirolactone by

mirroring our proposed biosynthetic pathway.

The first synthesis of rhodonoids C and D, and murrayakonine D was achieved. The key

biomimetic step was the acid catalysed rearrangement of an epoxide, forming 3 stereocenters

and 2 rings in 1 step.

The biomimetic total synthesis of yezo’otogirin C was achieved via an oxidative radical

cyclization cascade reaction, forming 2 rings, 2 stereocenters, 1 C=C bond, 1 C-C bond and 1

C-O bond in 1 step.

VI

List of abbreviations

ºC degree Celsius

Å Angstrom 1H Hydrogen-1 13C Carbon-13

18-crown-6 1,4,7,10,13,16-Hexaoxacyclooctadecane

Ac acetyl

AIBN azobisisobutyronitrile

aq. aqueous

atm atmospheric

Bn benzyl

br broad

Bu butyl

c concentration for specific optical rotation measurements

CAN ceric ammonium nitrate

cm-1 wavenumber

conc. correlation spectroscopy

CSA 1-(S)-(+)-10-camphorsulfonic acid

DBU 1,8-diazobicycloundec-7-ene

DDQ 2,3-dichloro-5,6-dicyano-para-benzoquinone

DIBAL-H diisobutylaluminium hydride

DMF dimethylformamide

DMSO dimethyl sulfoxide

dr diastereomeric ratio

ESI electrospray ionization

epi epimer

equiv. equivalents

Et ethyl

g grams

h hours

HMBC heteronuclear multiple bond correlation spectroscopy

HPLC high performance liquid chromatography

HRMS high resolution mass spectrometry

HSQC heteronuclear single quantum correlation spectroscopy

VII

Hz Hertz

hν light

i-Pr isopropyl

IR infrared

J coupling constant

KHMDS potassium hexamethyldisilazide

KO-tBu potassium tert-butoxide

LDA lithium diisopropylamine

m-CPBA meta-chloroperoxybenzoic acid

Me methyl

MHz megahertz

min minutes

Mp melting point

Ms mesyl

NBS N-bromosuccinimide

n-BuLi n-butyllithium

NMO N-methylmorpholine

NMR nuclear magnetic resonance

NOESY Nuclear Overhauser Effect Spectroscopy

Nu nucleophile

o-DCB 1,2-dichlorobenzene

o-quinone methide ortho-quinone methide

p-TsOH para-toluenesulfonic acid

PCC pyridinium chlorochromate

Pd2(dba)3 tris(dibenzylideneacetone)dipalladium (0)

PDC pyridinium dichromate

Pd/C palladium on activated carbon

PhI(OAc)2 (Diacetoxyiodo)benzene

PhMe toluene

P(o-tol)3 Tri(o-tolyl)phosphine

ppm part per million

Rf retention factor

VIII

Rh2[(R)-RTAD]4 tetrakis[(R)-(–)-(1-adamantyl)-(N-

phthalimido)acetate]dirhodium (II)

rt room temperature

SN1 unimolecular nucleophilic substitution

SN2 bimolecular nucleophilic substitution

TBAF tetrabutylammonium fluoride

TBAB tetrabutylammonium bromide

TBAI tetrabutylammonium iodide

TBDPS tert-butyldiphenylsilyl

TBS tert-butyldimethylsilyl

TEMPO 2,2,6,6-tetramethyl-1-piperidinyloxy

TFA trifluoroacetic acid

Tf trifluoromethanesulfonate

THF tetrahydrofuran

TLC thin layer chromatography

TMS trimethylsilyl

TPAP tetrapropylammonium perruthenate

w/w mass percentage

IX

Table of Contents

Declaration ............................................................................................................................. IIIAcknowledgements ................................................................................................................ IVAbstract ................................................................................................................................... VList of abbreviations .............................................................................................................. VI Chapter 1 - General Introduction

1.1. Natural products synthesis ........................................................................................... 11.2. Biomimetic total synthesis of natural products .......................................................... 41.3. References ...................................................................................................................... 7 Chapter 2 - Biomimetic Total Synthesis of Hyperjapones A-I, and Hyperjaponols A and C2.1. Introduction ................................................................................................................... 82.1.1. Diels-Alder reaction ..................................................................................................... 82.1.2. Chemistry of humulene (2.11) ..................................................................................... 92.1.3. Chemistry of caryophyllene (2.30) ............................................................................. 112.1.4. Isolation of hyperjapones and hyperjaponols ............................................................. 142.1.5. Proposed biosynthesis of hyperjapone A (2.49) and hyperjaponols A-C (2.54–2.56)152.2. Results and discussion ................................................................................................. 172.2.1. Synthesis of norflavesone (2.58) ................................................................................ 172.2.2. Biomimetic total synthesis of hyperjapones B (2.50) & D (2.52) .............................. 182.2.3. Investigation on the hetero-Diels-Alder reaction ....................................................... 192.2.4. Biomimetic total synthesis of hyperjapone A (2.49) .................................................. 222.2.5. Biomimetic total synthesis of hyperjaponol C (2.56) ................................................ 222.2.6. Biomimetic total synthesis of hyperjaponol A (2.54) ................................................ 252.2.7. Biomimetic total synthesis of hyperjapones C (2.51) and E (2.53) ........................... 282.2.8. Isolation of hyperjapones F to I (2.87–2.90) .............................................................. 302.2.9. Biomimetic total synthesis of hyperjapones F and G (2.87 & 2.88) .......................... 302.2.10. Biomimetic total synthesis of hyperjapone H (2.89) ................................................ 312.2.11. Biomimetic total synthesis of hyperjapone I (2.90) ................................................. 312.2.12. Preliminary theoretical calculations of the transition state of cationic alkene cyclization/1,2-shift ................................................................................................................. 322.3. Summary ...................................................................................................................... 342.4. References .................................................................................................................... 362.5. Experimental ................................................................................................................ 382.5.1. General methods ......................................................................................................... 382.5.2. Experimental procedures ............................................................................................ 392.5.3. NMR spectra .............................................................................................................. 612.5.4. Tables of 1H and 13C NMR data ............................................................................... 1192.5.5. Single crystal X-ray data .......................................................................................... 1292.5.6. Computational Data .................................................................................................. 1312.5.7. References ................................................................................................................ 142

X

Chapter 3 - Biomimetic Total Synthesis of Verrubenzospirolactone3.1. Introduction ............................................................................................................... 1433.1.1. Diels-Alder reaction of furan ................................................................................... 1433.1.2. Furan oxidation ........................................................................................................ 1433.1.3. Syntheses and reactions of 2H-chromene ................................................................ 1453.1.4. Isolation of verrubenzospirolactone ......................................................................... 1483.1.5. Aims of this study .................................................................................................... 1503.2. Results and discussion ............................................................................................... 1513.2.1. Synthesis of aldehyde 3.48 ....................................................................................... 1513.2.2. Synthesis of the Horner-Wadsworth-Emmons reagent 3.47 .................................... 1533.2.3. Biomimetic total synthesis of verrubenzospirolactone (3.38) .................................. 1533.2.4. Synthesis of capillobenzopyranol (3.39) and its oxidation ...................................... 1583.2.5. Biomimetic total synthesis of verrubenzospirolactone (3.38) .................................. 1603.2.6. Bioinspired cascade reaction .................................................................................... 1623.3. Summary .................................................................................................................... 1673.4. References .................................................................................................................. 1693.5. Experimental .............................................................................................................. 1713.5.1. General methods ....................................................................................................... 1713.5.2. Experimental procedures .......................................................................................... 1723.5.3. NMR spectra ............................................................................................................ 2023.5.4. Table of 1H and 13C NMR data ................................................................................ 2583.5.5. Single crystal X-ray data .......................................................................................... 2593.5.6. References ................................................................................................................ 263Chapter 4 - Biomimetic Total Synthesis of Rhodonoids C and D, and Murrayakonine D

4.1. Introduction ............................................................................................................... 2644.1.1. Isolation of rhodonoids and murrayakinone D ......................................................... 2644.1.2. Total synthesis of (±)-rhodonoids A (4.1) and B (4.2) by Hsung ............................ 2654.1.3. Proposed biosynthesis of rhodonoids C and D ......................................................... 2674.1.4. Epoxide cyclisation reaction in the synthesis of siccanin (4.28) by Trost ............... 2684.2. Results and discussion ............................................................................................... 2704.2.1. Biomimetic total synthesis of rhodonoids C and D .................................................. 2704.2.2. Investigation on the reactivity of the epoxide 4.18 .................................................. 2734.2.3. Synthesis of mahanimbine (4.5) ............................................................................... 2764.2.4. Biomimetic total synthesis of murrayakonine D (4.6) ............................................. 2774.2.5. Biomimetic total synthesis of rhodonoids C and D reported by Hsung ................... 2784.3. Summary .................................................................................................................... 2794.4. References .................................................................................................................. 2804.5. Experimental .............................................................................................................. 2814.5.1. General methods ....................................................................................................... 2814.5.2. Experimental procedures .......................................................................................... 2824.5.3. NMR spectra ............................................................................................................ 3064.5.4. Tables of 1H and 13C NMR data ............................................................................... 3464.5.5. Single crystal X-ray data .......................................................................................... 3504.5.6. References ................................................................................................................ 352

XI

Chapter 5 - Biomimetic Total Synthesis of Yezo'otogirin C

5.1. Introduction ............................................................................................................... 3535.1.1. Reductive radical cyclization ................................................................................... 3535.1.2. Oxidative radical cyclization .................................................................................... 3535.1.3. Isolation of yezo’otogirins A-C ................................................................................ 3555.1.4. Proposed biosynthesis of yezo’otogirn A (5.19) ...................................................... 3565.1.5. Previous biomimetic total synthesis of yezo’otogirin A (5.19) ............................... 3575.1.6. Previous bioinspired total synthesis of yezo’otogirin C (5.21) by Lee .................... 3585.1.7. Aims of this project .................................................................................................. 3595.2. Results and discussion ............................................................................................... 3605.2.1. Synthesis of 6-epi-pre-yezo’otogirin C (5.37) ......................................................... 3605.2.2. Synthesis of yezo’otogirin C (5.21) from 6-epi-pre-yezo’otogirin C (5.37) ............ 3615.2.3. Synthesis of yezo’otogirin C (5.21) from pre-yezo’otogirin C (5.38) ..................... 3625.2.4. Improved total synthesis of yezo’otogirin C (5.21) reported by Lee. ...................... 3655.3. Summary .................................................................................................................... 3665.4. References .................................................................................................................. 3675.5. Experimental .............................................................................................................. 3685.5.1. General methods ....................................................................................................... 3685.5.2. Experimental procedures .......................................................................................... 3695.5.3. NMR spectra ............................................................................................................ 3815.5.4. Table of 1H and 13C NMR data ................................................................................ 3925.5.5. References ................................................................................................................ 393

1

1. Introduction

1.1. Natural products synthesis

Mankind has achieved great discoveries due our curious and adventurous nature, from

looking for new species in rain forests and deep oceans, to searching for new subatomic

particles in the Large Hadron Collider. For organic chemists, a primary interest is in naturally

occurring small molecules. Nature has a great library of these secondary metabolites and we

have only discovered a fraction of it. Every week, there are isolation reports of new natural

products, varying in structural complexity and biological activity. These organic molecules

are not derived by chance or randomness, but by selective pressure in Nature. Therefore, each

natural product has its purpose and role that is crucial to the hosts (plants, bacteria, fungi).

These species are often limited in resources (precursors or reagents, narrow range of

temperature etc.), but still manage to generate molecules with intriguing and fascinating

structures.1 To organic chemists, the occurrence of these natural products is an intimidating

challenge presented by Nature, and we wonder if we could synthesize them in laboratory.

100 years ago, Professor Robert Burns Woodward was born, who later dedicated his career to

natural products synthesis and opened a new era in organic chemistry.2 He synthesized

numerous natural products, including cholesterol (1.1)3 and chlorophyll a (1.2) (Figure 1.1).4

One of the Woodward’s syntheses is the formal synthesis of vitamin B12 (1.3).5 Vitamin B12

(1.3) is the most structurally complex of all vitamins; the corrin ring contains 9 stereocenters

and 6 of them are contiguous. Woodward and Eschenmoser, along with 99 researchers,

together took 11 years to accomplish this great achievement.

Figure 1.1: Selected examples of Woodward’s syntheses.3,4,5,6,7,8

N N

NN

H2NOC

H

H2NOC

HH

H2NOC

H2NOC

H

H

CONH2CONHisopropanolphosphate

ribosedimethylbenzimidazole

Co

CN **

*****

**

1.3: vitamin B12

CONH2

HO

H

HH

H N

N N

N

O

Mg

CO2Me

O O

1.2: chlorophyll a1.1: cholesterol

2

Scheme 1.1: Formal synthesis of vitamin B12 by Woodward and Eschenmoser.5,7,8

N NH

OO

CO2Me

H

CO2MeH

O

1.4: β-corrnosterone

****

**

NH

O

MeO2C

MeO2C

NHH

MeO2C

CNBr

D

A***

***

N

O

O

HCO2Me

HN

SH

B

C

*

*

1.6: thiodextrolin1.5

KOt-BuNH

O

MeO2C

MeO2C

NHH

MeO2C

CN

D

A***

***

N

O

O

HCO2Me

HN

S

B

C

*

CO2Me

CO2Me

P(CH2CH2CN)3TFA, CH3NO2

NH

O

MeO2C

MeO2C

NHH

MeO2C

CN

D

A***

***

HN

O

O

HCO2Me

N

B

C

*

H

CO2Me

N N

NN

MeO2C

H

MeO2C

HH

MeO2C

Me2NOC

H

H

CO2MeNC

Zn

*

****

**

X

S CO2Me

N N

NN

MeO2C

H

MeO2C

HH

MeO2C

Me2NOC

H

H

CO2MeNC

Zn

*

****

**

X

S CO2Me

I2, MeOH

N N

NN

MeO2C

H

MeO2C

HH

MeO2C

Me2NOC

H

H

CO2MeNC

Co

*

****

* CN

CO2Me3 8

13CN

1. PPh3, TFA, DMF2. CoCl3, THF

N N

NN

MeO2C

H

MeO2C

HH

MeO2C

H

CO2MeNC

Co

*

****

* CN3

13CN

O

O

CO2Me*

N N

NN

MeO2C

H

MeO2C

HH

MeO2C

H

CO2MeNC

Co

*

****

* CN3

13CN

O

O

CO2Me*

PhS

SPh

N N

NN

MeO2C

H

MeO2C

HH

MeO2C

H

CO2MeNC

Co

*

****

* CN

13CN

*CO2Me

H

CO2Me

*

Raney Ni, CH2N2

O

ClSH

2.

1.

1. H2SO42. N2O4, NaOAcCCl4N N

NN

MeO2C

H

MeO2C

HH

MeO2C

H

CO2MeHOOC

Co

*

****

* CN

CN

*CO2Me

H

CO2Me

*liq. NH3, NH4Clethylene glycol

*

1.16: cobyric acid

N N

NN

H2NOC

H

H2NOC

HH

H2NOC

H

CONH2HOOC

Co

*

****

* CN

CN

*CONH2

H

CONH2

*

*

I2, AcOH

1.7

1.10 1.9 1.8

1.11 1.12 1.13

1.15 1.14

10

8

13

7

3

The synthesis of B12 began from preparation of β-corrnosterone (1.4) in 32 steps, which

possessed 6 contiguous asymmetric carbon atoms and the A-D ring of B12. β-Corrnosterone

(1.4) was then converted into 1.5, which was ready to be coupled with thiodextrolin (1.6).

Thiodextrolin (1.6) was prepared in 21 steps, and it existed as two diastereoisomers differing

on the stereocenter C-8 in ring B. The two diastereoisomers could be separated but the C-8

stereocenter was readily epimerised. Hence, thiodextrolin (1.6) was used as a mixture in the

coupling step. The thiolactam of thiodextrolin (1.6) was deprotonated using KOt-Bu, which

then attacked the bromide 1.5 to give 1.7. 1.7 was transformed into 1.8 by TFA which united

the A-D ring and the B-C ring with a C-C bond. However, in this process, the

stereochemistry at C-13 on ring C was lost. 1.8 was then converted into 1.9 which contained

a thiolactam and a terminal alkene. Oxidative cyclization of 1.9 using I2 afforded 1.10. 1.10

was then rearranged to the corrin ring by TFA and the Zn metal center was replaced by Co

ion to give 1.11. During the transformation of the thioether 1.10 to the corrin ring, the

stereocenter C-3 on ring A was lost. Thus, a total of 3 stereocenters in 1.11 were lost in the

sequence of these reactions and 1.11 was in fact in a mixture of 8 diastereoisomers. 1.11

underwent an oxidative cyclization to give 1.12 which contained a lactone. The formation of

the lactone corrected the stereochemistry at C-8 because of the amide at C-7 dictated the

stereochemistry at C-8 during the cyclization. The lactone ring also provided steric hindrance

to avoid substitution occurring at C-10 in the next step. The substitution was conducted using

benzyl chloromethyl ether, followed by substitution of chloride to phenylthiol ether which

gave 1.13. The presence of phenylthiol ether allowed the separation of the mono-substituted

and the di-substituted compounds. The phenylthiol ethers 1.13 was then reduced to methyl

group by Raney Ni; in the same step, the lactone on ring C was also cleaved and methylated

to give the methyl ester 1.14. At this stage, HPLC and high pressure liquid-liquid partition

chromatography were used to isolate 1.14 with the desired stereochemistry at C-3. The two

diastereoisomers differing at C-13 could be separated at this point but it was not important

because in the next step, when the cyanide group was hydrolysed into an amide group using

H2SO4, the stereocenter C-13 would be epimerised and hence the two diastereoisomers of

1.14 (at C-13) were used in the hydration step. The amide with the correct stereochemistry

would then be isolated from HPLC, followed by conversion to carboxylic acid 1.15 using

nitrogen tetroxide. All methyl esters on 1.15 were converted into amide by liquid NH3 with

catalytic NH4Cl to give cobryic acid (1.16). Cobryic acid (1.16) was previously converted

into Vitamin B12 (1.3) by Friedrich.9 This concluded the formal synthesis of B12 by

Woodward and Eschenmoser.5,7,8

4

Recently, I was lucky to meet Professor Ian Fleming and Professor Leon Ghosez, and they

were very kind to share their stories, particularly about working with Professor Woodward as

postdoctoral researchers. Their memorable time included discussing chemistry with Professor

Woodward, and witnessing him tremendously excited (no less than the researchers) when

someone produced perfect crystals.

Today, I am grateful to work with my supervisor Dr. Jonathan George, and had experienced

great satisfaction when we synthesized and isolated natural products in the laboratory,

especially when the NMR data from the isolation and the synthetic sample is perfectly

matched. I believe this is the ultimate motivation for organic chemists to pursue total

synthesis.

1.2. Biomimetic total synthesis of natural products

A natural product can be synthesized by numerous possible pathways, and we are only

limited by our imagination. Our group is interested in synthesizing these organic molecules

by mimicking how they could be derived in Nature, specifically if they are generated from a

pre-disposed, non-enzymatic biosynthesis. Assuming the biosynthetic hypothesis is correct,

organic chemists should be able to reproduce the chemistry in a laboratory setting.

Scheme 1.2: Biomimetic total synthesis of tropinone (1.20) reported by Robinson.10

Sir Robert Robinson reported the first example of a biomimetic total synthesis 100 years ago

in the synthesis of tropinone (1.20), which was prepared from a three-component one-pot

synthesis (Scheme 1.2). Not only does the molecular complexity increase dramatically in one

step, but the connection of the new rings and the relative stereochemistry in the molecule are

all correctly installed in this reaction.

Thus, the initial phase of biomimetic synthesis would require speculation on how rings and

stereocenters of natural products are derived from their corresponding biosynthetic precursors.

Subsequently, these compounds would be synthesized while mirroring the proposed

biosynthesis using simple chemical reagents. At the end of the synthesis, organic chemists

would gain insights onto the biosynthetic pathways of these natural products, as a feedback to

the biosynthetic proposal.

COH

COH

1.17: succinaldehyde

MeNH2

1.18: methylamine

O

CO2H

CO2H1.19: 3-oxopentanedioic acid

N

O

heat +CO2+H2O

1.20: tropinone

5

While the biosynthetic precursors may not be synthesized using a biomimetic approach, we

aim to develop concise methods to construct those molecules. For instance, we would avoid

unnecessary redox reactions, and minimise functional group and protecting group

manipulations. Since the report of tropinone synthesis by Robinson, organic chemists have

been utilising this philosophy and strategy to synthesize natural products, as the biomimetic

approach is arguably the quickest and most economical way to access a natural product. One

recent example is the biomimetic total synthesis of homodimericin A (1.28). (±)-

Homodimericin A (1.28) was isolated by Clardy in 2016 from a pair of species, bacteria

Streptomyces sp. 4231 and fungi Trichoderma harzianum.11 Homodimericin A (1.28) was

isolated as a racemate and hence suggesting it is likely to be derived via a pre-disposed, non-

enzymatic biosynthesis. As outlined in our proposed biosynthesis (Scheme 1.3), oxidation of

1.21 could give quinone 1.22. Dimerisation of 1.22 via a Michael reaction could afford 1.23,

followed by a second Michael reaction to give 1.24. Oxidation of 1.24 could give 1.25, which

then undergoes intramolecular Diels-Alder reaction to give 1.26. Tautomerisation of the enol

1.26 (highlighted in blue) could afford 1.27. Intramolecular aldol reaction of 1.27 could then

afford homodimericin A (1.28). The isolation chemists also proposed a similar biosynthesis

with a different order of Michael reaction and oxidation but the overall proposal is the

same.11 In June 2017, the biomimetic total synthesis of homodimericin A (1.28) was reported

by three independent groups (Tang12, Wang13, Yang14). Each reported a unique way to

synthesize the monomer 1.21, but the chemistry to achieve homodimericin A (1.28) was

identical. This showcases biomimetic total synthesis of natural products is highly robust, and

also remarkably attractive to organic chemists as shown in all three reports.

6

Scheme 1.3: Our proposed biosynthesis of homodimericin A (1.28). Also later reported

by Tang12 and Wang13.

OH

OH

HO

OHoxidation

O

O

HO

OH

O

O

HO

OH

O

O

HO

OO

O

OH

HOH

OOH

O

OH

OHO

OH

OH

OO

O

OH

OHO

OH

OH

O

O

HO

O

O

OH

HOO

O

O

HO

O

O

OH

OOH

Michael addition/dimerisation

Michael addition

oxidationDiels-Alder

reaction

formalaldol reaction

1.21

1.22

1.22

1.23

1.241.25

1.27 1.28: (±)-homodimericin A

O

O

HO

O

O

OH

OOH

1.26

tautomerisation

7

1.3. References

1. Nicolaou, K. C.; Vourloumis, D.; Winssinger, N.; Baran, P. S. Angew. Chem. Int. Ed., 2000, 39, 44.

2. Halford, B. Chemical and Engineering News, 2017, 95. 3. Woodward, R. B.; Sondheimer, F.; Taub, D. J. Am. Chem. Soc., 1951, 73, 3548. 4. Woodward, R. B.; Ayer, W. A.; Beaton, J. M.; Bickelhaupt, F.; Bonnett, R.;

Buchschacher, P.; Closs, G. L.; Dutler, H.; Hannah, J.; Hauck, F. P.; Ito, S.; Langemann, A.; Legoff, E.; Leimgruber, W.; Lwowski, W.; Sauer, J.; Valenta, Z.; Volz, H. J. Am. Chem. Soc., 1960, 82, 3800.

5. Woodward, R. B. Angew. Chem. Int. Ed., 1963, 75, 871. 6. Woodward, R. B. Science, 1966, 153, 487. 7. Woodward, R. B. Pure and applied chemistry. Chimie pure et appliquee, 1968, 17,

519. 8. Woodward, R. B. Pure and applied chemistry. Chimie pure et appliquee, 1971, 25,

283. 9. Friedrich, W.; Gross, G.; Bernhauer, K.; Zeller, P. Helv. Chim. Acta., 1960, 43, 704. 10. Robinson, R. J. Chem. Soc., Trans., 1917, 111, 762. 11. Mevers, E.; Sauri, J.; Liu, Y.; Moser, A.; Ramadhar, T. R.; Varlan, M.; Williamson, R.

T.; Martin, G. E.; Clardy, J. J Am Chem Soc, 2016, 138, 12324. 12. Feng, J.; Lei, X.; Guo, Z.; Tang, Y. Angew. Chem. Int. Ed., 2017, 56, 7895. 13. Ma, D.; Liu, Y.; Wang, Z. Angew. Chem. Int. Ed., 2017, 56, 7886. 14. Huang, J.; Gu, Y.; Guo, K.; Zhu, L.; Lan, Y.; Gong, J.; Yang, Z. Angew. Chem. Int.

Ed., 2017, 56, 7890.

8

Chapter 2

Biomimetic Total Synthesis of Hyperjapones A-I, Hyperjaponols A and C

2.1. Introduction

2.1.1. Diels-Alder reaction

Figure 2.1: An illustration of Diels-Alder reaction.

The Diels-Alder reaction is a classic reaction in organic synthesis, where by a diene and a

dienophile undergo a concerted cycloaddition to give a 6-membered ring (Figure 2.1).1 There are

numerous examples in the literature where Diels-Alder reactions are involved in natural product

syntheses.2,3,4 For example, in the total synthesis of (–)-furaquinocin C (2.6) reported by Smith5

(Scheme 2.1), two silyl enol ethers were generated from the deprotonation of the ketone 2.1 to give

diene 2.3. Diene 2.3 and dienophile 2.4 then underwent a Diels-Alder reaction to give intermediate

2.5, followed by elimination, rearomatization and desilylation to give (–)-furaquinocin C (2.6) in 1

step.

Scheme 2.1: Total synthesis of (–)-furaquinocin C (2.6) by Smith.5

A reaction is classified as a hetero-Diels-Alder reaction when it involves one or more heteroatoms

during the cycloaddition. An example is the total synthesis of variecolortide A (2.10) by Trauner6

(Scheme 2.2), where the heterodiene hydroxyviorcristin (2.7) and the dienophile isoechinulin B (2.8)

underwent a hetero-Diels-Alder reaction to afford intermediate 2.9. 2.9 was oxidized by air in the

same pot to give (±)-variecolortide A (2.10).6 More recent examples of hetero-Diels-Alder reactions

in natural product synthesis have been summarised elegantly by Heravi.7

"diene""dienophile"

Diels-Alder reaction

O

OMeO

O

OH

2.6: (−)-furaquinocin C51%

O

OMeO

O

OTMS

Br

TMSOO

OMeO

O

OTMS

TMSO

BrDiels-Alderreaction

elimination/rearomatization/

desilylation

2.5 2.32.4

O

OTMS

TMSO

2.3

O

OTMS

O

2.2

O

O

O

2.1

LDA, TMSClTHF, –78 °C LDA, TMSCl

9

Scheme 2.2: Total synthesis of variecolortide A (2.10) by Trauner.6

2.1.2. Chemistry of humulene (2.11)

Figure 2.2: Structure of humulene (2.11).

Humulene (2.11) is a cyclic sesquiterpene natural product containing three alkenes (Figure 2.2).

Each alkene possesses different reactivity, as shown in an epoxidation study by Fujita (Scheme 2.3).

When humulene (2.11) was treated with one equivalent of m-CPBA, the major product of the

reaction was epoxide 2.12. The results from this study suggested that the Δ1,2-alkene in humulene

(2.11) is the most reactive, followed by the Δ8,9-alkene and lastly the Δ4,5-alkene.8 The hypothesis is

in good agreement with the results from the diepoxidation of humulene (2.11), which afforded

epoxide 2.15 (Scheme 2.3).

Scheme 2.3: Epoxidation of humulene (2.11) by Fujita.8

In addition, humulene epoxide 2.13 has been shown to undergo an acid catalysed rearrangement

reaction. Roberts reported a synthesis of 2.19 by treating humulene epoxide 2.13 with SnCl4 in

CH2Cl2 at –60 ºC. The proposed mechanism starts from the isomerisation of alkene 2.13 to give

2.16, followed by an alkene cyclisation to form a 6-membered ring 2.17, which then undergoes a

O

OOH

HO

OH

HNNH

O

O

HN

2.10: (±)-variecolortide A48%

O

OHOH

HO

O

HNNH

O

O

HN

oxidation/tautomerisation

O

OHOH

HO

O

HNNH

O

O

HN

2.7: hydroxyviorcristin

2.8: isoechinulin B


2.9

o-DCB, air, 180 °C

1

25

4

89

2.11: humulene

45 21

8 9

OO

O++

m-CBPA (1 eq.)CH2Cl2,−10 °C to rt

m-CBPA (2 eq.)CH2Cl2,−10 °C to rt

2.15 2.12 2.13 2.142.11: humulene(75%) (14%) (5%)(30%)

O

O45 2

1

8 9

10

1,2-alkyl shift to give the tertiary carbocation 2.18. Finally, a 1,2-hydride shift followed by

deprotonation to give 2.19 (Scheme 2.4).9

Scheme 2.4: Synthesis of 2.19 from acid catalysed rearrangement from 2.13 reported by

Roberts.9

Humulene (2.11) has also been used as a dienophile in hetero-Diels-Alder reactions, such as the

biomimetic total syntheses of guajadial B (2.23) by Liu10 (Scheme 2.5) and lucidene (2.27) by

Baldwin11,12 (Scheme 2.6). Guajadial B (2.23) was synthesized in a three-component, one-pot

reaction, presumably derived from the formation of o-quinone methide intermediate 2.22 via a

Knoevenagel condensation between benzaldehyde (2.20) and 2.21, followed by hetero-Diels-Alder

reaction with humulene (2.11). The biomimetic synthesis afforded 45% yield of guajadial B (2.23),

along with 19% yield of 2.24.

Scheme 2.5: Biomimetic total synthesis of guajadial B (2.23) by Liu.10

1,2-H shift/deprotonation

HOHO

H

H

HO

1,2-alkyl shift

2.13 2.17

2.182.19

25%

O

SnCl4, CH2Cl2−60 °C

2.16

Oisomerisation

alkenecyclization

O

H

CHOOH

CHOOH

2.23: (±)-guajadial B45%

O

H

CHOOH

CHOOH

2.2419%

+

2.11: humulene3 equiv.

OCHO

OH

CHOOH

2.11: humulene 2.22

hetero-Diels-Alderreaction

O

CHO

OHCHO

OHO

2.20: benzaldehyde2 equiv.

2.21

NaOAc, AcOH, 80 °C++ H

H

11

Similarly, lucidene (2.27) was synthesized by heating 2.25 and humulene (2.11) in a sealed tube,

where 2.25 first underwent elimination to give o-quinone methide intermediate 2.26, followed by

hetero-Diels-Alder reactions on the Δ1,2-alkene and Δ8,9-alkene of humulene (2.11) to give lucidene

(2.27) (Scheme 2.6). Both monoadduct 2.29 and isolucidene (2.28) were also isolated in the same

reaction.11,12 The synthesis of lucidene (2.27) and guajadial B (2.28) indicates the hetero-Diels-

Alder reaction between humulene (2.11) and o-quinone-methide is highly diastereoselective and

regioselective.

Scheme 2.6: Biomimetic total synthesis of lucidene (2.27) by Baldwin.11,12

2.1.3. Chemistry of caryophyllene (2.30)

Figure 2.3: Structure of caryophyllene (2.30).

Caryophyllene (2.30) is an enantiopure bicyclic sesquiterpene natural product with two alkenes

(Figure 2.3). Caryophyllene (2.30) could also undergo epoxidation, where the Δ4,5-alkene can be

oxidized spontaneously under air to give caryophyllene oxide (2.31).13 The trans-Δ4,5-alkene in the

9-membered ring of caryophyllene (2.30) is highly reactive because the ring strained in

caryophyllene (2.30) would be released after the reaction. Furthermore, caryophyllene oxide (2.31)

could also rearrange under reductive conditions to give 2.33 as the predominate product (Scheme

2.7).14

O

O

H

H

O

O


O

O

H

H

O

H

HO

HO

2.252.05 equiva.2.11: humulene

xylene, 170 °Cseal tube+

2.26

1

2

98

2.27: (±)-lucidene 2.28: (±)-isolucidene2.29

++

17%, 2.27/2.28 = 2.5:128%

H

H

2.30: caryophyllene

4

58

15

12

Scheme 2.7: Reductive acid-catalysed rearrangement reaction of caryophyllene oxide (2.31)

by Barrero.14

Alternatively, caryophyllene oxide (2.31) could be ring opened by tetracyanoethylene

(NC)2C=C(CN)2 to give 2.37 and 2.38 (Scheme 2.8). The authors hypothesized that the low energy

π* orbital in (NC)2C=C(CN)2 could interact with the electron-rich epoxide, followed by

fragmentation of epoxide to generate alkenes 2.37 and 2.38.15

Scheme 2.8: Cleavage of caryophyllene oxide (2.31) using (NC)2C=C(CN)2 reported by

Marcias-Sanchez.15

Unsurprisingly, caryophyllene (2.30) has also been used as a dienophile in hetero-Diels-Alder

reactions. In the synthesis of cytosporolide model 2.41 by the George group, o-quinone methide

2.40 was generated from 2.39 and HC(OEt)3, which then underwent a hetero-Diels-Alder reaction

with caryophyllene (2.30) to give 2.41 (Scheme 2.9).16 This synthesis of 2.41 supported the

structural reassignment of cytosporolides A–C.16 The total synthesis of cytosporolide A (2.45) was

later completed by Takao (Scheme 2.10), in which the key step was the hetero-Diels-Alder reaction

between a highly functionalised diene 2.43 and dienophile 2.42 to give 2.44.17 Deprotection of 2.44

gave cytosporolide A (2.45) in 63% over two steps.

H

H

2.30: caryophyllene

H

H

O

H

H

O

OH

H

H OH

H

H OH

H

H OH

H

H+++

Cp2TiCl2, Mn, 2,4,6-collidineTMSCl, THF, rt

+

55%, 2.31:2.32, d.r. 4:1

90%, 2.33:2.34:2.35:2.36, d.r. 20:9:5:1

m-CPBA, CH2Cl2, rt

2.31: caryophyllene oxide 2.32

2.33 2.34 2.35 2.36

H

H

O

H

H

OH

H

H

OH

71%13%

(NC)2C=C(CN)2acetone, reflux

+

2.31 2.37 2.38

13

Scheme 2.9: Synthesis of cytosporolide model 2.41 by the George group.16

Scheme 2.10: Total synthesis of (+)-cytosporolide A (2.45) by Takao.17

In a similar fashion, caryophyllene (2.30) was also incorporated in the syntheses of guajadial (2.46)

and psidial A (2.47) by Lee and coworkers.18 o-Quinone methide 2.22 was generated from

Knoevenagel condensation of benzaldehyde (2.20) and 2.21, followed by a hetero-Diels-Alder

reaction with caryophyllene (2.30) to give a mixture of guajadial (2.46) and psidial A (2.47),

alongside 2.48 (Scheme 2.1).18

Scheme 2.11: Biomimetic total synthesis of guajadial (2.46) and psidial A (2.47) by Lee and

coworkers.18

The 9-membered ring in caryophyllene (2.30) is flexible and it can adopt different conformations.

Calculations from Toma suggested a 33:44:23 ratio of the βα:αα:ββ conformations in caryophyllene

O

H

H

H

O

OH

MeO O

H

O

O

OH

MeO O

H

H

2.30: caryophyllene 2.40 2.41


MeO O

OH

HO

HO HC(OEt)3, TFA100 °C

2.3953%

O

H

HO

H

O

OH

HO O

OH OMeH

C7H15

OH

O

O

OH

HO O

H

OH

2.43

OMe

OBz

TESO

C7H15

2.42


O

HOH

H

O

OH

HO O

OBz OMeH

C7H15

OTES

1. DIBAL, CH2Cl2, –78 °C2. HF·pyridine, THF, rt

63% over 2 steps

2.45: (+)-cytosporolide A2.44

O

H

H

H

CHOOH

CHOOH

O

H

H

H

CHOOH

CHOOH

O

H

H

H

CHOOH

CHOOH

++

OCHO

OH

CHOOHH

H

2.30: caryophyllene


2.22

CHO

OHCHO

OHHO

OH

H

2.30: caryophyllene 2.20: benzaldehyde 2.21

5% w/w PTS (aq)100 °C

+

*PTS = PEG-600/α-Tocopherol-based diester of Sebacic acid

2.46: guajadial 2.47: psidial A 2.48

25%, 2.46:2.47:2.48, d.r. 3:1:1

H

+

1'1'1'

19

19

19

14

(2.30) (Figure 2.4).19 2.48 is presumably generated from the less abundant ββ caryophyllene

conformer, whereas guajadial (2.46) and psidial A (2.47) are derived from the more abundant βα

and αα conformers. Note that reacting with βα and αα conformers does not change the relative

stereochemistry between C-1 and C-9 with respect to the Δ4,5-alkene in caryophyllene (2.30). The

stereochemistry difference at C-1’ in guajadial (2.46) and psidial A (2.47) can be derived from the

steric/kinetic effect of the E/Z isomer of o-quinone methide 2.22.

Figure 2.4: Conformers of caryophyllene (2.30) and theirs theoretical population calculated

by Toma.19

2.1.4. Isolation of hyperjapones and hyperjaponols

Figure 2.5: Hyperjapones A-E (2.49–2.53)20 and hyperjaponols A-C (2.54–2.56).21

Hyperjapones A-E (2.49–2.53) are structurally related meroterpenoids that were isolated from

Hypericum japonicum by Xu (Figure 2.5).20 Hyperjapone A (2.49) is a racemic molecule containing

an 11/6/6 ring system, whereas all hyperjapones B-E (2.50–2.53) are enantiopure and possess a

4/9/6/6 ring system. Shortly after the isolation of hyperjapones, Zhang reported the isolation of

hyperjaponols A-C (2.54–2.56) from the same plant (Figure 2.5).21 Hyperjaponol C (2.56) contains

a 5/7/6/6 ring system with an unusual trans-isodaucane structure, and is the most stereochemically

complex among the three hyperjaponols. The racemic nature of hyperjaponols (2.54–2.56) implies

the presence of a non-enzymatic, highly pre-disposed biosynthesis.

βα33%

αα44%

ββ23%

αβ0%

H

H

2.30: caryophyllene

19

4

5 19

45 1

4

5

91

9

45

19

45

O

OH

O

OH

(±)-2.49: hyperjapone A

O

OH

O

OH

H

H

O

OH

O

OH

H

H

2.50: hyperjapone B 2.52: hyperjapone D

O

OH

O

OH

H

H

O

OH

O

OH

H

H

2.51: hyperjapone C

2.53: hyperjapone E

H

HO

OH

O

OH

H

HO

(±)-2.56: hyperjaponol C

O

OH

O

OHHO

(±)-2.54: hyperjaponol A

O

OH

O

OHHO

(±)-2.55: hyperjaponol B

15

2.1.5. Proposed biosynthesis of hyperjapone A (2.49) and hyperjaponols A-C (2.54–

2.56)

Scheme 2.12: Proposed biosynthesis of hyperjaponols A-C (2.54–2.56).

We propose the biosynthesis of hyperjaponols A-C (2.54–2.56) is derived from hyperjapone A

(2.49) (Scheme 2.12). Our proposed biosynthetic pathway begins from the trimethylation of

acylphloroglucinol 2.57, which gives norflavesone (2.58), a natural product isolated from a

flowering plant Lepsospermum scoparium.22 Oxidation of norflavesone (2.58) would give a

heterodiene intermediate 2.59, which undergoes a Diels-Alder reaction with humulene (2.11) to

form hyperjapone A (2.49). From the examples shown in the synthesis of lucidene (2.27)11,12 and

guajadial B (2.23),10 we predict that the hetero-Diels-Alder reaction would take place onto the Δ1,2-

alkene of humulene (2.11).

The X-ray crystal structure of hyperjapone A (2.49) shows that the Δ8,9-alkene adopting a

conformation such that one face of the alkene is exposed, while the other face is not accessible due

to the steric hindrance of the macrocycle.20 Therefore, the epoxidation of hyperjapone A (2.49)

should take place on the exposed face of Δ8,9-alkene to give 2.60. Epoxide 2.60 could be ring-

opened by acid to give tertiary carbocation 2.61, followed by cyclization onto the Δ4,5-alkene to

form a 6/7 membered ring system and a secondary carbocation 2.62.9 We predict that the

cyclization of 2.61 should be diastereoselective based on the geometry and the conformation of the

macrocycle of 2.61. A stereoselective 1,2-alkyl shift of 2.62 could generate the tertiary carbocation

2.63. The loss of a proton from the methyl group in carbocation 2.63 could afford hyperjaponol C

H

O O

OH O

HO OH

OH

HO O

OH O

2.58: norflavesone 2.11: humulene 2.59


2.49: (±)-hyperjapone A

trimethylation oxidation

humulene (XX)

epoxidation

1,2-alkyl shift

cation-alkene cyclization

H

2.57

concerted, asynchronous cation-alkene cyclization/1,2-alkyl shift

HO

H

O

HOH

O

O

2.60

HO

HH

OH

O

O

2.61

HO

HO

HH

OH

O

O

HO H

2.62

2.63

HO OH

O

O

HO H

HH H

O OH

O

O

HO H

2.56: (±)-hyperjaponol C

HH

ring-opening of epoxide

− H

− H

HO

HH

OH

O

O

2.54: (±)-hyperjaponol A 2.55: (±)-hyperjaponol B

H

HO

HH

OH

O

O

HOH

HO

HH

OH

O

O

HO

2.49: (±)-hyperjapone A

+

O

8 9

5 4

12

16

(2.56), while deprotonation of carbocation 2.61 would generate hyperjaponol A (2.54) or

hyperjaponol B (2.55).

In regards to the alkene cyclisation of carbocation 2.61 and the 1,2-alkyl shift in our proposed

biosynthesis of hyperjaponol C (2.56), it is possible that these processes might occur in a concerted,

asynchronous rearrangement, as supported by Tantillo’s hypothesis.23,24 Tantillo’s investigation into

the cationic rearrangement reactions of terpene natural products using theoretical calculations often

show that these rearrangements are not stepwise, but rather occur in a concerted manner.24 For

example, the proposed biosynthesis of presilphiperfolanol (2.67) involves a 1,2-alkyl shift/alkene

cyclisation of 2.64 to presilphiperfolanyl cation (2.66) (Scheme 2.13).25 Tantillo’s calculations

suggested the secondary carbocation 2.65 was not involved in the biosynthesis, but rather a 1,2-shift

and alkene cyclization of 2.64 occurred simultaneously to give 2.67 via a single transition state.23

We have also consulted Tantillo on the biosynthesis of hyperjaponol C (2.54), and he predicted that

it is likely to occur in a concerted, asynchronous rearrangement.

Scheme 2.13: Proposed biosynthesis of (–)-presilphiperfolanol (2.67).23,25

H

H H HH1,2-alkylshift

alkenecyclization

asynchronous, concerted rearrangment

2.662.652.64

HH

2.67: (–)-presilphiperfolanol

OHH2O

1,3-hydride shift/

17

2.2. Results and discussion

2.2.1. Synthesis of norflavesone (2.58)

Scheme 2.14: Acylation of phloroglucinol (2.68).

The synthesis began with the Friedel-Crafts acylation of phloroglucinol (2.68) using AlCl3 and i-

PrCOCl in PhNO2 at 65 ºC,26 the reaction worked smoothly and can be scaled up to 10 g (Scheme

2.14). We have also lowered the amount of isobutyryl chloride from 2 equiv. to 1.2 equiv. without

any loss of yield.

Scheme 2.15: Dearomative trimethylation reported by Nguyen.27

Scheme 2.16: Synthesis of norflavesone (2.58).

Nguyen and coworkers27 have reported a dearomative trimethylation on 2.69 using KOt-Bu and

MeI (Scheme 2.15), which was applied to acylphloroglucinol 2.57 and afforded norflavesone (2.58)

in good yield (Scheme 2.16). We also investigated whether using fewer equivalents of base and MeI

could give dimethylated acylphloroglucinol 2.71. Interestingly, we did not observe 2.71, but a lower

yield of trimethylated acylphloroglucinol 2.58. We hypothesize after the first methylation of 2.57,

the reactivity of the molecule increases until the third methylation has completed. This observation

was different from the prenylation of acylphloroglucinol 2.57 reported by George, where he

observed a mixture of diprenylated 2.72/2.73 and triprenylated acylphloroglucinol 2.74 (Scheme

2.17).28

HO OH

OH

HO OH

OH O2.68: phloroglucinol 2.57

i-PrCOCl, AlCl3PhNO2, 65 °C

87%

HO O

OH O

2.70

MeI, KOt-BuMeOH, reflux

HO

OH

2.69

72%

OH

O

HO O

OH O

2.58: norflavesone

MeI, KOt-Bu, MeOH, 65 °C

HO OH

OH O

2.57

79%

HO OH

OH O

HO O

OH O

not observed

2.71

18

Scheme 2.17: Dearomative prenylation reported by George28.

2.2.2. Biomimetic total synthesis of hyperjapones B (2.50) & D (2.52)

In the biomimetic total synthesis of hyperguinone B (2.77) reported by George, 2.75 was oxidized

by PhI(OAc)2 and TEMPO to give a heterodiene intermediate 2.76, which underwent a 6π

electocyclization to give hyperguinone B (2.77) (Scheme 2.18). We hoped that in a similar fashion,

norflavesone (2.58) could be oxidized to give the heterodiene intermediate 2.59, then undergoes a

hetero-Diels-Alder reaction with humulene (2.11) or caryophyllene (2.30).

Scheme 2.18: Biomimetic total synthesis of hyperguinone B (2.77) by George28.

To our delight, reaction with caryophyllene (2.30) and norflavesone (2.58) in the presence of

PhI(OAc)2 and TEMPO gave a 2.5:1 mixture of hyperjapones B (2.50) and D (2.52) in 26% overall

yield (Scheme 2.19). The ratio of hyperjapones B and D was in good agreement with the population

of conformers in caryophyllene (2.30), where the predominant βα and αα conformers reacted with

the heterodiene intermediate 2.59 to give hyperjapone B (2.50), while the less abundant ββ

conformer gave hyperjapone D (2.52).19 We found that the mixture of hyperjapones B and D were

impossible to separate by flash column chromatography or HPLC. Interestingly, we observed the

hyperjapones B (2.50) and D (2.52) mixture was not soluble in most organic solvents, where

hyperjapone B (2.50) could be selectively recrystallized from MeOH. Unfortunately, the filtrate still

contained a 1:1 mixture of hyperjapones B (2.50) and D (2.52). We have attempted to recrystallise

the hyperjapones B (2.50) and D (2.52) mixture with various other solvents, but to no avail. At this

point, we did not pursue further on the purification of hyperjapone D (2.52). The optical rotation of

hyperjapone B (2.50) is [!]!!" +10º (c 0.62, MeOH), which matches with the natural product [!]!!"

+5º (c 0.15, MeOH), and hence confirmed the absolute configuration of hyperjapone B (2.50).

HO O

OH O

39%

prenyl bromide, KOt-BuMeOH, 65 °C

HO OH

OH O

2.57

HO OH

OH O

HO O

OH O

30% 10%

2.742.72 2.73

+ +

HO O

OH O

PhI(OAc)2, TEMPO, THF−78 °C to rt O O

OH O

O O

OH O

2.77: hyperguinone B2.762.75

6π electrocyclization

73%

19

Scheme 2.19: Biomimetic total synthesis of hyperjapones B (2.50) and D (2.52).

2.2.3. Investigation on the hetero-Diels-Alder reaction

We then further investigated the oxidation of norflavesone (2.58) by screening different conditions

in an attempt to improve the yield for the oxidative cycloaddition (Table 2.1). First, we discovered

the reaction did not proceed at –78 °C to –40 °C, and the starting material would decompose if the

reaction started at room temperature. It suggests that the heterodiene 2.59 would be formed between

–40 °C and room temperature. We also performed a few control experiments to show that a

stoichiometric amount of TEMPO is essential for this oxidation. We have also attempted to improve

the reaction by screening various co-oxidants. For instance, Ag2O has been used as an oxidant to

generate an o-quinone methide 2.79 in the total synthesis of schefflone (2.80) (Scheme 2.20).29

From the collective results, we found that the combination of Ag2O and TEMPO gave the highest

overall yield of 60%.

Scheme 2.20: Biomimetic total synthesis of schefflone (2.80) using Ag2O as an oxidant by

Lei.29

2.58: norflavesone

O

OH

O

OH

H

H

O

OH

O

OH

H

H+


26%, d.r. 2.5:1 2.50/2.52

H

H

caryophyllene (2.30)PhI(OAc)2, TEMPO

THF, –78 °C to rtHO O

OH O

O

MeO

OOMe

OOMe

OMe

OMe

OMe

2.80: schefflone

O

MeO

O

MeO

OOMe

OMe

OMeOMe

OMe

OHOMe

Ag2O, benzene, rt

72%


2.782.79

20

Table 2.1: Conditions screened for the oxidative hetero-Diels-Alder reaction

caryophyllene (2.30)

(no of equiv.) oxidant(s) solvent conditions

combined yield of 2.50/2.52

2 DDQ (3 equiv.) PhMe rt, 1 h decomposition

1.2 DDQ (1.1 equiv.) PhMe −78 °C to rt, 16 h decomposition

2 PDC (1.2 equiv.) CH2Cl2 −78 °C to rt decomposition

2 MnO2 (4 equiv.) Et2O −78 °C to rt, 16 h decomposition

2 K3Fe(CN)6 (2 equiv.) MeCN/H2O 0 °C to rt, 16 h decomposition

2 CAN (1.2 equiv.) MeOH 0 °C, 1 h decomposition

2 Ag2O (1.2 equiv.) benzene rt, 4 h decomposition

2 PhI(OAc)2 (1.2 equiv.) THF −78 °C to rt, 4 h decomposition

2 IBX (1.5 equiv.) MeCN −40 °C to rt, 16 h 20%

2 PhI(OAc)2 (1.1 equiv.), TEMPO

(2 equiv.) THF −78 °C to rt, 4 h 26%

2 PhI(CF3COO)2 (1.1 equiv.),

TEMPO (2 equiv.) THF −78 °C to rt, 5 h 26%

2 PhI(OAc)2 (1.1 equiv.), TEMPO

(2 equiv.) THF rt, 1 h decomposition

1.2 PhI(OAc)2 (1.1 equiv.), TEMPO

(2 equiv.) THF −78 °C to rt, 4 h 26%


(2 equiv.) THF −78 °C to −40 °C, 2 h no reaction


(1.2 equiv.) THF −78 °C to 60 °C, 4 h 26%


(1.2 equiv.) Et2O −78 °C to rt, 4 h

32%

2 CAN (1.2 equiv.), TEMPO (1.2

equiv.) MeOH −78 °C to rt 4 h 39%

1.2 Ag2O (1.1 equiv.), TEMPO (1.2

equiv.) Et2O −78 °C to rt, 16 h 60%

2 Ag2O (1.1 equiv.), TEMPO (0.4


2 Ag2O (1.1 equiv.), TEMPO (0.2


2 TEMPO (2 equiv.) Et2O −78 °C to rt, 2 d 40%

2.58: norflavesone

O

OH

O

OH

H

H

O

OH

O

OH

H

H+


d.r. 2.5:1 2.50/2.52

H

H

caryophyllene (2.30)HO O

OH O

21

Here, we proposed two possible oxidation pathways for the formation of heterodiene 2.59 (Scheme

2.21). The first pathway involves a single electron oxidation of TEMPO to a reactive species 2.81,

which then reacts with norflavesone (2.58) via a hydride transfer to give heterodiene 2.59. The

second pathway suggests norflavesone (2.58) undergoing a single electron oxidation by TEMPO to

give a radical intermediate 2.82, which then further oxidized to heterodiene 2.59. From the control

experiment where 2 equiv. of TEMPO was used for the oxidative hetero-Diels-Alder reaction, and

40% yield of hyperjapones B (2.50) and D (2.52) was obtained, we propose the second oxidation

pathway is more plausible.

Proposed mechanism 1:

Proposed mechanism 2:

Scheme 2.21: Proposed oxidation mechanism of norflavesone (2.58) by TEMPO.

NO

[O]NO

O O

OH O

+O O

OH O

NOH

TEMPO-H

+

TEMPO 2.58: norflavesone 2.59

H

H

2.81

2.58: norflavesone

HO O

OH O

NO

TEMPOO O

OH O

[O]O O

OH O

NOH

TEMPO-H

2.82 2.59

e.g. Ag2O,PhI(OAc)2,

CAN,TEMPO

22

2.2.4. Biomimetic total synthesis of hyperjapone A (2.49)

Scheme 2.22: Biomimetic total synthesis of hyperjapone A (2.49).

With the optimized conditions, we moved to the total synthesis of hyperjapone A (2.49). By

changing the dienophile to humulene (2.11), the oxidative hetero-Diels-Alder reaction afforded

hyperjapone A (2.49) in 32% yield (Scheme 2.22). The yield was almost halved from the reaction

with caryophyllene (2.30). This was expected as the Δ4,5-alkene in caryophyllene (2.30) is more

reactive than the Δ1,2-alkene in humulene (2.11). For example, caryophyllene (2.30) can be oxidized

by air readily while humulene (2.11) cannot.13

Nonetheless, the hetero-Diels-Alder reaction was chemoselective and regioselective as we did not

observe any reaction on the Δ4,5 and Δ8,9-alkenes. The reaction was also diastereoselective, where

the relative stereochemistry was pre-determined by the Z-configuration of the Δ1,2-alkene of

humulene (2.11). We then investigated whether it was possible for a second hetero-Diels-Alder

reaction to take place on the Δ8,9-alkene by reducing the equivalents of humulene (2.11), as shown

in the biomimetic total synthesis of lucidene (2.27) by Baldwin.11,12 However, we observed

hyperjapone A (2.49) was the only product. We have also heated the reaction in a sealed tube, but

no second Diels-Alder reaction was observed.

2.2.5. Biomimetic total synthesis of hyperjaponol C (2.56)

With hyperjapone A (2.49) in hand, we moved onto the total synthesis of hyperjaponols A to C.

Treating hyperjapone A (2.49) with m-CPBA in standard conditions gave epoxide 2.60 (Scheme

2.23). The epoxidation was chemoselective, as there was no epoxidation on the Δ4,5-alkene. A

similar observation was reported in the diepoxidation on humulene (2.11) by Fujita.8

HO O

OH O2.58

humulene (2.11)TEMPO, Ag2O

THF, −78 °C to rtO

OH

O

OH


32%

1

25

4

8 9

23

Scheme 2.23: Epoxidation of hyperjapone A (2.49).

