Phát triển chuyển giao silylene xúc tác kim loại đến các hợp chất carbonyl

UNIVERSITY OF CALIFORNIA, IRVINE Development of Metal-Catalyzed Silylene Transfer to Carbonyl Compounds and Applications in Natural Product Synthesis DISSERTATION submitted in partial satisfaction of the requirements for the degree of DOCTOR OF PHILOSOPHY in Chemistry by Stacie Anne Calad Dissertation Committee: Professor Keith A. Woerpel Professor Scott D. Richard Chamberlin 2007 UMI Number: 3243256 INFORMATION TO USERS The quality of this reproduction is dependent upon the quality of the copy submitted. Broken or indistinct print, colored or poor quality illustrations and photographs, print bleed-through, substandard margins, and improper alignment can adversely affect reproduction.

In the unlikely event that the author did not send a complete manuscript and there are missing pages, these will be noted. Also, if unauthorized copyright material had to be removed, a note will indicate the deletion. ® UMI UMI Microform 3243256 Copyright 2007 by ProQuest Information and Learning Company. All rights reserved.

This microform edition is protected against unauthorized copying under Title 17, United States Code. ProQuest Information and Learning Company 300 North Zeeb Road P. Box 1346 Ann Arbor, MI 48106-1346 © 2007 Stacie Anne Calad The dissertation of Stacie Anne Calad is approved and is acceptable in quality and form for publication on microfilm and digital formats: = — ⁄Z⁄⁄ + ⁄ ; Committee Chair University of California, Irvine 2006 ii DEDICATION To my mother Kathleen Calad Thank you for your constant love and support. Your caring nature and your personal strength are an inspiration.

ill Table of Contents List of Figures Vii List of Tables Vili Acknowledgements ix Curriculum Vitae | X Abstract of the Dissertation xI Chapter 1. Silylene Transfer to Carbonyl-Containing Compounds 1 Chapter 2. Metal-Catalyzed Silylene Transfer to Carbonyl-Containing Compounds 2.3 Results and Discussion 15 2.1 Metal-Catalyzed Silylene Transfer to Esters and Ketones 15 2.3 Reactions of Oxasilacyclopentenes 23 2.6 Experimental Section 34 Chapter 3. Silylene Transfer to œ,B-nsaturated Esters and Subsequent Ireland—Claisen Rearrangements: Application to the Synthesis of (+)-5-epi-Acetomycin 3.3 Results and Discussion 69 3.1 Ireland—Claisen Rearrangement of Silylene Transfer Products 69 iv 3.2 Functionalizations and Carbon-Silicon Bond Oxidation 72 3.3 Chirality Transfer From an Allylic Stereocenter 77 3.4 Total Synthesis of (+)-5-epi-Acetomycin 78 3.7 X-ray Crystallographic Data 111 Chapter 4.

Synthesis of (+)-epi-Stegobinone Utilizing Silacyclopropanes as Synthetic Intermediates 4.3 Results and Discussion | 150 4.7 X-ray Crystallographic Data | 173 LIST OF FIGURES Figure 2.1 Aldol transtion states for benzyl acrylate-derived oxasilacyclopentenes 30 Figure 2.2 Aldol transtion states for B-substituted oxasilacyclopentenes 30 Figure 2.3 Aldol transtion states for œ-substituted oxasilacyclopentenes 30 Figure 3.1 Enolization transition states 66 Figure 3.2 Silacyclopropene product | 71 Figure 3.3 Trajectory of nucleophilic attack on a silalactone 73 Figure 3.1 Transition States for Ireland—Claisen rearrangement Figure 4.2 Chelation of a B-benzyloxy group in syn,syn-selective aldol reactions 148 Figure 4.3 Transition state for B-benzyloxy-substituted anti,anti-selective aldol reactions 150 Figure 4.4 Antiperiplanar approach of silyl enol ether 37 152 vi LIST OF TABLES Table 2.1 Oxasilacyclopentene product formation 19 Table 2.2 Hydrolysis of ester-derived oxasilacyclopentenes 21 Table 2.3 Hydrolysis of ketone-derived oxasilacyclopentenes 22 Table 2.4 Lewis acid screen in the aldol reaction 26 Table 2.5 Optimization of aldol reaction conditions 28 Table 3.1 Optimization of the carbonyl reduction reaction 75 Table 3.2 Optimization of the carbon—silicon bond oxidation 76 Table 3.3 Optimization of silylene transfer reactions 81 Table 4.1 Syn,syn-selective aldol reaction conditions 147 Table 4.2 Syn,syn-selective aldol reaction conditions 148 Table 4.3 Anti,syn-selective aldol reaction conditions | 149 Vil ACKNOWLEDGEMENTS First, I would like to thank my advisor, Professor Keith Woerpel, for being a wonderful teacher and colleague. You have taught me so much about chemistry, writing, and life in general. Thank you for your constant encouragement and guidance. It has been a true pleasure working with you.

