Article

Mechanistic insight into benzenethiol catalyzed amide bond formations from thioesters and primary amines

Organic & Biomolecular Chemistry, Royal Society of Chemistry (RSC), ISSN 1477-0539

Volume 12, 30, 2014

DOI:10.1039/c4ob00073k, Dimensions: pub.1038869995, PMID: 24967660,

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  1. (1) University of Copenhagen, grid.5254.6, KU
  2. (2) University of Helsinki, grid.7737.4

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Denmark

Finland

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Europe

Description

The influence of arylthiols on cysteine-free ligation, i.e. the reaction between an alkyl thioester and a primary amine forming an amide bond, was studied in a polar aprotic solvent. We reacted the ethylthioester of hippuric acid with cyclohexylamine in the absence or presence of various quantities of thiophenol (PhSH) in a slurry of disodium hydrogen phosphate in dry DMF. Quantitative conversions into the resulting amide were observed within a few hours in the presence of equimolar amounts of thiophenol. Ab initio calculations showed that the reaction mechanism in DMF is similar to the well-known aqueous reaction mechanism. The energy barrier of the catalyzed amidation reaction is approximately 40 kJ mol(-1) lower than the non-catalyzed amidation reaction. At least partially this can be explained by a hydrogen bond from the amine to the π-electrons of the thiophenol, stabilizing the transition state in the aromatic thioester amidation reaction. Under similar conditions, cysteine-free ligation was achieved by coupling a fully side-chain protected 15 amino acid phosphopeptide thioester to the free N-terminal of a side-chain protected 9 amino acid peptide producing the corresponding 24 amino acid phosphopeptide.

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University of Copenhagen

Danish Open Access Indicator

2014: Unused

Research area: Science & Technology

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2014: Level 2

Research area: Science & Technology

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Times Cited: 7

Field Citation Ratio (FCR): 0.91

Relative Citation ratio (RCR): 0