Luận án tiến sĩ tổng hợp sản phẩm tự nhiên - Nicole Goodwin Caltech

APPLICATION OF IMINIUM ACTIVATION TECHNOLOGIES TO NATURAL PRODUCT SYNTHESIS: Total Syntheses of the Spiculisporic Acids, Progress Towards the Total Synthesis of Cylindrocyclophane F, and Formal Synthesis of Cylindrocyclophane A. Thesis by Nicole Cathleen Goodwin In Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy California Institute of Technology Pasadena, California 2007 (Defended July 17, 2006) UMI Number: 3244117 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.

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ProQuest Information and Learning Company 300 North Zeeb Road P. Box 1346 Ann Arbor, MI 48106-1346 © 2007 Nicole Cathleen Goodwin All Rights Reserved Acknowledgements I am deeply indebted to my advisor, Dave MacMillan, for demanding the best from all of his graduate students, including myself. The work ethic, intelligence, and “normalness” of this group are first-rate and I have thoroughly enjoyed my past five years working with all of them. I feel lucky to have been given the chance to study at Caltech under Dave’s supervision, and ] cannot thank him enough for allowing me to be a part of the greatness that this group has achieved.

WhenI arrived in the group in June 2001, the first people I met were Profs. Tehshik Yoon and Vy Dong. Tehshik’s brutal honesty, cynicism, and sense of humor made me look forward to daily conversations with him. Vy is a wonderful, warm, funny, and caring person whom I am thankful to have met.

I look forward to seeing what their individual careers behold. For the first summer, I worked alongside JIIHIIMMMMMM Falsey. Jim is an amazing chemist who taught me everything from how to run a proper column to how leaning into one’s hood can diminish unwanted noises. I am very fortunate to count these people as colleagues and friends.

I had the opportunity to work with some of the finest people I could ask for. I would to now recognize the other half of Team Goodweiner: Dr. Jake Weiner, who had the courage to brave the direct route between the Hawaiian islands, get stuck on a reef (which is probably the reason we were forbidden from said route), yet still beat Team Korea to the finish line. Jake Weiner was always there when you needed him, unless he was playing football.

To Brian Kwan: BROILER!! You have always kept me in the dark when it came to your “secret life,” but I still consider you one of my favorite people. Sean Brown was the baymate I spent the most time with. Despite our having the same deficiency with our verbal abilities, I think we were quite the duo in bay 20B and I thank him for mentoring me in those early years. When it came to discussing the latest in entertainment gossip or sending out invaluable Sig Alerts in room 3, Dr.

Roxanne Kunz, Teresa Beeson, Casey Jones, Angie Olsen, and Dr. Nina Gommermann provided the right amount of necessary relief. Sandy Lee is one of those people who just make you feel better by being in their presence. She is inexplicably funny, incredible at making faces, and one of my favorite people.

Katie Saliba is one of the most selfless, generous, and caring individuals that I have ever had the privilege to call my friend. I hope our story does not end here, and seriously Katie, get some sleep. Kate Ashton also just makes me smile. She is warm, funny, and a great friend, plus she is Mieka’s second mommy.

Simon Blakey, the other half of Team Nickel, provided much wisdom on metals and played terrible music in the glovebox. I am glad I got to work with him. Not only are Rob Knowles and Dr. Alan Northrup walking, talking Evans notes, but they are enthusiastic chemists and good, down- to-earth people who have been invaluable in my graduate experience.

Rob “DOUGLAS” Moncure has always provided laughter and entertainment, and I truly think he should focus his efforts on becoming the next office linebacker. Abbas Walji and Young Chen have provided much entertainment and wisdom — I will leave the geographical jokes to their imagination. Jamie Tuttle is acknowledged for his unwavering optimism and his ability to brighten my day by just hearing him laugh. Joel Austin and Chris Borths both have huge hearts and a keen yet often misunderstood sense of humor (Grab-your- baymate’s-ass Friday) — you never knew what to expect! Dr.

lan Mangion and I constitute the only class to have a 100% retention rate. He’s the only one who has been there side-by- side with me for five years, and Ian’s wit and humor are one of a kind. Although she did not occupy a space in the basement of Church, I managed to see Dian Buchness more than I probably should have. She is a wonderful, caring person around whom the graduate chemistry world revolves.

I would have been a mess without you! To my ladies in the DMac lab: Dr. Nadine Bremeyer, Diane Carrera, Teresa, Dr. Maud Reiter, Casey, Kate, and Sandy, the best part about moving to Princeton is that I do not have to say goodbye to most of you. Thank you for making the past year so much fun! I whole-heartedly need to thank Sandy Lee, Dr.

Kate Ashton, Dr. Greg Beutner, Katie Saliba, Dr. Abbas Walji, and Rob Knowles for editing this thesis and other manuscripts. To my previous mentors at the University of Delaware: Profs.

Burnaby Munson, John Burmeister, and Douglass Taber. I am where I am today because you made learning y at UD the best experience of my life. A student can only hope to have professors like you cross their path. I value our friendships and look forward to seeing you in Newark again in the near future.

I would like to thank my thesis committee for their invaluable time and advice: Profs. Jackie Barton, Linda Hsieh- Wilson, and Dennis Dougherty. Dennis and Jackie — I cannot thank you enough for your support throughout the years, you are number one in my book! I would also like to thank Prof. Bob Grubbs for just stopping to ask the normal things, like “how are you?” and “how is your day?”— it made me feel like less of a little fish in a really smart pool.

To Pete Kekenes-Huskey: I have no words to describe the past 3.5+ years so you at least get your own paragraph. We’ve been through a lot, and I know that I couldn’t have made it without you. I hope that I have done the same for you. You are my best friend and I look forward to seeing what happens next.

