Strategies for the Synthesis and Use of Β-Stereogenic Α

STRATEGIES FOR THE SYNTHESIS AND USE OF -STEREOGENIC -KETO ESTERS Kimberly Michelle Steward A dissertation submitted to the faculty of the University of North Carolina at Chapel Hill in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Department of Chemistry. Chapel Hill 2012 Approved by: Jeffrey S. Johnson Maurice S. Brookhart Erik J. Alexanian Michel R. Gagné Valerie S. Ashby © 2012 Kimberly Michelle Steward ALL RIGHTS RESERVED ii ABSTRACT KIMBERLY MICHELLE STEWARD: Strategies for the Synthesis and Use of -Stereogenic -Keto Esters (Under the direction of Jeffrey S. Johnson) I. Extant Methods for the Preparation of -Keto Esters An overview of the synthetic methods to prepare -keto esters is presented, with a particular focus on strategies to incorporate a stereocenter at the -position. II. Catalytic Nucleophilic Glyoxylation of Aldehydes The synthesis of -silyloxy -keto esters via a cyanide catalyzed benzoin-type reaction with silyl glyoxylates and aldehydes is described. Critical to the success of the i reaction was identifying Yb(O Pr)3 and acetone cyanohydrin as a mild source of cyanide to prevent isomerization of the products to the corresponding -silyloxy -keto esters. Several secondary transformations add to the utility to the -keto ester products. Of the methods available to prepare -hydroxy -keto acid derivatives, this method provides the most direct route and displays the broadest substrate scope. iii III. Asymmetric Synthesis of -Keto Esters via Cu(II)-Catalyzed Aerobic Deacylation of Acetoacetate Alkylation Products A simple and efficient method for the preparation of -stereogenic -keto esters is described using a copper(II)-catalyzed aerobic deacylation of substituted acetoacetate esters. The substrates for the title process arise from catalytic, enantioselective conjugate addition and alkylation reactions of acetoacetate esters. The mild conditions do not induce racemization of the incipient enolizable -keto ester. The reaction is tolerant of a number esters, certain ketones, ketals and nitro groups and establishes synthetic equivalency between acetoacetate esters and the glyoxylate anion synthon. IV. Dynamic Kinetic Resolution of -Keto Esters via Asymmetric Transfer Hydrogenation The development of the first highly selective dynamic kinetic resolution of - stereogenic -keto esters via asymmetric transfer hydrogenation using a newly designed (arene)Ru(monosulfonamide) catalyst is described. For substrates incorporating a diester at the -postion, spontaneous lactonization of the nascent -hydroxyl group onto the pendant ester occurs to provide trisubstituted -butyrolactones with complete diastereocontrol. iv Extension of this method to -substituted -diketo esters results in chemoselective dynamic reduction of the -keto ester providing highly enriched -keto -hydroxy esters. v ACKNOWLEDGEMENTS First and foremost, I would like to express my deepest gratitude to my advisor, Professor Jeffrey Johnson, for his guidance and support throughout my graduate career. I consider it a privilege to have worked under his tutelage and have come to realize that having an advisor as patient, respectful, and humble as Jeff is a rarity. His genuine enthusiasm for chemistry and continuous flow of ideas and suggestions for the synthetic hurdles I have encountered over the years has been an incredible source of motivation for me. I have always appreciated Jeff’s open-door policy and willingness to entertain any idea, no matter how misguided, that I have had; I sincerely value all of our “teaching moments”. As I matured as a chemist, Jeff granted me the freedom to independently explore my ideas, which has taught me to read and think critically about the literature and to always seek the most straightforward and simple solutions. In addition to supporting my intellectual development, Jeff has also nurtured my leadership capabilities. I am honored that he trusted me to make sure it was business as usual in the Johnson lab while he was on sabbatical. The value of an advisor as encouraging and supportive as Jeff cannot be overstated. I would like to thank Professors Michel Gagné, Erik Alexanian, Valerie Ashby, and Maurice Brookhart for serving on my final defense committee, as well as Joe Templeton for serving on my preliminary defense committee. I have had the privilege of working with a talented and ambitious group of people over the years for which there was never a dull day. For always providing a positive and scientific engaging work environment, I would like to thank former and current group members: Shanina Sanders, Matthew Campbell, Andrew Satterfield, Stephen Greszler, Chris Tarr, Andrew Parsons, Austin Smith, Mike Slade, Dan Schmitt, Greg Boyce, Justin Malinowski, Michael Corbett, Dung Do, Ryan vi Carris, Scott Krabbe, Robert Sharp and Guy Goodman. I particularly would like to thank Shanina, Matthew and Steve for making my transition into the Johnson group a “smooth operation”. I also extend thanks to Emily Gentry, my undergraduate colleague, and Guy Goodman who were instrumental in completing the two DKR projects. And finally I would like to thank Michael Corbett, aka “Bump Master C”, for daily intellectual conversations about chemistry. I cannot extend enough gratitude and appreciation to my family and who has supported me and my academic endeavors over the years. I want to acknowledge my siblings, Andrea, Brandon, and Malynda, for always showing an interest in my research even though they didn’t always understand what I was working on. Enough cannot be said about the love and support I have received from my parents Denise and William Steward. They have always done everything in their power and have made selfless sacrifices to help me achieve my goals. I would not have made it this far without them. vii To my family and in loving memory of my grandmother Erma R. Durden (19312011) viii TABLE OF CONTENTS LIST OF TABLES ............................................................................................................................. xiii LIST OF FIGURES AND SCHEMES ............................................................................................ xiv LIST OF ABBREVIATIONS AND SYMBOLS ............................................................................ xvii CHAPTER 1 EXTANT METHODS FOR THE PREPARATION OF -KETO ESTERS ......................................................................................... 1 1.1 Introduction .................................................................................................................. 1 1.2 Synthetic Strategies for the Preparation of Achiral -Keto Esters ............................... 3 1.2.1 Oxalic Acid Derivatives ............................................................................................... 3 1.2.2 Acylation Reactions ..................................................................................................... 4 1.2.2.1 Umpolung Reagents ........................................................................................ 4 1.2.2.2 Pummerer Rearrangement ............................................................................... 6 1.2.2.3 Divergent Reactivity of Ethyl Cyanoformate .................................................. 6 1.2.2 PEP Equivalents ........................................................................................................... 7 1.3 Synthetic Strategies for the Synthesis of -Stereogenic -Keto Esters 1.3.1 Racemic Methods ......................................................................................................... 9 1.3.2 Asymmetric Methods ................................................................................................. 12 1.3.2.1 Chiral Enolates .............................................................................................. 12 1.3.2.2 Asymmetric Claisen Rearrangement ............................................................. 15 1.3.2.3 Asymmetric Nucleophilic Glyoxylation ....................................................... 17 ix 1.4 Summary and Outlook................................................................................................ 20 References ............................................................................................................................................ 22 10 CHAPTER 2 CATALYTIC NUCLEOPHILIC GLYOXYLATION OF ALDEHYDESS ..................................................................................... 25 2.1 Introduction ................................................................................................................ 25 2.1.1 Umpolung Reactivity ................................................................................................. 25 2.1.2 Acyl Anion Catalysis.................................................................................................. 27 2.2 Background ................................................................................................................ 31 2.2.1 Development of Silyl Glyoxylates ............................................................................. 31 2.2.2 Origin of the Title Reaction ........................................................................................ 32 2.3 Results and Discussion ............................................................................................... 33 2.3.1 Identification of a Viable Nucleophilic Catalyst ........................................................ 33 2.3.2 Reaction Scope ..........................................................................................................

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