New amidophosphine-phosphinites (tLANOPs) as chiral ligands for asymmetric hydrogenation reactions

The new amidophosphine-phosphinite (AMPP) ligands 4a–g (called tLANOP ligands) derived from the chiral hydroxy amide (R)- or (S)-2-hydroxy-3,3,N-trimethylbutyramide have been prepared in 48–83% yield. The crystal structures of the square planar complexes [(SP-4-3)-Pd((R)-dmphea)((S)-4a)]BF₄ and [Rh((R)-4a)(COD)]BF₄ have allowed the absolute configurations of the ligands to be assigned. In both complexes the 7-membered chelating ring of 4a has virtually the same twist-boat conformation. With this class of ligands the rhodium catalyzed asymmetric hydrogenation of 4-oxoisophorone enol acetate gave (S)-phorenol acetate in up to 71% ee. The iridium catalyzed asymmetric hydrogenation of the cyclic iminium salts 16a and 16b afforded after work-up the corresponding cyclic secondary amine (S)-17 in up to 86% ee, when bulky groups were present on the phenyl substituents on the two phosphorus atoms.     

Asymmetric hydroesterification of styrene using catalysts with planar-chiral ferrocene oxazoline ligands

Chiral P,N-ferrocene ligands, 1-diphenylphosphino-1′-[(S)-4-isopropyl-2.5-oxazolinyl]-2′-(S_p)-(trimethylsilyl)-ferrocene and its diastereomer, and 1-diphenylphosphino-1′-[(S)-4-isopropyl-2.5-oxazolinyl]-2′(S_p)-(diphenylphosphino)-ferrocene and its diastereomer were used in the palladium-catalyzed asymmetric hydroesterification of styrene. The role of these ligands, which contain central, axial, and planar chirality, on the stereochemical outcome was investigated. A significant effect of using CuCl₂ as a co-catalyst on the reaction was observed. Excellent regioselectivity (b/n >99:1) with low ee (28%) was obtained in the presence of CuCl₂; moderate enantioselectivity (64% ee) but low regioselectivity (b/n, 40/60) was obtained in the absence of CuCl₂.     

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.     

Synthesis of electron-deficient (Sa,R,R)-(CF3)2-C3-TunePhos and its applications in asymmetric hydrogenation of α-iminophosphonates

A novel electron-deficient chiral diphosphine ligand bearing trifluoromethyl groups at the 6- and 6′-positions of the biphenyl backbone, (S_a,R,R)-(CF₃)₂-C₃-TunePhos, has been synthesized from the commercially available chiral 2,4-pentanediol. The above ligand was successfully applied to palladium-catalyzed asymmetric hydrogenation of linear and cyclic α-iminophosphonates with up to 99%?ee.     

Diamidophosphites with remote P1-stereocentres and their performance in Pd-catalyzed enantioselective reactions

Diamidophosphite ligands based on 1,1′-bis(hydroxymethyl)ferrocene or N¹,N²-bis((S)-1-hydroxy-3,3-dimethylbutan-2-yl)oxalamide and bearing 1,3,2-diazaphospholidine rings with stereogenic phosphorus atoms were obtained. The use of these ligands provides up to 96% ee in Pd-catalyzed asymmetric allylations of (E)-1,3-diphenylallyl acetate, up to 70% ee in Pd-catalyzed desymmetrizations of N,N′-ditosyl-meso-cyclopent-4-ene-1,3-diol bis-carbamate and up to 80% ee in Pd-catalyzed allylic alkylations of cinnamyl acetate with ethyl 2-oxocyclohexane-1-carboxylate. Results obtained with a diamidophosphite containing an oxalamide framework show the considerable potential of such ligands in enantioselective catalysis.     

Synthesis of novel β-amino alcohols and their application in the catalytic asymmetric sulfoxidation of sulfides

Novel chiral norephedrine-based β-amino alcohol ligands containing a thiophene ring were prepared from norephedrine and substituted furan carbaldehydes (methyl- or ethyl-substituted) and used in combination with VO(acac)₂ for the asymmetric oxidation of aryl methyl sulfides using H₂O₂ as an oxidant. Amino alcohol derived Schiff bases 4,5a–b gave higher enantiomeric excesses than amino alcohol-derived reduced Schiff based ligands 6,7a–b. Of these chiral ligands, (1S,2R)-5b and (1S,2R)-7b gave high yields (90%) with moderate to high enantioselectivities (78%, 96% ee, respectively). The oxidation of other aryl methyl sulfides with (1S,2R)-5b and (1S,2R)-7b as ligands afforded the corresponding sulfoxides in 60–89% yields and with 92–99% ee.     

