Synthetic studies of kampanols, novel p21 farnesyltransferase inhibitors: an efficient synthesis of the tetracyclic ABCD ring system of kampanols

An enantioselective synthesis of the tetracyclic ABCD ring system (4) of kampanols, novel Ras farnesyltransferase inhibitors from a microorganism, was efficiently achieved for the first time starting from the known trans-decalone derivative 9. The synthetic method involves the following two key steps: (i) a conjugate addition reaction between the α-methylene ketone 6 and the Grignard reagent (7) of the ortho-disubstituted bromobenzene derivative 8 to deliver the coupling product 21 with stereoselectivity at the C9 position and (ii) a phenylselenium-mediated cyclization reaction of the phenol derivative 5 to stereoselectively construct the requisite tetracyclic intermediate 25 possessing the cis-fused connectivity of the B/C rings.