Catalytic dendrophanes as enzyme mimics: Synthesis, binding properties, micropolarity effect, and catalytic activity of dendritic thiazolio-cyclophanes

Catalytic dendrophanes 9 and 10 were prepared as functional mimics of the t hiamine-diphosphate-dependent enzyme pyruvate oxidase, and studied as catal ysts in the oxidation of naphthalene-2-carbaldehyde (4) to methyl naphthale ne-2-carboxylate (8) (Scheme 1). They are composed of a thiazolio-cyclophan e initiator core with four generation-2 (G-2) poly(etheramide) dendrons att ached. The two dendrophanes were synthesized by a convergent growth strateg y by coupling dendrons 11 and 12, respectively (Scheme 2), with (chlorometh yl)-cyclophane 42 (Scheme 5) and subsequent conversion with 4-methylthiaaol e (Scheme 7). The X-ray crystal structures of cyclophane precursors 30 (Sch eme 3), 37 and 38 (Scheme 5) on the way to dendrophanes were determined (Fi g. I). The crystal-structure analysis of the benzene clathrate of 37 reveal ed the formation of channel-like stacks by the cyclophane which incorporate its morpholinomethyl side chain and the enclathrated benzene molecule (Fig . 2). The interactions of the enclathrated benzene molecule with the phenyl rings of the two adjacent cyclophane molecules in the stack closely resemb le those between neighboring benzene molecules in crystalline benzene (Fig. 3). The characterization by MALDI-TOF-MS (Fig. 4) and H-1- and C-13-NMR sp ectroscopy (Fig. 5) proved the monodispersity of the G-2 dendrophanes 9 and 10 with molecular weights up to 11500 Da (Eor 10). H-1-NMR and fluorescenc e binding titrations in H2O and aqueous MeOH showed that 9 and 10 form stab le 1:1 complexes with naphthalene-2-carbaldehyde (4) and 6-(p-toluidino)nap hthalene-2-sulfonate (48, TNS) (Tables 1 and 2). The evaluation of the fluo rescence-emission maxima of bound TNS revealed that the dendritic branching creates a microenvironment of distinctly reduced polarity at the cyclophan e core by limiting its exposure to bulk solvent. Initial rate studies for t he oxidation of naphthalene-2-carbaldehyde to methyl naphthalene-2-carboxyl ate in basic aqueous MeOH in the presence of flavin derivative 6 revealed o nly a weak catalytic activity of dendrophanes 9 and 10 (Table 3), despite t he favorable micropolarity at the cyclophane active site. The low catalytic activity in the interior of the macromolecules was explained by steric hin drance of reaction transition states by the dendritic branches.