Efforts Toward the Syntheses of Natural Products: Part A: Paeoniflorin Part B: (+)-Taxusin

A thesis presented by

Rebecca J. Carazza

B.S. Chemistry University of Massachusetts, Amherst, 1993

Submitted to the Department of Chemistry in partial fulfillment of the requirements for the degree of Doctor of Philosophy in Chemistry at the Massachusetts Institute of Technology June 1998

© 1998 Massachusetts Institute of Technology. All rights reserved.

SinatureofAuthor:

SignatureT- -~- -- .. -uof -Author: -- I------D4pdrtment o('ihemistry May 26, 1998

Certified by: ,Scott C. Virgil Thesis Advisor

Acceuted bv: Dietmar Seyferth Chairman, Departmental Committee on Graduate Students

O-V .Z\ .

JUN 1 51998 Science

UR PAES This doctoral thesis has been examined by a committee of the Department of Chemistry as follows:

Professor Rick L. Danheiser - Chairman

Professor Scott C. Virgil / Th/sis Supervisor

Professor Peter H. Seeberger Efforts Toward the Syntheses of Natural Products: Part A: Paeoniflorin Part B: (+)-Taxusin

by Rebecca J. Carazza

Submitted to the Department of Chemistry on May 26, 1998

in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy in Chemistry

Massachusetts Institute of Technology

ABSTRACT Part A Efforts toward the synthesis of the monoterpene glycoside

paeoniflorin (1) are discussed. Optimization of the previous synthetic route

was successful. Synthesis of the key cc-diazo intermediate 30 was achieved and the construction of the carbocyclic frame was completed. Key reactions of

the strategy involve a ring contraction via a Wolff rearrangement, and

formation of the lactone 78 which undergoes diisobutylaluminum hydride reduction followed by acid catalyzed cyclization to the paeoniflorin ring system 80. A new synthetic strategy was initiated to prepare the key [3.2.1]bicyclooctanone 81 using a palladium mediated olefin cyclization of the acyloin substrate 82. CH 3

OH Paeoniflorin 1, O

BnO

O TMSO TBSO TCH O 3 CH 3 TMSO 0O OH

78

Part B Efforts toward the synthesis of the diterpenoid natural product

(+)-taxusin (110) are discussed. An alternative route to the key intermediate photoprecursor 130 was achieved employing a cerium trichloride mediated addition of an aryl lithium 132 to an aldehyde 141. A mechanism for the

exclusive formation of a cis 150 or trans 149 B-C ring system was proposed.

Attempts were made to cyclize the A-ring of both cis and trans ring fused intermediates. Ac AcO OAc 0l

OCH3 OAc

130 Taxusin, 110

OCH 3

OCH3 0O

150 149 132

Thesis Supervisor: Scott C. Virgil Title: Assistant Professor of Chemistry Acknowledgments

I would like to take this opportunity to thank all of the people that have been a major part of my life during my stay at MIT. First and foremost, I am grateful to my mentor, my friend Professor Scott Virgil. The enthusiasm he has for chemistry is matched by none. Scott has been an inspirational advisor who constantly offers positive encouragement. I would like to thank all of the members of the Virgil lab both past and present for their guidance and friendship. Many thanks to Dr. Paige Mahaney, Dr. Richard Allen (mind bomb. mind bomb, mind bomb!), Dr.

Edcon Chang, and Dr. Jeffrey Eckert all of whom taught me the important aspects of total synthesis. Justin Miller has taught me all the tricks to

ChemDraw, which helped tremendously in writing this thesis. Teaching with Justin has been fruitful and fun. MIT undergraduates that have worked on my projects, or who just can't be left out are Federico Bernal, Junko Tamiya, Sarah Folscraft, Juliet Midgley and Joseph Lee. Not only did the group offer support and guidance, they provided a friendly atmosphere to work in.

Thanks to Chris Garrett for making my first two years here enjoyable. I would like to thank Matt Martin for his friendship and for editing my thesis. Evan Powers, may your team always win! I would like to acknowledge the financial support that I received from the Chemistry Department.

I am grateful for having such a supportive and encouraging family.

They believed in me and helped me maintain my sanity when things got rough. Thanks Mom, Dad, Mike and Chandler. I would like to dedicate this thesis to all of you. Table of Contents Part A: Paeoniflorin

Chapter I. Introduction 1.1 B ioactiv ity ...... 7 1.2 Degradation Products of Paeoniflorin ...... 9 1.3 Synthetic Strategy...... 11

Chapter II. Formation of the Carbocyclic Framework 2.1 Retrosynthetic Analysis...... 16 2.2 a-D iazoketone Synthesis...... 17

Chapter III. Attempts to Form the Paeoniflorin Fing System 3.1 Aldehyde Formation Promoted Side Reactions...... 26 3.2 Successful Construction of the Paeoniflorin Ring System ...... 33

Chapter IV. Revised Strategy 4.1 Novel Approach to Carbocyclic System...... 38 4.2 Oxygenation of the C-3 Position...... 42 4.3 Future Prospects with the Barton Reaction...... 45

Part B: (+)-Taxusin

Chapter V. Introduction 5.1 Biological Activity...... 47 5.2 Stru ctu re ...... 53 5.3 Synthetic Strategy...... 55

Chapter VI. Synthetic Modifications 6.1 Retrosynthetic Analysis...... 60 6.2 Modifications to the Original Synthetic Route...... 61

Chapter VII. B-Ring Formation 7.1 Previous Work ...... 68 7.2 New Proposed Mechanism...... 70 7.3 Oxidative Cleavage Attempts...... 72

Chapter VIII. A-Ring Cyclization Attempts 8.1 Swindell's A-Ring Cyclization...... 74 8.2 A-Ring Cyclization Attempts with the trans-Fused Ring System ...... 75 8.3 A-Ring Cyclization Attempts with the cis-Fused R in g System ...... 79

Experimental Section and Selected Spectra...... 83 Chapter I: Introduction

1.1 Bioactivity Paeoniae Radix i (Shaoyao) is an important herbal drug widely used in traditional Chinese medicine. It consists of a crude mixture of substances derived from the roots of several species of Paeoneaceae; major harvests are from Paeonia lactiflora and Paeonia Suffruticosa.2 Shaoyao has been used for centuries as an analgesic, antispasmodic, astringent and sedative. The interesting bioactivity displayed by this drug sparked interest in identifying the components responsible for the therapeutic behavior. Efforts began in the

1960's and several highly oxygenated terpenoids were isolated and characterized. 3

HOCH 2 PhCO 2 /O

HO~ OH -- CH 3 OH 1, Paeoniflorin

Paeoniflorin (1) was the most abundant of the components and it was determined to be a highly oxygenated, complex, cage-like monoterpene

l(a) Kimura, M.; Kimwla. I.,Nojirna, H.; Takashi, K.; Hayashi, T.; Shimizu, M.; Morita, N. Jpn. J. Pharmacol. 1984, 35, 61. (b)Hikino, H.; In Economic and Medicinal Plant Research; Wagner, H., Hikino, H., Farnsworth, N. R, Eds.; Academic Press, Inc.: London, 1985, pp. 5 5 - 8 5 . 2 yu, J.; Elix, J.A.; Iskander, M. N. Phvtochemistrv 1990, 29, 3859. 3(a) Hattori, M.; Shu, Y. Z.; Shimizu, M.; Hayashi, T.; Morita, N.; Kobayashi, K.; Xu, G. J.; Nanba, T. Chem. Pharm. Bull. 1985, 33, 3838. (b) Akao, T.; Shu, Y. Z.; Matsuda, Y.; Hattori, M.; Namba, T.; Kobayashi, K. Clihemn. Pharm. Bull. 1988, 36, 3043. (c) Shibata, S.; Nakahara, M. Chem. Pharm. Bull. 1963, 11, 372. ChapterI: Introduction * 8 gylcoside. 4 Other components included lactiflorin (2)2, albiflorin (3)4c and aglycones paeonisuffrone (4)5 and paeonilactones A (5) and C (6), (Scheme 1).6

Scheme 1: Minor components of the herbal drug Paeoniae Radix.

0 0 0 0 HOCH 2 PhCO 2 0 HOCH 2 0N H O OH HOHO OH CH BzO H 2, Lactiflonn 3, Albiflorin

HO HH

HO CH3 HO O R

5, Paeonilactone A: R=Me 4, Paeonisuffrone 6, Paeonilactone C: R=CH 20Bz

Many research groups conducted experiments to evaluate paeoniflorin's therapeutic potential. Paeoniflorin has provided positive results in a wide range of studies. Recently paeoniflorin has been reported to exhibit anti-inflammatory, anticoagulant and sedative activities.la Paeony root extracts have been found to exhibit protective effects against neuron damage in the hippocampus when induced by metallic cobalt (an epilepsy

4 (a) Shibata, S.; Aimi, N.; Watanabe, M. Tetrahedron Lett. 1964, 20, 1991. (b) Aimi, N.; Inaba, M.; Watanabe, M.; Shibata, S. Tetrahedron Lett. 1969, 25, 1825. (c) Kaneda, M.; litaka, Y.; Shibata, S. Tetrahedron 1972, 28, 4309. 5 (a) Hatakeyama, S.; Kawamura, M.; Mukagi, Y.; Irie, H. Tetrahedron Lett. 1995, 36, 267. (b) Yoshikawa, M.: Harada, E.; Kawaguchi, A.; Yamahara, J.; Murakami, N.; Kitagaqa, I. Chem. Pharm. Bull. 1993, 41, 630. 6 (a) Hayashi, T.; Shinbo, T.; Simizu, M.; Arisawa. M.; Morita. N.; Kimura, M.; Matsuda, S.; Kikuchi, T. Tetrahedron Lett. 1985, 31, 3699. (b) Yoshikawa, M.; Harada, E.; Kawaguchi, A.; Yamahara, M.; Murakami, N.; Kitagawa, I. Chem. Pharm. Bull. 1993, 41, 630. (c) Hatakeyama, S.; Kawamura, M.; Shimanuke, E.; Takano, S. Tetrahedron Lett. 1992, 33, 333. (d) Kadota, S.; Takeshita, M.; Makino, K.; Kikuchi, T. Chem. Pharm. Bull. 1989, 37, 843. (e) Richardson, D. P.; Smith, T. E.; Lin, W. W.; Kiser, C. N.; Mahon, B. R. Tetrahedron Lett. 1990, 31, 5973. ChapterI: Introduction * 9 model).7 Another Chinese medicine, Shimotsu-to, contains a mixture of herbs from various plant roots, one of which is the paeony root. This medicine has been reported to improve spatial working memory in rats, and paeoniflorin was listed as a candidate for a cognitive enhancer. 8 Toki- Shakuyaku-San, an herbal medicine prepared from Paeoniae Radix, was found to exhibit therapeutic potential in Alzheimer's disease by diminishing cognitive disruption caused by cholinergic dysfunction. 9 A study on the absorption and excretion of paeoniflorin found that paeoniflorin has low bioavailability. The amount absorbed is mainly excreted. 10 This suggests that the metabolites may be responsible for the pharmacological action of the paeony root. This result was intriguing because one of the degradation products of paeoniflorin resembles ibuprofen.

1.2 Degradation Products of Paeoniflorin

Often times, natural products are so complex that in order to determine their structure, they are broken down into smaller, more easily defined subunits. During these initial reactions to determine the structure of paeoniflorin, an interesting rearrangement was observed. When aglycone 7 was treated with acid, an aromatic acid (aglycone F) was isolated (Scheme 2). Notice the resemblance of 8 to the anti-inflammatory drug ibuprofen. It is possible that this compound, or one similar, is a paeoniflorin metabolite and exhibits the anti-inflammatory behavior reported by Takagi and Harada.1l

7Tsuda, T.; Sugaya, A.; Ohguchi, H.; Kishida, N.; Sugaya, E. Expt. Neurology 1997, 146, 518. 8Watanabe, H. Behav. Brain Res. 1997, 83, 135. 9 Fujiwara, M. Jpn. J. Neuropsychopharmacology 1990, 12, 217. 10 Takeda, S.; Isono, T.; Wakui, Y.; Matsuzaki, Y.; Sasaki, H.; Amagaya, S.; Maruno, M. J. Pharm. Pharmacology 1995, 47, 1036. 11Takagi, K.; Harada, M. Yakugaku Zavshi, 1969, 89, 887. ChapterI: Introduction * 10

Scheme 2: Acid catalyzed rearrangement product resembles ibuprofen.

CH 3 CH 3 H BzO HO 3 C

H® OH OH OCH 3 H3C OH C H 3

8, Aglycone F Ibuprofen

A series of reactions was performed that could give insight into the mechanism by which the aromatic aglycone was formed (Scheme 3). First, paeoniflorin pentaacetate was oxidized with chromium trioxide to afford lactone 10. Treating this keto lactone with hydroxide ion afforded the keto acid 11. Exposure of keto acid 11 to aqueous acid afforded aglycone F.

Scheme 3: Stepwise procedure to obtain the aglycone F 8.

BzO 0 BzO BzO' OH OH" CH H+ RO0 0 Cr0 3 RC 3 CH SCH 3 3

OAc O

9 10

The proposed mechanism of the rearrangement is depicted in Scheme

4. The first step involves the hydrolysis of the glucose substituent and the

oxygen bridges to afford aldehyde 12. Following hydrolysis, the cyclobutane is cleaved (most likely not concerted) to afford intermediate 13 which readily

tautomerizes and oxidizes to the aromatic product 15. There were several Chapter I: Introduction * 11 other experiments on similar molecules to test the consistency of this mechanism, and each one led to the same result.

Scheme 4: Proposed mechanism for the rearrangement.

Hydrolysis CH 3 Fragmentation CH 3 H3 OAc 130 CH CH3 3 HO HO Tautomerize Oxidize OH H OH

Because of the high degree of oxygenation, treating paeoniflorin or its derivatives with acid can lead to interesting rearrangement products, most of which are initiated through the cleavage of the cyclobutane ring.

1.3 Synthetic Strategy The first total synthesis of paeoniflorin was achieved by Corey in 1993.12 Shortly thereafter, Hatakeyama and coworkers published their synthesis, which produced paeoniflorin in its natural form. 13 Each of these groups used radical reactions to generate the paeoniflorin skeleton, but in different fashions.

There is a great deal of similarity between an intermediate in Corey's sequence 16 and the natural product paeonilactone A (5). This molecule

12Corey, E. J.; Wu, Y.-J. J. Am. Chem. Soc. 1993, 115, 8871. 13Hatakeyama, S.; Kawamura, M.; Tekano, S. J. Am. Chem. Soc. 1994, 116, 4081. Chapter I: Introduction * 12 contains the cyclohexane portion of the natural product as well as one of the ether linkages. This synthetic route first focuses on bridging the second ether linkage then forming the strained cyclobutane ring via a novel samarium iodide radical reaction.

Scheme 5: Corey's intermediate resembles paeonilactone A.

OTIPS H H H O 3 HO 0O 0 H R H CN

16 Corey's 5, Paeonilactone A: R=Me intermediate 6, Paeonilactone C: R=CH 2OBz

Corey and co-workers began their synthesis by employing a manganese (III) promoted annulation between the silyl ether double bond and cyanoacetic acid. 14 Intermediate 16 contained the 10 carbons that are present in the final terpenoid product.

Scheme 6: Corey's approach to obtain the caged frame.

CH 3 CH3 CH 3 MnO 3(OAc) 7 3 steps H... .-. OTIPS -- OTIPS NCCH2CO 2H 44% 48% NC OTIPS OH 18

NC 1. PCC 0 TMSOTf 2. Sml 2, TH F HO O 35% 93% - . CH3 CH 3 OTIPS OTIPS 20

14(a) Corey, E. J.; Gross, A. W. Tetrahedron 1985, 26, 4291. (b) Corey, E. J.; Ghosh, A. Chem. Lett. 1987, 223. ChapterI: Introduction * 13

Generating epoxide 18, followed by a Lewis acid mediated epoxide opening and intramolecular cyclization afforded 19 with the complete oxacyclic framework intact. After oxidation with PCC, samarium iodide radical mediated ring closure provided the complete cage-like frame. In five steps, they were prepared for the gylcosylation reaction. Intermediate 21 in Hatakeyama's synthesis resembles a natural product isolated from Paeoniae Radix, paeonisuffrone (4). This synthetic approach was designed to provide the carbocyclic cage-like structure before cyclizing the ether bridges.

Scheme 7: Hatakeyama's intermediate is similar to paeonisuffrone (4).

CH3CO2 HO H3C 0 0

OH 3 O 0 0

21 4, Paeonisuffrone

Hatakeyama and co-workers began their synthesis by employing a photochemical [2+2] enone-olefin cyclization of 22 (which was prepared in

four steps). This reaction provided cyclobutyl ketone 21, which contained the complete carbocyclic frame. Functional group interconversion afforded 23, which upon generaton of the hypoiodite, underwent a radical reaction which led to the formation of 24. After five additional steps, they were prepared for the gylcosylation reaction. Chapter I: Introduction * 14

Scheme 8: Hatakeyama's approach.

0 ,H [2+2], hv 2 steps 3 C H kCH3 64% 3 74% CO 2CH 3 O NC OH

21 23

Phl(OAc) 2 12, hv 92%

Both groups had essentially the same structure (25 and 26) for the glycosylation reaction, but employed different coupling reactions (Scheme 9). Corey and co-workers chose to couple a 1-dimethylphosphite derivative of the tetrabenzyl ether of 1-glucose (27) with 25 in the presence of zinc (II) chloride and silver perchlorate. After deprotection, paeoniflorin was obtained in 18% yield (3 steps).

Scheme 9: Glycosylation reactions by Corey and Hatakeyama.

BnO 0 BnO \ OP(OCH ) B n O . _ - \ -- 3 2 OBn BzO 27 0 Orey Deprotection 1 BnO 0 BnO \a OO BnO 01Aa OR BnO 0 CC3 25 R=TIPS, Corey 28 26 R=CO 2Bn, Hatakeyama ChapterI: Introduction * 15

Hatakeyama and co-workers employed the use of an imidate derivative of the tetrabenzyl ether of 1-glucose (28) for the glycosylation. They successfully achieved the exclusive formation of the 1-glycoside. After

deprotection (-)-paeoniflorin was obtained in 67% yield (2 steps). Chapter II: Formation of the Carbocyclic Framework

2.1 Retrosynthetic Analysis

The two ether bridges of paeoniflorin make it sensitive to acid as described in the previous section. Because of this, it was decided that these ether linkages would be installed at the end of the synthesis. Thus our initial focus was on the carbocyclic framework.

Scheme 10: Retrosynthetic analysis of paeoniflorin.

HOCH 2 PhC( Glycosylation/ Ring HO Ring Closure CH 3 Contraction HO OH

TBSO CH3

OCH Ring 3 OTBS CH Expansion CH Diels-Alder 3 TBSO- 3 33 OTBS O /-0/ O

OCH 3

30 X=N 2 31 X=H 2

Starting with paeoniflorin, removal of the glycoside and interconversion of the benzoyl functional group and opening of the oxacyclic rings affords aldehyde 29. The oxidation state of the aldehyde is consistent with the closed

system, and the structure appears to be a reasonable candidate to produce the

desired cyclized product. The cyclobutyl aldehyde is a Wolff rearrangement

retron, and cyclobutyl carbonyl 29 can be synthesized from a ring contraction

of oc-diazocyclopentanone 30. Bicyclic ketone 31 should be available from - Chapter IH: a-Diazoketone Synthesis * 17 cyclohexene 32 via a ring expansion and functional group interconversion. Cyclohexene 32 is a Diels-Alder retron available from methyl acrylate and the novel bis-silyloxy diene 33.

2.2 a-Diazoketone Synthesis

Dr. Richard Allen 15 began this project and was successful in completing

the synthesis up to, but not including, oa-diazoketone 30. Modifications of the original synthetic route were made and those changes will be discussed. The reactions leading to the ring expansion are depicted below (Scheme 11).

Scheme 11: Synthesis of the ring expansion precursor.

0

i. 10 equiv. Et3N, THF-Hexane TBSO CH 3 O CH3 1.0 equiv. TBSCI, 0 o' 23 0C OCH 3 ii. 1.0 equiv. TBSOTf, O OTBS Toluene, rt -78 0C --- 0 oC 88% 34 87%

O CH 0H 2 03, -78 oC OCH 3 1. CH 2CI2 . MeOH; LiAIH , THF 4 CH3 then Me S TBSO \ TBSO \ 2 -78 oC --4 0 0C 2. Mel, K2CO 3, OTBS OTBS DMF

endo:exo [3 : 1] 36, 37 90 % (based on recovered 32, 35 starting material)

HOH, O II LiCH OH 2 P(OMe) 2 - CH 3 TBSO OH 3 equiv. THF CO 2Me -78 0C CO 2 Me 97 % " P(OMe) 2 O II O 39, 59%

15Allen, R. D. Studies Towark the Synthesis of Lactiflorin and Paeoniflorin. Ph.D. Thesis, Massachusetts Institute of Technology, Cambridgy, MA, June 1996. Chapter II: a-Diazoketone Synthesis * 18

Formation of bis-silyloxy diene 33 can be achieved in a one pot sequence using tert-butyldimethylsilyl trifluoromethanesulfonate, but it was in our best interest to employ a more cost effective approach. The incorporation of the first silyl enol ether was achieved using tert- butyldimethylsilyl chloride in the presence of triethylamine. Silylation of the second enol ether required tert-butyldimethylsilyl trifluoromethanesulfonate, again with triethylamine as the base. Using this modified procedure, large quantities of bis-silyloxy diene 33 were obtained in 86% yield.

At this point, the previous strategy involved a Diels-Alder reaction of bis-silyloxy diene 33 with methyl propiolate to afford the unsaturated ester product. Sodium borohydride reduced the unsaturated ester forming exclusively the desired endo isomer 32 in excellent yield (Scheme 12).

Scheme 12: Previous route to endo-ester 32.

0 H3CO OCH3 TBSO CH 3 OCH3

OCH 3 CH 3 NaBH4 _ CH 3 OTBS Toluene, rt TBSO \ MeOH, 25 C TBSO \ OTBS 93% OTBS

33 41 32

However, the mixture of endo and exo isomers 32 and 35 could be obtained

directly using methyl acrylate as the dienophile (Scheme 11). Dr. Allen discovered that theendo isomer underwent the ring expansion, but the exo isomer led to a complex mixture of products. Previously it was decided that

the amounts of the desired endo isomer were unacceptable, but recent modifications increased the endo to exo ratio as well as the yield, and made it

a worthwhile procedure. -Chapter II: a-Diazoketone Synthesis * 19

Esters 32, 35 could be reduced using lithium triethylborohydride but scaling up the reaction proved problematic, possibly because of the slow reaction and complications with dissociation of the boron complexed from the alcohol. A moderate scale reduction (1.4 g 32, 35) using lithium aluminum hydride produced the alcohol in 98% yield. Unfortunately, the large scale (7.4 g 32 and 35) version was not as successful, as the desired reaction was accompanied by cleavage of the TBS enol ether. To employ this method on large scale, it was necessary to terminate the reaction prematurely to prevent this unwanted side reaction. Alcohols 36 and 37 were isolated in

71% yield (90% yield based on recovered starting material). Because the previous reactions were performed on such a large scale, it was sensible to cut steps and employ the use of less expensive reagents. Although the yields were slightly lower than those previously reported, we were able to produce large quantities of material quickly and cost effectively.

Scheme 13: Previous route to enone 45.

