POLYKETIDES SYNTHESIS, CONFORMATION, AND BIOSYNTHESIS

这项建议包括三个互相关连但又各不相同的项目 处理聚酮化合物化学和生物化学的重要方面。 这些是：（1）综合。 本项目分为两个部分。 （1-1） 不对称合成 由于非对称的特殊意义 在复杂的天然产物合成中，我们清楚地认识到， 探索实现（接近）完美不对称诱导的方法 在基本的有机反应中，包括（a）羟醛缩合反应（到 构建一些基本的1，3-二醇体系），（B）Diels-Alder反应，（c） 硼氢化，（d）酮还原，和（e）环氧化。 (1-1)总 苔藓抑素1（C47 H68 O 17），一种海洋产品（分离自 具有显著生物活性的稻纵卷叶螟（Bugula neritina）， 白血病患者的平均寿命延长了52-95%， 小鼠 (2)多羟基无环体系的构象分析。 我们 我们将继续努力建立可靠的计算机程序， 构象分析的多羟基化的非环状系统，这往往是 嵌入具有生物学意义的天然产物（例如，海葵毒素）中， 以及用于产生这些化合物的合成中间体。 因此，NMR 光谱学将用于确定溶液的目的 这些无环系统的构象。 (3)关于“三位一体”的机制研究 β-酮酰硫解酶催化的碳-碳键形成反应 从动胶菌中分离出的纯硫解酶供应充足 ramigera现在在我们手中，我们将启动一个长期项目，旨在 这一生物克莱森缩合的机制阐明。 阐述 首先进行动力学研究，然后是氨基酸 通过基因克隆技术对酶进行测序。 的 通过晶体学的催化剂的三维视图和 酶促反应的机理解释将完成 项目 试图回答酶如何 降低Δ H以及Δ S将在最后带来一个新的 设计催化剂和试剂的一个或多个概念， 有机化学。

This proposal consists of three interrelating but different projects dealing with important aspects of polyketide chemistry and biochemistry. These are: (1) SYNTHESIS. This project is divided into two parts. (1-1) Asymmetric Synthesis. Because of the special significance of asymmetric induction clearly recognized in complex natural products synthesis, we plan to explore methodologies for effecting (near-) perfect asymmetric induction in fundamental organic reactions, including (a) the aldol reaction (to construct some basic 1,3-diol systems), (b) the Diels-Alder reaction, (c) hydroboration, (d) ketone reduction, and (e) epoxidation. (1-1) Total synthesis of bryostatin 1 (C47H68O17), a marine product (isolated from Bugula neritina) that exhibits significant biological activities as demonstrated by a 52-95% extension of the average lifetime of leukemic mice. (2) CONFORMATIONAL ANALYSIS OF POLYHYDROXYLATED ACYCLIC SYSTEMS. We will continue our attempts to establish reliable computer programs for the conformational analysis of polyhydroxylated acyclic systems which are often embedded in natural products of biological significance (e.g. palytoxin) as well as in synthetic intermediates leading to these compounds. Thus, NMR spectroscopy will serve the purpose of determining the solution conformation of these acyclic systems. (3) MECHANISTIC STUDIES ON THE CARBON-CARBON BOND FORMING REACTION CATALYZED BY BETA-KETOACYL THIOLASE. With an abundant supply of the pure thiolase isolated from Zoogloea ramigera now in our hands, we will launch a long-range project aimed at the mechanistic elucidation of this bilogical Claisen condensation. Elaborate kinetic studies to be undertaken first will be followed by the amino acid sequencing of the enzyme through the gene-cloning technique. The three-dimensional view of the catalyst through crystallography and the mechanistic interpretation of the enzymatic reaation will complete the project. Efforts to answer the fundamental question of how the enzyme lowers Delta H as well as Delta S will bring about, at the end, a new concept or concepts in designing catalysts and reagents, an important goal of organic chemistry.