SYNTHESIS OF THE SPIROKETAL SUBUNIT OF REVEROMYCIN A

瑞维霉素 A 螺酮亚基的合成

• 批准号: 6028231
• 负责人: KEITH Thomas MEAD
• 金额: $ 10.43万
• 依托单位: MISSISSIPPI STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-05-01 至 2003-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6028231
• 关键词: antineoplastic antibiotics; biological products; chemical structure function; conformation; cyclization; drug design /synthesis /production; ketal; pyrans; spirane; stereochemistry

DESCRIPTION: (Applicant's Abstract) The long-term goal of this research is to develop a stereocontrolled synthetic route to the antitumor agent reveromycin A. Toward this goal, as detailed in this application, we propose to synthesize the spiroketal subunit bearing the C10-C24 framework of this natural product. Isolated from a soil actinomycete, reveromycin A is an inhibitor of mitogenic activity induced by epidermal growth factor, and is also active against human tumor cell lines KB and K562. This research is important for two main reasons. First, through synthesis, we eventually hope to confirm the absolute structure assigned to the natural product by Ubukata and co-workers using NOE experiments. Second, a large-scale, practical route to this molecule would provide access to analogues for structure-activity studies. A study of intramolecular reactions on the 6,6-spiroketal framework is proposed. It is hoped that the conformational rigidity of the spirocyclic ring systems will make the intended ring closures entropically favored. Using this strategy we wish to establish the stereorelationship between the C19- and C11- stereocenters of the natural product molecule. A hypothesis to be addressed is whether an inntramolecular axial bond can be made to C2 on a spiroketal ring (C19 in reveromycin A) from an equatorial C8-substituent (C11 in reveromycin A). Cyclizations by both one- and two-electron processes will be studied. In one project, a C2-centered radical will be generated and added to a beta-stannyl ester in endocyclic fashion on the C8-side chain. The intended outcome is an intramolecular radical substitution with loss of the beta-stannyl group. The interconnective aliphatic chain will be chosen so that lactone cleavage in the product would yield C2- and C8-groups which could be converted to the C19- and C11-side chains, respectively, of reveromycin A. In another study, attempts will be made to generate and trap a C2-oxonium ion intramolecularly by allyl- and vinylsilanes on the C8-side chain. This strategy will be investigated as an alternative route to the reveromycin A spiroketal.

（申请人摘要）本研究的长期目标是