Synthetic Challenge Research Articles

Activation and C−C Coupling of Aryl Iodides via Bismuth Photocatalysis

AbstractWithin the emerging field of bismuth redox catalysis, the catalytic formation of C−C bonds using aryl halides would be highly desirable; yet such a process remains a synthetic challenge. Herein, we present a chemoselective bismuth‐photocatalyzed activation and subsequent coupling of (hetero)aryl iodides with pyrrole derivatives to access C(sp2)−C(sp2) linkages through C−H functionalization. This unique reactivity is the result of the bismuth complex featuring two redox state‐dependent interactions with light, which 1) activates the Bi(I) complex for oxidative addition via MLCT, and 2) promotes the homolytic cleavage of aryl Bi(III) intermediates through a LLCT process.

Unlocking Photocycloaddition Reactivity of Tropolone by Cage-Confined Visible-Light Photocatalysis for Multilevel Selective Transformation.

The precise asymmetric photochemical transformation of organic compounds containing multiple reactive sites presents significant progress in synthetic chemistry. Herein, we report an unprecedented visible-light-induced cascade transformation of tropolone cyclic triene derivatives by using chiral photoactive metal-organic cages (cPMOCs) as enzyme-mimicking multipocket photocatalysts. The cage-confined photocatalysis promotes three successive elementary steps, i.e., enantioselective [2 + 2] photocycloaddition with chalcone, regio-, and diastereoselective α-ketol rearrangement, and a stereoselective 1,3-acyl shift, resulting in bicyclo[3.2.2]nonane skeleton with multichiral-centers unattainable by other methods. This study demonstrates how complex synthetic challenges of peri-, chemo-, and stereoselectivities could be subtly manipulated by cage-confined supramolecular catalysis for exploration of new reactivities.

Host‐Guest Assemblies of Polyoxovanadate Clusters as Supramolecular Catalysts

Supramolecular functional materials can be used to overcome some of the most challenging tasks in materials science, where the dynamic nature of supramolecular interactions can be leveraged to fine‐tune the properties of the material. The Lindqvist hexavanadate family of polyoxometalates are interesting candidates for supramolecular materials due to their redox and Lewis acid properties that enable their application in energy conversion or catalysis. Despite their promising potential, hexavanadate clusters are underrepresented in supramolecular materials, mainly due to the synthetic challenges related to their inherent reactivity. In this work, pillar[5]arene was successfully grafted onto a Lindqvist hexavanadate and the resulting structure was confirmed by single crystal X‐ray diffraction, presenting the first example of a crystal structure of a polyoxometalate covalently functionalized with a pillar[5]arene. By introducing a ditopic guest molecule that could interlink pillar[5]arene moieties, host‐guest interactions were leveraged as the driving force for the formation of supramolecular assemblies incorporating hexavanadate clusters in a controlled manner. The enhanced catalytic performance of the resulting aggregates confirmed their potential application as functional catalytic materials. This novel approach for developing hexavanadate‐based catalysts reported here showcases the potential of using host‐guest interactions as a means to introduce catalytically active metal‐oxo clusters into supramolecular frameworks.

Host-Guest Assemblies of Polyoxovanadate Clusters as Supramolecular Catalysts.

Supramolecular functional materials can be used to overcome some of the most challenging tasks in materials science, where the dynamic nature of supramolecular interactions can be leveraged to fine-tune the properties of the material. The Lindqvist hexavanadate family of polyoxometalates are interesting candidates for supramolecular materials due to their redox and Lewis acid properties that enable their application inenergy conversion or catalysis. Despite their promising potential, hexavanadate clusters are underrepresented in supramolecular materials, mainly due to the synthetic challenges related to their inherent reactivity. In this work, pillar[5]arene was successfully grafted onto a Lindqvist hexavanadate and the resulting structure was confirmed by single crystal X-ray diffraction, presenting the first example of a crystal structure of a polyoxometalate covalently functionalized with a pillar[5]arene. By introducing a ditopic guest molecule that could interlink pillar[5]arene moieties, host-guest interactions were leveraged as the driving force for the formation of supramolecular assemblies incorporating hexavanadate clusters in a controlled manner. The enhanced catalytic performance of the resulting aggregates confirmed their potential application as functional catalytic materials. This novel approach for developing hexavanadate-based catalysts reported here showcases the potential of using host-guest interactions as a means to introduce catalytically active metal-oxo clusters into supramolecular frameworks.

