Previously, we showed that smaller 2-oxabicyclo[2. 1.1]hexane could be assembled via the iodocyclization reaction of the corresponding cyclobutane alkenyl alcohols. The reaction proceeded with I2/NaHCO3 in the mixture of water and MeOtBu at room temperature. In the beginning, we were confident that similar cyclization would also easily take place with cyclohexane 5 (please, see its preparation further). Therefore, we set the reaction overnight under analogous conditions. Sadly, in the morning we realized that the expected product 6 was not formed at all (Table , entry 1). We repeated the synthesis several times varying the time and the temperature, however, with the same negative outcome (entries 2-4). The addition of the iodine molecule to the double C=C bond did take place, but the cyclization did not happen. Subsequently, we realized that in contrast to the already conformationally preorganized small cyclobutane, the flexible larger cyclohexane ring should adopt first the highly energetic boat conformation (Table ). And this entropic penalty seems to prevent cyclization to occur. We also tried other combinations of solvents still with no success, however (entries 5-8). Being already in a depression, we finally tried pure dipolar aprotic solvents. Indeed, in dimethyl formamide, formation the traces of the needed product was finally seen (entry 9). A similar situation was observed in dimethyl sulfoxide and N-methyl pyrrolidone (entries 10, 11). Analogously, in acetonitrile the reaction proceeded much better, and the needed iodide 6 was isolated in a 56% yield (entry 12). Increasing the reaction temperature or using bromine instead of iodine did not increase the yield (entries 13, 14). Synthesis. Having a working procedure in hand, we studied its scalability. The whole synthesis scheme commenced from the commercially available ketoester 7 (ca. 3€/g, Scheme 3). Wittig reaction gave alkene 8 in 82% yield. Treatment of the latter with LDA/methyl formate followed by the reduction of the intermediate aldehyde with NaBH4 gave alcohol 5 in 86% combined yield. Finally, the key cyclization was attempted on a multigram scale. Pure iodide 6 was obtained as a white crystalline solid after column chromatography with a 36% yield. Despite the lower yield, this protocol allowed us to obtain 135 g of the product in a single run. Scope. Next, we studied the generality of the developed protocol. Treatment of alkene 8 with LDA/acetaldehyde gave the intermediate alcohol that was used in the subsequent cyclization under the developed conditions. The expected iodide 9 with three exit vectors was isolated in 50% yield after column chromatography (Scheme 4). Initially, we isolated the transition alcohol, but subsequently, we understood that performing the two-step procedure with a simple solvent swap ensured a better yield of the final product.