STEROID AND TERPENOID SYNTHESIS AND RELATED STUDIES

本申请的一个主要目的是改善所述系统的状态。 仿生多烯环化的技术，使其可用于 合成具有生物学和医学重要性的物质， 特别是类固醇和类似物，从而使它们更容易 容易接近计划开发一种基本上新的方法， 加强和控制这些环化的机构， 阳离子稳定（“C-S”）功能位于底物中的位点， 注定要在过渡状态中发展积极的性格。 该方法的开发包括具体的应用目标 涉及下列类型产物的不对称合成 已知或潜在的药用价值;矿物质和非矿物质 皮质激素（用于治疗各种疾病，例如，关节炎）和 19-降甾体化合物（用于口服避孕）。此外，计划 用于合成lazaroid（U-74006 F，用于治疗CNS 创伤和局部缺血）。在这些综合研究的过程中， 将有机会制备大量的8-氟 类固醇类似物。这类未知的化合物可能具有重要的 生物学特性和筛选测试的安排已经完成 通过道格拉斯R.小莫顿 使用C-S辅助剂的精液阳性结果导致 氧化角鲨烯酶促环化反应机理探讨 基于酶提供的负点电荷的控制。这 这一机制反过来又导致了新结构的合理设计， 可能的过渡态类似物抑制剂，其中一些具有 可用于调节胆固醇的生物合成， 哺乳动物（抗低血糖作用）和真菌中的麦角固醇。 这些结构的合成已经开始， 的OS环化酶将由P. Benveniste（University of 斯特拉斯堡）。安排抗真菌试验正在与W。 杜邦公司农产品部的Kolimeyer。如果这些化合物 被证明是很好的抑制剂，它们也应该是有用的， 用作引发单克隆抗体的半抗原的物质 其可用作多烯环化的催化剂（见下文）。 抗体研究将与J. H。格里芬 （斯坦福大学）谁将执行生物实验。长期的 目标包括，除了确定的机制， 氧化角鲨烯环化酶，催化剂的发展， 合成底物高产率环化， 具有重要药用价值的产品。

A major objective of the present application is to improve the state of the art of biomimetic polyene cyclization so that it may be employed for the synthesis of substances of biological and medicinal importance, particularly steroids and analogs, thus making them more readily accessible. It is planned to exploit a basically new approach for the enhancement and control of these cyclizations by the agency of cation-stabilizing ("C-S") functions located at sites in the substrate that are destined to develop positive character in the transition state. Exploitation of this methodology includes the specific aims of application to the asymmetric synthesis of members of the following types of products of known or potential medicinal value: mineralotropic and antiinflammatory corticoids (for treatment of various diseases, e.g., arthritis) and 19-norsteroidal compounds (for oral_contraception). In addition plans are presented for the synthesis of lazaroid (U-74006F (for treatment of CNS trauma and ischemia). In the course of these synthetic studies, the opportunity will become available for preparing a number of 8-fluoro steroid analogs. This unknown class of compounds may have important biological properties and arrangements for screening tests have been made with the Upjohn Company through Douglas R. Morton, Jr. Seminal positive results on the use of C-S auxiliaries have led to the suggestion of a mechanism for the enzymatic cyclization of oxidosqualene based on control by negative point charges provided by the enzyme. This mechanism has, in turn, led to the rational design of new structures for possible transition state analog inhibitors, some of which have the potential of being useful in moderating the biosynthesis of cholesterol in mammals (antihypocholesteremic effect) and of ergosterol in fungi. Syntheses of these structures have been commenced and tests for inhibition of OS cyclases will be conducted by P. Benveniste (University of Strasbourg). Arrangements for antifungal tests are being made with W. Kolimeyer at DuPont's Agricultural Products Department. If these compounds prove to be good inhibitors, they also should be useful in developing substances that will serve as haptens for eliciting monoclonal antibodies which may serve as catalysts for polyene cyclizations (see below). The antibody study is to be conducted in collaboration with J. H. Griffin (Stanford) who will perform the biological experiments. Long range objectives include, in addition to determining the mechanism of oxidosqualene cyclases, the development of catalysts for the asymmetric high-yield cyclization of synthetic substrates leading to steroidal products of medicinal importance.