Planar and central chiral [2.2]paracyclophane-based N,O-ligands as highly active catalysts in the diethylzinc addition to aldehydes

The application of planar and central chiral [2.2]paracyclophane-based N,O-ligands in asymmetric diethylzinc additions to various aldehydes is described revealing an unusual substrate spectrum for the catalysts and their remarkably high activity.     

The asymmetric dialkylzinc addition to imines catalyzed by [2.2]paracyclophane-based N,O-ligands

The first highly enantioselective dialkylzinc addition to imines in the presence of catalytic amounts of N,O-ligands is reported. N-formyl-alpha-(p-tolysulfonyl)benzylamines are the readily available starting materials easily obtained in a one-pot synthesis from benzaldehydes, formamide, and p-tolylsulfinic acid. Upon deprotonation, the sulfinate is eliminated to give the acyl imine. The acyl imines further react with alkylzinc reagents in the presence of catalytic amounts of [2.2]paracyclophane-based N,O-ligands L yielding the alkylated N-(1-phenylpropyl)formamides with excellent yields and enantioselectivities.     

Enantioselective alkynylation of aldehydes catalyzed by [2.2]paracyclophane-based ligands

[reaction: see text] [2.2]Paracyclophane-based ketimine ligands were evaluated as catalysts for the enantioselective addition of in situ-prepared alkynylzinc reagents to aldehydes. The initial high activity and enantioselectivity of these ligands could be improved by an additive screening. The final protocol gives chiral propargyl alcohols in up to >98% ee.     

Enantioselective addition of diethylzinc to benzaldehyde catalyzed by ferrocenic amino-alcohols combining centered and planar chiralities

Diastereomeric ferrocenic amino-alcohols combining three elements of chirality (one of which is a ferrocenic plane) are tested as catalysts in the alkylation of benzaldehyde with diethylzinc. Good to excellent yields and ees were obtained and show correlation between the metallocenic chirality and the configuration of the resulting 1-phenyl-1-propanol.     

Enantioselective addition of diethylzinc to aldehydes catalyzed by optically active 1,4-aminoalcohols

Enantioselective addition reactions of diethylzinc to aldehydes were performed by catalytic reactions with chiral 1,4-aminoalcohols. Optically active 1,4-aminoalcohols were synthesized from (+)-camphor and (−)-fenchone through four steps involving iodine-mediated lactonization of 3-hydroxy acids.     

Theoretical approach towards the understanding of asymmetric additions of dialkylzinc to enals and iminals catalysed by [2.2]paracyclophane-based N,O-ligands

The 1,2- and 1,4-asymmetric additions of dialkylzinc reagents (ZnMe(2) and ZnEt(2)) to cinnamaldehyde and N-formylbenzylimine catalysed by [2.2]paracyclophane-based N,O-ligands were studied with quantum chemical methods. High level LPNO-CEPA/1 (local pair natural orbital coupled electron pair approximation 1) calculations were performed to obtain reliable reaction barriers and binding energies. The calculations supported the experimentally observed selectivities. In the reaction, the alkyl transfer takes place on a binuclear zinc complex. Regioselectivity can be traced back to changes in π-conjugation. Because the less conjugated N-formylbenzylimine is more flexible, it is better suited for 1,4-additions. Moreover, bulky ligands were shown to be important for stereoselectivity. The reason is that the tricyclic motif present in the transition states is sterically less hindered in the anti conformation. Based on the LPNO-CEPA/1 data, a set of popular theoretical methods are validated. Although it was possible to set up a procedure to obtain the stereoselectivities with computationally less demanding methods, this was not possible for the regioselectivity of the reactions.     

Enantioselective addition of diethylzinc to aldehydes catalyzed by 5-cis-substituted proline derivatives

5-Cis-substituted prolinols, prolinamines, and prolinamine sulfonamides proved to be efficient ligands for the enantioselective addition of diethylzinc to aldehydes, providing up to 99% ee. The sense of asymmetric induction can be controlled by the nature of the exocyclic functional group (CPh₂OH vs. CH₂NHR vs. CH₂NHSO₃R). The additional 5-cis substituent exerts a strong beneficial effect on the chirality transfer since it rigidifies the catalyst structure. The stereochemical outcome of the reactions is discussed in detail on the respective transition states.     

Enantioselective addition of diethylzinc to aryl aldehydes catalyzed by novel chiral imino alcohol ligands

The enantioselective alkylation of aryl aldehydes by diethylzinc in the presence of catalytic amounts of several novel chiral imino alcohol ligands, synthesized from the reaction of (R)-2-amino-1-butanol with aromatic aldehydes, was studied. The influence of temperature and ligand structure was investigated and enantioselectivity up to 81% was obtained.     

Enantioselective addition of diethylzinc to aryl aldehydes catalyzed by 1,2,3,4-tetrahydroisoquinoline β-amino alcohol

<正>A highly effective,new chiral 1,2,3,4-tetrahydroisoquinoline catalyst 1 for the diethylzinc addition to aryl aldehydes has been investigated.Using 10 mol%of this chiral catalyst,secondary alcohols can be obtained in up to 87%yield and 99.5%ee under mild conditions.     

