CORE Metadata, citation and similar papers at core.ac.uk Provided by University of Saskatchewan's Research Archive ALDOL COUPLINGS OF CHIRAL FRAGMENTS WITH KINETIC RESOLUTION: SCOPE AND LIMITATIONS A thesis submitted to the College of Graduate Studies and Research in partial fulfillment of the requirements for the degree of Master of Science in the Department of Chemistry University of Saskatchewan Saskatoon by Alieh Kazemeini © Copyright Alieh Kazemeini December, 2011. All rights reserved. Permission to Use In presenting this thesis in partial fulfillment of the requirements for a Postgraduate degree from the University of Saskatchewan, I agree that the Libraries of this University may make this thesis freely available for inspection. I further agree that permission for copying of this thesis in any manner, in whole or in part, for scholarly purposes may be granted by the professor or professors who supervised the thesis work, or in their absence, by the Head of the Department, or the Dean of the College in which the thesis work was done. It is understood that any copying or publication or use of this thesis or parts thereof for financial gain shall not be allowed without my written permission. It is also understood that due recognition will be given to me and to the University of Saskatchewan in any scholarly use which may be made of any material in this thesis. Requests for permission to copy or to make other use of material in this thesis in whole or in part should be addressed to: The Head Department of Chemistry University of Saskatchewan 110 Science Place Saskatoon, SK S7N 5C9 CANADA i Acknowledgements First of all, I would like to express my deepest and greatest gratitude to my supervisor, Dr. Dale Ward for his continuous support, valuable suggestions and especially constructive discussions during these years. I am very much grateful to Dr. Michel Gravel for his comments and discussion during our joint group meetings where I have learned many different things and broadened my knowledge of organic chemistry. I would like to express my appreciation to Dr. Marek Majewski and Dr. Jens Mueller for giving nice courses; the instructions given during these courses were very valuable and really improved my chemistry knowledge and skills. I would like to thank the Department of Chemistry and the University of Saskatchewan for the opportunity to pursue my education in Saskatchewan. In particular, I am very grateful to Dr. David Palmer, Head of the Department of Chemistry and Dr. Ron Steer for their great support. My cordial appreciation goes also to the rest of academic and support staff including: Ms. Cathy Surtees, Mr. Dwight Reynaud, Dr. Keith Brown, Dr. Alexandra Bartole- Scott, Dr. Pia Wennek, Mr. Ken Thoms, Mr. Devin Beaudoin, Mr. Rick Elvin and Mr. Garth Parry. I would like to express my sincere gratitude to the past and current Ward group members: Ms. Nikki Theaker, Dr. Garrison Beye, Dr. Marcelo Sales, Mr. Pramod Jadhav, Mr. Yasu Miyazaki, Mr. Athanasios (Thano) Karagiannis, Ms. Fabiola Becerril- Jiménez, Mr. Muxi Cheng, Mr. Zhou Yuan (Jackie) Lu and Mr. Mojtaba Biniaz. I am grateful to my friends: Ms. Janice Holmes, Mr. Myron Wilde, Mr. Li Wang, Mr. Sida Zhou, Mr. Khalil Delawarally, Ms. Amanda Oberhofer and Ms. Jaclyn O'Brien. I thank you all for your friendly company. I wish to sincerely thank Ms. Yulia Skovpen one of my best friends at Saskatoon for being always ready to help. Now I get to the point to thank my family, my very special ones, for their continuous support as early as I have known myself until now and forever. I have been treating with love, care and unsparing support in entire my life. I just want to announce that I owe my family all I have. My devoted mother: I will never forget your constant care. When I look back I can not find even one second in my life without your love, care and support. It was you who taught me my first steps, answered my first questions and corrected my first wrongs. You spent your entire life for me and I cannot do but saying thanks. What I have is indeed because of your endless love. My father: You are the most hopeful man I have ever seen! Thank you for all your support and inspiration. My older brothers Hamed and Hesam: Thanks for your continuous help and support. Thanks for making my life path easier to continue. My younger brother Hossein, Poor guy! You always listen to my orders as your older sister!! It is now time to thank you for being so kind to me, for helping me whenever I needed. I am really proud of you all and I feel fortunate for having you. ii Table of Contents Permission to Use ................................................................................................... i Acknowledgements.............................................................................................. ii Table of Contents ................................................................................................. iii Abstract .................................................................................................................... v List of Tables ....................................................................................................... viii List of Figures ....................................................................................................... ix List of Schemes ....................................................................................................... x List of Abbreviations ......................................................................................... xii 1. INTRODUCTION ............................................................................................. 1 1.1. Polypropionates ........................................................................................................ 1 1.2. The thiopyran route to polypropionate ............................................................. 2 1.2.1. Overview .............................................................................................................................. 2 1.2.2. First aldol reaction: the tetrapropionate synthon ................................. 4 1.2.3. Second aldol reaction : the hexapropionate synthon ........................... 5 1.3. Stereoselectivity in the second aldol reaction: stereocontrol elements of the aldol reaction .............................................................................................................. 7 1.3.1. Relative topicity of the aldol coupling: aldol reaction of an achiral enolate with an achiral aldehyde ......................................................................................... 7 1.3.2. Diastereofacial selectivity of the enolate: aldol reaction of a chiral enolate with an achiral aldehyde ........................................................................ 11 1.3.3. Diastereofacial selectivity of the aldehyde: aldol reaction of an achiral enolate with a chiral aldehyde ........................................................................... 13 1.4. Stereoselectivity in the aldol reaction with kinetic resolution .................. 18 1.4.1. Double stereodifferentiation and mutual kinetic enantioselection in the aldol reaction: aldol reaction of a chiral enolate with a chiral aldehyde .............................................................................................................................................. 18 1.4.2. Multiplicativity rule in the aldol reaction .................................................. 22 1.4.3. Rational design of aldol reactions with kinetic resolution ............. 30 iii 2. RESULTS AND DISCUSSION ....................................................................... 37 2.1. Research objectives ................................................................................................ 37 2.2. Synthesis of starting materials ............................................................................ 39 2.3. The diastereoselectivity of the aldol reaction of 8ss with aldehydes 7a-g .............................................................................................................................................. 44 2.3.1. Anti -selective relative topicity with boron enolates ........................... 44 2.3.2. Syn -selective relative topicity with titanium "ate" enolates .......... 50 2.3.3. MKE and KR from the aldol reactions of (±)-8ss (R = MOM or Et 3Si) with aldehyde (±)-7f and (±)-7h ........................................................................... 55 2.3.4. Summary of results for boron and titanium "ate" mediated reactions (±)-8ss (R = MOM or Et 3Si) with aldehydes (±)-7a-g ...................... 58 2.4. Structure determination of aldol adducts 72 and 73 .................................... 63 2.4.1. Determination of the relative configurations of aldol adducts 72b and 73b ...................................................................................................................................... 63 2.4.2. Determination of the relative configurations of aldol adducts 72c and 73c ................................................................................................................................................. 65 2.4.3. Determination of the relative configurations of aldol adducts 72d and 73d ...................................................................................................................................... 67 2.4.4. Determination of the relative configurations of aldol adducts 72e and 73e ......................................................................................................................................