Highly Enantioselective Access to syn-α,γ-Dihydroxycarbonyl Building Blocks via Organocatalyst-mediated Aldol Reaction as a Key Step

An efficient synthesis of chiral syn-alpha,gamma-dihydroxycarbonyl units from readily available achiral precursors in three pots under mild conditions was developed. This method explored the asymmetric direct cross-aldol reaction of two different aldehydes in the presence of an organocatalyst to generate a chiral beta-hydroxyaldehyde, which was converted into a 4-nitromethyl-1,3-dioxane derivative as a diastereo-mixture via a sequence of nitroalkane addition and acetalization. The 4-nitromethyl-1,3-dioxane derivative was then transformed either to a carboxylic ester or to an aldehyde/ketone. The chiral syn-alpha,gamma-dialkoxy esters and aldehydes/ketones were all obtained with excellent enantiopurity and diastereoselectivity after a base-promoted epimerization.