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Model Studies Towards the Total Synthesis of Lyconadin A via An Model Studies Towards the Total Synthesis of Lyconadin A via An

Acyl Radical Cascade Reaction Acyl Radical Cascade Reaction

Koudi Zhu Brigham Young University - Provo

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MODEL STUDIES TOWARDS THE TOTAL SYNTHESIS OF LYCONADIN A VIA

AN ACYL RADICAL CASCADE REACTION

by

Koudi Zhu

A thesis submitted to the faculty of

Brigham Young University

In partial fulfillment of the requirements for the degree of

Master of Science

Department of Chemistry & Biochemistry

Brigham Young University

August 2006

ABSTRACT

MODEL STUDIES TOWARDS THE TOTAL SYNTHESIS OF LYCONADIN A

VIA AN ACYL RADICAL CASCADE REACTION

Koudi Zhu

Department of Chemistry and Biochemistry

Master of Science

N

HN

O

H

H

H H

H

Lyconadin A, 1

Lyconadin A is an alkaloid possessing a unique structure and antitumor activity.

The total synthesis of Lyconadin A was proposed via an acyl radical cascade reaction. To

investigate the possibility and stereoselectivity of the cascade cyclization, phenyl

selenoester 16 was chosen as a model substrate to study the 7-exo-5-exo radical

cyclization. A synthetic route to phenyl selenoester 16 was developed. The 7-exo-5-exo

radical cyclization was found to occur with a high yield and excellent stereoselectivty.

Attempts were also tried to synthesize another radical precursor 14 albeit with less

success. A synthetic pathway to the synthesis of 14 as well as its potential use in the

context of the synthesis of Lyconadin A was proposed.

O

O

PhSe

O

O

O

PhSe

OTBS

O

14 15

7-exo-6-endo

7-exo-5-exo

16 17a, 17b

H

H

TBSO

ACKNOWLEDGMENTS

First of all, I would like to thank my advisor Dr. Castle to give me a chance to

study in his group. He gave me invaluable suggestions and encouragement during my

whole project.

I would also thank our former research associate Dr. Srikanth. He is a very

knowledgeable organic chemist. He helped me design some of the synthetic routes

reported in this study.

Finally, great thanks come to my husband Binghe. He is also a graduate student in

the Department of Chemistry and Biochemistry at BYU. It is quite challenging for both

of us to study while taking care of our two-year-old boy Kenneth. He tried his best to do

a good job both at home and at school. Without his support, it is impossible for me to

finish this project. It is to him and our lovely son that this thesis is dedicated.

I

TABLE OF CONTENTS

Table of Contents…………………………………………………………………….. i

List of Figures………………………………………………………………………... iii

List of Schemes……………………………………………………………………… iv

Chapter 1. Introduction…………………………………………………………….…. 1

1.1 Lyconadin A………………………………………………………………. 1

1.2 Bioactivities of Lycopodium Alkaloids…………………………………... 1

1.3 Proposed Synthetic Approaches to Lyconadin A………………………… 3

1.4 Acyl Radicals……………………………………………………………... 5

1.5 7-Exo Cyclization……………………………………………………….....6

1.6 Acyl Radical Cascade Reactions…………………………….…………… 8

Chapter 2. Synthesis of the Radical Cascade Precursors……………………………. 15

2.1 Synthesis of Bromide 44…………………………………..……..…..….. 15

2.2 Alkylations…………………………………………………………...….. 16

2.3 Attempts to the Synthesize Phenyl Selenoester 14………………….… 19

2.4 Synthesis of Phenyl Selenoester 16…………………………………..…. 22

Chapter 3. Model Acyl Radical Cascade Reaction…………………………………. 25

Chapter 4. Future Work and Conclusion……………………………………………. 29

4.1 Future Work…………………………………………………………….. 29

4.2 Conclusion………………………………………………………………. 31

Chapter 5. Experimental and Spectroscopic Data………………………………….. 32

5.1 General Methods………………………………………………………... 32

II

5.2 Experimental Details……………………………………………………. 33

5.3 Selected NMR Spectra………………………………………………….. 47

III

LIST OF FIGURES

Chapter 1. Introduction

Figure 1. Structure of Lyconadin A and Photo of Lycopodium Complanatum 1

Figure 2. Structures of Lycopodium alkaloids HupA and ZT-1……………… 3

Chapter 3. Model Acyl Radical Cascade Reaction………………………………….. 25

Figure 1. Stereochemistry of Compound 17a and 17b…………………….... 26

Figure 2. Proposed Pathway of 7-exo-5-exo Tandem Cyclization………….. 27

IV

LIST OF SCHEMES

Chapter 1. Introduction

Scheme 1. Retrosynthesis of Lyconadin A…………………………………… 4

Scheme 2. Model 7-exo Reactions…………………………………………… 5

Scheme 3. Synthesis Methods of Phenyl Selenoesters……………………….. 6

Scheme 4. 7-exo Cyclizations Reported by Boger and Mathvink……………. 7

Scheme 5. 7-exo Cyclizations Reported by Evans…………………………… 7

Scheme 6. 7-exo Cyclizations Reported by Bonjoch et al……………………. 8

Scheme 7. 7-exo Cyclizations Reported by Ryu……………………………... 8

Scheme 8. 5-exo Acyl Radical Cascade Reaction……………………………. 9

Scheme 9. 6-endo Acyl Radical Cascade Reaction…………………………. 10

Scheme 10. 7-endo Acyl Radical Cascade Reaction…………………………11

Chapter 2. Synthesis of the Radical Cascade Precursors

Scheme 1. Retrosynthesis of the Phenyl Selenoesters 14 and 16…………… 15

Scheme 2. Synthesis of Bromide 44………………………………………… 16

Scheme 3. Alkylation Attempts with Compounds 51 and 53……………….. 17

Scheme 4. Alkylation Attempt with Sodium Salt 55………………………... 18

Scheme 5. Alkylation with Diethyl Malonate 56……………………………. 18

Scheme 6. Reduction of the Alkylation Product 57………………………… 19

Scheme 7. Monoxidation of the Symmetric Diol 58………………………... 20

Scheme 8. Pathway to the Synthesis of Diene 64…………………………… 21

Scheme 9. Pathway to the Synthesis of Diene 43…………………………… 22

V

Scheme 10. Pathway to the Synthesis of Phenyl Selenoester 16……………. 23

Chapter 3. Model Acyl Radical Cascade Reaction

Scheme 1. Acyl Radical 7-exo-5-exo Cascade Cyclization………………… 26

Chapter 4. Future Work and Conclusion

Scheme 1. Tandem Cyclization of Enone 14………………………………... 29

Scheme 2. Proposed Acyl Radical Cascade Approach towards Lyconadin A 30

1

CHAPTER 1. INTRODUCTION

1.1 Lyconadin A

Lyconadin A (1) is a novel alkaloid, which was isolated from Lycopodium

Complanatum by Kobayashi and coworkers.1 Lycopodium Complanatum belongs to a

member of the club moss family commonly known as ground cedar.2 Lyconadin A has a

unique skeleton consisting of one five-membered ring, three six-membered rings, and one

�-pyridone ring. In addition to its unique structure, 1 exhibits cytotoxity against murine

lymphoma L 1210 cells (IC50 = 0.46 µg/mL) and human epidermoid carcinoma KB cells

(IC50 = 1.70 µg/mL).1 The combination of its unique structure and antitumor properties

makes Lyconadin A an attractive target for total synthesis. Surprisingly, only very limited

reports could be found for the synthesis of this natural product.3,4 No total synthesis has

been disclosed.

N

HN

O

H

H

H H

H

Lyconadin A, 1

Figure 1. Structure of Lyconadin A and photo of Lycopodium Complanatum

1.2 Bioactivities of Lycopodium Alkaloids

Lycopodiums are characterized by low, evergreen, coarsely moss-like and club-

shaped strobili at the tips of moss-like branches. They have a long history of use to

benefit human health. Qian Ceng Ta (the whole plant of Huperzia serrata Thunb Trev.)

Lycopodium Complanatum

2

and other species of Huperziaceae and Lycopodiaceae (Lycopodium s. l., club mosses)

have been used earlier as Chinese folk medicine for the treatment of contusions, strains,

swellings, schizophrenia, myasthenia gravis and organophosphate poisoning.5,6 In Europe

and North America, ground cedar are dried, powdered and used to make a medicinal tea

to increase urine production, stimulate menstrual flow and relieve spasms.

Lycopodium alkaloids have been classified into four structural classes:

lycopodine, lycodine, fawcettimine and miscellaneous groups.7 Pharmacological studies

have demonstrated that Lycopodium alkaloids have definite effects in the treatment of

diseases that affect the cardiovascular or neuromuscular systems, or that are related to

cholinesterase activity. These alkaloids have also been shown to have positive effects on

learning and memory.6,8,9 The most potent of these is huperzine A (HupA, 2). HupA was

discovered in the 1980s. Since then, it has been extensively evaluated for bioactivity,

especially for activity toward cholinesterases and for treatment of Alzheimer's disease

(AD). HupA has been found to be a potent, reversible and selective acetylcholinesterase

inhibitor (AChEI).8,10,11 It can cross the blood–brain barrier smoothly, and shows high

specificity for acetylcholinesterase (AChE) with a prolonged biological half-life.12 In

attempts to look for drugs against AD that are even more effective than HupA, many

analogs of HupA have been prepared. Among these, only a few compounds demonstrate

obvious AChEI activity. ZT-1 (3) is the most potent one.13 It is a Schiff base prepared by

a condensation reaction between HupA and 5-chloro-2-hydroxy-3-methoxybenzaldehyde.

Experimental data demonstrated that ZT-1 possesses AChEI activity similar to HupA. It

has similar properties to HupA regarding the ability to cross the blood–brain barrier, its

3

oral bioavailability, and its longevity of action. However, it has more selective inhibition

on AChE as well as less toxicity in mice than HupA.

NH

H2NO

HupA

NH

NO

HO

MeO Cl

ZT-1

2 3

Figure 2. Structures of Lycopodium alkaloids HupA and ZT-1.

