Synthesis of Chiral α-Aminophosphonate Derivatives through Copper(I)-Catalyzed Enantioselective Alkylation

Abstract

Abstract Efficient methodologies for the catalytic asymmetric synthesis of α-aminophosphonic acid derivatives remain limited, particularly those involving carbon-carbon (C-C) bond formation. Herein, we report a copper(I)-catalyzed enantioselective alkylation of N-protected aminomethylthiophosphonates with alkyl halides, which provides a versatile strategy for accessing diverse chiral α-aminophosphonate derivatives. A wide range of alkyl halides, including allyl bromides, propargyl bromide, benzyl bromides, and alkyl iodides, act as efficient alkylating agents. Control experiments demonstrate that the employment of the 9H-fluoren-9-ylidene group and the incorporation of a sulfur atom into the phosphonate moiety are crucial for facilitating efficient deprotonation. NMR studies indicate that N-protected aminomethylthiophosphonate undergoes effective chelation with the copper(I) catalyst, a process that plays a pivotal role in promoting the reaction. Finally, both cleavage of the imine moiety and oxidation of the thiophosphonate group can be readily achieved under mild reaction conditions.