Functionalized 1,4-Oxathianes – Saturated Six-Membered Heterocycles with Tunable Physicochemical Profile
Тип публікації :
Препринт
Дата випуску :
26 червня 2026 р.
Автор(и) :
Andrii V. Bondarenko
Yevhenii Kozyriev
Oleksii S. Slon
Anton A. Baryshpol
Illia O. Doroshenko
Denys Bylina
Valentyn Chigrinov
Petro Borysko
Bohdan V. Vashchenko
Oleksandr O. Grygorenko
eKNUTSHIR URL :
Журнал :
ChemRxiv
Цитування :
[APA 7] Andrii, V. B., Yevhenii, K., Oleksii, S. S., Anton, A. B., Illia, O. D., Denys, B., Valentyn, C., Petro, B., Bohdan, V. V., & Oleksandr, O. G. (2026). Functionalized 1,4-Oxathianes – Saturated Six-Membered Heterocycles with Tunable Physicochemical Profile. ChemRxiv,. https://doi.org/10.26434/chemrxiv.15005239/v1
[ДСТУ] Functionalized 1,4-Oxathianes – Saturated Six-Membered Heterocycles with Tunable Physicochemical Profile / V. B. Andrii та ін. ChemRxiv. 2026. DOI: 10.26434/chemrxiv.15005239/v1 (дата звернення: 11.09.2026).
Functionalized 1,4-oxathianes were developed as tunable isosteres of saturated six-membered heterocycles, exploiting the accessible oxidation states of sulfur to modulate physicochemical properties within a fixed molecular skeleton. Two structurally distinct series were prepared: 3-monosubstituted derivatives bearing primary amine or carboxylic acid groups, accessed via regioselective electrophilic chlorination of 1,4-oxathiane, and spirocyclic 2,2-disubstituted counterparts with an annulated piperidine or azetidine ring, obtained through α,β-unsaturated sulfoxide formation and intramolecular oxa-Michael cyclization. Most building blocks were prepared in both sulfide and sulfone oxidation states on multigram scale. Basicity (p K a ) and lipophilicity (Log P ) were determined experimentally and compared against tetrahydropyran, 1,4-dioxane, morpholine, and piperidine analogs. The sulfone introduction reduced the amine basicity by 0.4–1.6 p K a units and lipophilicity – by 0.4–0.5 Log P units, while the sulfide moiety increased Log P by 0.45 units relative to 1,4-dioxane. Overall, the 1,4-oxathiane scaffold spanned ca. 0.85 Log P units through oxidation state manipulation. One of the spirocyclic building blocks, 5-oxa-8-thia-2azaspiro[3.5]nonane 8,8-dioxide, closely matched morpholine in both properties, confirming its potential as an isostere. A virtual library based on the presented scaffolds demonstrated their full compliance with drug- and leadlikeness criteria.
Якщо не вказано інше, ця робота розповсюджується на умовах ліцензії Attribution 4.0 International