The 50 most-cited articles in The Journal of Organic Chemistry, 2021

Abstract N-Nitrosamines are a class of compounds notorious both for the potent carcinogenicity of many of its members and for their widespread occurrence throughout the human environment, from air and water to our diets and drugs. Considerable effort has been dedicated to understanding N-nitrosamines as contaminants, and methods for their prevention, remediation, and detection are ongoing challenges. Understanding the chemistry of N-nitrosamines will be key to addressing these challenges. To facilitate such understanding, we focus in this Perspective on the structure, reactivity, and synthetic applications of N-nitrosamines with an emphasis on alkyl N-nitrosamines. The role of N-nitrosamines as water contaminants and the methods for their detection are also discussed.

DP4+ is a popular tool for structural elucidation using GIAO NMR calculations. The method was built with 16 statistical parameters [μ,σ,ν], which depend on the level of theory. Herein, we deeply analyzed the sensitivity of DP4+ when using improper [μ,σ,ν] sets, a common situation found in the literature. The results led us to develop a customizable DP4+ methodology that allows preliminary calculations at any desired level of theory using a small set of training molecules.

A quinoline-linked and ionic liquid-decorated covalent organic framework was prepared by incorporation of a multicomponent Povarov reaction and postsynthetic modification. The imidazolium and sulfonic acid-decorated COF-IM-SO 3 H can be a highly efficient Brønsted acid catalyst to promote the Biginelli reaction under solvent-free conditions in a heterogeneous way. In addition, a scaled-up Biginelli reaction has been readily realized over a COF-IM-SO 3 H@chitosan aerogel-based cup reactor.

Sonochemistry, the use of sound waves, usually within the ultrasonic range (>20 kHz), to boost or alter chemical properties and reactivity constitutes a long-standing and sustainable technique that has, however, received less attention than other activation protocols despite affordable setups.Even if unnecessary to underline the impact of ultrasound-based strategies in a broad range of chemical and biological applications, there is considerable misunderstanding and pitfalls regarding the interpretation of cavitational effects and the actual role played by the acoustic field.In this Perspective, with an eye on mechanisms in particular, we discuss the potentiality of sonochemistry in synthetic organic chemistry through selected examples of past and recent developments.Such examples illustrate specific controlling effects and working rules.Looking back at the past while looking forward to advancing the field, some essentials of sonochemical activation will be distilled."Alfred L. Loomis, Wall Street banker and scientist, with a beautif ully equipped research laboratory at his Tuxedo…

Microwave-assisted organic synthesis has been widely studied and deliberated, opening up some controversial issues as well. Nowadays, microwave chemistry is a mature technology that has been well demonstrated in many cases with numerous advantages in terms of the reaction rate and yield. The strategies toward scaling up find an ally in continuous-flow reactor technology comparing dielectric and conductive heating.

F-fluorination is an important and growing field in organic synthesis that has attracted many chemists in the recent past. Here we present our own, biased perspective with a focus on our own chemistry that evaluates recent advances in the field and provides our opinion on the challenges for the development of new chemistry, so that it may have an impact on imaging. We hope that the manuscript will provide a useful guide to chemists to develop reliable and robust reaction chemistry suitable for radiofluorination to have a real impact on human health.

Redox reactions are ubiquitous in organic synthesis and intrinsic to organic electrosynthesis. The language and concepts used to describe reactions in these domains are sufficiently different to create barriers that hinder broader adoption and understanding of electrochemical methods. To bridge these gaps, this Synopsis compares chemical and electrochemical redox reactions, including concepts of free energy, voltage, kinetic barriers, and overpotential. This discussion is intended to increase the accessibility of electrochemistry for organic chemists lacking formal training in this area.

The proper choice of solvent is of major importance for all studies in supramolecular chemistry, including molecular recognition in host–guest systems, intramolecular folding, self-assembly, and supramolecular polymerization. In this Perspective, the usefulness of linear free energy relationships (LFERs) is highlighted to unravel the effect of solvents on coordinate bonding (e.g., cation-crown ether), hydrogen bonding, halogen bonding, dipolar aggregation, and π–π-stacking. For all of these intermolecular interactions widely applied in supramolecular systems, LFER relationships between the Gibbs binding energies and common solvent polarity scales including E T (30), π*, α or β based on solvatochromic dyes, scales derived from binding processes such as Gutmann donor and acceptor numbers or hydrogen bond donor and acceptor scales, or physical functions like the Kirkwood–Onsager or the Liptay–Onsager functions could be demonstrated. These relationships can now be applied toward a better understanding of the prevailing intermolecular forces for supramolecular interactions. They further…

Molecular rearrangements are a powerful tool for constructing complex structures in an atom- and step-economic manner, translating multistep transformations into an intrinsically more sustainable process. Mechanochemical molecular rearrangements become an even more appealing eco-friendly synthetic approach, especially for preparing active pharmaceutical ingredients (APIs) and natural products. Still in their infancy, rearrangements promoted by mechanochemistry represent a promising approach for chemists to merge molecular diversity and green chemistry perspectives toward more selective and efficient syntheses with a reduced environmental footprint.

