Instant ligand libraries. Parallel synthesis of monodentate phosphoramidites and in situ screening in asymmetric hydrogenation

Chiral phosphoramidites have been identified as excellent ligands for various metal-catalyzed enantioselective transformations. Taking advantage of their easy preparation and modular nature, we designed a fully automated protocol for the parallel preparation of a library of 32 phosphoramidites and its screening in asymmetric hydrogenation of amino acid precursors. This initial study led to the discovery of a new ligand for the preparation of an enantiopure beta(3)-homoalanine precursor. [structure--see text]     

Hydrogen bonding makes a difference in the rhodium-catalyzed enantioselective hydrogenation using monodentate phosphoramidites

A new generation of monodentate phosphoramidite ligands bearing a primary amine moiety was found to display comparable or better efficiency than bisphosphines in the Rh-catalyzed asymmetric hydrogenation of challenging substrates, such as (Z)-methyl alpha-acetoxyacrylate or (E)-beta-aryl itaconate derivatives, affording the corresponding hydrogenation products with excellent enantioselectivities (up to >99% ee). The presence of intermolecular hydrogen bonding (HB) between two monodentate ligands in the catalyst was found to be critical for excellent catalyst performance. This finding provides a basis for design and development of further catalyst systems using this type of monodentate phosphoramidite ligands.     

Mixtures of chiral and achiral monodentate ligands in asymmetric Rh-catalyzed olefin hydrogenation: reversal of enantioselectivity

The recently described method of combinatorial asymmetric transition metal catalysis based on the use of mixtures of chiral monodentate P-ligands has been extended to include mixtures of chiral and achiral monodentate P-ligands, reversal of enantioselectivity in Rh-catalyzed olefin hydrogenation being possible in appropriate cases.     

Imine hydrogenation catalyzed by iridium complexes comprising monodentate chiral phosphoramidites and N-donor ligands

The relatively inexpensive chiral monodentate phosphoramidite (S)-MONOPHOS may be used in combination with pyridines to prepare iridium complexes effective for catalysis of asymmetric imine hydrogenation with comparable enantioselectivity to some of those containing more costly chiral bidentate phosphines. [Ir(cod)((S)-MONOPHOS)(L)]BArF (cod = 1,5-cyclooctadiene; L = 3-methylisoquinoline, acridine, 2,6-lutidine, acetonitrile, or 2,3,3-trimethylindolenine; BArF = tetrakis[3,5-bis(trifluoromethyl)phenyl]borate) are efficient catalysts for the asymmetric hydrogenation of 2,3,3-trimethylindolenine. An important observation is that the catalyst containing acridine is more enantioselective than the catalyst derived from 2,3,3-trimethylindolenine which suggests that the other N-donor ligands are not readily displaced by the substrate during the catalytic cycle.     

Bulky monodentate phosphoramidites in palladium-catalyzed allylic alkylation reactions: aspects of regioselectivity and enantioselectivity

A series of bulky monodentate phosphoramidite ligands, based on biphenol, BINOL and TADDOL backbones, have been employed in the Pd-catalysed allylic alkylation reaction. Reaction of disodium diethyl 2-methyl malonate with monosubstituted allylic substrates in the presence of palladium complexes of the phosphoramidite ligands proceeds smoothly at room temperature. The regioselectivities observed depend strongly on the leaving group and the geometry of the allylic starting compounds. Mono-coordination occurs when these ligands are ligated in [Pd(allyl)(X)] complexes (allyl=C3H5, 1-CH3C3H4, 1-C6H5C3H4, 1,3-(C6H5)2C3H3; X=Cl, OAc). The solid-state structure determined by X-ray diffraction of [Pd(C3H5)(1)(Cl)] reveals a non-symmetric coordination of the allyl moiety, caused by the stronger trans influence of the phosphoramidite ligand relative to X-. In all of these complexes, the syn,trans isomer is the major species present in solution. Because of fast isomerisation and high reactivity of the syn,cis complex, the major product formed upon alkylation is the linear product, especially for monosubstituted phenylallyl substrates in the presence of halide counterions. In the case of biphenol- and BINOL-based phosphoramidites, however, a strong memory effect is observed when 1-phenyl-2-propenyl acetate is employed as the substrate. In this case, nucleophilic attack competes effectively with the isomerisation of the transient cinnamylpalladium complexes. The asymmetric allylic alkylation of 1,3-diphenyl-2-propenyl acetate afforded the chiral product in up to 93 % ee. Substrates with smaller substituents gave lower enantioselectivities. The observed stereoselectivity is explained in terms of a preferential rotation mechanism, in which the product is formed by attack on one of the isomers of the intermediate [Pd[1,3-(C6H5)2C3H3](L)(OAc)] complex.     