I thank the faculty at UCI for their commitment to education. Specifically, I would like to thank Professor Scott Rychnovsky and Professor Dick Chamberlin for serving on my dissertation committee and for their helpful discussions over the years. The Woerpel lab has been a great place to do science and I would like to thank the group members for making lab fun and interesting. Jelena Cirakovic was my collaborator on the stegobinone project and I thank her for teaching me so much about metal- catalyzed silylene transfer chemistry and also for her friendship.

Sidd Shenoy has been one of my best friends at UCI and I’ll always remember the lunches and coffee breaks. I thank Susan Billings for being a great roommate and friend over the last years. I’m looking forward to more good times out in Philly! Janice Loy has been a fabulous baymate over the last three years and I thank her for always lending an ear. I’d like to thank all of my close girlfriends in the lab for all the fun lunches, cupcake runs, and nights out: Dr.

Laura Anderson, Laura Bourque, Dr. Pamela Cleary, Renee Link, Sarah Ludlum, and Dr. Other past and present lab members that I would like to thank include Dr. Jason Tenenbaum, Dr.

Tim Clark, Matt Beaver, Jason Harris, Brett Howard, Nick Leonard, Zulimar Nevarez, Armando Ramirez, Tony Romero, Walter Salamant, Andrew Thomas, Christian Ventocilla, and Mike Yang. I thank my family and friends for all their love and support over the years. I never could have come this far without them. Thank you, Mom, Dad, Cari, and Ryan for being such a great family.

Thank you, Eric, for all of your patience and support over the years. Also, I would like to thank the Becker family for being so welcoming and encouraging. I would like to thank Alexis, Amani, Amy, Ariel, Briita, Cathie, Karen, Katy, Lauren, Sarah, and Stefanie for being a great group of friends. John Greaves for mass spectrometry, Dr.

Phil Dennison for assistance with NMR spectroscopy, and Dr. Joe Ziller for X-ray crystallography. I thank the National Institutes of Health for a predoctoral fellowship. Vili CURRICULUM VITAE Stacie A.

Calad Education 2001-2006 Ph., Organic Chemistry, University of California, Irvine 1997-2001 B., Chemistry, University of California, Berkeley Experience 2001-2006 Graduate Research Associate, University of California, Irvine, Thesis Advisor: Keith A. Woerpel 2001-2002 Teaching Assistant, University of California, Irvine 2000-2001 Undergraduate Research Assistant, University of California, Berkeley, Research Advisor: Clayton H. Heathcock 1999 Chemistry Instructor, University of California, Berkeley, Mathematics, Engineering, and Science Achievement (MESA) Summer Academy 1998 General Chemistry Tutor, University of California, Berkeley Honors and Awards 2002-2006 National Institute of Health (NIH) Predoctoral Fellowship 2006 Smitrovich Award, University of California, Irvine 2004 Women’s Chemist Committee/ Eli Lilly Travel Award 1997-2001 California Alumni Leadership Scholarship Recipient 1997-2001 College of Chemistry Scholars Program 1999-2000 Delta Gamma Scholastic Excellence Award Community Involvement 2005-2006 Iota Sigma Pi, Calcium Chapter, Membership Activities Coordinator 2005-2006 Girls, Inc., presented hands-on chemistry experiments 2003-2006 Orange County Cal Alumni Club, college fair volunteer 2003-2005 Ask-a-Scientist Night, Irvine Unified School District ix Publications and Presentations 7, ‘Formation of Chiral Quaternary Carbon Stereocenters by Silylene Transfer: Enantioselective Total Synthesis of (+)-5-epi-Acetomycin. Manuscript in preparation.

“Synthesis of (+)-epi-Stegobinone Utilizing Silacyclopropanes as Synthetic Intermediates. “Silylene Transfer to Carbonyl Compounds and Subsequent Aldol Reactions and Ireland—Claisen Rearrangements,” S. Presented at the Graduate Student and Postdoctoral Colloquium, University of California, Irvine, October 7, 2005. “Silylene Transfer to Carbonyl Compounds and Subsequent Ireland—Claisen Rearrangements to Control Formation of Quaternary Carbon Stereocenters.

“Metal-Catalyzed Silylene Transfer to Carbonyl Compounds,” S. Woerpel, Presented at the 228th National Meeting of the American Chemical Society, Philadelphia, PA, August 2004; paper ORGN 336. “Investigations into the Metal-Catalyzed Reactions of Cyclohexenesilacyclopropane in the Presence of Carbonyl Compounds,” S. Presented at the Graduate Student and Postdoctoral Colloquium, University of California, Irvine, April 2003.

