SYNTHESIS OF BIOLOGICALLY ACTIVE NATURAL PRODUCTS

生物活性天然产物的合成

• 批准号: 3279312
• 负责人: MICHAEL E JUNG
• 金额: $ 7.56万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 1983
• 资助国家: 美国
• 起止时间: 1983-01-01 至 1985-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3279312
• 关键词: Diels Alder reaction; alkaloids; codeine; cortisone; drug design /synthesis /production; estrone; lignans; morphine; reserpine; stereochemistry; steroids

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.

该提案旨在开发和测试几种新方法 多种具有药用活性的天然产物的全合成。 目标分子的结构复杂性差异很大，范围 来自复杂的五环生物碱（吗啡、可待因、利血平和 Herquline）和四环类固醇（可的松、雌酮）和生物素 （去甲基表鬼臼毒素）转化为简单的双环生物碱slaframine。 所有合成方法的关键步骤是分子内合成 反应或重排需要通过分子内 过程中，优先形成所需的立体化学异构体 给所有其他人。 这些合成中使用的分子内过程是 Diels-Alder 反应、[3,3]-σ 位移和亲核加成 （迈克尔添加或亚铵盐添加）。 在所有情况下， 合成被设计得非常短（吗啡的 9 个步骤，7 雌酮等的步骤）并且足够通用，因此许多其他结构 相关系统可以很容易地形成。 制定的原则 这些合成 - 例如，通过 oxy-Cope 形成四元中心 重排，内部立体化学的空间控制 环加成，1-氮杂丁二烯的​​轻松生成和环化， 除其他外 - 适用于有机合成并且具有巨大价值 一般来说。 由于合成过程极其短暂， 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。