Chiral Iridium Catalysts Research Articles

Palladium-catalyzed asymmetric hydrogenation of lactones under base-free conditions.

Asymmetric hydrogenation of esters through homogeneous catalysis is a significantly important transformation in organic synthesis. The systems developed so far mainly focused on chiral iridium and ruthenium catalysts, which required a base to facilitate the activity. Herein, we present a palladium-catalyzed asymmetric hydrogenation of lactones under base-free conditions through dynamic kinetic resolution and kinetic resolution. The reaction exhibits high enantioselectivity and excellent functional group tolerance. Remarkably, the hydrogenation proceeds smoothly at the gram scale, and the products can be transformed into several chiral potential building blocks without loss of optical purity. This work provides a new strategy for asymmetric hydrogenation of esters under base-free conditions.

Total Synthesis of Aporphine Alkaloids via Benzyne Chemistry: Progress Towards a Late‐Stage Enantioselective Hydrogenation and Neuroprotective Activity Evaluations

AbstractA dehydroaporphine intermediate obtained via benzyne chemistry was used to accomplish the enantioselective total synthesis of (S)‐nuciferine, the first total synthesis of (±)‐urabaine, and our second‐generation total synthesis of lysicamine. (S)‐Nuciferine was obtained by an unprecedented late‐stage asymmetric hydrogenation employing a chiral iridium(I) catalyst. The first total synthesis of (±)‐urabaine and the second‐generation total synthesis of lysicamine, which exhibited low cytotoxicity and neuroprotective activity, were completed by oxidation reactions in 7 and 6 steps, respectively.

Iridium‐Catalyzed Chemo‐, Diastereo‐, and Enantioselective Allyl‐Allyl Coupling: Accessing All Four Stereoisomers of (E)‐1‐Boryl‐Substituted 1,5‐Dienes by Chirality Pairing

AbstractHere, we report a highly chemo‐, diastereo‐, and enantioselective allyl‐allyl coupling between branched allyl alcohols and α‐silyl‐substituted allylboronate esters, catalyzed by a chiral iridium complex. The α‐silyl‐substituted allylboronate esters can be chemoselectively coupled with allyl electrophiles, affording a diverse set of enantioenriched (E)‐1‐boryl‐substituted 1,5‐dienes in good yields, with excellent stereoselectivity. By permuting the chiral iridium catalysts and the substrates, we efficiently and selectively obtained all four stereoisomers bearing two consecutive chiral centers. Mechanistic studies via density functional theory calculations revealed the origins of the diastereo‐ and chemoselectivities, indicating the pivotal roles of the steric interaction, the β‐silicon effect, and a rapid desilylation process. Additional synthetic modifications for preparing a variety of enantioenriched compounds containing contiguous chiral centers are also included.

Iridium-Catalyzed Chemo-, Diastereo-, and Enantioselective Allyl-Allyl Coupling: Accessing All Four Stereoisomers of (E)-1-Boryl-Substituted 1,5-Dienes by Chirality Pairing.

Here, we report a highly chemo-, diastereo-, and enantioselective allyl-allyl coupling between branched allyl alcohols and α-silyl-substituted allylboronate esters, catalyzed by a chiral iridium complex. The α-silyl-substituted allylboronate esters can be chemoselectively coupled with allyl electrophiles, affording a diverse set of enantioenriched (E)-1-boryl-substituted 1,5-dienes in good yields, with excellent stereoselectivity. By permuting the chiral iridium catalysts and the substrates, we efficiently and selectively obtained all four stereoisomers bearing two consecutive chiral centers. Mechanistic studies via density functional theory calculations revealed the origins of the diastereo- and chemoselectivities, indicating the pivotal roles of the steric interaction, the β-silicon effect, and a rapid desilylation process. Additional synthetic modifications for preparing a variety of enantioenriched compounds containing contiguous chiral centers are also included.

