Ir-catalyzed Asymmetric Hydrogenation Research Articles

Spiro-Josiphos Ligands for the Ir-Catalyzed Asymmetric Synthesis of Chiral Amines under Hydrogenation Conditions.

Transition metal-catalyzed asymmetric hydrogenation possesses unparalleled advantages to prepare chiral amines. Here we reported a novel ligand that combined Josiphos and a spirobiindane scaffold and simultaneously investigated its application in Ir-catalyzed asymmetric hydrogenation for the synthesis of chiral amines. Excellent catalytic activity (5000 TON), high enantioselectivity (up to 99% ee), and broad substrate scope (different C═N substrates) make it highly promising for both academic research and industrial applications.

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.

Ir-catalyzed asymmetric hydrogenation of 2-Aryl-3H-indoles with chiral phosphine-phosphoramidite ligands

An asymmetric synthesis of indolines has been described by using an Ir-catalyzed asymmetric hydrogenation of 2-aryl-3H-indoles with unsymmetrical hybrid chiral phosphine-phosphoramidite ligands. The result indicated that the catalytic performance could be significantly improved by the H8-binaphthyl moiety on this ligand motif. This method is characterized by a high asymmetric induction and a reasonable functional group tolerance, thus providing a concise and efficient approach toward chiral indoline and their derivatives with up to 94 % ee.

Chemoselective and Divergent Synthesis of Chlorohydrins and Oxaheterocycles via Ir-Catalyzed Asymmetric Hydrogenation.

Chlorohydrins and oxaheterocycles are synthetically valuable building blocks for diverse natural products and therapeutic substances. A highly efficient Ir/f-phamidol-catalyzed asymmetric hydrogenation of ω-chloroketones was successfully developed, and various chlorohydrins and oxaheterocycles were obtained divergently with excellent yields and enantioselectivities (up to >99% yield and >99% ee). Synthetic utilities of this divergent transformation were demonstrated by gram-scale synthesis of key intermediates of several enantiomerically enriched drugs via this catalytic methodology.

One-Pot Synthesis of Chiral 1-Aryl-2-Aminoethanols via Ir-Catalyzed Asymmetric Hydrogenation.

A straightforward synthesis approach to chiral 1-aryl-2-aminoethanols via the one-pot asymmetric hydrogenation catalyzed by Ir catalyst was developed. This tandem process involves the in situ generation of α-amino ketones via the nucleophilic substitution of α-bromoketones with amines and the Ir-catalyzed asymmetric hydrogenation of ketone intermediates to provide diverse enantiomerically enriched β-amino alcohols. The excellent yields and enantioselectivities (up to 96% yield and up to >99% ee) with a wide substrate scope in this one-pot strategy were obtained.

Synthetic Study of Dragmacidin E: Enantioselective Construction of the Seven-Membered Ring-Fused Indole Skeleton with Contiguous Stereocenters.

We developed an enantioselective synthetic method of constructing a seven-membered ring-fused indole skeleton with contiguous stereocenters for the synthesis of dragmacidin E. Introduction of chirality at the benzylic position was achieved by Ir-catalyzed asymmetric hydrogenation. After construction of the tricyclic molecular framework using Pd-catalyzed cascade cyclization, the tetrasubstituted carbon center was created using the Ag nitrene-mediated C-H amination reaction. The developed method provided access to the functionalized seven-membered ring-fused indole skeleton with a hydroxymethyl branch in the tetrasubstituted carbon.

The Ir-Catalyzed Asymmetric Hydrogenation of α-Halogenated Ketones Utilizing Cinchona-Alkaloid-Derived NNP Ligand to Produce (R)- and (S)-Halohydrins.

The asymmetric hydrogenation of α-halogenated ketones with iridium catalyst was developed, utilizing easily accessed cinchona-alkaloid-based NNP ligands. Various α-chloroacetophenones, heterocyclic thienyl and furanyl substrates, and even bromoketones were completely converted to the desired chiral halohydrins by this protocol. Both (R)- and (S)-chiral halohydrins can be prepared by changing the configurations of the chiral ligand NNP with up to 99.6% ee (enantiomeric excess) and 98.8% ee, respectively. Also, a gram-scale experiment was carried out efficiently.

Front Cover Picture: Filling the Gaps in the Challenging Asymmetric Hydrogenation of Exocyclic Benzofused Alkenes with Ir−P,N Catalysts (Adv. Synth. Catal. 2/2023)

The front cover picture is an artistic rendering illustrating the inside of the pressure reactor during an Ir-catalyzed asymmetric hydrogenation of benzofused exocyclic olefins. The schematic orange ball represents the new simple Ir/phosphine-triazole catalytic system which, surpassing previous limitations, hydrogenate in high enantioselectivities (ee's up to 99%) a wide range of exocyclic olefins bearing benzofused five- and six-membered ring pattern. Details can be found in the Research Article by Montserrat Diéguez and co-workers (M. Biosca, P. de la Cruz-Sánchez, D. Tarr, P. Llanes, E. A. Karlsson, J. Margalef, O. Pàmies, M. À. Pericàs, M. Diéguez, Adv. Synth. Catal. 2023, 365, 167–177; DOI: 10.1002/adsc.202200870).

