Copper-catalyzed enantioselective conjugate addition of Grignard reagents to acyclic enones using monodentate phosphoramidite ligands

Herein, we report efficient catalysts based on phosphoramidites for the asymmetric copper-catalyzed conjugate addition of Grignard reagents to acyclic α,β-unsaturated ketones. A variety of Grignard reagents can be added to aliphatic and aromatic acyclic enones with good yields and moderate to good enantioselectivities.     

Highly enantioselective copper-catalyzed conjugate addition of diethylzinc to cyclic enones with spirocyclic phosphoramidite ligands

A series of spirocyclic phosphoramidite ligands 6-9 with different substituents on the amine moiety were synthesized from the chiral spirocyclic diol (R)-5. These monodentate ligands have been applied in copper-catalyzed conjugate addition of diethylzinc to cyclic enones. Excellent enantioselectivities (up to 99% ee) can be achieved by the use of ligand (R,S,S)-9 bearing stereochemically matched structure derived from the C₂-symmetric (S,S)-bis(α-methylbenzyl)amine.     

Rhodium-catalyzed asymmetric conjugate additions of boronic acids using monodentate phosphoramidite ligands

Monodentate phosphoramidites have been used for the first time as chiral ligands in the Rh-catalyzed enantioselective conjugate addition of arylboronic acids to enones, unsaturated esters, lactones, and nitro alkenes. High reaction rates and ee's up to 89% have been obtained.     

Organocatalytic enantioselective conjugate additions to enones

Conjugate addition reactions of a wide range of nucleophilic enol species with enones, catalyzed by a cinchona alkaloid derived thiourea organocatalyst, have been developed with attending good yields and high enantioselectivities under a mild reaction condition. The general method provides an efficient approach to the preparation of versatile building blocks possessing various functional groups.     

Modular monodentate phosphoramidite ligands for rhodium-catalyzed enantioselective hydrogenation

A new class of monodentate phosphoramidite ligands (DpenPhos) has been developed on the basis of the modular concept for Rh(I)-catalyzed asymmetric hydrogenations of a variety of olefin derivatives, affording the corresponding optically active compounds in excellent yields and enantioselectivities. The ligands have the advantages of facile preparation, tunable structure, and broad scope of substrates in their Rh(I) complex-catalyzed asymmetric hydrogenations.     

Highly enantioselective conjugate addition of diethylzinc to enones using aziridine-functionalized tridentate sulfinyl ligands

Enantiomerically pure tridentate heteroorganic catalysts, containing hydroxyl, sulfinyl, and aziridine moieties, have proven to be highly efficient in the enantioselective conjugate diethylzinc addition to chalcone and cyclohexenone to give the desired products in very high yields (up to 95%) and with ee’s up to 93%. The influence of the stereogenic centers located on the sulfinyl sulfur atom and in the aziridine moiety on the stereochemical course of the reaction is discussed.     

Highly enantioselective conjugate addition of diethylzinc to acyclic enones with fine-tunable phosphite-pyridine ligands

A new series of fine-tunable phosphite-pyridine (P,N) ligands derived from (S)-2-amino-2'-hydroxy-6,6'-dimethyl-1,1'-biphenyl and (S)-2-amino-2'-hydroxy-4,4',6,6'-tetramethyl-1,1'-biphenyl was employed in Cu(I)-catalyzed conjugate addition of diethylzinc to acyclic enones. Excellent enantioselectivities (up to 98% ee) and highly catalytic activities were achieved for a variety of acyclic enones.     

Design and synthesis of new bidentate phosphoramidite ligands for enantioselective copper-catalyzed conjugate addition of diethylzinc to enones

Several thioaryl- and phosphino-phosphoramidite ligands have been synthesized from commercially available β-aminoalcohols. This new family of bidentate ligands are highly active in the enantioselective copper-catalyzed conjugate addition of diethylzinc to both cyclic and acyclic enones showing moderate to good enantiomeric excesses of up to 81%.     

Catalytic enantioselective addition of organometallic reagents to N-formylimines using monodentate phosphoramidite ligands

The asymmetric synthesis of protected amines via the copper/phosphoramidite-catalyzed addition of organozinc and organoaluminum reagents to N-acylimines, generated in situ from aromatic and aliphatic alpha-amidosulfones, is reported. High yields of optically active N-formyl-protected amines and enantioselectivities up to 99% were obtained. Under the reaction conditions, partial oxidation of the phosphoramidite ligand to the corresponding phosphoric amide was detected. A preliminary study on the origin and the effect on the catalytic addition reaction is presented.     

