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.     

Malonate-type bis(oxazoline) ligands with sp hybridized bridge carbon: synthesis and application in Friedel-Crafts alkylation and allylic alkylation

A series of simple and new C₂-symmetric diphenylmethylidene malonate-type bis(oxazoline) ligands were synthesized and applied to the Friedel-Crafts reaction and allylic alkylation. The Cu(II) complex of ligand 4b bearing the benzyl group afforded good to excellent enantioselectivity for the F-C adducts (up to >99% ee) between indole and alkylidene malonate, and the palladium complex of ligand 4c bearing the phenyl group afforded excellent enantioselectivity (up to 94% ee) for the allylic alkylation product.     

Allylic alkylations catalyzed by palladium-bis(oxazoline) complexes derived from heteroarylidene malonate derivatives

A series of simple heteroarylidene malonate-type bis(oxazoline) ligands 4 and 5 were applied to the palladium-catalyzed allylic alkylation reaction, and the ligand 4a bearing a phenyl group afforded excellent enantioselectivity (up to 96% ee) for the allylic alkylation product. Other substrates were also examined, giving the allylic alkylated products in high yield but with poor ee values.     

Polymer-Supported Chiral Monodentate Phosphoramidites in Palladium-Catalyzed Allylic Alkylation Reactions

A new and simple method for immobilization of monodentate chiral ligand on the cheap resin has been developed. A series of resin-immobilized phosphoramidite ligands based on BINOL and TADDOL backbones have been synthesized and characterized with gel-phase NMR. The immobilized ligands have been applied to the Pd-catalyzed asymmetric allylic alkylation of 1,3-diphenyl-2-propenyl acetate. Among four ligands, the supported bulky monodentate phosphoramidite ligand based on TADDOL backbone afforded the chiral product with ee up to 65%; moreover, this ligand could be recycled for 3 times without substantial decrease of the conversion and ee.     

Asymmetric hydrogenation of imines catalyzed by iridium complexes with phosphine-phosphite ligands: importance of backbone flexibility

Chiral phosphine-phosphites provide an alternative class of ligands for the iridium catalyzed enantioselective hydrogenation of imines. Optimization of ligand structure has afforded enantioselectivities up to 84% ee in the reduction of N-aryl imines. A significant influence of backbone nature on enantioselectivity has also been observed.     

Asymmetric palladium-catalyzed annulation of benzene-1,2-diol and racemic secondary propargylic carbonates bearing two different substituents

The palladium-catalyzed cyclization of benzene-1,2-diol with various racemic secondary propargyl carbonates having no acetylenic hydrogen in the presence of (R)-Binap as the chiral ligand afforded the two regioisomers of the corresponding 2,3-dihydro-1,4-dioxin derivatives in quite good yields, and also in enantioselectivities going from 40 to 97%. The cyclization of benzene-1,2-diol with methyl (R)-1-methyl-3-phenylpro-2-yn-1-yl carbonate in the presence of dppb as the achiral ligand afforded 2-benzylidene-3-methyl-2,3-dihydro-1,4-benzodioxine as the major product with 15% ee. The use of (R)-Binap as the chiral ligand afforded the (+) cyclized compound in 45% ee, when the (−) enantiomer was obtained with 77% ee in the presence of (S)-Binap. All the results suggest that in this case the enantioselective step is the diastereoselective protonation of the palladium-carbene intermediates.     

Chiral ferrocenyl amidophosphine ligand for highly enantioselective addition of diethylzinc to N-diphenylphosphinoylimines

The asymmetric addition of diethylzinc to N-diphenylphosphinoylimines afforded N-diphenylphosphinoylamides with enantioselectivity of up to 90% ee in the presence of a catalytic amount of chiral ligand (S)-N-ferrocenoyl-2-[(diphenylphosphino)methyl]-pyrrolidine 13 (7 mol %) and Cu(OTf)₂ (15 mol %). The remarkable improvement of enantioselectivities, as compared with the same type of chiral ligand 6, could be explained by the unique structure of ferrocenyl amidophosphine ligand combining with the reactive intermediate of this addition reaction.     

From tropos to atropos: 5,5′-bridged 2,2′-bis(diphenylphosphino)biphenyls as chiral ligands for highly enantioselective palladium-catalyzed hydrogenation of α-phthalimide ketones

A class of atropisomeric diphosphine ligands with a wide range of dihedral angles has been developed. X-ray study of the Pd(II) complexes of these ligands showed that as the bridge length increased, the dihedral angles and the ligand bite angles increased as well, while an excessive increase in bridge length had a reverse effect. It was found that there was a correlation between the ligand dihedral angles and the enantioselectivity in Pd-catalyzed asymmetric hydrogenation of α-phthalimide ketones, and excellent enantioselectivities of up to 99% ee were afforded.     

