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

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 2H-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.