High efficiency and enantioselectivity in the rh-catalyzed conjugate addition of arylboronic acids using monodentate phosphoramidites

A very fast reaction and enantioselectivities >98% have been reached in the rhodium-catalyzed arylboronic acid addition to enones using a monodentate phosphoramidite ligand. Temperature-dependent studies show that monodentate phosphoramidites form stable complexes with metals and can induce high enantioselectivities even at high temperatures in polar solvents.     

Synthesis of new chiral monodentate phosphite ligands and their use in catalytic asymmetric hydrogenation

[reaction: see text] New monodentate phosphite ligands have been developed from axially chiral biphenols, which show excellent enantioselectivity in the Rh(I)-catalyzed hydrogenation of dimethyl itaconate. The new chiral ligand system is suitable to create libraries and possesses fine-tuning capability.     

Bidentates versus monodentates in asymmetric hydrogenation catalysis: synergic effects on rate and allosteric effects on enantioselectivity

C 1-Symmetric phosphino/phosphonite ligands are prepared by the reactions of Ph 2P(CH 2) 2P(NMe 2) 2 with ( S)-1,1'-bi-2-naphthol (to give L A ) or ( S)-10,10'-bi-9-phenanthrol (to give L B ). Racemic 10,10'-bi-9-phenanthrol is synthesized in three steps from phenanthrene in 44% overall yield. The complexes [PdCl 2( L A,B )] ( 1a, b), [PtCl 2( L A,B )] ( 2a, b), [Rh(cod)( L A,B )]BF 4 ( 3a, b) and [Rh( L A,B ) 2]BF 4 ( 4a, b) are reported and the crystal structure of 1a has been determined. A (31)P NMR study shows that M, a 1:1 mixture of the monodentates, PMePh 2 and methyl monophosphonite L 1a (based on ( S)-1,1 '-bi-2-naphthol), reacts with 1 equiv of [Rh(cod) 2]BF 4 to give the heteroligand complex [Rh(cod)(PMePh 2)( L 1a )]BF 4 ( 5) and homoligand complexes [Rh(cod)(PMePh 2) 2]BF 4 ( 6) and [Rh(cod)( L 1a ) 2]BF 4 ( 7) in the ratio 2:1:1. The same mixture of 5- 7 is obtained upon mixing the isolated homoligand complexes 6 and 7 although the equilibrium is only established rapidly in the presence of an excess of PMePh 2. The predominant species 5 is a monodentate ligand complex analogue of the chelate 3a. When the mixture of 5- 7 is exposed to 5 atm H 2 for 1 h (the conditions used for catalyst preactivation in the asymmetric hydrogenation studies), the products are identified as the solvento species [Rh(PMePh 2)( L 1a )(S) 2]BF 4 ( 5'), [Rh(S) 2(PMePh 2) 2]BF 4 ( 6') and [Rh(S) 2( L 1a ) 2]BF 4 ( 7') and are formed in the same 2:1:1 ratio. The reaction of M with 0.5 equiv of [Rh(cod) 2]BF 4 gives exclusively the heteroligand complex cis-[Rh(PMePh 2) 2( L 1a ) 2]BF 4 ( 8), an analogue of 4a. The asymmetric hydrogenation of dehydroamino acid derivatives catalyzed by 3a, b is reported, and the enantioselectivities are compared with those obtained with (a) chelate catalysts derived from analogous diphosphonite ligands L 2a and L 2b , (b) catalysts based on methyl monophosphonites L 1a and L 1b , and (c) catalysts derived from mixture M. For the cinnamate and acrylate substrates studied, the catalysts derived from the phosphino/phosphonite bidentates L A,B generally give superior enantioselectivities to the analogous diphosphonites L 2a and L 2b ; these results are rationalized in terms of delta/lambda-chelate conformations and allosteric effects of the substrates. The rate of hydrogenation of acrylate substrate A with heterochelate 3a is significantly faster than with the homochelate analogues [Rh( L 2a )(cod)]BF 4 and [Rh(dppe)(cod)]BF 4. A synergic effect on the rate is also observed with the monodentate analogues: the rate of hydrogenation with the mixture containing predominantly heteroligand complex 5 is faster than with the monophosphine complex 6 or monophosphonite complex 7. Thus the hydrogenation catalysis carried out with M and [Rh(cod) 2]BF 4 is controlled by the dominant and most efficient heteroligand complex 5. In this study, the heterodiphos chelate 3a is shown to be more efficient and gives the opposite sense of optical induction to the heteromonophos analogue 5.     

Synthesis of new monodentate spiro phosphoramidite ligand and its application in Rh-catalyzed asymmetric hydrogenation reactions

[reaction: see text] A new spirocyclic diol, 9,9'-spirobixanthene-1,1'-diol, was synthesized in two steps from readily available starting material m-phenoxyanisole. Resolution of the racemic diol was achieved by cocrystallization with N-benzylcinchonidinium chloride and N-benzylquininium chloride in acetonitrile. The corresponding spiro monodentate phosphoramidite ligand has been prepared for Rh-catalyzed asymmetric hydrogenation of alpha-dehydroamino acid derivatives and itaconic acid with excellent enantioselectivities (up to >99% ee).     

