Asymmetric Hydrogenation Of Olefins Research Articles

Iridium-Catalyzed Enantioselective Transfer Hydrogenation of 1,1-Dialkylethenes with Ethanol: Scope and Mechanism.

Despite half a century's advance in the field of transition-metal-catalyzed asymmetric alkene hydrogenation, the enantioselective hydrogenation of purely alkyl-substituted 1,1-dialkylethenes has remained an unmet challenge. Herein, we describe a chiral PCNOx-pincer iridium complex for asymmetric transfer hydrogenation of this alkene class with ethanol, furnishing all-alkyl-substituted tertiary stereocenters. High levels of enantioselectivity can be achieved in the reactions of substrates with secondary/primary and primary/primary alkyl combinations. The catalyst is further applied to the redox isomerization of disubstituted alkenols, producing a tertiary stereocenter remote to the resulting carbonyl group. Mechanistic studies reveal a dihydride species, (PCNOx)Ir(H)2, as the catalytically active intermediate, which can decay to a dimeric species (κ3-PCNOx)IrH(μ-H)2IrH(κ2-PCNOx) via a ligand-remetalation pathway. The catalyst deactivation under the hydrogenation conditions with H2 is much faster than that under the transfer hydrogenation conditions with EtOH, which explains why the (PCNOx)Ir catalyst is effective for the transfer hydrogenation but ineffective for the hydrogenation. The suppression of di-to-trisubstituted alkene isomerization by regioselective 1,2-insertion is partly responsible for the success of this system, underscoring the critical role played by the pincer ligand in enantioselective transfer hydrogenation of 1,1-dialkylethenes. Moreover, computational studies elucidate the significant influence of the London dispersion interaction between the ligand and the substrate on enantioselectivity control, as illustrated by the complete reversal of stereochemistry through cyclohexyl-to-cyclopropyl group substitution in the alkene substrates.

Structural and functional characterization of a new thermophilic-like OYE from Aspergillus flavus

Old yellow enzymes (OYEs) have been proven as powerful biocatalysts for the asymmetric reduction of activated alkenes. Fungi appear to be valuable sources of OYEs, but most of the fungal OYEs are unexplored. To expand the OYEs toolbox, a new thermophilic-like OYE (AfOYE1) was identified from Aspergillus flavus strain NRRL3357. The thermal stability analysis showed that the T1/2 of AfOYE1 was 60 °C, and it had the optimal temperature at 45 °C. Moreover, AfOYE1 exhibited high reduction activity in a wide pH range (pH 5.5–8.0). AfOYE1 could accept cyclic enones, acrylamide, nitroalkenes, and α, β-unsaturated aldehydes as substrates and had excellent enantioselectivity toward prochiral alkenes (> 99% ee). Interestingly, an unexpected (S)-stereoselectivity bioreduction toward 2-methylcyclohexenone was observed. The further crystal structure of AfOYE1 revealed that the “cap” region from Ala132 to Thr182, the loop of Ser316 to Gly325, α short helix of Arg371 to Gln375, and the C-terminal “finger” structure endow the catalytic cavity of AfOYE1 quite deep and narrow, and flavin mononucleotide (FMN) heavily buried at the bottom of the active site tunnel. Furthermore, the catalytic mechanism of AfOYE1 was also investigated, and the results confirmed that the residues His211, His214, and Tyr216 compose its catalytic triad. This newly identified thermophilic-like OYE would thus be valuable for asymmetric alkene hydrogenation in industrial processes.Key pointsA new thermophilic-like OYE AfOYE1 was identified from Aspergillus flavus, and the T1/2of AfOYE1 was 60 °CAfOYE1 catalyzed the reduction of 2-methylcyclohexenone with (S)-stereoselectivityThe crystal structure of AfOYE1 was revealedv

Chiral 1‐Phosphabarrelene‐Pyridines as Suitable Ligands for the Rh/Ir‐Catalyzed Asymmetric Hydrogenation of Olefins

