Asymmetric Synthesis of Akt Kinase Inhibitor Ipatasertib

• DOI: 10.1021/acs.orglett.7b02228
• Publication Date: 2017-08-31T19:05:32Z
• Authors: Chong Han; Scott Savage; Mohammad Al-Sayah; Herbert Yajima; Travis Remarchuk; Reinhard Reents; Beat Wirz; Hans Iding; Stephan Bachmann; Serena M. Fantasia; Michelangelo Scalone; André Hell; Pirmin Hidber; Francis Gosselin
• Keywords: 01 natural sciences; 0104 chemical sciences

A highly efficient asymmetric synthesis of the Akt kinase inhibitor ipatasertib (1) is reported. The bicyclic pyrimidine 2 starting material was prepared via a nitrilase biocatalytic resolution, halogen-metal exchange/anionic cyclization, and a highly diastereoselective biocatalytic ketone reduction as key steps. The route also features a halide activated, Ru-catalyzed asymmetric hydrogenation of a vinylogous carbamic acid to produce α-aryl-β-amino acid 3 in high yield and enantioselectivity. The API was assembled in a convergent manner through a late-stage amidation/deprotection/monohydrochloride salt formation sequence.