H H H SOTBS OTBS

TBSO H3 Imidazole TBSO CH3 THF, rt CH3 DMF 75%

P(OMe) 2 86% P(OMe) 2 O 11 O O O O 40 42 43

SeCN H 2 C OH 1. aq. HF, n-Bu P, THF, rt TBSO CH 3 CH 2C12, CH 3CN TBSO CH3 3

-22 0C 2. aq. H20 2, THF 86% o0 80% O Chapter II: a-Diazoketone Synthesis * 20

The next sequence involved the ring expansion to form the [3.2.1]bicyclooctane system followed by the preparation of the ring contraction precursor, c-diazoketone 30. The ring expansion did not require modification and was performed as previously described (Scheme 13).

The ketalization, however, presented room for improvement. This reaction was sensitive; it had to be refluxed for at least three hours, but too much time allowed an undesired rearrangement to take place.

Scheme 14: Formation of ketal 46 and rearranged product 50.

H2 C H C 2 CH 2

TBSO CH3 (CH20H)2, TsOH TBSO CH3 H3 Benzene, reflux O O O 77% L O (90% based on 45 recovered enone) 46 50

Ketal 46, along with many other synthetic intermediates in this synthesis, was sensitive to acid. Running the reaction overnight led to the formation of a rearranged product that was determined to be the [2.2.2]bicyclooctane system 50; the proposed mechanism for its formation is depicted in Scheme 15. Opening the ketal led to the allylic oxonium ion. The partial positive charge at the allylic carbon promoted vinyl group migration to give the oxygen stabilized cation 49. Loss of the TBS group from this oxonium ion to ethylene glycol converted 49 to a ketal affording bis-ketal 50 in as much as 47% yield.

Because of the unsaturation in the position oa, to the ketal, it is

extremely sensitive to acid and precautions must be taken or the system self- destructs. Chapter II: a-Diazoketone Synthesis * 21

Scheme 15: Acid promoted vinyl migration.

H H2C 2C

C C Ketal CH3 H TBSO H3 TBSO 3 Protonation 0- H O- H o6 .OH . OH

CH 2

CH Vinyl Formation of 3

migration CH 3 bis-ketal 0

Continuation of the sequence involved conversion of the exo methylene ketal 46 to a ketone via a two step process involving dihydroxylation with osmium tetroxide and oxidative cleavage with lead tetraacetate. Yields obtained for the dihydroxylation were 92-98% using a stoichiometric amount of osmium tetroxide. This was certainly not ideal, due to the cost and toxicity of the reagent, especially on large scale.

Scheme 16: Formation of the ca-diazoketone.

H2q 0

CH TrisN , Benzene CH 1. 3 3 CH 3 Os0 4 , THF, py 3 60 % KOH-H 20 cat. 2. Pb(OAc) 4 O phase tran. 92% (2 steps) /O 65%

Running this reaction with catalytic amounts of osmium tetroxide (5-10

mol%) in the presence of excess quantities of 4-methylmorpholine-N-oxide - Chapter II: a-Diazoketone Synthesis * 22

(NMO) as the catalyst regenerating agent, resulted in yields ranging from 56-

82%. An unusual byproduct was isolated from the reaction, and was determined by NMR analysis to be the osmate dimer 51. This result was peculiar because we did not observe a dimer of both terminal methylenes 52, which was clearly the reaction site preferred by the bulky reagent.

Scheme 17: endo-exo Osmate dimer 51 vs. exo-exo osmate dimer 52.

CH H 2 C 3 3 SCH O

Os- O0 TBSO 0 CH O- 0 O 3 TBSO

HH

OTBS H CH 3 51, Observed 52, Not observed

Due to the large steric requirements of the reagent, preferential addition to the less hindered exo face of the terminal methylene is favored. Oxidative hydrolysis of the osmate ester by NMO was apparently the slow step, as the formation of dimer 51 competed with it. The osmium bound to the terminal methylene preferentially formed the dimer with the more substituted double bond, as the addition to another terminal methylene 52 (on the exo face) would cause the cyclopentane rings to collide (Scheme 17). Attacking the internal double bond from the exo face did not elicit the same unfavorable steric interaction.

With large quantities of NMO in a dilute reaction solution we were

able to increase the yield to 82%; unfortunately, the dimer was still observed.

With five mole percent of osmium tetroxide present, a loss of 10% to dimer

formation was observed. Additional amounts of osmium tetroxide were - ChapterII: a-Diazoketone Synthesis * 23 necessary to make up for the loss of catalyst, which in turn formed more dimer. It was clear that using stoichiometric amounts of osmium tertoxide was preferable to catalytic osmium tetroxide since the loss of 20-40% material at this step would hinder our progress in the synthesis. Oxidative cleavage of the diol was achieved in excellent yields using lead tetraacetate. With ketone 31 in hand, preparation of a-diazoketone 30 was accomplished as previously described (Scheme 16).16 Monitoring this reaction was quite difficult because the intermediate of the reaction and the product had nearly the same Rf by thin layer chromatography. However, color could be used to indicate the conversion of the intermediate to the product as the intermediate was magenta and the product pink-orange after staining with p-anisaldehyde. Also, the product exhibited a strong UV absorption via thin layer chromatography. Interestingly, the NMR spectrum of the isolated product did not match that obtained previously. We determined that a-diazoketone 30 was indeed the product of the reaction but we were unable to determine the product isolated previously. A byproduct isolated was concluded to be the triisopropylbenzene sulfonamide 54, and the mechanism of its formation is depicted below. Enolate attack of the trisyl azide can proceed either via path A or B. The internal nitrogen of the azide is more sterically hindered, and intermediate 53 of path A is less stable due to the proximity of the bicyclic ring to the bulky aryl substituents. These factors combined to make this pathway higher in energy, both in the transition state and the intermediate, therefore producing only small quantities of 54 after

loss of nitrogen. On the other hand, in path B attack can occur at the more

easily accessible terminal nitrogen, and the intermediate formed has the

bicyclic ring four atoms removed from the aryl substituents. This distance

16 Lombardo, L.; Mander. L. N. Synthesis 1980, 368. Chapter II: a-Diazoketone Synthesis * 24 dramatically lessens the steric interference displayed in the intermediate of path A. Loss of the triisopropylbenzene sulfonamide afforded o-diazoketone

30 in 65 % yield.

Scheme 18: Reactions with trisyl azide.

00 NN N= N N- S- N=

tA B A

N=N 0 H O N- S-Ar SN- S-Ar 0

A CH TBSO CH 3 TBSO 3 Loss of N2

Protonate O amine O

53 54 O O0 N= S- Ar N2 Loss of B TBSO CH3 TBSO CH 3 H2NSO2Ar

0---

30

In summary, modifications were made to the previous procedure to

obtain alcohols 36 and 37 in a more efficient and practical manner. This was

achieved by altering the conditions of the first three reactions in the sequence.

In the subsequent reactions, the goal was to increase product yields. Although the ketal formation reaction was the only reaction which exhibited an

improved yield, the increase was more than 20%. Finally, close monitoring Chapter II: ac-Diazoketone Synthesis * 25 of the diazo transfer reaction allowed for the isolation of a-diazoketone 30, which had not previously been synthesized. With the a-diazoketone in hand, we were one step away from obtaining the complete carbocyclic frame. Dr. Allen had successfully completed the ring contraction of molecule 56, so we were hopeful that our system would also undergo the transformation.

Scheme 19: Previous Wolff rearrangement.

O CO02CH 3 N2 hv, 23 'C TBSO CH TBSO CH 3 Rayonet, 254 nm 3 MeOH 50% MOMO MOMO 56 2:1 endo:exo

Thus, irradiation of a-diazoketone 30 at 0 OC in a mixture of dichloromethane and methanol afforded the desired Wolff rearrangement providing cyclobutyl ester as a mixture of endo and exo isomers in excellent yield.

Scheme 20: Formation of the a-diazoketone.

0 C0 2CH 3 N2

-- CH TBSO CH 3 0 C hv 3

- 0 CH 2C12, MeOH 0 95%

30 57, 58 1.5:1 endo:exo Chapter III: Attempts to Form The Paeoniflorin Ring System

3.1 Aldehyde Formation Promotes Side Reactions With the synthesis of the carbocyclic ring system complete, the focus was now directed toward the alkylation of the cyclobutane ring and bridging of the cyclic ether functionalities to form the cage-like ring structure. Our strategy involves the Wolff rearrangement to provide esters 57 and 58, and then alkylation of the cyclobutane followed by closure of aldehyde 29 to form the ether bridges. Although it would have been ideal to incorporate the benzoyl moiety onto the cyclobutane ring at this point, this functionality was incompatible with the subsequent reduction step. We chose to alkylate with benzyloxymethyl chloride, 17 then convert it to the benzoyl functionality once the oxygen bridges were installed. The mixture of endo and exo isomers formed from the Wolff rearrangement was separated in order to perform the alkylations independently. We believed the alkylation of the mixture would lead to problems due to the differences in reactivity between the two isomers. Endo isomer 57 had a more accessible hydrogen and the deprotonation would likely be more facile than the deprotonation of exo isomer 58. The reactions were slightly different, with endo isomer 57 giving a slightly higher yield. Both reactions afforded alkylated ester 59 in 65-71% yield. An interesting byproduct

of the reaction was determined to be 60. This byproduct was peculiar as ketals

are usually uneffected by base. This product actually gave insight to an

alteration in the synthetic plan that will be discussed later in this chapter.

17 Fang, C., Suganuma. K.; Sucmune, H.; Sakai, K. J. Chem. Soc. Perkin Trans. 1 1991, 1549. ChapterIII: Attempts to Form the PaeoniflorinRing System * 27

Scheme 21: Alkylation of ester affords desired exo alkylation product 59.

0 BnO CO CH C O 2C 2 3 BnO H3

OCH 3 LDA, THF-HMPA TBSO CH3 -20 TBSO CH3 TBSO

40. n then BOMCI o O .o -78 oC .o OH

57 59 60 71% 17%

Reduction of esters to the corresponding aldehydes can be achieved using diisobutylaluminium hydride (DIBAL) at -78 oC.18 Cooling the DIBAL by adding it along the side of the flask is necessary to avoid any increase in temperature. It is crucial to run this reaction at -78 'C as warming would allow for an additional reduction to take place. A critical aspect of this procedure is the stability of the aluminum complex formed after the first hydride transfers to the ester. If the complex is unstable, the reaction can be driven to dissociation. Once dissociated, another reduction can easily occur. Because the ester is located in close proximity to the ketal, we believed that an

unfavorable interaction between the aluminum complexed acetal and the

ketal would promote the dissociation, so we felt it was necessary to reduce the ester completely to the alcohol then oxidize it to the aldehyde.

Scheme 22: Reduction of ester 59 to alcohol 61.

BnO CO2CH3 BnO OH

CH TBSO CH3 DCHiBAI-H, -30 TBSO 3

Hexane, 99% O O 61 59 61

18 Garner. P.; Park, J. M. J. Org. Chem. 1987, 52, 2361. Chapter III: Attempts to Form the PaeoniflorinRing System * 28

Completely reducing the ester to the alcohol successfully afforded alcohol 61 in 99% yield. This product, like many others in this synthesis, was extremely sensitive to acid. Glacial acetic acid was used to quench the reaction and during one experiment too much acid was added which caused deprotection of the ketal. The alcohol immediately cyclized into the unsaturated ketone affording cyclic ether 62. This intermediate closely resembles intermediate 21 in Hatakeyama's synthesis (Scheme 23). Although forming the cyclic ether was unfortunate, it was encouraging in that it was the type of cyclization we wanted the hydrated aldehyde to undergo. Because of this favorable cyclization, the ketal cannot be removed before the aldehyde is formed.

Scheme 23: Acid promoted cyclization affords cyclic ether 62 which is similar to an intermediate in Hatakeyama's Synthesis.

BnO OH BnO BzO

TBSO - CH3 H TBSO CH3 CH3

O 0 - 0

62 Hatakeyama's intermediate 61 21

Because of its high sensitivity towards acidic solutions, we chose to oxidize alcohol 61 to the aldehyde using a neutral reagent. We felt that if the

ketal was removed, the molecule would instantaneously cyclize, not allowing

the aldehyde to be isolated, or if the ketal was removed before the oxidation

cyclic ether 62 would be obtained. The Dess-Martin periodinane is a strong

oxidizing agent that oxidizes under neutral conditions. 19 After the oxidation,

19 Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155. Chapter III: Attempts to Form the PaeoniflorinRing System * 29 crude NMR analysis of the isolated product showed a surprising mixture of two compounds, one of which was an aldehyde. Because of the solvents interfering in the crude NMR, the sample was placed under reduced pressure for a few hours with hopes that a clearer NMR could be obtained. Indeed that was the case. Unfortunately this time the aldehyde product was no longer evident. A single compound was present which was determined to be retro- Claisen rearrangement product 64.

Scheme 24: Oxidation to the aldehyde is followed by the retro-Claisen rearrangement.

H AcO OH , ,OAc OAc facile 0 -CH3 O CH 3 rearrangement ' : CH (Dess-Martin 3 BnO O reagent) OTBS 61 61

We did not expect the aldehyde to readily rearrange because Monti and

co-workers synthesized 65, a similar compound that was stable at room

temperature.20

Scheme 25: The tert-butyldimethylsilyl ether facilitates the retro-Claisen rearrangement.

Retro-Claisen CH 3 rearrangement CH 3

2 0 Larsen, S. D.; Monti, S. A. J. Am. Chem. Soc. 1977, 99, 8015. ChapterIII: Attempts to Form the PaeoniflorinRing System * 30

Claisen rearrangements are concerted [3,3]-sigmatropic rearrangements that occur through a six-membered transition state. These rearrangements provide y,6 unsaturated carbonyl compounds from the corresponding allyl vinyl ethers. In our system, the reverse was favored thermodynamically.

The rigid conformation of the bicyclic system cannot easily adopt the favored chair transition state usually seen in these rearrangements. By assuming the boat conformation, aldehyde 63 would adopt the orbital overlap necessary for the retro-Claisen rearrangement to occur. Although this reaction is usually unfavorable in this direction, there are three factors which contribute to the driving force in the conversion of aldehyde 63 to rearranged product 64. The predominant thermodynamic driving force is the cleavage of the cyclobutane ring which relieves -26 kcal/mol of strain energy. Secondly, the tert-butyldimethylsilyl ether plays a key role in the rearrangement process as it is located in the position at which the newly formed double bond can be stabilized as a vinyl ether. The silyloxy group also stabilizes the transition state and facilitates the rearrangement at room temperature. Without its presence, isolation of the aldehyde would likely have been possible, as it was for Monti's synthetic studies. It may also be important that the large tert-butyldimethylsilyl ether and the methyl benzyl ether which in the cyclobutane were adjacent to one another become far removed from each other in the product. This is best depicted in Scheme 24.

We found it worthwhile to attempt the oxidation with PCC on

alumina with delayed addition of acid in hopes of deketalizing the ketone,

making the [-position a more desirable site for the aldehyde to attack.

Unfortunately this oxidation attempt generated the retro-Claisen ChapterIII: Attempts to Form the PaeoniflorinRing System * 31 rearrangement as well. Apparently the double bond could not be present within the bicyclic ring system when the aldehyde was being generated. A new approach was investigated to generate the cyclobutyl carboxaldehyde without undergoing a retro-Claisen rearrangement. By protecting the enone, as a silyl dienol ether similar to the byproduct 60 discussed earlier, perhaps the retro-Claisen would not occur. The exo methylene carbon would be far enough away from the aldehyde that it would be very difficult to achieve a retro-Claisen rearrangement.

Treatment of the alkylated product 59 with 1% hydrochloric acid in acetone afforded in nearly quantitative yield the enone 66. Silyl dienol ether was prepared under kinetic enolate trapping conditions. To a mixture of enone 66 and 1.2 equivalents of tert-butyldimethylsilyl trifluoromethane- sulfonate at -78 'C was added lithium diisopropylamide. After work-up, diene 67 was obtained and was used in the next step without further purification.

Scheme 26: Synthesis of silyl dienol ether 67.

O O O OCH BnO OCH3 BnO OCH3 BnO 3

TBSO CH 3 HCI, Acetone TBSO CH 3 LDA, TBSOTf TBSO 98% ZTHF O 0 OTBS

59 66 67

Silyl dienol ether 67 would next be converted to the aldehyde and

deprotected to test this new strategy for the oxacyclic ring system synthesis.

Instead of reducing the ester to the alcohol then oxidizing it to the aldehyde,

we chose to form the aldehyde directly. The tert-butyldimethylsilyl enol ether Chapter III: Attempts to Form the PaeoniflorinRing System * 32

67 was not expected to pose the same steric effect which we felt was present in the ketal compound 59. Two equivalents of diisobutylaluminum hydride solution were added to the silyl dienol ether 67 at -78 'C and after quenching at -78 oC, the aldehyde 68 was isolated in 18% yield (51% based on recovered starting material). It may have been best to employ the sequence used on the other system after all. Because of the presence of two tert-butyldimethylsilyl ether moieties in aldehyde 68, we chose aqueous hydrogen fluoride as selective deprotection conditions. Surprisingly, the reaction of aldehyde 68 with aqueous hydrogen fluoride proceeded at 0 'C to afforded a 2:1 diastereomeric mixture of aldol products 69 and 70. The facile protonation of the aldehyde made it susceptible to attack by the tert-butyldimethylsilyl enol ether in a Mukaiyama-type aldol reaction.

Scheme 27: Successful formation of aldehyde 68 and Mukaiyama-type aldol reaction.

O 0 OH DiBAI-H, -78 OC HF aq., 0 C BnO

TBSO Toluene/Hexane TBSO CH 3CN/H20 TBSO H 51% (based on 34% recovered 67)

OTBS OTBS 69, 70 67 68

Employing the use of an aldehyde to obtain the ether bridges was unsuccessful because its high reactivity led to the generation of undesired products. The aldehyde needed to be replaced by another functional group,

preferably with the same oxidation state. Of the possibilities, none were very

promising as the conversions to desired functional groups could likely lead to

complications. The formation of lactone 10 and carboxylic acid 11 from the ChapterIII: Attempts to Form the PaeoniflorinRing System * 33 degradation reactions discussed in Chapter I (Scheme 3) gave the insight for the following sequence.

Scheme 28: Focus directed toward synthesizing carboxylic acid 71.

O O O BzO 0o BzO OH BnO OH

CH RO R O 3 TBSO CH3 CH3

O O O

10 11 71

Perhaps an acidic solution would favor the closure of the acid 71 to afford a lactone intermediate similar to 10. Reduction of the lactone to a lactol would then allow closure of the paeoniflorin ring system without involving the intermediacy of an aldehyde. Based on this literature precedent we decided to direct our efforts towards the formation carboxylic acid 71 instead of the aldehyde 29.

3.2 Successful Construction of the PaeoniflorinRing System There were two competing choices available for the production of

carboxylic acid 71. The Wolff rearrangement could be performed in an aqueous mixture (instead of the methanolic solution) so that the ketene generated from the rearrangement would provide the acid 72 and 73. Alternatively, the methyl ester derived from the Wolff rearrangement could

be hydrolyzed. Although these reactions seem straightforward, each led to

complications described below.

The Wolff rearrangement was attempted first and indeed was

successful. The crystalline acid was obtained without optimization, in 58%

yield. Because of the difficulty in analyzing the aqueous mixture, the reaction ChapterIII: Attempts to Form the PaeoniflorinRing System * 34 may have been exposed to the intense light source for a duration longer than necessary, possibly causing undesirable side reactions. The alkylation optimized for the synthesis of ester 59 was employed using two equivalents of lithium diisopropylamide in tetrahydrofuran-hexamethylphosphoramide

(HMPA) at -20 'C. After the addition of benzyloxymethyl chloride, only the benzyloxymethyl ester 74 was obtained. Unfortunately this O-alkylation result was the only product observed suggesting that the expected dianion was not formed.

Scheme 29: Wolff rearrangement provided acids 72 and 73, but O-alkylation was observed

CO02 H CO 2CH20OBn

H 0 THF, BOMCI 0 . THF,H20OTHF, 2 L.O 58% LO LO

30 72, 73 74

If the acid was cyclized first, the alkylation would still be unsuccessful as basic treatment of the lactone would afford the open form as seen with the studies by Aimi (Scheme 3).4b This dianion alkylation approach was therefore abandoned, and the focus turned toward the hydrolysis of ester 59 obtained from the ester enolate alkylation. Ester 59 was unreactive towards deprotection by standard conditions including lithium hydroxide in aqueous dimethoxyethane 21 and lithium iodide in dimethylformamide. 2 2 Treatment with sodium iodide and

trimethylsilyl chloride resulted in deprotection of the ketal but not the

2 1Corey, E. J.; Narasaka, K.; Shibaski, M. J. Am. Chem. Soc. 1976, 98, 6417. 2 2Magnus, P.; Gallagher, T. Chem. Commun. 1984, 389. Chapter III: Attempts to Form the PaeoniflorinRing System * 35 methyl ester. 23 Fortunately, the ester could not withstand the force of lithium ethyl mercaptide. 24 Preparation of 0.5 molar lithium ethyl mercaptide in HMPA was followed by addition of the ester 59. After extended

reaction at room temperature, the acid 75 was isolated in 77% yield. The

nucleophilic displacement of the methyl ester by ethyl mercaptan was

successful only with HMPA as the solvent.

Scheme 30: Ester hydrolysis with lithium ethyl mercaptide.

0 0

BnO OCH 3 BnO OH

TBSO CH3 HMPA, EtSLi TBSO CH 3 rt, 3d O 77% O O O

59 75

We learned earlier that the allylic ketal was sensitive to aqueous acid

treatment therefore we chose anhydrous methanesulfonic acid for the lactone

formation. With the ketal still present, the selective reduction with

diisobutylaluminum hydride would be possible immediately following the

lactonization. Unfortunately, the reaction mixture was not completely anhydrous, and we isolated two products from this reaction which were determined to be 71 and 76. To our surprise, when the ketal was removed, the equilibrium favored the open form 71, but when the ketal was present it preferred to cyclize 76.

2 3Heck, M. P.: Monthillcr, S.; Mioskowski, C.; Guidot, J. P.; Le Gall, T. Tetrahedron Lett. 1994, 35, 5445. 2 4 Vaughn, W. R.; Baumann, J. B. J. Org. Chem. 1962, 27, 730. Chapter III: Attempts to Form the PaeoniflorinRing System * 36

Scheme 31: Lactone cyclization of acid 75.

O O 0 BnO OH BnO OH BnO

TBSO CH3 CH3SO 3H TBSO CH3 TBSO CH3 O O o O kO

75 71 76

Treatment of lactone 76, with diisobutylaluminum hydride at -78 'C in dichloromethane afforded the lactol 77 as a 6:1 mixture of diastereomers in

50% yield with 50% recovery of lactone 76. Based on the downfield shift (5.81 ppm) of the hydroxyl proton in the 1H NMR spectrum, it seemed reasonable that the predominant product was the desired lactol 77. With the hydroxyl group in close proximity to the ketal oxygen, intramolecular hydrogen bonding would deshield the hydroxyl proton and lock the conformation about the C-O bond. This interaction is consistent with a 13.2 Hz coupling constant. The stereochemistry of the major isomer 77 is understandable based on the less sterically hindered approach of diisobutylaluminum hydride from the exo face of the lactone. Reaction of the mixture of lactol isomers with hydrochloric acid and acetone at 0-425 oC resulted in formation of a new bridged acetal product. After purification by column chromatography, the NMR spectrum revealed that the paeoniflorin caged ring system had formed.

