Total Synthesis by Asymmetric Catalytic Methods

该计划的目标是合成结构和生物学上有趣的天然产物 通过创造性地应用不对称催化方法。不同结构和 选择立体化学复杂性来说明和挑战最近发现用于 对映选择性合成，并激发新的催化反应的发展。 比平那丁I（1）是新近发现的西松膜二萜类化合物， 剂该靶标具有密集官能化的14元碳环结构，并呈现出 新合成方法应用的杰出平台。我们建议采用新的 丁烯二酰亚胺方法和反需求异狄尔斯桤木化学，沿着更建立 不对称环氧化反应以引入1中存在的大部分立构中心。完成 该合成将依赖于底物导向的非对映选择性转化以有效地产生 其余的立体中心，包括关键的大环化事件。 在抗癌剂peloruside A（2）中的九个立体中心中，我们计划引入四个立体中心， 对映体纯末端环氧化物的创新开环。除了一个外，其余的立体中心都将 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 非对映选择性的背景。 Eclasin（3）和elisapterosin B是复杂的四环海洋天然产物， 所有的碳立体中心都是相邻的。我们提出了简洁的合成，通过应用不对称 为这些靶特异性发现的催化反应产生双环醌中间体， 随后进行后期分子内环加成反应。 我们计划利用这一优势，完成奎宁（4）的首次不对称催化合成。 最近发现的不对称迈克尔加成和环氧化方法来获得这一经典目标 以简洁和有选择的方式。

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.