AbstractHerein, we report the synthesis of chiral phosphabarrelene‐pyridine ligands. Their synthesis benefit from modified reaction conditions to overcome the low yields normally associated with the [4+2] cycloaddition reaction of phosphinines with hexafluoro‐2‐butyne, which is a key to install the P‐stereocenter in the phosphabarrelene. Their potential as chelating ligands in asymmetric catalysis was assessed in the Rh‐ and Ir‐catalyzed hydrogenation of cyclic β‐enamides and β‐dehydroamino acid derivatives. The catalytic system containing a tert‐butyl substituent at the ortho position of the phosphabarrelene moiety successfully hydrogenates a range of cyclic β‐enamides (ee's between 92% to 94%) and β‐dehydroamino acid derivatives (ee's between 93% to 95%). Moreover, the reactions can be carried out in the environmentally friendly 1,2‐propylene carbonate as solvent with no loss of enantioselectivity. Mechanistic studies with the Rh/P,N catalytic systems agree with the Landis‐Halpern mechanism and explain the influence of the substituent at the phosphabarrelene on enantioselectivity. Finally, the hydrogenation reactions can be carried out at large scale maintaining high enantioselectivities.

Recent advances in the metal-catalyzed asymmetric alkene hydrogenation of cyclic conjugated carbonyl compounds

This review summarizes the recent advances (2016–2023) in the stereoselective metal-catalyzed hydrogenation of cyclic α,β-unsaturated ketones, lactams and lactones since considerable developments were made. Where possible the application of these methodologies in synthesis is outlined.

Unlocking the Asymmetric Hydrogenation of Tetrasubstituted Acyclic Enones

AbstractAsymmetric hydrogenation (AH) of tetrasubstituted olefins generating two stereocenters is still an open topic. There are only a few reports on the AH of tetrasubstituted olefins with conjugated functional groups, while this process can create useful intermediates for the subsequent elaboration of relevant end products. Most of the tetrasubstituted olefins successfully submitted to AH belong to a small number of functional classes; remarkably, the AH of tetrasubstituted acyclic enones still represents an unsolved challenge. Herein, we disclose a class of air‐stable Ir−P,N catalysts, prepared in three steps from commercially available amino alcohols, that can hydrogenate, in minutes, a wide range of electronically and sterically diverse acyclic tetrasubstituted enones (including exocyclic ones) with high yields and high enantioselectivities. The factors responsible for the excellent selectivities were elucidated by combining deuterogenation experiments and theoretical calculations. The calculations indicated that the reduction follows an IrI/IrIII mechanism, in which enantioselectivity is controlled in the first migratory insertion of the hydride to the most electrophilic olefinic Cβ and the formation of the hydrogenated product via reductive elimination takes place prior to the coordination of dihydrogen and the subsequent oxidative addition. The potential of the new catalytic systems is demonstrated by the derivatization of hydrogenation products.

Unlocking the Asymmetric Hydrogenation of Tetrasubstituted Acyclic Enones.

Asymmetric hydrogenation (AH) of tetrasubstituted olefins generating two stereocenters is still an open topic. There are only a few reports on the AH of tetrasubstituted olefins with conjugated functional groups, while this process can create useful intermediates for the subsequent elaboration of relevant end products. Most of the tetrasubstituted olefins successfully submitted to AH belong to a small number of functional classes; remarkably, the AH of tetrasubstituted acyclic enones still represents an unsolved challenge. Herein, we disclose a class of air-stable Ir-P,N catalysts, prepared in three steps from commercially available amino alcohols, that can hydrogenate, in minutes, a wide range of electronically and sterically diverse acyclic tetrasubstituted enones (including exocyclic ones) with high yields and high enantioselectivities. The factors responsible for the excellent selectivities were elucidated by combining deuterogenation experiments and theoretical calculations. The calculations indicated that the reduction follows an IrI /IrIII mechanism, in which enantioselectivity is controlled in the first migratory insertion of the hydride to the most electrophilic olefinic Cβ and the formation of the hydrogenated product via reductive elimination takes place prior to the coordination of dihydrogen and the subsequent oxidative addition. The potential of the new catalytic systems is demonstrated by the derivatization of hydrogenation products.

