Highly enantioselective diethylzinc addition to imines employing readily available N-monosubstituted amino alcohols

An easily accessible chiral ligand 3c, which promoted diethylzinc addition to imines with 96-98% ee, has been found by finely screening N,N-disubstituted and N-monosubstituted amino alcohols. N-monosubstituted amino alcohols, on average, gave slightly higher enantioselectivities than their N,N-disubstituted analogues. These results imply that the restricted and rigid structure of amino alcohol is not the absolute requirement for the highly enantioselective dialkylzinc addition to diphenylphosphinoylimines. [structure: see text]     

Evaluation of chiral oxazolines for the highly enantioselective diethylzinc addition to N-(diphenylphosphinoyl) imines

On the basis of the principle that the incorporation of the structurally rigid and conformationally restricted skeleton in beta-amino alcohols is beneficial to the enantioselective diethylzinc addition to imines, a series of chiral oxazolines, which had been designed and conveniently prepared from commercially available (1S,2S)-2-amino-1-phenylpropane-1,3-diol, were applied in the diethylzinc addition to diphenylphosphinoyl imines to give high yields of 68-84% and excellent ee values of 90-95%. The configuration of the product was controlled by the chirality of the carbon bonded to the hydroxyl group in the oxazoline. Oxazolines bearing a para- or meta-substituted phenyl group generally offered higher enantioselectivity than those containing an ortho-substituted phenyl. The X-ray structures of 4f and 4j, in combination with the proposed transition state, preliminarily explained why oxazolines with a para- or meta-substituent on the phenyl group gave higher enantioselectivities than those bearing an ortho-substituent. This successful example using chiral oxazolines to promote the titled reaction implies that a large family of chiral compounds containing an oxazoline ring moiety have the potential to be developed for promoting the highly enantioselective dialkylzinc addition to N-(diphenylphosphinoyl) imines.     

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]     

Hydroxyamides versus amino alcohols in the enantioselective addition of diethylzinc to benzaldehyde

Two series of structurally related enantiopure isoborneols (10-amino- and 10-amino-10-oxoisoborneols) have been obtained from ketopinic acid and compared as chiral ligands for the enantioselective addition of diethylzinc to benzaldehyde in the absence of Ti(O-i-Pr)₄. The results obtained (chemical yields and enantiomeric excesses) show that identical structural factors (functionalization grade and symmetry group) exert very different effects on both series. The observed differences have been rationalized on the basis of the coordination ability of each ligand type to form the corresponding reactive zinc-chelate catalyst.     

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.     

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.     

New silica-immobilized chiral amino alcohol for the enantioselective addition of diethylzinc to benzaldehyde

[reaction: see text] A readily available chiral amino alcohol has been immobilized on silica by sol-gel synthesis and grafting. The solid prepared according to the latter method led to the best enantioselectivity (77% ee) described for the asymmetric addition of diethylzinc to benzaldehyde using inorganic solids.     

Catalytic enantioselective addition of diethylzinc to trifluoromethyl ketones

A procedure for nucleophilic addition of diethylzinc to trifluoromethyl ketones was developed. The TMEDA-catalyzed method converts aromatic substrates to the corresponding 2-aryl-1,1,1-trifluorobutan-2-ols in up to 99% yield, and it is also applicable to less reactive aliphatic ketones if stoichiometric ligand amounts are employed. The first asymmetric variant producing tertiary alcohols with up to 61% ee when TBOX is used as catalyst is described.     

Highly enantioselective addition of diethylzinc to N-diphenylphosphinylimines using dendritic chiral ligands with hydrocarbon backbones

Chiral dendrimers bearing three or six chiral β-amino alcohols on the hyperbranched hydrocarbon chain-ends act as efficient chiral ligands for the enantioselective addition of diethylzinc to N-diphenylphosphinylimines to afford enantiomerically enriched N-diphenylphosphinylamines with up to 94% e.e.     

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.     

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.     

