One Stone, Three Birds: One-Pot Synthesis of Pyrido[3,2-a]phenoxazin-5-one Derivatives from o-Aminophenols with Triple Roles, Paraformaldehyde, and Enaminones via the Povarov Reaction.

A novel multicomponent cascade cyclization reaction in one pot for the preparation of pyrido[3,2-a]phenoxazin-5-ones from simple o-aminophenols, paraformaldehyde, and enaminones has been established. It is noteworthy that o-aminophenol plays multiple roles serving as both a bis-nucleophile and an iminoquinone precursor, which can in situ generate aminophenoxazinones to undergo the Povarov reaction for the first time to yield pyrido[3,2-a]phenoxazin-5-ones with a high efficiency. Moreover, the photoluminescence of pyrido[3,2-a]phenoxazin-5-ones has polarity sensitivity and features aggregation-induced emission (AIE) characteristics, which is promising for bioimaging and theranostic applications.

Successive Promotion of Formal [3+2] Cycloaddition of Aryl Methyl Ketones by I2 and Zn: Access to 2-Hydroxy-4-morpholin-2,5-diarylfuran-3(2H)-ones with a Quaternary Carbon Center.

2-Hydroxy-4-morpholin-2,5-diarylfuran-3(2H)-one derivatives were constructed sequentially using iodine and zinc dust from simple and readily available methyl ketone and morpholine as the starting materials. Under mild conditions, C-C, C-N, and C-O bonds formed in a one-pot synthesis. A quaternary carbon center was successfully constructed, and the active drug fragment morpholine was introduced into the molecule.

I2-Promoted gem-Diarylethene Involved Aza-Diels-Alder Reaction and Wagner-Meerwein Rearrangement: Construction of 2,3,4-Trisubstituted Pyrimido[1,2-b]indazole Skeletons.

A [3 + 1 + 2] cyclization-rearrangement reaction scheme was developed to synthesize pyrimido[1,2-b]indazoles from aryl methyl ketones, 3-aminoindazoles, and gem-diarylethenes. This metal-free process proceeds via a sequential aza-Diels-Alder reaction and Wagner-Meerwein rearrangement, and a possible reaction mechanism was demonstrated based on control experiments. This method exhibits good substrate compatibility and allows simple reaction conditions. Moreover, the products display significant aggregation-induced emission characteristics after simple modifications.

Direct Hydrodefluorination of CF3-Alkenes via a Mild SN2' Process Using Rongalite as a Masked Proton Reagent.

A concise and efficient hydrodefluorination process was developed for the synthesis of gem-difluoroalkenes. This reaction employs rongalite as a masked proton source and does not require any additional catalysts or reductants. Notably, trifluoromethyl alkenes having both terminal and internal double bonds are compatible with this process, allowing for a wider range of substrates. The successful late-stage functionalizations of pharmaceuticals and gram-scale syntheses were used to demonstrate the viability of this method.

Aniline assisted dimerization of phenylalanines: convenient synthesis of 2-aroyl-3-arylquinoline in an I2-DMSO system.

We herein report an efficient synthesis of 2-aroyl-3-arylquinolines from phenylalanines and anilines. The mechanism involves I2-mediated Strecker degradation enabled catabolism and reconstruction of amino acids and a cascade aniline-assisted annulation. Both DMSO and water act as oxygen sources in this convenient protocol.

A Pummerer Reaction-Enabled Modular Synthesis of Alkyl Quinoline-3-carboxylates and 3-Arylquinolines from Amino Acids.

Concise synthesis of functionalized quinolines has received continuous research attention owing to the biological importance and synthetic potential of bicyclic N-heterocycles. However, synthetic routes to the 2,4-unsubstituted alkyl quinoline-3-carboxylate scaffold, which is an important motif in drug design, remain surprisingly limited, with modular protocols that proceed from readily available materials being even more so. We herein report an acidic I2-DMSO system that converts readily available aspartates and anilines into alkyl quinoline-3-carboxylate. This method can be extended to a straightforward synthesis of 3-arylquinolines by simply replacing the aspartates with phenylalanines. Mechanistic studies revealed that DMSO was activated by HI via a Pummerer reaction to provide the C1 synthon, while the amino acid catabolized to the C2 synthon through I2-mediated Strecker degradation. A formal [3 + 2 + 1] annulation of these two concurrently generated synthons with aniline was responsible for the selective formation of the quinoline core. The synthetic utility of this protocol was illustrated by the efficient synthesis of human 5-HT4 receptor ligand. Moreover, an unprecedented chemoselective synthesis of 2-deuterated, 3-substituted quinoline, featuring this reaction, has been established.

Synthesis of Tetrahydro-2H-thiopyran 1,1-Dioxides via [1+1+1+1+1+1] Annulation: An Unconventional Usage of a Tethered C-S Synthon.

An unprecedented [1+1+1+1+1+1] annulation process has been developed for the construction of tetrahydro-2H-thiopyran 1,1-dioxides. Notably, rongalite acted as a tethered C-S synthon in this reaction and can be chemoselectively used as triple C1 units and as a source of sulfone. Mechanistic investigation indicated that two different carbon-increasing models are involved in this reaction in which rongalite serves as C1 units.

One-Pot Synthesis of Diaryl 1,2-Diketones via Zn-Mediated Reductive Coupling.

A reductive coupling reaction was established for the synthesis of diaryl 1,2-dicarbonyl compounds from aryl methyl ketones in good yields. The mechanistic study showed the reaction undergoes C(CO)-C(sp3) bond cleavage, with the reductive coupling reaction occurring through an electron transfer process. Notably, the reaction not only is simple to operate but also has mild reaction conditions and a wide range of applicable substrates.

