Catalytic asymmetric conjugate addition of grignard reagents to alpha,beta-unsaturated sulfones

A highly efficient method is reported for the asymmetric conjugate addition of Grignard reagents to alpha,beta-unsaturated 2-pyridylsulfones. Using a Cu/TolBinap complex, excellent enantioselectivities and high yields are obtained for a wide variety of aliphatic substrates.     

Catalytic asymmetric addition of dialkylzinc reagents to alpha-aldiminoesters

[reaction: see text] The first catalytic, enantioselective addition of organozinc reagents to alpha-aldiminoesters is described. The use of a Lewis acid/Lewis base containing bifunctional catalyst preorganizes both reactive substrates to promote enantioselective addition over the racemic background reaction and alternative addition modes. Alcohol additives were found to enhance the enantioselection. The addition product was also found to cyclize with remaining substrate to provide imidazolidines.     

Chiral amidophosphane-copper-catalyzed asymmetric conjugate addition of dialkylzinc reagents to nitroalkenes

The copper-amidophosphane-catalyzed asymmetric addition reaction of dialkylzinc reagents with β-aryl and β-alkylnitroalkenes afforded the corresponding nitroalkanes with moderate to good enantioselectivities (54-80% ee). The performance was highly dependent on the reaction procedure where the addition of nitroalkene to the mixture of copper-amidophosphane and dialkylzinc gave higher ee than the addition of dialkylzinc to a mixture of copper-amidophosphane and nitroalkene.     

Unprecedented copper-catalyzed asymmetric conjugate addition of organometallic reagents to alpha,beta-unsaturated lactams

For the first time, an excellent enantioselectivity has been obtained in the conjugate addition of hard organometallic reagents to alpha,beta-unsaturated lactams bearing appropriate protecting-activating groups on the nitrogen.     

Catalytic enantioselective conjugate addition of dialkylzinc reagents to N-substituted-2,3-dehydro-4-piperidones

The first, highly enantioselective, copper/phosphoramidite-catalyzed conjugate addition of dialkylzinc reagents to N-substituted 2,3-dehydro-4-piperidones is described.     

N-Benzyl-l-prolinol: an efficient catalyst for the enantioselective addition of dialkylzinc reagents to N-(diphenylphosphinoyl)imines

Commercially available N-benzyl-l-prolinol has shown to be a very efficient catalyst for the enantioselective addition of dialkylzinc reagents to N-(diphenylphosphinoyl)imines. The use of 0.5 equiv of this β-aminoalcohol as a catalyst leads to the expected addition products in good yields and with ees up to 92% in a reaction time of only 4 h at room temperature. This ee is almost equal to the highest value reported so far using 0.5 equiv of an aminoalcohol as promoter, although the reaction time is much shorter in our case. The amount of the catalyst can be reduced to 0.25 equiv with a slight decrease in the ee. An interesting effect of the addition rate and temperature on the enantioselectivity has been observed.     

Copper-catalyzed enantioselective conjugate addition of dialkylzinc reagents to (2-pyridyl)sulfonyl imines of chalcones

[reaction: see text] The enantioselective catalytic 1,4-addition to alpha,beta-unsaturated ketimines is an unprecedented process. Herein, we document the copper-catalyzed addition of dialkylzinc reagents to (2-pyridylsulfonyl)imines of chalcones. This process occurs rapidly in the presence of a chiral phosphoramidite ligand to afford exclusively the 1,4-addition product. In the case of addition of dimethylzinc, enantioselectivities in the range 70-80% ee are obtained. The presence of the metal-coordinating 2-pyridylsulfonyl group proved to be essential for this reaction to proceed.     

Asymmetric conjugate addition of copper reagents to alpha,beta-unsaturated tert-butanesulfinyl imines

[reaction: see text] Addition of organocuprates to N-sulfinyl alpha,beta-unsaturated imines proceeds in good yields and with good diastereoselectivities. alpha,beta-Unsaturated sulfinyl ketimines and aldimines have both been shown to be suitable substrates for this reaction.     

Polymer-supported l-prolinol-based catalysts for the enantioselective addition of dialkylzinc reagents to N-(diphenylphosphinyl)imines

l-Prolinol-based ligands anchored to Merrifield or Wang-type resins have been shown to form efficient catalysts for the enantioselective addition of dialkylzinc reagents to N-(diphenylphosphinyl)imines. The enantioselectivity achieved with the polymeric catalyst (ee up to 88%) is slightly lower than the one obtained with the homogeneous ligand N-benzyl-l-prolinol, but the polymer-supported ligand presents the advantage of its recyclability: it can be recovered and used in up to six consecutive catalytic cycles with only a slight decrease in the enantiomeric excess. The phosphinamides obtained as addition products can be transformed into the corresponding enantiomerically enriched α-branched primary amines under mild acidic conditions.     

