SYNTHESIS OF BIOLOGICALLY ACTIVE NATURAL PRODUCTS

该提案旨在开发和测试几种新的方法，以 全合成多种具有药用活性的天然产物。 目标分子在其结构复杂性方面差异很大，范围 从复杂的五环生物碱(吗啡、可待因、利血平和 大黄素)、四环类固醇(可的松、雌酮)和生物碱 (去甲基表鬼臼毒素)为简单的双环生物碱斯发来明。 所有合成方法的关键步骤是分子内 反应或重排，需要通过分子内的 过程中，优先形成立体化学所需的异构体 敬所有其他人。这些合成中使用的分子内过程是 Diels-Alder反应、[3，3]-Sigmatrotic位移和亲核加成反应 (迈克尔添加或添加到胺盐中)。在所有情况下， 合成被设计成相当短的(吗啡的9步，7步 发情的步骤等)而且足够广泛，以至于许多其他结构上的 相关制度可以很容易地形成。中制定的原则 这些合成--例如，通过含氧化合物形成四元中心 重排，立体控制的内部立体化学 环加成反应，1-氮杂丁二烯的简单生成和环化， 在其他方面-将适用于有机合成并具有极大的价值 总体而言。由于合成过程极其简短， 目标的重要性，以及方法的高内在价值 对化学做出重要贡献的可能性是 相当高。

This proposal is designed to develop and test several new approaches to the total synthesis of a wide variety of medicinally active natural products. The target molecules vary greatly in their structural complexity, ranging from the complex pentacyclic alkaloids (morphine, codeine, reserpine, and herquline) and tetracyclic steriods (cortisone, estrone) and bionans (desmethyl epipodophyllotoxin) to the simple bicyclic alkaloid slaframine. The key step of all of the synthetic approaches is an intramolecular reaction or rearrangement which requires, by the intramolecularity of the process, the formation of the stereochemically desired isomer in preference to all others. The intramolecular processes used in these syntheses are Diels-Alder reations, [3,3]-sigmatropic shifts, and nucleophilic additions (Michael additions or additions to immonium salts). In all cases, the syntheses are designed so as to be quite short (9 steps to morphine, 7 steps to estrone, etc.) and general enough so that many other structurally related systems could be formed quite easily. The principles developed in these synthese - e.g., formation of quaternary centers via an oxy-Cope rearrangement, steric control of the stereochemistry of internal cycloadditions, the facile generation and cyclization of 1-azabutadienes, among others - would be applicable and of great value to organic synthesis in general. Because of the extreme shortness of the syntheses, the importance of the targets, and the high intrinsic value of the methods themselves, the likelihood of an important contribution to chemistry is quite high.