Stereoselective synthesis of 1,2,3-triazolyl-functionalized isoxazolidines, via two consecutive 1,3-dipolar cycloadditions, as precursors of unnatural amino acids

1,3-Dipolar cycloaddition of a (-)-menthone-derived nitrone to allyl bromide under microwave irradiation afforded, stereoselectively, the corresponding chiral isoxazolidine in 98% yield. After substitution of the bromine atom by an azide group (98% yield), another 1,3-cycloaddition with various alkynes led to a series of 1,2,3-triazolyl-functionalized isoxazolidines (similar to 85% yield). Removal of the chiral auxiliary under acid-catalysis appeared to be a limiting step toward 5-substituted isoxazolidines, which were isolated in modest yields. For a general and reliable access to 5-(triazolyl)methyl-substituted isoxazolidines, which are new compounds and valuable precursors of unnatural amino acids, performing the CuAAC cycloaddition as the final step is recommended. (C) 2013 Elsevier Ltd. All rights reserved.