P-stereogenic P/N hybrid ligands: a remarkable switch in enantioselectivity in palladium-catalyzed asymmetric allylation

Optically active P-stereogenic phosphine/oxazoline bidentate ligands (1) were prepared and applied to palladium-catalyzed allylic substitution of 1,3-diphenyl-1-acetoxy-2-propene with dimethyl malonate. The absolute configuration of the allylation product was remarkably switched by changing a palladium/ligand ratio between 1/1 and 1/2.     

Synthesis of chiral 2-alkyl-8-quinolinyl-oxazoline ligands: reversal of enantioselectivity in the asymmetric palladium-catalyzed allylic alkylation

New chiral 2-alkyl-8-quinolinyl-oxazolines were synthesized from 2-alkyl-8-quinolinecarboxylic acids and enantiomerically pure amino alcohols using a convenient procedure. Enantioselective palladium-catalyzed allylic alkylation of 1,3-diphenyl-2-propenyl acetate with dimethyl malonate in the presence of 2-alkyl-8-quinolinyl-oxazolines provided an alkylation product with an opposite configuration compared to those obtained from unsubstituted quinolinyl-oxazoline ligands.     

Stereoselective synthesis of substituted 1,2-ethylenediaziridines and their use as ligands in palladium-catalyzed asymmetric allylic alkylation

The double addition of organometallic reagents to fused oxazino-oxazines prepared from glyoxal and (S)-phenylglycinol afforded C₂- or C₁-symmetric 1,2-ethylenebis(β-aminoalcohols), depending on the nature of the organometallic reagent. This route was modified by the use of (S)-valinol and phenylglyoxal as starting materials, and by reduction of the oxazino-oxazines by diborane. Cyclization of the β-aminoalcohol moieties gave 1,2-ethylenediaziridines bearing one substituent/stereocenter on the ring carbon and one, two or no substituents/stereocenters in the ethylene tether. These bis(aziridines) were used as ligands in the Pd-catalyzed allylic alkylation of dimethyl malonate. It was established that the substituent(s) in the carbon tether and the configuration of the corresponding stereocenters have limited influence on the enantioselectivity.     

Pd-catalyzed asymmetric reactions using resorcinol- and hydroquinone-based P∗,P∗-bidentate diamidophosphites

Readily available isomeric bisdiamidophosphites with P∗-stereocentres have been prepared using resorcinol and hydroquinone as simple and cheap starting materials. Palladium catalytic systems containing these P∗,P∗-bidentate ligands afforded 99% and 70% ees in asymmetric allylic substitution and desymmetrization processes, respectively. The influence of the precatalyst, substrate, nucleophile, and solvent on the enantioselectivity is discussed.     

Synthesis of novel N,P chiral ligands for palladium-catalyzed asymmetric allylations: the effect of binaphthyl backbone on the enantioselectivity

A series of novel chiral aminophosphine ligands with a 5,5,6,6′,7,7′,8,8′-octahydro-1,1′-binaphthyl backbone (H₈-MAPs) have been synthesized. The application of these ligands in asymmetric allylic substitutions was examined and higher enantioselectivity was observed than that by using the parent ligand (MAP). Under the optimized conditions, the allylation product can be obtained in up to 90.9% ee with H₈-MAP having 3,5-xylyls as chiral inducer. The dramatic effect of the binaphthyl backbone on the enantioselectivity of the reaction can be attributed to the change of the bite angle in H₈-MAPs/Pd complexes.     

Nonsimple relationships between the P-chiral diamidophosphite and the arylphosphine moieties in Pd-catalyzed asymmetric reactions: combinatorial approach and P,P-bidentate phosphine-diamidophosphites

A small family of P,P^∗-bidentate C₁-symmetric ligands containing 1,3,2-diazaphospholidine rings with stereogenic phosphorus atoms has been prepared. Palladium catalytic systems with these phosphine-diamidophosphites afforded 95% and 63% ees in asymmetric allylic substitution and desymmetrization processes, respectively. The influence of the nature of both the phosphine and diamidophosphite moieties of these compounds on the enantioselectivity is discussed. The ‘mixed-ligand approach’ in Pd-catalyzed asymmetric allylation with participation of some new P^∗-monodentate diamidophosphites and PPh₃ is also considered.     

