Iridium-Catalyzed Asymmetric Hydrogenation Research Articles

Highly Efficient and Enantioselective Iridium-Catalyzed Asymmetric Reductive Cycloetherification.

A catalytic protocol for the iridium-catalyzed asymmetric hydrogenation (AH) of γ- or δ-hydroxy ketones to rapidly assemble various aliphatic enantioenriched tetrahydrofurans (THFs) or tetrahydropyrans (THPs) is disclosed. A wide range of enantioenriched THFs or THPs were obtained in high yields and excellent enantioselectivities (up to 99% and up to 96.5:3.5 er). The dynamic kinetic resolution asymmetric hydrogenation (DKR-AH) process was also achieved, simultaneously constructing enantioenriched THP scaffolds with two contiguous stereogenic centers with high yields and stereoselectivities (up to 92% yield, up to 98.5:1.5 er and >20:1 dr). Mechanistic investigation indicates that the key step of the reaction involves the AH of the challenging cyclic, aliphatic oxocarbenium ions. Furthermore, this catalytic enantioselective approach could be carried out on a gram scale, and various enantioenriched cyclic ethers were further transformed into an array of useful building blocks for enantioenriched natural products and bioactive molecules.

Chiral Polymeric Diamine Ligands for Iridium-Catalyzed Asymmetric Transfer Hydrogenation.

A series of polymeric chiral diamine ligands are developed by diboron-templated asymmetric reductive couplings, and their iridium complexes Ir-polydiamines are efficient and recyclable catalysts for asymmetric transfer hydrogenation (ATH) of functionalized ketones, affording a series of optically active secondary alcohols in excellent enantioselectivities (up to 99% ee) and unprecedentedly high total TONs (12,000, six cycles). Ir-polydiamine catalysts with longer chains offered higher reactivities, providing a plausible deactivation mechanism and practical solutions of ATH for vitamin B5 and phenylephrine.

Cyclometallated Imides as Templates for the H-Bond Directed Iridium-Catalyzed Asymmetric Hydrogenation of N-Methyl, N-Alkyl and N-Aryl Imines.

A combined computational and experimental approach allowed us to develop overall the most selective catalyst for the direct hydrogenation of N-methyl, N-alkyl and N-aryl imines described to date. Iridium catalysts with a cyclometallated cyclic imide group provide selectivity of up to 99 % enantiomeric excess. Computational studies show that the selectivity results from the combined effect of H-bonding of the imide C=O with the substrate iminium ion and a stabilizing π-π interaction with the cyclometallated ligand. The cyclometallated ligand thus exhibits a unique mode of action, serving as a template for the H-bond directed approach of the substrate which results in enhanced selectivity. The catalyst (2) has been synthesized and isolated as a crystalline air-stable solid. X-ray analysis of 2 confirmed the structure of the catalyst and the correct position of the imide C=O groups to engage in an H-bond with the substrate. 19F NMR real-time monitoring showed the hydrogenation of N-methyl imines catalyzed by 2 is very fast, with a TOF of approx. 3500 h-1.

Iridium-Catalyzed Asymmetric Hydrogenation of Heteroaromatics with Multiple N Atoms via Substrate Activation: An Entry to 4,5,6,7-Tetrahydropyrazolo[1,5-a]pyrimidine-3-carbonitrile Core of a Potent BTK Inhibitor.

The chiral 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine is the key core skeleton of potent Bruton's tyrosine kinase (BTK) inhibitor Zanubrutinib, and the catalyst-controlled asymmetric hydrogenation of planar multinuclear pyrimidine heteroarenes with multiple N atoms could provide an efficient route toward its synthesis. Owing to the strong aromaticity and poisoning effect toward chiral transition metal catalyst, asymmetric hydrogenation of pyrazolo[1,5-a]pyrimidines with multiple nitrogen atoms is still a challenge for synthesizing the chiral 4,5,6,7-tetrahydropyrazolo[1,5-a]-pyrimidine. Herein, an efficient iridium-catalyzed asymmetric hydrogenation of pyrazolo[1,5-a]pyrimidines has been developed using substrate activation strategy, with up to 99% ee. The decagram scale synthesis further demonstrated the potential and promise of this procedure in the synthesis of Zanubrutinib. In addition, a mechanistic study indicated that the hydrogenation starts with 1,2-hydrogenation.

Cinchona-Alkaloid-Derived NNP Ligand for Iridium-Catalyzed Asymmetric Hydrogenation of β-Keto Ester.

The Ir-catalyzed asymmetric hydrogenation of β-keto esters with Cinchona-alkaloid-derived NNP ligands has been developed. β-Hydroxy esters of opposite configuration were afforded smoothly with 91.5-99.1 and 81.6-99.3% ee, respectively, using NNP L2 and L7 derived from quinidine and quinine separately even on the gram scale. The protocol for the preparation of β-hydroxy esters of opposite configuration by the simple conversion of ligand configurations offered further opportunities for the synthesis of biologically active molecules and drugs.