Intermolecular Oxidopyrylium (5 + 2) Cycloaddition/Reductive Ring-Opening Strategy for the Synthesis of α-Methoxytropones.

α-Methoxytropone is a structural motif found in various natural products and other compounds of interest to the scientific community but remains a synthetic challenge. The present Note describes the synthesis of variously substituted α-methoxytropones and related compounds through an intermolecular 3-hydroxy-4-pyrone-based oxidopyrylium (5 + 2) cycloaddition followed by a samarium iodide-mediated reductive ring-opening. The strategy is highlighted in the synthesis of a novel AC-ring analogue of colchicine to compare it to existing methods.

A Multiresponsive Ferrocene‐Based Chiral Overcrowded Alkene Twisting Liquid Crystals

AbstractThe reversible modulation of chirality has gained significant attention not only for fundamental stereochemical studies but also for numerous applications ranging from liquid crystals (LCs) to molecular motors and machines. This requires the construction of switchable molecules with (multiple) chiral elements in a highly enantioselective manner, which is often a significant synthetic challenge. Here, we show that the dimerization of an easily accessible enantiopure planar chiral ferrocene‐indanone building block affords a multi‐stimuli‐responsive dimer (FcD) with pre‐determined double bond geometry, helical chirality, and relative orientation of the two ferrocene motifs in high yield. This intrinsically planar chiral switch can not only undergo thermal or photochemical E/Z isomerization but can also be reversibly and quantitatively oxidized to both a monocationic and a dicationic state which is associated with significant changes in its (chir)optical properties. Specifically, FcD acts as a chiral dopant for cholesteric LCs with a helical twisting power (HTP) of 13 μm−1 which, upon oxidation, drops to near zero, resulting in an unprecedently large redox‐tuning of the LC reflection color by up to 84 nm. Due to the straightforward stereoselective synthesis, FcD, and related chiral switches, are envisioned to be powerful building blocks for multi‐stimuli‐responsive molecular machines and in LC‐based materials.

An engineered aldolase enables the biocatalytic synthesis of 2′-functionalized nucleoside analogues

AbstractNucleosides functionalized at the 2′-position play a crucial role in therapeutics, serving as both small-molecule drugs and modifications in therapeutic oligonucleotides. However, the synthesis of these molecules often presents substantial synthetic challenges. Here we present an approach to the synthesis of 2′-functionalized nucleosides based on enzymes from the purine nucleoside salvage pathway. Initially, active-site variants of deoxyribose-5-phosphate aldolase were generated for the highly stereoselective synthesis of d-ribose-5-phosphate analogues with a broad range of functional groups at the 2-position. Thereafter, these 2-modified pentose phosphates were converted into 2′-modified purine analogues by construction of one-pot multienzyme cascade reactions, leading to the synthesis of guanosine (2′-OH) and adenosine (2′-OH, 2′-Me, 2′-F) analogues. This cascade allows for the control of the 2′-functional group alongside 2-stereochemistry. Our findings demonstrate the capability of these biocatalytic cascades to efficiently generate 2′-functionalized nucleosides, starting from simple starting materials.

Epitaxial Growth of Silver Clusters from Ag57 to Ag72 via Laminating Multiple Different Anion Templates.

