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 开发抗肿瘤药物利维霉素的立体控制合成路线 A. 为了实现这一目标，正如本申请中详述的，我们建议综合 带有该天然产物的 C10-C24 框架的螺酮亚基。 reveromycin A 从土壤放线菌中分离出来，是一种有丝分裂抑制剂 由表皮生长因子诱导的活性，对人类也有活性 肿瘤细胞系KB和K562。这项研究之所以重要有两个主要原因。 首先，通过合成，我们最终希望确认绝对结构 Ubukata 和同事使用 NOE 分配给天然产物 实验。其次，这种分子的大规模、实用途径将 提供用于结构活性研究的类似物。 6,6-螺缩酮骨架分子内反应的研究 建议的。希望螺环的构象刚性 系统将使预期的闭环变得熵有利。使用这个 我们希望在 C19- 和 C11- 之间建立立体关系的策略 天然产物分子的立体中心。要解决的假设是 螺酮环上的C2是否可以形成分子内轴向键 （Reveromycin A 中的 C19）来自赤道 C8 取代基（Reveromycin A 中的 C11） 一个）。 将研究单电子和双电子过程的环化。合而为一 项目中，将生成以 C2 为中心的自由基并将其添加到 β-甲锡烷基 以环内方式位于 C8 侧链上的酯。预期的结果是 分子内自由基取代并失去β-甲锡烷基。这 将选择互连的脂肪链，以便内酯在 产物将产生C2-和C8-基团，它们可以转化为C19-和 reveromycin A 的 C11 侧链。 在另一项研究中，将尝试生成并捕获 C2-氧鎓离子 分子内通过 C8 侧链上的烯丙基和乙烯基硅烷形成。这个策略 将作为瑞维霉素 A 螺缩酮的替代途径进行研究。