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

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.

Cobalt‐Catalyzed Asymmetric Hydrogenation: Substrate Specificity and Mechanistic Variability

“…Performing similar chemistry with dehydro-amido esters as substrate, Chirik and co-workers reported the synthesis of 4-aniline-and indazole-containing amido ester derivatives based on the interest of active pharmaceutical synthesis via Co-catalyzed AH as the key step for enantioselection. [54] Surprisingly, both the Co(II)/Zn method and the cationic Co(I) catalyst were active in the hydrogenation of functionalized olefins although a substrate specificity was recognized upon altering either acid/ester or amide substituents (Scheme 19). As an example, the conversion and ee significantly dropped upon changing the aryl part from the anilinederivative (> 99 % conversion, 99 % ee) to the indazolecontaining-amido esters (15 % conversion, 74 % ee) by using the same Co(I) complex.…”

“…This results showed how (coordinating) substrates indeed play an important role in Cocatalyzed AH by altering one electron chemistry at the metal center. [54] Chiral carboxylic acids are present in several pharmaceuticals, agrochemicals, fragrances, and flavors. Development of an efficient method for the synthesis of chiral carboxylic acid is always in demand in both academia and industry.…”

“…AH dehydroamino ester derivatives and synthesis of a pharma intermediate. [54] conversion was found using the corresponding (ethyl) ester derivative (Scheme 20), which suggested that the carboxylic acid acts as activator (via the free OH group) which helps to mediate the activation process. Dissociation of one acac group from Co(acac) 2 by the substrate led to formation of the Co(II)-substrate complex which eventually forms the CoÀ H (A, Scheme 20) under Zn-free conditions.…”

Cobalt‐Catalyzed Asymmetric Hydrogenation: Substrate Specificity and Mechanistic Variability

“…AH dehydroamino ester derivatives and synthesis of a pharma intermediate. [54] Angewandte Chemie conversion was found using the corresponding (ethyl) ester derivative (Scheme 20), which suggested that the carboxylic acid acts as activator (via the free OH group) which helps to mediate the activation process. Dissociation of one acac group from Co(acac) 2 by the substrate led to formation of the Co(II)-substrate complex which eventually forms the CoÀ H (A, Scheme 20) under Zn-free conditions.…”

Cobalt‐Catalyzed Hydrogenation and Deuteration Reactions of Bicyclic Alkenes in an Aqueous Environment

“…Prior research has primarily concentrated on homogenous cobalt catalysts, often necessitating intricate phosphine and amine ligands. [1][2][3][4][5][6][7][8][9] An alternative approach has led to the generation of supported and unsupported cobalt nanoparticles via the reduction of cobalt salts with Grignard or hydride reagents without accompanying ligands. [10][11][12][13][14][15][16] Moreover, leveraging the abundance, cost-effectiveness, and safe handling of water, the hydrogenation of alkenes using H 2 O as a stoichiometric hydrogen source is an appealing alternative to exogenous gas.…”