Synthesis of α-carboxyphosphinopeptides derived from norleucine.
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.
Pícha
Jan
J
Institute of Organic Chemistry and Biochemistry, v. v. i., Academy of Sciences of the Czech Republic, Flemingovo náměstí 2, 166 10, Prague 6, Czech Republic.
Buděšínský
Miloš
M
Fiedler
Pavel
P
Sanda
Miloslav
M
Jiráček
Jiří
J
D004151:Dipeptides / Q000138:chemical synthesis* / Q000737:chemistry; D015394:Molecular Structure; D009646:Norleucine / Q000737:chemistry*; D010721:Phosphinic Acids / Q000138:chemical synthesis* / Q000737:chemistry; D013237:Stereoisomerism
D004151:Dipeptides; D010721:Phosphinic Acids; D009646:Norleucine