发展新颖高效的不对称合成策略构建手性螺环二酚

As known to all, the axially chiral 1,1’-spirobiindane-7,7’-diol (SPINOL) has been proved to be one of the most fundamental and important privileged structures in the field of asymmetric catalysis, from which a great deal of useful chiral ligands and catalysts containing a 1,1’-spirobiindane backbone have been synthesized. However, the asymmetric synthesis of the SPINOL remains largely unexplored. The large-scale production of optically pure SPINOL, however, still relies on conventional resolution, which requires the stoichiometric use of chiral reagents, and the resulting expensive cost restricts to a great extent the industrial application of the relative research achievements. Therefore, the development of a catalytic asymmetric synthetic approach to axially chiral SPINOL derivatives is very attractive and highly challenging. This project aims to construct the SPINOL via a tandem cyclization of chiral α,β-substituted ketone catalyzed by Brønsted acid or Lewis acid, generating the spiro chiral center by a substrate-controlled inductive effect. And such chiral ketone would be synthesized by using organocatalytic asymmetric strategies such as transfer hydrogenation, Michael addition or Mannich reaction. Meanwhile, we are trying to investigate the reaction mechanism in detail by DFT calculation and control experiments to guide the subsequent research. After evaluating the catalytic performances of the constructed chiral SPINOLs with the proven model reactions, a more simple and efficient industrial synthetic route of the best catalyst will be designed and accomplished.

在不对称催化领域，手性螺环二酚是一类具有鲜明特色的催化剂，同时也是极其重要的催化剂前体，基于该优势骨架已发展了大量的手性配体和手性催化剂。然而，尽管手性螺环二酚有着非常优异的催化性能和广泛用途，其不对称合成方法还鲜有报道，而传统的拆分方式导致其生产成本很难下降，较贵的市场价格成为了该领域相关研究成果快速转化的瓶颈。因此，发展简洁高效的方法构建手性螺环二酚是一项具有重要意义且充满无限挑战的课题。本课题旨在以有机催化为核心手段，通过不对称转移氢化、迈克尔加成和曼尼希反应等合成策略构建α，β-取代的手性酮，之后再通过底物诱导实现螺手性控制的串联环化反应构建光学选择性的螺环二酚。并通过控制实验和DFT计算深入理解反应机制，为新反应的设计提供指导。同时，对构建的手性螺环二酚催化性能进行评估，发现具有更高催化效率的骨架，开发其适合工业应用的合成路线。

轴手性联芳基结构广泛存在于天然产物、药物分子和手性配体和催化剂中。高效构建策略的匮乏使得多种优势骨架的价额昂贵，限制了科学与应用研究的开展。基于此，本项目聚焦轴手性构建的新策略开发并取得了一些优异成果。首先，利用手性磷酸为有机双功能催化剂，成功实现了醌类化合物与吲哚的高区域选择性和高立体选择性偶联，高效构建了两类新型的轴手性骨架，初步的应用研究证实了该类骨架作为手性配体的应用潜力。其次，基于芳烃极性翻转策略，发展了2-萘偶氮酯与2-萘酚、2-萘胺、咔唑和硼酸的不对称交叉偶联，高效构建了多种优势轴手性联芳基骨架，该策略打破了金属催化垄断的局面并推动了有机催化的发展。此外，发展了无金属参与的脱氢氧化偶联用于阻旋异构的芳基异喹啉骨架构建，并以此为基础实现了氮杂卡宾催化的QUINOL N-oxide的动力学拆分，高效合成了两种有用的手性路易斯碱催化剂。这些方法学的研究能够为新型手性配体和催化剂的开发提供了有用的平台。