However, the presence of a CH 2CH 20H group unexpectedly indicated that the ketal group was only partially deprotected. The oxacyclic acetal 78 was therefore obtained and this reaction is currently under optimization. Chapter III: Attempts to Form the PaeoniflorinRing System * 37

Scheme 32: Successful synthesis of the oxacyclic acetal 78.

BnO

TBSO O DiBAI-H, (aq) CH CH 2C12 HCI 3 CH 3 -78 CH3 e -78 "C Acetone 0 76 OH

76

Perhaps, further treatment with acid may be successful in completing the removal of the ketal protecting group. Alternatively, elimination of the hydroxyl ethyl group could afford a vinyl ether which could then be easily hydrolyzed. Chapter IV: Revised Strategy

4.1 Novel Approach to Carbocyclic System

Bicyclic ketone 31 was originally synthesized in thirteen steps as described in Chapter II. Several of the intermediates in this route were sensitive and had a tendency to undergo undesired rearrangements and cyclizations. Because of these potential problems, it was in our best interest to obtain the bicyclic ketone 31 via a new sequence, preferably with fewer steps. A new strategy was designed; the retrosynthetic analysis is described in Scheme 33.

Scheme 33: Retrosynthetic analysis of key intermediate 31.

Functional Heck group Reaction TMSO

Interconversion TMSO

0 0

Acyloin Grignard J Condensation Addition H3CO OCH 3 H 3 CO 84 H3CO

Functional group interconversion of the bicyclic ketone 81 was planned to

provide the key intermediate ketone 31. Disconnection of the

[3.2.1]bicyclooctanone ring system was envisioned to generate the symmetrical

bis-trimethylsilyl enol ether 82. Among many organometallic reaction ChapterIV: Revised Strategy * 39 methods possible, the palladium mediated cyclization of the olefin to the enol ether is well precedented. 25 The bis-trimethylsilyl enol ether 82 is a prochiral precursor which could be investigated in enantioselective versions of the intramolecular palladium mediated cyclization as well. The acyloin reaction being the only recourse for the synthesis of bis-silyl enol ethers requires the 3- alkyl gluterate precursor 83.26 Removal of the side chain gives the starting materials for this synthesis, trans-dimethyl glutaconate (84) and 4-bromo-1- butene.

Overman 27 developed a procedure to obtain 3-alkylated glutarate esters from the copper-catalyzed addition of Grignard reagents to trans-dimethyl glutaconate. For the addition to proceed, they found it was necessary to activate the unsaturated ester using excess amounts of trimethylsilyl chloride; when no trimethylsilyl chloride was present, no reaction was observed.

Because of the acidity of dimethyl glutaconate's c-hydrogens, it is necessary to form the silyl ketene acetal of one of the esters before the addition of the

Grignard reagent. If this is not accomplished, one equivalent of the Grignard

will be wasted on the enolization of the ester. Due to the expense of 4-bromo- 1-butene, we chose to form the trimethylsilyl ketene acetal.

An important improvement to Overman's procedure was achieved by performing the reaction under inverse addition conditions. Dimethyl glutaconate (84) was treated with triethylamine and trimethylsilyl trifluoromethanesulfonate in tetrahydrofuran-hexane and removal of the byproduct triethylammonium triflate afforded the moisture sensitive silyl

ketene acetal 85. The solution of dimethyl glutaconate ketene acetal 85,

chlorotrimethylsilane and 0.2 equivalents of cuprous iodide in

25 Kende, A. S.; Roth, B.; Sanfilippo, P. J. J. Am. Chem. Soc. 1982, 104, 1784. 26 Ruhlmann, K. Synthesis 1971, 236. 27 Leotta (III), G. J.; Overman, L. E.; Welmaker, G. S. J. Org. Chem. 1994, 59, 1946. ChapterIV: Revised Strategy * 40 tetrahydrofuran was cooled to -35 -C. The dropwise addition of the preformed Grignard reagent to the solution of 85 was monitored via thin layer chromatography until the complete consumption of starting material was apparent. The reaction afforded diester 83 in 79% yield.

Scheme 34: Synthesis of 3-substituted glutarate diester 83.

O O O OTMS NEt 3, TMSOTf, 0 0C THF/Hexane H3CO OCH3 H 3CO OCH 3

85

O i. THF, Mg, 40 0C

ii. Cul, -35 "C H CO Br 3 iii. 85, 79% H3CO

With the diester in hand, we were prepared to perform the acyloin condensation. Because diester 83 was similar to several molecules in the literature, we expected this reaction to run smoothly, and indeed it did, affording the bis-silyl enol ether 82 in 97% yield. It was necessary to use this product immediately because the compound undergoes hydrolysis readily.

Scheme 35: Acyloin synthesis of Bis-trimethylsilyl enol ether 82.

O TMSO i. Na, Tol, A H3 CO H3CO ii. TMSCI, 83 1 h, A 97% TMSO

It is well known in the literature that unsaturated silyl ethers can undergo intramolecular cyclization with a pendant olefinic group in the ChapterIV: Revised Strategy * 41 presence of palladium (II) if a five-, six-, or seven-membered ring can be formed.28 This method has been employed to obtain spiro and bridged bicyclo ketones. The cyclization is thought to involve the nucleophilic attack of the enol ether double bond onto the palladium-coordinated olefin. 29 In our system, the silyl ether double bond can attack the olefin via a 7-endo or 6-exo pathway (Scheme 36).

Scheme 36: Options available to the silyl ether double bond.

TMS O. O O \ -OAc

A: 7-endo TMSO -TMSOAc TMSO TMSO

A -HOAc, Pd 87 88 TMSO -Pd(OAc) 2 86 B TMSO, TMS. + \ -OAc \\

82 Pd(OAc) -TMSOAc B:- TMSO - TMSO -HOAc, Pd

89 81

The 7-endo route leads to the formation of bicyclononenones 87 and 88 after P-hydride elimination of the palladium. With the 6-exo route, there is only one option for P-hydride elimination leading exclusively to [3.2.1]bicyclooctanone 81. Both entropy and enthalpy favor the cyclization to proceed via the 6-exo pathway. Addition of 1.5 equivalent of palladium (II) acetate to an acetonitrile solution of bis-silyl enol ether 82 and dry sodium

acetate at room temperature for eight hours afforded the [3.2.1]bicylclo-

octanone 81 in 44-58% yield. The presence of sodium acetate in the reaction

28 Heck, R. F.; InPalladium Reagents in Organic Syntheses; Katritzky, A. R., Meth-Cohn, O., Rees, C. W.; Eds; Academic Press Inc.: London 1985, pp 222-225. 2 9 Kende, A. S.; Roth, B.; Sanfilippo, P. J.;Blacklock, T. J. J. Am. Chem. Soc. 1982, 104, 5808. ChapterIV: Revised Strategy * 42 mixture was found to buffer the acetic acid generated during the reaction.

Otherwise, the acidic solution could promote the cleavage of the trimethyl ether, and exposure of the alcohol to acid may lead to complications in the reaction. It is important to note that the low yield of ketone 81 may be due to product loss associated with the isolation of this volatile product from the reaction mixture.

Scheme 37: Palladium mediated cyclization affording 81.

0 TMSO Pd(OAc) 2 NaOAc

CH 3CN, rt TMSO TMSO 44-58%

82 81

It is not uncommon to isolate olefin regioisomers that could not have been formed directly from the initial P-hydride elimination. Possibly the short-lived palladium-bound olefin is responsible for such isomerizations.

NMR analysis of the crude product did in fact show the presence of a small amount of a product with the double bond isomerized to the more stable

endo location. This procedure provides the bicyclic ketone 81 in three steps from

dimethyl glutaconate in 44% overall yield. This expedient synthesis of the [3.2.1]bicyclooctanone ring system compares admirably with our previous thirteen step sequence. The overall yield could possibly be increased by

optimizing the isolation of product 81 from the Heck reaction.

4.2 Oxygenation of the C-3 Position

This new successful route was encouraging because we were able to ChapterIV: Revised Strategy * 43 attain the desired ring structure in three steps. There was one problem with this system-it lacked the correct oxygenation at the C-3 position. How could we obtain this oxygenation, and in what part of the sequence would it be best to incorporate it? Surprisingly, we found a case in the literature in which a ketal could withstand the reductive conditions of an acyloin condensation. 24

This precedent gave us the initiative to functionalize the C-3 position before the acyloin reaction (Scheme 38).

Scheme 38: Desired ketal precursor for acyloin condensation and the numbering scheme for paeoniflorin.

0 8

H3CO O HOCH2 CO2CH2 0 H3CO HO O / o HOO o-)- - 10 O OH ,CH 3 5 4 2 90 OH

An umpolung approach would be required to add a masked ketone to the glutaconate. Perhaps a dithiane would provide the desired conjugate addition to the glutaconate. Because the dithiane would not be able to withstand the acyloin conditions, it would be necessary to convert it to the ketal after addition to the glutaconate. Corey et al, have developed a procedure for a one step conversion to the ketal.30 Dithiane anions undergo conjugate additions to a,p-unsaturated ketones at -78 'C in the presence of HMPA or cuprous iodide- trimethylphosphite complex. 3 1 The conjugate addition to ua,1-unsaturated

3 0 Corey, E. J.; Andersen. N. H.; Carlson, R. M.; Paust, J.; Vedejs, E.; Vlattas, I.; Winter, R. E. K. J. Am. Chem. Soc. 1968, 90, 3245. 3 1(a) Ziegler, F. E.; Tam, C. C. Tetrahedron Lett. 1979, 49, 4717. (b) Lucchetti, J.; Dumont, W.; Krief, A. Tetrahedron Lett. 1979, 29, 2695. (c) Brown, C. A.; Yamaichi, A. J. Chem. Soc., Chem. Commun. 1979, 100. Chapter IV: Revised Strategy * 44 aldehydes is also observed in the presence of tetrahydorfuran-HMPA. 32 The allyl dithiane was synthesized successfully and the ketene acetal of the glutaconate was generated. The reaction was attempted using a combination of the Overman approach and the conditions stated above. The glutaconate- ketene acetal 85 was added to two equivalents of lithiodithiane 91 at -78 'C followed by the addition of HMPA and chlorotrimethylsilane (if the order of the addition of chlorotrimethylsilane and the glutaconate-ketene acetal was reversed, the dithiane anion was silylated). The double addition product 93 was isolated from this reaction in 23% yield. We suspect that the dithiane anion adds to the ester first to form the intermediate 92 followed by the conjugate addition of a second nucleophile to the ox,f-unsaturated ketone.

Several different variations of this reaction were performed, in each case affording the same product 93.

Scheme 39: Favorable formation of bis-dithiane 93.

s s

91 HMPA, THF, TMSCI, -78 C S S OCH3

O OTMS [1,2] addition 92 H CO 3 OCH 3 85 0 H 3CO TMSO [1,4] addition S S S

93

Perhaps treatment of ketone 81 with acid would allow isomerization to

3 2 E1-Bouz, M.; Wartski, L. Tetrahedron Lett. 1980, 21, 2897. ChapterIV: Revised Strategy * 45 the more substituted olefin. With the endo double bond, it would be possible to employ an allylic oxidation procedure.

Scheme 40: Functionalization of the bicyclic system.

O O O

TMSO .. m riato.. TMSO .-.. . -.---...... TMSO Oxidation \

81 94 95

Under mild acid conditions the trimethylsilyl ether is readily cleaved affording the o-hydroxyl ketone 96 in 90% yield. Stronger acid conditions may be necessary to isomerize the double bond.

Scheme 41: Acid treatment removes trimethylsilyl protecting group.

0 0

HCI, THF TMSO 90% HO

81 96

At this point, we believe it was worthwhile to replace the trimethylsilyl ether with a tert-butyldimethylsilyl ether, as from prior experience, the tert- butyldimethyldilyl ether was stable to moderate acidic solution. With this

protected alcohol, the isomerization of the double bond may be achieved. With the isomerization complete, the allylic oxidation could be attempted.

4.3 Future Prospects with The Barton Reaction

If the C-3 position can not be oxidized before the Wolff rearrangement,

there is still a possibility of oxidizing the carbocycle via a Barton oxidation ChapterIV: Revised Strategy * 46 after the ring contraction is complete. Starting with the butyldimethylsilyl protected ether, the alkylated acid 97 could be obtained via the procedure recently developed and discussed in Chapter III. Treating 97 with acid could lead to the lactone which when treated with DIBAL would afford lactol 98.

The hydroxyl of the lactol is in close proximity to the C-3 position and

oxidation of this position via a radical procedure is promising. Forming

nitrite ester 99 could be accomplished with the exposure of the lactol to nitrosyl chloride and pyridine. By employing the Barton reaction, it is

reasonable to expect the C-3 hydrogen to be abstracted by the oxygen radical

generated when photolyzed. The cyclobutyl radical could then form the

oxime 100 by reacting either in a terminal fashion, or a radical chain process.

Hydrolysis of the oxime would afford the desired hydroxy ketone 101 and acid

induced closure would provide the cage-like structure of paeoniflorin.

Scheme 42: Proposed strategy to provide the desired oxidation at C-3

0 0 OH BnO OH BnO 0 TBSPrev ios.. TBSO Lactone TBSO TBSO Lactol CH3

81 97 98 O O-N OH BnO BnO Formation of Barton Reaction O Hydrolyze nitrite ester TBSO TBSO Oxime CH3 CH 3

99 100 N-OH

OH BnO BnO O 0 Ring Closure TBSO CH3. .. - TBSO OH3 \ CH3

101 0 102 Chapter V: Introduction

5.1 Biological Activity

Taxol® 33 (103) was originally isolated from bark extracts of the western yew tree (Taxus brevifolia) by Barclay. 34 In 1964, Wani and co-workers reported that Taxol@ exhibited cytotoxicity against 9KB and various leukemia

systems. 35 In a number of studies since its isolation,36 Taxol@ has been shown to exhibit antitumor activity against several different tumor models,

including ovarian tumors, MX-1 mammary tumors, and B16 melanoma. 3 7 Recently the FDA approved the use of Taxol@ for the treatment of metastatic

ovarian and breast tumors. 38

Scheme 43: The natural product, Taxol®.

AcO 0 OH

Ph 0

BzHN 0" : H OH HO OBz OAc

Taxol®, 103

Unfortunately, nature does not provide usable quantities of Taxol®.

One large scale harvest required ca. 12,000 trees, equaling 60,000 tons of bark,

33 Taxol is the registered trademark for the molecule with the generic name paclitaxel. 3 4 Junod, T. Life 1992, 15, 71. 3 5 Wani, M. C.; Taylor, H. L.; Wall, M. E.; Coggan, P.; McPhail, A. T. J. Am. Chem. Soc. 1971, 93, 2325. 36Reviews: (a) Rowinsky, E. K.; Onetto, N.; Canetta, R. M.; Arbuck, S. G. Semin. Oncol. 1992, 19, 646. (b) Holmes, F. A.; Walters, R. M.; Theriault, R. L.; Forman, A. D.; Newton, L. K.; Raber, M. N.; Buzdar, A. U.; Frye, D. K.; Hortobagyi, G. N. J. Natl. Cancer Inst. 1991, 83, 1797. (c) Nicolaou, K. C.; Dai, W.-M.; Guy, R. K. Angew. Chem., Int. Ed. Eng. 1994, 33, 15. 37 (a) Wiernik, P. H.; Schwartz, E. L.; Strauman, J. J.; Dutcher, J. P.; Lipton, R. B.; Paietta, E. Cancer Res. 1987, 47, 2486. (b) Mathew, A. E.; Mejillano, M. R.; Nath, J. P.; Himes, R. H.; Stella, V. J. J. Med. Chem. 1992, 35, 145. 3 8Slichenmeyer, W. J.; Von Hoff, D. D. Anti-Cancer Drugs 1991, 2, 519. Chapter V: Introduction * 48 and yielded 2.5 kg of Taxol®. Treatment of one patient typically requires two grams of Taxol@. The high demand for Taxol@ has depleted the northwestern rain forests of this venerable species and upset the ecosystem.

To avoid this devastation, several research groups set forth to design a semi- synthesis of Taxol@, with major contributions from Holton, Ojima and

Greene. 39 In 1988, Holton was successful in synthesizing Taxol@ from a compound known as baccatin III (104) via reaction with p-lactam 106 (Scheme

44). First the C-7 alcohol of baccatin III was protected as the triethylsilyl ether, then after treating 105 with DMAP and pyridine with p-lactam 106, product

107 was obtained. Deprotection afforded Taxol@ in good yield.

Scheme 44: Semi-synthesis of Taxol@ from baccatin III and p-lactam 106.

AcO Ph AcO 0 OTES AcO O OR

O>- O O Ph O

1 0 6 Ph Ph N H H = H HO OBzOAc HO' O HO OBz OAc DMAP, pyr O 107

R=H: Baccatin III, 104 R=TES, 105 Taxol, 103

The importance of this semi-synthesis is due to the fact that baccatin III is isolated from the needles of the European yew (Taxus baccata). Harvesting

the needles does not threaten the survival of the tree, as unlike the bark, they are easily regenerated. 40

39 (a) Holton, R. A. Eur. Pat. App. 400971, 1990. (b) Ojima, I.; Habus, I.; Zhao, M.; Georg, G.; Jayasinghe, 1. R. J. Org. Chem. 1991, 56, 1681. (c) Ojima, I.; Habus, I.; Zhao, M.; Zucco, M.; Park, Y. H.; Sun, C. m.; Brigaud, T. Tetrahedron 1992, 48, 6985. 40 (a) Denis, J.-N.; Greene, A. E.; Gudritte-Voegelein, F.; Mangatal, L.; Potier, P. J.Am. Chem. Soc. 1988, 110, 5917. (b) McCormick, D. Bio/Technology 1993, 11, 26. Chapter V: Introduction * 49

Taxol@ is a member of a class of antimitotic compounds including colchicine and podophyllotoxin (Scheme 45). Because these compounds efficiently arrest cell division, they are a main focus of cancer research and therapy. In 1979, Horwitz and coworkers found the mode of action exhibited by Taxol@ to be unique for this class of antimitotic compounds. 4 1

Scheme 45: Other antimitotic compounds.

OH

H 3 CO 0o

I.... NHCOCH 3 0 3. H3CO 0

CH30 / H

OCH 3 H3CO OCH 3 OCH 3

Colchicine Podophyllotoxin

During the metaphase (M phase) of cell division, it is essential for the mitotic spindle to form and move the chromosomes toward the poles of the cell. After the migration is complete, the cell divides. Inability of the mitotic

spindle to perform its duties leads to cell arrest. The mitotic spindle consists

of a complex network of microtubules and associated proteins. Each microtubule contains 13 parallel columns of protofilaments which adopt a cylindrical shape. The protofilaments are made up of two types of protein: ta-

tubulin and P-tubulin, referred to in units as p dimers, or tubulin. These xp dimers are arranged 'head to tail' and assemble/disassemble sequentially in a

helical fashion in the longitudinal direction. Microtubules

assemble/disassemble on either end, but there is a preference for addition of tubulin in one direction where the other prefers dissociation of tubulin

4 1Schiff, P. B.: Fant, J.; Horwitz, S. B. Nature, 1979, 277, 665.

0O Chapter V: Introduction * 50 subunits. The net growth of microtubules is dependent upon the hydrolysis of bound GTP and the availability of GTP-tubulin subunits. Tubulin favors dissociation at low temperatures or in the presence of Ca 2+. Polymerization and depolymerization of the dimers exists in a dynamic steady state; an alteration of this state could lead to cell arrest.

Prior to 1979, antimitotic compounds were known to block cell division by inhibiting the polymerization of tubulin. Colchicine had the most profound effect, but because of its toxicity it could not be used for anti- cancer treatment. There exists a high-affinity binding site for colchicine on the tubulin subunits, and once colchicine binds to the unit it ceases growth causing a net loss of microtubules and an accumulation of tubulin. In the presence of colchicine, the mitotic spindle does not form and the chromosomes are not moved to the poles of the cell, leading to cell arrest.

Taxol@, however, was the first compound discovered to promote the formation of microtubules even in the absence of GTP and does not disassemble in the presence of Ca 2+ or low temperatures.#6 Once Taxol@- bound microtubules form, they are resistant to depolymerization, and without depolymerization the cell will not divide, promoting cell death. Recently, three different compounds with structures unlike that of Taxol@ were discovered and found to exhibit the characteristic microtubule assembly/stabilization properties of Taxol@. These compounds were (+)- discodermolide, epothilones A and B, and eleutherobin (Scheme 46). Chapter V: Introduction * 51

Scheme 46: Compounds with the same mode of action as Taxol®.

OH

N N OH

R=H epothilone AOH CH3

R=H epothilone A R=CH 3 epothilone B Eleutherobin

OH HO O

OH HO Discodermolide

Discodermolide was isolated from a Caribbean marine sponge, discoderma

dissoluta, and was found to possess immunosuppressive and cytotoxic

activities. 4 2 In more recent studies, discodermolide was shown to bind to

tubulin in mictotubules in a 1:1 ratio with a higher affinity than Taxol®.4 3

The overall effect was the net polymerization of microtubules in the absence

of microtubule associated proteins (MAPS) or GTP. Furthermore, the disassembly was not induced at low temperatures or in high concentrations of Ca 2 +.44 Epothilones A and B were isolated from myxobacteria of the genus Sorangium and were found to have a broad activity against eukaryotic cells. They were first classified as antifungal cytotoxic compounds; 4 5 subsequent

4 2Gunasekera, S. P.; Gunasckera, M.; Longley, R. E.; Schulte, G. K. J. Org. Chem. 1990, 55, 4912. 4 3 Hung, D. T.; Chen. J.: Schreiber, S. L. Chem. Biol. 1996, 3, 287. 4 4 terHaar, E.; Kowalski, R. J.; Jamel, E.; Lin, C. M.; Longley, R. E.; Gunasekera, S. P.; Rosenkranz, H. S.; Day, B. W. Biochem. 1996, 35, 243. 4 5 (a) Gerth, K.; Bcdorf, N.; Hofle, G,; Irschik, H.; Reichenbach, H. J. Antibiot. 1996, 49, 560. (b) Hofle, G.; Bedorf, N.; Steinmetz, H.; Schomburg, D.; Gerth, K.; Reichenbach, H. Angew. Chem., Int. Ed. 1996, 35, 1567. Chapter V: Introduction * 52 studies by a Merck based research group determined that they stabilize microtubules by the same mechanism as Taxol@. Epithilones A and B compete for the same binding site as Taxol@. 46 Eleutherobin is the most recently isolated compound to resemble the mode of action of Taxol@, and it too competes for the same binding site as Taxol®.47 These compounds may eventually join Taxol@ as chemotherapeutic compounds. Nearly every taxane isolated has been screened for bioactivity, but no 48 other natural taxane matches the potency or effectiveness of Taxol@. When Taxol@ was isolated and characterized, the tetraol (108) was one of the degradation products which exhibited 0.001 times the activity of Taxol@

(Scheme 47).35

Scheme 47: A Taxol@ degradation product, and a synthetic analogue.

