ASYMMETRIC SYNTHESIS OF C-1 SUBSTITUTED COCAINE ANALOGUES USING SULFINIMINE (N-SULFINYL IMINE) CHEMISTRY AND VINYLALUMINUM ADDITION TO SULFINIMINES (N-SULFINYL IMINES) FOR THE ASYMMETRIC SYNTHESIS OF α-SUBSTITUTED-β-AMINO ESTERS A Dissertation Submitted to the Temple University Graduate Board In Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy By Narendra Varma Gaddiraju On August 2013 Examining Committee Members Dr. Franklin A. Davis, Research Advisor, Department of Chemistry Dr. Rodrigo B. Andrade, Committee Chair, Department of Chemistry Dr. William M. Wuest, Committee Member, Department of Chemistry Dr. Kevin C. Cannon, External Committee Member, Department of Chemistry, Penn State Abington i DEDICATION This dissertation is dedicated to My mother Ramasita Gadhiraju My brother Surender Varma Gadhiraju And To my friends Naresh Theddu and Lan Nguyen Theddu ii ABSTRACT ASYMMETRIC SYNTHESIS OF C-1 SUBSTITUTED COCAINE ANALOGUES USING SULFINIMINE (N-SULFINYL IMINE) CHEMISTRY AND VINYLALUMINUM ADDITION TO SULFINIMINES (N-SULFINYL IMINES) FOR THE ASYMMETRIC SYNTHESIS OF α-SUBSTITUTED- β-AMINO ESTERS Narendra Varma Gaddiraju Doctor of Philosophy Temple University, 2013 Organic nitrogen containing chiral compounds are widely found in nature, and a number of them exhibit important biological and medicinal properties. The main objective of this research is to develop new methods for the asymmetric synthesis of cocaine analogues having methyl (Me), ethyl (Et), n-propyl (n-Pr), n-pentyl (n-C5H11) and phenyl (Ph) groups at the C-1 bridgehead position. The second project concerned the asymmetric synthesis of anti-α-alkyl substituted β-amino esters, a new chiral building block, utilizing chiral sulfinimine (N-sulfinyl imine) chemistry. The easy availability and abuse of (R)-(-)-cocaine is a global problem and has resulted in many efforts aimed at the preparation of therapeutically useful cocaine analogues. However, to iii date analogues of cocaine for the treatment of cocaine addiction have not been reported. The requirement of a cis relationship between C-2 and C-3 substituents in the cocaine tropane skeleton where C-2 carbomethoxy group occupies the thermodynamically unfavorable axial position is the main reason for the difficulty in designing efficient asymmetric syntheses of cocaine analogues. In this study, diastereomerically pure N-sulfinyl β-amino esters were prepared by the addition of the sodium enolate of methyl acetate to masked oxo sulfinimines, novel sulfinimines having a protected carbonyl group. Reduction of the β-amino esters gave the corresponding β- amino aldehydes and a Roush-Masamune modified Horner-Wadsworth-Emmons (HWE) reaction afforded the trans-N-sulfinyl α,β-unsaturated δ-amino esters in good yield. Acid hydrolysis of the esters unmasked the carbonyl group and deprotected the amines resulting in an intramolecular cyclization to produce the key dehydropyrrolidines. Regioselective oxidation of the dehydropyrrolidines using catalytic methyl trioxorhenium and urea-hydrogen peroxide gave the corresponding pyrrolidine nitrones in excellent yield. On heating with the Lewis acid catalyst Al(O-t-Bu)3 the nitrones underwent a novel, stereospecific, intramolecular [3+2] cycloaddition reaction to give tricyclic isoxazolidines. Importantly, the isoxazolidine establishes the necessary cis relationship between C-2 and C-3 substituents in cocaine skeleton. The tricyclic isoxazolidines were readily converted to the N-Me quaternary ammonium salts on heating with methylmethanesulfonate and hydrogenolysis with Pd/C at 1 atm of H2 cleaved the N-O bond to afford the ecgonine methyl ester, the tropane alcohol. In contrast to other C-3 (R = Me, Et, n-Pr, Ph) isoxazolidine quaternary ammonium salts, the C-3 n-C5H11 analogue did not undergo N-O bond cleavage under the hydrogenolysis conditions. This analogue rearranged to a bridged bicyclic [4.2.1]isoxazolidine. It was found iv that all C-3 isoxazolidine N-Me quaternary ammonium salts undergo this rearrangement on treatment with triethylamine. Fortunately, hydrogenolysis of n-C5H11 isoxazolidine quaternary ammonium salt at 4 atm of H2 cleaved the N-O bond to give the desired alcohol, ecgonine methyl ester. Benzolylation of methyl ester of ecgonine alcohols afforded the C-1 substituted cocaine analogues in 75-95% yield. This new methodology, for the first time, afforded cocaine analogues having Me, Et, n-Pr, n-C5H11 and Ph groups at the C-1 position. In another study, new methodology was devised for the asymmetric synthesis of anti-α- alkyl-β-amino esters, valuable new chiral building blocks for the synthesis of β-amino acids β- lactams. The aza-Morita-Baylis-Hillman (aza-MBH) reaction of various vinylaluminum/NMO reagents with N-sulfinyl imines resulted in the formation of α-vinyl-β-amino esters in good yield and with 7:1 to 12:1 anti/syn selectivity. Addition of the aza-MBH reagent takes place from the least hindered direction via a nonchelation control mechanism. Hydrogenation of aza-Morita- Baylis-Hillman adducts using a cationic rhodium (I) catalyst gave