Rhodium-Catalyzed Asymmetric Hydrogenation Research Articles

Rigid P-Chiral Phosphine Ligands with tert-Butylmethylphosphino Groups for Rhodium-Catalyzed Asymmetric Hydrogenation of Functionalized Alkenes

Both enantiomers of 2,3-bis(tert-butylmethylphosphino)quinoxaline (QuinoxP*), 1,2-bis(tert-butylmethylphosphino)benzene (BenzP*), and 1,2-bis(tert-butylmethylphosphino)-4,5-(methylenedioxy)benzene (DioxyBenzP*) were prepared in short steps from enantiopure (S)- and (R)-tert-butylmethylphosphine-boranes as the key intermediates. All of these ligands were crystalline solids and were not readily oxidized on exposure to air. Their rhodium complexes exhibited excellent enantioselectivities and high catalytic activities in the asymmetric hydrogenation of functionalized alkenes, such as dehydroamino acid derivatives and enamides. The practical utility of these catalysts was demonstrated by the efficient preparation of several chiral pharmaceutical ingredients having an amino acid or a secondary amine component. A rhodium complex of the structurally simple ligand BenzP* was used for the mechanistic study of asymmetric hydrogenation. Low-temperature NMR studies together with DFT calculations using methyl α-acetamidocinnamate as the standard model substrate revealed new aspects of the reaction pathways and the enantioselection mechanism.

Phosphine–phosphite ligands: chelate ring size vs. activity and enantioselectivity relationships in asymmetric hydrogenation

A series of new phosphine-phosphite ligands P(C)(n)OP (n = 1-4) have been synthesized and used for rhodium-catalyzed asymmetric hydrogenation of prochiral olefins in order to study the effect of the chelate ring size. Excellent ees (up to 97.5%) were obtained in the hydrogenation of dimethyl itaconate and an increase of activity and enantioselectivity was observed in the hydrogenation of (Z)-α-acetamidocinnamic acid methyl ester with the increasing length of the backbone of the ligands.

Rhodium-Catalyzed Asymmetric Hydrogenation of Unsaturated Phosphonates

Rhodium-Catalyzed Asymmetric Hydrogenation of Unsaturated Phosphonates

Chemoenzymatic synthesis of a mixed phosphine–phosphine oxide catalyst and its application to asymmetric allylation of aldehydes and hydrogenation of alkenes

The chemoenzymatic synthesis of a Lewis basic phosphine-phosphine oxide organocatalyst from a cis-dihydrodiol metabolite of bromobenzene proceeds via a palladium-catalysed carbon-phosphorus bond coupling and a novel room temperature Arbuzov [2,3]-sigmatropic rearrangement of an allylic diphenylphosphinite. Allylation of aromatic aldehydes were catalysed by the Lewis basic organocatalyst giving homoallylic alcohols in up to 57% ee. This compound also functioned as a ligand for rhodium-catalysed asymmetric hydrogenation of acetamidoacrylate giving reduction products with ee values of up to 84%.

Reverse‐Flow Adsorption for Process‐Integrated Recycling of Homogeneous Transition‐Metal Catalysts

Supramolecular strategies, based on hydrogen bonds and ionic interactions, were investigated as tools for the recovery and recycling of homogeneous transition-metal catalysts by using reverse-flow adsorption (RFA) technology. The association (in solution) and adsorption (on support) of new functionalized host materials and phosphine guest ligands, functionalized with the complementary binding motifs, were fine-tuned for the application of these materials in a RFA reactor. The RFA technology for process-integrated recycling of homogeneous catalysts using these tailor-made phosphine ligands and silica-supported host materials resulted in a stable, semicontinuous catalytic system. Rhodium-catalyzed asymmetric hydrogenation of methyl acetamidoacrylate and asymmetric hydrosilylation of acetophenone were studied as test reactions. Depending on the catalytic process the metal complex could be recycled several times without significant loss in conversion.

Modular optimization of enantiopure epoxide-derived P,S-ligands for rhodium-catalyzed hydrogenation of dehydroamino acids

The optimization of P,S-ligands derived from enantiopure (2S,3S)-phenylglycidol for asymmetric rhodium-catalyzed hydrogenation of dehydroamino esters is described. The exceptionally high modular character of the (2S,3S)-phenylglycidol platform is demonstrated by systematic modification of the ether and thioether moieties, the skeletal aryl substituent and the stereo and regiochemistry of the ligands. An experimentally useful method for the monitoring of hydrogenation reactions is also described and used for obtaining relevant data of the catalytic systems studied.

Asymmetric Rhodium-Catalyzed Hydrogenation of β-Amino Ketones

Optically pure β-amino ketones are useful synthetic intermediates for biologically active molecules. In this paper, a rhodium-catalyzed hydrogenation yields these products in high conversions and high enantioselectivity.

