Late-Stage Saturation of Drug Molecules.

The available methods of chemical synthesis have arguably contributed to the prevalence of aromatic rings, such as benzene, toluene, xylene, or pyridine, in modern pharmaceuticals. Many such sp2-carbon-rich fragments are now easy to synthesize using high-quality cross-coupling reactions that click together an ever-expanding menu of commercially available building blocks, but the products are flat and lipophilic, decreasing their odds of becoming marketed drugs. Converting flat aromatic molecules into saturated analogues with a higher fraction of sp3 carbons could improve their medicinal properties and facilitate the invention of safe, efficacious, metabolically stable, and soluble medicines. In this study, we show that aromatic and heteroaromatic drugs can be readily saturated under exceptionally mild rhodium-catalyzed hydrogenation, acid-mediated reduction, or photocatalyzed-hydrogenation conditions, converting sp2 carbon atoms into sp3 carbon atoms and leading to saturated molecules with improved medicinal properties. These methods are productive in diverse pockets of chemical space, producing complex saturated pharmaceuticals bearing a variety of functional groups and three-dimensional architectures. The rhodium-catalyzed method tolerates traces of dimethyl sulfoxide (DMSO) or water, meaning that pharmaceutical compound collections, which are typically stored in wet DMSO, can finally be reformatted for use as substrates for chemical synthesis. This latter application is demonstrated through the late-stage saturation (LSS) of 768 complex and densely functionalized small-molecule drugs.

Piezoelectric Catalysis Induces Tumor Cell Senescence to Boost Chemo-Immunotherapy.

Cellular senescence, a vulnerable state of growth arrest, has been regarded as a potential strategy to weaken the resistance of tumor cells, leading to dramatic improvements in treatment efficacy. However, a selective and efficient strategy for inducing local tumor cellular senescence has not yet been reported. Herein, piezoelectric catalysis is utilized to reduce intracellular NAD+ to NADH for local tumor cell senescence for the first time. In detail, a biocompatible nanomedicine (BTO/Rh-D@M) is constructed by wrapping the piezoelectric BaTiO3/(Cp*RhCl2)2 (BTO/Rh) and doxorubicin (DOX) in the homologous cytomembrane with tumor target. After tumors are stimulated by ultrasound, negative and positive charges are generated on the BTO/Rh by piezoelectric catalysis, which reduce the intracellular NAD+ to NADH for cellular senescence and oxidize H2O to reactive oxygen species (ROS) for mitochondrial damage. Thus, the therapeutic efficacy of tumor immunogenic cell death-induced chemo-immunotherapy is boosted by combining cellular senescence, DOX, and ROS. The results indicate that 23.9% of the piezoelectric catalysis-treated tumor cells senesced, and solid tumors in mice disappeared completely after therapy. Collectively, this study highlights a novel strategy to realize cellular senescence utilizing piezoelectric catalysis and the significance of inducing tumor cellular senescence to improve therapeutic efficacy.

Anticancer Study on IrIII and RhIII Half-Sandwich Complexes with the Bipyridylsulfonamide Ligand.

Organometallic half-sandwich complexes [(η5-Cp)IrCl(L)]PF6 (1) and [(η5-Cp)RhCl(L)]PF6 (2) were prepared using pentamethylcyclopentadienyl chloride dimers of iridium(III) or rhodium(III) with the 4-amino-N-(2,2'-bipyridin-5-yl)benzenesulfonamide ligand (L) and ammonium hexafluorophosphate. The crystal structures of L, 1, and 2 were analyzed in detail. The coordination reactions of the ligand with the central ions were confirmed using various spectroscopic techniques. Additionally, the interactions between sulfaligand, Ir(III), and Rh(III) complexes with carbonic anhydrase (CA), human serum albumin (HSA), and CT-DNA were investigated. The iridium(III) complex (1) did not show any antiproliferative properties against four different cancer cell lines, i.e., nonsmall cell lung cancer A549, colon cancer HCT-116, breast cancer MCF7, lymphoblastic leukemia Nalm-6, and a nonmalignant human embryonic kidney cell line HEK293, due to high binding affinity to GSH. The sulfonamide ligand (L) and rhodium(III) complex (2) were further studied. L showed competitive inhibition toward CA, while complexes 1 and 2, uncompetitive. All compounds interacted with HSA, causing a conformational change in the protein's α-helical structure, suggesting the induction of a more open conformation in HSA, reducing its biological activity. Both L and 2 were found to induce cell death through a caspase-dependent pathway. These findings position L and 2 as potential starting compounds for pharmaceutical, therapeutic, or medicinal research.