Interestingly, we observed a minor isomer in the 13C NMR of epoxide 2.60 in d6-acetone, which we

hypothesized to be the tautomer of epoxide 2.60a. Note that we did not observe any tautomer in the

NMR spectra of hyperjapone A (2.49) or hyperjapone B (2.50) in d6-acetone. To investigate

whether the minor product in epoxide 2.60 is a tautomer or a diastereoisomer, we performed NMR

studies on the same epoxide sample in different solvents, and compared the ratio of the heptet (H-20)

around 4 ppm (Figure 2.6). The most distinctive results were from d6-acetone and CDCl3, where the

ratio of the two isomers was 10:1 in d6-acetone and 4:1 in CDCl3. With this piece of information,

we concluded the minor isomer observed in the NMR spectra was in fact a tautomer.

epoxide 2.60, 1H NMR (500 MHz, d6-acetone)

10:1 isomers epoxide 2.60, 1H NMR (500 MHz, CDCl3)

4:1 isomers

epoxide 2.60, 1H NMR (500 MHz, d6-DMSO)

20:1 isomers (poor solubility) epoxide 2.60, 1H NMR (500 MHz, C6D6)

7:1 isomers Figure 2.6: 1H NMR spectra of epoxide 2.60 in d6-acetone, CDCl3, d6-DMSO and C6D6.

O

OH

O

OH


O

OH

O

OH

O

2.60

m-CPBA CH2Cl2, 0 °C

76%

O

O

OH

OH

O

2.60a

HMBC HMBC

20

20

24

We then focused on the acid-catalysed rearrangement of the epoxide 2.60 to hyperjaponols A to C.

We first tried p-TsOH in CH2Cl2 at room temperature, which gave hyperjaponol C (2.56) in 43%

yield, presumably derived from the cationic alkene-cyclization/1,2-alkyl shift cascade reaction

(Scheme 2.24). The reaction could also be done with catalytic p-TsOH (0.1 equiv.) with no loss of

yield.

Scheme 2.24: Biomimetic total synthesis of hyperjaponol C (2.56).

In the acid-catalysed rearrangement reaction, we observed impurities that shared similar Rf to

hyperjaponol C (2.56), which could not be separated by column chromatography. We read a

purification modification of column chromatography involving doping AgNO3 with SiO2,30,31 which

is an underutilized trick that is used more often in natural product isolation than in organic synthesis.

It is believed that the Ag+ can interact with the π electrons in alkenes, which differentiates organic

molecules with varied alkene systems and thus providing a secondary interaction in silica.30,31 This

modified purification worked perfectly and we obtained pure hyperjaponol C (2.56) in 43% yield

(Figure 2.7).

O

OH

O

OH

O

2.60

p-TsOH·H2O CH2Cl2, rt

O

OH

O

OH

H

HO


43%

O

O

OH

OH

H

HO

2.56a

HMBC HMBC

25

Figure 2.7: 1H NMR spectra of hyperjaponol C (2.56) (500 MHz, CDCl3). a) (purified with

SiO2), b) (purified with AgNO3 doped SiO2).

Similar to the epoxide 2.60, a tautomer of hyperjaponol C (2.56) was also observed in the NMR

spectra, with a ratio of 10:1 in d6-acetone and 5:1 in CDCl3 respectively. To further investigate the

acid-catalysed rearrangement reaction, we screened a series of protic acids and Lewis acids (Table

2.2). We discovered treating epoxide 2.60 with concentrated H2SO4 in acetone/H2O under reflux

gave hyperjaponol C (2.56) in 8% yield, while BF3·OEt2 gave hyperjaponol C (2.56) in 16% yield.

Other Lewis acids (e.g. TiCl4, SnCl2) led to decomposition.

2.2.6. Biomimetic total synthesis of hyperjaponol A (2.54)

Scheme 2.25: Biomimetic total synthesis of hyperjaponol A (2.54).

O

OH

O

OH

O

2.60

O

OH

O

OHHO


(NC)2C=C(CN)2LiBr, acetone, 50 °C

59%

O

O

OH

OHHO

2.54a

26

We then investigated the use of (NC)2C=C(CN)2 for the ring opening reaction of epoxide 2.60, as it

has been used in a similar reaction with caryophyllene oxide (2.31) reported by Marcias-Sanchez.15

We were delighted to observe hyperjaponol A (2.54) in 59% yield in this reaction (Scheme 2.25).

We believed hyperjaponol B (2.55) could be generated from similar conditions. Our hypothesis was

the formation of the endocyclic alkene would be favoured under thermal conditions. However,

when a higher boiling point solvent pent-2-one was used, it gave hyperjaponol A (2.54) in a lower

yield (42%) and other solvents led to decomposition (Table 2.2). Unfortunately, we have yet to

observe hyperjaponol B (2.55) in our synthetic work.

Table 2.2: Conditions screened for the acid-catalysed rearrangement reaction

reagents solvent conditions product, yield

(NC)2C=C(CN)2 (0.2 equiv.), LiBr (5 equiv.)

acetone rt no reaction


acetone 50 °C, 2 h hyperjaponol A (2.54),

59%


pentan-2-one reflux, 2.5 h hyperjaponol A (2.54),

42%


PhMe reflux, 1 d decomposition


EtOH reflux, 4 h decomposition


CH2Cl2 rt, 2 d no reaction

(NC)2C=C(CN)2 (0.1 equiv.)

DMSO rt, 16 h no reaction

(NC)2C=C(CN)2 (0.1 equiv.)

DMSO reflux, 16 h decomposition

1 M HCl CHCl3 rt, 2 h no reaction

1 M HCl CHCl3 reflux, 3 h no reaction

conc. HCl CHCl3 rt, 3 h hyperjaponol A (2.54),

30%

conc. HCl CHCl3 reflux, 2 h hyperjaponol A (2.54),

O

OH

O

OHHO


O

OH

O

OH

H

HO

or

2.56: hyperjaponol C

O

OH

O

OH

O

2.60

conditions

27

30%

H2SO4 acetone/H2O, 9:1 reflux, 3 h hyperjaponol C (2.56), 8%

H2SO4 acetone/H2O, 9:1 rt, 1 d no reaction

TFA CH2Cl2 –20 °C, 2 h hyperjaponol C (2.56), 7%

p-TsOH·H2O (1 equiv.) CH2Cl2 –20 °C, 3 h hyperjaponol C (2.56),

30%

p-TsOH·H2O (1 equiv.) CH2Cl2 0 °C to rt, 2 h hyperjaponol C (2.56),

43%

p-TsOH·H2O (1 equiv.) CHCl3 0 °C to rt, 4 h no reaction

p-TsOH·H2O (1 equiv.) acetone 50 °C, 1 d hyperjaponol C (2.56),

20%

p-TsOH·H2O (0.1 equiv.) CH2Cl2 rt, 3 h hyperjaponol C (2.56),

37%

p-TsOH·H2O (0.1 equiv.) MeOH/H2O 1:1 60 °C, 4 h no reaction

CSA (1 equiv.) CH2Cl2 0 °C, 2 h no reaction

CSA (1 equiv.) CH2Cl2 rt, 1 d hyperjaponol C (2.56),

30%

sodium formate formic acid rt, 1 h decomposition

sodium acetate acetic acid rt, 2 d no reaction

BF3·OEt2 (1 equiv.) CH2Cl2 –78 °C no reaction

BF3·OEt2 (1 equiv.) CH2Cl2 –78 °C to –20

°C, 6 h hyperjaponol C (2.56),

16%

TiCl4 (1 equiv.) CH2Cl2 0 °C, 30 min decomposition

SnCl2 (1 equiv.) CH2Cl2 0 °C, 30 min decomposition

28

In the synthesis of hyperjaponol C (2.56), both epoxidation and acid-catalysed rearrangement

reactions were robust and clean, so it was natural to attempt a one pot reaction.32 Indeed, the

reaction went extraordinarily well. After the addition of m-CPBA to hyperjapone A (2.49), the

reaction was monitored by TLC carefully; when all of the hyperjapone A (2.49) was consumed,

catalytic p-TsOH was added. The reaction went to completion overnight and gave 33% yield of

hyperjaponol C (2.56), which was approximately the combined yield of the two separate steps

(Scheme 2.26). Alternatively, m-CPBA and p-TsOH could be added simultaneously to hyperjapone

A (2.49) in CH2Cl2 and gave hyperjaponol C (2.56) in 26% yield.

Scheme 2.26: One pot epoxidation and acid-catalysed rearrangement reaction of hyperjapone

A (2.49) to give hyperjaponol C (2.56).

2.2.7. Biomimetic total synthesis of hyperjapones C (2.51) and E (2.53)

Scheme 2.27: Total synthesis of norisoleptospermone (2.84).

After the total synthesis of hyperjaponols A (2.54) and C (2.56), we moved onto the synthesis of

hyperjapones C (2.51) and E (2.53). The synthesis started from Friedel-Crafts acylation of

phloroglucinol (2.68) with AlCl3 and (S)-EtCH(Me)COCl.33 The reaction went smoothly and gave

acylphloroglucinol 2.83 in good yield. Trimethylation of acylphloroglucinol 2.83 by KOt-Bu and

MeI gave norisoleptospermone (2.84) in 69% yield (Scheme 2.27), which is also a natural product

isolated from a flowering plant Lepsospermum scoparium.22

m-CPBA, CH2Cl20 °C then

p-TsOH·H2O, rtO

OH

O

OH


O

OH

O

OH

H

HO


33%

orm-CPBA, p-TsOH·H2O

CH2Cl2 rt26%

HO OH

OH

HO OH

OH O

2.68: phloroglucinol 2.83

(S)-EtCH(Me)COCl, AlCl3PhNO2, 65 °C H

71%

HO O

OH O2.84: norisoleptospermone

MeI, KOt-BuMeOH, 65 °C H

69%

29

Scheme 2.28: Biomimetic total synthesis of hyperjapones C (2.51) and E (2.53).

With norisoleptospermone (2.84) in hand, we proceeded to the oxidative hetero-Diels-Alder

reaction with caryophyllene (2.30). Under the optimized conditions, the reaction gave a 2.5:1

mixture of hyperjapones C (2.51) and E (2.53) in 61% yield (Scheme 2.28). We could not separate

the two isomers by flash column chromatography or HPLC.

Scheme 2.29: Biomimetic total synthesis of hyperjapones analogues 2.85 and 2.86.

Since we believe the biosynthesis of hyperjapones A-E is highly predisposed and non-enzymatic,

the hyperjapone analogues 2.85 and 2.86 derived from norisoleptospermone (2.84) and humulene

(2.11) could be two undiscovered natural products. The addition of TEMPO and Ag2O to

noisoleptospermone (2.84) and humulene (2.11) in THF gave a 1:1 mixture of 2.85 and 2.86 with

35% overall yield (Scheme 2.29).

HO O

OH O

2.84: norisoleptospermone

H O

OH

O

OH

H

H

O

OH

O

OH

H

H+

2.51: hyperjapone C 2.53: hyperjapone E

H H

61%, d.r. 2.5:1 2.51/2.53

H

H

caryophyllene (2.30)TEMPO, Ag2O

THF, –78 °C to rt

2.85 2.86

+O

OH

O

OH

O

OH

O

OH

HHHO O

OH O

H

35%, d.r. 1:1 2.85/2.86



2.84: norisoleptospermone

undiscovered natural products?

30

2.2.8. Isolation of hyperjapones F to I (2.87–2.90)

Figure 2.8: Structures of hyperjapones F to I (2.87–2.90).

After we published our work on the total synthesis of hyperjapones and hyperjaponols,34 the

isolation of hyperjapones F-I (2.87–2.90) was reported by Xu (Figure 2.8).35 These natural products

were also isolated from Hypericum japonicum, and they are presumably biosynthesized from the

hetero-Diels-Alder reaction with 2.59. Note the absolute configurations of hyperjapones H (2.89)

and I (2.90) were not determined from the isolation. Therefore, we aimed to synthesize both

enantiomers of hyperjapones H (2.89) and I (2.90) and determine the absolute configuration of the

natural products.

2.2.9. Biomimetic total synthesis of hyperjapones F and G (2.87 & 2.88)

Scheme 2.30: Biomimetic Total synthesis of hyperjapones F (2.87) and G (2.88).

Similar to our previous synthesis of hyperjapones, norflavesone (2.58) was oxidised and reacted

with (–)-sabinene (2.91) to give a 1:1 mixture of hyperjapones F (2.87) and G (2.88) (Scheme 2.30).

O

OH

O

O2.89: (+)-hyperjapone H

OH

O

O

2.90: (+)-hyperjapone I

O

H

O

OH

O

O2.87: (–)-hyperjapone F

O

OH

O

O2.88: (+)-hyperjapone G

O O

OH O

2.59

H+

2.91: (–)-sabinene (–)-2.92: (–)-(β)-pinene

(+)-2.92: (+)-(β)-pinene

(–)-2.93: (–)-(α)-pinene

(+)-2.93: (+)-(α)-pinene

hetero-Diels-Alder reaction

*absolute configurations of hyperjapones H (2.89) and I (2.90)were not determined from isolation

HO O

OH O2.58: norflavesone

(−)-sabinene (2.91)Ag2O, TEMPO


OH

O

O2.87: hyperjapone F

13%

H

O

OH

O

O2.88: hyperjapone G

+

1:1

31

The yield of this reaction was only 13%, as the terminal alkene of (–)-sabinene (2.91) is less

reactive compared to the strained trans-alkenes of caryophyllene (2.30) and humulene (2.11).

2.2.10. Biomimetic total synthesis of hyperjapone H (2.89)

Scheme 2.31: Biomimetic total synthesis of hyperjapone H (2.89).

Interestingly, the oxidative hetero-Diels-Alder reaction did not proceed as well with (β)-pinene

(2.92) using Ag2O and TEMPO. The reaction gave hyperjapone H (2.89) as well as some complex

side products, which were difficult to separate by column chromatography. The AgNO3 doped SiO2

column chromatography did not work on this occasion. Looking back at the Table 2.1, we repeated

the reaction using our second-best conditions with CAN and TEMPO in MeOH. To our delight,

treating (+)-(β)-pinene (+)-2.92 and norflavesone (2.58) with CAN and TEMPO gave a 25% yield

of (+)-hyperjapone H (+)-2.89; while using (–)-(β)-pinene (–)-2.92 gave a 27% yield of (−)-

hyperjapone H (−)-2.89 (Scheme 2.31). The optical rotations of (+)-2.89 and (−)-2.89 are [!]!!"

+24º (c 1.0, MeOH) and [!]!!" −20° (c 1.0, MeOH). The natural sample has an optical rotation of

[!]!!" +3° (c 0.12, MeOH). Since the racemic (β)-pinene (2.92) is naturally occurring, we suspect

that natural hyperjapone H (2.92) is a racemate, if not a scalemic mixture.

2.2.11. Biomimetic total synthesis of hyperjapone I (2.90)

Scheme 2.32: Biomimetic total synthesis of hyperjapone I (2.90).

HO O

OH O

2.58: norflavesone

(−)-(β)-pinene (−)-2.92CAN, TEMPO

MeOH, −78 °C to rt O

OH

O

O(−)-2.89: (−)-hyperjapone H

27%

(+)-(β)-pinene (+)-2.92CAN, TEMPO

MeOH, −78 ºC to rtO

OH

O

O(+)-2.89: (+)-hyperjapone H

25%

HO O

OH O

2.58: norflavesone

(−)-(α)-pinene (−)-2.93CAN, TEMPO

MeOH, −78 ºC to rt

OH

O

O

(−)-2.90: (−)-hyperjapone I

5%

O

H

(+)-(α)-pinene (+)-2.93CAN, TEMPO


OH

O

O

(+)-2.90: (+)-hyperjapone I

8%

O

H

32

In the synthesis of hyperajapone I (2.90), we again observed inseparable side products using Ag2O

and TEMPO, and hence we chose to use CAN and TEMPO for the reaction. The yield was 8% with

(+)-(α)-pinene (+)-2.93 and 5% with (–)-(α)-pinene (+)-2.93 (Scheme 2.32). The yield of this

reaction was relatively low, due to the poor reactivity of the tri-substituted alkene in (α)-pinene

(2.93). The optical rotations are [!]!!" = +95° (c 1.0, MeOH) for (+)-2.90 and [!]!!" = −98° (c 1.0,

MeOH) for (−)-2.90. The natural product has an optical rotation of [!]!!" = +51° (c 0.13, MeOH).

Therefore, we suspect that natural hyperjapone I (2.90) is possibly a scalemic mixture, or the natural

sample might be impure. We also managed to recrystallise hyperjapone I (2.90) from MeOH and

obtained an X-ray structure to confirm the relative stereochemistry (Figure 2.9).

Figure 2.9: X-ray structure of hyperjapone I (2.90).

2.2.12. Preliminary theoretical calculations of the transition state of cationic alkene-

cyclization/1,2-shift

To investigate the concerted, asynchronous cationic alkene-cyclization/1,2-alkyl shift hypothesis,

we performed calculations on each proposed carbocation intermediate and their corresponding

transition states.

From the diagram (Figure 2.10), the energy of the first carbocation 2.61 is the highest, and the

energy of the final carbocation 2.63 is the lowest. It suggests the overall reaction profile is

enthalpically favoured.

On the left of the diagram, it represents the asynchronous cation-alkene cyclization/1,2-alkyl shift,

where 2.61 rearranges to 2.63 in a single transition state. On the right side of the diagram, it

illustrates the stepwise process: the alkene-cyclization of 2.61 gives 2.62, followed by 1,2-alkyl

shift to give 2.63.

The calculation shows that the asynchronous cation-alkene cyclization/1,2-alkyl shift is a

reasonable pathway. In the transition state 2.61–2.63, the distance between C-4 and C-9 is 1.71 Å

(from 3.85 Å in 2.61), which shows partial single bond character (1.54 Å for a C-C single bond).

33

And the double bond between C-4 and C-5 is elongated to 1.41 Å (from 1.33 Å in 2.61). And the

ring is slightly twisted, which is in position for the 1,2-alkyl shift.

However, the calculation for the stepwise process is problematic. First, in the optimised structure of

2.62, the distance between C-4 to C-9 is 1.84 Å, which is slightly longer than a single bond,

suggesting it is unlikely for 2.62 to have a 6/7 membered ring structure. In addition, the transition

state from 2.61 to 2.62 could not be calculated. Moreover, in the transition state 2.62–2.63, the

distance between C-4 and C-9 is elongated to 2.02 Å, which suggests the single bond between C-4

and C-9 is broken. Therefore, it is not a simple 1,2-alkyl shift to reach 2.63 from 2.62. To conclude,

our calculations agreed with Tantillo’s hypothesis, suggesting the concerted, asynchronous process

is favoured over the stepwise process.23,24

Figure 2.10: Energy diagram of the carbocation rearrangements. All ground states were

calculated from 6-31G+(d,p), with Density Functional Theory m062x. The transition states

were calculated from 6-31+G(d), with Density Functional Theory m062x.

–32.66 kJ mol-1

–209.48 kJ mol-1

transitin state 2.61-2.63

+116.13 kJ mol-1

no transition from 2.61 to 2.62

–207.64 kJ mol-1

+146.95 kJ mol-1

transition state 2.62-2.63

O

OH

O

OH

O

OH

O

OH

H

HO

HO O

OH

O

OH

H

HO

49

5

49

2.63

2.61

2.62

34

2.3. Summary

We have developed a concise biomimetic total synthesis of hyperjapones A-I via an oxidative

hetero-Diels-Alder reaction. We have also converted hyperjapone A into hyperjaponol C via an

epoxidation and an acid-catalysed rearrangement cascade reaction, which generated 2 rings, and 4

stereocenters in 1 step. The overall synthesis is protecting group free with good pot economy

(Figure 2.11).36,37 It is also noteworthy that the total synthesis mirrored our biosynthetic proposal

precisely.

The synthesis of hyperjaponol C highlights the reactivity of all 3 alkenes in humulene, where each

alkene is reacted sequentially in a chemoselective, stereoselective and regioselective manner:

hetero-Diels-Alder reaction on the Δ1,2-alkene, epoxidation on the Δ8,9-alkene and the acid-

catalysed rearrangement on the Δ4,5-alkene. The synthesis suggests a highly predisposed

biosynthesis of hyperjaponol C.

Figure 2.11: Summary of the biomimetic total synthesis of hyperjaponol C (2.56).

The syntheses of hyperjapones B, H and I confirmed the absolute configuration of these natural

products. We plan to distribute both enantiomers of hyperjapones H and I, epoxide 2.60 and

hyperjapones analogues 2.85/2.86 to the isolation chemists. We hope the synthesis of hyperjapones

and hyperjaponols could help identify and characterise natural products that are yet to be isolated.

After our publication on the synthesis of hyperjapones and hyperjaponols, there were a few reports

on the isolation and biomimetic total synthesis of structurally related natural products.38,39,40 These

natural products were synthesized via a hetero-Diels-Alder reaction with caryophyllene or

humulene (Figure 2.12).

O

OH

O

OH

H

HO

(±)-2.56: hyperjaponol CMeI

OH

OHHO

Cl

O

4 steps7% overall yield

6 C-C bonds6 stereocentres

3 rings

35

Figure 2.12: Isolation and synthesis of frutescones by Wang38, rhodomentones A and B by

Qiu39 and rhodomyrtials A and B by Luo and Kong40.

∗∗

O

H

H

HO

OHO

OMe

*S, 2.96: frutescone E *R, 2.97: frutescone F

OMe

2.98: (±)-frutescone G

∗∗

O

H

H

H

O

*S, 2.94: frutescone B *R, 2.95: frutescone C

OMe

O

H

H

OO

2.99: rhodomentone A

O

H

H

OO

2.100: rhodomentone B

OH

OH

∗∗

O

H

H

O

O

HO

O

O

*S, 2.101: rhodomyrtial A*R, 2.102: rhodomyrtial B

36

2.4. References

1. Clayden, J.; Greeves, N.; Warren, S. G., Organic chemistry. Oxford University Press: Oxford; New York, 2012.

2. Nicolaou, K. C.; Snyder, S. A.; Montagnon, T.; Vassilikogiannakis, G. Angew. Chem. Int. Ed., 2002, 41, 1668.

3. Snyder, S. A.; Kontes, F. Isr. J. Chem., 2011, 51, 378. 4. Nicolaou, K. C.; Snyder, S. A. Proceedings of the National Academy of Sciences of the

United States of America, 2004, 101, 11929. 5. Smith, A. B.; Sestelo, J. P.; Dormer, P. G. J. Am. Chem. Soc., 1995, 117, 10755. 6. Kuttruff, C. A.; Zipse, H.; Trauner, D. Angew. Chem. Int. Ed., 2011, 50, 1402. 7. Heravi, M. M.; Ahmadi, T.; Ghavidel, M.; Heidari, B.; Hamidi, H. RSC Adv., 2015, 5,

101999. 8. Zigon, N.; Hoshino, M.; Yoshioka, S.; Inokuma, Y.; Fujita, M. Angew. Chem. Int. Ed., 2015,

54, 9033. 9. Bryson, I.; Roberts, J. S.; Sattar, A. Tetrahedron Lett., 1980, 21, 201. 10. Gao, Y.; Wang, G. Q.; Wei, K.; Hai, P.; Wang, F.; Liu, J. K. Org. Lett., 2012, 14, 5936. 11. Adlington, R. M.; Baldwin, J. E.; Pritchard, G. J.; Williams, A. J.; Watkin, D. J. Org. Lett.,

1999, 1, 1937. 12. Rodriguez, R.; Moses, J. E.; Adlington, R. M.; Baldwin, J. E. Org. Biomol. Chem., 2005, 3,

3488. 13. Steenackers, B.; Campagnol, N.; Fransaer, J.; Hermans, I.; De Vos, D. Chem. Eur. J., 2015,

21, 2146. 14. Barrero, A. F.; Herrador, M. M.; del Moral, J. F. Q.; Arteaga, P.; Sanchez, E. M.; Arteaga, J.

F.; Piedra, M. Eur. J. Org. Chem., 2006, 3434. 15. Collado, I. G.; Hanson, J. R.; MaciasSanchez, A. J. Tetrahedron, 1996, 52, 7961. 16. Spence, J. T. J.; George, J. H. Org. Lett., 2011, 13, 5318. 17. Takao, K.; Noguchi, S.; Sakamoto, S.; Kimura, M.; Yoshida, K.; Tadano, K. J. Am. Chem.

Soc., 2015, 137, 15971. 18. Lawrence, A. L.; Adlington, R. M.; Baldwin, J. E.; Lee, V.; Kershaw, J. A.; Thompson, A.

L. Org. Lett., 2010, 12, 1676. 19. Clericuzio, M.; Alagona, G.; Ghio, C.; Toma, L. J. Org. Chem., 2000, 65, 6910. 20. Yang, X. W.; Li, Y. P.; Su, J.; Ma, W. G.; Xu, G. Org. Lett., 2016, 18, 1876. 21. Hu, L. Z.; Zhang, Y.; Zhu, H. C.; Liu, J. J.; Li, H.; Li, X. N.; Sun, W. G.; Zeng, J. F.; Xue,

Y. B.; Zhang, Y. H. Org. Lett., 2016, 18, 2272. 22. Killeen, D. P.; Larsen, L.; Dayan, F. E.; Gordon, K. C.; Perry, N. B.; van Klink, J. W. J. Nat.

Prod., 2016, 79, 564. 23. Tantillo, D. J. Chem. Soc. Rev., 2010, 39, 2847. 24. Tantillo, D. J. Nat. Prod. Rep., 2011, 28, 1035. 25. Hong, A. Y.; Stoltz, B. M. Angew. Chem. Int. Ed., 2014, 53, 5248. 26. Crombie, L.; Jones, R. C. F.; Palmer, C. J. J. Chem. Soc., Perkins Trans. 1, 1987, 317. 27. Nguyen, N. T.; Pham, V. C.; Litaudon, M.; Gueritte, F.; Bodo, B.; Nguyen, V. T.; Nguyen,

V. H. Tetrahedron, 2009, 65, 7171. 28. George, J. H.; Hesse, M. D.; Baldwin, J. E.; Adlington, R. M. Org. Lett., 2010, 12, 3532. 29. Liao, D. H.; Li, H. H.; Lei, X. G. Org. Lett., 2012, 14, 18. 30. Mander, L. N.; Williams, C. M. Tetrahedron, 2016, 72, 1133. 31. Williams, C. M.; Mander, L. N. Tetrahedron, 2001, 57, 425. 32. Markwell-Heys, A. W.; Kuan, K. K. W.; George, J. H. Org. Lett., 2015, 17, 4228. 33. Fobofou, S. A. T.; Franke, K.; Porzel, A.; Brandt, W.; Wessjohann, L. A. J. Nat. Prod.,

2016, 79, 743.

37

34. Lam, H. C.; Spence, J. T. J.; George, J. H. Angew. Chem. Int. Ed., 2016, 55, 10368. 35. Li, Y. P.; Yang, X. W.; Xia, F.; Yan, H.; Ma, W. G.; Xu, G. Tetrahedron Lett., 2016, 57,

5868. 36. Gaich, T.; Baran, P. S. J. Org. Chem., 2010, 75, 4657. 37. Hayashi, Y. Chem. Sci., 2016, 7, 866. 38. Hou, J. Q.; Guo, C.; Zhao, J. J.; He, Q. W.; Zhang, B. B.; Wang, H. J. Org. Chem., 2017, 82,

1448. 39. Liu, H. X.; Chen, K.; Yuan, Y.; Xu, Z. F.; Tan, H. B.; Qiu, S. X. Org. Biomol. Chem., 2016,

14, 7354. 40. Zhang, Y. L.; Chen, C.; Wang, X. B.; Wu, L.; Yang, M. H.; Luo, J.; Zhang, C.; Sun, H. B.;

Luo, J. G.; Kong, L. Y. Org. Lett., 2016, 18, 4068.

38

2.5. Experimental

2.5.1. General methods

All chemicals used were purchased from commercial suppliers and used as received. All reactions

were performed under an inert atmosphere of N2. All organic extracts were dried over anhydrous

magnesium sulfate. Thin layer chromatography was performed using aluminium sheets coated with

silica gel F254. Visualization was aided by viewing under a UV lamp and staining with ceric

ammonium molybdate or KMnO4 stain followed by heating. All Rf values were measured to the

nearest 0.05. Flash chromatography was performed using 40-63 micron grade silica gel. Melting

points were recorded on a digital melting point apparatus and are uncorrected. Infrared spectra were

recorded using an FT-IR spectrometer as the neat compounds. High field NMR was recorded using

a 500 MHz spectrometer (1H at 500 MHz, 13C at 125 MHz). Solvents used for spectra were d6-

acetone or CDCl3 unless otherwise specified. 1H chemical shifts are reported in ppm on the δ-scale

relative to TMS (δ 0.0) or CDCl3 (δ 7.26) and 13C NMR are reported in ppm relative to CDCl3 (δ

77.00). Multiplicities are reported as (br) broad, (s) singlet, (d) doublet, (t) triplet, (q) quartet, (quin)

quintet, (sext) sextet, (hept) heptet and (m) multiplet. All J-values were rounded to the nearest 0.1

Hz. ESI high resolution mass spectra were recorded on a ESI-TOF mass spectrometer. Optical

rotations were measured on a modular circular polarimeter.

39

2.5.2. Experimental procedures

To a solution of phloroglucinol (2.68) (5.0 g, 39.6 mmol) in PhNO2 (50 mL) at room temperature

was added AlCl3 (21.2 g, 159 mmol) portionwise, followed by slow addition of isopropyl chloride

(4.59 mL, 43.6 mmol). The mixture was heated at 65 ºC for 3.5 h. The solution was cooled to room

temperature, then quenched with 1 M HCl (30 mL) and diluted with MeOH (10 mL). The mixture

was extracted with EtOAc (2 × 50 mL). The combined organic layers were extracted with 1 M

NaOH (2 × 50 mL). The aqueous extracts were acidified by conc. HCl. The aqueous layer was

extracted with EtOAc (3 × 70 mL). The combined organic extracts were washed with brine (200

mL), dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by flash

column chromatography on SiO2 (4:1 → 2:1, petrol/EtOAc gradient elution) to give 2.57 as a

yellow solid (6.75 g, 87%). Data for 2.57 matched that of the published data.1

Rf = 0.45 (1:1, petrol/EtOAc) 1H NMR (500 MHz, CD3OD): δ 5.81 (s, 1H), 3.97 (hept, J = 6.7 Hz, 1H), 1.13 (d, J = 6.8 Hz,

6H). 13C NMR (125 MHZ, CD3OD): δ 211.6, 165.82, 165.75, 104.6, 95.8, 39.9, 19.7.

HO OH

OH

HO OH

OH O2.68: phloroglucinol 2.57

i-PrCOCl, AlCl3PhNO2, 65 °C

87%

40

To a solution of 2.57 (2.84 g, 14.4 mmol) in MeOH (30 mL) at room temperature was added KOt-

Bu (6.00 g, 53.6 mmol) and MeI (2.69 mL, 43.2 mmol). The solution was heated at 65 °C for 3 h.

The reaction was cooled to room temperature, then acidified by 1 M aqueous HCl solution (40 mL).

The aqueous solution was extracted with EtOAc (2 × 30 mL). The combined organic extracts were

washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified

by flash column chromatography on SiO2 (4:1, petrol/EtOAc) to give norflavesone 2.58 as a white

gum (2.61 g, 79%). Data for 2.58 matched that of the isolation data.2

Rf = 0.40 (1:1, petrol/EtOAc)

IR (neat): 3171, 2981, 2929, 1643, 1575, 1514, 1462, 1376, 1334, 1223, 1181, 1165 cm-1. 1H NMR (500 MHz, d6-DMSO): δ 19.13 (br s, 1H), 3.90 (hept, J = 6.8 Hz, 1H), 1.78 (s, 3H), 1.29

(s, 6H), 1.04 (d, J = 6.8 Hz, 6H). 13C NMR (125 MHz, d6-DMSO): δ 206.5, 195.8, 189.1, 176.1, 103.5, 101.8, 48.5, 34.6, 24.3,

18.9, 7.4.

HRMS (ESI): calculated for C13H17O4 237.1132 [M−H]-, found 237.1135.

HO O


MeI, KOt-BuMeOH, 65 °C

HO OH

OH O2.57

79%

41

To a solution of 2.58 (1.80 g, mmol), and α-humulene (2.11) (1.24 g, 6.07 mmol) in Et2O (30 mL)

at −78 °C was added Ag2O (1.97 g, 6.49 mmol) and TEMPO (1.42 g, 9.10 mmol). The reaction was

stirred at −78 °C for 1 h, then warmed to room temperature and stirred for 16 h. The solution was

filtered and concentrated in vacuo. The residue was purified by flash column chromatography on

SiO2 (1:0 → 30:1, petrol/EtOAc gradient elution) to give (±)-hyperjapone A (2.49) as a white solid

(860 mg, 32%).

Mp: 174 – 175 °C


IR (neat): 2968, 2934, 2861, 1656, 1619, 1509, 1473, 1381, 1265, 1190, 1158, 1103 cm-1. 1H NMR (500 MHz, d6-acetone): δ 19.26 (br s, 1H), 5.23 (d, J = 15.7 Hz, 1H), 5.11 (dd, J = 12.0,

3.2 Hz, 1H), 5.04 (ddd, J = 15.9, 10.5, 2.7 Hz, 1H), 3.98 (hept, J = 6.8 Hz, 1H), 2.78 (m, 1H), 2.56

(d, J = 14.6 Hz, 1H), 2.46 (dd, J = 14.7, 10.6 Hz, 1H), 2.24 (d, J = 12.5 Hz, 1H), 2.12 (dd, J = 12.7,

7.2 Hz, 1H), 1.92 (t, J = 12.2 Hz, 1H), 1.85 – 1.83 (m, 2H), 1.75 (dd, J = 13.0, 4.5 Hz, 1H), 1.65 (s,

3H), 1.45 – 1.40 (m, 1H), 1.35 (s, 3H), 1.29 (s, 3H), 1.25 – 1.20 (m, 1H), 1.17 (s, 3H), 1.11 (d, J =

6.0 Hz, 3H), 1.09 (d, J = 5.6 Hz, 3H), 1.05 (s, 3H), 1.03 (s, 3H). 13C NMR (125 MHz, d6-acetone): δ 207.9, 196.7, 189.4, 173.7, 143.8, 137.4, 123.8, 120.7, 103.1,

85.9, 48.9, 42.6, 42.2, 38.8, 38.3, 35.8, 35.6, 30.6, 30.4, 25.2, 24.4, 24.2, 22.5, 20.3, 19.4, 19.2,

17.2.

HRMS (ESI): calculated for C28H41O4 441.2999 [M+H]+, found 441.3000.

HO O

OH O2.58



OH

O

OH


32%

42

To a solution of (±)-hyperjapone A (2.49) (474 mg, 1.08 mmol) in CH2Cl2 (20 mL) at 0 °C was

added m-CPBA (77%, 265 mg, 1.18 mmol). The reaction was stirred at 0 °C for 1 h, then quenched

with saturated aqueous NaHCO3 solution. The organic layer was separated and the aqueous layer

was extracted with CH2Cl2 (2 × 20 mL). The combined organic extracts were washed with brine (50


column chromatography on SiO2 (4:1, petrol/EtOAc) to give epoxide 2.60 as a white solid (493 mg,

76%).

Mp: 220 – 223 °C


IR (neat): 2958, 2933, 2871, 1703, 1658, 1623, 1517, 1473, 1380, 1316, 1237, 1195 cm-1.

10:1 mixture of tautomers in d6-acetone

Data for major tautomer 2.60: 1H NMR (500 MHz, d6-acetone): δ 19.23 (s, 1H), 5.53 (dd, J = 15.7, 1.2 Hz, 1H), 5.32 (ddd, J =

15.7, 10.1, 4.0 Hz, 1H), 3.97 (hept, J = 6.7 Hz, 1H), 2.73 (d, J = 10.9 Hz, 1H), 2.69 (d, J = 10.8 Hz,

1H), 2.65 – 2.60 (m, 2H), 2.13 (dd, J = 13.6, 9.0 Hz, 1H), 1.81 – 1.75 (m, 2H), 1.70 (d, J = 13.6 Hz,

1H), 1.62 (dd, J = 14.4, 9.9 Hz, 1H), 1.36 (s, 3H), 1.32 – 1.30 (m, 1H), 1.29 (s, 3H), 1.29 (s, 3H),

1.25 – 1.23 (m, 1H), 1.19 (s, 3H), 1.17 (s, 3H), 1.10 (d, J = 5.2 Hz, 3H), 1.09 (d, J = 5.2 Hz, 3H),

1.04 (s, 3H), 0.99 (dd, J = 13.6, 9.9 Hz, 1H). 13C NMR (125 MHz, d6-acetone): δ 207.9, 196.7, 189.4, 173.7, 142.1, 121.2, 105.1, 103.3, 84.6,

61.9, 60.7, 84.9, 42.8, 41.1, 38.3, 37.6, 36.2, 35.7, 31.3, 26.2, 25.4, 24.4, 24.2, 22.3, 19.8, 19.4,

19.2, 17.6.

O

OH

O

OH


O

OH

O

OH

O

2.60

m-CPBA CH2Cl2, 0 °C

76%

O

O

OH

OH

O

2.60a

43

Partial data for minor tautomer 2.60a: 1H NMR (500 MHz, d6-acetone): δ 5.51 (d, J = 11.3 Hz, 1H), 4.24 (hept, J = 6.6 Hz, 1H). 13C NMR (125 MHz, d6-acetone): δ 205.8, 199.4 183.1, 166.0, 142.8, 121.5, 108.6, 103.1, 82.7,

61.9, 60.8, 49.0, 42.9, 41.1, 38.3, 37.7, 36.5, 36.2, 30.6, 26.4, 25.3, 24.4, 24.2, 23.2, 19.6, 19.34,

19.29, 17.6.

4:1 mixture of tautomers in CDCl3

Data for major tautomer 2.60: 1H NMR (500 MHz, CDCl3): δ 19.14 (s, 1H), 5.39 (d, J = 15.7 Hz, 1H), 5.23 – 5.18 (m, 1H), 3.97

(hept, J = 6.3 Hz, 1H), 2.73 (dd, J = 16.6, 4.8 Hz, 1H), 2.65 – 2.62 (m, 2H), 2.43 (dd, J = 14.0, 10.9

Hz, 1H), 2.18 (dd, J = 13.4, 9.4 Hz, 1H), 1.82 – 1.78 (m, 2H), 1.75 – 1.67 (m, 1H), 1.60 (td, J =

11.7, 4.7 Hz, 1H), 1.49 – 1.43 (m, 2H), 1.38 (s, 3H), 1.32 (s, 3H), 1.29 (s, 3H), 1.16 (s, 3H), 1.15 (d,

J = 7.9 Hz, 3H), 1.14 (d, J = 5.8 Hz, 3H), 1.11 (s, 3H), 1.05 (s, 3H), 1.03 – 0.99 (m, 1H). 13C NMR (125 MHz, CDCl3): δ 207.8, 196.7, 188.6, 172.6, 142.5, 120.2, 104.7, 102.5, 83.3, 61.8,

60.9, 48.4, 42.5, 40.3, 37.6, 36.9, 35.7, 35.5, 30.9, 25.7, 25.3, 24.2, 23.9, 21.8, 19.7, 19.2, 19.0,

17.4.

Partial data for minor tautomer 2.60a: 13C NMR (125 MHz, CDCl3): δ 210.5, 198.6, 183.4, 165.9, 142.2, 120.5, 107.9, 107.8, 81.8, 61.9,

60.9, 43.3, 42.6, 40.3, 37.7, 36.9, 36.3, 35.7, 30.9, 25.9, 25.2, 24.3, 24.2, 22.5, 19.5, 19.2, 19.1,

17.5.


44

To a solution of 2.60 (82 mg, 0.18 mmol) in CH2Cl2 (3 mL) at room temperature was added p-

TsOH·H2O (38 mg, 0.20 mmol) and stirred for 1 h. The reaction was quenched with saturated

aqueous NaHCO3 solution. The organic layer was separated and the aqueous layer was extracted

with CH2Cl2 (2 × 5 mL). The combined organic extracts were washed with brine, dried over

MgSO4, filtered and concentrated in vacuo. The residue was purified by flash column

chromatography on SiO2 (doped with 10% w/w AgNO3, 3:1, petrol/EtOAc) to give (±)-

hyperjaponol C (2.56) as a white solid (35 mg, 43%).

Mp: 161 – 163 °C.


IR (neat): 3448, 2973, 2930, 2869, 1649, 1612, 1570, 1523, 1472, 1451, 1380, 1165 cm-1.


Data for major tautomer 2.56: 1H NMR (500 MHz, CDCl3): δ 19.08 (s, 1H), 4.77 (s, 1H), 4.73 (s, 1H), 3.96 (hept, J = 6.8 Hz,

1H), 3.73 (t, J = 9.1 Hz, 1H), 2.45 (dd, J = 16.5, 4.9 Hz, 1H), 2.26 (td, J = 11.2, 5.6 Hz, 1H), 2.05

(dd, J = 17.4, 14.3 Hz, 1H), 2.00 (d, J = 16.5 Hz, 1H), 1.95 – 1.85 (m, 3H), 1.83 – 1.80 (m, 1H),

1.74 (dd, J = 10.2, 6.0 Hz, 1H), 1.72 – 1.70 (m, 1H), 1.67 (s, 3H), 1.61 (br s, 1H), 1.52 – 1.41 (m,

2H), 1.30 (s, 3H), 1.28 – 1.27 (m, 1H), 1.26 (s, 3H), 1.15 (d, J = 6.8 Hz, 3H), 1.13 (d, J = 5.9 Hz,

3H), 1.12 (s, 3H), 0.82 (s, 3H). 13C NMR (125 MHz, CDCl3): δ 208.0, 197.1, 188.6, 173.7, 146.0, 111.1, 104.7, 103.6, 84.3, 82.3,

48.5, 47.0, 46.9, 41.4, 41.3, 40.6, 39.3, 36.0, 35.6, 26.2, 25.8, 24.7, 23.4, 20.4, 19.5, 19.14, 19.11,

12.3.

O

OH

O

OH

O

2.60

p-TsOH·H2O CH2Cl2, rt

O

OH

O

OH

H

HO


43%

O

O

OH

OH

H

HO

2.56a

45

Data for minor tautomer 2.56a: (partially characterised) 1H NMR (500 MHz, CDCl3): δ 18.56 (br s, 1H), 4.21 (hept, J = 6.8 Hz, 1H). 13C NMR (125 MHz, CDCl3): δ 210.5, 198.8, 183.7, 166.9, 146.2, 111.0, 104.7, 103.6, 82.8, 82.3,

48.5, 47.2, 46.9, 43.3, 41.3, 40.8, 39.3, 36.3, 36.0, 26.3, 25.6, 25.5, 23.8, 20.2, 19.5, 19.2, 19.1,

13.4.


10:1 mixture of tautomers in d6-acetone

Data for major tautomer 2.56: 1H NMR (500 MHz, d6-acetone): δ 19.19 (s, 1H), 4.75 (s, 2H), 3.95 (hept, J = 7.0 Hz, 1H), 3.75

(br s, 1H), 3.73 – 3.71 (m, 1H), 2.42 (dd, J = 16.3, 4.9 Hz, 1H), 2.30 (td, J = 11.5, 5.7 Hz, 1H), 2.07

– 2.05 (overlapped m, 2H), 1.97 – 1.93 (m, 2H), 1.91 – 1.85 (m, 2H), 1.84 – 1.78 (m, 2H), 1.69 (s,

3H), 1.53 – 1.48 (m, 2H), 1.35 – 1.32 (m, 1H), 1.27 (s, 3H), 1.24 (s, 3H), 1.19 (s, 3H), 1.10 (d, J =

7.4 Hz, 3H), 1.08 (d, J = 8.6 Hz, 3H), 0.84 (s, 3H). 13C NMR (125 MHz, d6-acetone): δ 208.1, 196.8, 189.4, 174.6, 147.6, 111.0, 105.0, 104.3, 85.4,

82.1, 49.0, 48.0, 47.6, 42.0, 41.2, 40.0, 36.6, 35.8, 26.8, 25.9, 25.3, 23.7, 20.5, 19.5, 19.30, 19.28,

12.6.

46

To a solution of of (±)-hyperjapone A (2.49) (220 mg, 0.50 mmol) in CH2Cl2 (20 mL) at 0 °C was

added m-CPBA (77%, 123 mg, 0.55 mmol). The reaction was stirred at 0 °C for 1 h. p-TsOH·H2O

(105 mg, 0.55 mmol) was added. The reaction was warmed to room temperature and stirred for 1 h,

then quenched with saturated aqueous NaHCO3 solution. The organic layer was separated and the

aqueous layer was extracted with CH2Cl2 (2 × 20 mL). The combined organic extracts were washed

with brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by flash

column chromatography on SiO2 (doped with 10% AgNO3, 3:1, petrol/EtOAc) to give (±)-

hyperjaponol C (2.56) as a white solid (75 mg, 33%).

m-CPBA, CH2Cl20 °C then

p-TsOH·H2O, rtO

OH

O

OH


O

OH

O

OH

H

HO


33%

O

O

OH

OH

H

HO

2.56a

47

To a solution of 2.60 (22 mg, 0.048 mmol) in acetone (3 mL) at room temperature was added

tetracyanoethylene (1 mg, 9.6 µmol) and LiBr (21 mg, 0.24 mmol). The solution was heated at 50

°C for 2 h. The reaction was quenched with H2O (5 mL). The aqueous layer was extracted with

Et2O (4 × 10 mL). The combined organic extracts were washed with brine, dried over MgSO4,


SiO2 (2:1, petrol/EtOAc) to give (±)-hyperjaponol A (2.54) as a colourless oil (13 mg, 59%).

Data for 2.54:

Rf = 0.70 (petrol/EtOAc, 1:1, petrol/EtOAc)

IR (neat): 3448, 2956, 2933, 2869, 1731, 1655, 1619, 1595, 1534, 1473, 1382, 1349, 1309 cm-1.


Data for major tautomer 2.54: 1H NMR (500 MHz, CDCl3): δ 19.16 (s, 1H), 5.39 (d, J = 15.7 Hz, 1H), 5.21 (s, 1H), 5.16 (ddd, J

= 15.4, 9.9, 4.0 Hz, 1H), 4.96 (s, 1H), 3.97 (hept, J = 6.6 Hz, 1H), 3.89 (d, J = 9.0 Hz, 1H), 2.83 (d,

J = 11.6 Hz, 1H), 2.52 (dd, J = 13.8, 3.9 Hz, 1H), 2.48 (dd, J = 13.2, 8.6 Hz, 1H), 2.39 (dd, J =

14.1, 10.0 Hz, 1H), 2.12 (dd, J =13.7, 9.7 Hz, 1H), 2.05 (dd, J = 13.4, 10.1 Hz, 1H), 1.85 – 1.79 (m,

2H), 1.64 – 1.60 (m, 2H), 1.40 – 1.39 (m, 1H), 1.37 (s, 3H), 1.31 (s, 3H), 1.17 (d, J = 8.1 Hz, 3H),

1.15 (d, J = 7.0 Hz, 3H), 1.11 (s, 3H), 1.09 (s, 3H), 1.04 (s, 3H). 13C NMR (125 MHz, CDCl3): δ 207.9, 196.9, 188.6, 172.8, 155.5, 144.4, 120.0, 113.7, 104.7,

102.5, 83.8, 72.9, 49.0, 48.2, 43.7, 37.4, 35.9, 35.5, 32.7, 32.1, 30.6, 25.3, 24.6, 24.1, 22.1, 19.5,

19.2, 19.1.

Data for minor tautomer 2.54a: (partially characterised) 1H NMR (500 MHz, CDCl3): δ 18.59 (s, 1H), 5.37 (d, J = 15.7 Hz, 1H), 5.19 (s, 1H), 4.95 (s, 1H),

4.23 (hept, J = 6.71 Hz, 1H). 13C NMR (12t MHz, CDCl3): δ 210.5, 198.7, 183.6, 166.0, 155.8, 144.1, 120.4, 113.6, 107.8,

102.6, 82.3, 72.8, 49.0, 43.7, 43.3, 47.6, 36.3, 36.0, 32.7, 30.6, 29.9, 25.2, 24.6, 24.3, 22.8, 19.5,

9.29, 19.25.


O

OH

O

OH

O

2.60

O

OH

O

OHHO


(NC)2C=C(CN)2LiBr, acetone, 50 °C

59%

O

O

OH

OHHO

2.54a

48

To a solution of 2.58 (350 mg, 1.47 mmol) and caryophyllene (2.30) (0.66 mL, 2.94 mmol) in Et2O

(10 mL) at −78 °C was added Ag2O (209 mg, 1.76 mmol) and TEMPO (459 mg, 2.94 mmol). The

mixture was stirred for −78 °C for 1 h, then warmed to room temperature over 30 min and stirred at

room temperature for 16 h. The solution was filtered and concentrated in vacuo. The residue was

purified by flash column chromatography on SiO2 (1:0 → 30:1, petrol/EtOAc gradient elution) to

give hyperjapones B (2.50) and D (2.52) as a yellow gum (388 mg, 60%, d.r. 2.5:1). A small sample

of hyperjapones B (2.50) and D (2.52) was recrystallized from MeOH to give hyperjapone B (2.50)

as white crystals.

Mp = 140 − 142 °C


Data for hyperjapone B (2.50):

IR (neat): 2930, 2870, 1659, 1627, 1519, 1472, 1380, 1368, 1321, 1275, 1245, 1199 cm-1.

[!]!!" = +10.2° (c 0.62, MeOH) 1H NMR (500 MHz, d6-acetone): δ 19.23 (br s, 1H), 4.92 (s, 1H), 4.90 (s, 1H), 3.97 (hept, J = 6.8

Hz, 1H), 2.54 – 2.46 (m, 2H), 2.38 (dd, J = 16.5, 5.1 Hz, 1H), 2.27 – 2.17 (m, 2H), 2.08 – 2.03

(overlapped m, 1H), 1.98 – 1.92 (m, 3H), 1.83 – 1.76 (m, 2H), 1.73 (t, J = 10.4 Hz, 1H), 1.60 (dd, J

= 10.5, 7.6 Hz, 1H), 1.57 – 1.45 (m, 2H), 1.32 (s, 3H), 1.28 (s, 3H), 1.20 (s, 3H), 1.10 (d, J = 5.4

Hz, 3H), 1.08 (d, J = 5.3 Hz, 3H), 1.01 (s, 3H), 0.97 (s, 3H). 13C NMR (125 MHz, d6-acetone): δ 207.9, 196.7, 189.4, 173.6, 152.9, 110.7, 105.0, 102.9, 85.4,

54.0, 49.0, 42.8, 37.9, 37.1, 35.9, 35.8, 34.6, 34.2, 33.8, 30.4, 25.4, 25.3, 24.3, 23.4, 22.3, 21.2,

19.33, 19.26.


2.58

O

OH

O

OH

H

H

O

OH

O

OH

H

H

+2.50: hyperjapone B

2.52: hyperjapone D

60%, d.r. 2.5:1 2.50/2.52

H

H

caryophyllene (2.30)TEMPO, Ag2OTHF, –78 °C to rt

HO O

OH O

49

Data for hyperjapone D (2.52): 1H NMR (500 MHz, d6-acetone): δ 19.24 (br s, 1H), 4.84 (br s, 1H), 4.76 – 4.75 (m, 1H), 4.01 –

3.94 (overlapped m, 1H), 2.79 – 2.75 (overlapped m, 1H), 2.66 (dd, J = 16.5, 5.2 Hz, 1H), 2.54 –

2.46 (overlapped m, 1H), 2.27 – 2.11 (overlapped m, 3H), 1.91 – 1.87 (overlapped m, 1H), 1.84 –

1.74 (overlapped m, 1H), 1.73 – 1.68 (overlapped m, 2H), 1.62 – 1.55 (overlapped m, 3H), 1.53 –

1.46 (overlapped m, 2H), 1.33 (s, 3H), 1.27 (s, 3H), 1.13 (s, 3H), 1.11 – 1.08 (overlapped m, 6H),

1.00 (s, 3H), 0.98 (s, 3H). 13C NMR (125 MHz, d6-acetone): δ 207.9, 196.7, 189.3, 173.9, 155.9, 110.3, 105.0, 102.9, 85.6,

57.2, 49.0, 43.0, 39.3, 37.3, 35.8, 35.2, 34.5, 34.2, 33.9, 29.9, 25.4, 24.2, 24.1, 23.3, 22.6, 20.1,

19.4, 19.2.

50

To a solution of phloroglucinol (2.68) (0.95 g, 7.53 mmol) in PhNO2 (10 mL) at room temperature

was added AlCl3 (4.02 g, 30.1 mmol) portionwise, followed by slow addition of (S)-methylbutyric

acyl chloride (1.18 g, 9.79 mmol). The mixture was heated at 65 ºC for 16 h. The solution was

cooled to room temperature, then quenched with 1 M HCl (10 mL) and diluted with MeOH (5 mL).

The mixture was extracted with EtOAc (3 × 10 mL). The combined organic layers were extracted

with 1 M NaOH (2 × 10 mL). The aqueous extracts were acidified by conc. HCl. The aqueous layer

was extracted with EtOAc (3 × 30 mL). The combined organic extracts were washed with brine,

dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by flash column

chromatography on SiO2 (4:1 → 2:1, petrol/EtOAc gradient elution) to give 2.83 as a yellow solid

(1.11 g, 71%). Data for 2.83 matched that of the published data.3

Data for 2.83:


[!]!!" = +26.8° (c 0.25, CHCl3) 1H NMR (500 MHz, CD3OD): δ 6.05 (s, 2H), 4.10 (sext, J = 6.8 Hz, 1H), 2.06 (dp, J = 14.1, 7.2

Hz, 1H), 1.61 (dp, J = 14.5, 7.4 Hz, 1H), 1.36 (d, J = 6.7 Hz, 3H), 1.15 (t, J = 7.4 Hz, 3H). 13C NMR (125 MHZ, CD3OD): δ 211.4, 165.84, 165.78, 105.2, 95.9, 46.7, 28.1, 17.1, 12.3.

