Concise Synthesis, Conformational Study, and Aroma Properties of Carba-Homologues of Helvetolide and Serenolide

We have designed, prepared, and evaluated a set of racemic (un)saturated carba-homologues of prominent musks Helvetolide and Serenolide. The short synthesis employs commercially available Artemone and/or Herbac, that are transformed in three steps to the target compounds. Their qualitative olfactory analysis revealed that incorporation of methylene bridge into the backbone chain of parent compounds completely erases the original musk scent and such new derivatives exhibit a pleasant and often intense sweet(ish) aroma of fruit with floral and herbal aspects. The results of computational modelling suggest that previously postulated horseshoe shape conformation might be necessary but not sufficient prerequisite for musk-scented compounds. Thus, we offer an alternative hypothesis based on the structural differences between metallocomplexes of Helvetolide and/or Serenolide vs. their (un)saturated carba-homologues with zinc-atom as a model for the putative metal-binding site in human olfactory receptors.

Automated summary

We have designed, prepared, and evaluated a set of racemic (un)saturated carba-homologues of Helvetolide and Serenolide, two prominent musks. The new derivatives, which incorporate a methylene bridge into the backbone chain, exhibit a pleasant and often intense sweet(ish) aroma of fruit with floral and herbal aspects. Computational modelling suggests that the previously postulated horseshoe shape conformation might not be sufficient for musk-scented compounds, and we propose an alternative hypothesis based on the structural differences between metallocomplexes and carba-homologues.