Palladium-catalysed directed C(sp3)–H functionalisation of saturated N-heterocycles at unactivated C4 positions

Saturated N-heterocycles are prevalent motifs in bioactive compounds and represent important structures for pharmaceutical screening. As such, synthetic methods that can readily access these derivatives with high regio- and stereocontrol would be of significant value for the discovery of new therapeutics. Catalytic C–H functionalisation offers high potential for the iterative and divergent synthesis of substituted N-heterocycles from simple cyclic precursors. The research in this thesis describes the selective synthesis of cis-3,4-disubstituted pyrrolidines and piperidines by Pd-catalysed C(sp3)–H functionalisation with aryl iodides. As described in chapter 3, high regio- and stereoselectivity is achieved using an aminoquinoline amide directing group at C(3), with C(4)-functionalisation always preferred over competing C(2). Divergent directing group removal delivers various biologically relevant building blocks, containing amide, carboxylic acid and alcohol functionalities. The synthetic utility of this protocol for drug discovery applications is described in chapter 4. C(4)–H arylation followed by directing group removal enables the stereocontrolled formal synthesis of antidepressant (–)-paroxetine and the total synthesis of enantiopure Br- and I-paroxetine analogues. Furthermore, the synthesis of a library of arylated pyrrolidine and piperidine fragments for pharmaceutical screening is demonstrated. Mechanistic investigations into the observed regio- and stereoselectivity are discussed in chapter 5. Deuteration studies, kinetic analysis and DFT calculations suggest reversible C–H activation to occur at different positions on the ring. Subsequent stereodetermining oxidative addition of PdII to PdIV and turnover-limiting reductive elimination deliver the C(4)-arylated products as cis-diastereomers. During this study, evidence for a fast catalyst deactivation process is observed. Attempts to overcome this limitation are finally discussed in chapter 6. This ultimately results in the development of an improved 4-dimethylamino-8-quinolinyl amide directing group. This novel removable auxiliary provides a faster reaction rate, higher yields and a broader substrate scope, and enables the late-stage functionalisation of complex biorelevant compounds.Open Acces

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

The selective synthesis of <i>cis</i>-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

Ruthenium-catalysed C‒H amidation for the late-stage synthesis of PROTACs

PROteolysis TArgeting Chimeras (PROTACs) are a powerful modality in drug discovery, offering 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 compounds are highly desirable. Here, we describe a robust ruthenium-catalysed late-stage C‒H amidation strategy, to provide modular access to both fully elaborated PROTACs and drug conjugates. 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 PROTAC and biotin conjugates is demonstrated, showcasing the potential of this methodology to provide efficient and sustainable access to advanced therapeutics and chemical biology tools

Stereoselective Palladium-Catalyzed C(sp3)–H Mono-Arylation of Piperidines and Tetrahydropyrans with a C(4) Directing Group

A selective Pd-catalyzed C(3)–H cis-functionalization of piperidine and tetrahydropyran carboxylic acids is achieved using a C(4) aminoquinoline amide auxiliary. High mono- and cis-selectivity is attained by using mesityl carboxylic acid as an additive. Conditions are developed with significantly lower reaction temperatures (≤50 °C) than other reported heterocycle C(sp3)–H functionalization reactions, which is facilitated by a DoE optimization. A one-pot C–H functionalization-epimerization procedure provides the trans-3,4-disubstituted isomers directly. Divergent aminoquinoline removal is accomplished with the installation of carboxylic acid, alcohol, amide and nitrile functional groups. Overall fragment compounds suitable for screening are generated in 3–4 steps from readily-available heterocyclic carboxylic acids

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