C(15)-isomer was observed (Suppl. Fig. ). Further, the reactivity of the C(15)-isomer towards a thiol nucleophile under the reaction conditions was assessed. On the reaction time scale, no conversion was observed (Suppl. Tab. 10). Thus, initial formation of the C(15)-isomer, followed by subsequent SN2' or SN2''-reactions with thiol can be excluded. In absence of a thiol, an intramolecular reaction of Fdx to the previously described 15S-THF derivative (2b) was observed (see SI). To exclude an initial intramolecular reaction, followed by an opening of the derivative 2b by SN2' or SN2''-type attack by the thiol, the derivative 2b was subjected to the reaction conditions. Neither the 15S-derivative 2b, nor the 15R-derivative 2a underwent significant reaction on the reaction time scale (Suppl. Tab. 10). The reaction was also not affected by the presence of butylated hydroxytoluene (BHT), rendering a radical mechanism unlikely (Suppl. Fig. ). Because all the experimental data suggest an SN1 mechanism as the probable mode of operation in the reaction under consideration, we decided to analyze the system with DFT (density functional theory) simulation. The goal of the simulation was to determine the most stable conformer of the forming carbocation together with its electronic properties, which in turn might give us deeper understanding of the observed regio-and stereoselectivity, potentially providing means of altering the selectivity. For the sake of computation efficiency, the rhamnose sidechain was substituted with a methyl group. The conformational space was explored with the GFN2-xTB semiempirical method. The generated structures were further refined using the r 2 SCAN-3c method and the energies together with electronic properties of the found structures were computed at the wB97M-V/def2-TZVPP level of theory (Fig. ). It was found that in the most stable conformer of the carbocation, the plane of the pentadienylic system is almost perpendicular to the plane of the macrocycle ensuring sterical hindrance of one of the faces of the carbocation. Therefore, only the outer face of the p-system is reactive to nucleophiles (inner-annular stereocontrol). This