SYNTHESIS OF THE SPIROKETAL SUBUNIT OF REVEROMYCIN A

瑞维霉素 A 螺酮亚基的合成

• 批准号: 6473754
• 负责人: KEITH Thomas MEAD
• 金额: $ 0.97万
• 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 2003-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6473754
• 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.

描述：（申请人摘要）本研究的长期目标是 发展立体控制合成抗肿瘤药物回复霉素的路线 A.为了实现这一目标，如本申请中所详述的，我们提出合成 具有这种天然产物的C10-C24骨架的螺缩酮亚单位。 从土壤放线菌中分离得到的回复霉素A是一种促有丝分裂的抑制剂， 活性由表皮生长因子诱导，并且还对人 肿瘤细胞系KB和K562。这项研究之所以重要，主要有两个原因。 首先，通过合成，我们最终希望确认其绝对结构 由Ubukata及其同事使用NOE分配给天然产品 实验其次，大规模的，实用的路线，这种分子将 为结构-活性研究提供类似物。 研究了6，6-螺缩酮骨架上的分子内反应 提出了人们希望螺环的构象刚性 系统将使预期的环闭合熵有利。使用此 我们希望建立C19-和C11-之间的立体关系的策略， 天然产物分子的立体中心。要解决的假设是 是否可以在螺缩酮环上的C2上形成分子内轴向键 (C19在回复霉素A中）从赤道C8-取代基（回复霉素中的C11 A）。 将研究单电子和双电子过程的环化。在一个 项目，将生成一个以C2为中心的自由基，并将其添加到β-甲锡烷基中。 C8侧链上以内环方式的酯。预期的结果是 失去β-甲锡烷基的分子内自由基取代。的 将选择相互连接脂族链，使得 产物将产生C2-和C8-基团，其可以转化为C19-和C18-基团。 C11-侧链，分别为回复霉素A。 在另一项研究中，将尝试产生并捕获C2-氧鎓离子 通过C8-侧链上的烯丙基-和乙烯基硅烷分子内聚合。这一战略 将作为回复霉素A螺缩酮的替代途径进行研究。