Intramolecular [3+2] nitrone cycloaddition to unsaturated C-C bonds and its application to the efficient preparation of 3-substituted cephems

Abstract

It is demonstrated that the intramolecular [3+2] cycloaddition of nitrones to alkynes is facile when the length of the tether connecting the two reacting sites is appropriate. The resulting [3+2] cycloaddition products, isoxazolidines, can be further converted into 3-hydroxy-3-pyrrolin2-ones and α-keto-β,γ-unsaturated esters by reductive and oxidative cleavage, respectively. N-[1-methyl-6-(methoxycarbonyl)-5-hexynylidene] methylamine-N-oxide, a ketonitrone which was prepared from the reaction between methyl 7-oxo-oct-2-ynoate and N-methylhydroxylamine, rearranged thermally into two isomeric bicyclic compounds instead of the expected intramolecular [3+2] cycloadduct. An aldonitrone, N-[6-(methoxycarbonyl)-5-hexynylidene]-N-oxide also provided the corresponding rearranged product. Transformation of the 3-alkylidene cephalosporanic acid derivatives into 3-subsituted cephems was investigated in order to extend the utility of 3-alkylidene cephalosporanic acid derrivatives which were prepared with the aid of samarium(II) iodied. The intramolecular [3+2] cycloaddition reaction via the nitrones derived from the 3-alkylidene derivatives prepared furnished the isoxazolidines, which were converted to the cephams with a hydroxyl group as well as the substituted at 3-position. Synthesis of the 3-substituted-$Δ^3$-cephem was then achieved by treating the 3-hydroxy cephams with excess methanesulfonyl chloride and triethylamine in $CH_2Cl_2$. Also, the transformation of isoxazoline cycloadduct, obtained from the intramolecular [3+2] cycloaddition reaction of the corresponding nitrile oxide derived from the 3-alkylidene cephalosporanic acid derivative, into the $Δ^3$-cephem with a cyclic group as a 3-substituent was successfully carried out.