Asymmetric Synthesis of Akt Kinase Inhibitor Ipatasertib.

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-ß-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.

Palladium-catalyzed α-arylation of sultams with aryl and heteroaryl iodides.

Palladium(0)-catalyzed conditions for the α-arylation of sultams with aryl and heteroaryl iodides have been developed. Arylation of 3-substituted 1,3-propanesultams gave rise to high yields and high diastereomeric ratios, leading to the thermodynamically favored cis product. The arylation was broadly applicable to various electron-rich and electron-poor (hetero)aromatic iodides.