Synthesis and application of novel chiral phosphino-oxazoline ligands with 1,1′-binaphthyl skeleton

C₁-Symmetric phosphino-oxazolines, (S,S)- and (S,R)-2-[4-(isopropyl)oxazol-2-yl]-2′-diphenylphosphino-1,1′-binaphthyl, which possess both phosphine and oxazoline moieties, were prepared from racemic binaphthol and enantiomerically pure (S)-(+)-2-amino-3-methyl-1-butanol in high yields. Reaction of 1,3-diphenyl-2-propenyl acetate with dimethyl sodiomalonate in the presence of 2 mol% of palladium catalysts bearing the new chiral ligands proceeded with high enantioselectivity to give allylic alkylation products of up to 91% ee.     

Diastereomeric P1-chiral diamidophosphites with terpene fragments in asymmetric catalysis

Diamidophosphite P¹-monodentate, ligands based on terpene alcohols and (S)- or (R)-(2-anilinomethyl)pyrrolidine, induce high enantioselectivities (ee’s up to 99%) in Pd-catalyzed allylic substitution reactions. In the Pd-catalyzed deracemization of ethyl (E)-1,3-diphenylallyl carbonate up to 92% enantioselectivity has been achieved. The Rh-catalyzed asymmetric hydrogenation of α-dehydrocarboxylic acid esters leads to a maximum of 56% ee with quantitative conversion. Diastereomeric diamidophosphites prepared from [(1S)-endo]-(−)-borneol were found to be the most efficient stereoselectors.     

Asymmetric synthesis of novel 1,4-aminoalcohol ligands with norbornene and norbornane backbone: use in the asymmetric diethylzinc addition to benzaldehyde

The asymmetric synthesis of cis-1,4-aminoalcohols with norbornene and norbornane backbone was performed starting with (2S,3R)-(−)-cis-hemiester 1 (98% ee). Chemoselective amination with HMPTA followed by Grignard reactions and subsequent LAH reductions afforded compounds 5a–d. cis-Hemiester 1 was also transformed into chiral ligands 7a–f and 9a–d with the DCC coupling method followed by LAH reduction using acyclic, heterocyclic amines and various aniline derivatives and p-toluenesulfonamide, respectively. The chiral ligands were subjected to asymmetric diethylzinc addition to examine their effectiveness as chiral catalysts. Among these, arylamine and tosyl substituted chiral ligands 9a–d exhibited the highest selectivities (up to 97% ee).     

A new strategy in enantioselective intramolecular hetero Diels-Alder reaction: catalytic double asymmetric induction during the tandem transetherification-intramolecular hetero Diels-Alder reaction of methyl (E)-4-methoxy-2-oxo-3-butenoate with rac-6-methyl-5-hepten-2-ol

An efficient catalytic double asymmetric induction during the tandem transetherification-intramolecular hetero Diels-Alder reaction has been developed. The enantioselective tandem reaction of methyl (E)-4-methoxy-2-oxo-3-butenoate with rac-6-methyl-5-hepten-2-ol has been achieved to provide methyl (2R,4aS,8aR)-3,4,4a,8a-tetrahydro-2,5,5-trimethyl-2H,5H-pyrano[4,3-b]-pyran-7-carboxylate in good yield with effective kinetic resolution (up to 95% selectivity), high diastereoselectivity (up to 92% de), and high enantioselectivity (up to 97% ee) in the presence of (S,S)-tert-Bu-bis(oxazoline)-Cu(SbF₆)₂ and 5 Å molecular sieves.     

Palladium-catalyzed asymmetric allylic alkylation of indoles by C–N bond axially chiral phosphine ligands

The palladium-catalyzed asymmetric allylic alkylation of indoles with 1,3-diphenyl-2-propenyl acetate using P/N-type ligands such as N-aryl indole, C–N bond axially chiral aminophosphine (aS)-L4, gave the desired products 1 in good yields and with moderate to high enantioselectivities (up to 90% ee).     

