International Symposium of Glycosciences
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Olefin Metathesis for Site-Selective Protein Modifications
Yuya A. Lin, Justin M. Chalker, Benjamin G. Davis*
Department of Chemistry, University of Oxford, Chemistry Research Laboratory, Oxford OX1 3TA, UK
Precise modification of proteins is an important strategy for better understanding of the natural
post-translational modifications of proteins in biology.1 Olefin metathesis has recently emerged as a
useful reaction for selective carbon–carbon bond formation on biomolecules.2 Our preliminary work
showed remarkable reactivity of S-allylcysteine (Sac) in aqueous cross-metathesis (CM).3 The
enhanced CM reactivity of allyl sulfides was explained with a mechanism invoking sulfur
pre-coordination to ruthenium in the second-generation precatalyst leading to rapid catalyst activation.
Enhanced reactivity of allyl sulfide in CM motivated us to develop chemical means of converting
cysteine to Sac on protein surfaces.4 Ready access to Sac on protein surfaces indeed enabled the first
examples of protein modification by CM.3 In order to further understand the scope and limitation of CM
on protein, the substrate scope, linker selection and steric effects were all considered. Allyl
chalcogenides were found to be generally reactive substrates in olefin metathesis. Allyl selenides, in
particular, were found to be more reactive than allyl sulfides in metathesis allowing greater range of
protein modifications which were difficult to achieve with allyl sulfides. The concepts examined not
only provided useful guidelines for reliable protein modification using CM, they served further
understanding of allylic chalcogen activation in olefin metathesis, which can be beneficial in general
synthetic applications.
(1) (a) Carrico, I. S. Chem. Soc. Rev. 2008, 37, 1423-1431. (b) Gamblin, D. P.; van Kasteren, S. I.;
Chalker, J. M.; Davis, B. G. FEBS J. 2008, 275, 1949-1959. (c) Chalker, J. M.; Bernardes, G. J. L.;
Lin, Y. A.; Davis, B. G. Chem.–Asian J. 2009, 4, 630-640. (d) Basle, E.; Joubert, N.; Pucheault, M.
Chem. Biol. 2010, 17, 213-227.
(2) (a) Lin, Y. A.; Chalker, J. M.; Davis, B. G. ChemBioChem 2009, 10, 959-969. (b) Binder, J. B.;
Raines, R. T. Curr. Opin. Chem. Biol. 2008, 12, 767-773.
(3) Lin, Y. A.; Chalker, J. M.; Floyd, N.; Bernardes, G. J. L.; Davis, B. G. J. Am. Chem. Soc. 2008, 130,
9642-9643.
(4) Chalker, J. M.; Lin, Y. A.; Boutureira, O.; Davis, B. G. Chem. Commun. 2009, 3714-3716.