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Synthesis of quaternary amino acids bearing a (2'Z)-fluorovinyl alpha-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]

SUBMITTER: Berkowitz DB

PROVIDER: S-EPMC5575781 | biostudies-literature | 2004 May

REPOSITORIES: biostudies-literature

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Synthesis of quaternary amino acids bearing a (2'Z)-fluorovinyl alpha-branch: potential PLP enzyme inactivators.

Berkowitz David B DB de la Salud-Bea Roberto R Jahng Wan-Jin WJ

Organic letters 20040501 11

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 f ...[more]

PMID: 15151423

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Project description:Developing specific chemical functionalities to deploy in biological environments for targeted enzyme inactivation lies at the heart of mechanism-based inhibitor development but also is central to other protein-tagging methods in modern chemical biology including activity-based protein profiling and proteolysis-targeting chimeras. 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 with β,β-difluorovinyl phenyl sulfone, a new (1'-fluoro)vinyl cation equivalent, and an electrophile that previously eluded synthesis, capture and characterization. A significant variety of biologically relevant AA side chains are tolerated including those for alanine, valine, leucine, methionine, lysine, phenylalanine, tyrosine, and tryptophan. Following addition/elimination, the resulting transoid α-(1'-fluoro)-β-(phenylsulfonyl)vinyl AA-esters undergo smooth sulfone-stannane interchange to stereoselectively give the corresponding transoid α-(1'-fluoro)-β-(tributylstannyl)vinyl AA-esters. Protodestannylation and global deprotection then yield these sterically encumbered and densely functionalized quaternary amino acids. The α-(1'-fluoro)vinyl trigger, a potential allene-generating functionality originally proposed by Abeles, is now available in a quaternary AA context for the first time. In an initial test of this new inhibitor class, α-(1'-fluoro)vinyllysine is seen to act as a time-dependent, irreversible inactivator of lysine decarboxylase from Hafnia alvei. The enantiomers of the inhibitor could be resolved, and each is seen to give time-dependent inactivation with this enzyme. Kitz-Wilson analysis reveals similar inactivation parameters for the two antipodes, L-α-(1'-fluoro)vinyllysine (Ki = 630 ± 20 μM; t1/2 = 2.8 min) and D-α-(1'-fluoro)vinyllysine (Ki = 470 ± 30 μM; t1/2 = 3.6 min). The stage is now set for exploration of the efficacy of this trigger in other PLP-enzyme active sites.

Dataset Information

Synthesis of quaternary amino acids bearing a (2'Z)-fluorovinyl alpha-branch: potential PLP enzyme inactivators.

Publications

Synthesis of quaternary amino acids bearing a (2'Z)-fluorovinyl alpha-branch: potential PLP enzyme inactivators.

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