Homogeneous asymmetric catalysis by means of chiral metal complexes of 2,3-bis(dimenthylphosphino)maleic anhydride and of 2,3-bis(dimenthylphosphino)maleimide derivatives

2,3-Bis(dimenthylphosphino)maleic anhydride and also 2,3-bis(dimenthylphosphino)maleimide derivatives have been prepared from 2,3-dichloromaleic anhydride, 2,3-dichloro-N-phenylmaleimide and 2,3-dichloro-N-methylmaleimide, respectively, and dimenthyl(trimethylsilyl)phosphine. These compounds have been used as ligands for Rh complexes in the asymmetric hydrogenation and hydrosilylation. Ni and Pd complexes of these ligands were tested in the Grignard cross-coupling reaction.

The hydrogenation of -acetamido cinnamic acid gave 70% enantiomeric excess (ee) and hydrogenation of acetophenone up to 47% ee. Hydrosilylation of acetophenone led to 42% ee.

Attempts to asymmetric cross-coupling reactions resulted in very low enantiomeric excess.     

Rh-catalysed asymmetric hydrogenations with a dynamic library of chiral tropos phosphorus-ligands

A library of 16 chiral tropos phosphorus-ligands, based on a chiral P-bound alcohol or secondary amine and a flexible (tropos) P-bound biphenol unit, was synthesised. This ligand library allowed the screening of 16 homocombinations and 115 heterocombinations for the rhodium catalysed asymmetric hydrogenation of methyl N-acetamido acrylate. The screening resulted in the identification of a phosphite/phosphoramidite heterocombination, which proved to be extremely effective and enantioselective (100% yield, 94% ee).     

A Library Approach to the Development of BenzaPhos: Highly Efficient Chiral Supramolecular Ligands for Asymmetric Hydrogenation

A library of chiral supramolecular ligands, named BenzaPhos, of straightforward preparation (two steps from commercially or readily available starting materials) and modular structure, was designed and synthesized. The ligands were screened in the search for new rhodium catalysts for the enantioselective hydrogenation of several benchmark and industrially relevant substrates. Once a series of hits were identified, structural modifications were introduced on three of the best ligands and a small second-generation library was created. Members of the latter library showed outstanding levels of activity and enantioselectivity in the hydrogenation of challenging olefins, such as enamide S4 and β-dehydroamino ester S5 (>99?%?ee: best value ever reported in both cases). A series of control experiments were undertaken to clarify the role of hydrogen bonding in determining the catalytic properties of the new ligands. The results of these experiments, together with those of computational studies carried out on four dihydride complexes involved in the catalytic hydrogenation of substrate S4, strongly suggest that a substrate orientation takes place in the catalytic cycle by formation of a hydrogen bond between the ligand amide oxygen atom and the substrate amide NH atom.     

Olefins as steering ligands for homogeneously catalyzed hydrogenations

Iridium(I) complexes containing a (5H-dibenzo[a,d]cyclohepten-5-yl)-phosphane (tropp(R); R = phosphorus-bound substituent = Ph, Cyc) as a rigid, concave-shaped, mixed phosphane olefin ligand were prepared and tested as catalyst precursors in the hydrogenation of imines. With the complex [Ir(tropp(Cyc))(cod)]OTf, turnover frequencies (TOFs) of >6000 h(-1) were reached in the hydrogenation of N-phenyl-benzylidenamine, PhN==CHPh. Lower activities (TOF>80 h(-1)) are observed with N-phenyl-(1-phenylethylidene)amine, PhN==CMePh. Chiral tropp-type ligands were prepared in few simple steps. Monosubstitution of the olefinic unit in the dibenzo[a,d]cycloheptenyl moiety with (R)- or (S)-mentholate gave mixtures of diastereomers that could be separated and isolated in enantiomerically pure form. Iridium(I) complexes with these ligands are rare examples of side-on bonded enolether complexes. In catalytic imine hydrogenations, complete conversion (>98 %) was reached in all cases (conditions: p[H(2)] = 50 bar, T = 50 degrees C, t = 2 h, substrate/catalyst 100:1). The best enantiomeric excess (ee = 86 % S isomer) was reached with PhN==CMePh as substrate and the R,R form of the (10-menthyloxy-5H-dibenzo[a,d]cyclohepten-5-yl)diphenylphosphane ligand. The iridium(I) complex containing the same phosphane gave a 60 % ee (S isomer) with the enamide N-(1-phenylvinyl)acetamide as substrate (conditions: p[H(2)] = 4 bar, T = 50 degrees C, t = 18 h, substrate/catalyst = 50:1). These reactions constitute the first examples in which chiral olefins have been used as steering ligands in catalytic enantioselective hydrogenations.     

