Photochemical Radical Bicyclization of 1,5-Enynes: Divergent Synthesis of Fluorenes and Azepinones.

A dual nickel- and iridium-photocatalyzed radical cascade bicyclization reaction for the synthesis of highly complex molecular structures in an atom- and step-economic manner has been described. A series of radical precursors are utilized for the divergent synthesis of diversely substituted fluorenes and indenoazepinones bearing quaternary carbons by using cascade cyclization reactions of 1,5-enynes. This reaction is characterized by its mild conditions, broad substrate scope, excellent selectivity, and satisfactory yield including facile scale-up synthesis.

A Regioselective [3 + 2] Cycloaddition of Alkynols and Ketones To Access Diverse 1,3-Dioxolane Scaffolds.

This study presents a stepwise exoselective [3 + 2] cycloaddition reaction of alkynols with ketones, leading to the synthesis of 4-methylene-1,3-dioxolane derivatives. Remarkably, without any Thorpe-Ingold induced effect, the cyclization reaction was demonstrated with complete regio- and chemoselectivity, which was solely promoted by cesium carbonate. A wide range of unactivated ketones are viable under these mild reaction conditions, and both primary and tertiary alkynols are compatible with these cyclization reactions. We have prepared a diverse array of highly dense exomethylene 1,3-dioxolane rings demonstrating a remarkable tolerance for various functional groups.

Manipulating Diastereomeric Bicyclononynes to Sensitively Determine Enzyme Activity and Facilitate Macromolecule Conjugations.

Bicyclo[6.1.0]nonyne (BCN) is one of the most commonly used cycloalkynes in strain-promoted azide-alkyne cycloaddition (SPAAC). The synthesis of BCN produces two diastereomers, exo-BCN and endo-BCN. The potential significance of the different steric structures of the tricyclic fused rings in SPAAC products synthesized from the BCN diastereomers has not been previously studied. We first demonstrated that only endo-BCN could reduce the level of fluorescence quenching in SPAAC reaction products. The reduction was likely due to the presence of extended tricyclic fused ring systems. This hypothesis was supported by the synthesis of a fluorescence always-on construct by substituting endo-BCN for exo-BCN in a previously reported chemical probe that was characterized with good contact fluorescence quenching. We also synthesized bis-BCN derivatives to enhance the steric structural differences in the corresponding SPAAC products. A constitutional isomer of the azido-derivatized 5(6)-carboxyfluorescein [5(6)-FAM] was reacted with both bis-exo-BCN and bis-endo-BCN compounds. However, one form of the bis-exo-BCN-based product did not augment contact fluorescence quenching, while a second bis-exo-BCN product could not further reduce contact fluorescence quenching. Nevertheless, a new fluorescence turn-on chemical probe was employed to determine the activities of two serum biomarkers, butyrylcholinesterase and paraoxonase 1. Moreover, bis-endo-BCN was exploited to successfully conjugate BSA with a 5-FAM derivative compound.

Light-mediated sulfonyl-iodination of ynamides and internal alkynes.

We synthesized tetrasubstituted olefins regioselectively and stereoselectively from ynamides and internal alkynes with sulfonyl iodides under blue LEDs in few minutes. The key features are being metal-free, easy to handle, simple, broad in scope, and environmentally friendly. Furthermore, a gram-scale experiment was conducted, and the synthesized corresponding sulfonyl-iodinated products were smoothly altered into various other products.

Visible-light-induced oxidant/additive-free atom-economic synthesis of multifunctionalized cyclopropanes via energy transfer.

Herein we describe intramolecular cascade reactions enabling the synthesis of bridged cyclopropanes, via the photoinduced energy-transfer catalysis of tethered conjugated dienes. Photocatalysis affords the efficient synthesis of complex tricyclic compounds that exhibit multiple stereocenters from readily accessible starting materials that would otherwise be difficult to obtain. This single-step reaction is characterized by its broad substrate scope, atom-economy, excellent selectivity, and satisfactory yield, which includes a facile scale-up synthesis and synthetic transformation. An in-depth mechanistic study reveals that the reaction proceeds via an energy-transfer pathway.

Correction: Visible light-assisted Ni-/Ir-catalysed atom-economic synthesis of spiro[furan-3,1'-indene] derivatives.

