Synthetic Study of HIF-1α Inhibitor, Manassantin B

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This project aimed to develop a novel synthetic strategy of manassantin B and the derivatives having potent inhibitory activity against HI-α, which is considered as an intermediate of cancer, cerebral infarction, and cardiac infarction.1) Synthesis of tetrasubstituted 2,5-diayl THF skeletonTo establish a synthetic method of 2,5-daryl THF skeleton, we have investigated a diastereoselective Michael addition to γ-oxy-α,β-unsaturated ketone. As a result, we found that the reaction proceeded in good yield and with excellent diastereoselectivity to give the anti-isomer by using Gilman reagent (71%, 30:1 dr) or Gilman reagent and BF_3・ether (72%, 33:1 dr). Subsequent α-methylation of the ketone also underwent in almost quantitatively with 14:1 dr when KHMDS was employed as a base in the presence of HMPA. Finally, re1-(7S,8S,7'R,8'S)-7,.7'-epoxylignan skeleton was constructed via THF ring formation.2) Synthetic research of chiral tetrasubstituted 2,5-diayl THF skeletonTo construct two of four stereogenic centers enantioselectively, asymmetric [2,3]-Wittig rearrangement of functionalized allyl benzyl ethers was examined as a key reaction. Using a chiral di-tert-butyl bis(oxazoline) ligand, the reaction proceeded with excellent diastereo- and enantioselectivity when no methoxy substituent was present at the ortho-position on the benzyl group. On the other hand, the enantioselectivity was drastically decreased in the presence of an ortho-methoxy group. Scope and limitation of the reaction were investigated for application to the target molecules.