Iridium‐Catalyzed Intermolecular Asymmetric Allylic Amination with Pyridones

AbstractWe report herein a catalytic synthetic method for enantioenrichedN‐substituted pyridones. By employing chiral iridium catalyst generated from the Carreira [P/olefin] ligand, intermolecular asymmetric allylic amination of allyl alcohols with pyridones proceeded smoothly with excellent chemo‐, regio‐ and enantioselectivities (>19:1N/O, >19:1 b/l and ≥89% ee). The reaction was a kinetic resolution process under mild conditions and displayed a broad substrate scope for both pyridones and allylic alcohols. The potential of this method was demonstrated by a gram‐scale reaction with only 0.6 mol% catalyst loading and diverse transformations of the amination products to useful skeletons.magnified image

Keeping Z-olefins intact with iridium

Organic Chemistry Transition metal catalysis offers a versatile means of modifying carbon centers adjacent to carbon-carbon double bonds. However, in the course of these reactions, the double bond tends to get weakened, allowing its substituents to swivel back and forth. Thus, if two large groups start out on the same side of the bond axis (a geometry known as a Z -olefin), they end up on opposite sides in the product. Jiang et al. report a chiral iridium catalyst that prevents this swiveling just long enough to substitute the adjacent carbon enantioselectively (see the Perspective by Malcolmson). Science , this issue p. [380][1]; see also p. [345][2] [1]: /lookup/doi/10.1126/science.abd6095 [2]: /lookup/doi/10.1126/science.abf8851

Asymmetric Synthesis of a Key Intermediate for Tofacitinib via a Dynamic Kinetic Resolution-Reductive Amination Protocol

We report the first example of a catalytic asymmetric reductive amination under dynamic kinetic resolution (DKR) conditions for the preparation of a chiral amine as a key intermediate toward Tofacitinib, an active pharmaceutical ingredient developed by Pfizer. Such a protocol allows the preferential formation of a single product out of four possible diastereomers of the chiral amine starting from the corresponding racemic ketone. The chiral iridium catalyst able to perform such a feast was discovered through a mix of high-throughput screening, racemization study, and reaction optimization.

Synthesis, Crystal Structure of Chiral Ferrocenyl Amino Alcohols, and Its Use for Asymmetric Transfer Hydrogenation

Two chiral ferrocenyl amino alcohols (IIIa and IIIb) have been synthesized for the iridium catalyzed asymmetric transfer hydrogenation of aromatic ketones. The structures of two chiral ferrocenyl amino alcohols have been determined by single crystal X-ray diffraction (CIF files CCDC nos. 1056737 (IIIa) and 1056734 (IIIb)). The results show that the activity and enantioselectivity of the chiral iridium catalyst are very sensitive to the substrate structure. Ir(I)-catalyzed asymmetric transfer hydrogenation of acetophenone resulted in moderate to good yield and lower enantioselectivity; asymmetric transfer hydrogenation of proopiophenone and 2-benzoylpyridine resulted in lower yield and lower enantioselectivity; as for 4-benzoylpyridine, good results have been achieved.

Ir‐Catalyzed Enantioselective Intra‐ and Intermolecular Formal C−H Conjugate Addition to β‐Substituted α,β‐Unsaturated Esters

AbstractAn enantioselective intramolecular formal C−H conjugate addition of 4‐methyl 1‐aryl 2‐methylfumarates proceeded using a chiral iridium catalyst. A benzoylamide group served as a directing group, and chiral γ‐lactones with a quaternary all‐carbon stereogenic center were obtained with up to excellent ee. In the intermolecular reaction of N‐arylbenzamides with β‐substituted acrylates, C−H bond activation selectively occurred at the ortho‐position of carbonyl groups, and highly enantioselective formal C−H conjugate addition proceeded.

Recovery and Recycling of Chiral Iridium(N,P Ligand) Catalysts from Hydrogenation Reactions

AbstractDespite the high efficiency and broad scope of chiral iridium(N,P ligand) complexes as catalysts for asymmetric hydrogenation, the problem of catalyst recovery and recycling has so far attracted little attention. We have found that at the end of a hydrogenation reaction, iridium(N,P ligand) catalysts form dimeric Ir(III) dihydride complexes, which can be converted back to the original precatalysts by addition of COD. Based on these findings, a practically simple protocol for catalyst recovery was devised. The recovered complexes showed essentially the same reactivity and enantioselectivity as the original catalysts. Especially large‐scale applications and hydrogenations of less reactive substrates that require high catalyst loadings will benefit from this protocol that allows recovery and reuse of expensive iridium complexes.magnified image

Sequential asymmetric hydrogenation and photoredox chemistry with a single catalyst

A single chiral iridium catalyst promotes two mechanistically distinct reaction types in a sequential fashion, namely asymmetric hydrogenation (two-electron mechanism) and photoredox chemistry (one-electron mechanism).

