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硫酸是重要的化学物质。在不对称合成中，它们传递立体化学偏见，在过渡金属介导的催化中，它们用作配体，在有机刻分析中，它们是刘易斯碱基。此外，具有构型均匀硫原子的亚硫氧化物代表了几种众所周知的药物的活性原理。迄今为止，如上所述的最拟南芥纯净的纯亚硫氧化物如上所述，源自外消旋材料的分辨率，硫化物的不对称氧化以及碳或硫磺电力器的功能。我们的预备研究确定了一种新的硫氧化物的机会。它是基于“甲氧化甲氧化物的去对称性”。在当前项目中，应改进，扩展并应用于选定药物的不对称合成。通过脱位反应的攻击性（甚至可能是手持核）底物转化为非流感产物，这需要两个A -priori优势。具有镜平面的底物可能可以通过合成来访问，在此期间，单个操作中形成了成对的类似键，而不是顺序形成。这节省了步骤。此外，在原位进行动力学分辨率的去对称性会导致具有更高水平的对映体控制的产物，而不是在常规环境中。这两种改进都强烈激励着寻求新的脱对策略。通过不对称修饰的磺胺/镁换反应，可以实现甲氧化甲氧化甲氧化物的脱水量。日二硫化氧化物用作底物，二异丙基镁作为镁来源，并透射（R）构造的双酸盐作为不对称的诱导剂。这些物种的合奏给出了（S）配置的芳基异丙基磺氧化物，EE高达91％。 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二苯甲酰磺氧化物。 2）我们要探索除了IPR2MG外，还要探索dialkylmagesium化合物ME2MG，ET2MG，Cyclohecyl2mg，T-Bu2mg和BN2MG是否可与硫代/镁的反应相邻。 binol支架应探测为可能改善的不对称诱导剂。4）硫化氧化物/镁交换反应应构成对映体纯硫化硫代药物埃索美吡唑（用于胃溃疡），莫达非尼（用于睡眠disorders）和硫酸盐（用于抗硫酸盐的治疗）的关键步骤。