Chernykh AV,
Liashuk OS,
Hurieva AM,
Lesyk D,
Holota Y,
Borysko P,
Shishkina SV,
Volochnyuk DM,
Grygorenko OO *.
Taras Shevchenko National University of Kyiv, Ukraine
Fluorine-Containing 6-Azabicyclo[3.1.1]heptanes: Bicyclic Piperidine Analogs for Drug
Discovery.
Eur. J. Org. Chem. 2025;
28: e202500022
DOI:
10.1002/ejoc.202500022
Keywords
piperidines - physicochemical properties - fluorination - bicyclic systems - bioisosteres
Significance
The utility of bridged azabicyclic systems as piperidine isosteres provides advantages
in terms not only of enhancing the overall conformational control but also defining
the exit vectors of the substituents on the ring system. The ability of fluorine substitution
to enhance both the physicochemical properties and binding affinity of biologically
active molecules has been well documented. The current report describes the synthesis
of a series of fluorine-containing 6-azabicyclo[3.1.1]heptanes, and details an overview
of their pK
a values, LogP values and exit vectors, benchmarking these against the corresponding monocyclic
derivatives.
Comment
For the synthesis of the gem-difluorinated derivatives, direct deoxyfluorination of the parent ketone gave only
complex mixtures of unidentified products and led to the successful implementation
of selective fluorodecarboxylation of a malonic acid derivative, in which the initial
fluorination occurs with good diastereoselectivity for the equatorial COOH group. For
the pK
a, introduction of a fluorine substituent increased the acidity of the protonated amino
groups with the bicyclic compounds observed to be more basic when compared to their
monocyclic counterparts. For the lipophilicity, again differences were observed between
the trans- and cis-isomers with the former demonstrating increased lipophilicity, while analysis of
the molecular structures indicates that the bicyclic fluorinated compounds adopt similar
conformations (distorted chair/boat) compared to the corresponding monocyclic derivatives.