1.3 Proposed Synthetic Approaches to Lyconadin A

The five fused rings in the structure of Lyconadin A make the synthesis very

challenging. We propose to synthesize this natural product via a key reaction which

allows the formation of the bicyclo[5.4.0] ring system in a single step. Scheme 1 shows

the retrosynthesis of Lyconadin A. If we break the amine bridge and protect the primary

amine, we will obtain compound 4. We hope to form the bridged polycyclic framework

of 1 from a tricyclic intermediate via a one-pot sequence of two intramolecular reductive

aminations. Based on our model study, the cascade radical cyclization will provide the

trans-fused rings at C-7. Thus, the inversion of the stereochemistry at C-7 and the

reduction of the carbonyl at C-13 of 4 will give trans-fused intermediate 5. Because the

cis-fused isomer is less stable than the trans-fused isomer, the transformation of 5 to 4

could be a very challenging step in the synthesis. Compound 5 is proposed to be formed

via a novel 7-exo-trig/6-exo-trig cyclization cascade from diene 6. The diene 6 can be

prepared from 1,3-diol 7, which is a candidate for a desymmetrization process.

4

Alkylation of bromide 8 with diethylmalonate and the subsequent reduction will provide

diol 7. With α-keto ester 9 as a precursor, the pyridine 8 can be prepared via the

Kozikowski pyridone synthesis.14 α-Keto ester 9 will be obtained from aldehyde 10

using Overman’s method.15 Finally, optically pure 10 will be prepared from known triol

derivative 1116 with enzymatic asymmetrization17 as a key step.

N

HNO

H

H

H H

HO

BocNO

NBoc2

O

H

H

BocNO

NBoc2

O

H

HOTBS

BocN

NBoc2

O

HOTBS

PhSe

O

BocN

NBoc2

OTBSO

HO

HO

BocN

O

Br NBoc2

TBSO

CO2Me

BnO NHBoc

O O

BnO NHBoc

O O

HO

1 4 5 6

7 8 9 10 11

1

2

34

5

6

78

910

1112

1314

1516

The key step in our proposed synthesis of Lyconadin A is the acyl radical cascade

cyclization (6 → 5). Because this reaction is in the later steps of the total synthesis and

there are no published examples of 7-exo cascade cyclization, we will begin with simpler

substrates for investigation of the feasibility and stereoselectivity. In Scheme 2, the

phenyl selenoesters 12 and 14 are the model substrates used to investigate the 7-exo-6-

exo and 7-exo/6-endo cyclization. These two synthetic routes can be applied to the total

synthesis. In addition to 12 and 14, the closely related phenyl selenoester 16 will also be

used to investigate the 7-exo/5-exo cyclizations. The 7-exo/6-exo cascade reaction has

been studied and found to proceed smoothly by our group.18 The goal of this Master’s

thesis project is to prepare phenyl selenoesters 14 and 16, and use them to explore the

Scheme 1. Retrosynthesis of Lyconadin A

5

proposed acyl radical cascade reaction. By comparing the efficiency of the 7-exo-6-exo

and 7-exo/6-endo cyclizations in the model studies, we hope to determine the best

synthetic route to Lyconadin A.

O

O

PhSeO

O

O

PhSe

OTBS

O

12 13

14 15

7-exo-6-endo

7-exo-5-exo

O

PhSe

OTBS

O

TBSO

16 17

7-exo-6-exo

1.4 Acyl Radicals

The slower reduction rates of acyl radicals relative to alkyl radicals make them

useful in a wide range of cyclizations.19, 20 Three methods have been developed to

generate acyl radicals.20 The first is the homolytic rupture of a RC(O)-X bond. The

second involves the carbonylation of a carbon-centered radical (R.), and the third is the

fragmentation of a C-C bond. Of the three methods, the first one has been the most

widely utilized, especially for the acyl radicals generated from selenoesters. This is due to

the very weak RCO-SeR’ bond, rendering it reactive with stannyl or silyl radicals.

Scheme 2. Model 7-exo Reactions

6

Another reason is that selenoesters can be isolated and purified by silica gel

chromatography. In our model study, we will use phenyl selenoesters as the radical

precursor. The phenyl selenoesters can be prepared from their corresponding carboxylic

acids (shown in Scheme 3).21, 22

RCO2H RCO2H RCO2H

(PhSe)2Bu3P

N-PSP

Bu3P(EtO)2POClPhSeNa

PhSeNa RCOClPhSeH

pyrRCOCl

R SePh

O

1.5 7-exo Cyclization

It is uncommon to synthesize seven-membered rings via radical cyclization. Only

a few examples utilizing specialized substrates were demonstrated.23 Acyl radicals have

been used in 7-exo radical cyclization processes, mainly due to their slower reduction

rates as compared with alkyl radicals.19, 20 Detailed description of the use of acyl radicals

undergoing 7-exo cyclization is provided below.

The first example was reported by Boger and Mathvink (Scheme 4), where they

used phenyl selenoesters as the radical precursors and tributyltin hydride as the radical

chain carriers to perform the cyclizations.24, 25 Conversion of 19a to 19b demonstrated

that the additions of acyl radicals to the electron-deficient alkenes are more efficient than

to the non-activated alkenes.

Scheme 3. Synthesis Methods of Phenyl Selenoesters

7

SePh

O

XO

X

18a X = H 18b X = H, 74%19a X = CO2CH3 19b X = CO2CH3, 92%

Bu3SnH, AIBN

C6H6, reflux

COSePh

CO2CH3

O

CO2CH3

Bu3SnH, AIBN

C6H6, reflux

71%

20 21

Evans’s group also made significant contributions to the area of acyl radical 7-

exo addition reactions. They found that these reactions can proceed with excellent

diastereoselectivity.26-29 Examples of their work are shown in Scheme 5.

O

COSePh

SO2Ph O SO2Ph

O(TMS)3SiH, Et3B

C6H6, r.t.

O

COSePh

CO2iPr

CH3

(TMS)3SiH, Et3B

C6H14, r.t.81%

O CO2iPr

O

HCH3

+

O CO2iPr

O

HCH3

SePh

O

R

N O

O

O

(TMS)3SiH, Et3B

C6H6, 0 oC to r.t.N O

O

O

OH

R

22 23

24 25a 26b

27a, R = Me 27b, R = Me, 87%, dr ≥ 19:1 28a, R = Ph 28b, R = Ph, 68%, dr ≥ 19:1

Scheme 4. 7-exo Cyclizations Reported by Boger and Mathvink

Scheme 5. 7-exo Cyclizations Reported by Evans

8

The only example of a 7-exo acyl radical cyclization forming a bridged bicyclic

compound was reported by Bonjoch and coworkers (Scheme 6). They described the

decarbonylation of α-amino acyl radicals but not of the corresponding β-amino acyl

radicals.30, 31

N

CN

SeCH3

OBn

(TMS)3SiH, AIBN

C6H6, reflux

71%

N

O

Bn

CN

H

H

29 30

Scheme 7 shows another 7-exo cyclization reported by Ryu and coworkers, where

the acyl radicals are added to the nitrogen atom of imines. The acyl radicals are generated

by carbonylation of vinyl radicals.32, 33

N N

O

G

G = Bu3Sn, 69%, E:Z = 19:81G = (TMS)3Si, 54%, E:Z = 85:15

Bu3SnH or(TMS)3SiHAIBN, CO(80-90 atm)

C6H6, reflux

1.6 Acyl Radical Cascade Reactions

Acyl radicals have also been applied in radical cascade reactions, in which

multiple C-C bonds and more than one ring are formed in a single chemical

transformation. Chatgilialoglu et al. have reviewed the use of acyl radicals in radical

α:β = 5:2

Scheme 6. 7-exo Cyclizations Reported by Bonjoch et al.

Scheme 7. 7-exo Cyclizations Reported by Ryu

9

cascade reactions.19 Some examples of 5-exo, 6-endo and 7-endo radical cascade

cyclizations are summarized as follows.

Swartz and Curran reported a 5-exo acyl radical cascade reaction for the

construction of the congested angular triquinane portion of the tetraquinane Crinipellin A

(Scheme 8).34 This cascade cyclization involves a unique 1,4-functionalization of a

cyclopentadiene nucleus via 1,3-transposition of an allylic radical, which results from the

first 5-exo cyclization. It produces two diastereomeric triquinanes 32 and 33 in a 1:5.5

ratio along with a bicyclic ketone 34 as a byproduct.

SeCH3O

0.018 M

"5-exo/1,3-transposition/5-exo"Bu3SnH (3.8 equiv), AIBN

C6H6, 85 oC, 8.5h

O

+ +

62% 1:5:2

31

32 3334

Boger and Mathvink reported the formation of fused bicyclo [4.4.0] decanes by

sequential 6-endo-trig/6-exo-trig cyclization reactions (Scheme 9).36 This reaction can be

successfully extended to the 6-endo-trig/6-exo-dig mode of cyclization. The main

drawback of this reaction is its poor stereochemical control at the decalin ring junction.

Scheme 8. 5-exo Acyl Radical Cascade Reaction

10

SePh

O

O0.012 M

Bu3SnH (1.25equiv)AIBN, syringepump

C6H6, 80 oC, 1.5h

71%

57:11:11:12

SePh

O

0.009 M

PhBu3SnH (1.3 equiv)AIBN, syringepump

C6H6, 80 oC, 1.5h

82%

Ph

O

O3, Me2S

86%

O

O

cis:trans = 58:42

35 36

3738

39

7-Endo radical cascade cyclization has also been reported. Crich and co-workers

investigated 7-endo-trig/5-exo-dig radical cascade cyclizations with enantiomerically

pure cyclization precursors (Scheme 10). Reaction of substrate 40 with tributyltin hydride

provides an isolated yield of approximately 45% of the combined steroisomers of bicycle

[5.3.0] decan-2-one 41.36, 37 The cyclohexanone derivative 42 is also isolated from this

reaction mixture in 20% yield as a 1:1 mixture of isomers.

Scheme 9. 6-endo Acyl Radical Cascade Reaction

11

SePhOO O

Bu3SnH (1.22equiv)AIBN, syringe pump

C6H6, 80 oC, 24h

0.012 M

O

O O

7-endo

O

O O

H

H+

O

O O

45% (44:29:18:9) 20% (50:50)

5-exo

40

41 42

To the best of our knowledge, no 7-exo radical cascade reactions have been

reported to date. Thus it would be very important to investigate this cascade reaction, and

hopefully it can be used in our total synthesis of Lyconadin A.

References

1. Kobayashi, J.; Hirasawa, Y.; Yoshida, N.; Morita, H.; J. Org. Chem. 2001, 66,

5901.

