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University of Tennessee, Knoxville TRACE: Tennessee Research and Creative Exchange Doctoral Dissertations Graduate School 12-2013 Design and Synthesis of Novel Sultams as Non-nucleoside Inhibitors of HIV Reverse Transcriptase Brian Chadwick LeCroix University of Tennessee, Knoxville, [email protected] Follow this and additional works at: https://trace.tennessee.edu/utk_graddiss Part of the Heterocyclic Compounds Commons, Medicinal-Pharmaceutical Chemistry Commons, Organic Chemicals Commons, and the Organic Chemistry Commons Recommended Citation LeCroix, Brian Chadwick, "Design and Synthesis of Novel Sultams as Non-nucleoside Inhibitors of HIV Reverse Transcriptase. " PhD diss., University of Tennessee, 2013. https://trace.tennessee.edu/utk_graddiss/2590 This Dissertation is brought to you for free and open access by the Graduate School at TRACE: Tennessee Research and Creative Exchange. It has been accepted for inclusion in Doctoral Dissertations by an authorized administrator of TRACE: Tennessee Research and Creative Exchange. For more information, please contact [email protected]. To the Graduate Council: I am submitting herewith a dissertation written by Brian Chadwick LeCroix entitled "Design and Synthesis of Novel Sultams as Non-nucleoside Inhibitors of HIV Reverse Transcriptase." I have examined the final electronic copy of this dissertation for form and content and recommend that it be accepted in partial fulfillment of the equirr ements for the degree of Doctor of Philosophy, with a major in Chemistry. David C. Baker, Major Professor We have read this dissertation and recommend its acceptance: Shawn R. Campagna, David Jenkins, Hong Guo Accepted for the Council: Carolyn R. Hodges Vice Provost and Dean of the Graduate School (Original signatures are on file with official studentecor r ds.) Design and Synthesis of Novel Sultams as Non-nucleoside Inhibitors of HIV Reverse Transcriptase A Dissertation Presented for the Doctor of Philosophy Degree The University of Tennessee, Knoxville Brian Chadwick LeCroix December 2013 Dedication To my wife, Becky LeCroix, who has been with me throughout my entire time at the University of Tennessee even in these last two years we spent eight hours apart. Thank you for being my support through it all. I love you and I dedicate this to you. To both my parents, who have supported me through my whole life. For helping me throughout my undergraduate studies with whatever you could. I wouldn’t be here today if it wasn’t for you two, “Not letting me work on the farm so that I couldn’t end up enjoying it and becoming a farmer.” ii Acknowledgements I first want to give acknowledgments to Dr. David C. Baker, my major professor, for giving this farm boy from Alabama the guidance and teaching needed to complete my studies at the University of Tennessee. You were always there to offer any kind of advice, help, or joke to aid in the laboratory; whether it be fixing equipment, offering a new idea for a reaction, just sitting in your office talking stories about anything from chemistry to farming. Thank you for giving me this project to sort of speak, “add the final chapter to the book.” You are an amazing chemist, and I am proud to follow in your footsteps. To this day, I do not regret and will never regret choosing the University of Tennessee and in choosing you as my advisor. I hope that although I may leave here to move across the country we will stay in contact through e-mail or phone. I would also like to mention my committee members, Dr. Shawn Campagna, Dr. David Jenkins, and Dr. Hong Guo. Thank you for your time in helping me through my first research proposal in my second year. And thank you for any advice you gave along the way. Now I would like to acknowledge former and current members of the Baker group. To Dr. Samson Francis and Dr. Julio Gutierrez for being there to show me the ropes of the lab when I first joined. To Dr. Samson Francis for being my host when I came to Knoxville for the Open House weekend, and brewing great cups of coffee. To Dr. Julio Gutierrez for helping out in showing me the ropes of the NMR. I also want to mention Dr. Costyl Njiojob and Dr. Irene Abia who had to deal with me throughout their iii time at UT; you two made the lab entertaining in either just someone to talk to and laugh with or in providing someone to play pranks on, Costyl. To the current members of the Baker group, Yundi Gan and Bo Meng, keep at it; you’ll reach your goals soon. Thank you guys for always making me jealous of your lunch with the Chinese food you’d bring in everyday. To all the undergraduates that passed through the Baker group in my time at UT. To first off Andy Hahn for just being around to talk to about whatever and for turning red at any of Dr. Baker’s jokes. To Andy Rowe for helping