Pyrrolidines and piperidines are prevalent structural motifs in natural products and pharmaceuticals with wide-ranging biological activity. Desirable physico-chemical properties, accompanied by a high sp3 character, make them attractive fragments and building blocks for drug discovery. As such, there is enormous interest in developing efficient, rapid and divergent synthetic routes to these valuable compounds, particularly with control of regio- and stereochemistry. In recent years, transition metal-catalyzed functionalization of C(sp3)–H bonds, has emerged as a powerful strategy to streamline the synthesis of complex molecules. This offers high potential for the iterative and divergent synthesis of heterocyclic derivatives with different substitution patterns and defined stereochemistry. However, C–H functionalization of saturated N-heterocycles is little developed, in particular at positions remote from the heteroatom (i.e. unactivated positions). This presentation will describe the selective synthesis of cis-3,4-disubstituted pyrrolidine and piperidine derivatives, via C(4)–H arylation. Excellent regio- and stereoselectivity is achieved using Pd catalysis and an aminoquinoline directing group at C(3), with C(4) functionalization always preferred over competing C(2). A minor trans-derivative is observed for piperidine arylation, deriving from a trans-palladacyclic intermediate. Divergent removal of the directing group delivers varied biologically relevant building blocks, containing amide, carboxylic acid and alcohol functionalities, and enabled the stereocontrolled formal synthesis of antidepressant drug (–)-paroxetine.

Regio- and stereoselective palladium-catalyzed C(sp3)–H arylation of pyrrolidines and piperidines with C(3) directing groups

2019 Fall National Meeting

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