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2006-06-30
Model Studies Towards the Total Synthesis of Lyconadin A via An 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
O O O PhSe 7-exo-6-endo H H HN O O 14 15 H
O N H O H 7-exo-5-exo H PhSe Lyconadin A, 1 TBSO H OTBS 16 17a, 17b
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.
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.
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
I 5.2 Experimental Details……………………………………………………. 33
5.3 Selected NMR Spectra………………………………………………….. 47
II 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
III 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
IV 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
V 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
1 (IC50 = 1.70 µg/mL). 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.
O H H HN
H
N H H Lyconadin A, 1 Lycopodium Complanatum
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.)
1 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
2 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 O N
HO NH O H2N MeO Cl
HupA 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.
3 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.
O PhSe O O O O O BocN BocN 1 BocN H 16 8 H HN H 15 H O 7 5 2 H12 6 14 11 4 3 13 N H NBoc2 H NBoc2 10 H H NBoc2 OTBS H 9 O OTBS 1 4 5 6 O O CO Me TBSO BocN 2 BocN O O O O HO TBSO
BnO NHBoc BnO NHBoc HO Br NBoc2 HO NBoc2
9 7 8 10 11
Scheme 1. Retrosynthesis of Lyconadin A
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
4 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 PhSe 7-exo-6-exo
TBSO
OTBS 12 13
O O PhSe 7-exo-6-endo
O O 14 15
O O 7-exo-5-exo PhSe
OTBS 16 17
Scheme 2. Model 7-exo Reactions
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.
5 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
RCO H RCO H RCO2H 2 2 N-PSP (EtO) POCl (PhSe) Bu P 2 2 3 PhSeNa Bu3P
O PhSeH PhSeNa RCOCl RCOCl pyr R SePh
Scheme 3. Synthesis Methods of Phenyl Selenoesters
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.
6 SePh O X X Bu3SnH, AIBN O
C6H6, reflux
18a X = H 18b X = H, 74% 19a X = CO2CH3 19b X = CO2CH3, 92%
COSePh Bu3SnH, AIBN O
C6H6, reflux CO2CH3 71% CO2CH3 20 21
Scheme 4. 7-exo Cyclizations Reported by Boger and Mathvink
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.
COSePh (TMS)3SiH, Et3B O SO Ph O 2 C6H6, r.t. O SO2Ph 22 23
O O COSePh (TMS)3SiH, Et3B + O CO2iPr O CO2iPr O CO2iPr C6H14, r.t. H H CH CH 3 81% 3 CH3 26b 24 25a O H SePh O O (TMS) SiH, Et B O 3 3 N O N O o C6H6, 0 C to r.t. O R O R
27a, R = Me 27b, R = Me, 87%, dr ≥ 19:1 28a, R = Ph 28b, R = Ph, 68%, dr ≥ 19:1
Scheme 5. 7-exo Cyclizations Reported by Evans
7 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
O Bn Bn N SeCH3 H N
(TMS)3SiH, AIBN
C6H6, reflux H O CN 71% CN 29 30 α:β = 5:2
Scheme 6. 7-exo Cyclizations Reported by Bonjoch et al.
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
Bu3SnH or (TMS)3SiH O AIBN, CO G N (80-90 atm) N
C6H6, reflux
G = Bu3Sn, 69%, E:Z = 19:81 G = (TMS)3Si, 54%, E:Z = 85:15
Scheme 7. 7-exo Cyclizations Reported by Ryu
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
8 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.
SeCH3 O "5-exo/1,3-transposition/5-exo" Bu3SnH (3.8 equiv), AIBN
o C6H6, 85 C, 8.5h O 0.018 M
31
+ +
34 32 33
62% 1:5:2
Scheme 8. 5-exo Acyl Radical Cascade Reaction
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.
9 Bu3SnH (1.25 equiv) AIBN, syringe pump
O o C6H6, 80 C, 1.5h SePh 71% O 0.012 M 57:11:11:12 35 36
Ph Ph Bu3SnH (1.3 equiv) AIBN, syringe pump O C H , 80 oC, 1.5h SePh 6 6 82% O 0.009 M
38 37 O O3, Me2S
86%
O
cis:trans = 58:42
39
Scheme 9. 6-endo Acyl Radical Cascade Reaction
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.
10 Bu3SnH (1.22 equiv) AIBN, syringe pump
SePh o C6H6, 80 C, 24h O O O O O H 0.012 M + 40 O O H O O 7-endo 41 42 O 45% (44:29:18:9) 20% (50:50)
5-exo
O O
Scheme 10. 7-endo Acyl Radical Cascade Reaction
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.
11 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,
64, 837.