HO O OH HO O OH

Ph 0

H HO" " H t-BuO 2CHN 0" HO OBz OAc OH HO OBz OAc

108 109, Taxotere

The major drawback of Taxol@ is its low water solubility which leads to complications in its formulation. Several research groups have focused their efforts on synthesizing derivatives of Taxol@ from noncytotoxic natural product extracts. 49 The emphasis of these studies is on the synthesis of new

4 6 Bollag, D. M.; McQuency, P. A.; Zhu, J.; Hensens, O.; Koupal, L.; Liesch, J.; Goetz, M.; Lazarides, E.; Woods, C. M. Cancer Res. 1995, 55, 2325. 4 7Lindel, T.; Jensen, P. R.; Fenical, W.; Long, B. H.; Casazza, A. M.; Carboni, J.; Fairchild, C. R. J. Am. Chem. Soc. 1997, 119, 8744 and references cited within. 4 8 Taxane Anticancer 4gents: Basic Science and Current Status: Georg, G. I.; Chen, T. T.; Ojima, I.; Vays, D. M., Eds.: ACS Symposium Series 583; American Chemical Society: Washington, 1995. 4 9 (a) Kingston, D. G. I.; Samaranayake, G.; Ivey, C. A. J. Nat. Prod. 1990, 53, 1. (b) Gu6ritte- Voefelein, F.; Gu6nard, D.; Lavelle, F.; Le Goff, M.-T.; Mangatal, L.; Potier, R. J. Med. Chem. 1991, 34, 992. (c) Swindell, C. S.; Krauss, N. E. J. Med. Chem. 1991, 34, 1176. (d) Mathew, A. E.; Chapter V: Introduction * 53 structures with increased water solubility without a decrease in the potency or effectiveness of the drug. Many of the Taxol@ analogues synthesized to date contain modifications of the side chain and/or altered functional groups at various positions. Unfortunately, most of the compounds synthesized have little effect on microtubule assembly, the exception being the synthetic analogue, taxotere (109) (Scheme 47).5 0 Taxotere has shown greater levels of cytotoxic activity than Taxol@, and its water solubility is much higher than that of Taxol@. Taxotere can be obtained in large quantities form baccatin III and the appropriate p-lactam. 5 1 Although this analogue has met and surpassed the challenge of Taxol@, it has yet to be approved clinically in the United States.5 2

5.2 Structure

Taxanes are a class of diterpene natural products that are isolated from various Yew (taxus) species. Over 100 isolated taxane derivatives have been

shown to contain the characteristic tricyclic core structure depicted below.

Scheme 48: Taxane framework and numbering system.

7

H3 C 8

133 4 1 2H

This structurally congested molecule contains several synthetically challenging aspects. The A-B unit is a bicyclo[3.5.1]undecane system that

Mejillano, M. R.; Nath, J. P.; Jimes, R. H.; Stella V. J. J. Med. Chem. 1992, 35, 145. (e) Georg, G. I.; Cheruvallath, Z. S. J. Med. Chem. 1992, 35, 4230. 50 Bissery, M.-C.; Gu6nard, D.; Gu6ritte-Voegelein, F.; Lavelle, F. Cancer Res. 1991, 51, 4845. 5 10jima, I.; Sun, C. M.; Zucco, M.; Park, Y. H.; Duclos, O.; Kuduk, S. Tetrahedron Lett. 1993, 34, 4149. 5 2(a) Georg, G. I.; Chen, T. T.; Ojima, I.; Vyas, D. M. Taxane Anticancer Agents: American Cancer Society: San Diego, 1995. (b) Kingston, D. G. I.; Molinero, A. A.; Rimoldo, J. M. Progress in the Chemistry of Organic Natural Products 61; Springer-Verlag: New York, 1993. Chapter V: Introduction * 54 contains a bridgehead double bond, and attached to the eight membered ring is a trans-fused cyclohexane. These features, combined with the high degree of oxygenation and the number of stereocenters, make taxanes extremely challenging synthetic targets. In addition to the intricacies of the taxane ring system, Taxol@ contains an additional oxetane ring as well as oxygenation at C-1, C-2, C-4, C-7, C-9, and

C-10. C-13 is not only oxygenated, it has a side chain with two stereocenters.

These features have challenged the synthetic community for decades. Several different schemes have been devised to construct the congested framework, but only few have been rewarded with the completed total synthesis. Taxusin (110) was isolated from the heartwood of taxus cuspidata in

1968 by Shimizu and coworkers. 53 To date, taxusin has been synthesized by two groups but neither group has made the product in its natural form. 55 Holton 54 and coworkers synthesized taxusin's enantiomer and Kuwajima and coworkers synthesized taxusin as its racemate.

Scheme 49: (+)-Taxusin.

AcO OAc

HO"" H OAc H

Taxusin, 110

Although taxusin is one the least functionalized in the taxane family, it contains many of the challenges encountered with the other taxanes. In

addition to the taxane ring structure, taxusin has an exo double bond on the

53 Miyazaki, M.: Shimizu, D.; Mishima, H.; Kurabayashi, M. Chem. Pharm. Bull. 1968, 16, 546. 5 4 Holton, R. A.; Juo, R. R.; Kim, H. B.; Williams, A. D.; Harusawa, S.; Lowenthal, R. E.; Yogai, S. J. Am. Chem. Soc. 1988, 110, 6558. 5 5 Hara, R.; Furukawa, T.; Horiguchi, Y.; Kuwajima, I. J. Am. Chem. Soc. 1996, 118, 9186. Chapter V: introduction * 55 cyclohexane ring and oxygenation at C-5, C-9, C-10 and C-13. Although taxusin does not exhibit bioactivity, much can be learned about the taxane system through its synthesis.

5.3 Synthetic Strategy

With its high bioactivity and interesting structure, Taxol@ has attracted

much interest in the field of total synthesis, with four syntheses published to

date: Holton 56, Nicolaou 57, Mukaiyama5 8 and Danishefsky 59 .

Scheme 50: Disconnections of the taxane system to afford actual intermediates used to synthesize Taxol@.

CO 2 Me BnO 0 0 OTES I : BC -- ABC AB -+ ABC C 0 A C H H A TESO OBn O,. 0 Mukaiyama T. B1 A,C -- ABC 111 R. Holton 112

0 0

K.C. Nicolaou 113

5 6 Holton, R. A.; Somoza, C.; Kim, H.-B.; Liang, F.; Biediger, R. J.; Boatman, P. D.; Shimdo, M.; Smith, C. C.: Kim, S.; Nadizadch. H.; Yukio, S.; Tao, C.; Vu, P.; Tang, S.; Shang, P.; Murthi, K. K.; Gentile, L. N.;Liu, J. H. J. Am. Chem. Soc. 1994, 116, 1597. 57 Nicolaou, K. C.; Yang, Z.; Liu, J. J.; Ueno, H.; Nantermet, P. G.; Guy, R. K.; Claiborne, C. F.; Renaud, J.; Couladouros, E. A.; Paulvannan, K.; Sorensen, E. J. Nature 1994, 367, 630. 5 8Shiina, I.; Saitoh, K.; Frechard-Ortuno, I.; Mukaiyama, T. Chem. Lett. 1998, 3. 5 9 Danishefsky, S. J.; Masters, J. J.; Young, W. B.; Link, J. T.; Snyder, L. B.; Magee, T. V.; Jung, D. K.; Isaacs, R. C. A.; Bornmann, W. G.; Alaimo, C. A.; Coburn, C. A.; Di Grandi, M. J. J. Am. Chem. Soc. 118, 2843. Chapter V: Introduction * 56

The key feature and most challenging aspect of Taxol@ is its tricyclic core. One can envision three different disconnections to construct this tricycle (A, B, C below). Interestingly, each of these approaches has been explored in the various syntheses of Taxol@.

Approach A involves closure of the A ring onto the BC ring. The disconnection at the ring juncture double bond has an advantage over other disconnections within the A ring because of the lack of stereochemistry at that position and the handful of ring closures that lead to double bonds. However, this particular cyclization also has its disadvantages as the conformation of the B ring required for the A ring cyclization may not be easily attained due to steric constraints.

Disconnection B involves formation of the A and C rings separately followed by a coupling of A and C, and then cyclization to form the complete ABC system. This strategy is the most convergent but the formation of eight membered rings is quite difficult, and usually low yielding, and it is undesirable to have such a questionable reaction near the end of the synthesis. Finally, approach C involves the synthesis of the AB unit then

tethering on the C ring. The advantage of this approach is that there are a number of reactions that could form the C-ring. The disadvantage is the

potential isomerization of the stereocenters located at the ring juncture. A review of the key steps of each of the previous syntheses will show how these advantages were exploited and how the drawbacks were addressed.

In their recent synthesis of Taxol@, Mukaiyama and coworkers

utilized approach A to design their synthetic route around three key

cyclizations. A samarium(II) iodide mediated cyclization of 114 was

employed, followed by functional group protection and interconversion to Chapter V: Introduction * 57 give the cyclooctenone intermediate 115. This strategy allows for modification or incorporation of functional groups on the B-unit. 60 Selective changes in the system may permit the synthesis of novel candidates that could have superior water solubility when compared to Taxol@. The next phase of their strategy involves an intramolecular aldol cyclization of a

Michael adduct which completes the C-ring. This cyclization provides the trans-ring system in surprisingly high yields. A pinacol coupling between the methyl ketone and the cyclooctanone yields the complete carbocyclic framework.

Scheme 51: Approach A: B--BC-+ABC; Employed by Mukaiyama et al.

1. Sml 2, THF -78 'C OBn Br BnO 2. Ac2O, DMAP H 3. DBU, benzene O, O O ,O 54% overall yield PMBO OBn TBS PMB

114 115

NaOMe, MeOH,

THF 0 C, 98%

PMBO OBn PMBO OBn 116 117

BnO 0 0 HO HO TiCI 2 , LiAIH 4,

O0 THF, 35 0C, 52% TBSO OBn

111 118

6 0Yamada, K.; Tozawa, T.; Saitoh, K.; Mukaiyama, T. Chem. Pharm. Bull. 1997, 45, 2113. Chapter V: Introduction * 58

Approach B was first utilized by Nicolaou and, more recently, by Danishefsky. Nicolaou and coworkers began their synthesis with the construction of A and C rings, incorporating the functionalization that could withstand the conditions necessary for the B ring cyclization. 6 1 The Shapiro reaction was employed to couple the bottom portion of the eight membered ring affording compound 113. Later in the synthesis, cyclization of the B ring was accomplished using a McMurry coupling reaction. 62

Scheme 52: Approach B: A,C--ABC; employed by Nicolaou, et al.

OBn TPSO OTPS OBn OTBS 1. 119, n-BuLi, THF TPSO' I -78 0C -* 25 0C + H H "'0O 2. Cool to 0 oC, SH NNHSO 2Ar add 120, 82% HO 119 120 113 O OBn HO OH OBn

(TiCI3)2-(DME) 3

Zn-Cu, DME, 70 oC _H O H O0 O O O OO 0 YK 0

121 122

Approach C was employed by Holton and coworkers. Starting with

camphor they were able to synthesize compound 123 which was designed to 6 3 undergo an alcohol fragmentation to afford the AB ring system. Epoxidation of 123 followed by the acid catalyzed rearrangement gave 124 in

excellent overall yield. The next task was the incorporation of the C-1

6 1Nicolaou, K. C.; Hwang, C.-K.; Sorensen, E. J.; Claiborne, C. F.; J. Chem. Soc., Chem. Commun. 1992, 1117. 62 Nicolaou, K. C.; Yang, Z.; Sorensen, E. J.; Nakada, M. J. Chem. Soc., Chem. Commun. 1993, 1024. 6 3 Holton, R. A. J. Am. Chem. Soc. 1984, 106, 5731. Chapter V: Introduction * 59 hydroxyl, accomplished by treating 125 with LTMP followed by addition of (+)-camphorsulfonyl oxaziridine.

Scheme 53: Approach C; AB--ABC; employed by Holton, et al.

OTES

1. t-BuOOH, Ti(O'Pr)4 CH 2C12 'OTES TESO""0 OH 2. BF3-OEt2 , CF 3SO3 H CH 2C12, 93% overall yield 124 123

OTES LTMP, - 10 oC

then CSO, - 40 0C HO 0 88%

125 EtO OTES OH OTES LDA, THF, -78 "C TS,/ OEt then HOAc, 84% TESO_' H O O OH O TESO" -HH O O 0

127 112

After reduction of the C-2 ketone and protection of the diol with phosgene,

the focus then shifted to the C-ring cyclization. This was achieved by a Dieckmann condensation of the ethyl ester and the lactone of 112 to afford

127.64

64 Gardner, P. D.; Jaynes, G. R.; Brandon, R. L. J. Org. Chem. 1957, 22, 1206. Chapter VI: Synthetic Modifications

6.1 Retrosynthetic Analysis The complexity of the taxane system lies in the formation of the ABC ring as a complete unit. It has been shown that the individual rings can be synthesized quite readily on their own; it is the joining of the rings that is most difficult. The system is sterically crowded and congested. Outlined in

Scheme 54 is our synthetic plan to obtain taxusin in its natural from. A retro aldol reaction would open ring A of 110 leading to diketone 128. This particular disconnection was chosen because of work by Swindell and coworkers that will be discussed in Chapter VIII.

Scheme 54: Retrosynthetic analysis.

O 10 9 CH3 8 O 8 0 H C 3 3 OAc O0- 1H O H HO' / OCH 3 128 129

Br OCH 3 O H O 131 132

0 OCH3 SOH

CH3 130 H Br NO2

O

133 134 Chapter VI: Synthetic Modifications * 61

Due to the difficulty of eight membered ring cyclizations, we were interested in opening a fused bicyclic ring system at the central bond. Of the few options available for forming eight membered rings, we chose to form a bicyclo[6.4.0] ring system. By connecting C-3 to C-10 in 128, the next key intermediate was cyclobutane, 129. Cyclobutanes are easily accessible via photochemical reactions, so it was then a matter of which olefin precursor would present the most straightforward target to synthesize. Disconnecting C-3 and C-10 from C-

8 and C-9 would afford enone-olefin 130, which could be synthesized far more readily than the compound formed from the disconnection of C-10 and C-9 from C-3 and C-8. Photo precursor 130 is disconnected at the aryl side chain which allows for several types of coupling reactions for its formation. The chiral triflate slightly resembled a rearranged and ring expanded natural product (1S-)-(+)-camphorsulfonic acid (133). Starting with the inexpensive enantiomerically pure compound, the synthesis was centered around the stereochemistry already fixed at the C-1 position. The synthesis of the aryl side chain from commercially available 1-bromo-5-nitrotoluene (134) was designed by Dr. Paige Mahaney; its significance will be discussed in Chapter VII. 65

6.2 Modifications to the original synthetic route The original synthetic strategy developed by Dr. Edward Licitra was

designed to provide flexibility in the type of side chain that would be joined to the system prior to photocyclization. Formation of the enol triflate 131 would

accommodate the desire to synthesize a diverse selection of photo precursors

by employing cuprate coupling reactions with various side chains. The target

65 Mahaney, P. E. Efforts Toward The Synthesis of Taxane Natural Porducts. Ph.D. Thesis, Massachusetts Institute of Technology, Cambridge, MA, June 1996. Chapter VI: Synthetic Modifications * 62 enol-triflate resembles an intermediate (135) in Liu's synthesis of khusimone 66 and was constructed in a similar fashion. Liu's intermediate (135) is depicted below with enol triflate 131 and the preferred aryl side chain.

Scheme 55: Liu's intermediate with synthetic intermediates 131 and 132.

0 0

CH 3O OCH3 O OTf 0 H

135 131 132

The synthesis of enol triflate 131 was accomplished in eight steps starting with

(1S-)-(+)-camphorsulfonic acid following the scheme outlined below. 67

Scheme 56: Synthesis of enol triflate 131.

i. NaH, Benzene/Hex ii. DMF, (COCI) 0 0C H KOH, 180 oC HO 2 then HCI(aq) iii. CH 2CI2/THF O 76% H EtMgBr, Cul -15 0C H HO3S O 80% 136 1S-(+)-camphor- R-campholenic acid sulfonic acid, 133 O RuCI3 , NalO 4, )CH ) , TsOH NaHCO 2 2 3 00 CN Benzene CC14:H20:CH3 OR 94% --O H 75% 0 H O 137 CH R=H, 138

R=CH 3 , 139

O 0 NaH, THF NaH, MeOH i. ii. PhN(Tf) DMSO/THF 2 OTf 56% O 0 H 68% 0 H

140 131

6 6 Liu, H.- J.; Chan. W. H. Can. J. Chem. 1979, 57, 708. 67 Crist, B. V.; Rodgers, S. L.; Lightner, D. A. J. Am. Chem. Soc. 1982, 104, 6040. Chapter VI: Synthetic Modifications * 63

We felt that the original route contained numerous steps and that the reproducibility of the oxidative cleavage of the cyclopentene 137 on a large scale was not optimal. Several alterations were made to make this route a more desirable one. The first modification was the one-pot conversion of the

R-campholenic acid to ethyl ketone 136. This decreased the sequence by one step and increased the yield by 10%. The oxidative cleavage was problematic due to the presence of the acid labile ketal. In the procedure developed by

Sharpless and coworkers, sodium periodate is added to catalytic ruthenium trichloride to generate the active ruthenium tetroxide oxidizing agent. This mixture forms an acidic solution. Therefore, the addition of several portions of sodium bicarbonate is necessary to adjust the pH of the system which in turn effects the performance of the ruthenium oxidation. Potassium but permanganate successfully oxidized the olefin to afford the keto acid 138 in only 38% yield. After several attempts to optimize the oxidative cleavage, we decided that a more straightforward cleavage of the ring was essential to the success of this scheme. Employing an ozonolysis reaction would provide the keto aldehyde 141, not the desired keto acid 138. However, the ozonolysis was not a dead end. It was shown by Kuwajima and coworkers that the addition of an aryl lithium to an aldehyde in the presence of an enone could be accomplished in good yields with the presence of equimolar amounts of cerium trichloride. 69 After Mahaney discovered the preferred side chain was the aryl bromide 132, the ozone cleavage reaction became attractive. The

ozonolysis seemed to be straightforward because the molecule did not contain

any sensitive groups. Several attempts at the ozonolysis gave a maximum

6 8 Carlsen, P. H. J.; Katsuki, T.; Martin, V. S.; Sharpless, K. B. J. Org. Chem. 1981, 46, 3936. 6 9 Seto, M.; Morihira, K.; Katagiri, S.; Furukawa, T.; Horiguchi, Y.; Kuwajima, I. Chem. Lett. 1993, 133. Chapter VI: Synthetic Modifications * 64 yield of only 59%. When performed in a mixture of methanol and dichloromethane, the reaction resulted in a mixture of the keto aldehyde and the compound with the aldehyde in the hemiketal form. The hemiketal could be converted to the keto acid, but again, the yield was not greater than 59%. Unfortunately our new approach was more difficult than we originally expected. Although the ozonolysis yield did not surpass that of the original cleavage, this route offered fewer steps to the target molecule.

Scheme 57: Oxidative cleavage with ozone.

03, Sudan Red 0 CH 2C12

then Me 2S H 0 H 59% 0 H 137 141

With the desired keto aldehyde in hand, we turn our focus to the aryl addition previously described by Kuwajima. 69 Kuwajima's system had an unencumbered aldehyde and a cyclic enone that was blocked by geminal di- methyls. Our system resembled that of Kuwajima's in that the aldehyde was easily accessible, and although our ketone was blocked by geminal dimethyls,

it was only a methyl ketone.

Scheme 58: Comparison of keto-aldehyde intermediates.

O Ac H 0 142 141 Chapter VI: Synthetic Modifications * 65

The addition of the aryl bromide was accomplished in the presence of cerium trichloride leading to a mixture of open and closed forms of the lactols 143 and 144.

Scheme 59: Cerium mediated aryl lithium addition to aldehyde 141.

t-Bu Li, Et20, -90 oC, HO CH 3 CeC13 , -90 oC- -50 C '

Br OCH3 O Br CH3 Aldehyde 141, H OCH3 66%

132 143, 144

Due to the difficulty in separation, the oxidation to the diketone was performed on the mixture of compounds. During the oxidation with

PCC/alumina, we discovered that only one of the isomers formed a new product. After isolation and purification the new product was indeed the desired diketone 145.

Scheme 60: Lactol oxidation to diketone 145.

HO CH 3 0

PCC/Alumina -

I OCH3 CH 2CI2, Pyridine, rt OCH3 O H 47% 0 H

143,144 145

The unreactive compound was identified as the lactol 143 and was assigned the structure shown below. This structure is referred to as the S-isomer (the stereochemistry at the newly formed stereocenter). Considering the anomeric effect, the alcohol will occupy the axial position with the two bulky side chains in the equatorial positions. NMR analysis of the CH 2 position of the Chapter VI: Synthetic Modifications * 66 ring was consistent with two axial-axial coupling constants, and two equatorial-axial coupling constants. The axial methyl has only one 1,3-diaxial interaction due to the oxygen in the ring. This lactol was unreactive to a number of oxidation reactions, including PDC, Swern oxidation, S0 3-pyridine complex and silver carbonate on celite.

Scheme 61: Unreactive lactol in favorable conformation.

H OH

CH 3 O O1

CH3

OMe

Stable lactol, 143

The R isomer forms a strained lactol with the aryl side chain occupying an axial position in the chair conformation shown in Scheme 62. This instability allows the ring to open, and in the presence of PCC/alumina the alcohol is oxidized to the desired diketone product. NMR analysis of the mixture confirms a methyl ketone at 2.1 ppm.

Scheme 62: Unfavorable interaction provides equilibrium with open form.

Unfavorable 1,3- MeO diaxial interaction O

H OH OH

OH CH OCH 3 O H R 3

CH 3

144 Chapter VI: Synthetic Modifications * 67

Although the failure to oxidize the S isomer was a disappointment, we were only one step away from the desired photo precursor. Treatment of the diketone with potassium hydroxide in methanol provided enone 130 in 98% yield. With this new route, the key photo precursor was obtained in seven steps in comparable yield to the previous nine step route.

Scheme 63: Formation of the key photo precursor 130.

O 0O 0 KOH/MeOH

OCH 3 980/o OCH 3 0 H 0 H i

145 130 Chapter VII: B-Ring Formation

7.1 Previous Work

A [2+2] intramolecular photocyclization 70 between the enone and the olefin of 146 afforded the desired tricyclic fused system 147 as well as 148 (Scheme 64). Licitra's system favored the formation of 148, the undesired addition product.

Scheme 64: Previous photocyclization gives a mixture of products.

O O S H - H hv, - 780C

0 H 3 C 0 H 3 C " o H H H

146 Solvent 147 Ratio of Products 148

CH2CI2/Hex 1 7 Hexane 1 1.5

The conditions of the photocyclization reaction were optimized by Mahaney. Mahaney's task was to design a side chain that could control olefin addition

to the top face of the enone. 6 5 Mahaney found that changing the exo

methylene to an aromatic ring was crucial to the success of the photocyclization. Initial studies found the stabilization of the -radical with an aromatic ring coupled with the more rigid conformation, favored the addition of the olefin to the top face of the molecule. The methoxy moiety was added to the phenyl ring in order to control the cleavage of the aryl

portion later in the synthesis. With this new side chain, exclusive formation

of cyclobutane 129 was obtained in excellent yield (Scheme 65).

70 de Mayo, P. Acc. Chem. Res. 1971, 4, 41. Chapter VII: Oxidative Cleavage Attempts * 69

Scheme 65: Aryl system designed to give the correct addition product.

hv, Pyrex, 0 0C 0

OCH 3 Benzene/Hexane 89% O

OCH 3 130 129

The reductive cleavage of the tricyclic fused system would lead to the

correct stereochemistry at C-8. However, the protonation at position C-3 was

unpredictable at this point, and it was believed that a mixture of cis and trans

fused products would be obtained. After several experiments and

modifications, it was found the either the cis or the trans isomer could be

formed exclusively in excellent yields (Scheme 66).71

Scheme 66: Reductive cleavage affords cis or trans ring juncture exclusively.