Rhodium complexes containing chiral P-donor ligands as catalysts for asymmetric hydrogenation in non conventional media

Rhodium-catalysed asymmetric hydrogenation using P-donor ligands, such as new fluorinated (R)-BINOL and azadioxaphosphabicyclo[3.3.0]octane derivatives was carried out in different reaction media such as organic solvent (CH2Cl2), ionic liquid ([BMI][PF6]), supercritical carbon dioxide (scCO2) and [BMI][PF6]/scCO2 mixture. The best enantioselectivities were obtained in neat [BMI][PF6], allowing a recycling up to ten times without activity loss. However, the enantioselectivity was lost due to ligand leaching. The ionic liquid phase containing rhodium molecular species was supported on functionalized multi-walled carbon nanotubes in order to improve the recycling, but unfortunately the asymmetric induction was lost upon catalyst immobilization. Rh-catalysed asymmetric hydrogenation was carried out in different reaction media (dichloromethane, scCO2, [BMI][PF6] and the mixture of scCO2/[BMI][PF6]) using chiral P-donor ligands under soft conditions. The best catalytic system was obtained in ionic liquid medium and could be recycled up to ten times without activity loss. The ionic liquid catalytic phase supported on functionalized multi-walled carbon nanotubes did not improve its catalytic behaviour.

Rhodium-catalyzed asymmetric hydrogenation of β-acetylamino acrylonitriles

The rhodium-catalyzed asymmetric hydrogenation of β-acetylamino acrylonitriles was investigated by using monophosphine and bisphosphine ligands. It was found that an Rh-QuinoxP ∗ complex exhibited high enantioselectivities for β-aryl substituted β -acetylamino acrylonitriles and the Rh-JosiPhos CyPF- t-Bu complex was proven to be effective for the hydrogenation of tetrasubstituted olefins from cyclic β-acetylamino acrylonitriles.

Rhodium-Catalyzed Asymmetric Hydrogenation of Phosphonobutenoates

In this paper, the authors report a protocol that allows the synthesis of highly optically active phosphonates via direct rhodium asymmetric hydrogenation of 3-aryl-4-phosphonobutenoates with a modified P-stereogenic ­BoPhoz-type ligand. Various substituents on the aromatic ring are well tolerated and the enantio­selectivities as well as yields are very high.

Dynamic kinetic resolution in the stereoselective synthesis of 4,5-diaryl cyclic sulfamidates by using chiral rhodium-catalyzed asymmetric transfer hydrogenation

The dynamic kinetic resolution of 4,5-diaryl cyclic sulfamidate imines was achieved via asymmetric transfer hydrogenation using a HCO(2)H/Et(3)N mixture as the hydrogen source and chiral Rh catalysts (R,R)- or (S,S)-RhCl(TsDPEN)Cp* affording the corresponding cyclic sulfamidates in good yields with up to >20 : 1 dr and up to >99% ee.

Rhodium-Catalyzed Asymmetric Hydrogenation with a P-Stereogenic Ligand

The authors synthesized a P-­stereogenic bisphosphine ligand and used it in the highly efficient rhodium-catalyzed asymmetric hydrogenation of various olefinic substrates. The achieved catalytic turnover and enantioselectivities are extremely high.

Chiral Phosphine−Phosphite Ligands with a Substituted Ethane Backbone. Influence of Conformational Effects in Rhodium-Catalyzed Asymmetric Olefin Hydrogenation and Hydroformylation Reactions

A family of chiral (3,3′-di-tert-butyl-5,5′,6,6′-tetramethyl-2,2′-biphenol-derived) phosphine−phosphite ligands (P−OP) with a substituted ethane backbone has been synthesized and the performance of these ligands in the Rh-catalyzed enantioselective hydrogenation and hydroformylation of several representative olefins analyzed. Corresponding cationic rhodium complexes provide highly enantioselective catalysts for the hydrogenation of methyl (Z)-α-acetamidocinnamate (MAC) and dimethyl itaconate. The catalyst comparison indicates that, for the two substrates, product configuration is determined by the configuration of the phosphite. Regarding matching and mismatching effects in these hydrogenations, small effects were observed in the reduction of MAC, while for the itaconate the bigger difference between the matched and mismatched cases was of 21% ee. On the other hand, Rh catalysts based on P−OP ligands showed good levels of activity and regioselectivity in the hydroformylation of styrene and allyl cyanide, ...

A Local Pair Natural Orbital Coupled Cluster Study of Rh Catalyzed Asymmetric Olefin Hydrogenation.

