Development of a synthetic route towards optically active beta -amino alcohols via epoxids

Abstract

Regioselective aminolysis and other nucleophilic ring opening of styrene oxide and other oxiranes has been of interest as a powerful mean to synthesize β -aminoalcohols, but in general due to the opposing steric and electronic effect of the phenyl substituent in the styrene oxide such synthesis of desired regioisomers has been inefficient. In this study, we found that anionic nucleophiles (N₃; Pht) react with styrene oxide in DMF to provide mainly the β product, especially for pht The β selectivity for ring opening with azide may be increased by addition of crown ether. We have demonstrated how protic solvents can efficiently promote regioselectivity and reactivity of the aminolysis of styrene oxide by a variety of primary and secondary aliphatic and aromatic amines without the need for Lewis acid catalysts. The reactivity and regioselectivity of reactions of styene oxide ring opening with amines in protic solvents largely depends on the acidity of the alcohols which simultaneously activates the oxirane by hydrogen bonding and deactivates the amines by acid-base interaction as determined by pKa of the solvents and pKah of the amines. The lower the pKa of the solvents (higher-acidity), the higher the reaction rate and the higher the regioselectivity for alpha- to beta-attack. Reactions in HFIP, however, did not take place with highly nucleophilic amines as a result of amine-HFIP interaction. The reactivity and regioselectivity of other oxiranes ring opening of other oxiranes including benzyl glycidyl ether, β -naphthyloxirane, and cyclohexene oxide were also investigated. Their results were in parallel with those of styrene oxide. It was also confirmed that the stereochemical information in the ring opening of styrene oxide with morpholine was almost completely preserved for both regioisomers.