A Practical Synthesis of Renin Inhibitor MK-1597 (ACT-178882) via Catalytic Enantioselective Hydrogenation and Epimerization of Piperidine Intermediate

Molinaro, Carmela; Shultz, Scott; Roy, Amélie; Lau, Stephen; Trinh, Thao; Angelaud, Rémy; O’Shea, Paul D.; Abele, Stefan; Cameron, Mark; Corley, Ed; Funel, Jacques-Alexis; Steinhuebel, Dietrich; Weisel, Mark; Krska, Shane

doi:10.1021/jo102070e.s001

jo102070e_si_001.pdf (1.11 MB)

A Practical Synthesis of Renin Inhibitor MK-1597 (ACT-178882) via Catalytic Enantioselective Hydrogenation and Epimerization of Piperidine Intermediate

journal contribution

posted on 2011-02-18, 00:00 authored by Carmela Molinaro, Scott Shultz, Amélie Roy, Stephen Lau, Thao Trinh, Rémy Angelaud, Paul D. O’Shea, Stefan Abele, Mark Cameron, Ed Corley, Jacques-Alexis Funel, Dietrich Steinhuebel, Mark Weisel, Shane Krska

A practical enantioselective synthesis of renin inhibitor MK-1597 (ACT-178882), a potential new treatment for hypertension, is described. The synthetic route provided MK-1597 in nine steps and 29% overall yield from commercially available p-cresol (7). The key features of this sequence include a catalytic asymmetric hydrogenation of a tetrasubstituted ene−ester, a highly efficient epimerization/saponification sequence of 4 which sets both stereocenters of the molecule, and a short synthesis of amine fragment 2.