Skip navigation
Please use this identifier to cite or link to this item:
Title: Bis(phosphine) Cationic Co(I)- and Neutral Co(0)- Catalyzed Asymmetric Hydrogenation of Pharmaceutically-Relevant Functionalized Enamides
Authors: Esposito, Maddie
Advisors: Chirik, Paul J
Department: Chemistry
Certificate Program: Environmental Studies Program
Class Year: 2023
Abstract: Transition metal-catalyzed asymmetric hydrogenation is an atom-economical process used in the industrial synthesis of chiral active pharmaceutical ingredients (APIs). Precious metal (such as rhodium) catalysts that operate by well-studied 2-electron pathways are frequently used in this process. Studying earth-abundant metal (such as cobalt) catalysts can provide insight into novel single-electron differentiated reactivity and could provide alternatives to prevalent, costly precious metal catalysts with high global warming potentials. This work examines the functional tolerance of cationic bis(phosphine) Co(I) and neutral bis(phosphine) Co(0) precatalysts toward two model substrate classes: indazole-containing enamides (en route to Zavegepant, a CGRP receptor antagonist used to treat migraines) and carboxylic-acid containing enamides (en route to L-DOPA, a well-studied API used to treat Parkinson’s disease). High-pressure asymmetric hydrogenation reactions revealed the active and selective cationic Co(I)-catalyzed hydrogenation of indazole-containing enamides with optimal precatalyst [(R,R)-(BenzP*)Co(η6-C6H6)][BArF4]. Full conversion to product was observed in the asymmetric hydrogenation of carboxylic acid-containing enamides with BenzP* cationic Co(I) and neutral Co(0) precatalysts—this study reports the first synthesis of L-DOPA precursors by Co-catalyzed asymmetric hydrogenation. In-situ studies monitored by 1H and 31P NMR spectroscopy investigated precatalyst stability and precatalyst-substrate interactions in THF-d8 and MeOH-d4. These studies revealed that [(R,R)-(BenzP*)Co(η6-C6H6)][BArF4] (in either solvent) forms an unidentified substrate-independent and diamagnetic phosphorus-containing species visible by 31P NMR spectroscopy. Overall, this study demonstrates the tolerance of single-electron differentiated Co catalysts for the indazole-, carboxylic acid-, and free phenol- containing enamides examined here and provides preliminary insight into cationic BenzP* Co(I) precatalyst activation in MeOH.
Type of Material: Princeton University Senior Theses
Language: en
Appears in Collections:Chemistry, 1926-2023

Files in This Item:
File Description SizeFormat 
ESPOSITO-MADDIE-THESIS.pdf3.65 MBAdobe PDF    Request a copy

Items in Dataspace are protected by copyright, with all rights reserved, unless otherwise indicated.