SYNTHESIS OF THE SPIROKETAL SUBUNIT OF REVEROMYCIN A

描述：(申请人摘要)这项研究的长期目标是 开发立体控制合成抗癌药瑞曲霉素的路线 答：为了实现这一目标，正如本申请中所详细描述的那样，我们建议综合 螺酮亚基带有这种天然产物的C10-C24骨架的螺酮亚基 从土壤放线菌中分离出来的反转霉素A是一种有丝分裂的抑制剂 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，主要有两个原因。 首先，通过综合，我们最终希望确定绝对结构 由Ubukata和同事使用NOE分配给天然产品 实验。第二，获得这种分子的大规模、实用的途径 为结构活性研究提供类似物的途径。 6，6-螺酮骨架上分子内反应的研究 建议。人们希望螺环的构象刚性 系统将使预期的环关闭受到极大的青睐。使用这个 战略我们希望在C19和C11之间建立立体关系- 天然产物分子的立体中心。需要解决的一个假设是 螺酮醇环上的C2能否形成分子内轴键 (反转霉素A中的C19)来自赤道C8-取代基(反转霉素中的C11) a)。 我们将研究单电子和双电子过程的环化反应。合而为一 项目中，将生成C2中心的自由基并将其添加到β-锡基上 C8侧链上以内环形式存在的酯。预期的结果是一个 失去β-锡基的分子内自由基取代。这个 相互连接的脂肪链将被选择，以便内酯在 产物将产生C2-和C8-基团，这些基团可以转化为C19-和 反转霉素A的C11侧链。 在另一项研究中，将尝试产生并捕获C2-氧离子 分子内由C8侧链上的烯丙基和乙烯基硅烷组成。这一战略 将作为反转霉素A螺旋酮的替代途径进行研究。

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.