NEW APPROACH TO ENANTIOPURE OXYGEN HETEROCYCLES

各种各样的杂环化合物，包括morpholines， dihydropyran和dihydrofurans等化合物已被证明具有重要的生物活性。本文提出了一种合成杂环含氧对映纯杂环的新方法。这种新的合成方法是基于烷基钛试剂催化不对称加成到非手性缩醛的方法。该方法除了提供了一条合成手性仲醇和叔醇的新途径外，还提供了一条以环缩醛为底物合成对映纯杂环的新途径；缩醛加成后的醇产物可进一步转化为杂环。本提案详细介绍了不对称加成方法的发展，涉及底物范围、催化剂开发和反应条件的优化。介绍了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化合物SR 144190（一种NK-1抑制剂）、Mangone- a（一种PAF拮抗剂）和Sesaminone（一种抗生素）。

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).