The noviose-derived sugar at C (11) of Fdx is indispensable for the biological activity. However, the O-glycosidic bond to the noviose moiety causes Fdx to be acid labile. The Oatom readily undergoes protonation, rendering the noviose a good leaving group. Under acidic conditions, the products of a formal intramolecular SN2''-attack of the C(18)-OH at C(15) were observed (2, Fig. ). In presence of nucleophilic solvents (i.e. MeOH), the corresponding MeOH adduct was reported. As S-atoms are less basic than their O-counterparts, we envisaged a single atom exchange in the O-glycosidic bond could overcome the acid lability (Fig. ). To access the O-/S-exchanged product, we made use of the acid-mediated reactivity towards nucleophiles to introduce thiols. Despite initially an acid-mediated SN2''-type reaction of Fdx was suggested, we envisioned an SN1-type mechanism to be feasible. While the prevalent mechanism for acid-mediated heterolysis of the C-O bond in O-glycosidic linkages involves the formation of an oxocarbenium ion, we suggest the allylic nature of the aglycone in Fdx to favor the formation of a carbenium ion at the aglycone. Further, the formation of the oxocarbenium ion is disfavored by the presence of an electron-withdrawing b C-O bond, rendering its formation relatively slow. For aglycones that can form a stabilized carbocation upon aglycone-O-bond fission, faster hydrolysis rates were observed. We therefore suggest the formation of a pentadienylic carbocation, following C-O-bond fission in Fdx under acidic conditions. Herein, we present our strategy to intercept the acidic degradation by trapping the proposed carbocation with thiol nucleophiles (Fig. ). A 1-thionoviose derivative as the nucleophile gave access to the single atom exchanged S-analogue of Fdx (S-Fdx, 3a-C( )) in a single, operationally simple step. Moreover, the intrinsic high nucleophilicity of thiols allowed to conduct the reactions directly on unprotected Fdx, effectively competing with intramolecular reactions with OH-groups. This strategy presents a way to access structurally diverse thioglycoside derivatives of Fdx, while also introducing a more acid stable S-glycosidic bond.