Total Synthesis by Asymmetric Catalytic Methods

不对称催化全合成

• 批准号: 6739093
• 负责人: ERIC N JACOBSEN
• 金额: $ 40.35万
• 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 2007-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6739093
• 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不对称催化方法的创造性应用合成结构和生物学上有趣的天然产物。选择不同结构和立体化学复杂性的靶标来说明和挑战最近发现的对映选择性合成方法，并激发新催化反应的开发。 Bipinnatin I (1) 是最近发现的西松二萜类化合物的成员，也是一种有前途的细胞毒剂。该靶标具有密集功能化的14元碳环结构，为新合成方法的应用提供了一个出色的平台。我们建议应用新的丁烯内酯方法和逆需求杂狄尔斯阿尔德化学，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生成剩余的立体中心，包括关键的大环化事件。在抗癌剂 peloruside A (2) 的九个立体中心中，我们计划通过对映体纯末端环氧化物的创新开环引入四个。然后，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，将建立除其中一个之外的所有剩余立体中心。 Columbiasin (3) 和 elisapterosin B 是复杂的四环海洋天然产物，包含两个连续的全碳立体中心。我们提出通过应用专门针对这些目标发现的不对称催化反应来生成双环醌中间体，然后进行后期分子内环加成反应来进行简洁的合成。我们建议利用最近发现的不对称迈克尔加成和环氧化方法，以简洁和选择性的方式实现奎宁（4）的首次不对称催化合成。