(+)-Majoranolide analogues from regioselective Baeyer-Villiger reactions mediated by hypervalent iodine(III) reagents.

A series of enantiopure (+)-majoranolide analogues has been synthesized from the cellulose-derived chiral platform chemical (-)-Cyrene. The bicyclic ketone was substituted at C3 with a variety of benzylidene moieties via base-catalysed aldol condensations and a subsequent Baeyer-Villiger oxidation was achieved using the hypervalent iodine(III) reagent (diacetoxyiodo)benzene (PIDA) in combination with methanesulfonic acid. The reaction proceeded via an intermediate hemiketal, with rate and yield enhancement using solvent mixtures containing 2,2,2-trifluoroethanol. PIDA gave higher yields than peroxyacid mediated reactions due to improved selectivity in the migratory insertion. (+)-Majoranolide analogues had good anticancer activity with IC50 values as low as 6.0 µg mL-1 against A-549 lung carcinoma cells and 6.3 µg mL-1 against HeLa cervical carcinoma cells. Only the natural product (+)-majoranolide B exhibited significant antimicrobial activity, limited to S. aureus (MIC = 3.1 µg mL-1). Several compounds displayed anti-quorum sensing activity exceeding 80% inhibition, with the alkylidene ketone precursors similar to the benzylidene lactones.