The 1,5-disubs tuted stellane scaffold is seen as a first true bioisoster of ortho-subs tuted benzenes as both comprise the in-plane loca on of the side groups. Its structural features contribute to improved aqueous solubility and reduced nonspecific binding, making stellane deriva ves valuable tools in drug discovery and crop protec on. The key step of the synthesis involves the lithia on of the corresponding diester followed by oxida on with iodine. We have demonstrated that the stereochemistry of the intermediate diester plays a crucial role in determining the reac on outcome, with the endo,endo isomer leading to an intramolecular Claisen condensa on product while the exo,exo and exo,endo isomers yield the desired stellane deriva ve quan ta vely. The lithia on of 2 involves complex equilibria and isomeriza ons that significantly influence the reac on outcome. Deuterium labeling experiments and computa ons provided a mechanis c ra onale for the observed stereochemical preferences in the lithia on/I2-mediated oxida on sequence. The developed synthe c protocol has been successfully scaled up, allowing for the produc on of stellane deriva ves in up to 50 grams from a single synthe c run u lizing commercially available star ng materials and involves a limited number of synthe c steps. We now an cipate that stellane deriva ves will find broad applica ons and to the development of novel therapeu c agents and agrochemicals.