Lee Hooseung, Nam Hyeongwoo, Lee Sarah Yunmi
Department of Chemistry, Yonsei University, Seoul 03722, Republic of Korea.
J Am Chem Soc. 2024 Feb 7;146(5):3065-3074. doi: 10.1021/jacs.3c09911. Epub 2024 Jan 28.
Chiral 1-pyrrolines containing a nitrile motif serve as crucial structural scaffolds in biologically active molecules and exhibit diversity as building blocks owing to their valuable functional groups; however, the asymmetric synthesis of such compounds remains largely unexplored. Herein, we present an enantio- and diastereoselective method for the synthesis of α-chiral nitrile-containing 1-pyrroline derivatives bearing vicinal stereocenters through the design and introduction of chiral cyclopropenimine-based bifunctional catalysts featuring a thiourea moiety. This synthesis entails a highly stereoselective conjugate addition of α-iminonitriles to a wide array of enones, followed by cyclocondensation, thereby affording a series of cyanopyrroline derivatives, some of which contain all-carbon quaternary centers. Moreover, we demonstrate the synthetic utility of this strategy by performing a gram-scale reaction with 1% catalyst loading, along with a variety of chemoselective transformations of the product, including the synthesis of a vildagliptin analogue. Finally, we showcase the selective synthesis of all four stereoisomers of the cyanopyrroline products through -to- isomerization, highlighting the versatility of our approach.
含有腈基序的手性1-吡咯啉是生物活性分子中的关键结构骨架，由于其具有重要的官能团，作为构建单元表现出多样性；然而，此类化合物的不对称合成在很大程度上仍未得到探索。在此，我们通过设计和引入具有硫脲部分的基于手性环丙烯亚胺的双功能催化剂，提出了一种对映和非对映选择性方法，用于合成带有邻位立体中心的含α-手性腈的1-吡咯啉衍生物。该合成过程包括α-亚氨基腈对多种烯酮的高度立体选择性共轭加成，随后进行环缩合反应，从而得到一系列氰基吡咯啉衍生物，其中一些含有全碳季碳中心。此外，我们通过以1%的催化剂负载量进行克级反应，以及对产物进行各种化学选择性转化，包括合成维格列汀类似物，证明了该策略的合成实用性。最后，我们通过顺反异构化展示了氰基吡咯啉产物的所有四种立体异构体的选择性合成，突出了我们方法的多功能性。