2. Ayer, W. A. Nat. Prod. Rep. 1991, 8, 455.

3. Crich, D.; Neelamkavil, S. Org. Lett. 2002, 4, 2573.

4. Tracey, M. R.; Hsung, R. Towards the Total Synthesis of Lyconadin A, abstracts

of papers, 226th National Meeting of the American Chemical Society, NY;

American chemical society: Washington, DC, 2003; ORGN 721.

Scheme 10. 7-endo Acyl Radical Cascade Reaction

12

5. Liu, J.; Yu, C.; Zhou, Y.; Han, Y.; Wu, F.; Qi, B.; and Zhu, Y. Acta Chim. Sin.

(Engl. Ed.) 1986, 44, 1035.

6. Liu, S.; Zhu, Y.; Yu, C.; Zhou, Y.; Han, Y.; Wu, F.; Qi, B. Can. J. Chem. 1986,

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Diego, 1994.

8. Tang, X.; Han, F.; Chen, X.; Zhu, X. Acta Pharmacol. Sin. 1986, 7, 507.

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10. Tang, X.; Sarno, P.; Sugaya, K.; Giacobini, E. J. Neurosci. Res. 1989, 24, 276.

11. Tang, X. Acta Pharmacol. Sin. 1996, 17, 481.

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13. Xiong, Z.; Tang, X.; Lin, J.; Zhu, Y. Acta Pharmacol. Sin.1995, 16, 21.

14. Kozikowski, A. P.; Reddy, E. R.; Miller, C. P. J. Chem. Soc., Perkin Trans. 1,

1990, 195.

15. Bélanger, G.; Hong, F. T.; Overman, L. E.; Rogers, B. N.; Tellew, J. E.; Trenkle,

W. C. J. Org. Chem. 2002, 67, 7880.

16. Harnden, M. R.; Wyatt, P. G.; Boyd, M. R.; Sutton, D. J. Med. Chem. 1990, 33,

187.

17. Schoffers, E.; Golebiowski, A.; Johnson, C. R. Tetrahedron 1996, 52, 3769.

18. Grant, S. W.; Master’s Thesis “An Acyl Radical Cascade Model for the Total

Synthesis of Lyconadin A”, Brigham Young University, 2005.

19. Chatgilialoglu, C.; Crich, D.; Komastu, M.; Ryu, I. Chem. Rev. 1999, 99, 1991.

20. Boger, D. L. Israel J. Chem. 1997, 37, 119.

13

21. (a) Pfenniger, J.; Heuberger, C.; Graf, W. Helv. Chim. Acta 1980, 63, 2328. (b)

Ryu, I.; Kusano, K.; Masumi, N.; Yamazaki, H.; Ogawa, A.; Sonoda, N.

Tetrahedron Lett. 1990, 31, 6887. (c) Chatgilialoglu, C.; Lucarini, M.

Tetrahedron Lett. 1995, 36, 1299.

22. Fisher, H.; Paul, H. Acc. Chem. Res. 1987, 20, 200.

23. (a) Justicia, J.; Oller-L�pez, J. L.; Campa�a, A. G.; Oltra, J. E.; Cuerva, J. M.;

Bu�uel, E.; C�rdenas, D. J. J. Am. Chem. Soc. 2005, 127, 14911. (b) Lang, S.;

Corr, M.; Muir, N.; Khan, T. A.; Sch�nebeck, F.; Murprhy, J. A.; Payne, A. H.;

Williams, A. C. Tetrahderon Lett. 2005, 46, 4027. (c) Srikrishna, A. In Radicals

in Organic Synthesis; Renaud, P., Sibi, M. P., Eds.; Wiley-VCH: Weinheim,

2002, Vol. 2, pp 163−187.

24. Boger, D. L.; Mathvink, R. J. J. Org. Chem. 1988, 53, 3377.

25. Boger, D. J.; Mathvink, R. J. J. Org. Chem. 1992, 57, 1429.

26. Evans, P. A.; Manangan, T. Tetrahedron Lett. 1997, 38, 8165.

27. Evans, P. A.; Manangan, T. J. Org. Chem. 2000, 65, 4523.

28. Evans, P. A.; Raina, S.; Ahsan, K. Chem. Commun. 2001, 2504.

29. Evans, P. A.; Manangan, T.; Rheingold, A. L. J. Am. Chem. Soc. 2000, 122,

11009.

30. Quirante, J.; Escolano, C.; Bonjoch, J. Synlett 1977, 179.

31. Quirante, J.; Vila, X.; Escolano, C.; Bonjoch, J. J. Org. Chem. 2002, 67, 2323.

32. Ryu, I.; Miyazato, H.; Matsu, K.; Tojino, M.; Fukuyama, T.; Minakata, S.;

Komatsu, M. J. Am. Chem. Soc. 2003, 125, 5632.

14

33. Tojino, M.; Otsuka, M.; Fukuyama, T.; Schiesser, C. H.; Kuriyama, H.; Miyazato,

H.; Minakata, S.; Komatsu, M.; Ryu, I. Org. Biomol. Chem. 2003, 1, 4262.

34. Schwartz, C. E.; Curran, D. P. J. Am. Chem. Soc. 1990, 112, 9272.

35. Boger, D. J.; Mathvink, R. J. J. Am. Chem. Soc. 1990, 112, 4003.

36. Crich, D.; Batty, D. J. Chem. Soc. Perkin Trans. 1 1992, 3193.

37. Batty, D.; Crich, D. Tetrahedron Lett. 1992, 33, 875.

15

CHAPTER 2. SYNTHESIS OF THE RADICAL CASCADE PRECURSORS

Suitable radical precursors must be prepared in order to investigate the proposed

7-exo/5-exo and 7-exo/6-endo cascade reactions. The retrosynthesis of two radical

precursors, phenyl selenoesters 14 and 16, are shown in Scheme 1. By deprotection of the

TBS group, oxidation to acids, and phenylselenation, diene 43 will provide 14 or 16. The

7-exo/6-endo cascade radical precursor 14 can also be prepared directly from 16. A

suitable alkylation substrate reacted with bromide 44 will afford the diene 43. The

bromide 44 can be synthesized from the known compound 45.1

O

O

PhSe

OTBS

Br

+SuitableAlkylationSubstrate

O

PhSe

TBSO

OTBS

OTBS

O

O

1416

43 44 45

2.1 Synthesis of Bromide 44

The synthesis of the bromide 44 has been developed by our group, and is shown

in Scheme 2.2 Starting from isochroman 46, lactone 45 was prepared by oxidation. In

basic conditions, lactone 45 was hydrolyzed into a hydroxy acid. By protection of the

Scheme 1. Retrosynthesis of the Phenyl Selenoesters 14 and 16

16

hydroxyl groups with PMB groups and reduction of the ester with LAH, mono-PMB-

protected diol 47 was obtained. Protection of the free alcohol with TBS and deprotection

of the PMB group gave compond 48. Finally, bromination of the mono-TBS-protected

diol 48 resulted in the bromide 44.

OO

O

OPMB

OTBS

OH

FeCl3, Picolinic acid

70% t-BuOOH

1. NaOH2. NaH, n-Bu4NI, PMB-Cl

3. LiAlH4

1. TBSCl, imid

2. DDQ

OTBS

Br

Et3N, MsCl, LiBr

THF

(52%) (60%)

(80%) (95%)

OH

46 45 47

48 44

2.2 Alkylations

It was quite challenging to find a suitable alkylation substrate for the bromide 44.

The first alkylation substrate tried was compound 51, which was prepared from a known

compound 49 via four steps (Scheme 3). Protection of the alcohol on compound 49 as a

PMB ether followed by acid hydrolysis of the acetonide gave compound 50. Selective

protection of the primary alcohol with a triphenylmethyl group and oxidation of the

secondary alcohol provided the desired compound 51. Because the triphenylmethyl is a

very bulky protecting group, the alkylation reaction is expected to proceed at the other

side of the carbonyl group. In order to obtain a good regioselectivity, KHMDS was

chosen as a bulky base for this reaction.3 Surprisingly, the alkylation reaction did not

Scheme 2. Synthesis of Bromide 44

17

happen. Instead, a �-elimination reaction was observed to provide compound 52,

resulting from the departure of the PMB group under strongly basic conditions. Another

base, LDA, was tried to replace KHMDS to run this reaction. Unfortunately, no reaction

was observed with either commercial LDA or a batch made by us. To avoid the

undesirable �-elimination, the PMB group in compound 51 was deprotected with DDQ,

and the alkylation was tried on compound 53 with KHMDS as the base.4 Interestingly,the

enolate of 53 promoted an undesired elimination of the bromide 44, and styrene 54 was

obtained. The reactions are shown in Scheme 3.

O O

OH

HO OH

OPMB

1. NaH, PMBCl, TBAI2. HCl

1. Trcl, DMAP, Et3N2. (COCl)2, DMSO, Et3N

ß-elimination

(68% for 2 steps) (60% for 2 steps)

O

OH

OTr

DDQ

OTBS

Br

+

OTBS

KHMDS

OTr

OPMB

O

OTr

49

O

50 51

52

5354

OPMB

O

OTr51

1. LDA2. Bromide 44 N.R

1. KHMDS

2. Bromide 44

Another alkylation substrate tried was the sodium salt 55 (Scheme 4). Initially, the

reaction was performed at 60 ˚C in acetonitrile. Only a trace of desired product was

obtained, while most of the bromide remained unreacted. Other solvents, THF or DMSO,

Scheme 3. Alkylation Attempts with Compounds 51 and 53

18

were used to replace the acetonitrile to run this reaction. No improvement of yield was

obtained. An increase of reaction temperature to 80˚C still yielded negligible product.

Thus, the reaction temperature was further increased to 90˚C. Unfortunately, most of the

bromide 44 was turned into the styrene 54.

EtO CO2Et

OOOTBS

Br+

CH3CN, or THFor DMSONa

Only trace ofdesiredproduct wasobserved

NaI

55 44

Finally, a symmetrical diester 56 was tried as the alkylation substrate (Scheme 5).

Fortunately, with sodium hydride as base, this alkylation reaction proceeded smoothly at

60 ˚C in acetonitrile. 12 hrs were required to run this reaction and a high yield of 90%

was obtained.

