Enantioselective Total Synthesis of [3]-Ladderanol through Late-Stage Organocatalytic Desymmetrization

Ladderane phospholipids, with their unusual ladder-like arrangement of concatenated cyclobutane rings, represent an architecturally unique class of natural products. However, despite their fascinating structure and other necessary impetus, only a few synthetic studies of these molecules have been reported so far. We have now devised a concise total synthesis of [3]-ladderanol, a component of natural ladderane phospholipids, using an organocatalytic enantioselective desymmetrizing formal C(sp(2))-H alkylation. Our synthetic strategy rests on the late-stage introduction of chirality, thus allowing facile access to both enantiomers of [3]-ladderanol as well as an analogue. This is the first time a desymmetrization strategy is applied to the synthesis of [3]-ladderanol. The scope of this desymmetrizing C(sp(2))-H alkylation of meso-cyclobutane-fused cyclohexenediones is also presented.

Automated summary

In this study, a total synthesis of [3]-ladderanol was achieved using a novel desymmetrizing reaction strategy. The synthetic method is concise and efficient, and can be applied to the synthesis of similar molecules.