The goals of this work are to develop syntheses of antitubercular agents based on natural product leads. This will involve the total synthesis of the natural products pseudopteroxazole, seco-pseudopteroxazole, erogorgiaene, ileabethin, elisapterosin B and elisabethin A. Testing of targets and intermediates will be performed by the Tuberculosis Antimicrobial Acquisition and Coordinating Facility (TAACF). A unifying methodology will be developed in pursuing these goals. This involves the synthesis of enantiomerically pure benzothiazines through the intramolecular, stereoselective addition of sulfoximine carbanions to unsaturated esters. The development of this methodology will be coupled with aspects of other new chemistry to achieve the synthetic goals. Of particular importance will be the development of a stereoselective, intramolecular radical ring closure reaction as a means of establishing a six-membered ring. Two approaches to this general type of process will be explored. Benzothiazine chemistry will be further developed, particularly in the context of the synthesis of elisabethin A, during which the study of benzothiazine carbanions as nucleophiles in Michael addition reactions will be undertaken. The compounds to be prepared in this study will contribute to the goal of developing chemotherapeutics for tuberculosis. Since the targets are related to pseudopterosins, compounds with potent analgesic and antiinflammatory properties, the work will have an impact in this area as well. More generally, the methodology to be developed should have extremely broad impact, as it can be applied to the generation of stereogenic centers in a large number of compounds of biological and medicinal interest.
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