Copper-Catalyzed Conjugate Addition Of Diethylzinc Research Articles

Stereoselective Synthesis of Densely Functionalized Pyrrolidin-2-ones by a Conjugate Addition/Nitro-Mannich/Lactamization Reaction

Copper-catalyzed conjugate addition of diorgano zinc reagents to nitroacrylate 1 followed by a subsequent nitro-Mannich reaction and in situ lactamization leads to an efficient one-pot synthesis of 1,3,5-trisubstituted 4-nitropyrrolidin-2-ones (5). The versatility of the reaction is shown for a wide range of N-p-(methoxy)phenyl protected aldimines 3 derived from alkyl, aryl, and heteroaryl aldehydes. The densely functionalized pyrrolidin-2-ones 5 are isolated as single diastereoisomers (40 examples, 33-84% yield). An enantioselective copper-catalyzed conjugate addition of diethylzinc led to highly crystalline products that could be recrystallized to enantiopurity in high yield. A range of successful chemoselective transformations were investigated, which widens the applicability of the pyrrolidn-2-ones as stereochemically pure building blocks for further organic synthesis.

The effects of solvent on switchable stereoselectivity: copper-catalyzed asymmetric conjugate additions using D2-symmetric biphenyl phosphoramidite ligands

A highly enantioselective copper-catalyzed conjugate addition of diethylzinc to acyclic aromatic enones was developed with phosphoramidite ligands bearing a D(2)-symmetric biphenyl backbone. This type of reaction demonstrated that toluene and THF solvents can completely reverse the absolute configuration of the products, thus simplifying the process of accessing either enantiomer (S: 92% ee, 94% yield; R: 99% ee, 96% yield).

Bisphenylene homologues of BINOL-based phosphoramidites: synthesis, stereostructure, and application in catalysis

Bis-ortho- and bis-meta-phenylene homologues of BINOL-based N,N-dimethylphosphoramidites were prepared from the corresponding diols by treatment with hexamethyltriaminophosphane. Phosphoramidites derived from bulkier secondary amines were synthesized by 5-phenyl-1H-tetrazole-promoted amine exchange. All the phosphoramidites were obtained as single diastereomers. Their configurations at the C(naphthyl)–C(phenyl) axes were determined by vibrational circular dichroism (VCD) spectroscopy. Preliminary testing of the ligands in copper-catalyzed conjugate addition of diethylzinc to acyclic enones and nitrostyrene gave the corresponding products in up to 74% ee.

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%.

Novel chiral bis(oxazolines): synthesis and application as ligands in the copper-catalyzed enantioselective conjugate addition of diethylzinc to enones

Novel chiral C 2-symmetric bis(oxazolines) were prepared from tartaric acid. They were applied as ligands in the copper-catalyzed conjugate addition of diethylzinc to chalcone and 2-cyclohexenone. Maximum enantiomeric excesses of 50% and 53% were obtained, respectively. The sense of induction was found to depend on the configuration of the stereogenic centre in the oxazoline ring, and not on the stereogenic centres of the 1,4-dioxane backbone.

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 C 2-symmetric ( S, S)-bis(α-methylbenzyl)amine.

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-catalyzed conjugate addition of diethylzinc to nitroalkenes.

Copper-catalyzed asymmetric conjugate addition of diethylzinc to nitroalkenes using new chiral monodentate phosphoramidite ligands proceeds with high enantioselectivity up to 99% ee. [reaction: see text]

A new chiral 2-sulfonylamino-2′-phosphino-1,1′-binaphthyl ligand for highly enantioselective copper-catalyzed conjugate addition of diethylzinc to benzylideneacetones

A new axially chiral phosphine–sulfonamide ligand was prepared via a chiral component (R)-2-amino-2′-diphenylphosphinyl-1,1′-binaphthyl, which was conveniently synthesized through a new route involving hydrolysis of (R)-2-cyano-2′-phosphinyl-1,1′-binaphthyl followed by Hofmann rearrangement of the amide group. The new ligand was found to be very efficient in copper-catalyzed enantioselective conjugate addition of diethylzinc to acyclic enones such as benzylideneacetones, providing very high enantioselectivity up to 99% ee.

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.

Chiral diphosphites derived from d-glucose in the copper-catalyzed conjugate addition of diethylzinc to cyclohexenone

A series of diphosphite ligands 1– 3 derived from readily available d-(+)-glucose and bisphenol or binaphthol derivatives have been applied as ligands in the Cu-catalyzed 1,4-addition of diethylzinc to cyclohexenone. Excellent reaction rates (TOF>1200 h −1) and good enantioselectivities (e.e. of up to 84%) were achieved. The modular nature of these ligands allows easy systematic variation in the configuration of the stereocenters (C(3), C(5)) at the ligand backbone and in the biaryl substituents, so the optimum configuration for maximum enantioselectivity in the asymmetric 1,4-addition can be determined. The results obtained show that the enantioselectivity induced by the ligand depends strongly on the absolute configuration of the C(3) stereogenic centre, while the sense of the enantiodiscrimination is predominantly controlled by the configuration of the biaryl groups of the phosphite moieties.

Enantioselective copper-catalyzed conjugate addition of diethylzinc to enones using new chiral P,N ligands composed of ( S)-2-alkyl-2-aminoethylphosphines and α-substituted pyridines

New P,N ligands prepared from ( S)-2-alkyl-2-aminoethylphosphines and α-substituted pyridines are efficient chiral ligands for the copper-catalyzed conjugate addition of diethylzinc to 2-cyclohexen-1-one and chalcone. The best result (90–91% ee) for the cyclohexenone was obtained with Cu(OTf) 2 (0.7–1 mol%) and a P,N ligand 4 derived from ( S)-1-(diphenylphosphino)-3-methyl-2-butanamine and 6-methylpyridine-2-carboxaldehyde.

Highly active and enantioselective copper-catalyzed conjugate addition of diethylzinc to cyclohexenone using sugar derivative diphosphites

High enantioselectivity combined with unprecedented high catalytic activity (81% ee and TOF≈1200 h −1) are achieved in the copper-catalyzed 1,4-addition of diethylzinc to 2-cyclohexenone with new C 1-chiral diphosphites derived from the readily available d-(+)-xylose.