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.     

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 novel diphosphite ligands derived from d-mannitol and their application in Cu-catalyzed enantioselective conjugate addition of organozinc to enones

A series of novel chiral diphosphite ligands have been synthesized from d-mannitol derivatives and chlorophosphoric acid diary ester, and were successfully employed in the copper catalyzed enantioselective conjugate addition of organozinc reagents diethylzinc and dimethylzinc to cyclic and acyclic enones. The stereochemically matched combination of d-mannitol and (R)-H₈-binaphthyl in ligand 1,2:5,6-di-O-isopropylidene-3,4-bis[(R)-1,1′-H₈-binaphthyl-2,2′-diyl] phosphite-d-mannitol was essential to afford 93% ee for 3-ethylcyclohexanone, 92% ee for 3-ethylcyclopentanone, and 90% ee for 3-ethylcycloheptanone in toluene, using Cu(OTf)₂ as a catalytic precursor. The results clearly indicated that the chiral organocopper reagent exhibited high enantioselectivies for cyclic enones bearing different ring sizes. As for the backbone of this type of ligand, it has been demonstrated that 1,2:5,6-di-O-isopropylidene-d-mannitol was more efficient than 1,2:5,6-di-O-cyclohexylidene-d-mannitol. The sense of the enantiodiscrimination was mainly determined by the configuration of the diaryl phosphite moieties in the 1,4-addition of cyclic enones.     

Enantioselective copper-catalyzed cyclopropanation of styrene by means of chiral bispidine ligands

Enantiopure C₁- and C₂-symmetric bispidine ligands have been synthesized and screened in the asymmetric copper-catalyzed cyclopropanation of styrene. In order to improve the enantiomeric excesses (ee) of the cyclopropane derivatives, the best performing C₁-symmetric diamine ligand was selected for studies on the reaction conditions. The optimized procedure allowed us to obtain up to 91% ee for the cis-cyclopropane derivative and up to 79% ee for the trans one.     

Synthesis of 1,5-P,N-phosphino-sulfoximines through phospha-Michael reaction of alkenyl sulfoximines and their evaluation as ligands in palladium-catalyzed allylic alkylation

We describe a modular synthesis of cyclic and acyclic 1,5-P,N-phosphino-sulfoximines by using a phospha-Michael reaction of the corresponding alkenyl sulfoximines with HPPh₂/KOtBu as key step, which proceeds with medium diastereoselectivity. The palladium-catalyzed allylic alkylation of racemic 1,3-diphenyl allyl acetate with malonate in the presence of a S_SR_CR_C-configured N-benzyl-substituted cyclic phosphino-sulfoximine gave the corresponding alkene with 97% ee in 98% yield. A comparative study of N-substituted phosphino-sulfoximines showed the selectivity of the Pd(0)-catalyst to be dependent not only on the chiral backbone of the ligand but also on the N-substituent and configuration of the sulfoximine group.     

Manganese catalyzed asymmetric transfer hydrogenation of ketones

The asymmetric transfer hydrogenation (ATH) of a wide range of ketones catalyzed by manganese complex as well as chiral P_xN_y-type ligand under mild conditions was investigated. Using 2-propanol as hydrogen source, various ketones could be enantioselectively hydrogenated by combining cheap, readily available [MnBr(CO)₅] with chiral, 22-membered macrocyclic ligand (R,R,R',R')-CyP₂N₄ (L5) with 2 mol% of catalyst loading, affording highly valuable chiral alcohols with up to 95% ee.     

Chiral furanoside phosphite–phosphoroamidites: new ligands for asymmetric catalytic hydroformylation

We have designed a new series of phosphite–phosphoroamidites ligands 1–4 based on a furanoside backbone. These ligands were screened in the Rh-catalyzed asymmetric hydroformylation of styrene, inducing high regioselectivities with 2-phenylpropanal and moderate enantioselectivities (up to 65% e.e.). The results showed that the configuration of the stereogenic carbon atom C(3) at the ligand backbone had remarkable effects on the activity and enantioselectivity. Replacing the tert-butyl substituents with methoxy substituents at the para positions of the biphenyl moieties improved the enantioselectivities. We have also studied the solution structures of HRh(PP)(CO)₂ complexes.     

