Practical Syntheses of Chiral α-Amino Acids and Chiral Half-Esters by Kinetic Resolution of Urethane-Protected α-Amino Acid N-Carboxyanhydrides and Desymmetrization of Cyclic meso-Anhydrides with New Modified Cinchona Alkaloid Catalysts

The large-scale applications of the kinetic resolution of urethane-protected α-amino acid N-carboxyanhydrides (UNCAs) and the desymmetrization of cyclic meso-anhydrides using modified cinchona alkaloids are described. These asymmetric reactions are effective organocatalytic methods for the synthesis of chiral α-amino acids 6 and chiral half-esters 2 on an industrial scale, because the organocatalyst recovery and product purification can be carried out by a simple extractive procedure obviating a chromatographic purification step. The modified cinchona alkaloid catalysts (DHQD)2AQN and (DHQ)2AQN, as reported by Deng and co-workers, are not readily available and therefore not suitable for industrial-scale synthesis. Various O-alkylated quinidine and quinine derivatives were prepared and screened as catalysts for the kinetic resolution of phenylalanine UNCA with alcohol. The readily prepared O-propargylquinidine (OPQD) and O-propargylquinine (OPQ) were discovered to be highly enantioselective and practical catalysts. These new catalysts were applied to the synthesis of chiral propargylglycine 24 and the key intermediate of BAY10-8888/PLD-118, 26, on an industrial scale, by the kinetic resolution of UNCA 22 and the desymmetrization of cyclic meso-anhydride 25, respectively.