Structural characterization and in silico toxicity prediction of degradation impurities of roxadustat.

Roxadustat is the first drug approved for anemia due to chronic kidney disease. Drug degradation profile is very crucial for assessing the quality and safety of the drug substances and their formulations. Forced degradation studies are conducted for quick prediction of drug degradation products. Forced degradation of roxadustat was carried out as per ICH guidelines, and nine degradation products (DPs) were observed. These DPs (DP-1 to DP-9) were separated using the reverse phase HPLC gradient method with an XBridge column (250 mm × 4.6 mm, 5 µm). The mobile phase consisted of 0.1% formic acid (solvent A) and acetonitrile (solvent B) at a flow rate of 1.0 ml/min. The chemical structures of all the DPs were proposed by using LC-Q-TOF/MS. DP-4 and DP-5, the two major degradation impurities, were isolated, and NMR was used to confirm their chemical structures. Based on our experiments, the roxadustat was found stable to thermal degradation in solid state and oxidative conditions. However, it was unstable in acidic, basic, and photolytic conditions. A very remarkable observation was made about DP-4 impurity. DP-4 was generated as a common degradation impurity in alkaline hydrolysis, neutral hydrolysis as well as photolysis conditions. DP-4 has a similar molecular mass to roxadustat but is structurally different. DP-4 is chemically, (1a-methyl-6-oxo-3-phenoxy-1,1a,6,6a-tetrahydroindeno [1,2-b] aziridine-6a-carbonyl) glycine. In silico toxicity study was conducted using Dereck software to gain the best knowledge of the drug and its degradation products towards carcinogenicity, mutagenicity, teratogenicity, and skin sensitivity. A further study using molecular docking confirmed the potential interaction of DPs with proteins responsible for toxicity. DP-4 shows a toxicity alert due to the presence of aziridine moiety.

Rh(III)-Catalyzed C-H Annulation of Sulfoxonium Ylides and 1,3-Diynes: A Rapid Access to Alkynyl-1-Naphthol Derivatives.

An effective redox-neutral strategy to synthesize aryl/alkynyl and alkyl/alkynyl substituted 1-naphthol derivatives has been efficaciously developed by Rh(III)-catalyzed [4+2]-annulation of sulfoxonium ylides and 1,3-diynes with excellent regio- and chemoselectivity. Subsequently, the same strategy was extended to furnish various unsymmetrical binaphthol motifs in one-pot manner. Interestingly, the TMS-derived 1,3-diyne predominantly delivered the 3-alkynyl-1-naphthol via desilylation pathway. The salient features such as traceless directing group, broad substrate scope, good functional group tolerance, and operationally simple conditions made the present protocol more valuable and appealing.

1,3-Diynes: A Versatile Precursor in Transition-Metal Catalyzed (Mediated) C-H Functionalizations.

Transition metal-catalyzed C-H functionalization of diverse arenes with alkyne units has attracted enormous attention for decades since they provide straightforward access to various functionalization/annulations, which are commonly present in bioactive compounds and natural products. Recently, conjugated alkynes (1,3-diynes) have been utilized as key coupling partner in many C-H activation reactions due to their versatile characteristic properties. The presence of two C≡C bonds in conjugated 1,3-diyne brings the new diversity in synthetic transformations, such as chemo-, regioselective pathways, mono-bis functionalizations, cascade annulations, etc. Herein, we summarized the latest developments in the realm of transition-metal-catalyzed C-H functionalizations of diverse arenes with 1,3-diynes. Moreover, we highlighted the diverse transformations, conditions, mechanisms and applications of the corresponding reaction in detail.

Iodonium ylides: an emerging and alternative carbene precursor for C-H functionalizations.

The metal-catalyzed successive activation and functionalization of arene/heteroarene is one of the most fundamental transformations in organic synthesis and leads to privileged scaffolds in natural products, pharmaceuticals, agrochemicals, and fine chemicals. Particularly, transition-metal-catalyzed C-H functionalization of arenes with carbene precursors via metal carbene migratory insertion has been well studied. As a result, diverse carbene precursors have been evaluated, such as diazo compounds, sulfoxonium ylides, triazoles, etc. In addition, there have been significant developments with the use of iodonium ylides as carbene precursors in recent years, and these reactions proceed with high efficiencies and selectivities. This review provides a comprehensive overview of iodonium ylides in C-H functionalizations, including the scope, limitations, and their potential synthetic applications.

