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.     

Salicylaldehyde based oxazolidines as catalysts for the asymmetric addition of diethylzinc to aldehydes

A series of oxazolidines have been prepared by condensation of N‐isopropyl norephedrine with a variety of salicylaldehyde derivatives. Despite the stereochemical relationship of (1R,2S)‐norephedrine with (1R,2S)‐ephedrine, the resultant oxazolidines 12‐14 were determined to have a stronger stereochemical relationship with (1S,2S)‐pseudoephedrine based oxazolidines. The resultant oxazolidines were used as catalytic ligands in the addition of diethylzinc to several aldehydes. It was determined that the oxazolidine derivative 12 gave the highest yield and a moderate enantioselectivity.     

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.     

Aziridine sulfides and disulfides as catalysts for the enantioselective addition of diethylzinc to aldehydes

Chiral aziridine sulfides and disulfides were synthesized from readily available and inexpensive R-cysteine by a Mitsunobu reaction; their application in the addition of diethylzinc to aldehydes provides secondary alcohols with up to 99% ee and S-configuration.     

Catalytic asymmetric addition of diethylzinc to aldehydes via chiral,non-racemic β-hydroxy and β-methoxy salicylhydrazone catalysts

(1S,2S)-Pseudoephedrine and (1S,2S)-pseudonorephedrine have been converted to their corresponding hydrazines and condensed with either o-salicylaldehyde or 2-hydroxy-1-naphthaldehyde to afford a series of β-hydroxysalicylhydrazones that have been employed in the asymmetric addition of diethylzinc to 2-naphthaldehyde in up to 56% ee. In addition to this, the Ephedra hydrazines were also condensed with the o-hydroxyacetophenone derivative to form related hydrazones. The use of these corresponding hydrazones in the asymmetric addition reaction with the diethylzinc did not yield improved enantioselectivities. Finally, Enders’ hydrazine was used as a chiral scaffold for the synthesis of β-methoxysalicylhydrazones. These compounds were employed in the asymmetric addition of diethylzinc to a variety of aromatic aldehydes with enantiomeric excesses as high as 68% ee.     

Chiral pyrrolidine derivatives as catalysts in the enantioselective addition of diethylzinc to aldehydes

A series of pyrrolidine derivatives with β-amino alcohol moieties prepared from (S)-proline were found to catalyze the enantioselective addition of diethylzinc to aldehydes to yield optically active secondary alcohols with high enantioselectivities. A mechanism accounting for the configurational change with the bulkiness of chiral ligands is proposed.     

New bis-steroidal axially chiral diols as ligands for the asymmetric addition of diethylzinc to aldehydes

New axially chiral steroidal binaphthols, prepared from estrone, were applied in the form of their Ti-alkoxides as catalysts for the addition of diethylzinc to aldehydes. The addition reactions proceeded with high yields and enantioselectivities up to 86%.     

Salen-derived catalysts containing secondary basic groups in the addition of diethylzinc to aldehydes

A set of modular bifunctional salen catalysts which contain Lewis acid and Lewis base activating groups is described. These groups can be altered independently to control nucleophilic and electrophilic activation of the reacting substrates. These salen-derived catalysts show enhanced reactivity in the addition of diethylzinc to aldehydes with respect to most other salen, amino alcohol, and diamine derived catalysts and reactivity comparable to that of Ti complexes of bis-sulfonamides and diols. Structure: see text.     

Novel thiazolidine derivatives as chiral catalysts in the enantioselective addition of diethylzinc to aldehydes

New chiral thiazolidine derivatives were synthesized conveniently from natural l-cysteine and showed good enantioselectivity (up to 90% ee) in the addition of diethylzinc to aldehydes. The catalytic efficiency of the thiazolidine derivatives is influenced by the different structures of the thiazolidine rings and the bulkiness of R moiety in the ester groups.     

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.     

N-Pyridylmethylephedrine derivatives in the catalytic asymmetric addition of diethylzinc to aldehydes and diphenylphosphinoylimines

N-Pyridylmethyl-substituted Ephedra derivatives were synthesized by either direct alkylation or reductive alkylation of (1R,2S)-norephedrine, (1S,2S)-pseudo norephedrine, and (1R,2S)-ephedrine. These derivatives were then employed in asymmetric addition reactions with diethylzinc and aldehydes and diphenylphosphinoylimines. The use of the diastereomers from the Ephedra family allowed for a systematic evaluation of the contribution of the N-pyridylmethyl.     