“Metal-Catalyzed Synthesis and Reactions of Silacyclopropanes: New Reactions and Stereoselective Methods for Organic Synthesis,” K. Presented at the 225" National Meeting of the American Chemical Society, New Orleans, LA, March 2003; paper ORGN 001. Abstract of Dissertation Development of Metal-Catalyzed Silylene Transfer to Carbonyl Compounds and Applications in Natural Product Synthesis By Stacie Anne Calad Doctor of Philosophy in Chemistry University of California, Irvine, 2007 Professor Keith A. Woerpel Silylene transfer products can undergo stereoselective carbon-carbon bond-forming reactions, including the generation of quaternary carbon stereocenters, which demonstrate their utility in synthetic organic chemistry.

Our laboratory has developed a metal- catalyzed method for di-tert-butylsilylene transfer to an alkene, providing silacyclopropane products. This dissertation describes the application of the metal- catalyzed silylene transfer conditions to carbonyl compounds. Metal-catalyzed silylene transfer to a range of œ,-unsaturated esters proved to be a general method for the formation of oxasilacyclopentene products containing a cyclic silyl ketene acetal functionality. These oxasilacyclopentenes are useful synthetic intermediates that can undergo facile and selective aldol addition reactions and Ireland—Claisen rearrangements to provide products with multiple contiguous stereocenters and quaternary carbon centers.

By applying this methodology to enantiomerically pure esters, products containing chiral quaternary carbon centers have been accessed, and the total synthesis of (+)-5-epi-acetomycin has been achieved. xi Chapter One: Silylene Transfer to Carbonyl-Containing Compounds Over the past 30 years, the reaction of silylenes (R2Si) with carbonyl compounds has been studied extensively. While several examples of stable silylenes exist, they are typically transient species that can be generated by thermolysis, photolysis, or metal- catalysis. Silylenes can react with the carbon-oxygen double bond of aldehydes, ketones, and esters to provide oxasilacyclopropane and silacarbonyl ylide intermediates.

These reactive compounds can undergo further transformations to provide cyclic siloxane and silyl enol ether products. The reactions of silylenes with carbonyl compounds often require harsh conditions or a large excess of carbonyl substrates, which restrict the synthetic utility of these transformations. Two examples of isolated oxasilacyclopropane products derived from silylene transfer to a ketone have been reported.'” Silylene transfer to hindered ketone 2 under photolytic conditions provided sterically encumbered oxasilacyclopropane 4, whose structure was confirmed by X-ray crystallography (eq 1)! Belzner and coworkers isolated oxasilacyclopropane 8 from the thermal silylene transfer reaction of cyclotrisilane 5 with adamantanone (eq 2).” The steric hindrance around the silicon atom and on the ketones stabilized the oxasilacyclopropanes and allowed for their isolation. Me Me Me Me Me,Si7~ Mes Cre Mes°" 61% ie] Me3Si.Mes + hv Mes.’ Theoretical calculations also support the formation of an oxasilacyclopropane from an initially-formed silacarbonyl ylide.*° Me Me Me Me hy (>460 nm) Me Me MesSi.Mes + 0 hv _ ora SiMes2 (3) Me3Si~~ “Mes (254 nm) $ 82) ny (254 nm) Ò \ Mẹ Me me Me Me Me 2 9 4 Several reactions of oxasilacyclopropane 4 have been demonstrated, but are of limited synthetic utility.”* Photolysis of oxasilacyclopropane 4 in the presence of tetracyanoethylene (a known electron-transfer reagent) provided indene 12 and silanediol 13 as the major products (eq 4).

Carbene 10 and silanone 11 were proposed as intermediates in the reaction. A 1,2-methyl migration in carbene 10 would explain the formation of product 12. A different fragmentation pattern was observed when oxasilacyclopropane 4 was photolyzed in the presence of methanol. Under these reaction conditions, methanolysis product 14 was obtained in addition to ketone 2 (Scheme 1).

When oxasilacyclopropane 4 was photolyzed in the presence of adamantanone, dioxasilacyclopentane 15 was isolated (Scheme 1). Ando and coworkers proposed that a free silylene (3) was liberated from oxasilacyclopropane 4 upon photolysis and this intermediate reacted further with MeOH or adamantanone. The formation of siloxane 15 can be explained by the formation of a new adamantanone-derived oxasilacyclopropane (similar to oxasilacyclopropane 8), which undergoes an insertion of a second ketone molecule. Me Me Me Me Me Me h pMe@;, iW_ HạO : + Mes,Si=O _> [ ) Me + Mes2Si(OH), (4) 0 Me NC.

CN —< Me 1 13 Me NC’ ‘CN Me 40 Me 12 Scheme 1 Me Me Me Me MeOH Mes SiMesy hv Mes | T7 6) pi Me Mes Me Me Me 3 4 2 ò 0 Hô) Si-Mes Oo" Mes 15 Silylene transfer from a variety of silylene sources to sterically hindered or non- enolizable ketones also provided cyclic siloxane products.