New G-quadruplex DNA catalysts in enantioselective sulfoxidation reaction

DNA-based asymmetric catalysis has recently attracted increasing attention becoming a particularly interesting tool for organic chemical synthesis. G-quadruplex DNA is one of the alternative conformations that guanine-rich DNA strands can adopt and met with growing success in catalysis, being these structures able to induce sensible levels of enantioselectivity in several asymmetric reactions1. G-quadruplexes show two peculiar structural features: a central core, formed by stacked G-tetrads, that plays a very important role in recognizing planar aromatic ligands through stacking interactions, and some loops that provide the special environment of the organic reaction, affecting both the reaction rate and the enantiospecificity. The natural telomeric G-quadruplex HT21 has been extensively utilized as G4 DNA-based catalytic system for enantioselective reactions2. In order to explore the role of the residues in the loops and to improve the performances of G4 DNA catalysts, a series of HT21 analogues have been prepared, in which each sequence contains a chemically modified monomer replacing, one at a time, natural adenosines in the TTA loops with 8-bromo-2'-deoxyadenosine (ABr), 8-oxo-2'-deoxyadenosine (Aoxo) or β-L-2'-deoxyadenosine (AL) at different single loop positions. The activity and the enantioselectivity of G4 DNA metalloenzyme in the sulfoxidation reaction have been tested to obtain enantiomerically pure sulfoxides that have interesting potentials both in pharmaceutics3 and in asymmetric synthesis4. The substitution of an adenosine in the loops of HT21 with these modified residues has a negligible impact on the G4 DNA structural features, thermal stability and catalytic activity. Indeed, CD data strongly suggest that all modified HT21 derivatives adopt a hybrid-type G4 structure strictly similar to that of the natural telomeric sequence and they can catalyze a full conversion of the thioanisole substrate. On the other hand, enantioselectivity data clearly reveal the priority role of loops in inducing product chirality, since minor chemical modifications are enough to influence significantly the enantiomeric excesses obtained, considering that in most cases the DNA modified catalysts have induced lower enantioselectivities compared to the natural one (56% ee). On the contrary, the use of L-DNA is a promising strategy in modulating the enantioselectivity of a reaction, since the introduction of a single residue with opposite chirality to the rest of the sequence in specific loops consents to obtain ee values strictly comparable or also higher than those shown by the natural sequence. Particularly, the introduction of an AL residue in the first loop has significantly proved to be capable of producing about 84% enantiomeric excess, the highest enantioselectivity for DNA based oxidation reaction to date.