Chiral Formamides as Lewis-Base Catalyst - Enantioselective SN2 Substitutions and Beyond

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In the synthesis of pharmaceuticals and other bioactive compounds SN2 substitution reactions of the Mitsunobu- and Appel-type play a fundamental role. Surprisingly, to date enantioselective variants of these reactions applying chiral catalysts, which would give rise of optically active products, are entirely unknown. As the optical activity of a drug can be crucial for its effect (e.g. Contergan), enantioselective substitution reactions are highly desirable.In this context the major objective of the project is the development of enantioselective and catalytic SN2 substitution reactions. The advised methodology would create a novel and more efficient entry (compared to existing methods) to optical active amines, ethers, carboxylic acids, amides and sulfoxides. As these functional groups represent structural key motifs in numerous pharmaceuticals and natural products, the synthetic access to many pharmaceuticals would be improved significantly.Based on the high catalytic activity of dimethyl formamide in esterifications we propose novel chiral formamides as Lewis-base catalysts suitable for these substitution reactions. Notably, the proposed catalyst concept deviates strongly from the classical motifs in (distantly) related iminium catalysis and enantioselective acylations.