I2-Promoted In Situ Cyclization-Rethiolation Reaction: Synthesis of 2-Aliphatic- or Aromatic-Substituted Indolizines.

An efficient I2-promoted one-pot one-step three-component reaction for the synthesis of sulfhydryl indolizines from methyl ketones, 2-pyridylacetate derivatives, and sulfonyl hydrazides via an in situ cyclization-rethiolation strategy has been developed. This protocol shows excellent substrate compatibility, including for chain and cyclic aliphatic methyl ketones, natural product pregnenolone acetate, and phosphorus-containing methyl ketones, affording a series of valuable aliphatic-substituted indolizines in good yields.

Pd-Catalyzed Hydroxyl-Directed Cascade Hydroarylation/C-H Germylation of Nonterminal Alkenes and Aryl Iodides.

Pd-catalyzed cascade hydroarylation and C-H germylation of nonterminal alkenes and aryl iodides enabled by hydroxyl assistance have been developed. The key step in this C-H germylation cascade is the formation of a highly reactive oxo-palladacycle intermediate, which markedly restrained the ß-H elimination process. Mechanistically, control experiments indicated that the hydroxyl group played an important role in this process. This transformation shows excellent reactivity and selectivity for most substrates investigated.

Rongalite as C1 Synthon and Sulfone Source: A Practical Sulfonylmethylation Based on the Separate-Embedding Strategy.

Rongalite has been used in several challenging synthetic transformations with operationally simple and effective protocols. However, the employment of multiple characteristics of rongalite in synthetic chemistry is comparatively little known. Herein we report a separate-embedding type sulfonylmethylation of sulfoxonium ylides in which rongalite concurrently acted as a sulfone source, C1 synthon, radical initiator, and potential reducing reagent for the first time. Notably, this facile and easy-handling reaction does not require a catalyst or prefunctionalized sulfonylmethylation reagents.

Discovery of Next-Generation Tropomyosin Receptor Kinase Inhibitors for Combating Multiple Resistance Associated with Protein Mutation.

Tropomyosin receptor kinase (TRK) inhibition is an effective therapeutic approach for treatment of a variety of cancers. Despite the use of first-generation TRK inhibitor (TRKI) larotrectinib (1) resulting in significant therapeutic response in patients, acquired resistance develops invariably. The emergence of secondary mutations occurring at the solvent-front, xDFG, and gatekeeper regions of TRK represents a common mechanism for acquired resistance. However, xDFG mutations remain insensitive to second-generation macrocyclic TRKIs selitrectinib (3) and repotrectinib (4) designed to overcome the resistance mediated by solvent-front and gatekeeper mutations. Here, we report the structure-based drug design and discovery of a next-generation TRKI. The structure-activity relationship studies culminated in the identification of a promising drug candidate 8 that showed excellent in vitro potency on a panel of TRK mutants, especially TRKAG667C in the xDFG motif, and improved in vivo efficacy than 1 and 3 in TRK wild-type and mutant fusion-driven tumor xenograft models, respectively.

Grignard Reagent Utilization Enables a Practical and Scalable Construction of 3-Substituted 5-Chloro-1,6-naphthyridin-4-one Derivatives.

A robust, practical, and scalable approach for the construction of 3-substituted 5-chloro-1,6-naphthyridin-4-one derivatives 13 via the addition of Grignard reagents to 4-amino-2-chloronicotinonitrile (15) was developed. Starting with various Grignard reagents, a wide range of 3-substituted 5-chloro-1,6-naphthyridin-4-one derivatives 13 were conveniently synthesized in moderate-to-good yields through addition-acidolysis-cyclocondensation. In addition, the robustness and applicability of this synthetic route was proven on a 100 g scale, which would enable convenient sample preparation in the preclinical development of 1,6-naphthyridin-4-one-based MET-targeting antitumor drug candidates.

[Relationship between cytoplasmic phospholipase A2 and nuclear factor κB in one lung ventilation-induced lung injury in rabbits].

OBJECTIVE: To elucidate the mechanisms of up regulated expression of cytoplasmic phospholipase A2 (CPLA2) induced by one lung ventilation (OLV) by investigating the interactions between nuclear factor kappaB (NF-κB) and C-PLA2. METHODS: Forty-eight healthy Japanese white rabbits were randomized into control group, solvent treatment group (group S), NF-κB inhibitor (PDTC)/solvent treatment group ( group PS), C-PLA2 inhibitor (AACOCF3)/solvent treatment group (group AS), OLV group (group O), solvent treatment plus OLV group (SO group), NFκB inhibitor (PDTC)/solvent treatment plus OLV group (group PSO) and CPLA2 inhibitor (AACOCF3)/solvent treatment plus OLV group (group ASO). ELISA was used to detect arachidonic acid (AA) content in the lung tissues, and NFκB and CPLA2 expressions were detected by Western blotting and quantitative PCR. Lung injuries were assessed based on the lung histological score, and the polymorphonuclear leukocyte count in the bronchial alveolar lavage fluid, myeloperoxidase (MPO) content in the lung tissues, and lung wet/dry weight (W/D) raito were determined. RESULTS: Treatment of the rabbits with the solvent did not produce any adverse effects. OLV caused obvious lung injury in the rabbits and up regulated the expressions of CPLA2 and NFκB in the lung tissues (P<0.05). In rabbits without OLV, treatment with AACOCF3 or PDTC significantly down regulated both CPLA2 and NFκB expressions without affecting the other parameters. In rabbits with OLV, treatment with AACOCF3 or PDTC obviously lowered CPLA2 and NFκB expressions and lessened the OLV-induced lung injuries. CONCLUSION: Both C-PLA2 and NF-κB play important roles and show interactions in OLV-induced lung injury in rabbits.