Synthesis of Quaternary Amino Acids Bearing a (2‘Z)-Fluorovinyl α-Branch:  Potential PLP Enzyme Inactivators

Abstract

Protected alpha-formyl amino acids, themselves available from the corresponding alpha-vinyl amino acids, are stereoselectively transformed into the (Z)-configured alpha-(2'-fluoro)vinyl amino acids via a three-step sequence. The route employs McCarthy's reagent, diethyl alpha-fluoro-alpha-(phenylsulfonyl)methyl phosphonate, and proceeds via the intermediate (E)-alpha-fluorovinyl sulfones and (E)-alpha-fluorovinylstannanes. The latter may either be exploited as novel cross-coupling partners for fluorovinyl branch extension or be globally deprotected, to provide the title compounds. [structure: see text]

Synthesis and Deployment of an Elusive Fluorovinyl Cation Equivalent: Access to Quaternary α-(1′-Fluoro)vinyl Amino Acids as Potential PLP Enzyme Inactivators

“…This is notable because radical sulfide-stannane interchange reactions are known to sometimes lead to scrambling of alkene geometry. 58b,59 That said, for α-fluorovinylsulfones, both we 39b and McCarthy 60 have observed that radical vinyl sulfone/stannane proceeds with clean retention of configuration, with examples of both geometric isomers in McCarthy’s case, providing strong experimental evidence for a stereospecific transformation, at least in these cases. In this regard, it is important to note that classic studies showed that simple vinyl stannanes can be isomerized upon heating in the presence of trialkyltin radical.…”

“…26c As DFMO is utilized to treat African sleeping sickness, 26d and in clinical trials as a chemotherapeutic, 65 this property should not be regarded as limiting the potential utility of this inhibitor in chemical biology or biomedicine. That said, it is somewhat surprising that both enantiomers inactivate LDC here given the quite different behavior with the α-(l′-fluoro)vinyl trigger, 39a for example. Clearly, future investigations are warranted here to understand the mechanistic underpinnings of these different enantiospecifities of inhibition.…”

“…Given the great interest in fluorinated alkene functionality in chemical biology, for example, as latent triggers for enzyme inactivation, 30,32c,32d,39a as masked aldehyde 32a or carboxylate 32b equivalents, or as peptide bond isosteres, 40 there has been a significant effort in methodology development in this area. Approaches to monofluorovinyl group installation most commonly are formal nucleophilic fluoromethylenations, whereby a EWG-CY(-)-F reagent is condensed with a carbonyl center.…”

“…Lysine decarboxylase (LDC) was chosen as, in our hands, this enzyme had proven to be a useful model system to in which to examine the behavior of mechanism-based inhibitor candidates. 12b,39a LDC was purified from the native bacterial source, Hafnia alvei , as this organism naturally produces high titers of the enzyme. Following sequential hydrophobic chromatography (Phenyl-Sepharose) and size exclusion chromatography (Sephacryl S300), homogeneous LDC was obtained, as evidenced by both specific activity and gel electrophoresis (SDS-PAGE).…”

“…An initial test of this motif for PLP enzyme inactivation showed great promise and highlighted the value of incorporating fluorine into the inactivation trigger. 39 This chemistry begins from quaternary, α-vinyl AAs, and so, leverages the chemistry we have developed to access these unnatural AAs. That said, the chemistry is not particularly convergent and is limited to accessing 2′-fluorinated vinylic triggers.…”