Desymmetrization of Prochiral Sulfoxides: A Novel Asymmetric Synthesis of Sulfoxides

• Applicant: Professor Dr. Reinhard Brückner
• Subject Area: Organic Molecular Chemistry - Synthesis and Characterisation
• Term: from 2014 to 2017
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 252159727

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).

• DFG Programme: Research Grants