Metal-Free Heterogeneous Asymmetric Hydrogenation of Olefins Promoted by Chiral Frustrated Lewis Pair Framework.

The development of metal-free and recyclable catalysts for significant yet challenging transformations of naturally abundant feedstocks has long been sought after. In this work, we contribute a general strategy of combining the rationally designed crystalline covalent organic framework (COF) with a newly developed chiral frustrated Lewis pair (CFLP) to afford chiral frustrated Lewis pair framework (CFLPF), which can efficiently promote the asymmetric olefin hydrogenation in a heterogeneous manner, outperforming the homogeneous CFLP counterpart. Notably, the metal-free CFLPF exhibits superior activity/enantioselectivity in addition to excellent stability/recyclability. A series of in situ spectroscopic studies, kinetic isotope effect measurements, and density-functional theory computational calculations were also performed to gain an insightful understanding of the superior asymmetric hydrogenation catalysis performances of CFLPF. Our work not only increases the versatility of catalysts for asymmetric catalysis but also broadens the reactivity of porous organic materials with the addition of frustrated Lewis pair (FLP) chemistry, thereby suggesting a new approach for practical and substantial transformations through the advancement of novel catalysts from both concept and design perspectives.

Nickel-Catalyzed Asymmetric Hydrogenation of α-Substituted Vinylphosphonates and Diarylvinylphosphine Oxides.

Chiral α-substituted ethylphosphonate and ethylphosphine oxide compounds are widely used in drugs, pesticides, and ligands. However, their catalytic asymmetric synthesis is still rare. Of the only asymmetric hydrogenation methods available at present, all cases use rare metal catalysts. Herein, we report an efficient earth-abundant transition-metal nickel catalyzed asymmetric hydrogenation affording the corresponding chiral ethylphosphine products with up to 99% yield, 96% ee (enantiomeric excess) (99% ee, after recrystallization) and 1000 S/C (substrate/catalyst); this is also the first study on the asymmetric hydrogenation of terminal olefins using a nickel catalyst under a hydrogen atmosphere. The catalytic mechanism was investigated via deuterium-labelling experiments and calculations which indicate that the two added hydrogen atoms of the products come from hydrogen gas. Additionally, it is believed that the reaction involves a Ni(II) rather than Ni(0) cyclic process based on the weak attractive interactions between the Ni catalyst and terminal olefin substrate.

Nickel‐Catalyzed Asymmetric Hydrogenation of α‐Substituted Vinylphosphonates and Diarylvinylphosphine Oxides

AbstractChiral α‐substituted ethylphosphonate and ethylphosphine oxide compounds are widely used in drugs, pesticides, and ligands. However, their catalytic asymmetric synthesis is still rare. Of the only asymmetric hydrogenation methods available at present, all cases use rare metal catalysts. Herein, we report an efficient earth‐abundant transition‐metal nickel catalyzed asymmetric hydrogenation affording the corresponding chiral ethylphosphine products with up to 99 % yield, 96 % ee (enantiomeric excess) (99 % ee, after recrystallization) and 1000 S/C (substrate/catalyst); this is also the first study on the asymmetric hydrogenation of terminal olefins using a nickel catalyst under a hydrogen atmosphere. The catalytic mechanism was investigated via deuterium‐labelling experiments and calculations which indicate that the two added hydrogen atoms of the products come from hydrogen gas. Additionally, it is believed that the reaction involves a NiII rather than Ni0 cyclic process based on the weak attractive interactions between the Ni catalyst and terminal olefin substrate.

Enantioselective Synthesis of α-Chiral Amides by Catalytic Hydrogenation with Iridium N,P-Complexes

AbstractThe catalytic asymmetric hydrogenation of olefins constitutes a powerful method for the preparation of chiral compounds. A series of prochiral unsaturated amides were efficiently reduced with high enantioselectivities by means of an iridium N,P-complex-catalyzed hydrogenation. Its application in the synthesis of fenpropidin and the possibility of using isomeric mixtures of starting materials are attractive features of the method.

