Synthesis and reactions of 3-unsubstituted 2-isoxazolines

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Kemian tekniikan korkeakoulu | Doctoral thesis (article-based)
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Kemian laitos
Department of Chemistry
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Verkkokirja (1006 KB, 62 s.)
Aalto University publication series DOCTORAL DISSERTATIONS , 24/2011
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.
2-isoxazoline, enantioselective synthesis, oxime transfer, amine catalysis, acid catalysis
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  • [Publication 1]: Antti Pohjakallio and Petri M. Pihko. 2008. A versatile entry to 3-unsubstituted 2-isoxazolines. Synlett, volume 2008, number 6, pages 827-830. © 2008 Georg Thieme Verlag. By permission.
  • [Publication 2]: Antti Pohjakallio and Petri M. Pihko. 2009. Enantioselective synthesis of 2-isoxazolines by a one-flask conjugate addition/oxime-transfer process. Chemistry - A European Journal, volume 15, number 16, pages 3960-3964.
  • [Publication 3]: Antti Pohjakallio, Petri M. Pihko, and Ulla M. Laitinen. 2010. Synthesis of 2-isoxazolines: Enantioselective and racemic methods based on conjugate additions of oximes. Chemistry - A European Journal, volume 16, number 37, pages 11325-11339.
  • [Publication 4]: Antti Pohjakallio, Petri M. Pihko, and Jun Liu. 2010. Base-catalyzed isomerization of 2-isoxazolines enables a two-step enantioselective synthesis of β-hydroxynitriles from enals. The Journal of Organic Chemistry, volume 75, number 19, pages 6712-6715.