STEROID AND TERPENOID SYNTHESIS AND RELATED STUDIES

类固醇和萜类化合物的合成及相关研究

• 批准号: 3224415
• 负责人: WILLIAM S JOHNSON
• 金额: $ 21.15万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1975
• 资助国家: 美国
• 起止时间: 1975-06-01 至 1990-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3224415
• 关键词: androgens; antifungal agents; corticosteroids; cortisol; cyclization; cycloalkene; drug design /synthesis /production; drug screening /evaluation; enzymes; estrogens; female antifertility drug; heterocyclic compounds; hormones; juvenile hormones; ketones; pheromone; plant growth regulators; polyenes; progestins; rheumatoid arthritis; skeletal disorder chemotherapy; stereochemistry; steroids; terpenes

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.

类固醇最有前途的全合成方法之一是通过 仿生多烯环化方法。 这项建议的主要目的是 是扩展这种方法的现有技术， 可用于合成某些药用（见下文）， 化合物，使它们比目前可用的更容易获得 方法. 高度优先的项目包括制定新概念的计划， 合理设计：（a）改进的环化引发剂功能， 在它们的亲电性方面进行微调，和（B）改善 环化终止剂功能，其影响高度区域和 非对映选择性闭环，得到具有 可以容易地操作用于生产有用的结构，例如， 皮质激素侧链 另一个优先项目是测试一种新的 串联环化的概念如下。 一个（串联）函数是 其部分沿着基材的多烯链定位， 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， 有效地引发进一步的环化。 因此四环化是 设想通过两个连续的高产率双环化来实现 流程. 所有上述方法研究将在 实现不对称环化和合成产物的背景 已知或潜在的药用价值。 直接目标是，例如， 促盐和抗炎皮质激素（用于治疗各种 疾病，例如，关节炎），19-降甾体化合物（用于口服 维生素D3代谢物和类似物（用于控制 涉及钙代谢的疾病，例如，骨发育不良）和胆汁 酸如鹅去氧胆酸（用于溶解胆结石）。 辅助研究包括酶模型的开发以及 模板系统，可以帮助仿生多烯环化。 它还建议利用任何特别有前途的新行为 在上述研究中发现。