SYNTHESIS OF BIOLOGICALLY ACTIVE MARINE NATURAL PRODUCTS

该提案旨在开发和测试几个通用和 对映选择性全合成的有效途径 种类繁多的有用的生物活性天然产品 都是从海洋来源分离出来的。目标分子是： 伪蝶毛菌素A，一种极其有效的抗炎和 止痛剂；表现出抗菌作用的敌草酮， 抗真菌，有很强的细胞毒性；刺梨内酯A和 B，它们是细胞分裂抑制物；最后，Reiswigin A和 B，在体外表现出非常强的抗病毒活性 抵御各种病毒。在合成过程中的关键步骤 这些分子中的每一个通常涉及环化(在一个 情况下，1，4-加成)，其中远端和 最终可移除的手性中心产生所需的对映体 将形成的关键中间体。在所有情况下，合成的 设计得相对较短(12个步骤即可达到 D，16个步骤用于油桐内酯A和B)，并且足够普遍，因此 可能会形成许多其他结构上相关的系统 很容易。在每个合成方案的末尾，我们描述 各种天然产品的类似物，我们将准备和 已经测试过了。在这些合成中发展的原理--例如， 分子内苯炔二烯环加成反应，其中一个苄基 手性中心决定了相对立体化学， 铜酸盐在不饱和体系中的不对称1，4-加成反应 具有相邻的同手性缩酮，由烯丙基对映体控制 路易斯酸催化的分子内(苯硫基)甲基 立体选择性的十四烷基四烯的Diels-Alder反应 手性环氧醇引发的聚烯烃环化反应 和立体专一性Lewis酸促进的环氧醇片呐醇型 重排以得到联苯类衍生物-将是适用的 对有机合成具有重要的应用价值。因为 靶标的药用价值，粘合的效率 在合成中的构造，以及 新方法本身，可能会做出重要贡献 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.