Ca, NH3-THF OCH 3 - 35 OC, quench immediately 149

0

OCH3 Li, NH3-THF 129 .OCH 3 - 35 'C, allow for further reduction 150

Formation of the trans ring fused system with one equivalent of the

reducing agent was instantaneous at -30 OC in good yield. Because small

amounts of the starting material were initially recovered, the reaction was

7 10ppolzer, W. Acc. Chem. Res. 1982, 15, 135. Chapter VII: Oxidative Cleavage Attempts * 70 performed with excess metal. The hope was that higher yields of the trans ring fusion product that was fully reduced to the alcohol would be isolated. However, after oxidation of the alcohol with PCC/alumina a completely different product was isolated; it was the cis fused ketone. The exclusive formation of the cis ring fusion was puzzling to us for quite some time.

However, there has been new insight which has led to a new proposed mechanism.

7.2 New Proposed Mechanism We have recently proposed a mechanism that accounts for the formation of each of the ring opening products. During the metal reduction, one electron adds to the ketone forming radical-anion 151. Cleavage of the cyclobutane relieves the -26 kcal/mol strain of the ring, and forms an enolate and a stabilized phenyl radical. A second electron is added to the system producing an anion which is protonated preferentially on the bottom face affording the trans fused juncture, 149. With only one equivalent of reducing agent present, the reaction stops at trans fused product 149 (Scheme 67).

Scheme 67: Reductive ring opening to exclusively afford trans ring juncture.

o o H H

S H3C Ca, NH 3-THF H3C

O H- 35 C H

CH 3 CH 3 Reduction then

O OCH 3 Protonation " OCH3

H 152 149 Chapter VII: Oxidative Cleavage Attempts * 71

With an excess of dissolved metal, the cyclooctanone can be reduced to radical anion 154. Once the cyclooctanone anion 154 adopts a conformation like that shown in scheme 68, it can react intramolecularly and abstract the benzylic hydrogen through a six-membered transition state. This forms a stable benzylic radical which, after further reduction, favors protonation of the top face of the molecule, giving exclusively the cis ring fused alcohol 150.

Scheme 68: Further reduction to exclusively afford the cis ring juncture.

CH3 CH3 H H OCH Li, NH -THF 0 " OCH3 O/O 3 3

35 oC H3 H H3C H CH 3 0 CH 3 0_

149 H-abstraction 154

O OCH Reduction 3 then H3C H O_ * OCH3 H H 3C Protonation H 3C H 3C O_

155 K) 150

Although the epimerization of the cis system to the trans system has not been studied, the fact that the taxane family contains the trans ring fusion makes it likely that the stereocenter could be epimerized. The ability to form either

ring fused product expands our reaction possiblities. The molecules have the

same functionality, but exist in different conformations. The conformations

have an effect on the reactivity and in the following chapter, the reactions of

the trans and cis ring fused systems will be discussed. Chapter VII: Oxidative Cleavage Attempts * 72

7.3 Oxidative Cleavage Attempts The reductive cleavage of cyclobutane 129 proved to be a versatile reaction, allowing the formation of either the desired trans ring fusion or the cis ring fusion. We also considered performing an oxidative cleavage on cyclobutane 129 which could possibly allow for the introduction of functionality at different areas of the B and C rings. The initial plan was to use a Lewis acid to promote the ring opening to give a stable benzyl cation that could lead to a styrene like compound (Scheme 69).72

Scheme 69: Proposed acid catalyzed ring opening reaction.

LA 0 LA IH CH3 "0 0 H3C ------OM e O H 0 H

OCH 3

129 156

However, the cyclobutane would not open after employing several

different Lewis acids, including boron trifluoride diethyl etherate, titanium

tetrachloride, titanium trichloride mono-isopropoxide, dimethylaluminum chloride, as well as triflic acid and trifluoroacetic acid. Under all conditions, starting material was either recovered or destroyed. Using TMSC1 as the Lewis acid, it seemed reasonable for the coordinated ketone to weaken the ring fusion and in the presence of a strong base, facilitate abstraction of the y

hydrogen. This process would generate the desired styrene 156b.

7 2 Cargill, R. L.; Jackson, T. E.; Peet, N. P.; Pond, D. M. Acc. Chem. Res. 1974, 7, 106. Chapter VII: Oxidative CleavageAttempts * 73

Scheme 70: Proposed y-hydrogen abstraction.

TMSCI /MS O O 0 H Proposed y-hydrogen CH3 SH 3C abstraction O

0 HHH H HOCH OCH 3 / OCH 3 129 156b

Excess trimethylsilyl chloride was added to the ketone at -78 oC to coordinate to the ketone before the LDA was added. A new product began to form within 30 minutes as the solution was warmed to 0 oC. NMR analysis of the product did not show the presence of a styrene, nor the presence of hydrogen adjacent to the carbonyl. Further analysis including 13C NMR revealed the presence of a silyl enol ether exo to the cyclobutane ring. Although this enolization was not originally anticipated, it was intriguing that this highly

strained ring system was formed in high yield.

Scheme 71: Unexpected formation of trimethylsilyl enol ether.

0 OSiMe 3 - H

0 H C TMSCI, THF 0 H3C K--~3 O H LDA, -78C 0 H

OCH 3 / OCH3 129 157

Oxidation of the benzylic position was unattainable via these oxidative

means. It is likely that the incorporation of a functional group in the y

position could be attained earlier in the synthesis. CH3

Chapter VIII: A-Ring Cyclization Attempts:

8.1 Swindell's A-Ring Cyclization In the original synthetic plan, the A ring cyclization was designed to employ the work of Swindell and coworkers. 73 They demonstrated that the bridged ring system could be synthesized from three different intermediates that contained the BC-ring unit in its correct form (Scheme 72).

Scheme 72: Swindell's A-ring cyclizations.

CH CH 3 3

1. Pd/H 2, 82%

_ H 2. KOtBu 85-90% O i 0 H OH 159 Et OH 158 CH 3 tBuOOH KOtBu Triton B 80:20, 74% 85-90% H OH 160 O AcO OAc OH 3 C DBU, LiCI, H Ac 20, THF - 70% H OAc Et OH 162 161

First, they performed an intramolecular aldol cyclization and

dehydration of the ethyl ketone with the cyclooctenone of 158 to afford 160.

Hydrogenation of the double bond gave the cyclooctanone and successful

aldol cyclization and dehydration gave 159. The most useful ring cyclization

7 3 Swindell, C. S.; Patel, B. P. J. Org. Chem. 1990, 55, 3. Chapter VIII: A-Ring Cyclization Attempts * 75 designed was that for epoxide 161. Following the aldol cyclization, the alcohol intermediate underwent a Payne rearrangement with the neighboring epoxide. Subsequent elimination afforded cyclohexenone 162 with the correct stereochemistry and functionality at C-9 and C-10.

8.2 A-Ring Cyclization Attempts with the trans-FusedRing System

Although Swindell reported three ways of obtaining the A-ring cyclization, we were originally interested in obtaining the epoxide compound as that would lead to the product with the correct functionalization in the B- ring. The tert-butyl hydroperoxide nucleophilic epoxidation conditions developed by Swindell were unreactive towards epoxidation of our enone

151. This failed reaction was troubling because our system was behaving differently than Swindell's enone 158 in this crucial first reaction. Because of the inability to epoxidize enone 151 directly, a new method was developed to synthesize epoxide 165 (Scheme 73).

Scheme 73: Synthesis of key epoxy-ketone 165.

CH3 CH3

LiAIH 4 , THF HO .H -78 oC --->-20 C O H 96% O H

149 163

o oq CH3 VO(acac) 2, CH 3 1. PCC/Alumina tBuOOH HO.... CH 2CI2, 94% 0 HCI OCH CH 20 2, 95% OCH 3 2. Acetone, H 98% 0" H O H H

164 165 Chapter VIII: A-Ring Cyclization Attempts * 76

Previous preparation included the reduction of enone 153 to allylic alcohol

163. Fortunately, the conformation of the cyclooctanone was such that the si face of the carbonyl was more easily accessible to the hydride, thus, exclusively forming the (-hydroxyl stereochemistry. A selective epoxidation of alcohol

163 with VO(acac) 2 and tert-butyl hydroperoxide afforded epoxy alcohol 164 as a single diastereomer. In the previous epoxidation procedure, the mixture was allowed to react for nine hours, and the epoxide was isolated via an aqueous work-up. These combined factors led to a mixture of products, and only produced the desired epoxide in 67% yield. We found the reaction proceeded to completion at room temperature in five minutes. The reaction mixture was concentrated and purified immediately via column chromatography, affording the epoxide in 95% yield. None of the byproducts formerly encountered were produced. The previous strategy used for the oxidation and ketal removal reactions were employed and the yields increased from 87% and 88%/0 to 94% and 98%, respectively. The desired epoxy diketone was synthesized in 84% overall yield form enone 153. With epoxy diketone 165 in hand, we were prepared to attempt the

cyclization procedure developed by Swindell. Using Swindell's conditions

(lithium chloride, acetic anhydride and DBU in THF), no reaction was observed. Several variations in the reaction conditions were made. Changes in concentration, temperature and varying of solvent gave no reaction. Because Swindell and coworkers cyclized compound 158 and its saturated version using potassium tert-butoxide as the base, we applied it to our

epoxide system. The substrate did, in fact, react but no cyclization was

observed; NMR spectroscopy was used to identify the product, and it is

thought to be trans epoxide 166, resulting from epimerization of the

stereogenic center a to the ketone. The eight membered ring can Chapter VIII: A-Ring Cyclization Attempts * 77 accommodate the trans epoxide and after conformational analysis, it appears to be less strained than the cis epoxide.

Scheme 74: Epimerization of the epoxide.

0 0 CH 3 - CH 3 KtOBu, THF H SHOCH3 0" OCH3

H H 165 166

We were quite pleased with the formation of the trans epoxide as it could possibly accommodate a more favorable transition state for the

intramolecular aldol cyclization. The conformation of the trans system could

facilitate the cyclization by allowing the side chain a less hindered approach to

the re face of the ketone (Scheme 75). This was displayed on Quanta, a

molecular modeling program. Several reactions were performed, but

unfortunately no cyclized products were isolated.

Scheme 75: Conformational analysis of the trans epoxide 166.

H H3/ O I CH3 OCH3

166

Because the B-ring of taxusin has oxygenation at C-9 and C-10, it was

proposed that dihydroxylation of enone 153 could provide a potential

candidate for the ring cyclization. Perhaps the epoxide was not allowing

enough flexibility in the ring system, which could possibly be provided by the Chapter VIII: A-Ring Cyclization Attempts * 78 less constrained diol. We observed the double bond was unreactive when employing stoichiometric amounts of osmium tetroxide. There was the option to take the same detour used previously for the epoxidation, but in order to differentiate the alcohols, the allylic alcohol would require protection before the dihydroxylation. It was worthwhile to examine the other types of systems that were successful for Swindell (Scheme 72). Previous attempts to cyclize cyclooctanone 167 afforded tetracyclic fused system 168, formed from a retro-

Michael reaction followed by an aldol condensation. The retro-Michael

reaction proceeds through the thermodynamic enolate of the acyclic ketone. The energy required for the molecule to adopt the favorable conformation is not present when the kinetic enolate is generated.

Scheme 76: Attempted cyclization leads to tetracyclic ring system 168.

CH3 H3C 0 ,. OH KtOBu, HOtBu OCH 3 O. OC H3 0 "" H H

167 168

Although the previous result was not promising, we felt it was necessary to attempt the cyclization of the enone. Treating 149 with acid unveiled ethyl

ketone 169 in excellent yield. Treating this diketone with bases led to the formation of several products. None of the products generated formed the

cyclized product. If the cyclization was successful, a characteristic vinyl

methyl would be observed via spectral analysis. Chapter VIII: A-Ring Cyclization Attempts * 79

Scheme 77: Formation of diketone 169.

CH 3 _ CH3 0 0

0 OCH 3 HCI, Acetone OCH 3 H 95% 0 H 0 H H 149 169

The numerous attempts showed no signs of A-ring cyclization so our efforts were directed toward cyclization of the system with the cis fused BC-ring system.

8.3 A-Ring Cyclization Attempts with the cis-Fused Ring System Failure to cyclize the A-ring was certainly disappointing, but we had

the opportunity to attempt the cyclization on the cis-fused ring system. Since taxusin contains a trans ring fusion between rings B and C, this would require

an isomerization strategy at a later stage. Enone 170 is more conformationally mobile than the trans-fused

enone 153 and therefore we expected it to be less hindered towards attack by

osmium tetroxide. Indeed, a stoichiometric osmium tetroxide addition to enone 170 proceed in tetrahydrofuran at room temperature. After reductive work-up, a single diol isomer 171 was obtained in 72% yield. Based on the conformation of the eight-membered ring, attack of osmium tetroxide form the top face of enone 170 was severely sterically hindered. The diol 171 offered a convenient one-step protection/deprotection

opportunity to expedite our synthesis. Treatment of diol 171 with 1%

hydrochloric acid and 2,2-dimethoxypropane in acetone at room temperature

effected rapid formation of the acetonide followed by the deprotection of the

ketal. nOe Experiments were performed to confirm the stereochemisty of the Chapter VIII: A-Ring Cyclization Attempts * 80 acetonide. Upon irradiation of the benzylic ring fused proton we observed a 4.8% nOe on the proton P to the carbonyl. Upon irradiation of the proton oc to the carbonyl, we observed a 8.0 % nOe on the same P proton. These results confirm the addition of the osmium tertoxide occured from the bottom face of the molecule. The crystalline acetonide 172 was obtained in 83% yield. The molecule was ready for investigation under aldol condensation conditions.

Scheme 78: Fromation of the cis ring fused, cis diol 171.

HO OH

CH 3 CHC 3

0 Os0 4, THF 0 0 OCH 3 0 OCH 3 H then NaHSO , EtOAc H O H72% 3 H

170 171

HO OH O O

CH 3 - CH 3 O HCI, Acetone 0

o OCH3 83% OCH 3

O H H 171 172

The conformation of this system has many desirable aspects. The

acetonide system is unique because it has the alcohols protected but not conformationally locked like the epoxide systems 165 and 166. The added flexibility of this systems possibly allows the additional mobility of the cyclooctanone ring as well as the side chain. We began the A-ring cyclization attempts with potassium tert-butoxide in benzene at room temperature.

What we observed was believed to be the isomerization to the trans

acetonide. This was determined by spectral analysis, including dqcosy and

dqnoesy experiments. Other efforts to cyclize the cis or trans acetonide were Chapter VIII: A-Ring CyclizationAttempts * 81 unsuccessful. There was yet another cis ring fused compund that could not be ignored, enone 175.

Scheme 79: Formation of the trans acetonide 173.

HOtBu H3 OH3 KtOBu,

OCH3 OCH3 S H 0 H H H 172 173

We focused our attention on cyclizing compound 175. It was readily prepared from the deketalization reaction of ketal 174 in 81% yield. Treatment of the diketone with potassium tert-butoxide in benzene afforded a new product.

Scheme 80: Dekalization of ketal 174 to afford enone 175.

CH3 CH3

O "'OCH 3 HCI, Acetone OCH 3 81% 0 H O H H H

174 175

This product was unlike any product we observed to date. By NMR analysis, it was obvious that the ethyl ketone was still present, but it was not until we

performed dqcosy and dqnosey experiments that we were able to determine the product to be the Michael addition of the thermodynamic enolate to the

enone. The formation of this compound was exciting because it indicates that

the side chain ethyl ketone can in fact approach from the bottom face of the B- Chapter VIII: A-Ring Cyclization Attempts * 82 ring for an intramolecular cyclization. It is this type of conformation that the system needs to adopt in order to have the A-ring cyclize.

Scheme 79: Michael addition reaction.

0H CH 3 CH 3 'CH 3 0 KtOBu, benzene 0 CH3

OCH 3 75%

H OCH 3 175 176

In summary, although attempts to cyclize the A-ring were

unsuccessful, several new and interesting products were isolated. These new

products gave insight to the conformation of the diketone system and the

strain of the bridgehead double bond. Closing the A-ring to give the

bridgehead double bond was far more difficult a task than envisioned.

Synthesis of the epoxide system used by Swindell and co-workers was

successful, but unfortunately our system did not cyclize the A-ring after

several attempts. The interesting cyclizations that the various molecules underwent were fascinating and the structures were challenging to solve.

Overall, our approach to obtaining the BC unit of the taxane ring system is quite successful. It would be worth while to try a pinacol type coupling employed by Mukaiyama and co-workers to cyclize the A-ring. With that type of coupling, attaining the complete ring system would be feasible. Experimental Procedures

General Procedures

Reaction mixtures were stirred using a magnetic stirring apparatus unless otherwise indicated. All moisture or air sensitive reactions were carried out under a positive pressure of argon, and were performed in glassware that was oven and/or flame dried. Solvents and liquid reagents were transferred via syringe or cannula. Reactions were monitored by thin layer chromatography as described below. Organic solvents were removed through concentration using a Bichi rotary evaporator at 20 - 40 mmHg.

Materials

Commercial solvents and reagents were used without further purification with the following exceptions:

Solvents

Acetonitrile was distilled under argon from calcium hydride.

Benzene was distilled under argon from calcium hydride. Deuteriochloroform was stored over granular anhydrous potassium carbonate.

Dichloromethane was distilled under nitrogen from phosphorus pentoxide. N,N-Diisopropylamine was distilled under nitrogen from calcium hydride.

Diethyl ether was distilled under argon from sodium benzophenone ketyl.

Hexanes were distilled under nitrogen from calcium hydride. Hexamethylphosphoramide was distilled at low pressure.

Pyridine was distilled under argon from calcium hydride. ExperimentalProcedures * 84

Tetrahydrofuran was distilled under argon from sodium benzophenone ketyl. Toluene was distilled under nitrogen from sodium.

Triethylamine was distilled under nitrogen from calcium hydride.

Reagents

t-Butyldimethylsilyl chloride was distilled under argon.

n-Butyllithium in hexanes was titrated prior to use with s-butanol in tetrahydrofuran at 0 OC using 1,10 - phenanthroline as an indicator. 42 t-Butyllithium in pentane was titrated prior to use with s-butanol in diethyl ether at -78 'C using 1,10 - phenanthroline as an indicator. Lithium diisopropylamide was prepared by the addition of 2.47 M n- butyllithium (4.05 mL) to a solution of N,N-diisopropylamine (1.54 mL) in tetrahydrofuran (4.41 mL) at -78 OC followed by warming to 0 OC. The molarity was determined by titration with s-butanol in tetrahydrofuran at 00C using 1,10-phenanthroline as an indicator. Methanesulfonyl chloride was distilled at 20 mmHg.

Trimethylsilyl chloride was distilled under argon from calcium hydride. Ozone was generated from a Welsbach ozone generator using the following settings: 1.5 S.L.P.M., 90 V and 5.5 kg/cm 2.

Chromatography

Flash column chromatography was performed using Merck 230-400

mesh silica gel. HPLC grade solvents were used.

42 Watson, S.C.; Eastham. J.F. J. Organomet. Chem. 1967, 9, 165. Experimental Procedures * 85

Thin layer chromatography (TLC) was performed as an analytical tool using Baker high performance precoated glass silica gel (SiO 2, approx. 5 mm particle size) plates (200 mm thickness). The plates were assimilated with 254 nm fluorescent indicator. The procedure used was to elute using the solvent mixture indicated in the text, followed by an observation by illumination with a 254 nm ultraviolet light, and staining by dipping in an ethanolic solution of 2.5% p - anisaldehyde (3.5 % sulfuric acid and 1.0 % acetic acid) followed by heating on a hot plate.

Instrumentation

Melting points were determined on a Fisher - Johns hot stage apparatus and are uncorrected.

FTIR spectra were recorded on a Perkin-Elmer spectrometer equipped with an internal polystyrene sample as a reference.

1 H NMR were recorded on either a Varian Gemini 300 MHz spectrometer, a Varian XL 300 MHz spectrometer, a Varian Unity 300 MHz spectrometer or a Varian VXR 500 MHz spectrometer. Chemical shifts are reported as 8 in units of parts per million (ppm) downfield from

tetramethylsilane (8 0.0) using the residual chloroform signal (6 7.26) or benzene signal (8 7.16) as a standard. Multiplicities are reported in the

following abbreviations: s (singlet), d (doublet), t (triplet), q (quartet), qnt

(quintet), m (multiplet), dd (doublet of doublets), ddd (doublet of doublets of doublets), etc. 13C NMR were recorded on a Varian 300 NMR at 75 MHz or a Varian

VXR 500 NMR at 125 MHz. The deuteriochloroform signal (8 77.0) was used

as a standard. Experimental Procedures * 86

Optical rotations were determined using a Perkin-Elmer 241 polarimeter using a sodium lamp (D line) at 23 0C. Mass spectra and high resolution mass spectra (HRMS) were recorded on a Finnigan MAT System 8200, double focusing, magnetic sector, mass spectrometer. The spectra were recorded using either electron impact (EI), generating (M++1). Spectra were recorded in units of mass to charge (m/e). Experimental Procedures * 87

CH 0CH 3 i. 10 equiv. Et3 N: THF-Hexane TBSO 3 O H3 1.0 equiv. TBSCI, 0 °-- 23 0C

O ii. 1.0 equiv. TBSOTf, OTBS -78 oC - 0 oC 34 87% 33 O

O OCH3

TBSO CH3 OH

____ TBSO \ OTBS Toluene, rt &X OTBS 88% 33 enod:exo [3: 1] 32, 35

Methyl esters 32 and 35

A 200 mL round-bottomed flask containing 2-methyl-1,3-cyclopentanedione

(34) (2.59 g, 23.1 mmoles) under argon was charged with tetrahydrofuran (40 mL) and triethylamine (32 mL). Once the starting material was completely dissolved, hexane (100 mL) was added. t-Butyldimethylsilyl chloride (3.6 g, 1 equiv.) was added at rt and triethylamine-hydrochloride began to precipitate immediately. After 20 min the reaction was filtered under argon and rinsed with hexane (3 X 20 mL). The solute was then cooled to -78 oC. t-

Butyldimethylsilyl trifluoromethanesulfonate (5.16 mL, 1.05 equiv.) was added to the solution and the reaction mixture was slowly warmed to 0 oC. The reaction was left for ca. 1h. The triethylamine-trifluoromethanesulfonic acid was not soluble in the reaction media and formed a separate, more dense layer. The reaction was quenched by slowly pouring the mixture into a 1 L separatory funnel containing ice cold water (500 mL) containing sodium bicarbonate (3.0 g). The product was extracted with a 10% ether/hexane solution (3 X 125 mL) then dried over magnesium sulfate. Removal of the solvent afforded bis-silyloxydiene, 33, as a white crystalline solid, (6.84 g) in Experimental Procedures * 88

87% yield. The crude diene was used without further purification. The spectroscopic properties were identical to that described previously. 15 A 200 mL round-bottomed flask containing bis-silyloxydiene 33 (6.84 g, 20.1 mmoles) under argon was charged with toluene (50 mL) and cooled to 0 'C.

