4-Alkoxycarbonyl- and Aminocarbonyl-Substituted Isoxazoles as Masked Acrylates and Acrylamides in the Asymmetric Synthesis of Δ2-Isoxazolines

• Published in: Journal of organic chemistry 2006-04, Vol.71 (8), p.3221-3231
• Main Authors: Lee, Connie K. Y, Herlt, Anthony J, Simpson, Gregory W, Willis, Anthony C, Easton, Christopher J
• Format: Article
• Language: English
• Subjects: Chemistry; Exact sciences and technology; Heterocyclic compounds; Heterocyclic compounds with n hetero atom and also o and/or s, se, te hetero atoms; Organic chemistry; Preparations and properties
• ISSN: 0022-3263; 1520-6904
• DOI: 10.1021/jo0602569

4-Alkoxycarbonyl and aminocarbonyl-substituted isoxazoles undergo conjugate reduction to give Δ2-isoxazolines on treatment with sodium borohydride and sodium trifluoroacetoxyborohydride, respectively. They are also alkylated at C5 through sonication with secondary and tertiary alkyl iodides in the presence of zinc dust and copper(I) iodide. These reactions are analogous to those observed with acrylates and acrylamides. The behavior is characteristic of the 4-substituted isoxazoles but not the 5-substituted regioisomers. The reductions of 4,5-disubstituted isoxazoles and the C5 alkylations of 4-substituted isoxazoles generally afford trans-4,5-disubstituted isoxazolines. Incorporating chiral auxiliaries into the alkoxycarbonyl group maintains this relative stereoselectivity. It does not provide significant levels of asymmetric induction in the reductions, but the alkylations occur with good levels of stereocontrol at both C4 and C5. Because both enantiomers of the auxiliaries are available, this provides access to either enantiomer of the products, in 93 to ≥98% de. The methodology, therefore, provides a complementary approach to nitrile oxide cycloadditions to alkenes for the asymmetric synthesis of Δ2-isoxazolines.