Modular amino acid amide chiral ligands for enantioselective addition of diethylzinc to aromatic aldehydes

Enantioselective addition of diethylzinc to a series of aromatic aldehydes was developed using a modular amino acid amide chiral ligand (2S)‐3‐phenyl‐N‐((R)‐1‐phenyl‐ethyl)‐2‐(tosylamino)propanamide without using titanium complex. The catalytic system employing 10 mol% of 1g was found to promote the addition of diethylzinc (ZnEt₂) to a wide range of aromatic aldehydes with electron‐donating and electron‐withdrawing substituents, giving up to 82% ee of the corresponding secondary alcohol under mild conditions. Copyright © 2011 John Wiley & Sons, Ltd.     

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 C₁-chiral diphosphites derived from the readily available d-(+)-xylose.     

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.     

Salicylhydrazone ligands for enantioselective addition of diethylzinc to aldehydes

A family of chiral salicylhydrazones was designed and synthesized for application in asymmetric catalysis. The ability of newly prepared binaphthyl-containing salicylhydrazones as the chiral ligand was examined in the addition of diethylzinc to aldehyde, with the desired product obtained in up to 80% ee.     

(+)-Camphor-derived amino alcohols as ligands for the catalytic enantioselective addition of diethylzinc to benzaldehydes

1,7,7-Trimethyl-3-(pyrid-2-ylmethyl)bicyclo[2.2.1]heptan-2-ol 4 and its 2-phenyl, 2-methyl and 2-butyl analogs 5–7 were synthesized, characterized and used as ligands for the addition of diethylzinc to benzaldehydes. Best results were attained with 5 mol% of amino alcohol trans-4 (2-exo,3-endo), in hexane/toluene at rt. Thus, (1S)-1-phenylpropanol was obtained in 96% yield and 89% e.e. An increase of the size of the 2-substituent had a dramatic effect on enantioselectivity and yield.     

Catalytic asymmetric diethylzinc addition to diphenylphosphionyl imines using chiral tert-butanesulfinylphosphine ligands

A class of novel chiral tert-butanesulfinylphosphine ligands were designed and synthesized by a concise two-step route with high yields. High activities and enantioselectivities (up to 94% ee) were achieved when using them in catalytic asymmetric diethylzinc addition to diphenylphosphionyl imines.     

Chiral ferrocenyl amidophosphine ligand for highly enantioselective addition of diethylzinc to N-diphenylphosphinoylimines

The asymmetric addition of diethylzinc to N-diphenylphosphinoylimines afforded N-diphenylphosphinoylamides with enantioselectivity of up to 90% ee in the presence of a catalytic amount of chiral ligand (S)-N-ferrocenoyl-2-[(diphenylphosphino)methyl]-pyrrolidine 13 (7 mol %) and Cu(OTf)₂ (15 mol %). The remarkable improvement of enantioselectivities, as compared with the same type of chiral ligand 6, could be explained by the unique structure of ferrocenyl amidophosphine ligand combining with the reactive intermediate of this addition reaction.     

Catalytic enantioselective addition of diethylzinc to (hetero)aromatic aldehydes

The asymmetric alkylation with diethylzinc of five heterocyclic aldehydes and benzaldehyde (for comparison) has been studied in the presence of two optically active amino alcohols: (S)-2-amino-1-butanol (AB) and (1S,2R)-N,N-dibutylnorephedrine (DBNE). A number of chiral (hetero)aromatic secondary alcohols were synthesized in high yields (95–98%) with enantioselectivity up to 92% enantiomeric excess (ee) in the presence of DBNE catalyst. Optically active thienyl and 4-pyridyl derivatives were prepared for the first time by catalytic asymmetric alkylation. The influence of the amount of DBNE on the enantioselectivity was investigated. In contrast to benzaldehyde, 2-furan- and 2-thiophene-carbaldehydes, in the case of 3- and 4-pyridinecarbaldehydes the ee values depend directly on the catalyst concentration. © 1998 John Wiley & Sons, Ltd.