Asymmetric addition of diethylzinc to aromatic aldehydes by chiral ferrocene-based catalysts

A series of chiral C₁- and C₂-symmetric ferrocenyl Schiff bases (1a-c), ferrocenyl aminoalcohols (2a), ferrocenylphosphinamides (2b-c), 1,1′-ferrocenyl-diol (3), and 1,1′-ferrocenyl-disulfonamide (4) were prepared and employed as base catalysts or as ligand for titanium(IV) complexes in the asymmetric addition of diethylzinc to aromatic aldehydes. High enantioselectivity up to almost 100% ee was achieved for the alkylation of benzaldehyde and p-methoxybenzaldehyde with 1 or 3. In contrast, however, the β-aminoalcohol (2a) and phosphinamides (2b and c) that are ubiquitous classes of base catalysts for this reaction proved inefficient in our hands, regardless of the types of substrates or reaction conditions. Comparative studies show that there exist various reaction parameters governing not only chemical yields but also optical yields. These include steric and electronic environment of the substrate, the solvent, the reaction temperature, and the nature of the ferrocene moieties.     

Stereocontrolled enantioselective addition of diethylzinc to aldehydes using new chiral aminoalcohols

The new chiral β-aminoalcohols of indolinylmethanols ( 1 ) and their reduced derivatives ( 2 ) were synthesized from (S)-indoline-2-carboxylic acid. Both (R) and (S) enantiomers of the optically active secondary alcohols have been successfully obtained in high enantiomeric excess from the stereoselective addition of diethylzinc to the aldehydes catalyzed by the chiral aminoalcohols ( 1 and 2 ). The sense of the asymmetric induction and the degrees of enantioselectivities turned out to be highly dependent on the structure of the catalysts: The presence of the catalyst 1 afforded the (S)-configuration of the corresponding alcohols; on the other hand, the presence of 2 afforded the (R)-configuration of the alcohols in high enantiomeric selectivity.     

Synthesis of chiral plane-extended pyridyl alcohols for the enantioselective addition of diethylzinc to aldehydes

Enantiomerically pure pyridyl alcohols, 1 and 2, were prepared from readily available racemic pyridyl alcohol 3 and applied to the enantioselective addition of diethylzinc to aldehydes resulting in moderately high enantiomeric excess (90%) in the case of benzaldehyde. In this study the first example of an alteration in the configuration of the product upon change of a non-chiral and non-coordinating part of the catalyst was 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.     

Catalytic enantioselective addition of diethylzinc to aldehydes using aziridine based chiral ligands

The readily available ferrocenyl substituted aziridinylmethanol 1 (FAM-1) was used as a chiral catalyst in the diethylzinc addition reaction to aromatic and aliphatic aldehydes to give secondary alcohols in high yields and up to 99% enantiomeric excess at room temperature. The catalyst can be recovered and used without losing its activity.     

Synthesis of chiral ferrocenyl aziridino alcohols and use in the catalytic asymmetric addition of diethylzinc to aldehydes

A series of novel chiral ferrocenyl aziridino alcohols 5a–i were conveniently synthesized from L-serine and ferrocenecarboxaldehyde. These compounds have been used as chiral catalysts in the asymmetric addition of diethylzinc to aldehydes and the effects of the ligand structures on the enantioselectivity was studied. Enantioselectivities up to 98.8% have been obtained.     

Chiral ferrocenyl amino alcohols for enantioselective additions of diethylzinc to aldehydes

Optically active ferrocenyl amino alcohols have been prepared from commercially available l-alaninol, l-leucinol and l-valinol. They have been utilized as chiral ligands in the catalytic addition of diethylzinc to aldehydes. The influence of the substituents on the stereogenic centers of the ligand has been studied. Enantioselectivities up to 95% have been obtained.     

Efficient asymmetric addition of diethylzinc to aldehydes using C2‐novel chiral pyridine β‐amino alcohols as chiral ligands

A series of novel C₂‐symmetric chiral pyridine β‐amino alcohol ligands have been synthesized from 2,6‐pyridine dicarboxaldehyde, m‐phthalaldehyde and chiral β‐amino alcohols through a two‐step reaction. All their structures were characterized by ¹H NMR, ¹³C NMR and IR. Their enantioselective induction behaviors were examined under different conditions such as the structure of the ligands, reaction temperature, solvent, reaction time and catalytic amount. The results show that the corresponding chiral secondary alcohols can be obtained with high yields and moderate to good enantiomeric excess. The best result, up to 89% ee, was obtained when the ligand 3c (2S,2′R)‐2,2′‐((pyridine‐2,6‐diylbis(methylene))bisazanediyl))bis(4‐methyl‐1,1‐diphenylpentan‐1‐ol) was used in toluene at room temperature. The ligand 3g (2S,2′R)‐2,2′‐((1,3‐phenylenebis(methylene))bis(azanediyl))bis(4‐methyl‐1,1‐diphenylpentan‐1‐ol) was prepared in which the pyridine ring was replaced by the benzene ring compared to 3c in order to illustrate the unique role of the N atom in the pyridine ring in the inductive reaction. The results indicate that the coordination of the N atom of the pyridine ring is essential in the asymmetric induction reaction. Copyright © 2014 John Wiley & Sons, Ltd.     

