Chiral ligands play a central role in enantioselective transition-metal catalysis. The success of achiral N-heterocyclic carbenes (NHCs) as stable electron-rich neutral ligands in homogeneous catalysis led to the development of a manifold of chiral NHCs as stereodirecting ancillary ligands for various enantioselective transformations. Due to the modular design of NHCs and the ease of access to their azolium salt precursors, tailor-made NHCs are readily available. Many chiral NHC scaffolds have been synthesised and tested in catalysis. Herein, we highlight only those NHC structures which have enabled high degrees of enantioselectivity in transition-metal catalysis. Following a brief introduction to the field of chiral NHCs, this tutorial review introduces different categories of chiral NHCs and provides a guide to the structural fine-tuning of ligand requirements and stereochemical models.

Piperidines and fluorine-substituents are both independently indispensable components in pharmaceuticals, agrochemicals and materials. Logically, the incorporation of fluorine atoms into piperidine scaffolds is therefore an area of tremendous potential. However, synthetic approaches towards the formation of these architectures are often impractical. The diastereoselective synthesis of substituted monofluorinated piperidines often requires substrates with pre-defined stereochemistry. That of multifluorinated piperidines is even more challenging, and often needs to be carried out in multistep syntheses. In this report, we describe a straightforward process for the one-pot rhodium-catalyzed dearomatization–hydrogenation (DAH) of fluoropyridine precursors. This strategy enables the formation of a plethora of substituted all-cis-(multi)fluorinated piperidines in a highly diastereoselective fashion through pyridine dearomatization followed by complete saturation of the resulting intermediates by hydrogenation. Fluorinated piperidines with defined axial/equatorial orientation of fluorine-substituents were successfully applied in the preparation of commercial drugs analogues. Additionally, fluorinated PipPhos as well as fluorinated ionic liquids were obtained by this DAH process.

We report a method to convert readily available silylated arenes into silylated saturated carbo- and heterocycles by arene hydrogenation. The scope includes alkoxy- and halosilyl substituents. Silyl groups can be derivatized into a plethora of functionalities and find application in organic synthesis, materials science, and pharmaceutical, agrochemical, and fragrance research. However, silylated saturated (hetero- ) cycles are difficult to access with current technologies. The yield of the hydrogenation depends on the amount of the silica gel additive. This silica effect also enables a significant improvement of a previously disclosed method for the hydrogenation of highly fluorinated arenes (e.g., to all-cis-C H F ).

The α-alkylation of a broad range of methylene ketones was achieved using a ruthenium­(II)-NHC catalyst under borrowing hydrogen conditions. Primary alcohols served as alkylating agents and could be used in a one-to-one stoichiometry with respect to the ketone. The selectivity of the process for methyl over branched ketones enabled a one-pot double alkylation protocol utilizing two different alcohols with a single catalyst. Moreover, this methodology could be applied directly to the one-step synthesis of donepezil, the best-selling drug for the treatment of Alzheimer’s disease.

A novel asymmetric hydrogenation of vinylthioethers was developed using a ruthenium(II) NHC complex. This method provides an efficient approach to optically active 1,5-benzothiazepines featuring stereocenters with C-S bonds. Excellent enantioselectivities (up to 95 % ee) and high yields (up to 99 %) were obtained for a variety of substrates bearing a range of useful functional groups. Moreover, this methodology could be directly applied to the synthesis of the antidepressant drug R-(-)-thiazesim.