New functional chiral P-based ligands and application in ruthenium-catalyzed enantioselective transfer hydrogenation of ketones

Metal-catalyzed asymmetric transfer hydrogenation is a powerful and practical method for the reduction of ketones to produce the corresponding secondary alcohols, which are valuable building blocks in the pharmaceutical, perfume, and agrochemical industries. Hence, a series of novel chiral β-amino alcohols were synthesized by chiral amines with regioselective ring opening of (S)-propylene oxide or reaction with (S)-(+)-2-hydroxypropyl p-toluenesulfonate by a straightforward method. The chiral ruthenium catalytic systems generated from [Ru(arene)(μ-Cl)Cl]₂ complexes and chiral phosphinite ligands based on amino alcohol derivatives were employed in asymmetric transfer hydrogenation of ketones to give the corresponding optically active alcohols; (2S)-1-{[(2S)-2-[(diphenylphosphanyl)oxy]propyl][(1R)-1-phenylethyl]amino}propan-2-yldiphenylphosphinitobis[dichol-oro(η⁶-benzene)ruthenium(II)] acts an excellent catalyst in the reduction of α-naphthyl methyl ketone, giving the corresponding alcohol with up to 99% ee. The substituents on the backbone of the ligands were found to have a remarkable effect on both the conversion and enantioselectivity of the catalysts. Furthermore, this transfer hydrogenation is characterized by low reversibility under these conditions.     

Synthesis of new bis-BINOL-2,2′-ethers and bis-H8BINOL-2,2′-ethers evaluation of their Titanium complexes in the asymmetric ethylation of benzaldehyde

The preparation by means of different synthetic paths of a series of bis-BINOL and bis-H₈BINOL ligands is described. The ligands consist of two BINOL or H₈BINOL fragments, joined by diverse linkages through the oxygen at the 2′-position of the arylic fragments. These ligands were applied to the Ti(OⁱPr)₄ catalyzed asymmetric alkylation of benzaldehyde with Et₂Zn. The performance of these catalysts is very sensitive to the nature of the ether linkage. The ligand with a propylene link shows better enantioselectivity (ca. 70%) than those with two or four carbon atoms joining the BINOL fragments. Furthermore, using the propylene link, but replacing (R)-BINOL by (R)-H₈BINOL, a significant improvement in the stereoselectivity of the catalysts was achieved (ca. 80% ee in (R)-1-phenylpropan-1-ol). A cooperative effect was observed between the chirality at the BINOL fragment and that of a (S,S)-4,5-bis(methylene)-2,2-dimethyl-1,3-dioxolane link, derived from tartaric acid. When this chiral link combines with two (S)-BINOL fragments, the alkylation of benzaldehyde in toluene produces 70% ee of (S)-1-phenylpropan-1-ol, while the (R)-BINOL derivative ligand with the same link, in identical conditions, yields only 40% ee of the (R)-alcohol.     

A new electronically deficient atropisomeric diphosphine ligand (S)-CF3O-BiPhep and its application in asymmetric hydrogenation

A new electronically deficient atropisomeric diphosphine ligand (S)-CF₃O-BiPhep was synthesized from 1-bromo-3-(trifluoromethoxy)benzene in high yield. The key steps included oxidative coupling with anhydrous ferric chloride and optical resolution by (+)-DMTA. The ligand afforded high performance for Ir-catalyzed asymmetric hydrogenation of quinolines with ee up to 92% and TON up to 25,000. It was also successfully applied to the Pd-catalyzed asymmetric hydrogenation of simple indoles with ee up to 87% and Rh-catalyzed asymmetric 1,4-addition of phenylboronic acid to 2-cyclohexenone with 97% ee.     