Axially chiral tridentate isoquinoline derived ligands for diethylzinc addition to aldehydes

The synthesis and resolution of new tridentate isoquinoline-derived ligands has been developed. The key steps in the synthetic sequence include successive, chemo-selective Suzuki-Miyaura cross-couplings of 1,3-dichloroisoquinoline with suitable arylboronic acids. The new ligands prepared in this manner were resolved either via molecular complexation with N-benzylcinchonidinium chloride as with 1-[3-(2-hydroxyphenyl)isoquinolin-1-yl]naphthalen-2-ol or via chromatographic separation of its epimeric camphorsulfonates as for 1,3-bis-(2-hydroxynaphthalen-1-yl)isoquinoline. 4-tert-Butyl-2-chloro-6-[1-(2-hydroxymethylnaphthalen-1-yl)isoquinolin-3-yl]phenol was resolved by chiral semi-preparative HPLC. The application of these ligands in the diethylzinc addition to aldehydes was investigated. In certain cases, the desired secondary alcohols were obtained in high yield with excellent enantiomeric excess (ee?>?99%) at low catalyst loading (1?mol%).     

Novel polymer-supported chiral catalysts for the asymmetric addition of diethylzinc to aldehydes

Newly synthesized polymer-supported chiral amino alcohol catalysts 5a and 5b have been proved to be effective for the enantioselective addition of diethylzinc to aldehydes, affording the corresponding sec-alcohols in moderate enantiomeric excesses with good to excellent yields. The recycled catalyst could be reused in the same reaction without significant deterioration in performance.     

The synthesis of chiral amino diol tridentate ligands and their enantioselective induction during the addition of diethylzinc to aldehydes

A series of C₂-symmetric chiral amino diol tridentate ligands 3a–g were prepared from achiral bulky organolithiums, achiral bulky primary amines, and optically active epichlorohydrin (ECH). The prepared C₂-symmetric chiral amino diol tridentate ligands were capable of inducing enantioselectivity in the model reaction of aromatic and aliphatic aldehydes with diethylzinc with an ee of up to 96%. The enantioselectivity can be modulated by adjusting the steric hindrance of the achiral reagents employed in the synthesis of the chiral ligand. The configuration of the addition product depended on the configuration of the amino diol ligands, which can be simply controlled as desired by using the ECH with the desired configuration during the preparation of the ligand.     

Enantioselective addition of diethylzinc to aldehydes in the presence of chiral aprotic ligands

Optically active amino thiocyanate derivatives of (−)-norephedrine were found to act as effective aprotic ligands for enantioselective addition of diethylzinc to aldehydes. This reaction provided optically active secondary alcohols with ee up to 96%.     

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.     

3-Aminoquinazolinones as chiral ligands in catalytic enantioselective diethylzinc and phenylacetylene addition to aldehydes

A series of readily known enantiomerically pure 3-aminoquinazolinones 1a–d were synthesised from easily accessible chiral pool α-hydroxy acids and α-amino acids in only four steps without any requirement of chromatography. These quinazolinones were examined as chiral ligands for catalytic enantioselective diethylzinc and phenylacetylene additions to aldehydes. For enantioselective alkylations, the effects of temperature, solvent, diethylzinc and ligand criteria were analysed, and the desired chiral alcohols were obtained in up to 86% ee. 3-Aminoquinazolinones 1a–d were also shown to be very useful ligands in enantioselective alkynylations of aldehydes. Based upon the optimised conditions, the corresponding propargylic alcohols were obtained in up to 94% ee.     

Efficient asymmetric addition of diethylzinc to aldehydes using 3‐hydroxyazetidine derivatives as chiral ligands

A new series of chiral 3‐hydroxyazetidines has been prepared from (S)‐1‐(4‐methoxyphenyl)ethylamine. These ligands have shown excellent catalytic activities and enantiomeric selectivities in asymmetric addition of diethylzinc to aromatic aldehydes. Copyright © 2008 John Wiley & Sons, Ltd.     

Synthesis of Chiral N-Ferrocenylmethylaminoalcohols and their Application in Enantioselective Addition of Diethylzinc to Aldehydes

Three chiral N-ferrocenylmethylaminoalcohols were synthesized from readily available natural L-valine, leucine and phenylanine, and used as chiral ligands in the enantioselective addition of diethylzinc to aldehydes.     

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 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]     

Enantioselective addition of diethylzinc to aldehydes using immobilized chiral BINOL–Ti complex on ordered mesoporous silicas

A chiral (S)-BINOL ligand has been covalently grafted on ordered mesoporous silicas—MCM-41 and SBA-15 and the resulting inorganic–organic hybrid materials used as chiral auxiliaries in Ti-promoted enantioselective addition of diethyl zinc to aldehydes under heterogeneous conditions. These heterogeneous catalysts showed promising activity and enantioselectivity. The catalyst having a larger pore diameter with capping of free silanol moiety with trimethylsilyl (TMS) group was found to be more active with enantioselectivities up to 81% being achieved. The catalyst worked well up to three cycles with retention of enantioselectivity after washing with 10% HCl in methanol.