ABSTRACT
We report the design, synthesis, and optimization of the first, selective activators of cardiac myosin. Starting with a poorly soluble, nitro-aromatic hit compound (1), potent, selective, and soluble myosin activators were designed culminating in the discovery of omecamtiv mecarbil (24). Compound 24 is currently in clinical trials for the treatment of systolic heart failure.
ABSTRACT
The addition of a stabilized sulfur ylide (generated by the rhodium-catalyzed reaction of Ph(2)S with ethyl diazoacetate) to N-acylhydrazones promoted by a chiral silane Lewis acid leads to the highly diastereo- and enantioselective synthesis of beta-chloro-alpha-hydrazido esters. The addition of electron-rich arenes and ZnCl(2) to the reaction mixture leads to the highly diastereo- and enantioselective one-pot synthesis of diarylalanine derivatives. In both cases, the silane Lewis acid responsible for the first reaction performs the second function of activating the aziridine intermediate toward nucleophilic attack.
ABSTRACT
[Structure: see text] Phenols are effective directing and activating groups for our allylchlorosilane reagents, allowing the highly enantioselective allylation of a range of 2-aminophenol-derived aldimines. When the phenol is incorporated into the substrate ketimines may be allylated highly enantioselectively, leading to the experimentally simple synthesis of a range of tertiary carbinamine structures.
