STEROID AND TERPENOID SYNTHESIS AND RELATED STUDIES

最有希望的完全合成类固醇的方法之一是通过 仿生多烯环化方法学。这项建议的主要目的是 就是扩展这一方法论的现状，以便它 可以用来合成某些医学上有用的(见下文) 化合物，使它们比目前可用的更容易获得 方法：研究方法。 高度优先的项目包括制定新概念的计划 合理设计：(A)改进的环化启动器功能，可以 对其亲电性进行微调，并(B)改进 环化终止子功能，对区域和 非对映选择性环关闭，使产品具有以下功能 可以容易地被操纵以产生有用的结构，例如， 皮质激素侧链。另一个最优先的项目是测试一个新的 串联环化的概念如下。(串联)函数为 沿着底物的多烯链部分地放置，以便当 环化过程达到这一点，辅助功能是 转化为已知类型的共振稳定阳离子，应该是 有效地启动进一步的环化反应。因此，四环化反应是 设想通过两次连续的高收益自行车骑行来实现 流程。 上述所有方法学研究都将在 实现不对称环化反应和合成产物的背景 已知的或潜在的药用价值。直接目标是，例如， 矿化和抗炎皮质激素(用于治疗各种 疾病，如关节炎)，19-去甲甾体化合物(口服 避孕)、维生素D3代谢物及其类似物(用于控制 涉及钙代谢的疾病，如骨质疏松症)和胆汁 鹅去氧胆酸等酸(用于溶解胆结石)。 辅助研究涉及酶模型的开发以及 可辅助仿生多烯环化反应的模板系统。 它还被提议利用任何特别有希望的新奇行为 在上述研究中遇到的。

One of the most promising totally synthetic approaches to steroids is via biomimetic polyene cyclization methodology. The major aim of this proposal is to expand the present state of the art of this methodology so that it may be employed to synthesize certain medicinally (see below) useful compounds, making them more readily accessible than by presently available methods. High priority projects include plans for developing new concepts for the rational design of: (a) improved cyclization initiator functions that can be fine-tuned with respect to their electrophilicity and (b) improved cyclization terminator functions that effect highly regio- and diastereoselective ring closure to give products with functionality that can be readily manipulated for the production of useful structures, e.g., the corticoid side-chain. Another top priority project is to test a new concept of tandem cyclization as follows. A (tandem) function is positioned part way along the polyene chain of the substrate so that when the cyclization process reaches this point, the auxiliary function is converted into a resonance-stabilized cation of a known type that should be effective for initiating further cyclization. Thus a tetracyclization is envisaged as being achieved by two sequential high yield bicyclization processes. All of the aforementioned methodology studies will be addressed within the context of realizing asymmetric cyclizations and synthesizing products of known or potential medicinal value. Immediate targets are, e.g., mineralotropic and anti-inflammatory corticoids (for treatment of various diseases, e.g., arthritis), 19-norsteroidal compounds (for oral contraception), vitamin D3 metabolites and analogs (for control of disorders involving calcium metabolism, e.g., osteodystophy), and bile acids such as chenodesoxycholic acid (for dissolution of gallstones). Ancillary studies involve the development of enzyme models as well as template systems that may assist biomimetic polyene cyclizations. It is proposed also to exploit any especially promising novel behavior encountered in the aforementioned studies.