含吡咯及吲哚基团的N-N轴手性化合物的酶催化合成

Biocatalytic atroposelective synthesis of N−N axially chiral pyrroles and indoles

摘要:

目前轴手性的生物催化合成面临一定挑战。为拓展轴手性化合物的生物合成方法，本研究进行了醇脱氢酶催化的含吡咯和吲哚基团的N−N轴手性醛的还原反应，通过对92种醇脱氢酶进行筛选得到2种立体选择性相反的菌株，利用动力学拆分以最高72%转化率、98% e.e.合成了具有良好选择性的R以及S构型产物。确定了N−N轴的绝对构型以及旋转能垒，并通过量级合成和衍生化实验展示了当前方法的实用性。本研究首次提供了具有潜在药用价值的N−N轴手性化合物的酶促合成策略，为酶催化轴手性化合物的合成奠定了良好基础。

Abstract:

The biocatalytic synthesis of atropisomeric scaffolds remains challenging. Herein, to expand the biosynthetic approaches to axial chiral compounds, we present the alcohol dehydrogenase-catalyzed stereodivergent reduction of N−N axially chiral aldehydes with pyrroles and indoles, two strains with opposite stereoselectivity were obtained by screening 92 alcohol dehydrogenases, affording both R- and S-configured products with moderate to excellent selectivity (up to 72% conversion and 98% e.e.). The conformational stability was confirmed, and upscaled synthesis and synthetic transformations demonstrated the utility of the current methodology. This study provides the first enzymatic strategy to access N−N axially chiral compounds with potential pharmaceutical applications.