7. Ayer, W. A.; Trifonov L. S. in Lycopodium Alkaloids, Academic Press, San
Diego, 1994.
8. Tang, X.; Han, F.; Chen, X.; Zhu, X. Acta Pharmacol. Sin. 1986, 7, 507.
9. Zhu, X.; Tang, X. Yaoxue Xuebao 1987, 22, 812.
10. Tang, X.; Sarno, P.; Sugaya, K.; Giacobini, E. J. Neurosci. Res. 1989, 24, 276.
11. Tang, X. Acta Pharmacol. Sin. 1996, 17, 481.
12. Jiang, H.; Luo, X.; Bai, D. Curr. Med. Chem. 2003, 10, 2231.
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.
12 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-López, J. L.; Campaña, A. G.; Oltra, J. E.; Cuerva, J. M.;
Buñuel, E.; Cárdenas, D. J. J. Am. Chem. Soc. 2005, 127, 14911. (b) Lang, S.;
Corr, M.; Muir, N.; Khan, T. A.; Schönebeck, 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.
13 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.
14 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 PhSe
O TBSO 16 14
OTBS OTBS O Suitable Alkylation + O Substrate Br OTBS 45 43 44
Scheme 1. Retrosynthesis of the Phenyl Selenoesters 14 and 16
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
15 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.
O 1. NaOH O FeCl3, Picolinic acid OH O 2. NaH, n-Bu4NI, PMB-Cl 70% t-BuOOH 3. LiAlH4 OPMB (52%) (60%) 47 46 45
1. TBSCl, imid OTBS Et3N, MsCl, LiBr OTBS THF Br 2. DDQ OH (95%) (80%) 44 48
Scheme 2. Synthesis of Bromide 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
16 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 1. NaH, PMBCl, TBAI 1. Trcl, DMAP, Et3N HO OH O O 2. HCl 2. (COCl)2, DMSO, Et3N OPMB OTr (68% for 2 steps) OPMB (60% for 2 steps) OH 50 51 49 O
ß-elimination DS M 4 OTr KH e 4 1. id 52 om O Br 2. OPMB 1 . L OTr DA 2 51 . B rom ide 44 N.R DDQ
OTBS O OTBS KHMDS OH +
OTr Br 53 54
Scheme 3. Alkylation Attempts with Compounds 51 and 53
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,
17 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.
Only trace of O O NaI + OTBS desired product was Br EtO CO2Et CH3CN, or THF observed Na or DMSO 55 44
Scheme 4. Alkylation Attempt with Sodium Salt 55
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 O O OTBS 1. NaH, THF + Br CO2Et EtO OEt 2. NaI, CH3CN, 60 °C CO2Et (90%) 57 56 44
Scheme 5. Alkylation with Diethyl Malonate 56
18 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 DIBALH (1eq - 4eq) (Most of the SM recovered) CO2Et THF, -78 °C CO2Et 57
OTBS OTBS LAH
CO2Et Anhydrous Ether OH ( > 90%) CO2Et OH 57 58
Scheme 6. Reduction of the Alkylation Product 57
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
5 6 7 Cp2ZrH2, PhI(OAc)2, or Dess Martin Reagent, the oxidation did not proceed well, with
19 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 OTBS Various conditions
OH CHO
OH OH 58 59
Reaction Conditions Results
Cp2ZrH2, Cyclohexanone Didn't work
Swern Up to 30% of the monoaldehyde yeilded
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
Scheme 7. Monoxidation of the Symmetric Diol 58
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
20 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).
OTBS OTBS 1, (COCl) , DMSO, Et N OTBS NaH, PMBCl, TBAI 2 3 2, MePPh3Br, n-BuLi OH (Y = 58%) OH OPMB (yield up to 70% OH OPMB for 2 steps) 58 60 61
OTBS O 1, DDQ OH 2, (COCl) , DMSO, Et N 2 3 OH MnO H TBAF OH 2 O 3, Vinyl magnesium bromide ( Y= 87%) ( 24% for 3 steps)
62 64 63
Scheme 8. Pathway to the Synthesis of Diene 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
21 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 1, (COCl)2, DMSO, Et3N OTBS OTBS 2, Vinyl magnesium bromide OH TBSCl, imidazole OTBS OH ( 73% over 2 steps) (Y= 84%) OPMB OPMB OPMB 60 65 66
1, (COCl) , DMSO, Et N OTBS 2 3 OTBS DDQ 2, MePPh Br, n-BuLi OTBS 3 OTBS (Y = 77%) OH ( 72% over 2 steps) 67 43
Scheme 9. Pathway to the Synthesis of Diene 43
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).
