The Effect of Conformational Freedom vs Restriction on the Rate in Asymmetric Hydrogenation: Iridium-Catalyzed Regio- and Enantioselective Monohydrogenation of Dienones.

Transition metal-catalyzed asymmetric hydrogenation constitutes an efficient strategy for the preparation of chiral molecules. When dienes are subjected to hydrogenation, control over regioselectivity still presents a large challenge and the fully saturated alkane is often yielded. A few successful monohydrogenations of dienes have been reported, but hitherto these are only efficient for dienes comprised of two distinctly different olefins. Herein, the reactivity of a conjugated carbonyl compound as a function of their conformational freedom is studied, based on a combined experimental and theoretical approach. It was found that alkenes in the (s)-cis conformation experience a large rate acceleration while (s)-trans restrained alkenes undergo hydrogenation slowly. Ultimately, this reactivity aspect was exploited in a novel method for the monohydrogenation of dienes based on conformational restriction ((s)-cis vs (s)-trans). This mode of discrimination conceptually differs from existing monohydrogenations and dienones constructed of two olefins similar in nature could efficiently be hydrogenated to the chiral alkene (up to 99 % ee). The extent of regioselection is even powerful enough to overcome the conventional reactivity order of substituted olefins (di>tri>tetra). This high yielding and atom-economical protocol provides an interesting opportunity to instal a stereogenic center on a carbocycle, while leaving a synthetically useful alkene untouched.

Iridium-Catalyzed Double Convergent 1,3-Rearrangement/Hydrogenation of Allylic Alcohols.

Enantioconvergent catalysis has the potential to convert different isomers of a starting material to a single highly enantioenriched product. Here we report a novel enantioselective double convergent 1,3-rearrangement/hydrogenation of allylic alcohols using an Ir-N,P catalyst. A variety of allylic alcohols, each consisting of a 1:1:1:1 mixture of four isomers, were converted to the corresponding tertiary alcohols with two contiguous stereogenic centers, in up to 99% ee and 99:1 d.r. DFT calculations, and control experiments suggest that the 1,3-rearrangement is the crucial stereodetermining element of the reaction.

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

Chiral iridium complexes derived from Crabtree's catalyst are highly useful in modern hydrogenations of olefins attributed to high reactivity, stereoselectivity, and stability. Despite that these precatalysts are pH neutral, the reaction mixtures turn acidic under hydrogenation conditions. This Perspective is devoted to the implications of the intrinsic Brønsted acidity of catalytic intermediates in asymmetric hydrogenation of olefins. Despite that the acidity has often been used only as a rationale for side-product formation, more recent methodologies have started to use this property advantageously. We hope that this Perspective serves as a stimulant for the development of such compelling and new asymmetric hydrogenations. The inherent scientific opportunities in utilizing or annihilating the generated Brønsted acid are enormous, and potential new innovations are outlined toward the end.

Catalytic enantioselective synthesis of fluoromethylated stereocenters by asymmetric hydrogenation.

Fluoromethyl groups possess specific steric and electronic properties and serve as a bioisostere of alcohol, thiol, nitro, and other functional groups, which are important in an assortment of molecular recognition processes. Herein we report a catalytic method for the asymmetric synthesis of a variety of enantioenriched products bearing fluoromethylated stereocenters with excellent yields and enantioselectivities. Various N,P-ligands were designed and applied in the hydrogenation of fluoromethylated olefins and vinyl fluorides.

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

Asymmetric hydrogenation of prochiral substrates such as ketones and olefins constitutes an important instrument for the construction of stereogenic centers, and a multitude of catalytic systems have been developed for this purpose. However, due to the different nature of the π-system, the hydrogenation of olefins and ketones is normally catalyzed by different metal complexes. Herein, a study on the effect of additives on the Ir-N,P-catalyzed hydrogenation of enones is described. The combination of benzamide and the development of a reactive catalyst unlocked a novel reactivity mode of Crabtree-type complexes toward C═O bond hydrogenation. The role of benzamide is suggested to extend the lifetime of the dihydridic iridium intermediate, which is prone to undergo irreversible trimerization, deactivating the catalyst. This unique reactivity is then coupled with C═C bond hydrogenation for the facile installation of two contiguous stereogenic centers in high yield and stereoselectivity (up to 99% ee, 99/1 d.r.) resulting in a highly stereoselective reduction of enones.

