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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).

含有立体硫原子的对映体纯亚砜是重要的化学品，原因有几个。在不对称合成中，它们传递立体化学偏差，在过渡金属介导的催化中，它们充当配体，在有机催化中，它们是刘易斯碱。此外，具有构型均匀的硫原子的亚砜代表了几种众所周知的药物的活性成分。迄今为止，大多数对映体纯的亚砜，如上述那些来自外消旋物质的拆分，硫化物的不对称氧化，以及碳或硫亲电试剂的官能化。我们的预备研究建立了一个新的途径，这样的亚砜。它是基于“前手性亚砜的去对称化”。在本项目中，这一途径将得到改进、扩大，并应用于选定药物的不对称合成。通过去对称化反应将非手性-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。具有镜像平面的基底可能可以通过合成来获得，在合成过程中，成对的类似键在一次操作中形成，而不是依次形成;这节省了步骤。此外，desymmetrizations，随后在原位的动力学决议导致产品具有更高水平的enantiocontraction比在常规设置。这两个改进强烈地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，二异丙基镁作为镁源，并且二硫代（R）-构型的BINOLate作为不对称诱导剂。这些物种的集合得到了（S）-构型的芳基异丙基亚砜，其ee值高达91%.One such sulfoxide is carried on to a所谓的“P，O ligands”，这是一种以前以不同方式获得的并被认为是一种有用的不对称催化助剂。本项目旨在研究去对称化亚砜/镁交换反应，目标如下：1）底物范围应扩展至二（杂）芳基、二乙烯基、二炔基、二烯丙基和二苄基亚砜。也应该包括亚硫酸盐和磺酰胺。2）我们想要探索除了i-Pr 2 Mg之外，二烷基镁化合物Me 2 Mg、Et 2 Mg、环己基2 Mg、t-Bu 2 Mg和Bn 2 Mg是否适合于亚砜/镁交换反应。3）酚盐，烷氧基酚盐，基于BINOL支架的氨基酚类化合物应被探索为潜在的改善的不对称诱导剂。镁交换反应将构成合成对映体纯亚砜药物艾美拉唑（用于治疗胃溃疡）、莫达非尼（用于治疗睡眠障碍）和舒林酸（抗炎剂）的关键步骤。