Electrochemical Synthesis of Added Valuable Purine Alkaloid Metabolites from Caffeine Feedstock Employing a Structure Electro-Activity Relationship (SeAR) Approach

The development of electrochemical approaches to the valorization of abundant natural products into high value medications and metabolites is of pharmaceutical interest. In this study, we explored the electrosynthetic behavior of the abundant legal psychoactive, caffeine, a representative member of the purine alkaloid class. Initial screening of the cyclic voltammetric behavior of eleven exemplar purine alkaloids revealed a predicted structure electroactivity relationship (SeAr). Optimization of the current controlled electrochemical (CCE) reaction informed by cyclic voltammetry measurements enabled the dialing-in/out of differential oxidative metabolic products. Sequential desmethylation around the purine ring was observed both by isolation and comparison of reference standards using HPLC. Amide, imide, and a novel N-methyl heteroaryl oxidation mechanism are observed. Tractable quantities of the high-value theophylline (medication) and paraxanthine (dietary supplement) were isolated in 17% and 8% b.r.s.m. employing an electrolyte recovery strategy. This approach offers a marked improvement compared to other approaches (chemical 0.8% and enzymatic 0.97% yields) and may have potential in other natural product and drug discovery settings.