轴手性环己二烯类化合物的催化不对称合成研究

    轴手性化合物是一类普遍存在的手性化合物，从结构上可以分为阻转异构体、联烯、螺环化合物等几种不同类型。轴手性分子在手性配体、催化剂、生物活性分子以及手性材料等领域都有着广泛应用。近些年来，对于轴手性化合物的研究得到了快速发展，但主要集中于对已有优势骨架的应用和不对称合成，而新型骨架的开发相对较少。开发新型轴手性骨架，不仅可以拓展轴手性化合物的种类，也可以为含轴手性医药分子的筛选以及新型轴手性材料的进一步发展提供重要支撑。结合阻转异构体和联烯两类轴手性化合物的手性特征，本论文设计并合成了一类基于环己二烯骨架的新型轴手性分子。在这种新型骨架中，环己二烯平面与环外双键处于共平面，环外双键的Z/E构型与环己二烯环内立体中心的构型共同影响该类化合物的手性特征。本论文通过催化不对称去芳构化、不对称缩合及去对称化三种策略完成了对该类新型轴手性骨架的构建，具体的研究内容包括：

    使用手性磷酸作为催化剂，以不同取代基的螺环环己二烯酮和羟胺为原料，通过不对称缩合反应高效合成了轴手性环己二烯基肟类化合物，反应可扩大到克级规模。该反应通过控制环己二烯环外双键的构型来控制反应的对映选择性。通过手性磷酸边臂的调整，可以实现对螺环内酯类环己二烯酮和氧化吲哚类环己二烯酮底物的兼容，高效、高对映选择性得到37个轴手性环己二烯基肟类化合物（收率最高可达96%，ee值最高可达96%）。利用产物结构上不同类型取代基进行多样性衍生化能够得到丰富多样的轴手性分子，拓展化合物的范围。化合物的手性稳定性测试显示，产物在100 ℃下，在不同的溶剂中都能保持稳定的ee值，说明环己二烯基肟骨架具有稳定的轴手性。动力学实验显示催化剂的对映体纯度与产物ee值之间呈线性相关关系，反应速率与催化剂浓度之间呈一级动力学关系，说明单个催化剂分子参与该反应的速率和立体化学决定步骤。

    在手性磷酸催化下吲哚与偶氮苯对位反应，实现了苯环的催化不对称去芳构化，合成了轴手性环己二烯基腙类化合物。反应中使用偶氮作为活化基和导向基，实现了苯环对位的选择性活化。该反应突破了去芳构化反应仅用于中心手性产物合成的局限性，拓展了催化不对称去芳构化反应的应用场景。反应得到的27个轴手性环己二烯基腙类化合物收率最高可达97%，ee值最高可达99%。值得一提的是，该反应体系的催化剂用量仅为0.5 mol%，突破了有机小分子催化反应中催化剂用量高的局限性。化合物手性稳定性测试显示，产物分子的消旋能垒为135 kJ/mol，说明该类化合物具有稳定的轴手性。反应的动力学实验结果显示反应产物的对映体过量值随催化剂ee值的升高呈线性上升趋势，反应速率随催化剂浓度提高而线性提升，说明该反应的速率和立体化学决定步骤由单个催化剂分子决定。该反应具有操作简单、反应收率高、立体选择性好等优点，而且可以放大到克级规模制备。

    将环己二烯环外碳氮双键拓展到碳碳双键，合成了环己二烯基烯类轴手性化合物。以螺环环己二烯基烯烃为核心骨架，通过在烯烃末端引入对称性的醛基，利用手性磷酸催化的醛胺缩合反应，实现了轴手性环己二烯基烯的不对称构建。反应中手性磷酸展现出较好的催化效果，得到的16个轴手性环己二烯基烯化合物收率最高可达82%，ee值最高可达90%。该类产物可以通过另一侧保留的醛基进行衍生化，能够一锅法与呋喃-2-甲酰肼发生第二次缩合得到双醛基转化的产物，丰富轴手性分子的多样性。

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