BINOL-derived diphosphoramidites bearing unsymmetrical 1,2-diamine link and their application in asymmetric catalysis

New P,P-bidentate diastereomeric diphosphoramidite chiral ligands with mixed stereogenic elements and a C₁ backbone symmetry have been prepared from (S_a)- and (R_a)-1,1′-binaphthyl-2,2′-diol (BINOL) and (S)-N-benzyl-1-(pyrrolidin-2-yl)methanamine and are fully characterized. The use of these ligands provides up to 84% ee in the Pd-catalyzed asymmetric allylic substitution of (E)-1,3-diphenylallyl acetate and up to 95% ee in the Rh-catalyzed asymmetric hydrogenation of α-dehydrocarboxylic acid esters. The results indicate that the catalytic performance is highly affected by the axial chirality of the binaphthyl moieties of the ligand and the nature of the solvent.     

Novel C2-symmetric bisoxazolines with a chiral trans-(2R,3R)-diphenylcyclopropane backbone: preparation and application in several enantioselective catalytic reactions

Various chiral bisoxazoline ligands with a chiral trans-(2R,3R)-diphenylcyclopropane backbone have been efficiently synthesized (five examples). These chiral ligands were tested and compared in palladium(0)-catalysed enantioselective allylic alkylations (up to 97% ee), copper(I)-catalysed enantioselective cyclopropanations (up to 89% ee) and aziridinations (up to 90% ee). We observed that the presence of a stereogenic centre on the oxazoline moiety is mandatory in order to obtain acceptable enantioselectivities.     

1,1′-Binaphthyl ligands with bulky 3,3′-tertiaryalkyl substituents for the asymmetric alkyne addition to aromatic aldehydes

The BINOL ligand (R)-2 that contains bulky 3,3′-tertiaryalkyl groups shows improved catalytic properties over the previously reported 3,3′-substituted BINOL ligands in the asymmetric alkyne addition to aromatic aldehydes. It catalyzes the phenylacetylene addition to aromatic aldehydes with high enantioselectivity (86-94% ee) and good yields without using Ti(OⁱPr)₄ and a Lewis base additive. The catalytic properties of several analogs of (R)-2 in the asymmetric alkyne addition to aldehydes have also been studied.     

Substituted salen–Ru(II) complexes as catalysts in the asymmetric cyclopropanation of styrene by ethyl diazoacetate: the influence of substituents and achiral additives on activity and enantioselectivity

A series of alkyl-, halogen- and nitro-substituted salen ligands, 1, have been employed in the asymmetric cyclopropanation of styrene with ethyl diazoacetate by its ruthenium(II) complex with [RuCl₂(p-cymene)]₂ or RuCl₂(PPh₃)₃ as precursors. The introduction of appropriate electron withdrawing groups in the salen ligands benefited the enantioselectivity of the reaction. Some additives, including O-donor, N-donor and P-donor ligands, were added to the reaction to improve the enantioselectivity and activity, and e.e.s of up to 80% were achieved. In the salen/[RuCl₂(p-cymene)]₂ system, the (1R,2S)-isomer was obtained in 80.2% e.e. by using the salen ligand 1f derived from 3,5-dibrominated salicylaldehyde with Et₃N as additive. E.e.s of up to 81.3% for (1S,2R)-isomers were achieved by using the complex 2 synthesized from the nitro-substituted ligand 1m and RuCl₂(PPh₃)₃. A possible mechanism was also discussed.     

The synthesis of chiral amino diol tridentate ligands and their enantioselective induction during the addition of diethylzinc to aldehydes

A series of C₂-symmetric chiral amino diol tridentate ligands 3a–g were prepared from achiral bulky organolithiums, achiral bulky primary amines, and optically active epichlorohydrin (ECH). The prepared C₂-symmetric chiral amino diol tridentate ligands were capable of inducing enantioselectivity in the model reaction of aromatic and aliphatic aldehydes with diethylzinc with an ee of up to 96%. The enantioselectivity can be modulated by adjusting the steric hindrance of the achiral reagents employed in the synthesis of the chiral ligand. The configuration of the addition product depended on the configuration of the amino diol ligands, which can be simply controlled as desired by using the ECH with the desired configuration during the preparation of the ligand.     

