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

为了生产多环γ-内酯，人们做出了大量的努力，不仅考虑到它们在自然界中的丰度，而且考虑到它们作为多功能合成构件的用途。近年来，稀土金属盐在碳-碳键形成反应中起着重要的作用，各种分子内反应已成为人们关注的焦点。特别是，钐（II）碘化（SmI_2）诱导的级联环化是非常有用的一步过程，有效地产生多环体系。在smi_2诱导的环化过程中，我们发现了酮二酯生成双环的顺序环化反应：还原环化- dieckmann缩合-内酯化[4]。[0]含γ-内酯的烷酮（n= 1,2）。为了显示该反应的合成效用，我们选择了几种具有生物活性的天然产物作为合成靶点。本研究最重要的成果是全合成了植物激素赤霉素A_1，它是最典型的赤霉素之一，具有独特的8个不对称中心的结构特征。我们的合成策略包括smi_2诱导的级联反应，作为关键步骤。以3-甲氧基-2-环己烯-1- 1为起始原料，经立体选择性醛醇反应、1,2-加成副基、引入甲氧基羰基甲基、利用smi_2 - hmpa诱导还原偶联构建d环、在酯羰基a位上立体选择性引入羟甲基、利用Still's法生成Z-α， β-不饱和酯基等17步制备了关键中间体。中间体用SmI_2处理，室温下THF反应10min，得到具有理想立体化学性质的赤霉素骨架。（±）-赤霉素A_1是由赤霉素骨架经4步合成的。本研究还发现了一种新的smi_2诱导的环重组反应。

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.