Catechol-derived propargyl diol cyclizations with malonyl dichloride: substituent effects on the formation of macrocyclic esters and their hydrochlorinated adducts.

A series of catechol-derived propargyl diols were synthesized in the current study, and submitted to cyclization with malonyl dichloride, under basic conditions, to afford the corresponding 13-membered macrocyclic diesters. Product distribution appeared to be associated with the choice of protecting group for the catechol hydroxy substituents. Diverse protecting groups, able to fine-tune the (stereo)electronic contribution of each substituent to the π-conjugated system were investigated. In the cases of a trifluoromethanesulfonate-substituted or a conformationally-restricted cyclohexyl dioxolane-comprising propargyl diol substrate, as well as the O-substituent-free propargyl diol counterpart, the reaction led to the expected macrocyclization, alongside traces of a 26-membered macrocyclic tetraester, without any indication of a competing hydrochloride addition to a propargyl triple bond. However, upon switching to silyl or methyl groups as catecholic O-atom protecting groups, hydrochloride addition occurred on a triple bond under the cyclization conditions, leading to formation of macrocyclic, vinyl chloride adducts, along with the expected intact 13-membered macrocycle. In either case, no metal catalysis was required, while the reaction was performed at ambient temperature. Control experiments involving alternative conditions and hydrochlorination agents, which may form