Application of Sulfurane Chemistry in the Assembly of HIV Protease Inhibitors

University Of South Alabama, Mobile AL

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Abstract

[unreadable] DESCRIPTION (provided by applicant): My research program lies primarily in the area of synthetic organic chemistry. A large component is dedicated toward the development of new synthetic methods. The success of the program is heavily dependent upon the involvement of motivated and talented undergraduate students. Funds requested through the NIH AREA program will allow for the involvement of high school chemistry teachers active in the statewide-funded program Alabama Science in Motion (ASIM), postdoctoral research associates, and undergraduate research students. Their involvement will, in terms of maturation, bring our research program to the next level. This is my first application to NIH. The construction of three-membered rings represents an extremely useful synthetic transformation for the introduction of functionality into organic molecules. Of the common disconnections available to assemble three-membered rings, the sulfur ylide approach offers potential advantages of atom efficiency, facility for stereocontrol and catalysis. Our research plans are to build upon preliminary data with the intent to explore catalysis, asymmetry, and natural product synthesis. By reversing the role of the sulfur atom, we will have a completely new method in the generation of sulfur ylides. The carboxylate dianions generated in situ will displace the halide bound to the sulfurane and generate carboxymethyl betaine functionality directly. Upon decarboxylation, the sulfur ylide will react with a host of ?-acceptors affording three-membered ring carbocycles. Advantages include the ease by which one can modify the ylide reagent. Developing this technology would be a significant advancement to the field as witnessed to date especially when using chiral nonracemic sulfurane promoters to conduct alkylidene transfers. Concurrent with the development of the sulfurane chemistry will be the application of the sulfur ylide technology in the preparation of HIV protease inhibitors. Our approach is conceptually unique in that it has as the key step, assembly of the hydroxyethylene three-carbon building block using butane-2,3-diacetals of glyceraldehyde (BDA). The BDA derivative will allow for stereospecific methylidene transfers. Once formed, the ring(s) can be opened and within two steps, the three-carbon building block found in the HIV protease inhibitors of amprenavir, atazanavir, fosamprenavir, lopinavir, nelfinavir, ritonavir, and saquinavir can be furnished. This approach significantly improves upon how these materials are currently prepared. [unreadable] [unreadable] PUBLIC HEALTH RELEVANCE: We have a synthetic plan which will offer the synthetic chemist the most efficient means to perform methylidene transfers onto a @-system. The materials prepared using this method will significantly streamline how modern HIV protease inhibitors are prepared. A savings in time and resources will ultimately translate to cost. [unreadable] [unreadable] [unreadable] [unreadable]