HO OH

OH

HO OH

OH O2.68 2.83

(S)-EtCH(Me)COCl, AlCl3PhNO2, 65 °C H

71%

51

To a solution of 2.83 (700 mg, 3.33 mmol) in MeOH (25 mL) at room temperature was added KOt-

Bu (1.23 g, 10.99 mmol) and MeI (0.69 mL, 10.99 mmol). The reaction was stirred at 65 °C for 5 h,

then cooled to room temperature. The reaction mixture was acidified with 1 M HCl (30 mL), then

extracted with EtOAc (3 × 30 mL). The combined organic extracts were washed with brine, dried

over MgSO4, filtered and concentrated in vacuo. The residue was purified by flash column

chromatography on SiO2 (4:1 → 2:1, petrol/EtOAc gradient elution) to give norisoleptosperone

(2.84) as a yellow gum (580 mg, 69%). Data for 2.84 matched that of the isolation data.2

Data for 2.84:


[!]!!" = +19.0° (c 0.87, CHCl3)

IR (neat): 3229, 2969, 2934, 2876, 1648, 1583, 1518, 1473, 1378, 1228, 1180, 1164 cm-1. 1H NMR (500 MHz, d6-DMSO): δ 19.21 (br s, 1H), 3.78 (sext, J = 6.8 Hz, 1H), 1.78 (s, 3H), 1.62

(sext, J = 7.2 Hz, 1H), 1.29 (overlapped m, 7H), 1.03 (d, J = 6.7 Hz, 3H), 0.83 (t, J = 7.4 Hz, 3H). 13C NMR (125 MHz, d6-DMSO): δ 205.9, 195.9, 189.2, 175.8, 104.3, 101.9, 94.3, 48.5, 40.9,

26.2, 24.4, 24.0, 16.5, 11.7, 7.3.


HO O

OH O2.84: norisoleptospermone

MeI, KOt-BuMeOH, 65 °C H

69%

HO OH

OH O

H

2.83

52

To a solution of 2.84 (118 mg, 0.40 mmol), and caryophyllene (2.30) (0.18 mL, 0.79 mmol) in Et2O

(5 mL) at −78 °C was added Ag2O (111 mg, 0.48 mmol) and TEMPO (123 mg, 0.79 mmol). The

reaction was stirred at −78 °C for 1 h, then warmed to room temperature and stirred for 3 h. The

solution was filtered and concentrated in vacuo. The residue was purified by flash column

chromatography on SiO2 (1:0 → 50:1, petrol/EtOAc gradient elution) to give hyperjapones C (2.51)

and E (2.53) as a yellow gum (129 mg, 61%, d.r. 2.5:1).

Data for hyperjapone C (2.51):


IR (neat): 2952, 2930, 2870, 2659, 1627, 1519, 1472, 1380, 1368, 1199 cm-1. 1H NMR (500 MHz, d6-acetone): δ 19.28 (s, 1H), 4.92 (s, 1H), 4.90 (s, 1H), 3.90 – 3.83

(overlapped m, 1H), 2.52 – 2.46 (overlapped m, 2H), 2.38 (dd, J = 16.5, 5.1 Hz, 1H), 2.27 – 2.16

(overlapped m, 2H), 2.27 – 2.16 (overlapped m, 2H), 2.05 (overlapped m, 1H), 1.99 – 1.92

(overlapped m, 1H), 1.86 – 1.68 (overlapped m, 4H), 1.60 (dd, J = 10.5, 7.6 Hz, 1H), 1.58 – 1.54

(overlapped m, 1H), 1.53 – 1.48 (overlapped m, 1H), 1.39 – 1.35 (overlapped m, 1H), 1.32 (s, 3H),

1.27 (s, 3H), 1.20 (s, 3H), 1.09 (d, J = 6.8 Hz, 3H), 1.01 (s, 3H), 0.97 (s, 3H), 0.87 (t, J = 7.4 Hz,

3H). 13C NMR (125 MHz, d6-acetone): δ 207.2, 196.9, 189.4, 173.5, 152.9, 110.7, 105.9, 103.0, 85.4,

54.0, 49.1, 42.8, 42.2, 37.9, 37.1, 35.9, 34.7, 34.2, 33.8, 30.4, 27.4, 25.5, 25.3, 23.9, 23.4, 22.3,

21.2, 17.1, 12.2.

HO O

OH O2.84

H

O

OH

O

OH

H

H

O

OH

O

OH

H

H

+2.51: hyperjapone C

2.53: hyperjapone E

H

H

61%, d.r. 2.5:1 2.51/2.53

H

H

caryophyllene (2.30)TEMPO, Ag2O


53

Data for hyperjapone E (2.53): 1H NMR (500 MHz, d6-acetone): δ 19.31 (br s, 1H), 4.84 (s, 1H), 4.75 (t, J = 1.7 Hz, 1H), 3.90 –

3.83 (overlapped m, 1H), 2.80 – 2.78 (overlapped m, 1H), 2.67 (dd, J = 16.5, 5.2 Hz, 1H), 2.52 –

2.47 (overlapped m, 1H), 2.27 – 2.16 (overlapped m, 2H), 2.12 – 2.08 (m, 1H), 1.98 – 1.87

(overlapped m, 1H), 1.64 – 1.83 (overlapped m, 5H), 1.62 – 1.58 (overlapped m, 1H), 1.53 – 1.46

(overlapped m, 3H), 1.40 – 1.35 (m, 1H), 1.33 (s, 3H), 1.27 (s, 3H), 1.13 (s, 3H), 1.08 (d, J = 6.7

Hz, 3H), 1.00 (s, 3H), 0.98 (s, 3H), 0.91 – 0.88 (overlapped m, 3H). 13C NMR (125MHz, d6-acetone): δ 207.3, 196.8, 189.4, 173.9, 156.0, 110.5, 105.9, 103.0, 85.6,

57.2, 49.0, 43.0, 42.1, 39.4, 39.3, 37.3, 35.2, 34.5, 33.9, 29.9, 27.5, 25.2, 24.4, 24.1, 23.3, 22.6,

20.1, 17.0, 12.2.


54

To a solution of 2.84 (93 mg, 0.39 mmol), and humulene (2.11) (160 mg, 0.78 mmol) in Et2O (5

mL) at −78 °C was added Ag2O (108 mg, 0.47 mmol) and TEMPO (122 mg, mmol). The reaction

was stirred at −78 °C for 1 h, then warmed to room temperature and stirred for 16 h. The solution

was filtered and concentrated in vacuo. The residue was purified by flash column chromatography

on SiO2 (1:0 → 50:1, petrol/EtOAc gradient elution) to give a mixture of 2.85 and 2.86 as a white

solid (59 mg, 35%, d.r. 1:1).


IR (neat): 2964, 2934, 2869, 1660, 1627, 1523, 1472, 1382, 1189. 1158 cm-1. 1H NMR (500 MHz, d6-acetone): δ 19.32 (br s, 1H), 5.23 (d, J = 15.9 Hz, 1H), 5.13 – 5.11 (m,

1H), 5.05 (ddd, J = 15.9, 10.6, 2.6 Hz, 1H), 3.87 (pent, J = 6.7 Hz, 1H), 2.78 (s, 1H), 2.58 – 2.55

(m, 1H), 2.46 (dd, J = 14.6, 10.6 Hz, 1H), 2.24 (t, J = 2.26 Hz, 1H), 2.12 (dd, J = 12.7, 7.3 Hz, 1H),

1.93 – 1.88 (m, 1H), 1.84 – 1.80 (m, 2H), 1.76 – 1.69 (m, 2H), 1.65 (s, 3H), 1.45 – 1.38 (m, 2H),

1.35 (s, 3H), 1.29 (s, 3H), 1.23 – 1.20 (m, 1H), 1.17 (s, 3H), 1.09 (t, J = 6.7 Hz, 3H), 1.05 (s, 3H),

1.03 (s, 3H), 0.90 (t, J = 7.5 Hz, 3H). 13C NMR (125 MHz, d6-acetone): δ 207.3, 196.8, 189.5, 173.7, 143.8, 137.4, 123.8, 120.7, 105.8,

103.2, 85.9, 49.0, 42.2, 42.1, 38.8, 38.3, 35.6, 30.4, 30.1, 29.9, 27.4, 24.9, 24.7, 24.2, 22.5, 20.3,

17.2, 17.0, 12.2.


2.85

2.86

+

O

OH

O

OH

O

OH

O

OH

H

H

HO O

OH O

H

35%, d.r. 1:1 2.85/2.86



2.84

55

To a solution of noflavesone (2.58) (200 mg, 0.84 mmol) and (−)-sabinene (2.91) (75%, 0.27 mL,

1.68 mmol) in anhydrous THF (10 mL) at −78 °C was added Ag2O (233 mg, 1.00 mmol) and

TEMPO (157 mg, 1.00 mmol). The mixture was stirred at −78 °C for 1 h, then warmed to room

temperature and stirred for an addition of 16 h. The reaction was filtered, then concentrated in

vacuo. The residue was purified by flash column chromatography on SiO2 (100:1, petrol/EtOAc) to

give a 1:1 mixture of hyperjapone F (2.87) and hyperjapone G (2.88) as a colourless oil (40 mg,

13%).

Partial Data for 2.87 and 2.88:


NMR data for hyperjapone F (2.87): 1H NMR (500 MHz, d6-acetone): δ 3.97 (hept, J = 6.7 Hz, 1H), 2.54 – 2.43 (overlapped m, 1H),

2.34 – 2.27 (m, 1H), 2.00 – 1.93 (overlapped m, 1H), 1.90 – 1.84 (overlapped m, 2H), 1.79 – 1.72

(overlapped m, 1H), 1.66 (dd, J = 12.1, 8.1 Hz, 1H), 1.48 – 1.43 (overlapped m, 1H), 1.41 – 1.35

(overlapped m, 1H), 1.33 (s, 3H), 1.30 (s, 3H), 1.09 (d, J = 6.8 Hz, 6H), 1.03 (d, J = 6.9 Hz, 3H),

0.96 (overlapped d, J = 6.8 Hz, 3H), 0.54 (dd, J = 8.3, 5.5 Hz, 1H), 0.48 – 0.47 (overlapped m, 1H). 13C NMR (125 MHz, d6-acetone): δ 208.0, 196.7, 189.6, 174.0, 105.1, 103.5, 49.2, 35.8, 35.3,

33.19, 33.15, 31.2, 28.3, 25.9, 25.5, 24.8, 20.4, 20.0, 19.32, 19.30, 17.2, 13.2.

NMR data for hyperjapone G (2.88): 1H NMR (500 MHz, d6-acetone): δ 3.97 (hept, J = 6.7 Hz, 1H), 2.54 – 2.43 (overlapped m, 2H),

2.00 – 1.93 (overlapped m, 1H), 1.90 – 1.84 (overlapped m, 1H), 1.79 – 1.72 (overlapped m, 2H),

1.62 – 1.56 (m, 1H), 1.41 – 1.35 (overlapped m, 1H), 1.32 – 1.31 (m, 1H), 1.30 (s, 3H), 1.27 (s,

3H), 1.09 (d, J = 6.8 Hz, 6H), 0.96 (overlapped d, J = 6.9 Hz, 3H), 0.91 (d, J = 6.9 Hz, 3H), 0.90 –

0.88 (m, 1H), 0.48 – 0.47 (m, 1H). 13C NMR (125 MHz, d6-acetone): δ 208.0, 196.7, 189.7, 175.2, 105.1, 103.2, 89.2, 49.2, 35.8,

34.4, 33.3, 30.0, 25.3, 25.2, 24.5, 19.83, 19.82, 19.32, 19.30, 16.3, 12.1.


HO O


(−)-sabinene (2.91)Ag2O, TEMPO

THF, −78 ºC to rtO

OH

O


13%

H

O

OH

O


+

1:1

56

To a solution of norflavesone (2.58) (200 mg, 0.84 mmol) and (+)-(β)-pinene (+)-2.92 (0.16 mL,

1.01 mmol) in MeOH (10 mL) at −78 °C was added ceric ammonium nitrate (552 mg, 1.01 mmol)

and TEMPO (158 mmol, 1.01 mmol). The mixture was stirred at −78 °C for 10 min, then warmed

to room temperature and stirred for 16 h. The reaction was diluted with H2O (10 mL), then

extracted with Et2O (2 × 20 mL). The combined organic extracts were washed with H2O (40 mL),

brine (40 mL), dried over MgSO4, filtered and concentrated in vacuo. The residue was partially

purified by flash column chromatography on SiO2 (100:1 → 20:1 gradient elution, petrol/EtOAc).

The product was purified by flash column chromatography on SiO2 (1:1, petrol/CH2Cl2) to give (+)-

hyperjapone H (+)-2.89 as a light yellow oil (78 mg, 25%).

Data for (+)-2.89:


IR(neat): 2974, 2927, 2870, 1655, 1623, 1518, 1472, 1457, 1386, 1367, 1353, 1251, 1186 cm-1.

[!]!!" = +23.5° (c 1.0, MeOH)

Data for major tautomer: 1H NMR (500 MHz, d6-acetone): δ 19.21 (br s, 1H), 3.97 (hept, J = 6.8 Hz, 1H), 2.37 (t, J = 6.6

Hz, 2H), 2.31 – 2.26 (m, 1H), 2.16 (t, J = 5.1 Hz, 1H), 2.02 – 1.97 (m, 4H), 1.95 – 1.92 (m, 2H),

1.82 (dt, J = 13.8, 6.8 Hz, 1H), 1.67 (d, J = 10.2 Hz, 1H), 1.31 (s, 3H), 1.30 (s, 3H), 1.26 (s, 3H),

1.09 (d, J = 6.8 Hz, 6H), 1.04 (s, 3H). 13C NMR (125 MHz, d6-acetone): δ 207.9, 196.7, 189.4, 174.0, 105.0, 103.2, 86.3, 50.4, 49.3,

41.4, 38.9, 35.8, 32.6, 29.1, 27.8, 27.0, 25.4, 25.0, 24.9, 23.4, 19.32, 19.30, 15.8.

Data for minor tautomer: 1H NMR (500 MHz, d6-acetone): δ 18.60 (br s, 1H), 4.25 (hept, J = 6.8 Hz, 1H), 2.37 (t, J = 6.6

Hz, 2H), 2.31 – 2.26 (m, 1H), 2.11 (t, J = 5.1 Hz, 1H), 2.02 – 1.97 (m, 4H), 1.95 – 1.92 (m, 2H),

1.73 (td, J = 13.7, 7.0 Hz, 1H), 1.68 (d, J = 9.8 Hz, 1H), 1.45 (s, 3H), 1.40 (s, 3H), 1.31 (s, 3H),

1.30 (s, 3H), 1.26 (s, 3H), 1.12 (d, J = 7.0 Hz, 6H), 1.03 (s, 3H). 13C NMR (125 MHz, d6-acetone): δ 210.9, 199.3, 183.2, 166.3, 108.7, 103.0, 84.3, 50.4, 41.5,

36.5, 35.9, 33.1, 30.6, 29.0, 27.9, 27.2, 25.5, 25.2, 25.1, 23.5, 16.5.

HO O


(+)-(β)-pinene (+)-2.92CAN, TEMPO


OH

O


25%

57


To a solution of norflavesone (2.58) (200 mg, 0.84 mmol) and (−)-(β)-pinene (−)-2.92 (0.16 mL,

1.01 mmol) in MeOH (10 mL) at −78 °C was added ceric ammonium nitrate (552 mg, 1.01 mmol)

and TEMPO (158 mmol, 1.01 mmol). The mixture was stirred at −78 °C for 10 min, then warmed

to room temperature and stirred for 16 h. The reaction was diluted with H2O (10 mL), then

extracted with Et2O (2 × 20 mL). The combined organic extracts were washed with H2O (40 mL),

brine (40 mL), dried over MgSO4, filtered and concentrated in vacuo. The residue was partially

purified by flash column chromatography on SiO2 (100:1→20:1 gradient elution, petrol/EtOAc).

The product was purified by flash column chromatography on SiO2 (1:1, petrol/CH2Cl2) to give (−)-

hyperjapone H (−)-2.89 as a light yellow oil (83 mg, 27%).

Data for (−)-2.89:


IR(neat): 2972, 2929, 2871, 1656, 1624, 1523, 1474, 1387, 1312, 1252, 1193 cm-1.

[!]!!" = −19.7° (c 1.0, MeOH)

Data for major tautomer: 1H NMR (500 MHz, d6-acetone): δ 19.21 (br s, 1H), 3.97 (hept, J = 6.8 Hz, 1H), 2.37 (t, J = 6.6

Hz, 2H), 2.31 – 2.26 (m, 1H), 2.16 (t, J = 5.1 Hz, 1H), 2.01 – 1.97 (m, 4H), 1.96 – 1.92 (m, 2H),

1.82 (dt, J = 13.8, 6.8 Hz, 1H), 1.67 (d, J = 10.2 Hz, 1H), 1.31 (s, 3H), 1.30 (s, 3H), 1.26 (s, 3H),

1.09 (d, J = 6.8 Hz, 6H), 1.04 (s, 3H). 13C NMR (125 MHz, d6-acetone): δ 207.9, 196.7, 189.5, 174.0, 105.0, 103.2, 86.3, 50.4, 49.3,

41.4, 38.9, 35.8, 32.7, 29.1, 27.8, 27.0, 25.4, 25.0, 24.9, 23.4, 19.31, 19.29, 15.8.

Data for minor tautomer: 1H NMR (500 MHz, d6-acetone): δ 18.60 (br s, 1H), 4.25 (hept, J = 6.8 Hz, 1H), 2.37 (t, J = 6.6

Hz, 2H), 2.31 – 2.26 (m, 1H), 2.11 (t, J = 5.1 Hz, 1H), 2.01 – 1.97 (m, 4H), 1.96 – 1.92 (m, 2H),

1.73 (td, J = 13.7, 7.0 Hz, 1H), 1.68 (d, J = 9.8 Hz, 1H), 1.45 (s, 3H), 1.40 (s, 3H), 1.31 (s, 3H),

1.30 (s, 3H), 1.26 (s, 3H), 1.12 (d, J = 7.0 Hz, 6H), 1.03 (s, 3H).

HO O


(−)-(β)-pinene (–)-2.92CAN, TEMPO


OH

O


27%

58

13C NMR (125 MHz, d6-acetone): δ 210.9, 199.3, 183.2, 166.3, 108.7, 103.0, 84.3, 50.4, 41.5,

36.5, 35.9, 33.1, 30.6, 29.0, 27.9, 27.2, 25.5, 25.2, 25.1, 23.5, 16.5.


59

To a solution of noflavesone (2.58) (1.00 g, 4.19 mmol) and (+)-(α)-pinene (+)-2.93 (1.33 mL, 8.38

mmol) in MeOH (50 mL) at −78 °C was added ceric ammonium nitrate (2.76 g, 5.03 mmol) and

TEMPO (838 mg, 5.03 mmol). The mixture was stirred at −78 °C for 1 h, then warmed to room

temperature and stirred for 2 d. The reaction was diluted with H2O (50 mL), then extracted with

Et2O (2 × 100 mL). The combined extracts were washed with H2O (100 mL), brine (100 mL), dried

over MgSO4, filtered and concentrated in vacuo. The residue was purified by flash column

chromatography on SiO2 (doped with 1% w/w AgNO3, 100:1, petrol/EtOAc) to give (+)-

hyperjapone I (+)-2.90 as a white solid (130 mg, 8%).

Data for (+)-2.90:


M.p.: 110 – 111 °C

IR(neat): 2972, 2922, 2873, 1650, 1617, 1516, 1472, 1439, 1388, 1343, 1317 cm-1.

[!]!!" = +95° (c 1.0, MeOH)

Data for major tautomer: 1H NMR (500 MHz, d6-acetone): δ 19.31 (br s, 1H), 3.98 (hept, J = 6.8 Hz, 1H), 2.83 – 2.77 (m,

1H), 2.45 (dd, J = 16.2, 1.8 Hz, 1H), 2.39 (dd, J = 16.3, 6.8 Hz, 1H), 2.26 – 2.19 (m, 3H), 1.93 (dd,

J = 9.6, 4.5 Hz, 1H), 1.43 (s, 3H), 1.37 – 1.32 (overlapped m, 1H), 1.33 (s, 3H), 1.29 (s, 3H), 1.28

(s, 3H), 1.15 (s, 3H), 1.11 (d, J = 6.8 Hz, 3H), 1.09 (d, J = 6.7 Hz, 3H), 0.92 – 0.88 (m, 1H). 13C NMR (125 MHz, d6-acetone): δ 207.5, 196.6, 189.9, 174.8, 105.0, 100.4, 87.1, 55.1, 49.2,

41.8, 40.3, 35.8, 35.7, 31.2, 30.1, 28.9, 28.8, 26.2, 23.9, 23.2, 23.0, 19.6, 19.4, 19.3.

Data for minor tautomer: 1H NMR (500 MHz, d6-acetone): δ 18.64 (br s, 1H), 4.27 (hept, J = 6.7 Hz, 1H), 2.73 (dd, J =

17.0, 7.8 Hz, 1H), 1.44 (s, 3H). 13C NMR (125 MHz, d6-acetone): δ 210.7, 199.3, 183.2, 167.2, 105.7, 100.2, 84.9, 55.3, 49.2,

44.0, 36.5, 36.0, 31.7, 26.0, 24.3, 23.1, 20.4, 19.5.


HO O


(+)-(α)-pinene (+)-2.93CAN, TEMPO


OH

O

O(+)-2.90: (+)-hyperjapone I

8%

O

H

60

To a solution of norflavesone (2.58) (1.0 g, 4.19 mmol) and (−)-(α)-pinene (−)-2.93 (1.33 mL, 8.38

mmol) in MeOH (30 mL) at −78 °C was added ceric ammonium nitrate (2.76 g, 5.03 mmol) and

TEMPO (828 mmol, 5.03 mmol). The mixture was stirred at −78 °C for 10 min, then warmed to

room temperature and stirred for 5 d. The reaction was diluted with H2O (20 mL), then extracted

with Et2O (2 × 50 mL). The combined organic extracts were washed with H2O (100 mL), brine (100

mL), dried over MgSO4, filtered and concentrated in vacuo. The residue was partially purified by

flash column chromatography on SiO2 (100:1→50:1 gradient elution, petrol/EtOAc). The product

was purified by flash column chromatography on SiO2 (doped with 1% w/w AgNO3, 100:1,

petrol/EtOAc) to give (−)-hyperjapone I (−)-2.90 as a white solid (81 mg, 5%).

Data for (−)-2.90:


M.p.: 111 – 113 °C

IR (neat): 2980, 2923, 2869, 1650, 1619, 1514, 1471, 1441, 1388, 1343, 1318, 1251 cm-1.

[!]!!" = −98° (c 1.0, MeOH)

Data for major tautomer: 1H NMR (500 MHz, d6-acetone): δ 19.31 (br s, 1H), 3.97 (hept, J = 6.8 Hz, 1H), 2.83 – 2.78 (m,

1H), 2.45 (dd, J = 16,3m 1.9 Hz, 1H), 2.39 (dd, J = 16.2, 6.8 Hz, 1H), 2.26 – 2.19 (m, 3H), 1.94 –

1.91 (m, 1H), 1.43 (s, 3H), 1.36 – 1.34 (m, 1H), 1.33 (s, 3H), 1.29 (s, 3H), 1.28 (s, 3H), 1.15 (s,

3H), 1.11 (d, J = 6.8 Hz, 3H), 1.09 (d, J = 6.8 Hz, 3H), 0.92 – 0.88 (m, 1H). 13C NMR (500 MHz, d6-acetone): δ 207.5, 196.6, 189.9, 174.8, 105.0, 100.3, 87.1, 55.1, 49.2,

41.8, 40.3, 35.8, 35.7, 31.2, 30.1, 28.9, 28.8, 26.2, 23.9, 23.0, 19.6, 19.4, 19.3.

Data for minor tautomer: 1H NMR (500 MHz, d6-acetone): δ 18.64 (br s, 1H), 4.27 (hept, J = 6.8 Hz, 1H), 2.76 – 2.70 (m,

1H), 1.44 (s, 3H). 13C NMR (500 MHz, d6-acetone): δ 210.7, 199.3, 183.2, 167.1, 105.7, 100.2, 84.9, 55.3, 49.2,

44.0, 36.5, 36.0, 31.7, 26.0, 24.3, 23.1, 20.4, 19.5.


HO O


(−)-(α)-pinene (–)-2.93CAN, TEMPO


OH

O

O(−)-2.90: (−)-hyperjapone I

5%

O

H

61

2.5.3. NMR spectra

HO OH

OH O

2.57

1H NMR500 MHzCD3OD

HO OH

OH O

2.57

13C NMR125 MHzCD3OD

62

HO O

OH O

1H NMR500 MHzd6-DMSO

2.58: norflavesone

HO O

OH O


2.58: norflavesone

63

HO O

OH O

13C NMR125 MHzd6-DMSO

2.58: norflavesone

64

O

OH

O

OH

(±)-2.49: hyperjapone A1H NMR500 MHz

d6-acetone

O

OH

O

OH


d6-acetone

65

O

OH

O

OH

(±)-2.49: hyperjapone A13C NMR125 MHz

d6-acetone

66

O

OH

O

OH

(±)-2.49: hyperjapone ACOSY

500 MHzd6-acetone

O

OH

O

OH

(±)-2.49: hyperjapone AHSQC

500 MHzd6-acetone

67

O

OH

O

OH

(±)-2.49: hyperjapone AHMBC

500 MHzd6-acetone

O

OH

O

OH

(±)-2.49: hyperjapone ANOESY500 MHz

d6-acetone

68

O

OH

O

OH


CDCl3

O

OH

O

OH


CDCl3

69

O

OH

O

OH

(±)-2.49: hyperjapone A13C NMR125 MHz

CDCl3

70

O

OH

O

OH

O

1H NMR500 MHz

d6-acetone

2.60

O

OH

O

OH

O

1H NMR500 MHz

d6-acetone

2.60

71

O

OH

O

OH

O

13C NMR125 MHz

d6-acetone

2.60

O

OH

O

OH

O

COSY500 MHz

d6-acetone

2.60

72

O

OH

O

OH

O

HSQC500 MHz

d6-acetone

2.60

O

OH

O

OH

O

HMBC500 MHz

d6-acetone

2.60

73

O

OH

O

OH

O

1H NMR500 MHz

CDCl3

2.60

O

OH

O

OH

O

1H NMR500 MHz

CDCl3

2.60

74

O

OH

O

OH

O

13C NMR125 MHz

CDCl3

2.60

75

O

OH

O

OH

H

HO

(±)-2.56: hyperjaponol C1H NMR500 MHz

CDCl3

O

OH

O

OH

H

HO


CDCl3

76

O

OH

O

OH

H

HO

(±)-2.56: hyperjaponol C13C NMR125 MHz

CDCl3

77

O

OH

O

OH

H

HO


COSY500 MHz

CDCl3

O

OH

O

OH

H

HO


HSQC500 MHz

CDCl3

78

O

OH

O

OH

H

HO


HMBC500 MHz

CDCl3

O

OH

O

OH

H

HO


ROESY500 MHz

CDCl3

79

O

OH

O

OH

H

HO


d6-acetone

O

OH

O

OH

H

HO


d6-acetone

80

O

OH

O

OH

H

HO

(±)-2.56: hyperjaponol C13C NMR125 MHz

d6-acetone

81

O

OH

O

OHHO

(±)-2.54: hyperjaponol A1H NMR500 MHz

CDCl3

O

OH

O

OHHO

(±)-2.54: hyperjaponol A1H NMR500 MHz

CDCl3

82

O

OH

O

OHHO

(±)-2.54: hyperjaponol A13C NMR125 MHz

CDCl3

83

O

OH

O

OHHO


COSY500 MHz

CDCl3

O

OH

O

OHHO


HSQC500 MHz

CDCl3

84

O

OH

O

OHHO


HMBC500 MHz

CDCl3

O

OH

O

OHHO


ROESY500 MHz

CDCl3

85

O

OH

O

OH

H

H

O

OH

O

OH

H

H+


d.r. 2.5:11H NMR500 MHz

d6-acetone

O

OH

O

OH

H

H

O

OH

O

OH

H

H+


d.r. 2.5:11H NMR500 MHz

d6-acetone

86

O

OH

O

OH

H

H

O

OH

O

OH

H

H+


d.r. 2.5:113C NMR125 MHz

d6-acetone

87

O

OH

O

OH

H

H

2.50: hyperjapone B1H NMR500 MHz

d6-acetone

O

OH

O

OH

H

H

2.50: hyperjapone B1H NMR500 MHz

d6-acetone

88

O

OH

O

OH

H

H

2.50: hyperjapone B13C NMR125 MHz

d6-acetone

89

O

OH

O

OH

H

H

2.50: hyperjapone B

COSY500 MHz

d6-acetone

O

OH

O

OH

H

H

2.50: hyperjapone B

HSQC500 MHz

d6-acetone

90

O

OH

O

OH

H

H

2.50: hyperjapone B

HMBC500 MHz

d6-acetone

O

OH

O

OH

H

H

2.50: hyperjapone B

NOESY500 MHz

d6-acetone

91

HO OH

OH O

H

1H NMR500 MHzCD3OD

2.83

HO OH

OH O

H

13C NMR125 MHzCD3OD

2.83

92

HO O

OH O

H

(+)-2.84: norisoleptospermone1H NMR500 MHzd6-DMSO

HO O

OH O

H

(+)-2.84: norisoleptospermone1H NMR500 MHzd6-DMSO

93

HO O

OH O

H

(+)-2.84: norisoleptospermone13C NMR125 MHzd6-DMSO

94

O

OH

O

OH

H

H

O

OH

O

OH

H

H+


H H

d.r. 2.5:11H NMR500 MHz

d6-acetone

O

OH

O

OH

H

H

O

OH

O

OH

H

H+


H H

d.r. 2.5:11H NMR500 MHz

d6-acetone

95

d.r. 2.5:113C NMR125 MHz

d6-acetone

O

OH

O

OH

H

H

O

OH

O

OH

H

H+


H H

96

2.85 2.86

+O

OH

O

OH

O

OH

O

OH

HH

d.r. 1:11H NMR500 MHz

d6-acetone

2.85 2.86

+O

OH

O

OH

O

OH

O

OH

HH


d6-acetone

97

2.85 2.86

+O

OH

O

OH

O

OH

O

OH

HH

d.r. 1:113C NMR125 MHz

d6-acetone

98

2.85 2.86

+O

OH

O

OH

O

OH

O

OH

HH


CDCl3

2.85 2.86

+O

OH

O

OH

O

OH

O

OH

HH


CDCl3

99

2.85 2.86

+O

OH

O

OH

O

OH

O

OH

HH


CDCl3

100

O

OH

O


O

OH

O


+

1:11H NMR500 MHz

d6-acetone

O

OH

O


O

OH

O


+

1:11H NMR500 MHz

d6-acetone

101

O

OH

O


O

OH

O


+

1:113C NMR125 MHz

d6-acetone

O

OH

O


O

OH

O


+

1:1

COSY500 MHz

d6-acetone

102

O

OH

O


O

OH

O


+

1:1

HSQC500 MHz

d6-acetone

O

OH

O


O

OH

O


+

1:1

HMBC500 MHz

d6-acetone

103

O

OH

O


1H NMR500 MHz

d6-acetone

O

OH

O


1H NMR500 MHz

d6-acetone

104

O

OH

O


13C NMR125 MHz

d6-acetone

105

O

OH

O


COSY500 MHz

d6-acetone

O

OH

O


HSQC500 MHz

d6-acetone

106

O

OH

O


HMBC500 MHz

d6-acetone

O

OH

O


NOESY500 MHz

d6-acetone

107

O

OH

O


1H NMR500 MHz

d6-acetone

O

OH

O


1H NMR500 MHz

d6-acetone

108

O

OH

O


13C NMR125 MHz

d6-acetone

109

O

OH

O


COSY500 MHz

d6-acetone

O

OH

O


HSQC500 MHz

d6-acetone

110

O

OH

O


HMBC500 MHz

d6-acetone

O

OH

O


NOESY500 MHz

d6-acetone

111

OH

O


O

1H NMR500 MHz

d6-acetone

H

OH

O


O

1H NMR500 MHz

d6-acetone

H

112

OH

O


O

13C NMR125 MHz

d6-acetone

H

113

OH

O


O

COSY500 MHz

d6-acetone

H

OH

O


O

HSQC500 MHz

d6-acetone

H

114

OH

O


O

HMBC500 MHz

d6-acetone

H

OH

O


O

NOESY500 MHz

d6-acetone

H

115

OH

O


O

1H NMR500 MHz

d6-acetone

H

OH

O


O

1H NMR500 MHz

d6-acetone

H

116

OH

O


O

13C NMR125 MHz

d6-acetone

H

117

OH

O


O

COSY500 MHz

d6-acetone

H

OH

O


O

HSQC500 MHz

d6-acetone

H

118

OH

O


O

HMBC500 MHz

d6-acetone

H

OH

O


O

NOESY500 MHz

d6-acetone

H

119

2.5.4. Tables of 1H and 13C NMR data

Comparison of the 1H and 13C NMR spectra of natural and synthetic hyperjapone A (2.49).

Assignment Natural sample 1H NMR,

d6-acetone, 600 MHz

Synthetic sample, 1H NMR,

d6-acetone, 500 MHz

Natural sample 13C NMR,

d6-acetone, 150 MHz

Synthetic sample, 13C NMR,

d6-acetone, 125 MHz

1 104.9 105.0

2 189.3 189.4

3 102.9 103.0

4 2.77, br d (J = 11.8 Hz)

1.82, m

2.77, m

1.85 – 1.83, overlapped m 22.3 22.5

5 1.83, m 1.85 – 1.83, overlapped m 35.5 35.6

6 1.41, t (J = 12.8 Hz)

1.20, m

1.42, dd (J = 15.0, 11.7 Hz)

1.25 – 1.20, m 30.2 30.3

7 2.10, dd (J = 12.8, 7.6 Hz)

1.89, t (J = 12.8 Hz)

2.12, dd (J = 12.8, 7.4 Hz)

1.91, t (J = 12.3 Hz) 38.2 38.3

8 137.3 137.4

9 5.10, d (J = 12.4 Hz) 5.12, dd (J = 11.3, 3.3 Hz) 123.7 123.8

10 2.23, t (J = 12.4 Hz) 2.24, t (J = 12.4 Hz) 42.1 42.2

11 38.7 38.8

12 5.22, d (J = 15.8 Hz) 5.23, d (J = 15.7 Hz) 143.7 143.8

13 5.03, dd (J = 15.8, 10.8 Hz) 5.04, ddd (J = 15.5, 10.6,

2.5 Hz) 120.6 120.7

14 2.55, d (J = 14.3 Hz)

2.45, dd (J = 14.3, 11.2 Hz)

2.56, d (J = 14.8 Hz)

2.46, dd (J = 14.6, 10.7Hz) 42.5 42.6

15 85.5 85.9

16 173.7 173.7

17 48.8 48.9

18 196.6 196.7

19 207.8 207.9

20 3.96, hept (J = 6.8 Hz) 3.98, hept (J = 6.8 Hz) 35.7 35.8

21 1.08, d (J = 6.8 Hz) 1.09, overlapped d (J = 6.3

Hz) 19.2 19.3

22 1.09, d (J = 6.8 Hz) 1.10, overlapped d (J = 6.3 19.3 19.4

O

OH

O

OH


153

6

10

12

7

11

8

249

13

22

211716

19

14

1520

18

23

2827262425

120

Hz)

23 1.64, s 1.65, s 17.2 17.2

24 1.02, s 1.03, s 24.1 24.2

25 1.03, s 1.05, s 30.3 30.4

26 1.15, s 1.17, s 20.2 20.3

27 1.34, s 1.35, s 24.3 24.2

28 1.28, s 1.29, s 25.1 25.2

OH-2 19.26

121

Comparison of the 1H and 13C NMR spectra of natural and synthetic hyperjapone B (2.50).


d6-acetone, 600 MHz


d6-acetone, 500 MHz


d6-acetone, 150 MHz


d6-acetone, 125 MHz

1 104.9 150.0

2 189.6 189.4

3 102.7 102.9

4 2.36, dd (J = 16.5, 5.0 Hz)

1.91, m

2.38, dd (J = 16.5, 5.1 Hz)

1.94 – 1.92, m 25.2 25.3

5 2.05, m 2.09 – 2.07, m 34.5 34.6

6 1.77, m

1.57, m

1.83 – 1.76, m,

1.57 – 1.45, m 33.7 33.8

7 2.47, m

2.18, m

2.54 – 2.46, m

2.27 – 2.17, m 35.8 35.9

8 152.8 152.9

9 2.49, m 2.54 – 2.46, m 42.7 42.8

10 1.71, t (J = 10.5 Hz)

1.59, dd (J = 10.5, 7.7 Hz)

1.73, t (J = 10.4 Hz)

1.60, dd (J = 10.5, 7.6 Hz) 36.9 37.1

11 34.1 34.2

12 1.94, m 1.98 – 1.95, m 53.8 54.0

13 1.78, m

1.47, m

1.83 – 1.76, m

1.57 – 1.45 m 23.3 23.4

14 2.23, m

1.94, m

2.27 – 2.17, m

1.98 – 1.95, m 37.8 37.9

15 85.3 85.4

16 173.5 173.6

17 48.9 49.0

18 196.6 196.7

19 207.8 207.9

20 3.95, hept (J = 6.8 Hz) 3.97, hept (J = 6.8 Hz) 35.7 35.8

21 1.08, d (J = 6.8 Hz) 1.08, d (J = 5.3 Hz) 19.2 19.26

22 1.09, d (J = 6.8 Hz) 1.10, d (J = 5.4 Hz) 19.3 19.33

23 4.90, s 4.92, s 110.6 110.7

O

OH

O

OH

H

H

2.50: hyperjapone B

153

6

1012

7

11

824

9

13

22

211716

19

14

1520

18

23

28272624

25

122

4.89, s 4.90, s

24 0.99, s 1.01, s 22.3 22.3

25 0.96, s 0.97, s 30.3 30.4

26 1.19, s 1.20, s 21.1 21.2

27 1.26, s 1.28, s 25.3 25.4

28 1.31, s 1.32, s 24.2 24.3

OH-2 19.23

* The 1H NMR spectra data from the isolation was incorrectly referenced at 2.06 ppm for d6-acetone.

123

Comparison of the 1H and 13C NMR spectra of natural and synthetic hyperjaponol C (2.56).


CDCl3, 600 MHz


CDCl3, 500 MHz


CDCl3, 150 MHz

Synthetic sample, 13C

NMR, CDCl3, 125 MHz

1 104.8 104.7

2 188.7 188.6

3 103.6 103.6

4 2.43, dd (J = 16.4, 4.9 Hz)

2.02, dd (J = 16.4, 12.0 Hz)

2.45, dd (J = 16.5, 4.9 Hz)

2.05, dd (J = 17.4, 14.3 Hz) 24.8 24.7

5 1.77, m 1.83 – 1.80, m 40.7 40.6

6 1.46, m

1.37, d (J = 9.1 Hz) 1.52 – 1.41, m* 26.2 26.2

7 1.81, m

1.25, m

1.95 – 1.85, overlapped m

1.28 – 1.27, m 41.35 41.3

8 47.0 46.9

9 3.71, t (J = 9.0 Hz) 3.73, t (J = 9.1 Hz) 82.3 82.3

10 1.89, m

1.66, m

1.95 – 1.85, overlapped m

1.72 – 1.70, m 36.0 36.0

11 2.24, td (J = 11.4, 5.5 Hz) 2.26, td (J =11.2, 5.6 Hz) 47.1 47.0

12 1.85, m 1.95 – 1.85, overlapped m 41.5 41.4

13 1.97, d (J = 13.5 Hz)

1.70, dd (J = 13.5, 4.8 Hz)

2.00, d (J =16.4 Hz)

1.72 – 1.70, m 39.3 39.3

14 84.3 84.3

15 173.8 173.7

16 48.6 48.5

17 197.1 197.1

18 208.1 208.0

19 3.93, hept (J = 6.8 Hz) 3.96, hept (J = 6.8) 35.6 35.6

20 1.10, d (J = 6.8 Hz) 1.13, d (J = 5.9 Hz) 19.18 19.11

21 1.12, d (J = 6.8 Hz) 1.15, d (J = 6.8 Hz) 19.20 19.14

22 0.79, s 0.82, s 12.4 12.3

23 146.0 146.0

O

OH

O

OH

H

HO


153

6

10 12

7

11

8

24

9

13

22 21

1716

1914 15

20

18

23

282726

24 25

124

24 1.64, s 1.67, s 19.5 19.5

25 4.74, s

4.70, s

4.77, s

4.73, s 111.2 111.1

26 1.10, s 1.12, s 20.4 20.4

27 1.27, s 1.30, s 23.5 23.4

28 1.23, s 1.26, s 25.9 25.8

OH-2 19.08, s

OH-9 1.61, br s

* the doublet at 1.37 ppm reported in literature should be 2 methyl groups at 1.40 and 1.38 ppm

from the minor tautomer, corresponding to carbon at 23.8 and 25.5 ppm.

125

Comparison of the 1H and 13C NMR spectra of natural and synthetic hyperjaponol A (2.54).


CDCl3, 600 MHz


CDCl3, 500 MHz


CDCl3, 150 MHz


NMR, CDCl3, 125 MHz

1 104.8 104.7

2 188.7 188.6

3 102.5 102.5

4 2.80, m

1.77, m

2.83, d (J = 11.6 Hz)

1.85 – 1.70, m 22.2 22.1

5 1.78 m 1.85 – 1.70, m 37.5 37.4

6 1.56, m

1.37, m

1.64 – 1.60, m

1.40 – 1.39, m 32.7 32.7

7 2.45, m

2.02, m

2.48, dd (J = 13.2, 8.6 Hz)

2.05, dd (J = 13.4, 10.1 Hz) 32.2 32.1

8 155.6 155.5

9 3.87, d (J = 9.0 Hz) 3.89, d (J = 9.0 Hz) 73.0 72.9

10 2.10, dd (J = 13.8, 9.0 Hz)

1.61, m

2.12, dd (J = 13.7, 9.7 Hz)

1.64 – 1.60, m 49.0 49.0

11 36.0 35.9

12 5.36, d (J = 15.8 Hz) 5.39, d (J = 15.7 Hz) 144.5 144.4

13 5.14, ddd (J = 15.8, 10.0, 4.0

Hz) 5.16, ddd (J = 15.4, 9.9, 4.0 Hz) 120.1 120.0

14 2.48, dd (J = 14.2, 4.0 Hz)

2.37, dd (J = 14.2, 10.0 Hz)

2.52, dd (J = 13.8, 3.9 Hz)

2.39, dd (J = 14.1, 10.0 Hz) 43.7 43.7

15 83.9 83.8

16 172.9 172.8

17 48.5 48.2

18 197.0 196.9

19 208.0 207.9

20 3.96, hept (J = 6.8 Hz) 3.97, hept (J = 6.6 Hz) 35.6 35.5

21 1.12, d (J = 6.8 Hz) 1.15, d (J = 7.0 Hz) 19.17 19.1

22 1.14, d (J = 6.8 Hz) 1.17, d (J = 8.1 Hz) 19.24 19.2

23 5.19, s 5.21, s 113.8 113.7

O

OH

O

OHHO


153

6

10

12

7

11

824

9

13

22

211716

19

14

1520

18

23

282726

24

25

126

4.93, s 4.96, s

24 1.09, s 1.11, s 24.7 24.6

25 1.01, s 1.04, s 30.6 30.6

26 1.07, s 1.09, s 19.5 19.5

27 1.35, s 1.37, s 24.2 24.1

28 1.28, s 1.31, s 25.3 25.3

OH-2 19.16, s

127

Comparison of the 1H and 13C NMR spectra of natural and synthetic (+)-hyperjapone H (+)-2.89.

Assignment Natural sample 1H NMR, d6-

acetone, 600 MHz


d6-acetone, 500 MHz


d6-acetone, 150 MHz


d6-acetone, 125 MHz

1 104.8 105.0

2 189.4 189.4

3 103.0 103.2

4 174.0 174.0

5 49.1 49.3

6 196.6 196.7

7 207.9 207.9

8 3.96 (hept, J = 6.6 Hz) 3.97 (hept, J = 6.8 Hz) 35.7 35.8

9 1.07 (d, J = 6.6 Hz) 1.09 (d, J = 6.6 Hz) 19.2 19.32

10 1.06 (d, J = 6.6 Hz) 1.09 (d, J = 6.6 Hz) 19.2 19.30

11 2.37 (dd, J = 7.2, 6.4 Hz) 2.37 (t, J = 6.6 Hz) 15.6 15.8

12 1.28, s 1.31, s 24.9 25.0

13 1.23, s 1.26, s 24.8 24.9

1’ 1.96, m

1.79, m

2.02 – 1.97, m

1.82 (dt, J = 13.8. 6.8 Hz) 32.4 32.6

2’ 86.2 86.3

3’ 2.13 (t, J = 5.4 Hz) 2.16 (t, J = 5.1 Hz) 50.1 50.4

4’ 38.7 38.9

5’ 1.95, m 2.02 – 1.97, m 41.1 41.4

6’ 1.99, m

1.89, m

2.02 – 1.97, m

1.95 – 1.92, m 25.2 25.4

7’ 1.98, m

1.90, m

2.02 – 1.97, m

1.95 – 1.92, m 28.8 29.1

8’ 2.26, m

1.64 (d, J = 10.2 Hz)

2.31 – 2.26, m

1.67 (d, J = 10.2 Hz) 26.9 27.0

9’ 1.28, s 1.30, s 27.6 27.8

10’ 1.01, s 1.04, s 23.3 23.4

OH-2 19.21, s

123

45

67

8

9

1011

O

OH

O


2'

3'4'5'

6'7'

8'

9' 10'

1'

12 13

128

Comparison of the 1H and 13C NMR spectra of natural and synthetic (–)-hyperjapone I (–)-2.90.

Assignment Natural sample 1H NMR, d6-

acetone, 600 MHz

Synthetic sample, 1H NMR, d6-

acetone, 500 MHz

Natural sample 13C

NMR, d6-acetone, 150

MHz


NMR, d6-acetone, 125

MHz

1 104.9 105.0

2 189.8 189.9

3 100.3 100.3

4 174.9 174.8

5 49.2 49.2

6 196.6 196.6

7 207.5 207.5

8 3.96 (hept, J = 6.6 Hz) 3.97 (hept, J = 6.8 Hz) 35.6 35.7

9 1.08 (d, J = 6.6 Hz) 1.11 (d, J = 6.6 Hz) 19.3 19.4

10 1.07 (d, J = 6.6 Hz) 1.09 (d, J = 6.6 Hz) 19.2 19.3

11 2.44 (dd, J = 16.0, 2.0 Hz)

2.38 (dd, J = 16.0, 6.6 Hz)

2.45 (dd, J = 16.0, 1.9 Hz)

2.39 (dd, J = 16.2, 6.8 Hz) 19.6 19.6

12 1.27, s 1.28, s 26.1 26.2

13 1.28, s 1.29, s 23.9 23.9

1’ 1.42, s

1.43, s 28.7 28.8

2’ 87.1 87.1

3’ 2.20, m 2.26 – 2.19, m 55.0 55.1

4’ 40.3 40.3

5’ 1.92, m 1.94 – 1.92, m 41.7 41.8

6’ 2.19, m

1.29, m

2.26 – 2.19, m

1.36 – 1.34, m 35.8 35.8

7’ 2.80, m 2.83 – 2.78, m 31.1 31.2

8’ 2.22, m

0.90 (dd, J = 10.0, 6.8 Hz)

2.26 – 2.19, m

0.92 – 0.88, m 30.2 30.1

9’ 1.32, s 1.33, s 28.8 28.9

10’ 1.13, s 1.15, s 22.9 23.0

OH-2 19.31, s

123

45

67

8

9

1011

O

OH

O


2'

3'

4'

5'6'

7'8'

9'

10'

1' 12 13

H

129

2.5.5. Single crystal X-ray data

Single crystals were mounted in paratone-N oil on a plastic loop. X-ray diffraction data were

collected at 150(2) K on an Oxford X-Calibur single crystal diffractometer (λ = 0.71073 Å). Data

sets were corrected for absorption using a multi-scan method, and structures were solved by direct

methods using SHELXS-974 and refined by full-matrix least squares on F2 by SHELXL-2014,5

interfaced through the program X-Seed.6 In general, all non-hydrogen atoms were refined

anisotropically and hydrogen atoms were included as invariants at geometrically estimated

positions. X-ray experimental data is given in the Table below. Table 2.5.1. X-ray experimental

data for hyperjapone I 2.90.

Compound hyperjapone I 2.90 Emp. formula C23H32O4

Fw 372.48 Crystal system monoclinic Space group P21

a (Å) 8.9461(6) b (Å) 12.7932(6) c (Å) 10.0330(8)

90 β (º) 115.162(9)

90 Volume (Å3) 1039.31(14)

Z 2 Density (calc.) (Mg/m3) 1.190 Abs. coefficient (mm-1) 0.080

F(000) 404 Crystal size (mm3) 0.69×0.53×0.36

θ range (º) 3.90 to 29.43 Reflns collected 19434

Obs. reflns [R(int)] 4468 [0.0388] GoF2 1.021

R1 [I>2σ(I)] 0.0414 wR2 (all data) 0.0949

Largest diff. peak and hole (e.Å-3) 0.201 & -0.203

130

Figure S1. A representation of the structure of hyperjapone I 2.90 with ellipsoids shown at the

50% probability level (carbon – grey; hydrogen – white; oxygen – red).

131

2.5.6. Computational Data

Molecular geometries, energies, and free energies of reactants, products, and transition states

were computed by density functional theory using the Gaussian 09 (Revision D.01) software

package. Geometries were optimized in the gas phase at the M062X/6-31G(d,p) for stable state

or M062X/6-31G(d) for transition state. The optimized geometries were identified as stable or

transition states by the number of imaginary frequencies (0 or 1, respectively).

