Lactones are present in many bioactive natural products, generally acting as a pharmacophore. In addition, chiral lactones are highly valuable components in the fragrance industry, such as γ-decalactone with peach flavour, γ-nonalactone with coconut odor or δ-octalactone with a creamy note. On the other hand, their reduced analogues, chiral lactols, can be used as chiral auxiliary. Specifically, (S)-6-methyl-δ-lactol has been extensively employed as chiral water equivalent in the stereoselective oxy-Michael addition to different Michael acceptors such as nitroalkenes, α,β-unsaturated malonate esters or β,γ-unsaturated α-keto esters, amongst others. These methodologies furnish the different Michael adducts with excellent levels of stereocontrol, which after removal of the methyltetrahedropyrane (THP*) auxiliary by simple acidic methanolysis allow the obtaining of a wide range of enantiopure oxygenated products. Although a broad set of racemic lactones are commercially available and cheap, the enantiopure ones either are not commercially available or they are much more expensive. Despite the existence of few methodologies for their enantiopure synthesis, these protocols are based in multi-step synthesis starting form chiral expensive reagents. Herein we present the direct chiral resolution of racemic lactols with secondary amines. Inspired in the highly selective formation of downstream intermediates observed in some organocatalytic reactions, and with the exo-anomeric effect as a key factor of the process, a set of racemic lactols have been resolved, allowing the direct recovery of both unmodified enantiomers with high levels of enantiopurity.

New mode of chiral recognition for the chiral resolution of lactols

251st National Meeting (2016)

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