New phosphorus dendrimers with chiral ferrocenyl phosphine-thioether ligands on the periphery for asymmetric catalysis

Chiral ferrocenyl phosphine-thioether ligands have been covalently bound on the periphery of 4 phosphorus dendrimers (generations 1-4) having a cyclotriphosphazene core and on one model compound. These new dendrimers proved to be efficient ligands for the palladium-catalyzed asymmetric allylic substitution reaction (ee up to 93%).     

New dihydroxy bis(oxazoline) ligands for the palladium-catalyzed asymmetric allylic alkylation: experimental investigations of the origin of the reversal of the enantioselectivity

The origin of the reversal of the enantioselectivity in the palladium-catalyzed allylic alkylation of rac-1,3-diphenyl-2-propenyl acetate with dimethyl malonate anion using chiral dihydroxy bis(oxazoline) "BO" ligands derived from (1S,2S)-(+)-2-amino-1-phenyl-1,3-propanediol was investigated. To determine the structural effects of the dihydroxy BO ligand on this unique phenomenon, new homochiral dihydroxy BO ligands were prepared from L-threonine and L-serine and were assessed in the transformation. The results obtained with these novel BO ligands, compared with the one obtained by using the dihydroxy BO ligands derived from (1S,2S)-(+)-2-amino-1-phenyl-1,3-propanediol, reveal that the reversal in the enantioselectivity observed with the dihydroxy BO ligand depends on the structure of the ligand. The effect of different bases used to generate the dimethyl malonate anion was also examined. The results are discussed in terms of the interaction of one hydroxy group in the intermediate pi-allyl palladium complex with the dimethyl malonate anion.     

(N,N) vs. (N,S) chelation of palladium in asymmetric allylic substitution using bis(thiazoline) ligands: A theoretical and experimental study

New thiazoline-containing ligands including non-symmetric bis(thiazolines) and oxazoline-thiazolines were synthesized and then compared to C₂-symmetric bis(thiazolines) in the palladium-catalyzed allylic substitution. The experimental results obtained in this study support the hypothesis of a competition between the (N,N) and the (N,S) palladium chelation, when sterically hindered bis(thiazolines) are used as ligands. A quantum chemical study performed on the Pd-complexes derived from three selected ligands, two C₂-symmetric bis(thiazolines) and one oxazoline-thiazoline, also supports this hypothesis.     

N-Phosphano nitrogen-containing five-membered aromatic chiral α-sulfoxides as new chiral ligands in asymmetric palladium-catalyzed allylic alkylation: stereoelectronic effects of the substituents on the aromatic rings

New chiral ligands, N-diphenylphosphano nitrogen-containing five-membered aromatic compounds bearing chiral sulfinyl groups as the sole chiral source has been developed. The structure of a palladium intermediate derived from the new chiral sulfoxide ligand was determined as a palladium complex with a five-membered chelate ring formed by coordination of the phosphano group and the sulfinyl sulfur atom involved. The stereoelectronic effects of substituents on the aromatic rings are discussed.     

Various P-chiral phosphite-type ligands: their synthesis, stereochemistry and use in Pd-catalysed allylation

A new family of readily available modular phosphite, phosphoramidite and diamidophosphite ligands with P^∗-stereocentres have been prepared from inexpensive optically active precursors. Using these novel ligands, up to 91% ee was achieved in Pd-catalysed asymmetric allylic amination. The catalytic performance is affected greatly by the structure of the phosphocentre of the ligand.     

Screening of a phosphite-phosphoramidite ligand library for palladium-catalysed asymmetric allylic substitution reactions: the origin of enantioselectivity

We have designed a new library of readily available, highly modular phosphite-phosphoramidite ligands for asymmetric allylic substitution reactions. They are easily prepared in one step from commercially available chiral 1,2-amino alcohols. The introduction of a phosphoramidite moiety into the ligand design is highly advantageous for the product outcome. This ligand library affords high reaction rates (TOFs of up to 800 mol (mol h)(-1)) and enantioselectivities (ees of up to 99%) and, at the same time, contains a broad range of disubstituted hindered and unhindered substrate types. NMR study of the Pd-pi-allyl intermediates provide a deeper understanding of the effect of the ligand parameters on the origin of enantioselectivity.     

