Practical and Scalable Access to 3-Functionalized 1,5-Oxazocanes: Unlocking a Scarce Medium-Sized Scaffold

Oleksandr Kaliberda; Dmytro Leha; Vladyslav Peredrii; Kostiantyn Levchenko; Evgenij V. Zarudnitskii; Serhiy V. Ryabukhin; Dmytro M. Volochnyuk

doi:10.26434/chemrxiv.15002522/v1

Practical and Scalable Access to 3-Functionalized 1,5-Oxazocanes: Unlocking a Scarce Medium-Sized Scaffold

Тип публікації :

Препринт

Дата випуску :

28 квітня 2026 р.

Автор(и) :

Oleksandr Kaliberda

Dmytro Leha

Vladyslav Peredrii

Kostiantyn Levchenko

Evgenij V. Zarudnitskii

Serhiy V. Ryabukhin

Dmytro M. Volochnyuk

eKNUTSHIR URL :

https://ir.library.knu.ua/handle/15071834/34289

DOI :

10.26434/chemrxiv.15002522/v1

Журнал :

ChemRxiv

Цитування :

[APA 7] Oleksandr, K., Dmytro, L., Vladyslav, P., Kostiantyn, L., Evgenij, V. Z., Serhiy, V. R., & Dmytro, M. V. (2026). Practical and Scalable Access to 3-Functionalized 1,5-Oxazocanes: Unlocking a Scarce Medium-Sized Scaffold. ChemRxiv,. https://doi.org/10.26434/chemrxiv.15002522/v1

[ДСТУ] Practical and Scalable Access to 3-Functionalized 1,5-Oxazocanes: Unlocking a Scarce Medium-Sized Scaffold / K. Oleksandr та ін. ChemRxiv. 2026. DOI: 10.26434/chemrxiv.15002522/v1 (дата звернення: 11.09.2026).

A long-standing challenge in the chemistry of medium-sized heterocycles is the gap between conceptual accessibility and practical synthetic availability. Here, we address this problem for the 1,5-oxazocane scaffold by developing a scalable and operationally simple route to 3-functionalized derivatives from readily available commercial reagents. A NaH-mediated heterocyclization provides multigram access to a 3-exo-methylene platform, which can be further transformed into a complementary ketone intermediate, together enabling broad downstream diversification. These platforms support a range of transformations, including direct alkene functionalization and ketone-based derivatization, providing access to the parent 1,5-oxazocane as well as to a diverse set of amino-, hydroxy-, carboxy-, epoxide-, and gem-difluoro-substituted derivatives. By translating a formally simple transformation into a robust preparative method, this work establishes practical access to a previously underexplored class of eight-membered O,N-heterocycles and demonstrates that classical heterocyclizations can serve as powerful and scalable solutions for the synthesis of medicinal chemistry-relevant building blocks.