Christof Sparr

Molecular design strategies that profit from the intrinsic stereoelectronic and electrostatic effects of fluorinated organic molecules have mainly been restricted to bio-organic chemistry. Indeed, many fluorine conformational effects remain academic curiosities with no immediate application. However, the renaissance of organocatalysis offers the possibility to exploit many of these well-described phenomena for molecular preorganization. In this minireview, we highlight examples of catalyst refinement by introduction of an aliphatic C-F bond which functions as a chemically inert steering group for conformational control.

Owing to their favorable molecular topology, atropisomers represent particularly valuable chiral scaffolds for numerous applications throughout academic research and industry. Nevertheless, whereas various well-established catalyst-controlled methodologies allow addressing stereocenter configuration, efficient procedures to prepare axially chiral compounds in high isomeric purity are still scarce. Complementary to the comprehensive reviews in the area, this Perspective features representative advances for the catalyst-stereocontrolled synthesis of atropisomeric scaffolds. With a focus on axially chiral motifs frequently utilized in catalysis or medicinal chemistry, selected recent examples encompassing unique stereoselective transition metal, hydrogen bond, ion pairing, chiral phosphoric acid, and amine catalysis are highlighted.

While aromatic hydrocarbons are ubiquitous in organic chemistry, they are typically not associated with chirality and stereoisomerism. Due to the planarity and symmetry of simple arenes, methods to assemble aromatic rings are not routinely considered for the stereoselective synthesis of chiral compounds. The aim of this tutorial review is to contrast this common perception with the counterintuitive circumstance that stereoselective arene formation offers a means to stereoselectively prepare an exceptional range of chiral aromatic structures. The versatility of these methods across various types of molecular scaffolds allows to control stereocentre configuration, helical chiral compounds, the configuration of rotationally restricted stereogenic axes, planar chiral molecules or curved polyaromatic systems. Furthermore, stereoselective arene formation holds great promise for the selective construction of extended but structurally well-defined chiral structures.

Axially chiral compounds are of significant importance in modern synthetic chemistry and particularly valuable in drug discovery and development. Nonetheless, current approaches for the preparation of pure atropisomers often prove tedious. We demonstrate here a synthetic method that efficiently transfers the stereochemical information of a secondary amine organocatalyst into the axial chirality of tri-ortho-substituted biaryls. An aromatic ring is formed during the dehydration step of the described aldol condensation cascade, leading to highly enantioenriched binaphthyl derivatives. The fundamental course of the reaction is related to the biosynthesis of aromatic polyketides.

The gauche effect that is induced upon reversible formation of an iminium ion (see structure: green F, blue N) provides a powerful method for the preorganization of transient intermediates that are central to secondary amine catalyzed processes. This phenomenon has been exploited in the design of a novel organocatalyst and is showcased in the stereoselective epoxidation of alpha,beta-unsaturated aldehydes.