Asymmetric Reactions with Bifunctional Organocatalysis

摘要：在过去的几年里，我们的研究计划在以下方面取得了重大进展 广谱手性碱/亲核催化剂金鸡纳生物碱的开发与应用 不对称合成及在阐明催化剂-底物氢键相互作用的基础上 用于高效和普遍的不对称催化。拟开展的工作主要集中在设计和开发上 新型金鸡纳生物碱可调实用酸碱双功能催化剂的研究 重要的不对称C-C键形成反应。具体目标是：1)催化剂的发展 直接和立体控制的三取代碳亲核试剂的不对称共轭加成反应 鞋底全碳取代的四元立体中心及其相邻的四元-三元结构 2)催化、不对称串联共轭加成-质子化反应的发展 一步法创建1，3-四元-三元立体中心，这是一种具有重要生物学意义的常见结构主题 目前典型的多步法合成化合物；3)催化剂的开发 酮的不对称亲核加成反应构建含氧四取代物 碳立体中心(O-取代的四元立体中心)；4)设计、合成和筛选 新型C6‘-羟基金鸡纳生物碱衍生物的发现和开发 双功能手性催化剂。为了说明这些反应的合成效用，我们概述了简明和 利用这些反应制备各种光学活性手性化合物的一般合成路线 积木和具有生物意义的化合物。打开新的，从根本上说很重要 构建所有碳和氧取代的四元中心的方法，这些新的 合成方法有望对生物医学研究产生重大影响，因为它极大地促进了 以目标为导向以及以多样性为导向的多种生物重要化合物的合成。

Abstract: During the last several years our research program has made signiificant progress in the development and application of cinchona alkaloids as broadly useful chiral base/nucleophilic catalysts for asymmetric synthesis and in the elucidation of catalyst-substrate hydrogen bonding interaction as the basis for efficient and general asymmetric catalysis. The proposed work focuses on the design and development of novel cinchona alkaloids as tunable and practical acid-base bifunctional catalysts for synthetically important asymmetric C-C bond forming reactions. The specific aims are: 1) Development of catalytic asymmetric conjugate additions with trisubstituted carbon nucleophiles for direct and stereocontrolled construction of sole all carbon substituted quaternary stereocenter and adjacent quaternary-tertiary stereocenters; 2) Development of catalytic, asymmetric tandem conjugate addition-protonation reactions for one-step creation of 1,3-quaternary-tertiary stereocenters, a common structural motif in biologically important compounds that are now typically constructed by multistep process; 3) Development of catalytic enantioselective nucleophilic additions to ketones for the construction of oxygen-substituted tetrasubstituted carbon stereocenters (O-substituted quaternary stereocenters); 4) The design, synthesis and screening of novel C6'-OH cinchona alkaloid derivatives for the discovery and development of new and powerful bifunctional chiral catalysts. To illustrate the synthetic utility of these reactions, we outline concise and general synthetic routes which utilize these reactions for the preparation of various optically active chiral building blocks and biologically interesting compounds. Opening new and fundamentally important approaches for the construction of all carbon and oxygen-substituted quaternary centers, these new synthetic methods are expected to have a major impact on biomedical research by greatly facilitating the target-oriented as well as diversity-oriented synthesis of numerous biologically important compounds.