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.     

Copper(II)-catalyzed enantioselective conjugate addition of nitro esters to 2-enoyl-pyridine N-oxides

A highly enantioselective Michael addition of nitro esters to 2-enoyl-pyridine N-oxides was developed by using chiral copper catalysts. The Michael addition products can be obtained in high yields and with up to 96% ee.     

Highly enantioselective Michael addition of isobutyraldehyde to nitroalkenes

The asymmetric catalytic Michael reaction between isobutyraldehyde and nitroalkanes with chiral primary amine thiourea organocatalysts was described. In the presence of 10 mol % of 1-((1R,2R)-2-amino-1,2-diphenylethyl)-3-benzylthiourea, the desired products were achieved in excellent enantioselectivity (up to>99% ee) with up to 98% yield.     

Diastereo- and enantioselective conjugate addition of 3-substituted oxindoles to enones via bifunctional catalysts

This paper presents a synthetically challenging vicinal quaternary-tertiary C–C forming reaction of 3-substituted oxindoles and chalcones by a simple aryl substituted bifunctional thiourea catalyst. The reactions work with a broad range of chalcones, giving chiral 3,3′-substituted oxindoles type compounds with adjacent quaternary-tertiary stereocenters in high yields (up to 99%), very good dr (up to >98:2) and very good ee (up to 96%).     

Highly enantioselective addition of linear alkyl alkynes to linear aldehydes

It is discovered that the use of biscyclohexylamine (Cy₂NH) as an additive can greatly enhance the enantioselectivity for the reaction of linear alkyl alkynes with linear aldehydes. The combination of (S)-BINOL (20 mol %), Cy₂NH (5 mol %), ZnEt₂ (2 equiv), and Ti(OⁱPr)₄ (0.5 equiv) catalyzes the reaction at room temperature in diethyl ether solution with 81-89% ee and 57-77% yield.     

Catalytic enantioselective borane reduction of arylketones with pinene-derived amino alcohols

Both cis- and trans-1,2-amino alcohols 5 and their N-alkylated derivatives 6 were prepared from (−)-α-pinene 7 as chirality source and utilized in asymmetric borane reduction of arylketones 12 employing a one-pot multi-substrate screening. The oxazaborolidine catalysts were generated in situ from amino alcohols 5 and 6 and trimethyl borate.     

Copper-catalyzed asymmetric propargylic etherification of oximes promoted by chiral tridentate P,N,N-ligand

A copper-catalyzed asymmetric etherification of propargylic acetates with oximes as O-nucleophiles has been developed. The employment of a chiral tridentate P,N,N-ligand proved to be crucial for the success of the reaction. The reaction features a broad scope on either reaction partners and led to a variety of etherification products in good yields and enantioselectivities.     

Novel bifunctional sulfonamides catalyze an enantioselective conjugate addition

A new bifunctional organocatalyst with a novel structural and functional motif has been developed. This bifunctional sulfonamide organocatalyst was used in the conjugate addition of 1,3-dicarbonyl compounds (13) to β-nitrostyrenes (12). Yields up to 91% and enantiomeric excesses up to 79% were obtained in this reaction. This catalyst activates both 13 via its basic moiety and 12 through hydrogen bonding.     

Chiral bispyridylamide metal complexes as catalysts for the enantioselective addition of TMSCN to aldehydes

The use of (1R,2R)-N,N′-bis(2-pyridinecarboxyamido)-1,2-diphenylethane metal complexes as catalysts for the enantioselective addition of trimethylsilyl cyanide to aldehydes is described. Enantioselectivities up to 70% ee were obtained with a Ti(IV) catalyst. Complexes with Zr(IV), Sc(III), Yb(III) and Cu(II) afforded less selective catalysts. For the Zr(IV) complex, a rate and selectivity enhancement was observed when adding 0.5 equiv. of water with respect to the catalyst. Studies of the metal complexes involved in the reaction were carried out by means of ¹H NMR spectroscopy. A Zr complex was shown by X-ray crystallography to exhibit distorted octahedral coordination, with the four nitrogen atoms of the doubly deprotonated ligand essentially in one plane.     

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.     

Copper-catalyzed enantioselective conjugate addition of triethylaluminum to 2-cyclopentenone

Bidentate phosphites were prepared starting from BINOL, H₈-BINOL or 3,3′, 5,5′-tetra-tert-butyl-2,2′-biphenol. Utilization of these ligands in the copper-catalyzed enantioselective conjugate addition of triethylaluminum to 2-cyclopentenone afforded 3-ethylcyclopentanone in up to 94.0% ee.     

Enantioselective conjugate addition of diethylzinc to acyclic enones using a copper phosphino-phenol complex as catalyst

Newly designed phosphino-phenol 1c was found to be an efficient chiral auxiliary for copper-mediated asymmetric conjugate addition of diethylzinc to acyclic enones. High enantioselectivity up to >99% ee was achieved in the reaction of acyclic α,β-enones.     

Catalytic enantioselective intermolecular reductive aldol reaction to ketones

We describe the first example of a catalytic enantioselective intermolecular reductive aldol reaction. Three types of reactions were studied: (1) reactions between acetophenone and methyl acrylate; (2) reactions between symmetric ketones and β-substituted α,β-unsaturated esters; and (3) reactions between acetophenone derivatives and an allenic ester. Although only moderate enantioselectivity was obtained in the first reaction type, high to excellent enantioselectivity was realized in the enantio-induction at the α-position in the second reaction type and at the δ-position in the third reaction type. Specifically, the third reaction type afforded the corresponding tertiary alcohols with up to 99% ee. Pre-activation of the nucleophile by silyl enolate formation is not necessary in these one-pot catalytic enantioselective reductive aldol reactions.     

Catalytic enantioselective aryl transfer: asymmetric addition of boronic acids to aldehydes using pyrrolidinylmethanols as ligands

Pyrrolidinylmethanols, easily accessible from readily available (S)-proline, were applied in zinc-catalyzed addition of arylboronic acids to aromatic aldehydes; the reaction was found to proceed in excellent yields and high enantioselectivities (up to 98% ee).     

Copper-catalyzed enantioselective conjugate addition of grignard reagents to acyclic enones

A highly enantioselective Cu-catalyzed addition of Grignard reagents to acyclic aliphatic enones is described. In the presence of 5 mol % of CuBr.SMe2 and 6 mol % of JosiPhos diphosphine aliphatic enones react with Grignard reagents to provide beta-substituted linear ketones with high yields, regio-, and enantioselectivities.     

Bidentate ligand-catalyzed enantioselective addition of RZnX to benzaldehyde

Enantioselective addition of RZnX (R = alkyl, X = Cl, OAc) was studied using chiral chelating agents, particularly metal-alkoxides. Moderate enantioselectivity was achieved in the presence of magnesium-TADDOLate using RZnOAcMg(OAc)Br as the alkylating agent.