Systematic Studies of Functional Group Tolerance and Chemoselectivity in Carbene-Mediated Intramolecular Cyclopropanation and Intermolecular C-H Functionalization.

Generating reliable data on functional group compatibility and chemoselectivity is essential for evaluating the practicality of chemical reactions and predicting retrosynthetic routes. In this context, we performed systematic studies using a functional group evaluation kit including 26 kinds of additives to assess the functional group tolerance of carbene-mediated reactions. Our findings revealed that some intermolecular heteroatom-hydrogen insertion reactions proceed faster than intramolecular cyclopropanation reactions. Lewis basic functionalities inhibited rhodium-catalyzed C-H functionalization of indoles. While performing these studies, we observed an unexpected C-H functionalization of a 1-naphthol variant used as an additive.

Antiproliferative in Vitro Evaluation of Terpenic Amines Synthesized via a Rhodium-catalyzed Hydroaminomethylation.

Terpene-derived alkaloids show a variety of biological activities, including antioxidant, anti-inflammatory, antimicrobial and cytotoxicity effects. In this work, homologated monoterpene amines have been prepared via a rhodium-catalyzed hydroaminomethylation of biomass-based alkenes, such as (R)-limonene, linalool, myrcene and camphene, in combination with secondary amines of aliphatic and aromatic nature, namely morpholine and N-methylaniline, leading to highly chemo- and regioselective processes. The as-prepared amines were obtained in 50-99 % overall yields, and in vitro tested on a human colon cancer cell line (HCT-116) to evaluate their cytotoxic potential. The lead compound of the series (3 a) showed cytotoxicity in the micromolar range (IC50 52.46 µM) via the induction of cell death by apoptosis, paving the way towards further structure-activity relationship studies.

The Rhodium Analogue of Coenzyme B12 as an Anti-Photoregulatory Ligand Inhibiting Bacterial CarH Photoreceptors.

Coenzyme B12 (AdoCbl; 5'-deoxy-5'-adenosylcobalamin), the quintessential biological organometallic radical catalyst, has a formerly unanticipated, yet extensive, role in photoregulation in bacteria. The light-responsive cobalt-corrin AdoCbl performs this nonenzymatic role by facilitating the assembly of CarH photoreceptors into DNA-binding tetramers in the dark, suppressing gene expression. Conversely, exposure to light triggers the decomposition of this AdoCbl-bound complex by a still elusive photochemical mechanism, activating gene expression. Here, we have examined AdoRhbl, the non-natural rhodium analogue of AdoCbl, as a photostable isostructural surrogate for AdoCbl. We show that AdoRhbl closely emulates AdoCbl in its uptake by bacterial cells and structural functionality as a regulatory ligand for CarH tetramerization, DNA binding, and repressor activity. Remarkably, we find AdoRhbl is photostable even when bound "base-off/His-on" to CarH in vitro and in vivo. Thus, AdoRhbl, an antivitamin B12, also represents an unprecedented anti-photoregulatory ligand, opening a pathway to precisely target biomimetic inhibition of AdoCbl-based photoregulation, with new possibilities for selective antibacterial applications. Computational biomolecular analysis of AdoRhbl binding to CarH yields detailed structural insights into this complex, which suggest that the adenosyl group of photoexcited AdoCbl bound to CarH may specifically undergo a concerted non-radical syn-1,2-elimination mechanism, an aspect not previously considered for this photoreceptor.

Chemoenzymatic Synthesis of 13-Oxoverruculogen.