Ru(II)-Catalyzed C-H Functionalization of 2-Arylbenzimidazoles with Iodonium Ylides: A Straightforward Access to Bridgehead Polycyclic N-Heterocycles.

Herein, we disclose an efficient ruthenium-catalyzed C-H functionalization of 2-arylbenzimidazoles/2-arylimidazoles with iodonium ylides leading to substituted tetracyclic and pentacyclic bridgehead N-heterocycles, wherein iodonium ylide acts as a carbene precursor. For the first time, iodonium ylide proceeds through a Ru-carbenoid intermediate. Further, the synthetic utility of this protocol was successfully shown for gram-scale synthesis and useful synthetic transformations.

Synthesis of Indenone Derivatives by Rh(III)-Catalyzed C-H Functionalization of Sulfoxonium Ylides with 1,3-Diynes.

The transition-metal-catalyzed C-H functionalization of sulfoxonium ylides with alkynes formally participates in [4 + 2] annulations to deliver the naphthol scaffolds. In contrast, herein we disclose the first Rh(III)-catalyzed C-H activation, followed by redox-neutral [3 + 2] annulation of sulfoxonium ylides with 1,3-diynes, which delivers the alkynated indenone derivatives. This protocol features a good functional group tolerance, a broad substrate scope, moderate to excellent yields, and mild reaction conditions. The reaction mechanism was supported through ESI-HRMS by characterizing key intermediates in the catalytic cycle.

The solvent-controlled Rh(III)-catalyzed switchable [4+2] annulation of 2-arylIndoles with iodonium ylides.

Highly selective and switchable [4+2] annulations of 2-arylindoles with iodonium ylides were achieved by performing solvent-controlled Rh(III)-catalyzed C-H activations. When using DCM as a solvent, the C-H functionalization of 2-arylindoles with iodonium ylides selectively delivered indolo[2,1-a]isoquinoline derivatives. In contrast, the same catalytic system with a polar HFIP solvent predominately provided benzo[a]carbazole moieties.

A comprehensive review on potential therapeutic inhibitors of nosocomial Acinetobacter baumannii superbugs.

Acinetobacter baumannii, a Gram-negative, glucose non-fermentative coccobacilli are responsible for causing a wide range of opportunistic nosocomial infections, thus listed as a WHO "critical priority pathogen", for which identification and development of new antibacterial agents are an urgent unmet medical need. The current review attempts to present an overview of various mechanisms (enzymatic and non-enzymatic), virulence factors responsible for A. baumannii resistance. Furthermore, inhibitors of A. baumannii are categorized into different classes highlighting their MDR inhibition properties. In addition, novel adjuvants that potentiate existing antibiotics, as well as natural and synthetic compounds that limit biofilm formation in A. baumannii infections are discussed.

Rhodium-Catalyzed Enal Transfer with N-Methoxypyridazinium Salts.

Herein, we report a simple method for functionalized enals involving enal-transfer reaction of water-soluble N-methoxypyridazinium salts. This open-flask reaction proceeds under mild aqueous basic conditions through [2,3]-sigmatropic rearrangement of propargyl/allyl sulfur-ylides derived from in situ-generated Rh-(E)-enalcarbene. Various synthetically challenging allene- and allyl-functionalized (E)-enals with a γ-C(sp3) quaternary center were obtained in good to high yields. InCl3-catalyzed cascade cyclization of allenyl-enal and aniline gave a valuable pyrrolo[1,2-a]quinoline motif.

Rh(III)-Catalyzed Chemodivergent Annulations between Indoles and Iodonium Carbenes: A Rapid Access to Tricyclic and Tetracyclic N-Heterocylces.

Herein, we report an acid-controlled highly tunable selectivity of Rh(III)-catalyzed [4 + 2] and [3 + 3] annulations of N-carboxamide indoles with iodonium ylides lead to form synthetically important tricyclic and tetracyclic N-heterocycles. Here, iodonium ylide serves as a carbene precursor. The protocol proceeds under operationally simple conditions and provides novel tricyclic and tetracyclic scaffolds such as 3,4-dihydroindolo[1,2-c]quinazoline-1,6(2H,5H)-dione and 1H-[1,3]oxazino[3,4-a]indol-1-one derivatives with a broad range of functional group tolerance and moderate to excellent yields. Furthermore, the protocol synthetic utility was extended for various chemical transformations and was easily scaled up to a large-scale level.

Recent advances in Rh(III)/Ir(III)-catalyzed C-H functionalization/annulation via carbene migratory insertion.