with the project and for harassing me via text messaging during Alabama Tennessee football games even though you knew Alabama would end up winning. To Andrew Moss, who started off in my third year in the program as just a freshman. You’re definitely an intelligent student who would make a fine chemist, it’s a shame the field will lose you to the medical field. I also want to acknowledge Dr. Carlos Steren. You helped me in training me on the new 500 MHz NMR and were always willing to talk about anything with NMR experiments or analysis. I enjoyed learning how to maintain the NMR under your tutelage and just discussing things about Argentina as we performed helium fills on the magnet. I would also like to mention the friends I had coming into UT and the ones I made at UT. So many of you to name, but John West, Cal Woodruff, Aaron Edwards, Chuck Smith, Bob Kress, Adam Condra, Evan Jones, Chris and Allyn Milojevich, Blake and Andy Hicks, Stefanie Bragg, and Kelly Hall thank you for just being around to provide a stress outlet with either a night out drinking or just talking about old times at either BSC or in high school. iv I also want to thank Dr. David J.A. Schedler for inspiring me to go into the field of Organic Chemistry from your lectures and your research projects at Birmingham- Southern College. Finally, I want to thank all in the Department of Chemistry at the University of Tennessee. So many things could not function within the department if it weren’t for so many of you. It has been a long road to this day, but I have finally made it. I thank all of you, and even some I have not mentioned. And last but not least, Roll Tide. v Abstract The compound 2-methyl-3-phenyl-2,3-dihydro-1,2-benzisothiazole 1,1-dioxide (NSC 108406) was identified as an HIV-1 reverse transcriptase inhibitor by the National Cancer Institute. Using this lead, the Baker group has developed a series of analogues with various groups at the 3-position that show a spectrum of biological activities. In the end, the substituents used could not compare to the biological activity of the inhibitor efavirenz (Sustiva® [trademark]), and so it was decided to synthesize sultams with alkylethynyl substituents at the 3-position of the sultams in an attempt to mimic the activity of efavirenz. Previous research analyzed the proposed novel sultams in the modeling program FlexiDock contained in the SYBYL package. The FlexiDock modeling performed by Riyam Kafri gave evidence for unique binding of the proposed sultams in both wild type and Y181C reverse transcriptase. Another in silico method applied to the novel sultams was the CoMFA analysis, which looks at the similarities between common compounds with known biological activities and uses this information to calculate predicted activities for untested compounds. Synthesis of the novel ethynyl sultams is achieved by reacting the desired lithiated alkylethynyl reagent with 3-chloro-1,2-benzoisothiazole 1,1-dioxide, pseudo- saccharin chloride. Methods were designed to yield either the mono-alkylated or the bis- alkylated products. Various methods for reducing the mono-substituted compounds were applied to attempt to achieve the desired S enantiomer. Other methods resulted in the production of a racemic mixture of the reduced compounds. The reduced mono- vi sultams or the bisalkylated sultams are then methylated to yield the desired final product. An aryl sultam was also synthesized in a similar method employed by Baker and co-workers by reacting saccharin with two equivalents of a Grignard reagent of 3- bromostyrene. The compound was reduced with the catalyst (R)-Cp*RhCl[(1S,2S)-p- TsNCH(C6H5)CH(C6H5)NH2] [(R)-pentalmethylcyclopentadienylrhodium chloride- (1S,2S)-p-toluenesulfonyl-1,2-diphenylethylenediamine] and alkylated with base and iodomethane. The vinyl group was reacted in a modified SimmonsSmith fashion to produce a cyclopropyl group in the meta position on the phenyl ring. vii Table of Contents Chapter I. Introduction .................................................................................................... 1 A. AIDS and HIV—The Beginning .............................................................................. 1 B. Possible Origins of HIV .......................................................................................... 4 C. The Lifecycle of HIV ............................................................................................... 5 1. Overview........................................................................................................... 5 2. Viral Entry—Fusion ........................................................................................... 8 3. Reverse Transcription .....................................................................................

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