Jian‐Hua Xie

Angewandte Chemie International EditionVolume 57, Issue 22 p. 6381-6381 Author ProfileFree Access Jian-Hua Xie First published: 27 December 2017 https://doi.org/10.1002/anie.201712466AboutSectionsPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat Graphical Abstract “I can never resist the temptation of spicy food. The best advice I have ever been given is love what you do, and do your best ...” This and more about Jian-Hua Xie can be found on page 6381. Jian-Hua Xie The author presented on this page has published more than 10 articles in Angewandte Chemie in the last 10 years, most recently: “Nickel(0)-Catalyzed Hydroarylation of Styrenes and 1,3-Dienes with Organoborons”: Q.-L. Zhou, L.-J. Xiao, L. Cheng, W.-M. Feng, M.-L. Li, J.-H. Xie, Angew. Chem. Int. Ed. 2018, 57, 461; Angew. Chem. 2018, 130, 470. The work of J.-H. Xie has been featured on the back cover of Angewandte Chemie: “An Additional Coordination Group Leads to Extremely Efficient Chiral Iridium Catalysts for Asymmetric Hydrogenation of Ketones”: J.-H. Xie, X.-Y. Liu, J.-B. Xie, L.-X. Wang, Q.-L. Zhou, Angew. Chem. Int. Ed. 2011, 50, 7329; Angew. Chem. 2011, 123, 7467. Date of birth: July 21, 1968 Position: Professor of Chemistry, Nankai University, Tianjin E-mail: jhxie@nankai.edu.cn Homepage: http://zhou.nankai.edu.cn/index.php/staffs/prof-jian-hua-xie ORCID: 0000-0003-3907-2530 Education: 1992 BSc, Sichuan Normal College, Nanchong 1997 MSc with Prof. Tian-Lin Liu, Nankai University 2003 PhD with Prof. Qi-Lin Zhou, Nankai University 2007–2008 Postdoctoral fellow with Prof. Michael P. Doyle, University of Maryland Awards: 2013 National Science Fund for Distinguished Young Scholars, National Natural Science Fundation of China (NSFC) Research: Asymmetric catalysis, synthetic methodology, synthesis of biologically active natural products Hobbies: Reading, walking, drinking tea, cooking I can never resist the temptation of spicy food. The best advice I have ever been given is love what you do, and do your best. My favorite food is twice-cooked pork (Hui Guo Rou), one of the most famous Sichuan dishes. My favorite piece of music is The Butterfly Lovers Violin Concerto (Liang Shang Bo yu Zhu Ying Tai in Chinese). My favorite motto is “no pain, no gain”. The most significant scientific advance of the last 100 years has been the discovery of antibiotics. The biggest problem that scientists face is to understand everything in nature at the molecular level. When I'm frustrated, I take a walk or do something else for a while. The most important thing I learned from my parents is to be sincere, polite, and patient. My favorite place on earth is my hometown Luzhou, a city in Sichuan Province. If I were not a scientist, I would be a high-school teacher. My biggest motivation is to discover more useful reactions and molecules with important biological activities. Guaranteed to make me laugh is watching episodes of Tom and Jerry. My 5 top papers: 1“Asymmetric Hydrogenation of α,α′-Disubstituted Cycloketones through Dynamic Kinetic Resolution: An Efficient Construction of Chiral Diols with Three Contiguous Stereocenters”: C. Liu, J.-H. Xie, Y.-L. Li, J.-Q. Chen, Q.-L. Zhou, Angew. Chem. Int. Ed. 2013, 52, 593; Angew. Chem. 2013, 125, 621. (A useful method for the synthesis of cyclic alcohols with multiple chiral centers.) 2“Remote Ester Group Leads to Efficient Kinetic Resolution of Racemic Aliphatic Alcohols via Asymmetric Hydrogenation”: X.-H. Yang, K. Wang, S.-F. Zhu, J.-H. Xie, Q.-L. Zhou, J. Am. Chem. Soc. 2014, 136, 17426. (A highly efficient approach to optically active δ-alkyl-δ-hydroxy esters and δ-alkyl-1,5-diols in high yield and high enantioselectivity.) 3“Iridium-catalyzed asymmetric hydrogenation of racemic α-substituted lactones to chiral diols”: X.-H. Yang, H.-T. Yue, N. Yu, Y.-P. Li, J.-H. Xie, Q.-L. Zhou, Chem. Sci. 2017, 8, 1181. (An efficient dynamic kinetic resolution that gives chiral diols with high enantioselectivity.) 4“Asymmetric Total Synthesis of Gracilamine and Determination of Its Absolute Configuration”: X.-D. Zuo, S.-M. Guo, R. Yang, J.-H. Xie, Q.-L. Zhou, Org. Lett. 2017, 19, 5240. (This biomimetic asymmetric synthesis also provides experimental support for the biogenetic hypothesis of gracilamine.) 5“Bioinspired enantioselective synthesis of crinine-type alkaloids via iridium-catalyzed asymmetric hydrogenation of enones”: X.-D. Zuo, S.-M. Guo, R. Yang, J.-H. Xie, Q.-L. Zhou, Chem. Sci. 2017, 8, 6202. (This stereodivergent resolution method provides a rapid and collective synthesis of the crinine-type alkaloid family.) Volume57, Issue22May 28, 2018Pages 6381-6381 ReferencesRelatedInformation

Iridium-Catalyzed Asymmetric Hydrogenation of Unsaturated Carboxylic Acids.