OTBS

Br+

1. NaH, THF

2. NaI, CH3CN, 60 °C

(90%)

OTBS

CO2Et

CO2EtEtO OEt

OO

56 44 57

Scheme 4. Alkylation Attempt with Sodium Salt 55

Scheme 5. Alkylation with Diethyl Malonate 56

19

2.3 Attempts to Synthesize Phenyl Selenoester 14

Our first attempt at converting 57 into phenyl selenoester 14 involved selectively

reducing one of the esters to obtain the corresponding aldehyde. With 1 eq DIBALH as

the reducing agent, most of the starting material 57 remained unreacted. Increasing the

amount of DIBALH to 2 eq or 4 eq did not improve the yield. Later, it was realized that

even though one of the esters could be reduced to the aldehyde, problems would occur

with the following Wittig or Grignard reaction. Because the proton on the �-carbon of the

carbonyl groups is very acidic, it will be unstable under basic conditions. Thus, no further

attempts were made to optimize this reaction. Instead, the diester 57 was reduced with

LAH into a symmetrical diol 58 with high yield (>90%). The reduction attempts are

shown in Scheme 6.

OTBS

CO2Et

CO2Et

DIBALH (1eq - 4eq)

THF, -78 °C

(Most of the SM recovered)

57

OTBS

CO2Et

CO2Et

OTBS

OH

OH

LAH

Anhydrous Ether

( > 90%)

57 58

After the diol 58 was obtained, attempts were tried to oxidize one of its alcohols.

A variety of oxidizing agents were used, and the results are shown in Scheme 7. Using

Cp2ZrH2,5 PhI(OAc)2,6 or Dess Martin Reagent,7 the oxidation did not proceed well, with

Scheme 6. Reduction of the Alkylation Product 57

20

most of the starting material recovered. Using TEMPO/PhI(OAc)2 or Swern oxidation

conditions,8 only part of the diol was oxidized to the desired product 59. When

TEMPO/Bleach was used, most of the starting material was gone, probably due to its

strong oxidation ability for this reaction.9 However, dialdehyde rather than the desirable

monoaldehyde was the major product. All of these observations are based on the crude

NMRs.

OTBS

OH

OH

OTBS

CHO

OH

Reaction Conditions Results

Swern Up to 30% of the monoaldehyde yeilded

Cp2ZrH2, Cyclohexanone Didn't work

PhI(OAc)2 Most of the SM recovered,trace of aldehydes found

Dess Martin Reagent Most of the SM recovered,trace of aldehydes found

TEMPO/ Bleach SM has gone, dialdehyde is the major product

TEMPO/ PhI(OAc)2 Ratio of diol: monoaldehyde = 9: 1

Various conditions

58 59

Because the direct monooxidation of the diol 58 did not work well, it was decided

to protect one of its alcohols with a PMB group to obtain 60. The free alcohol of 60 was

then oxidized to the aldehyde under Swern conditions.10 Subsequent treatment of the

aldehyde with a Wittig reagent11 provided alkene 61. The PMB ether was deprotected

Scheme 7. Monoxidation of the Symmetric Diol 58

21

with DDQ, the resulting alcohol was oxidized to the aldehyde under Swern conditions

without migration of the alkene, and the resulting aldehyde was made into the diene 62

by a Grignard reaction.10 The TBS group on the diene 62 was deprotected with TBAF to

obtain diol 63.12 Unfortunately, when the diol 63 was oxidized to compound 64 using

several oxidation reagents (e.g. Swern oxidation reagent, Dess Martin reagent), migration

was a significant problem. The alkene was found to migrate to the � position of the

carbonyl group to make a conjugated system, which is more stable than compound 64.

Among the oxidation reagents investigated, MnO2 was the only one that did not promote

migration. However, the reaction was very slow. Another problem is that the alkene

tended to migrate into conjugation with the aldehyde when the Grignard reaction was run

in larger scale (100 mg). These problems make this pathway less practical due to the low

yield of the diene 64 obtained (Scheme 8).

1, (COCl)2, DMSO, Et3N

2, MePPh3Br, n-BuLi

2, (COCl)2, DMSO, Et3N

3, Vinyl magnesium bromide

TBAF MnO2

(yield up to 70%for 2 steps)

( 24% for 3 steps)( Y= 87%)

OTBS

NaH, PMBCl, TBAI

1, DDQ

OH

OH

H

O

O

OH

OH

OTBS

OH

OTBS

OPMB

OTBS

OPMB

OH(Y = 58%)

58 60 61

6263 64

Considering the difficulties encountered for the synthesis of the phenyl

selenoester 14 and the limited time for this project, we decided to access phenyl

Scheme 8. Pathway to the Synthesis of Diene 64

22

selenoester 16 instead. This substrate would allow us to investigate the 7-exo/5-exo

radical cascade cyclization.

2.4 Synthesis of Phenyl Selenoester 16

Starting from 60, compound 65 was obtained as 1:1 mixture of diastereomers by

the oxidation and Grignard reactions (Scheme 9). The resulting alcohol was protected

with a TBS group to get compound 66, and the PMB ether was deprotected with DDQ,

resulting in compound 67. Then the free alcohol on compound 67 was oxidized to the

aldehyde and the aldehyde was turned into the diene 43 using a Wittig reagent. The diene

43 is a 1:1 mixture of diastereomers.

OTBS

OH

OPMB

1, (COCl)2, DMSO, Et3N OTBS

OH

OPMB

OTBS

OH

OTBSOTBS

OTBS

2, Vinyl magnesium bromide

( 72% over 2 steps)

( 73% over 2 steps)

TBSCl, imidazole

DDQ1, (COCl)2, DMSO, Et3N

2, MePPh3Br, n-BuLi

60 65

6743

OTBS

OTBS

OPMB66

(Y= 84%)

(Y = 77%)

Scheme 10 shows the synthesis of phenyl selenoester 16 from the diene 43.

Deprotection of the primary TBS ether with CSA gave benzyl alcohol 68. After

oxidization of the alcohol to an aldehyde under Swern conditions and oxidization of the

resulting aldehyde to the acid with sodium chlorite, PhSeSePh and Bu3P were used to

perform the phenyl selenation.13 The phenyl selenoester 16 was obtained as a 1:1 mixture

of the diastereomers with a moderate yield (Scheme 10).

Scheme 9. Pathway to the Synthesis of Diene 43

23

COSePh

OTBS

( 62% over 4 steps)

CSA

1, Swern Oxidation

2, , NaOClO, NaH2PO4

3, PhSeSePh, Bu3P

16

OTBS

OTBS

43

OH

OTBS

68

(Y = 60%)

References

1. Kim, S. S.; Sar, S. K.; Tamrakar, P. Bull. Korean Chem. Soc. 2002, 23, 937.

2. Grant, S. W.; Master’s Thesis “An Acyl Radical Cascade Model for the Total

Synthesis of Lyconadin A,” Brigham Young University, 2005.

3. Palomo, C.; Oiarbide, M.; Mielgo, A.; González, A.; García, J. M.; Landa, C.;

Lecumberri, A.; Linden, A. Org. Lett. 2001, 3, 3249.

4. Kahn, M.; Fujita, K. Tetrahedron 1991, 47, 1137.

5. Nakano, T.; Terada, T.; Ishii, Y.; Ogawa, M. Synthesis, 1986, 774.

6. Yen, C.; Peddint, R. K.; Liao, C. Org. Lett. 2000, 2, 2909.

�� Dess, D. B.; Martin, J. C. J. Org. Chem.�1983, 48, 4155.�

8. Momán, E.; Nicoletti, D.; Mouriño, A. J. Org. Chem. 2004, 69, 4615.

9. Mickle, S. J.; Sedelmeier, G. H.; Niederer, D.; Daeffler, R.; Osmani, A.;

Schreiner, K.; Seeger-Weibel, M.; Bérod, B.; Schaer, K.; Gamboni, R. Org. Proc.

Res. & Devel. 2004, 8, 92.

10. Momán, E.; Nicoletti, D.; Mouriño, A.��J. Org. Chem. 2004, 69, 4615.

11. Nishiguchi, G. A.; Little, R. D��J. Org. Chem. 2005, 70, 5249.

12. Lautens, M.; Stammers, T. A. Synthesis, 2002, 1993.

Scheme 10. Pathway to the Synthesis of Phenyl Selenoester 16

24

13. Coleman, R. S.; Gurrala, S. R. Org. Lett. 2004, 6, 4025.

14. Singh, U.; Ghosh, S. K.; Chadha, M. S.; Mamdapur, V. R. Tetrahedron Lett.

1991, 32, 255.

25

CHAPTER 3. MODEL ACYL RADICAL CASCADE REACTION

Following the synthesis of the radical precursor 16, the acyl radical 7-exo/5-exo

cascade cyclization was investigated. A similar cascade cyclization, 7-exo/6-exo cascade

cyclization, has been studied by our group.1 It demonstrated that Evan’s method2 could

be successfully applied to the cyclization reaction while Boger’s method3 did not provide

the desired product. Thus, Evan’s method was also used in this study.

Scheme 1 shows the 7-exo/5-exo cascade cyclization. Et3B/O2 was used as the

radical initiator, and (TMS)3SiH was used as the chain carrier. The cascade reaction was

found to proceed very slowly in the first trial. Most of the starting material was recovered

after several days. It is quite surprising in consideration of the relatively fast reaction in

the 7-exo/6-exo cascade cyclization.1 Because 6-exo and 5-exo cyclizations are much

faster than 7-exo cyclizations, it is unlikely that the new substrate 16, which has one less

carbon that that used in the 7-exo/6-exo cascade cyclization,1 slowed down the

cyclization dramatically. It is possible that the decomposition of Et3B and (TMS)3SiH

during prolonged storage might prevent the cyclization. However, by using newly

purchased reagents to run the reaction, no improvement was observed. After several

trials, stirring speed was found to be an important variable for the reaction. Under fast

stirring conditions, the reaction proceeded smoothly. Complete conversion of the staring

material could be accomplished in 24 h, and a 1:1 mixture of diastereomers 17a and 17b

was obtained in good yield. It is hypothesized that vigorous stirring brought more oxygen

into the reaction mixture, which reacts with Et3B to initiate the reaction. The

diastereomers were separated using preparative TLC.

26

COSePh

OTBSEt3B, O2, (TMS)3SiH

PhH, r.t., 81%

( 7-exo-5-exo cyclization)

O H

OTBSH

O H

OTBSH

+

16 17a 17b

(1:1)

The stereochemistry of the diastereomers was elucidated by 1D and 2D NMR

spectroscopy. From the 1H NMR of compound 17a, the coupling constant between the

proton 10 and proton 14 is 11.5 Hz. This large coupling constant indicates a trans ring

configuration. Furthermore, when the proton 11 was irradiated, the signal at proton 10

was increased. The signal at proton 12 was enhanced when proton 14 was irradiated.