Parallel library synthesis is an important tool for drug discovery because it enables the synthesis of closely related analogues in parallel via robust and general synthetic transformations. In this perspective, we analyzed the synthetic methodologies used in >5000 parallel libraries representing 15 prevalent synthetic transformations. The library data set contains complex substrates and diverse arrays of building blocks used over the last 14 years at AbbVie. The library synthetic methodologies that have demonstrated robustness and generality with proven success are described along with their substrate scopes. The evolution of the synthetic methodologies for library synthesis over the past decade is discussed. We also highlight that the combination of parallel library synthesis with high-throughput experimentation will continue to facilitate the discovery of library-amenable synthetic methodologies in drug discovery.

Organic materials possessing solid-state emission responsive to external stimuli have significance in a variety of material, biomedical, and optoelectronic applications. Organic molecules having different donor–acceptor architectures integrated with aggregation-induced emission (AIE) fluorophores have been utilized in development of mechanofluorochromic (MFC) materials. In this work, we have designed and synthesized phenanthroimidazole (PI) based derivatives TPE-PI-1, TPE-PI-2, TPE-PI-3, PTZ-PI-1, PTZ-PI-2, and PTZ-PI-3 where in donors tetraphenylethylene-TPE (D) and phenothiazine-PTZ (D′) of contrasting donor abilities are attached to the N and C atom positions of PI. The position and mode of attachment of the donors have been changed, and an additional PTZ spacer has been introduced which has a direct consequence on their photophysical and electronic properties. The PI derivatives manifest AIE, solvatochromic, and mechanochromic behavior. The single crystal X-ray analysis of TPE-PI-1 and PTZ-PI-2 reveals bent structures for the PTZ unit and a twisted conformation for TPE moieties.…

Electrosynthesis involves transferring charge between two electrodes to promote chemical reactions by applying potential. The modes of controlling the current and potential can affect the reaction mechanism, product distribution and yields, and add a control factor for reaction optimization. In this Synopsis, theoretical discussion is applied to specific case studies from the literature to illustrate methods of adjusting and tracking electrical parameters for the optimization and monitoring of electroorganic reactions.

This short overview describes the historical development of the physics and chemistry of organic solvents and solutions from the alchemist era until the present time based on some carefully selected examples that can be considered landmarks in the history of solution chemistry.

A visible-light-induced decarboxylation reaction was developed for the synthesis of alkylated benzimidazo[2,1- a ]isoquinoline-6(5 H )-ones and indolo[2,1- a ]isoquinolin-6(5 H )-ones under metal-free conditions. Impressively, metal catalysts and traditionally volatile organic solvents could be effectively avoided.

An efficient protocol for the synthesis of thioether directly from heteroarenes has been developed in the presence of visible light in a one-pot manner at room temperature. This method involves two sequential reactions in a single pot where the formation of the iodinated heteroarene is followed by a transition-metal-free C-S coupling reaction. A wide range of heteroarene and thiol partners (including aliphatic thiols) have been used for the synthesis of thioethers. NMR studies and DFT calculations revealed the presence of a halogen bond between the thiolate anion (halogen bond acceptor) and iodoheteroarene (halogen bond donor). This halogen bonded complex on photoexcitation facilitates the electron transfer from the thiolate anion to the iodoheteroarene at room temperature.

Daphnenoids A–C ( 1 – 3 ), three unusual sesquiterpenes with distinctive ring skeletons, together with a biogenetically related daphnenoid D ( 4 ) were obtained from the herb of Daphne penicillata by molecular networking strategies. Daphnenoid A ( 1 ) possesses a unique caged tetracyclo [5.3.2.0 1, 6 .0 4, 11 ] dodecane scaffold by unexpected cyclizations of C-1/C-11 and C-2/C-14. Daphnenoids B and C ( 2 and 3 ) were the first discovered natural sesquiterpenes with unique 5/5 spirocyclic systems in nature. Their structures were determined by NMR spectroscopic analysis, computer-assisted structure elucidation methods, quantum chemical calculations, and X-ray diffraction. A hypothetical biogenetic pathway begins with typical guaiane sesquiterpene ( a ), including a key intermediate ( 4 ) was proposed. Daphnenoids B and C ( 2 and 3 ) exhibited potential inhibitory activities on the production of NO against LPS-induced BV2 microglial cells.

