基于有机小分子催化脱羧-Aldol反应的三氟甲基酮不对称转化

Now α-trifluoromethyl substituted compounds are widely used in the field of pharmaceuticals, agrochemistry and materials. Chemists have been seeking simple and effective strategies to synthesis such compounds. The synthesis of α-trifluoromethyl β-tert-alcohols with chiral quaternary carbon compounds is not easy and still in great demand.In this project, we focus on the chiral small organic molecule catalyzed decarboxylation-Aldol reaction of trifluoromethyl ketones and malonic acid half oxyesters. The project which target products are potentially physiologically active compound, mainly use environmentally friendly chiral small organic molecule catalysts. This is a novel method to of chiral α-trifluoromethyl β-tert-alcohol compounds. The preliminary test results show that the modified cinchona alkaloids catalyze addition - decarboxylation reaction of malonic acid half oxyesters with trifluoromethyl ketones. When commercially (DHQD)2AQN is used as the catalyst, it affords products in excellent yield (99% yield) with moderated enantioselectivity (68% ee). Next we intend to synthesis three types of chiral organic amine catalyst for template reaction .And the introduction of larger groups in catalyst molecule will enhance the shielding effect of N atoms which play a key role in the reaction. We expect to realize the asymmetry conversion of the trifluoromethyl ketones by catalyst screening and optimization of reaction conditions.

由于含三氟甲基化合物在医药、农药、材料等领域日渐广泛的应用，化学工作者一直寻求简便快捷构建该类化合物的方法。本项目针对含手性季碳的α-三氟甲基β-叔醇类化合物不易合成的问题，将脱羧-Aldol反应用于三氟甲基酮类的不对称转化领域，通过手性有机小分子催化三氟甲基酮与马来酸单酯反应得到目标化合物；这是合成手性α-三氟甲基β-叔醇化合物的新途径。本项目主要采用环境友好的手性有机小分子胺做为催化剂，产物α-三氟甲基β-叔醇具有潜在生理活性。初步试验结果表明，有机碱Et3N对此类反应有良好催化效果，但产物是外消旋体；金鸡纳碱衍生物（DHQD）2AQN仅对模板反应有中等手性诱导作用（ee值68%）。拟合成三类手性有机胺做为催化剂，在胺的适当位置引入较大基团增加对处于活化中心N原子的屏蔽，实现更有效手性传递，高收率高对映选择性得到目标产物。通过催化剂筛选与结构优化，实现三氟甲基酮的催化不对称转化。