Based on these results, the stereochemistry of compound 17a is derived and shown in

Figure 1. For the determination of the stereochemistry of compound 17b, similar

experiments were performed. A large coupling constant was also found between proton

10 and proton 14, indicating a trans ring junction. When proton 14 was irradiated, nOe

was found between protons 14 and 12. From these results, it is believed that compound

17b has the stereochemistry as shown in Figure 1.

OH

OTBSH

17a

OH

OTBSH

12

34

5

6 78 9

10 11

131214 15

H

H

nOe

nOeJ = 11.5 Hz

OH

OTBSH

17b

H

H

nOe

J = 8.5 or 11.5 Hz

Scheme 1. Acyl Radical 7-exo/5-exo Cascade Cyclization

Figure 1. Stereochemistry of Compound 17a and 17b

27

Evans has postulated pseudechairlike transition states for other stereoselective 7-

exo-trig radical cyclizations.4 According to his model, the proposed pathway of our 7-

exo/5-exo cyclization is shown in Figure 2.

OTBS

OH

OTBSH

SePh

O

HTBSO

O

HTBSO

O

16 17a, 17b

Since we started from a 1:1 mixture of diastereomers of phenyl selenoester 16 and

obtained the cyclization products as a 1:1 mixture of diastereomers too, it is believed that

the 7-exo/5-exo radical cyclization is highly stereoselective, with each diastereomer of

the starting material delivering a single product. To verify this, the diastereomeric

phenylselenoesters should be isolated and subjected to the cyclization reactions

separately.

References

1. Grant, S. W.; Master’s Thesis “An Acyl Radical Cascade Model for the Total

Synthesis of Lyconadin A”, Brigham Young University, 2005.

Figure 2. Proposed Pathway of 7-exo/5-exo Tandem Cyclization

28

2. Evans, P. A.; Manangan, T.; Rheingold, A. L. J. Am. Chem. Soc. 2000, 122,

11009.

3. Boger, D. L.; Mathvink, R. J. J. Org. Chem. 1992, 57, 1429.

4. Evans, P. A.; Roseman, J. D. J. Org. Chem. 1996, 61, 2252.

29

CHAPTER 4. FUTURE WORK AND CONCLUSION

4.1 Future Work

As proposed in Scheme 1 in Chapter 2, the phenyl selenoester 14 will be

synthesized for the investigation of a 7-exo/6-endo acyl radical cascade reaction. Because

of the difficulties for the synthesis of 14 from the alkylation product 57, compound 43

will be used instead (Scheme 1 below).

OTBS

OTBS

OH

OH

SePh

O O

O

OH

H

O

OH

HPhSe

H2O2

O

OH

H

Bu6Sn2hv

Et3B, TTMSS

PhH, rt

1. MnO22. NaClO2, NaPH2PO4

2-methyl-2-butene

3. PhSeSePh, Bu3PCH2Cl2

TBAF

43 63 14 15

69 70

Deprotection of 43 with the use of TBAF will provide diol 63, which can be used

to prepare the phenyl selenoster 14. It might be challenging because of the potential

migaration of the �-alkene to the � position to make the more stable conjugated system

upon oxidation. Use of mild oxidant MnO2 will inhibit this migration problem in the first

step. However, this problem may still persist in subsequent steps. Assuming compound

14 could be successfully prepared, it could be used as the radical precursor to perform the

7-exo/6-endo radical cyclizaton to provide compound 15. This is because the electron

withdrawing carbonyl group is next to the conjugated alkene, its terminal position will be

more electron-deficient. As a result, 6-endo rather than 5-exo cyclization will proceed

Scheme 1. Tandem Cyclization of Enone 14

30

following the 7-exo cyclization. The compound 15 contains the bicyclo [5.4.0] ring

system, which is found in Lyconadin A. However, the methyl group is absent because

cyclization occurs via a 6-endo fashion. Thus, it can only be used to investigate the model

7-exo/6-endo radical cyclizaton. Alternatively, cyclizaton with Bu6Sn2 could be

performed to provide 69, with the phenylseleno group transferred to the � position of its

carbonyl carbon in the 6-membered ring.1,2 In the presence of H2O2, oxidation-

elimination of 69 will provide 70 which can be transformed further by conjugate

addition.3

This cyclization can be applied in the total synthesis of Lyconadin A (Scheme 2).

The phenyl selenoester 71, an analogue of compound 6, can be synthesized from

compound 7. It will then be used as the radical precursor to run the 7-exo/6-endo

cyclization. The resulting product will be treated with H2O2, and the methyl group will be

introduced to the resulting compound.4 Finally, compound 4 will be obtained by

epimerization.5

BocN

SePh

O

O NBoc2H

BocNO

O

H

H NBoc2

O

O1. Bu6Sn2, hv2. H2O2

3. CuBr, MeLi4. epimerization

71 4

Scheme 2. Proposed Acyl Radical Cascade Approach towards Lyconadin A

31

4.2 Conclusion

In summary, the model 7-exo/5-exo cascade reaction to form a bicyclo[5.3.0] ring

system was investigated. Alkylation substrate 56 was found suitable for the preparation

of the compond 57, which was then used to provide the radical precursor phenyl

selenoester 16. With the use of Et3B and O2 as radical initiator and (TMS)3SiH as chain

transfer agent, the tandem cyclization of 16 was found to proceed smoothly. It is believed

that this model 7-exo cascade cyclization was performed with high yield and excellent

stereoselectivity. The diene 43 was proposed to provide the radical precursor 14, which

will be used to investigate the 7-exo/6-endo cascade reaction. Future efforts will be

directed to the total synthesis of Lyconadin A.

References

1. Byers, J. “Atom Transfer Reaction,” In Radicals in Organic Synthesis;

Renaud, P.; Sibi, M. P.; Eds.; Wiley-VCH: Weinheim, 2001; Vol. 1, Chapter

1.5 (pp 72–89).

2. Bennasar, M. L.; Roca, T.; Ferrando, F. Tetrahedron Lett. 2004, 45, 5605.

3. Grieco, P. A.; Nishizawa, M. J.Chem. Soc. Chem. Commun. 1976, 582.

4. Karl, D. R.; Bharat, L.; Niranjan, D.; Janice, D. W. Tetrahedron Lett. 1990,

31, 4105.

5. Zimmerman, H. E. Acc. Chem. Res. 1987, 20, 263.

32

CHAPTER 5. EXPERIMENTAL AND SPECTROSCOPIC DATA

5.1 General Methods

Tetrahydrofuran, acetonitrile, ether, dimethylsulfulfoxide, methylene chloride,

triethylamine, N,N-dimethylformamide, methanol and benzene were dried by passing

through a Glass Contour solvent drying system containing cylinders of activated

alumina.1 Flash chromatography was carried out using 60–230 mesh silica gel. 1H NMR

spectra were obtained on either a Varian 300 MHz or a Varian 500 MHz spectrometer as

indicated, with chloroform (7.27 ppm) or tetramethylsilane (0.00 ppm) as internal

reference. Signals are reported as follows: s (singlet), d (doublet), t (triplet), q (quartet),

dd (doublet of doublets), dt (doublet of triplets), m (multiplet). Coupling constants are

reported in hertz (Hz). 13C NMR spectra were obtained on one of two Varian

spectrometers operating at 75 or 125 MHz respectively (as indicated), with chloroform

(77.23 ppm) as internal reference. The intensities of 1H–1H COSY and 1H NOSEY

correlations are reported as follows: w (weak), m (medium), s (strong). Infrared spectra

were obtained on a Nicolet Avatar 360 FTIR spectrometer. Mass spectral data were

obtained using FAB and ESI techniques by the Brigham Young University mass

spectrometry facility.

References

1. Pangborn, A. B.; Giardello, M. A.; Grubbs, R. H.; Rosen, R. K.; Timmers, F. J.

Organometallics, 1996, 15, 1518.

33

5.2 Experimental Details

OTBS

CO2Et

CO2Et

Diethyl 2-(2-((tert-butyldimethylsilyloxy)methyl)phenethyl)malonate (57). To

a suspension of NaH (60% dispersion in mineral oil, 160 mg, 4.00 mmol) in anhydrous

THF (4 mL) at rt under Ar was added dimethyl malonate (607 µl, 640 mg, 4.00 mmol)

dropwise, with wild evolution of gas. The mixture was stirred at rt for 10 min, bromide

44 (329.35 mg, 1.00 mmol) was added, and most of the THF was removed in vacuo. The

residue was dissolved in anhydrous acetonitrile (2 mL), a NaI (74.95 mg, 0.5 mmol)

solution in anhydrous acetonitrile (2 mL) was added, and the reaction mixture was stirred

at 60 °C for 12 h. The reaction was cooled to rt and quenched with 1 M HCl (until the pH

value of the mixture was around 6). The organic phase was collected, the aqueous phase

was extracted with EtOAc (3 × 7 mL), and the combined organic phase was washed with

brine (15 mL), dried (NaSO4), and concentrated in vacuo. The residue was purified by

flash chromatography (SiO2, 2.0 × 15 cm, 5–15% EtOAc in hexanes) to give the desired

product (326 mg, 0.8 mmol, 80%) as a yellow oil: 1H NMR (CDCl3, 300 MHz) δ 7.41–

7.38 (m, 1H), 7.22–7.11 (m, 3H), 4.72 (s, 2H), 4.18 (q, J = 7.2 Hz, 4H), 3.36 (t, J = 7.5

Hz, 1H), 2.63 (m, 2H), 2.16 (m, 2H), 1.24 (t, J = 6.9 Hz, 6H), 0.91 (s, 9H), 0.07 (s, 6H);

13C NMR (CDCl3, 75 MHz) δ 169.4 (2C), 139.0, 138.1, 129.2, 127.5, 127.4, 126.5, 63.0,

61.6 (2C), 51.9, 29.9 (2C), 26.1 (3C), 18.6, 14.3 (2C), –5.1 (2C); IR (film) νmax 2955,

34

2856, 1732, 1471, 1463, 1389, 1369, 1255, 1181, 1116, 838, 776 cm–1; HRMS (ESI)

409.2405 (MH+, C22H37O5Si, requires 409.2405).