Synthesis of Chiral Tetrahydro-3-benzazepine Motifs by Iridium-Catalyzed Asymmetric Hydrogenation of Cyclic Ene-carbamates.

A highly efficient N,P-ligated iridium complex is presented for the simple preparation of chiral tetrahydro-3-benzazepine motifs by catalytic asymmetric hydrogenation. Substrates bearing both 1-aryl and 1-alkyl substituents were smoothly converted to the corresponding hydrogenated product with excellent enantioselectivity (91-99% ee) and in isolated yield (92-99%). The synthetic value of this transformation was demonstrated by a gram-scale hydrogenation and application in the syntheses of trepipam and fenoldopam.

Iridium-catalyzed enantioconvergent hydrogenation of trisubstituted olefins.

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, ß-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.

Asymmetric Full Saturation of Vinylarenes with Cooperative Homogeneous and Heterogeneous Rhodium Catalysis.

Homogeneous and heterogeneous catalyzed reactions can seldom operate synergistically under the same conditions. Here we communicate the use of a single rhodium precursor that acts in both the homogeneous and heterogeneous phases for the asymmetric full saturation of vinylarenes that, to date, constitute an unmet bottleneck in the field. A simple asymmetric hydrogenation of a styrenic olefin, enabled by a ligand accelerated effect, accounted for the facial selectivity in the consecutive arene hydrogenation. Tuning the ratio between the phosphine ligand and the rhodium precursor controlled the formation of homogeneous and heterogeneous catalytic species that operate without interference from each other. The system is flexible in terms of both the chiral ligand and the nature of the external olefin. We anticipate that our findings will promote the development of asymmetric arene hydrogenations.

Site- and Enantioselective Iridium-Catalyzed Desymmetric Mono-Hydrogenation of 1,4-Dienes.

The control of site selectivity in asymmetric mono-hydrogenation of dienes or polyenes remains largely underdeveloped. Herein, we present a highly efficient desymmetrization of 1,4-dienes via iridium-catalyzed site- and enantioselective hydrogenation. This methodology demonstrates the first iridium-catalyzed hydrogenative desymmetriation of meso dienes and provides a concise approach to the installation of two vicinal stereogenic centers adjacent to an alkene. High isolated yields (up to 96 %) and excellent diastereo- and enantioselectivities (up to 99:1 d.r. and 99 % ee) were obtained for a series of divinyl carbinol and divinyl carbinamide substrates. DFT calculations reveal that an interaction between the hydroxy oxygen and the reacting hydride is responsible for the stereoselectivity of the desymmetrization of the divinyl carbinol. Based on the calculated energy profiles, a model that simulates product distribution over time was applied to show an intuitive kinetics of this process. The usefulness of the methodology was demonstrated by the synthesis of the key intermediates of natural products zaragozic acid A and (+)-invictolide.

Highly Enantioselective Iridium-Catalyzed Hydrogenation of Conjugated Trisubstituted Enones.

Asymmetric hydrogenation of conjugated enones is one of the most efficient and straightforward methods to prepare optically active ketones. In this study, chiral bidentate Ir-N,P complexes were utilized to access these scaffolds for ketones bearing the stereogenic center at both the α- and ß-positions. Excellent enantiomeric excesses, of up to 99%, were obtained, accompanied with good to high isolated yields. Challenging dialkyl substituted substrates, which are difficult to hydrogenate with satisfactory chiral induction, were hydrogenated in a highly enantioselective fashion.

Cationic NHC-Phosphine Iridium Complexes: Highly Active Catalysts for Base-Free Hydrogenation of Ketones.

Novel bidentate N-heterocyclic carbene-phosphine iridium complexes have been synthesized and evaluated in the hydrogenation of ketones. Reported catalytic systems require base additives and, if excluded, need elevated temperature or high pressure of hydrogen gas to achieve satisfactory reactivity. The developed catalysts showed extremely high reactivity and good enantioselectivity under base-free and mild conditions. In the presence of 1 mol % catalyst under 1 bar hydrogen pressure at room temperature, hydrogenation was complete in 30 minutes giving up to 96 % ee. Again, this high reactivity was achieved in additive-free conditions. Mechanistic experiments demonstrated that balloon pressure of hydrogen was sufficient to form the activate species by reducing and eliminating the 1,5-cyclooctadiene ligand. The pre-activated catalyst was able to hydrogenate acetophenone with 89 % conversion in 5 min.