Verruculogens are rare fumitremorgin alkaloids that contain a highly unusual eight-membered endoperoxide. In this paper, we report a concise chemoenzymatic synthesis of 13-oxoverruculogen using enzymatic C-H peroxidation and rhodium-catalyzed C-C bond activation reactions to install the eight-membered endoperoxide and the pentacyclic core of the natural product, respectively. Our strategy involves the use of 13-epi-fumitremorgin B as a substrate analog for endoperoxidation by verruculogen synthase, FtmOx1. The resulting product, 13-epi-verruculogen, is the first unnatural endoperoxide generated by FtmOx1 and is used in the first synthesis of 13-oxoverruculogen. This strategy enables a 10-step synthesis of this natural product from commercially available starting materials and illustrates a hybrid approach utilizing biocatalytic and transition-metal-catalyzed reactions to access challenging alkaloid architectures. Moreover, this work demonstrates the use of native enzyme promiscuity as a viable strategy for the chemoenzymatic synthesis of natural products.

Transition Metal-Catalyzed Biaryl Atropisomer Synthesis via a Torsional Strain Promoted Ring-Opening Reaction.

Arising from the restricted rotation of a single bond caused by steric or electronic effects, atropisomerism is one of the few fundamental categories for molecules to manifest their three-dimensional characters into which axially chiral biaryl compounds fall. Despite the widespread occurrence of axially chiral skeletons in natural products, bioactive molecules, and chiral ligands/organocatalysts, catalytic asymmetric methods for the synthesis of these structures still lag behind demand. Major challenges for the preparation of these chiral biaryls include accessing highly sterically hindered variants while controlling the stereoselectivity. A couple of useful strategies have emerged for the direct asymmetric synthesis of these molecules in the last two decades.Recently, we have engaged in catalytic asymmetric synthesis of biaryl atropisomers via transition metal catalysis, including asymmetric ring-openings of dibenzo cyclic compounds. During these studies, we serendipitously discovered that the two substituents adjacent to the axis cause these dibenzo cyclic molecules to be distorted to minimize steric repulsion. The distorted compounds display higher reactivity in the ring-opening reactions than the non-distorted molecules. In other words, torsional strain can promote a ring-opening reaction. On the basis of this concept, we have successfully realized the catalytic asymmetric ring-opening reaction of cyclic diaryliodoniums, dibenzo silanes, and 9H-fluoren-9-ols, which delivered several differently substituted ortho tetra-substituted biaryl atropisomers in high enantioselectivity. The torsional strain not only activates the substrates toward ring-opening under mild conditions but also changes the chemoselectivity of bond-breaking events. In the palladium-catalyzed carboxylation of S-aryl dibenzothiophenium, the torsional strain inversed the bond selectivity from exocyclic C-S bond cleavage to the ring-opening reaction.In this Account, we summarize our studies on copper-, rhodium-, or palladium-catalyzed asymmetric ring-opening reactions of dibenzo cyclic compounds as a useful collection of methods for the straightforward preparation of ortho tetra-substituted biaryl atropisomers with high enantiopurity on the basis of the above-mentioned torsional strain-promoted ring-opening coupling strategy. In the last part, the torsional strain energies are also discussed with the aid of density functional theory (DFT) calculations.

Transition Metal-Catalyzed Regioselective Direct C-H Amidation: Interplay between Inner- and Outer-Sphere Pathways for Nitrene Cross-Coupling Reactions.