Synthesis of diphosphite ligands derived from glucopyranoside and their application in the Cu-catalyzed asymmetric 1,4-addition of organozinc to enones

Novel chiral diphosphite ligands derived from glucopyranoside and H₈-binaphthol were synthesized, and successfully employed in the Cu-catalyzed asymmetric 1,4-addition of organozinc reagents dimethylzinc, diethylzinc, and diphenylzinc to cyclic and acyclic enones with up to 96% ee. The stereochemically matched combination of d-glucopyranoside backbone and (R)-H₈-binaphthyl in the ligand 2,4-bis{[(R)-1,1′-H₈-binaphthyl-2,2′-diyl] phosphite}-phenyl 3,6-anhydro-β-d-glucopyranoside was essential for inducing high enantioselectivity. A significant dependence of stereoselectivity on the type of enones and the ring size of cyclic enones was observed. Moreover, the sense of the enantiodiscrimination of the products was mainly determined by the configuration of the H₈-binaphthyl moieties.     

TARTROL-derived chiral phosphine–phosphite ligands and their performance in enantioselective Cu-catalyzed 1,4-addition reactions

By using (R,R,R,R)-2,3-dimethoxy-2,3-dimethyl-1,4-dioxane-5,6-bis-diphenylmethanol (TARTROL) as a chiral building block, a set of six modular phosphine–phosphite ligands (with a 1,2-phenylene backbone) were synthesized and evaluated in the Cu-catalyzed asymmetric 1,4-addition of Grignard reagents to cyclohexenone. Ligands with bulky substituents at the ortho- and para-positions to the chiral phosphite moiety were found to be the most selective affording the 1,4-addition products with enantioselectivities of up to 84% ee.     

Study of the origin of enantioselectivity in cyclopropanation reactions using the chiral iron carbene complex [(η5-C5H5)(CO)2FeCH[(η6-o-MeOC6H4)Cr(CO)3]]+

During our low temperature NMR studies we observed two rotational isomers of the carbene complex [(η⁵-C₅H₅)(CO)₂FeCH[(η⁶-o-MeOC₆H₄)Cr(CO)₃]]+ (3) with the O–Me group either anti or anti to the Fp moiety. While the Cr(CO)₃ group very effectively shields one face of the carbene complex from attack by the olefin, the presence of anti and anti isomers allows for the formation of both R and S configuration on C-1 of the cyclopropane through a backside or a frontside ring closure mechanism. The reaction of olefin with anti R-3 can result in R-configuration of the cyclopropane carbon C-1 through a frontside closure mechanism, or in S-configuration if backside closure takes place. In a similar manner, anti R-3 may produce S-configuration through frontside closure or R-configuration through backside closure. We previously have shown by crystallography that reaction the R-isomer of 3 with 2-methyl-propene induces predominantly a R-configuration at C-1 of the resulting cyclopropane (RR-(−)-2,2 dimethyl-1-o-methoxyphenyl(tricarbonyl chromium)cyclopropane, whereas the S-carbene results in the corresponding SS isomer. These findings are consistent with cyclopropane formation from the syn isomer through a frontside closure mechanism or from anti isomer through a backside closure mechanism. In the case of [(η⁵-C₅H₅)(CO)₂FeCH[(η⁶-o-MeC₆H₄)Cr(CO)₃]]+ (4), only anti isomer is observed and optical rotation data indicate that the methylcarbene exhibits the same asymmetric induction (i.e., R-carbene yields R-cyclopropane C-1 and S-carbene yields S-cyclopropane C-1) as the methoxy analogue, and the assumption of the anti isomer being the reactive one then implies that the reaction proceeds through a backside closure mechanism rather a frontside mechanism. It is very likely that this preference is also valid for the methoxy substituted complex 4. Our results on 4 indicate that the enantioselectivity of the cyclopropanation reaction is not determined by the relative abundance of the isomers. As the syn isomer is the more abundant one, the anti isomer has to be the more reactive one compared to the syn isomer. Interchange of syn and anti isomers occurs fast compared to the rate of reaction of the carbene with olefin. The fast rate of interchange of syn and anti isomers relative to the rate of reaction with olefin precludes the direct observation of any differential reactivity form a change in the syn to anti ratio in the NMR spectrum. However, the in general lower ee values observed for 3 compared with 4 are consistent with the fact that the reactive isomer is less abundant in this case. Our data thus show that enantioselectivity of cyclopropanation with “chiral at carbene” complexes is controlled by the higher reactivity of the anti isomer and occurs through a backside ring closure mechanism.     

