An insight into the radical thiol/yne coupling: the emergence of arylalkyne-tagged sugars for the direct photoinduced glycosylation of cysteine-containing peptides.

An explorative study of the Thiol-Yne Coupling (TYC) reaction has been carried out using an aliphatic (1-octyne) and an aromatic alkyne (phenylacetylene) and two alkanethiols (methyl thioglycolate and N-acetyl-L-cysteine methyl ester). The outcomes of the TYC reactions strongly depend on the experimental conditions (e.g., temperature, solvent, and alkyne/thiol ratio), but these can be properly adjusted to achieve selective production of either mono- or bis-coupling products. With respect to 1-octyne, phenylacetylene undergoes notably easier radical hydrothiolation, further showing a notably higher aptitude for monohydrothiolation exclusive of bis-hydrothiolation. The overall findings were exploited in glycosylation of cysteine derivatives as well as of cysteine-containing peptides. A sugar featuring an arylacetylene moiety gave rise to a true click-reaction, that is, glycosylation of the tripeptide glutathione in its native form, by means of virtually equimolar amounts of reagents. This reaction was successfully applied, under physiological conditions, to a cysteine-containing nonapeptide with marked advantages over the analogous Thiol-Ene Coupling (TEC) derivatization. A TYC/TEC sequence affording bis-armed cysteine derivatives through dual functionalization of an alkynyl sugar was additionally devised.

Citation

Matteo Minozzi, Alessandro Monesi, Daniele Nanni, Piero Spagnolo, Nicola Marchetti, Alessandro Massi. An insight into the radical thiol/yne coupling: the emergence of arylalkyne-tagged sugars for the direct photoinduced glycosylation of cysteine-containing peptides. The Journal of organic chemistry. 2011 Jan 21;76(2):450-9

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PMID: 21175145

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