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

在药物和其他生物活性化合物的合成中，Mitsunobu-和Appl-型的SN2取代反应起着基础性的作用。令人惊讶的是，到目前为止，使用手性催化剂的这些反应的对映选择性变体完全未知，这将产生光学活性产物。由于药物的光学活性对其效果至关重要(例如康特根)，因此对映体选择性取代反应是非常可取的。在此背景下，该项目的主要目标是发展对映体选择性和催化的SN2取代反应。建议的方法将创造一种新的和更有效的进入光学活性胺、醚、羧酸、酰胺和亚硫醚的方法(与现有方法相比)。由于这些官能团代表了许多药物和天然产物中的结构关键基序，许多药物的合成途径将大大改善。基于二甲基甲酰胺在酯化反应中的高催化活性，我们提出了适合于这些取代反应的新型手性甲酰胺催化剂。值得注意的是，所提出的催化剂概念在(远)相关的亚胺催化和对映体选择性酰化反应中与经典的主题有很大的偏离。

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.