Asymmetric synthesis of the cytotoxic marine natural product (+)-awajanomycin and its C-11 epimer.

Full details of the convergent synthetic approach to awajanomycin, and the first total syntheses of the marine natural product (+)-awajanomycin (1) and its C-11 epimer 38 by an improved 13-step approach, are described. The key elements of the synthetic strategy resided in the use of (R)-18 as the chiral building block to construct the gamma-lactone-delta-lactam core 3 and cross-olefin metathesis as the key reaction to couple the latter with the allylic alcohol segment (R- or S-4). The efficient construction of the core 3 was realized by taking advantage of the inherent multiple reactivities of the chiral building block (R)-18. A highly diastereoselective one-pot transformation of 6 to 26 was achieved in a "one stone four birds" manner. On the other hand, enantioselective synthesis of both enantiomers of the segment 4 has been undertaken by an alternative and more efficient two-step procedure. Both awajanomycin (1) and 11-epi-awajanomycin 38 have been synthesized with overall yields of 3.8% and 3.6%, respectively. Quantum chemical calculations were undertaken to reveal the low reactivity of compound 27 toward methoxycarbonylation and to get an insight into the favored conformations of the intermediates 25-27. In addition, the geometry of the side product 39 arising from the homocoupling of the allylic alcohol moiety 4 was revised as E, and an unusual cyclopropanation reaction was discovered.