手性1,2-二氢吡啶化合物的合成研究进展

Recent Advances in Synthesis of Chiral 1,2-Dihydropyridines

手性1,2-二氢吡啶化合物是重要的手性砌块,可通过还原或环加成反应来方便构建药物分子中十分重要的手性含氮杂环化合物如哌啶等,因此其高效合成对于新药研发具有重要的研究意义.利用手性源和手性辅基诱导的策略需要使用化学计量的手性试剂,发展不对称催化的方法来合成结构多样性的手性1,2-二氢吡啶化合物无疑十分重要.自2004年报道首例对活化吡啶的不对称C2位亲核加成反应以来,该策略被成功用于发展合成C2位芳基、烷基、炔基等取代的手性1,2-二氢吡啶化合物的不对称催化新方法.最近,一种新的基于亚胺不对称转化的串联反应策略也被设计开发用于多样性合成这类手性含氮杂环化合物.本综述概述了相关研究进展,并介绍了相关研究难点和未来的发展空间.

Chiral 1,2-dihydropyridines represent a class of versatile building blocks that can undergo diversifying reactions of conjugated dienes such as reduction or cycloaddition reaction,allowing facile synthesis of chiral piperidines and other nitrogen-containing heterocycles,prominent structural motifs in drugs and bioactive compounds.The efficient synthesis of chiral 1,2-dihydropyridines is highly desirable and beneficial for the drug discovery and development.The chiral pool strategy and chiral auxiliary based synthesis require the use of stoichiometric chiral reagents,so it is much sought-after to develop catalytic asymmetric methods to synthesize structurally diverse chiral 1,2-dihydropyridines.Since the pioneering catalytic enantioselective addition of nucleophiles to the C2 position of achiral activated pyridine derivatives in 2004,this strategy has been successfully employed for the catalytic synthesis of optically active 1,2-dihydropyridines bearing an aryl,alkyl or alkynyl group at the C2 position.Recently,tandem sequences was reported based on the asymmetric conversion of C=N bonds as an emerging strategy for the synthesis of multisubstituted chiral 1,2-dihydropyridines.This review summarizes the advances in this field,and discusses the challenges and synthetic opportunities for future development.