TOTAL SYNTHESIS BY ASSYMETRIC CATALYTIC METHODS

该建议概述了生物活性天然的合成 通过高效的立体化学反应， 手性结构单元的组装。多个目标在一个 通过利用急剧扩大的 通过现代不对称催化， 方法. 细胞毒性剂龙眼苷（1）的四个立体中心中有三个是 沿着延伸的烃链显示。一个直截了当 合成计划描述涉及缩合四个光学 通过催化水解动力学拆分获得的活性环氧化物 最近在我们的实验室里发现的。 牛海绵蛋白A（2）显示出抗DNA聚合酶β的双重活性 和HIV逆转录酶。2中的所有三个立体中心都可以是 通过有效的不对称催化方法获得，从而允许 天然的立体化学类似物的直接制备 产品 Fostriecin（3）是一种很有前途的细胞毒性药物，目前正在研究中。 欧洲的临床试验提出了一种新的方法， 涉及水解动力学的单磷酸化邻二醇核 环氧酮的拆分和非对映选择性烷基化。合成 的δ-不饱和内酯的33将进行研究， 一氧化丁二烯的加工，最近可容易地获得 通过多相和均相催化技术。所得 天然产物的路线设置三个四个立体中心的手性 催化，并且高度适用于制备立体异构体， 和结构类似物。 FR 901464（4）的合成旨在说明我们的合成。 一个更详细的目标，通过组装相对 复杂的手性结构单元。一种有用的合成药物的开发 路线将作为合作的基础， 阐明这种转录调节剂的作用方式。这 这项研究还将有助于说明目标结构如何确定需要 并指导新的不对称催化方法的发展。

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.