I would like to thank my family for being there for the past five years. Just knowing that I could call for anything was truly a gift. Dad always listens to my chemistry and gives me advice on working in the real world, and Jamie has patiently taken my phone calls when I think I am ailing of something. My “little” brothers are adorable and I know they will always be there to protect me.

I am so proud of you guys! I would like to acknowledge my Nana and my late Grumps for allowing me a spare room in their house in Ventura whenever I wanted — I wish I got to use it more often! They live life they way we should all aspire to: travel the world, do everything first class, and end the day with a glass of champagne! Finally, I would like to thank my mother. Without her constant selflessness, love, and support, I would not be half the person that I am today. She has supported me 100% in whatever path I wanted to take, even when it took me 2800 miles away. I hope that I have made her proud, and thank her for everything she has done for me.

I also would like to thank her for sending presents of candy and cookies to the lab — it brightened our days and gave us cavities. I dedicate this work and everything that I have ever accomplished to her. ABSTRACT The first enantioselective, catalytic vinylogous Mukaiyama-Michael reaction of siloxyfurans with simple œ,Ð-unsaturated aldehydes has been reported using chiral imidazolidinones. This methodology provides access to enantioenriched y-butenolides, a privileged motif in organic synthesis.

The utility of this organocatalytic Mukaiyama- Michael reaction was highlighted by the total syntheses of (—)-spiculisporic acid and (—)-5- epi-spiculisporic acid. Investigations into the total syntheses of cylindrocyclophanes A and F necessitated the development of a novel B-alkyl Suzuki cross-coupling of trimethylanilinium salts using a nickel(0) catalyst and bulky phosphine ligand. This methodology study revealed a very competitive nickel-catalyzed demethylation pathway, which produced dimethylaniline byproducts. A possible explanation for this side reaction is discussed.

This technology was applied to a dimerization strategy for the C2-symmetric cylindrocyclophane F. Synthesis of a dimerization precursor included an enantioselective organocatalytic 1,4- addition of 3,5-dimethoxy-N,N-dimethylaniline into an a,f-unsaturated aldehyde. However, the B-alkyl Suzuki cross-coupling was unsuccessful in promoting a dimerization. Next, the synthesis of cylindrocyclophane A was explored using an alternative ring- closing metathesis dimerization strategy.

A dimerization precursor was to be assembled via the cross-coupling of trimethylanilinium salts with potassium (vinyl)trifluoroborate salts, whose syntheses featured an organocatalytic 1,4-conjugate reduction of a ÿ,B- disubstituted enal. This cross-coupling strategy revealed olefin isomerization as a major vũ side-reaction in the nickel-catalyzed Suzuki dimerization, making this route a non- productive approach to the natural product. Lastly, formal synthesis of cylindrocyclophane A was accomplished using (i) a nickel-catalyzed Stille cross-coupling of an activated vinyl stannane with a judiciously chosen trimethylanilinium salt and (ii) an asymmetric palladium-catalyzed allylic alkylation of an acyclic ketone. The latter represents the first example of application of the Pd,(dba);3/t-Bu-PHOX catalyst system to effect an asymmetric allylic alkylation on an acyclic system with good stereoselectivity.

This route constituted a formal synthesis of cyclindrocyclophane A in eight linear steps, making it more efficient than the published route to the same advanced intermediate reported by Smith, which was synthesized in eleven steps. Table of Contents AcknowledgỹemmerI§.-- -- c HH HH HH Hee 1V 0¬ 120 1 —. vi Table of 6o.4 Vili List Of SCHEMES 0. xii List Of FÏBUF€S.

nh HT TT TT TT kg XIV List Of k:I)- —. XVili List Of „(002 /0i). XX Chapter 1: Enantioselective LUMO-Lowering Organocatalysis. set Ha HH KH ng HT HH HH1 11111111111101010111” 1 II.

A General Approach to Enantioselective LUMO-lowering catalysis. 5 i, Chiral imidazolidinones as privileged organocataÌysfS. Summary of Thesis Researchh.‹ có ch HH HH HH 101 re. 10 Chapter 2: Total Syntheses of the Spiculisporic Acids: Exploitation of the Organocatalytic Vinylogous Mukaiyama-Michael Addition.

HH HH HH Hà TH HT HH 90001111 11 1. y-Butanolide archIt€CfUT©.- HH HH ng ng 1á n0 01110111101 11 ii. The Mukaiyama-Michael reactiOI. hàn HH HH HH ke 15 iii.

Mukaiyama-Aldol versus Mukaiyama-Michael addition. Organocatalytic Vinylogous Mukaiyama-Michael Reaction. cuc HH HH gà Hà HH Hàng 19 ii. Scope of the organocatalytic Mukaiyama-Michael reaction.

Total Syntheses of the Spiculisporic Aclds. ch th Hà o42010131111111141411711171110110. Investigation of key organocatalytic Mukaiyama-Michael reaction. Completion of 5-epi-spiculisporic aCÍd.

cong Hiên 30 iv. Reassessment of the organocatalytic step. Completion of spiculisporic aCÍ. chưngeo 34 IV.

Proposed Explanation for the Change in DiastereoselectiVify. Approach of the nucleophile onto the iminium system. Mukaiyama-Michael into methyl-4-oxobutenoafe. Mukaiyama-Michael into /er/-butyl-4-oxobutenoate.

Mukaiyama-Michael into crotonaldehyde. Another transition state considerafÏO.- «HH ào 42 ConcluSÏON. tt H11 10 1010110111110 43 Supporting InforrmafÏO'.