A Highly Diastereoselective and Enantioselective Synthesis of Polysubstituted Pyrrolidines via an Organocatalytic Dynamic Kinetic Resolution Cascade

Highly functionalized pyrrolidine and piperidine analogues, with up to three stereogenic centers, were synthesized in good yield (50–95%), excellent dr (single isomer), and high ee (>90%) using a Cinchona alkaloid-derived carbamate organocatalyst. High stereoselective synergy was achieved by combining a reversible aza-Henry reaction with a dynamic kinetic resolution (DKR)-driven aza-Michael cyclization. Whereas both reactions proceed with moderate enantioselectivities (50–60% for each step), high enantioselectivities are obtained for the overall products devoid of dr sacrifice.

本研究采用金鸡纳生物碱（Cinchona alkaloid）衍生的氨基甲酸酯类有机催化剂，成功合成了至多含三个手性中心（stereogenic center）的高官能化吡咯烷（pyrrolidine）与哌啶（piperidine）类似物，反应收率良好（50%~95%），非对映选择性比（dr, diastereomeric ratio）优异（仅生成单一异构体），对映体过量值（ee, enantiomeric excess）高于90%。通过将可逆氮杂亨利（aza-Henry）反应与动态动力学拆分（DKR）驱动的氮杂迈克尔（aza-Michael）环化反应相结合，实现了优异的立体选择性协同效应。尽管两步反应各自的对映选择性中等（单步仅为50%~60%），但最终产物仍可获得高对映选择性，且未牺牲非对映选择性。