NEW APPROACH TO ENANTIOPURE OXYGEN HETEROCYCLES

许多杂环化合物，包括吗啡、二氢吡喃和二氢呋喃等化合物，已被证明具有重要的生物活性。这项建议描述了一种合成杂环中含有氧的对映体杂环的新方法。这种新的合成方法是基于烷基钛试剂与无手性缩醛的催化不对称加成反应。除了提供了一条合成手性仲醇和叔醇的新路线外，如果以环缩醛为底物，该方法还提供了一条合成杂环对映体的新路线；缩醛加成得到的醇产品可以进一步转化为杂环。本建议详细介绍了不对称加成方法在底物范围、催化剂开发和反应条件优化方面的发展。描述了可用于将加成产物转化为杂环的一般策略。然后将这些策略应用于合成具有生物活性的杂环SR 144190(NK-1抑制剂)、芒果-A(PAF拮抗剂)和塞米农(抗生素)。

A wide variety of heterocyclic compounds, including compounds such as morpholines, dihydropyrans, and dihydrofurans have been shown to have important biological activities. This proposal describes a new approach to the synthesis of enantiopure heterocycles which contain an oxygen in the heterocyclic ring. This new synthetic approach is based on a method for the catalytic asymmetric addition of alkyltitanium reagents to achiral acetals. The addition to providing a new route to chiral secondary and tertiary alcohols, this method provides a new route to enantiopure heterocycles if cyclic acetals are used as substrates; the alcohol products resulting from the addition to the acetal may be further transformed to heterocycles. This proposal details the development of the asymmetric addition methodology with respect to substrate scope, catalyst development, and optimization of the reaction conditions. General strategies which could be used to transform the addition products into heterocycles are described. These strategies are then applied to the synthesis of the biologically active heterocycles SR 144190 (a NK-1 inhibitor), Mangone- A (a PAF antagonist), and Sesaminone (an antibiotic).