Catalytic Cyclophanes. Part XI. A Flavo-thiazolio-cyclophane as a Biomimetic Catalyst for the Preparative-Scale Electro-oxidation of Aromatic Aldehydes to Methyl Esters

Article abstract of DOI:10.1002/hlca.19970800516

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 percent 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, whith 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.