The Berkowitz Group has a longstanding interest in the rational development of mechanism-based inactivators for vitamin B6 (PLP)-dependent enzymes. A key design element revolves around the installation of a �,?-unsaturated functionality along the a-branch of the native amino acid (AA), resulting in a so-called quaternary, a-vinyl AA design. Such targets present a formidable synthetic challenge, owing to the density of functionality present, steric congestion about the a-carbon, and the need to control absolute stereochemistry at this a-center. The �,?-unsaturated functional group is unreactive until it undergoes conjugation with the extended p-system afforded by the pyridoxal nucleus in the enzyme active site, minimizing collateral damage. Interestingly, our group has found that fluorination of the vinylic functionality can be advantageous from both a mechanistic and an analytical point of view. Moreover, antipodal, quaternary a-vinylic AAs often display very different behavior with their target PLP enzymes, underscoring the need to develop enantioselective syntheses of these enzyme inhibitor candidates.This presentation will overview the development of a suite of asymmetric methods toward the synthesis of the quaternary, unsaturated AAs, leading up to the catalytic chemistry that is currently under development. Key mechanistic observations with a model PLP enzyme and recent efforts to more precisely define the inactivation pathways for the most promising leads at the structural biological level will be discussed.

Quaternary amino acids bearing �,?-unsaturation as mechanism-based enzyme inactivators for PLP-enzymes: Synthetic, mechanistic, and structural biological advances

247th National Meeting (2014)

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