Cobalt-Catalyzed Enantioconvergent Hydrogenation of Minimally Functionalized Isomeric Olefins.

Investigation on asymmetric hydrogenation of olefins is of great importance in both pharmaceutical molecule synthesis and chemical industry due to the high demand for enantiopure compounds. The established methods often require geometrically pure olefins. The enantioconvergent reaction provided the possibility to access a single stereoisomer via hydrogenation of E/Z-olefin mixtures; however, a polar functional group next to the carbon-carbon double bond was usually necessary. Here, we reported a cobalt-catalyzed enantioconvergent hydrogenation of readily available minimally functionalized E/Z-olefin mixtures. This strategy shows good functional group tolerance and provides an alternative means to enantioconvergent transformation. The preliminary mechanistic studies indicated that cobalt-catalyzed isomerization was the key to achieve the convergent transformation.

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.

Controlling the Enantioselectivity in an Adaptable Ligand by Biomimetic Intramolecular Interlocking.

For the preparation of chiral drugs, both stereochemically stable and flexible catalysts in combination with chiral auxiliaries can be used. Here, chiral induction plays an important role in generating an enantiomerically pure catalyst. We demonstrate a successful approach to the spontaneous deracemization of tropos ligands for asymmetric catalysis. Three different constitutional isomers of a bisphosphinite ligand decorated with l-valine moieties (interaction units) linked to the flexible biphenyl system by a phenylene bridge for inducing a chiral switch were prepared. The substitution pattern's influence on the attached intermolecular recognition sites was systematically investigated. We can show that biomimetic intramolecular hydrogen bonding leads to a pronounced diastereoselective enrichment of one of the ligand stereoisomers. As a result, in the asymmetric Rh-catalyzed hydrogenation of prochiral olefins using these ligands, enantiomeric ratios of up to 95.8:4.2 (S) were obtained. Of particular note is the inversion of enantioselectivity relative to the previously reported BIBIPHOS-Rh catalyst due to the altered orientation of the biphenyl moiety from (Rax) to (Sax). The enantioselectivities achieved by appropriate intramolecular interlocking are remarkable for a tropos ligand/catalyst. The strategy presented here represents a powerful approach for the spontaneous alignment of tropos ligands, yielding high enantioselectivities in asymmetric catalysis.

Cover Feature: Azole‐Directed Cobalt‐Catalyzed Asymmetric Hydrogenation of Alkenes (Chem. Eur. J. 44/2022)

Cover Feature: Azole‐Directed Cobalt‐Catalyzed Asymmetric Hydrogenation of Alkenes (Chem. Eur. J. 44/2022)

Machine Learning Prediction of Structure‐Performance Relationship in Organic Synthesis

Comprehensive SummaryData‐driven approach has emerged as a powerful strategy in the construction of structure‐performance relationships in organic synthesis. To close the gap between mechanistic understanding and synthetic prediction, we have made efforts to implement mechanistic knowledge in machine learning modelling of organic transformation, as a way to achieve accurate predictions of reactivity, regio‐ and stereoselectivity. We have constructed a comprehensive and balanced computational database for target radical transformations (arene C—H functionalization and HAT reaction), which laid the foundation for the reactivity and selectivity prediction. Furthermore, we found that the combination of computational statistics and physical organic descriptors offers a practical solution to build machine learning structure‐performance models for reactivity and regioselectivity. To allow machine learning modelling of stereoselectivity, a structured database of asymmetric hydrogenation of olefins was built, and we designed a chemical heuristics‐based hierarchical learning approach to effectively use the big data in the early stage of catalysis screening. Our studies reflect a tiny portion of the exciting developments of machine learning in organic chemistry. The synergy between mechanistic knowledge and machine learning will continue to generate a strong momentum to push the limit of reaction performance prediction in organic chemistry. How do you get into this specific field? Could you please share some experiences with our readers?Based on my study experience in Prof. Houk's lab and Prof. Nørskov's lab, my major idea since the beginning of my lab is to combine the key design principles of homogeneous catalysis (transition state model) and heterogeneous (scaling relationship) catalysis. This idea eventually evolved to our explorations of mechanism‐based machine learning in organic chemistry.How do you supervise your students?I try my best to give them enough space and freedom, so they can experience the joy in chemistry research.What are your hobbies?I enjoy science fiction movies and novels.What is the most important personality for scientific research?Chemistry has unlimited frontiers. Targeting a hardcore question, developing someone's own approach is the most important merit in fundamental scientific research.How do you keep balance between research and family?Work‐life balance is certainly one of the biggest challenges for junior faculty. I try to work in fragmented time, so I would be available for both my family and my students.Who influences you mostly in your life?My high‐school experience in Chemistry Olympiad has influenced me dramatically, which cultivated my independent learning ability to tackle new questions. This has helped me a lot throughout my career.

