Temperature regiocontrol of intramolecular cyclization of di-hydroxysecoacids

A simple and efficient regiocontrol of the macrolactonization reaction can be obtained by controlling the reaction temperature. In fact, while energetic factors favour the formation of the smaller ring, entropic factors drive the cyclization toward the formation of the larger ring. There are two different physico-chemical factors which contribute to the entropic term: the higher number of conformers of the larger ring and vibrational contributions arising from low frequency modes. Work aimed to better elucidate the relative weight of these two factors is in progress.