Synthesis and reactions of 3-unsubstituted 2-isoxazolines

Abstract

2-Isoxazolines are five-membered heterocyclic compounds that serve as versatile synthetic intermediates in organic chemistry. A number of important functional groups, including 1,3-hydroxycarbonyl compounds, β-hydroxynitriles, 1,3-diamines and α,β-unsaturated carbonyl compounds can be accessed via these heterocycles. The powerful 1,3-dipolar cycloaddition reaction between nitrile oxides and alkenes has long served as the most important method to synthesize 2-isoxazolines. This thesis describes the discovery and development of a new synthetic approach to 3-unsubstituted 2-isoxazolines via subsequent conjugate addition and oxime transfer reactions. Small organic amines combined with various acids were found to catalyze the conjugate additions of oximes and N-hydroxycarbamates to α,β-unsaturated aldehydes. In the case of oximes, the conjugate addition intermediates underwent intramolecular oxime transfer reactions that resulted in the formation of 3-unsubstituted 2-isoxazoline products. Mechanistic studies verified that the isoxazoline formation proceeds via the conjugate addition intermediate and pointed out to acid catalysis in the oxime transfer process. The best catalyst, N-methylanilinium diphenylphosphate, enabled the synthesis of a broad range of racemic 3-unsubstituted 2-isoxazolines from enals with good efficiency. The acid mediated oxime transfer process was combined with a known enantioselective oxime conjugate addition reaction to provide the first enantioselective method for the synthesis of 3-unsubstituted 2-isoxazolines. The 3-unsubstituted 2-isoxazolines can be converted to β-hydroxynitriles by a base catalyzed isomerization reaction. An improved method for the isomerization process was developed, and combining this with the newly developed enantioselective 2-isoxazoline synthesis was shown to enable an easy two-step synthesis of highly enantioenriched β-hydroxynitriles.