Synthetic studies on bioactive organic molecules utilizing of the combination of rare-earth metal-induced sequential cyclizations and convergent process

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Numerous efforts have been made to produce polycyclic γ-lactones, not only in consideration of their abundance in nature, but also their usefulness as versatile synthetic building blocks. Recently rare-earth metal salts have been found effective in carbon-carbon bond forming reactions and considerable attention has been focused on various intramolecular processes. Especially, samarium(II) iodide (SmI_2)-induced cascade cyclizations are quite useful as a one-step process for effectively producing polycyclic ring systems. During a study on SmI_2-induced cyclization, we found a sequential cyclization reaction, reductive cyclization-Dieckmann condensation-lactonization, of keto diesters to produce bicyclo[4.n.0] alkanones(n=1, 2) bearing γ-lactone. In order to show the synthetic utility of this reaction, we choose several bioactive natural products as synthetic targets. The most important result of this research is the total synthesis of plant hormone gibberellin A_1 which is one of the most typical gibberellins and has a unique structural feature with eight asymmetric centers.Our synthetic strategy involves SmI_2-induced cascade reaction, as a crucial step. The key intermediate was prepared by 17 steps from 3-methoxy-2-cyclohexen-1-one involving stereoselective aldol reaction, 1,2-addition of a propagyl group, introduction of methoxycarbonylmethyl group, construction of D-ring using SmI_2-HMPA-induced reductive coupling, stereoselective introduction of hydroxymethyl group in to a-position of ester carbonyl and formation of Z-α, β-unsaturated ester group using Still's method. Treatment of the intermediate with SmI_2, in THF for 10min at room temperature gave gibbane skeleton with desire stereochemistry. (±)-Gibberellin A_1 was easily synthesized form the gibbane skeleton by 4 steps. A novel SmI_2-induced ring recombination reaction was also found in this study.