Synthesis of Atisine-type Alkaloids · 2020. 8. 28. · 2 Education: 1980–1984 B.S., Shandong University 1984–1989 Ph.D., Shanghai Institute of Organic Chemistry (Xiyan Lu) 1990–1994

Synthesis of Atisine-type Alkaloids

Literature Report III

Reporter Checker

Date

: Yang Zhao : Zhou-Hao Zhu : 2018-7-16

Ma, D. et al. Angew. Chem. Int. Ed. 2018, 57, 6676 Baran, P. S. et al. J. Am. Chem. Soc. 2014, 136, 12592

2

Education: 1980–1984 B.S., Shandong University

1984–1989 Ph.D., Shanghai Institute of Organic Chemistry (Xiyan Lu)

1990–1994 Postdoc., University of Pittsburgh and Mayo Clinic, U.S.A.

1995– now Prof., Shanghai Institute of Organic Chemistry

Research: Total synthesis of complex natural products

New synthetic methodologies: Copper-catalyzed coupling

reactions; Asymmetric Michael additions, Henry reaction;

Intramolecular Dearomative Oxidative Coupling

Biochemistry

CV of Prof. Dawei Ma

Contents

3

1

2

Introduction

3

4

Semisynthesis of (-)-Isoatisine

Summary

Total Syntheses of Azitine

Introduction

4

N

OHMe

N

Me

hetisine-type

nominine

hetidine-type

HOO

(-)-spirafine III

atisine-type

N

OHMe

(-)-isoatisine

N

OHMe

azitine

O

C20 diterpenoid alkaloids

Introduction

Atisine-type diterpenoid alkaloids isolated from Aconitum

Folk medicine for the treatments of rheumatism and neuralgia

Bicycle[2,2,2]octane system with the attached allylic alcohol

5

N

OHMe

O

(-)-Isoatisine Aconitum

Yao, B.-H. et al. J. Pharm. Anal. 2011, 1, 57 Baran, P. S. et al. J. Am. Chem. Soc. 2014, 136, 12592

N

OHMe

O

Me

MeMe

O

OAc

Me

Me

OHHO O

(-)-Steviol

Hofmann-Löffler-Freytag Reaction

Me

Me

NH

P(O)(OEt)2 OH4

20

NH

P(O)(OEt)2

Mukaiyama Oxidation/Fragmentation

7

(-)-Isoatisine

2020

Retrosynthetic Analysis

6

Barton-McCombie Deoxygenation Reaction

R OH

Y X

S

Base

O Y

S

R

thioxoester

AIBN, PhCH3reflux

(n-Bu)3SnHR H

Initiation step:

N

CN

Me

MeN

CN

Me

Me heatMe

CN

Me

2 + N2

(n-Bu)3Sn MeCN

Me(n-Bu)3Sn+Me

CN

MeH

Propagation step:

O Y

S

R

Sn(n-Bu)3

RO Y

SSn(n-Bu)3

R

S

YO

Sn(n-Bu)3

H Sn(n-Bu)3 R H + Sn(n-Bu)3

H

7

X = Cl, imidazolyl; Y=SMe, imidazolyl, OPh, OMe; R-OH = 1o, 2o or 3o alcohol

Hofmann-Löffler-Freytag Reaction

R1N

R2

XN

R1

HR2

NR1

R2

Base

-HX

∆ or hv orradical initiator

X

R1N

R2

X

H

acidic or neutralor weakly basic

medium

HN

XR2

R1

∆ or hv orradical initiator

HN

R1

X

R2H- X

HN

R1

H

R2

1,5-Habstraction

N

HR2

R1

alkyl radical

H

+ XHN

R1

H

R2X

δ-halogenated amine

:B

-BH

:N

R1

HR2

X- X

NH

R1R2

:BH

-BHN

R1

R2

8

X = Cl, Br, I

80%

1 2

Me

Me

HO O

EDCl, HOBt,NH4OH

Me

Me

H2N O

LiAlH4Me

Me

H2N94%

Me

Me

NH

P(O)(OEt)2

P(OEt)2(O)Cl,DIPEA

93% Me

Me

NH

P(O)(OEt)2

Co(acac)2, Et3SiH, O2

59%

O

MeO

OH OH OH

OH

Me

MeMe

O

OHNH

P(O)(OEt)2

Ac2O, Et3N,DMAP

90%

Amberlyst® 15

87%

Me

MeMe

O

OAcNH

P(O)(OEt)2

47%Me

OAcMe

OH

MeNH

P(O)(OEt)2

NaBH4

3

4 5

6 7 8

Mukaiyama Oxidation/Fragmentation

20

Necessary directing group for C20 C-H activation


9

N

OHMe

O

1) thio CDI2) (TMS)3SiH, AIBN

85%Me

OAcMe

OH

MeNH

P(O)(OEt)28

Me

OAcMe

MeNH

P(O)(OEt)29

OHMe

Me

O 11H I

PIDA, I2, 90-W sunlamp

OAcMe

MeN

P(O)(OEt)210

I

thenK2CO3, MeOH

71%

Martin's Sulfurane

91%

Me

O 12H I

SeO2, tBuOOH

63%

Me

O 13H I

OH

95%

Me

N

(-)-isotisine

OH

O

+Me

N

OH

O

epi-minor

NH2HO

Barton-McCombiedeoxygenation

Hofmann-Löffler-Freytag reaction

Selective C20 C-H activation

(C6H5)2S

OC(CF3)2C6H5

OC(CF3)2C6H5

6

2

2013

20

10


N

OHMe

O

Introduction

11

Ma, D. et al. Angew. Chem. Int. Ed. 2018, 57, 6676

Atisine-type

N

OHMe

(-)-Isoatisine

N

OHMe

Azitine

O

Me

Me

OHHO O

(-)-Steviol

CN

O

α,β-Unsaturated nitrile

CN CN

MeO

O

CNOMe

OH

OAc

CN

OH

OTBS

MeO

ClMg

a) Oxidative Dearomatizationb) Diels-Alder Cycloaddition

Chelation-ControlledConjugate Addition

OAc CN

OMe

OH

Reductive Cyclization

N

OHMe

Azitine

14

6

62 8

+

CN

O1

Retrosynthetic Analysis

12

Luche Reduction

13

R1 R2

ONaBH4, CeCl3,

ROH

R1 R2

OH

B

H

H H

H

+ [BH3(OR)]Ce3+

[BH2(OR)2] ROH

B

H

RO ORH

OR2

R1

H OR

Ce3+

OR2

R1

H ROH OHR2

R1

HRO

- H2

Both acyclic and cyclic enones are reduced to corresponding allylic alcohols

Chelation-Controlled Conjugate Addition

14

R1 CN

OH

tBuMgClR2MgX OR1

CMgN MgX2

R2

OR1

Mg

R2

H

CN

MgX2

R3X R1 CN

OH

R2

R3

R1 CN

OH

R1 CN

OH

R2

R3

tBuMgCl, R2MgX

then R3X

γ-hydroxy group in an α,β-unsaturated nitrile could promote the conjugate addition by chelation to the Grignard reagent

Steward, O. W. et al. Angew. Chem. Int. Ed. 2004, 43, 1126

Swern Oxidation

15

R1 R2 R1 R2

OOH (COCl)2 or TFAA, DMSO then Et3N

S OMe

Me(COCl)2

S OMe

MeCl

O

O

Cl

S ClMe

MeCO, CO2

Cl-

R1 R2

OH

S OMe

Me

H

R1

R2

B

SMe2

R1 R2

O

1o or 2o alcohols

Low temperature/Solvent

Van Leusen Reaction

16

OR2

R1 Me SO2CH2N=C

tBuOK

O

NC

TosCH2N C TosCHN C

OR2

R1

O

N

R1

R2H

Tos

R1

R2H

Tos

O

N

R1

R2

Tos H

R1

R2 Tos

NO

H

-TosC N

O

H

RO

R2

R1

C NR2

R1 O

H

OR

C NR2

R1-HCOOR R1

R2

H

C N

tBuOK

H

R1

R2

H

C N

5-endo-dig

I

II

III

Van Leusen, A. M. et al. J. Org. Chem. 1977, 42, 3115

97%

1 2

NaBH4, CeCl3MeOH tBuMgCl then 8

CN

O Mg

3

CN

O

CN

OH

OMe

OTBS

OAc CN

4

OMe

OTBS

O

then AcClthen

NaBH4, MeOH

61% OAc CN

5

OMe

OTBS

OH

OAc CN

6

OMe

OH

Matin's sulfuranethen TBAF

74%

PIDA, MeOHNaHCO3 then

toluene, 105 oC

88%

7

Luche ReductionChelation-Controlled Conjugate Addition

(C6H5)2S

OC(CF3)2C6H5

OC(CF3)2C6H5

OAc CN

OOMe

OMe


17

N

OHMe

N

OHMe

OTBS

OMe

HO

SOCl2, pyridine

81%

OTBS

OMe

Cl

Mg, 90 oC

OTBS

OMe

ClMg

18 19 8

Preparation of Grignard Reagent 8

18

CN13

O

ONC

CN14

O

O

CN

Me

TosMic, tBuOKtBuOH

LDA, MeI

68% for 2 steps15

O

OMe

NH NH

7OAc CN

OOMe

OMe

9OAc CN

O (CH2OH)2

OAc CNO

O

Dibal-H

OH CNO

O (COCl)2, DMSOthen Et3N

CN12

OO

O

10

11

SmI2 (4 eq.)

