Convergent Total Synthesis of Kalmanol

Kalmanol (1) is the first isolated kalmane-type grayanoid featuring a highly oxidized 5/8/5/5 tetracyclic carbon skeleton and 9 contiguous stereocenters. We have accomplished the efficient and asymmetric total synthesis of 1 in 16 steps from known compounds (20 steps from commercially available starting materials) by a modular synthetic strategy. A tetracyclic intermediate was prepared in a convergent manner through a Grignard reaction and a subsequent ring-closing metathesis reaction of two enantiomerically enriched fragments. The polyhydroxy groups were introduced by late-stage stereo- and regioselective oxidations.