Date of Award

12-2013

Degree Type

Dissertation

Degree Name

Doctor of Philosophy

Major

Chemistry

Major Professor

David C. Baker

Committee Members

Shawn R. Campagna, David Jenkins, Hong Guo

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- 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 Simmons-Smith fashion to produce a cyclopropyl group in the meta position on the phenyl ring.

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