Correction for 'Visible light-assisted Ni-/Ir-catalysed atom-economic synthesis of spiro[furan-3,1'-indene] derivatives' by Babasaheb Sopan Gore et al., Chem. Commun., 2022, 58, 4087-4090, https://doi.org/10.1039/D2CC00717G.

Time-dependent effects of storage at -80 °C on the stability of butyrylcholinesterase activity in human serum.

Objectives: Butyrylcholinesterase (BChE) is an important biomarker in serum, and aberrant BChE activity indicates onset and progression of human diseases. The duration of serum storage at -80 °C may introduce variability into and compromise the reproducibility of BChE activity measurements. Design and Methods: We collected serum samples from eight healthy volunteers and determined serum BChE activity in these samples using a sensitive fluorescence assay at various time points during a six-month storage period at -80 °C. Changes in averaged BChE activity over storage time were assessed by repeated measures analysis of variance (ANOVA). Sidak multiple comparisons test was also used to perform post-hoc analysis. Results: Almost all determined BChE activity values lay within the normal physiological range of BChE activity. However, repeated measures ANOVA using mean BChE activity vs. storage time showed that BChE activity values from two time points were significantly different. Analysis by Sidak multiple comparisons test provided no substantial change of BChE activity during the first 90 days of storage, but BChE activity noticeably decreased after 90 days. Conclusions: Serum samples stored in -80 °C for up to 90 days can be exploited to accurately determine BChE activity.

Time and Atom Economical Regio- and Chemoselective Radical Cyclization of Unactivated 1,6-Enynes Under Metal- and Oxidant-Free Conditions.

We developed time-atom economic regio- and chemoselective sulfonyl radical triggered 5-exo-dig cyclization of unactivated 1,6-enynes with sulfonyl halides under metal, additive-free reaction conditions to achieve highly substituted five-membered heterocyclic compounds. This transformation creates three new bonds, such as C-SO2 , C-C, and active C-I/Br bonds. Importantly, one-pot protocols produce desired products directly from sodium sulfinates and have an additional advantage such as minimising chemical waste, saving time, and simplifying practical aspects compared to existing protocols.

Sensitive Assay for the Lactonase Activity of Serum Paraoxonase 1 (PON1) by Harnessing the Fluorescence Turn-On Characteristics of Bioorthogonally Synthesized and Geometrically Controlled Chemical Probes.

The lactonase activity of paraoxonase 1 (PON1) has a crucial antiatherogenic function, and also serves as an important biochemical marker in human blood because the aberrant lactonase activity of PON1 is a key indicator for a number of diverse human diseases. However, no sensitive fluorescence assays that detect PON1 lactonase activity are available. We report the synthesis of two fluorescence turn-on chemical probes 16a and 16b (16) able to quantify PON1 lactonase activity. The chemical probes were constructed utilizing a disulfide-containing bicyclononyne, derivatives of rhodamine B and carboxyfluorescein, and reactions including copper-free azide-alkyne cycloaddition. Fluorescence quenching in 16 was characterized by spectroscopic studies and was mainly attributed to the effect of contact quenching. Kinetic analysis of 16b confirmed the outstanding reactivity and specificity of 16b with thiols in the presence of general base catalysts. The 16b-based assay was employed to determine PON1 lactonase activity, with a linear range of 10.8-232.1 U L-1 and detection limit (LOD) of 10.8 U L-1, to quantify serum PON1 activity in human sera, and to determine the Ki of 20.9 µM for the 2-hydroxyquinoline inhibition of PON1 lactonase. We are employing 16b to develop high-throughput assays for PON1 lactonase activity.

Photoinduced ynamide structural reshuffling and functionalization.

The radical chemistry of ynamides has recently drawn the attention of synthetic organic chemists to the construction of various N-heterocyclic compounds. Nevertheless, the ynamide-radical chemistry remains a long-standing challenge for chemists due to its high reactivity, undesirable byproducts, severe inherent regio- and chemoselective problems. Importantly, the ynamide C(sp)-N bond fission remains an unsolved challenge. In this paper, we observe Photoinduced radical trigger regio- and chemoselective ynamide bond fission, structural reshuffling and functionalization of 2-alkynyl-ynamides to prepare synthetically inaccessible/challenging chalcogen-substituted indole derivatives with excellent step/atom economy. The key breakthroughs of this work includes, ynamide bond cleavage, divergent radical precursors, broad scope, easy to handle, larger-scale reactions, generation of multiple bonds (N-C(sp2), C(sp2)-C(sp2), C(sp2)-SO2R/C-SR, and C-I/C-Se/C-H) in a few minutes without photocatalysts, metals, oxidants, additives. Control experiments and 13C-labeling experiments supporting the conclusion that sulfone radicals contribute to ynamide structural reshuffling processes via a radical pathway.

