Saturated (Hetero)cyclic α-Fluoro-β-Keto Esters for the Scalable Synthesis of Advanced Fluorinated Building Blocks For Drug Discovery
6 affiliations
- 1Enamine Ltd., Winston Churchill Street 78, Kyїv, Ukraine, 02094
- 2Taras Shevchenko National University of Kyiv , Volodymyrska Street 60, Kyїv, 01601
- 3Winston Churchill Street 67
- 4Enamine Scientific Research Institute
- 5Institute of Organic Chemistry, National Academy of Sciences of Ukraine, Akademik Kukhar Street 5, Kyїv, 02066
- 6V. P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry, National Academy of Sciences of Ukraine, Akademik Kukhar Street 1, Kyїv, Ukraine, 02066
Abstract
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.
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BibTeX
@misc{bondarenko2026saturated,
title = {{Saturated (Hetero)cyclic α-Fluoro-β-Keto Esters for the Scalable Synthesis of Advanced Fluorinated Building Blocks For Drug Discovery}},
author = {Semen I. Bondarenko and Oleksandr S. Liashuk and Oleksandr I. Marchenko and Andriy S. Malashchuk and Bohdan Razhik and Marina A. Bondarenko and Anastasiia Hurieva and Svetlana V. Shishkina and Dmytro Lesyk and Petro Borysko and Kostiantyn P. Melnykov and Oleksandr O. Grygorenko},
howpublished = {ChemRxiv},
year = {2026},
month = sep,
doi = {10.26434/chemrxiv.15008426/v1},
url = {https://chemrxiv.org/doi/full/10.26434/chemrxiv.15008426/v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Saturated (Hetero)cyclic α-Fluoro-β-Keto Esters for the Scalable Synthesis of Advanced Fluorinated Building Blocks For Drug Discovery
AU - Semen I. Bondarenko
AU - Oleksandr S. Liashuk
AU - Oleksandr I. Marchenko
AU - Andriy S. Malashchuk
AU - Bohdan Razhik
AU - Marina A. Bondarenko
AU - Anastasiia Hurieva
AU - Svetlana V. Shishkina
AU - Dmytro Lesyk
AU - Petro Borysko
AU - Kostiantyn P. Melnykov
AU - Oleksandr O. Grygorenko
PY - 2026
DA - 2026/09/07
PB - ChemRxiv
DO - 10.26434/chemrxiv.15008426/v1
UR - https://chemrxiv.org/doi/full/10.26434/chemrxiv.15008426/v1
AB - 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.
ER -