132

Carbocation 2.61 1 1 C -5.43592700 0.98919800 0.85568100 C -5.72333100 -0.51974700 0.67173500 C -3.95043400 1.17753400 0.65603800 C -5.63509300 -1.08927000 -0.81401300 C -3.33951300 1.74420600 -0.38390100 C -1.86775500 1.79863600 -0.70089700 C -0.83485400 0.93374700 0.04754600 C -4.42100600 -1.91966800 -0.83245600 C -3.11297300 -1.35167600 -1.17783800 C -2.06796600 -1.40377100 -0.01998700 C -0.81141600 -0.57174300 -0.34097400 C -4.56179600 -3.34464000 -0.54491600 C -5.78540800 1.32223200 2.31808400 C -6.30654800 1.84421000 -0.06700000 C -0.82237000 1.16407500 1.56392000 H -3.35535200 0.72544100 1.44610700 H -5.52823700 -0.25172800 -1.51410800 O 0.38831600 1.51421700 -0.47566900 C 1.56059300 0.87883600 -0.26260000 C 1.62635100 -0.40303700 0.14903900 C 0.39449000 -1.23872500 0.33125200 C 2.74975700 1.76204900 -0.49777200 C 4.10541300 1.03175800 -0.37047400 C 4.14165400 -0.32721200 0.16148600 C 2.92785600 -0.99646200 0.39422800 C 2.75081300 2.86539400 0.58449700 C 2.66466500 2.39655100 -1.89675800 C 5.36658200 -1.06086300 0.45922100 C 6.74738300 -0.50360100 0.21403600 C 7.05980300 -0.66128800 -1.28630500 C 7.78857300 -1.21988000 1.07135000 H -0.64590400 -0.59596100 -1.42836900 O 5.09914100 1.66455400 -0.69572500 O 2.89892400 -2.21683300 0.84473100 O 5.27399600 -2.22724200 0.91349300 H 6.72940700 0.56505200 0.44042300 H 8.76880900 -0.76588500 0.90374400 H 7.55235900 -1.14633100 2.13630200 H 7.84701600 -2.28011800 0.81378800 H 8.05395700 -0.25523300 -1.49096600 H 7.05886100 -1.72101300 -1.56183300 H 6.34023700 -0.12268000 -1.90622200 H 3.93304900 -2.47070000 0.96736700 H 3.60980200 3.51848600 0.41469500 H 1.83062000 3.45247400 0.52398000 H 2.83377500 2.43396500 1.58774500 H 2.62922300 1.62710000 -2.67450600 H 1.77135600 3.01999900 -1.97565300 H 3.55405500 3.00812800 -2.05609400 H 0.19232400 -1.41242100 1.39846200 H 0.56182500 -2.22821200 -0.10740200 H -1.12498100 2.18810700 1.79696200 H -1.47890900 0.47599700 2.10220700 H 0.18749100 1.00886200 1.95234400 H -1.53048900 2.83691000 -0.58158300 H -1.74156200 1.59143100 -1.77298400 H -3.95353000 2.23577500 -1.14036800 H -1.76461100 -2.44560300 0.12259200 H -2.52276000 -1.08120200 0.91942200 H -2.72462700 -2.00961500 -1.97383100 H -3.21562800 -0.34209200 -1.56900900

133

H -5.31187100 -3.53110300 0.23046700 H -5.03358600 -3.75583200 -1.45814500 H -5.08784100 -1.09331600 1.36063600 H -6.75475600 -0.75691900 0.96098200 H -6.12540800 2.90491600 0.12764800 H -6.11950400 1.67734300 -1.13215100 H -7.36682100 1.64904900 0.12572000 H -5.56762100 2.37383600 2.52265500 H -6.84699300 1.14790200 2.51861000 H -5.19981400 0.71429400 3.01567400 H -3.61761200 -3.85453900 -0.36049900 O -6.72798700 -1.91271300 -1.11471900 H -7.54013500 -1.39149200 -1.15501400 EM062X/6-31G+(d,p)

-3851472.657 kJ mol-1

134

Carbocation 2.62 1 1 C -5.71490800 1.11846900 0.55012100 C -6.26843600 0.42463700 -0.71067000 C -4.23782700 0.83097400 0.58980200 C -5.54727600 -0.91802900 -0.96453500 C -3.49693000 0.71605300 -0.57500700 C -2.02308500 1.00025200 -0.78287200 C -0.88656400 0.26544600 -0.05821600 C -4.14805600 -0.97456300 -0.27682800 C -3.13088300 -1.74731700 -1.16075600 C -1.77163900 -2.13167900 -0.56569300 C -0.62850200 -1.11995500 -0.67507500 C -4.20492300 -1.67079300 1.10147400 C -6.46876100 0.68669200 1.81780200 C -5.80926300 2.66079600 0.42122700 C -1.00388400 0.27519800 1.46380900 H -3.72642200 0.81620600 1.55312000 H -5.38350600 -1.04029300 -2.04474600 O 0.22517200 1.12259600 -0.39574200 C 1.48245300 0.63620800 -0.22937500 C 1.73704800 -0.67412100 -0.05123500 C 0.65296200 -1.71308900 -0.08733200 C 2.51887400 1.71954500 -0.24278000 C 3.97047600 1.19917700 -0.13063600 C 4.20892700 -0.21571300 0.13096700 C 3.11335600 -1.09417300 0.15998500 C 2.28559300 2.63345500 0.98004600 C 2.40240400 2.53742700 -1.54192700 C 5.52844800 -0.79708400 0.36352800 C 6.80713600 0.00253200 0.30623200 C 7.17224600 0.20174700 -1.17747700 C 7.93182300 -0.70576900 1.05835900 H -0.44725800 -0.92659100 -1.74302100 O 4.85582700 2.03408100 -0.24431100 O 3.26674600 -2.36674700 0.37792500 O 5.61110600 -2.02793700 0.58805400 H 6.61365000 0.98745200 0.73775100 H 8.83086100 -0.08441000 1.03263000 H 7.66658200 -0.88554800 2.10359800 H 8.16221800 -1.67090500 0.60096100 H 8.09330200 0.78655900 -1.24550500 H 7.34593500 -0.76792500 -1.65541900 H 6.38974900 0.73884300 -1.71717600 H 4.32020200 -2.48156800 0.51440200 H 3.04371400 3.41977300 0.97761700 H 1.29246000 3.08731100 0.92556800 H 2.37024000 2.07028400 1.91573600 H 2.53715700 1.89901100 -2.42079000 H 1.42346700 3.01862700 -1.60159900 H 3.18390300 3.29905500 -1.54389800 H 0.46884700 -2.11706200 0.91847000 H 0.98379000 -2.56362100 -0.69206300 H -1.24521700 1.28262800 1.81701200 H -1.75600300 -0.42620100 1.82885500 H -0.04872200 -0.01263100 1.91077600 H -1.91219900 2.06669700 -0.54445000 H -1.81985800 0.91458200 -1.85444000 H -4.05311500 0.91502700 -1.49043800 H -1.43905500 -3.02206300 -1.11081200 H -1.88120000 -2.46516100 0.47110700 H -3.69098800 -2.67318900 -1.35618500 H -3.00514000 -1.25475100 -2.13168600

135

H -5.04348200 -1.36059700 1.71682400 H -4.33406600 -2.73615000 0.89625400 H -6.16006700 1.07636000 -1.58376200 H -7.34113700 0.24621900 -0.59165900 H -5.44053200 3.15982900 1.32217300 H -5.25204800 3.03262800 -0.44363600 H -6.86133200 2.93145200 0.29546100 H -5.90300000 0.92192900 2.72522900 H -7.41368100 1.23405500 1.86723400 H -6.71630000 -0.37627000 1.81358700 H -3.28597700 -1.54344300 1.66626700 O -6.25823400 -2.02825800 -0.46011200 H -6.99556500 -2.24397300 -1.04348700 EM062X/6-31G+(d,p)

-3851505.321 kJ mol-1

136

Carbocation 2.63 1 1 C -5.07677000 1.79628800 0.02135300 C -4.72593700 0.42942000 -2.10617300 C -4.13751000 1.24225100 -0.94801500 C -4.84875700 -1.03343500 -1.61121300 C -3.11356500 0.15252500 -0.34138500 C -2.37347000 0.49849000 0.94390900 C -0.97863700 -0.14869700 1.09686900 C -3.93349700 -1.16416900 -0.34524700 C -3.01240000 -2.39536000 -0.49604800 C -1.85704300 -2.51673600 0.50498800 C -0.77115300 -1.45244400 0.30148600 C -4.76077500 -1.32465400 0.93664400 C -4.61895700 2.77061800 1.02646400 C -6.51083600 1.48941900 -0.01224400 C -0.66693900 -0.28218400 2.58765400 H -3.49258300 2.07658100 -1.25743200 H -4.48735300 -1.71407000 -2.38940400 O -0.07566000 0.83678600 0.53902300 C 1.21546600 0.45833500 0.35789600 C 1.61431300 -0.83019900 0.40335300 C 0.64218400 -1.96683100 0.56765400 C 2.13257500 1.63041500 0.16369000 C 3.58055300 1.23691000 -0.20597700 C 4.00270300 -0.14818900 -0.03643500 C 3.02964400 -1.12255600 0.24840600 C 2.23107300 2.38515700 1.51008200 C 1.58067600 2.56723800 -0.92224400 C 5.38198900 -0.60663700 -0.16782700 C 6.52769600 0.30940200 -0.52522300 C 6.51197000 0.50599200 -2.05317600 C 7.86047400 -0.27281000 -0.05937400 H -0.78460500 -1.16052000 -0.75871300 O 4.31656200 2.13945000 -0.57821400 O 3.34542300 -2.37693600 0.38015400 O 5.63021700 -1.82487000 -0.00600500 H 6.34745900 1.28182600 -0.06119600 H 8.66523200 0.42579000 -0.30343900 H 7.86878300 -0.44462000 1.02029000 H 8.06478400 -1.22650500 -0.55169100 H 7.33381100 1.16730700 -2.34026300 H 6.65409900 -0.45569400 -2.55708100 H 5.57783400 0.95945000 -2.39135300 H 4.40132700 -2.39750800 0.24195600 H 1.23906800 2.72200200 1.82378400 H 2.65200600 1.74434200 2.29181300 H 2.88379200 3.25165500 1.37937600 H 1.45265600 2.03641700 -1.87090800 H 0.61675100 2.97795600 -0.61256300 H 2.29210800 3.37981800 -1.07540700 H 0.72196400 -2.42257800 1.56403100 H 0.88895300 -2.75954400 -0.14592300 H -0.90440900 0.65591900 3.09853200 H -1.26030700 -1.08342100 3.03862000 H 0.38944600 -0.49879400 2.75656800 H -2.98224800 0.23798100 1.81523800 H -2.17701800 1.57381700 1.00256400 H -2.38084600 0.11451900 -1.15725800 H -1.40158000 -3.50228500 0.36006300 H -2.21984000 -2.51486100 1.54015400 H -2.57753900 -2.38999900 -1.50506400 H -3.64873700 -3.28712000 -0.43738100

137

H -5.30830100 -0.41781800 1.22053200 H -5.50325800 -2.11269100 0.80852300 H -4.01355500 0.48655100 -2.93445100 H -5.68264100 0.80369100 -2.47963300 H -6.90321600 2.19671100 -0.76999500 H -6.73674200 0.48525600 -0.38404200 H -7.01514200 1.72173900 0.92769000 H -5.38293100 3.53559400 1.19934800 H -4.54453000 2.21257800 1.97656400 H -3.65135000 3.21865400 0.80894900 H -4.12212000 -1.58948500 1.78155400 O -6.19113500 -1.36980000 -1.29217400 H -6.62290500 -1.77105600 -2.05445100 EM062X/6-31G+(d,p)

-3851566.010 kJ mol-1

138

Transition state 2.61-2.63 1 1 C -5.91007000 1.32987700 0.02702200 C -6.47347100 -0.13162200 -0.07081400 C -4.48970900 1.14346500 0.39438400 C -5.48583000 -1.12191000 -0.68672500 C -3.51602000 0.54968900 -0.43339700 C -2.04769300 0.98893900 -0.24145800 C -0.87142500 0.14170700 0.29747000 C -4.06971400 -1.02593000 -0.05378500 C -3.11327000 -1.93900200 -0.84504500 C -1.72966100 -2.23419400 -0.27445600 C -0.64351400 -1.17299600 -0.46436000 C -4.11101600 -1.39113600 1.43065300 C -6.67073300 2.11083800 1.10458600 C -6.04129500 2.03362600 -1.34348300 C -0.83624700 -0.02661100 1.82148900 H -4.18831500 1.37685500 1.42146700 H -5.38369900 -0.94838500 -1.76938500 O 0.19923100 1.06231600 -0.02986000 C 1.47432300 0.60596900 -0.02466300 C 1.77592100 -0.70592000 -0.01722800 C 0.71318500 -1.76601500 -0.06513500 C 2.48097900 1.71575900 0.00702700 C 3.94414800 1.23223100 -0.10247200 C 4.24238800 -0.19359500 0.01341100 C 3.17431300 -1.09833800 0.03771000 C 2.36715900 2.43238700 1.37156300 C 2.20763800 2.71123300 -1.13315600 C 5.60232700 -0.74248300 0.09710500 C 6.83963800 0.12493100 0.05185800 C 7.13041500 0.45587600 -1.42406400 C 8.02752200 -0.58488200 0.69834900 H -0.59945900 -0.90626900 -1.53186000 O 4.79400100 2.09860500 -0.24399500 O 3.35677300 -2.39205400 0.11097600 O 5.75072000 -1.97776400 0.18591300 H 6.62509100 1.06275100 0.57004800 H 8.89677100 0.07952400 0.68576600 H 7.81762000 -0.85692400 1.73721500 H 8.28245700 -1.49983000 0.15731000 H 8.01812100 1.09275100 -1.48327700 H 7.33161300 -0.46440100 -1.98373400 H 6.29959300 0.99018400 -1.89131800 H 4.38247000 -2.52229700 0.15490600 H 3.10138100 3.24164000 1.40550800 H 1.36401900 2.85115000 1.49606800 H 2.57068500 1.74325500 2.19908900 H 2.25476900 2.21429400 -2.10796300 H 1.21966500 3.16359000 -1.01431700 H 2.96995400 3.49222500 -1.10687700 H 0.63492100 -2.27476300 0.90722100 H 1.00042300 -2.54169800 -0.78298500 H -1.28868500 0.83406200 2.32465800 H -1.32367300 -0.94018100 2.16469400 H 0.20548300 -0.08913600 2.14997000 H -2.04583000 1.90637400 0.35883300 H -1.72306300 1.30394100 -1.23826900 H -3.78700900 0.57026800 -1.49020000 H -1.37310700 -3.13629700 -0.78625500 H -1.80476900 -2.52124100 0.78130500 H -3.67427400 -2.88298200 -0.89100500 H -3.02888400 -1.57564900 -1.87795900

139

H -4.96211100 -0.95278500 1.95921000 H -4.20453000 -2.47779700 1.51247200 H -6.74748000 -0.48989500 0.92611500 H -7.39668500 -0.07929300 -0.66004500 H -5.51623800 2.99350300 -1.34971600 H -5.66802500 1.42525500 -2.17112900 H -7.10190600 2.23061600 -1.52371900 H -6.34136300 3.15392200 1.14459700 H -7.74030600 2.10775900 0.87625000 H -6.53757500 1.66224700 2.09473100 H -3.20511100 -1.08364700 1.94962000 O -5.91106000 -2.44567800 -0.44212200 H -6.67200100 -2.66746200 -0.99866300 EM062X/6-31G+(d)

-3851356.534 kJ mol-1

140

Transition state 2.62-2.63 1 1 C -5.93862900 1.17895700 -0.03729700 C -6.64112600 -0.18522600 -0.12820100 C -4.48924500 0.88892000 0.37279100 C -5.61632000 -1.15147700 -0.68873800 C -3.40494800 0.76913400 -0.47094800 C -2.00534100 1.21453000 -0.11869300 C -0.82639100 0.30798300 0.32407100 C -4.25459200 -0.98462400 0.06941800 C -3.19790700 -1.79625800 -0.72387600 C -1.80264600 -2.03893800 -0.15280300 C -0.70701100 -1.01120600 -0.45394200 C -4.31963300 -1.44484200 1.52242900 C -6.56779400 2.06203100 1.04688200 C -5.99589200 1.90691700 -1.38975000 C -0.79305400 0.13317000 1.84191800 H -4.25150500 1.05591800 1.42525100 H -5.43034800 -0.93361200 -1.74841000 O 0.27409400 1.17472800 -0.01873500 C 1.53183300 0.65807400 -0.04154200 C 1.76337100 -0.66359900 -0.09202400 C 0.65088500 -1.66522000 -0.16279100 C 2.57894500 1.73166900 0.00562400 C 4.01691400 1.19077400 -0.14206600 C 4.26101000 -0.24952700 -0.04017600 C 3.13861200 -1.17228100 -0.05760600 C 2.51371900 2.42275200 1.38542700 C 2.32677200 2.76235600 -1.10813000 C 5.55865800 -0.78328300 0.05768600 C 6.83993500 0.00247400 0.09374900 C 7.26512600 0.28144800 -1.36122600 C 7.93879600 -0.74368400 0.85315600 H -0.74260100 -0.75146000 -1.52355500 O 4.89813700 2.02084900 -0.30532600 O 3.29024700 -2.41394000 -0.03978800 O 5.73550400 -2.07429300 0.10666700 H 6.63498100 0.96249800 0.57103300 H 8.82558900 -0.10567300 0.90859200 H 7.63114400 -0.99104600 1.87366400 H 8.21445500 -1.67237200 0.34714400 H 8.19431700 0.85877000 -1.35831800 H 7.44743500 -0.66003800 -1.89060900 H 6.50612500 0.85803700 -1.89488600 H 4.82593900 -2.52064200 0.04318300 H 3.27607800 3.20514400 1.42708800 H 1.52899200 2.87659800 1.53226100 H 2.70062900 1.70857500 2.19535600 H 2.34516200 2.28694800 -2.09464000 H 1.35633600 3.24485400 -0.96650200 H 3.11436900 3.51734500 -1.07441300 H 0.60469200 -2.24225000 0.77222100 H 0.87550100 -2.40108800 -0.94268100 H -0.70591100 1.11591300 2.31437700 H -1.69365100 -0.35193700 2.22294700 H 0.06940100 -0.46584200 2.14672300 H -2.10164500 1.99793300 0.64126500 H -1.65244500 1.70490500 -1.03325700 H -3.61334800 0.66176800 -1.53416100 H -1.46141200 -2.98252600 -0.59474700 H -1.84662100 -2.23462600 0.92546400 H -3.71110000 -2.76632500 -0.78265600 H -3.12900400 -1.44495500 -1.75957900

141

H -5.21260900 -1.08375900 2.03845000 H -4.33614300 -2.54062200 1.52160100 H -7.53137900 -0.13484900 -0.76266800 H -6.96717500 -0.51570400 0.86756000 H -5.38717800 2.81706900 -1.37447800 H -5.66388800 1.28427300 -2.22657800 H -7.02978500 2.19909200 -1.59576000 H -6.07045700 3.03585300 1.10689100 H -7.62182000 2.23917100 0.81313900 H -6.51556800 1.58482300 2.03193300 H -3.44952400 -1.13209600 2.09846400 O -5.99396500 -2.50141300 -0.64085600 H -6.60243200 -2.65765000 0.09754200 EM062X/6-31G+(d)

-3851358.369 kJ mol-1

142

2.5.7. References

1. Crombie, L.; Jones, R. C. F.; Palmer, C. J. J. Chem. Soc., Perkins Trans. 1, 1987, 317. 2. Killeen, D. P.; Larsen, L.; Dayan, F. E.; Gordon, K. C.; Perry, N. B.; van Klink, J. W. J.

Nat. Prod., 2016, 79, 564. 3. Fobofou, S. A. T.; Franke, K.; Porzel, A.; Brandt, W.; Wessjohann, L. A. J. Nat. Prod.,

2016, 79, 743. 4. Sheldrick, G. M. Acta Crystallogr A, 1990, 46, 467. 5. Sheldrick, G. M. Acta Crystallographica a-Foundation and Advances, 2015, 71, 3. 6. Barbour, L. J. J. Supramol. Chem., 2003, 1, 189.

143

Chapter 3

Biomimetic Total Synthesis of Verrubenzospirolactone

3.1. Introduction

3.1.1. Diels-Alder reaction of furan

Scheme 3.1: Diels-Alder reaction between furan (3.1) and maleic anhydride (3.3).1,2

Furan (3.1) is a 5-membered aromatic compound that can behave as a diene in Diels-Alder

reactions (Scheme 3.1), as first reported by Diels and Alder in the reaction with maleic

anhydride (3.2).1 The product 3.3 was later elucidated by Woodward (Scheme 3.1).2 Since

then, there have been numerous reports on the Diels-Alder reaction of furans in organic

synthesis.3

3.1.2. Furan oxidation

Diels-Alder reactions are not limited to carbogenic systems. For instance, furan (3.1) could

also undergo a Diels-Alder reaction with singlet oxygen 3.4 to form an endoperoxide 3.5,

which could be ring opened by a nucleophile to give peroxide 3.6 (Scheme 3.2). An example

of this chemistry is the synthesis of leucosceptroid O (3.11) by Magauer (Scheme 3.3).4

Singlet oxygen was generated using a photosensitizer (rose bengal)5 and reacted with

leucosceptroid A (3.7) to give endoperoxide 3.8. Intramolecular ring opening of 3.8 would

give peroxide 3.9, followed by Kornblum-DeLaMare rearrangement6 of 3.10 to give

leucosceptroid O (3.11).

Scheme 3.2: Diels-Alder reaction between furan (3.1) with singlet oxygen 3.4.

O

3.1: furan

O OO

3.2: maleic anhydride

OOO

OH

Hexo-3.3

+

O

3.1: furan

1O O

3.4: singlet oxygen

Diels-Alder OO O

3.5

NuO OOHNu

3.6

+

144

Scheme 3.3: Biomimetic synthesis of leicosceptroid O (3.11) by Magauer.4

Alternatively, endoperoxide 3.5 could undergo Kornblum-DeLaMare rearrangement

promoted by base to give γ-hydroxybutenolide 3.12. This reaction was reported by Faulkner

in the oxidation of 3.13 to 3.14 (Scheme 3.4).7 Faulkner observed i-Pr2NEt gave the best

yield for this reaction relative to other amine bases (e.g. 2,2,6,6-tetramethylpiperidine).8,9

Scheme 3.4: Kornblum-DeLaMare rearrangement promoted by i-Pr2NEt.7

H

OHO

OO

H

O

HOO

H

OHO

OO

H

O

OAcO

H

N

Ac2O, pyridine

H

OHO

OO

H

O

O

H

OHO

H

O

HO

OO

O

H

OHO

H

O

HO

O

Rose bengal, O2, hνMeOH, –78 °C

Kornblum-DeLaMarerearrangement

3.7: leucosceptroid A

3.11: leucosceptroid O26%

3.8 3.9

3.10

OO O

3.5

O OHO

3.12

i-Pr2NEt Hα β

γ

γ-hydroxybutenolide

O

OH

O

OH

O

HO

rose bengal, i-Pr2NEt–78 °C, CH2Cl2

80%

3.13 3.14

145

Furans can also be oxidized to γ-hydroxybutenolides directly by alternative reagents. For

example, 3.15 has been oxidized to γ-hydroxybutenolide 3.16 by m-CPBA (Scheme 3.5).10

3.18 has been oxidized by PCC to give γ-hydroxybutenolide intermediate followed by

elimination to give 3.19 (Scheme 3.6).11

Scheme 3.5: Furan oxidation by m-CPBA reported by Wiesner.10

Scheme 3.6: Furan oxidation by PCC reported by Sha.11

3.1.3. Syntheses and reactions of 2H-chromene

Figure 3.1: Structure of 2H-chromene 3.20 and 4H-chromene 3.21.12,13

Chromene is an aromatic ring fused with a pyran that can be either a 2H-chromene 3.20 or

4H-chromene 3.21 (Figure 3.1).12,13 An early example of a 2H-chromene synthesis was

reported by Nummy in 1951. The lactone in 3-methyl-coumarin 3.22 was attacked by

MeMgBr, followed by elimination of 3.23 to give the o-quinone methide reactive

intermediate 3.24. 3.24 underwent 6π-electrocyclization to give chromene 3.25 (Scheme

3.7).14

OHO

OH H

O

H H

H

HH

O

OHO

OH H

O

H H

H

HH

O

OHO

OH H

O

H H

H

HH

O

m-CBPA, NaOAc, AcOHCH2Cl2, rt

NaBH4MeOH/H2O, rt

71% over 2 steps

O

HO

O

3.15 3.16 3.17

OO OTBSH OO OTBSPCC, celite, CH2Cl2, rt

65%

3.18 3.19

O

O1

2

34

O1

2

34

3.202H-chromene

3.214H-chromene

146

Scheme 3.7: Synthesis of 2H-chromene 3.25 reported by Nummy.14

A classic example of biomimetic synthesis using a chromene is the synthesis of deoxybruceol

analogue 3.31 reported by Crombie.15 Starting from resorcinol 3.26 with citral (3.27),

Knoevenagel condensation gave o-quinone methide 3.28, followed by 6π-electrocyclization

to give chromene 3.29. Base-promoted tautomerisation of chromene 3.29 gave o-quinone

methide 3.30, which then underwent an intramolecular Diels-Alder reaction to give 3.31

(Scheme 3.8). Chromene 3.29 was also found to undergo a [2+2] cycloaddition under light to

give 3.33.

O OMeMgBr

OH

OO

elimination

6π-electrocyclization

3.22 3.23

3.25 3.24

1 2

OH

147

Scheme 3.8: Synthesis of deoxybruceol analogue 3.31 reported by Crombie.15

To the best of our knowledge, there has been only one report of a Diels-Alder reaction

involving a 2H-chromene as a dienophile. Theodorakis and co-workers16 attempted to

synthesize chromene 3.36 by prenylation of 3.35. They reported the major product from the

reaction was the undesired 3.37. The authors speculated this dimeric product 3.37 could be

derived from the intermolecular Diels-Alder reaction of 3.36 (Scheme 3.9). Unfortunately,

3.37 was not fully characterised and no data of 3.37 was reported. In our opinion, the

structural assignment of 3.37 is questionable.

HO O

O

O OH

H

O O

H

citral (3.27)2,6-di-tert-butylpyridine

160 °C

3.311%

HO O

H

HH

[2+2]cycloaddition

3.29

3.30

(+15% of chromene 3.29)

hυ, acetone ,rt

3.3318%


3.26

HO O

3.28

Knoevenagelcondensation

6πelectrocyclization

tautomerisation

HO O

3.29

HO O

+

3.328%

3.34: deoxybruceol

H

OO

O

O

OO

148

Scheme 3.9: Diels-Alder reaction with chromene reported by Theodorakis.16

3.1.4. Isolation of verrubenzospirolactone

Figure 3.2: Verrubenzospirolactone and its related natural products.17,18,19

(+)-Verrubenzospirolactone (3.38) and (+)-capillobenzopyranol (3.39) were isolated from the

soft coral Sinularia verruca by Gustafson and Yan in 2016 (Figure 3.2).19 (+)-

Capillobenzopyranol (3.39) was previously isolated from Sinularia capillosa along with

furanquinone (3.40) by Duh in 2010.18 Furanoquinone (3.40) and furanoquinol (3.41) were

first isolated from Sinularia capillosa by Coll.17 From the structural similarities among these

four natural products and their co-isolation, we propose there is a biosynthetic link that

connects all of these meroterpenoids.

OO

OMe

MeO

O OMe

MeOOH

OMe

OMeO OH

OMe

OMeO OH

NaH, prenyl bromidePhMe, –30 °C

3.35 3.36

3.3755%

(not characterised)

Diels-Alder reaction/dimerisation

+20% of chromene 3.36

OHO

OMeO OMe

MeOOH

3.36

OHO

OMe

MeO

O OMe

MeOOH

3.37

tautormerisation

MeO

O

OH

H H

H

O

O

O

OH

O

3.39: capillobenzopyranol3.38: verrubenzospirolactone

OH

OH

OO

O

O

3.41: furanoquinol3.40: furanoquinone

149

Scheme 3.10: Proposed biosynthesis of verrubenzospirolactone (3.38).

Our proposed biosynthesis begins from oxidation of furanoquinol (3.41) to give

furanoquinone (3.40).20 Tautomerisation of 3.40 could give o-quinone methide 3.42 which

undergoes 6π-electrocyclization to give capillobenzopyranol (3.39).14 Capillobenzopyranol

(3.39) could undergo a Diels-Alder reaction with singlet oxygen to give endoperoxide 3.43.5

Ring opening of endoperoxide 3.43 by H2O could give peroxide 3.44, which can undergo the

Kornblum-DeLaMare rearrangement to give γ-hydroxybutenolide 3.45,6 followed by a

stereoselective dehydration to give Z-3.46. Intramolecular Diels-Alder reaction of Z-3.46

would give verrubenzospirolactone (3.38). It is crucial that the alkene in 3.46 is in Z-

configuration, which will dictate the relative stereochemistry of the spirocycle of

verrubenzospirolactone (3.38).

OH

OH

O

3.41: furanoquinol

O

O

O

3.40: furanoquinone

O

OH

O

H

O

OH

O

3.39: capillobenzopyranol

O

OH

O

O

OH

O

O

OH

O

OH

H H

H

O

O

- H2O

intramolecularDiels-Alder reaction

O

HOOO

1O2

Z Z

Eexo TS

OO

H2O

O

OH

O

HOO

OH

3.44

3.45

oxidation tautomerisation


ring opening of endoperoide

Kornblum-DeLaMarerearrangement

elimination

3.42

3.43

3.46 3.38: verrubenzospirolactone

150

3.1.5. Aims of this study

Scheme 3.11: Retrosynthetic analysis of 3.46.

The aims of this project were to synthesize 3.46 from relatively simple starting materials. In

addition, we planned to investigate the intramolecular Diels-Alder reaction of 3.46 to give

verrubenzospirolactone (3.38), which would be the first example to use 2H-chromene as a

dienophile in a Diels-Alder reaction. In addition, we would like to investigate the synthesis of

capillobenzopyranol (3.39) and then convert it into verrubenzospirolactone (3.38) via our

proposed biosynthetic pathway. 3.46 could be accessed through a Horner-Wadsworth-

Emmons reaction between 3.47 and 3.48. Aldehyde 3.48 could be derived from methyl

hydroquinone (3.49) and citral (3.27).

O

OH

O O OH

OH

O

HO OP

O

OEtEtO

Z-3.46 3.49: methylhydroquinone 3.27: citral3.47

O

OH

OH

3.48

151


3.2.1. Synthesis of aldehyde 3.48

Scheme 3.12: Synthesis of chromene 3.54 reported by Gembus.21

Scheme 3.13: Synthesis of chromene 3.55.

The synthesis began with the union of methyl hydroquinone (3.49) and citral (3.27) via

Knoevenagel condensation followed by 6π-electrocyclization to form chromene 3.55

(Scheme 3.13). This reaction was quite challenging for various reasons. First, hydroqinone

(3.50) is not a good substrate for chromene synthesis as shown in the example reported by

Gembus,21 where only 40% yield of chromene 3.54 was isolated in this step (Scheme 3.12).

In addition, there could be regioselectivity issues with methyl hydroquinone (3.49) as a

substrate. Indeed, a mixture of side products (3.56, 3.57 and 3.58) was observed from the

reaction (Scheme 3.13). The purification was difficult and we attempted to separate the

mixtures with AgNO3 doped SiO222,23 but it was unsuccessful. We eventually discovered

using 1:1 petrol/CH2Cl2 as eluent gave the best separation, where our desired chromene 3.55

would elute first, followed by co-elution of 3.56, 3.57 and 3.58. Subsequent purifications of

the remaining mixture of side products allowed us to isolate pure samples of 3.56, 3.57 and

3.58 for characterisation. To date, our optimal conditions allow this reaction to run on a 8 g

O

OH

OMe

MeO+

3.50: hydroquinone 3.51

pyridine, reflux, 6 d

O

OH3.5440%

H

O

OH3.53

O

OH

OMe

H

Knoevenagel condensation


3.52

O

OH

OH

OH

O

H

PhB(OH)2, AcOHPhMe, 110 °C

3.49: methyl hydroquinone

3.27: citral

3.5514%

O

OHO

OH

H

H+ + +

O

OH

H

H

3.56 3.57 3.58

152

scale and consistently give 14% yield of our desired chromene 3.55. We could have designed

a longer synthetic route to selectively synthesize chromene 3.55, but considering both citral

(3.27) and methyl hydroquinone (3.49) are quite cheap ($0.13 for 1 g of citral, $0.25 for 1 g

of methyl hydroquinone), we could access chromene 3.55 from this faster and more

economical 1-step approach.

Scheme 3.14: Riley oxidation of chromene 3.55.

The next step was a Riley oxidation24 of chromene 3.55, which gave alcohol 3.59 in 33%

yield, along with 7% yield of aldehyde 3.48 and 35% yield of recovered starting material 3.55

(Scheme 3.14). We attempted to drive the reaction to completion by leaving it overnight,

which led to the consumption of chromene 3.55. However, we also observed a complex

mixture of products where alcohol 3.59 or aldehyde 3.48 could not be isolated. Therefore, we

concluded our best strategy was to leave the reaction for 2 to 3 h, then isolate 3.59 and 3.48.

Scheme 3.15: Oxidation of alcohol 3.59 to aldehyde 3.48.

The oxidation of alcohol 3.59 to aldehyde 3.48 was also problematic. We attempted the

oxidation using various reagents including Dess-Martin periodinane, TPAP/NMO, PCC,

MnO2, PhI(OAc)2/TEMPO,25 we observed no aldehyde 3.48 in these conditions. Eventually,

we discovered alcohol 3.59 could be oxidized to 3.48 by Swern oxidation, and it was crucial

to limit the amount of oxalyl chloride to 1 equiv. to avoid complications of the reaction.

During the Swern reaction, we observed solid residue when the Swern reagent was first

added to alcohol 3.59. It was essential to warm the reaction to room temperature and allowed

this solid to dissolve in solution, before cooling back to –78 ºC and adding Et3N. We

O

OH3.55

O

OH

CH2OH

3.59

33% (+ 7% of 3.48)

SeO2, t-BuOOHCH2Cl2, rt

O

OH

CHO

+

3.48

O

OH

CH2OH

3.59

O

OH

CHO

3.48

(COCl)2, DMSO, Et3NCH2Cl2, −78 °C to rt

66%

153

discovered if the solid was not fully dissolved before addition of Et3N, no aldehyde 3.48

would be formed. Otherwise, the reaction gave aldehyde 3.48 in 66% yield consistently.

3.2.2. Synthesis of the Horner-Wadsworth-Emmons reagent 3.47

Scheme 3.16: Synthesis of Horner-Wadsworth-Emmons reagent 3.47.26

With the aldehyde 3.48 in hand, our focus moved onto the synthesis of Horner-Wadsworth-

Emmons reagent 3.47, following a procedure from Li26 with slight modifications. For the

bromination reaction, Li used NBS and benzoyl peroxide (BPO) in CCl4,26 we substituted

BPO with AIBN as a radical initiator;27 we have also used benzene over CCl4 because of

limited access to CCl4 in Australia. The bromination of 3.60 gave 3.61 in 97% yield. The next

step was a Michaelis-Arbuzov reaction28 of 3.61 in neat P(OEt)3, which gave 3.47 in good

yield (Scheme 3.16).26 These reactions could be done on 10 g scale.

3.2.3. Biomimetic total synthesis of verrubenzospirolactone (3.38)

Scheme 3.17: Horner-Wadsworth-Emmons reaction between 3.48 and 3.47.

For the Horner-Wadsworth-Emmons reaction, we initially used KOt-Bu and LDA as base but

the yield was relatively poor (45% and 35% respectively). After switching to n-BuLi, the

reaction proceeded smoothly and gave E-3.46 in 79% yield as a mixture of E/Z isomers. The

E/Z ratio ranged from 3.3:1 to 4.5:1. The stereochemistry of the E/Z isomers could be

confirmed by NOESY analysis (Figure 3.3).

OO BrOONBS, AIBN

benzene, reflux

97%

3.613.60

OO PO

OEtOEt

P(OEt)3, 110 °C

88%

3.47

O

OH

HH

O

H

O

EO

OH

CHO

OO PO

OEtOEt3.47 =

3.47, n-BuLiTHF, −78 °C to rt

79%

E/Z = 4.5:13.48 3.46

154

Figure 3.3: NOESY spectra of 3.46.

Scheme 3.18: Biomimetic total synthesis of verrubezospirolactone (3.38).

In our proposed biosynthesis of verrubenzospirolactone (3.38) (Scheme 3.10), it is crucial for

3.46 to be in the Z-configuration to give the desired product. In contrast to Z-3.46,

intramolecular Diels-Alder reaction of E-3.46 would lead to the formation of 9-epi-

verrubenzospirolactone (3.62). Indeed, when E-3.46 was heated in various solvents, we

observed two products, verrubenzospirolactone (3.38) and 9-epi-verrubenzospirolactone

(3.62). Both compounds are solid and we managed to recrystallise 3.38 and 3.62 from PhMe.

The relative stereochemistry of verrubenzospirolactone (3.38) and 3.62 were confirmed by X-

ray single crystallography (Figure 3.4). Interestingly, from the reaction, the ratio of 3.62 and

verrubenzospirolactone (3.38) was roughly 2:1, which was less than the 4.5:1 ratio in E-3.46.

We hypothesized that there was some degree of isomerisation occurring before the

intramolecular Diels-Alder reaction took place. To investigate the isomerisation and the

O

OH

Me

HH

O

H

O

E

E/Z = 4.5:1NOESY500 MHz

CDCl3

3.46

O

OH

HH

O

H

O

E


CDCl3

3.46

PhMe, 1 hO

OH

HH

O

H

O

E O

OH

H H

H

O

O

O

OH

H H

H

O

O3.38: verrubenzospirolactone

29%3.62: 9-epi-verrubenzospirolactone

51%

+

E/Z = 4.5:13.46

9

155

Diels-Alder reaction, we screened a series of conditions, using different solvents, temperature

and time (Table 3.1).

verrubenzospirolactone (3.38) 9-epi-verrubenzospirolactone (3.62)

Figure 3.4: X-ray structures of 3.38 and 3.62.

Table 3.1: Conditions for isomerisation and Diels-Alder reaction of 3.46.

Starting Material Conditions Results

E-3.46 Z-3.46 solvent temp. time E-3.46 Z-3.46 3.62 3.38 % conversion

4.5 1 PhMe 110 °C 1 h 0 0 1.8 1 100%

4.5 1 PhMe rt (16 h); then 110 °C (1 h) 0 0 1 1 100%

4.5 1 CHCl3 rt 1 week 1 5 4 1.2 46%

4.5 1 CHCl3 rt 2 weeks 1 6.3 8.8 5 65%

3.3 1 CHCl3 30 °C 16 h 1.7 5.5 2 1 29%

3.3 1 CHCl3 30 °C 90 h 1 3.9 3.8 2.1 55%

3.3 1 CHCl3 50 °C 16 h 1 6.5 7.8 6.6 66%

3.3 1 H2O 30 °C 16 h 2.6 2 1.7 1 37%

3.3 1 H2O 30 °C 90 h 1 4 6.6 4.2 68%

4.5 1 H2O 40 °C 16 h 1.3 2.2 3.9 1 58%

3.3 1 H2O 50 °C 16 h 1 2.5 4 3 67%

4.5 1 H2O 50 °C 40 h 0 0 1 1.1 100%

*From the Horner–Wadsworth-Emmons reaction, the E/Z ratio of 3.46 varied from 3.3:1 to

4.5:1. Ratios of the starting materials and reaction products were determined by 1H NMR

analysis of the mixtures.

O

OH

HH

O

H

O

E O

OH

H H

H

O

O

O

OH

H H

H

O

O

+conditions

E/Z = 4.5:13.46 3.62 3.38

9

156

As shown in Table 3.1, we observed isomerisation and Diels-Alder reaction occurred in all

three solvents investigated. We were also delighted to observe the reaction occurred in H2O, a

biologically relevant solvent. At 30 ºC in H2O, 68% of E-3.46 was converted to 3.38 and 3.62

in 90 h; when the temperature was elevated to 50 ºC, we observed 100% conversion in 40 h.

Considering Sinularia verruca is a soft coral from tropical oceans, it is possible for sea water

to be heated up to slightly above room temperature and promote such reaction. Therefore, we

believe the biosynthesis of verrubenzospirolactone (3.38) could occur spontaneously instead

of catalysed by Diels-Alderase enzymes.29,30 However, from collective results across all

conditions, there was no strong evidence to suggest H2O catalysing the Diels-Alder reaction

faster than organic solvents.31,32

Scheme 3.19: Attempted synthesis of Still-Gennari reagent 3.63.

Since the Horner-Wadsworth-Emmons reaction between 3.48 and 3.47 predominately gave

E-3.46, we were curious of the possible outcome of a Still-Gennari modification of the

Horner-Wadsworth-Emmons reaction, which would expect to give the desired Z-3.46.33 We

attempted to synthesize the Still-Gennari reagent 3.63 using a variety of bases (DBU,34

NaH,35 Cs2CO3,36 KOtBu, n-BuLi) but all conditions gave no reaction or decomposition

(Scheme 3.19).

Scheme 3.20: Isomerisation of E-3.46 by Pd(II) catalyst.37

With our failed attempt to synthesize the Still-Gernnari reagent 3.63, the next objective was

to optimize the isomerisation of E-3.46 into Z-3.46 without giving any Diels-Alder product.

We first investigated the isomerisation using conventional methods (e.g. light38, I239) but all

led to decomposition of E-3.46. Spencer have reported an isomerisation of Z-alkenes to the

OO Br

3.61

OO PO

OCH2CF3

OCH2CF3

base

3.63

OPH(OCH2CF3)2

Pd(MeCN)2Cl2, DMF, rt

E/Z = 4.5:1

O

OH

HH

O

H

O

E O

OH

HH

O O

H

Z

Z/E = 7.5:1

79%

3.46 3.46

157

E-alkenes using catalytic Pd(MeCN)2Cl2.37 To our delight, this condition isomerised E-3.46

into Z-3.46 in a ratio of 7.5:1 favoured the Z-3.46 (Scheme 3.20).

Scheme 3.21: Biomimetic total synthesis of verrubenzospirolactone (3.38) from Z-3.46.

We then studied the intramolecular Diels-Alder reaction of Z-3.46, and observed that

verrubenzospirolactone (3.38) was the predominant product in both PhMe and H2O (Scheme

3.21). The ratio of 3.38 and 3.62 was similar to the ratio in Z-3.46, which suggests there was

no further isomerisation of 3.46.

Scheme 3.22: Attempted synthesis of verrubenzospiralactone (3.38) by Knoevenagel

condensation and Diels-Alder reaction.

We have also investigated the synthesis of verrubenzospirolactone (3.38) from Knoevenagel

condensation between 3.48 and 3.60 to generate Z-3.46 in situ, followed by intramolecular

Diels-Alder reaction to give verrubenzospirolactone (3.38). However, the reaction was not

selective as we observed both 3.62 and 3.38 in low yield (Scheme 3.22).

PhMe, 110 ̊ C

O

OH

HH

O O

H

ZO

OH

H H

H

O

O

O

OH

H H

H

O

O

3.38: verrubenzospirolactone

+

Z/E = 7.5:1

H2O, 50 ̊ C

3.46

12% 69%

3.62: 9-epi-verrubenzospirolactone

10% 61%

piperidine, t-BuOH, refluxO

OH

CHO

3.48

OO

3.60 O

OH

H H

H

O

O

O

OH

H H

H

O

O

3.38: verrubenzospirolactone (25%)3.62 (8%)

+

158

3.2.4. Synthesis of capillobenzopyranol (3.39) and its oxidation

Scheme 3.23: Total synthesis of capillobenzopyranol (3.39).

After the synthesis of verrubenzospirolactone (3.38) from Z-3.46, we were interested to

synthesize capillobenzopyranol (3.39), the proposed biosynthetic precursor of

verrubenzospirolactone (3.38), and attempt to convert capillobenzopyranol (3.39) into

verrubenzospirolactone (3.38) via our proposed biosynthetic pathway (Scheme 3.10). A

convenient approach to access capillobenzopyranol (3.39) was from a reduction of polyene

3.46. Consulting the literature, there are a few reaction conditions known to reduce furanones

to furans.4,40,41 To our delight, reduction of 3.46 with LiAlH4 gave capillobenzopyranol (3.39)

in 52% yield (Scheme 3.23). NMR of 3.39 matched from the isolation data.18

Scheme 3.24: Oxidation of 3.39 to γ-methoxybutenolide 3.65.

Our next objective was to oxidize capillobenzopyranol (3.39) with singlet oxygen. When

capillobenzopyranol (3.39) was exposed to light in the presence of rose bengal and O2, the

reaction gave peroxide 3.64, which we presumed the endoperoxide 3.43 was ring opened by

MeOH. Kornblum-DeLaMare rearrangement of 3.64 with Ac2O and pyridine gave γ-

methoxybutenolide 3.65 (Scheme 3.24).42 The yield of the two steps was quite low due to the

instability of 3.64 and the unselective esterification on the free phenol of 3.64 by Ac2O and

pyridine. Nonetheless, elimination of MeOH would allow access of polyene 3.46. However,

with our best effort, heat, acids or bases gave no reaction.

Our attention returned to the oxidation of capillobenzopyranol (3.39), to explore other

possibilities, for instance if we could change the methoxy group to a hydroxy group, we

could further convert it into a better leaving group (e.g. -OMs or -OTf). Therefore, we

O

OH

O


O

OH

O O LiAlH4, Et2O, 0 °C

52%

E

3.46

O

OH

O

O

OMeAc2O, pyridine, rt

21% over 2 steps

O

OH

O


O2, rose bengalMeOH, hν, 0 ºC

O

OH

O

OOH

OMe

3.64 3.651:1 d.r.

159

changed the solvent from MeOH to water for the oxidation. Surprisingly, we did not observe

any product but slow decomposition of capillobenzopyranol (3.39). We thought perhaps

water was not a strong enough nucleophile to attack the endoperoxide, and we chose a

stronger nucleophile (hydroxide) in the reaction. However, only decomposition was observed.

We also suspected capillobenzopyranol (3.39) was not soluble in H2O, so we introduced co-

solvents (e.g. DMSO, DMF, MeCN, THF etc.) but all gave no reaction.

Literature also showed i-Pr2NEt could be used as a base to promote Kornblum-DeLaMare

rearrangement of an endoperoxide to give a γ-hydroxybutenolide in one pot.4,8,9,43 However

we observed slow decomposition using this reagent. We also tested different combinations of

solvent and base but with no success. In addition, we have investigated a different

photosensitiser, TPP, but to no avail.4,44,45,46

Scheme 3.25: Undesired oxidation of capillobenzopyranol (3.39).

We then investigated a direct oxidation (using DDQ47, PCC11, m-CPBA48 and NBS49) of

furan 3.39 to γ-hydroxybutanolide 3.45, but all conditions led to decomposition. In one

reaction with PDC, we isolated 3.66 as a 2:1 mixture of diastereoisomers (Scheme 3.25). 3.66

could be derived from an oxidation of the phenol.

We went back to the literature and we found Clive50,51 and Salomon52 reported the use of

NaClO2 to oxidize furan to γ-hydroxybutenolide.50,51 It was an accidental discovery for Clive

and co-workers as they were using NaClO2 for a standard Pinnick oxidation, and there was no

oxidation on the aldehyde but on the furan.51 To our delight, using NaClO2 in t-BuOH/H2O,

capillobenzopyranol (3.39) was converted into γ-hydroxybutenolide 3.45 as a 1:1 mixture of

diastereoisomers in 46% overall yield (Scheme 3.26).

PDC, DMF, rt

16%

O

OH

O

3.39 3.66

O

O

OHO

2:1 d.r.

160

Scheme 3.26: Oxidation of capillobenzopyranol (3.39).

3.2.5. Biomimetic total synthesis of verrubenzospirolactone (3.38)

Scheme 3.27: Total synthesis of verrubenzospirolactone (3.38) from 3.45.

To our surprise, γ-hydroxybutenolide 3.45 was quite stable for standard elimination

conditions. We tried bases (e.g. i-Pr2NEt, i-Pr2NH, Et3N) or acids (e.g. p-TsOH, HCl, H2SO4)

or heat, but it gave no reaction. We also attempted to convert the hydroxy group into -OMs or

-OTf but it gave no reaction or decomposition when the temperature was elevated. Finally,

with Ac2O and pyridine, we managed to eliminate the hydroxy group to give Z-3.67.

However, the elimination reaction was not selective and esterification of phenol was

observed. Standard hydrolysis of acetate group with K2CO3 gave Z-3.46 as a single

stereoisomer. Only Z-3.46 was observed without trace of E-3.46 (see Figure 3.5), thus

suggesting a highly stereoselective elimination of 3.45. Heating polyene Z-3.46 in PhMe

gave verrubenzospirolactone (3.38) in quantitative yield. From this result, we proposed 3.45

and Z-3.46 are undiscovered natural products.

O

OH

O


NaClO2, NaH2PO4t-BuOH/H2O, rt

O

OH

O

O

OH

3.45

46%

1:1 d.r.

O

OH

O Ac2O, pyridine, rtO

OAc

O

O

3.67

46%

single stereoiosmer

OOH

3.45

Z

PhMe, reflux

100%

O

OH

H H

H

O

O


K2CO3, MeOH, rt

O

OH

O

O

3.46

70%

Z

161

Figure 3.5: 1H NMR (500 MHz, CDCl3) of polyene 3.46.

a) 7.5:1 Z/E-3.46 (red)

b) pure Z-3.46 (green)

*Most peaks from E-3.46 and Z-3.46 are overlapped in NMR, only a few peaks of E-3.46

are not overlapped (highlighted in spectra). The other minor compound appeared in both

spectra was verrubenzospirolactone (3.38), as intramolecular Diels-Alder reaction

occurred in Z-3.46 spontaneously.

162

3.2.6. Bioinspired cascade reaction

After the biomimetic total synthesis of verrubenzospirolactone (3.38), we wanted to

synthesize verrubenzospirolactone (3.38) by a cascade reaction (Scheme 3.28): Knoevenagel

condensation between methyl hydroquinone (3.49) and polyene 3.68 could give ortho-

quinone methide 3.69, followed by oxa-6π-electrocyclization to form chromene 3.46, and

finally an intramolecular Diels-Alder reaction would generate verrubenzospirolactone (3.38).

Scheme 3.28: Potential cascade reaction to give verrubenzospirolactone (3.38).

However, our previous synthesis of chromene 3.55 showed that there were issues with the

selectivity and reactivity of methylhydroquinone (3.49). Hence, we decided to synthesize an

alternative molecule containing the verrubenzospirolactone skeleton. First, we decided to

substitute methylhydroquinone (3.49) with phloroglucinol (3.70), which is highly reactive

and symmetrical. In addition, when we examined the X-ray structure of 9-epi-

verrubenzospirolactone (3.62) (Figure 3.6), the aromatic proton at H-3’ is in close proximity

to the C-10 of furanone. When the aromatic ring is replaced with phloroglucinol (3.70), the

free hydroxyl group at C-3’ could potentially undergo an intramolecular oxa-Michael

reaction onto the C-10 of the furanone after the intramolecular Diels-Alder reaction which

would add one more step on top of the original cascade reaction proposal (Scheme 3.29).

Therefore, we chose to use polyene E-3.68 over Z-3.68 for the bioinspired cascade reaction,

as this would lead to the desired stereochemistry which allow the final Michael reaction.

O

O

OO

O

H

OO


exo TS

Z

Z

3.49: methylhydroquinone

Knoevenagel condensation

3.46

Z-3.68

OH

HO

O

OH

H H

H

O

O


H

O

OH

O

O

Z

3.69

oxa-6π-electrocyclization

163

Scheme 3.29: Proposed bioinspired quadruple cascade reaction.

Figure 3.6: X-ray structure of 3.62 shows the proximity of proton H-3’ and C-10.

Scheme 3.30: Synthesis of aldehyde 3.79.

OH

OHHO

O

H

H

HO

H

O

OO

OHO

OO

O

H

H

HO

H

O

O

HO

O

H OO

HO


exo TS

intramolecularoxa-Michael reaction

E

E

3.70: phloroglucinol

Knoevenagel condensation, oxa-6π-electrocyclization

11

3.71 3.72

3.74

O

H

H

HO

H

O

O

HO

11

3.75

or

E-3.68

O

H

H

HO

H

O

O

HO

3.73

+ H

HO

3.76: geraniol

Imidazole, TBSCl, DMF,rt100% TBSO

3.77

SeO2, t-BuOOHsalicylic acid, CH2Cl2, rt

TBSO

3.78

OH TBSO

3.79

O+H

2%30%

TPAP, NMO4Å molecular sieve, CH2Cl2, rt

42%

H-3’

C-10

164

To synthesize aldehyde 3.68, we started by protecting geraniol (3.76) with a TBS group to

afford 3.77, followed by Riley oxidation to give 3.78.53 At first, we conducted the allylic

oxidation using standard procedure53 but we found the reaction gave a complex mixture of

products. Consulting the literature, we found salicylic acid was often used as an additive for

this reaction.54,55,56 We then added salicylic acid to the reaction mixture and it gave a

reasonable yield of alcohol 3.78 and aldehyde 3.79, alongside 25% of recovered starting

material 3.77. Alcohol 3.78 was then converted to aldehyde 3.79 by Ley oxidation (Scheme

3.30).

Scheme 3.31: Bioinspired cascade synthesis of 3.74 & 3.75.

Horner-Wadsworth-Emmons reaction between 3.79 and 3.47 gave 3.80 as a 4:1 mixture of

E/Z isomers, which could not be separated by column chromatography (Scheme 3.31). We

proceeded with the synthesis by removing the TBS group with TBAF to give 3.81, followed

by Ley oxidation to give 3.68 in 70% overall yield with a 4:1 ratio of E/Z isomers. At this

point, there was some separation between E-3.68 and Z-3.68 by column chromatography

where we could purify E-3.68 as a single stereoisomer (Scheme 3.31).

With the aldehyde E-3.68 in hand, we investigated the bioinspired cascade reaction. We first

used our previous chromene synthesis conditions with PhB(OH)2 and AcOH,57,58 but the

reaction was unsuccessful and degradation of E-3.68 was observed (Table 3.2). Consulting

the literature, Ca(OH)2 has been used as an alternative milder reagent for chromene synthesis

with phloroglucinol (3.70).59,60 To our delight, when E-3.68 and phloroglucinol (3.70) were

heated with Ca(OH)2 in EtOH, a 3:1 mixture of 3.74/3.75 with 46% overall yield was isolated.

The difference between 3.74 and 3.75 was in the stereochemistry at C-11. The relative

TBSOO

3.47, n-BuLiTHF, –78 °C to rt

85%

TBAF, THF, rt

80%

3.79 3.80E/Z = 4:1

3.81E/Z = 4:1

TPAP, NMO, 4Å MS, CH2Cl2, rt

48%

H

E

E-3.68single stereoisomer

OO PO

OEtOEt

O

H

H

HO

H

O

O

HO

O

H

H

HO

H

O

O

HO

+

3.74:3.75

Ca(OH)2, EtOHreflux

46%

1111

3:1 d.r.

OO

TBSO EO

OHO

EO

OH

O

OH

OHHO

3.70: phloroglucinol

165

stereochemistry at C-11 was determined by NOESY (see Figure 3.7). Although 3.74 and 3.75

could not be separated by flash column chromatography, 3.74 could be selectively

recrystallized from EtOH. An X-ray structure of 3.74 was collected and hence confirmed the

relative stereochemistry of 3.74 (Figure 3.8). This bioinspired cascade synthesis of 3.74 and

3.75 from E-3.68 and phloroglucinol (3.70) was rather spectacular, presumably proceeding

via Knoevenagel condensation, 6π-electrocyclization, Diels-Alder reaction and Michael

reaction, forming 4 rings, 7 contiguous stereocenters, 3 C-C bonds and 2 C-O bonds in 1 step.

Table 3.2: Conditions for quadruple cascade reaction between 3.68 and 3.70.

Conditions Results

base/acid solvent temperature time 3.74 3.75 yield

Ca(OH)2 MeOH reflux 24 h 4.9 1 31%

Ca(OH)2 H2O reflux 2 d 1.8 1 10%

Ca(OH)2 EtOH reflux 24 h 3.0 1 46%

Ca(OH)2 n-PrOH reflux 24 h 11 1 10%

Ca(OH)2 MeOH rt 2 d 12 1 4%

PhB(OH)2,

AcOH57,58 PhMe reflux 24 h 0 0 decomposition

PhB(OH)2, AcOH PhMe 90 °C 24 h 0 0 decomposition

Piperidine,

Ac2O61,62

EtOAc,

PhMe 90 °C 3 h 0 0 decomposition

O

H

H

HO

H

O

O

HO

O

H

H

HO

H

O

O

HO

E-3.68

conditions

OH

OHHO

+E+

3.70 3.74 3.75

OO

H

O

166

Figure 3.7: NOESY spectra of 3.74 and 3.75.

Figure 3.8: X-ray structure of 3.74.

OMe

H

H

HO

H

O

O

HO

Me

H

NOESY500 MHz

CDCl3

3.75

OMe

H

H

HO

H

O

O

HO

H

H

NOESY500 MHz

CDCl3

3.74

167

3.3. Summary

We have developed a concise total synthesis of verrubenzospirolactone from commercially

available materials. The overall synthetic strategy was protecting group free with good step

economy (Figure 3.9).63 Although the undesired E-3.46 was synthesized, thermal

isomerisation gave Z-3.46, followed by intramolecular Diels-Alder reaction to afford

verrubenzospirolactone. The structures of verrubenzospirolactone and 9-epi-

verrubenzospirolactone were confirmed by X-ray crystallography. In addition, E-3.46 was

isomerised by Pd(CN)2Cl2 to give predominant Z-3.46 which then converted into

verrubenzospirolactone. The transformation from E-3.46 and Z-3.46 to

verrubenzospirolactone occurred in H2O at mild temperature suggesting that a Diels-Alderase

may not be involved in the biosynthesis.

Figure 3.9: Summary of biomimetic total synthesis of verrubenzospirolactone.

We have completed a total synthesis of capillobenzopyranol by reducing E-3.46, and

successfully oxidized capillobenzopyranol to γ-hydroxybutenolide 3.45. Dehydration of γ-

hydroxybutenolide gave Z-3.67, and hydrolysis of acetate group gave the proposed

biosynthetic precursor Z-3.46 as a single stereoisomer. Z-3.46 underwent intramolecular

Diels-Alder reaction to give verrubenzospirolactone (3.38) in quantitative yield (Figure 3.10).

This synthesis suggested a highly predisposed biosynthesis of verrubenzospirolactone. We

then proposed 3.45 and Z-3.46 are undiscovered natural products. We are in the process of

sending γ-hydroxybutenolide 3.45 and Z-3.46 to the isolation chemists to investigate whether

they could be found from the coral extracts.

OH

OH

O

H O

OH

H H

H

O

O

5 steps

O

O

4 C-C bonds5 stereocentres

3 rings

verrubenzospirolactone

PO

OEtOEt

168

Figure 3.10: Summary of the synthesis of verrubenzospirolactone from

capillobenzopyranol.

The biomimetic synthesis of verrubenzospirolactone also inspired a quadruple cascade reaction, in

which the molecular complexity increases drastically, i.e. 7 stereocenters, 4 rings, 3 C-C bonds, 2 C-O

bonds were generated from 2 achiral molecules in 1 step (Figure 3.11). It is an unusual cascade

reaction, where each of the reaction is unique (unlike a radical cascade or Diels-Alder cascade

reaction). However, the reaction did produce a minor diastereoisomer (differing at C-11), which was

derived after the oxa-Michael reaction. The structure of the major isomer was confirmed by X-ray

crystallography.

Figure 3.11: Summary of the bioinspired quadruple cascade reaction.

