Asymmetric Reactions with Bifunctional Organocatalysis

文摘：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： 金鸡纳生物碱作为广泛有用的手性碱/亲核催化剂的开发和应用 不对称合成和在阐明催化剂-底物氢键相互作用的基础上 用于高效和一般的不对称催化。建议的工作重点是设计和开发 新型金鸡纳生物碱作为可调和实用的酸碱双功能催化剂合成 重要的不对称C-C键形成反应。具体目标是：1）催化剂的开发 用于直接和立体控制的与三取代碳亲核试剂的不对称共轭加成 构建唯一的全碳取代的季立构中心和相邻的季-叔立构中心 立体中心; 2）开发催化的不对称串联共轭加成-质子化反应， 一步创建1，3-季-三级立体中心，这是生物学上重要的常见结构基序， 现在通常通过多步过程构建的化合物; 3）催化剂的开发 酮的对映选择性亲核加成反应， 碳立构中心（O-取代的季立构中心）; 4）设计、合成和筛选 新的C6 ′-OH金鸡纳生物碱衍生物，用于发现和开发新的和强有力的 双功能手性催化剂为了说明这些反应的合成效用，我们简要概述了这些反应， 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 构建块和生物学上有趣的化合物。开放新的和根本重要的 方法的建设所有碳和氧取代的季中心，这些新的 合成方法有望对生物医学研究产生重大影响， 目标导向以及多样性导向的许多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.