Isoxazoline route

Uses of Nitrile Oxide Cycloadditions in the Isoxazoline Route... 

Uses of Nitrile Oxide Cycloadditions in the Isoxazoline Route Toward Mono- and Bicyclic Imino Acids and Imino Polyols... 

R. M. Paton and A. A. Young, The nitrile oxide-isoxazoline route to higher-carbon dialdoses, J. Chem. Soc. Chem. Commun. p. 993 (1994). 

Isoxazolines are used in organic synthesis because they mask a number of functionalities such as p-hydroxyketones or y- or P-amino alcohols. While they are not affected by the reaction conditions of many organic transformations, they can be easily unmasked in later steps of the synthesis. In fact, because of its wide applicability, this cycloaddition-reductive opening procedure has been termed the "isoxazoline route". 

The following three examples illustrate the numerous synthetic applications of the isoxazoline route [89]. 

Ghabrial, S.S., I. Thomsen, and K.B.G. TorsseU. 1987. Synthesis of biheteroaromatic compounds via the isoxazoline route. Acta Chem Scand 41 426-434. 

A convenient route to A -isoxazoline N-oxides has been developed from nitrostyrenes using dimethylsulfoxonium methylide. The addition of the ylide (572) to the nitrostyrene (571) was greatly facilitated by the presence of copper(I) salts, the isoxazoline N-oxide (573) being obtained in excellent yield (76JOC4033). 

Previous reviews on the chemistry of isoxazole dealt primarily with the synthetic routes and the nucleophilic cleavage of isoxazole derivatives. The first part of the present review is concerned with new investigations in the synthetic field, but the main attention is devoted to a study of the properties of isoxazoles. The review covers studies undertaken during this decade though some earlier works are mentioned when necessary. No complete coverage of the chemistry of partly or fully reduced isoxazoles and their oxo derivatives is attempted, but those aspects of the chemistry of isoxazolines and isoxazolidines that are closely related to the problems under discussion are also mentioned. 

One of the most important routes to isoxazole and isoxazoline rings involving the formation of the 1—5 and 2—3 bonds involves the condensation of hydroxylamine with a,/8-unsaturated carbonyl compounds. This method was previously widely used, but it is now of no preparative value, though it has been recently applied to determine the configuration of oximes. " The only new modification of this synthesis is the use of the acetals (27) of a,/8-acetylenic aldehydes for preparation of 5-substituted isoxazoles (28)... 

Hassner and coworkers have developed a one-pot tandem consecutive 1,4-addition intramolecular cycloaddition strategy for the construction of five- and six-membered heterocycles and carbocycles. Because nitroalkenes are good Michael acceptors for carbon, sulfur, oxygen, and nitrogen nucleophiles (see Section 4.1 on the Michael reaction), subsequent intramolecular silyl nitronate cycloaddition (ISOC) or intramolecular nitrile oxide cycloaddition (INOC) provides one-pot synthesis of fused isoxazolines (Scheme 8.26). The ISOC route is generally better than INOC route regarding stereoselectivity and generality. 

A rapid access to carbocyclic nucleosides, containing a fused isoxazoline ring has been proposed, starting from cyclopentadiene. The route involves a het-ero Diels-Alder cycloaddition reaction of nitrosocarbonylbenzene followed by a 1,3-dipolar cycloaddition of nitrile oxides, cleavage of the N-0 tether and transformation of the heterocyclic aminols into nucleosides via construction of purine and pyrimidine heterocycles (457). 

An efficient synthetic route to (10Z)- and (10 )-19-lluoro-la,25-dihydroxy vitamin D3 has been developed (488). The key feature of this pathway is the introduction of a 19-fluoromethylene group to a (5 )-19-nor-10-oxo-vitamin D derivative. The 10-oxo compound 445 has been obtained via a 1,3-dipolar cycloaddition reaction of (5 )-la,25-dihydroxyvitamin D with in situ generated nitrile oxide, followed by ring cleavage of the formed isoxazoline moiety with molybdenum hexacarbonyl. Conversion of the keto group of (5 )-19-nor-10-oxo-vitamin D to the E and Z fluoromethylene group has been achieved via a two-step sequence, involving a reaction of lithiofluoromethyl phenyl sulfone, followed by the reductive de-sulfonylation of the u-lluoro-j3-hydroxysulfone. The dye-sensitized photoisomerization of the (5 )-19-fluorovitamin D affords the desired (5Z)-19-fluorovitamin D derivatives, (10Z)- and (10 )-19-fluoro-la,25-dihydroxy-vitamin D3. 

Spiro-isoxazoline 57 (Scheme 16) undergoes thermolytic rearrangement followed immediately by cyclization of the intermediate enaminone to bicyclic 58 (89J(P1)1253). Imine 59 when heated gives iminium salt 60, hence providing a new and efficient route to parent substance 2 (03T3099). 

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