Highly enantioselective copper-catalyzed conjugate addition of diethylzinc to enones using chiral spiro phosphoramidites as ligands

Novel monodentate chiral spiro phosphoramidite ligands have been readily synthesized in good yields from enantiomerically pure 1,1'-spirobiindane-7,7'-diol. The new ligands were highly efficient in the copper-catalyzed conjugate addition of Et(2)Zn to enones with up to 98% enantiomeric excess.     

Highly enantioselective nickel-catalyzed hydrovinylation with chiral phosphoramidite ligands

Readily available chiral phosphoramidites are a promising class of ligands for nickel-catalyzed asymmetric hydrovinylation of vinyl arenes. Cooperative effects are operative when ligands with more than one element of chirality are used. Choosing the proper stereochemistry in each part of the modular ligand system leads to high chemoselectivities and excellent enantioselectivities up to 94%. Moreover, the catalysts derived from these ligands proved extremely efficient and remarkably robust performing up to 8300 catalytic turnovers at an initial turnover frequency beyond 1000 h-1. The large potential for structural variation and their straightforward synthesis make the phosphoramidites currently the best lead structure for catalyst development in this field.     

Biphenol-based phosphoramidite ligands for the enantioselective copper-catalyzed conjugate addition of diethylzinc

Phosphoramidite ligands, based on ortho-substituted biphenols and a chiral amine, induce high enantioselectivities (ee's up to 99%) in the copper-catalyzed conjugate addition of dialkylzinc reagents to a variety of Michael acceptors. Particularly, the best reported ee's were obtained for acyclic nitroolefins.     

Highly enantioselective copper(I)-phosphoramidite-catalysed additions of organoaluminium reagents to enones

Simple phosphoramidite ligands afford good to excellent levels of enantioselectivity in 1,4-additions of AlR3 species to enones; sequential carboalumination-ACA cascades are possible.     

Solid-phase development of chiral phosphoramidite ligands for enantioselective conjugate addition reactions

The development of a method for the optimization of chiral ligands for the steric steering of enantioselective Cu-catalyzed conjugate additions of Znalkyls to enones is described. The method is based on combinatorial principles and solid-phase techniques. It includes the combinatorial synthesis of chiral bispidine-derived ligands embodying a phosphoramidite group on the solid phase and their investigation in immobilized form in the conjugate addition of ZnEt2 to cyclohexenone as test reaction. The best identified ligands were also synthesized separately and investigated in its soluble form. The results obtained for the polymer-bound ligands correctly mirrored the performance of the soluble ligands. The library embodied members giving ee values varying between 3 and 67%. The "positional scanning" approach proved to be invalid for the study of the ligand system, indicating that this approach in general should be applied with care. Taken together, the method allowed for rapid and efficient optimization of the ligands and led to the development of the first enantioselective, Cu-catalyzed conjugate addition reaction with a polymer-bound ligand.     

Highly enantioselective rhodium-catalyzed conjugate addition of arylboronic acids to enones at room temperature

The rhodium-phosphoramidite-catalyzed asymmetric conjugate addition of arylboronic acids to enones proceeds at room temperature using [Rh(OH)(cod)]₂ or [RhCl(cod)]₂/KOH as stable and readily available catalyst precursors.     

Highly enantioselective conjugate addition of AlMe3 to linear aliphatic enones by a designed catalyst

2-Hydroxy-2'-alkylthio-1,1'-binaphthyl compounds are catalytic promoters of the 1,4-addition of AlMe(3) to linear aliphatic enones in THF at -40 to -48 degrees C in the presence of [Cu(MeCN)(4)]BF(4). At ligand loadings of 5-20 mol %, enantioselectivities of 80-93 % are realised for most substrates. To attain these values, the use of highly pure AlMe(3) is mandatory. The presence of methylalumoxane (MAO), derived by hydrolysis, leads to reduced enantioselectivity and a conjugate addition product.     

Copper-catalyzed enantioselective conjugate addition of dialkylzinc reagents to enones with new peptidyl phosphane ligands

Copper catalysts based on new peptidyl phosphane ligands have been developed for enantioselective conjugate additions of dialkylzinc reagents to cyclic enones. Enantioselectivities greater than 97% ee have been observed.     

Phosphonite ligands for enantioselective copper(I)-catalysed conjugate addition of diethylzinc to enones

A wide variety of novel chiral monodentate phosphonite ligands derived from binaphthol and biphenanthrol have been tested as ligands in the copper(I)-catalysed conjugate addition of diethylzinc to enones, resulting in e.e.s of up to 82% for chalcone.