In the past two decades, transition metal-catalyzed C-H functionalization followed by annulations with various coupling partners has received much attention in organic synthesis. In particular, Rh(iii) or Ir(iii) catalyzed regioselective C-H functionalization followed by the cyclization of diverse arenes with metal carbene precursors has become a highly investigated research field in recent years. The purpose of this review is to provide a comprehensive essay on the Rh(iii)/Ir(iii) catalyzed C-H functionalizations/annulations via carbene migratory insertion, focusing on the diverse metal carbene precursors with arenes/alkenes reported so far. The highlighted examples are categorized by nitrogen, oxygen, sulfur-containing heterocycles and carbocyclizations. Further, key mechanistic approaches are also briefly described.

Co(III), Rh(III) & Ir(III)-Catalyzed Direct C-H Alkylation/Alkenylation/Arylation with Carbene Precursors.

Metal carbenes play a pivotal role in transition-metal-catalyzed synthetic transfer reactions. The metal carbene is generated either from a diazo compound through facile extrusion of N2 with a metal catalyst or in situ generated from other sources like triazoles, pyriodotriazoles, sulfoxonium ylides and iodonium-ylide. On the other hand, Co(III), Rh(III) & Ir(III)-catalyzed C-H functionalizations have been well established as a key synthetic step to enable the construction of various synthetic transformations. Interestingly, in recent years, merging of these two concepts C-H activation and carbene migratory insertion gained much attention, in particular group 9 metal-catalyzed arene C-H functionalizations with carbene precursors via carbene migratory insertion. In this review, we summarize recent advances in Co(III), Rh(III) & Ir(III)-catalyzed direct C-H alkylation/alkenylation/arylation with carbene precursors and also discuss key synthetic intermediates within the catalytic cycles.

[1+1+3] Annulation of Diazoenals and Vinyl Azides: Direct Synthesis of Functionalized 1-Pyrrolines through Olefination.

A dirhodium carboxylate catalyzed [1+1+3] annulation reaction of diazoenals and vinyl azides that gives synthetically important enal-functionalized 1-pyrroline derivatives was developed. The reaction involves a novel rhodium-catalyzed olefination of diazoenals with vinyl azides via electrophilic enal carbenoids, resulting in a new class of enal acrylates. The annulation reaction was used for the direct synthesis of valuable deuterated 1-pyrrolines. Structural diversification of the enal-functionalized 1-pyrrolines resulted in the biologically important pyrrolidine-fused oxaziridine, amino acid derivatives, and a 6-azabicyclo[3.2.1]octane motif present in polycyclic alkaloids.

Pyridazine N-Oxides as Precursors of Metallocarbenes: Rhodium-Catalyzed Transannulation with Pyrroles.

Pyridazine N-oxides are used for the first time as precursors of metallocarbenes. These nitrogen-rich heterocycles led to the discovery of a novel acceptor and donor-acceptor enalcarbenoids. The synthetic utility of these metallocarbenes was demonstrated in the rhodium-catalyzed denitrogenative transannulation of pyridazine N-oxides with pyrroles to the valuable alkyl, 7-aryl, and 7-styryl indoles. The transannulation strategy was applied to the synthesis of a potent anticancer agent.

Synergistic rhodium(II) carboxylate and brønsted acid catalyzed multicomponent reactions of enalcarbenoids: direct synthesis of α-pyrrolylbenzylamines.

The design of a synergistic rhodium(II) carboxylate and BINOL phosphoric acid catalyzed efficient multicomponent reaction of enaldiazo compounds, arylamines, and aryl aldehydes leading to the first transition-metal-catalyzed direct synthesis of valuable α-pyrrolylbenzylamines is disclosed. The reaction is proposed to involve a transient ammonium ylide of a new class of electrophilic rhodium enalcarbenoid, its regioselective Mannich reaction, and a cyclocondensation cascade. The methodology was used in a highly diastereoselective synthesis of a binaphthyl based chiral pyrrole.

Rhodium enalcarbenoids: direct synthesis of indoles by rhodium(II)-catalyzed [4+2] benzannulation of pyrroles.

Disclosed herein is the design of an unprecedented electrophilic rhodium enalcarbenoid which results from rhodium(II)-catalyzed decomposition of a new class of enaldiazo compounds. The synthetic utility of these enalcarbenoids has been successfully demonstrated in the first transition-metal-catalyzed [4+2] benzannulation of pyrroles, thus leading to substituted indoles. The new benzannulation has been applied to the efficient synthesis of the natural product leiocarpone as well as a potent adipocyte fatty-acid binding protein inhibitor.