Enantioselective construction of remote quaternary stereocentres

Abstract

Small molecules that contain all-carbon quaternary stereocentres—carbon atoms bonded to four distinct carbon substituents—are found in many secondary metabolites and some pharmaceutical agents. The construction of such compounds in an enantioselective fashion remains a long-standing challenge to synthetic organic chemists. In particular, methods for synthesizing quaternary stereocentres that are remote from other functional groups are underdeveloped. Here we report a catalytic and enantioselective intermolecular Heck-type reaction of trisubstituted-alkenyl alcohols with aryl boronic acids. This method provides direct access to quaternary all-carbon-substituted β-, γ-, δ-, ε- or ζ-aryl carbonyl compounds, because the unsaturation of the alkene is relayed to the alcohol, resulting in the formation of a carbonyl group. The scope of the process also includes incorporation of pre-existing stereocentres along the alkyl chain, which links the alkene and the alcohol, in which the stereocentre is preserved. The method described allows access to diverse molecular building blocks containing an enantiomerically enriched quaternary centre.

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Figure 1: Approaches to constructing acyclic all-carbon quaternary stereocentres.
Figure 2: Enantioselective construction of remote quaternary stereocentres.
Figure 3: Evaluation of alkene substrates containing a branch point.

Accession codes

Data deposits

Data for the crystallized product (a derivative of 2f) have been deposited in the Cambridge Crystallographic Data Centre under accession number CCDC 988090.

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Acknowledgements

We thank the US National Institutes of Health (NIGMS GM063540) for financial support.

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T.-S.M. and H.H.P. performed the experiments and analysed the data. T.-S.M. and M.S.S. designed the experiments. T.-S.M. and M.S.S. prepared this manuscript with feedback from H.H.P.

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Correspondence to Matthew S. Sigman.

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Mei, T., Patel, H. & Sigman, M. Enantioselective construction of remote quaternary stereocentres. Nature 508, 340–344 (2014). https://doi.org/10.1038/nature13231

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