TOTAL SYNTHESIS BY ASSYMETRIC CATALYTIC METHODS

不对称催化法全合成

• 批准号: 6520014
• 负责人: ERIC N JACOBSEN
• 金额: $ 25.49万
• 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 2003-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6520014
• 关键词: chemical structure function; chemical synthesis; cytotoxicity; drug design /synthesis /production; reverse transcriptase inhibitors; stereochemistry

This proposal outlines the synthesis of biological active natural products of varying stereochemical complexity through the efficient assembly of chiral building blocks. Several targets are accessed in a convergent manner by taking advantage of the dramatically expanded "chiral pool" made readily available through modern asymmetric catalytic methods. Three of the four stereocenters of the cytotoxic agent longanin (1) are displayed along an extended hydrocarbon chain. A straightforward synthesis plan is described involving condensation of four optically active epoxides obtained by a catalytic hydrolytic kinetic resolution recently discovered in our labs. Taurospongin A (2) displays dual activity against DNA polymerase beta and HIV reverse transcriptase. All three stereocenters in 2 can be accessed by efficient asymmetric catalytic methods, thereby allowing the straight-forward preparation of stereochemical analogs of the natural product. Fostriecin (3) is a promising cytoxic agent currently undergoing clinical trials in Europe. New methodology is proposed to access its monophosphorylated vicinal diol core involving hydrolytic kinetic resolution and diastereoselective alkylation of epoxyketones. Synthesis of the delta-unsaturated lactone of 33 will be investigated by elaboration of butadiene monoxide, recently made readily available through heterogeneous and homogenous catalytic technology. The resulting route to the natural products sets three of four stereocenters by chiral catalysis and is highly adaptable to the preparation of stereoisomeric and structural analogs. The synthesis of FR901464 (4) is intended to illustrate our synthetic approach on a more elaborate target through assembly of relatively complex chiral building blocks. The development of a useful synthetic route will serve as the basis for a collaboration directed toward elucidation of the mode of action of this transcription regulator. This study will also serve to show how a target structure can define the need and guide the development of new asymmetric catalytic methods.

该提议概述了生物活性天然的合成 通过有效的立体化学复杂性有所不同的产品 手性构建块的组装。在一个目标中访问了几个目标 通过利用巨大扩展的收敛方式 通过现代的不对称催化，“手性池”很容易获得 方法。 细胞毒性剂longanin（1）的四个立体中心中的三个是 沿着扩展的烃链显示。直接 描述了合成计划，涉及四个光学上的凝结 通过催化水解动力学分辨率获得的活性环氧 最近在我们的实验室中发现。 Taurospongin A（2）显示针对DNA聚合酶β的双重活动 和HIV逆转录酶。 2中的所有三个立体中心都可以 通过有效的不对称催化方法访问，从而允许 天然立体化学类似物的直接制备 产品。 Fostriecin（3）是目前正在经历的有前途的细胞毒性剂 欧洲的临床试验。提出了新方法来访问其 涉及水解动力学的单磷酸化囊泡二醇核心 环酮酮的分辨率和映选择性烷基化。合成 33的三角洲不饱和内酯在 丁二烯一氧化丁烷的详细说明，最近很容易获得 通过异质和同质催化技术。结果 通往天然产品的途径设置了手性的四个立体中心中的三个 催化，高度适应立体异构体的制备 和结构类似物。 FR901464（4）的合成旨在说明我们的合成 通过组装相对较高的目标接近更精致的目标 复杂的手性构建块。有用的合成的发展 路线将作为指向合作的基础 阐明该转录调节器的作用方式。这 研究还将表明目标结构如何定义需求 并指导新的不对称催化方法的发展。