ASYMMETRIC SYNTHESIS OF SILANEDIOL INHIBITORS FOR ACE, FXIa, AND CHYMASE A Dissertation Submitted to the Temple University Graduate Board In Partial Fulfillment of the Requirements for the Degree DOCTOR OF PHILOSOPHY by Hoan Quoc Duong May 2013 Examining Committee Members: Scott McN. Sieburth, Advisor, Department of Chemistry Franklin A. Davis, Committee Chair, Department of Chemistry Rodrigo B. Andrade, Department of Chemistry Kevin C. Cannon, Penn State University © Copyright 2013 By Hoan Quoc Duong All Rights Reserved ii ABSTRACT Dialkylsilanediols, a novel class of non-hydrolyzable analogues of the tetrahedral intermediate of amide hydrolysis, have been shown to be good inhibitors of the HIV-1 protease, angiotensin converting enzyme (ACE), thermolysin, and the serine protease α- chymotrypsin. Synthesis and biological evaluation of silanediols are therefore a priority in this research. Asymmetric intramolecular hydrosilylation (AIH) of allyl silyl ethers gives silafurans which can be used directly to make chiral β-silyl acids needed for the silanediol peptide mimics. Absolute configuration determination of AIH products remains a challenge. Proton nuclear magnetic resonance (1H NMR) of the Mosher ester derivative was used to confirm the absolute configuration. This has proven to be a simple method to determine the absolute configuration of silicon-containing primary carbinols. Dialkylsilanediols (1.52) are known as good inhibitors of angiotensin converting enzyme (ACE), with inhibition constants from 3.8 to 207 nM. However, the synthesis of these silandiol peptide mimics involved a long synthetic route. A short, asymmetric synthesis of silanediol ACE inhibitors was developed using asymmetric hydrosilylation and addition of a silyllithium to a sulfinimine, 8 linear steps with an 8% over all yield. Specific inhibitors of the FXIa protease could inhibit thrombosis without completely interrupting normal hemostasis, and prevent or minimize the risk of hemostasis complications. Based on the FXIa substrate, the design and synthesis of the first five guanidine-containing silanediol FXIa inhibitors was developed: Ac-Arg-[Si]- Ala-NHMe (4.15), Ac-Ala-Arg-[Si]-Ala-NHMe (4.16), Ac-Leu-Ala-Arg-[Si]-Ala-NHMe iii (4.17), Ac-Pro-Ala-Arg-[Si]-Ala-NHMe (4.18), and Ac-Arg-[Si]-Ala-Ala-NHMe (4.19). Synthesis of these targets was achieved using our newly developed silyllithium preparation and silyl dianion addition to the Davis sulfinimine, 11 linear steps, gave silanediol precursor 4.60 in 1.7% yield. Inhibition constant of the FXIa inhibitors was good in range of 76 - 980µM. Human heart chymase (HHC), a chymotrypsin-like serine protease present in the left ventricular tissues of the human heart, converts angiotensin I to angiotensin II, raising blood pressure. Although the physiological role of HHC has not been fully elucidated, it may be involved in various pathological states, particularly in cardiovascular diseases. Synthesis of silanediol inhibitors of HHC, therefore, may contribute to the understanding of its physiological functions and a better treatment for cardiovascular diseases. Synthesis of a silanediol chymase inhibitor has been investigated. iv ACKNOWLEDGEMENTS First of all, I would like to thank my research advisor, Dr. Scott Sieburth, for all the great guidance, support, extreme patience, and encouragement through the course of my research, especially at times when success seemed so far to me. I admire his professional spirit and enthusiasm for science, and I hope to carry it on in my future career. Also, I would like to thank my committee members, Dr. Franklin Davis, Dr. Rodrigo Andrade, and Dr. Kevin Cannon for their valuable time, comments and suggestions for this work. I also would like to thank Dr. Peter Walsh, Dr. Dipali Sinha and Dr. Wenman Wu at Temple Medical School gave valuable suggestions and screening the inhibition of silanediols for FXIa. I am also grateful to my teachers during these six years, especially Dr. Grant Krow, Dr. Kevin Cannon, Dr. DeBrosse, Dr. Williams and Dr. Andrade. I am deeply grateful to thank Prof. Robert J. Levis, Prof. Frank C. Spano, and Prof. Hai-Lung Dai for accepting my Ph.D application in 2007 and giving me a good chance to improve my skills at teaching and doing research at Temple University. I also thank for the help from the Dr. Sieburth group: Dr. Yingjian Bo, Dr. Swapnil Singh, Svitlana Kulyk, Cui Cao, Paul Finn, and Buddha Khatri. They give me a professional environment in the Sieburth’s group. Paul Finn has spent a lot of time on screening forty mass spectroscopy samples. I am also thankful to Dr. Serge Jasmin for his advice in my research. Thanks also go out to Qingquan Zhao, and Chongsong Xu in Dr. Chris Schafmeister’s group for their generous help in doing my