Catalytic C-N bond cross-coupling reactions have been a subject of fundamental importance in synthetic organic and medicinal chemistry because amides and amines are ubiquitous motifs in natural products, functional materials, and pharmaceuticals. Since the pioneering works of Breslow and Mansuy on the metalloporphyrin-catalyzed direct hydrocarbon amidation using sulfonyliminoiodinane reagents, substantial development has been achieved toward practical and selective amination protocols. Notably, Du Bois's group developed the dirhodium(II,II) carboxylate catalytic system for direct C(sp3)-H amidations via Rh-sulfonyl nitrene intermediates. Yet, this protocol suffers from competitive alkene aziridination and is limited to electron-rich tertiary and ethereal C-H bonds; analogous direct amidation of arenes remained ineffective.This Account discusses our early effort to explore cyclopalladated complexes for ortho-selective C(aryl)-H amidations. While Buchwald-Hartwig amination cannot be directly applied to arenes, effective amidation of the 2-arylpyridines occurred when an external oxidant such as K2S2O8 was employed. Preliminary studies suggested that the amidation may proceed through reactive Pd-nitrene intermediates. Aiming to develop more diversified amidation protocols, we employed nosyloxycarbamates as nitrene precursors for the Pd-catalyzed ortho-amidation of N-pivalanilides. Likewise, we developed the ortho-selective amidation of benzoic acids to produce anthranilic acids, which are versatile precursors for many medicinally valuable heterocycles. In an attempt to expand the C(aryl)-N coupling reactions to amines, we studied the d6 piano-stool Cp*Rh(III) systems [Cp* = pentamethylcyclopentadienyl]. Our work established a sound reaction platform based on the electrophilic aminating reagents including N-chloroamines, hydroxyamides, and N-carboxyhydrazides for effective C(aryl)-N bond formation in aryl-metal complexes.Building upon the metal-nitrene reaction platform, we moved forward to examine γ-lactam synthesis by intramolecular carbonyl nitrene C(sp3)-H insertion. Noted that carbonyl nitrenes are prone to undergo Curtius-type rearrangement to form isocyanate; we found that the π-basic Ru(II) center effectively decomposes dioxazolones to afford the carbonyl nitrene for regioselective γ-C(sp3)-H insertion. With chiral diphenylethylenediamines (dpen) as ligands bearing electron-withdrawing arylsulfonyl substituents, the [(p-cymene)Ru(dpen)] complex catalyzed the decomposition of the dioxazolones to afford chiral γ-lactams by formal carbonyl nitrene C(sp3)-H insertion. Enantioselective nitrene insertion to allylic and propargylic C(sp3)-H bonds was also achieved with remarkable tolerance to the C═C and C≡C bonds. Notably, the selectivity of the [(p-cymene)Ru] system switched to C(aryl)-H bonds to give dihydroquinolinones when l-proline was employed as ligand. Recently, we aimed to address the regiocontrolled amidation of unactivated methylene C-H bonds using NiH catalyst. While tertiary and benzyl C-H bonds can be differentiated by their bond dissociation energies and steric properties, methylene groups making up the hydrocarbon skeleton display similar electronic and steric properties. In this context, we exploited the five-membered nickelacycle formation to terminate the NiH-mediated chain-walk isomerization, and the nickelacycle reacted with dioxazolones to furnish the C(sp3)-N bond at the γ-methylene position.This Account summarizes our contribution to the development of C-N bond cross-coupling reactions via C-H activation. By exploiting the inner-sphere and outer-sphere reaction pathways, we successfully developed regioselective protocols that target C(sp3)-H and C(aryl)-H bonds. The mechanistic underpinning of the selectivity of different C-H bonds and related studies on the affiliated catalytic systems will be discussed.

Rhodium-Based Nanozymes: Recent Advances and Challenges.

Rhodium (Rh) is a non-toxic transition metal used as various nanomaterials with unique structures and properties. Rh-based nanozymes can mimic the activities of natural enzymes, overcome the limitation of the application scope of natural enzymes, and interact with various biological microenvironments to play a variety of functions. Rh-based nanozymes can be synthesized in various ways, and different modification and regulation methods can also enable users to control catalytic performance by adjusting enzyme active sites. The construction of Rh-based nanozymes has attracted great interest in the biomedical field and impacted the industry and other areas. This paper reviews the typical synthesis and modification strategies, unique properties, applications, challenges, and prospects of Rh-based nanozymes. Next, the unique features of Rh-based nanozymes are emphasized, including adjustable enzyme-like activity, stability, and biocompatibility. In addition, we discuss Rh-based nanozymes biosensors and detection, biomedical therapy, and industrial and other applications. Finally, the future challenges and prospects of Rh-based nanozymes are proposed.

Intramolecular Hydroarylation of Arenes via Imidazole-Directed C-H Activation in Aqueous Methanol Using Rhodium(III) as the Catalyst and Mechanistic Study.

A mild and greener approach for intramolecular regioselective hydroarylation is described for the efficient and elegant preparation of a number of dihydrobenzofurans and dihydrobenzo[b]thiophenes using imidazole as a directing group and Rh(III) as a catalyst. Moreover, the protocol may be extended to the formation of indoline and chromane derivatives. Deuterium scrambling experiments and characterization of isolated rhodacycle intermediate were explored to understand the mechanism in a better way.

Rhodium-Catalyzed Synthesis of 2-Methylindoles via C-N Bond Cleavage of N-Allylbenzimidazole.