Enantioselective hydrogenation of functionalized olefins catalyzed by Rh-chiral bidentatephosphite complexes

A novel catalytic system for the hydrogenation of dimethyl itaconate has been developed by using rhodium–diphosphite complexes. These chiral diphosphite ligands were derived from glucopyranoside, d-mannitol derivatives, and binaphthyl or H₈-binaphthyl phosphochloridites. The ligands based on the methyl 3,6-anhydro-α-d-glucopyranoside backbone and (R)- and (S)-binaphthol and/or (R)- and (S)-2,2′-dihydroxy-5,5′,6,6′,7,7′,8,8′-octahydro-1,1′-binaphthol gave almost complete conversion of the dimethyl itaconate and both enantiomers of dimethyl 2-methylsuccinate with excellent enantioselectivities. The stereochemically matched combination of methyl 3,6-anhydro-α-d-glucopyranoside and H₈-(S)-binaphthyl in ligand 2,4-bis{[(S)-1,1′-H₈-binaphthyl-2,2′-diyl]-phosphite} methyl 3,6-anhydro-α-d-glucopyranoside was essential to afford dimethyl 2-methylsuccinate with up to 98% ee. The sense of the enantioselectivity of products was predominantly determined by the configuration of the biaryl moieties of the ligands. An initial screening of [Rh(cod)₂]BF₄ with these ligands in the hydrogenation of (E)-2-(3-butoxy-4-methoxybenzylidene)-3-methylbutanoic acid was carried out. Good enantioselectivity (75% ee) and low yield for (R)-2-(3-butoxy-4-methoxybenzyl)-3-methylbutanoic acid were obtained.     

Enantioselective Rh-catalyzed hydrogenation of N-formyl dehydroamino esters with monodentate phosphoramidite ligands

Enantioselectivities up to >99% ee were achieved in the rhodium-catalyzed asymmetric hydrogenation of N-formyl dehydroamino esters using monodentate phosphoramidites as chiral ligands. The substrates were synthesized by condensation of methyl isocyanoacetate with a range of aldehydes and with cyclohexanone. A highly convenient multigram scale one step synthesis of methyl 2-(formamido)acrylate was developed. This compound was used in the synthesis of methyl 2-(formamido)cinnamate via a solvent free Heck reaction. Moreover, full conversion and >99% ee were obtained in 1 h in the hydrogenation of methyl 2-(formamido)acrylate with 0.2 mol % catalyst and 2 bar hydrogen pressure. The versatility of the formyl protection was established by its removal under mild conditions.     

Asymmetric hydrogenation of aromatic ketones catalyzed by the TolBINAP/DMAPEN-ruthenium(II) complex: a significant effect of N-substituents of chiral 1,2-diamine ligands on enantioselectivity

Asymmetric hydrogenation of acetophenone in the presence of Ru(II) catalysts coordinated by TolBINAP and a series of chiral 1,2-diamines was studied. The sense and degree of enantioselectivity were highly dependent on the N-substituents of the diamine ligands. The N-substituent effect was discussed in detail. Among these catalysts, the (S)-TolBINAP/(R)-DMAPEN-Ru(II) complex showed the highest enantioselectivity. The mode of enantioface selection was interpreted by using transition state models based on the X-ray structure of the catalyst precursor. The chiral catalyst effected the hydrogenation of alkyl aryl ketones and arylglyoxal dialkyl acetals to afford the chiral alcohol in >99% ee in the best cases. Hydrogenation of racemic benzoin methyl ether with the chiral catalyst through dynamic kinetic resolution gave the anti-alcohol (syn:anti = 3:97) in 98% ee, while the reaction of alpha-amidopropiophenones resulted in the syn-alcohols (syn:anti = 96:4 to >99:1) in >98% ee.     

