Synthesis Of Novel C₂-Pyridine β-amino Alcohol Ligands And Their Asymmetric Induction In The Addition Of Diethylzinc To Aldehydes

Abstract:A great many of natural drugs, spiceries and pesticides contain the structure of chiral secondary alcohols. There are two methods for preparation of chiral secondary alcohols:catalytic asymmetric addition of organozinc to aldehydes and asymmetric reduction of prochiral ketones. The asymmetric addition of diethylzinc to aldehydes is the major method for synthesis of chiral secondary alcohol.Ephedrine and its derivatives are commonly used as chiral ligands and played an important role in asymmetric addition reaction, the new chiral ephedrine analogues have been designed, synthesized and used in the asymmetric addition reaction. In the paper, novel chiral ligands for the addition of diethylzinc to aldehyde were designed and prepared and their asymmetric induction werte investigated. Thus, starting from readily available chiral amino acid as the chiral pool,2,6-pyridine dicarboxylic acid underwent esterification, reduction followed by oxidation to form2,6-pyridinedicarboxaldehyde, whereas chiral amino acid underwent esterification, Grignard reaction to provide a series of β-amino alcohols (la-1f). By the condensation of2,6-pyridine dialdehyde with β-amino alcohols (1a-1f), the Schiff bases (2a-2f) were obtained, after the further reduction using NaBH(OAc)3, novel2,6-novel pyridine-containing β-amino alcohols3a-3f were achieved together with an additional no pyridine-containing ligand3g to make a comparison with ligand3c in the asymmetric addition reaction. All the novel compounds were charecterized by1H NMR,13C NMR as well as IR. The optimization of reaction condition was also carried out. As a result, the yields reached50%.The asymmetric inductions were performed by the reactions of diethylzinc and benaldehyde. The results suggest that the ligand3c (2S,2’R)-2,2’-((pyridine-2,6-diylbis(methylene))bis(azanediyl))bis(4-meth yl-1,1-diphenylpentan-l-ol) could catalyze the addition reaction efficient-ly, high yield (83%) and enantioselectivity (86%) are obtained under moderate conditions that room-temperature and its catalytic results are far better than the ligand3g ((2S,2’R)-2,2’-((1,3-phenylenebis(methyle ne))bis(azanediyl))bis(4-methyl-1,1-diphenylpentan-1-ol)). This result indicates that the coordination of N atom of pyridine ring is essential in the asymmetric induction reaction. Besides, the ligands containing CH2group at thea-carbon have good induction activity. The study of universality shows that the ligand3c is beneficial to induce the addition of diethylzinc to non-heterocyclic aldehydes with good stereoselectivi-ty(ee up to89%) Finally, reaction mechanism was preliminary discussed.