Catalytic enantioselective conjugate addition of cyanide to alpha,beta-unsaturated N-acylpyrroles

A catalytic enantioselective conjugate addition of cyanide to alpha,beta-unsaturated N-acylpyrroles was developed using the chiral gadolinium catalyst generated from Gd(OiPr)3 and d-glucose-derived ligand 2. Generally high enantioselectivity was obtained from a wide range of substrates; substrates with beta-aryl and beta-vinyl substituents and alpha,beta-disubstituted substrates can now be used. Using this reaction as a key step, short-step syntheses of several pharmaceuticals and their lead compounds were achieved, including the beta-phenyl-substituted GABA analogue and pregabalin.     

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.     

Catalytic asymmetric conjugate addition of Grignard reagents to coumarins--synthesis of versatile chiral building blocks

A new protocol for the Cu-catalysed asymmetric conjugate addition of Grignard reagents to coumarins has been developed. The corresponding products are formed in high yields and enantioselectivities. Through a sequential protocol involving conjugate addition followed by nucleophilic ring opening of the chiral enolate, chiral esters and amides are readily accessible.     

Highly versatile enantioselective conjugate addition of Grignard reagents to alpha,beta-unsaturated thioesters

Herein, we report efficient catalysts for the asymmetric copper-catalyzed conjugate addition of Grignard reagents to alpha,beta-unsaturated thioesters. MeMgBr adds to aromatic alpha,beta-unsaturated thioesters with excellent enantioselectivities and moderate to good yields using Josiphos/CuBr and Tol-BINAP/CuI complexes. The use of bulky Grignard reagents leads to unprecedented enantioselectivities in the 1,4-addition to a broad range of aromatic and aliphatic alpha,beta-unsaturated thioesters using Tol-BINAP/CuI. The highest enantioselectivities reported so far for the addition of Grignard reagents to crowded beta-substituted aliphatic substrates are achieved with Tol-BINAP/CuI.     

Enantioselective addition of dialkylzinc reagents to N-(diphenylphosphinoyl)imines catalyzed by β-aminoalcohols with the prolinol skeleton

Several β-aminoalcohols with the prolinol framework are shown to be very efficient catalysts for the enantioselective addition of dialkylzinc reagents to N-(diphenylphosphinoyl)imines. The use of 0.5 equiv of the catalyst leads to the expected addition products in good yields and with ee up to 94% in a reaction time of only 4 h at room temperature. This ee is the highest value reported so far using 0.5 equiv of an aminoalcohol as a promoter. High enantioselectivities are obtained in the addition of dialkylzincs to both aromatic and aliphatic imines. The amount of the catalyst can be reduced to 0.25 equiv with a slight decrease in the ee. A very interesting effect of the addition rate and temperature on the enantioselectivity was also observed.     

An iterative catalytic route to enantiopure deoxypropionate subunits: asymmetric conjugate addition of grignard reagents to alpha,beta-unsaturated thioesters

A highly enantioselective (up to 96% ee) conjugate addition of Grignard reagents, in particular, MeMgBr, to alpha,beta-unsaturated thioesters is provided as well as its application to a diastereo- and enantioselective iterative route to syn- and anti-1,3-dimethyl arrays and deoxypropionate subunits. The versatility of the method is illustrated in the synthesis of (-)-lardolure, a multimethyl-branched insect natural pheromone.     

Catalytic asymmetric conjugate addition of nitroalkanes to cycloalkenones

Nitroalkanes add to cyclic and acyclic enones in an enantioselective manner in the presence of catalytic quantities of L-proline and trans-2,5-dimethylpiperazine as excess additive.     

Enantioselective conjugate addition of dialkylzinc to cyclic enones catalyzed by chiral binaphthyldiamine-copper(I) complexes

The enantioselective conjugate addition of dialkylzinc (R₂Zn) to cyclic enones was examined using chiral binaphthyldiamine-copper(I) catalysts. Under the present reaction conditions, chiral C₂-symmetric [RZn(II)]₂-diamine-Cu(I) complexes were formed from chiral binaphthyldiamine, R₂Zn, and copper(I or II) chloride in situ. The reaction of 2-cyclohexenone with Et₂Zn proceeded smoothly in the presence of the corresponding chiral copper(I) complex (5 mol %) and achiral 2,6-diphenylaniline (10 mol %), and the desired Et-adduct was obtained with up to 76% ee in 95% yield.