LAH

88% for 4 stepsS

O O

MeN C

Van Leusen Reaction

Swern Oxidation

4

4

4

19


N

OHMe

15

O

OMe

NH NH

Li/NH3(l)

16

O

OMe

NH NHLi

e-path b

path a

path a

19 24% yield (2 steps)

O

OMe

N

O

OMe

NH

NHLi

path b

O

OMe

NH NH

O

OMe

N

17

18

20

46% yield (2 steps)further

reduction

THF/iPrOH

19 : 20 = 1 : 2

20


TsOH, Acetone/H2OO

OMe

N 20

Me

N 22

Me

Nazitine

91% for 2 steps

SeO2, TBHP

56%

OH

Me

N 21

O PPh3MeBr, nBuLi

21


Summary

22

CN CN

MeO

OCNOMe

OH

OAc

N

OHMe

Azitine

CN

O

N

OHMe

O

Me

MeMe

O

OAcMe

Me

OHHO O

(-)-Steviol

Me

Me

NH

P(O)(OEt)2 OH

20 NH

P(O)(OEt)2

(-)-Isoatisine

4

10



Baran, P. S. et al. J. Am. Chem. Soc. 2014, 136, 12592


Summary

17 steps, 5.4% overall yield Chelation-trigged conjugate addition Oxidative dearomatization/ Diels-Alder cycloaddition Reduction of a dinitrile intermediate

23

N

OHMe

O

(-)-Isoatisine

N

OHMe

Azitine

13 steps, 4.6% overall yield Mukaiyama oxidation/fragmentation Hofmann-Löffler-Freytag reaction (Suárez modification)



Baran, P. S. et al. J. Am. Chem. Soc. 2014, 136, 12592


The First Paragraph

24

Owing to their caged and polycyclic ring systems, the C20 diterpenoid

alkaloids are recognized among the most architecturally complex natural

products, and have elicited considerable interest from the synthetic

community over the past several decades. These synthetic campaigns

culminated in the completion of formal and total syntheses of a subset of C20

diterpenoid alkaloids, namely nominine, atisine, isoatisine and so on.

However, most of these synthetic routes require a large number of steps

and are restricted to a very particular structure. There is plenty of room for

developing more concise total syntheses towards atisine- and hetidine-type

alkaloids. Herein, we report a short and efficient approach for the assembly

of a tetracyclic dinitrile compound. By making use of this common

intermediate, we achieved the first total synthesis of azitine, an anti-

leishmanial atisine-type diterpenoid alkaloid that was first isolated from

Consolida hellespontica.

25

In conclusion, we have described a unified approach towards the

atisane-type C20 diterpenoid alkaloids, as exemplified by the first total

syntheses of azitine. The syntheses feature a number of key

transformations, including a) chelation-triggered conjugate addition to

control the contiguous three stereogenic centers in the cyclohexane unit,

b) oxidative dearomatization/Diels–Alder cycloaddition to forge the crucial

bicyclo[2.2.2]octane moiety with a free cyano group at the C20 position, c)

reduction of a dinitrile intermediate to form an N-heterocycle with the

correct oxidation state at the C20 position. If other Grignard reagents with

functional groups at C6/C7 and functionalized α,β-unsaturated nitriles were

employed in the chelation-controlled conjugate addition, it should be facile

to assembly other functionalized diterpenoid alkaloids. Thus the present

synthetic strategy provides a reliable and efficient approach for diverse

syntheses of diterpenoid alkaloids and their analogues.

The Last Paragraph

Acknowledgement

26

27

Mukaiyama Hydration

R

RH

L2Co3+

L2Co2+

RH

O2

RH

OL2Co2+

RH

OO

L2Co3+

L2Co3+ H

Et3SiH

RH

OOSiEt3 L2Co2+

O2, Et3SiHRH

OH

O

From Fan-Jie Meng

Allylic Hydroxylation of Alkenes with SeO2

28

R1 R2

HSeO O

R1 R2

SeHO O

R1 R2

OSe

OH

R1 R2

OH

ene [2,3]-sigmatropic

R1 R2 R1 R2

OHSeO2

R1

O

MeO OMe

SmI2R2R1

O

MeO OMe

R2MeOH

R1

OH

MeO OMe

R2

SmI2R1

OH

MeO OMe

R2R1

OH

OMe

R2

R1

O

OMe

R2SmI2

R1

O

OMe

R2MeOH

R1

OH

OMe

R2

SmI2R1

OH

OMe

R2

R1

OH

R2R1

O

R2

29

Removal of Two Methoxyl Group with SmI2

Documents

Synthesis of Atisine-type Alkaloids · 2020. 8. 28. · 2 Education: 1980–1984 B.S., Shandong University 1984–1989 Ph.D., Shanghai Institute of Organic Chemistry (Xiyan Lu) 1990–1994