Iridium-catalyzed enantioconvergent hydrogenation of trisubstituted olefins

Abstract

Asymmetric hydrogenation of olefins constitutes a practical and efficient method to introduce chirality into prochiral substrates. However, the absolute majority of the developed methodologies is enantiodivergent and thus require isomerically pure olefins which is a considerable drawback since most olefination strategies produce (E/Z)-mixtures. Although some advances have been reported, a general enantioconvergent hydrogenation featuring a broad functional group tolerance remains elusive. Here, we report the development of a general iridium-catalyzed enantioconvergent hydrogenation of a broad range of functionalized trisubstituted olefins. The substitution pattern around the olefin is critical; whereas α-prochiral olefins can undergo an enantioconvergent hydrogenation, β-prochiral olefins react in an enantiodivergent manner. The presented methodology hydrogenates α-prochiral substrates with excellent control of enantioselection and high isolated yields. Most importantly, both isomerically pure alkenes as well as isomeric mixtures can be hydrogenated to yield the same major enantiomer in excellent enantiomeric excesses which is unusual in transition-metal catalyzed asymmetric hydrogenations.

The Implications of the Brønsted Acidic Properties of Crabtree-Type Catalysts in the Asymmetric Hydrogenation of Olefins

“…Most iridium-catalyzed hydrogenations require starting from isomerically pure olefins since the double bond isomerism normally governs the stereochemical outcome . Traditional olefination methods often produce isomeric mixtures that thus require tedious and waste-producing separation prior to hydrogenation.…”

“…Lastly, the absolute majority of iridium-catalyzed asymmetric hydrogenations are enantiodivergent in which different olefin geometries of a given olefin are hydrogenated to opposite enantiomers in favor . The strong Brønsted acidic media during hydrogenation offers the possibility for the development of convergent catalysis via acid-catalyzed isomerization of alkenes.…”

Mechanistic Aspects of the Crabtree‐Pfaltz Hydrogenation of Olefins ‐ An Interplay of Experimentation and Quantum Chemical Computation

“…While numerous functionalized trisubstituted olefins were used as substrates experimentally, [27,29a,30c] the results were mostly analyzed with Andersson's quadrant model. More extensive analyses, for example for enantioselective hydrogenations of allylic alcohols, [45] enoates [46] and enones [47] have been reported recently. For certain enones Andersson's quadrant model fails, which was commented by Andersson et al: [47] "The failure of the model to predict the correct stereochemical outcome for the α-disubstituted enones indicates that this class of substrates might undergo hydrogenation via a different mechanism."…”

“…More extensive analyses, for example for enantioselective hydrogenations of allylic alcohols, [45] enoates [46] and enones [47] have been reported recently. For certain enones Andersson's quadrant model fails, which was commented by Andersson et al: [47] "The failure of the model to predict the correct stereochemical outcome for the α-disubstituted enones indicates that this class of substrates might undergo hydrogenation via a different mechanism." A corresponding conclusion was stated by Gridnev et al on the basis of dft calculations on hydrogenations of exocyclic α,β-unsaturated lactones.…”

Stereoselective Iridium-N,P-Catalyzed Double Hydrogenation of Conjugated Enones to Saturated Alcohols

“…In these two separate systems, catalysts that perform well in olefin hydrogenation are usually not efficient for carbonyl reduction and vice versa. As an example, nearly perfect chemoselectivity is observed when enones are reduced using Crabtree-type iridium catalysts and molecular hydrogen and give chiral ketones in high yields . This is demonstrated by contributions from Bolm and Qiu where Ir-N,P catalysts were used to produce chiral ketones starting from enones (Scheme b).…”