Expedient synthesis of 1,3-substituted benzene peptidomimetics

Anders Bach; Kristian Strømgaard

doi:10.1055/s-0030-1258425

Expedient synthesis of 1,3-substituted benzene peptidomimetics

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Abstract

A synthetic route for replacing the central amino acid in the tripeptide Thr-Ala-Val (TAV) with a 1,3-substituted benzene ring was developed. l-Threonine was introduced into the benzene ring by a Grignard reaction with protected l-threoninal, where the nature of the side-chain protecting group was found to be of utmost importance. Subsequently, l-valine was introduced by a copper-mediated amination. Overall, the tripeptide analogue was obtained in six steps with an overall yield of 18%. An orthogonal protecting group strategy allowed attachment of the tripeptide analogue to a solid support and subsequent preparation of the corresponding pentapeptide analogue. Both compounds were tested in a plasma stability assay, showing improved stability compared to their peptide counterparts.

Originalsprog	Engelsk
Tidsskrift	Synthesis
Vol/bind	2011
Udgave nummer	5
Sider (fra-til)	807-815
ISSN	0039-7881
DOI	https://doi.org/10.1055/s-0030-1258425
Status	Udgivet - 8 feb. 2011

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title = "Expedient synthesis of 1,3-substituted benzene peptidomimetics",

abstract = "A synthetic route for replacing the central amino acid in the tripeptide Thr-Ala-Val (TAV) with a 1,3-substituted benzene ring was developed. l-Threonine was introduced into the benzene ring by a Grignard reaction with protected l-threoninal, where the nature of the side-chain protecting group was found to be of utmost importance. Subsequently, l-valine was introduced by a copper-mediated amination. Overall, the tripeptide analogue was obtained in six steps with an overall yield of 18%. An orthogonal protecting group strategy allowed attachment of the tripeptide analogue to a solid support and subsequent preparation of the corresponding pentapeptide analogue. Both compounds were tested in a plasma stability assay, showing improved stability compared to their peptide counterparts.",

keywords = "Former Faculty of Pharmaceutical Sciences",

author = "Anders Bach and Kristian Str{\o}mgaard",

note = "Keywords: amino acids, peptides, Grignard reaction, nucleophilic aromatic substitution, copper",

year = "2011",

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day = "8",

doi = "10.1055/s-0030-1258425",

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journal = "Synthesis",

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TY - JOUR

T1 - Expedient synthesis of 1,3-substituted benzene peptidomimetics

AU - Bach, Anders

AU - Strømgaard, Kristian

N1 - Keywords: amino acids, peptides, Grignard reaction, nucleophilic aromatic substitution, copper

PY - 2011/2/8

Y1 - 2011/2/8

N2 - A synthetic route for replacing the central amino acid in the tripeptide Thr-Ala-Val (TAV) with a 1,3-substituted benzene ring was developed. l-Threonine was introduced into the benzene ring by a Grignard reaction with protected l-threoninal, where the nature of the side-chain protecting group was found to be of utmost importance. Subsequently, l-valine was introduced by a copper-mediated amination. Overall, the tripeptide analogue was obtained in six steps with an overall yield of 18%. An orthogonal protecting group strategy allowed attachment of the tripeptide analogue to a solid support and subsequent preparation of the corresponding pentapeptide analogue. Both compounds were tested in a plasma stability assay, showing improved stability compared to their peptide counterparts.

AB - A synthetic route for replacing the central amino acid in the tripeptide Thr-Ala-Val (TAV) with a 1,3-substituted benzene ring was developed. l-Threonine was introduced into the benzene ring by a Grignard reaction with protected l-threoninal, where the nature of the side-chain protecting group was found to be of utmost importance. Subsequently, l-valine was introduced by a copper-mediated amination. Overall, the tripeptide analogue was obtained in six steps with an overall yield of 18%. An orthogonal protecting group strategy allowed attachment of the tripeptide analogue to a solid support and subsequent preparation of the corresponding pentapeptide analogue. Both compounds were tested in a plasma stability assay, showing improved stability compared to their peptide counterparts.

KW - Former Faculty of Pharmaceutical Sciences

U2 - 10.1055/s-0030-1258425

DO - 10.1055/s-0030-1258425

M3 - Journal article

SN - 0039-7881

VL - 2011

SP - 807

EP - 815

JO - Synthesis

JF - Synthesis

IS - 5

ER -

Expedient synthesis of 1,3-substituted benzene peptidomimetics

Abstract

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