Highly Enantioselective Iridium-Catalyzed Hydrogenation of o-Amidophenyl Ketones Enabled by 1,2-Diphenylethylenediamine-Derived P,N,N-Ligands with Tertiary Amine Terminus.

A readily available and highly modular class of chiral P,N,N-ligands based on a structurally flexible nonchiral phosphine-amine framework with an optically active 1,2-diphenylethylenediamine unit bearing a tertiary amine terminus as the chiral source have been developed and successfully applied in the Ir-catalyzed asymmetric hydrogenation of o-amidophenyl ketones. These tridentate P,N,N-ligands exhibited excellent activity, enantioselectivity, and substrate tolerance, thus furnishing various optically active o-amidobenzhydrols in up to 99% yields and with >99% ee. The utility of this protocol has been proven by synthetically diverse product transformation and highly enantioselective production of a rice plant growth regulator, (S)-inabenfide.

Ir-Catalyzed Asymmetric Hydrogenation of Unprotected Indoles: Scope Investigations and Mechanistic Studies

Ir-Catalyzed Asymmetric Hydrogenation of Unprotected Indoles: Scope Investigations and Mechanistic Studies

Ir-catalyzed asymmetric hydrogenation of ketones using novel PNO phosphine ligands

<p indent=0mm>The asymmetric hydrogenation of ketones continue to be a hot research topic because of the importance of secondary chiral alcohols in the production of pharmaceuticals and many other products. For example, based on the asymmetric hydrogenation of ketones, our group has synthesized Duloxetine and Ezetimibe, which were important and best selling antidepressant and antihyperlipidemic drugs. On the other hand, phosphine ligands were found to be the critical factor to increase the activity of metal catalysts. Thus, since the successful application of BINAP by Noyori and co-workers, hundreds of phosphine ligands have been developed for the more efficient transformation of ketones into chiral alcohols. For example, BPE ligand reported by Burk group in 1993, Miniphos ligand synthesized by Imamoto and coworkers in 1999, series of SDP ligands developed by Zhou group since 2002, were both efficient and successful ligands for the asymmetric transformation of different ketones. Since 1997, our group also contributed many improved ligands for this reaction, such as, Binapine, f-amphox, et al. Despite significant achivements, there are still some questions to be solved in this area. For example, the synthesis of needed ligands demands hash reaction conditions and expensive starting materials, and sometimes the purification of the corresponding ligands was hard. Thus, new ligands or new synthetic methods are still in need for the more efficient transformation. Recently, we got interested in the introduction of prolinols as building blocks for the modification of ligands to control the enantioselectivity of this transformation. As a class of commercial available chiral building blocks, prolinol and its derivatives were increasingly applied as ligands or additives in the controls of enantioselectivity of organic transformations. In this context, combining our long standing interests in the developing of ferrocene based ligands, we designed and synthesized some novel PNO type phosphine ligands through three simple steps. Notably, the applied starting materials for these ligands were both commercially available chiral building blocks. The corresponding ligands have the advantages of easily available starting material, convenient synthesis, and simple purification. With these ligands in hand, we tested their catalytic activity on Ir-catalyzed asymmetric hydrogenation of acetophenone, which gave 99% conversion and high ee value of the product. Encourage by these positive result, we further optimized the reaction conditions including the solvent, base species, H₂ pressure, and the catalyst loading. THF was the best solvent among the test solvents. Since most of the tested base species giving similar results, we assumed base has only slight effect on both the conversion of acetophenone and the enantioselectivity of corresponding product. In some additional reaction conditions screening experiments, we found that a higher H₂ pressure or a higher catalyst loading was favorable for the conversion of acetophenone and the enantioselectivity of corresponding product. Thereafter, various different ketones were tested using the optimal reaction conditions. This catalytic system was compatible well with halides substitutions, methoxy gourps, and -CF₃ gourps, and also possible for the application in the transformation of heterocycles. Herein, an efficient and practical protocol was developed for the asymmetric hydrogenation of ketones. The proposed catalytic system gave the corresponding chiral secondary alcohols in up to >99% yield, 99% ee, and 100000 TON. In view of the high efficiency and easy synthesis of the ligand, we assume this work has remarkable potential regarding industrial process in the near future.

Chiral Indolizidine Synthesis through the Ir-Catalyzed Asymmetric Hydrogenation of Cyclic Pyridinium Salts

The Ir-catalyzed asymmetric hydrogenation of cyclic pyridinium salts is presented as a new strategy for the convenient and efficient synthesis of chiral indolizidines. The asymmetric hydrogenation of cyclic pyridinium salts derived from 2-(2-acylphenyl)pyridines proceeded smoothly in the presence of [Ir(cod)Cl]2 and (R)-DM-SegPhos to provide the desired chiral 7,8-benzoindolizidines 6 in high to excellent yields with moderate enantioselectivity (up to 86:14 er) and excellent diastereoselectivity (>20:1 dr). The enantiomeric purity of 6j was increased to 92:8 through recrystallization.