O

OH

O


O

OH

O Oreduction

E

E-3.46

O

OH

O

O

OH

3.45

oxidationO

OH

O

O

Z-3.46

elimination/hydrolysis

O

OH

H H

H

O

O


Z

intramolecularDiels-Alder

reaction

isomerisation/intramolecular

Diels-Alderreaction

E

O

H

H

HO

H

O

O

HO

3.74E-3.683.70: phloroglucinol

OH

OHHO

Knoevenagel condensation/6π-electrocyclization/Diels-Alder reaction/

Michael addition

quadruple cascade reaction4 rings

7 contiguous stereocenters3 C-C bonds2 C-O bondsin one step

11

3:1 d.r. (Me-11)

OO

H

O

169

3.4. References

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5889. 10. Wiesner, K.; Tsai, T. Y. R.; Jin, H. Helv. Chim. Acta., 1985, 68, 300. 11. Peng, S. Z.; Sha, C. K. Org. Lett., 2015, 17, 3486. 12. Pratap, R.; Ram, V. J. Chem. Rev., 2014, 114, 10476. 13. Ferreira, S. B.; da Silva, F. D.; Pinto, A. C.; Gonzaga, D. T. G.; Ferreira, V. F. J.

Heterocyclic Chem., 2009, 46, 1080. 14. Nummy, W. R.; Tarbell, D. S. J. Am. Chem. Soc., 1951, 73, 1500. 15. Crombie, L. W.; Crombie, W. M. L.; Firth, D. F. J. Chem. Soc., Perkins Trans. 1,

1988, 1263. 16. Tisdale, E. J.; Vong, B. G.; Li, H. M.; Kim, S. H.; Chowdhury, C.; Theodorakis, E. A.

Tetrahedron, 2003, 59, 6873. 17. Bowden, B. F.; Coll, J. C.; Desilva, E. D.; Decosta, M. S. L.; Djura, P. J.; Mahendran,

M.; Tapiolas, D. M. Aust. J. Chem., 1983, 36, 371. 18. Cheng, S. Y.; Huang, K. J.; Wang, S. K.; Wen, Z. H.; Chen, P. W.; Duh, C. Y. J. Nat.

Prod., 2010, 73, 771. 19. Yuan, W. P.; Cheng, S. M.; Fu, W. T.; Zhao, M.; Li, X. B.; Cai, Y. P.; Dong, J. Y.;

Huang, K. X.; Gustafson, K. R.; Yan, P. C. J. Nat. Prod., 2016, 79, 1124. 20. Rosa, C. P.; Kienzler, M. A.; Olson, B. S.; Liang, G.; Trauner, D. Tetrahedron, 2007,

63, 6529. 21. Gembus, V.; Sala-Jung, N.; Uguen, D. Bull. Chem. Soc. Jpn., 2009, 82, 843. 22. Williams, C. M.; Mander, L. N. Tetrahedron, 2001, 57, 425. 23. Mander, L. N.; Williams, C. M. Tetrahedron, 2016, 72, 1133. 24. Riley, H. L.; Friend, N. A. C. J. Chem. Soc., 1932, 2342. 25. Williams, D. R.; Atwater, B. A.; Bawel, S. A.; Ke, P.; Gutierrez, O.; Tantillo, D. J.

Org. Lett., 2014, 16, 468. 26. Yang, P.; Yao, M.; Li, J.; Li, Y.; Li, A. Angew. Chem. Int. Ed., 2016, 55, 6964. 27. Hugelshofer, C. L.; Magauer, T. Angew. Chem. Int. Ed., 2014, 53, 11351. 28. Bhattacharya, A. K.; Thyagarajan, G. Chem. Rev., 1981, 81, 415. 29. Anagnostaki, E. E.; Zografos, A. L. Org. Lett., 2013, 15, 152. 30. Stocking, E. M.; Williams, R. M. Angew. Chem. Int. Ed., 2003, 42, 3078. 31. Narayan, S.; Muldoon, J.; Finn, M. G.; Fokin, V. V.; Kolb, H. C.; Sharpless, K. B.

Angew. Chem. Int. Ed., 2005, 44, 3275. 32. Butler, R. N.; Coyne, A. G. Chem. Rev., 2010, 110, 6302. 33. Still, W. C.; Gennari, C. Tetrahedron Lett., 1983, 24, 4405. 34. Gavara, L.; Petit, C.; Montchamp, J. L. Tetrahedron Lett., 2012, 53, 5000. 35. Brittelli, D. R. J. Org. Chem., 1981, 46, 2514.

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36. Cohen, R. J.; Fox, D. L.; Eubank, J. F.; Salvatore, R. N. Tetrahedron Lett., 2003, 44, 8617.

37. Yu, J.; Gaunt, M. J.; Spencer, J. B. J. Org. Chem., 2002, 67, 4627. 38. Singh, K.; Staig, S. J.; Weaver, J. D. J. Am. Chem. Soc., 2014, 136, 5275. 39. Dickinson, R. G.; Lotzkar, H. J. Am. Chem. Soc., 1937, 59, 472. 40. Boegman, N.; During, F.; Garbers, C. F. Chem. Commun. (London), 1966, 600. 41. Morand, P.; Salvator, J.; Kayser, M. M. J. Chem. Soc. Chem. Comm., 1982, 458. 42. Seah, K. Y.; Macnaughton, S. J.; Dallimore, J. W. P.; Robertson, J. Org. Lett., 2014,

16, 884. 43. Patil, S. N.; Liu, F. J. Org. Chem., 2008, 73, 4476. 44. Chen, I. T.; Baitinger, I.; Schreyer, L.; Trauner, D. Org. Lett., 2014, 16, 166. 45. Ferreiro-Mederos, L.; Lanners, S.; Henchiri, H.; Fekih, A.; Hanquet, G. Nat. Prod.

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Chem., 2013, 1356. 60. Saimoto, H.; Yoshida, K.; Murakami, T.; Morimoto, M.; Sashiwa, H.; Shigemasa, Y.

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171

3.5. Experimental







nearest 0.05. Flash chromatography was performed using 40-63 micron grade silica gel. Melting

points were recorded on a digital melting point apparatus and are uncorrected. Infrared spectra were

recorded using an FT-IR spectrometer as the neat compounds. High field NMR spectra were

recorded using a 500 MHz spectrometer (1H at 500 MHz, 13C at 125 MHz). Solvent used for spectra

were CDCl3 unless otherwise specified. 1H chemical shifts are reported in ppm on the δ-scale

relative to TMS (δ 0.0) and 13C NMR are reported in ppm relative to CDCl3 (δ 77.00). Multiplicities

are reported as (br) broad, (s) singlet, (d) doublet, (t) triplet, (q) quartet, (quin) quintet, (sext) sextet,

(hept) heptet and (m) multiplet. All J-values were rounded to the nearest 0.1 Hz. ESI high

resolution mass spectra were recorded on a ESI-TOF mass spectrometer.

172


To a suspension of methylhydroquinone (3.49) (8.0 g, 64.4 mmol), citral (3.27) (16.5 mL, 96.7

mmol), PhB(OH)2 (9.4 g, 77.3 mmol) and AcOH (4.4 mL, 77.3 mmol) in PhMe (300 mL) was

heated at reflux for 24 h using a Dean-Stark apparatus. The reaction was cooled to room

temperature, filtered through SiO2 and concentrated in vacuo. The residue was purified by flash

column chromatography on SiO2 (10:1, petrol/EtOAc) which gave a 2.6:1:1:1 mixture of

3.55:3.56:3.57:3.58, followed by a second flash column chromatography purification on SiO2 (1:1,

petrol/CH2Cl2) to give chromene 3.55 as a yellow oil (2.4 g, 14%). 3.56, 3.57 and 3.58 were later

eluted, with only a few of fractions that were pure for characterisation.

Data for 3.55:


IR (neat): 3388, 2969, 2915, 1656, 1496, 1452, 1377, 1257, 1178 cm-1. 1H NMR (500 MHz, CDCl3): δ 6.56 (s, 1H), 6.40 (s, 1H), 6.23 (d, J = 9.8 Hz, 1H), 5.52 (d, J = 9.8

Hz, 1H), 5.10 – 5.07 (m, 1H), 4.58 (s, 1H), 2.17 (s, 3H), 2.14 – 2.05 (m, 2H), 1.73 – 1.67 (m, 1H),

1.66 (s, 3H), 1..59 – 1.57 (m, 1H), 1.57 (s, 3H), 1.35 (s, 3H). 13C NMR (125 MHz, CDCl3): δ 147.5, 146.8, 131.7, 129.9, 124.7, 124.3, 122.6, 119.8, 118.3,

112.7, 78.2, 41.0, 26.1, 15.8, 22.9, 17.7, 16.0.


Data for 3.56:


IR (neat): 3360, 2968, 2923, 2855, 1592, 1465, 1376, 1312, 1194 cm-1. 1H NMR (500 MHz, CDCl3): δ 6.47 (d, J = 2.8 Hz, 1H), 6.32 (d, J = 3.0 Hz, 1H), 6.25 (d, J = 9.8

Hz, 1H), 5.58 (d, J = 9.8 Hz, 1H), 5.11 – 5.08 (m, 1H), 4.41 (s, 1H), 2.13 (s, 3H), 2.11 – 2.07 (m,

2H), 1.68 – 1.67 (m, 1H), 1.66 (s, 3H), 1.65 – 1.63 (m, 1H), 1.57 (s, 3H), 1.36 (s, 3H). 13C NMR (125 MHz, CDCl3): δ 148.6, 145.1, 131.7, 130.9, 126.5, 124.4, 123.0, 121.5, 117.2,

110.4, 78.0, 41.0, 26.0, 25.8, 22.8, 17.7, 15.6.


O

OH

OH

OH

O

H

PhB(OH)2, AcOHPhMe, reflux

3.49: methyl hydroquinone

3.27: citral

3.5514%

O

OHO

OH

H

H+ + +

O

OH

H

H

3.56 3.57 3.58

173

Data for 3.57 and 3.58:


IR (neat): 3388, 2975, 2832, 1499, 1456, 1413, 1367, 1274, 1186 cm-1. 1H NMR (500 MHz, CDCl3): δ 6.74 (s, 1H), 6.68 (s, 1H), 6.58 (s, 1H), 6.54 (s, 1H), 5.84 – 5.82

(m, 2H), 4.45 (s, 1H), 4.43 (s, 1H), 3.46 (s, 1H), 3.11 (d, J = 10.7 Hz, 1H), 2.17 (s, 3H), 2.15 (s,

3H), 2.10 – 2.09 (m, 2H), 2.02 – 1.98 (m, 1H), 1.92 (dd, J = 17.6, 5.5 Hz, 1H), 1.88 – 1.78 (m, 3H),

1.72 (s, 3H), 1.69 (s, 3H), 1.68 – 1.63 (m, 1H), 1.60 – 1.52 (m, 3H), 1.40 (m, 6H), 1.38 – 1.26 (m,

3H), 1.25 (s, 3H), 1.14 (s, 3H). 13C NMR (125 MHz, CDCl3): δ 147.5, 147.13, 147.05, 145.7, 135.3, 135.1, 123.1, 122.09, 122.05,

119.10, 119.08, 114.4, 111.9, 111.3, 107.5, 75.6, 60.6, 44.9, 43.9, 39.5, 34.2, 32.3, 31.0, 30.5, 30.1,

28.1, 27.7, 26.7, 25.8, 25.5, 25.1, 24.8, 23.7, 23.6, 23.0, 21.2, 20.7, 20.0, 19.4, 17.8, 15.7, 14.3.

174

To a solution of 3.55 (2.28 g, 8.83 mmol) in CH2Cl2 (150 mL) at room temperature was added SeO2

(196 mg, 1.76 mmol) and t-BuOOH (5.5 M, 5.8 mL, 31.7 mmol). The reaction was stirred at room

temperature for 2 h, then quenched with saturated Na2SO3 aqueous solution (50 mL). The aqueous

layer was separated and extracted with CH2Cl2 (50 mL). The combined organic extracts were

washed with brine (100 mL), dried over MgSO4, filtered and concentrated in vacuo. The residue

was purified by flash column chromatography on SiO2 (6:1 → 2:1, petrol/EtOAc gradient elution)

to give alcohol 3.59 as a yellow oil (803 mg, 33%), further elution gave aldehyde 3.48 as a yellow

oil (167 mg, 7%).

Data for alcohol 3.59:


IR (neat): 3357, 2976, 2924, 2857, 1669, 1625, 1497, 1458, 1427, 1376, 1265, 1177 cm-1. 1H NMR (500 MHz, CDCl3): δ 6.55 (s, 1H), 6.42 (s, 1H), 6.27 (d, J = 9.8 Hz, 1H), 5.52 (d, J = 9.8

Hz, 1H), 5.40 (t, J = 7.11 Hz, 1H), 4.32 (s, 1H), 3.97 (s, 2H), 2.22 – 2.13 (overlapped m, 2H), 2.18

(s, 3H), 1.76 – 1.66 (m, 2H), 1.63 (s, 3H), 1.36 (s, 3H). 13C NMR (125 MHz, CDCl3): δ 147.6, 146.7, 134.9, 129.7, 126.2, 124.8, 122.8, 119.6, 118.2,

112.7, 78.1, 69.1, 40.7, 26.3, 22.6, 16.1, 13.8.

HRMS (ESI): calculated for C17H22O3Na 297.1461 [M+Na]+, found 297.1456.

Data for aldehyde 3.48:


IR (neat): 3390, 2972, 2925, 1671, 1638, 1496, 1458, 1427, 1377, 1265, 1178 cm-1. 1H NMR (500 MHz, CDCl3): δ 9.35 (s, 1H), 6.54 (s, 1H), 6.51 (dt, J = 7.36, 1.38 Hz, 1H), 6.44 (s,

1H), 6.29 (d, J = 9.8 Hz, 1H), 5.50 (d, J = 9.8 Hz, 1H), 5.23 (s, 1H), 2.55 – 2.45 (m, 2H), 2.18 (s,

3H), 1.89 – 1.77 (m, 2H), 1.70 (s, 3H), 1.39 (s, 3H). 13C NMR (125 MHz, CDCl3): δ 195.8, 155.3, 148.0, 146.3, 139.3, 128.8, 125.3, 123.9, 119.2,

118.2, 112.8, 77.8, 39.5, 26.4, 24.3, 16.1, 9.2.


O

OH3.55

O

OH

CH2OH

3.59

33% (+ 7% of 3.48)

SeO2, t-BuOOHCH2Cl2, rt

O

OH

CHO

+

3.48

175

To a solution of DMSO (0.34 mL, 4.73 mmol) in CH2Cl2 (30 mL) in −78 °C was added oxalyl

chloride (0.2 mL, 2.37 mmol). The mixture was stirred at −78 °C for 10 min, then added to a

solution of 3.59 (590 mg, 2.15 mmol) in CH2Cl2 (10 mL) at −78 °C. The solution was warmed to

room temperature for 10 min, then cooled to −78 °C. Et3N (1.79 mL, 12.9 mmol) was added at −78

°C. The mixture was warmed to room temperature over 20 min, then quenched with H2O (30 mL).

The aqueous layer was separated and extracted with CH2Cl2 (30 mL). The combined organic

extracts were washed with brine (100 mL), dried over MgSO4, filtered and concentrated in vacuo.

The residue was purified by flash column chromatography on SiO2 (4:1, petrol/EtOAc) to give 3.48

as a yellow oil (386 mg, 66%). Data for 3.48 matched that previously obtained.

O

OH

CH2OH

3.59

O

OH

CHO

3.48

(COCl)2, DMSO, Et3NCH2Cl2, −78 °C to rt

66%

176

To a solution of 3.60 (5.04 g, 51.4 mmol) in benzene (100 mL) at room temperature was added

NBS (10.1 g, 56.5 mmol) and AIBN (83 mg, 0.51 mmol). The reaction was heated at reflux for 2 h,

then cooled to room temperature and concentrated in vacuo. The residue was purified by flash

column chromatography on SiO2 (3:1, petrol/EtOAc) to give 3.61 as a yellowish oil (8.85 g, 97%).

Data of 3.61 matched from literature.1

Data for 3.61:


IR (neat): 3320, 1745, 1667, 1440, 1349, 1208, 1096, 1009 cm-1. 1H NMR (500 MHz, CDCl3): δ 7.20 (s, 1H), 6.83 (s, 1H), 2.01 (s, 3H).

OO BrOO

NBS, AIBNbenzene, reflux

97%

3.613.60

177

To a solution of 3.61 (8.85 g, 50.0 mmol) was added in P(OEt)3 (8.57 mL, 50.0 mmol). The mixture

was stirred at 110 °C for 3 h. The crude was purified by flash column chromatography on SiO2 (1:3,

petrol/EtOAc) to give 3.47 as a colourless oil (10.3 g, 88%). Data of 3.47 matched from literature.2

Data for 3.47:


IR (neat): 2987, 2933, 2913, 1767, 1654, 1479, 1446, 1394, 1371, 1243, 1225, 1164 cm-1. 1H NMR (500 MHz, CDCl3): δ 7.19 (s, 1H), 5.16 (d, J = 15.5 Hz, 1H), 4.25 – 4.08 (m, 4H), 1.98

(s, 3H), 1.37 (t, J = 7.5 Hz, 3H), 1.32 (dd, J = 13.9, 7.0 Hz, 3H). 13C NMR (125 MHz, CDCl3): δ 173.4 (d, J = 1.5 Hz), 142.8 (d, J = 6.2 Hz), 131.3 (d, J = 8.2 Hz),

76.4 (d, J = 166.0 Hz), 64.4 (d, J = 7.0 Hz), 64.0 (d, J = 7.0 Hz), 16.4 (d, J = 5.6 Hz), 10.8 (d, J =

2.1 Hz).

OO PO

OEtOEt

OO Br P(OEt)3, 110 °C

88%

3.473.61

178

To a solution of 3.47 (1.0 g, 4.27 mmol) in THF (20 mL) at −78 °C was added n-BuLi (2.0 M

solution in cyclohexane, 1.96 mL, 3.93 mmol). The reaction was stirred and gradually warmed to

room temperature over 15 min. A solution of 3.48 (427 mg, 1.57 mmol) in THF (10 mL) was added

at room temperature. The mixture was stirred at room temperature for 2 h. The reaction was

quenched with 1 M HCl (20 mL). The aqueous layer was separated and extracted with Et2O (20

mL). The combined organic extracts were washed with brine (30 mL), dried over MgSO4, filtered

and concentrated in vacuo. The residue was purified by flash column chromatography on SiO2 (4:1,

petrol/EtOAc) to give an inseparable mixture of E-3.46 and Z-3.46 (4.5:1) as a yellow oil (435 mg,

79%).


IR (neat): 3397, 2972, 2923, 1725, 1620, 1598, 1497, 1458, 1426, 1371, 12487, 1174, 1060 cm-1.


Data for E-3.46: 1H NMR (500 MHz, CDCl3): δ 7.42 (s, 1H), 6.55 (s, 1H), 6.43 (s, 1H), 6.28 (d, J = 9.8 Hz, 1H),

6.21 (s, 1H), 5.76 (t, J = 7.5 Hz, 1H), 5.52 – 5.50 (m, 1H), 4.42 (s, 1H), 2.39 – 2.30 (m, 2H), 2.18

(s, 3H), 2.03 (s, 3H), 1.88 (s, 3H), 1.81 – 1.70 (m, 2H), 1.37 (s, 3H). 13C NMR (125 MHz, CDCl3): δ 170.7, 147.8, 146.9, 146.6, 139.6, 135.1, 130.8, 130.1, 129.3,

124.9, 123.1, 119.53, 119.45, 118.3, 112.7, 77.9, 40.4, 26.4, 23.8, 16.1, 15.5, 11.0.

Data for Z-3.46: 1H NMR (500 MHz, CDCl3): δ 6.99 (s, 1H), 6.55 (s, 1H), 6.43 (s, 1H), 6.27 (d, J = 9.8 Hz, 1H),

5.79 (t, J = 7.5 Hz, 1H), 5.52 – 5.50 (m, 2H), 4.80 (s, 1H), 2.38 – 2.30 (m, 2H), 2.18 (s, 3H), 2.01

(s, 3H), 1.99 (s, 3H), 1.80 – 1.70 (m, 2H), 1.37 (s, 3H). 13C NMR (125 MHz, CDCl3): δ 171.9, 147.8, 146.6, 145.2, 139.7, 139.4, 129.3, 127.2, 125.0,

123.0, 119.6, 119.5, 118.3, 117.5, 112.7, 77.9, 40.3, 26.3, 23.7, 16.1, 15.1, 15.1.

O

OH

HH

O

H

O

EO

OH

CHO

OO PO

OEtOEt3.47 =

3.47, n-BuLiTHF, −78 °C to rt

79%

E/Z = 4.5:13.48 3.46

179

1H NMR (500 MHz, d6-DMSO): δ 8.70 (s, 1H), 7.43 (s, 1H), 6.47 (s, 1H), 6.45 (s, 1H), 6.32 (d, J

= 9.8 Hz, 1H), 5.85 (t, J = 7.6, 1H), 5.78 (s, 1H), 5.61 (d, J = 9.8 Hz, 1H), 2.25 – 2.21 (m, 2H), 2.03

(s, 3H), 1.91 (s, 3H), 1.90 (s, 3H), 1.69 – 1.66 (m, 2H), 1.28 (s, 3H). 13C NMR (125 MHz, d6-DMSO): δ 170.7, 148.9, 144.8, 144.7, 140.5, 139.1, 131.3, 129.1, 126.1,

124.6, 122.7, 118.7, 117.6, 116.6, 112.0, 77.2, 39.3, 25.6, 23.0, 16.0, 14.6, 10.1.

180

To a solution of 3.47 (354 mg, 1.51 mmol) in THF (10 mL) at 0 ºC was added KOt-Bu (141 mg,

1.26 mmol). The mixture was stirred at 0 ºC for 20 min, followed by addition of 3.48 (137 mg, 0.50

mmol) in THF (5 mL). The reaction was stirred at 0 ºC for 30 min, then warmed to room

temperature and stirred for 1 h, then quenched with 1 M HCl (10 mL). The organic layer was

separated and the aqueous layer was extracted with EtOAc (2 × 10 mL). The combined organic


The residue was purified by flash column chromatography on SiO2 (4:1, petrol/EtOAc) to give an

inseparable mixture of E-3.46 and Z-3.46 (4.5:1) as a yellow oil (75 mg, 45%). Data of E-3.46 and

Z-3.46 matched previously obtained.

To a solution of 3.47 (250 mg, 1.07 mmol) in THF (5 mL) at –78 ºC was added LDA (2.0 M, 0.54

mL, 1.07 mmol). The mixture was stirred at –78 ºC for 5 min, warmed to room temperature and

stirred for 15 min, then cooled back to –78 ºC. 3.48 (97 mg, 0.36 mmol) in THF (5 mL) was added

to the mixture. The reaction was stirred at –78 ºC for 30 min, then warmed to room temperature and

stirred for 3 h, then quenched with saturated NH4Cl solution (10 mL). The organic layer was

separated and the aqueous layer was extracted with Et2O (2 × 10 mL). The combined organic


The residue was purified by flash column chromatography on SiO2 (4:1, petrol/EtOAc) to give an

inseparable mixture E-3.46 and Z-3.46 (4:1) as a yellow oil (44 mg, 35%). Data of E-3.46 and Z-

3.46 matched previously obtained.

O

OH

HH

O

H

O

EO

OH

CHO

OO PO

OEtOEt3.47

3.47, KOt-BuTHF, −78 °C to rt

45%

E/Z = 4.5:13.48 3.46

O

OH

HH

O

H

O

EO

OH

CHO

OO PO

OEtOEt3.47 =

3.47, LDATHF, −78 °C to rt

35%

E/Z = 4.5:13.48 3.46

181

A solution of a 4.5:1 mixture of E-3.46 and Z-3.46 (133 mg, 0.377 mmol) in PhMe (8 mL) was

heated at reflux for 1 h. The solution was cooled to room temperature and the resultant precipitate

was collected by vacuum filtration to give 3.62 (68 mg, 51%) as a white solid. The filtrate was

concentrated in vacuo and the residue was purified by flash column chromatography on SiO2 (4:1,

petrol/EtOAc) to give verrubenzospirolactone (3.38) as a white solid (39 mg, 29%).

Data for 3.62:

Rf = 0.55 (petrol/EtOAc, 3:1)

IR (neat): 3348, 2965, 1737, 1656, 1627, 1516, 1462, 1442, 1418, 1372, 1191 cm-1.

MP: 220 – 224 °C 1H NMR (500 MHz, d6-DMSO): δ 8.73 (s, 1H), 6.79 (d, J = 1.5 Hz, 1H), 6.45 (s, 1H), 6.33 (s,

1H), 6.04 – 6.03 (m, 1H), 3.46 (d, J = 9.22 Hz, 1H), 3.32 (s, 3H), 2.54 – 2.48 (m, 1H), 2.06 – 2.01

(m, 1H), 1.99 (s, 3H), 1.97 – 1.91 (m, 2H), 1.82 (dd, J = 12.1, 9.3 Hz, 1H), 1.75 (s, 3H), 1.68 (d, J =

1.5 Hz, 3H), 1.58 – 1.51 (m, 1H). 13C NMR (125 MHz, d6-DMSO): δ 173.2, 151.6, 149.0, 145.4, 143.5, 126.6, 123.7, 122.0, 119.8,

117.8, 114.8, 88.6, 81.8, 48.5, 41.3, 38.7, 37.3, 23.7, 22.4, 19.2, 15.7, 10.1. 1H NMR (500 MHz, CDCl3): δ 6.57 (s, 1H), 6.53 (s, 1H), 6.39 (s, 1H), 5.54 (s, 1H), 5.12 (s, 1H),

3.60 (d, J = 9.7 Hz, 1H), 2.62 – 2.56 (m, 1H), 2.18 (dd, J = 7.1, 1.7 Hz, 1H), 2.15 (s, 3H), 2.06 –

1.99 (m, 2H), 1.84 (dd, J = 12.2, 9.8 Hz, 1H), 1.80 (s, 3H), 1.78 (s, 3H), 1.60 – 1.51 (m, 1H), 1.22

(s, 3H). 13C NMR (125 MHz, CDCl3): δ 175.1, 151.2, 148.5, 147.1, 143.8, 128.0, 124.6, 122.2, 120.8,

118.8, 115.0, 89.7, 82.7, 49.7, 42.4, 39.5, 37.9, 24.6, 23.0, 19.6, 15.9, 10.4.


Data for verrubenzospirolactone (3.38):


IR (neat): 3385, 2929, 1730, 1663, 1500, 1437, 1412, 1189 cm-1

MP: 189 – 193 °C

O

OH

HH

O

H

O

E O

OH

H H

H

O

O

O

OH

H H

H

O

O


+PhMe, reflux

E/Z = 4.5:13.46

182

1H NMR (500 MHz, CDCl3): δ 7.31 (s, 1H), 7.11 (d, J = 1.4 Hz, 1H), 6.54 (s, 1H), 5.08 (s, 1H),

4.88 (s, 1H), 3.24 (d, J = 4.6 Hz, 1H), 2.59 – 2.53 (m, 1H), 2.15 (s, 3H), 2.12 – 2.09 (m, 1H), 2.01 –

1.98 (m, 1H), 1.96 (d, J = 1.3 Hz, 3H), 1.94 – 1.91 (m, 1H), 1.81 (dd, J = 11.9, 4.8 Hz, 1H), 1.67 (s,

3H), 1.40 – 1.36 (m, 1H), 1.33 (s, 3H). 13C NMR (125 MHz, CDCl3): δ 174.2, 153.5, 147.6, 146.5, 143.2, 128.2, 124.6, 120.1, 119.8,

117.0, 115.6, 89.2, 82.1, 50.3, 40.9, 39.2, 36.7, 25.2, 24.0, 20.4, 15.8, 10.6.


183

A solution of a 4.5:1 mixture of E-3.46 and Z-3.46 (135 mg, 0.383 mmol) in PhMe (8 mL) was

stirred at room temperature for 16 h. The solution was heated reflux for a further 1 h. The solution

was cooled to room temperature and the resultant precipitate was collected by vacuum filtration to

give 3.62 (57 mg, 42%) as a white solid. The filtrate was concentrated in vacuo and the residue was

purified by flash column chromatography on SiO2 (4:1, petrol/EtOAc) to give

verrubenzospirolactone (3.38) as a white solid (54 mg, 40%). Data for 3.62 and 3.38 matched that

previously obtained.

A suspension of a 4.5:1 mixture of E-3.46 and Z-3.46 (142 mg, 0.403 mmol) in H2O (20 mL) was

stirred at 50 °C for 40 h. The mixture was cooled to room temperature and extracted with EtOAc (3

× 10 mL). The combined organic extracts were washed with brine (20 mL) dried over MgSO4,

filtered and concentrated in vacuo. The residue was suspended in toluene and the solid was

collected by vacuum filtration to give 3.62 (38 mg, 38%) as a white solid. The filtrate was

concentrated in vacuo and the residue was purified by flash column chromatography on SiO2 (4:1,

petrol/EtOAc) to give verrubenzospirolactone (3.38) as a white solid (58 mg, 41%). Data for 3.62

and 3.38 matched that previously obtained.

PhMe, rt, 16 h, then reflux, 1 h

O

OH

HH

O

H

O

E O

OH

H H

H

O

O

O

OH

H H

H

O

O3.38: verrubenzospirolactone (40%)3.62 (42%)

+

E/Z = 4.5:13.46

H2O, 50 ̊ CO

OH

HH

O

H

O

E O

OH

H H

H

O

O

O

OH

H H

H

O

O3.38: verrubenzospirolactone (41%)3.62 (38%)

+

E/Z = 4.5:13.46

184

To a solution of a 4.5:1 mixture of E-3.46 and Z-3.46 (254 mg, 0.721 mmol) in DMF (20 mL) was

added Pd(MeCN)2Cl2 (27 mg, 0.10 mmol) at room temperature. The mixture was stirred at room

temperature for 40 h. The mixture was quenched with H2O and extracted with EtOAc (3 × 10 mL).

The combined organics were washed with brine (20 mL), dried over MgSO4, filtered and

concentrated in vacuo. The residue was purified by flash column chromatography on SiO2 (4:1,

petrol/EtOAc) to give an inseparable 7.5:1 mixture of Z-3.46 and E-3.46 as a yellow oil (201 mg,

79%). Data for Z-3.46 and E-3.46 matched that previously obtained.

A solution of a 7.5:1 mixture of Z-3.46 and E-3.46 (108 mg, 0.306 mmol) in PhMe (7 mL) was

heated at reflux for 1 h. The solution was cooled to room temperature and concentrated in vacuo.

The residue was purified by flash column chromatography on SiO2 (6:1 → 2:1, petrol/EtOAc

gradient elution) to give 3.62 as a white solid (13 mg, 12%). Further elution gave

verrubenzospirolactone (3.38) as a white solid (75 mg, 69%). Data for 3.62 and 3.38 matched that


A suspension of a 7.5:1 mixture of Z-3.46 and E-3.46 (110 mg, 0.312 mmol) in H2O (15 mL) was

stirred at 50 °C for 60 h. The mixture was cooled to room temperature and extracted with EtOAc (3

× 10 mL). The combined organic extracts were washed with brine (20 mL) dried over MgSO4,


SiO2 (6:1 → 2:1, petrol/EtOAc gradient elution) to give 3.62 as a white solid (11 mg, 10%). Further

Pd(MeCN)2Cl2, DMF, rt

E/Z = 4.5:1

O

OH

HH

O

H

O

E O

OH

HH

O O

H

Z

Z/E = 7.5:1

79%

3.46 3.46

PhMe, refluxO

OH

HH

O O

H

ZO

OH

H H

H

O

O

O

OH

H H

H

O

O


+

Z/E = 7.5:13.46

H2O, 50 ̊ CO

OH

HH

O O

H

ZO

OH

H H

H

O

O

O

OH

H H

H

O

O

XX: verrubenzospirolactone (61%)XX (10%)

+

Z/E = 7.5:1XX

185

elution gave verrubenzospirolactone (3.38) as a white solid (67 mg, 61%). Data for 3.62 and 3.38

matched that previously obtained.

To a solution of 3.48 (10 mg, 0.04 mmol) in t-BuOH (3 mL) at room temperature was added 3.60

(12 mg, 0.12 mmol) and piperidine (0.02 mL, 0.19 mmol). The reaction was stirred at reflux for 2 d,

then cooled to room temperature. The reaction was quenched with 1 M HCl (5 mL), then extracted

with Et2O (2 × 10 mL). The combined organic extracts were dried over MgSO4, filtered and


petrol/EtOAc) to give 3.62 as a white solid (1 mg, 8%). Further elution gave

verrubenzospirolactone (3.38) as a white solid (3 mg, 25%). Data of 3.62 and 3.38 matched


To a solution of 3.48 (17 mg, 0.06 mmol) in MeOH (10 mL) at room temperature was added 3.60

(19 mg, 0.19 mmol) and piperdine (0.02 mL, 0.19 mmol). The reaction was stirred at reflux for 12

h, then cooled to room temperature and concentrated in vacuo. The residue was purified by flash

column chromatography on SiO2 (3:1, petrol/EtOAc) to give verrubenzospirolactone (3.38) as a

white solid (3 mg, 14%). Data of 3.38 matched previously obtained.

piperdine, t-BuOH, refluxO

OH

CHO

3.48

OO

3.60 O

OH

H H

H

O

O

O

OH

H H

H

O

O


+

piperdine, MeOH, refluxO

OH

CHO

3.48

OO

3.60 O

OH

H H

H

O

O


14%

186

A suspension of a 4.5:1 mixture of E-3.46 and Z-3.46 (1.67 g, 4.74 mmol) in Et2O (60 mL) at 0 °C

was added LiAlH4 (540 mg, 14.2 mmol). The reaction was stirred at room temperature at 0 °C for 1

h, then quenched with 1 M HCl (75 mL). The organic extract was separated and the aqueous layer

was extracted with Et2O (2 × 50 mL). The combined organic extracts were washed with brine (50


column chromatography on SiO2 (8:1, petrol/EtOAc) to give capillobenzopyranol (3.39) as a

colourless oil (840 mg, 52%).

Data for 3.39:


IR (neat): 3416, 2924, 1497, 1457, 1426, 1371, 1175, 1114, 918, 871 cm-1. 1H NMR (500 MHz, CDCl3) δ 7.05 (s, 1H), 6.55 (s, 1H), 6.40 (s, 1H), 6.24 (d, J = 9.8 Hz, 1H),

5.85 (s, 1H), 5.52 (d, J = 9.8 Hz, 1H), 5.20 (td, J = 7.1, 1.1 Hz, 1H), 4.37 (s, 1H), 3.20 (s, 2H), 2.21

– 2.09 (m, 2H), 2.17 (s, 3H), 1.97 (d, J = 1.0 Hz, 3H), 1.76 – 1.62 (m, 2H), 1.57 (s, 3H), 1.35 (s,

3H). 13C NMR (125 MHz, CDCl3) δ 154.3, 147.4, 146.7, 137.7, 132.0, 129.7, 126.4, 124.5, 122.4,

120.5, 119.6, 118.1, 112.5, 108.8, 77.9, 40.7, 38.4, 26.0, 22.8, 15.9, 15.8, 9.8.


O

OH

O


O

OH

O O LiAlH4, Et2O, 0 °C

52%

E

3.46

187

To a solution of capillobenzopyranol (3.39) (98 mg, 0.29 mmol) in MeOH (8 mL) at 0 °C was

added rose bengal (1 mg). The solution was stirred under O2 with 500 Wlamp for 2 h. The solution

was concentrated in vacuo to give 3.64 (116 mg) which was unstable to chromatography and used

in next step without purification.

Partial data for 3.64:

Rf = 0.10 (3:1, petrol/EtOAc) 1H NMR (500 MHz, CDCl3): δ 8.81 (s, 1H), 6.56 (s, 1H), 6.43 (s, 1H), 6.26 (d, J = 9.8 Hz, 1H),

5.60 (s, 1H), 5.52 (d, J = 9.8 Hz, 1H), 5.16 (q, J = 7.3 Hz, 1H), 4.40 (d, J = 9.1 Hz, 3H), 3.49 (s,

1H), 3.21 (s, 3H), 2.50 � 2.41 (m, 2H), 2.18 (s, 3H), 2.16 � 2.06 (m, 2H), 1.79 (s, 3H), 1.72 � 1.56

(m, 2H), 1.62 (s, 3H), 1.35 (s, 3H). 13C NMR (125MHz, CDCl3): δ 147.4, 146.7, 137.08, 137.07, 130.3, 129.7, 129.6, 129.52, 129.51,

129.38, 129.37, 124.6, 124.5, 122.5, 119.6, 118.2, 118.1, 114.2, 114.1, 112.51, 112.47, 110.63,

110.62, 77.9, 77.8, 50.6, 48.68, 48.65, 40.7, 40.6, 26.0, 25.9, 22.9, 22.8, 17.62, 17.58, 15.9, 12.12,

12.10.

O

OH

O


O2, rose bengalMeOH, hν, 0 °C

O

OH

O

OOH

OMe

3.64

188

To a solution of 3.64 (116 mg, 0.29 mmol) in pyridine (5 mL) was added Ac2O (25 mg, 0.25 mmol)

at room temperature and stirred for 20 min. The mixture was diluted with EtOAc (15 mL) and

washed sequentially with H2O (10 mL), saturated CuSO4 solution (2 x 10 mL), brine (10 mL), dried

over MgSO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography

on SiO2 (4:1, petrol/EtOAc) to give 3.65 (1:1 mixture of diastereoisomers) as a colourless oil (23

mg, 24% over 2 steps).

Data for 3.65:


IR (neat): 3430, 2925, 1747, 1457, 1427, 1178, 1141, 965, 872, 759 cm-1. 1H NMR (500 MHz, CDCl3): δ 6.67 (dd, J = 3.2, 1.5 Hz, 1H), 6.55 (s, 1H), 6.42 (s, 1H), 6.26 (d, J

= 9.8 Hz, 1H), 5.52 – 5.49 (m, 1H), 5.20 (t, J = 6.8 Hz, 1H), 4.44 (s, 1H), 3.19 (s, 3H), 2.59 – 2.48

(m, 2H), 2.18 (s, 3H), 2.16 – 2.04 (m, 2H), 1.91 (d, J = 1.6 Hz, 3H), 1.71 – 1.56 (m, 2H), 1.61 (s,

3H), 1.34 (s, 3H). 13C NMR (125 MHz, CDCl3): δ 171.3, 147.5, 146.6, 146.0, 133.5, 130.99, 130.96, 129.6, 129.5,

128.7, 128.6, 124.6, 122.60, 122.56, 119.5, 118.11, 118.09, 112.48, 112.46, 109.1, 77.9, 77.8, 51.0,

46.94, 46.93, 40.54, 40.47, 29.7, 26.1, 26.0, 22.91, 22.86, 17.58, 17.56, 15.9, 10.46, 10.45.

HRMS (ESI): calculated for C23H28O5Na 407.1829 [M+H]+, found 407.1832.

O

OH

O

O

OMeAc2O, pyridine, rt

21% over 2 steps

O

OH

O

OOH

OMe

3.64 3.65d.r. 1:1

189

To a solution of capillobenzopyranol (3.39) (48 mg, 0.14 mmol) in DMF (4 mL) was added PDC

(80 mg, 0.21 mmol) at room temperature and stirred for 2 h. The mixture was quenched with H2O

(10 mL) and extracted with EtOAc (3 x 10 mL). The combined organic extracts were washed with

brine (3 x 20 mL), dried over MgSO4, filtered and concentrated in vacuo. The residue was purified

by flash chromatography on SiO2 (6:1 � 4:1 gradient elution, petrol/EtOAc) to give 3.66 (2:1

mixture of diastereoisomers) as a colourless oil (8 mg, 16%).

Data for 3.66:


IR (neat): 3382, 2926, 1674, 1620, 1368, 1258, 1058, 1006, 950, 892 cm-1. 1H NMR (500 MHz, CDCl3): δ 7.05 (s, 1H), 6.55 (s, 1H), 6.43 (d, J = 10.1 Hz, 1H), 6.13 (d, J =

10.2 Hz, 1H), 5.91 (s, 1H), 5.84 (s, 1H), 5.13 (t, J = 6.8 Hz, 1H), 3.17 (s, 2H), 2.79 (s, 1H), 1.97 (s,

3H), 1.98 � 1.87 (m, 2H), 1.90 (s, 3H), 1.70 � 1.59 (m, 2H), 1.54 (s, 3H), 1.53 (s, 3H). 13C NMR (125 MHz, CDCl3): δ 186.8, 154.2, 153.9, 147.2, 147.1, 142.5, 141.6, 140.1, 140.0,

137.8, 137.7, 134.4, 132.2, 126.9, 126.0, 121.6, 120.5, 120.4, 120.3, 120.2, 109.1, 108.8, 88.5, 88.3,

76.6, 42.6, 40.5, 38.41, 38.36, 28.4, 27.0, 22.7, 22.2, 16.0, 15.9, 15.4, 9.8.


PDC, DMF, rt

16%

O

OH

O

3.39 3.66

O

O

OHO

d.r. 2:1

190

To a solution of capillobenzopyranol (3.39) (50 mg, 0.15 mmol) in t-BuOH (2.5 mL) and H2O (0.5

mL) was added NaH2PO4.2H2O (34 mg, 0.22 mmol) and NaClO2 (39 mg, 0.44 mmol) was added at

room temperature and stirred for 1 h. The mixture was diluted with H2O (10 mL) and extracted with

EtOAc (3 x 10 mL). The combined organic extracts were washed with brine (20 mL), dried over

MgSO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography on

SiO2 (2:1, petrol/EtOAc) to give 3.45 (1:1 mixture of diastereoisomers) as a colourless oil (25 mg,

46%).

Data for 3.45:


IR (neat): 3379, 2924, 1744, 1426, 1177, 982, 872 cm-1. 1H NMR (500 MHz, CDCl3): δ 6.77 (s, 1H), 6.55 (s, 1H), 6.43 (s, 1H), 6.26 (d, J = 9.8 Hz, 1H),

5.50 (d, J = 9.8 Hz, 1H), 5.35 (dd, J = 16.2, 7.6 Hz, 1H), 4.95 (br s, 1H), 4.13 (br s, 1H), 2.53 – 2.44

(m, 2H), 2.22 – 2.16 (m, 2H), 2.17 (s, 3H), 1.89 (d, J = 0.9 Hz, 3H), 1.75 – 1.61 (m, 2H), 1.71 (s,


132.8, 132.7, 132.24, 132.22, 129.4, 129.3, 128.8, 128.7, 124.80, 124.78, 122.81, 122.76, 119.4,

118.2, 112.6, 112.5, 104.41, 104.37, 78.0, 77.9, 47.8, 40.41, 40.36, 26.04, 25.98, 23.12, 23.07,

17.57, 17.56, 15.93, 15.91, 10.4.


O

OH

O


NaClO2, NaH2PO4t-BuOH/H2O, rt

O

OH

O

O

OH

3.45

46%

1:1 d.r.

191

To a solution of 3.45 (23 mg, 0.062 mmol) in pyridine (2 mL) was added Ac2O (19 mg, 0.19 mmol)

at room temperature and stirred for 16 h. The reaction was concentrated in vacuo. The residue was

purified by flash chromatography on SiO2 (6:1, petrol/EtOAc) to give 3.67 as a colourless oil (11

mg, 46%).

Data for 3.67:


IR (neat): 2924, 1746, 1497, 1365, 1193, 1165, 988, 755 cm-1. 1H NMR (500 MHz, CDCl3): δ 6.99 (d, J = 1.4 Hz, 1H), 6.63 (s, 1H), 6.62 (s, 1H), 6.29 (d, J = 9.9

Hz, 1H), 5.79 (t, J = 7.5 Hz, 1H), 5.52 (d, J = 9.6 Hz, 1H), 5.51 (s, 1H), 2.36 – 2.28 (m, 2H), 2.29

(s, 3H), 2.09 (s, 3H), 2.02 (s, 3H), 2.00 (s, 3H), 1.83 – 1.77 (m, 1H), 1.74 – 1.68 (m, 1H), 1.39 (s,

3H). 13C NMR (125 MHz, CDCl3): δ 171.5, 169.6, 150.4, 145.1, 142.6, 139.5, 138.9, 132.3, 130.7,

129.0, 127.0, 122.5, 119.2, 119.1, 118.0, 117.1, 78.4, 40.4, 26.6, 23.5, 20.7, 16.2, 15.0, 10.4.


O

OH

O Ac2O, pyridine, rtO

OAc

O

O

3.67

46%

single stereoiosmer

OOH

3.45

Z

192

To a solution of 3.67 (49 mg, 0.12 mmol) in MeOH (4 mL) was added K2CO3 (68 mg, 0.49 mmoL)

at rt. The mixture was stirred at room temperature for 30 min. The mixture was quenched with 1 M

HCl (10 mL) and extracted with EtOAc (3 x 10 mL). The combined organic extracts were washed

with brine (20 mL), dried over MgSO4, filtered and concentrated in vacuo. The residue was

purified by flash chromatography on SiO2 (4:1, petrol/EtOAc) to give Z-3.46 as a colourless oil (30

mg, 70%).

Data for Z-3.46:


IR (neat): 3397, 2972, 2923, 1725, 1620, 1598, 1497, 1458, 1426, 1371, 1248, 1174, 1060 cm-1. 1H NMR (500 MHz, CDCl3): δ 6.99 (s, 1H), 6.55 (s, 1H), 6.44 (s, 1H), 6.27 (d, J = 9.8 Hz, 1H),

5.79 (t, J = 7.5 Hz, 1H), 5.52 (s, 1H), 5.51 (d, J = 9.8 Hz, 1H), 4.80 (s, 1H), 2.34 – 2.28 (m, 2H),

2.18 (s, 3H), 2.01 (s, 3H), 1.99 (s, 3H), 1.80 – 1.68 (m, 2H), 1.37 (s, 3H). 13C NMR (125 MHz, CDCl3): δ 171.9, 147.8, 146.6, 145.2, 139.7, 139.4, 129.3, 127.2, 124.9,

123.0, 119.6, 119.5, 118.3, 117.5, 112.7, 77.9, 40.3, 26.3, 23.7, 16.1, 15.13, 15.10.


K2CO3, MeOH, rtO

OH

O

O

3.46

70%

ZO

OAc

O

O

3.67

Z

193

A solution of Z-3.46 (30 mg, 0.085 mmol) in PhMe (3 mL) was heated at reflux for 1 h. The

solution was cooled and concentrated in vacuo to yield verrubenzospirolactone 3.38 as a white solid

(30 mg, 100%). Data for 3.38 matched that previously obtained.

O

OH

O

O

3.46

PhMe, reflux100%

O

OH

H H

H

O

O


Z

194

To a solution of geraniol (3.76) (10.0 g, 64.8 mmol) in DMF (100 mL) at room temperature was

added Imidazole (8.82 g, 13.0 mmol) and TBSCl (12.7 g, 8.42 mmol). The reaction was stirred at

room temperature for 2 d, then diluted with H2O (50 mL) and extracted with Et2O (2 × 100 mL).

The combined organic extracts were washed with H2O (200 mL), brine (200 mL), dried over


chromatography on SiO2 (20:1, petrol/EtOAc) to give 3.77 as a yellow oil (17.4 g, 100%). Data of

3.77 matched from literature.3

Data for 3.77:


IR (neat): 2968, 2928, 2861, 1719, 1651, 1455, 1378, 1060 cm-1. 1H NMR (500 MHz, CDCl3): δ 5.30 (t, J = 6.3 Hz, 1H), 5.10 (t, J = 6.2 Hz, 1H), 4.19 (d, J = 6.2

Hz, 2H), 2.09 (dd, J = 14.6, 7.1 Hz, 2H), 2.00 – 1.99 (m, 2H), 1.68 (s, 3H), 1.62 (s, 3H), 1.60 (s,

3H), 0.91 (s, 9H), 0.07 (s, 3H), 0.07 (s, 3H). 13C NMR (125 MHz, CDCl3): δ 136.9, 131.5, 124.4, 124.1, 60.4, 39.5, 26.4, 26.0, 25.7, 18.4, 17.7,

16.3, -5.0.

HO

3.76: geraniol

Imidazole, TBSCl, DMF,rt

100% TBSO3.77

195

To a solution of 3.77 (10.0 g, 37.2 mmol) in CH2Cl2 (100 mL) at room temperature was added

salicylic acid (514 mg, 3.72 mmol), t-BuOOH (5 ~ 6 M, 11 mL, 55.0 mmol) and SeO2 (413 mg,

3.72 mmol). The reaction was stirred at room temperature for 17 h, then quenched with saturated

NaHCO3 solution (100 mL). The organic layer was separated and the aqueous layer was extracted

with CH2Cl2 (2 × 100 mL). The combined organic extracts were dried over MgSO4, filtered and

concentrated in vacuo. The residue was purified by flash column chromatography on SiO2 (20:1 →

10:1, petrol/EtOAc gradient elution) to give 3.77 as a yellowish oil (2.45 g, 25%). Further elution

gave 3.79 as a yellowish oil (200 mg, 2%). Further elution gave 3.78 as a yellowish oil (3.05 g,

33%). Data of 3.78 and 3.79 match from literature.4,5

Data for 3.78:


IR (neat): 3404, 2972, 2857, 1718, 1645, 1457, 1380, 1063 cm-1. 1H NMR (500 MHz, CDCl3): δ 5.39 (t, J = 6.9 Hz, 1H), 5.31 (t, J = 6.3 Hz, 1H), 4.19 (d, J = 6.3

Hz, 2H), 3.99 (br s, 2H), 2.16 (dd, J = 14.9, 7.4 Hz, 2H), 2.06 – 2.03 (m, 2H), 1.67 (s, 3H), 1.63 (s,

3H), 0.91 (s, 9H), 0.07 (s, 6H). 13C NMR (125 MHz, CDCl3): δ 136.4, 135.0, 125.9, 124.7, 69.0, 60.3, 39.1, 26.0, 25.8, 25.7, 16.3,

13.7, –5.1.

Data for 3.79:


IR (neat): 2972, 2941, 1738, 1370, 1229, 1219 cm-1. 1H NMR (500 MHz, CDCl3): δ 9.39 (s, 1H), 6.47 (t, J = 7.1 Hz, 1H), 5.35 (t, J = 6.3 Hz, 1H), 4.20

(d, J = 6.2 Hz, 2H), 2.48 (q, J = 7.2 Hz, 2H), 2.20 (t, J = 7.6 Hz, 2H), 1.75 (s, 3H), 1.66 (s, 3H),

0.90 (s, 9H), 0.07 (s, 6H). 13C NMR (125 MHz, CDCl3): δ 195.2, 153.9, 139.5, 135.2, 125.7, 60.2, 37.8, 27.1, 26.0, 18.4,

16.3, 9.2, –5.1.

TBSO

3.77

SeO2, t-BuOOHsalicylic acid, CH2Cl2, rt

TBSO3.78

OHTBSO

3.79

O+

H

2%30%

TBSO3.7725%

+

196

To a solution of 3.78 (3.05 g, 10.7 mmol) in CH2Cl2 (300 mL) at room temperature was added

NMO (1.88 g, 16.1 mmol), 4Å molecular sieve (3.0 g) and TPAP (198 mg, 0.54 mmol). The

reaction was stirred at room temperature for 16 h, then filtered through a pad of SiO2 and washed

with CH2Cl2 (200 mL). The filtrate was concentrated in vacuo to give 3.79 as a yellowish oil (1.27

g, 42%). Data of 3.79 matched previously obtained.

TBSO

3.78

TPAP, NMO4Å molecular sieve, CH2Cl2, rt

TBSO3.79

OOH42%

H

197

To a solution of 3.47 (1.55 g, 6.60 mmol) in anhydrous THF (10 mL) at −78 °C was added n-BuLi

(2.0 M solution in cyclohexane, 3.30 mL, 6.60 mmol). The mixture was stirred at −78 °C for 30

min. A solution of 3.79 (932 mg, 3.30 mmol) in anhydrous THF (20 mL) was added. The reaction

was stirred at −78 °C for 15 min, then warmed to room temperature and stirred for 1 h. The reaction

was quenched with saturated NH4Cl aqueous solution. The aqueous layer was separated and

extracted with Et2O (2 × 30 mL). The combined organic extracts were washed with brine (50 mL),


chromatography on SiO2 (10:1 → 5:1 gradient elution, petrol/EtOAc) to give 3.80 as an inseparable

4:1 mixture of regioisomers as colourless oil (1.02 g, 85%).

Data for 3.80:


IR (neat): 2952, 2929, 2857, 1777, 1671, 1475, 1463, 1384, 1257, 1058 cm-1.

Data for E-3.80 (major) 1H NMR (500 MHz, CDCl3): δ 7.44 (s, 1H), 6.22 (s, 1H), 5.73 (t, J = 7.2, 1H), 5.32 (t, J = 5.7 Hz,

1H), 4.19 (d, J = 6.1 Hz, 2H), 2.34 – 2.30 (m, 2H), 2.11 (t, J = 7.5 Hz, 2H), 2.03 (s, 3H), 1.92 (s,

3H), 1.63 (s, 3H), 0.89 (s, 9H), 0.06 (s, 6H). 13C NMR (125 MHz, CDCl3): δ 170.5, 146.8, 139.0, 135.8, 134.9, 130.7, 130.0, 125.2, 119.2,

60.2, 38.6, 26.9, 26.0, 16.3, 15.5, 10.9, –5.1.

Data for Z-3.80 (minor) 1H NMR (500 MHz, CDCl3): δ 6.99 (s, 1H), 5.77 – 5.75 (m, 1H), 5.53 (s, 1H), 5.32 (t, J = 5.7 Hz,

1H), 4.19 (d, J = 6.1 Hz, 2H), 2.34 – 2.30 (m, 2H), 2.11 (t, J = 7.5 Hz, 2H), 2.05 (s, 3H), 2.00 (s,


60.2, 39.0, 26.8, 25.9, 16.3, 15.0, 10.5, -5.1.

HRMS (ESI): calculated for C21H34O3K 401.1909 [M+K]+, found 401.1911.

TBSOO

3.47, n-BuLiTHF, –78 °C to rt

85%

3.80E/Z = 4:1

E

3.79H

OO PO

OEtOEt

OO

TBSO

198

To a solution of 4:1 mixture of 3.80 (1.02 g, 2.81 mmol) in anhydrous THF (10 mL) at room

temperature was added TBAF (1.0 M in THF, 3.10 mL, 3.10 mmol). The reaction was stirred at

room temperature for 1.5 h, then diluted with H2O (10 mL). The aqueous layer was separated and

extracted with Et2O (2 × 10 mL). The combined organic extracts were washed with brine (20 mL),


chromatography on SiO2 (1:1, petrol/EtOAc) to give 3.81 as an inseparable 4:1 mixture of

regioisomers as colourless oil (557 mg, 80%).

