SYNTHESES 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 从复杂的多环生物碱(吗啡、可待因、利血平、 哌嗪霉素、去氧布瓦丁、大黄碱和萜类化合物(可的松、 雌酮、胡萝卜素C和木脂素(去甲基表鬼臼毒素) 到大环素转菌素。几乎所有合成技术的关键一步 方法是分子内的反应或重排，这需要， 通过分子内的过程，形成了 立体化学要求同分异构体优先于所有其他异构体。这个 这些合成中使用的分子内过程是Diels-Alder反应， (3，3)-信号移位和亲核加成(Michael加成或 添加到免疫盐中)。在所有情况下，合成物都是这样设计的 相当短(吗啡8步，动情7步等)和 足够通用，以至于许多其他结构上相关的系统可以 很容易形成。在这些合成中发展的原理--例如， 通过符号重排、空间构型形成四元中心 控制内部环加成的立体化学，新的保护 氨基酸的序列，以及其他的-将是适用的和很有意义的 对有机合成有普遍的价值。因为它的极短 目标的综合性、重要性和高内在价值 这些方法本身，有可能对 化学成分相当高。

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 polycyclic alkaloids (morphine, codeine, reserpine, piperazinomycin, deosybouvardin and herquline and terpenes (cortisone, estrone, plaunol C, ajugarins) and lignans (desmethyl epipodophyllotoxin) to the macrocycle invermectin. The key step of nearly all of the synthetic approaches is an intramolecular reaction or rearrangement which requires, by the intramolecularity of the process, the formation of the stereochemistry desired isomer in preference to all others. The intramolecular processes used in these syntheses are Diels-Alder reactions, (3,3)-signatropic shifts, and nucleophilic additions (Michael additions or additions to immonium salts). In all cases, the syntheses are designed so as to be quite short (8 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 syntheses - e.g., formation of quaternery centers via signmatropic rearrangements, steric control of the stereochemistry of internal cycloadditions, new protection sequence for amino acids, 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 dhemistry is quite high.