High Resolution Image Download MS PowerPoint Slide The poorly understood mode of activation and catalysis of bidentate iodine(III)-based halogen donors have been quantitatively explored in detail by means of state-of-the-art computational methods. To this end, the uncatalyzed Diels–Alder cycloaddition reaction between cyclohexadiene and methyl vinyl ketone is compared to the analogous process mediated by a bidentate iodine(III)-organocatalyst and by related, highly active iodine(I) species. It is found that the bidentate iodine(III)-catalyst accelerates the cycloaddition by lowering the reaction barrier up to 10 kcal mol –1 compared to the parent uncatalyzed reaction. Our quantitative analyses reveal that the origin of the catalysis is found in a significant reduction of the steric (Pauli) repulsion between the diene and dienophile, which originates from both a more asynchronous reaction mode and a significant polarization of the π-system of the dienophile away from the incoming diene. Notably, the activity of the iodine(III)-catalyst can be further enhanced by increasing the…

Without employing an external oxidant, the simple synthesis of 3-halochromones and various halogenated electron-rich arenes has been realized with electrode oxidation by employing the simplest sodium halide (NaX, X = Cl, Br, I) as halogen source. This electrochemical method is advantageous for the simple and mild room temperature operation, environmental friendliness as well as broad substrate scope in both C-H bond donor and halogen source components.

We report a Minisci-type cross-dehydrogenative alkylation in an aerobic atmosphere using abundant and inexpensive cerium chloride as a photocatalyst and air as an oxidant. This photoreaction exhibits excellent tolerance to functional groups and is suitable for both heteroarene and alkane substrates under mild conditions, generating the corresponding products in moderate-to-good yields. Our method provides an alternative approach for the late-stage functionalization of valuable substrates.

Excited-state intramolecular proton transfer (ESIPT) dyes typically show strong solid-state emission, but faint fluorescence intensity is observed in the solution state owing to detrimental molecular motions. This article investigates the influence of direct (hetero)arylation on the optical properties of 2-(2'-hydroxyphenyl)benzoxazole ESIPT emitters. The synthesis of two series of ESIPT emitters bearing substituted neutral or charged aryl, thiophene, or pyridine rings is reported herein along with full photophysical studies in solution and solid states, demonstrating the dual solution-/solid-state emission behavior. Depending on the nature of substitution, several excited-state dynamics are observed: quantitative or partially frustrated ESIPT process or deprotonation of the excited species. Protonation studies revealed that pyridine substitution triggered a strong increase of quantum yield in the solution state for the protonated species owing to favorable quinoidal stabilization. These attractive features led to the development of a second series of dyes with alkyl or aryl…

Electrooxidative-induced synthesis of structurally diverse seleno-dibenzocyclohepten-5-ones and seleno-spiro[5.5]trienones by selenylative carbannulation of biaryl ynones with diaryl diselenide has been developed. The switchable reactivity, intramolecular ortho-annulation or dearomative ipso-annulation, is directed by the substituent present on the ortho-aryl group of aryl-ynone. The prominent features of this method include metal-free, external chemical oxidant-free conditions, and readily accessible substrates.

The oxidation of diaryl sulfides and aryl alkyl sulfides to the corresponding sulfoxides and sulfones under electrochemical conditions is reported. Sulfoxides are selectively obtained in good yield under a constant current of 5 mA for 10 h in DMF, while sulfones are formed as the major product under a constant current of 10 or 20 mA for 10 h in MeOH. The oxygen of both the sulfoxide and sulfone function is derived from water.

A red-light-mediated n Pr-DMQA + -catalyzed cascade intramolecular trifluoromethylation and dearomatization of indole derivatives with Umemoto’s reagent has been developed. This protocol provides a facile and efficient approach for the construction of functionalized and potentially biologically important CF 3 -containing 3,3-spirocyclic indolines with moderate to high yields and excellent diastereoselectivities under mild conditions. The success of multiple gram-scale (1 and 10 g) experiments further highlights the robustness and practicality of this protocol and the merit of the employment of red light. Mechanistic studies support the formation of a crucial CF 3 radical species and a dearomatized benzyl carbocation intermediate.

