Isovanillyl sweeteners. Synthesis, conformational analysis, and structure–activity relationship of some sweet oxygen heterocycles

New benzodioxin, benzodioxole, benzodioxepine and isoflavan analogues of the natural isovanillyl sweetener phyllodulcin have been synthesized and their sweetness assessed. Molecular-mechanics calculations on 15 members of the class of the isovanillyl sweet compounds indicated a preferential quasi-orthogonal orientation of the isovanillyl ring with respect to the heterocyclic ring. Experimental confirmation was obtained by a detailed study of transient NOE (nuclear Overhauser effect) experiments on 2-(3-hydroxy-4-methoxyphenyl)-1,4-benzodioxane. A theoretical treatment of these experiments is given. As, however, the energy barrier for the rotation of the isovanillyl ring around the bond linking it to the heterocyclic ring is low, geometrical parameters independent of this rotation were sought and an empirical correlation with sweetness potency established. The results are discussed in terms of the current hypotheses on the receptor shape.