Solution and solid phase synthesis of isoxazoline containing heterocycles

An efficient, multi-gram synthesis of a spiroisoxazolinoproline-based amino acid requiring minimal purification, delivering good cis:trans diastereoselectivity (ca. 1:4) and providing good yields is reported. Surface bound studies of the reduction of an aryl-nitro group in the presence of an isoxazoline ring with tin(II) dichloride dihydrate were undertaken to confirm the stability of the isoxazoline ring. Full derivitization of this spiroisoxazolinoproline-based amino acid scaffold was performed during the synthesis of a library. This work is described in Chapter 1.;Condensation of 3-chloropentane-2,4-dione with thioamides gives 1-(thiazol-5-yl)ethanones and subsequent Wittig olefination followed by nitrile oxide 1,3-dipolar cycloaddition to the resulting prop-1-en-2-yl moiety delivers racemic 5-(thiazol-5-yl)-4,5-dihydroisoxazoles. Biological evaluation of these diheterocycles showed promising fungicidal activity. This work is described in Chapter 2.;A route to 2-(4,5-dihydroisoxazol-5-yl)-1,3,4-oxadiazoles has been developed. Acid hydrazide starting materials underwent an EDC-mediated coupling with acrylic acid derivatives to form diacyl hydrazides. Cyclodehydration of the diacyl hydrazide in the presence of triphenylphospine and hexachloroethane gave 1,3,4-oxadiazoles. Lastly, in situ nitrile oxide formation and subsequent 1,3-dipolar cycloaddition to the exomethylene moiety delivered 2-(4,5-dihydroisoxazol-5-yl)-1,3,4-oxadiazoles. Biological evaluation of these diheterocycles showed weak insecticidal activity. This work is described in Chapter 3.;A library of novel, propeller-shaped dispirotriheterocyclic isoxazolinopiperidinochromanones is reported. Each rigid dispirotriheterocycle was prepared in five linear steps from commercially available tert-butyl 4-oxopiperidine-1-carboxylate plus various derivatives of 1-(2-hydroxyphenyl)ethanone, benzaldehyde oxime, and carboxylic acids. Computational chemistry was employed to analyze the three-dimensional geometries of these dispirotriheterocycles as well as to generate chemoinformatic bioavailability data. X-ray crystallographic structure determination verified the regioselectivity of the nitrile oxide 1,3-dipolar cycloaddition reaction. This work is described in Chapter 4.;A route to spiroisoxazolinopiperidinylbenzamides has been developed. N-Boc-4-piperidone underwent a Wittig olefination and Boc deprotection followed by an ipso substitution with 4-fluoro-3-nitrobenzoic acid to yield the starting scaffold in excellent yields. Diversification of the acid with primary amines, followed by in situ nitrile oxide formation and subsequent 1,3-dipolar cycloaddition to the exomethylene moiety delivered the spiroisoxazolinopiperdine intermediates. Reduction of the arylnitro followed by acylation or reductive amination yielded the spiroisoxazolinopiperidinylbenzamide library. This work is described in Chapter 5.