Methanol can be employed as a green and sustainable methylating agent to form C–C and C–N bonds via borrowing hydrogen (BH) methodology. Herein we explored the activity of the acridine-derived SNS-Ru pincer for the activation of methanol to apply it as a C1 building block in different reactions. Our catalytic system shows great success toward the β-C(sp 3 )-methylation reaction of 2-phenylethanols to provide good to excellent yields of the methylated products. We investigated the mechanistic details, kinetic progress, and temperature-dependent product distribution, which revealed the slow and steady generation of in situ formed aldehyde, is the key factor to get the higher yield of the β-methylated product. To establish the environmental benefit of this reaction, green chemistry metrics are calculated. Furthermore, dimerization of 2-naphthol via methylene linkage and formation of N -methylation of amine are also described in this study, which offers a wide range of substrate scope with a good to excellent yield.

A systematic study of arene-perfluoroarene interactions in solution is presented. Using a combination of NMR titration experiments, X-ray crystallography, and computational analysis, we analyze the effects of fluorination, substituents, ring size, and solvation on the arene-perfluoroarene interaction. We find that fluorination, extension of the π systems, and enhancement of solvent polarity greatly stabilize the stacking energy up to 3 orders of magnitude ( K a = <1 to 6000 M –1 ), with the highest K a achieved for the interaction of water-soluble variants of perfluoronaphthalene and anthracene in buffered D 2 O (pD = 12). Combining computational and experimental results, we conclude that this impressive binding energy is a result of enthalpically favorable electrostatic and dispersion interactions as well as the entropically driven hydrophobic effect. The enhanced understanding of arene-perfluoroarene interactions in aqueous solution sets the stage for the implementation of this abiotic intermolecular interaction in biology and medicine.

Abstract The concept of nucleophilicity is at the basis of most transformations in chemistry. Understanding and predicting the relative reactivity of different nucleophiles is therefore of paramount importance. Mayr’s nucleophilicity scale likely represents the most complete collection of reactivity data, which currently includes over 1200 nucleophiles. Several attempts have been made to theoretically predict Mayr’s nucleophilicity parameters N based on calculation of molecular properties, but a general model accounting for different classes of nucleophiles could not be obtained so far. We herein show that multivariate linear regression analysis is a suitable tool for obtaining a simple model predicting N for virtually any class of nucleophiles in different solvents for a set of 341 data points. The key descriptors of the model were found to account for the proton affinity, solvation energies, and sterics.

A ruthenium complex [( p -cymene)Ru(2,2′-bpyO)(H 2 O)] was found to be a general and efficient catalyst for the N -methylation of amines with methanol in the presence of carbonate salt. Moreover, a series of sensitive substituents, such as nitro, ester, cyano, and vinyl groups, were tolerated under present conditions. It was confirmed that OH units in the ligand are crucial for the catalytic activity. Notably, this research exhibited the potential of metal–ligand bifunctional ruthenium catalysts for the hydrogen autotransfer process.

A visible light (white light-emitting diode/direct sunlight)-driven photochemical synthesis of a new series of biologically interesting 3-(alkyl/benzylthio)-4-hydroxy-2 H -chromen-2-ones has been achieved through a cross-dehydrogenative C 3 –H sulfenylation of 4-hydroxycoumarins with thiols at ambient temperature in the presence of rose bengal in acetonitrile under an oxygen atmosphere. The notable features of this newly developed method are mild reaction conditions, energy efficiency, metal-free synthesis, good to excellent yields, use of low-cost materials, and eco-friendliness.

The transition metal catalyzed amide bond forming reaction of esters with amines has been developed as an advanced approach for overcoming the shortcomings of traditional methods. The broad scope of substrates in transition metal catalyzed amidations remains a challenge. Here, a manganese(I)-catalyzed method for the direct synthesis of amides from a various number of esters and amines is reported with unprecedented substrate scope using a low catalyst loading. A wide range of aromatic, aliphatic, and heterocyclic esters, even in fatty acid esters, reacted with a diverse range of primary aryl amines, primary alkyl amines, and secondary alkyl amines to form amides. It is noteworthy that this approach provides the first example of the transition metal catalyzed amide bond forming reaction from fatty acid esters and amines. The acid-base mechanism for the manganese(I)-catalyzed direct amidation of esters with amines was elucidated by DFT calculations.

