Total Synthesis by Asymmetric Catalytic Methods

不对称催化全合成

• 批准号: 7048641
• 负责人: ERIC N JACOBSEN
• 金额: $ 41.62万
• 依托单位: HARVARD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-04-01 至 2008-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7048641
• 关键词: Diels Alder reaction; antineoplastics; biological products; chemical addition; chemical synthesis; cyclization; cytotoxicity; diterpenes; drug design /synthesis /production; epoxides; marine toxins; quinine; quinones; stereochemistry

DESCRIPTION (provided by applicant): This program has as its goal the synthesis of structurally and biologically interesting natural products through creative application of asymmetric catalytic methodologies. Targets of varying structural and stereochemical complexity are selected to both illustrate and challenge recently discovered methods for enantioselective synthesis, and to inspire development of new catalytic reactions. Bipinnatin I (1) is a recently discovered member of the cembrane diterpenoids and a promising cytotoxic agent. This target has a densely functionalized 14-membered carbocyclic structure, and presents an outstanding platform for the application of new synthetic methodologies. We propose to apply novel butenolide methodology and inverse demand hetero-Diels Alder chemistry, along with more established asymmetric epoxidation reactions to introduce the majority of the stereocenters present in 1. Completion of the synthesis will rely on substrate-directed diastereoselective transformations for the efficient generation of the remaining stereocenters, including the key macrocyclization event. Of the nine stereocenters in the anti-cancer agent peloruside A (2), we plan to introduce four through innovative ring-openings of enantiopure terminal epoxides. All but one of the remaining stereocenters will then be established by extending known catalytic, enantioselective methods to catalyst-controlled diastereoselective contexts. Colombiasin (3) and elisapterosin B are complex tetracyclic marine natural products incorporating two contiguous all carbon-stereogenic centers. We propose concise syntheses through application of asymmetric catalytic reactions discovered specifically for these targets to generate bicyclic quinone intermediates, followed by late stage intramolecular cycloaddition reactions. We propose to accomplish the first asymmetric catalytic synthesis of quinine (4), taking advantage of recently discovered asymmetric Michael addition and epoxidation methodologies to access this classic target in a concise and selective manner.

描述(由申请人提供)：该项目的目标是通过创造性地应用不对称催化方法来合成具有结构和生物意义的天然产物。选择不同结构和立体化学复杂性的目标既是为了说明和挑战最近发现的对映选择性合成方法，也是为了激励新催化反应的发展。Bipinnatin I(1)是近几年发现的一种新的膜二萜类化合物，是一种很有前途的细胞毒剂。该目标化合物具有高度官能化的14元碳环结构，为新的合成方法的应用提供了一个突出的平台。我们建议应用新的丁烯内酯方法和反向需求异Diels Alder化学，以及更成熟的不对称环氧化反应来引入1中存在的大多数立体中心。合成的完成将依赖于底物导向的非对映选择性转化来有效地产生剩余的立体中心，包括关键的大环化事件。在抗癌剂Peloruside A(2)中的9个立体中心中，我们计划通过创新的对映末端环氧化物开环引入4个。所有剩余的立体中心将通过将已知的催化、对映选择性方法扩展到催化剂控制的非对映选择性环境来建立。哥伦比亚菌素(3)和伊利沙蝶菌素B是复杂的四环海洋天然产物，含有两个毗连的全碳立体中心。我们建议通过应用专为这些目标发现的不对称催化反应来合成双环苯二酚中间体，然后进行后期的分子内环加成反应。我们打算完成第一次不对称催化合成奎宁(4)，利用最近发现的不对称Michael加成和环氧化方法来以简明和选择性的方式实现这一经典目标。