Azole‐Directed Cobalt‐Catalyzed Asymmetric Hydrogenation of Alkenes

The azole-directed cobalt-catalyzed asymmetric hydrogenation of alkenes has been developed with high efficiency. With this approach, chiral pyrazole compounds were obtained in quantitative yields and excellent enantioselectivities (up to 99 % ee) under mild conditions, and the hydrogenation was conducted on a gram scale with up to 2000 TON. Several useful applications were demonstrated including the convenient introduction of β-chirality to a drug intermediate containing an azole ring.

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, 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.

Density Functional Theory-Inspired Design of Ir/P,S-Catalysts for Asymmetric Hydrogenation of Olefins

In silico-based optimization of Ir/P,S-catalysts for the asymmetric hydrogenation of unfunctionalized olefins using (E)-1-(but-2-en-2-yl)-4-methoxybenzene as a benchmark olefin has been carried out. DFT calculations revealed that the thioether group has a major role in directing the olefin coordination. This, together with the configuration of the biphenyl phosphite group, has an impact in maximizing the energy gap between the most stable transition states leading to opposite enantiomers. As a result, the optimized catalyst proved to be efficient in the hydrogenation of a range of alkenes with the same substitution pattern and olefin geometry as the benchmark olefin, regardless of the presence of functional groups with different coordination abilities (ee values up to 97%). Appealingly, further modifications at the thioether groups and at the biaryl phosphite moiety allowed the highly enantioselective hydrogenation of olefins with different substitution patterns (e.g., α,β-unsaturated lactones and lactams, 1,1′-disubstituted enol phosphinates, and cyclic β-enamides; ee values up to >99%).

Front Cover Picture: Indene Derived Phosphorus‐Thioether Ligands for the Ir‐Catalyzed Asymmetric Hydrogenation of Olefins with Diverse Substitution Patterns and Different Functional Groups (Adv. Synth. Catal. 19/2021)

Front Cover Picture: Indene Derived Phosphorus‐Thioether Ligands for the Ir‐Catalyzed Asymmetric Hydrogenation of Olefins with Diverse Substitution Patterns and Different Functional Groups (Adv. Synth. Catal. 19/2021)

Straightforward Synthesis of Chiral Terpenoid Building Blocks by Ru-Catalyzed Enantioselective Hydrogenation.

Starting from commercially available (R)- and (S)-β-citronellol, two strategies were designed to synthesize all four stereoisomers of 2,6-dimethyloctane monoterpene chirons in four or five steps in 32-47% overall yield. The desired fragments were obtained by a key Ru-catalyzed asymmetric olefin hydrogenation step under moderate temperature (50 °C), pressure (4 bar), and low catalyst loadings (0.5 mol %) under optimized conditions. Screening of commercially available catalysts highlighted the key role of DM-SEGPHOS as an economically advantageous alternative to commonly used H8-BINAP for equal performances. These results open new possibilities for versatile and scalable syntheses of these useful building blocks.