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 stereo-selectivity 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

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

Interplay between Ionization and Tautomerism in Bioactive β-Enamino Ester-Containing Cyclic Compounds: Study of Annulated 1,2,3,6-Tetrahydroazocine Derivatives

Depending on the chemical scaffold, the bioactive species could reflect the interplay between ionization and tautomerism, often complicated by the possibility to populate different conformational states in the case of flexible ligands. In this context, theoretical methods can be valuable to discern the role of these factors, as shown here for β-enamino esters of 1,2,3,6 tetrahydroazocino fused ring systems, some of which had proven to be suitable scaffolds for designing novel acetylcholinesterase inhibitors. The compounds investigated herein form two clusters with distinctive experimental pKa values (i.e., α,β-diesters and β-esters ranging within 6.1-7.3 and 8.2-9.0 pKa intervals, respectively), which implies a drastic difference in the most populated species at physiological conditions. While chemoinformatic tools did not provide a consistent description of the actual pKa values, the theoretical analysis performed for the protonated and neutral species of these compounds revealed a marked change in the tautomeric preference of the tetrahydroazocine moiety upon (de)protonation. Excellent agreement between calculated and experimental pKa values was found when the tautomeric preference of protonated and neutral species was considered. Overall, this study highlights the potential use of high-level computational methods to disclose the mutual influence between ionization, tautomerism and conformational preferences in multifunctional (bio)organic compounds

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

Transition metal-catalyzed directed C(sp3)–H functionalization of saturated heterocycles

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. Introduction 2 alpha-C–H Functionalization with directing group on nitrogen 3 C–H Functionalization at unactivated C(3), C(4) and C(5) positions 3.1 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 functionalization 5 Conclusio

On the mechanism and selectivity of palladium catalyzed C(sp3)–H arylation of pyrrolidines and piperidines at unactivated C4 positions: discovery of an improved dimethylamino-quinoline (DMAQ) mide directing group

Directed C–H functionalization is a powerful means to functionalize otherwise unreactive C‒H bonds, for which aminoquinoline amides provide a powerful and frequently used directing group. Saturated N-heterocycles are crucial motifs in medicinal chemistry. However, the C–H functionalization of N-heterocycles has posed considerable chal-lenges, often giving incomplete conversions. On unsymmetrical substrates, poorly understood regio- and stereoselectivity considerations have prevented more forcing conditions and further limited yields. Here we present a combined experimental and computational study on the regio- and stereoselective C4 arylation of pyrrolidines and piperidines with C3 aminoquinoline amide directing groups. Detailed mechanistic experiments are presented including deuteration, kinetics investigations, and isolation of palladacycles. The palladacycle formation is reversible and proceeds preferentially at C4, though activation of both C–H bonds at C4, cis and trans to the directing group, occurs equally. The cis-selectivity results from strain in the trans-palladacycle (ΔΔGtrans-cis ~6 kcal∙mol–1), that is retained in subsequent transition states. Hence, the oxidative addition step is stereodetermining. However, the turnover-limiting step for the catalytic cycle is reductive elimination, and reduced rates and yields were observed with electron poor aryl iodides. Importantly, kinetics experiments reveal a rapid loss of active Pd catalyst, likely due to the build-up of iodide, and a role for K2CO3/PivOH in catalyst turnover. Finally, we present the discovery of an improved 4-dimethylamine-8-aminoquinoline directing group (DMAQ). This removable auxiliary achieves >2x rate acceleration, generally im-proved yields, as well as improved cis-selectivity, by promoting reductive elimination. A broad reaction scope of aryl iodides is demonstrated, including the late-stage functionalization of drug compounds which is enabled by the use of only one equivalent of functionalized iodides

Interplay between Ionization and Tautomerism in Bioactive β-Enamino Ester-Containing Cyclic Compounds: Study of Annulated 1,2,3,6-Tetrahydroazocine Derivatives

Depending on the chemical scaffold, a bioactive species could reflect the interplay between ionization and tautomerism, which is often complicated by the possibility of populating different conformational states, in the case of flexible ligands. In this context, theoretical methods can be valuable to discern the role of these factors, as shown here for β-enamino esters of 1,2,3,6-tetrahydroazocino-fused ring systems, some of which had proven to be suitable scaffolds for designing novel acetylcholinesterase inhibitors. The compounds investigated herein form two clusters with distinctive experimental pKa values (i.e., α,β-diesters and β-esters ranging within 6.1-7.3 and 8.2-9.0 pKa intervals, respectively), which implies a drastic difference in the most populated species at physiological conditions. While chemoinformatic tools did not provide a consistent description of the actual pKa values, the theoretical analysis performed for the protonated and neutral species of these compounds revealed a marked change in the tautomeric preference of the tetrahydroazocine moiety upon (de)protonation. Excellent agreement between the calculated and experimental pKa values was found when the tautomeric preference of the protonated and neutral species was considered. Overall, this study highlights the potential use of high-level computational methods to disclose the mutual influence between ionization, tautomerism, and conformational preferences in multifunctional (bio)organic compounds

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

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

Bioisosteres provide valuable design elements for medicinal chemists to adjust the structural and pharmacokinetic characteristics of bioactive compounds towards viable drug candidates. Aryl oxetane amines offer exciting potential as bioisosteres for benzamides, an extremely common pharmacophore, but are rarely examined due to the lack of available synthetic methods. Here, we describe a new class of reactions for sulfonyl fluorides to form aminooxetanes 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