Palladium complexes of phosphinamine ligands in the intramolecular asymmetric Heck reaction

The synthesis of two novel cyclisation substrates for the asymmetric intramolecular Heck reaction is reported. Their cyclisation, in addition to a known substrate for cis-decalin formation, were tested with palladium complexes of BINAP and heterobidentate oxazoline-containing ligands. In general BINAP provides a more active catalyst system for the range of substrates tested although excellent enantioselectivities of up to 85% were obtained with the P,N ligands studied. A trend was noted whereby the t-leucine-derived oxazoline ligands were more reactive and enantioselective than the valine-derived analogues. Similarly, the diphenylphosphinoferrocenyloxazoline ligands were more reactive and selective than the corresponding diphenylphosphinophenyloxazoline ligands.     

Unexpected reversal of the enantioselectivity using chiral quinolylmethyl- and acridininyloxazolines as ligands for asymmetric palladium-catalyzed allylic alkylation

New chiral quinolylmethyloxazolines and acridininyloxazolines were prepared and assessed in the enantioselective palladium-catalyzed allylic substitution of 1,3-diphenylprop-2-enyl acetate with dimethyl malonate. The introduction of a benzo-fused substituent on the pyridine ring not containing the chiral backbone resulted in the switch of the expected chiral sense of enantioselection of the reaction. Enantiomeric excesses up to 78% were obtained.     

Novel biferrocene-based phosphoramidite ligands: The combination of a rather unexplored chiral backbone and a privileged ligand scaffold

A small library of novel chiral monodentate phosphoramidite ligands, characterized by a dihydroazepine-biferrocene backbone was prepared. In order to obtain this biferrocene substructure, a mild and efficient homocoupling was developed. This allowed to synthesize the dihydroazepine ligand precursor and the phosphoramidite ligands with good overall yields and high enantiomeric excess. These ligands were successfully tested in a rhodium(I)-catalyzed hydrogenation of activated olefins.     

Novel benzoferrocenyl chiral ligands: Synthesis and evaluation of their suitability for asymmetric catalysis

Four benzoferrocenyl phosphorus chiral ligands were conveniently prepared in good overall yields. These ligands were found to be stable in solid form and in solution. Two of the four ligands were resolved by chiral HPLC. Unlike a reported bis(phosphino-η⁵-indenyl)iron(II) complex, in which the indenyl ligands undergo ring flipping through an η¹-intermediate, these two ligands were found to be configurationally stable in solution and in solid state. The suitability of these ligands for enantioselective catalysis was assessed in studies on allylic alkylation reactions. When the two less sterically hindered ligands were used, excellent chemical yields were obtained, but the other two more sterically hindered ones gave lower yields. When the two enantiopure ligands were used, enantioselectivity of up to 51% ee was observed. These findings suggest that benzoferrocene derivatives may be used as chiral ligands for asymmetric catalysis.     

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.     

Chiral diphosphine ligands based on camphor: synthesis and applications in asymmetric hydrogenations

The synthesis of a novel class of atropisomer chiral diphosphine ligands with a bornene framework is described. The new ligands showed in Rh catalyzed asymmetric hydrogenation of α- and β-enamides very high ee’s (more than 99%).     

Tridentate chiral NPN ligands based on bis(oxazolines) and their use in Pd-catalyzed enantioselective allylic substitution in molecular and ionic liquids

NPN ligands based on the bis(oxazoline) skeleton can be prepared by a divergent method, which allows a high modularity both in the type of phosphorous group (phosphinite, phosphate, phosphane) and the substitution in the methylene bridge. The Pd complexes of these ligands can efficiently promote the allylic substitution both in molecular solvents and ionic liquids, with important effect of the nature of ligand, which also controls the partial recovery of the Pd catalyst in ionic liquid.