Abstract
A general and efficient kinetic resolution of urethane-protected α-amino acid N-carboxyanhydrides (UNCA) that generates highly enantiomerically enriched α-amino acid derivatives in excellent yields is developed. Numerous UNCAs with different N-carbamoyl protecting groups and with a wide range of α-alkyl, α-aryl as well as α-alkenyl side chains are resolved with enzyme-like efficiency via this strategy. This modified cinchona alkaloid-catalyzed kinetic resolution of UNCA via alcoholysis provides a versatile and reliable route to optically active amino acid derivatives that are suitably protected for further synthetic elaborations. The reaction utilizes readily accessible substrates, cheap reagents, commercially available and fully recyclable catalysts and simple experimental protocols. These characteristics of the reaction render it a highly efficient, flexible and practical method for the asymmetric synthesis of α-amino acids. The further successful improvement of this cinchona alkaloid-catalyzed alcoholysis into a practical tool for large scale synthesis is made possible through the development of new and easily accessible cinchona alkaloid-based catalysts. The practical utility of this new resolution method for large scale synthesis is highlighted in a multi kilogram scale asymmetric synthesis of propargylglycine, an unnatural amino acid that is a useful pharmaceutical intermediate but difficult to prepare using metal-catalyzed asymmetric hydrogenation of dehydro-amino acids.