OTBS

OH

OH

2-(2-((tert-Butyldimethylsilyloxy)methyl)phenethyl)propane-1,3-diol (58). To

a solution of 57 (22.5mg, 0.055 mmol) in anhydrous ether (1 mL) was added LAH (1.0 M

in ether, 116 µl, 0.116 mmol) at 0 °C under Ar. The reaction was allowed to warm up to

rt and stirred for 5 h. The reaction was quenched with 1M HCl (until the pH value of the

mixture was around 6) and diluted with distilled H2O (5 mL). The organic phase was

collected, the aqueous phase was extracted with CH2Cl2 (3 × 5 mL), and the combined

organic phase was washed with brine (5 mL), dried (NaSO4), and concentrated in vacuo.

The residue was purified by flash chromatography (SiO2, 2.0 × 10 cm, 20–50% EtOAc in

hexanes) to give the desired product (16.2 mg, 0.05 mmol, 91%) as a white solid: 1H

NMR (CDCl3, 500 MHz) δ 7.42–7.40 (m, 1H), 7.22–7.20 (m, 2H), 7.17–7.16 (m, 1H),

4.76 (s, 2H), 3.83 (dd, J = 3.5, 11.0 Hz, 2H), 3.68 (dd, J = 7.0, 10.5 Hz, 2H), 3.19 (s, 2H),

2.69–2.65 (m, 2H), 1.85–1.80 (m, 1H), 1.59–1.55 (m, 2H) 0.96 (s, 9H), 0.13 (s, 6H); 13C

NMR (CDCl3, 125 MHz) δ 139.6, 138.5, 129.0, 127.7, 127.5, 126.3, 65.9 (2C), 63.3,

42.1, 29.9, 28.9, 26.1 (3C), 18.6, –5.0 (2C); IR (film) νmax 3357, 2929, 1471, 1255, 1215,

1078, 838, 776 cm–1; ES m/z 347.2010 (MNa+, C18H32O3SiNa requires 347.2012).

35

OTBS

OH

OPMB

4-(2-((tert-Butyldimethylsilyloxy)methyl)phenyl)-2-((4-

methoxybenzyloxy)methyl)butan-1-ol (60). To a solution of 58 (126.40 mg, 0.39

mmol) in anhydrous THF (0.42mL) and DMSO (0.10 mL) at 0 °C under Ar was added

NaH (60% dispersion in mineral oil, 15.60 mg, 0.39 mmol) with evolution of gas. The

reaction mixture was warmed to rt and stirred at rt for 1 h. The reaction mixture was

cooled to 0 °C again, tetrabutylammonium iodide (25.00 mg, 0.07 mmol) was added, and

4-methoxybenzyl chloride (53 µl, 61.08 mg, 0.39 mmol) was added dropwise. The

reaction mixture was stirred at rt for 10 h. The reaction was quenched with sat NH4Cl (2

mL). The organic phase was collected, the aqueous phase was extracted with EtOAc (3 ×

3 mL), and the combined organic phase was washed with brine (3 mL), dried (NaSO4),

and concentrated in vacuo. The residue was purified by flash chromatography (SiO2, 2.0

× 20 cm; 20% EtOAc in hexanes) to give the desired product (100.30 mg, 0.226 mmol,

58%) as a yellow oil: 1H NMR (CDCl3, 500 MHz) δ 7.41–7.38 (m, 1H), 7.25–7.11 (m,

5H), 6.90–6.80 (m, 2H), 4.72 (s, 2H), 4.45 (d, J = 4.4 Hz, 2H), 3.80 (s, 3H), 3.78–3.62

(m, 3H), 3.50–3.47 (m, 1H), 2.70–2.58 (m, 3H), 1.97–1.90 (m, 1H), 1.66–1.51 (m, 2H),

0.93 (s, 9H), 0.09 (s, 6H); 13C NMR (CDCl3, 125 MHz) δ 159.5, 139.6, 138.8, 130.2,

129.5 (2C), 128.9, 127.6, 127.4, 126.2, 114.1 (2C), 73.9, 73.4, 66.2, 63.2, 55.5, 40.8,

30.0, 29.4, 26.2 (3C), 18.6, –5.0 (2C); IR (film) νmax 3357, 2953, 2938, 2856, 1513, 1250,

36

1082, 1038, 838, 776 cm–1; HRMS (FAB) m/z 467.2589 (MNa+, C26H40O4SiNa requires

444.27).

OTBS

OPMB

HO

6-(2-((tert-Butyldimethylsilyloxy)methyl)phenyl)-4-((4-

methoxybenzyloxy)methyl)hex-1-en-3-ol (65). To a solution of oxalyl chloride (869 µl,

1.28 g, 10.1 mmol) in anhydrous CH2Cl2 (3.90 mL) at –78 °C under Ar was added

DMSO (1.65 mL, 1.82 g, 23.3 mmol) in anhydrous CH2Cl2 (11.40 mL) dropwise. The

solution was stirred at –78 °C under Ar for 30 min, then the monoPMB compound 60

(1.50 g, 3.38 mmol) in anhydrous CH2Cl2 (4.20 mL + 4.20 mL × 2 rinse), and the

resulting mixture was stirred at –78 °C under Ar for 1 h. Et3N (7.18 mL, 5.22 g, 51.6

mmol) was added to the mixture dropwise, then the reaction was warmed up to 0 °C, and

the mixture was stirred at 0 °C for another hour. The reaction was quenched with brine

(50 mL). The organic phase was collected and the aqueous phase was extracted with Et2O

(3 × 50 mL). The combined organics were washed with brine (100mL), dried (Na2SO4),

and concentrated in vacuo to give the aldehyde.

To a solution of the crude aldehyde (1.49 g, 3.4 mmol, based on the alcohol) in

anhydrous THF (16.00 mL) at 0 °C under Ar was added vinyl magnesium bromide (1.0

M in THF, 5.06 mL, 5.06 mmol) dropwise. The mixture was stirred at 0 °C under Ar for

1 h. The reaction was quenched with sat aq NH4Cl (30 mL). The organic phase was

collected and the aqueous phase was extracted with CH2Cl2 (3 × 40 mL). The combined

37

organics were dried (Na2SO4) and concentrated in vacuo. The residue was purified by

flash chromatography (SiO2, 2.5 × 30 cm, 5% EtOAc in hexanes) to afford the alkene 26

(1.16 g, 2.46 mmol, 73% over two steps) as a yellow oil: 1H NMR (CDCl3, 500 MHz) δ

7.42 (q, J = 4.5 Hz, 1H), 7.27–7.10 (m, 5H), 6.89 (dd, J = 3.0, 9.0 Hz, 2H), 5.90–5.83 (m,

1H), 5.30 (dd, J = 1.5, 17.0 Hz, 1H) and 5.20– 5.16 (m, 1H), 4.74 and 4.72 (2s, 2H),

4.47–4.41 (m, 2H), 4.34 and 4.25–4.20 (s and m, 1H), 3.82 and 3.81 (2s, 3H), 3.75 (dd, J

= 3.40, 9.30, 1H), 3.55–3.52 (m, 1H), 3.59, 3.21 and 3.17 (2d, J = 5.5, 6.0 Hz, 1H), 2.66–

2.58 (m, 2H), 2.05–1.99 and 1.88–1.81 (2m, 1H) 1.77–1.49 (m, 2H), 0.94 (s, 9H), 0.10 (s,

6H); 13C NMR (CDCl3, 75 MHz) δ 159.5, 140.2, 139.5, 138.8 and 138.5, 130.1, 129.6

and 129.5, 128.9 (2C), 127.3 (2C), 126.2, 115.7, 115.6, 114.1, 75.6 and 75.3, 73.4, 71.9

and 71.2, 63.1, 55.5, 43.6, 30.4 and 30.0, 29.6 and 27.8, 26.2 (3C), 18.9, –5.0 (2C); IR

(film) νmax 3473, 3071, 3002, 2954, 2929, 2856, 1613, 1514, 1463, 1250, 1086, 1038,

837, 776 cm–1; HRMS (FAB) m/z 493.2742 (MNa+, C28H42O4SiNa requires 493.2745).

OTBS

OPMB

TBSO

6-(2-((tert-Butyldimethylsilyloxy)methyl)phenyl)-4-((4-

methoxybenzyloxy)methyl)-2-(tert-butyldimethylsilyloxy)-hex-1-en-3-ol (66). To a

solution of the alkene-alcohol 65 (1.16 g, 2.46 mmol) in anhydrous DMF (28 mL) was

added imidazole (503 mg, 7.39 mmol) and tert-butyldimethylsilyl chloride (1.11 g, 7.39

mmol) and the reaction was stirred at rt under Ar for 23 h. The mixture was diluted with

Et2O (10 mL) and H2O (10 mL). The organic phase was collected and the aqueous phase

was extracted with Et2O (3 × 10 mL). The combined organics were washed with brine

38

(10 mL), dried (NaSO4), and concentrated in vacuo. The residue was purified by flash

chromatography (SiO2, 2.5 × 35 cm, 5% Et2O in hexanes) to give the desired product 54

(1.21 g, 2.06 mmol, 84%) as a yellow oil: 1H NMR (CDCl3, 300 MHz) δ 7.41–7.44 (m,

1H), 7.08–7.26 (m, 5H), 6.85 (d, J = 8.7 Hz, 2H), 5.84–5.70 (m, 1H), 5.19–5.04 (m, 2H),

4.71 (s, 2H), 4.47–4.24 (m, 3H), 3.87 (s, 3H), 3.55–3.39 (m, 2H), 2.70–2.47 (m, 2H),

1.83–1.65 (m, 2H), 1.56–1.40 (m, 1H), 0.93 (s, 9H), 0.87 (s, 9H), 0.07, 0.06, 0.02 and –

0.01 (4s, 12H); 13C NMR (CDCl3, 75 MHz) δ 159.3, 140.4 and 139.8, 139.6, 138.9,

130.9, 129.4 and 129.3, 128.9 (2C), 127.1(2C), 126.8, 126.0, 115.5, 114.8 and 114.0,

74.5, 73.4 and 73.0, 70.4 and 70.0, 63.0, 55.4, 45.6 and 45.5, 30.8 and 30.5, 28.4 and

27.7, 26.2 (3C), 26.1 (3C), 18.6, 18.4, –4.0 and –4.1, –4.7 and –4.8, –5.0 (2C); IR (film)

νmax 3072, 2999, 2954, 2929, 2885, 2856, 1613, 1514, 1471, 1463, 1251, 1078, 1038,

1006, 836,776 cm–1; HRMS (ESI) 607.3614 (MNa+, C34H56O4Si2Na requires 607.3609).

