Asymmetric 1,3-Dioxane Synthesis by Using Bifunctional Thiourea Catalysis

The hemiacetalization/oxy-Michael addition cascade reaction of δ-hydroxy-α,β-unsaturated carbonyl compounds forming 1,3-dioxanes is known to be an efficient method for the stereoselective synthesis of optically active 1,3-diol structures, which are found in a number of pharmaceutically-relevant compounds. However, to date, no catalytic enantioselective reactions using carboxylic acid derivatives as Michael acceptors have been reported. In this study, a catalytic asymmetric hemiketalization/oxy-Michael addition cascade reaction was developed using phenyl trifluoromethyl ketone as the carbonyl reagent and chiral bifunctional thiourea catalysts. The reaction proceeded in good yields with high enantio- and diastereoselectivity. This method is applicable not only to δ-hydroxy-α,β-unsaturated ketones but also to carboxylic acid derivatives, thereby leading to synthetic flexibility based on high oxidation states.