Our recent efforts have centered on developing new methodologies that enable the efficient synthesis of heterocycles from simple and easy to obtain starting materials. Our research in this area has led to novel discoveries in the area of oxidative chemistry, both in oxidative cyclizations of dienes to access THF cores and oxidative cleavage of olefins. We now possess a repertoire of reactions that deliver products with complete fidelity in transfer of stereochemistry. We have developed methodologies for the regiocontrolled opening of epoxides to secure a variety of THF and THP rings. The functional group directed epoxide-opening methodology has been utilized to synthesize the proposed structure of mucoxin. Efforts towards elucidation of the real structure of mucoxin are planned. The synthetic work on mucoxin will be parlayed into SAR studies with a variety of structural and stereochemical analogs against a panel of tumor cells. We also propose the design of a library of acetogenin analogs for a thorough investigation in cell-based assays, along with microsomal screens. Our studies will also focus on discovering the cellular target(s) of acetogenins through photoaffinity crosslinking efforts. Synthesis of mucoxin has also led to the discovery of a new triol cyclization methodology to secure THF and THP rings. Investigations in this area will lead to new chemistries for the one- step synthesis of oxarings and carbocycles form 1,2-diols with regio- and stereochemical control. Our postulated mechanism for the oxidative cleavage of olefins involves the nucleophilic attack of Oxone (peroxysulfate), with the subsequent cleavage of the C-C bond and expulsion of sulfate. This mechanism has inspired us to develop new chemistry, i.e.;the use of good nucleophiles that contain within them good leaving groups. We have demonstrated the use of sulfoxonium ylides in concert with 2,3-epoxy alcohols leads to the formation of THF rings with regio- and stereochemical control. Extension of this methodology for use with alternate ylides that would yield more complex ring systems is proposed. Furthermore, use of hydroxy- aziridines, leading to the stereochemically controlled formation of pyrrolidines has great potential for developing strategies for heterocyclic framework. Preliminary results indicate that this is a robust and efficient method for synthesizing a variety of substituted pyrrolidines. We have also discovered a simple, metal-free, hydroamination of acetylenes (tandem aza-Payne/hydroamination) that leads to a highly versatile synthon. This chemistry will be developed fully, and its use will be highlighted through an efficient synthesis of salinosporamide A, lactacystin, and their analogs (the analogs could be potent 20S proteasome inhibitors). This proposal concerns itself with developing new synthetic methodologies that utilize simple molecules from the chiral pool, and in a regio- and stereoselective manner expands upon the repertoire of molecules that are attainable through the proposed transformations. This proposal concerns itself with developing new reaction methodologies that are geared towards the synthesis of molecular scaffolds of interest for the biomedical and pharmaceutical fields. We also propose to study the function of two families of bioactive natural products, namely, the acetogenins and beta-lactam containing 20S proteasome inhibitors. Acetogenins exhibit very high activity against many cancer cell lines, and so do inhibitors of the 20S proteasome, which are also emerging as exciting candidates for cancer therapy.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Synthetic and Biological Chemistry B Study Section (SBCB)
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Hagan, Ann A
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Michigan State University
Schools of Arts and Sciences
East Lansing
United States
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Soltanzadeh, Bardia; Jaganathan, Arvind; Staples, Richard J et al. (2015) Highly Stereoselective Intermolecular Haloetherification and Haloesterification of Allyl Amides. Angew Chem Int Ed Engl 54:9517-22
Kulshrestha, Aman; Salehi Marzijarani, Nastaran; Dilip Ashtekar, Kumar et al. (2012) 3,4-Dihydroxypyrrolidines via modified tandem aza-Payne/hydroamination pathway. Org Lett 14:3592-5
Hart, Stewart R; Whitehead, Daniel C; Travis, Benjamin R et al. (2011) Catalytic oxidative cleavage of olefins promoted by osmium tetroxide and hydrogen peroxide. Org Biomol Chem 9:4741-4
Ashtekar, Kumar Dilip; Staples, Richard J; Borhan, Babak (2011) Development of a formal catalytic asymmetric [4+2] addition of ethyl-2,3-butadienoate with acyclic enones. Org Lett 13:5732-5
Kulshrestha, Aman; Schomaker, Jennifer M; Holmes, Daniel et al. (2011) Selectivity in the addition reactions of organometallic reagents to aziridine-2-carboxaldehydes: the effects of protecting groups and substitution patterns. Chemistry 17:12326-39
Whitehead, Daniel C; Yousefi, Roozbeh; Jaganathan, Arvind et al. (2010) An organocatalytic asymmetric chlorolactonization. J Am Chem Soc 132:3298-300
Yan, Jun; Garzan, Atefeh; Narayan, Radha S et al. (2010) A minimalist NMR approach for the structural revision of mucoxin. Chemistry 16:13749-56
Whitehead, Daniel C; Staples, Richard J; Borhan, Babak (2009) A simple and expedient method for the preparation of N-chlorohydantoins. Tetrahedron Lett 50:656-658
Schomaker, Jennifer M; Borhan, Babak (2008) Total synthesis of haterumalides NA and NC via a chromium-mediated macrocyclization. J Am Chem Soc 130:12228-9