Isoxazoline-3-carboxylic acids

Chandrasekhar et al. synthesized a library of 15 isoxazolines 61 from ni-troalkanes 13 and polymer-bound electron-deficient olefins 60 under Hassner conditions (B0C2O, DMAP) (Scheme 18) [112]. The isoxazoline carboxylic acids 62 were then liberated from the resin on treatment with TFA in CH2CI2 (1 4). 

Isoxazoles, isoxazolines, isoxazolidines and benzisoxazoles are all thermally stable, distilling without decomposition, but the stability of the system depends on the substitution pattern. For example, aminoisoxazoles distill unchanged but the isoxazole carboxylic acids usually decompose at or above their melting points without giving the corresponding isoxazole. 

The treatment of 3-benzoyl-2-phenylisoxazolidine with strong base generated an aldehyde and a ketimine <74X1121). Under these conditions dimethyl 2-a-methoxyisoxazolidine-3,3-dicarboxylic acid (186) produced isoxazoline-2-carboxylic acid. Reaction of the monomethyl amide (187) gave the corresponding isoxazoline-2-carboxamide (Scheme 60). CD was used in the conformational studies <79X213). 

When compound (443), which contains alkene and alkyne moieties, was reacted with benzonitrile oxide, both an isoxazoline (444) and isoxazole (445) were produced, with the former predominating. Oxidation of (444) with permanganate produced 3-phenyl-2-isoxazoline-5-carboxylic acid (446) (67ZOR82i). The reaction of 1-trimethylsilylbut-l-yne-3-ene produced only a compound which reacted at the alkenic unit. Oxidation of the adduct also produced (446) (68ZOB1820). These reactions are shown in Scheme 102. 

The synthesis of isoxazolines usually takes the most thermodynamically favorable course to yield solely the more stable isomer. However, cinnamic acids (38) give not only isoxazoline-4-carboxylic acids (39) but also, as a by-product, the less stable isoxazoline-5-carboxylic acids (40)" which on heating undergo retro-addition. ... 

Hydrogenolytic cleavage of isoxazolines has also proved useful in preparation of -dihydroxy ketones and -hydroxy carboxylic acids (47). The isoxazolines were prepared by a [3 -1- 2] cycloaddition. 

Namely, allyl alcohol is successively treated with diethylzinc, (R,R) dipropyl tartrate, and 4-methoxybenzohydroximinoyl chloride (163) to afford the enantiomeric isoxazoline alcohol 166, which under the Jones oxidation conditions affords the corresponding carboxylic acid derivative (167). Treatment of compound 167 with hydroxylamine-O-triflate followed by tri-fluoroacetic acid gives rise to the desired enantiomeric 165 in high excess enantiomeric yield. The synthesis of other isosteric analogues of 165 was reported in the same paper. None of the isosteric analogues exhibits LpxC inhibitory and antibacterial activities [103]. 

The methyl and benzyl esters of proline were also used as chiral auxiliaries in respective acrylamides, but the isoxazoline cycloadducts were obtained with only poor to modest stereoselectivity (189,190). The related indoline-2-carboxylic acid derivative 33, however, showed excellent ability to direct nitrile oxide attack, favoring one rotamer (Scheme 6.37), and thereby leading to 3-phenylisoxazoline-5-carboxamide... 

Isoxazoline-4-carboxylic acid, N-methyl-5-oxo ethyl ester... 

The same technique was also applied to the synthesis of a 10 member Ugi 4CC-derived solution library, where the fluorous tag was embedded into the carboxylic acid structure. The synthesis of the tag and the library synthetic scheme is shown in Figure 7.22. The tag was derived from a bromosilyl perfluorinated compound (C10F21CH2CH2, rather than C6Fi3CFI2CF[2, as for the isoxazolines) reacted with an orthothiobenzoate [164] and further elaborated with trivial chemistry. The library was produced using classical Ugi 4CC conditions and the tag detachment was obtained via treatment with... 

Saponification of the isoxazoline ring and subsequent decarboxylation of compound (243) afforded the 5-cyano-l,4-dihydropyridine-3-carboxylic acid ester (244) <89JOC5585>. If the acid (243) was first reesterified with ( — )-menthol, the resulting diastereomeric esters were separable. Saponification of the individual enantiomers followed by decarboxylation afforded a method to prepare 3-cyano-l,4-dihydropyridines (244) stereospecifically. 

Carboxylic acids. /3-hydroxy-, synthesis via isoxazolines, 60, 298, 301 Cardiotonics, 2,4,6,8-... 

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