Chiral carboxylic acid moieties are widely found in pharmaceuticals, agrochemicals, flavors, fragrances, and health supplements. Although they can be synthesized straightforwardly by transition-metal-catalyzed enantioselective hydrogenation of unsaturated carboxylic acids, because the existing chiral catalysts have various disadvantages, the development of new chiral catalysts with high activity and enantioselectivity is an important, long-standing challenge. Ruthenium complexes with chiral diphosphine ligands and rhodium complexes with chiral monodentate or bidentate phosphorus ligands have been the predominant catalysts for asymmetric hydrogenation of unsaturated acids. However, the efficiency of these catalysts is highly substrate-dependent, and most of the reported catalysts require a high loading, high hydrogen pressure, or long reaction time for satisfactory results. Our recent studies have revealed that chiral iridium complexes with chiral spiro-phosphine-oxazoline ligands and chiral spiro-phosphine-benzylamine ligands exhibit excellent activity and enantioselectivity in the hydrogenation of α,β-unsaturated carboxylic acids, including α,β-disubstituted acrylic acids, trisubstituted acrylic acids, α-substituted acrylic acids, and heterocyclic α,β-unsaturated acids. On the basis of an understanding of the role of the carboxy group in iridium-catalyzed asymmetric hydrogenation reactions, we developed a carboxy-group-directed strategy for asymmetric hydrogenation of olefins. Using this strategy, we hydrogenated several challenging olefin substrates, such as β,γ-unsaturated carboxylic acids, 1,1-diarylethenes, 1,1-dialkylethenes, and 1-alkyl styrenes in high yield and with excellent enantioselectivity. All these iridium-catalyzed asymmetric hydrogenation reactions feature high turnover numbers (up to 10000) and turnover frequencies (up to 6000 h-1), excellent enantioselectivities (greater than 95% ee with few exceptions), low hydrogen pressure (<12 atm), and operational simplicity. These features make chiral iridium catalysts superior or comparable to well-established chiral ruthenium and rhodium catalysts for asymmetric hydrogenation of unsaturated carboxylic acids. A number of chiral natural products and pharmaceuticals have been prepared by concise routes involving an iridium-catalyzed asymmetric hydrogenation of an unsaturated carboxylic acid as a key step. As part of a mechanistic study of iridium-catalyzed asymmetric hydrogenation of unsaturated acids, we isolated, for the first time, the migratory insertion intermediate in the iridium-catalyzed asymmetric hydrogenation of olefins, and this result strongly supports the involvement of an Ir(III)/Ir(V) catalytic cycle. The rigid, bulky scaffold of the chiral spiro-P,N-ligands of the catalysts not only prevents them from undergoing deactivating aggregation under the hydrogenation conditions but also is responsible for the efficient chiral induction. The carboxy group of the substrate acts as an anchor to ensure coordination of the substrate to the iridium center of the catalyst during the reaction and makes the hydrogenation proceed smoothly.

Enantioselective Formal C-H Conjugate Addition of Acetanilides to β-Substituted Acrylates by Chiral Iridium Catalysts.

The Ir-catalyzed enantioselective reaction of substituted acetanilides with β-substituted α,β-unsaturated esters provided chiral 3,3-disubstituted propanoates in high yield with good-to-excellent enantiomeric excess (up to 99 % ee). This transformation, initiated by sp2 C-H bond activation, is the first example of enantioselective formal C-H conjugate addition to β-substituted α,β-unsaturated carbonyl compounds. The starting materials are commercially available and/or readily accessible.

ChemInform Abstract: Asymmetric Hydrogenation of Isoxazolium Triflates with a Chiral Iridium Catalyst.

