A Synthetic Approach to Calyxins and Epicalyxins I and J

描述(由申请人提供)：高良姜的三种成分，即花蕾蛋白I、花蕾蛋白J和表儿茶素J，由于其对人纤维肉瘤HT-1080和小鼠结肠26-L5癌细胞的体外活性而成为本提案的主题。本研究的长期目标是通过独立合成来验证这些化合物的绝对结构。具体地说，这项提议将集中在拼图的一个部分，即开发一种立体控制的方法来处理每种化合物共有的稠环系统。研究设计分为三大部分。在第一节中，我们将研究取代二氢吡喃与N-酰亚胺的杂化Diels-Alder反应，得到稠环双环缩醛。第二节重点研究了这些[4+2]环加合物与各种亲核试剂的Lewis酸环裂解反应。预期的C-芳基吡喃糖苷产品将通过富含电子的芳环与由这些双环缩醛生成的氧卡宾离子的亲核加成而得到。第三部分将集中讨论这种方法论在综合中的应用。每个环裂解的产物都应该在四氢吡喃环的C-2上含有一个侧链，该侧链带有酰胺部分。将设计一系列实验，通过添加具有增强电子吸收能力的基团来逐渐增加该酰胺部分的电子缺陷。我们假设，在Lewis酸环境中，如果邻近基团有足够的稳定性，酰胺官能团的单分子解离将导致碳正离子的形成，从而允许分子内从附近的亲核中心进行取代。该步骤旨在提供上述三元稠环系统。这些成分的体外抗癌活性使它们成为治疗人类肿瘤的潜在候选药物。与校园里的生物学家合作，他们的实验室合成最终将导致确定它们是如何杀死癌细胞的。利用这些信息，设计出具有更好和更具选择性的抗癌特性的类似物应该是可能的。

DESCRIPTION (provided by applicant): Three constituents of Alpinia blepharocalyx, namely calyxin I, calyxin J and epicalyxin J, are the subject of this proposal owing to their in vitro activity against human fibrosarcoma HT-1080 and murine colon 26-L5 carcinoma cells. The long-term objective of this research is to verify the absolute structures of these compounds by independent synthesis. Specifically this proposal will focus on one part of the puzzle, that being to develop a stereocontrolled approach to the fused ring system common to each compound. The research design is divided into three major sections. In section one, hetero Diels-Alder reactions between substituted dihydropyrans and N-acyl imines, leading to fused ring bicyclic acetals, will be studied. Section two focuses on Lewis acid ring cleavage reactions of these [4 + 2] cycloadducts with a variety of nucleophiles. The intended C-aryl pyranoside products will arise from nucleophilic addition of electron rich aromatic rings to oxocarbenium ions generated from these bicyclic acetals. The third section will concentrate on the application of this methodology to synthesis. Each product of ring cleavage should contain a side chain on C-2 of the tetrahydropyran ring which bears an amide moiety. A set of experiments will be designed to gradually increase the electron deficiency of this amide moiety by adding groups with increasing electron withdrawing capabilities. We hypothesize that in a Lewis acid environment, and with sufficient stabilization from neighboring groups, unimolecular dissociation of the amide functionality will lead to carbocation formation, allowing intramolecular substitution from a near-by nucleophilic center. This step is designed to provide the aforementioned three-membered fused ring system. The in vitro anti-cancer activity of these constituents makes them potential drug candidates for the treatment of human tumors. In collaboration with biologists on campus, their laboratory synthesis would eventually lead to the determination of how they kill cancer cells. Using this information, the design of analogues with superior and more selective cancer fighting properties should be possible.