The established capability of anion templates in precisely manipulating the size, geometry, and function of metal clusters is well acknowledged. However, the development of a systematic methodology for orchestrating the assembly of silver clusters, particularly those encompassing multiple distinct types of anion templates, remains elusive due to the formidable synthetic challenge. In this work, we report two novel silver clusters, Ag57 and Ag72, using two and three different anion templates, respectively. Ag57 features a gyroscope-like monovalent cation with an Ag3 triangle core sandwiched by one [SiW9O34]10- and a triad of Cl- anion templates. By intentionally introducing the third anion template, SO42-, the structure is expanded to the unprecedented Ag72 (with 15 silver atoms epitaxially grown on top of Ag57) resembling a tumbler, inside of which two Ag3 layers are laminated by one [SiW9O34]10-, seven Cl- and one SO42- anion templates in parallel with respect to longitudinal orientation. It is noteworthy that Ag72 exhibits remarkable structural complexity and represents a pioneering achievement as the first silver cluster incorporating three distinct types of anion templates. In addition, Ag72 demonstrates a significant advantage over Ag57, particular in terms of applications such as luminescent thermometers and remote laser ignition.

Epitaxial Growth of Silver Clusters from Ag57 to Ag72 via Laminating Multiple Different Anion Templates

The established capability of anion templates in precisely manipulating the size, geometry, and function of metal clusters is well acknowledged. However, the development of a systematic methodology for orchestrating the assembly of silver clusters, particularly those encompassing multiple distinct types of anion templates, remains elusive due to the formidable synthetic challenge. In this work, we report two novel silver clusters, Ag57 and Ag72, using two and three different anion templates, respectively. Ag57 features a gyroscope‐like monovalent cation with an Ag3 triangle core sandwiched by one [SiW9O34]10− and a triad of Cl− anion templates. By intentionally introducing the third anion template, SO42−, the structure is expanded to the unprecedented Ag72 (with 15 silver atoms epitaxially grown on top of Ag57) resembling a tumbler, inside of which two Ag3 layers are laminated by one [SiW9O34]10−, seven Cl− and one SO42− anion templates in parallel with respect to longitudinal orientation. It is noteworthy that Ag72 exhibits remarkable structural complexity and represents a pioneering achievement as the first silver cluster incorporating three distinct types of anion templates. In addition, Ag72 demonstrates a significant advantage over Ag57, particular in terms of applications such as luminescent thermometers and remote laser ignition.

Isothiourea‐Catalysed Acylative Kinetic Resolution of Tertiary Pyrazolone Alcohols

AbstractThe development of methods for the selective acylative kinetic resolution (KR) of tertiary alcohols is a recognised synthetic challenge with relatively few successful substrate classes reported to date. In this manuscript, a highly enantioselective isothiourea‐catalysed acylative KR of tertiary pyrazolone alcohols is reported. The scope and limitations of this methodology have been developed, with high selectivity observed across a broad range of substrate derivatives incorporating varying substitution at N(2)‐, C(4)‐ and C(5)‐, as well as bicyclic constraints within the pyrazolone scaffold (30 examples, selectivity factors (s) typically >100) at generally low catalyst loadings (1 mol %). The application of this KR method to tertiary alcohols derived directly from a natural product (geraniol), alongside pharmaceutically relevant drug compounds (indomethacin, gemfibrozil and probenecid), with high efficiency (s >100) is also described. The KR process is readily amenable to scale up using bench grade solvents and reagents, with effective resolution on a 50 g (0.22 mol) scale demonstrated. The key structural motif leading to excellent selectivity in this KR process has been probed through computation, with an NC=O⋅⋅⋅isothiouronium interaction from substrate to acylated catalyst observed within the favoured transition state. Similarly, the effect of C(5)‐aryl substitution that leads to reduced experimental selectivity is probed, with a competitive π–isothiouronium interaction identified as leading to reduced selectivity.

Activation and C-C Coupling of Aryl Iodides via Bismuth Photocatalysis.

