CUTTING-EDGE STRATEGIES IN THE ASYMMETRIC SYNTHESIS OF α-AMINOCYCLOPROPANE CARBOXYLIC ACIDS: ESSENTIAL SCAFFOLDS FOR DRUG DISCOVERY

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Abstract
α-Aminocyclopropanecarboxylic acid (ACC) and its derivatives are widely distributed in the plant kingdom, fulfilling diverse roles ranging from regulation of plant life cycles to defensive mechanisms. The sterically constrained structure of ACC has proven invaluable in the design of numerous drugs, particularly hepatitis C virus (HCV) NS3/4A protease inhibitors. Indeed, ACC has been instrumental in the development of multiple generations of potent HCV treatments, with ongoing efforts focused on further improvements and refinements. The inherent steric constraints of these derivatives present a significant challenge for their synthesis, especially in enantiomerically pure form. This article provides a comprehensive overview of synthetic methodologies reported in the literature for the preparation of ACC and its derivatives. The synthetic strategies discussed herein are organized based on key transformations, including dialkylation of nucleophilic glycine equivalents, cyclopropanation of carbenoid glycine equivalents, and addition reactions to dehydroamino acids. Particular emphasis is placed on asymmetric approaches that enable the preparation of these tailor-made amino acids in enantiomerically pure form. Furthermore, aspects of Self-Disproportionation of Enantiomers (SDE) relevant to enantioselective catalysis are highlighted. By compiling these methodologies, we aim to provide a comprehensive resource and a source of inspiration for researchers in synthetic and medicinal chemistry, as well as drug discovery.

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