Novel nitrone 1,3-dipolar cycloadditions

Abstract

1,3-Dipolar cycloadditions are a group of pericyclic reactions between a dipolarophile and a dipole that efficiently form five-membered heterocycles, important structures in pharmaceuticals and other biologically relevant compounds. The aim of this work was to optimise the cycloadditions between aliphatic nitrones and chiral thioimides, catalysed by an achiral nickel(II) complex for the synthesis of isoxazolidines. Previous studies, including research carried out within the group, reported that catalysed reactions involving aliphatic nitrones afford poor diastereoselectivities. The main strategy involved modifying the steric hindrance of both the nitrone and thioimides. Since an achiral catalyst was employed, the thioimides used were chiral, required to induce stereoselectivity. These thioimides were derived from commercially available L-β-amino alcohols and L-α-amino acids. A series of cycloadditions were carried out and the yield, conversion and diastereoselectivity were evaluated and quantified by 1H NMR. The results showed that the steric demand of the C4-substituents of the thioimide greatly affected the stereochemical outcome of the reaction, leading to less control over the diastereoselectivity. Overall, the reactions resulted in a mixture of four diastereoisomers, both exo and endo, with one or two diastereoisomers predominating. The relative configuration of the major diastereoisomer is still to be determined. The best results were obtained from the thioimide synthesised from L-phenylglycinol as starting material and the N-benzyl-C-ethyl nitrone. The reaction afforded high yield, almost complete conversion, and a diastereomeric ratio of 79:18:3:0.2.