OTBS

OH

TBSO

3-(tert-Butyl-dimethyl-silanyloxy)-2-{2-[2-(tert-butyl-dimethyl-

silanyloxymethyl)-phenyl]-ethyl}-pent-4-en-1-ol (67). The compound 66 (1.21 g, 2.06

mmol) was dissolved in CH2Cl2 (29.3 mL) and distilled H2O (1.46 mL), and 2,3-

dichloro-5,6-dicyano-1,4-benzoquinone (DDQ, 469 mg, 2.06 mmol) was added. The

solution was stirred at rt under N2 for 1 h. The reaction was quenched with sat aq

NaHCO3 (15 mL). The organic layer was collected and the aqueous layer was extracted

with CH2Cl2 (3 × 10 mL). The combined organics were successively washed with sat.

aqueous NaHCO3 (15 mL) and brine (15 mL), dried (NaSO4), and concentrated in vacuo.

39

The residue was purified by flash chromatography (SiO2, 2.5 × 35 cm, 15% EtOAc in

hexanes) to give the desired product 28 (774 mg, 1.59 mmol, 77 %) as a yellow oil: 1H

NMR (CDCl3, 300 MHz) δ 7.53–7.48 (m, 1H), 7.30–7.20 (m, 3H), 6.04–5.89 (m, 1H),

5.39–5.23 (m, 2H), 4.84 and 4.81 (2s, 2H), 4.38 and 4.23 (2t, J = 4.5, 5.0 Hz, 1H), 3.94–

3.65 (m, 2H), 3.20 and 2.90 (2s, 1H), 2.88–2.63 (m, 2H), 2.07–2.01 and 1.87–1.74 (2m,

1H), 1.66–1.40 (m, 2H), 1.03, 1.02 and 0.99 (3s, 18H), 0.19, 0.17and 0.14(3s, 12H); 13C

NMR (CDCl3, 75 MHz) δ 140.3, 139.6, and 139.5, 138.9, 138.8 and 137.5, 129.0 and

128.9, 127.6 and 127.4, 127.3 and 127.2, 126.3 and 126.2, 116.5, 115.8, 78.4, 64.1 and

63.2, 63.1 and 62.9, 46.3 and 45.9, 30.5 and 30.1, 29.3 and 28.7, 26.2 (3C), 26.1 and 26.0

(3C), 18.6, 18.3 and 18.2, –3.9 and –4.3, –4.7 and –4.9, –5.0 (2C); IR (film) νmax 3448,

2955, 2929, 2885, 2857, 1472, 1463, 1254, 1121, 1075, 1028, 1005, 837, 776 cm–1;

HRMS (ESI) 487.3042 (MNa+, C26H48O3Si2Na requires 487.3034).

OTBS

TBSO

1-(tert-Butyl-dimethyl-silanyloxymethyl)-2-[4-(tert-butyl-dimethyl-

silanyloxy)-3-vinyl-hex-5-enyl]-benzene (43). To a solution of oxalyl chloride (134 µl,

198 mg, 1.56 mmol) in anhydrous CH2Cl2 (5.50 mL) at –78 °C under Ar was added

DMSO (232 µl, 255.4 mg, 3.27 mmol) in anhydrous CH2Cl2 (1.60 mL) dropwise. The

solution was stirred at –78 °C under Ar for 30 min, then the compound 67 (220 mg, 0.47

mmol) in anhydrous CH2Cl2 (0.6 mL + 0.6 mL × 2 rinse) was added, and the resulting

mixture was stirred at –78 °C under Ar for 1 h. Et3N (1.0 mL, 733.7 mg, 7.25 mmol) was

40

added to the mixture dropwise, then the reaction was warmed up to 0 °C, and the mixture

was stirred at 0 °C for another hour. The reaction was quenched with brine (7 mL). The

organic phase was collected and the aqueous phase was extracted with Et2O (3 × 7 mL).

The combined organics were washed with brine (14 mL), dried (Na2SO4), and

concentrated in vacuo to give the aldehyde.

To a suspension of methyltriphenylphosphonium bromide (1.01 g, 2.84 mmol) in

anhydrous THF (14.5 mL) at –15 °C under Ar was added n-BuLi (2.5 M in hexanes, 0.95

mL, 2.37 mmol) dropwise. The yellow mixture was stirred at –15 °C under Ar for 30

min. The crude aldehyde was dissolved in anhydrous THF (3.1 mL) and the prepared

Wittig reagent was added to the solution. The mixture was stirred at –10 °C to –15 °C

under Ar for 1 h and then warmed up to rt and stirred at rt under Ar for 10 h. The reaction

was quenched with sat aq NH4Cl (15 mL). The organic layer was collected and the

aqueous phase was extracted with Et2O (3 × 15 mL). The combined organics were

washed with brine (30 mL), dried (Na2SO4), and concentrated in vacuo. The residue was

purified by flash chromatography (SiO2, 2.5 × 20 cm, 5% EtOAc in hexanes) to give the

desired product 56 (157 mg, 0.34 mmol, 52%) as a yellow oil: 1H NMR (CDCl3, 300

MHz) δ 7.40–7.28 (m, 1H), 7.14–7.05 (m, 3H), 5.78–5.57 (m, 2H), 5.11–4.99 (m, 4H),

4.67 (s, 2H), 4.00 (t, J = 5.0 Hz, 1H), 2.64–2.54 (m, 1H), 2.44–2.32 (m, 1H), 2.14–2.05

(m, 1H), 1.83–1.73 (m, 1H), 1.49–1.36 (m, 1H), 0.89 (9H), 0.94 and 0.83 (2s, 9H), 0.04

(6H), –0.02, –0.03 and –0.05 (3s, 6H); 13C NMR (CDCl3, 75 MHz) δ 139.8, 139.7, 139.3,

138.9, 134.1 and 133.8, 129.0, 128.7 and 128.6, 127.2 and 127.0, 126.0, 117.1, 116.7,

115.1 (2C), 77.1, 63.0, 51.6, 51.4, 30.9, 30.2 and 30.0 (1C), 26.29 (2C), 26.19 (2C),

26.16 (2C), 18.7, 18.5, –3.9 and –4.0, –4.6, –5.0 (2C); IR (film) νmax 2955, 2929, 2885,

41

2857, 1253, 1078, 837, 776 cm–1; HRMS (ESI) 483.3094 (MNa+, C27H48O2Si2Na

requires 483.3085).

OH

TBSO

{2-[4-(tert-Butyl-dimethyl-silanyloxy)-3-vinyl-hex-5-enyl]-phenyl}-methanol

(68). To a solution of diene 43 (300 mg, 0.47 mmol) in anhydrous CH2Cl2 (5.2 mL) at 0

°C under Ar was added a solution of (1S)-(+)-(10)-camphorsulfonic acid (21.8 mg, 0.09

mmol) in anhydrous MeOH (5.2 mL). The mixture was stirred at 0 °C under Ar for 1 h

and 40 min. The reaction was quenched with sat aq NaHCO3 (8 mL) and diluted with

CH2Cl2 (3 mL) and distilled H2O (3 mL). The organic layer was collected and the

aqueous phase was extracted with CH2Cl2 (3 × 8 mL). The combined organics were dried

(Na2SO4) and concentrated in vacuo. The residue was purified by flash chromatography

(SiO2, 2.5 × 25 cm, 5% EtOAc in hexanes) to give the desired product 30 (132 mg, 0.39

mmol, 84%) as a yellow oil: 1H NMR (CDCl3, 300 MHz) δ 7.40–7.37 (m, 1H), 7.27–7.18

(m, 3H), 5.85–5.64 (m, 2H), 5.19–5.05 (m, 4H), 4.71 (s, 2H), 4.07 (q, J = 2.5, 7.0 Hz,

1H) 2.79–2.69 (m, 1H), 2.60–2.48 (m, 1H), 2.21–2.12 (m, 1H), 1.93–1.80 (m, 1H), 1.59–

1.45 (m, 2H), 0.90 and 0.89 (2s, 9H), 0.04, 0.03 and 0.02 (3s, 6H); 13C NMR (CDCl3, 75

MHz) δ 141.0 and 140.9, 139.9 and 139.7, 139.5 and 139.3, 129.6 and 129.5, 128.3 and

128.1, 126.3, 117.2, 116.8, 115.2, 115.1, 77.1 and 77.0, 63.3, 51.4 and 51.2, 31.3 and

30.9, 30.4 and 30.3, 26.1 and 26.0 (3C), 18.4, –4.0, –4.1, –4.6, –4.7; IR (film) νmax 3322,

42

3075, 2955, 2929, 2885, 2857, 2360, 2342, 1471, 1462, 1252, 1080, 1028, 1005, 837,775

cm–1; HRMS (ESI) 369.2219 (MNa+, C21H34O2SiNa requires 369.2220).

O

TBSO

SePh

2-[4-(tert-Butyl-dimethyl-silanyloxy)-3-vinyl-hex-5-enyl]-selenobenzoic acid

Se-phenyl ester (16). To a solution of oxalyl chloride (13.8 µl, 27.8 mg, 0.22 mmol) in

anhydrous CH2Cl2 (0.76 mL) at –78 °C under Ar was added DMSO (32 µL, 35.5 mg,

0.46 mmol) in anhydrous CH2Cl2 (0.22 mL) dropwise. The solution was stirred at –78 °C

under Ar for 30 min, then benzyl-alcohol 30 (23 mg, 0.07 mmol) in anhydrous CH2Cl2

(0.1 mL + 0.1 mL × 2 rinse) was added, and the resulting mixture was stirred at –78 °C

under Ar for 1 h. Et3N (140 µL, 102 mg, 1.01 mmol) was added to the mixture dropwise,

then the reaction was warmed up to 0 °C, and the mixture was stirred at 0 °C for another

hour. The reaction was quenched with brine (2 mL). The organic phase was collected and

the aqueous phase was extracted with Et2O (3 × 2 mL). The combined organics were

washed with brine (4 mL), dried (Na2SO4), and concentrated in vacuo to give the

aldehyde.

