Iodocyclization as a Hub Reaction for Lead- and Diversity-Oriented Synthesis of sp3-Enriched Six-Membered O- and N-Heterocycles
Тип публікації :
Препринт
Дата випуску :
26 серпня 2026 р.
Автор(и) :
Andrii M. Dubyna
Denys D. Hubii
Taras S. Diachuk
Dmytro S. Granat
Illia O. Doroshenko
Bohdan S. Sosunovych
Alexander Yu. Lyapunov
Bohdan V. Vashchenko
Oleksandr O. Grygorenko
eKNUTSHIR URL :
Журнал :
ChemRxiv
Цитування :
[APA 7] Andrii, M. D., Denys, D. H., Taras, S. D., Dmytro, S. G., Illia, O. D., Bohdan, S. S., Alexander, Y. L., Bohdan, V. V., & Oleksandr, O. G. (2026). Iodocyclization as a Hub Reaction for Lead- and Diversity-Oriented Synthesis of sp3-Enriched Six-Membered O- and N-Heterocycles. ChemRxiv,. https://doi.org/10.26434/chemrxiv.15007900/v1
[ДСТУ] Iodocyclization as a Hub Reaction for Lead- and Diversity-Oriented Synthesis of sp3-Enriched Six-Membered O- and N-Heterocycles / M. D. Andrii та ін. ChemRxiv. 2026. DOI: 10.26434/chemrxiv.15007900/v1 (дата звернення: 11.09.2026).
Iodocyclization was applied as a single hub reaction to a uniformly prepared set of 50 precursors, providing the monocyclic, spirocyclic, and fused versions of four saturated six-membered heterocycles: 1,4-dioxanes, tetrahydropyrans, morpholines, and piperidines. Under mild conditions (I 2 , NaHCO 3 , MeCN), the reaction worked well for 1,4-dioxanes and tetrahydropyrans, but became substrate-specific once the ring contained nitrogen. In particular, the alkenylamine-derived precursors provided morpholines, whereas their alkenol-derived counterparts did not, and the free alkenylamines polymerized instead of giving piperidines. The limitations were defined by the nature of nucleophile rather than by the ring itself – replacing the amine with carbamate enabled the cyclization, and ring closure of 1,2-amino alcohols with epichlorohydrin provided the morpholine-derived cores, so that the scaffold collection remained complete across all four classes. Further transformations of the iodide handle did not depend on the scaffold, delivering amines, alcohols, carboxylic acids, esters, sulfonyl chlorides, sulfonamides, and amino acid derivatives (95% of the transformations attempted) on up to 50 g scale. The resulting 44 distinct heterocyclic scaffolds and 252 building blocks occupied lead-like chemical space (median MW 186 Da, median F sp 3 0.92). The matched molecular pair analysis showed that replacing a ring oxygen atom with CH 2 increased the mean cLog P value by ca. one unit, equally in the 1,4-dioxane/tetrahydropyran and the morpholine/piperidine pairs. One-point virtual decoration provided a compound library that fitted well the lead-likeness criteria, whereas the two-point decoration left the resulting library members drug-like but no longer lead-like.
Якщо не вказано інше, ця робота розповсюджується на умовах ліцензії Attribution 4.0 International