Enantioselective Total Synthesis of (+)-Wortmannin

A concise and enantioselective total
synthesis of the potent PI3K
inhibitor (+)-wortmannin is described. A Pd-catalyzed cascade reaction
was first developed to connect a synthon derived from Hajos–Parrish
ketone to a furan moiety. The subsequent Friedel–Crafts alkylation
of the β-position of a furan ring to an epoxide was optimized
to establish the C10 quaternary center. (+)-Wortmannin was eventually
accomplished by transformations following a late-stage oxidation of
the furan allylic position. Kinome profiling and in vitro enzymatic assays were performed on 17-β-hydroxy-wortmannin
and an epoxide analogue.