Data for 3.81:


IR (neat): 3432, 2926, 1757, 1668, 1625, 1446, 1382, 1266 cm-1.

Data for E-3.81 (major): 1H NMR (500 MHz, CDCl3): δ 7.45 (s, 1H), 6.23 (s, 1H), 5.73 (t, J = 7.3 Hz, 1H), 5.44 (t, J = 6.8

Hz, 1H), 4.17 (d, J = 6.9 Hz, 2H), 2.36 – 2.30 (m, 2H), 2.16 – 2.13 (m, 2H), 2.04 (s, 3H), 1.93 (s,


59.3, 38.7, 26.9, 16.3, 15.5, 10.9.

Data for Z-3.81 (minor): 1H NMR (500 MHz, CDCl3): δ 7.00 (s, 1H), 5.79 (t, J = 7.0 Hz, 1H), 5.54 (s, 1H), 5.44 (t, J = 6.8

Hz, 1H), 4.17 (d, J = 6.9 Hz, 2H), 2.36 – 2.30 (m, 2H), 2.16 – 2.13 (m, 2H), 2.05 (s, 3H), 2.00 (s,


59.4, 38.6, 26.8, 16.2, 15.2, 10.5.


3.80E/Z = 4:1

TBAF, THF, rt

80%

3.81E/Z = 4:1

E EO

OHO

OO

TBSO

199

To a solution of 3.81 (557 mg, 2.24 mmol) in CH2Cl2 (10 mL) at room temperature was added

NMO (394 mg, 3.36 mmol), 4Å molecular sieve (557 mg) and tetrapropylammonium perruthenate

(39 mg, 0.11 mmol). The reaction was stirred at room temperature for 4 h, then concentrated in

vacuo. The residue was purified by flash column chromatography on SiO2 (2:1, petrol/EtOAc) to

give 4:1 mixture of E-3.68 and Z-3.68 (386 mg, 70%) as a yellow oil. The mixture was purified by

flash column chromatography on SiO2 (2:1, petrol/EtOAc) to give E-3.68 as yellow solid (264 mg,

48%).

Data for E-3.68:


IR (neat): 2984, 2928, 2857, 1752, 1669, 1633, 1444, 1374, 1242, 1195, 1124 cm-1.

Data for E-3.68 (major):

MP: 70 – 73 °C 1H NMR (500 MHz, CDCl3): δ 10.00 (d, J = 7.9 Hz, 1H), 7.42 (s, 1H), 6.20 (s, 1H), 5.88 (d, J =

7.9 HZ, 1H), 5.67 (t, J = 7.2 Hz, 1H), 2.44 – 2.40 (m, 2H), 2.35 – 2.32 (m, 2H), 2.19 (s, 3H), 2.03

(s, 3H), 1.93 (s, 3H). 13C NMR (125 MHz, CDCl3): δ 191.0, 170.3, 162.2, 147.3, 136.5, 134.7, 131.7, 130.5, 127.5,

118.5, 39.6, 26.2, 17.6, 15.5, 10.9.

Data for Z-3.68 (minor): 1H NMR (500 MHz, CDCl3): δ 9.99 (d, J = 7.8 Hz, 1H), 7.00 (s, 1H), 5.89 (d, J = 7.9 Hz, 1H),

5.72 (t, J = 6.9 Hz, 1H), 5.51 (s, 1H), 2.45 – 2.39 (m, 2H), 2.35 – 2.32 (m, 2H), 2.18 (s, 3H), 2.06


116.4, 39.7, 26.1, 17.5, 15.2, 10.5.


3.81E/Z = 4:1

TPAP, NMO, 4Å MS, CH2Cl2, rt

70%

O

OO

3.68E/Z = 4:1

E EHO

OHO

200

To a solution of E-3.68 (26 mg, 0.11 mmol) in MeOH (3 mL) at room temperature was added

phloroglucinol (3.70) (27 mg, 0.21 mmol) and Ca(OH)2 (16 mg, 0.21 mmol). The mixture was

stirred at reflux for 24 h, then cooled to room temperature and quenched with 1 M HCl solution (3

mL). The aqueous layer was then extracted with Et2O (2 × 10 mL). The combined organic extracts

were dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by flash

column chromatography on SiO2 (2:1, petrol/EtOAc) to give an inseparable 4.9:1 mixture of 3.74

and 3.75 as a white solid (12 mg, 31%).

Data for 3.74 & 3.75:


IR (neat): 3415, 2937, 1757, 1712, 1626, 1601, 1501, 1361 cm-1.

Data for 3.74 (major) 1H NMR (500 MHz, d6-acetone): δ 8.35 (s, 1H), 6.08 (d, J = 2.1 Hz, 1H), 6.00 (d, J = 2.2 Hz, 1H),

5.43 (s, 1H), 3.90 (d, J = 5.7 Hz, 1H), 3.36 – 3.30 (m, 1H), 3.05 (d, J = 5.8 Hz, 1H), 2.28 – 2.22 (m,

1H), 2.17 – 2.07 (m, 2H), 2.01 – 1.97 (m, 1H), 1.84 (dd, J = 12.2, 5.9 Hz, 1H), 1.79 (s, 3H), 1.58

(dd, J = 11.7, 7.3 Hz, 1H), 1.40 (s, 3H), 1.33 (d, J = 7.2 Hz, 3H). 13C NMR (125 MHz, d6-acetone): δ 177.6, 159.0, 158.3, 154.3, 144.7, 120.7, 99.8, 99.5, 98.2,

88.1, 85.6, 84.3, 46.2, 40.6, 39.8, 39.3, 32.1, 25.0, 23.8, 20.5, 8.9.

Data for 3.75 (minor) 1H NMR (500 MHz, d6-acetone): δ 8.31 (s, 1H), 6.00 (d, J = 2.2 Hz, 1H), 5.94 (d, J = 2.2 Hz, 1H),

5.30 (s, 1H), 4.18 (d, J = 6.0 Hz, 1H), 3.14 (d, J = 4.8 Hz, 1H), 3.00 – 2.94 (m, 1H), 2.28 – 2.22 (m,

1H), 2.17 – 2.07 (m, 2H), 2.01 – 1.97 (m, 1H), 1.89 (dd, J = 12.3, 4.9 Hz, 1H), 1.77 (s, 3H), 1.62 –

1.50 (m, 1H), 1.44 (s, 3H), 1.41 (d, J = 7.6 Hz, 3H). 13C NMR (125 MHz, d6-acetone): δ 176.3, 159.1, 158.8, 154.8, 145.3, 121.9, 99.5, 98.5, 98.1,

86.0, 84.4, 83.1, 46.3, 42.7, 40.7, 40.6, 31.1, 25.3, 24.8, 20.6, 14.4.

HRMS (ESI): calculated for C21H21O5 353.1394 [M–H]–, found 353.1396.

O

H

H

HO

H

O

O

HO

O

H

H

HO

H

O

O

HO

O

OO

E-3.68

Ca(OH)2, MeOHreflux31%

OH

OHHO

+E

4.9:1 d.r. (3.74:3.75)

+

3.70

H

201

To a solution of E-3.46 (20 mg, 0.081 mmol) in EtOH (3 mL) at room temperature was added

phloroglucinol (3.70) (31 mg, 0.244 mmol) and Ca(OH)2 (18 mg, 0.244 mmol). The mixture was

stirred at reflux for 24 h, then cooled to room temperature and concentrated in vacuo. The residue

was diluted with 1 M HCl solution (3 mL), then extracted with Et2O (2 × 10 mL). The combined

organic extracts were dried over MgSO4, filtered and concentrated in vacuo. The residue was

purified by flash column chromatography on SiO2 (2:1, petrol/EtOAc) to give an inseparable 3.0:1

mixture of 3.74 and 3.75 as a white solid (13 mg, 46%). Data for 3.74 and 3.75 matched that


O

H

H

HO

H

O

O

HO

O

H

H

HO

H

O

O

HO

O

OO

E-3.68

Ca(OH)2, EtOHreflux46%

OH

OHHO

+E

3:1 d.r. (3.74:3.75)

+

3.70

H

202

3.5.3. NMR spectra

O

OH

3.551H NMR500 MHz

CDCl3

O

OH

3.5513C NMR125 MHz

CDCl3

203

O

OH

3.561H NMR500 MHz

CDCl3

O

OH

3.5613C NMR125 MHz

CDCl3

204

O

OH

H

H+

O

OH

H

H

3.57 3.58

1H NMR500 MHz

CDCl3

O

OH

H

H+

O

OH

H

H

3.57 3.58

13C NMR125 MHz

CDCl3

205

O

OH

CH2OH

3.5913C NMR125 MHz

CDCl3

O

OH

CH2OH

3.591H NMR500 MHz

CDCl3

206

O

OH

CHO

3.48

13C NMR125 MHz

CDCl3

O

OH

CHO

3.48

1H NMR500 MHz

CDCl3

207

OO Br

3.611H NMR500 MHz

CDCl3

208

OO PO

OEtOEt

3.471H NMR500 MHz

CDCl3

OO PO

OEtOEt

3.4713C NMR125 MHz

CDCl3

209

O

OH

HH

O

H

O

E

E/Z = 4.5:11H NMR500 MHz

CDCl3

3.46

O

OH

HH

O

H

O

E

E/Z = 4.5:113C NMR125 MHz

CDCl3

3.46

210

O

OH

HH

O

H

O

E

E/Z = 4.5:1COSY

500 MHzCDCl3

3.46

O

OH

HH

O

H

O

E

E/Z = 4.5:1HSQC

500 MHzCDCl3

3.46

211

O

OH

HH

O

H

O

E

E/Z = 4.5:1HMBC

500 MHzCDCl3

3.46

O

OH

HH

O

H

O

E


CDCl3

3.46

212

O

OH

HH

O

H

O

E


CDCl3

3.46

O

OH

Me

HH

O

H

O

E


CDCl3

3.46

213

O

OH

HH

O O

H

Z

Z/E = 7.5:11H NMR500 MHz

CDCl3

XX

O

OH

HH

O O

H

Z

Z/E = 7.5:113C NMR125 MHz

CDCl3

XX

214

O

OH

HH

O O

H

Z

Z/E = 7.5:11H NMR500 MHzd6-DMSO

3.46

O

OH

HH

O O

H

Z

Z/E = 7.5:113C NMR125 MHzd6-DMSO

3.46

215

O

OH

HH

O O

H

Z

Z/E = 7.5:1COSY

500 MHzd6-DMSO

3.46

O

OH

HH

O O

H

Z

Z/E = 7.5:1HSQC

500 MHzd6-DMSO

3.46

216

O

OH

HH

O O

H

Z

Z/E = 7.5:1HMBC

500 MHzd6-DMSO

3.46

O

OH

HH

O O

H

Z

Z/E = 7.5:1NOESY500 MHzd6-DMSO

3.46

217

O

OH

HH

O O

H

Z

Z/E = 7.5:1NOESY500 MHzd6-DMSO

3.46

218

O

OH

H H

H

O

O


3.62

O

OH

H H

H

O

O

13C NMR125 MHzd6-DMSO

3.62

219

O

OH

H H

H

O

O

COSY500 MHzd6-DMSO

3.62

O

OH

H H

H

O

O

COSY500 MHzd6-DMSO

3.62

220

O

OH

H H

H

O

O

HMBC500 MHzd6-DMSO

3.62

O

OH

H H

H

O

O

NOESY500 MHzd6-DMSO

3.62

221

O

OH

H H

H

O

O

1H NMR500 MHz

CDCl3

3.62

O

OH

H H

H

O

O

13C NMR125 MHz

CDCl3

3.62

222

O

OH

H H

H

O

O

COSY500 MHz

CDCl3

3.62

O

OH

H H

H

O

O

HSQC500 MHz

CDCl3

3.62

223

O

OH

H H

H

O

O

HMBC500 MHz

CDCl3

3.62

O

OH

H H

H

O

O

NOESY500 MHz

CDCl3

3.62

224

O

OH

H H

H

O


1H NMR500 MHz

CDCl3

O

OH

H H

H

O


13C NMR125 MHz

CDCl3

225

O

OH

H H

H

O


COSY500 MHz

CDCl3

O

OH

H H

H

O


HSQC500 MHz

CDCl3

226

O

OH

H H

H

O


HMBC500 MHz

CDCl3

O

OH

H H

H

O


NOESY500 MHz

CDCl3

227

O

OH

O


1H NMR500 MHz

CDCl3

O

OH

O


13C NMR125 MHz

CDCl3

228

O

OH

O


COSY500 MHz

CDCl3

O

OH

O


HSQC500 MHz

CDCl3

229

O

OH

O


HMBC500 MHz

CDCl3

230

O

OH

O

OOH

OMe

3.64


CDCl3

O

OH

O

OOH

OMe

3.64


CDCl3

231

O

OH

O

O

OMe

3.65


CDCl3

O

OH

O

O

OMe

3.65


CDCl3

232

O

OH

O

O

OMe

3.65

d.r. 1:1COSY

500 MHzCDCl3

O

OH

O

O

OMe

3.65

d.r. 1:1HSQC

500 MHzCDCl3

233

O

OH

O

O

OMe

3.65

d.r. 1:1HMBC

500 MHzCDCl3

234

3.66

O

O

OHO


CDCl3

3.66

O

O

OHO


CDCl3

235

3.66

O

O

OHO

d.r. 2:1COSY

500 MHz CDCl3

3.66

O

O

OHO

d.r. 2:1HSQC

500 MHz CDCl3

236

3.66

O

O

OHO

d.r. 2:1HMBC

500 MHz CDCl3

237

O

OH

O

O

OH

3.451:1 d.r.

1H NMR500 MHz

CDCl3

O

OH

O

O

OH

3.451:1 d.r.

13C NMR125 MHz

CDCl3

238

O

OH

O

O

OH

3.451:1 d.r.COSY

500 MHzCDCl3

O

OH

O

O

OH

3.451:1 d.r.HSQC

500 MHzCDCl3

239

O

OH

O

O

OH

3.451:1 d.r.HMBC

500 MHzCDCl3

240

O

OAc

O

O

3.67single stereoisomer

Z

1H NMR500 MHz

CDCl3

O

OAc

O

O

3.67single stereoisomer

Z

13C NMR125 MHz

CDCl3

241

O

OH

O

O

3.46

Z

1H NMR500 MHz

CDCl3

O

OH

O

O

3.46

Z

1H NMR500 MHz

CDCl3

242

O

OH

O

O

3.46

Z

COSY500 MHz

CDCl3

O

OH

O

O

3.46

Z

HSQC500 MHz

CDCl3

243

O

OH

O

O

3.46

Z

HMBC500 MHz

CDCl3

244

TBSO3.77

1H NMR500 MHz

CDCl3

TBSO3.77

13C NMR125 MHz

CDCl3

245

TBSO3.78

OH

1H NMR500 MHz

CDCl3

TBSO3.78

OH

1H NMR500 MHz

CDCl3

246

TBSO3.79

O

H1H NMR500 MHz

CDCl3

TBSO3.79

O

H1H NMR500 MHz

CDCl3

247

1H NMR500 MHz

CDCl3

3.80E/Z = 4:1

EO

OTBSO

13C NMR125 MHz

CDCl3

3.80E/Z = 4:1

EO

OTBSO

248

1H NMR500 MHz

CDCl3

3.81E/Z = 4:1

EO

OHO

13C NMR125 MHz

CDCl3

3.81E/Z = 4:1

EO

OHO

249

1H NMR500 MHz

CDCl3

3.68E/Z = 4:1

EO

OO

H

13C NMR125 MHz

CDCl3

3.68E/Z = 4:1

EO

OO

H

250

1H NMR500 MHz

CDCl3

3.68

EO

OO

H

13C NMR125 MHz

CDCl3

3.68

EO

OO

H

251

COSY500 MHz

CDCl3

3.68

EO

OO

H

HSQC500 MHz

CDCl3

3.68

EO

OO

H

252

HMBC500 MHz

CDCl3

3.68

EO

OO

H

NOESY500 MHz

CDCl3

3.68

EO

OO

H

253

NOESY500 MHz

CDCl3

3.68

EO

OO

HH H

NOESY500 MHz

CDCl3

3.68

EO

OO Me

H

H

254

O

H

H

HO

H

O

O

HO

O

H

H

HO

H

O

O

HO

+

4.9:1 d.r. (3.74:3.75)1H NMR500 MHz

CDCl3

O

H

H

HO

H

O

O

HO

O

H

H

HO

H

O

O

HO

+

3:1 d.r. (3.74:3.75)1H NMR500 MHz

CDCl3

255

O

H

H

HO

H

O

O

HO

O

H

H

HO

H

O

O

HO

+

4.9:1 d.r. (3.74:3.75)13C NMR125 MHz

CDCl3

O

H

H

HO

H

O

O

HO

O

H

H

HO

H

O

O

HO

4.9:1 d.r. (3.74:3.75)COSY

500 MHzCDCl3

256

O

H

H

HO

H

O

O

HO

O

H

H

HO

H

O

O

HO

+

4.9:1 d.r. (3.74:3.75)HSQC

500 MHzCDCl3

O

H

H

HO

H

O

O

HO

O

H

H

HO

H

O

O

HO

+

4.9:1 d.r. (3.74:3.75)HMBC

500 MHzCDCl3

257

O

H

H

HO

H

O

O

HO

O

H

H

HO

H

O

O

HO

4.9:1 d.r. (3.74:3.75)NOESY500 MHz

CDCl3

OMe

H

H

HO

H

O

O

HO

H

H

NOESY500 MHz

CDCl3

3.74

OMe

H

H

HO

H

O

O

HO

Me

H

NOESY500 MHz

CDCl3

3.75

258

3.5.4. Table of 1H and 13C NMR data

Comparison of the 1H and 13C NMR spectra of natural and synthetic verrubenzospirolactone (3.38).


CDCl3, 600 MHz

Synthetic sample, 1H

NMR, CDCl3, 500 MHz


CDCl3, 150 MHz


NMR, CDCl3, 125 MHz

1 3.24, d (J = 4.8 Hz) 3.24, d (J = 4.6 Hz) 36.6 36.7

2 1.80, dd (J = 12.0, 4.8 Hz) 1.81, dd (J = 11.9, 4.8 Hz) 50.1 50.3

3 82.0 82.1

4 2.10, m

1.93, m

2.12 – 2.09, m

1.94 – 1.91, m 39.0 39.2

5 1.99, m

1.37, m

2.01 – 1.98, m

1.40 – 1.36, m 25.1 25.2

6 2.56, m 2.59 – 2.53, m 40.7 40.9

7 143.1 143.2

8 4.88, s 4.88, s 119.9 120.1

9 89.0 89.2

10 7.11, s 7.11, d (J = 1.4 Hz) 153.5 153.5

11 128.0 128.2

12 174.0 174.2

13 1.96, s 1.96, d (J = 1.3 Hz) 10.4 10.6

14 1.68, s 1.67, s 20.2 20.4

15 1.33, s 1.33, s 23.8 24.0

1’ 146.4 146.5

2’ 116.8 117.0

3’ 7.29, s 7.31, s 115.4 115.6

4’ 147.4 147.6

5’ 124.5 124.6

6’ 6.54, s 6.54, s 119.7 119.8

7’ 2.15, s 2.15, s 15.6 15.8

OH, 4’ 5.08, s

O

OH

H H

H

O

O

(±)-3.38: verrubenzospirolactone

1

23

4

14

1311

10

9 8

76

515

7' 5'

6'

3'

2'

12

1'

4'

259


Single crystals were mounted in paratone-N oil on a plastic loop. X-ray diffraction data were


sets were corrected for absorption using a multi-scan method, and structures were solved by direct

methods using SHELXS-976 and refined by full-matrix least squares on F2 by SHELXL-2014,7

interfaced through the program X-Seed.8 In general, all non-hydrogen atoms were refined

anisotropically and hydrogen atoms were included as invariants at geometrically estimated

positions. X-ray experimental data is given in the Table below. CIF data have been deposited with

the Cambridge Crystallographic Data Centre, CCDC reference numbers CCDC 1508091 (3.38),

1508092 (3.62) and 1525505 (3.74).

Table 3.5.5.1. X-ray experimental data for compounds 3.38, 3.62 and 3.74.

Compound 3.38 [(±)-Verrubenzospirolactone] 3.62 3.74

Emp. formula C22H24O4 C22H24O4 C21H22O5

Fw 352.41 352.41 354.48

Crystal system monoclinic monoclinic Triclinic

Space group P21/c P21/n P-1

a (Å) 10.4686(6) 10.1643(3) 7.9458(7)

b (Å) 22.5050(18) 11.0045(4) 10.8748(8)

c (Å) 7.8319(7) 16.5691(5) 11.4355(9)

90 90 115.998(7)

β (º) 97.782(7) 100.231(3) 96.814(7)

90 90 96.924(6)

Volume (Å3) 1828.2(2) 1823.84(10) 865.22(13)

Z 4 4 2

Density (calc.) (Mg/m3) 1.280 1.283 1.360

Abs. coefficient (mm-1) 0.087 0.087 0.097

F(000) 752 752 376

Crystal size (mm3) 0.23×0.16×0.03 0.34×0.15×0.08 0.27×0.15×0.07

θ range (º) 3.35 to 28.27 3.47 to 29.38 3.39 to 28.11

Reflns collected 17714 20774 12843

Obs. reflns [R(int)] 3932 [0.0935] 4530 [0.0624] 3680 [0.0871]

GoF2 1.015 1.034 1.035

R1 [I>2σ(I)] 0.0687 0.0534 0.0820

wR2 (all data) 0.1157 0.1147 0.2020

Largest diff. peak and hole (e.Å-3) 0.189 & -0.203 0.278 & -0.213 0.630 & -0.338

260

Figure S1. A representation of the structure of compound 3.38 with ellipsoids shown at the 50%

probability level (carbon – grey; hydrogen – white; oxygen – red).

261



262



263

3.5.6. References

1. Ishii, H.; Ishige, M.; Matsushima, Y.; Tohojoh, T.; Ishikawa, T.; Kawanabe, E. J. Chem. Soc., Perkin Trans. 1, 1985, 2353.

2. Yang, P.; Yao, M.; Li, J.; Li, Y.; Li, A. Angew. Chem. Int. Ed., 2016, 55, 6964. 3. Volkert, M.; Uwai, K.; Tebbe, A.; Popkirova, B.; Wagner, M.; Kuhlmann, J.; Waldmann, H.

J. Am. Chem. Soc., 2003, 125, 12749. 4. Cole, K. P.; Hsung, R. P. Org. Lett., 2003, 5, 4843. 5. Hu, T.; Corey, E. J. Org Lett, 2002, 4, 2441. 6. Sheldrick, G. M. Acta Crystallogr A, 1990, 46, 467. 7. Sheldrick, G. M. Acta Crystallographica a-Foundation and Advances, 2015, 71, 3. 8. Barbour, L. J. J. Supramol. Chem., 2003, 1, 189.

264

Chapter 4

Biomimetic Total Synthesis of Rhodonoids C and D, and Murrayakonine D

This project was conducted in collaboration with Mr Aaron Day

4.1. Introduction

4.1.1. Isolation of rhodonoids and murrayakinone D

Figure 4.1: Rhodonoids A-D.1,2

Rhodonoid C (4.3) contains a unique 6/6/5/6 ring system with 4 stereocenters, 3 of which are

contiguous, while rhodonoid D (4.4) has a 6/6/5/5 ring system with 4 contiguous

stereocenters (Figure 4.1). Rhodonoids C and D1 along with biosynthetically related

rhodonoids A (4.1) and B (4.2)2 were isolated from the aerial part of a flowering plant

Rhododendron capitatum by Liao. All rhodonoids were isolated as scalemic mixtures (Table

4.1), suggesting these natural products could be derived from a pre-disposed, non-enzymatic

biosynthesis.

Table 4.1: Ratio of enantiomers of natural rhodonoids A-D.

Ratio of enantiomer + –

rhodonoid A 1 5 rhodonoid B 1 2 rhodonoid C 10 1 rhodonoid D 1 4

Figure 4.2: Murrayakonine D (4.6) and mahanimbine (4.5).3

O

OH OH

H

H

4.4: rhodonoid D4.3: rhodonoid C

O

OOH

O

HOH

H

O

HOH

H

H

O

4.2: rhodonoid B4.1: rhodonoid A

O

O

NH

4.5: mahanimbine 4.6: murrayakonine D

O

ONH

4.3: rhodonoid C

O

OOH

265

Consulting the literature, a natural product called murrayakinone D (4.6) also shares the same

skeleton with rhodonoid C (4.3), where murrayakonine D (4.6) has a carbazole ring (Figure

4.2). Murrayakonine D (4.6) was isolated from the leaves of a curry tree Murraya koenigii,

alongside mahanimbine (4.5), which we proposed to be the biosynthetic precursor of 4.6.3

4.1.2. Total synthesis of (±)-rhodonoids A (4.1) and B (4.2) by Hsung

Scheme 4.1: Total synthesis of rhodonoid A (4.1).4

The total synthesis of rhodonoids A and B was reported by Hsung in 2017.4 The total

synthesis of rhodonoid A (4.1) started from Knoevenagel condensation/6π-electrocyclization

of orcinol (4.7) and citral (4.8) to give chromene 4.9. The free phenol of 4.9 was protected as

the benzyl ether 4.10. 4.10 was then epoxidized to give 4.11 as a 1:1 mixture of

diastereoisomers. Ring opening of epoxide 4.11 by Al(i-PrO)3 in PhMe at 110 ºC gave 4.12

as a mixture of diastereoisomers, which was oxidized by Dess-Martin periodinane to give the

unsaturated ketone 4.13. 4.13 underwent a [2+2] cycloaddition under light to give 4.14,

followed by benzyl deprotection to give rhodonoid A (4.1) (Scheme 4.1).4

OH

OH

4.7: orcinol

H

O

4.8: citralAc2O, piperidine

PhMe, reflux

OH

O

4.9

OBn

O

4.13

O

BnBr, K3PO4TBAB, H2O, rt

O

BnOH

H

O

HOH

H

hυ, hexane40%

OO

Pd(OH)2, H2,THF, MeOH

2+2 cycloaddition

4.1: rhodonoid A4.14

75%

92%

OBn

O

4.10

OBn

O

4.11

O

d.r. 1:1

m-CPBACH2Cl2, 0 °C

87%

53%

OBn

O

4.12

HO

d.r. 1:1

Al(i-PrO)3PhMe, 110 °C

Dess-Martin periodinaneNaHCO3, CH2Cl2, rt

266

Scheme 4.2: Total synthesis of rhodonoid B (4.2).4

The total synthesis of rhodonoid B (4.2) started from chromene Z-4.16, which was

synthesized from orcinol (4.7) and aldehyde 4.15. Z-4.16 then underwent a [2+2]

cycloaddition with Fe(OTf)3 to give 4.17. This reaction was conducted at low temperature, as

the Z-alkene would be readily isomerised and underwent [2+2] cycloaddition to give 12-epi-

4.17. The synthesis continued by functionalising the alkene of 4.17 to an unsaturated ketone

which gave rhodonoid B (4.2) in 8 steps (Scheme 4.2).4

The total synthesis of rhodonoids A (4.1) and B (4.2) was the only example of the synthesis

of rhodonoids. To date, there is no biosynthetic speculation or total synthesis of rhodonoids

C (4.3) and D (4.4) reported in the literature. Our aim is to propose how rhodonids C and D

could be derived in Nature, and to synthesize them via our proposed biosynthetic pathways.

OH

OH

4.7: orcinol

O

HZ

4.15Ac2O, piperidine

PhMe, reflux

OH

O

O

HOH

H

H

O

O

HOH

H

H8 steps

2+2 cycloaddition Fe(OTf)3. CH2Cl2–40 °C

Z

Z-4.16

4.174.2: rhodonoid B

OH

O

E

E-4.16

Fe(OTf)3. CH2Cl2rt

63%d.r. 11:1

O

HOH

H

H

2+2 cycloaddition

12-epi-4.1754%

d.r. 2:1

12

69%

267

4.1.3. Proposed biosynthesis of rhodonoids C and D

Scheme 4.3: Proposed biosynthesis of rhodonoids C and rhodonoid D.

Our biosynthetic proposal for rhodonoids C and D is outlined in Scheme 4.3. The proposed

biosynthesis starts from chromene 4.9, which is an unnamed natural product that was

previously isolated from Rhododendron anthopogonides.5 Stereoselective epoxidation of 4.9

could give 4.18, which then convert into rhodonoids C (4.3) and D (4.4) via acid-catalysed

rearrangements. A 6-endo-tet6 ring opening of epoxide 4.18 (probably via an SN1 mechanism

under acidic conditions) by electron-rich chromene double bond could give o-quinone

methide 4.21, which could cyclize via nucleophilic attack of the resultant alcohol back onto

the o-quinone methide 4.21 to give rhodonoid C (4.3) (pathway a). The ring opening of

epoxide in pathway a is classified as 6-endo-tet according to Baldwin’s rule,6 whereas

Alabugin suggested “6-exo-tet”7 and Jamison suggested “fused 6-endo-tet”.8 We decided to

follow Baldwin’s classification in this chapter.

Alternatively, initial 5-exo-tet ring opening of epoxide 4.18 (via an SN2 mechanism, which

leads to the inversion at C-12) could give o-quinone methide 4.20, the tertiary alcohol attacks

the o-quinone methide to give rhodonoid D (4.4) (pathway b).

OH

O

4.9

OH

O

4.18

H

O H

6-endo-tet

O

O

H H

OH

O

OOH

O

O

4.18

H

OH

O

OH

H

HO

12

O

OH OH

H

H

4.4: rhodonoid D

orepoxidation

pathway a pathway b

5-exo-tet

4.21

4.20

4.3: rhodonoid C

H

O

O

4.19

H OH

H

ring closure

ring closure

268

Scheme 4.4: Proposed biosynthesis of murrayakonine D (4.6).

We also propose the biosynthesis of murrayakonine D (4.6) to be identical with that in

rhodonoid C (4.3) (Scheme 4.4). Starting from mahanimbine (4.5), stereoselective

epoxidation gives 4.22, and ring opening of 4.22 under acidic conditions would give

carbocation 4.23. A 6-endo-tet cyclization would give aza-ortho-quinone methide 4.24, the

resultant alcohol would cyclize back onto the aza-ortho-quinone methide 4.24 to give

murrayakonine D (4.6).

4.1.4. Epoxide cyclization reaction in the synthesis of siccanin (4.28) by Trost

In the total synthesis of siccanin (4.28) by Trost, he initially attempted to rearrange epoxide

4.25 into siccanin (4.28) using Lewis acids via an acid-catalysed cyclization cascade reaction

(Scheme 4.5), which is similar to our pathway a cyclization pathway to give rhodonoid C (4.3)

(Scheme 4.5). However, Trost observed no reaction or decomposition of 4.25. He later

achieved the total synthesis of siccanin (4.28) using a radical cyclization approach (Scheme

4.6).9,10

Scheme 4.5: Attempted acid-catalysed rearrangement of 4.25 to siccanin by Trost.9,10

4.22

H

6-endo-tet

epoxidation

pathway a

O

NH

4.5: mahanimbine

O

NHO

H

O

NH

OHH

O

NH

H

OH

4.6: murrayakonine D

O

ONH

4.23

4.24

O

OMe

H

O

4.25

O

HO

H

O

H

H

4.28: siccanin

BF3·OEt2SnCl2

TiCl2(Oi-Pr)2Yb(OTf)3

FeCl3

no reactionor

decomposition

O

OH

H

O

4.26

LA

O

O

H

O

H

4.27

LA

alkene cyclization

269

When epoxide 4.25 was treated with CpTiIIICl2, 4.33 and 5-epi-methoxysiccanin (4.32) were

observed.9,10 The proposed mechanism began from a single electron reduction of epoxide

4.25 by Ti3+ to give radical intermediate 4.29, followed by a 6-exo-tet cyclization to generate

2 diastereoisomers, 4.30 and 4.31. 4.30 underwent a 6-exo-tet cyclization to give 5-epi-

methoxysiccanin (4.32) in 61% yield, while the desired 4.31 intermediate did not undergo 6-

exo-tet cyclization, but a single electron reduction to give alcohol 4.33 in 20% yield. 4.33 was

then oxidized by I2 and PhI(OAc)2 under light to give 4.34, followed by deprotection using

EtSNa to give siccanin (4.28) (Scheme 4.6). From the total synthesis of siccanin (4.28), we

were interested to apply the radical cyclization methodology into the epoxide cyclization of

4.9 to rhodonoid C (4.3) or D (4.4).

Scheme 4.6: Total synthesis of siccanin (4.28) by Trost.9,10

O

OMe

H

OCp2TiIIICl

reductive ring opening O

OMe

H

OTiIV

O

OMe

H

OTiIV

O

MeO

H

O

H

H

H

4.32: 5-epi-methoxysiccanin

5

O

OMe

H

OTiIV

H

5

O

OMe

HH

HO

6-exo-tet

6-exo-tet

single electronreduction

6-exo-tet

4.29 4.304.25

O

HO

H

O

H

H

4.28: siccanin

5

6-exo-tet

4.314.33

O

MeO

H

O

H

H

4.34

PhI(OAc)2, I2hν, benzene, rt65%

EtSNa, DMF, rt86%

61%

20%

270


4.2.1. Biomimetic total synthesis of rhodonoids C and D

Scheme 4.7: Synthesis of epoxide 4.9.

The synthesis began with chromene 4.9, which was prepared from orcinol (4.7) and citral (4.8)

facilitated by EDDA.11 However, it was difficult to purify chromene 4.9 from the unreacted

citral (4.8) by column chromatography. Treatment of the mixture with NaBH4, which reduced

excess citral (4.8) to geraniol, allowed an easier purification of chromene 4.9. Epoxidation of

chromene 4.9 gave a 51% yield of epoxide 4.18 as a 1:1 mixture of diastereoisomers, along

with 27% yield of recovered chromene 4.9 (Scheme 4.7). To our surprise, the epoxidation

never went to completion. We modified the reaction conditions (e.g. excess m-CPBA, longer

reaction time, added NaHCO3, or carefully heating up the reaction) and none gave any

improvement.

Scheme 4.8: Biomimetic total synthesis of rhodonoids C and D.

For the acid-catalysed rearrangement reaction, we first used p-TsOH in CHCl3 and the result

was promising. We isolated rhodonoid C (4.3) in 21% yield, followed by rhodonoid D (4.4)

in 2% yield. There are some drastic changes on the 1H NMR spectra of 4.3 and 4.4. First, we

observed the loss of chromene signals from the epoxide 4.18 at δ 6.64 ppm (H-7) and δ 5.44

ppm (H-8). In addition, the structure of rhodonoid C (4.3) was confirmed by the key doublet

at δ 5.05 ppm (H-7) which coupled to δ 1.78 ppm (H-8). Similarly, the signal at δ 2.82 ppm

OH

OH

H

O

4.8: citralEDDA, PhMe, 110 °C

74%

OH

O

4.7: orcinol 4.9

O

OHO

1:1 d.r.

H

4.18

m-CPBA, CH2Cl2, rt

51%

OH

O

4.9

+

27% recovery

p-TsOH, CHCl3, rt

SnCl4, CHCl3, −60 °C

21%

32%

5%

21%

2%

5%

O

OHO

1:1 d.r.

H

O

OHO

O

OH OH

H

H


+ +O

OOH

4.18 4.35

78

78

78

12

271

(H-8) which coupled to δ 4.92 ppm (H-7) and 2.56 ppm (H-12) confirmed the structure of

rhodonoid D (4.4).

Ketone 4.35 was also observed from the reaction, presumably derived from ring opening of

epoxide 4.18 under acidic conditions to form carbocation 4.19, followed by a formal 1,2-

hydride shift to give ketone 4.35 (Scheme 4.9). We then conducted an extensive screening

with various Lewis acids and protic acids for this reaction (Table 4.2). We found SnCl4 in

CHCl3 gave the best overall yield with 32% of rhodonoid C (4.3), 5% of rhodonoid D (4.4)

and 21% of 4.35. Only the epoxide with the correct relative stereochemistry could rearrange

to give rhodonoids C and D, so the maximum theoretical yield of this reaction is 50%.

Therefore, to achieve 37% overall yield of rhodonoids is more than acceptable. We then

speculated that ketone 4.35 was likely derived from the non-natural stereoisomer of epoxide

4.18a.

We also observed side products when 1.0 M HCl solution or Lewis acids (TiCl4 or BF3·OEt2)

were used. We proposed under acidic conditions or heat, the epoxide 4.18 might be ring

opened to give carbocation 4.19 and subsequently attacked by Cl– to give 4.36, or attacked by

F– to give 4.37, or attacked by OH– to give 4.38 (Scheme 4.10). Unfortunately, we discovered

bases could not promote the pathway b rearrangement to form rhodonoid D (4.4).

Scheme 4.9: Proposed mechanism for the formation of ketone 4.35.

O

OHO

H

4.18

O

OH

H

4.19

OHacid or heat

O

OHHO

4.35

O

OHO

4.35

deprotonation

d.r. 1:1

272

Table 4.2: Conditions screened for the rearrangement of epoxide 4.18.

reagents conditions rhodonoid C (4.3) rhodonoid D (4.4) 4.35 side products

p-TsOH·H2O (1.0 eq) CH2Cl2, rt, 10 min 12% 1% 2% 0%

p-TsOH·H2O (1.0 eq) CH2Cl2, –78 ˚C, 1 h no reaction

p-TsOH·H2O (1.0 eq) CH2Cl2, –78 ˚C to rt, 1 h 15% 2% 4% 0%

p-TsOH·H2O (1.0 eq) DMF, rt, 30 min 0% 0% 2% 4.39, 28%

p-TsOH·H2O (1.0 eq) CHCl3, rt, 15 min 13% 2% 5% 0%

p-TsOH·H2O (0.1 eq) CHCl3, rt, 30 min 21% 2% 5% 0%

PPTS (1.0 eq) CH2Cl2, rt, 5 h 11% 3% 6% 0%

CSA (1.0 eq) CH2Cl2, 0 ˚C, 10 min 21% 2% 0% 0%

TFA (1.0 eq) CH2Cl2, 0 ˚C, 15 min 20% 0% 28% 0%

1.0 M HCl EtOH (1:1), rt, 1d 0% 0% 0% 4.36, 26%

4.38, 9%

AcOH (1.0 eq) CH2Cl2, rt, 3 d no reaction

Ca(OH)2 (1.0 eq) EtOH, rt, 1 d no reaction

Ni(OH)2 (1.0 eq) EtOH, reflux, 1 d no reaction

NaH (1.0 eq) THF, rt, 16 h no reaction

K2CO3 (1.0 eq) DMF, rt, 3 d no reaction

t-BuOK (1.0 eq) THF, 0 ˚C to rt, 1 d no reaction

t-BuOK (1.0 eq) t-BuOH, reflux, 1 d no reaction

PhMe, 110 ˚C, 16 h no reaction

H2O, 100 ˚C, 16 h 4% 0% 3% 4.38, 44%

SnCl4 (1.0 eq) CH2Cl2, –78 ˚C, 10 min 25% 0% 6% 0%

SnCl4 (0.5 eq) CH2Cl2, –78 ˚C, 15 min 26% 3% 29% 0%

TiCl4 (1.0 eq) CH2Cl2, –78 ˚C, 5 min 26% 0% 15% 4.36, 17%

FeCl3 (0.5 eq) CH2Cl2, –78 ˚C, 75 min 25% 2% 35% 0%

FeCl3.6H2O (1.0 eq) CH2Cl2, –78 ˚C to 0 ˚C 23% 0% 40% 4.36, 4%

BF3·OEt2 (1.0 eq) CH2Cl2, –78 ˚C, 30 min 0% 0% 0% 4.37, 18%

conditions

O

OHO

H

O

OHO

O

OH OH

H

H


+ +O

OOH

4.18 4.35

273

Scheme 4.10: Formation of side products from the acid-catalysed rearrangement

reactions.

4.2.2. Investigation on the reactivity of the epoxide 4.18

Scheme 4.11: Study on the reactivity of two diastereoisomers of epoxide 4.18.

To investigate whether the non-natural epoxide could give the ketone 4.35 in the acid-

catalysed rearrangement conditions, we first attempted to separate the two epoxides 4.18a

and 4.18b by HPLC but it was unsuccessful. Alternatively, we intended to separate the two

epoxides chemically, perhaps one isomer would react faster than the other one in the acid

catalysed rearrangement reaction. Therefore, our goal was to stop the reaction halfway before

it went to completion. We chose the SnCl4 conditions in this study because that reaction was

performed at low temperature and the rate of the reaction was quite slow.

We first lowered the equiv. of SnCl4 to 0.5 equiv. (from 1 equiv.), which reduced the rate of

reaction significantly. We monitored the reaction carefully by TLC, and when approximately

O

OHHO

Cl

4.36

O

OHO

H

4.18

O

OH

H

4.19

OHacid or heat

1 M HClEtOH, rt

orFeCl3•6H2OCH2Cl2, rt

orTiCl4, CH2Cl2

–78 °C

d.r. 1:1

H2O, 100 ºC

O

OHHO

OH

4.38d.r. 1:1

p-TsOH, DMF, rt

O

OHO

OH

4.39d.r. 1:1

H O

O

OHHO

F

4.37d.r. 1:1

BF3•OEt3CH2Cl2, –78 °C

d.r. 1:1

4-26%

28%44%

18%

SnCl4, CHCl3, −60 °C 22% 8%3%

d.r. 1:1

O

OHO

O

OH OH

H

H


+ +O

OOH

O

OHO

H

O

OHO

H +

4.18ad.r. 3.3:1

39%

4.18b

4.35

O

OHO

H

O

OHO

H

+

4.18a

4.18b

274

halved of epoxide 4.18 was consumed, the reaction was quenched at –60 ºC. To our delight,

we isolated 22% yield of rhodonoid C (4.3), 3% yield of rhodonoid D (4.4), 8% yield of

ketone 4.35 and 39% yield of recovered starting material. The recovered epoxide 4.18 was in

3.3:1 ratio of the two diastereoisomers. Since we observed a significant conversion of

rhodonoids C (4.3) and D (4.4) from epoxide 4.18, we would assume the major isomer in the

recovered epoxide 4.18 was the non-natural epoxide 4.18a.

Scheme 4.12: Reaction of epoxide 4.18 (diastereomeric ratio of 3.3:1).

Indeed, when 4.18a was treated under the standard conditions, we observed 13% yield of

rhodonoid C (4.3) and 32% yield of ketone 4.35. The ratio of 4.35 to rhodonoid C (4.3) was

3:1 which showed good agreement with the ratio of 4.18a and 4.18b (Scheme 4.12).

Scheme 4.13: One pot reaction of chromene 4.9 to rhodonoids C and D.

We also attempted a one-pot epoxidation and acid-catalysed rearrangement reaction.

However, the result was underwhelming. The TLC showed complex mixtures and little of the

natural products were isolated. The yield from this reaction was much worse than the

combined yield from the two steps synthesis (Scheme 4.13).

Scheme 4.14: Epoxide rearrangement with radical cyclization.9,10

O

OHO

H

O

OHO

H +

4.18a3.3:1 d.r.


13% 32%

O

OHO

4.3: rhodonoid C

+O

OOH

4.18b 4.35

m-CPBA, CH2Cl2, rt;then p-TsOH

5% 4%2%

O

OHO

O

OH OH

H

H


+ +O

OOH

4.35

OH

O

4.9

Mn, Cp2TiCl2THF, rt

O

OHO

H

4.40d.r. 1:1

O

OH

4.18

OHH

51%8

16

14

275

We also attempted a radical cyclization on epoxide 4.18.9,10 We did not observe the desired

rhodonoid structure but a 1:1 mixture of diastereoisomers 4.40, presumably derived from the

reductive radical cyclization (Scheme 4.14). The relative stereochemistry between C-8 and C-

16 can be confirmed by the NOESY analysis (Figure 4.3).

We also attempted to oxidize alcohol 4.40 into the corresponding ketone for easier

characterisation, however Dess-Martin oxidation, Swern oxidation or Ley oxidation led to

decomposition of 4.40.

Figure 4.3: NOESY of 4.40 (1:1 mixture of diastereoisomers).

4.40a

O

OH MeOH

Me

H

4.40b

O

OH MeOH

Me

H

4.40b

O

OHOH

H H

276

4.2.3. Synthesis of mahanimbine (4.5)

Scheme 4.15: Synthesis of amine 4.43.12

We then shifted our focus onto the total synthesis of murrayakonine D (4.6). We first

prepared mahanimbine (4.5) following a procedure reported by Knolker.12 The synthesis

started with benzyl protection of 2-methyl-5-nitrophenol (4.41). The reaction went smoothly

and gave 4.42 in good yield. However, when the reaction was scaled up to 10 g, we observed

the unreacted BnBr was too difficult to separate from 4.42, and the mixture would be carried

through in the following step where BnBr could then be separated by column

chromatography. Reduction of nitro group 4.42 with Fe gave amine 4.43 in good yield

(Scheme 4.15).

Scheme 4.16: Synthesis of carbazole 4.45.12

For the coupling reaction of amine 4.43, the procedure from Knolker used PhBr, XPhos and

Pd(OAc)2 to give 4.44.12 However, we decided to adapt a procedure from Dethe et al., where

20% of Cu(OAc)2 and PhB(OH)2 were used for this reaction.13 We encountered problems

with this reaction where the yield was around 10% to 20%. In addition, elemental copper was

observed at the end of the reaction, suggesting all the Cu(OAc)2 was reduced. Consulting the

literature, we found examples using stoichiometric or excess of Cu(OAc)2 for similar

reactions with boronic acid.14,15,16 When the amount of Cu(OAc)2 was increased to 2 equiv.,

the yield of this reaction improved to 69%. The next reaction was an intramolecular oxidative

coupling reaction using Pd(OAc)2 in pivalic acid to form carbazole 4.45 in 63% yield

(Scheme 4.16).

NO2

OH

4.41: 2-methyl-5-nitrophenol

BnBr, K2CO3acetone , 56 ºC

NO2

OBn

4.42

Fe, AcOH, 45 ºC

NH2

OBn

4.43

66% over 2 steps

NH2

OBn K2CO3, Cu(OAc)2benzoic acid, PhB(OH)2

PhMe, reflux

HN

OBn

4.444.43

69%

4.45

NH

OBn

K2CO3, Pd(OAc)2pivalic acid, 85 °C

63%

277

Scheme 4.17: Synthesis of mahaimbine (4.5).12

Deprotection of the benzyl group of 4.45 by hydrogenation was surprisingly slow, taking

over 1 day to go to completion. Nonetheless, the reaction gave carbazole 4.46 in good yield.

Mahanimbine (4.5) was synthesized from 4.46 and citral (4.8) with Ti(Oi-Pr)4,12 and we had

to reduce the unreacted citral (4.8) to geraniol with NaBH4 for an easier purification of

mahanimbine (4.5) (Scheme 4.17).

4.2.4. Biomimetic total synthesis of murrayakonine D (4.6)

Scheme 4.18: Biomimetic total synthesis of murrayakonine D (4.6).

Epoxidation of mahanimbine (4.5) gave 4.22 as a 1:1 inseparable mixture of diastereoisomers.

When epoxide 4.22 was treated with p-TsOH, we observed a 7.4:1 ratio of murrayakonine D

(4.6) and the undesired ketone 4.47. Murrayakonine D (4.6) and 4.47 could not be separated

by flash column chromatography (including AgNO3 doped SiO217). To our delight,

murrayakonine D (4.6) is a solid and we triturated the mixture with MeOH to give pure

murrayakonine D (4.6) in 33% yield (Scheme 4.18). We purified the filtrate to get a pure

sample of 4.47 for characterisation. We also repeated the reaction using SnCl4 in CH2Cl2 but

the yield (21% of 4.6) was not as good as with p-TsOH. Unfortunately, we have yet to

observe any product with the rhodonoid D skeleton from this reaction. Perhaps the decreased

nucleophilicity of the carbazole inhibits the pathway b rearrangement (Scheme 4.3). Last but

not least, we managed to recrystallise murrayakonine D (4.6) and collected an X-ray structure

to confirm the relative stereochemistry (Figure 4.4).

4.46

NH

OH

4.45

NH

OBn

H2, Pd/C, CH2Cl2MeOH, rt

88%O

NH

4.5: mahanimbine

4.8: citralTi(Oi-Pr)4, PhMe, −78 ºC to rt;

then NaBH4, MeOH, rt

74%

O

H

m-CPBACH2Cl2, rt

61%O

NH

4.5: mahanimbine

1:1 d.r.

O

NHO

H

p-TsOH, CH2Cl2, rt

SnCl4, CH2Cl2, −78 ºC


O

ONH

33%

21%

O

NHO

+

4.22 4.47

278

Figure 4.4: X-ray structure of murrayakonine D (4.6).

4.2.5. Biomimetic total synthesis of rhodonoids C and D reported by Hsung

Scheme 4.19: Biomimetic total synthesis of rhodonoids C and D by Hsung.18

After we published our work,19 Hsung also reported a synthesis of rhodonoids C and D using

a similar approach (Scheme 4.19).18 The epoxide 4.18 was synthesized with a higher overall

yield by protecting the free phenol with an acetate group. They also discovered heating

epoxide 4.18 in SiO2 gave 14% of rhodonoid C (4.3) and 8% of rhodonoid D (4.4), where the

yield of rhodonoid D (4.4) was improved compared to our synthesis.18

O

OHO

H

O

OHO

O

OH OH

H

H


+ +O

OOH

4.18

4.35

OH

O

4.9

OAc

O

4.48

Ac2O, DMAPEt3N, CH2Cl2, rt

1. m-CPBACH2Cl2, 0 °C2. K2CO3MeOH, rt

98% over 2 steps85%

SiO2, PhMereflux

14% 8% 26%

d.r. 1:1

279

4.3. Summary

We have developed a concise synthesis of rhodonoids C and D. The overall synthesis of

rhodonoids was protecting group free with good step economy, where rhodonoids C and D

were synthesized from simple starting materials in 3 steps. The key step was the acid

catalysed rearrangement of the epoxide 4.18 forming 2 rings and 3 new stereocenters which

gave both rhodonoids C and D in 1 step (Figure 4.5).

It showcases the power of biomimetic synthesis as the molecular complexity increases in

relative short steps with high stereoselectivity. We have also applied the same methodology

for the synthesis of murrayakonine D. These syntheses of rhodonoids and murrayakonine D

strengthen our belief that the biosynthesis of these natural products is highly pre-disposed and

likely non-enzymatic.

Figure 4.5: Summary of the biomimetic total synthesis of rhodonoids C and D.

OH

OH

4.7: orcinol

H

O

O

OH OH

H

H


+O

OOH

3 steps

3 rings4 stereocenters

4.8: citral

280

4.4. References

1. Liao, H. B.; Huang, G. H.; Yu, M. H.; Lei, C.; Hou, A. J. J. Org. Chem., 2017, 82, 1632.

2. Liao, H. B.; Lei, C.; Gao, L. X.; Li, J. Y.; Li, J.; Hou, A. J. Org. Lett., 2015, 17, 5040. 3. Nalli, Y.; Khajuria, V.; Gupta, S.; Arora, P.; Riyaz-Ul-Hassan, S.; Ahmed, Z.; Ali, A.

Org. Biomol. Chem., 2016, 14, 3322. 4. Wu, H.; Hsung, R. P.; Tang, Y. J. Org. Chem., 2017, 82, 1545. 5. Iwata, N.; Kitanaka, S. Chem. Pharm. Bull., 2011, 59, 1409. 6. Baldwin, J. E. J. Chem. Soc. Chem. Comm., 1976, 734. 7. Alabugin, I. V.; Gilmore, K. Chem Commun, 2013, 49, 11246. 8. Vilotijevic, I.; Jamison, T. F. Mar. Drugs, 2010, 8, 763. 9. Trost, B. M.; Shen, H. C.; Surivet, J. P. Angew. Chem. Int. Ed., 2003, 42, 3943. 10. Trost, B. M.; Shen, H. C.; Surivet, J. P. J. Am. Chem. Soc., 2004, 126, 12565. 11. Luo, G. Y.; Wu, H.; Tang, Y.; Li, H.; Yeom, H. S.; Yang, K.; Hsung, R. P. Synthesis,

2015, 47, 2713. 12. Hesse, R.; Gruner, K. K.; Kataeva, O.; Schmidt, A. W.; Knolker, H. J. Chem. Eur. J.,

2013, 19, 14098. 13. Dethe, D. H.; Das, S.; Dherange, B. D.; Mahapatra, S. Chem. Eur. J., 2015, 21, 8347. 14. Chen, S. Y.; Huang, H.; Liu, X. J.; Shen, J. K.; Jiang, H. L.; Liu, H. J. Comb. Chem.,

2008, 10, 358. 15. Elhalem, E.; Bailey, B. N.; Docampo, R.; Ujvary, I.; Szajnman, S. H.; Rodriguez, J. B.

J. Med. Chem., 2002, 45, 3984. 16. Vantourout, J. C.; Miras, H. N.; Isidro-Llobet, A.; Sproules, S.; Watson, A. J. B. J.

Am. Chem. Soc., 2017, 139, 4769. 17. Williams, C. M.; Mander, L. N. Tetrahedron, 2001, 57, 425. 18. Wu, H.; Hsung, R. P.; Tang, Y. Org. Lett., 2017. 19. Day, A. J.; Lam, H. C.; Sumby, C. J.; George, J. H. Org Lett, 2017, 19, 2463.

281

4.5. Experimental







nearest 0.05. Flash column chromatography was performed using 40-63 micron grade silica gel.

Melting points were recorded on a digital melting point apparatus and are uncorrected. Infrared

spectra were recorded using an FT-IR spectrometer as the neat compounds. High field NMR spectra

were recorded using a 500 MHz spectrometer (1H at 500 MHz, 13C at 125 MHz). Solvent used for

spectra were CDCl3 unless otherwise specified. 1H chemical shifts are reported in ppm on the δ-

scale relative to TMS (δ 0.0) and 13C NMR are reported in ppm relative to CDCl3 (δ 77.00).

Multiplicities are reported as (br) broad, (s) singlet, (d) doublet, (t) triplet, (q) quartet, (quin)

quintet, (sext) sextet, (hept) heptet and (m) multiplet. All J-values were rounded to the nearest 0.1

Hz. ESI high resolution mass spectra were recorded on a ESI-TOF mass spectrometer.

