Fandrick KR * et al. Boehringer-Ingelheim Pharmaceuticals Inc., Ridgefield, USA and Boehringer Ingelheim (Canada) Ltd., Laval, Canada
Concise and Practical Asymmetric Synthesis of a Challenging Atropisomeric HIV Integrase Inhibitor.
Angew. Chem. Int. Ed. 2015;
54: 7144-7148
Key words
HIV integrase inhibitor - transfer hydrogenation - Suzuki–Miyaura reaction -
tert-butyl ethers
Significance
The target molecule is an atropisomeric integrase inhibitor that is of interest for the treatment of HIV. Noteworthy steps in the synthesis depicted include (1) a copper(I)-catalyzed acylation of quinoline A, (2) an asymmetric transfer hydrogenation of the α-keto ester C mediated by the ligand D, and (3) a ligand-controlled asymmetric Suzuki–Miyaura reaction mediated by the ligand F.
Comment
The installation of the tert-butyl ether group on the bis(quinoline) scaffold of I was challenging, because intermediate I contains two basic nitrogen atoms and the tert-butyl ether is buried within a very sterically crowded environment. Best results were obtained using the trichloroacetimidate J together with bis(trifluoromethane)sulfonimide.