Synthesis and application in asymmetric C-C bond formation of solution phase ligand libraries of monodentate phosphoramidites

A library of 96 unique monodentate phosphoramidite ligands has been synthesized in solution and used in the asymmetric conjugate addition of potassium vinyltrifluoroborate to enones resulting in up to 88% ee.     

Hybrid bidentate phosphorus ligands in asymmetric catalysis: privileged ligand approach vs. combinatorial strategies

In this perspective the development of chiral phosphorus ligands for asymmetric catalysis is discussed, with a special focus on hybrid bidentate phosphorus ligands, in particular phosphine-phosphoramidites. An attempt is made to compare privileged ligand and combinatorial approaches to ligand development--for which the class of phosphine-phosphoramidite ligands is well suited--highlighting differences, similarities and their complementary use.     

The combinatorial approach to asymmetric hydrogenation: phosphoramidite libraries, ruthenacycles, and artificial enzymes

For a more general implementation of asymmetric catalysis in the production of fine chemicals, the screening for new catalysts and ligands must be dramatically accelerated. This is possible with a high-throughput experimentation (HTE) approach. However, implementation of this technology requires the rapid preparation of libraries of ligands/catalysts and consequently dictates the use of simple ligands that can be readily synthesised in a robot. In this concept article, we describe how the development of new ligands based on monodentate phosphoramidites enabled the development of an integral HTE protocol for asymmetric hydrogenation. This "instant ligand library" protocol makes it possible to synthesise 96 ligands in one day and screen them the next day. Further diversity is possible by using mixtures of monodentate ligands. This concept has already led to an industrial application. Other concepts, still under development, are based on chiral ruthenacycles as new transfer hydrogenation catalysts and the use of enzymes as ligands for transition-metal complexes.     

Organic solvent nanofiltration in asymmetric hydrogenation: enhancement of enantioselectivity and catalyst stability by ionic liquids

This communication describes the enhancement of the enantioselectivity and the stability of Ru-BINAP with the ionic liquid trihexyl(tetradecyl)phosphonium chloride (CyPhos101), and the use of organic solvent nanofiltration for the efficient separation of the catalyst and ionic liquid from the hydrogenation product, followed by simultaneous recycling of the catalyst and ionic liquid.     

Synthesis of monodentate chiral spiro phosphonites and the electronic effect of ligand in asymmetric hydrogenation

New monodentate chiral phosphonites were synthesized from enantiomerically pure 1,1'-spirobiindane-7,7'-diol. The phosphonites 2 were efficient ligands for the Rh-catalyzed asymmetric hydrogenation of alpha- and beta-dehydroamino acid derivatives, providing the amino acids in high enantioselectivities. The study of electronic effect showed that the electron-withdrawing substitutent on the P-phenyl ring of the phosphonite ligand dramatically decreased both the reactivity and enantioselectivity of the ligand.     

High enantioselectivity in the asymmetric hydrogenation of ketones by a supported Pt nanocatalyst on a mesoporous modified MCM-41 support

Catalysts containing metal nanotubes were prepared by the adsorption of platinum metal nano‐tubes onto functionalized and modified silica surfaces (MCM‐41 and fumed silica). (3‐Chloropro‐pyl)trimethoxysilane and cinchonidine were used for functionalization and modification, respec‐tively. Potassium chloroplatinate was used as the metal precursor to impregnate platinum metal nanotubes on the pretreated functionalized and modified silica surfaces. The solid catalysts were characterized by ESEM, TEM, EDAX, and XPS. The MCM‐41 supported platinum nanotube catalyst showed>98%to~100%enantioselectivity towards the hydrogenation of a range of pharmaceuti‐cally important chemicals such as methyl pyruvate, ethyl pyruvate, and acetophenone with nearly full conversion.     

Application of monodentate secondary phosphine oxides,a new class of chiral ligands,in Ir(i)-catalyzed asymmetric imine hydrogenation

Secondary phosphine oxides were prepared from R(1)PCl(2) and R(2)MgBr, followed by hydrolysis. They were obtained in an enantiopure form by preparative chiral HPLC. These new monodentate ligands were tested in the iridium-catalyzed hydrogenation of imines at 25 bar. Enantioselectivities up to 76% were obtained at L/Ir = 2. Addition of pyridine (Pyr/Ir = 1:2) raised the ee to 83%. Using pyridine as an additive allowed reduction of the L/Ir ratio to 1 without reduction of ee. [reaction: see text]     

Enhancement of enantioselectivity by alcohol additives in asymmetric hydrogenation with bis(oxazolinyl)phenyl ruthenium catalysts

Bis(oxazolinyl)phenyl ruthenium(II) complexes were found to catalyze asymmetric hydrogenation of ketones, in which chiral bulky alcohol additives showed significant enhancement of enantioselectivity even in protic solvents.