Visible light-assisted Ni-/Ir-catalysed atom-economic synthesis of spiro[furan-3,1'-indene] derivatives.

An atom-economic, efficient, and highly convenient construction of spiro[furan-3,1'-indene] skeletons from isocyanides and 1,5-enynes by synergistic nickel- and iridium-photocatalysis is reported. Spirocyclization was developed under practical and mild conditions, which features excellent functional group tolerance, gram-scale synthesis and representative synthetic transformations for the obtained products and broad substrate scope. Primary mechanistic studies demonstrated that the reaction proceeds through energy-transfer-mediated excitation of intermediate catalytic species.

A metal-free strategy for the cross-dehydrogenative coupling of 1,3-dicarbonyl compounds with 2-methoxyethanol.

Here, we report a metal-free approach for the construction of methylene-bridged bis-1,3-dicarbonyl compounds via cross-dehydrogenative coupling of 1,3-dicarbonyl compounds with 2-methoxyethanol. In addition, we have extended this methodology to synthesize tetra-substituted pyridine derivatives using 1,3-dicarbonyl, 2-methoxyethanol and NH4OAc in one step. The key advantages include accepting a wide range of substrates, utilizing O2 as the sole oxidant, and synthesizing biologically active compounds such as 1,4-dihydropyridine and pyrazole.

Arsenic leads to autophagy of keratinocytes by increasing aquaporin 3 expression.

Exposure to arsenic, a ubiquitous metalloid on Earth, results in human cancers. Skin cancer is the most common arsenical cancers. Both autophagy and aquaporin pathway are known to promote carcinogenesis. However, the mechanisms by which arsenic regulates aquaporin and autophagy in arsenical skin cancers remain elusive. This study aims to address how arsenic regulates aquaporin-3, the predominant aquaporin in epidermal keratinocytes, and how this process would induce autophagy. Quantitative real-time PCR and immunofluorescence were used to measure the expression of aquaporin 3 in arsenical skin cancers and arsenic-treated keratinocytes. Beclin-1 expression and autophagy were measured. We examined if blocking aquaporin 3 could interfere arsenic-induced autophagy in keratinocytes. Expression of aquaporin 3 is increased in arsenical cancers and in arsenic-treated keratinocytes. Arsenic induced autophagy in primary human keratinocytes. Notably, the arsenic-induced autophagy was inhibited by pretreatment of keratinocytes with aquaporin inhibitors Auphen or AgNO3, or RNA interference against aquaporin 3. The data indicates that the aquaporin 3 is an important cell membrane channel to mediate arsenic uptake and contributes to the arsenic-induced autophagy.

Unusual C3-acetylation of quinoxalin-2(1H)-one via oxidative C-C and C-O bond cleavages of PEG-400.

Aerobic oxidative tandem conversion of PEG-400 to acetyl radical via C-C and C-O bond cleavages followed by silver-catalyzed menisci-type addition to the C3 position of quinoxalin-2(1H)-one is described. This reaction involves the in situ formation of the acetyl radical from PEG-400 via a sequence of acetaldehyde, 2-oxopropanal and, 2-oxopropanoic acid formation and successive oxidative cleavage to form the acetyl radical. This protocol uses cheap, readily available and environmentally-friendly PEG-400 as the acetyl source and solvent. The in situ generated acetyl radicals from PEG-400 have been coupled to a broad range of electron-deficient quinoxalin-2(1H)-one compounds in a menisci-type reaction.

De Novo Protocol for the Construction of Benzo[a]fluorenes via Nitrile/Alkene Activation.

