转氨作用
化学
非对映体
立体化学
组合化学
肽键
拟肽
酰胺
药效团
乌吉反应
立体中心
对映选择合成
肽
催化作用
酶
有机化学
生物化学
异氰
作者
Nobuyoshi Yasuda,Ed Cleator,Birgit Kosjek,Jianhua Yin,Bangping Xiang,Fanglin Chen,Shen-Chun Kuo,Kevin M. Belyk,Peter R. Mullens,Adrian Goodyear,John S. Edwards,Brian Bishop,Scott S. Ceglia,Justin K. Belardi,Lushi Tan,Zhiguo J. Song,Lisa DiMichele,Robert A. Reamer,Fabien L. Cabirol,Weng Lin Tang,Guiquan Liu
标识
DOI:10.1021/acs.oprd.7b00293
摘要
The development of a scalable asymmetric route to a new calcitonin gene-related peptide (CGRP) receptor antagonist is described. The synthesis of the two key fragments was redefined, and the intermediates were accessed through novel chemistry. Chiral lactam 2 was prepared by an enzyme mediated dynamic kinetic transamination which simultaneously set two stereocenters. Enzyme evolution resulted in an optimized transaminase providing the desired configuration in >60:1 syn/anti. The final chiral center was set via a crystallization induced diastereomeric transformation. The asymmetric spirocyclization to form the second fragment, chiral spiro acid intermediate 3, was catalyzed by a novel doubly quaternized phase transfer catalyst and provided optically pure material on isolation. With the two fragments in hand, development of their final union by amide bond formation and subsequent direct isolation is described. The described chemistry has been used to deliver over 100 kg of our desired target, ubrogepant.
科研通智能强力驱动
Strongly Powered by AbleSci AI