gem-Difluoro-3-azabicyclo[3.n.1]alkanes and Their Derivatives - Bicyclic Fluorinated Piperidine Isosteres for Drug Discovery

An approach to gem-difluoro-3-azabicyclo[3.n.1]alkane- derived building blocks through double-Mannich addition- deoxofluorination sequence is described. The scope of the method was demonstrated for a series of saturated (hetero)cyclic ketones or ketoesters (including five- to seven-membered cycloalkane derivatives and N-, O-, S-containing saturated heterocycles). Further transformations of functional groups produced various bifunctionalized difluorinated building blocks, namely, N-protected aminoacids, mono-N-Boc-protected diamines, and unprotected aminoalcohols in good to excellent overall yields. For the azabicyclo[3.3.1]alkane series, a potential for isosteric replacements is demonstrated by evaluation of the key physicochemical properties (i. e., pK(a)(H) and LogP).