Methyl acrylate (5.61 mL, 3.1 equiv.) was added and the solution was slowly warmed to rt with stirring overnight. The toluene was removed under reduced pressure and the product was purified by column chromatography

(3% ethyl acetate/2% triethylamine/95% hexane). The reaction afforded Diels-Alder products 32 and 35 (7.50 g) as a mixture of diastereomers in a 3:1 (endo:exo) ratio in 88% overall yield. The mixture of diastereomers was carried on to the next step. ExperimentalProcedures * 89

E

rn

U)

oo O 00 0 \Al

- m

n

F

F- r

Ii K I- t ExperimentalProcedures * 90

0

OCH 3 CH 2OH

CH 3 LiAIH 4, THF CH 3 TBSO \ TBSO \ -78 oC -, 0 C OTBS OTBS

endo:exo [3 : 1] 36,37 90% (based on recovered 32, 35 starting material)

Alcohol mixture 36 and 37:

A 500 mL round-bottomed flask containing a mixture of methyl esters 32 and

35 (7.41 g, 17.3 mmoles) under argon was charged with diethyl ether (200 mL). The solution was cooled to -65 'C and a thermocouple thermometer was inserted into the reaction media to monitor the temperature. Lithium aluminum hydride (0.58 equiv., 1 M solution) was added in 1 mL portions to avoid large increases in temperature. Because a byproduct appeared on thin layer chromatography, the reaction was quenched following the procedure in

Fieser and Fieser 74 : 1 mL water was added followed by 1 mL water with 0.05 g

sodium hydroxide followed by 3 mL water. Once the reaction mixture

warmed to rt the solution was dried over magnesium sulfate, filtered and concentrated. The product was purified by column chromatography (5% ethyl

acetate/1% triethylamine/94% hexane - 10% ethyl acetate/1% triethylamine/89% hexane) affording alcohols 36 and 37 (4.91 g) in 71% yield

(90% based on recovered starting material) and starting material ester 32 and 35 (1.39 g) in 19% yield. The spectroscopic properties were identical to that described previously.15

74 Fieser, L. F., Feiser, M.; In Reagentsfor Organic Synthesis; John Wiley and sons, Inc.: New York, 1967, Vol. 1, 584. Experimental Procedures * 91

H C H C 2 2 CH 2

C H BSO h CH3 (CH 20H) 2, TsOH TBSO 3 CH3 Benzene, reflux O 0 0 O 77 % L/O (90% based on 45 recovered enone) 46 50

Ketal 46:

A 100 mL round-bottomed flask containing enone 45 (1.09 g, 3.9 mmoles) was charged with benzene (50 mL). Ethylene glycol (10 mL, ca. 50 equiv.) and p- toluenesulfonic acid (10 mg, cat.) were added and the solution was heated to reflux for 3 h. The reaction was cooled to rt and was quenched by the addition of a saturated solution of sodium bicarbonate (10 mL). The organics were removed under reduced pressure and the aqueous phase was extracted with diethyl ether (3 X 25 mL). The combined organics were dried over

magnesium sulfate and concentrated. The product was purified by column chromatography (2'%, ethyl acetate/hexane-- 5% ethyl acetate/hexane),

affording ketal 46 (0.97 g) in 77% yield and starting material (159 mg) in 15%

yield. Rf 0.60 (30% ethyl acetate/hexane). If the experiment was exposed to

acid for extended periods of time, rearranged product 50 would be generated. 15 The spectroscopic properties were identical to that described previously. Experimental Procedures * 92

1*

V

-

i-

0

0j c O 7- ----r

I- Experimental Procedures * 93

I

C-)

S O 17 L rHW- IL ! I IFtzt(I

19 ExperimentalProcedures * 95

O 0

N2 CH3 TrisN3 , Ben. CH TBSO 3 60 % KOH-H 20 TBSO 3 On. phase tran. cat. O 65% O

31 30

o-Diazoketone 30:

A 10 mL round-bottomed flask containing ketone 31 (40 mg, 0.12 mmoles) under argon was charged with benzene (2 mL). Tetra-nbutylammonium bromide (37 mg, 10 equiv.), 18-crown-6 (6 mg, 0.2 equiv.) and trisyl azide (71 mg, 2 equiv.) was added followed by the addition of saturated aqueous potassium hydroxide (2 mL). After 5 min, it was apparent by thin layer chromatography that the addition of the azide was complete, as the starting material was no longer visible and there was a new bright pink spot. The

reaction was stirred vigorously for 8 h. After the bright pink spot changed to a more orange color the reaction was quenched by the addition of a saturated

solution of sodium bicarbonate (10 mL). The organics were removed under

reduced pressure and the aqueous phase was extracted with diethyl ether (3 X

5 mL). The combined organics were dried over magnesium sulfate and concentrated. The product was purified by column chromatography (20% ethyl acetate/hexane). uo-Diazoketone 30 (29 mg) was obtained in 65% yield. 1 Rf0.19 (20% ethyl acetate/hexane). H NMR (300 MHz, CDCl3) 6 5.17 (qnt, 1H, J=1.4 Hz), 4.13-3.94 (m, 4H), 3.29 (dd, 1H, J=2.5, 4.8 Hz), 2.37 (dd, 1H, J=0.98, 10.8

Hz), 1.77 (d, 1H, J=1.6 Hz), 0.90 (s, 9H), 0.18 (s, 3H), 0.05 (s, 3H). Analysis

calculated for C17H2 6N 20 4Si: C 58.26%; H 7.48%. Found: C 58.36%; H 7.81%. Experimental Pr-ocedures 96

E cl cl

- e-.

- r77-

0

~i-- -r~r

-2 Experimental Procedures * 97

I

C o N~ 0 z Experimental Procedures * 98

" I--,,-liE

zI " oj 1 -

S i

C-D

O=~i~=O -U- Experimental Procedures * 99

0 C02CH3

TBSO CH 3 0 C hv TBS CH 3 O O CH 2C12, MeOH 0 95% O

30 57, 58 1.5:1 endo:exo

Methyl esters 57 and 58: c-Diazoketone 30 (265 mg, 0.752 mmoles) was transferred into a 250 mL Pyrex well with dichloromethane (ca. 5 mL). A 450 watt medium-pressure Conrad-

Hanovia immersion lamp was placed into the Pyrex immersion well with a cooling system separating the reaction mixture from the light source. The container was evacuated and purged with argon, three times. Anhydrous methanol (100 mL) and dichloromethane (100 mL) were added. The

apparatus was placed into an ice bath and cooled to 0 oC. The system was attached to an oil bubbler to allow for the escape of argon and nitrogen

generated during the reaction. Argon was bubbled through the solution for 30 min prior to the start of the reaction to remove any dissolved oxygen in

the solvents. The reaction was irradiated for 1 h. The solution was added to a 500 mL round-bottomed flask and concentrated. The product was purified by

column chromatography (SiO 2, 20% ethyl acetate/Hexane) to give a mixture of isomers 57 and 58 (275 mg) in 95% yield.

exo Ester 58: Rf 0.59 (40% ethyl acetate/hexane). FTIR (thin film, cm-1) 2953, 2985, 2858, 1734, 1462, 1437, 1361, 1340, 1288, 1211, 1145, 1091, 1022, 970, 887, 837,

1 777, 676. H NMR (300 MHz, CDC13) 8 5.14 (sept., 1H, J=1.2 Hz) 4.00-3.90 (m,

4H, ketal), 3.71 (s, 3H), 3.21 (d, 1H, J=5.5 Hz), 2.99 (t, 1H, J=8.0 Hz), 2.68 (dd, 1H,

J=2.4, 7.4 Hz), 2.21 (dd, 1H, J=5.8, 8.2 Hz), 1.82 (d, 1H, J=1.2 Hz), 0.88 (s, 9H), 0.08 ExperimentalProcedures * 100

13 (s, 3H), 0.04 (s, 3H). C NMR (75 MHz, CDC13 ) 8 171.0, 155.6, 117.5, 110.2, 64.8, 60.6, 51.6, 44.1, 36.7, 25.7, 18.2, 17.9, 2.7, -3.0.

1 endo Ester 57: Rf 0.52 (40% ethyl acetate/hexane). H NMR (300 MHz, CDC13) 8 5.07 (td, 1H, J=1.5, 3.0 Hz) 4.07-3.95 (m, 4H, ketal), 3.64 (s, 3H), 3.21 (d, 1H, J=7.3 Hz), 2.76 (dt, 1H, J=3.0, 6.9 Hz), 2.16 (dd, 1H, J=6.7, 8.2 Hz), 2.11 (d, 1H,

J=8.2 Hz), 1.86 (d, 1H, J=1.5 Hz), 0.89 (s, 9H), 0.10 (s, 3H), 0.09 (s, 3H). Experimental Procedures • 101

,F II

Sr-

o LA, I II r

0 '

C1- O~ Ln"

m

Sr

I-

i- I

--, Experimental Procedures * 102

1-.

K FoJ

OOL 0 m -r

L -I C

r

LF Experimental Procedures * 103

CO2CH 3 BnO C0 2CH 3

TBSO OH 3 LDA, THF-HMPA O H3 \ -20 oC then BOMCI O -78 oC O endo: 70%, exo: 66% 57, 58 59

Cyclobutyl ester 59:

A 50 mL round-bottomed flask containing ester 57 (189 mg, 0.49 mmoles) under argon was charged with tetrahydrofuran (4 mL) and the solution was cooled to -78 'C. Hexamethylphosphoramide (30 [tL, 4 equiv.) was added followed by the addition of lithium diisopropylamide (90 tL, 2 equiv.). The reaction was slowly warmed to -45 'C over 45 min The reaction was recooled to -78 'C, benzyloxymethyl chloride (12 jiL, 2 equiv.) was added and the mixture was slowly warmed to 0 oC. After no starting material was visible via

thin layer chromatography, the reaction was quenched by the addition of a

saturated solution of sodium bicarbonate (2 mL). The organics were removed

under reduced pressure and the aqueous phase was extracted with diethyl

ether (3 X 10 mL). The combined organics were dried over magnesium

sulfate and concentrated. The product was purified by column chromatography (20% ethyl acetate/1% triethylamine/79% hexane). The alkylated product 59 (175 mg) was obtained in 70% yield. Rf 0.58 (45% ethyl acetate/hexane). FTIR (thin film, cm-1) 2951, 2856, 1745, 1436, 1343, 1309, 1238, 1 1201, 1115, 1090, 1022, 898, 836, 773, 698. H NMR (300 MHz, CDC13 ) 8 7.40-7.20

(m, 5H), 5.10 (s, 1H), 4.63 (d, 1H, J=12.4 Hz), 4.43 (d, 1H, J=12.4 Hz), 4.06-3.82 (m,

4H), 3.80 (s, 2H), 3.63 (s, 3H), 2.59 (dd, 1H, J=2.8, 7.4 Hz), 2.44 (dd, 1H, J=8.1, 8.2

Hz), 2.14 (d, 1H, J=2.1 Hz), 1.86 (s, 3H), 0.87 (s, 9H), 0.04 (s, 6H). 13C NMR (125 ExperimentalProcedures * 104

MHz, CDC13 ) 8 171.9, 155.2, 138.0, 128.3, 127.8, 127.6, 116.8, 109.7, 73.4, 70.7, 66.4, 65.5, 63.9, 51.1, 42.8, 41.8, 25.9, 18.8, 18.3, -2.3, -3.0. Experimental Procedures * 105

•10 ExprienaIProedre

-j C71

--

J i r

0 - 0 O0 O OO

c c

-t 0

cl ~i~, fn

L(D i

7_ N

Id Experimental Procedures 106 !lrE

Tu L i i' ______g ;iL

j

------c ---~c

-- ~------

------Experimental Procedures * 107

BnO CO2CH 3 BnO OH

TBSO CH 3 DiBAI-H, -30 C TBSO CH3 Hexane, 99% O O O O 59 61

Alcohol 61:

A 25 mL round-bottomed flask containing alkylated ester 59 (175 mg, 0.347 mmoles) under argon was charged with hexane (10 mL). This solution was cooled to -78 'C then diisobutylaluminum hydride (1.75 mL, 5 equiv., 1 M) was added dropwise. The reaction was slowly warmed to -30 'C for 15 min and was then quenched by the addition of ca. 0.5 mL glacial acetic acid and a saturated solution of sodium bicarbonate (3 mL). A drop of triethylamine was added to avoid removal of the ketal. The layers were separated and the aqueous phase was extracted with a 30% ethyl acetate/hexane solution containing a small amount of triethylamine. The combined organics were dried over magnesium sulfate and concentrated. The product was purified by column chromatography (20% ethyl acetate/ 1% triethylamine/79% hexane) affording alcohol 61 (163 mg) in 99% yield. Rf 0.2 (4% diethyl

1 ether/dichloromethane). H NMR (300 MHz, CDC13) 8 7.32 (m, 5H), 5.27 (t, 1H, J=1.5 Hz), 4.65 (d, 1H, J=11.7 Hz), 4.52 (d, 1H, J=12.2 Hz), 3.80 (m, 8H), 2.65 (t, 1H, J=8.1 Hz), 2.37 (dt, 2H, J=4.2, 7.4 Hz), 2.09 (d, 1H, J=8.8 Hz), 1.78 (s, 3H), 0.84 (s, 9H), 0.05 (s, 3H), 0.02 (s, 3H). Experimental Procedures * 108

0 CIO 0 (D 0-- Experimental Procedures * 109

H AcO BnO OH OAc BnO O I OAc 0 facile 0 O TBSO CH3 TBSO CH3 rearrangement

O , o- CH 3 O (Dess-Martin O O reagent) O BnO OTBS

61 63 64

Claisen product 64:

A 25 mL round-bottomed flask containing alcohol 61 (56 mg, 0.12 mmoles)

under argon was charged with dichloromethane (6 mL). Pyridine (0.37 itL) was added followed by the Dess-Martin reagent (102 mg, 2.1 equiv.). The solution was stirred for 1.5 h. after which time starting material was no longer

visible via thin layer chromatography. The reaction was filtered through a plug of silica gel and magnesium sulfate and thoroughly rinsed with ether.

After concentration, NMR analysis of the crude product showed a mixture of

two compounds: aldehyde 63 and retro-Claisen product 64. At rt the aldehyde

readily converted to the rearranged product (47 mg, 85% yield). Each of the products are characterized below.

1 Aldehyde 63: Rf 0.34 (30% ethyl acetate/hexane). H NMR (300 MHz, CDC13 ) 8 9.88 (s, 1H), 7.32 (m, 5H), 5.13 (dd, 1H, J=1.5, 2.9 Hz), 4.57 (d, 1H, J=12.2 Hz), 4.42 (d, 1H, J=12.2 Hz), 4.06-3.82 (m, 4H), 2.81 (dd, 1H, J=2.9, 7.3 Hz), 2.52 (dd,

1H, J=7.8, 8.8 Hz), 2.14 (d, 1H, J=9.3 Hz), 1.77 (d, 3H, J=2.0 Hz), 0.85 (s, 9H), 0.018 (s, 3H), 0.014 (s, 3H). Claisen rearrangement 64: Rf0.34 (30% ethyl acetate/hexane). 1H NMR (300

MHz, CDC13 ) 6 7.32 (m, 5H), 6.26 (s, 1H), 4.50 (d, 1H, J=11.7 Hz), 4.34 (d, 1H, J=11.2 Hz), 4.05 (m, 7H), 3.86 (d, 1H, J=12.2 Hz), 2.62 (ddd, 1H, J=2.2, 4.6, 16.4

Hz), 2.38 (td, 1H, J=2.3, 4.6 Hz), 2.25 (td, 1H, J=1.5, 16.6 Hz), 1.69 (t, 1H, J=2.0 Hz),

0.92 (s, 9H), 0.095 (s, 3H), 0.086 (s, 3H). Experimental Procedures * 110

C.) O'

Oc mf Experimental Procedures * 111

O O

BnO OCH3 BnO OCH 3

TBSO CH 3 HCI, Acetone TBSO CH 3 98% O o

59 66

Keto ester 66:

A 10 mL round-bottomed flask containing alkylated ester 59 (25 mg, 0.049 mmoles) was charged with acetone (2 mL). Hydrochloric acid (1 drop, conc.) was added at rt and after 2 min was quenched by the addition of a saturated solution of sodium bicarbonate (2 mL). The organics were removed under reduced pressure and the aqueous phase was extracted with diethyl ether (3 X

4 mL). The combined organics were dried over magnesium sulfate and concentrated. The product was purified by column chromatography (SiO 2, 30% ethyl acetate/hexane) affording alcohol 66 (23 mg) in 98% yield. Rf 0.52 (30% ether/hexane). FTIR (thin film, cm- 1) 2953, 2930, 2858, 1738, 1696, 1454,

1434, 1361, 1257, 1234, 1206, 1131, 1008, 896, 836, 776, 699. 1H NMR (300 MHz,

CDC13) 6 7.38-7.17 (m, 5H, phenyl), 5.55 (t, 1H, J=1.3 Hz) 4.58 (d, 1H, J=12.2 Hz), 4.49 (d, 1H, j=12.1 Hz), 3.90 (d, 1H, J=9.9 Hz), 3.84 (d, 1H, J=9.8 Hz), 3.61 (s, 3H), 3.18 (dd, 1H, J=2.3, 7.3 Hz), 2.73 (dd, 1H, J=8.0, 8.1 Hz), 2.42 (d, 1H, J=9.0 Hz), 1.97

(s, 3H), 0.92 (s, 9H), 0.086 (s, 3H), 0.072 (s, 3H). 13C NMR (125 MHz, CDC13 ) 5 199.9, 172.5, 172.2, 137.5, 128.4, 128.4, 127.8, 127.8, 119.7, 78.6, 73.5, 71.4, 69.4, 66.1,

51.7, 47.0, 46.4, 25.8, 25.8, 25.8, 19.3, 18.3, -2.4, -3.0. Experimental Procedures * 112

ExpeimenaI Pocedres 11

5

o I C3 O I O O

0

tT

r c

r Experimental Procedures * 113

BnO OCH3 BnO OCH 3

TBSO CH 3 LDA, TBSOTf TBSO THF

O OTBS

66 67

Silyl dienol ether 67:

A 25 mL round-bottomed flask containing enone-methyl ester 66 (27 mg,

0.063 mmoles) was charged with THF (5 mL) under argon. The solution was cooled to -78 "C and TBSOTf (21 kL, 1.5 equiv.) was added followed by the addition of LDA (94 tL, 1.5 equiv.). After five minutes, only partial conversion was detected by thin layer chromatography, so additional TBSOTf

(21 gL, 1.5 equiv.) and LDA (94 pL, 1.5 equiv.) were added. When the starting material was no longer visible via thin layer chromatography the reaction was quenched by the addition of a saturated solution of sodium bicarbonate.

The organics were removed under reduced pressure and the aqueous phase was extracted with ether (3 X 20 mL portions). The combined organics were

dried over magnesium sulfate and concentrated, affording the mono-silyloxy

diene product 67. The product was used in the next step without further purification. Rf0.72 (30"%ethyl acetate/hexane). FTIR (thin film, cm -1) 2954, 2930, 2857, 1740, 1633, 1608, 1472, 1351, 1314, 1254, 1198, 1121, 1006, 973, 892, 870,

1 838, 779, 745, 698. H NMR (500 MHz, C6D 6) 6 7.25-7.02 (m, 5H), 5.40 (d, 1H, J=3.0 Hz), 5.17 (d, 1H, J=1.5 Hz), 4.80 (d, 1H, J=1.4 Hz), 4.40 (d, 1H, J=12.2 Hz),

4.32 (d, 1H, J=12.2 Hz), 4.10 (d, 1H, J=9.8 Hz), 3.90 (d, 1H, J=10.1 Hz), 3.39 (s, 3H),

2.93 (dd, 1H, J=2.8, 6.7 Hz), 2.41 (t, 1H, J=7.5 Hz), 2.01 (d, 1H, J=8.2 Hz), 1.01 (s,

9H), 0.99 (s, 9H), 0.30 (s, 3H), 0.24 (s, 3H), 0.07 (s, 3H), 0.00 (s, 3H). 13C NMR (125 Experimental Procedures * 114

MHz, CDC13 ) 8 172.3, 164.8, 148.7, 139.0, 127.9, 127.8, 127.6, 103.0, 102.5, 80.5, 73.9, 71.4, 66.7, 51.5, 42.9, 39.8, 26.6, 26.2, 19.0, 18.6, -2.0, -2.3, -3.9, -4.0. Experimental Procedures * 115

0 O

0 al

sa*1

6'SAr-t

-.---- L.8" ExperimentalProcedures * 116

O 0 H BnO BnO OCH 3 DiBAI-H, -78 C BnO

TBSO Toluene/Hexane TBSO 51% (based on recovered 67)

OTBS OTBS

67 68

Aldehyde 68:

A 10 mL round-bottomed flask containing crude methyl ester 67 (14 mg, 0.026 mmoles) was charged with hexane (1 mL) and THF (1 mL) under argon. The solution was cooled to -78 'C and DIBAL (40 iL, 1.5 equiv.) was slowly added dropwise along the side of the flask. After 30 min the reaction was quenched by the addition of a solution of glacial acetic acid (0.1 mL) in hexane (1 mL).

After 5 min, a saturated solution of sodium bicarbonate (3 mL) was added.

The organics were removed under reduced pressure and the aqueous phase was extracted with ether (3 X 5 mL portions). The combined organics were dried over magnesium sulfate and concentrated. The product was purified via column chromatography (SiO 2, 3% ethyl acetate/1% triethylamine/96% hexane) affording aldehyde 68 (2 mg) in 18% yield (51% based on recovered starting material) and starting material methyl ester 67 (9.3 mg) in 65% yield.

