Versatile Solid-Phase Synthesis of Chromenes Resembling Classical Cannabinoids

A novel solid-phase approach toward classical cannabinoids is described. The desired tricyclic natural product analogues are assembled in only four atom economic steps: domino oxa-Michael-aldol condensation, Wittig reaction/enol-ether formation, Diels–Alder cycloaddition and cleavage. The synthesis is designed to allow combinatorial chemistry at several stages of the sequence. The variation of commercially available reagents at three of the reactions (enals/enones, Wittig salts, and dienophiles) allows the introduction of various diversity points. As proof of concept, a small library of 20 members has been synthesized with overall yields ranging from 10% to 60%.