| Over the past ten years, the number of amino acid based pharmaceuticals has risen steadily. The increase in the use of amino acids as building blocks for drug discovery has, in turn, sparked an increased demand for commercial availability of enantiomerically pure unnatural amino acids and their derivatives. Pyridoxal-5'-Phosphate (PLP) is a versatile enzymatic cofactor which can modify the alpha, beta, or gamma carbon on amino acids. Although PLP catalyzes a wide variety of reactions, the general mechanism involves activation of at the amino acid alpha-carbon to form the corresponding stabilized enolate. Inspired by PLP's mechanism, a highly modular Lewis acid based catalyst was developed by our group. In the presence of picolinaldehyde and Lewis acids, amino acid esters can be activated by mild bases to generate tridentate anionic imine chelates, in situ. Our group has explored the reactivity of these chelates as both bases and azomethine ylides, thereby facilitating racemization and [2+3] cycloaddition reactions respectfully. Our mild racemization conditions proved to be well suited for dynamic kinetic resolution (DKR) of amino acids in which the biocatalyst Alcalase was employed as resolving agent. Furthermore, the anionic intermediate, when exposed to electron-poor olefins, underwent a concerted [2+3] cycloaddition to yield highly substituted pyrrolidines (Proline analogues). After exploring various Lewis acids and chiral ligands, an enantioselective synthesis was developed, thus demonstrating the first asymmetric, room temperature, multicomponent pyrrolidine synthesis that is tolerant to air and moisture. |