Synthesis of novel ferrocenylphosphine-amidine ligands with central and planar chirality and their diastereomeric effect in Pd-catalyzed asymmetric allylic alkylation

Some novel ferrocenylphosphine-amidine ligands with central and planar chirality were prepared from (R,S_p)-PPFNH₂-R 3 and its diastereomer (S,S_p)-PPFNH₂ 3a. The efficiency and diastereomeric impact of these ferrocenylphosphine-amidine ligands in the palladium-catalyzed asymmetric allylic substitution was examined, and up to 96% e.e. with 98% yield was achieved by the use of ligand (R,S_p)-4a with a methyl group in the amidino moiety. The results also indicated that (R)-central chirality and (S_p)-planar chirality in these ferrocenylphosphine-amidine ligands were matched for the palladium-catalyzed asymmetric allylic alkylation.     

A P,N ligand with central and axial chiral elements: synthesis and application in allylic alkylation

Two epimers of 4-({5-[(diphenylphosphino)methyl]-2,2-dimethyl-1,3-dioxolan-4-yl}methyl)-4,5-dihydro-3H-dinaphtho[1,2-e:2′,1′-c]azepine were prepared starting from (2S,3S)-4-amino-2,3-O-isopropylidenebutane-1,2,3-triol and (R)- and (S)-binaphthol. These ligands, in association with Pd(0) gave enantioselectivities up to 89% (S) and 36% (R) ee for the (S_A,4S,5R) and the (R_A,4S,5R) ligands in the alkylation of racemic 1,3-diphenylprop-2-enyl acetate with dimethyl malonate, showing that the binaphthyl moiety is the most important structure in the enantioselective creation of the new stereogenic center.     

Application of the asymmetric hydrogenation of enamines to the preparation of a beta-amino acid pharmacophore

(3R)-3-[N-(tert-Butoxycarbonyl)amino]-4-(2,4,5-trifluorophenyl)butanoic acid 7a has been synthesized by an asymmetric hydrogenation of enamine ester 3 using chiral ferrocenyl ligands I and II in conjunction with [Rh(COD)Cl]₂. The direct reduction of 3 provides amino ester 1b in 93% ee, which was isolated as an (S)-camphorsulfonic acid salt to upgrade the enantiomeric excess to >99%. A more concise approach was developed involving the in situ protection of 1b using di-tert-butyldicarbonate. This approach provided the desired N-Boc amino ester 7b directly from the hydrogenation with 97% ee, which was upgraded to >99% ee upon crystallization.     

A class of readily available optically pure 7,7′-disubstituted BINAPs for asymmetric catalysis

A class of optically pure 7,7′-disubstituted BINAPs have been prepared starting with a catalytic asymmetric oxidative coupling reaction. A general, concise, and straightforward synthetic procedure has been established, and is suitable for all optically pure 7,7′-disubstituted BINAPs 1a-h, regardless of the substituents' structure in the 7,7′-positions. The catalytic potential of this class of ligands has been investigated in the highly enantioselective Rh-catalyzed 1,4-addition of aryl boronic acids to enones (up to 99.8% ee), and Ru-catalyzed asymmetric hydrogenation of simple aromatic ketones (up to S/C=100,000, up to 98% ee) and β-ketoesters (up to S/C=10,000, up to 99.8% ee), respectively.     

Asymmetric transfer hydrogenation of aromatic ketones by Rh(I)/bimorpholine complexes

The asymmetric hydride transfer reduction of aromatic ketones, using a [Rh(cod)Cl]₂ complex as a catalyst and (3S,3′S)-bimorpholine as a chiral ligand, was studied. By varying the amount of ligand, basic co-catalyst and temperature, high yields (>90%) and good enantiomeric excesses of the alcohols (ee up to 83%) were achieved.     

Palladium-catalyzed asymmetric allylic substitution using novel phosphino-ester (PHEST) ligands with 1,1′-binaphthyl skeleton

The asymmetric allylic alkylation of rac-1,3-diphenyl-2-propenyl acetate 1 with dimethyl malonate 2a proceeded smoothly in the presence of lithium acetate, BSA (N,O-bis(trimethylsilyl)acetamide), [Pd(η³-C₃H₅)Cl]₂, and the chiral ligand (R)-i-Pr₂N-PHEST (R)-5a to give the allylic alkylation product (R)-3a in 89% yield with 99% ee. Furthermore, the asymmetric allylic amination of 1 with potassium phthalimide 2c has been carried out using the same ligand to give the allylic amination product (S)-3c in 10% yield with 66% ee.