LC-MS samples, Dr. Charles v DeBrosse’s support with NMR instrument and Dr. Shivaiah Vaddypally and Clifton Hamilton for X-ray analysis. Special thanks to Department of Chemistry and Dr. Alfred Findeisen and Dr. Lawlor for supporting me as a teaching assistant, and Shapiro Regina, Johnson Bobbi, Sharon Kass, Ford Jeanette for organizing all paper works for me when I need their help. I would like to extent my sincere thanks to my M.S. degree advisor, Prof. David P. Brown at St.john’s University who encouraged me apply to Ph.D program at Temple and gave me so many helpful backgroups for Ph.D program when I worked in his lab. I also would like to thank Prof. Victor Cesare, Prof. Alison G. Hyslop for their support when I did application for Ph.D program, and Prof. Gina M. Florio, Prof. Joseph M. Serafin and Prof. Enju Wang for helpful courses when I did M.S. degree at St.John’s University. I also would like to thank Dr. Hung P. Le and his family for their help when I was in New York. I would like to thank Hanoi National University of Education (HNUE), Chemistry Department and Organic division for patience when I did M.S. and Ph.D programs. I also would like to thank Prof. Dinh H. Nguyen, Prof. Nguyet M. Bui, Prof. Quang D. Bui, Prof. Oanh T. Dang, and Prof. Thu X. Dang for their supports. Finally, I would like to thank my parents, parents-in-law, sisters, sister-in-law and my brother for their loyal support, and generous love from my wife, son, and daughter. vi g{|á w|ááxÜàtà|ÉÇ |á wxw|vtàxw àÉ Åç ÑtÜxÇàá? á|áàxÜá? uÜÉà{xÜá? Åç ã|yx ?Åç áÉÇ? tÇw Åç wtâz{àxÜ yÉÜ à{x|Ü ÄÉäx? âÇwxÜáàtÇw|Çz tÇw áâÑÑÉÜàA vii TABLE OF CONTENTS ABSTRACT…………………………………………………………………………….iii ACKNOWLEDGEMENTS………………………………………………….…………v LIST OF FIGURES……………………………………………………………………xii LIST OF SCHEMES…………………………………………………………………...xv LIST OF TABLES…………………………………………………………………………xix LIST OF ABBREVIATIONS…………………………………………………………xxi CHAPTER 1: INTRODUCTION .................................................................................... 1 1.1 Silicon .................................................................................................................. 1 1.2 Silicon versus Carbon ......................................................................................... 1 1.3 Bioactive organosilicon compounds .................................................................. 6 1.3.1 Where do organosilanes come from? ............................................................ 7 1.3.2 Examples of bioactive organosilanes ............................................................ 7 1.4 Designed organosilane drugs ............................................................................. 9 1.4.1 Random screening ......................................................................................... 9 1.4.2 Drug design ................................................................................................. 10 1.5 Design and synthesis of silanediols as therapeutic peptidomimics .............. 16 1.5.1 Silanediol stability and silanol acidity ........................................................ 16 1.5.2 Design, synthesis of silanediols as therapeutic peptidomimics pioneered by the Sieburth group ..................................................................................................... 17 1.6 The original approach for silanediol protease inhibitor synthesis .............. 19 1.7 29Si Nuclear magnetic resonance (NMR) ....................................................... 22 viii CHAPTER 2: CATALYTIC ASYMMETRIC INTRAMOLECULAR HYDROSILYLATION OF SILYL ETHERS .............................................................. 24 2.1 Introduction ...................................................................................................... 24 2.2 Asymmetric intramolecular hydrosilylation (AIH) of allyl silyl ethers ...... 24 2.2.1 Introduction ................................................................................................. 24 2.2.2 Improved AIH of allyl silyl ethers .............................................................. 26 2.3 Results and discussion ...................................................................................... 28 2.3.1 Synthesis of oxygen-containing allylic alcohols ......................................... 28 2.3.2 Determination of absolute configuration .................................................... 35 CHAPTER 3: A SHORT, ASYMMETRIC SYNTHESIS OF SILANEDIOL INHIBITORS OF ANGIOTENSIN-CONVERTING ENZYME (ACE) ................... 43 3.1 Introduction ...................................................................................................... 43 3.2 Four silanediol ACE inhibitors ....................................................................... 43 3.2.1 Retrosynthesis