1 Rf 0.42 (5% ethyl acetate/hexane). H NMR (300 MHz, CDC13) 8 9.52 (s. 1H), 7.31 (m,5H), 5.22 (d, 1H, J=2.8 Hz), 4.94 (d, 1H, J=1.3 Hz), 4.63 (s, 1H), 4.56 (d, 1H, J=11.9 Hz), 4.43 (d, 1H, J=11.9 Hz), 3.95 (d, 1H, J=10.1 Hz), 3.79 (s, 1H, J=10.1

Hz), 2.69 (dd, 1H, J=2.8, 6.7 Hz), 2.56 (t, 1H, J=7.5 Hz), 1.99 (d, 1H, J=8.2 Hz), 0.94

(s, 9H), 0.90 (s, 9H), 0.21 (s, 6H), 0.04 (s, 6H). - udci i I~i I I I I I I I I[t~~

t

2/ I II I I

99

-osei oug Experimental Procedures * 118

OOH BnO H BnO HF aq., 0 0C

TBSO CH 3CN/H 20 TBSO H 34%

OTBS 69, 70 68

Aldol Products 69 and 70:

A 10 mL round-bottomed flask containing aldehyde 68 (4 mg, 0.007 mmoles) was charged with acetonitrile (1 mL) and distilled water (1 mL) under argon. The solution was cooled to 0 'C and a 5% solution (1.5 mL) containing hydrofluoric acid (aq.) in acetonitrile was added. Additional portions of the HF solution (2 mL) was added until the starting material was no longer visible via thin layer chromatography. The reaction was quenched by the addition of a saturated solution of sodium bicarbonate (1 mL). The organics were removed under reduced pressure and the aqueous phase was extracted with ether (3 X 5 mL portions). The combined organics were dried over magnesium sulfate and concentrated. The product was purified via column chromatography (SiO 2, 20% ethyl acetate/hexane) affording the Mukaiyama aldol products 69 and 70 as a mixture of diastereomers (1 mg) in 34% yield. Rf0.40 (30% ethyl acetate/hexane). FTIR (mixture of diastereomers) (thin film, cm -1) 3434, 2930, 2858, 1754, 1255, 1198, 1096, 1023,

1 896, 837, 774. Major isomer(70): H NMR (300 MHz, CDC13 ) 8 7.38-7.27 (m, 5H), 5.23 (s, 1H), 4.59 (d, 1H, J=11.9 Hz), 4.54 (d, 1H, J=11.9 Hz), 4.15 (dd, 1H,

J=2.0, 9.0 Hz), 3.88 (d, 1H, J=10.4 Hz), 3.82 (d, 1H, J=10.4 Hz), 3.23 (t, 1H, J=2.0

Hz), 2.75 (t, 1H, J=9.5 Hz), 2.59 (dd, 1H, J=2.1, 9.4 Hz), 2.01 (d, 1H, J=8.9 Hz), 2.01

(d, 1H, J=9.8 Hz), 0.88 (s, 9H), 0.11 (s, 3H), 0.10 (s. 3H). Experimental Procedures * 119

1 Minor isomer(69): H NMR (300 MHz, CDC13) 8 7.38-7.27 (m, 5H), 5.01 (s, 1H), 4.99 (s, 1H), 4.59 (d, 1H, J=11.9 Hz), 4.54 (d, 1H, 1=11.9 Hz), 3.99 (d, 1H, J=9.9 Hz),

3.91 (d, 1H, J=9.8 Hz), 3.21 (s, 1H), 2.70 (t, 1H, J=9.6 Hz), 2.60 (dd, 1H, J=1.8, 10.7

Hz), 2.03 (d, 1H, J=9.8 Hz), 2.01 (d, 1H, J=9.6 Hz), 0.86 (s, 9H), 0.09 (s, 3H), 0.07 (s,

3H). Experimental Procedures * 120

L '

cc-s 899 L Experimental Procedures * 121

BnO OCH 3 BnO 'OH

TBSO CH 3 HMPA, EtSLi TBSO CH3 rt, 3 d O O O 0

59 75

Cyclobutyl carboxylic acid 75:

A 10 mL round-bottomed flask containing ester 59 (26 mg, 0.055 mmoles) was charged with HMPA (2 mL). A solution of ethyl mercapto lithium (0.5 M) was prepared in HMPA and 1 mL was added to the mixture. The solution was heated to 50 'C for 30 min The solution was cooled to rt then was quenched by the addition of a saturated solution of sodium bicarbonate (2 mL). The organics were removed under reduced pressure and the aqueous phase was extracted with 10 % diethyl ether/hexane (3 X 4 mL). The combined organics were dried over magnesium sulfate and concentrated

affording acid 75. The product was used in the next step without further

purification. ExperimentalProcedures * 122

BnO OH BnO OH BnO

TBSO CH 3 CH 3SO 3H TBSO CH 3 TBSO CH3 o5' CH 2012 o7

75 71 76

Lactone 76:

A 10 mL round-bottomed flask containing crude acid 75 (17 mg, 0.037 mmoles) was charged with dichloromethane (5 mL). Methane sulfonic acid

(20 tL) was added at 0 oC and after 2 min was quenched by the addition of a saturated solution of sodium bicarbonate (2 mL). The organics were removed under reduced pressure and the aqueous phase was extracted with diethyl ether (3 X 4 mL). The combined organics were dried over magnesium sulfate and concentrated. The product was purified by column chromatography (2 (SiO 2, 20% ethyl acetate/hexane) affording lactone 76 (6 mg) in 22% yield 1 steps). Rf 0.47 (30%/ ethyl acetate/hexane). H NMR (300 MHz, CDC13 ) 6 7.33

(m, 5H), 4.59 (d, 1H, J=11.5 Hz), 4.53 (d, 1H, J=11.5 Hz), 4.04-3.75 (m, 4H), 3.91 (d,

1H, J=9.9 Hz), 3.78 (d, 1H, J=9.9 Hz), 2.83 (d, 1H, J=7.0 Hz), 2.65 (dd, 1H, J=7.4, 10.2 Hz), 2.33 (d, 1H, J=14.7 Hz), 2.19 (d, 1H, J=14.4 Hz), 1.97 (d, 1H, J=10.3 Hz), 1.43 (s, 3H), 0.86 (s, 9H), 0.096 (s, 3H), 0.065 (s. 3H). Experimental Procedures * 123

r -

L

'-"

r

ivt h r Experimental Procedures * 124

BnO'

TBSO DiBAI-H, CH 2CI 2 I U CH3 CH3 -78 °C O O

78 79

Lactol 79:

A 5 mL round-bottomed flask containing lactone 78 (6 mg, 0.011 mmoles) was charged with dichloromethane (2 mL) under argon. The solution was cooled to -78 'C and DIBAL (24 jtL, 2 equiv.) was slowly added dropwise along the side of the flask. After 5 min the reaction was quenched by the addition of a solution of glacial acetic acid (0.1 mL) in diethyl ether (1 mL). After 5 min, a

saturated solution of sodium bicarbonate (3 mL) was added. The organics

were removed under reduced pressure and the aqueous phase was extracted with ether (3 X 5 mL portions). The combined organics were dried over

magnesium sulfate and concentrated. The product was purified via column

chromatography (SiO 2, 50% ethyl acetate/hexane) affording lactol 79 (3 mg) in 50% yield (100% based on recovered starting material), and lactone 78 (3 mg)

1 in 50% yield. H NMR (300 MHz, CDC13) 6 7.33 (m, 5H), 5.91 (d, 1H, J=12.8 Hz), 5.15 (d, 1H, J=12.8 Hz), 4.55 (s, 2H), 4.15-3.60 (m, 4H), 3.70 (d, 1H, J=9.8 Hz), 3.60 (d, 1H, J=10.1 Hz), 2.60 (d, 1H, J=7.6 Hz), 2.42 (dd, 1H, J=7.6, 9.8 Hz), 2.30 (d, 1H, J=13.8 Hz), 2.26 (d, 1H, J=13.8 Hz), 1.821 (d, 1H, J=10.1 Hz), 0.86 (s, 9H), 0.061 (s,

3H), 0.033 (s, 3H). Experimental Procedures 125

Cs*4

-S'2

I 00 -- I © "1

er "--'-,,. " Cs" si u6.C

93. Experimental Procedures * 126

O 0 H2 S0 4, MeOH, A O 0

HO OH 12 h. 89% H3CO OCH 3 trans-glutaconic acid 84

Dimethyl Glutaconate (84):

Trans-glutaconic acid (25.0 g, 192 mmoles) was added to a 250 mL round- bottomed flask. Methanol (100 mL) and conc. sulfuric acid (5 mL) were then added and the mixture was heated at reflux for 12 h. Once the acid was no longer visible via thin layer chromatography the reaction was cooled to rt.

Water (75 mL) was added and then the solution was made basic by the addition of solid sodium bicarbonate. The methanol was removed under reduced pressure and the aqueous phase was extracted with ether (3 X 50 mL

portions). The combined organics were dried over magnesium sulfate and

concentrated, affording dimethyl glutaconate 84 (27.2 g) in 89% yield. Rf0.60

(60% ethyl acetate/hexane). FTIR (thin film, cm -1) 2955, 1738, 1725, 1662, 1437,

1277, 1204, 1162, 986. 'H NMR (300 MHz, CDC13 ) 6 7.00 (td, 1H, J=7.2, 15.6 Hz),

5.93 (td, 1H, J=1.6, 15.6 Hz), 3.73 (s, 3H), 3.70 (s, 3H), 3.24 (dd, 2H, J=1.5, 7.2 Hz). 13 C NMR (75 MHz, CDC13) 6 170.1, 166.1, 139.7, 124.3, 52.1, 51.6, 37.2. Experimental Procedures * 127

Ul

I o

oL 0o 0 O I

00" Experimental Procedures * 128

0 0 NEt 3, TMSOTf, O "C 0 OTMS

H3CO OCH 3 THF/Hexane H3CO OCH3

84 85

i. THF, Mg, 40 0C 0

ii. Cul, -35 0C H3CO

iii. 85, 79% H3CO O

83

Butenyl glutarate 83:

A 250 mL round-bottomed flask containing magnesium turnings (1.03 g, 78.3 mmoles) was charged with THF (100 mL) under argon. To this solution, 4- bromo-l-butene (10 g, 2 equiv.) was added dropwise to retain a constant reflux. The reaction was olive green in color and small shaving of magnesium were still visible after 1 h. Meanwhile, the TMS ether was prepared. A 200 mL round-bottomed flask containing dimethyl glutaconate (84) (5.87 g, 37.1 mmoles) was charged with hexane (55 mL) and THF (50 mL) under argon. The solution was cooled to 0 C then triethylamine (27 mL, ca. 5 equiv.) and TMSOTf (7.5 mL, 1.1 equiv.) were added. The solution was stirred at 0 C for 20 min then it was warmed to rt for 40 min The Et 3N* HOTf formed an insoluble more dense layer that was removed via syringe. The solvents were removed en vacuo, and the TMS enol ether product (85) was used without further purification. THF (100 mL) was added to the crude silyl enol ether then was cooled to -60 C. TMSC1 (15 mL, 3 equiv.) and cuprous iodide (1.43 g, 0.2 equiv.) were added followed by the dropwise addition of the

Grignard solution. The reaction was not warmed above -30 C. Once the starting material was no longer visible via thin layer chromatography, the

reaction was quenched by the addition of a saturated solution of ammonium ExperimentalProcedures * 129 chloride (150 mL). The organics were removed under reduced pressure and the aqueous phase was extracted with ether (3 X 50 mL portions). The combined organics were dried over magnesium sulfate and concentrated.

The product was purified via column chromatography (SiO 2, 10% ethyl acetate/hexane) affording dimethyl ester 83 (6.27 g) in 79% yield. Rf0.35 (10% ethyl acetate/hexane). FTIR (thin film, cm -1) 2951, 1737, 1641, 1437, 1373, 1255,

1 1208, 1166, 997, 913. H NMR (300 MHz, CDC13) 5 5.77 (tdd, 1H, J=6.6, 10.1, 17.1

Hz), 5.02 (ddd, 1H, J=1.6, 3.4, 17.1 Hz), 4.96 (tdd, 1H, J=1.3, 2.0, 10.1 Hz), 3.66 (s,

6H), 2.38 (d, 5H, J=1.5 Hz), 2.09 (ddd, 1H, J=1.3, 6.5, 15.5 Hz), 1.45 (m, 2H). 13C

NMR (75 MHz, CDC13) 6 172.8, 137.9, 114.9, 51.5, 38.1, 33.1, 31.5, 30.8. Experimental Procedures * 130

X-

j j

i

I C r r=i i q

n L L

cll

,L

0 !

0 0 , L n Cm - I

SU,

rI, n i SmLA

r i ExperimentalProcedures * 131

0

A TMSO H3CO i. Na, Tol,

H3CO ii. TMSCI, # 1 h, A 97% TMSO 0 83 82

Bis-silyl enol ether 82:

A 500 mL 3-necked round-bottomed flask equipped with a condenser, an addition funnel and a glass coated stir bar was charged with toluene (200 mL) under argon. Sodium (2.58 g, 4.5 equiv.) was added in one piece and the solution was heated to reflux, at which time the sodium melted and the high speed stirring caused a fine dispersion. The addition funnel was charged with diester 83 (5.35 g, 25.0 mmoles), freshly distilled chloro-trimethylsilane (14.3 mL, 4.5 equiv.) and toluene (15 mL). This mixture was slowly added to the

refluxing reaction mixture over 1 h. The reaction was initially cloudy with a

yellow tint, and after ca. 45 min the precipitate turned to a light purple color. After the addition was complete, the addition funnel was rinsed with 2 X 10

mL portions of toluene. The reaction was left at reflux for lh and was then

cooled to rt. The mixture was filtered under argon, as the precipitate formed during the reaction was pyrophoric. The precipitate was rinsed with toluene and the filtrate was concentrated. The crude product was filtered through a mixture of silica gel (treated with triethylamine) and magnesium sulfate and

the solids were rinsed. The solution was concentrated affording bis-silyl enol ether 82 (7.20 g) in 97% yield. Rf 0.63 (10% ethyl acetate/hexane). FTIR (thin film, cm-1) 2959, 2924, 2846, 1707, 1642, 1340, 1310, 1251, 1097, 913, 870, 843, 754.

1 H NMR (300 MHz, CDC13 ) 8 5.81 (tdd, 1H, J=6.6, 10.1, 17.2 Hz), 5.00 (qd, 1H, J=1.7, 17.1 Hz), 4.94 (tdd, 1H, J=1.1, 2.3, 10.1 Hz), 2.37 (m, 2H), 2.20-1.87 (m, 5H), Experimental Procedures * 132

1.47 (q, 2H, J=7.6 Hz), 0.18 (s, 18H). 13C NMR (75 MHz, CDC13 ) 138.8, 129.5, 114.4, 36.9, 36.3, 31.7, 30.6, 0.76. Experimental Procedures * 133

CI

0 oc00 Experimental Procedures * 134

O Pd(OAc)2 TMSO NaOAc

CH 3CN, rt TMSO TMSO 44%

82 81

[3.2.1]Bicycloketone 81:

A 200 mL round-bottomed flask containing bis-silyl enol ether 82 (7.20 g, 24.1 mmoles) was charged with acetonitrile (100 mL) under argon. The solution was cooled to -10 'C then sodium acetate (3.96 g, 2 equiv.) and palladium II acetate (6.5 g, 1.2 equiv.) were added. The reaction was keep between -20 oC and -10 'C for 36 h. The mixture was filtered though a glass fritted funnel with a silica gel plug. The reaction was quenched by the addition of a saturated solution of sodium chloride (150 mL) and water (100 mL). The aqueous phase was extracted with pentane (3 X 50 mL portions). The combined organics were dried over magnesium sulfate and concentrated.

The product was purified via column chromatography (SiO 2, 10% ether

/pentane) affording the bicyclic ketone 81 (2.39 mg) in 44% yield. We believe the low yield is due to the volatile product formed. It may be worthwhile to distill the product in the future. Rf0.46 (10% ethyl acetate/hexane). FTIR (thin film, cm -1) 2951, 1756, 1454, 1403, 1249, 1211, 1171, 1113, 1025, 902, 841.

1 H NMR (300 MHz, CDC13 ) 8 5.10 (t, 1H, J=2.1 Hz), 4.78 (t, 1H, J=2.1 Hz), 2.65 (m, 1H), 2.46 (dd, 1H, J=4.9, 14.6 Hz), 2.44 (dd, 1H, J=7.6, 18.9 Hz), 2.24 (dd, 1H,

J=3.7, 18.9 Hz), 2.20 (dd, 1H, J=5.8, 11.6 Hz), 2.18 (d, 1H, J=3.7 Hz), 1.92 (dd, 1H,

1=3.4, 11.1 Hz), 1.74 (m, 1H), 1.64 (s, 3H). 13C NMR (75 MHz, CDC13 ) 8 217.6,

147.3, 105.9, 84.7, 45.0, 41.1, 31.0, 29.1, 28.5, 2.0. Experimental Procedures * 135

~~S

0 0

~-Th Experimental Procedures * 136

0 0

HCI, THF TMSO 90% HO

81 96

xo-Hydroxy ketone 96: A 25 mL round-bottomed flask containing TMS ether 81 (245 mg, 1.1 mmoles) was charged with THF (10 mL). Hydrochloric acid (conc. 1 drop) was added to the solution. The reaction was stirred for 15 min at rt. The reaction was quenched by the addition of a saturated solution of sodium bicarbonate (10 mL). The aqueous phase was extracted with pentane (3 X 15 mL portions).

The combined organics were dried over magnesium sulfate and concentrated.

The crystalline solid was rerystallized from pentane affording alcohol 96 (148 mg) in 90% yield. m.p. 56.0-57.5 'C. Rf0.53 (80% ethyl acetate/hexane). FTIR

(thin film, cm -1) 3456(b), 2940, 2860, 1748, 1645, 1450, 1403, 1320, 1202, 1167,

1 1150, 1100, 1068, 1010, 897, 636, 536. H NMR (300 MHz, CDC13) 8 5.12 (d, 1H,

J=1.5 Hz), 4.78 (s, 1H), 2.91 (s, 1H), 2.69 (d, 1H, J=3.0 Hz), 2.47 (dd, 1H, J=7.6, 19.4 Hz), 2.47 (dd, 1H, J=5.2, 9.8 Hz), 2.28 (dd, 1H, J=3.4, 19.2 Hz), 2.21 (m, 1H), 2.09

(dd, 1H, J=5.2, 11.3 Hz), 1.94 (dd, 1H, J=3.0, 11.3 Hz), 1.75 (m, 2H). 13C NMR (75

MHz, CDC13) 8 217.6, 147.3, 105.5, 82.5, 43.3, 40.2, 30.9, 29.1, 28.5. Experimental Procedures * 137 Experimental Procedures * 138

i. NaH, Ben/Hex - HO - ii. DMF, (COCI)2 0 C

O iii. CH 2C12/THF H EtMgBr, Cul -15 0C H

R-campholenic acid 80% 136

Ethylketone 136:

A 500 mL round-bottomed flask containing R-campholenic acid (10.0 g, 59.4 mmoles) under argon was charged with benzene (50 mL) and hexane (20 mL).

The solution was cooled to 0 OC then sodium hydride (1.57 g, 1.1 equiv.) was added in three equal portions. The reaction was stirred at 0 'C for 20 min Dimethyl formamide (3 drops) was added along with oxalyl chloride (6.23 mL,

1.2 equiv.). The reaction was stirred at 0 oC for 3 h. The solvent was removed under reduced pressure then THF (120 mL) and dichloromethane (60 mL) were added. The solution was cooled to -15 oC then to it was added cuprous

(I) iodide (0.566 g, 0.05%) followed by the dropwise addition of ethyl Grignard until the acid chloride was no longer visible via thin layer chromatography.

The reaction was quenched by the addition of a saturated solution of sodium bicarbonate (100 mL). The organic solvents were removed under reduced pressure and the aqueous phase was extracted with diethyl ether (4X100 mL). The product was purified by distillation, (67 'C/2 mm Hg) affording ethyl ketone 136 (8.6 g) in 80% yield. Rf 0.65 (50% diethyl ether/hexane). FTIR (thin film, cm - 1) 3036, 2954, 1713, 1459, 1412, 1374, 1360, 1285, 1211, 1112, 1015, 854,

1 797. H NMR (300 MHz, CDC13) 8 5.22 (s, 1H), 2.51-2.31 (m, 5H), 2.23 (ddd, 1H, J=3.9, 7.8, 11.7 Hz), 1.79 (ddd, 1H, J=2.4, 9.3, 15.6 Hz), 1.60 (s, 3H), 1.05 (t, 3H,

J=7.3 Hz), 0.98 (s, 3H), 0.77 (s, 3H). HRMS calculated for C 12 H 2 00 (M+):180.15142. Found: 180.15167. Experimental Procedures * 139

f--

i --

r 1

i . -~

7b Experimental Procedures * 140

03, Sudan Red CH 2C12 "-

then Me 2S H 0 H 59/o 0 H 137 141

Keto aldehyde 141:

A 200 mL round-bottomed flask containing cyclopentene 137 (9.50 g, 42.4 mmoles) was charged with dichloromethane (100 mL). Sudan III (5 mg) was used as an indicator. The solution was cooled to - 78 'C and ozone was bubbled through the solution until the pink color faded to clear then was removed. At - 78 'C dimethyl sulfide (15.6 mL, 5 equiv.) was added and the reaction was warmed to rt. The reaction was allowed to stir for 12 h. The reaction was quenched by the addition of a saturated solution of sodium bicarbonate (10 mL). The aqueous phase was extracted with ether (3X70 mL).

The combined organics were dried over magnesium sulfate, and concentrated. The product was purified by column chromatography (15% ethyl acetate/hexane), affording keto-aldehyde 141 (6.40 g) in 59% yield. Rf 1) 0.29 (50% ether/hexane). [ca] -6.66 (c=4.25, CHC13). FTIR (thin film, cm-

2973, 2883, 2720, 1722, 1702, 1466, 1355, 1202, 1112, 1054, 950, 904. 1H NMR (500

MHz, CDCl 3 ) 6 9.71 (t, 1H, J=1.0 Hz) 4.00 (m,4H), 2.71 (dtd, 1H, J=2.0, 5.0, 9.6 Hz), 2.61 (ddd, 1H, J=1.7, 5.1, 17.8 Hz), 2.39 (ddd, 1H, J=6.0, 5.1, 17.8 Hz), 2.18 (s, 3H), 1.62-1.49 (m,4H), 1.03 (s, 3H), 1.01 (s, 3H), 0.85 (t, 3H, J=7.5 Hz). 13C NMR

(75 MHz, CDC13) 6 213.4, 201.5, 111.6, 64.5, 64.2, 51.2, 46.8, 37.3, 32.3, 30.0, 35.1, 31.6, 20.3, 8.0. Experimental Procedures * 141

C2.C - ee-_- i -

I -t

O j C-K

0

'-

I i[ Experimental Procedures * 142

t-Bu Li, Et20, -90 oC, HO CH 3 CeC1 , -90 C-> -50C0 ' 3 0 0

Br 3 Aldehyde 141, OCH3 66%

132 143, 144

Lactols 143 and 144:

A 100 mL round-bottomed flask containing aryl bromide 132 (1.40 g, 1.15

equiv.), was charged with diethyl ether (20 mL) under argon. This solution

was cooled to -78 'C then to it was added t- butyllithium (7.59 mL, 1.45 M, 2.3 equiv.) The reaction was stirred at - 78 'C for 45 min, then to it was added

anhydrous cerium trichloride (1.18 g, 1.0 equiv.) in THF (15 mL) via

canulation. The reaction was stirred at -78 'C for 1 h. Keto-aldehyde 141 (1.23

g, 4.78 mmoles) was dissolved in THF (5 mL) then added via canulation, and

washed with three additional portions of THF (2 mL ea.). The reaction was

warmed to - 20 ' C over 1 h. When the starting material was no longer visible via thin layer chromatography, the reaction was quenched. A saturated

solution of sodium bicarbonate (30 mL) was added followed by the removal of

the organic solvent under reduced pressure. The aqueous phase was extracted with ether (3 X 30 mL portions). The combined organics were dried over

magnesium sulfate and concentrated. The product was purified by column chromatography (25% ether/hexane), affording a mixture of lactols 143 and 144 (1.36 g mixture) in 66% yield. Rf(R-isomer)0.29, Rf(S-isomer)0.31 (50%

ether/hexane). The following information is based on R-isomer. FTIR (thin

film, cm -1) 3424, 2964, 2933, 1649, 1584, 1464, 1374, 1259, 1165, 1092, 1070, 926,

1 799. H NMR (300 MHz, CDC13) 6 7.18 (dd, 1H, J=7.8, 7.8 Hz) 7.13 (dd, 1H, 1=1.4, 8.0 Hz), 6.77 (dd, 1H, 1=1.5, 7.7 Hz), 5.26 (dd, 1H, J=2.6, 11.9 Hz), 4.77 (m, 2H, ExperimentalProcedures * 143

vinyl CH 2 ), 3.95-3.85 (m, 4H, ketal), 3.80 (s, 3H), 2.90-2.72 (m, 2H), 2.20 (t, 2H, 1=8.2 Hz), 2.04 (td, 1H, J=3.2, 13.6 Hz), 1.85 (s, 3H), 1.81 (s, 3H), 1.77 (dd, 1H,

J=1.5, 14.3 Hz), 1.67 (q, 2H, J=7.5 Hz), 1.39 (s, 3H), 1.29 (dd, 1H, J=9.1, 14.4 Hz), 1 1.04 (s, 3H), 0.97 (s, 3H), 0.90 (t, 3H, J=7.4 Hz). 3C NMR (125 MHz, CDC13) 6

