In the design of new TCOs, we were inspired by our previous work on bicyclo [6.1.0]nonyne (BCN), where we demonstrated that the fusion of a cyclopropane with the cyclooctyne induced excellent conjugation rates and kinetics due to the increased ring strain. Cyclopropanated CCOs have also been isomerized by the Fox group to obtain strained TCOs (sTCOs), revealing an enhanced reactivity towards tetrazines as a result of the fusion with the cyclopropane ring. Our synthesis commenced with monocyclopropanation of 1,5-COD (1) by reaction with ethyl diazoacetate in the presence of a catalytic amount of copper(II) acetylacetonate under neat conditions to allow 1,5-COD recovery after completion. This afforded a mixture of the exoand endo-diastereomers of 2 (Scheme 1) in a 2:1 ratio, respectively (61% total yield), which were separated by silica gel chromatography. In our experience, substitution reactions on eightmembered rings have proven to be inefficient, therefore we envisioned that activating 2 with N-iodosuccinimide (NIS) in the presence of sodium acetate and acetic acid would incorporate both the iodide and acetate in a single step as in the work of Goto and co-workers. We were pleased to find that this reaction, which proceeds through the corresponding iodiranium ion, leads to highly diastereoselective acetate addition resulting in the acetylated iodohydrin 3 in 83% yield. Scheme 1. Synthesis of the difunctionalized TCO derivatives starting from commercially available cis,cis-1,5cyclooctadiene (1). i. copper(ii) acetylacetonate (0.01 equiv), ethyl diazoacetate (0.17 equiv), 90 °C, 18 h, 61% (exo/endo 2:1). ii. sodium acetate (3.0 equiv), acetic acid, NIS (1.2 equiv), 21 Compound 4 was then subsequently isomerized into the TCO derivative with UV irradiation at a wavelength of 254 nm in the presence of methyl benzoate (photosensitizer) in a continuous flow setup. Selective removal of the TCO with aqueous silver nitrate via liquid-liquid extraction coupled to the photoflow system gave access to multigram amounts of the desired TCO. With the isomerization a new stereoelement was introduced, giving rise to an inseparable mixture of the exo-diastereomers 5 and 6. Fortunately, the products could be easily separated with silica gel chromatography after ethanolysis of the acetate with potassium carbonate in ethanol to furnish the corresponding hydroxylated TCOs 7 and 8, having the allylic hydroxyl group available for functionalization with a payload.