Functionalized 1,2-Dioxetanes as Potential Chemotherapeutic Agents: The Synthesis of Dioxetane-Substituted Carbamates

Despite their labile nature¹, 1,2-dioxetanes can be chemically transformed under mild conditions thereby permitting chemical functionalization of these biologically potentially useful substances. For example, it was possible to show² that the hydroxydioxetane 1 ³ can be converted in high yields into carboxylic esters using such gentle methods as the Brewster-Ciotti and Mitsunobu esterifications. In these cases, the nucleophilic hydroxy group of the dioxetane can be conveniently derivatized with electrophilic biomolecules, e. g. fatty acids. A broader scope would be achieved, if nucleophilic biomolecules could be attached to dioxetanes. In this manner dioxetane-substituted sugars, steroids, pyrimidine bases, peptides, etc. could be made available as potential chemotherapeutic agents. In principle two synthetic approaches can be pursued to accomplish such derivatization. In the case of amines, the carbamate linkage is a logical choice to bind such nucleophiles to the nucleophilic hydroxydioxetane 1. Either the nucleophilic hydroxydioxetane 1 is transformed into the electrophilic carbonochloridate 2 and subsequently converted to the carbamates 3 (Scheme), or the nucleophilic amine is transformed into the electrophilic isocyanate and subsequently treated with the hydroxydioxetane 1. Presently we report that both synthetic sequences are feasible for derivatizing the hydroxydioxetane 1, leading to the carbamates 3 in good yields. The results are summarized in the Table.