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Synthesis of α-carboxyphosphinopeptides derived from norleucine

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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.

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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

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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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  1. 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

    Jan Pícha, Miloš Buděšínský, Pavel Fiedler, Miloslav Šanda & Jiří Jiráček

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  1. Jan Pícha
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  2. Miloš Buděšínský
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  3. Pavel Fiedler
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Correspondence to Jiří Jiráček.

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Pícha, J., Buděšínský, M., Fiedler, P. et al. Synthesis of α-carboxyphosphinopeptides derived from norleucine. Amino Acids 39, 1265–1280 (2010). https://doi.org/10.1007/s00726-010-0561-z

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