22 OTBS OH 1, Swern Oxidation COSePh OTBS CSA OTBS 2, , NaOClO, NaH2PO4 OTBS (Y = 60%) 3, PhSeSePh, Bu3P 43 68 ( 62% over 4 steps) 16
Scheme 10. Pathway to the Synthesis of Phenyl Selenoester 16
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.
7. 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.
23 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.
24 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.
25 O H O H COSePh Et3B, O2, (TMS)3SiH OTBS + PhH, r.t., 81% OTBS OTBS ( 7-exo-5-exo cyclization) H H 16 17a 17b
(1:1)
Scheme 1. Acyl Radical 7-exo/5-exo Cascade Cyclization
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.
nOe nOe
O O O H H H H 3 H 4 2 13 1 12 5 14 15 10 7 11 OTBS OTBS 6 H H H H 8 9 OTBS H J = 11.5 Hz J = 8.5 or 11.5 Hz nOe
17a 17b Figure 1. Stereochemistry of Compound 17a and 17b
26 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.
SePh O O H OTBS
H OTBS 16 17a, 17b
O O
TBSO H TBSO H
Figure 2. Proposed Pathway of 7-exo/5-exo Tandem Cyclization
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.
27 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.
28 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 OH SePh O 1. MnO2 H 2. NaClO2, NaPH2PO4 OTBS TBAF Et3B, TTMSS OH 2-methyl-2-butene O O PhH, rt 3. PhSeSePh, Bu3P H CH2Cl2 O 14 15 43 63
Bu6Sn2 hv
O O H H H2O2
H PhSe H O O 69 70 Scheme 1. Tandem Cyclization of Enone 14
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
29 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
1,2 carbonyl carbon in the 6-membered ring. 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
SePh O 1. Bu Sn , hv O Boc 6 2 H BocN O N O 2. H2O2
3. CuBr, MeLi H 4. epimerization H NBoc2 O NBoc2 O
71 4
Scheme 2. Proposed Acyl Radical Cascade Approach towards Lyconadin A
30 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.
31 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.
32 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
1 product (326 mg, 0.8 mmol, 80%) as a yellow oil: H 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);
13 C 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,
33 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,
–1 + 1078, 838, 776 cm ; ES m/z 347.2010 (MNa , C18H32O3SiNa requires 347.2012).
34 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,
1 58%) as a yellow oil: H 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),
13 0.93 (s, 9H), 0.09 (s, 6H); C 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,
35 –1 + 1082, 1038, 838, 776 cm ; HRMS (FAB) m/z 467.2589 (MNa , C26H40O4SiNa requires
444.27).
OTBS
HO
OPMB
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
36 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 (1.16 g, 2.46 mmol, 73% over two steps) as a yellow oil: H 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,
13 6H); C 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,
–1 + 837, 776 cm ; HRMS (FAB) m/z 493.2742 (MNa , C28H42O4SiNa requires 493.2745).
OTBS
TBSO
OPMB
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
37 (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 (1.21 g, 2.06 mmol, 84%) as a yellow oil: H 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 –
13 0.01 (4s, 12H); C 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,
–1 + 1006, 836,776 cm ; HRMS (ESI) 607.3614 (MNa , C34H56O4Si2Na requires 607.3609).
OTBS
TBSO
OH
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.
38 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
39 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
1 desired product 56 (157 mg, 0.34 mmol, 52%) as a yellow oil: H 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
13 (6H), –0.02, –0.03 and –0.05 (3s, 6H); C 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,
40 –1 + 2857, 1253, 1078, 837, 776 cm ; 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
1 mmol, 84%) as a yellow oil: H 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–
13 1.45 (m, 2H), 0.90 and 0.89 (2s, 9H), 0.04, 0.03 and 0.02 (3s, 6H); C 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,
41 3075, 2955, 2929, 2885, 2857, 2360, 2342, 1471, 1462, 1252, 1080, 1028, 1005, 837,775
–1 + cm ; HRMS (ESI) 369.2219 (MNa , C21H34O2SiNa requires 369.2220).
O
SePh TBSO
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
42 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%
1 over three steps) as a yellow oil: H 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),
13 0.02, 0.01, and –0.01 (3s, 6H); C 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).
43 nOe nOe
O O O H H H H 3 H 4 2 13 12 1 14 5 15 10 11 6 7 OTBS OTBS H H H H H 8 9 OTBS J = 11.5 Hz J = 8.5 or 11.5 Hz nOe
17a 17b
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
1 product (3.0 mg). The data for 17a: H NMR (CDCl3, 500 MHz) δ 7.81 (dd, J = 1.0, 8.0
44 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).
1 1 2D H– H 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).
1 The data for 17b: H 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,
45 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).
46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 73
74