Desymmetrization of Prochiral Sulfoxides: A Novel Asymmetric Synthesis of Sulfoxides

前手性亚砜的去对称化：亚砜的新型不对称合成

基本信息

批准号：
252159727
负责人：
Professor Dr. Reinhard Brückner
金额：
--
依托单位：
Institut für Organische Chemie
依托单位国家：
德国
项目类别：
Research Grants
财政年份：
2014
资助国家：
德国
起止时间：
2013-12-31 至 2016-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/252159727?language=en
关键词：
Desymmetrization Prochiral Sulfoxides Novel Asymmetric

项目摘要

Enantiomerically pure sulfoxides, which contain a stereogenic sulfur atom are important chemicals for several reasons. In asymmetric synthesis they transmit stereochemical biases, in transition-metal mediated catalysis they serve as ligands, and in organocatalysis they are Lewis bases. In addition, sulfoxides with a configurationally homogeneous sulfur atom represent the active principle of several well-known pharmaceuticals.To date most enantiomerically pure sulfoxides like those mentioned above originate from the resolution of racemic materials, the asymmetric oxidation of sulfides, and the functionalization of carbon or sulfur electrophiles. Our preparatory studies established a novel access to such sulfoxides. It was based on a "desymmetrization of prochiral sulfoxides". In the current project, this access shall be improved, broadened, and applied to the asymmetric synthesis of selected drugs.The transformation of achiral - and possibly prochiral - substrates into non-racemic products by desymmetrization reactions entails two a-priori advantages. Substrates with a mirror-plane are probably accessible by syntheses, during which pairs of analogous bonds are formed in a single operation rather than sequentially; this saves steps. Moreover desymmetrizations, which are followed in situ by a kinetic resolution lead to products with higher levels of enantiocontrol than in routine settings. Both improvements motivate strongly the quest for new desymmetrization strategies.Our desymmetrizations of prochiral sulfoxides were achieved by asymmetrically modified sulfoxide/magnesium exchange reactions. Diarylsulfoxides were used as substrates, diisopropylmagnesium as the magnesium source, and dilithiated (R)-configured BINOLate as an inducer of asymmetry. The ensemble of these species gave (S)-configured aryl isopropyl sulfoxides with up to 91% ee. One such sulfoxide was carried on to a so-called "P, O ligands", which had been obtained differently before and recognized as a useful aid for asymmetric catalysis.The present project aims at investigating desymmetrizing sulfoxide/magnesium exchange reactions with the following objectives:1) The substrate range shall be extended to di(hetero)aryl, divinyl, dialkynyl, diallyl, and dibenzyl sulfoxides. Sulphites and sulphonamides shall be included, too.2) We want to explore whether in addition to i-Pr2Mg the dialkylmagnesium compounds Me2Mg, Et2Mg, cyclohexyl2Mg, t-Bu2Mg, and Bn2Mg are amenable to sulfoxide/magnesium exchange reactions.3) Phenoxides, alkoxyphenoxides, and aminophenoxides based on the BINOL scaffold shall be probed as potentially improved inducers of asymmetry.4) Sulfoxide/magnesium exchange reactions shall constitute the key step of syntheses of the enantiomerically pure sulfoxide drugs esomeprazole (used against stomach ulcers), modafinil (for the treatment of sleep disorders) and sulindac (an anti-inflammatory agent).

出于多种原因，含有立体硫原子的对映体纯亚砜是重要的化学品。在不对称合成中，它们传递立体化学偏向，在过渡金属介导的催化中，它们充当配体，在有机催化中，它们是路易斯碱。此外，具有均一构型硫原子的亚砜代表了几种知名药物的活性成分。迄今为止，大多数对映体纯的亚砜（如上述那些）源自外消旋材料的拆分、硫化物的不对称氧化和碳的官能化或硫亲电子试剂。我们的预备研究建立了一种获取此类亚砜的新途径。它基于“前手性亚砜的去对称化”。在当前的项目中，这种途径应得到改进、扩大并应用于选定药物的不对称合成。通过去对称反应将非手性和可能的前手性底物转化为非外消旋产物具有两个先验优势。具有镜面的基底可能可以通过合成来获得，在此期间，在单个操作中而不是顺序地形成成对的类似键；这样可以节省步骤。此外，去对称化（随后进行原位动力学拆分）导致产物具有比常规设置更高水平的对映体控制。这两项改进都强烈激发了对新的去对称化策略的探索。我们的前手性亚砜的去对称化是通过不对称修饰的亚砜/镁交换反应实现的。使用二芳基亚砜作为底物，使用二异丙基镁作为镁源，使用二锂化(R)-构型的BINOLate作为不对称诱导剂。这些物种的集合产生了 (S)-构型的芳基异丙基亚砜，其 ee 高达 91%。一种这样的亚砜被连接到所谓的“P，O配体”上，这种配体之前以不同的方式获得，并被认为是不对称催化的有用辅助剂。本项目旨在研究亚砜/镁交换反应的去对称性，其目标如下:1) 底物范围应扩展到二（杂）芳基、二乙烯基、二炔基、二烯丙基和二苄基亚砜。亚硫酸盐和磺酰胺也应包括在内。2) 我们想探索除了 i-Pr2Mg 之外，二烷基镁化合物 Me2Mg、Et2Mg、环己基 2Mg、t-Bu2Mg 和 Bn2Mg 是否适合亚砜/镁交换反应。3) 酚盐、应探讨基于 BINOL 支架的烷氧基酚盐和氨基酚盐是否有潜在的改进4) 亚砜/镁交换反应是合成对映体纯亚砜药物埃索美拉唑（用于治疗胃溃疡）、莫达非尼（用于治疗睡眠障碍）和舒林酸（抗炎药）的关键步骤。