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

Lauren N. Mendelsohn, Connor S. Macneil, Madison R. Esposito, Tyler P. Pabst, David K. Leahy, Ian W. Davies, Paul J. Chirik

Research output: Contribution to journalArticlepeer-review

Abstract

The cobalt-catalyzed asymmetric hydrogenation of indazole-containing enamides relevant to the synthesis of the calcitonin gene-related peptide (CGRP) receptor antagonist, zavegepant (1), 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 (Z)-2-acetamido-3-(7-methyl-1H-indazol-5-yl)acrylate, was performed on a 20 g scale.

Original languageEnglish (US)
JournalOrganic letters
DOIs
StateAccepted/In press - 2023

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Physical and Theoretical Chemistry
  • Organic Chemistry

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