A rhodium-catalyzed oxidative C-H/N-H dehydrogenative [3 + 2] annulation strategy has been reported between anilines and N-allylbenzimidazole for the synthesis of 2-methylindole scaffolds. An N-allylbenzimidazole has been used as a 2C synthon for the synthesis of indole, and more importantly, this transformation involves the cleavage of the thermodynamically stable C-N bond of allylamine. Detailed mechanistic studies have been performed and a key intermediate was detected in HRMS. This transformation proceeds through a cascade of C(sp2)-H allylation followed by intramolecular cyclization.

Rhodium(I)-Catalyzed Direct Enantioselective C-H Functionalization of Indoles.

A highly regiospecific vinylogous carbene insertion protocol for direct asymmetric C-H functionalization of indoles with arylvinyldiazoacetates has been developed. Under the catalysis of simple Rh(I)/chiral diene complexes, the reaction occurs solely at the vinylogous position of the vinylcarbenoid with exceptional E selectivity and enantiocontrol. It provides an efficient way to obtain an interesting class of chiral indole scaffolds bearing an α,ß-unsaturated ester unit and a gem-diaryl carbon stereocenter in good yields (≤99%) with excellent enantioselectivities (≤96%) at room temperature.

Three-Component Chemo-Selective Synthesis of N-(o-Alkenylaryl) Pyrazoles by Pyrazole Annulation and Rh-Catalyzed Chemo-Selective Aryl C-H Addition Cascade.

By using readily available enaminones, aryl hydrazine hydrochlorides, and alkynes as starting materials, the chemo-selective three-component synthesis of atropisomeric N-(o-alkenylaryl) pyrazoles has been efficiently accessed with rhodium catalysis. Unlike Satoh-Miura reaction leading to the alkyne-based C-H benzannulation by using prior prepared N-phenyl pyrazoles and alkynes as substrates, this three-component protocol displays unprecedented selectivity of C-H alkenylation by blocking the second round metal alkenylation with the key protonation step in the presence of acids.

Synthesis of Dithia[5]helicenes and Enantioselective Synthesis of Helically Chiral Thia[6]helicenes via Rh-Catalyzed Intramolecular [2 + 2 + 2] Cycloaddition of Triynes.

Dithia[5]helicenes and helically chiral thia[6]helicenes were synthesized in high yields via a cationic Rh-catalyzed intramolecular [2 + 2 + 2] cycloaddition of triynes bearing sulfur-containing 1,6-diynes. Thia[6]helicene could be obtained with a high enantiomeric excess of P-isomers by using (S)-SEGPHOS as a chiral ligand. This protocol is the first example of the synthesis of thiahelicenes via [2 + 2 + 2] cycloaddition and can also be used for the asymmetric construction of an aza[6]helical skeleton.

Rhodium(III)-Catalyzed Conjugate Addition of ß-CF3-Enones with Quinoline N-Oxides.

The site-selective incorporation of a trifluoromethyl group into biologically active molecules and pharmaceuticals has emerged as a central topic in medicinal chemistry and drug discovery. Herein, we demonstrate the rhodium(III)-catalyzed conjugate addition of ß-trifluoromethylated enones with quinoline N-oxides, which result in the generation of ß-trifluoromethyl-ß'-quinolinated ketones. The reaction proceeds under mild conditions with complete functional group tolerance. The synthetic applicability was showcased by successful gram-scale experiments and valuable synthetic transformations of coupling products.

Modulating Escape Channels of Cycloheptatrienyl Rhodium Carbenes To Form Semibullvalene.

We describe the various escape channels available to dirhodium carbene intermediates from cycloheptatrienyl diazo compounds located with density functional theory. An intramolecular cyclopropanation would, in principle, provide a new route to semibullvalenes (SBVs). A detailed exploration of the potential energy surface reveals that methylating carbon-7 suppresses a competing ß-hydride migration pathway to heptafulvene products, giving SBV formation a reasonable chance. During our explorations, we additionally discovered unusual spirononatriene, spironorcaradiene, and metal-stabilized 9-barbaralyl cation structures as local minima.

Synthesis of Pyrazolidinone-Fused Benzotriazines through C-H/N-H Bond Functionalization of 1-Phenylpyrazolidinones with Oxadiazolones.

