Catalysis using G-quadruplexes (G-4) has shown promise as a way to perform asymmetric sulfoxidation of thioanisole derivatives. However, despite the relative simplicity of G-4, the mechanism of chiral control of sulfoxidation is still unknown, mainly because G-4 can adopt different topologies. To better understand the mechanism of G-4-catalyzed sulfoxidation, G-4 was chemically constrained into a unique topology. It was shown that either sulfoxidation can occur at the outer tetrads or at the grooves of G-4 and that different enantiomers can be generated depending on the region where catalysis occurs. By means of these G-4 mimics, the enantioselective control of the sulfoxidation reaction was unraveled.