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Synthesis of α-carboxyphosphinopeptides derived from norleucine.

Amino acids (2010-03-30)
Jan Pícha, Miloš Buděšínský, Pavel Fiedler, Miloslav Sanda, Jiří Jiráček
ABSTRACT

In the present study, we describe in detail the synthesis of a relatively rare class of phosphorus compounds, α-carboxyphosphinopeptides. We prepared several norleucine-derived α-carboxyphosphinic pseudopeptides of the general formula Nle-Ψ[PO(OH)]-Gly. These compounds could have important applications as transition state-mimicking inhibitors for methionine or leucine aminopeptidases or other enzymes. For the preparation of the key α-carboxyphosphinate protected precursors, we investigated, compared and improved two different synthetic methods described in literature: the Arbuzov reaction of a silylated N-protected phosphinic acid with a bromoacetate ester and the nucleophilic addition of a mixed O-methyl S-phenyl N-protected phosphonic acid or a methyl N-protected phosphonochloridate with tert-butyl lithioacetate. We also prepared two N-Fmoc protected synthons, Fmoc-Nle-Ψ[PO(OH)]-Gly-COOH and Fmoc-Nle-Ψ[PO(OAd)]-Gly-COOH, and demonstrated that these precursors are suitable building blocks for the solid-phase synthesis of α-carboxyphosphinopeptides.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
L-Norleucine, ≥98% (TLC)
Sigma-Aldrich
L-Norleucine, suitable for amino acid analysis, BioReagent