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

利用稀土金属诱导的顺序环化与收敛过程相结合的生物活性有机分子的合成研究

基本信息

批准号：
17590017
负责人：
NAGAOKA Hiroto
金额：
$ 2.46万
依托单位：
Meiji Pharmaceutical University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2005
资助国家：
日本
起止时间：
2005 至 2007
项目状态：
已结题

项目摘要

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.

已经进行了许多努力来生产多环γ-内酯，不仅考虑到它们在自然界中的丰富性，而且考虑到它们作为多功能合成结构单元的有用性。近年来，稀土金属盐在碳-碳键形成反应中表现出良好的催化活性，并引起了人们的广泛关注。特别是碘化钐（SmI_2）诱导的级联环化反应是一种非常有用的一步合成多环体系的方法。在SmI_2诱导的环化反应中，我们发现酮双酯发生还原环化-Dieckmann缩合-内酯化的顺序环化反应，生成含γ-内酯的双环[4.n.0]烷酮（n=1，2）。为了显示该反应的合成实用性，我们选择了几种具有生物活性的天然产物作为合成目标。本研究的最重要成果是全合成了具有八个不对称中心的植物激素赤霉素A_1，其中SmI_2诱导的级联反应是合成的关键步骤。以3-甲氧基-2-环己烯-1-酮为起始原料，经立体选择性的羟醛缩合、1，2-炔丙基加成、甲氧羰基甲基的引入、SmI_2-HMPA还原偶联成D环、酯羰基α位上羟甲基的立体选择性引入和Still法生成Z-α，β-不饱和酯基等17步反应制得关键中间体。在室温下，用SmI_2在THF中处理10 min，得到具有理想立体化学结构的三羟甲基丙烷骨架。（±）-赤霉素A_1是由赤霉素骨架经4步反应合成的。研究还发现了一种新的SmI_2诱导的环重组反应。