Within the emerging field of bismuth redox catalysis, the catalytic formation of C-C bonds using aryl halides would be highly desirable; yet such a process remains a synthetic challenge. Herein, we present a chemoselective bismuth-photocatalyzed activation and subsequent coupling of (hetero)aryl iodides with pyrrole derivatives to access C(sp2)-C(sp2) linkages through C-H functionalization. This unique reactivity is the result of the bismuth complex featuring two redox state-dependent interactions with light, which 1) activates the Bi(I) complex for oxidative addition via MLCT, and 2) promotes the homolytic cleavage of aryl Bi(III) intermediates through a LLCT process.

Nickel‐Catalyzed Reductive Protocol to Access Silacyclobutanes with Unprecedented Functional Group Tolerance

AbstractWhile significant progress has been made in the area of transition metal‐catalyzed ring‐opening and formal cycloaddition reactions of 1,1‐disubstituted silacyclobutanes (SCBs), synthesizing these SCBs—particularly those bearing additional functional groups—continues to present synthetic challenges. In this context, we present a novel Ni‐catalyzed reductive coupling reaction that combines 1‐chloro‐substituted silacyclobutanes with aryl or vinyl halides and pseudohalides, thereby obviating the need for organometallic reagents. This method facilitates the generation of 1,1‐disubstituted silacyclobutanes with a remarkable tolerance for various functional groups. This approach serves as a complementary and more step‐economical alternative to the commonly used yet moisture‐ and air‐sensitive nucleophilic substitution reactions involving Grignard or lithium reagents. Our initial mechanistic studies indicate that this reaction is initiated by oxidative cleavage of the Si−Cl bond in 1‐chlorosilacyclobutanes, which represents a distinct mechanism from the previously documented reductive coupling processes involving carbon electrophiles and chlorosilanes.

Nickel-Catalyzed Reductive Protocol to Access Silacyclobutanes with Unprecedented Functional Group Tolerance.

While significant progress has been made in the area of transition metal-catalyzed ring-opening and formal cycloaddition reactions of 1,1-disubstituted silacyclobutanes (SCBs), synthesizing these SCBs-particularly those bearing additional functional groups-continues to present synthetic challenges. In this context, we present a novel Ni-catalyzed reductive coupling reaction that combines 1-chloro-substituted silacyclobutanes with aryl or vinyl halides and pseudohalides, thereby obviating the need for organometallic reagents. This method facilitates the generation of 1,1-disubstituted silacyclobutanes with a remarkable tolerance for various functional groups. This approach serves as a complementary and more step-economical alternative to the commonly used yet moisture- and air-sensitive nucleophilic substitution reactions involving Grignard or lithium reagents. Our initial mechanistic studies indicate that this reaction is initiated by oxidative cleavage of the Si-Cl bond in 1-chlorosilacyclobutanes, which represents a distinct mechanism from the previously documented reductive coupling processes involving carbon electrophiles and chlorosilanes.

A Tricyclic Framework with Integrated B←N and Cyano Dual Functionalization for Superior n-Type Organic Electronics.

n-Type conjugated polymers featuring low-lying lowest unoccupied molecular orbital (LUMO) energy levels are essential for achieving high-performance n-type organic thin-film transistors (OTFTs) and organic thermoelectrics (OTEs). However, the synthesis of acceptors with strong electron-withdrawing characteristics presents a significant challenge. Herein, a peripheral functionalization strategy is employed on the widely used tricyclic framework anthracene by introducing dual N,O-bidentate BF2/B(CN)2 groups to enhance its electron-withdrawing capability. This approach successfully navigates synthetic challenges, leading to the development of two novel acceptor building blocks: DBNF and DBNCN. Compared to the counterparts with a single N,O-bidentate BF2/B(CN)2 moiety, DBNF and DBNCN exhibit an extended π-backbone, enhanced molecular packing, and improved electron-withdrawing properties. Utilizing these innovative acceptor monomers, copolymers, PDBNF and PDBNCN, are synthesized, which exhibit considerably suppressed LUMO ≈ -4.0 eV. The deep LUMO of PDBNF together with its favourable bimodal packing orientation leads to remarkable electron mobility of 3.04 cm² V⁻¹ s⁻¹ with improved stability in OTFTs. Importantly, efficient n-doping in OTEs is achieved with PDBNCN, exhibiting exceptional conductivity of 95.5 S cm⁻¹ and a maximum power factor of 147.8 μW m⁻¹ K⁻²-among the highest reported for solution-processed n-type polymers.