282


To a solution of orcinol (4.7) (15.0 g, 121 mmol) in PhMe (400 mL) at room temperature was added

citral (4.8) (18.4 g, 121 mmol) and ethylenediamine diacetate (440 mg, 2.42 mmol). The reaction

was stirred at reflux for 5 h. The mixture was cooled to room temperature, then concentrated in

vacuo. The residue was redissolved in MeOH (100 mL), followed by addition of NaBH4 (4.58 g,

121 mmol) to reduce unreacted citral (4.8) that is difficult to separate from 4.9. The reaction was

stirred at room temperature for 30 min, then quenched with 1 M HCl solution (200 mL). The

solution was extracted with Et2O (2 × 300 mL). The combined organic extracts were washed with

brine (300 mL), dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by

flash column chromatography on SiO2 (8:1, petrol/EtOAc) to give 4.9 as an orange oil (23.1 g,

74%). Data for 4.9 matched that previously reported in the literature.1

Data for 4.9:


IR (neat): 3387, 2970, 2924, 2857, 1625, 1578, 1509, 1450, 1377, 1330, 1250 cm-1. 1H NMR (500 MHz, CDCl3): δ 6.61 (d, J = 10.0 Hz, 1H), 6.24 (s, 1H), 6.11 (s, 1H), 5.49 (d, J =

10.0 Hz, 1H), 5.10 (t, J = 7.1 Hz, 1H), 4.71 (br s, 1H), 2.20 (s, 3H), 2.13 – 2.07 (m, 2H), 1.72 (dd, J

= 10.7, 5.9 Hz, 1H), 1.66 (s, 3H), 1.66 – 1.63 (m, 1H), 1.58 (s, 3H), 1.37 (s, 3H). 13C NMR (125 MHz, CDCl3): δ 154.1, 151.0, 139.5, 131.6, 127.2, 124.2, 117.0, 109.9, 108.3,

106.7, 78.2, 41.1, 26.2, 25.7, 22.7, 21.5, 17.6.

HRMS (ESI): calculated for C17H21O2 257.1547 [M-H]-, found 257.1539.

OH

OH

H

O

4.8: citralEDDA, PhMe, 110 °C

74%

OH

O

4.7: resocinol 4.9

283

To a solution of 4.9 (5.60 g, 21.7 mmol) in CH2Cl2 (250 mL) at room temperature was added m-

CPBA (77%, 3.92 g, 22.8 mmol). The reaction was stirred at room temperature for 30 min. The

solution was washed sequentially with saturated Na2S2O3 solution (2 × 200 mL) and saturated

NaHCO3 solution (2 × 200 mL). The organic layer was washed with brine (200 mL), dried over


chromatography on SiO2 (5:1 → 3:1, petrol/EtOAc gradient elution) to give recovered 4.9 as an

orange oil (1.51 g, 27%). Further elution gave epoxide 4.18 (d.r. = 1:1) as a brown oil (3.00 g,

51%).

Data for 4.18:


IR (neat): 3348, 2969, 2925, 2857, 1624, 1579, 1452, 1452, 1425, 1380, 1329, 1272 cm-1. 1H NMR (500 MHz, CDCl3): δ 6.64 (d, J = 10.0 Hz, 2H), 6.20 (s, 2H), 6.12 (s, 2H), 5.46 (d, J =

10.0 Hz, 1H), 5.43 (d, J = 10.0 Hz, 1H), 5.33 (br s, 2H), 2.77 (t, J = 6.2 Hz, 1H), 2.75 (t, J = 5.8 Hz,

1H), 2.19 (s, 6H), 1.83 (t, J = 8.1 Hz, 2H), 1.75 – 1.66 (m, 6H), 1.38 (s, 3H), 1.37 (s, 3H), 1.30 (s,


109.6, 109.5, 108.50, 108.46, 106.7, 106.5, 78.0, 77.6, 64.8, 64.5, 59.1, 58.9, 37.9, 37.4, 26.6, 26.1,

24.8, 23.9, 23.6, 21.5, 18.63, 18.57.


OH

O

4.9

O

OHO

1:1 d.r.

H

4.18

m-CPBA, CH2Cl2, rt

51%

OH

O

4.9

+

27% recovery

284

To a solution of 4.18 (d.r. = 1:1) (685 mg, 2.50 mmol) in CHCl3 (40 mL) at −60 ºC was added

SnCl4 (0.29 mL, 2.50 mmol) dropwise. The reaction was stirred at −60 ºC for 30 min, then

quenched with saturated NaHCO3 solution (50 mL) and warmed to room temperature. The layers

were separated and the organic phase was washed with saturated NaHCO3 solution (2 × 50 mL),


chromatography on SiO2 (5:1 → 3:1, petrol/EtOAc gradient elution) to give rhodonoid D (4.4) as a

white solid (33 mg, 5%). Further elution gave ketone 4.35 as a white solid (144 mg, 21%). Further

elution gave rhodonoid C (4.3) as a white solid (218 mg, 32%).

Data for rhodonoid C (4.3):


IR (neat): 3259, 2927, 2869, 1628, 1593, 1456, 1421, 1380, 1327, 1266, 1144, 1126 cm-1.

MP: 196 – 198 ºC. 1H NMR (500 MHz, CDCl3): δ 6.30 (s, 1H), 6.26 (s, 1H), 5.64 (br s, 1H), 5.05 (d, J = 4.2 Hz, 1H),

3.85 (s, 1H), 2.23 (s, 3H), 1.87 – 1.81 (m, 2H), 1.73 – 1.69 (m, 2H), 1.64 (s, 3H), 1.49 (dd, J = 14.6,

5.7 Hz, 1H), 1.29 (s, 3H), 1.26 (s, 3H). 13C NMR (125 MHz, CDCl3): δ 155.6, 152.6, 140.2, 109.8, 108.5, 107.8, 82.0, 77.5, 68.9, 51.1,

42.6, 30.1, 27.9, 27.6, 27.0, 23.0, 21.5.


Data for rhodonoid D (4.4):


IR (neat): 3435, 2970, 2921, 2853, 1636, 1586, 1460, 1370, 1326, 1299, 1278, 1190 cm-1.

MP: 162 – 165 ºC. 1H NMR (500 MHz, CDCl3): δ 6.92 (s, 1H), 6.35 (s, 1H), 6.29 (s, 1H), 4.92 (d, J = 9.1 Hz, 1H),

2.82 (t, J = 8.5 Hz, 1H), 2.56 (ddd, J = 9.9, 8.0, 3.8 Hz, 1H), 2.23 (s, 3H), 1.85 – 1.78 (m, 1H), 1.75

– 1.72 (m, 1H), 1.67 – 1.61 (m, 1H), 1.48 (s, 3H), 1.44 – 1.40 (m, 1H), 1.33 (s, 3H), 1.29 (s, 3H). 13C NMR (125 MHz, CDCl3): δ 156.1, 151.7, 139.9, 110.0, 109.2, 107.3, 83.2, 82.9, 68.8, 51.6,

51.5, 34.9, 28.0, 27.5, 24.13, 24.07, 21.5.


32% 21%5%

O

OHO

1:1 d.r.

H

O

OHO

O

OH OH

H

H


+ +O

OOH

4.18 4.35

285


Data for 4.35:


IR (neat): 3387, 2970, 2924, 2854, 1698, 1623, 1579, 1510, 1450, 1368, 1329, 1280 cm-1.

MP: 116 – 121 ºC. 1H NMR (500 MHz, CDCl3): δ 6.63 (d, J = 10.0 Hz, 1H), 6.22 (s, 1H), 6.12 (s, 1H), 5.41 (d, J =

10.0 Hz, 1H), 4.71 (br s, 1H), 2.68 – 2.54 (m, 3H), 2.20 (s, 3H), 1.99 – 1.94 (m, 2H), 1.36 (s, 3H),

1.07 (d, J = 7.1 Hz, 6H). 13C NMR (125 MHz, CDCl3): δ 214.8, 153.9, 151.2, 139.7, 126.4, 117.5, 109.7, 108.5, 106.4,

77.9, 41.0, 35.3, 34.9, 26.6, 21.5, 18.33, 18.27.


286

To a solution of 4.18 (d.r. = 1:1) (66 mg, 0.24 mmol) in CHCl3 (10 mL) at room temperature was

added p-TsOH⋅H2O (4.6 mg, 0.024 mmol). The reaction was stirred at room temperature for 30

min, then quenched with saturated NaHCO3 solution (10 mL). The organic layer was separated and

the aqueous layer was extracted with CH2Cl2 (2 × 10 mL). The combined organic extracts were

washed with brine (10 mL), dried over MgSO4, filtered and concentrated in vacuo. The residue was


give rhodonoid D (4.4) as a white solid (1.5 mg, 2%), further elution gave ketone 4.35 as a

colourless oil (3 mg, 5%), further elution gave rhodonoid C (4.3) as a white solid (14 mg, 21%).

Data for 4.3, 4.4 and 4.35 matched that previously obtained.

p-TsOH, CHCl3, rt

21% 5%2%

O

OHO

1:1 d.r.

H

O

OHO

O

OH OH

H

H


+ +O

OOH

4.18 4.35

287

To a solution of 4.18 (d.r. = 1:1) (2.02 g, 7.24 mmol) in CHCl3 (50 mL) at −60 ºC was added SnCl4

(0.42 mL, 3.62 mmol) dropwise. The reaction was stirred at −60 ºC for 30 min, then quenched with

saturated NaHCO3 solution (50 mL), warmed to room temperature. The mixture was filtered

through a pad of Celite, washed thoroughly with CH2Cl2. The layers were separated and the organic

phase was washed with saturated NaHCO3 solution (2 × 50 mL), dried over MgSO4, filtered and

concentrated in vacuo. The residue was purified by flash column chromatography on SiO2 (5:1 →

3:1, petrol/EtOAc gradient elution) to give rhodonoid D (4.4) as a white solid (69 mg, 3%). Further

elution gave ketone 4.35 as a white solid (152 mg, 8%). Further elution gave epoxide 4.18 (d.r. =

3.3:1) as a brown oil (792 mg, 39%). Further elution gave rhodonoid C (4.3) as a white solid (443

mg, 22%). Data for 4.3, 4.4 and 4.35 matched that previously obtained.

NMR data for 4.18a (major diastereomer): 1H NMR (500 MHz, CDCl3): δ 6.63 (d, J = 10.0 Hz, 1H), 6.21 (s, 1H), 6.12 (s, 1H), 5.44 (d, J =

10.0 Hz, 1H), 4.97 (br s, 1H), 2.75 (t, J = 6.2 Hz, 1H), 2.20 (s, 3H), 1.82 (d, J = 8.1 Hz, 1H), 1.74 –

1.64 (m, 3H), 1.38 (s, 3H), 1.28 (s, 3H), 1.23 (s, 3H). 13C NMR (125 MHz, CDCl3): δ 153.9, 151.2, 139.7, 126.4, 117.3, 109.6, 108.4, 106.5, 78.0, 64.6,

58.8, 37.9, 26.6, 24.9, 23.9, 21.5, 18.7.

NMR data for 4.18b (minor diastereomer): 1H NMR (500 MHz, CDCl3): δ 6.63 (d, J = 10.0 Hz, 1H), 6.21 (s, 1H), 6.12 (s, 1H), 5.47 (d, J =

10.0 Hz, 1H), 4.97 (br s, 1H), 2.73 (t, J = 5.9 Hz, 1H), 2.20 (s, 3H), 1.84 (d, J = 8.0 Hz, 1H), 1.74 –

1.64 (m, 3H), 1.38 (s, 3H), 1.29 (s, 3H), 1.24 (s, 3H). 13C NMR (125 MHz, CDCl3): δ 153.8, 151.2, 139.6, 126.7, 117.2, 109.7, 108.4, 106.5, 77.7, 64.4,

58.7, 37.5, 26.1, 24.9, 23.6, 21.5, 18.6.

SnCl4, CHCl3, −60 °C 22% 8%3%

O

OHO

1:1 d.r.

H

O

OHO

O

OH OH

H

H


+ +O

OOH

O

OHO

H

O

OHO

H +

4.18a3.3:1 d.r.

39%

4.18

4.18

4.35

288

To a solution of 4.18a (d.r. = 3.3:1) (99 mg, 0.36 mmol) in CHCl3 (5 mL) at −60 ºC was added

SnCl4 (0.04 mL, 0.36 mmol) dropwise. The reaction was stirred at −60 ºC for 15 min, then

quenched with saturated NaHCO3 solution (5 mL), warmed to room temperature. The aqueous layer

was separated and the organic extract was washed with saturated NaHCO3 solution (2 × 10 mL),

brine (10 mL), dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by

flash column chromatography on SiO2 (4:1 → 2:1, petrol/EtOAc gradient elution) to give ketone

4.35 as a white solid (32 mg, 32%). Further elution gave rhodonoid C (4.3) as a white solid (13 mg,

13%). Data for 4.3 and 4.35 matched that previously obtained.

O

OHO

H

O

OHO

H +

4.18a3.3:1 d.r.


13% 32%

O

OHO

4.3: rhodonoid C

+O

OOH

4.18b 4.35

289

To a solution of 4.18 (97 mg, 0.35 mmol) in H2O (10 mL) was heated at reflux for 16 h. The

reaction was cooled to room temperature, then extracted with Et2O (2 × 10 mL). The combined



give 4.35 as a white solid (3 mg, 3%). Further elution gave rhodonoid C (4.3) as a white solid (4

mg, 4%). Further elution gave 4.38 as a white solid (45 mg, 44%). Data of 4.3 and 4.35 matched


Data for 4.38:


IR (neat): 3342, 2971, 2929, 2865, 1623, 1578, 1510, 1450, 1421, 1366, 1329 cm-1.

MP: 55 ºC. 1H NMR (500 MHz, CDCl3): δ 6.63 (d, J = 10.0 Hz, 2H), 6.31 (br s, 2H), 6.19 (s, 2H), 6.13 (s,

2H), 5.44 (d, J = 9.9 Hz, 1H), 5.42 (d, J = 9.9 Hz, 1H), 3.37 (t, J = 9.6 Hz, 2H), 2.80 (br s, 2H), 2.45

(br s, 2H), 2.17 (s, 6H), 2.01 – 1.90 (m, 2H), 1.80 – 1.64 (m, 4H), 1.50 – 1.39 (m, 2H), 1.35 (s, 3H),

1.34 (s, 3H), 1.19 (s, 3H), 1.17 (s, 3H), 1.14 (s, 3H), 1.13 (s, 3H). 13C NMR (125 MHz, CDCl3): δ 153.6, 153.5, 151.6, 139.6, 139.5, 126.9, 126.5, 117.4, 109.4,

109.3, 108.8, 108.7, 106.9, 106.8, 78.9, 78.6, 78.4, 78.1, 73.51, 73.47, 38.2, 37.9, 26.43, 26.38,

26.36, 26.31, 25.89, 25.87, 23.3, 23.2, 21.5.


H2O, reflux

O

OHO

1:1 d.r.

H

O

OHHO

OH

1:1 d.r.4.384.18 4.3: rhodonoid C

O

OOH

O

OHO

++

44% 4% 3%

4.35

290

To a solution of 4.18 (124 mg, 0.45 mmol) in DMF (5 mL) at room temperature was added p-TsOH

(86 mg, 0.45 mmol). The reaction was stirred at room temperature for 30 min, then diluted with

H2O (10 mL). The mixture was extracted with Et2O (4 × 10 mL). The combined organic extracts

were dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by flash

column chromatography on SiO2 (5:1 → 3:1 → 1:1, petrol/EtOAc gradient elution) to give 4.35 as

a white solid (3 mg, 2%). Further elution gave 4.39 as a colourless oil (40 mg, 28%). Data of 4.35

matched of previously obtained.

Data for 4.39:


IR (neat): 3387, 2976, 2924, 1714, 1624, 1579, 1452, 1378, 1330, 1266 cm-1. 1H NMR (500 MHz, CDCl3): δ 8.18 (s, 1H), 8.18 (s, 1H), 6.64 (d, J = 10.0 Hz, 1H), 6.62 (d, J =

10.0 Hz, 1H), 6.21 (s, 1H), 6.20 (s, 1H), 6.12 (s, 2H), 5.43 (d, J = 10.0 Hz, 1H), 5.30 (d, J = 10.0

Hz, 1H), 4.89 – 4.87 (m, 2H), 2.19 (s, 6H), 1.90 – 1.62 (m, 8H), 1.23 (s, 6H), 1.21 (s, 6H), 1.20 (s,


117.6, 117.4, 109.62, 109.56, 108.55, 108.51, 106.60, 106.57, 80.4, 80.2, 78.0, 77.7, 72.47, 72.46,

37.7, 37.5, 26.54, 26.47, 26.2, 24.9, 24.8, 24.3, 24.0, 21.5.


p-TsOH, DMF, rt

O

OHO

1:1 d.r.

H

O

OHO

OH

1:1 d.r.4.394.18

28%

O

OHO

4.35

+

2%

O H

291

To a solution of 4.18 (40 mg, 0.15 mmol) in EtOH (5 mL) was added 1 M HCl (5 mL) was stirred

at room temperature for 1 d. The mixture was extracted with Et2O (2 × 10 mL). The combined


purified by flash column chromatography on SiO2 (2:1, petrol/EtOAc) to give 4.36 as a colourless

oil (12 mg, 26%). Further elution gave 4.38 as a white solid (4 mg, 9%). Data of 4.38 matched


Data of 4.36:


IR (neat): 3342, 2974, 2922, 1624, 1579, 1511, 1452, 1370, 1330 cm-1. 1H NMR (500 MHz, CDCl3): δ 6.64 (d, J = 10.1 Hz, 1H), 6.63 (d, J = 10.1 Hz, 1H), 6.23 (s, 2H),

6.12 (s, 2H), 6.48 (d, J = 10.0 Hz, 1H), 6.47 (d, J = 10.0 Hz, 1H), 4.97 (br s, 2H), 3.54 – 3.49 (m,

2H), 3.43 – 3.40 (m, 2H), 2.20 (s, 6H), 2.07 – 1.97 (m, 3H), 1.84 – 1.77 (m, 3H), 1.75 – 1.70 (m,

1H), 1.58 (s, 3H), 1.57 (s, 3H), 1.54 (s, 3H), 1.51 (s, 3H), 1.48 – 1.42 (m, 1H), 1.37 (s, 3H), 1.37 (s,

3H). 13C NMR (125 MHz, CDCl3): δ 153.9, 153.8, 151.2, 139.7, 139.6, 127.2, 126.7, 117.3, 117.2,

109.8, 109.7, 108.6, 108.5, 106.8, 106.7, 79.3, 79.2, 78.4, 78.0, 38.4, 37.9, 29.4, 29.2, 27.1, 26.9,

26.6, 26.4, 26.0, 25.9, 21.5, 16.1.

HRMS (ESI): calculated for C17H24ClO3 311.1408 [M+H]+, found 311.1410.

1 M HCl, EtOH, rt

O

OHO

1:1 d.r.

H

O

OHHO

1:1 d.r.4.364.18

Cl

26%

O

OHHO

1:1 d.r.4.38

OH

+

9%

292

To a solution of 4.18 (123 mg, 0.45 mmol) in CH2Cl2 (15 mL) at –78 ˚C was added BF3·OEt2 (0.05

mL, 0.45 mmol). The reaction was stirred at –78 ˚C for 30 min, then quenched with saturated

NaHCO3 solution (15 mL) and warmed to room temperature. The organic layer was separated and

the aqueous layer was extracted with CH2Cl2 (20 mL). The combined organic extracts were washed

with saturated NaHCO3 solution (3 × 20 mL), H2O (40 mL), dried over MgSO4, filtered and


petrol/EtOAc) to give 4.37 as a colourless oil (21 mg, 18%).

Data for 4.37:


IR (neat): 3356, 2974, 2927, 1623, 1579, 1451, 1376, 1330, 1246 cm-1. 1H NMR (500 MHz, CDCl3): δ 6.64 (d, J = 10.0 Hz, 2H), 6.22 (s, 1H), 6.12 (s, 1H), 5.46 (d, J =

10.0 Hz, 2H), 5.27 (br s, 2H), 3.58 (t, J = 11.0 Hz, 2H), 2.19 (s, 6H), 2.02 – 1.96 (m, 2H), 1.83 –

1.77 (m, 2H), 1.89 – 1.64 (m, 2H), 1.45 – 1.39 (m, 2H), 1.36 (s, 6H), 1.34 (s, 3H), 1.33 (s, 3H), 1.29

(s, 3H), 1.28 (s, 3H). 13C NMR (125 MHz, CDCl3): δ 153.8, 151.3, 139.6, 126.6, 117.3, 109.6, 108.5, 106.7, 98.8, 97.5,

78.4, 77.2, 38.2, 26.6, 26.12, 26.08, 23.8, 23.6, 21.5, 21.2, 21.0. 19F NMR (470 MHz, CDCl3): δ –144.69 (hept, J = 22.3 Hz), –144.72 (hept, J = 22.3 Hz).

HRMS (ESI): calculated for C17H22FO3 293.1558 [M-H]-, found 293.1559.

BF3·OEt2, CH2Cl2, −78 °C

O

OHO

1:1 d.r.

H

O

OHHO

1:1 d.r.4.374.18

F

18%

293

To a solution of 4.18 (123 mg, 0.41 mmol) in CH2Cl2 (15 mL) at –78 ˚C was added FeCl3·6H2O

(110 mg, 0.41 mmol). The reaction was stirred at –78 ˚C for 1.5 h, then warmed to room

temperature for 20 min. The reaction was quenched with saturated NaHCO3 solution (15 mL). The

organic layer was separated and the aqueous layer was extracted with CH2Cl2 (20 mL). The

combined organic extracts were washed with saturated NaHCO3 solution (3 × 20 mL), H2O (40


column chromatography on SiO2 (2:1, petrol/EtOAc) to give 4.35 as a white solid (45 mg, 40%).

Further elution gave rhodonoid C (4.3) as a white solid (26 mg, 23%). Further elution gave 4.36 as

a colourless oil (6 mg, 4%). Data of 4.3, 4.35 and 4.36 matched previously obtained.

To a solution of 4.18 (473 mg, 1.72 mmol) in CH2Cl2 (30 mL) at –78 ˚C was added FeCl3 (140 mg,

0.86 mmol). The reaction was stirred at –78 ˚C for 1.5 h. The reaction was quenched with saturated

NaHCO3 solution (30 mL), then warmed to room temperature. The organic layer was separated and

the aqueous layer was extracted with CH2Cl2 (30 mL). The combined organic extracts were washed

with saturated NaHCO3 solution (2 × 20 mL), H2O (40 mL), dried over MgSO4, filtered and


petrol/EtOAc) to give rhodonoid D (4.4) as a white solid (45 mg, 40%). Further elution gave 4.35 as

a white solid (165 mg, 35%). Further elution gave rhodonoid C (4.3) as a white solid (117 mg,

25%). Data of 4.3, 4.4 and 4.35 matched previously obtained.

FeCl3·6H2O, CH2Cl2, –78 °C to rt

O

OHO

1:1 d.r.

H

O

OHHO

1:1 d.r.4.364.18

Cl

4%23% 40%

O

OHO

4.3: rhodonoid C

O

OOH

4.35

+ +

FeCl3, CH2Cl2, –78 °C

25% 35%2%

O

OHO

O

OH OH

H

H


+ +O

OOH

4.35

O

OHO

1:1 d.r.

H

4.18

294

To a solution of 4.9 (1.0 g, 4.2 mmol) in CH2Cl2 (20 mL) was added m-CPBA (77%, 722 mg, 4.20

mmol). The reaction was stirred at room temperature for 30 min, followed by addition of p-TsOH

(80 mg, 0.42 mmol). The reaction was stirred at room temperature for 30 min, then quenched with

saturated NaHCO3 solution (30 mL). The organic layer was separated and the aqueous layer was

extracted with CH2Cl2 (2 × 30 mL). The combined organic extracts were washed with brine (100


column chromatography on SiO2 (5:1 → 3:1, petrol/EtOAc gradient elution) to give ketone 4.35 as

a white solid (41 mg, 4%). Further elution gave rhodonoid D (4.4) as a white solid (25 mg, 2%).

Further elution gave rhodonoid C (4.3) as a white solid (62 mg, 5%). Data of 4.3, 4.4 and 4.35

matched previously obtained.

m-CPBA, CH2Cl2, rt;then p-TsOH

5% 4%2%

O

OHO

O

OH OH

H

H


+ +O

OOH

4.34

OH

O

4.9

295

To a suspension of Mn (149 g, 2.71 mmol) and Cp2TiCl2 (168 mg, 0.68 mmol) in anhydrous THF

(5 mL) at room temperature was stirred until the solution changed from orange to dark green (1.5

h). 4.18 (93 mg, 0.34 mmol) in anhydrous THF (3 mL) was added and stirred for 2 h. The mixture

was filtered through Celite and washed with EtOAc (20 mL). The filtrate was concentrated in

vacuo. The residue was purified by flash column chromatography on SiO2 (3:1 → 2:1,

petrol/EtOAc) to give 4.40 (d.r. = 1:1) as an orange oil (48 mg, 51%).

Data for 4.40:


IR (neat): 3342, 2971, 2929, 1623, 1578, 1510, 1450, 1421, 1366, 1329 cm-1. 1H NMR (500 MHz, CDCl3): δ 6.21 (s, 2H), 6.17 (s, 2H), 5.62 (br s, 2H), 3.51 (br s, 1H), 3.38 (dd,

J = 11.8, 3.7 Hz, 1H), 2.80 – 2.65 (m, 4H), 2.19 (s, 6H), 2.16 (ddd, J = 11.8, 4.1, 2.1 Hz, 1H), 2.08

– 2.03 (m, 2H), 1.99 (dd, J = 14.1, 4.3 Hz, 1H), 1.93 – 1.87 (m, 2H), 1.81 – 1.77 (m, 1H), 1.67 –

1.58 (m, 3H), 1.46 (d, J = 7.7 Hz, 1H), 1.21 (s, 3H), 1.17 (s, 3H), 1.08 (s, 3H), 1.05 (s, 3H), 0.69 (s,

3H), 0.64 (s, 3H). 13C NMR (125 MHz, CDCl3): δ 155.03, 155.00, 153.38, 153.36, 136.8, 136.7, 110.09, 110.05,

107.4, 107.3, 106.5, 106.3, 78.4, 76.4, 74.9, 74.3, 43.5, 39.5, 37.90, 37.86, 37.3, 32.1, 27.3, 27.1,

26.44, 26.40, 26.38, 24.6, 21.8, 21.2, 17.8, 17.4, 14.0.

Mn, Cp2TiCl2, THF, rt

O

OHO

1:1 d.r.

H

4.401:1 d.r.

O

OH

4.18

51%H

OH

296

To a solution of 2-methyl-5-nitrophenol (4.41) (10.0 g, 65.3 mmol) and K2CO3 (13.5 g, 98.0 mmol)

in acetone (100 mL) was added BnBr (8.1 mL, 68.6 mmol). The mixture was heated at reflux or 3

h, then cooled to room temperature and diluted with CH2Cl2 (100 mL). The organic layer was

separated and washed with H2O (2 × 100 mL), brine (100 mL), dried over MgSO4, filtered through

a pad of SiO2 and washed with EtOAc (100 mL). The filtrate was concentrated in vacuo to give 4.42

as a colourless solid (15.9 g). 4.42 was used in next step without further purification. Data of 4.42

matched with literature.2

Data for 4.42:


IR (neat): 1713, 1594, 1511, 1451, 1416, 1355, 1254, 1221 cm-1. 1H NMR (500 MHz, CDCl3): δ 7.78 (d, J = 8.2 Hz, 1H), 7.75 (s, 1H), 7.46 (d, J = 7.0 Hz, 1H),

7.46 (s, 1H), 7.42 (t, J = 7.6 Hz, 2H), 7.37 – 7.35 (m, 1H), 7.29 (d, J = 8.2 Hz, 1H), 5.17 (s, 2H),

2.36 (s, 3H).

NO2

OH

4.41: 2-methyl-5-nitrophenol

BnBr, K2CO3acetone , reflux

NO2

OBn

4.42

297

To a solution of 4.42 (15.9 g, 65.3 mmol) in AcOH (200 mL) was adde Fe (36.5 g, 65.3 mmol). The

mixture was heated at 45 ºC for 14 h, then cooled to room temperature and diluted with EtOAc (200

mL). The mixture was filtered through Celite and washed with EtOAc (200 mL). The filtrate was


petrol/EtOAc) to give 4.43 as a red oil (9.14 g, 66% over 2 step). Data for 4.43 matched from

literauture.2

Data for 4.43:


IR (neat): 3448, 3366, 3072, 2924, 1709, 1616, 1588, 1512, 1454, 1436, 1361 cm-1. 1H NMR (500 MHz, CDCl3): δ 7.44 (d, J = 7.6 Hz, 1H), 7.44 (s, 1H), 7.39 (t, J = 7.6 Hz, 2H),

7.32 (t, J = 7.3 Hz, 1H), 6.93 (d, J = 7.8 Hz, 1H), 6.29 (d, J = 2.1 Hz, 1H), 6.24 (dd, J = 7.9, 2.0 Hz,

1H), 5.03 (s, 2H), 3.58 (br s, 2H), 2.18 (s, 3H). 13C NMR (125 MHz, CDCl3): δ 157.6, 145.4, 137.6, 131., 128.5, 127.7, 127.0, 117.0, 107.2,

100.0, 69.7, 15.5.

NO2

OBn

Fe, AcOH, 45 °C

NH2

OBn

4.434.42

66% over 2 steps

298

To a solution of 4.43 (9.14 g, 42.9 mmol), K2CO3 (5.90 g, 42.9 mmol), Cu(OAc)2 (15.6 g, 85.7

mmol), PhCO2H (5.93 g, 42.9 mmol) and PhB(OH)2 (13.1 g, 107 mmol) in toluene (200 mL) was

heated at reflux for 12 h. The reaction was cooled to room temperature and filtered through Celite,

then washed with EtOAc (200 mL). The filtrate was concentrated in vacuo. The residue was

purified by flash column chromatography on SiO2 (10:1 → 2:1, petrol/EtOAc) to give 4.44 as a

yellow solid (8.57 g, 69%). Data of 4.44 matched from literature.2

Data for 4.44:


IR (neat): 3400, 3036, 2925, 2857, 1712, 1633, 1609, 1498, 1458, 1361, 1344, 1307 cm-1. 1H NMR (500 MHz, CDCl3): δ 7.42 (d, J = 7.2 Hz, 1H), 7.42 (s, 1H), 7.39 (t, J = 7.5 Hz, 2H),

7.32 (t, J = 7.1 Hz, 1H), 7.22 (dd, J = 8.4, 7.5 Hz, 2H), 7.05 (d, J = 8.0 Hz, 1H), 6.95 (d, J = 7.7 Hz,

1H), 6.88 (t, J = 7.3 Hz, 1H), 6.67 (d, J = 2.0 Hz, 1H), 6.59 (dd, J = 7.9, 2.1 Hz, 1H), 5.61 (br s,

1H), 5.04 (s, 2H), 2.24 (s, 3H). 13C NMR (125 MHz, CDCl3): δ 157.3, 143.7, 141.7, 137.4, 131.1, 129.3, 128.5, 127.7, 127.0,

120.3, 120.0, 117.0, 110.8, 103.1, 69.7, 15.8.

NH2

OBn K2CO3, Cu(OAc)2benzoic acid, PhB(OH)2

PhMe, reflux

HN

OBn

4.444.43

69%

299

To a solution of 4.44 (6.39 g, 22.0 mmol), K2CO3 (304 mg, 2.20 mmol) and Pd(OAc)2 (450 mg,

2.20 mmol) in pivalic acid (30 mL) was heated at 85 ºC under air for 20 h. The reaction was cooled

to room temperature, followed by addition of saturated K2CO3 solution (50 mL). The mixture was

filtered through SiO2 and washed with EtOAc (200 mL). The filtrated was washed with saturated

K2CO3 (100 mL), brine (100 mL), dried over MgSO4, filtered and concentrated in vacuo. The

residue was purified by flash column chromatography on SiO2 (10:1, petrol/EtOAc) to give 4.45 as

a white solid (4.0 g, 63%). Data of 4.45 matched from literature.2

Data for 4.45:


IR (neat): 3381, 3032, 2924, 1710, 1615, 1560, 1510, 1496, 1454, 1411, 1362 cm-1. 1H NMR (500 MHz, CDCl3): δ 7.95 (d, J = 7.7 Hz, 1H), 7.86 (br s, 1H), 7.82 (s, 1H), 7.50 (d, J =

7.4 Hz, 2H), 7.41 (t, J = 7.5 Hz, 2H), 7.37 – 7.30 (m, 3H), 7.21 – 7.17 (m, 1H), 6.91 (s, 1H), 5.17


121.6, 119.7, 119.4, 119.3, 116.5, 110.2, 94.0, 70.2, 16.9.

HN

OBn

4.454.44

NH

OBn

K2CO3, Pd(OAc)2pivalic acid, 85 °C

63%

300

To a solution of 4.45 (4.39 g, 15.3 mmol) in MeOH/CH2Cl2 (3:1, 100 mL) at room temperature was

added Pd/C (5%, 800 mg). The mixture was stirred under H2 for 1.5 d, then filtered through SiO2

and washed with EtOAc (150 mL). The filtrated was concentrated in vacuo. The residue was


give 4.46 as a yellowish solid (2.65 g, 88%). Data of 4.46 matched from literature.2

Data of 4.46:


IR (neat): 3639, 3532, 3403, 1699, 1637, 1613, 1459, 1437, 1416, 1309, 1248 cm-1. 1H NMR (500 MHz, CDCl3): δ 9.92 (br s, 1H), 8.23 (br s, 1H), 7.92 (d, J = 7.8 Hz, 1H), 7.77 (s,

1H), 7.37 (d, J = 8.0 Hz, 1H), 7.22 (t, J = 7.6 Hz, 1H), 7.07 (t, J = 7.5 Hz, 1H), 6.96 (s, 1H), 2.34 (s,

3H).

4.46

NH

OH

4.45

NH

OBn

H2, Pd/C, CH2Cl2MeOH, rt

88%

301

To a solution of 4.46 (500 mg, 2.54 mmol) and citral (4.8) (443 mg, 5.08 mmol) in PhMe (10 mL)

at –78 ˚C was added Ti(Oi-Pr)4 (3.00 mL, 10.1 mmol). The solution was stirred at –78 ˚C for 15

min, then warmed to room temperature and stirred for 16 h. The reaction was quenched with

saturated hydroxylamine hydrochloride solution (10 mL). The mixture was filtered through Celite,

then washed with EtOAc (20 mL). The filtrate was washed sequentially with 1 M HCl solution (30

mL), brine (30 mL), dried over MgSO4, filtered and concentrated in vacuo. The residue was re-

dissolved in MeOH (10 mL), followed by addition of NaBH4 (182 mg, 5.08 mmol) to reduce

unreacted citral (4.8) that is difficult to separate from 4.5. The reaction was stirred at room

temperature for 30 min, then quenched with 1 M HCl solution (20 mL). The solution was extracted

with Et2O (2 × 30 mL). The combined organic extracts were washed with brine (30 mL), dried over


chromatography on SiO2 (4:1, petrol/EtOAc) to give mahanimbine (4.5) as a yellow oil (662 mg,

74%). Data for 4.5 matched that previously reported in the literature.2

Data for 4.5:


IR (neat): 3423, 1968, 2920, 2853, 1645, 1610, 1491, 1458, 1440, 1307 cm-1. 1H NMR (500 MHz, CDCl3): δ 7.89 (d, J = 7.7 Hz, 1H), 7.78 (br s, 1H), 7.64 (s, 1H), 7.31 – 7.27

(m, 2H), 7.16 (td, J = 6.5, 1.2 Hz, 1H), 6.54 (d, J = 9.8 Hz, 1H), 5.59 (d, J = 9.8 Hz, 1H), 5.11 (t, J

= 7.1 Hz, 1H), 2.32 (s, 3H), 2.20 – 2.11 (m, 2H), 1.75 (dd, J = 8.6, 8.1 Hz, 2H), 1.65 (s, 3H), 1.57


119.4, 119.2, 118.3, 117.5, 116.6, 110.4, 104.2, 78.1, 40.8, 25.8, 25.6, 22.7, 17.6, 16.1.

HRMS (ESI): calculated for C23H26NO 332.2009 [M+H]+, found 332.2004.

O

NH

4.5: mahanimbine

4.8: citralTi(Oi-Pr)4, PhMe, −78 °C to rt;

then NaBH4, MeOH, rt

74%

O

H

NH

OH

4.46

302

To a solution of mahanimbine (4.5) (623 mg, 1.88 mmol) in CH2Cl2 (10 ml) at room temperature

was added m-CPBA (77%, 509 mg, 2.07 mmol). The reaction was stirred at room temperature for

10 min, then quenched with saturated Na2S2O3 solution (10 mL). The organic layer was separated,

then washed sequentially with saturated NaHCO3 solution (10 mL), brine (10 mL), dried over


chromatography on SiO2 (4:1, petrol/EtOAc) to give 4.22 (d.r. = 1:1) as a grey solid (400 mg,

61%).

Data for 4.22:


IR (neat): 3333, 2972, 2925, 2853, 1646, 1612, 1459, 1441, 1405, 1323, 1214 cm-1. 1H NMR (500 MHz, CDCl3): δ 8.01 (s, 2H), 7.90 (d, J = 7.6 Hz, 2H), 7.65 (s, 1H), 7.64 (s, 1H),

7.34 (d, J = 8.1 Hz, 2H), 7.31 (t, J = 7.6 Hz, 2H), 7.16 (t, J = 7.4 Hz, 2H), 6.64 (d, J = 9.7 Hz, 2H),

5.61 (d, J = 9.8 Hz, 1H), 5.57 (d, J = 9.8 Hz, 1H), 2.78 (t, J = 6.2 Hz, 1H), 2.74 (t, J = 6.1 Hz, 1H),

2.31 (s, 3H), 2.30 (s, 3H), 1.92 – 1.85 (m, 4H), 1.79 – 1.71 (m, 4H), 1.44 (s, 3H), 1.43 (s, 3H), 1.28

(s, 3H), 1.27 (s, 3H), 1.23 (s, 6H). 13C NMR (125 MHz, CDCl3): δ 149.6, 149.5, 139.5, 134.9, 128.1, 127.6, 124.25, 124.22, 123.8,

121.31, 121.30, 119.43, 119.41, 119.27, 119.26, 118.2, 118.14, 118.13, 117.9, 116.8, 116.7, 110.39,

110.37, 104.1, 103.9, 78.0, 77.7, 64.5, 64.3, 58.7, 58.6, 37.7, 37.1, 26.3, 25.6, 24.84, 24.83, 24.0,

23.7, 18.63, 18.57, 16.04, 16.03.

HRMS (ESI): calculated for C23H26NO2 348.1958 [M+H]+, found 348.1959.

m-CPBACH2Cl2, rt

61%O

NH

4.5: mahanimbine

1:1 d.r.

O

NHO

H

4.22

303

To a solution of 4.22 (d.r. = 1:1) (200 mg, 0.58 mmol) in CH2Cl2 (5 mL) at room temperature was

added p-TsOH⋅H2O (11 mg, 0.058 mmol). The reaction was stirred at room temperature for 1 h,

then quenched with H2O (5 mL). The organic layer was separated and the aqueous phase was

extracted with CH2Cl2 (5 mL). The combined organic extracts were washed with brine (10 mL),


chromatography on SiO2 (5:1, petrol/EtOAc) to give 76 mg of a 7.4:1 mixture of murrayakonine D

(4.6) and ketone 4.47. This mixture was triturated with MeOH to give murrayakonine D (4.6) as a

white solid (65 mg, 33%). Trace quantities of ketone 4.47 were obtained for characterisation

purposes after repeated purification of the filtrate.

Data for murrayakonine D (4.6):


IR (neat): 3280, 2964, 2931, 2853, 1633, 1613, 1460, 1313, 1215 cm-1.

MP: 244 ºC 1H NMR (500 MHz, CDCl3): δ 8.28 (br s, 1H), 7.93 (d, J = 7.7 Hz, 1H), 7.75 (s, 1H), 7.36 (d, J =

8.07 Hz, 1H), 7.29 (t, J = 7.3 Hz, 1H), 7.17 (t, J = 7.4 Hz, 1H), 5.29 (d, J = 4.2 Hz, 1H), 3.90 (d, J =

4.2 Hz, 1H), 2.32 (s, 3H), 1.97 (d, J = 3.9 Hz, 1H), 1.95 – 1.90 (m, 1H), 1.81 – 1.75 (m, 1H), 1.74

(s, 3H), 1.72 – 1.67 (m, 1H), 1.53 (dd, J = 14.5, 7.1 Hz, 1H), 1.38 (s, 3H), 1.32 (s, 3H). 13C NMR (125 MHz, CDCl3): δ 149.0, 139.6, 138.4, 123.97, 123.95, 121.3, 119.3, 119.2, 118.5,

115.9, 110.6, 105.0, 82.1, 77.8, 70.4, 51.0, 42.7, 30.4, 28.1, 27.6, 27.1, 23.0, 16.3.


Data for 4.47:


IR (neat): 3369, 2971, 2926, 1703, 1646, 1611, 1459, 1443, 1405, 1310, 1265 cm-1. 1H NMR (500 MHz, CDCl3): δ 7.92 (br s, 1H), 7.91 (s, 1H), 7.67 (s, 1H), 7.38 (d, J = 8.0 Hz, 1H),

7.31 (t, J = 7.6 Hz, 1H), 7.18 (t, J = 7.8 Hz, 1H), 6.68 (d, J = 9.8 Hz, 1H), 5.60 (d, J = 9.8 Hz, 1H),

2.73 (ddd, J = 17.4, 9.2, 6.3 Hz, 1H), 2.65 (ddd, J = 16.9, 8.6, 5.8 Hz, 1H), 2.59 (hept, J = 6.9 Hz,

1H), 2.32 (s, 3H), 2.08 – 2.04 (m, 2H), 1.43 (s, 3H), 1.07 (d, J = 6.9 Hz, 6H).

p-TsOH, CH2Cl2, rt

1:1 d.r.

O

NHO

H


O

ONH

33% O

NHO

+

4.22 4.47

304

13C NMR (125 MHz, CDCl3): δ 214.6, 149.6, 139.5, 134.8, 127.8, 124.3, 123.8, 121.4, 119.5,

119.3, 118.24, 118.21, 116.8, 110.4, 103.9, 77.9, 41.1, 35.3, 34.7, 26.2, 18.33, 18.27, 16.1.


305

To a solution of 4.22 (d.r. = 1:1) (200 mg, 0.58 mmol) in CH2Cl2 (15 mL) at –78 ˚C was added

SnCl4 (0.06 mL, 0.58 mmol). The reaction was stirred at –78 ˚C for 15 min. The reaction was

quenched with saturated NaHCO3 solution (10 mL). The organic layer was separated and the

aqueous phase was extracted with CH2Cl2 (3 × 5 mL). The combined organic extracts were washed

with brine (2 × 10 mL), dried over MgSO4, filtered and concentrated in vacuo. The residue was

triturated with MeOH to give murrayakonine D (4.6) as a white solid (42 mg, 21%). Data of 4.6

matched previously obtained.

SnCl4, CH2Cl2, −78 °C

1:1 d.r.

O

NHO

H


O

ONH

21%4.22

306

4.5.3. NMR spectra

OH

O

4.91H NMR500 MHz

CDCl3

OH

O

4.913C NMR125 MHz

CDCl3

307

O

OHO

1:1 d.r.

H

4.18

1H NMR500 MHz

CDCl3

O

OHO

1:1 d.r.

H

4.18

13C NMR125 MHz

CDCl3

308

4.3: rhodonoid C

O

OOH

1H NMR500 MHz

CDCl3

4.3: rhodonoid C

O

OOH

13C NMR125 MHz

CDCl3

309

4.3: rhodonoid C

O

OOH

COSY500 MHz

CDCl3

4.3: rhodonoid C

O

OOH

HSQC500 MHz

CDCl3

310

4.3: rhodonoid C

O

OOH

HMBC500 MHz

CDCl3

311

O

OH OH

H

H

4.4: rhodonoid D1H NMR500 MHz

CDCl3

O

OH OH

H

H

4.4: rhodonoid D13C NMR125 MHz

CDCl3

312

O

OH OH

H

H

4.4: rhodonoid D

COSY500 MHz

CDCl3

O

OH OH

H

H

4.4: rhodonoid D

HSQC500 MHz

CDCl3

313

O

OH OH

H

H

4.4: rhodonoid D

HMBC500 MHz

CDCl3

O

OH OH

H

H

4.4: rhodonoid D

NOESY500 MHz

CDCl3

314

O

OHO

4.351H NMR500 MHz

CDCl3

O

OHO

4.3513C NMR125 MHz

CDCl3

315

O

OHO

4.35COSY

500 MHzCDCl3

O

OHO

4.35HSQC

500 MHzCDCl3

316

O

OHO

4.35HMBC

500 MHzCDCl3

317

O

OHO

H

O

OHO

H +

4.18a3.3:1 d.r.1H NMR500 MHz

CDCl3

4.18b

O

OHO

H

O

OHO

H +

4.18a3.3:1 d.r.13C NMR125 MHz

CDCl3

4.18b

318

O

OHHO

OH

1:1 d.r.4.38

1H NMR500 MHz

CDCl3

O

OHHO

OH

1:1 d.r.4.38

13C NMR125 MHz

CDCl3

319

O

OHHO

OH

1:1 d.r.4.38

COSY500 MHz

CDCl3

O

OHHO

OH

1:1 d.r.4.38

HSQC500 MHz

CDCl3

320

O

OHHO

OH

1:1 d.r.4.38

HMBC500 MHz

CDCl3

321

O

OHO

OH

1:1 d.r.4.39

O H

1H NMR500 MHz

CDCl3

O

OHO

OH

1:1 d.r.4.39

O H

13C NMR125 MHz

CDCl3

322

O

OHO

OH

1:1 d.r.4.39

O H

COSY500 MHz

CDCl3

O

OHO

OH

1:1 d.r.4.39

O H

HSQC500 MHz

CDCl3

323

O

OHO

OH

1:1 d.r.4.39

O H

HMBC500 MHz

CDCl3

324

O

OHHO

1:1 d.r.4.36

Cl

1H NMR500 MHz

CDCl3

O

OHHO

1:1 d.r.4.36

Cl

13C NMR125 MHz

CDCl3

325

O

OHHO

1:1 d.r.4.36

Cl

COSY NMR500 MHz

CDCl3

O

OHHO

1:1 d.r.4.36

Cl

HSQC NMR500 MHz

CDCl3

326

O

OHHO

1:1 d.r.4.36

Cl

HMBC NMR500 MHz

CDCl3

327

O

OHHO

F

1:1 d.r.4.37

1H NMR500 MHz

CDCl3

O

OHHO

F

1:1 d.r.4.37

13C NMR125 MHz

CDCl3

328

O

OHHO

F

1:1 d.r.4.37

COSY500 MHz

CDCl3

O

OHHO

OH

F

1:1 d.r.4.37

HSQC500 MHz

CDCl3

329

O

OHHO

F

1:1 d.r.4.37

HMBC500 MHz

CDCl3

O

OHHO

F

1:1 d.r.4.37

19F NMR470 MHz

CDCl3

330

4.401:1 d.r.

O

OH

HOH

1H NMR500 MHz

CDCl3

4.401:1 d.r.

O

OH

HOH

13C NMR125 MHz

CDCl3

331

4.401:1 d.r.

O

OH

HOH

COSY500 MHz

CDCl3

4.401:1 d.r.

O

OH

HOH

HSQC500 MHz

CDCl3

332

4.401:1 d.r.

O

OH

HOH

HMBC500 MHz

CDCl3

4.401:1 d.r.

O

OH

HOH

NOESY500 MHz

CDCl3

333

4.40a

O

OH MeOH

Me

H

4.40b

O

OH MeOH

Me

H

334

4.40b

O

OHOH

H H

335

NO2

OBn

4.421H NMR500 MHz

CDCl3

336

NH2

OBn

4.431H NMR500 MHz

CDCl3

NH2

OBn

4.4313C NMR125 MHz

CDCl3

337

HN

OBn

4.441H NMR500 MHz

CDCl3

HN

OBn

4.4413C NMR125 MHz

CDCl3

338

4.45

NH

OBn

1H NMR500 MHz

CDCl3

4.45

NH

OBn

13C NMR125 MHz

CDCl3

339

4.46

NH

OH

1H NMR500 MHz

d6-acetone

340

O

NH

4.5: mahanimbine

1H NMR500 MHz

CDCl3

O

NH

4.5: mahanimbine

13C NMR125 MHz

CDCl3

341

1:1 d.r.1H NMR500 MHz

CDCl3

O

NHO

H

4.22

1:1 d.r.13C NMR125 MHz

CDCl3

O

NHO

H

4.22

342


O

ONH

1H NMR500 MHz

CDCl3


O

ONH

13C NMR125 MHz

CDCl3

343


O

ONH

COSY500 MHz

CDCl3


O

ONH

HSQC500 MHz

CDCl3

344


O

ONH

HMBC500 MHz

CDCl3


O

ONH

NOESY500 MHz

CDCl3

345

O

NHO

4.471H NMR500 MHz

CDCl3

O

NHO

4.4713C NMR125 MHz

CDCl3

346

4.5.4. Tables of 1H and 13C NMR data

Comparison of the 1H and 13C NMR spectra of natural3 and synthetic rhodonoid C (4.3).

Assignment

Natural sample 1H NMR, CDCl3

400 MHz

Synthetic sample 1H NMR, CDCl3

500 MHz

Natural sample 13C NMR, CDCl3

150 MHz

Synthetic sample 13C NMR, CDCl3

125 MHz

1 155.7 155.6

2 6.30 (br s) 6.30 (s) 108.6 108.5

3 140.4 140.2

4 6.26 (br s) 6.26 (s) 110.0 109.8

5 152.8 152.6

6 108.0 107.8

7 5.04 (d, J = 4.3 Hz) 5.05 (d, J = 4.2 Hz) 69.1 68.9

8 1.83 (d, J = 4.3 Hz) 1.87 – 1.81 (m) 51.3 51.1

9 77.7 77.5

10 1.82 (dd, J = 13.7, 6.0 Hz)

1.49 (dd, J = 13.7, 6.0 Hz)

1.87 – 1.81 (m)

1.49 (dd, J = 14.6, 5.7

Hz)

27.7 27.6

11 1.71 (m) 1.73 – 1.69 (m) 27.1 27.0

12 3.85 (br s) 3.85 (s) 82.2 82.0

13 42.8 42.6

14 1.29 (s) 1.29 (s) 28.1 27.9

15 1.26 (s) 1.26 (s) 23.1 23.0

16 1.63 (s) 1.64 (s) 30.3 30.1

17 2.23 (s) 2.23 (s) 21.6 21.5

1-OH 5.64 (br s)

4.3: rhodonoid C

O

OOH1

3

13

1211

1098

7

6

5

2

4

14

17

15

16

347

Comparison of the 1H and 13C NMR spectra of natural3 and synthetic rhodonoid D (4.4).

Assignment


400 MHz


500 MHz


150 MHz


125 MHz

1 156.2 156.1

2 6.35 (br s) 6.35 (s) 109.3 109.2

3 140.0 139.9

4 6.30 (br s) 6.30 (s) 110.1 110.0

5 151.9 151.7

6 107.5 107.3

7 4.92 (d, J = 9.0 Hz) 4.92 (d, J = 9.1 Hz) 68.9 68.8

8 2.82 (t, J = 9.0 Hz) 2.82 (t, J = 8.5 Hz) 51.7 51.6

9 83.0 82.9

10 1.80 (m)

1.42 (m)

1.85 – 1.78 (m)

1.44 – 1.40 (m) 35.0 34.9

11 1.74 (m)

1.64 (m)

1.75 – 1.72 (m)

1.67 – 1.60 (m) 24.3 24.12

12 2.56 (m) 2.56 (ddd, J = 9.9, 8.0,

3.8 Hz) 51.6 51.6

13 83.3 83.2

14 1.33 (s) 1.33 (s) 28.2 28.0

15 1.29 (s) 1.29 (s) 24.2 24.08

16 1.48 (s) 1.48 (s) 27.6 27.5

17 2.24 (s) 2.24 (s) 21.6 21.5

1-OH 6.94 (br s) 6.92 (br s)

O

OH OH

H

H

4.4: rhodonoid D

1

3

13

1211

109

876

5

2

4

14

17

15

16

348

Comparison of the 1H and 13C NMR spectra of natural4 and synthetic murrayakonine D (4.6).

Assignment


400 MHz*


500 MHz


100 MHz


125 MHz

1 138.4 138.4

2 115.9 115.9

3 7.67 (s) 7.75 (s) 121.2 121.3

4 118.5 118.5

5 149.0 149.0

6 105.0 105.0

7 5.22 (d, J = 4.2 Hz) 5.29 (d, J = 4.2 Hz) 70.4 70.4

8 1.91 (d, J = 4.2 Hz) 1.97 (d, J = 3.9 Hz) 51.0 51.0

9 77.8 77.8

10 1.88 – 1.80 (m)

1.48 – 1.42 (m)

1.95 – 1.90 (m)

1.53 (dd, J = 14.5, 7.1

Hz)

27.6 27.6

11 1.55 (s)** 1.81 – 1.74 (m)

1.72 – 1.67 (m) 27.1 27.1

12 3.82 (d, J = 3.9 Hz) 3.90 (d, J = 4.2 Hz) 82.2 82.1

13 42.7 42.7

14 1.31 (s) 1.38 (s) 28.1 28.1

15 1.25 (s) 1.32 (s) 23.1 23.0

16 1.67 (s) 1.74 (s) 30.4 30.4

17 2.25 (s) 2.34 (s) 16.3 16.3

18 124.0 123.97

19 7.85 (d, J = 7.0 Hz) 7.93 (d, J = 7.7 Hz) 119.3 119.3

20 7.09 (t, J = 7.4 Hz) 7.17 (t, J = 7.4 Hz) 119.2 119.2

21 7.22 (d, J = 8.0 Hz) 7.29 (t, J = 7.3 Hz) 124.0 123.95

22 7.31 (d, J = 8.0 Hz) 7.36 (d, J = 8.0 Hz) 110.6 110.6


O

ONH

1

3

131211

10

98

7

6

5

2

4

14

17

15

16

1819

2320

21 22

349

23 139.7 139.6

1-NH 8.21 (s) 8.28 (s)

* 1H spectrum is incorrectly referenced (our chemical shift values for synthetic 4.6 are 0.07-0.09

ppm higher than for natural 4.6).

** Misassigned water peak.

350


A single crystal was mounted in paratone-N oil on a plastic loop and X-ray diffraction data were


was corrected for absorption using a multi-scan method, and the structure solved by direct methods

using SHELXS-975 and refined by full-matrix least squares on F2 by SHELXL-2014,6 interfaced

through the program X-Seed.7 All non-hydrogen atoms were refined anisotropically and hydrogen

atoms were included as invariants at geometrically estimated positions. X-ray experimental data is

given below. CIF data have been deposited with the Cambridge Crystallographic Data Centre,

CCDC reference number CCDC 1538308 (murrayakonine D).

