Metal-Templated Design: Enantioselective Hydrogen-Bond-Driven Catalysis Requiring Only Parts-per-Million Catalyst Loading

Abstract

Based on a metal-templated approach using a rigid and globular structural scaffold in the form of a bis-cyclometalated octahedral iridium complex, an exceptionally active hydrogen-bond-mediated asymmetric catalyst was developed and its mode of action investigated by crystallography, NMR, computation, kinetic experiments, comparison with a rhodium congener, and reactions in the presence of competing H-bond donors and acceptors. Relying exclusively on weak forces, the enantioselective conjugate reduction of nitroalkenes can be executed at catalyst loadings as low as 0.004 mol% (40 ppm), representing turnover numbers of up to 20 250. A rate acceleration by the catalyst of 2.5 × 10(5) was determined. The origin of the catalysis is traced to an effective stabilization of developing charges in the transition state by carefully orchestrated hydrogen-bonding and van der Waals interactions between catalyst and substrates. This study demonstrates that the proficiency of asymmetric catalysis merely driven by hydrogen-bonding and van der Waals interactions can rival traditional activation through direct transition metal coordination of the substrate.

Stereogenic‐Only‐at‐Metal Asymmetric Catalysts

“…By using rational design as a guiding principle to carefully modify the ligand sphere of such scaffolds, in combination with an iterative improvement of the catalyst performance, we were able to develop highly effective asymmetric catalysts for a variety of different transformations, such as transfer hydrogenations, Friedel–Crafts reactions, sulfa‐Michael additions, aza‐Henry reactions, and α‐amination of aldehydes . Figure shows a recently developed powerful catalyst Λ‐ 6 (Figure a) for the conjugate reduction of β,β‐disubstituted nitroalkenes with a Hantzsch ester as the reducing agent (Figure b), providing high yields and high enantioselectivities at parts‐per‐million catalyst loading . According to our proposed model in Figure c, catalyst, substrate, and reagent form a network of hydrogen bonds that bring both the nitroalkene and the Hantzsch ester into a proper orientation and provide electronic activation for hydride transfer followed by proton transfer.…”

Approaching sub-ppm-level asymmetric organocatalysis of a highly challenging and scalable carbon–carbon bond forming reaction

“…It is noteworthy that ppm-level loadings in organocatalysis have previously been reported, for instance, in silylative kinetic resolutions of racemic alcohols 33 and in asymmetric transfer hydrogenations. 34 To the best of our knowledge, however, approaching sub-ppm level loadings (<1 ppm, Fig. 3b and 3c) of an organocatalyst in a challenging carbon-carbon bond forming reaction with high enantioselectivity is unprecedented .…”

Exploiting Octahedral Stereocenters: From Enzyme Inhibition to Asymmetric Photoredox Catalysis

“…[19][20][21][22][23] All of these catalysts are based on bis-cyclometalated iridium(III) (Figure 3 b). [22] In this design, the nitroalkene substrate is activated through the formation of two hydrogen bonds to a coordinated amidopyrazole moiety while the Hantzsch ester [24] is activated towards hydride transfer and placed in a suitable position through the formation of a hydrogen bond …”