A Tricyclic Framework with Integrated B←N and Cyano Dual Functionalization for Superior n‐Type Organic Electronics

n‐Type conjugated polymers featuring low‐lying lowest unoccupied molecular orbital (LUMO) energy levels are essential for achieving high‐performance n‐type organic thin‐film transistors (OTFTs) and organic thermoelectrics (OTEs). However, the synthesis of acceptors with strong electron‐withdrawing characteristics presents a significant challenge. Herein, a peripheral functionalization strategy is employed on the widely used tricyclic framework anthracene by introducing dual N,O‐bidentate BF2/B(CN)2 groups to enhance its electron‐withdrawing capability. This approach successfully navigates synthetic challenges, leading to the development of two novel acceptor building blocks: DBNF and DBNCN. Compared to the counterparts with a single N,O‐bidentate BF2/B(CN)2 moiety, DBNF and DBNCN exhibit an extended π‐backbone, enhanced molecular packing, and improved electron‐withdrawing properties. Utilizing these innovative acceptor monomers, copolymers, PDBNF and PDBNCN, are synthesized, which exhibit considerably suppressed LUMO ≈ –4.0 eV. The deep LUMO of PDBNF together with its favourable bimodal packing orientation leads to remarkable electron mobility of 3.04 cm² V⁻¹ s⁻¹ with improved stability in OTFTs. Importantly, efficient n‐doping in OTEs is achieved with PDBNCN, exhibiting exceptional conductivity of 95.5 S cm⁻¹ and a maximum power factor of 147.8 μW m⁻¹ K⁻²—among the highest reported for solution‐processed n‐type polymers.

La2O2MQ2 phases: Stability and synthetic challenges

Oxychalcogenides containing transition metal or p block cations have potential for thermoelectric, photocatalytic and magnetic applications but the synthetic pathways to these quaternary phases are not fully understood. This presents a challenge to the design and preparation of new functional materials. Our combined experimental and computational study of La2O2MQ2 (M = +2 cation; Q = sulfide, selenide anion) systems explores the thermodynamic constraints on synthesis and highlights the subtle balance in stabilities of phases formed via competing reaction pathways.

Synthetic Challenges toward Modeling Formate Dehydrogenases Using [WVI≡S] Complexes Supported by a Tetradentate [N2S2]4- Ligand.

This report documents our attempts at synthesizing a terminal [WVI≡S] complex supported by a tetradentate, diamido/dithiolate ligand ([N2S2]4-). The target compound was selected because it would serve as a synthetic model for the active sites of formate dehydrogenase (FDH) enzymes. Although the desired [N2S2]WVI≡S species was observed as an NEt3 adduct by mass spectrometry in one case, generally unwanted side reactions prevented isolation and definitive characterization of the target compound. Instead, isolated products characterized by X-ray crystallography included {[N2S2]H}WVI(S2)Cl from redox chemistry of the terminal sulfide, ([N2S2]WVI)2(μ-[N2S2]) from dissociation of the terminal sulfide, ({[N2S2]H}WV)2(μ-S)2 from metal reduction and μ-sulfide bridge formation, and {[N2S2]H}2 from disulfide bond formation via thiolate redox chemistry. A product formed from adventitious exposure to air/moisture, {[N2S2]H2}WVI(O)2, was also characterized. The diverse range of products formed simply from attempted metalation of the [N2S2]4- ligand with Cl4WVI≡S highlights the synthetic challenges toward building active sites that are structurally faithful to FDH.