X-Ray experimental data for murrayakonine D (4.6): C23H25NO2, Fw 347.44, monoclinic, I2/a, a

20.969(3), b 10.2106(14), c 17.083(3) Å, β 99.423(16)º, Vol. 3608.3(9) Å3, Z = 8, density (calc.)

1.279 Mg/m3, abs. coefficient 0.081 mm-1, F(000) 1488, crystal size 0.34×0.18×0.11 mm3, θ range

3.36 to 28.47°, reflns collected 12832, Obs. reflns 1910 [R(int) = 0.1658], GoF2 0.974, R1 [I>2σ(I)]

0.0927, wR2 (all data) 0.3054, Largest diff. peak and hole 0.339 & -0.459 e.Å-3.

351

Figure S1. A representation of the structure of murrayakonine D (4.6) with ellipsoids shown at the

50% probability level (carbon – grey; hydrogen – white; nitrogen – blue; oxygen – red).

352

4.5.6. References

1. Luo, G. Y.; Wu, H.; Tang, Y.; Li, H.; Yeom, H. S.; Yang, K.; Hsung, R. P. Synthesis, 2015, 47, 2713.

2. Hesse, R.; Gruner, K. K.; Kataeva, O.; Schmidt, A. W.; Knolker, H. J. Chemistry, 2013, 19, 14098.

3. Liao, H. B.; Huang, G. H.; Yu, M. H.; Lei, C.; Hou, A. J. J. Org. Chem., 2017, 82, 1632. 4. Nalli, Y.; Khajuria, V.; Gupta, S.; Arora, P.; Riyaz-Ul-Hassan, S.; Ahmed, Z.; Ali, A. Org.

Biomol. Chem., 2016, 14, 3322. 5. Sheldrick, G. M. Acta Crystallogr A, 1990, 46, 467. 6. Sheldrick, G. M. Acta Crystallographica a-Foundation and Advances, 2015, 71, 3. 7. Barbour, L. J. J. Supramol. Chem., 2003, 1, 189.

353

Chapter 5

Biomimetic Total Synthesis of Yezo’otogirin C

5.1. Introduction

5.1.1. Reductive radical cyclization

Historically, most radical cyclizations in organic chemistry were conducted under reductive

conditions. For example, starting from an alkyl halide (e.g. 5.1), reductive radical initiation

using Bu3Sn· could generate the radical 5.2. 5.2 could undergo 5-exo-trig or 6-endo-trig

cyclization to give 5.3 and 5.4 respectively (Scheme 5.1). Although both reactions are not

forbidden under Baldwin’s rule,1 5-exo-trig cyclization is generally favoured from the kinetic

perspective.2

Scheme 5.1: An illustration of reductive radical cyclization.

The transition state of 5-exo-trig cyclization was proposed by Beckwith2,3,4 and Houk,5 their

calculations and experiments concluded that the chair-like transition state 5.2a is more stable

than the boat-like transition state 5.2b (Figure 5.1).

Figure 5.1: Transition states of 5-exo-trig cyclization.

5.1.2. Oxidative radical cyclization

In contrast to a reductive radical cyclization, oxidative radical cyclization does not require a

halide but often a dicarbonyl group.6,7 The mechanism is shown in Scheme 5.2, the

dicarbonyl 5.7 first binds to a metal ion (e.g. Mn3+), then the enolate 5.8 oxidizes to a radical

intermediate 5.9. The radical is stabilized by resonance effects on both carbonyl groups

(Scheme 5.2). Radical 5.9 then undergoes 5-exo-trig cyclization to give 5.10. Oxidation of

BrBu3Sn


6-endo-trig

5-exo-trig



5.65.35.5

5.45.25.1

chair-like transition state

boat-like transition state

5.2a 5.2b

354

radical 5.10 to the carbocation 5.11, followed by deprotonation to afford 5.12 and thus

terminate the radical cyclization.

Scheme 5.2: Mechanism of oxidative radical cyclization.7

An example of the oxidative radical cyclization is the biomimetic total synthesis of

garcibracteatone (5.18) by the George group (Scheme 5.3).7 The radical cyclization cascade

started from the oxidation of the Δ2,3-enol of weddellianone A (5.13) by Mn(OAc)3 which

gave radical 5.14, then subsequently underwent 7-endo-trig cyclization to the lavandulyl

alkene to give the tertiary radical 5.15. 5-exo-trig cyclization of 5.15 onto the Δ7,8-enol gave

5.16, which then underwent a 5-exo-trig cyclization onto the Δ17,18-alkene to give the tertiary

radical 5.17. 5.17 could either undergo an intramolecular aromatic radical substitution, or the

radical was oxidized to a carbocation which subsequently underwent a Friedel-Crafts reaction

to give gracibracteatone (5.18).8 This biomimetic synthesis of garcibracteatone showcases the

predisposed reactivity of weddellianone A (5.13), where 4 rings, 4 C-C bonds, and 4

stereocenters were formed in 1 step.

Scheme 5.3: Biomimetic total synthesis of garcibracteatone (5.18) by the George group.8

O O

R

O O

R

Mn3+ O O

RMn3+

single electronoxidation

5-exo-trig

O O

R

5.8 5.9 5.9

5.11 5.10 5.9

O O

R

O O

Re.g. Mn3+, Cu2+

deprotonation

5.12

O O

R


O O

R

5.7

O

OH

HO

Ph O

OHO O

OH

H

5.18:(±)-garcibracteatone14%

O

O

HO

Ph O

H

O

O

HO

Ph O

H

OPh

O

OH

HOOHO O

OH

H

5.13: weddellianone A

Mn(OAc)3, Cu(OAc)2AcOH, rt, 3 h

single electron oxidation

7-endo-trig

5-exo-trig

5-exo-trig

Intramolecular aromaticradical substitution

orsingle electron

oxidation followed byintramolecularFriedel-Crafts

5.17 5.16

5.14 5.15

2

37

8

18

355

5.1.3. Isolation of yezo’otogirins A-C

Figure 5.2: Yezo’otogirins A-C.9

Yezo’otogirins A-C were isolated from a flowering plant Hypericum yezoense, alongside an

unnamed natural product 5.22 which was proposed to be the biosynthetic precursor of

yezo’otogirin A (5.19) (we later named 5.22 as pre-yezo’otogirin A).9 5.22 was previously

co-isolated with hyperforin (5.23) from Hypericum perforatum (St. John’s Wort).10

Hyperforin (5.23) is the active ingredient in St. John’s Wort which is used as an anti-

depressant.11 We propose hyperforin (5.23), pre-yezo’otogirin A (5.22) and yezo’otogirin A

(5.19) are all biosynthetically linked (Figure 5.2).

O

H

O

H

5.21: yezo'otogirin C

O

H

O

H

5.19: yezo'otogirin A

O

H

O

H

5.20: yezo'otogirin B

O

OH

5.22: pre-yezo'otogirin A

O

O

5.23: hyperforin

O

OH

356

5.1.4. Proposed biosynthesis of yezo’otogirn A (5.19)

Scheme 5.4: Proposed biosynthesis of yezo’otogirin A (5.19).12

The detailed proposed biosynthesis is shown in Scheme 5.4, which begins from the

fragmentation of hyperforin (5.23) to give pre-yezo’otogirin A (5.22). We then propose pre-

yezo’otogirin A (5.22) can be converted into yezo’otogirin A (5.19) via an oxidative radical

cyclization. The cascade reaction could start from a single electron oxidation of the enolate of

pre-yezo’otogirin A (5.22) at C-2 to give radical 5.24. 5-exo-trig cyclization of 5.24 onto the

Δ14,15-alkene could give radical 5.25. For the 5-exo-trig cyclization to occur in radical 5.24, it

must adopt a boat-like transition state to avoid the steric clash between the Δ14,15-alkene and

the isopropyl group. After the cyclization, radical 5.25 could be oxidized to carbocation 5.26,

followed by ring closure by the carbonyl group at C-1 to give yezo’otogirin A (5.19) (Scheme

5.4).

O

OH


O

O

5.23: hyperforin

O

OHfragmentation

OO

Beckwith-Houk boat-like

transition state



ring closuresingle electron

oxidation

5-exo-trig

O

O

HH

O

O

HH

O

O

HH

5.24

5.255.26

1415

1

2

357

5.1.5. Previous biomimetic total synthesis of yezo’otogirin A (5.19)

Scheme 5.5: Biomimetic total synthesis of yezo’otogirin A.12

During my research studies as an honour student, we achieved a biomimetic total synthesis of

yezo’otogirin A (5.19). We started with 5.28, which was prepared from 3-ethoxy-2-

cyclohexenone (5.27) in 2 steps.13 Prenylation of 5.28 gave 5.29 where the prenyl group at C-

6 was in the unnatural relative stereochemistry. Conjugate addition of 5.29 with (4-

methylpent-3-enyl)magnesium bromide followed by aldol reaction with isobutyraldehyde

gave β-hydroxyketone 5.30. Oxidation of 5.30 gave 6-epi-pre-yezo’otogirin A (5.31). With

numerous conditions trialled, 6-epi-pre-yezo’otogirin A (5.31) failed to give yezo’otogirin A

(5.19) by oxidative radical cyclization. Epimerisation of 6-epi-pre-yezo’otogirin A (5.31) to

pre-yezo’otogirin A (5.22) was also unsuccessful.

We then attempted the epimerisation of β-hydroxyketone 5.30. We first protected the β-

hydroxyketone 5.30 using TMSCl, followed by epimerisation by LDA and subsequent

deprotection by TBAF to give 5.32.14 Oxidation of 5.32 using Dess-Martin periodinane gave

pre-yezo’otogirin A (5.22). Pre-yezo’otogirin A (5.22) was then converted to yezo’otogirin A

O

80%

prenyl bromideLDA, THF,–78 °C to rt

O

O

OHH

CuBr, Me2S, THF, 0 °C; then LDA; i-PrCHO

MgBr

5.28 5.29

5.30

O

OH

5.31: 6-epi-pre-yezo'otogirin A

6

O

OHH

5.32

19% over4 steps

Dess-Martin peridinaneNaHCO3, CH2Cl2, rt

36%over 2 steps

O

OH


6 Dess-Martin peridinaneNaHCO3, CH2Cl2, rt

67%


O

O

HH

Mn(OAc)3Cu(OTf)2

DMF, 150 °C29%

oxidative radical cyclization

cascade

6

6

O

OEt

5.27: 3-ethoxy-2-cyclohexenone

1. LDA, prenyl bromideTHF, –78 °C to rt2. MeLi, THF, –78 °C to rt

82% over 2 steps

1. TMSCl, imidazole, DMF, 0 °C to rt2. LDA, THF, –78 °C to –40 °C3. TBAF, THF, 0 °C

358

(5.19) using Mn(OAc)3 and Cu(OTf)2 in DMF at 150 °C, presumably proceeding via the

oxidative radical cyclization cascade (Scheme 5.5).

5.1.6. Previous bioinspired total synthesis of yezo’otogirin C (5.21) by Lee

Scheme 5.6: Bioinspired total synthesis of yezo’otogirin X (5.21) by Lee.15

While our manuscript on the total synthesis of yezo’otogirin A was in preparation, a

bioinspired total synthesis of yezo’otogirin C (5.21) was reported by Lee.15 Starting from

5.28, methylation of 5.28 gave 5.33. Conjugate addition of 5.33 with (4-methylpent-3-

enyl)magnesium bromide followed by trapping of the enolate with CNCO2Me gave 5.34.

5.34 was then oxidized by Mn(OAc)2 with catalytic co-oxidant Mn(OAc)3 under O2 to give

endoperoide 5.35 in 55% yield. Note this reaction was conducted at relatively mild conditions

(room temperature) compared to our system (150 °C) and the yield of 5.35 was quite high.

This suggests the Lee’s synthetic conditions are potentially more biomimetic than ours.

Reduction and ring closure of 5.35 by thiourea gave 5.36, which contains the skeleton of

yezo’otogirin C (5.19). Functional group conversion of the ester 5.36 to the isobutyryl group

in 4 steps then gave yezo’otogirin C (5.19) (Scheme 5.6).15

O

90%

LDA, MeI, THF,–78 °C to rt

OO

O

OH

CuBr, Me2S, THF, reflux; then CNCO2Me

MgBr

5.28 5.33 5.34

OO

OO

HO

Mn(OAc)2, Mn(OAc)3EtOH, air, rt

5.35

O

H

O

H


O

H

O O

H

5.36

55%

thiourea, MeOHreflux

92%60%over 4 steps

359

5.1.7. Aims of this project

Figure 5.3: Aims of this study.

Our aims were to synthesize 6-epi-pre-yezo’otogirin C (5.37) and pre-yezo’otogirin C (5.38)

(a proposed “undiscovered” natural product), and to convert 5.37 and 5.38 into yezo’otogirin

C (5.21) via the oxidative radical cyclization cascade12 or the stepwise cyclization developed

by Lee (Figure 5.3).15

O

OH

5.37: 6-epi-pre-yezo'otogirin C

6

O

OH

6

5.38: pre-yezo'otogirin C

O

H

O

H


oxidativeradical cyclization

cascade

orstepwise

cyclizationby Lee

undiscovered natural product?

360


5.2.1. Synthesis of 6-epi-pre-yezo’otogirin C (5.37)

Scheme 5.7: Synthesis of ketone 5.28.13

The synthesis started from prenylation of 3-ethoxy-2-cyclohexenone (5.27) which gave 5.39

in quantitative yield, followed by nucleophilic attack of the ketone by MeLi and elimination

to give 5.28 in 82% yield (Scheme 5.7).13 We discovered that it was crucial to use MeLi⋅LiBr

as the reagent for this reaction, whereas using MeLi⋅LiCl would decrease the yield to 50%.

Scheme 5.8: Synthesis of β-hydroxyketone 5.42.

Methylation of 5.28 gave 5.33 as an inseparable mixture of two diastereoisomers in a ratio of

7:1, unfortunately, favouring the isomer with the unnatural relative stereochemistry at C-6

which was also observed by Lee.15 We attempted to epimerise 5.33 at C-6 with various bases

but no reaction was observed. Despite having two diastereoisomers in 5.33, we always

obtained only a single diastereoisomer in the next reaction. Therefore, 5.33 would always be

used as a mixture in the following step.

Conjugate addition of 5.33 with (4-methylpent-3-enyl)magnesium bromide followed by an

aldol reaction of the enolate intermediate 5.40 with isobutyraldehyde (5.41) (Scheme 5.8)

O

OEt

O

OEtLDA, prenyl bromide, THF–78 °C to rt

99%

OMeLi·LiBr, THF–78 °C to rt

82%

5.27: 3-ethoxy-2-cyclohexenone 5.39 5.28

O

71%

LDA, MeI, THF,–78 °C to rt

O

O

OHH


MgBr

29%

5.28 5.33

5.421 stereoisomer

d.r. 7:1

6

O

O

H

5.41: isobutyraldehyde

5.40

361

afforded β-hydroxyketone 5.42. We discovered the addition of LDA before isobutyraldehyde

(5.41) would improve the yield of 5.42 to 29%. 5.42 was assigned as an anti-aldol product

because the enolate intermediate 5.40 could only adopt the Z-configuration due to the

restriction of the ring.

Scheme 5.9: Oxidation of 5.42 to 6-epi-yezo’otogirin C (5.37).

The oxidation of 5.42 with Dess-Martin periodinane was a clean reaction and gave 6-epi-

yezo’otogirin C (5.37) in excellent yield (Scheme 5.9). Unfortunately, epimerisation of 5.37

at C-6 to pre-yezo’otogirin C (5.38) was unsuccessful. We were aware the proton H-2 is most

likely to be deprotonated by base, and we attempted to use excess of LDA or n-BuLi to

achieve a secondary deprotonation at H-6 but this led to the decomposition of 5.37.16

5.2.2. Synthesis of yezo’otogirin C (5.21) from 6-epi-pre-yezo’otogirin C (5.37)

Scheme 5.10: Synthesis of yezo’otogirin C (5.21).

Despite the previous failure in the radical cyclization of 6-epi-pre-yezo’otogirin A (5.31) to

yezo’otogirin A (5.19), we were optimistic that the cyclization might occur with 6-epi-pre-

yezo’otogirin C (5.37). As the methyl group at C-6 is less bulky than a prenyl group, it is

more likely for the radical cyclization to overcome the interference from a methyl group in

the transition state 5.44 (Scheme 5.11). Indeed, when 6-epi-pre-yezo’otogirin C (5.37) was

heated with Mn(OAc)3 and Cu(OTf)2 in DMF, we observed a 5% yield of yezo’otogirin C

(5.21) (Scheme 5.10). The NMR of yezo’otogirin C matched the isolation data.9 We also

observed 5% yield of 5.43, presumably formed from the oxidative radical cyclization to give

intermediate 5.45. However, the cyclization of 5.46 did not take place from the enol at C-1 to

O

OH

Dess-Martin periodinane,NaHCO3, CH2Cl2, rt

O

OHH

92%

5.42

O

OH


base

epimersation


662

O

H

O

H

O

OH Mn(OAc)3·2H2O, Cu(OTf)2,

DMF, 150 °C

5% 5%

5.21: yezo'otogirin C 5.43

+


O6

14

1 O7

2

362

give yezo’otogirin C (5.21), but cyclized at C-6 to form a C-C bond (Scheme 5.11). The

structure of 5.43 could be confirmed by the loss of resonance signals at δ 4.00 ppm (H-2) and

the alkene at δ 5.00 ppm (H-14) in the 1H NMR. Furthermore, in the 13C NMR spectrum of

5.43, the carbonyl signals at δ 212.7 ppm and δ 211.5 ppm (C-1 and C-7) suggests that there

is no reaction on the ketones.

Scheme 5.11: Proposed mechanism for formation of 5.43.

5.2.3. Synthesis of yezo’otogirin C (5.21) from pre-yezo’otogirin C (5.38)

Scheme 5.12: Biomimetic total synthesis of yezo’otogirin C (5.21).

O

O


O

O

HH

5.465.43

6

O

O

OO6

Beckwith-Houk boat-like

transition state

5.44


O

O

HH

H

5.45

5-exo-trig

H


Mn(OAc)3Cu(OTf)2

DMF, 150 °C

O

OHH TMSCl, imidazole, DMF, rt

O

OTMSH

51%

LDA, THF, –78 °C to rt

O

OTMSH

79%

TBAF, THF, rt

O

OHH

71%


O

OH

94%O

H

O

H

Mn(OAc)3·2H2O, Cu(OTf)2, DMF, 150 °C

66%

5.42 5.47 5.48

5.495.21: yezo'otogirin C 5.38: pre-yezo'otogirin C

363

After the synthesis of yezo’otogirin C (5.21) from 6-epi-pre-yezo’otogirin C (5.37), our

attention moved to the synthesis of pre-yezo’otogirin C (5.38). We followed the same

epimerisation strategy that gave pre-yezo’otogirin A (5.22). We first protected the β-

hydroxyketone 5.42 using TMSCl and imidazole to give 5.47. Epimerisation of 5.47 with

LDA gave 5.48. However, 5.47 and 5.48 were completely identical on TLC and NMR

analysis. We could not determine the results of epimerisation until the deprotection of 5.48

which gave 5.49, where 5.42 and 5.49 differed in NMR (Figure 5.4) and TLC analysis. We

eventually discovered a complete epimerisation of 5.47 when the reaction was quenched at

room temperature.

Figure 5.4: 1H NMR spectra of 5.42 and 5.49.

Oxidation of 5.49 gave an excellent yield of pre-yezo’otogirin C (5.38), the proposed

biosynthetic precursor of 5.21. The 1H NMR spectra of pre-yezo’otogirin C (5.38) and 6-epi-

pre-yezo’otogirin C (5.37) are rather different, particularly at H-2, where the chemical shift is

δ 3.85 ppm in pre-yezo’otogirin C (5.38) whereas at δ 4.00 ppm in 6-epi-pre-yezo’otogirin C

(5.37) (Figure 5.5). Heating pre-yezo’otogirin C (5.38) with Mn(OAc)3 and Cu(OTf)2 in DMF

under reflux gave yezo’otogirin C (5.21) in 66% yield, which we presumed formed via the

oxidative radical cyclization cascade (Scheme 5.12).

O

OHH

5.49

62 7

8

O

OHH

5.42

62 7

8

364

Figure 5.5: 1H NMR spectra of a) pre-yezo’otogirin C (5.38) and b) 6-epi-pre-

yezo’otogirin C (5.37).

Scheme 5.13: Alternative attempts for radical cyclization.

Alternatively, we investigated the radical cyclization approach reported by Lee,15,17 using

Mn(OAc)2 and co-oxidant Mn(OAc)3, but we observed no reaction with various

combinations of temperature and solvent. We also considered a photoredox radical

cyclization using Ru catalyst18 but it led to the decomposition of pre-yezo’otogirin C (5.38)

(Scheme 5.13).

O

OH


Mn(OAc)2, Mn(OAc)3EtOH, air

5.50

O

H

O

H


[Ru(bpy)3]2+

hν OO

O

HO

O

OH

5.38

62

O

OH

5.37

62

365

5.2.4. Improved total synthesis of yezo’otogirin C (5.21) reported by Lee.

Scheme 5.14: Improved synthesis of yezo’otogirin C reported by Lee.17

After the completion of synthesis of yezo’otogirin C (5.21), Lee reported an improved

synthesis of yezo’otogirin C (5.21).17 Epimerisation and radical cyclization of 6-epi-pre-

yezo’otogirin C (5.37) was achieved in one pot by i-Pr2NH and Mn(OAc)3, the reaction gave

5.21 in 52% yield which is comparable to the yield of our synthesis from pre-yezo’otogirin C

(5.38). However, Lee and coworkers were not able to isolate 5.38.

O

H

O

H

O

OH Mn(OAc)3·2H2O, i-Pr2NH

EtOH, 90 °C

5.21: yezo'otogirin C5.37

52%

366

5.3. Summary

After the previous biomimetic synthesis of yezo’otogirin A, we have completed a total

synthesis of yezo’otogirin C using a similar strategy. We believe the transformation from pre-

yezo’otogirin C to yezo’otogirin C via an oxidative radical cyclization cascade is biomimetic,

in which a C=C bond, a C-C bond, a C-O bond, 2-rings and 2 stereocenters are formed in 1

step. We have also managed to convert 6-epi-pre-yezo’otogirin C to yezo’otogirin C,

although the yield of this transformation was 5%, the overall synthesis was protecting group

free with good step economy. We have sent our synthetic pre-yezo’otogirin C sample to the

isolation chemists, which may help to investigate whether this proposed biosynthetic

precursor could be found in the plant extracts.

Figure 5.6: Summary of the total synthesis of yezo’otogirin C.

O

OHH

5.42

3 stepsepimersation

6O

OHH

5.49

6

O

OH


6O

OH

6


O

H

O

H


oxidative radicalcyclisation

O

OEt

5.27: 3-ethoxy-2-cyclohexenone

oxidation oxidation

4 steps

367

5.4. References

1. Baldwin, J. E. J. Chem. Soc. Chem. Comm., 1976, 734. 2. Beckwith, A. L. J. Tetrahedron, 1981, 37, 3073. 3. Beckwith, A. L. J.; Schiesser, C. H. Tetrahedron Lett., 1985, 26, 373. 4. Beckwith, A. L. J.; Zimmerman, J. J. Org. Chem., 1991, 56, 5791. 5. Spellmeyer, D. C.; Houk, K. N. J. Org. Chem., 1987, 52, 959. 6. Julia, M. Acc. Chem. Res., 1971, 4, 386. 7. Snider, B. B. Chem. Rev. (Washington, D. C.), 1996, 96, 339. 8. Pepper, H. P.; Lam, H. C.; Bloch, W. M.; George, J. H. Org. Lett., 2012, 14, 5162. 9. Tanaka, N.; Kakuguchi, Y.; Ishiyama, H.; Kubota, T.; Kobayashi, J. i. Tetrahedron

Lett., 2009, 50, 4747. 10. Shan, M. D.; Hu, L. H.; Chen, Z. L. J. Nat. Prod., 2001, 64, 127. 11. Vollmer, J. J.; Rosenson, J. J. Chem. Educ., 2004, 81, 1450. 12. Lam, H. C.; Kuan, K. K.; George, J. H. Org. Biomol. Chem., 2014, 12, 2519. 13. Kuramochi, A.; Usuda, H.; Yamatsugu, K.; Kanai, M.; Shibasaki, M. J. Am. Chem.

Soc., 2005, 127, 14200. 14. Shimizu, Y.; Shi, S.-L.; Usuda, H.; Kanai, M.; Shibasaki, M. Angew. Chem., Int. Ed.,

2010, 49, 1103. 15. He, S. Z.; Yang, W.; Zhu, L. Z.; Du, G. Y.; Lee, C. S. Org. Lett., 2014, 16, 496. 16. Norris, M. D.; Perkins, M. V.; Sorensen, E. J. Org. Lett., 2015, 17, 668. 17. Yang, W.; Cao, J.; Zhang, M.; Lan, R.; Zhu, L.; Du, G.; He, S.; Lee, C. S. J. Org.

Chem., 2015, 80, 836. 18. Prier, C. K.; Rankic, D. A.; MacMillan, D. W. C. Chem. Rev., 2013, 113, 5322.

368

5.5. Experimental


All chemicals used were purchased from commercial suppliers and used as received. All reactions were

performed under an inert atmosphere of N2. All organic extracts were dried over anhydrous magnesium

sulfate. Thin layer chromatography was performed using aluminium sheets coated with silica gel F254.

Visualization was aided by viewing under a UV lamp and staining with ceric ammonium molybdate or

KMnO4 stain followed by heating. All Rf values were measured to the nearest 0.05. Flash column

chromatography was performed using 40-63 micron grade silica gel. Melting points were recorded on a

digital melting point apparatus and are uncorrected. Infrared spectra were recorded using an FT-IR

spectrometer as the neat compounds. High field NMR spectra were recorded using a 600 MHz or 500

MHz spectrometer (1H at 600/500 MHz, 13C at 150/125 MHz). Solvent used for spectra were CDCl3

unless otherwise specified. 1H chemical shifts are reported in ppm on the δ-scale relative to TMS (δ 0.0)

or CDCl3 (δ 7.26), and 13C NMR are reported in ppm relative to CDCl3 (δ 77.00). Multiplicities are

reported as (br) broad, (s) singlet, (d) doublet, (t) triplet, (q) quartet, (quin) quintet, (sext) sextet, (hept)

heptet and (m) multiplet. All J-values were rounded to the nearest 0.1 Hz. ESI high resolution mass

spectra were recorded on a ESI-TOF mass spectrometer.

369


To a solution of 3-ethoxy-2-cyclohexenoe (5.27) (1.00 g, 7.13 mmol) in anhydrous THF (3 mL) at –78

°C was added LDA (2 M in THF, 4.28 mL, 8.56 mmol) dropwise and stirred for 30 min. Prenyl

bromide (0.90 mL, 7.84 mmol) was added at –78 °C and stirred for 1 h before warming the reaction to

room temperature and stirred for 2 h. The mixture was quenched with saturated NH4Cl solution (10

mL). The organic layer was separated and aqueous layer was extracted with Et2O (2 × 10 mL). The

combined organic extracts were washed with saturated NH4Cl solution (30 mL) and brine (30 mL),


chromatography on SiO2 (10:1, petrol/EtOAc) to give 5.39 as a yellowish oil (1.49 g, 99%). Data of

5.39 matched from literature.1

Data for 5.39:


IR (neat): 2930, 1655, 1607, 1452, 1379, 1189 cm-1. 1H NMR (600 MHz, CDCl3): δ 5.33 (s, 1H), 5.13 – 5.10 (m, 1H), 3.92 – 3.87 (m, 2H), 2.56 – 2.52 (m,

1H), 2.42 – 2.40 (m, 2H), 2.22 – 2.18 (m, 2H), 2.13 – 2.07 (m, 1H), 2.03 (dd, J = 13.3, 4.9 Hz, 1H),

1.71 (s, 3H), 1.62 (s, 3H), 1.36 (t, J = 7.1 Hz, 3H). 13C NMR (CDCl3, 150 MHz): δ 201.3, 176.9, 133.3, 122.0, 102.4, 64.2, 45.6, 28.2, 28.1, 25.9, 25.8,

17.8, 14.2.

O

OEt

O

OEtLDA, prenyl bromide, THF–78 °C to rt

99%

5.27: 3-ethoxy-2-cyclohexenone 5.39

370

To a solution of 5.39 (1.49 g, 7.15 mmol) in anhydrous THF (10 mL) at –78 °C was added MeLi·LiBr

(1.5 M in Et2O, 7.1 mL, 10.7 mmol) dropwise and stirred for 2 h. The reaction mixture was warmed to

room temperature and stirred for 2 h, then acidified by 1 M HCl (10 mL). The organic layer was

separated and aqueous layer was extracted with Et2O (2 × 20 mL). The combined organic layer was

washed with saturated NaHCO3 solution (30 mL) and brine (30 mL), dried over MgSO4, filtered and


petrol/EtOAc) to give 5.28 as a colourless oil (1.05g, 82%).1

Data for 5.28:


IR (neat): 2917, 1669, 1625, 1439, 1378 cm-1 1H NMR (CDCl3, 600 MHz): δ 5.85 (s, 1H), 5.11 (ddd, J = 6.5, 4.6, 3.2 Hz, 1H), 2.44 (ddd, J = 17.2,

10.6, 5.2 Hz, 1H), 2.32 − 2.26 (m, 3H), 2.19 – 2.15 (m, 1H), 2.04 − 2.00 (m, 1H), 1.98 (s, 3H), 1.90 −

1.85 (m, 1H), 1.73 (s, 3H), 1.63 (s, 3H). 13C NMR (CDCl3, 150 MHz): δ 199.6, 165.6, 133.9, 126.9, 121.8, 40.0, 34.0, 29.8, 26.5, 25.8, 23.0,

17.9.

O

OEt OMeLi·LiBr, THF–78 °C to rt

82%

5.39 5.28

371

To a solution of 5.28 (5.00 g, 28.0 mmol) in anhydrous THF (20 mL) at –78 °C was added LDA (2.0 M

in THF, 16.9 mL, 33.7 mmol) and stirred for 30 min. MeI (1.92 mL, 30.8 mmol) was added at –78 °C

and stirred for 30 min. The reaction mixture was warmed to room temperature over 30 min and stirred

for 4 h. The reaction was quenched with saturated NH4Cl solution (20 mL). The organic layer was

separated and the aqueous layer was extracted with Et2O (2 × 20mL). The combined organic extracts

were washed with saturated NH4Cl solution (40 mL) and brine (40 mL), dried over MgSO4, filtered and

concentrated in vacuo. The residue was purified by flash column chromatography on SiO2 (10:1 → 4:1,

petrol/EtOAc gradient elution) to give a 7:1 mixture of 5.33 as a yellow oil (3.84 g, 71%). Data of 5.33

matched with literature.2

Data for 5.33:


IR (neat): 2966, 2914, 2971, 1670, 1444, 1377 cm-1

Data for major diastereoisomer: 1H NMR (600 MHz, CDCl3): δ 5.80 (s, 1H), 5.17 – 5.14 (m, 1H), 2.49 – 2.43 (m, 1H), 2.23 – 2.18 (m,

4H), 1.96 (d, J = 1.2 Hz, 3H), 1.95 – 1.94 (m, 1H), 1.74 (s, 3H), 1.63 (s, 3H), 1.11 (d, J = 6.8 Hz, 3H). 13C NMR (150 MHz, CDCl3): δ 201.9, 164.6, 133.8, 126.2, 122.3, 40.1, 36.1, 34.8, 29.7, 25.8, 22.9,

17.8, 15.4.

Data for minor diastereoisomer: 1H NMR (600 MHz, CDCl3): δ 5.89 (s, 1H), 5.05 – 5.03 (m, 1H), 2.49 – 2.43 (m, 1H), 2.23 – 2.18 (m,

4H), 1.97 (d, J = 2.8 Hz, 3H), 1.95 – 1.94 (m, 1H), 1.72 (s, 3H), 1.62 (s, 3H), 1.11 (d, J = 6.6 Hz, 3H). 13C NMR (150 MHz, CDCl3): δ 202.0, 163.6, 134.0, 127.8, 120.8, 41.2, 40.6, 36.8, 30.7, 25.9, 22.0,

18.0, 14.9.

HRMS (ESI): calculated for C13H20O 193.1592 [M+H]+, found 193.1588.

O

71%

LDA, MeI, THF−78 °C to rt

O

5.28 5.33d.r. 7:1

372

To a solution of Mg (316 mg, 13.4 mmol) in anhydrous THF (5 mL) was added 5-bromo-2-methyl-2-

pentene (0.70 mL, 5.20 mmol) at room temperature and the resultant mixture was stirred for 30 min.

The mixture was added to a suspension of CuBr (750 mg, 5.20 mmol), Me2S (0.40 mL, 5.20 mmol)

and 5.33 (500 mg, 2.60 mmol) in anhydrous THF (5 mL) at 0 °C and stirred for 2 h. LDA (2.0 M in

THF, 0.26 mL, 0.52 mmol) was added and stirred at 0 °C for 15 min. Isobutyraldehyde (0.34 mL, 3.70

mmol) was then added and stirred at 0 °C for 45 min. The mixture was quenched with saturated NH4Cl

solution (10 mL). The organic layer was separated and the aqueous layer was extracted with Et2O (2 ×

20 mL). The combined organic extracts were washed with saturated NaHCO3 solution (30 mL), brine

(30 mL), dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by flash

chromatography on SiO2 (100:1 → 30:1, petrol/EtOAc gradient elution) to give 5.42 (265 mg, 29%) as

a colourless oil. Data of 5.42 matched from literature.2

Data for 5.42:


IR (neat): 3520, 2966, 2928, 2869, 1693, 1455, 1377, 1265 cm-1 1H NMR (600 MHz, CDCl3): δ 5.07 (m, 2H), 3.70 (d, J = 3.7 Hz, 1H), 3.34 (dd, J = 9.0, 11.2 Hz, 1H),

2.88 (s, 1H), 2.47 (hept, J = 7.2 Hz, 1H), 2.13 – 2.16 (m, 1H), 1.95 – 2.06 (m, 2H), 1.74 – 1.83 (m, 4H),

1.72 (s, 3H), 1.69 (s, 3H), 1.62 (s, 3H), 1.60 (s, 3H), 1.55 – 1.58 (m, 3H), 1.23 (d, J = 7.3 Hz, 3H), 1.01

(d, J = 6.6 Hz, 3H), 0.97 (s, 3H), 0.85 (d, J = 6.7 Hz, 3H). 13C NMR (150 MHz, CDCl3): δ 214.6, 132.4, 131.5, 124.1, 123.7, 75.8, 60.1, 58.7, 41.5, 41.1, 40.4,

39.8, 35.1, 34.0, 27.7, 25.8, 25.7, 21.7, 20.2, 18.1, 18.0, 17.6, 14.8, 1.0, 0.9.


O

O

OHH


MgBr

29%

5.33 5.42d.r. 7:1

373

To a solution of hydroxyketone 5.42 (260 mg, 0.75 mmol) and NaHCO3 (81 mg, 0.97 mmol) in CH2Cl2

(5 mL) was added Dess-Martin periodinane (411 mg, 0.97 mmol) at room temperature. The mixture

was stirred for 30 min, then quenched with saturated NaHCO3 solution (5 mL). The organic layer was

separated and the aqueous layer was extracted with CH2Cl2 (2 × 10 mL). The combined organic

extracts were washed with saturated NaHCO3 solution (2 × 10 mL), brine (10 mL), dried over MgSO4,

filtered and concentrated in vacuo. The residue was purified by flash chromatography on SiO2 (10:1,

petrol/EtOAc) to give 6-epi-pre-yezo’otogirin C 5.37 (235 mg, 92%) as a colourless oil. Data for 5.37

matched from literature.2

Data for 6-epi-pre-yezo’otogirin C (5.37):


IR (neat): 2968, 2928, 1726, 1701, 1457, 1382 cm-1 1H NMR (600 MHz, CDCl3): δ 5.07 (t, J = 7.6 Hz, 1H), 4.99 (t, J = 6.7 Hz, 1H), 4.00 (s, 1H), 2.62 –

2.67 (m, 1H), 2.51 (hept, J = 6.9 Hz, 1H), 2.10 – 2.13 (m, 1H), 2.01 – 2.07 (m, 1H), 1.80 – 1.90 (m,

3H), 1.70 – 1.78 (overlapped m, 2H), 1.72 (s, 3H), 1.67 (s, 3H), 1.62 (s, 3H), 1.59 (s, 3H), 1.42 – 1.45

(m, 2H), 1.24 (d, J = 7.1 Hz, 3H), 1.07 (d, J = 6.9 Hz, 3H), 1.05 (d, J = 6.8 Hz, 3H), 1.05 (s, 3H). 13C NMR (150 MHz, CDCl3): δ 212.9, 211.3, 132.9, 131.8, 123.6, 123.2, 64.2, 45.3, 43.3, 43.1, 38.0,

37.9, 33.9, 26.9, 25.9, 25.7, 22.0, 18.1, 18.0, 18.0, 17.9, 17.7, 17.6.


O

OH


O

OHH

92%

5.42 5.37

374

To a solution of 5.37 (117 mg, 0.34 mmol) in degassed DMF (3 mL) at room temperature was added

Mn(OAc)3·2H2O (358 mg, 1.36 mmol) and Cu(OTf)2 (246 mg, 0.68 mmol). The mixture was heated at

150 °C for 1 h. The reaction mixture was cooled to room temperature and quenched with water. The

aqueous layer was extracted with Et2O (2 × 10 mL). The combined organic extracts were washed with

H2O (2 × 20 mL) and brine (20 mL), dried over MgSO4, filtered and concentrated in vacuo. The

residue was purified by flash column chromatography on SiO2 (100:1→20:1, petrol/EtOAc gradient

elution) to give yezo’otogirin C 5.21 (6 mg, 5%) as a colourless oil and rearranged product 5.43 (6 mg,

5%) as a colourless oil.

Data for yezo’otogirin C 5.21:


IR (neat): 2971, 2937, 2877, 1694, 1449, 1382, 1259 cm-1. 1H NMR (600 MHz, CDCl3): δ 5.13 – 5.10 (m, 1H), 3.19 (dd, J = 10.2, 9.0 Hz, 1H), 2.96 (hept, J =

6.6 Hz, 1H), 1.96 (dd, J =14.8, 11.6 Hz, 1H), 1.94 (dd, J = 11.1, 1.0 Hz, 1H), 1.86 (dd, J = 3.3, 15.5

Hz, 1H), 1.84 – 1.80 (m, 1H), 1.76 – 1.74 (m, 1H), 1.73 (s, 3H), 1.71 (s, 3H), 1.61 (s, 3H), 1.56 – 1.52

(m, 2H), 1.39 – 1.32 (m, 1H), 1.23 (tt, J = 11.4, 3.0 Hz, 1H), 1.18 (s, 3H), 1.15 (s, 3H), 1.02 (d, J = 3.4

Hz, 3H), 1.01 (d, J = 3.7 Hz, 3H), 0.75 (s, 3H). 13C NMR (150 MHz, CDCl3): δ 217.4, 149.2, 132.4, 124.2, 107.5, 83.4, 73.6, 54.9, 48.5, 47.0, 41.5,

37.9, 32.7, 29.6, 29.5, 25.9, 25.40, 25.37, 21.5, 19.6, 18.3, 17.9, 16.3.

HRMS (ESI): calculated for C23H35O2 343.2637 [M−H]−, found 343.2641.

Data for rearranged compound 5.43:

Rf = 0.60 (Petrol/EtOAc, 10:1)

IR (neat): 2971, 2937, 2877, 1695, 1449, 1381, 1259, 1104 cm-1 1H NMR (600 MHz, CDCl3): δ 5.07 – 5.05 (m, 1H), 3.52 (d, J = 10.0 Hz, 1H), 3.47 (hept, J = 6.6 Hz,

1H), 2.22 – 2.16 (m,1H), 2.02 – 2.00 (m, 3H), 1.84 – 1.82 (m, 3H), 1.68 (s, 3H), 1.57 (s, 3H), 1.44 (dd,

J = 7.7, 9.3 Hz, 2H), 1.26 (s, 3H), 1.21 (s, 3H), 1.12 (d, J = 6.5 Hz, 3H), 1.07 (d, J = 6.7 Hz, 3H), 0.94

(s, 6H).

O

H

O

H

O

OH Mn(OAc)3·2H2O, Cu(OTf)2

DMF, 150 °C

5% 5%

5.21: yezo'otogirin C 5.43

+

5.37

O

O

375

13C NMR (150 MHz, CDCl3): δ 211.7, 211.5, 132.2, 123.7, 73.5, 58.6, 49.4, 42.7, 42.3, 39.5, 35.2,

30.0, 28.9, 27.2, 25.6, 23.6, 23.5, 23.4, 21.0, 19.1, 17.6.


376

To a solution of 5.42 (530 mg, 1.52 mmol) in DMF (20 mL) at room temperature was added TMSCl

(0.58 mL, 4.56 mmol) and stirred for 2 hr. The reaction was quenched with saturated NaHCO3 solution

(15 mL). The organic layer was separated and the aqueous layer was extracted with Et2O (2 × 20 mL).

The combined organic extracts were washed with H2O (2 × 30 mL), saturated NaHCO3 solution (30

mL), brine (30 mL), dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by

flash column chromatography on SiO2 (50:1, petrol/EtOAc) to give 5.47 as a colourless oil (326 mg,

51%).

Data for 5.47:


IR (neat): 2965, 2929, 2873, 1708, 1452, 1376, 1252, 1055 cm-1 1H NMR (500MHz, CDCl3): δ 5.08 (t, J = 6.9 Hz, 1H), 5.00 (t, J = 6.8 Hz, 1H), 3.93 (t, J = 3.6 Hz,

1H), 2.81 – 2.72 (m, 1H), 2.34 (d, J = 3.0 Hz, 1H), 2.25 – 2.21 (m, 1H), 2.08 – 2.02 (m, 1H), 1.89 –

1.76 (m, 5H), 1.72 (s, 3H), 1.65 (s, 3H), 1.63 (s, 3H), 1.57 (s, 3H), 1.53 (s, 1H), 1.50 – 1.37 (m, 2H),

1.06 (s, 3H), 0.98 (d, J = 6.5 Hz, 3H), 0.93 (d, J = 6.9 Hz, 3H), 0.87 (d, J = 6.8 Hz, 3H), 0.11 (s, 9H). 13C NMR (125 MHz, CDCl3): δ 214.6, 132.4, 131.5, 124.1, 123.7, 75.8, 60.1, 58.7, 41.5, 41.1, 40.4,

39.8, 35.1, 34.0, 27.7, 25.8, 25.7, 21.7, 20.2, 18.1, 18.0, 17.6, 14.8, 1.0, 0.9.

HRMS (ESI): calculated for C26H49O2Si 421.3502 [M+H]+, found 421.3508.

O

OHH

TMSCl, imidazole, DMF, rt

O

OTMSH

51%

5.42 5.47

377

To a solution of 5.47 (316 mg, 0.75 mmol) in anhydrous THF (10 mL) at -78 °C was added LDA (2.0

M in THF, 1.1 mL, 2.20 mmol). The mixture was stirred for 3 hours and warmed to room temperature

over 30 min. The reaction was quenched with saturated NH4Cl solution (10 mL). The organic layer was

separated and the aqueous layer was extracted with Et2O (2 × 10 mL). The combined organic extracts

were washed with saturated NH4Cl solution (20 mL) and brine (20 mL), dried over MgSO4, filtered and


petrol/EtOAc) to give 5.48 as a colourless oil (249 mg, 79%).

Data for 5.48:


IR (neat): 2964, 2925, 2873, 1707, 1451, 1378, 1265, 1252 cm-1 1H NMR (500 MHz, CDCl3): δ 5.08 (t, J = 7.2 Hz, 1H), 5.00 (t, J = 7.0 Hz, 1H), 3.93 (t, J = 3.7Hz,

1H), 2.80 – 2.75 (m, 1H), 2.34 (d, J = 3.2 Hz, 1H), 2.25 – 2.21 (m, 1H), 2.08 – 2.02 (m, 1H), 1.89 –

1.77 (m, 5H), 1.72 (s, 3H), 1.65 (s, 3H), 1.64 (s, 3H), 1.57 (s, 3H), 1.53 (s, 1H), 1.50 – 1.39 (m, 2H),

1.06 (s, 3H), 0.98 (d, J = 6.5 Hz, 3H), 0.93 (d, J = 6.9 Hz, 3H), 0.88 (d, J = 6.7 Hz, 3H), 0.12 (s, 9H). 13C NMR (125 MHz, CDCl3): δ 214.7, 132.4, 131.5, 124.1, 123.8, 75.8, 41.6, 41.1, 40.4, 39.9, 35.1,

34.1, 27.7, 25.9, 25.7, 21.8, 20.3, 18.1, 18.0, 17.7, 14.9, 0.95.

HRMS (ESI): calculated for C26H49O2Si 421.3502 [M+H]+, found 421.3508.

LDA, THF, −78 °C to rt

O

OTMSH

O

OTMSH

79%

5.47 5.48

378

To a solution of 5.48 (240 mg, 0.57 mmol) in anhydrous THF (5 mL) at room temperature was added

TBAF (1.0 M in THF, 0.86 mL, 0.86 mmol). The mixture was stirred for 30 min. The reaction was

quenched with saturated NH4Cl solution (5 mL). The organic layer was separated and the aqueous layer

was extracted with Et2O (2 × 5 mL). The combined organic extracts were washed with brine (10 mL),


chromatography on SiO2 (30:1, petrol/EtOAc) to give 5.49 in a colourless oil (141 mg, 71%).

Data for 5.49:


IR (neat): 3514, 2965, 2929, 2872, 1695, 1451, 1377, 1248 cm-1 1H NMR (500MHz, CDCl3): δ 5.12 (t, J = 7.2 Hz, 1H), 5.07 (t, J = 7.0 Hz, 1H), 3.90 (d, J = 11.4 Hz,

1H), 3.33 (dd, J = 9.1, 11.0 Hz, 1H), 2.65 (s, 1H), 2.47 – 2.39 (m, 2H), 2.16 – 2.09 (m, 2H), 2.05 – 1.98

(m, 1H), 1.91 – 1.85 (m, 1H), 1.82 – 1.75 (m, 2H), 1.72 (s, 3H), 1.69 (s, 3H), 1.61 (s, 6H), 1.59 – 1.54

(m, 2H), 1.22 (q, J = 12.7 Hz, 1H), 1.00 (d, J = 6.6 Hz, 3H), 0.97 (d, J = 6.3 Hz, 3H), 0.93 (s, 3H), 0.84

(d, J = 6.7 Hz, 3H). 13C NMR (125 MHz, CDCl3): δ 219.3, 132.7, 131.7, 123.8, 123.3, 75.9, 55.5, 46.6, 46.3, 42.9, 38.2,

36.5, 34.4, 27.5, 25.9, 25.7, 21.1, 20.5, 19.9, 18.5, 17.9, 17.7, 14.1.


TBAF, THF, rt

O

OHH

O

OTMSH

71%

5.48 5.49

379

To a solution of 5.49 (130 mg, 0.37 mmol) in CH2Cl2 (5 mL) at room temperature was added Dess-

Martin periodinane (316 mg, 0.75 mmol) and NaHCO3 (63 mg, 0.75 mmol). The mixture was stirred

for 1.5 h, then quenched with saturated NaHCO3 solution (5 mL). The organic layer was separated and

the aqueous layer was extracted with CH2Cl2 (2 × 5 mL). The combined organic extracts were washed

with saturated NaHCO3 solution (10 mL) and brine (10 mL), dried over MgSO4, filtered and


petrol/EtOAc) to give pre-yezo’otogirin C (5.38) as a colourless oil (120 mg, 94%).

Data for pre-yezo’otogirin C (5.38):


IR (neat): 2968, 2928, 2872, 1723, 1703, 1453, 1378, 1280, 1252 cm-1 1H NMR (500 MHz, CDCl3): δ 5.12 (t, J = 7.0 Hz, 1H), 4.98 (t, J = 6.7 Hz, 1H), 3.85 (s, 1H), 2.50 –

2.43 (m, 2H), 2.13 – 2.01 (m, 3H), 1.86 – 1.75 (m, 2H), 1.73 (s, 3H), 1.71 – 1.68 (m, 1H), 1.66 (s, 3H),

1.61 (s, 3H), 1.58 (s, 3H), 1.50 – 1.46 (m, 2H), 1.26 – 1.18 (m, 1H), 1.06 (d, J = 6.8 Hz, 3H), 1.04 (d, J

= 7.0 Hz, 3H), 1.01 (d, J = 8.0 Hz, 3H), 1.00 (s, 3H). 13C NMR (125 MHz, CDCl3): δ 211.0, 210.6, 132.9, 131.7, 123.7, 123.0, 66.8, 45.5, 42.7, 42.5, 37.0,

36.6, 26.8, 25.9, 25.7, 21.9, 18.5, 18.0, 17.7, 17.7, 17.3, 14.3.


Dess-Martin periodinanNaHCO3, CH2Cl2, rt

O

OH

O

OHH

94%

5.49 5.38

380

To a solution of pre-yezo’otogirin C (5.38) (60 mg, 0.17 mmol) in degassed DMF (5 mL) at room

temperature was added Mn(OAc)3·2H2O (92 mg, 0.35 mmol) and Cu(OTf)2 (61 mg, 0.17 mmol). The

mixture was warmed to 150 °C for 2 hours, then cooled to room temperature. The reaction was diluted

with EtOAc (10 mL) and H2O (5 mL). The organic layer was separated and the aqueous layer was

extracted with EtOAc (2 × 10 mL). The combined organic extracts were washed with H2O (2 × 20 mL)

and brine (20 mL), dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by

flash column chromatography on SiO2 (50:1, petrol/EtOAc) to give yezo’otogirin C (5.21) as a

colourless oil (40 mg, 66%). Data for yezo’otogirin C (5.21) matched from previously obtained.

O

H

O

H

O

OH Mn(OAc)3·2H2O, Cu(OTf)2

DMF, 150 °C

66%

5.38: pre-yezo'otogirin C 4.21: yezo'otogirin C

381

5.5.3. NMR spectra

O

OEt

5.391H NMR600 MHz

CDCl3

O

OEt

5.3913C NMR150 MHz

CDCl3

382

O

5.281H NMR600 MHz

CDCl3

O

5.2813C NMR150 MHz

CDCl3

383

O

5.3313C NMR150 MHz

CDCl3

O

5.331H NMR600 MHz

CDCl3

384

O

OHH

5.421H NMR600 MHz

CDCl3

O

OHH

5.4213C NMR150 MHz

CDCl3

385

O

OH

5.37

1H NMR600 MHz

CDCl3

O

OH

5.37

13C NMR150 MHz

CDCl3

386

O

H

O

H

5.21: yezo'otogirin C1H NMR600 MHz

CDCl3

O

H

O

H

5.21: yezo'otogirin C13C NMR150 MHz

CDCl3

387

5.431H NMR600 MHz

CDCl3

O

O

5.4313C NMR150 MHz

CDCl3

O

O

388

O

OTMSH

5.471H NMR500 MHz

CDCl3

O

OTMSH

5.4713C NMR125 MHz

CDCl3

389

O

OTMSH

5.481H NMR500 MHz

CDCl3

O

OTMSH

5.4813C NMR125 MHz

CDCl3

390

O

OHH

5.491H NMR500 MHz

CDCl3

O

OHH

5.4913C NMR125 MHz

CDCl3

391

O

OH

5.381H NMR500 MHz

CDCl3

O

OH

5.3813C NMR125 MHz

CDCl3

392

5.5.4. Table of 1H and 13C NMR data

Comparison of the 1H and 13C NMR spectra of natural and synthetic yezo’otogirin C (5.21).


CDCl3, ? MHz


CDCl3, 600 MHz


CDCl3, ? MHz


CDCl3, 150 MHz

1 149.3 149.2

2 73.6 73.6

3 48.5 48.5

4 1.22 (m) 1.23 (tt, J = 11.4, 3.0 Hz) 47.0 47.0

5 1.98 (dd, J = 15.3, 11.4 Hz) 1.86 (dd, J = 15.3, 3.0 Hz)

1.96 (dd, J = 14.8, 11.6 Hz) 1.86 (dd, J = 15.5, 3.3 Hz)

32.8 32.7

6 107.5 107.5

7 217.4 217.4

8 2.96 (hept, J = 6.6 Hz) 2.96 (hept, J = 6.6 Hz) 37.9 37.9

9 1.01 (d, J = 6.6 Hz) 1.02 (d, J = 6.6 Hz) 18.3 18.3

10 1.01 (d, J = 6.6 Hz) 1.01 (d, J = 6.6 Hz) 21.5 21.5

11 0.75 (s) 0.75 (s) 19.6 19.6

12 1.75 (m) 1.46 (m)

1.76 – 1.74 (m) 1.56 – 1.52 (m)

41.5 41.5

13 1.54 (m) 1.56 – 1.52 (m) 25.4 25.4

14 3.18 (t, J = 9.6 Hz) 3.19 (dd, J = 10.2, 9.0 Hz) 54.9 54.9

15 83.4 83.4

16 1.14 (s) 1.15 (s) 29.4 29.5

17 1.18 (s) 1.18 (s) 25.4 25.4

18 1.93 (m) 1.81 (m)

1.94 (dd, J = 11.1, 1.0 Hz) 1.84 – 1.80 (m)

29.6 29.6

19 5.11 (t, J = 6.9 Hz) 5.13 – 5.10 (m) 124.2 124.2

20 132.3 132.4

21 1.72 (s) 1.73 (s) 25.8 25.9

22 1.60 (s) 1.61 (s) 17.8 17.9

23 1.70 (s) 1.71 (s) 16.3 16.3

* The operation frequency is not mentioned in the isolation paper, the NMR spectra were not attached

so we could not deduce the operation frequency from coupling constant.

O

H

O

H


2

17

161

1514

1312

11

10

9

8 764 5

3

18

19

20

21

22

393

5.5.5. References

1. Kuramochi, A.; Usuda, H.; Yamatsugu, K.; Kanai, M.; Shibasaki, M. J. Am. Chem. Soc., 2005, 127, 14200.

2. He, S.; Yang, W.; Zhu, L.; Du, G.; Lee, C.-S. Org. Lett., 2013, 16, 496.

Documents

University of Adelaide€¦ · IV Acknowledgements First, I would like to thank my supervisor Dr. Jonathan George for his guidance during my PhD. I remember when I first joined the