2-Pyridylsulfinamides as effective catalysts in the asymmetric alkylation of aldehydes with diethylzinc

Chiral 2-pyridylsulfinamides were shown to be effective catalysts in the alkylation of aryl and alkyl aldehydes with diethylzinc providing the corresponding alcohols in excellent enantioselectivity. Sulfinamide catalysts possessing solitary chirality at the sulfur center produced the product phenethyl alcohol in good enantioselectivity. Diastereomeric sulfinamides possessing chirality at the carbon-bearing nitrogen and at the sulfur of the sulfinamide increased the enantioselectivity of the product alcohols up to >99%. However, there is no effect of the match-mismatch pair of sulfinamide diastereomers on the outcome of the chiral induction of the product phenethyl alcohols. It was conclusively proved that chirality at the sulfur center is mandatory for obtaining good enantioselectivity in the reaction.     

Fructose derived pyridyl alcohol ligands: synthesis and application in the asymmetric diethylzinc addition to aldehydes

Easily available chiral ketones were employed for the synthesis of optically active pyridyl alcohols, which were applied in the asymmetric diethylzinc addition to aldehydes, up to 89.4% e. e. was obtained using D-fructose-derived pyridyl alcohol.     

The synthesis of silica-supported chiral BINOL: Application in Ti-catalyzed asymmetric addition of diethylzinc to aldehydes

Chiral BINOL was covalently anchored on two different pore sized mesoporous silica (SBA-15 (7.5 nm) and MCF (14 nm)). These heterogenized ligands were used in Ti-catalyzed asymmetric addition of diethylzinc to aldehydes. High catalytic activity with excellent enantioselectivity (up to 94% ee) for secondary alcohols was achieved using MCF supported chiral BINOL under heterogeneous reaction conditions. Good to excellent enantioselectivity (ee, 68–91%) was also achieved with various small to bulkier aldehydes. The MCF supported catalyst was reused in multiple catalytic runs without loss of enantioselectivity.     

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.     

Vasicine as tridentate ligand for enantioselective addition of diethylzinc to aldehydes

The first report of natural l-vasicine as tridentate chiral ligand for the enantioselective addition of diethylzinc to a variety of aliphatic and aromatic aldehydes is described. The ligand generates R-isomer of the secondary alcohols upto 98% ee. The quinazoline structure possibly imparts rigidity to the ligand and hence, consistently high enantioselectivity. The importance of the quinazoline ring was also supported by the reaction with other related ligands, partially lacking the structural features, thus resulting in poor enantioselectivity.     

Effective and recyclable dendritic catalysts for the direct asymmetric Michael addition of aldehydes to nitrostyrenes

Direct catalytic enantio- and diastereoselective Michael addition reaction of aldehydes to nitrostyrenes is described using a series of recyclable chiral 2-trimethylsilanyloxy-methyl-pyrrolidine-based dendritic catalysts. Good yields (up to 82%), and high diastereoselectivities (up to syn/anti = 95/5) and enantioselectivities (up to 99% ee) have been obtained.     

Aminosubstituted tert-butylsulfinylferrocenes as a new family of chiral ligands: asymmetric addition of diethylzinc to aldehydes

A ready access to a new family of planar chiral ferrocenes, the (RFc,RS)-2-amino substituted 1-tert-butylsulfinylferrocenes, is described; in the case of the sulfonamide series enantioselectivities of up to 96% were obtained in the addition of Et2Zn to aromatic aldehydes.     

Aromatic motifs in the design of Ephedra ligands for application in the asymmetric addition of diethylzinc to aldehydes and diphenylphosphinoylimines

Using N-benzylephedrine as a model, a collection of N-arylmethylephedrine derivatives has been prepared. These derivatives were prepared by treatment of ephedrine with selected aldehydes to create oxazolidines 8a–e. Reduction of the oxazolidines with lithium aluminum hydride afforded the target β-amino alcohols 9a–e. When applied in the catalytic asymmetric addition of diethylzinc to aldehydes and diphenylphosphinoylimines, the derivatives yielded product enantioselectivities that were comparable to those of N-benzylephedrine. An N-cyclohexylmethylephedrine derivative was also prepared; this β-aminoalcohol did not perform well in the catalytic addition of diethylzinc to 2-naphthaldehyde, thus suggesting that the aromatic motif is important in terms of maintaining a reasonable level of asymmetric induction. Finally, N-benzyl-N-methyl-2-amino-1,2-diphenyl-1-ethanol, an analogue of the N-benzylephedrine derivative, was prepared. This compound yielded comparable enantioselectivities in the catalytic asymmetric addition when employed as a ligand.     

New supported beta-amino alcohols as efficient catalysts for the enantioselective addition of diethylzinc to benzaldehyde under flow conditions

[formula: see text] Polymeric monoliths 10 containing an amino alcohol moiety derived from an industrial waste material represent one of the best ligands for the enantioselective catalytic addition of ZnEt2 to benzaldehyde (99% ee), being recoverable and usable under flow conditions.