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Amino Acids

, Volume 39, Issue 5, pp 1265–1280 | Cite as

Synthesis of α-carboxyphosphinopeptides derived from norleucine

  • Jan Pícha
  • Miloš Buděšínský
  • Pavel Fiedler
  • Miloslav Šanda
  • Jiří Jiráček
Original Article

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.

Keywords

Phosphinopeptides Pseudopetides Phosphinate Phosphinic pseudopeptides Solid-phase synthesis Norleucine 

Abbreviations

AdBr

1-Bromoadamantane

Ad

1-Adamantyl

BOP

(Benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate

BSA

N,O-bis(trimethylsilyl)acetamide

Cbz

Benzyloxycarbonyl

DIC

N,N′-Diisopropylcarbodiimide

DIPEA

N,N-Diisopropylethylamine

Fmoc

9-Fluorenylmethyloxycarbonyl

Fmoc-Cl

9-Flurenylmethoxycarbonyl chloride

Fmoc-OSu

N-(9-fluorenylmethoxycarbonyloxy) succinimide

LiSPr

Lithium n-propyl mercaptide

LDA

Lithium diisopropylamide

TEA

Triethylamine

TFA

Trifluoroacetic acid

TMSCl

Trimethylsilyl chloride

Notes

Acknowledgments

This project was supported by a grant from the Grant Agency of the Czech Republic (203/06/1405, to J.J.), by the Chemical Genetics Consortium of the Ministry of Education, Youth and Sports of the Czech Republic (LC060777, to J.J.) and by the Research Project Z4 055 0506 of the Academy of Sciences of the Czech Republic (to IOCB).

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Copyright information

© Springer-Verlag 2010

Authors and Affiliations

  • Jan Pícha
    • 1
  • Miloš Buděšínský
    • 1
  • Pavel Fiedler
    • 1
  • Miloslav Šanda
    • 1
  • Jiří Jiráček
    • 1
  1. 1.Institute of Organic Chemistry and Biochemistry, v. v. i.Academy of Sciences of the Czech RepublicPrague 6Czech Republic

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