Saturated (Hetero)cyclic α-Fluoro-β-Keto Esters for the Scalable Synthesis of Advanced Fluorinated Building Blocks For Drug Discovery
Тип публікації :
Препринт
Дата випуску :
7 вересня 2026 р.
Автор(и) :
Semen I. Bondarenko
Oleksandr S. Liashuk
Oleksandr I. Marchenko
Andriy S. Malashchuk
Bohdan Razhik
Marina A. Bondarenko
Anastasiia Hurieva
Svetlana V. Shishkina
Dmytro Lesyk
Petro Borysko
Kostiantyn P. Melnykov
Oleksandr O. Grygorenko
eKNUTSHIR URL :
Журнал :
ChemRxiv
Цитування :
[APA 7] Semen, I. B., Oleksandr, S. L., Oleksandr, I. M., Andriy, S. M., Bohdan, R., Marina, A. B., Anastasiia, H., Svetlana, V. S., Dmytro, L., Petro, B., Kostiantyn, P. M., & Oleksandr, O. G. (2026). Saturated (Hetero)cyclic α-Fluoro-β-Keto Esters for the Scalable Synthesis of Advanced Fluorinated Building Blocks For Drug Discovery. ChemRxiv,. https://doi.org/10.26434/chemrxiv.15008426/v1
[ДСТУ] Saturated (Hetero)cyclic α-Fluoro-β-Keto Esters for the Scalable Synthesis of Advanced Fluorinated Building Blocks For Drug Discovery / I. B. Semen та ін. ChemRxiv. 2026. DOI: 10.26434/chemrxiv.15008426/v1 (дата звернення: 11.09.2026).
Cyclic α-fluoro-β-keto esters were used as common precursors to two classes off luorinated building blocks: α,β,β-trifluorinated (hetera)cycloalkane carboxylic acids and their functionalized derivatives, and cyclic α-fluorinated β-amino acids. The key precursors were prepared via the Selectfluor-mediated α-fluorination ofthe commercially available cyclic β-keto esters. Deoxo fluorination of α-f luoro-β-keto esters with SF 4 in anhydrous HF gave α,β,β-trifluorinated esters, which were converted into a series of building blocks (carboxylic acids, alcohols, bromides, and amines). Reductive amination of the same key precursors with benzylamine proceeded cis -selectively for the six-membered scaffolds and, after debenzylation, hydrolysis, and N -Boc protection, delivered cyclic α-fluorinated β-amino acids and their protected derivatives. The 2–5-step reaction sequences were operationally simple and scalable, with individual steps performed on up to 150 g scale. α,β,β-Trifluorination lowered the carboxylic acid p K a by 1.24–1.90 units, whereas its effect on Log P was small and scaffold-dependent; in both cases, the α-F and β,β-F 2 contributions were non-additive. In the cyclic α-fluorinated β-amino acids, α-fluorination decreased the carboxylic acid p K a by 0.66–0.87 units and the ammonium p K a by 1.39–1.85 units relative to the non-fluorinated analogs.
Якщо не вказано інше, ця робота розповсюджується на умовах ліцензії Attribution 4.0 International