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.

描述：（申请人的摘要）这项研究的长期目标是 开发立体控制的合成途径到抗肿瘤毒素 答：正如本应用程序所详细介绍的那样，我们提出合成 具有这种天然产品的C10-C24框架的螺旋式亚基。 从土壤放线菌分离出来，神霉素A是有丝分裂的抑制剂 表皮生长因子诱导的活性，并且对人类也具有活性 肿瘤细胞系KB和K562。这项研究很重要，原因有两个。 首先，通过合成，我们最终希望确认绝对结构 使用NOE由Ubukata和同事分配给天然产品 实验。第二，通往该分子的大规模实用途径将 提供对结构活性研究的类似物的访问。 对6,6-螺旋体框架上分子内反应的研究是 建议的。希望螺旋环的构象刚性 系统将使预期的环闭环受到偏爱。使用此 我们希望建立C19-和C11-之间的立体关系 - 天然产物分子的立体中心。要解决的假设是 是否可以在螺旋环上与C2建立Inntramologular轴向键 （炎感霉素中的C19）来自赤道C8-屈服的（C11中的C11 一个）。 将研究一单电子和两电子过程的循环。一个 项目，将产生一个以C2为中心的自由基，并添加到β-斯坦基 C8侧链中的内循环方式以酯为单位。预期的结果是 分子内根治性取代，β-斯坦尼基损失。这 将选择互连的脂肪族链，以便在 产品将产生C2和C8组，可以转换为C19-和 Reveromycin A的C11侧链。 在另一项研究中，将尝试产生和捕获C2-氧气离子 分子在C8侧链上的烯丙基和乙烯基烷。这个策略 将研究作为旋霉素的替代途径。