We started out to investigate the reactivity of Fdx towards thiol nucleophiles under Lewis acidic (LA) conditions using benzylic and aromatic thiol nucleophiles as model substrates. Despite we aimed to synthesize S-Fdx by using a 1-thionoviose derivative, 1-thiosugars do not constitute the ideal substrates to study the feasibility of introducing thiol nucleophiles in all three regioisomeric positions. The commercial availability of 1-thiosugars is scarce demanding prior synthesis. Further, potential epimerization of the anomeric thiol could complicate the analysis of the reaction outcome. Therefore, as a proof of concept we studied the reactivity of Fdx with 4-methoxybenzyl mercaptan (4a). Preliminary screening of reaction conditions (Suppl. Tab. 1-3) indeed revealed the formation of the three regioisomeric products 5a-C(11), 5a-C(13), and 5a-C(15) (Fig. ). Copper (II) perchlorate (Cu[ClO4]2•6H2O) at a LA loading of 1 mol% in MeCN resulted in complete conversion of Fdx within 10 min at 25 °C. To employ the conditions for thiosugars, we aimed to keep the reaction time short to avoid potential epimerization at elevated reaction times under LA conditions. While initial screens were performed using an excess of thiol (5.0 equiv.) to compete with intramolecular side reactions, stoichiometric amounts were chosen in later experiments for reasons of operational simplicity and to avoid the use of excess amounts of precious 1-thiosugar. These conditions were successfully applied for aromatic thiols as nucleophiles (5b-c, Fig. ). The absolute configuration was assigned by 1-and 2-D NMR analysis and corroborated by DP4+ calculations (see SI_DP4+). The reactions proceeded with high diastereoselectivity at the newly formed stereogenic centers providing solely the epimer corresponding to a peripheral attack at the p-system. The diastereoselectivity is likely caused by macrocyclic stereocontrol.