Mechanism-based inhibitors (MBIs) are of important tools in contemporary chemical biology with applications ranging from specific enzyme inactivation to activity-based protein profiling (ABPP). We describe here a previously unknown class of potential PLP enzyme inactivators; namely, a family of quaternary, α-(1’-fluoro)vinyl amino acids, bearing the side chains of the cognate amino acids. These are obtained by the capture of suitably protected amino acid enolates a new 1’-fluorovinyl cation equivalent developed in this work. A significant variety of biologically relevant AA-side chains are tolerated including those for alanine, valine, leucine, methionine, lysine, phenylalanine, tyrosine and tryptophan, leading to their α-(1’-fluoro)vinyl amino acid analogues, eventually obtained in fully deprotected form. This chemistry is significant, considering that the key step involves formation of sterically encumbered, densely functionalized, quaternary amino acid esters. As a result of this chemistry, the α-(1’-fluoro)vinyl trigger, originally proposed by Abeles, is now available in a quaternary AA context for the first time. In an initial test of the Abelesian design in a PLP-dependent amino acid decarboxylase (AADC) active site, α-(1’-fluoro)vinyllysine is seen to act as an irreversible, time dependent inhibitor of lysine decarboxylase.

First synthesis of quaternary, α-(1'-fluoro)vinyl amino acids via formal fluorovinylation of AA enolates: A new class of potential mechanism-based PLP enzyme inactivators

254th National Meeting (2017)

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