Hit-to-lead optimization of 4,5-dihydrofuran-3-sulfonyl scaffold against Leishmania amazonensis. Effect of an aliphatic moiety

In line with our objective of designing new antileishmanial compounds for oral use, we report the synthesis and biological evaluation in vitro of original 4,5-dihydrofuran derivatives bearing an amidoxime group. Previous optimization focused on position 3 of the dihydrofuran ring involving aromatic fragments, resulting in the identification of the compound (HIT) 4-(5-benzyl-3-((4-fluorophenyl)sulfonyl)-5-methyl-4,5-dihydrofuran-2-yl)-N′-hydroxybenzimidamide (IC50 = 5.4 ± 1.0 μM, L. amazonensis promastigote, IC50 = 7.9 ± 1.1 μM, L. amazonensis intracellular amastigote). In the present work, position 3 was substituted with an aliphatic moiety. This modification was guided by a ligand-based approach, given the unknown biological target or mechanism of action for this compound. The 4,5-dihydrofuran derivatives were synthesized using microwave-assisted manganese (III) acetate-based oxidative cyclization of linear β-keto-carboxylic and β-keto-sulfone substrates, overcoming synthetic challenges to obtain aliphatic derivatives of 4,5-dihydrofuran-3-carboxamides. Finally, an unexpected and interesting biological activity with the 4,5-dihydrofuran-3-carboxylate (IC50 < 5 μM) against the amastigote form is discussed.

Photocatalytic furan-to-pyrrole conversion.

The identity of a heteroatom within an aromatic ring influences the chemical properties of that heterocyclic compound. Systematically evaluating the effect of a single atom, however, poses synthetic challenges, primarily as a result of thermodynamic mismatches in atomic exchange processes. We present a photocatalytic strategy that swaps an oxygen atom of furan with a nitrogen group, directly converting the furan into a pyrrole analog in a single intermolecular reaction. High compatibility was observed with various furan derivatives and nitrogen nucleophiles commonly used in drug discovery, and the late-stage functionalization furnished otherwise difficult-to-access pyrroles from naturally occurring furans of high molecular complexity. Mechanistic analysis suggested that polarity inversion through single electron transfer initiates the redox-neutral atom exchange processes at room temperature.

Benzoylation of Tetrols: A Comparison of Regioselectivity Patterns for O- and S-Glycosides of d-Galactose.

Efficient protecting group strategies are important for glycan synthesis and represent a unique synthetic challenge in differentiating sugar ring hydroxyl groups. Direct methods to enable regioselective protecting group installation are thus desirable. Herein, we explore a one-step regioselective benzoylation to deliver 2,3,6-protected d-galactose building blocks from tetrols across a variety of α- and β-, O- and S-glycoside substrates. We focus on benzoyl chloride as the esterifying reagent and a reaction temperature of -40 °C to screen the regioselectivity outcome for twenty-two different glycosides, based on isolated yields. Using this methodology, we demonstrate the capability for α-linked aryl and alkyl glycosides (O- and S- d-galactosides, d-galactosamines, and l-fucose), delivering consistent isolated yields (>65%) for 2,3,6-benzoylated products. We extend to explore β-linked systems, where the observed regioselectivity is not paralleled. We posit that both steric and electronic factors from the anomeric substituent contribute to modulating the reactivity competition between 2-OH and 4-OH, enabling the formation of regioisomeric mixtures. However, a certain balance of these factors within the aglycon can deliver 2,3,6-regioselectivity, notably for β-O-Et and β-O-CH2CF3 glycosides. The methodology contributes toward understanding the peculiarities of regioselective carbohydrate-protecting group installation, exploring the importance of the anomeric substituent upon ring hydroxyl group reactivity.