POLYKETIDES SYNTHESIS, CONFORMATION, AND BIOSYNTHESIS

该提案由三个相互关联但又不同的项目组成。 介绍聚酮化学和生物化学的重要方面。 它们是：(1)合成。该项目分为两个部分。(1-1) 不对称合成。由于非对称性的特殊意义 诱导在复杂的天然产物合成中得到明显认可，我们计划 探索实现(近乎)完美的不对称诱导的方法 在基本的有机反应中，包括(A)羟醛反应 构造一些基本的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)总计 海产品Bryostatin 1(C47H68O17)的合成 Bugula neritina)具有显著的生物活性 白血病的平均寿命延长了52%-95% 老鼠。(2)多羟基无环体系的构象分析。我们 将继续努力建立可靠的计算机程序 多羟基无环体系的构象分析 嵌入在具有生物意义的天然产品中(如羽衣藻毒素) 以及在合成中间体中导致这些化合物。因此，核磁共振 光谱学将服务于确定溶液的目的 这些非环系统的构象。(3)岩土力学研究。 β-酮酰基硫解酶催化的碳-碳键形成反应。 从动物胶中分离出的硫解酶供应充足 拉米格拉现在掌握在我们手中，我们将启动一个旨在 对这种生物克莱森凝聚的机械解释。详述 将首先进行动力学研究，然后再进行氨基酸 通过基因克隆技术对该酶进行测序。这个 通过结晶学和电子显微镜观察催化剂的三维结构 对酶反应的机械论解释将完成 项目。努力回答基本问题，即酶是如何 降低德尔塔H以及德尔塔S最终将带来一个新的 催化剂和试剂设计中的一个或多个概念，一个重要目标 有机化学的。

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.