Organocatalytic Asymmetric Synthesis of 5-Hydroxyisoxazolidines

Key words

domino reaction - 5-hydroxyisoxazolidines - amine catalysis - enantioselectivity

Significance

Here the authors report a highly enantioselective tandem conjugate-addition-hemiacetal-formation reaction between N-protected hydroxylamines and enals leading to an efficient entry to 5-hydroxyisoxazolidines. TMS-protected diphenyl prolinol 1 has been found to be the best catalyst for this reaction. With 20 mol% of catalyst 1, good to high yields (75-94%) and excellent enantioselectivities (er = 95.5:4.5 to 99.5:0.5) are obtained for different enals with N-Cbz- or N-Boc-protected hydroxylamines. In addition, the authors have developed a simple preparation of γ-amino alcohols and β-amino acids from their reaction products.

Comment

5-Hydroxyisoxazolidines are important chiral building blocks because of their utility in the preparation of chiral γ-amino alcohols and β-amino acids. While a Lewis acid catalyzed enantio­selective synthesis of 5-hydroxyisoxazolidines is known, chiral amine catalyzed syntheses have not been reported previously. The in situ oxidation of the products to the 5-isoxazolidinones and two-step conversion into β-amino acids with preservation of optical purity also looks attractive.