The iridium catalyst [IrCl(cod)]2 -phosphine-I2 (cod=1,5-cyclooctadiene) selectively reduced isoxazolium triflates to isoxazolines or isoxazolidines in the presence of H2 . The iridium-catalyzed hydrogenation proceeded in high-to-good enantioselectivity when an optically active phosphine-oxazoline ligand was used. The 3-substituted 5-arylisoxazolium salts were transformed into 4-isoxazolines with up to 95:5 enantiomeric ratio (e.r.). Chiral cis-isoxazolidines were obtained in up to 89:11 e.r., with no formation of their trans isomers, when the substrates had a primary alkyl substituent at the 5-position. The mechanistic studies indicate that the hydridoiridium(III) species prefers to deliver its hydride to the C5 atom of the isoxazole ring. The hydride attack leads to the formation of the chiral isoxazolidine via a 3-isoxazoline intermediate. Meanwhile, in the selective formation of 4-isoxazolines, hydride attack at the C5 atom may be obstructed by steric hindrance from the 5-aryl substituent.

Extended third ring is a charm for indole-annulated compounds

Fused-ring systems are special structural features of many natural product and synthetic compounds, contributing to the bioactivity that makes them useful as pharmaceuticals and agrochemicals. Chemists have numerous methods for generating small rings with six or fewer members, such as Diels-Alder and other cycloaddition reactions. They also have ways of constructing large rings with 10 or more members, including macrolactonization and ring-closing metathesis. However, the direct synthesis of medium-sized rings, especially enantioselectively, has remained a challenge because of steric constraints. Lin Huang, Li-Xin Dai, and Shu-Li You of Shanghai Institute of Organic Chemistry have now discovered a pathway around this roadblock by developing an intramolecular cascade reaction for building asymmetric seven- to nine-membered rings onto indole frameworks (J. Am. Chem. Soc. 2016, DOI: 10.1021/jacs.6b02678). As an example, the team found that a chiral iridium catalyst can drive dearomatization of an allylic carboline to form a bridged intermediate. A subsequent ring-opening

Asymmetric Hydrogenation of Isoxazolium Triflates with a Chiral Iridium Catalyst.

The iridium catalyst [IrCl(cod)]2 -phosphine-I2 (cod=1,5-cyclooctadiene) selectively reduced isoxazolium triflates to isoxazolines or isoxazolidines in the presence of H2 . The iridium-catalyzed hydrogenation proceeded in high-to-good enantioselectivity when an optically active phosphine-oxazoline ligand was used. The 3-substituted 5-arylisoxazolium salts were transformed into 4-isoxazolines with up to 95:5 enantiomeric ratio (e.r.). Chiral cis-isoxazolidines were obtained in up to 89:11 e.r., with no formation of their trans isomers, when the substrates had a primary alkyl substituent at the 5-position. The mechanistic studies indicate that the hydridoiridium(III) species prefers to deliver its hydride to the C5 atom of the isoxazole ring. The hydride attack leads to the formation of the chiral isoxazolidine via a 3-isoxazoline intermediate. Meanwhile, in the selective formation of 4-isoxazolines, hydride attack at the C5 atom may be obstructed by steric hindrance from the 5-aryl substituent.

Iridium-Catalyzed Asymmetric Hydrogenation of Heteroaromatics Bearing a Hydroxyl Group, 3-Hydroxypyridinium Salts

A highly enantioselective hydrogenation of heteroaromatics bearing a hydroxyl group, 3-hydroxypyridinium salts, has been successfully developed using chiral iridium catalyst, providing a direct access to trans 6-substituted piperidin-3-ols with up to 95% ee. Swern oxidation of the hydrogenation products affords chiral 6-substituted piperidin-3-ones, which are easily reduced to cis 6-substituted piperidin-3-ols using K-selectride.

Phosphine-free chiral iridium catalysts for asymmetric catalytic hydrogenation of simple ketones

Phosphine free iridium catalysts with simple structures show efficient enantioselectivities and activities in the asymmetric hydrogenation of simple ketones by using chiral iridium catalysts to chiral alcohols with up to 96% ee.

ChemInform Abstract: Development of Chiral Spiro P‐N‐S Ligands for Iridium‐Catalyzed Asymmetric Hydrogenation of β‐Alkyl‐β‐ketoesters.

The chiral tridentate spiro P-N-S ligands (SpiroSAP) were developed, and their iridium complexes were prepared. Introduction of a 1,3-dithiane moiety into the ligand resulted in a highly efficient chiral iridium catalyst for asymmetric hydrogenation of β-alkyl-β-ketoesters, producing chiral β-alkyl-β-hydroxyesters with excellent enantioselectivities (95-99.9% ee) and turnover numbers of up to 355,000.