Catalytic Cyclophanes. Part XI. A flavo-thiazolio-cyclophane as a biomimetic catalyst for the preparative-scale electro-oxidation of aromatic aldehydes to methyl esters

Flavo-thiazolio-cyclophane 6 was prepared on a gram scale by an 18-step synthesis (Schemes 3 and 4). This pathway involved the very efficient preparation of bromo-cyclophane 32 (37% yield over 13-steps), which can be readily modified to create various multiply functionalized receptors. This bromide 32 was subsequently converted into the corresponding boronic acid and connected to the 7-bromoflavin 10 (Scheme 2) via Suzuki coupling to give flavo-cyclophane 36 . The thiazolium unit was then introduced after quaternization of the tertiary amino groups of 36 . Flavo-thiazolio-cyclophane 6 , with both prosthetic groups attached in proximity to the well-defined cyclophane binding site, is a functional model for the enzyme pyruvate oxidase. In basic methanolic solution, 6 catalyzes the oxidation of aromatic aldehydes to their corresponding methyl esters. Cyclophane 6 shows saturation kinetics, and the turnover number calculated for the oxidation of naphthalene-2-carbaldehyde to methyl naphthalene-2-carboxylate (k_cat = 0.22 s^?1) is one of the highest reported for an artificial enzyme. Control experiments showed that the catalytic advantages of 6 result from the macrocyclic binding and reaction site as well as from the covalent attachment of both cofactors to this site. The catalytic cycle is completed by electrochemical re-oxidation of the reduced flavin moiety at a low working electrode potential (- 0.3 V vs. Ag/AgCl), and up to ca. 100 catalytic cycles can be performed on a preparative scale, The intramolecular nature of the electron transfer from the active aldehyde intermediate to the flavin is particularly conducive to the oxidation of unreactive aldehydes.