The Development of Brønsted Acid Catalysis Technologies and Mechanistic Investigations Therein Thesis by Diane Elizabeth Carrera In Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy California Institute of Technology Pasadena, California 2009 (Defended 4 September 2009) ii 2009 Diane Elizabeth Carrera All Rights Reserved iii Acknowledgements First and foremost I need to thank my research advisor, Prof. David MacMillan, for giving me the opportunity to work for him and surrounding me with fellow researchers of the highest caliber. Under his mentorship I have gained a true appreciation for the challenges and rewards inherent in studying organic chemistry and, most importantly, the perspective necessary to push the boundaries of what can be achieved by always thinking big. I would also like to thank the other members of my committee, Professors Jackie Barton, Brian Stoltz, and Peter Dervan for graciously giving their time and thought to my graduate studies as well as dealing with the additional hassles of scheduling exams from three thousand miles away. Without the support staff at both Princeton and Caltech it would have been impossible to do what is written in these pages, so it is with heartfelt appreciation that I thank Dian Buchness, Agnes Tong, Mona Shahgoli, Kim Faulkner, Joe Drew, Caroline Phillips, Istvan Pelczer, Phil Fairall, Kevin Wilkes and Vicky Lloyd. I would also like to thank Allan Watson, Ester Lee and Andrew Dilger for sacrificing their time in the proofreading of this manuscript as well as Hahn Kim, Jeff Van Humbeck, Mark Vanderwal, Spencer Jones and Joe Carpenter for doing the same for my proposals. To the MacMillan groups members past and present, you have all made these past years as enjoyable as they could possibly be and I will miss the camaraderie and friendships that I’ve made during my time in the group. In particular, I need to thank the original MacMillan ladies Nikki Goodwin, Sandra Lee, Kate Ashton, Nadine Bremeyer, Maud Reiter, Catherine Larsen, Casey Jones and Teresa Beeson, without whom life both in and outside of lab would not have been nearly as enjoyable. I could not in good faith iv complete these sentiments without also recognizing the members of Bay Awesome, which has been, without a doubt, the best place I can think of to spend ridiculous amounts of time storytelling, debating, and even doing chemistry. I’m especially going to miss my baymate of the past two years, David Nagib, whose constant smile and positive attitude have lifted my spirits on many occasions. I would like to end these notes with a final thank you to the most important people in my life without whom I would never have achieved half of what I have today. To my mom Sarah, no one could has served as a better inspiration and I hope you realize that everything I have accomplished can be attributed directly to you. To my father Carl and stepmother Cheryl, your love and support has served as a true haven for me and helped me to weather the ups and downs of these past few years. To Kate and James, now that we’re old enough not to fight about who sits in the middle, I count myself lucky to be able to call you my family. Finally, I dedicate this thesis to the memory of my grandparents whose love and pride in my accomplishments remain with me to this day. v ABSTRACT The enantioselective reductive amination of ketones with Hantzsch ester has been achieved through Brønsted acid catalysis. A novel triphenylsilyl substituted BINOL- derived phosphoric acid catalyst has been developed for this transformation, imparting high levels of selectivity when used with methyl ketones and aromatic amines. A stereochemical model for the observed selectivity based on torsional effects has been developed through molecular modeling and is further supported by a single crystal x-ray structure of an imine-catalyst complex. Mechanistic studies have revealed the importance of catalyst buffering and drying agent on reaction efficiency while a Hammett analysis of acetophenone derivatives offers insight into the key factors involved in the enantiodetermining step. Kinetic studies have shown that imine reduction is rate-determining and follows Michaelis-Menten kinetics. Determination of the Eyring parameters for the imine reduction has also been accomplished and suggests that the phosphoric acid catalyst behaves in a bifunctional manner by activating both the imine electrophile and the Hantzsch ester nucleophile. The intermolecular addition of vinyl, aromatic, and heteroaromatic potassium trifluoroborate salts to non-activating imines and enamines can also be accomplished through Brønsted acid activation. This analog of the Petasis reaction shows a wide substrate scope and is amenable to use with a variety of carbamate protected nitrogen electrophiles in the first example of metal-free 1,2-additions of trifluoroborate nucleophiles. The mechanistic underpinnings of benzyl trifluoroborate addition has also been explored and, in contrast to what is seen with π-nucleophilic species, appears to proceed through a intramolecular alkyl-transfer mechanism. vi Table of Contents Acknowledgements..............................................................................................iii Abstract................................................................................................................ v Table of Contents................................................................................................. vi List of Schemes .................................................................................................. vii List of Figures...................................................................................................... ix List of Tables....................................................................................................... xi List of Abbreviations.......................................................................................... xiii Chapter 1: Stereogenic Amines: Biological Importance and Synthesis I. Introduction................................................................................................................ 1 II. Asymmetric Imine Reduction ................................................................................... 3 III. Asymmetric Reductive Amination............................................................................ 5 Chapter 2: Development of a Novel Phosphoric Acid Catalyzed Asymmetric Organocatalytic Reductive Amination of Ketones I. Organocatalytic Activation Modes ......................................................................... 10 II. Hydrogen Bonding Catalysis .................................................................................. 12 III. Organocatalytic Imine Reduction ........................................................................... 15 IV. Asymmetric Organocatalytic Reductive Amination............................................... 20 V. Conclusion............................................................................................................... 28 Supporting Information.................................................................................................. 30 Chapter 3: Kinetic and Mechanistic Studies of the Brønsted Acid Catalyzed Enantioselective Reductive Amination I. Limitations in the Ketone Reductive Amination.................................................. 79 v ii II. Inhibition Studies .................................................................................................. 82 III. Hammett Study...................................................................................................... 84 IV. Crystal Structure.................................................................................................... 84 V. Role of Drying Agent............................................................................................ 87 VI. Reaction Kinetics .................................................................................................. 90 VII. Eyring Activation Parameters............................................................................... 94 VII. Conclusion ............................................................................................................ 96 Supporting Information................................................................................................... 98 Chapter 4: Development of an Acid Promoted Addition of Organotrifluoroborates to Non-Activating Electrophiles I. Introduction .......................................................................................................... 127 II. Development of an Organotrifluoroborate Petasis Reaction............................... 130 III. Investigations into reaction mechanism............................................................... 135 IV. Enantioselective induction ................................................................................... 138 V. Conclusion............................................................................................................... 143 Supporting Information................................................................................................ 144 v iii List of Schemes Chapter 1: Stereogenic Amines: Biological Importance and Synthesis Number Page 1. Reductive amination of an amine and a carbonyl compound ..................................................... 2 2. The first reported catalytic asymmetric reductive amination...................................................... 5 3. Asymmetric