Novel atropisomeric aminophosphine ligands with a bridge across the 5,5′-position of biphenyl for Rh(I)-catalyzed asymmetric hydrogenation

A new type of atropisomeric bisaminophosphine ligands 2 with a bridge across the 5,5′-position of biphenyl has been developed. The axial chirality of this type of ligands can be retained by macro-ring strain produced from 5,5′-linkage of biphenyl even without 6,6′-substituents on biphenyls. The ligand (R)-2a showed high catalytic activities and enantioselectivities (up to 95.3% ee and quantitative yields) for Rh(I)-catalyzed asymmetric hydrogenation of a variety of methyl (Z)-2-acetamido-3-arylacrylates.     

Supramolecular PhanePhos-analogous ligands through hydrogen-bonding for asymmetric hydrogenation

PhanePhos-analogous phosphorous ligands have been generated via self-assembly through hydrogen-bonding, and studied in rhodium-catalyzed asymmetric hydrogenation (up to 99% ee).     

Indirect and direct catalytic asymmetric reductive amination of 2-tetralone

Herein we report a one-pot catalytic asymmetric reductive amination of 2-tetralone. High-throughput screening of a small library of chiral ligands allowed us to perform the enantioselective hydrogenation of the intermediate enamine with up to 60% ee and a one-pot reaction with up to 47% enantiomeric excess of the desired amine.     

苯乙胺衍生的手性膦-亚磷酰胺酯配体在Rh-催化a-烯醇酯膦酸酯的不对称氢化反应中的应用

将苯乙胺衍生的手性膦-亚磷酰胺酯配体应用在Rh-催化α-烯醇酯膦酸酯的不对称氢化反应中,考察了配体结构及反应条件对反应结果的影响,并在优化的条件下研究了各种底物的适用范围,产物的对映选择性最高>99%ee.     

Efficient heterogeneous asymmetric transfer hydrogenation of ketones using highly recyclable and accessible silica-immobilized Ru-TsDPEN catalysts

[reaction: see text] Chiral Ru-TsDPEN [N-(p-toluenesulfonyl)-1,2-diphenylethylenediamine]-derived catalysts were first successfully immobilized onto amorphous silica gel and mesoporous silicas of MCM-41 and SBA-15 by an easily accessible approach. The catalyst immobilized on silica gel demonstrated remarkably high catalytic activities and excellent enantioselectivities (up to >99% ee) for the heterogeneous asymmetric transfer hydrogenation of various ketones. Particularly, the catalyst could be readily recovered and reused in multiple consecutive catalytic runs (up to 10 uses) with the completely maintained enantioselectivity.     

Cinchona alkaloid derived ligands in catalytic asymmetric transfer hydrogenation

A collection of chiral quinuclidine ligands, derived from the Cinchona alkaloids quinine and quinidine, has been evaluated in the catalytic asymmetric transfer hydrogenation of aromatic ketones. It was fond that [IrCl(COD)]2 complexes of the diamines QCI-Amine and QCD-Amine gave the most active catalysts, capable of reducing a range of aromatic ketones with excellent conversions and good enantioselectivities (up to 95% ee). These are the best selectivities reported for ligands based on the quinuclidine core in an asymmetric transformation, and advocate that these ligands, commercially available in both pseudo-enantiomeric forms, will find practical use in this and other catalytic processes.     

Highly enantioselective rhodium-catalyzed hydrogenation of beta-dehydroamino acid derivatives using monodentate phosphoramidites

New and very easily accessible monodentate phosphoramidite ligands have been developed that lead to excellent ee's and full conversions in the hydrogenation of (E)- and (Z)-beta-dehydroamino acid derivatives with both aliphatic and aromatic side chains. Particularly, two different catalytic systems were established for (E)-beta-(acylamino)acrylates (98-99% ee) and (Z)-beta-(acylamino)acrylates (92-95% ee) based on phosphoramidites 2 and 3, respectively.     

Mixed S/P Ligands from Carbohydrates: Synthesis and Utilization in Asymmetric Catalysis

Abstract

New chiral mixed sulfur/phosphorus ligands derived from carbohydrates are reported. These ligands were found to be efficient catalyst precursors for palladium-catalyzed asymmetric substitution of 1,3-diphenylpropenyl acetate with dimethyl malonate or benzylamine (up to 96% ee), and for rhodium-catalyzed methyl acetamidocinnamate hydrogenation (up to 92% ee).     