Chiral thiophosphoramide catalyzed asymmetric aryl transfer reactions for the synthesis of functional diarylmethanols

In this investigation, chiral thiophosphoramide 3d was easily prepared from chiral (1R,2R)-1,2-diphenylethylenediamine and then applied as an efficient chiral ligand in the catalytic asymmetric arylation reactions of various aromatic aldehydes. The corresponding diarylmethanol products were produced with good to excellent yields (up to 98%) and enantioselectivities (up to 94%). The recovery of chiral ligand 3d could be as high as 96%.     

Chiral (Diphosphonite)platinum Complexes in Asymmetric Hydroformylation

The chiral diphosphonite ligand (11bR,11′bR)‐4,4′‐(9,9‐dimethyl‐9H‐xanthene‐4,5‐diyl)bis[dinaphtho[2,1‐d:1′,2′‐f][1,3,2]dioxaphosphepin] ((R,R)‐XantBino; (R)‐ 1 ), based on a rigid xanthene backbone, was applied in the Pt/Sn‐catalyzed hydroformylation of styrene ( 4a ), 4‐methylstyrene ( 4b ), vinyl acetate ( 4c ), and allyl acetate ( 4d ), by using a Pt/Sn ratio of 1 : 1. High ee of up to 80% were observed, along with good regioselectivities towards the desired branched aldehydes. For styrene, an interesting inversion in the stereoselection process was observed at elevated temperatures, and a mechanism is proposed considering the temperature dependence of the regioselectivity. The complex [PtCl₂{(S,S)‐XantBino}] ((S)‐ 2 ) was characterized by X‐ray crystal‐structure analysis, revealing an unusual out‐of‐plane ligand coordination of the metal fragment. The complex [PtCl(SnCl₃){(R,R)‐XantBino}] ((R)‐ 3 ) was characterized by means of ³¹P‐NMR spectroscopy.     

Triosmium clusters with bridging terpenic thioureato-like ligands

The reaction of acetone-4-(2-methoxy-phenyl)thiosemicarbazone with triosmium cluster Os₃(CO)₁₁(NCMe) results in the formation of the cluster with the μ₂ chelate-bridging ligand coordinated by S and N¹ atoms, which was studied by X-ray diffraction analysis. Reaction of (3aR, 3bR, 4aR, 5aS)-5a-hydroxy-3,4,4-trimethyl-3a,3b,4,4a,5,5a-hexahydrocyclopropa[3, 4]cyclopenta[1,2-c]pyrazole-1-carbothioic acid amide with Os₃(CO)₁₁(NCMe) gives rise to the complex with the bridging ligand coordinated by sulphur atom. Further transformation of the complex in hot benzene results in tautomeric rearrangement of the organic ligand and the cleavage of the pyrazolinol cycle to form an open chain tautomer. Unusual silica gel induced oxidative cleavage of the cyclopropane ring in the open chain derivative and epoxidation of cycloalcane C-C bond are observed on the air.     

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.     

One-step synthesis of paclitaxel side-chain precursor: benzamide-based asymmetric aminohydroxylation of isopropyl trans-cinnamate

A highly enantioselective (up to 97% ee) one-step synthesis of paclitaxel side chain precursor, (2R,3S)-isopropyl 3-benzamido-2-hydroxy-3-phenylpropionate, has been achieved by osmium-catalyzed asymmetric aminohydroxylation of isopropyl trans-cinnamate with N-bromobenzamide as an oxidant/nitrogen source in the presence of (DHQ)₂PHAL as a chiral ligand. Simple recrystallization of crude product (containing regioisomer and diol) from ethyl acetate gave the enantiomerically pure product.