Iridium-catalyzed asymmetric hydrogenation of 5-hydroxypicolinate pyridinium salts under batch and flow: stereodefined access to cis-configurated hydroxypiperidine esters

An iridium-catalyzed asymmetric hydrogenation of 2-esteryl-5-hydroxypyridinium salts is reported, providing chiral cis-5-hydroxypiperidine-2-carboxylates in excellent yields with high levels of enantioselectivities and diastereoselectivities.

Iridium-Catalyzed Asymmetric Hydrogenation of Dialkyl Imines

Iridium-Catalyzed Asymmetric Hydrogenation of Dialkyl Imines

Access to Enantiomerically Pure P-Chiral 1-Phosphanorbornane Silyl Ethers.

Sulfur-protected enantiopure P-chiral 1-phosphanorbornane silyl ethers 5a,b are obtained in high yields via the reaction of the hydroxy group of P-chiral 1-phosphanorbornane alcohol 4 with tert-butyldimethylsilyl chloride (TBDMSCl) and triphenylsilyl chloride (TPSCl). The corresponding optically pure silyl ethers 5a,b are purified via crystallization and fully structurally characterized. Desulfurization with excess Raney nickel gives access to bulky monodentate enantiopure phosphorus(III) 1-phosphanorbornane silyl ethers 6a,b which are subsequently applied as ligands in iridium-catalyzed asymmetric hydrogenation of a prochiral ketone and enamide. Better activity and selectivity were observed in the latter case.

Iridium-Catalyzed Asymmetric Hydrogenation of Tetrasubstituted Exocyclic Olefins: An Efficient Access to Dexmethylphenidate

Iridium-Catalyzed Asymmetric Hydrogenation of Tetrasubstituted Exocyclic Olefins: An Efficient Access to Dexmethylphenidate

Iridium-Catalyzed Asymmetric Transfer Hydrogenation of 1-Aryl-1-alkylethenes with Ethanol.

Asymmetric transfer hydrogenation of 1-aryl-1-alkylethenes with ethanol was developed with a chiral (PCN)Ir complex as the precatalyst, featuring high enantioselectivities, good functional group tolerance, and operational simplicity. The method is further applied to formal intramolecular asymmetric transfer hydrogenation of alkenols without an external H-donor, producing a tertiary stereocenter and remote ketone group simultaneously. The utility of the catalytic system was highlighted by gram scale synthesis and the synthesis of the key precursor of (R)-xanthorrhizol.

Cinchona-Alkaloid-Derived NN Ligands and Achiral Phosphines for Iridium-Catalyzed Asymmetric Hydrogenation of Heteroaromatic and α-Chloroheteroaryl Ketones.

A concise synthesis of cinchona-alkaloid-derived NN ligands bearing alkyl substituents on chiral nitrogen atoms was described. Iridium catalysts containing new chiral NN ligands and achiral phosphines were effective for the asymmetric hydrogenation of heteroaromatic ketones, which afforded corresponding alcohols in up to 99.9% ee. The same protocol was applicable to the asymmetric hydrogenation of α-chloroheteroaryl ketones. Most importantly, the gram-scale asymmetric hydrogenation of 2-acetylthiophene and 2-acetylfuran proceeded smoothly even under 1 MPa of H2.

Concise Enantioselective Total Synthesis of Isopavine Alkaloids.

Herein, we report a concise asymmetric total synthesis of isopavine alkaloids, which feature a special azabicyclo[3.2.2]nonane tetracyclic skeleton. The key steps include iridium-catalyzed asymmetric hydrogenation of unsaturated carboxylic acids, Curtius rearrangement, and Eschweiler-Clarke methylation, which enable an enantioselective approach to isopavine alkaloids in 6-7 linear steps. Furthermore, for the first time, isopavine alkaloids, especially (-)-reframidine (3), are found to display effective antiproliferative effects on various cancer cell lines.

Enantioselective Ir-Catalyzed Hydrogenation of Terminal Homoallyl Sulfones: Total Synthesis of (-)-Curcumene.

A novel methodology for the preparation of chiral methyl benzylic compounds is reported. Terminal homoallyl sulfones were prepared from homoallyl alcohols, which are easily accessible through the recently reported Lewis acid isomerization of oxetanes. The iridium-catalyzed asymmetric hydrogenation of homoallylic sulfones afforded γ-chiral sulfones with excellent enantioselectivities (up to 98% ee). The synthetic potential of this novel methodology was demonstrated by the total synthesis of (R)-(-)-curcumene.

Synthesis of Tridentate PNO Ligands with Planar Chirality and Application in Iridium-Catalyzed Asymmetric Hydrogenation of Simple Ketones.