Remote dipole effects as a means to accelerate [Ru(amino alcohol)]-catalyzed transfer hydrogenation of ketones

A new generation of 2-aza-norbornyl amino alcohol ligands for the catalytic transfer hydrogenation reaction of aromatic ketones was synthesized. Extremely active catalysts were formed by introducing a ketal functionality at the rear end of the ligand. Acetophenone was reduced in 96% ee at low catalyst loading, substrate to catalyst ratio, S/C 5000, within 90 minutes with isopropyl alcohol as the hydrogen donor. It was found that the dioxolane substituent in the ligand increased the turnover frequency, TOF50, from 1050 h(-1) to 3000 h(-1) at an S/C ratio of 1000. Introduction of a methyl group at the carbinol carbon resulted in TOF50 as high as 8500 h(-1). Transfer hydrogenation of a range of aromatic ketones was evaluated and found to reach completion within 30 minutes at room temperature, and excellent enantioselectivity, up to 99 % ee, was obtained. A possible explanation for the enhanced activity was provided by density functional calculations, which showed that the presence of a remote dipole in the ligand lowered the transition state energy.     

Supraphos: a supramolecular strategy to prepare bidentate ligands

We report a new strategy for the preparation of chelating bidentate ligands, which involves just the mixing of two monodentate ligands functionalized with complementary binding sites. In the current example, the assembly process is based on selective metal-ligand interactions, using phosphite zinc(II) porphyrins 1-6 and the nitrogen donor ligands b-i. From only 16 monodentate ligands, a library of 60 palladium catalysts based on 48 bidentate ligand assemblies has been prepared. The relatively small catalyst library gave a large variety in the selectivity of the alkylation of rac-1,3-diphenyl-2-propenyl acetate. Importantly, small variations in the building blocks lead to large differences in the enantioselectivity imposed by the catalyst (up to 97% ee).     

Synthesis of optically active methyl 4-(4-biphenylyl)-3-hydroxybutanoate via enantioselective hydrogenation using a tartaric acid-modified nickel catalyst and recrystallization

Enantioselective hydrogenation of methyl 4-(4-biphenylyl)-3-oxobutanoate over a tartaric acid-modified Raney nickel catalyst gave the title compound in 82% ee, which was enantiomerically enriched by recrystallizations. The product was converted to an (R)-3-acetoxyglutaric acid half ester via a ruthenium-catalyzed oxidation.     

Highly enantioselective hydrogenation of alpha-dehydroamino esters and itaconates with triphosphorous bidentate ligands and the unprecedented solvent effect thereof

An X-ray diffraction experiment revealed an interesting triphosphorous bidentate coordination in a Pd(II) complex of a phosphine-phosphoramidite ligand 1, which showed excellent enantioselectivity (up to 99.4% ee) in Rh-catalyzed hydrogenation of alpha-dehydroamino esters in acetone. A dramatic solvent effect was found in the hydrogenation of itaconates, which induces opposite chiralities of the product with the same catalytic system by the use of different solvents (e.g., 99.6% ee (R) in TFE vs 71.2% ee (S) in methyl ethyl ketone).     

Structural requirements in chiral diphosphine-rhodium complexes. VII. Use of Z-methyl-α-acylaminocinnamtes as structural probes for Diop-rhodium(I) complexes.

(+)-(25,3S)-DIOP was used in neutral rhodium(I)-diphosphime complexes to catalyze the asymmetric hydrogenation of Z-methyl-u-acylaminocimnamates. Increasing steric bulk in the acyl function (NHCOR, where R is a hydrocarbon moiety) resulted in a decrease in optical purity of the N-acylphenylalanine methyl ester products. The optical purity decreased from 69 % ee (S) [Me], 15 % ee (S) [i-Pr], to 0 % ee [t-Bu and 1-adamantyl]. The α-formamido substrate decreased in optical purity [58 % ee (S)] relative to the Me analogue. The a-trifluoroacetamido analogue gave a reversal in chirality [22 % ee (R)].