Pseudopteroxazole and Related Antitubercular Agents

描述(申请人提供)：这项工作的目标是开发基于天然产品先导的抗结核药物的合成。这将涉及天然产物伪三唑类、二类伪三唑类、麦角烯、伊利贝菌素、伊利沙贝菌素B和伊利沙贝素A的全合成。目标和中间体的测试将由结核病抗菌素获取和协调机构(TAACF)进行。 在追求这些目标的过程中，将制定统一的方法。这涉及到通过分子内、立体选择性地将亚磺亚胺碳负离子加到不饱和酯上来合成对映体纯苯并噻嗪。这一方法学的发展将与其他新化学的方面相结合，以实现合成目标。特别重要的是发展立体选择性的分子内自由基环闭合反应，作为建立六元环的一种手段。将探索两种方法来处理这一一般类型的过程。苯并噻嗪化学将得到进一步发展，特别是在合成伊利沙贝菌素A的背景下，在此期间将开展苯并噻嗪碳负离子在Michael加成反应中作为亲核剂的研究。 这项研究中将要制备的化合物将有助于开发结核病化疗药物的目标。由于这些靶标与具有强大止痛和抗炎特性的化合物拟蝶形素有关，这项工作也将在这一领域产生影响。更广泛地说，将要开发的方法学应该会产生极其广泛的影响，因为它可以应用于在大量具有生物和医药价值的化合物中产生立体中心。

DESCRIPTION (provided by applicant): 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.