Late-stage synthesis of heterobifunctional molecules for PROTAC applications via ruthenium-catalysed C‒H amidation.

PROteolysis TArgeting Chimeras (PROTACs) are heterobifunctional molecules emerging as a powerful modality in drug discovery, with the potential to address outstanding medical challenges. However, the synthetic feasibility of PROTACs, and the empiric and complex nature of their structure-activity relationships continue to present formidable limitations. As such, modular and reliable approaches to streamline the synthesis of these derivatives are highly desirable. Here, we describe a robust ruthenium-catalysed late-stage C‒H amidation strategy, to access fully elaborated heterobifunctional compounds. Using readily available dioxazolone reagents, a broad range of inherently present functional groups can guide the C-H amidation on complex bioactive molecules. High selectivity and functional group tolerance enable the late-stage installation of linkers bearing orthogonal functional handles for downstream elaboration. Finally, the single-step synthesis of both CRBN and biotin conjugates is demonstrated, showcasing the potential of this methodology to provide efficient and sustainable access to advanced therapeutics and chemical biology tools.

Amino-oxetanes as amide isosteres by an alternative defluorosulfonylative coupling of sulfonyl fluorides.

Bioisosteres provide valuable design elements that medicinal chemists can use to adjust the structural and pharmacokinetic characteristics of bioactive compounds towards viable drug candidates. Aryl oxetane amines offer exciting potential as bioisosteres for benzamides-extremely common pharmacophores-but are rarely examined due to the lack of available synthetic methods. Here we describe a class of reactions for sulfonyl fluorides to form amino-oxetanes by an alternative pathway to the established SuFEx (sulfonyl-fluoride exchange) click reactivity. A defluorosulfonylation forms planar oxetane carbocations simply on warming. This disconnection, comparable to a typical amidation, will allow the application of vast existing amine libraries. The reaction is tolerant to a wide range of polar functionalities and is suitable for array formats. Ten oxetane analogues of bioactive benzamides and marketed drugs are prepared. Kinetic and computational studies support the formation of an oxetane carbocation as the rate-determining step, followed by a chemoselective nucleophile coupling step.

Chemical and structural investigation of the paroxetine-human serotonin transporter complex.

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.

Regio- and Stereoselective Palladium-Catalyzed C(sp3)-H Arylation of Pyrrolidines and Piperidines with C(3) Directing Groups.

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 K2CO3 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.

Recent advances in the chemistry of metallated azetidines.

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.

Bromomethyllithium-mediated chemoselective homologation of disulfides to dithioacetals.

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.