SYNTHESIS OF BIOLOGICALLY ACTIVE MARINE NATURAL PRODUCTS

该提案旨在开发和测试几种通用和 对映选择性全合成的有效途径 各种有用的生物活性天然产物， 已经从海洋中分离出来 靶分子为： pseudopterosin A是一种非常有效的抗肿瘤药物， 镇痛剂;地地烯酮，已经显示出抗菌性， 抗真菌和强细胞毒性特性; acalycixeniferma A和 B，它们是细胞分裂抑制剂;最后，reiswigin A和 B，它们在体外表现出很强的抗病毒活性 对抗各种病毒 合成的关键步骤是 这些分子中的每一个通常涉及环化（在一个实施例中， 情况下，1，4-加成）的前体，其中远端和 最终可除去的手性中心导致所需的对映体 关键中间体的形成。 在所有情况下， 被设计为相对较短（12步到地地米烯酮 D，对于acalycixenietine A和B有16个步骤），并且足够通用， 许多其他结构相关的系统可以形成相当 轻易 在每个合成方案的最后，我们描述了 我们将准备各种天然产物的类似物， 测试过了。 在这些合成中开发的原理-例如， 分子内苯炔二烯环加成反应， 手性中心决定相对立体化学， 铜酸盐对不饱和体系的对映选择性1，4-加成 具有相邻的纯手性缩酮，由烯丙基 刘易斯酸催化的分子内（噻吩基）甲基 十四碳四烯的Diels-Alder反应，立体选择性 用手性环氧醇作为引发剂的聚烯烃环化 和立体定向的刘易斯酸促进的环氧醇频哪醇型 重排得到肼烯衍生物-将是适用的 对一般的有机合成具有重要价值。 因为 目标的医学重要性，结合的效率 建筑在综合，和高内在价值的 新的方法本身，可能会作出重要贡献， 与健康相关的科学是相当高的。

This proposal is designed to develop and test several general and efficient approaches for the enantioselective total synthesis of a wide variety of useful biologically active natural products that have been isolated from marine sources. The target molecules are: pseudopterosin A, an extremely potent antiinflammatory and analgesic agent; the didemnenones, which have shown antibacterial, antifungal, and strong cytotoxic properties; acalycixeniolide A and B, which are cell division inhibitors; and finally, reiswigin A and B, which have exhibited very strong in vitro antiviral activity against a variety of viruses. The key step in the synthesis of each of these molecules generally involves a cyclization (in one case, a 1,4-addition) of a precursor in which a distal and ultimately removable chiral center causes the desired enantiomer of the key intermediate to be formed. In all cases, the syntheses are designed so as to be relatively short (12 steps to didemnenone D, 16 steps for acalycixeniolide A and B) and general enough so that many other structurally related systems could be formed quite easily. At the end of each synthetic scheme, we describe the various analogues of the natural products that we will prepare and have tested. The principles developed in these syntheses - e.g., intramolecular benzyne diene cycloaddition in which a benzylic chiral center determines the relative stereochemistry, enantioselective 1,4-addition of a cuprate to an unsaturated system having an adjacent homochiral ketal, enantiocontrol by an allylic (thiophenyl) methyl moiety in Lewis acid-catalyzed intramolecular Diels-Alder reaction of a tetradecatetraene, stereoselective polyolefinic cyclization with a chiral epoxy alcohol as initiator and stereospecific Lewis acid-promoted epoxy alcohol pinacol-type rearrangement to give hydrazulene derivatives - would be applicable and of great value to organic synthesis in general. Because of the medicinal importance of the targets, the efficiency of bond construction in the syntheses, and the high intrinsic value of the new methods themselves, the likelihood of an important contribution to health-related science is quite high.