anti-α-alkyl-β-amino esters in good yield and high dr (10:1) and is a useful new method for their preparation. The absolute configurations of the anti-α-alkyl-β-amino esters were established by the oxidation of the N- sulfinyl group to a tosylate with m-CPBA, hydrolysis with LiOH and cyclization to a -lactam of known absolute configuration. v ACKNOWLEDGEMENT Right from the first day, 20th August 2007, when I entered the United States of America, and Temple University, a great many number of people supported, advised and shaped me into the person I am today. I owe my gratitude and thank them all. To begin, I thank from the bottom of my heart, my research advisor Professor Franklin A. Davis. Both professionally and personally, he will inspire me for the rest of my life. Professionally, the Heterocyclic Chemistry and Sulfur Chemistry courses he taught and the discussions I had with him during the course of my research in his laboratory, in the group meetings and personally greatly changed my understanding of chemistry. On a personal level, he lifted my spirit up and helped me to come over difficulties I faced because of some un-wanted incidents happened. I will remember his humane qualities until my last day on the earth. I greatly appreciate my committee members Dr. Rodrigo B. Andrade, Dr. William M. Wuest and Dr. Kevin C. Cannon for their valuable time in reading and correcting my thesis. I thank Dr. Rodrigo B. Andrade for his course in asymmetric synthesis which helped a lot in understanding mechanisms; I will be grateful to him for writing letters of recommendation. I express thanks to Dr. Scott McN. Sieburth for his Organometallic Chemistry course and for writing letter of recommendation. I acknowledge Dr. DeBrosse for his spectroscopy course and for training and assistance in various NMR experiments. I show gratitude to Dr. Grant R. Krow and Dr. John R. Williams for their Physical Organic Chemistry and Organic Names Reactions courses. I acknowledge Dr. Michael J. Zdilla and Sandeep K. Kondaveeti for their help in solving one x-ray crystal structure. I express gratitude to Dr. Maarten E. A. Reith and Dr. Ellen M. vi Unterwald and their research groups for the assistance in obtaining biological data of our cocaine analogues. I will be grateful to Department of Chemistry – Temple University, NIH and NSF for their financial support without which none of the research work would have been possible. I express thanks to Dr. Alfred Findeisen and Dr. Michael Lawlor for their cooperation and flexible teaching assignments. I acknowledge Chemistry Department of staff Regina Shapiro, Bobbi Johnson, Jeanette Ford and Sharon S. Kass for their assistance and help. I recognize Christa Viola for her assistance in dealing with administrative matters. I am thankful to Lena Cherkashina and Christopher Wise, who are responsible for Department’s storeroom. I will be grateful to Mark Kemmerer for his help fixing computers in the lab, my laptop, and for his help in providing the necessary software. I express thanks to Beury hall manager Donald Deigh for his help in fixing the mechanical/electrical problems in the lab. I thank Dave Plasket for his help with glassware, moving equipment and chemicals from one lab to another. I cannot imagine myself at Temple University without my friends Dr. Naresh Theddu and Lan Nguyen Theddu. They are more than friends and they are the dearest to my heart. The memories we had are a valuable part of my life. I am also lucky to have friends like Dr. Bharat S. Wagh, Dr. Ramakrishna Edupuganti, Kavya Kollu Edupuganti, Dr. Gopal Sirasani who influenced me in many ways. I have a lot of respect for my present and past colleagues Dr. Paul Gaspari, Dr. Kerish A. Bowen, Dr. Hui Qui, Dr. Peng Xu, Joshua R. Hummel, Heng Chen, Dr. Venkata Murali velvadapu, Late Dr. Thapas Paul, Dr. Hoan Q. Duong, Dr. Svitlana Kulyk, Dr. Swapnil Singh, Kavitha Akula, Matthew vii Sender, Dr. Manasa mamunooru, Dr. Soujanya Singireddy Velvadapu, Dr. Rajesh Madathingal, Dr. Goutham Kodali, Dr. Swapna Gone and many more. Last but not least, I am grateful to my mother Ramasita Gadhiraju, to my brother Surender Varma Gadhiraju for their unconditional love and support. I am also grateful to my uncle and aunt Kosuri Suribabu and Kosuri Vijayalaxmi, to my cousin brothers Kosuri Srinivasa Raju (Chinni) and Kosuri Kumar Varma (Varma) for their unconditional love and support. I am also grateful to my grandma Kothapally Parvathi for her unconditional love. I am also grateful to Satyavathama garu and Maheboob Sahrif Baba (Guruvugaru) for their unconditional love and divine blessings. viii TABLE OF CONTENTS Page ABSTRACT……………………………………………………………………………………. iii ACKNOWLEDGEMENT…………………………………………………………………….. vi LIST OF TABLES……...…………………………………………………………………….. xiii LIST OF FIGURES…………………………………………………………………………… xv CHAPTER 1 SYNTHESIS OF COCAINE 1.1 Introduction 1.1.1 History……………………………………………………………………………. 1 1.1.2 Biosynthesis of cocaine…………………………………………………………... 2 1.2 Early synthesis of cocaine 1.2.1 Willstatter synthesis of cocaine from tropinone………………………………….