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Papers of the Week

Papers: 3 Jun 2023 - 9 Jun 2023

Basic Science

In Vitro Studies, Pharmacology/Drug Development

2023 Jun 04

Org Lett


Asymmetric Hydrogenation of Indazole-Containing Enamides Relevant to the Synthesis of Zavegepant Using Neutral and Cationic Cobalt Precatalysts.


Mendelsohn LN, MacNeil CS, Esposito MR, Pabst TP, Leahy DK, Davies IW, Chirik PJ


The cobalt-catalyzed asymmetric hydrogenation of indazole-containing enamides relevant to the synthesis of the calcitonin gene-related peptide (CGRP) receptor antagonist, zavegepant (), approved for the treatment of migraines, is described. Both neutral bis(phosphine)cobalt(II) and cationic bis(phosphine)cobalt(I) complexes served as efficient precatalysts for the enamide hydrogenation reactions, providing excellent yield and enantioselectivities (up to >99.9%) for a range of related substrates, though key reactivity differences were observed. Hydrogenation of indazole-containing enamide, methyl ()-2-acetamido-3-(7-methyl-1-indazol-5-yl)acrylate, was performed on a 20 g scale.