Temperature regiocontrol of intramolecular cyclization of di-hydroxysecoacids

Abstract

The synthesis of macrocycles from acyclic precursors is an important reaction class for both the realization of sizedesigned cavities to be used as building blocks in supramolecular chemistry and for the synthetic production of natural substances with pharmacological activity, the case of several macrolactones (macrolides), occurring in a wide variety of ring sizes. Although there is a large amount of literature on macrocyclization, most work has been concerned with the effect of acyclic precursor concentration on the yields of the competitive intramolecular and intermolecular reactions, so that little is yet known about the factors which play a role in controlling the ring size of macrocyclization products when competitive intramolecular cyclization pathways are available. Only a few selective macrocyclizations of dior tri-hydroxyacids without protection have been reported in the literature, but in these cases selectivity is achieved because of the very different sizes of the rings which can be formed, as discussed in several seminal papers. In this communication we report results concerning the macrocyclization of (15S,16S)-15,16-dihydroxy-octadecyl(6Z,9Z,12Z)-trienoic acid (1), leading to Aplyolide C (C) and Aplyolide E (E), showing that the reaction occurs under thermodynamic control and that the relative yields of the two products depend on the reaction temperature to such an extent that an efficient regiocontrol can be obtained by simply changing the reaction temperature, notwithstanding the similar size of the two cycles.