Application of chiral mixed phosphorus/sulfur ligands to enantioselective rhodium-catalyzed dehydroamino acid hydrogenation and ketone hydrosilylation processes

Chiral mixed phosphorus/sulfur ligands 1-3 have been shown to be effective in enantioselective Rh-catalyzed dehydroamino acid hydrogenation and ketone hydrosilylation reactions (eqs 1, 2). After assaying the influence of the substituents at sulfur, the substituents on the ligand backbone, the relative stereochemistry within the ligand backbone, and the substituents at phosphorus, ligands 2c (R = 3,5-dimethylphenyl) and 3 were found to be optimal in the Rh-catalyzed hydrogenation of a variety of alpha-acylaminoacrylates in high enantioselectivity (89-97% ee). A similar optimization of the catalyst for the Rh-catalyzed hydrosilylation of ketones showed that ligand 3 afforded the highest enantioselectivities for a wide variety of aryl alkyl and dialkyl ketones (up to 99% ee). A model for asymmetric induction in the hydrogenation reaction is discussed in the context of existing models, based on the absolute stereochemistry of the products and the X-ray crystal structures of catalyst precursors and intermediates.     

Rhodium-catalyzed asymmetric hydrogenation of functionalized olefins using monodentate spiro phosphoramidite ligands

Novel chiral monodentate phosphorus ligands, SIPHOS, were conveniently synthesized from 1,1'-spirobiindane-7,7'-diol. The Rh complexes of SIPHOS can catalyze the hydrogenation of alpha-dehydroamino esters in mild conditions, providing alpha-amino acid derivatives in up to 99% ee. Enamides and beta-dehydroamino esters can also be hydrogenated in good to excellent enantioselectivities (up to 99% and 94% ee, respectively). The SIPHOS ligand with smaller alkyl groups on the N-atom afforded higher enantioselectivity. The X-ray analysis of single crystal showed that the structure of Rh/SIPHOS catalyst is [Rh(COD)((S)-SIPHOS-Me)(2)](+), which clarified the configuration of the catalyst with the monodentate chiral phosphorus ligand in Rh-catalyzed asymmetric hydrogenation. A positive nonlinear effect in the relationship of the optical purities of ligand and product was observed in the hydrogenation of dehydroamino acid derivatives. The kinetic study of hydrogenation showed that the reaction is zero order in the concentration of substrate and first order in the concentration of Rh catalyst and the hydrogenation pressure. The rate of hydrogenation decreased when the Rh/L ratio changed from 1:1 to 1:4.     

Organocatalytic asymmetric alpha-bromination of aldehydes and ketones

The first organocatalytic enantioselective alpha-bromination of aldehydes and ketones is presented; a C2-symmetric diphenylpyrrolidine catalyst afforded the alpha-brominated aldehydes in good yields and up to 96% ee, while ketones were alpha-brominated by a C2-symmetric imidazolidine in up to 94% ee; furthermore, the organocatalytic enantioselective alpha-iodination of aldehydes is also demonstrated to proceed with up to 89% ee.     

Rh-catalyzed asymmetric hydrogenation using a furanoside monophosphite second-generation ligand library: scope and limitations

The ligand design of one of the most successful monophosphite ligand classes in Rh-catalyzed hydrogenation was expanded upon by introducing several substituents at the C-3 position of the furanoside backbone. A small but structurally important library of monophosphite ligands was developed by changing the substituents at the C-3 position of the furanoside backbone and the substituents/configurations at the biaryl phosphite group. These new furanoside monophosphite ligands were evaluated in the Rh-catalyzed asymmetric hydrogenation of α,β-unsaturated carboxylic acid derivatives and enamides. The results show that the effect of introducing a substituent at the C-3 position of the furanoside backbone on the enantioselectivity depends not only on the configuration at the C-3 position of the furanoside backbone and the binaphthyl group but also on the substrate. Thus, the new ligands afforded high to excellent enantioselectivities in the reduction of carboxylic acid derivatives (ee’s up to >99.9%) and moderate ee’s (up to 67%) in the hydrogenation of enamides.     

Pd‐Catalyzed Asymmetric Intramolecular Arylative Dearomatization of para‐Aminophenols†

Asymmetric arylative dearomatization reactions of para‐aminophenols are realized by a Pd‐catalyst consisting of a TADDOL (α,α,α',α'‐tetraaryl‐2,2‐disubstituted 1,3‐dioxolane‐4,5‐dimethanol)‐derived chiral phosphoramidite ligand. The tetracyclic products bearing the key skeleton of Erythrina alkaloids are afforded in reasonable yields (up to 73%) with good to excellent enantioselectivity (up to 97% ee). Concise total synthesis of (–)‐3‐demethoxyerythratidinone is achieved by employing this method as the key step.     