Enantiodivergent Synthesis of Chiral Tetrahydroquinoline Derivatives via Ir-Catalyzed Asymmetric Hydrogenation: Solvent-Dependent Enantioselective Control and Mechanistic Investigations

Enantiodivergent Synthesis of Chiral Tetrahydroquinoline Derivatives via Ir-Catalyzed Asymmetric Hydrogenation: Solvent-Dependent Enantioselective Control and Mechanistic Investigations

Ir-catalyzed asymmetric hydrogenation of 3-arylindenones for the synthesis of chiral 3-arylindanones

Abstract An efficient synthesis of chiral 3-arylindanones via iridium-catalyzed asymmetric hydrogenation of 3-arylindenones has been developed. The reaction showed good compatibility with various functional groups, delivering a variety of 3-arylindanones in excellent yields and with good enantioselectivities. The reaction was also carried out on a gram-scale, delivering the product in quantitative yield. In addition, the products can be easily derivatized and transformed into natural products and pharmaceutical agents.

Synthesis of Chiral Tridentate Ligands with a Ferrocene Framework and Their Applications in Ir-Catalyzed Asymmetric Hydrogenation

Synthesis of Chiral Tridentate Ligands with a Ferrocene Framework and Their Applications in Ir-Catalyzed Asymmetric Hydrogenation

Ir–Biaryl phosphite–oxazoline catalyst libraries: a breakthrough in the asymmetric hydrogenation of challenging olefins

This work describes our progress in the successful development of phosphite/phosphinite–oxazoline ligands for the Ir-catalyzed asymmetric hydrogenation of challenging olefins.

Josiphos-type binaphane ligands for the asymmetric Ir-catalyzed hydrogenation of acyclic aromatic N-aryl imines

The Ir-catalyzed asymmetric hydrogenation of acyclic aromatic N-aryl imines with Josiphos-type binaphane ligands has been described. Under the optimized conditions, a wide range of imines were hydrogenated to afford the corresponding chiral amines in high yields (up to 94%) and good to excellent enantioselectivities (up to >99% ee). The synthetic utility of the present protocol has been demonstrated through the asymmetric synthesis of the key chiral intermediates of calcium sensing receptor modulators on a gram scale.

Asymmetric Ir-catalyzed hydrogenation of 4-R-1,3-dihydro-2H-1,5-benzodiazepin-2-ones using a novel phosphoramidite ligand

A novel chiral phosphoramidite ligand, (Sa)-2-[N-ethyl-N-(1-naphthylmethyl)amino]-dinaphtho[2,1-d:1´,2´-f][1,3,2]dioxaphosphepane, was obtained and tested in Ir-catalyzed asymmetric hydrogenation of a series of 4-R-1,3-dihydro-2H-1,5-benzodiazepin-2-ones, wherein up to 74% ee was achieved. The structure of the resulting compounds was determined based on one- and two-dimensional NMR (1H, 13C, 31P, 1H—1H COSY, 1H—1H ROESY, 1H—13C HSQC and 1H—13C HMBC) spectroscopy data.

Ir-Catalyzed Double Asymmetric Hydrogenation of 3,6-Dialkylidene-2,5-diketopiperazines for Enantioselective Synthesis of Cyclic Dipeptides.

An Ir/spiro[4,4]-1,6-nonadiene-based phosphine-oxazoline ligand (SpinPHOX) complex-catalyzed double asymmetric hydrogenation of 3,6-dialkylidene-1,4-dimethylpiperazine-2,5-diones has been developed, providing efficient and practical access to a wide variety of chiral 3,6-disubstituted-2,5-diketopiperazines in high yields with exclusive cis-diastereo- and excellent enantioselectivities (>99% de, up to 98% ee). The synthetic utilities of the protocol have been demonstrated in a gram scale synthesis of 6a and efficient construction of chiral products 8, 14, and 17 as well as a 2-butenyl-bridged bicyclic diketopiperazine 10 and hydroxydiketopiperazine 11. With an analogous achiral Ir catalyst, the hydrogenation of enantiopure monohydrogenated intermediate 7a gave cis-6a as the only product, indicating that the second-step hydrogenation of the titled transformation is a chiral substrate controlled process. The reaction profile study for asymmetric hydrogenation (AH) of 5a revealed that the concentration of the monohydrogenation intermediate 7a remained at a low level (<8%) during the course of hydrogenation. The hydrogenation of 5a to 6a proceeded significantly faster than that of its half-hydrogenated intermediate ( S)-7a, indicating that the titled reaction involves primarily a processive mechanism, in which a single catalyst molecule performs consecutive hydrogenation of the two C═C double bonds in substrate 5a without dissociation of the partially reduced 7a. The present protocol represents a rare example of asymmetric catalytic consecutive hydrogenation of heterocycles and provides an alternative way for efficient construction of cyclic dipeptides.

Iridium-catalyzed asymmetric hydrogenation of β-keto esters with new phenethylamine-derived tridentate P,N,N-ligands

A new class of phenethylamine-derived tridentate P,N,N-ligands has been successfully developed. These ligands exhibited good performance in the Ir-catalyzed asymmetric hydrogenation of β-keto esters, affording the corresponding β-hydroxy esters in moderate to good enantioselectivities.