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Synergistic organocatalysis in the kinetic resolution of secondary thiols with concomitant desymmetrization of an anhydride

Abstract

Kinetic resolution is an important method for the separation of racemates into their component enantiomers. Thiols are precursors to a variety of organosulfur compounds, with high utility in both chemistry and chemical biology, yet there is a surprising dearth of methodologies for their direct and efficient catalytic kinetic resolution. Here, we demonstrate an organocatalytic process involving the highly enantioselective desymmetrization of an achiral electrophile with the simultaneous kinetic resolution of a racemic thiol. The preparative potential of the methodology is exemplified by the synthesis of a drug precursor antipode in excellent yield and enantioselectivity as a by-product of a process that also resolves a sec-thiol substrate with a selectivity of S = 226 (that is, both thiol antipodes produced in >95% ee at 51% conversion). In a second example a racemic sec-thiol representing the stereocentre-containing core of the anti-asthma drug (R)-Montelukast was resolved with synthetically useful selectivity under mild conditions.

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Figure 1: Kinetic resolution of thiol 28 with simultaneous enantioselective synthesis of an (R)-Pregabalin precursor.
Figure 2: Synthesis of the (R)-Montelukast structural core via a catalytic thiol kinetic resolution.

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Acknowledgements

This material is based on work supported by Science Foundation Ireland, The European Research Council and The Irish Research Council for Science, Engineering and Technology.

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S.J.C., B.P. and A.P. designed the research. S.J.C. analysed the data and prepared the manuscript. B.P., A.P. and C.J.O'C. performed the experimental work. All authors discussed the results and commented on the manuscript.

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Correspondence to Stephen J. Connon.

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The authors declare no competing financial interests.

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Peschiulli, A., Procuranti, B., O' Connor, C. et al. Synergistic organocatalysis in the kinetic resolution of secondary thiols with concomitant desymmetrization of an anhydride. Nature Chem 2, 380–384 (2010). https://doi.org/10.1038/nchem.584

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