Saturated nitrogen and oxygen heterocycles are prevalent in bioactive molecules and represent 50% of the top 10 ring motifs in marketed drugs. Drug discovery is increasingly interested in screening topologically diverse libraries of compounds with higher 3-dimensional character. In this context, saturated heterocycles represent attractive sp3-rich pharmacophores and fragments with defined vectors for elaboration in 3D space. As such, methods that can readily synthesize these compounds and selectively access the different exit vectors from the ring are of high potential value for the development of new therapeutic agents. Directed C(sp3)–H functionalization of simple heterocyclic precursors can rapidly provide diverse collections of such valuable derivatives, probing the full 3D space around the ring. However, catalytic functionalization of unactivated C–H bonds on saturated heterocycles is little developed. This poster describes our contributions to this field, including the Pd-catalyzed C–H arylation of proline derivatives at C(3), directed by a C(2)-linked aminoquinoline auxiliary. Excellent cis-stereoselectivity was obtained, providing access to enantiopure 2,3-disubstituted products. Related conditions were then successfully applied to the C(3)–H arylation of piperidine, tetrahydrofuran and tetrahydropyran systems. Most recently, we reported the regio- and stereoselective C(4)–H arylation of pyrrolidine and piperidine derivatives, using a directing group at C(3). Divergent directing group removal and application to the formal synthesis of antidepressant (–)-paroxetine demonstrated the high potential of these protocols in drug discovery programs.

C(sp3)–H functionalization of saturated heterocycles at unactivated positions: Exploring 3D vectors for fragment growth

2019 Fall National Meeting

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