Synthesis and Properties of Bicyclic Fluorinated Piperidine Derivatives

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.