Enantioselective addition of diethylzinc to aldehydes catalyzed by N-(9-phenylfluoren-9-yl) beta-amino alcohols

A set of secondary N-phenylfluorenyl beta-amino alcohols have been prepared and evaluated as catalysts for the enantioselective addition of diethylzinc to benzaldehyde. The influence of the substituents on the stereogenic centers of the ligand has been studied, and enantioselectivities up to 97% have been obtained. Those ligands with bulky groups in the carbinol stereocenter and small groups alpha to the nitrogen atom displayed the best catalytic activity and enantioselectivity. The most enantioselective ligand (4e) was found to possess general applicability for the enantioselective addition of diethylzinc to a variety of aromatic and aliphatic aldehydes.     

Enantioselective addition of diethylzinc to aromatic aldehydes catalyzed by C2-symmetric chiral diols

Optically pure C₂-symmetric diols have been synthesized with moderate yields in a straightforward manner, and are used as catalysts in the enantioselective alkylation of aromatic aldehydes with diethylzinc. The addition of diethylzinc to benzaldehyde and sterically hindered 1-naphthaldehyde was achieved with excellent enantioselectivities (97–99% ee) under catalysis with (1R,2R)-1,2-bis(3,5-dibromophenyl)-ethane-1,2-diol and (1R,2R)-1,2-bis(3,5-diphenylphenyl)-ethane-1,2-diol.     

Enantioselective Michael addition of aldehydes to nitroolefins catalyzed by pyrrolidine-HOBt

The oxytriazole catalyst “pyrrolidine-HOBt” developed for asymmetric Michael addition of cyclohexanone to nitroolefins is now evaluated for the asymmetric Michael addition of aldehydes to nitroolefins under similar reaction conditions. The results of this study indicate that, the oxytriazole catalyst “pyrrolidine-HOBt” is equally effective in promoting the Michael addition of aldehydes to nitroolefins on employing benzoic acid as an additive. The desired products, γ-nitrocarbonyl compounds were obtained in good yields and high enantioselectivities.     

Asymmetric addition of diethylzinc to aldehydes catalyzed by a camphor-derived β-amino alcohol

The asymmetric addition of diethylzinc to aromatic and aliphatic aldehydes, including linear aliphatic ones, catalyzed by 2 mol % of β-amino alcohol (1S, 2R)-7,7-dimethyl-1-morpholin-4-yl-bicyclo[2.2.1]heptan-2-ol 10 gave the corresponding secondary alcohols in high yields and with up to 94% ee at ambient temperature after 15 min.     

Enantioselective addition of diethylzinc to aldehydes catalyzed by γ-amino alcohols derived from (+)- and (−)-α-pinene

Primary, secondary and tertiary γ-amino alcohols 4, 5, 7 and 9 and 1,3-diamine 6 were synthesized from (+)- and (−)-α-pinene 1 via chiral N-Boc β-amino ester 3a and carboxamide 3b. The amino alcohols and diamine obtained were applied as chiral catalysts in the enantioselective addition of diethylzinc to aromatic aldehydes, resulting in chiral 1-aryl-1-propanols. The first evidence of the substituent-dependent enantioselectivity of 1,3-amino alcohol catalysts was observed, and the phenomenon interpreted by using molecular modelling at the ab initio level.     

Enantioselective addition of phenylacetylene to aldehydes catalyzed by 1,3-aminophenol ligand

The 1,3-aminophenol ligand (R)-1 was found to be a good catalyst for the zinc phenylacetylene addition to aldehydes. The high activity and enantioselectivity could be improved upon by basic additives. The enantioselectivity follows a linear free energy relationship with higher enantioselectivity obtained for the more reactive aryl aldehydes.     

Enantioselective allylic substitution of Morita–Baylis–Hillman adducts catalyzed by planar chiral [2.2]paracyclophane monophosphines

Planar chiral [2,2]cyclophane monophosphines are efficient catalyst in the reaction of Morita–Baylis–Hillman adducts with phthalimide. The corresponding allylic substituted products were afforded in high yields and in good to moderate ee.     

Enantioselective addition of diethylzinc to aldehydes induced by a new chiral Ti(IV) catalyst

A new chiral titanium reagent, derived from optically active trans-1,2-dicamphorsulfonamidocyclohexane 2a and Ti(OⁱPr)₄, was found to promote the enantioselective addition of diethylzinc to various aldehydes giving rise to the corresponding alcohols in high yields with moderate to high selectivity.     

Enantioselective addition of diethylzinc to aldehydes in the presence of chiral hydrazone and imine ligands

Optically active hydrazone and imine were found to act as effective ligands for enantioselective addition of diethylzinc to aldehydes. This reaction provided optically active secondary alcohols with ee up to 71%.