A series of [2,2]paracyclophane-based tridentate PNO ligands with planar chirality were designed and synthesized. The easily prepared chiral tridentate PNO ligands were successfully applied to the iridium-catalyzed asymmetric hydrogenation of simple ketones, giving chiral alcohols with high efficiency and excellent enantioselectivities (up to 99% yield and >99% ee). Control experiments revealed the indispensability of both N-H and O-H in the ligands.

Asymmetric Hydrogenation of Tetrasubstituted α,β-Unsaturated Ketones: Access to Chiral 2-Substituted Cyclopentyl Aryl Ketones

Asymmetric hydrogenation of tetrasubstituted alkenes is an important but challenging research topic. Herein, we report an efficient iridium-catalyzed asymmetric hydrogenation of tetrasubstituted α,β-unsaturated ketones for the synthesis of chiral 2-substituted cyclopentyl aryl ketones, an important chiral structural motif for the preparation of chiral pharmaceuticals and bioactive molecules. The reaction proceeded very well with good functional group compatibility and delivered the hydrogenated products in high yields and stereoselectivities (up to 99% yield, >20:1 dr and 99% ee). In addition, the reaction could be carried out on a gram-scale, and all four stereoisomers of the hydrogenated products bearing two contiguous stereocenters were obtained. Furthermore, the hydrogenated product can be transformed into the ERβ agonist Erteberel, and the reaction pathway was also studied via deuterium-labelling experiments.

New synthetic pathways to theAnastrepha ludenshost marking pheromone: harnessing iridium-catalysis with novel P,N-ligand for enantioselective construction

A highly efficient iridium-catalyzed asymmetric hydrogenation approach is described for the total synthesis of the biologically active (R,L)A. ludenshost marking pheromone (HMP).

On the Effect of Iodide and Acids in the Metolachlor Process

Iridium-catalyzed asymmetric imine hydrogenation is the key step in the industrial syntheses of dextromethorphan and metolachlor. Nevertheless, the mechanism of this reaction relying on ferrocenyldiphosphine ligands remains unclear. Through computational studies, we propose a mechanism that is in line with all experimental observations including the enantioselectivity. The calculated mechanism reveals the interplay of potentially three rate-determining transition states, namely, the migratory insertion, amido-ligand protonation, and heterolytic H2-activation. Most salient, the mechanism rationalizes the “magic iodide effect” in combination with proton co-catalysis, which improve the reaction rate as well as enantioselectivity. Acid additives accelerate both the protonation- and H2-splitting steps. Iodide further facilitates the protonation and potentially the H2-activation. Thus, these additives prevent that other elementary steps within the catalytic cycle compromise the enantioselectivity control exerted by the migratory insertion step.

Iridium-Catalyzed Double Asymmetric Hydrogenation of 2,5-Dialkylienecyclopentanones for the Synthesis of Chiral Cyclopentanones.

Herein, we report an efficient iridium-catalyzed double asymmetric hydrogenation of 2,5-dialkylienecyclopentanones, delivering the chiral 2,5-disubstituted cyclopentanones in excellent yields and stereoselectivities. The results of the kinetic experiments and control experiments indicated that the two C═C bonds were hydrogenated in a stepwise manner and the second stereocenter was synergistically controlled by the chiral catalyst and the chirality of monohydrogenated product. The hydrogenated products can be prepared on a gram-scale and are easily derivatized.

Iridium-Catalyzed Asymmetric Hydrogenation of an Indenopyridine: 11β-HSD-1 Inhibitor

Key words 11β-HSD-1 inhibitors - palladium catalysis - iridium catalysis - C–H activation - asymmetric synthesis - hydrogenation

Iridium-catalyzed enantioselective synthesis of chiral γ-amino alcohols and intermediates of (S)-duloxetine, (R)-fluoxetine, and (R)-atomoxetine

Chiral γ-amino alcohols are the prevalent structural motifs and building blocks in pharmaceuticals and bioactive molecules. Enantioselective hydrogenation of β-amino ketones provides a straightforward and powerful tool for the synthesis of chiral γ-amino alcohols, but the asymmetric transformation is synthetically challenging. Here, a series of tridentate ferrocene-based phosphine ligands bearing modular and tunable unsymmetrical vicinal diamine scaffolds were designed, synthesized, and evaluated in the iridium-catalyzed asymmetric hydrogenation of β-amino ketones. The system was greatly effective to substrates with flexible structure and functionality, and diverse β-tertiary-amino ketones and β-secondary-amino ketones were hydrogenated smoothly. The excellent reactivities and enantioselectivities were achieved in the asymmetric delivery of various chiral γ-amino alcohols with up to 99% yields, >99% ee values, and turnover number (TON) of 48,500. The gram-scale reactions with low catalyst loading showed the potential application in industrial synthesis of chiral drugs, such as (S)-duloxetine, (R)-fluoxetine, and (R)-atomoxetine.