The selective synthesis of cis-3,4-disubstituted pyrrolidines and piperidines is achieved by a Pd-catalyzed C-H arylation with excellent regio- and stereoselectivity using an aminoquinoline auxiliary at C(3). The arylation conditions are silver free, use a low catalyst loading, and employ inexpensive KCO as a base. Directing group removal is accomplished under new, mild conditions to access amide-, acid-, ester-, and alcohol-containing fragments and building blocks. This C-H arylation protocol enabled a short and stereocontrolled formal synthesis of (-)-paroxetine.

Antidepressants target the serotonin transporter (SERT) by inhibiting serotonin reuptake. Structural and biochemical studies aiming to understand binding of small-molecules to conformationally dynamic transporters like SERT often require thermostabilizing mutations and antibodies to stabilize a specific conformation, leading to questions about relationships of these structures to the bonafide conformation and inhibitor binding poses of wild-type transporter. To address these concerns, we determined the structures of ∆N72/∆C13 and ts2-inactive SERT bound to paroxetine analogues using single-particle cryo-EM and x-ray crystallography, respectively. We synthesized enantiopure analogues of paroxetine containing either bromine or iodine instead of fluorine. We exploited the anomalous scattering of bromine and iodine to define the pose of these inhibitors and investigated inhibitor binding to Asn177 mutants of ts2-active SERT. These studies provide mutually consistent insights into how paroxetine and its analogues bind to the central substrate-binding site of SERT, stabilize the outward-open conformation, and inhibit serotonin transport.

The almost unexplored four-membered heterocycles azetidines, represent a particularly interesting class of molecules, among the family of saturated nitrogen heterocycles. Although often challenging to synthesize, substituted azetidines strongly attract chemists because of their importance in catalysis, stereoselective synthesis and medicinal chemistry. This review aims to give a brief summary of modern developments in direct metal-based functionalization of the azetidine ring, focusing on the regio- and stereoselectivity of these reactions, as well as on some useful synthetic applications. It will be highlighted, in particular, how an interplay of factors such as structure, substitutions at both nitrogen and carbon atoms and coordinative phenomena deeply influence the reactivity of the corresponding metallated species, paving the way for easy planning a site-selective functionalization of azetidines.

An efficient, chemoselective homologation of disulfides and diselenides to the corresponding dithio- and diselenoacetals has been developed via the addition of bromomethyllithium. Chemoselectivity is fully preserved in the presence of concomitant electrophilic sites decorating the substrates. The synthetic potential of selected dithioacetals has been evaluated in Feringa-Fañanas-Mastral-type Pd-catalyzed coupling with an organolithium and in the unusual 1,4-addition to a Weinreb amide.

Synthetic methods that can readily access saturated heterocycles with different substitution patterns and with control of stereo- and regiochemistry are of huge potential value in the development of new medicinal compounds. Directed C–H functionalization of simple and commercially available precursors offers the potential to prepare diverse collections of such valuable compounds that can probe the different available exit vectors from a ring system. Nonetheless, the presence of the Lewis basic heteroatoms makes this a significant challenge. This review covers recent advances in the catalytic C–H functionalization of saturated heterocycles, with a view to different heterocycles (N, O, S), substitution patterns and transformations.1 Introduction2 α-C–H Functionalization with Directing Group on Nitrogen3 C–H Functionalization at Unactivated C(3), C(4), and C(5) Positions3.1 C–H Functionalization at C(3) with Directing Groups at C(2)3.2 C–H Functionalization at C(3), C(4), and C(5): Directing Groups at C(4) and C(3)4 Transannular C–H Functionalization5 Conclusion