Enantio- and Regioselective Copper-Catalyzed 1,2-Dearomatization of Pyridines

A copper-catalyzed dearomative alkynylation of pyridines is reported with excellent regio- and enantioselectivities. The synthetically valuable enantioenriched 2-alkynyl-1,2-dihydropyridine products afforded are generated from the readily available feedstock, pyridine, and commercially available terminal alkynes. The three-component reaction between a pyridine, a terminal alkyne, and methyl chloroformate employs copper chloride and StackPhos, a chiral biaryl P,N- ligand, as the catalytic system. Under mild reaction conditions, the desired 1,2-addition products are delivered in up to 99 % yield with regioselectivity ratios up to 25 : 1 and enantioselectivities values of up to 99 % ee. Activated and non-activated terminal alkynes containing a wide range of functional groups are well tolerated. Even acetylene gas delivered mono-alkynylated products in high yield and ee. Application of the methodology in an efficient enantioselective synthesis of the chiral piperidine indolizidine, coniceine, is reported.     

Carbenoid Pathways in Copper‐Catalyzed Intramolecular Cyclopropanations of Phenyliodonium Ylides

The enantioselectivity of the copper‐catalyzed intramolecular cyclopropanation of allyl diazomalonates and the corresponding phenyliodonium ylides was investigated with a series of chiral, non‐racemic ligands. The reaction of 6b in the presence of the bis[dihydrooxazole] ligand Xa in refluxing 1,2‐dichloroethane proceeded to 8b with an enantiomer excess (ee) of up to 72% under optimized conditions. In contrast, 8b resulting from reaction of ylide 7b with the same ligand, but in CH₂Cl₂ at 0°, had an ee of only 30%. With other ligands, diazomalonate 6b reacted with a lower enantioselectivity than ylide 7b , however. The intramolecular cyclopropanation of the acetoacetate‐derived phenyliodonium ylide 15b afforded 16b with 68% ee with ligand Xa , but the corresponding diazo compound was unreactive when exposed to chiral copper catalysts. The observation of asymmetric induction in the Cu‐catalyzed reactions of the ylides 7 and 15 is consistent with a carbenoid mechanism; however, the discrepancy of the enantioselectivities observed between diazomalonate 6b and ylide 7b suggests a competing unselective pathway for cyclopropanation outside of the coordination sphere of copper.     

t-Bu-QuinoxP* ligand: applications in asymmetric Pd-catalyzed allylic substitution and Ru-catalyzed hydrogenation

The potential of the t-Bu-QuinoxP* ligand (1) as a chiral ligand in asymmetric synthesis was examined. The ligand exhibited good to excellent asymmetric induction in Pd-catalyzed asymmetric allylic substitution of 1,3-diphenyl-2-propenyl acetate (up to 98.7% ee) and in Ru-catalyzed asymmetric hydrogenation of ketones (up to 99.9% ee).     

Synthesis of heteroarylidene malonate derived bis(thiazolines) and their application in the catalyzed Friedel–Crafts reaction

A series of novel heteroarylidene malonate derived bis(thiazoline) ligands 1 and 2 were synthesized and applied to a Friedel-Crafts reaction between indole and alkylidene malonate. The Cu(OTf)₂ complex of ligand 2b bearing a benzyl group afforded moderate to excellent enantioselectivity for the adducts (up to >99% ee).     

Concurrent induction of two chiral centers from symmetrical 3, 4-disubstituted and 3,3,4-trisubstituted 4-pentenals using Rh-catalyzed asymmetric cyclizations

Asymmetric cyclization of symmetrical 3,4-disubstituted and 3,3, 4-trisubstituted 4-pentenals was studied using Rh-complexes with chiral ligands. The cyclization of symmetrical 4-pentenals 4a,b by a neutral Rh[(R)-BINAP]Cl afforded cis-3,4-disubstituted (4R)-cyclopentanones 9a,b of >95% ee in 25-31% yields; on the other hand, the cyclization of 4a-c by a cationic Rh[(R)-BINAP]ClO(4) afforded trans-3,4-disubstituted (4S)-cyclopentanones 10a-c of >95% ee in 70-81% yields. All stereoisomers could be stereoselectively made by the selection of a neutral or cationic Rh-complex, and (R)- or (S)-BINAP ligand. The Rh-catalyzed cyclization could be applied to the construction of cyclopentanones 17 and 18 bearing a chiral quaternary carbon. The cyclization by the cationic Rh[(R)-BINAP]ClO(4) afforded the optically active trans-3,3, 4-trisubstituted cyclopentanones 18a-c of 92-95% ee in 75-83% yields. The catalytic cycle was also studied by using deuterium aldehyde, and the tentative mechanisms of the enantio- and diastereoselection were proposed.     

Enantioselective Michael reaction of malonates to nitroolefins catalyzed by bifunctional organocatalysts

Michael reaction of malonates to nitroolefins with chiral bifunctional organocatalysts, bearing both a thiourea and tertiary amino group, afforded Michael adducts with high yields and enantioselectivities (up to 95%, up to 93% ee).     

Simple chiral sulfonamide primary amine catalysed highly enantioselective Michael addition of malonates to enones

A chiral sulfonamide primary amine-organocatalysed, highly enantioselective Michael addition of malonates to enones has been developed. This reaction afforded the corresponding products in excellent yields (up to 99%) and excellent enantioselectivity (up to 99% ee).