To a solution of the crude aldehyde (22.7 mg, 0.07 mmol, based on the alcohol) in

t-BuOH (0.72 mL) and H2O (0.18 mL) was added successively 2-methyl-2-butene (83.9

µl, 55.6 mg, 0.79 mmol), NaH2PO4 (9.6 mg, 0.08 mmol), and NaClO2 (35.8 mg, 0.40

mmol). The orange solution was stirred at rt under Ar for 5 h. The reaction was quenched

43

with sat aq NH4Cl (2 mL) and extracted with CH2Cl2 (4 × 2 mL). The combined organics

were dried (Na2SO4) and concentrated in vacuo to give the acid.

To a solution of the crude acid (23.8 mg, 0.07 mmol, based on aldehyde) in

anhydrous CH2Cl2 (0.60 mL) at rt under Ar was added PhSeSePh (99 µL of a 1.0 M

solution in CH2Cl2, 30.9 mg, 0.10 mmol) and Bu3P (35.8 µL, 29.4 mg, 0.15 mmol)

dropwise. The orange solution was stirred at rt under Ar for 5 h and 40 min, after which

the TLC analysis indicated incomplete conversion. More PhSeSePh (49.5 µL of a 1.0 M

solution in CH2Cl2, 15.5 mg, 0.05 mmol) and Bu3P (17.9 µL, 14.7 mg, 0.08 mmol) were

added, and the solution was stirred at rt under Ar for additional 2.5 h, then quenched with

sat aq (1mL). The organic phase was collected and the aqueous layer was extracted with

Et2O (3× 2 mL). The combined organics were washed with brine (4 mL), dried (Na2SO4),

and concentrated in vacuo. The residue was purified by flash chromatography (SiO2, 1.0

× 25 cm, 1% Et2O in hexanes) to give the desired product 30 (20 mg, 0.04 mmol, 62%

over three steps) as a yellow oil: 1H NMR (CDCl3, 500 MHz) δ 7.83–7.82 (d, J = 8.0 Hz,

1H), 7.62–7.60 (m, 2H), 7.46–7.42 (m, 4H), 7.33–7.27(m, 2H), 5.81–5.74 (m, 1H), 5.72–

5.65 (m, 1H), 5.15–5.10 (m, 1H), 5.08–5.02 (m, 1H), 4.05–4.03 (m, 1H), 2.91–2.83 (m,

1H), 2.72–2.64 (m, 1H), 2.17–2.09 (m, 1H), 1.88–1.80 (m, 1H), 0.89 and 0.88 (2s, 9H),

0.02, 0.01, and –0.01 (3s, 6H); 13C NMR (CDCl3, 125 MHz) δ 194.3, 140.9, 139.9 and

139.7, 139.5 and 139.1, 136.2 (2C), 132.1, 131.1, 129.5 (2C), 129.1 and 128.6, 127.5,

126.2, 117.1, 116.7, 115.1, 115.0, 77.1, 51.2 and 50.9, 31.8 and 31.4, 31.1 and 30.0, 26.1

(3C), 18.4, -4.1 (2C); IR (film) νmax 3073, 2927, 2855, 2360, 2342, 1703, 1477, 1439,

1252, 1183, 1078, 1023, 919, 866, 836, 775 cm–1; HRMS (ESI) 523.1354 (MNa+,

C27H36O2SiSeNa requires 523.1542).

44

OH

OTBSH

17a

OH

OTBSH

12

34

5

6 78 9

10 11

131214 15

H

H

nOe

nOeJ = 11.5 Hz

OH

OTBSH

17b

H

H

nOe

J = 8.5 or 11.5 Hz

Tricycles 17a and 17b. The phenyl selenoester 16 (22.5 mg, 0.045 mmol) was

dried azetropically with anhydrous benzene (2 × 2.3 mL), then dissolved in anhydrous

benzene (4 × 2.8 mL) into a 3-necked round buttom flask under an atmosphere of dry air.

(TMS)3SiH (27.8 µl, 0.090 mmol) and Et3B (1.0 M in hexane, 80 µl, 0.080 mmol) were

added to the mixture, and additional Et3B (1.0 M in hexane, 0.82 ml, 0.82 mmol) was

then added slowly by syringe pump (80 µL/h, 10.25 h) while a continuous flow of

compressed air was passed over the reaction. The mixture was stirred vigorously

throughout the addition time. TLC analysis indicated incomplete conversion, so

additional (TMS)3SiH (27.8 µL, 0.090 mmol) was added, and another portion of Et3B

(1.0 M in hexane, 0.82 mL, 0.82 mmol) was added by syringe pump (13 µL/h, 63 h)

while the reaction was still stirring vigorously under air. Following the addition, the

reaction was stirred for an additional 12 h. TLC showed complete conversion. The

reaction mixture was concentrated in vacuo. The residue was purified by flash

chromatography (SiO2, 1.0 × 20 cm, 1% Et2O in hexanes) to give the desired

diastereomers 17a and 17b as 1 : 1 ratio (12.5 mg, 0.036 mmol, 81 % over three steps) as

yellow oils. Prep TLC purification afforded the syn product (3.5 mg), and the anti

product (3.0 mg). The data for 17a: 1H NMR (CDCl3, 500 MHz) δ 7.81 (dd, J = 1.0, 8.0

45

Hz, 1H), 7.42 (dt, J = 1.5, 7.5 Hz, 1H), 7.32(t, J = 7.5 Hz, 1H), 7.19 (d, J = 7.5 Hz, 1H),

3.89 (t, J = 3.0 Hz, 1H), 3.13 (dt, J = 4.5, 11.5 Hz, 1H), 2.97 (ddd, J = 6.0, 12.0, 14.5 Hz,

1H), 2.88 (ddd, J = 3.5, 6.0, 14.0 Hz, 1H), 2.44 (ddd, J = 4.0, 8.5, 13.0 Hz, 1H), 2.11–

2.05 (m, 1H), 2.00–1.93 (m, 1H), 1.95–1.88 (m, 1H), 1.81–1.74 (m, 1H), 1.79–1.70 (m,

1H), 0.97 (d, J = 7.0 Hz, 3H), 0.96 (s, 9H), 0.072 (s, 3H), 0.067 (s, 3H); 13C NMR

(CDCl3, 125 MHz) δ 208.8, 140.1, 138.5, 132.4, 130.3, 129.2, 127.0, 78.2, 52.9, 47.5,

40.0, 33.9, 32.0, 30.0, 26.3 (3C), 26.0, 15.4, –3.9, –3.7, ; IR (film) νmax 2927, 2855, 1677,

1461, 1252, 1023, 834, 773 cm–1; HRMS (ESI) 367.2060 (MNa+, C21H32O2SiNa requires

367.2064).

2D 1H–1H COSY NMR (CDCl3, 500 MHz) 3.89/2.00–1.93 (w, H-11/H-10),

3.89/1.95–1.88 (w, H-11/H12), 3.18/2.44 (w, H-14/H-13), 3.18/2.00–1.93 (s, H-14/H-10),

3.18/1.79–1.70 (s, H-14/H-13), 2.97/2.88 (s, H-8/H-8), 2.97/2.11–2.05 (w, H-8/H-9),

2.97/1.81–1.74 (s, H-8/H-9), 2.88/2.11–2.05 (w, H-8/H-9), 2.88/1.81–1.74 (w, H-8/H-9),

2.44/1.95–1.88 (m, H-13/H-12), 2.44/1.79–1.70 (s, H-13/H-13), 2.11–2.05/1.81–1.74 (s,

H-9/H-9), 2.00–1.93/1.81–1.74 (w, H-10/H-9), 1.95–1.88/1.79–1.70 (m, H-12/H-13),

1.95–1.88/0.97 (s, H-12/H-15); nOe NMR (CDCl3, 500 MHz) Irradiation of the signal at

3.89 led to an enhancement in the signal at 2.00–1.93 (H-11/H-10). Irradiation of the

signal at 3.18 led to enhancements in the signals at 1.95–1.88 (H-14/H-12) and 1.79–1.70

(H-14/H-13).

The data for 17b: 1H NMR (CDCl3, 500 MHz) δ 7.78 (dd, J = 1.5, 8.0 Hz, 1H),

7.41 (dt, J = 1.5, 7.5 Hz, 1H), 7.31 (dt, J = 1.0, 7.5 Hz, 1H), 7.21 (d, J = 7.0 Hz, 1H), 3.74

(dd, J = 2.0, 5.0, 1H), 3.20 (td, J = 8.5, 11.5 Hz, 1H), 3.03 (ddd, J = 5.5, 11.5, 14.5, 1H),

2.88 (td, J = 4.5, 14.5 Hz, 1H), 2.33–2.27 (m, 1H), 2.16–2.10 (m, 1H), 2.05–1.99 (m,

46

2H), 1.80–1.71 (m, 2H), 0.91 (d, J = 7.0, 3H), 0.91 (s, 9H), 0.07 (s, 3H), 0.6 (s, 3H); 13C

NMR (CDCl3, 125 MHz) δ 206.7, 141.5, 138.6, 132.3, 130.4, 128.9, 126.9, 82.2, 53.7,

44.4, 41.8, 32.9, 32.1, 29.9, 26.1 (3C), 25.6, 19.9, –4.6, –4.3; IR (film) νmax 2926, 2855,

1677, 1461, 1252, 1077, 835, 774 cm–1; HRMS (ESI) m/z 367.2056 (MNa+,

C21H32O2SiNa requires 367.2064).

2D 1H–1H COSY NMR (CDCl3, 500 MHz), 3.74/2.05–1.99 (w, H-11/H-12),

3.20/2.33–2.27 (w, H-14/H-13), 3.20/2.05–1.99 (m, H-14/H-10), 3.20/1.80–1.71 (m, H-

14/H-13), 3.03/2.88 (s, H-8/H-8), 3.03/2.16–2.10 (w, H-8/H-9), 3.03/1.80–1.71 (m, H-

8/H-9), 2.88/2.16–2.10 (w, H-8/H-9), 2.88/1.80–1.71 (w, H-8/H-9), 2.33–2.27/2.05–1.99

(w, H-13/H-12), 2.33–2.27/1.80–1.71 (s, H-13/H-13), 2.16–2.10/1.80–1.71 (s, H-9/H-9),

2.05–1.99/1.80–1.71 (w, H-12/H-13 or H-10/H-9), 2.05–1.99/0.91 (s, H-12/H-15); 1D

nOe NMR (CDCl3, 500MHz) Irradiation of the signal at 3.20 led to an enhancement in

the signal at 2.05–1.99 (H-14/H-12).

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