Presented herein is an efficient synthesis of pyrazolidinone-fused benzotriazines through the cascade reaction of 1-phenylpyrazolidinones with oxadiazolones. The formation of the title products is initiated by Rh(III)-catalyzed C-H/N-H bond metallation of 1-phenylpyrazolidinone and subsequent coordination with oxadiazolone followed by migratory insertion along with CO2 liberation, proto-demetallation, and intramolecular condensation. To our knowledge, this is the first synthesis of pyrazolidinone-fused benzotriazines based on the C-H bond activation strategy by using oxadiazolone as an easy-to-handle amidine surrogate. In general, this new protocol has advantages such as valuable products, easily accessible substrates, redox neutral conditions, concise synthetic procedure, high efficiency, and compatibility with diverse functional groups. Moreover, the usefulness of this method is further showcased by scale-up synthetic scenario and suitability to substrates derived from natural products such as thymol and nerol.

Visible Light-Assisted Coordination of a Rh(III)-BODIPY Complex to Guanine.

Most photodynamic therapeutics (PDTs) used in cancer treatment require oxygen to work efficiently to terminate cancer cells. These PDTs do not efficiently treat tumors in hypoxic conditions. Rh(III) polypyridyl complexes have been reported to have a photodynamic therapeutic effect in hypoxic conditions when exposed to UV light. UV light can damage tissue and cannot penetrate deep to reach cancer cells. This work proposes the coordination of a BODIPY fluorophore to a rhodium metal center to form a Rh(III)-BODIPY complex that enhances the reactivity of the rhodium under visible light. This complex formation is facilitated with the BODIPY as the highest occupied molecular orbital (HOMO), while the lowest unoccupied molecular orbital (LUMO) is localized on the Rh(III) metal center. Irradiation of the BODIPY transition at ∼524 nm can cause an indirect electron transfer from the orbital of the BODIPY-centered HOMO to the Rh(III)-centered LUMO, populating the dσ* orbital. In addition, photo binding of the Rh complex covalently coordinated to the N (7) position of guanine in an aqueous solution was also observed by mass spectrometry after chloride dissociation upon irradiation with green visible light (532 nm LED). Calculated thermochemistry values of the Rh complex reaction in methanol, acetonitrile, water, and guanine were determined using DFT calculations. All enthalpic reactions and Gibbs free energies were identified as endothermic and nonspontaneous, respectively. This observation supports the chloride dissociation using 532 nm light. This Rh(III)-BODIPY complex expands the class of visible light-activated Rh(III) photocisplatin analogs that may have potential photodynamic therapeutic activity for the treatment of cancers in hypoxic conditions.

Stabilization of Dinuclear Rhodium and Iridium Clusters on Layered Titanate and Niobate Supports.

Atomically dispersed organometallic clusters can provide well-defined nuclearity of active sites for both fundamental studies as well as new regimes of activity and selectivity in chemical transformations. More recently, dinuclear clusters adsorbed onto solid surfaces have shown novel catalytic properties resulting from the synergistic effect of two metal centers to anchor different reactant species. Difficulty in synthesizing, stabilizing, and characterizing isolated atoms and clusters without agglomeration challenges allocating catalytic performance to atomic structure. Here, we explore the stability of dinuclear rhodium and iridium clusters adsorbed onto layered titanate and niobate supports using molecular precursors. Both systems maintain their nuclearity when characterized using aberration-corrected high-angle annular dark-field scanning transmission electron microscopy (HAADF-STEM). Statistical analysis of HAADF-STEM images revealed that rhodium and iridium dimers had mean cluster-to-cluster distances very similar to what is expected from a random distribution of atoms over a large area, indicating that they are dispersed without aggregation. The stability of dinuclear rhodium clusters supported on titanate nanosheets was also investigated by X-ray absorption fine structure (EXAFS), DRIFTS, and first-principles calculations. Both X-ray absorption spectroscopy and HAADF-STEM simulations, guided by density functional theory (DFT)-optimized structure models, suggested that rhodium dimers adsorb onto the nanosheets in an end-on binding mode that is stable up to 100 °C under reducing conditions. This study highlights that crystalline nanosheets derived from layered metal oxides can be used as model supports to selectively stabilize dinuclear clusters, which could have implications for heterogeneous catalysis.