Unprecedented chemo- and regioselective synthesis of benzo[a]fluorenes and naphthamide-substituted benzo[a]fluorenes were constructed from the reaction of (E)-2-aroyl-3-(2-(arylalkynes/alkenes)aryl)acrylonitrile scaffolds under metal-free conditions via the activation of nitriles and alkenes, respectively. A tentative reaction mechanism was proposed for this homofunctionalization of nitriles. Control experiments showed that the reaction proceeds via selective nitrile or alkene protonation, depending upon the substrates. Additionally, we demonstrated an alternative expeditious route for the synthesis of disubstituted benzo[a]fluorenes in the presence of TfOH alone.

Metal-Free Solvent/Base-Switchable Divergent Synthesis of Multisubstituted Dihydrofurans.

A general protocol for the synthesis of multisubstituted 2,3-dihydrofuran-2-carbonitriles and 4,5-dihydrofuran-3-carbonitriles was demonstrated under a metal-free regime with the same oxidant, TBHP. By simply switching the reaction solvent and base, the reaction proceeds via two pathways. An unexpected -CN group migration rearrangement and hydroxylation have occurred in nonpolar and polar solvents, respectively, under the reported conditions. Furthermore, the source of the hydroxyl group and hydrogen in the reaction is indirectly confirmed with isotope labeling studies.

Lewis Acid Catalyzed Atom-Economic Synthesis of C2-Substituted Indoles from o-Amido Alkynols.

Herein we have disclosed a Zn(OTf)2 catalyzed synthesis of C2-alkyl substituted indole derivatives via unprecedented carbonyl group migration from o-amido alkynols. The key features of this protocol involve N,O-carbonyl group migration, broad substrate scope with varied functionality tolerance, moderate to good yields, and 100% atom economy. The crossover experiments proved that the migration is happening via an intramolecular pathway.

Acid-Promoted Intramolecular Decarbonylative Coupling Reactions of Unstrained Ketones: A Modular Approach to Synthesis of Acridines and Diaryl Ketones.

Herein, we reported Lewis acid- or Brønsted acid-promoted intramolecular C(sp2)-C(sp2) bond cleavage and a novel C(sp2)-C(sp2) bond-forming cascade reaction to synthesize the acridine motif. The metal-free oxidation of the alkyne motif generated the in situ ketone group extracted via a decarbonylation reaction. The mechanistic studies revealed that the electrophilic N-iodo species triggered key decarbonylation reactions via consecutive dearomatization/aromatization reactions. In addition, we exploited this acid-promoted C-C bond activation system with internal alkynes to synthesize bis(heteroaryl) ketones.

Regio- and chemoselective synthesis of nitrogen-containing heterocycles via the oxidative cascade cyclization of unactivated 1,n-enynes.

The development of a method for performing radical initiated intramolecular cascade cyclization of 1,n-enynes provided a competent protocol for producing structurally diverse complex heterocycles. Herein, we demonstrate I2/TBHP promoted, solvent controlled, regio- and chemoselective 5-exo-trig or 6-endo-trig radical cyclization of electronically unbiased 1,n-enynes to synthesize nitrogen-containing heterocycles. These metal-free protocols confer access to synthetically robust piperidine motif-bearing iodinated-homoallylic alcohol and pyrrolidine fused cyclopropane rings. The key factor in these methods is operational simplicity, and the environmentally friendly reaction system works under exceedingly mild conditions. Furthermore, the source of hydroxyl groups in the tertiary alcohols is indirectly confirmed with H218O labeled studies. Based on mechanistic studies, all of these cyclizations were initiated through single electron oxidation. The products with active C-I bonds present opportunities for further transformations.

FeCl3-Promoted ring size-dictating diversity-oriented synthesis (DOS) of N-heterocycles using in situ-generated cyclic imines and enamines.

The FeCl3-promoted ring size-controlled oxidative activation of o-alkynylanilines opens up a complementary appealing protocol for poly-N-heterocycle synthesis. When electron-poor π-alkyne iron species combine with cyclic enamines obtained from cyclohexanone and ß-tetralone, they undergo a regioselective 6-exo-dig cyclization to afford the corresponding dibenzo[b,j][1,10]phenanthrolines and 12-benzoylated dihydrobenzo[a]acridine skeletons. Later, these acridine motifs become completely unsaturated due to dehydrogenative aromatization via the aza-allyl oxidation intermediate. We obtained all quaternary carbon centre pseudoindoxyls through the Mannich-type alkylation of 2,3-dihydro-1H-inden-1-one with cyclic ketimines generated from the in situ intramolecular nucleophilic cyclization of o-alkynylanilines.