醇质子作为氢源的不对称还原

Alcohols are one of the common hydrogen sources in asymmetric reduction. The hydrogen atoms on C-H and O-H in alcohols are simultaneously used. However, the only utilization of the proton of alcohols as hydrogen source for asymmetric reduction is still highly challenging and no related reports were displayed. These difficulties can be attributed to the following factors including the compatibility of chiral metal catalyst and activator, and control of stereoselectivity in asymmetric reduction. To address these challenging issues, we propose the strategies of the regular of activator and catalyst activation. The activator should easily coordinate with oxygen atom of alcohols and the formation bond energy is higher than O-H bond energy of alcohols which promotes generation of metal hydride species. The regulation of catalyst solves the problem of stereoselectivity through tuning of steric and electronic effects. Based on the above strategies, we propose to develop the proton of alcohols as hydrogen source for the asymmetric reduction of unsaturated compounds including ketones, imines and heteroarenes, and figure out the reaction mechanism using HRMS, NMR, isotope experiments and density functional theory. This project provides an efficient method for the synthesis of chiral compounds, especially chiral deuterium compounds. Some of these proposals have been proved to be possible in the preliminary research.

在不对称还原反应中，醇（如异丙醇）是一类常见的氢源，其碳-氢和氧-氢的氢在还原过程中被同时使用。但是仅以醇的质子作为氢源的手性还原反应却未见报道。主要难点有：活化剂与催化剂之间的匹配性；反应的立体选择性控制。针对上述难点，本项目拟采用活化剂调控和催化剂调控策略。采用活化剂调控，使得活化剂与醇上氧优先结合，且络合键能大于醇上氧-氢键能，促使醇质子与金属催化剂反应生成金属-氢物种；调节催化剂的空间环境和电子效应实现还原反应的高立体选择性控制。计划开展以下两个方面研究：1）采用活化剂活化醇，实现醇质子与金属催化剂结合生成金属-氢物种，并将其应用于酮、亚胺和芳香杂环化合物的不对称还原反应；2）利用高分辨质谱、核磁共振、同位素实验和理论计算研究醇质子作为氢源的不对称还原机理。本项目研究为手性化合物，尤其是手性氘代化合物的合成提供简洁且有效的途径。目前，初步的实验结果证明了申请项目的可行性。

按照申请书的研究计划，开展了醇质子作为氢源的不对称还原：1）钯催化醇质子作为氢源的不对称还原反应。采用活化剂调控策略活化醇，实现醇质子与手性钯催化剂结合生成手性钯-氢物种，并将其应用于1,3-二酮和吲哚的不对称还原，高对映选择性制备手性β-羟基酮化合物和手性吲哚啉衍生物。通过核磁共振、高分辨质谱、氘代同位素效应实验和理论计算阐明反应机理。2）镍催化醇质子作为氢源的不对称还原反应。实现醇质子作为氢源，廉价金属镍催化环状磺酰亚胺的不对称还原反应，高对映选择性合成手性磺酰胺。通过对照实验和氘代同位素效应实验研究反应机理。上述工作为手性化合物，尤其是手性氘代化合物的合成提供有效的途径。项目执行期间共发表研究论文6篇，申请中国发明专利1件。