不对称催化的直接型插烯aldol反应及其在有机合成中的应用

This project is targeting the chiral copper(I) complex catalyzed direct vinylogous aldol reaction (DVAR) with high regioselectivity and high stereoselectivity, including normal vinylogous aldol reaction, homo-vinylogous aldol reaction and bis-vinylogous aldol reaction. The direct reaction does not need the preparation of the silicon dienolates beforehand and also does not lead to the formation of silanes as side products, which is a 100% atom-economic reaction. The project is planning to control the regioselectivity and stereoselectivity of DVAR through fine tuning of the steric hindrance and electronic properties of nucleophiles and chiral ligands, because bulky nucleophiles and ligands are beneficial in DVAR. In the normal vinylogous aldol reaction, the very bulky nucleophiles and ligands benefit the formation of the E olefin in the product (delta-hydroxyl-alpha,beta-unsaturated carbonyl compound) while the relatively less bulky nucleophiles and ligands favor the formation of the Z olefin in the product. In the homo-vinylogous aldol reaction, copper(I) enolate of cyclopropyl acetic ester or amide (nucleophile) with high electronic density is in favor of the opening of the cyclopropyl group and thus lead to homo-vinylogous addition to aldehyde. In the bis-vinylogous aldol reaction, an extra bulky metallic Lewis acid is required to form a bimetallic catalytic system with copper(I) trienolate to ensure the high enantioselectivity. The normal vinylogous aldol reaction would find application in the organic synthesis, which will be employed as a key methodology to be applied in the efficient asymmetric synthesis of Fostriecin and Atorvastatin. Fostriecin is a natural product with a broad-spectrum of antitumor activity and is a star molecule in the development of antitumor drugs. Atovastatin, the active ingredient in Lipitor, is in widespread clinical use for the treatment of hypercholesterolemia and was the first drug in human history with an annual sale over 10 billion US dollars. Furthermore, the homo-vinylogous aldol reaction and the bis-vinylogous aldol reaction are new, which would offer new possibilities of disconnection in the retro-synthetic analysis of natural products and drugs.

本项目以高活性的一价铜双膦络合物为催化剂，研发高区域选择性、高对映选择性的插烯aldol反应、高位插烯aldol反应和插二烯aldol反应。计划通过对亲核试剂以及手性配体的位阻和电子性质的精细调节，来避免alpha加成，实现插烯反应。在插烯aldol反应中，具有非常大的位阻的底物和手性配体有利于产物delta-羟基-alpha,beta-不饱和化合物中的双键呈反式构型，而具有一般大的位阻的底物和手性配体有利于产物中的双键呈顺式的构型。在高位插烯aldol反应中，通过调节底物和手性配体的结构来增加烯醇铜络合物的电子密度有利于环丙基的开环。在插二烯aldol反应中，使用大位阻的路易斯酸作为共催化剂与一价铜烯醇络合物形成双金属催化体系，有利于实现高的对映选择性。插烯aldol反应可以作为关键反应方法学，应用于抗癌活性分子Fostriecin和降血脂药物分子Atorvastatin的高效合成。

插烯反应是有机合成中一类非常重要的有机化学反应，被广泛应用于复杂天然产物分子和药物分子的合成中。本项目聚焦于铜催化的插烯反应研究，主要可以分为两个方面的内容：即亲核的插烯反应和亲电的插烯反应。在亲核的插烯反应中，我们完成了:（a）一价铜催化的β,γ-不饱和吡唑酰胺的不对称插烯、插二烯Mannich型反应；（b）一价铜催化的β,γ-不饱和酯的不对称插烯aldol反应；（c）铜催化的不饱和化合物（包括α,β-不饱和化合物和β,γ-不饱和化合物）的插烯氧化反应；（d）一价铜催化的γ-卤代-α,β-不饱和吡唑酰胺的不对称插烯Mannich型反应；（e）一价铜催化的烯丙基磷酸酯和烯丙基砜的不对称插烯aldol型反应；（f）一价铜催化的γ-烷基取代-α,β-不饱和吡唑酰胺的不对称插烯Mannich型反应；（g）一价铜催化的3-炔酸酯的不对称插炔aldol反应。基于我们在一价铜催化的不对称领域的系列研究，我们认为这类插烯反应中真实的反应中间体为烯丙基一价铜物种，而不是传统意义上认为的二烯醇铜物种。在亲电的插烯反应中，我们实现了（h）一价铜催化的烯丙基硼酸酯对α,β,γ,δ-不饱和化合物的1,6-共轭烯丙基化反应。