Development of practical methods for the synthesis of taxane diterpenoids

我们回顾了传统的连续Michael-Claisen[3+3]法(MC-[3+3])，并评价了其在现代有机合成中的应用潜力。确定了以酮(1·2当量)、烯醇酸酯(1·0当量)和t-丁酮(1·2当量)为溶剂，在0℃~40℃范围内的反应条件。20到30个例子被证明在这种条件下是有效的，包括合成可获得多克量的紫杉醇A，C环合成子。这些反应表现出显著的区域选择性，即Michael加成反应无一例外地通过受阻较多的酮中心进行亲核攻击，这意味着Claisen缩合反应导致受阻较少的酮中心与烯醇酸酯的酰基碳之间形成碳-碳键。此外，利用MC-[3+3]工艺的优点，还开发了一些合成六元碳环化合物的有效方法。已经进行了大量的对照实验，为MC-[3+3]过程的机理提供了强有力的支持信息。

We have revisited the traditional consecutive Michael-Claisen [3 + 3] process (MC-[3+3]) promising for the synthesis of a cyclohexane-1, 3-dione derivatives from non-activated simple ketones and enoates, and evaluated its potential in modern organic synthesis. The reaction conditions employing the ketones (1.2 equiv), enoate (1.0 equiv), and t-BuOK (1.2 equiv) in THF as a solvent at temperature range of 0℃ to 40℃ have been established. Twenty to thirty examples were demonstrated to be effective under such conditions including the synthesis of a taxol A, C-ring synthons available in multi-gram quantities. The reactions exhibited remarkable regioselectivity that the Michael addition proceeded through nucleophilic attack by more hindered site of the ketones without exceptions, which, in turn, means that Claisen condensation resulted in the formation of carbon-carbon bonds between less hindered site of the ketones and acyl carbon of the enoates. In addition, taking advantages of the MC- [3+3] process, a few useful methods for the synthesis of six membered carbocyclic compounds have also been developed. A number of control experiments have been conducted to provide strong supporting information for the mechanism of this MC-[3+3] process.