The recently developed local pair natural orbital coupled cluster theory with single and double excitations (LPNO-CCSD) was used to study the rhodium-catalyzed asymmetric hydrogenation of two prochiral enamides. The method was carefully calibrated with respect to its accuracy. According to calculations on a truncated model system, the effects of perturbative triples (T) on the reaction energetics are very limited, the LPNO approximation is accurate, and complete basis set extrapolation (CBS) causes only minor changes in the relative energies computed with a standard basis set (def2-TZVP). The results for the full system are thus believed to be within 1-2 kcal/mol of the CCSD(T)/CBS limit for the present systems. Relativistic effects were treated by a scalar relativistic Hamiltonian using the zeroth order regular approximation (ZORA). The results of the study were compared to density functional calculations on the same systems and with calculations available in the literature. All calculations predict the correct stereochemical outcome of the reaction that is determined by the relative energies of the transition states in the early stages of the catalytic cycle. In general, DFT calculations using the B3LYP functional are in reasonable agreement with the LPNO-CCSD results, although deviations of 3-5 kcal/mol exist that are also not entirely systematic in the minor and major reaction branches. The present case study thus demonstrates that catalytic reactions, which are well described by single-reference electronic structure theory, can now be routinely studied with confidence in systems with 50-100 atoms applying local correlation methods that are as easy to use as DFT methods.

Enantioselective Synthesis of Cyclic Sulfamidates by Using Chiral Rhodium-Catalyzed Asymmetric Transfer Hydrogenation

Asymmetric transfer hydrogenation (ATH) of cyclic sulfamidate imines 4 and 9, using a HCO(2)H/Et(3)N mixture as the hydrogen source and well-defined chiral Rh catalysts (S,S)- or (R,R)-2, Cp*RhCl(TsDPEN), effectively produces the corresponding cyclic sulfamidates with excellent yields and enantioselectivities at room temperature within 0.5 h. ATH of 4,5-disubstituted imines 9, having preexisting stereogenic centers, is shown to take place with dynamic kinetic resolution.

A combinatorial approach to the identification of self-assembled ligands for rhodium-catalysed asymmetric hydrogenation

An effective and efficient means to catalyst discovery is the high-throughput screening of catalyst libraries. However, the current status of this approach suffers from a number of limitations, namely access to structurally diverse and meaningful ligand libraries and the enormous effort required for massive parallel screening of the resulting catalysts. We report an integrated solution to these drawbacks, which combines a diversity-oriented ligand synthesis, a catalyst-generation process driven by self-assembly and, finally, a combinatorial iterative library deconvolution strategy to identify the optimal catalyst. As a test case, rhodium-catalysed asymmetric hydrogenation was studied and, from a library of 120 self-assembling catalysts, highly enantioselective catalysts for the asymmetric hydrogenation of different olefinic substrates were identified within 17 experiments. Comparison of the results of the iterative library deconvolution strategy with those of the classic parallel-screening process confirmed the validity of this approach.

ChemInform Abstract: Design Concepts for Developing Highly Efficient Chiral Bisphosphine Ligands in Rhodium-Catalyzed Asymmetric Hydrogenations

ChemInform Abstract: Design Concepts for Developing Highly Efficient Chiral Bisphosphine Ligands in Rhodium-Catalyzed Asymmetric Hydrogenations

ChemInform Abstract: Aminophosphine Phosphinites Derived from Chiral 1,2-Diphenyl-2-aminoethanols: Synthesis and Application in Rhodium-Catalyzed Asymmetric Hydrogenation of Dehydroamino Acid Derivatives.

Abstract A series of chiral aminophosphine phosphinites DPAMPPs was synthesized from optically active 1,2-diphenyl-2-aminoethanols. The erythro-DPAMPPs were found to serve as excellent ligands for rhodium-catalyzed asymmetric hydrogenation of dehydroamino acid derivatives. For an array of dehydroamino acid precursors, remarkably high enantioselectivity (up to 98.4% e.e.) and reactivity (the ratio of substrate/catalyst up to 10000) were observed. Some factors controlling the enantioselectivity were examined and discussed.

Synthesis of a Cathepsin S Inhibitor

Cathepsin S is a 24 kD cysteine protease that is implicated in the onset of autoimmune diseases, such as rheumatoid arthritis and multiple sclerosis. The target molecule J is a potent, selective, and reversible inhibitor of cathepsin S. The sole stereogenic center in the target molecule was installed by a rhodium-catalyzed asymmetric hydrogenation.

Readily available chiral phosphine–aminophosphine ligands derived from 1-phenylethylamine for Rh-catalyzed enantioselective hydrogenations

A series of new chiral phosphine–aminophosphine ligands have been prepared via a two- or three-step transformation from commercially available and inexpensive ( S)-1-phenylethylamine, and successfully used in the rhodium-catalyzed asymmetric hydrogenation of various enamides, β-dehydroamino acid esters, and dimethyl itaconate. The results show that the ligand structure plays an important influence on both the reactivity and enantioselectivity. Ligand 2d bearing a N–H proton and two F-atoms on the 3,5-positions of the phenyl ring of the aminophosphino moiety was most effective for the hydrogenation of enamides and ( Z)-β-aryl-β-(acylamino)acrylates, whereas ligand 1b showed the highest enantioselectivities in the hydrogenation of ( Z)-β-alkyl-β-(acylamino)acrylates and dimethyl itaconate.