157.4, 146.8, 141.8, 128.3, 126.8, 118.5, 112.5, 109.2, 109.1, 101.4, 68.4, 65, 34.6, 55.5,

38.8, 37.8, 37.0, 36.6, 35.0, 30.1, 25.5, 24.2, 22.8, 22.6, 17.6, 8.0. Experimental Procedures * 144

---~--~-c t ~~ SB " ----7 LS2a r--

e9"2

6W 2

61'2 18Ct 16"

I ,

26"1

i

8 'C F2 -** IO 66" I 00

0.../ T I I" / 0

E6 I

un

LS2O

E6LA -7 ExperimentalProcedures * 145

- O PCC/Alumina 0 OCO OCH OCH 3 CH 2 CI2 , Pyridine, rt 3 0 H 47/ 0 H

143 ,144 145

Aryl diketone 145:

A 250 mL round-bottomed flask containing lactols 143 and 144 (1.91 g, 4.41 mmoles), was charged with dichloromethane (100 mL) and pyridine (3 drops) under argon. PCC on alumina (8g, 1 g=1 mmole) was added at room temperature. The solution was left for 3 d. When the R-isomer was no longer visible via thin layer chromatography, the reaction terminated. The reaction was filtered through a glass fritted funnel with a celite and silica gel plug. The product was purified by column chromatography (20% ether/hexane), affording diketone 145 (0.89 g) in 47% yield. Rf0.50 (20% diethyl ether/hexane). FTIR (thin film, cm-1) 2962, 1701, 1456, 1355, 1262, 1108,

1 1055, 784, 737. H NMR (500 MHz, CDC13) 8 7.22 (t, 1H, J=7.9 Hz) 7.09 (dd, 1H,

J=1.1, 7.8 Hz), 6.92 (dd, IH, J=0.9, 8.2 Hz), 4.71(s, 2H), 4.02-3.84 (m, 4H, ketal), 3.84 (s, 3H), 3.81 (d, 1H, J=8.2 Hz), 3.11 (dd, 1H, J=3.5, 19.4 Hz), 3.01 (m, 1H), 2.83

(dd, 1H, J=5.2, 12.2 Hz), 2.80 (dd, 1H, J=5.5, 19.5 Hz), 2.72 (ddd, 1H, J=5.1, 11.4, 12.2 Hz), 2.25 (s, 3H), 1.78 (s, 3H), 1.61 (dq, 2H, J=2.4, 7.6 Hz), 1.56 (m, 3H), 1.05

(s, 3H), 1.02 (s, 3H), 0.88 (t, 3H, J=7.5 Hz). 13C NMR (125 MHz, CDC13) 8 214.4, 204.4, 157.9, 146.4, 141.7, 129.1, 126.5, 119.1, 112.1, 112.0, 109.2, 65.0, 64.7, 55.6, 51.7, 46.5, 38.2, 37.9, 32.4, 30.5, 25.4, 25.3, 22.6, 21.8, 20.3, 8.3. Experimental Procedures * 146

a

J'C

0, -77 t -r

N Ii Nr- em..--- 311- Experimental Procedures * 147

0 KOH/MeOH

OCH3 960/o 'O OCH 3

145 130

Aryl enone 130:

A 25 mL round-bottomed flask containing diketone 145 (116 mg, 0.269 mmoles), was charged with THF (5 mL) under argon. To this mixture was added a solution of potassium hydroxide (36 mg) in methanol (7 mL). The reaction was stirred at room temperature for 2 d. The reaction was quenched by the addition of a saturated solution of sodium bicarbonate (15 mL) followed by the removal of the organic solvent under reduced pressure. The aqueous phase was extracted with ether (3 X 15 mL portions). The combined organics were dried over magnesium sulfate and concentrated. Enone 130 (104 mg) was obtained in 98% yield. Rf 0.45 (50% diethyl ether/hexane). FTIR

(thin film, cm -1) 3854, 3750, 3676, 3649, 3069, 2967, 2935, 2880, 2363, 1668, 1576, 1 1456, 1437, 1381, 1261, 1198, 1150, 1098, 1069, 947. H NMR (500 MHz, CDC13 ) 8

7.17 (t, 1H, J=8.3 Hz) 6.81 (d, 1H, J=8.3 Hz), 6.67 (d, 1H, J=8.3 Hz), 5.89 (d, 1H, J=1.5 Hz), 4.68 (s, 1H), 4.65 (s, 1H), 3.95-3.83 (m, 4H, ketal), 3.82 (s, 3H), 2.89 (dd, 1H, J=4.9, 19.5 Hz), 2.73 (ddd, 1H, J=5.9, 11.2, 12.7 Hz), 2.64 (ddd, 1H, J=5.9, 10.8, 12.7 Hz), 2.50 (ddd, 1H, J=2.0, 9.3, 19.5 Hz), 2.19 (ddd, 1H, J=5.4, 14.7, 14.7 Hz), 2.14 (ddd, 2H, J=1.5, 4.9, 9.3 Hz), 1.90 (dd, 1H, 1=2.0, 14.7 Hz), 1.73 (s, 3H), 1.63 (q,

2H, J=7.3 Hz), 1.56 (dd, 1H, J=9.8, 14.7 Hz), 1.21 (s, 3H), 1.02 (s, 3H), 0.90 (t, 3H,

13 J=7.3 Hz). C NMR (125 MHz, CDC13) 8 204.3, 160.8, 157.6, 146.0, 142.0, 127.0,

126.8, 126.7, 119.2, 112.0, 109.8, 109.7, 65.0, 64.5, 55.5, 44.3, 39.6, 38.2, 36.6, 36.0,

29.9, 26.5, 22.5, 19.0, 8.1. Experimental Procedures * 148

-

- a

----_% cc, (uR)

Lr~

7- 0 0 Experimental Procedures * 149

0H OSiMe 3

0 H3C TMSCI, THF 0 H3 0 H LDA, -78 oC 0 H 81%

/ OCH 3 / OCH 3 129 157

TMS silyl enol ether 157:

A 5 mL round-bottomed flask containing cyclobutane 129 (23 mg, 0.055 mmoles), was charged with THF (1 mL) under argon. This solution was cooled to -78 'C then TMSC1 (63 IL., ca. 10 equiv.) and LDA (500 pL., 1 M, ca. 10 equiv.) were added. The solution was warmed to 0 'C over 30 min When the starting material was no longer visible via thin layer chromatography, the reaction was quenched. A saturated solution of sodium bicarbonate (1 mL) was added followed by the removal of the organic solvent under reduced pressure. The aqueous phase was extracted with ether (3 X 5 mL portions).

The combined organics were dried over magnesium sulfate and concentrated.

The product was purified by column chromatography (20% ether/hexane), affording TMS enol ether 157 (22 mg) in 81% yield. Rf 0.26 (10% ethyl acetate/hexane). FTIR (thin film, cm -1) 2955, 1736, 1697, 1582, 1469, 1362, 1336, 1252, 1221, 1159, 1117, 1071, 948, 890, 842, 760, 738. 1H NMR (500 MHz, CDC13) 6 7.15 (t, 1H, J=7.8 Hz) 7.02 (d, 1H, J=7.8 Hz), 6.72 (d, 1H, J=7.8 Hz), 3.92-3.80 (m,

4H, ketal), 3.83 (s, 3H), 2.96 (ddd, 1H, J=3.9, 3.9, 14.7 Hz), 2.32 (d, 1H, J=11.7 Hz), 2.31 (dd, 1H, J=5.9, 15.1 Hz), 2.25 (d, 1H, J=11.7 Hz), 2.21 (ddd, 1H, J=3.9, 12.2,

15.1 Hz), 1.82-1.75 (m, 2H), 1.29 (s, 3H), 1.20 (dd, 1H, J=8.5, 14.9 Hz), 1.12 (s, 3H),

1.04 (s, 3H), 0.97 (dd, 1H, J=12.4, 15.9 Hz), 0.86 (t, 3H, J=7.3 Hz), 0.16 (s, 3H). 13C

NMR (125 MHz, CDC13) 6 155.4, 150.6, 148.4, 128.9, 126.2, 118.9, 116.0, 112.4, Experimental Procedures * 150

107.5, 64.9, 64.5, 55.6, 53.0, 46.7, 44.3, 42.7, 38.5, 38.4, 37.9, 37.0, 30.0, 24.2, 22.2,

21.6, 19.8, 8.1, 0.56. Experimental Procedures * 151

C2

I O0

SO I Experimental Procedures * 152

OCH 3 HCI, Acetone OCH 3 95% H 0 H H 149 169

trans Diketone 169:

A 25 mL pear-shaped flask containing ketal 149 (34 mg, 0.083 mmoles) was charged with acetone (4 mL). To this mixture, 10 % aq. HC1 (3 drops) was added at rt. After 12 h. the reaction was quenched by the addition of a saturated solution of sodium bicarbonate (3 mL). The aqueous phase was extracted with ether (3 x 15 mL). The combined organics were dried over magnesium sulfate and concentrated, affording ketone 169 (29 mg) in 95% yield. Rf 0.43 (50% ether/hexane). FTIR (thin film, cm-1 ) 2969, 2936, 1714,

1682, 1582, 1460, 1438, 1375, 1258, 1174, 1080, 1061, 908, 778, 740. 1H NMR (500

MHz, CDC13) 8 7.10 (t, 1H, J=8.1 Hz), 6.89 (d, 1H, J=8.3 Hz), 6.64 (d, 1H, J=8.3 Hz), 5.84 (d, 1H, J=13.2 Hz), 5.71 (d, 1H, J=13.2 Hz), 3.79 (s, 3H), 3.18 (tdd, 1H, J=2.0,

9.8, 12.2 Hz), 2.92 (dd, 1H, J=2.9, 12.7 Hz), 2.73 (ddd, 1H, J=2.2, 5.1, 17.8 Hz), 2.57 (dd, 1H, J=2.0, 17.1 Hz), 2.52 (m, 1H), 2.48 (dq, 1H, J=7.3, 17.6 Hz), 2.36 (dq, 1H,

J=7.3, 17.6 Hz), 2.25 (dd, 1H, J=9.8, 17.1 Hz), 1.98 (ddd, 1H, J=3.5, 12.6, 14.5 Hz), 1.64 (dd, 1H, J=2.4, 5.4, 13.2 Hz), 1.45 (ddd, 1H, J=3.4, 12.7, 14.2 Hz), 1.42 (dt, 1H, J=4.9, 13.2 Hz), 1.17 (s, 3H), 1.13 (s, 3H), 1.03 (s, 3H), 1.07 (t, 3H, J=7.3 Hz). A

DQCOSY experiment (CDC13, 500 MHz) was performed to determine coupling partners. A NOESY experiment (CDC13, 500 MHz) was performed to

determine relative stereochemistry. 13C NMR (75 MHz, CDC13 ) 8 214.0, 210.1,

157.0, 146.4, 139.9, 137.9, 126.1, 125.8, 120.8, 119.4, 107.0, 55.4, 50.0, 44.4, 36.2, 38.8,

37.1, 36.9, 36.4, 26.8, 19.7, 17.6, 15.6, 7.8. _ _I_, ... -- Al_ L. L t l __I._L _,_-_ ---- J _- - - - ..------

691.

H H O

CHOO O 0 Experimental Procedures * 154

0 OCH3 OCH3

H UCH 2 GI2, 95% H

163 164

Epoxy alcohol 164:

A 10 mL round-bottom flask containing allylic alcohol 163 (41 mg, 0.10 mmoles) was charged with dichloromethane (2 mL). tButylhydroperoxide

(0.5 mL) was added followed by the addition of VO(acac) 2 (1 mg). After 5 min at rt, the reaction was complete. The solvent was removed under reduced pressure. The product was purified via column chromatography (25% ether/hexane) affording 164 (41 mg) in 95% yield. The spectroscopic properties were identical to that described previously. 65 Experimental Procedures * 155

r

H Lto L. Experimental Procedures * 156

OCH 3 0 0 OCH 3 then NaHSO3, EtOAc ", H 5 O 72% 0 H

170 171

Diol 171:

A 25 mL round-bottomed flask containing enone 170 (13 mg, 0.031 mmoles) was charged with THF (2 mL). The solution was cooled to 0 oC then pyridine

(22 tL) and Os04 (12 mg, 1.5 equiv.) were added. The reaction was stirred for

1.5 h. at 0 'C then warmed to rt for 24 h. after which time the starting material had completely converted to the osmate ester (baseline spot via thin layer chromatography). The osmate ester was reductive cleaved by the addition of ethyl acetate (5 mL) and 5% aq. sodium bisulfite solution (5 mL) with vigorous stirring for 20 h. A saturated solution of sodium bicarbonate (1 mL) was added followed by the removal of the organic solvent under reduced pressure. The aqueous phase was extracted with ethyl acetate (3 X 10 mL portions). The combined organics were dried over magnesium sulfate and concentrated. The product was purified by column chromatography (70% ether/hexane), affording diol 171 (10 mg) in 72% yield. Rf 0.10 (50% ether/hexane). FTIR (thin film, cm -1) 3445, 2971, 2882, 2836, 2246, 1694, 1586, 1464, 1437, 1382, 1372, 1312, 1257, 1206, 1154, 1135, 1078, 1039, 988, 911, 781, 733. 1H NMR (500 MHz, CDC13) 6 7.07 (t, 1H, J=7.8 Hz), 6.97 (d, 1H, J=7.3 Hz), 6.58 (d, 1H, J=7.8 Hz), 4.88 (t, 1H, 1=5.1 Hz), 4.38 (dd, 1H, J=4.6, 11.0 Hz), 4.18-4.01 (m,

4H, ketal), 4.10 (d, 1H, J=6.4 Hz), 3.78 (s, 3H), 3.44 (d, 1H, 1=10.7 Hz), 2.73 (dd,

1H, J=6.4, 18.1 Hz), 2.69 (d, 1H, J=11.2 Hz), 2.30 (ddd, 1H, J=6.8, 11.7, 18.1 Hz),

2.16 (ddd, 1H, J=3.7, 3.7, 9.3 Hz), 1.83 (d, 1H, J=14.7 Hz), 1.80 (m,1H), 1.76 (q, 1H,

J=7.3 Hz), 1.73 (q, 1H, J=7.3 Hz), 1.69 (ddd, 1H, J=2.9, 2.9, 16.1 Hz), 1.51 (dd, 1H, Experimental Procedures * 157

J=9.3, 14.6 Hz), 1.38 (ddd, 1H, J=3.9, 11.7, 16.1 Hz), 1.33 (ddd, 1H, J=6.8, 12.7, 12.7 Hz), 1.22 (s, 3H), 1.03 (s, 3H), 0.98 (t, 3H, J=7.3 Hz), 0.96 (s, 3H). 13C NMR (75

MHz, CDC13 ) 8 215.0, 207.4, 156.5, 144.1, 126.1, 123.8, 122.1, 112.1, 106.3, 76.0, 64.8, 64.5, 55.1, 51.0, 48.8, 42.5, 42.3, 39.3, 37.6, 30.1, 25.8, 24.0, 22.0, 19.9, 17.9, 15.3, 8.5. C, 4, , [ , 09 _ O _ ._I__ l L--J __ I \I_,_1 - --_ 1 _ I _ __ _,L _I _ ~_ iL _ ~. ---~ . .~ ... , - ,Y n-n ' --'

0

HOO ExperimentalProcedures * 159

HO OH 0 0

- CH 3 - CH3 0 O C HCI, Acetone O O .00CH 3 83% OCH3 0_.-OH H

171 172

Diketo acetonide 172:

A 25 mL round-bottomed flask containing diol 171 (70 mg, 0.157 mmoles) was charged with acetone (10 mL). To this solution, conc. HC1 (1 drop) and 2,2- dimethoxy propane (1 mL) were added. The mixture was stirred for 30 min

The reaction was neutralized by the addition of a saturated solution of sodium bicarbonate (1 mL) followed by the removal of the organic solvent under reduced pressure. The aqueous phase was extracted with ether (3 X 5 mL portions). The combined organics were dried over magnesium sulfate and concentrated. The product was purified by column chromatography (50% ether/hexane), affording diketone/acetonide 172 (58 mg) in 83% yield. Rf0.22

(50% ether/hexane). FTIR (thin film, cm-1 ) 2976, 2939, 1715, 1586, 1467, 1380,

1 1258, 1210, 1171, 1078, 1034, 731. H NMR (500 MHz, CDC13) 6 7.02 (t, 1H, J=7.8

Hz), 6.58 (d, 1H, J=7.8 Hz), 6.47 (d, 1H, J=7.8 Hz), 5.15 (d, 1H, J=7.8 Hz), 4.72 (d, 1H, J=7.3 Hz), 3.76 (s, 3H), 2.89 (d, 1H, J=11.7 Hz), 2.70 (dd, 1H, J=6.8, 18.6 Hz),

2.59 (m, 1H), 2.57 (dd, 1H, J=2.4, 16.6 Hz), 2.50 (m, 1H), 2.47 (m, 1H), 2.39 (dd, 1H, J=10.3, 16.6 Hz), 2.34 (ddd, 1H, J=8.3, 11.7, 18.1 Hz), 1.72 (dd, 1H, J=7.8, 13.7

Hz), 1.64 (s, 3H), 1.56 (ddd, 1H, J=7.3, 11.7, 14.1 Hz), 1.45 (ddd, 1H, J=3.2, 12.2,

16.1 Hz), 1.39 (s, 3H), 1.19 (s, 3H), 1.18 (t, 3H, J=7.3 Hz), 1.12 (ddd, 1H, J=3.0, 3.0,

13 16.1 Hz), 0.99 (s, 3H), 0.97 (s, 3H). C NMR (75 MHz, CDC13 ) 8 210.7, 209.0,

156.8, 143.9, 126.2, 123.9, 121.4, 106.5, 106.2, 86.0, 77.8, 55.1, 50.2, 48.4, 45.0, 41.8, 41.0, 37.2, 36.9, 26.4, 24.2, 24.0, 20.1, 19.9, 17.5, 15.3, 7.9. Experimental Procedures 160

[_L n- LA C_r? tIN

S J"

C)L C--

/ i

0 °/ i" 0 KK 0''

4! I Experimental Procedures * 161

0 0

SOCH 3 HCI, Acetone _ H OCH3 8 1% 0 H O H H

174 175

A 25 mL pear-shaped flask containing ketal 174 (22 mg, 0.053 mmoles) was charged with acetone (4 mL). To this mixture, 10 % aq. HC1 (3 drops) was

added at rt. After 12 h. the reaction was quenched by the addition of a

saturated solution of sodium bicarbonate (3 mL). The aqueous phase was

extracted with ether (3 x 15 mL). The combined organics were dried over magnesium sulfate and concentrated. The product was purified via column chromatography (silica gel, 20% ether/hexane) affording 16 mg 175 (81%

yield). Rf0.35 (500/, ether/hexane). FTIR (thin film, cm -1) 2966, 2932, 1712,

1 1686, 1586, 1467, 1367, 1258, 1074, 782, 753. H NMR (500 MHz, CDCl 3 ) 6 7.11 (t, 1H, J=7.8 Hz), 6.77 (d, 1H, J=7.8 Hz), 6.62 (d, 1H, J=7.8 Hz), 5.92 (d, 1H, J=13.2

Hz), 5.52 (d, 1H, J= 13.2 Hz), 3.78 (s, 3H), 2.73 (dd, 1H, J=6.6, 18.3 Hz), 2.63 (s, 1H), 2.48 (ddd, 1H, J=7.3, 12.2, 19.0 Hz), 2.46 (s, 1H), 2.46 (qd, 1H, J=7.3, 18.0 Hz), 2.37 (dd, 1H, J=1.5, 16.1 Hz), 2.26 (qd, 1H, J=7.5, 17.6 Hz), 2.15 (dd, 1H, J=10.1, 15.9 Hz), 1.92 (ddd, 1H, J=3.9, 10.2, 15.1 Hz), 1.80 (dt, 1H, J=7.1, 12.6 Hz), 1.50 (dd, 1H,

J=7.32, 13.2 Hz), 1.19 (s, 3H), 1.10 (s, 3H), 0.96 (t, 3H, J=7.3 Hz), 0.95 (s, 3H). 13C NMR (75 MHz, CDC13) 6 215.7, 209.8, 156.8, 143.4, 128.1, 126.5, 121.5, 121.4, 106.8, 55.1, 48.8, 47.0, 45.3, 44.4, 39.1, 38.8, 36.4, 29.1, 25.0, 24.1, 19.9, 18.6, 7.7. _;_ 1 ~.~ _i~__~______~______~_~~ ~_ __~___ ~C-~--~---c~---nl=-----s~---~-~~ _ = I;

Experimental Procedures * 162

L

;Z113IT

tu

ic

:I) 0

-to

r

-

8..H _ ExperimentalProcedures * 163

0 KtOBu, benzene O OCH O 3 75% H OCH3 175 176

A 25 mL pear-shaped flask containing enone 175 (8 mg, 0.022 mmoles) was charged with benzene (3 mL). Solid potassium tert-butoxide (24 mg, 10 equiv.) was added to the solution. The heterogeneous, yellow mixture was stirred at rt for 90 min The reaction was quenched by the addition of a saturated solution of sodium bicarbonate (1 mL). The aqueous phase was extracted with ether (3 x 15 mL). The combined organics were dried over magnesium sulfate and concentrated. The product was purified via column chromatography (silica gel, 20% ether/hexane) affording 6 mg 176 (75% yield).

Rf0.34 (40% ether/hexane). FTIR (thin film, cm-1) 2934, 1701, 1586, 1466, 1259,

1080, 779, 668. 1H NMR (500 MHz, CDC13 ) 8 7.08 (t, 1H, J=7.8 Hz), 6.64 (d, 1H, J=8.3 Hz), 6.58 (d, 1H, J=8.3 Hz), 3.8 (s, 3H), 3.17 (dd, 1H, J=5.6, 16.8 Hz), 2.92 (s, 1H), 2.83 (dd, 1H, J=7.3, 18.1 Hz), 2.82 (qd, 1H, J=7.3, 17.6 Hz), 2.66 (td, 1H, J=2.0,

16.6 Hz), 2.58 (s, 1H), 2.53 (m, 1H), 2.51 (qd, 1H, J =7.3, 17.6 Hz), 2.33 (dd, 1H,

J=2.0, 5.0 Hz), 2.25 (dd, 1H, J=4.6, 12.9 Hz), 2.13 (td, 1H, J=3.9, 14.7 Hz), 2.07 (dt, 1H, J=7.1, 12.6 Hz), 1.66 (dt, 1H, J=3.7, 13.8 Hz), 1.28 (s, 3H), 1.25 (m, 1H), 1.13 (t, 3H, J=7.3 Hz), 1.02 (s, 3H), 0.92 (s, 3H). A DQCOSY experiment (500 MHz,

CDC13) was performed to determine coupling partners. A NOESY experiment 13 (500 MHz, CDC13 ) was performed to determine relative stereochemistry. C

NMR (75 MHz, CDC13) 6 216.8, 213.6, 172.9, 157.1, 140.8, 126.3, 121.9, 107.0, 55.2, 50.4, 48.0, 46.6, 43.4, 40.0, 38.1, 37.7, 35.4, 33.1, 28.3, 27.5, 23.5, 21.9, 20.6, 8.2. Experimental Procedures * 164

OCH 3 176

I f I II I I I 1. I 1.0 p I 3.5 3.0 2.5 2.0 1.5 1 .0 ppm

F2 (PP

1.0

3.0'

3.5

3.5 3.0 2.5 2.0 1.5 1.0 0.5 F l (ppm)