Catalytic enantioselective diversity-oriented synthesis of a small library of polyhydroxylated pyrans inspired from thiomarinol antibiotics

Abstract

A small library of 30 thiomarinol analogues was successfully synthesised using as a key step–a catalytic enantioselective tandem oxa[4+2] cycloaddition/aldehyde allylboration methodology. With this method, highly substituted \(\alpha \)-hydroxyalkyl dihydropyrans were assembled in a single three-component reaction utilizing three different enol ethers and a wide variety of aldehydes, such as aromatic, heteroaromatic, unsaturated and aliphatic aldehydes. In a second operation, a mild and direct method for reducing an acetal unit in the \(\alpha \)-hydroxyalkyl dihydropyrans was optimised without the need for protecting a nearby hydroxyl group. This procedure facilitated the synthetic sequence, which was completed by a dihydroxylation of the residual olefin of \(\alpha \)-hydroxyalkyl 2\(H\)-pyrans to provide the desired library of dihydroxylated pyran analogues reminiscent of the thiomarinol antibiotics. The relative stereochemistry of the resulting library compounds was demonstrated by X-ray crystallography on one of the analogues.

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Acknowledgments

The authors thank the Natural Sciences and Engineering Research Council (NSERC) of Canada and the University of Alberta for financial support of this research.

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Correspondence to Dennis G. Hall.

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Al-Zoubi, R.M., Hall, D.G. Catalytic enantioselective diversity-oriented synthesis of a small library of polyhydroxylated pyrans inspired from thiomarinol antibiotics. Mol Divers 18, 701–719 (2014). https://doi.org/10.1007/s11030-014-9542-6

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Keywords

  • Allylboration
  • ATP mimics
  • Combinatorial library
  • Enantioselective catalysis
  • Hetero-Diels–Alder cycloaddition
  • Pyrans