Oligonucleotide drugs show promise to treat diseases afflicting millions of people. To address the need to manufacture large quantities of oligonucleotide therapeutics, the novel convergent liquid-phase synthesis has been developed for an 18-mer oligonucleotide drug candidate. Fragments containing tetra- and pentamers were synthesized and assembled into the 18-mer without column chromatography, which had a similar impurity profile to material made by standard solid-phase oligonucleotide synthesis. Two of the fragments have been synthesized at ∼3 kg/batch sizes and four additional tetra- and pentamer fragments were synthesized at >300-g scale, and a 34-mer was assembled from the fragments. Critical impurities are controlled in the fragment syntheses to provide oligonucleotides of purities suitable for clinical use after applying standard full-length product purification process. Impurity control in the assembly steps demonstrated the potential to eliminate chromatography of full-length oligonucleotides, which should enhance scalability and reduce the environmental impact of the…

A catalyst-free, environmentally friendly, and efficient electrochemical selenylation/cyclization of alkenes has been developed with moderate to excellent yields. This selenylated transformation proceeds smoothly and tolerates a wide range of synthetically useful groups to deliver diverse functionalized benzheterocycles, including iminoisobenzofuran, lactones, oxindoles, and quinolinones. Moreover, the present synthetic route could also be readily scaled up to gram quantity with convenient operation in an undivided cell.

As sp 2 –sp 3 disconnections gain acceptance in the medicinal chemist’s toolbox, an increasing number of potential drug candidates containing this motif are moving into the pharmaceutical development pipeline. This raises a new set of questions and challenges around the novel, direct methodologies available for forging these bonds. These questions gain further importance in the context of process chemistry, where the focus is the development of scalable processes that enable the large-scale delivery of clinical supplies. In this paper, we describe our efforts to apply a wide variety of standard, photo-, and electrochemical sp 2 –sp 3 cross-coupling methods to a pharmaceutically relevant intermediate and optimize each through a combination of high throughput and mechanistically guided experimentation. With data regarding the performance, benefits, and limitations of these novel methods, we evaluate them against a more traditional two-step palladium-catalyzed process. This work reveals trends and similarities between these sp 2 –sp 3 bond-forming methods and suggests a path forward…

A Rh(III)-catalyzed dehydrogenative annulation and spirocyclization of 2-arylindoles and 2-(1 H -pyrazol-1-yl)-1 H -indole with maleimides is described. The cascade protocol provided highly functionalized benzo[ a ]pyrrolo[3,4- c ]carbazole-1,3(2 H,8 H )-diones and spiro[isoindolo[2,1- a ]indole-6,3′-pyrrolidine]-2′,5′-diones in good to excellent. The developed reaction methodology exhibited broad substrate scope with good functional group tolerance and is operationally simple and scalable. Photophysical properties of the annulated products were investigated. The annulated product of 2-(1 H -pyrazol-1-yl)-1 H -indole showed high absorption and emission values with a large red-shift as compared to that of 2-phenylindole.

. Our results from a homogeneous system and bilayers prove that catecholamines act as effective, radical trapping antioxidants with activity depending on the ionization status of the catechol moiety, as well as microenvironment: organization of the lipid system (emulsions vs bilayers) and interactions of catecholamines with the biomembrane.

The current method represents an electrochemically driven synthetic route to access polysubstituted selenofuran derivatives through the diselenide-promoted cyclization of homopropargyl alcohols. The tandem electro-oxidative transformation operates at ambient temperature and in the absence of an external oxidant. This mild and efficient methodology exhibits good functional group compatibility, providing a broad range of substrate scopes up to 84% isolated yield. Further conversion of the seleno-functionality afforded other valuable furan derivatives.

Electrocarboxylation of organic halides is one of the most investigated electrochemical approaches for converting thermodynamically inert carbon dioxide (CO 2 ) into value-added carboxylic acids. By converting organic halides into their sulfone derivatives, we have developed a highly efficient electrochemical desulfonylative carboxylation protocol. Such a strategy takes advantage of CO 2 as the abundant C1 building block for the facile preparation of multifunctionalized carboxylic acids, including the nonsteroidal anti-inflammatory drug ibuprofen, under mild reaction conditions.

A Ru(II)-catalyzed facile and controllable protocol for C–H alkylation and spirocyclization of 2-arylquinoxalines with maleimides has been achieved under ambient air in high yields. Sequential ortho-C–H activation and C -annulation results in the formation of diverse polyheterocycles containing spiro[indeno[1,2- b ]quinoxaline-11,3′-pyrrolidine]-2′,5′-diones, which are of potent interest in medicinal chemistry. Mechanistic investigations suggest a reversible cleavage of the ortho-C–H bond in the turnover-limiting step.

High Resolution Image Download MS PowerPoint Slide Ball milling of aromatic, heteroaromatic, vinylic, and aliphatic esters with ethanol and calcium nitride afforded the corresponding primary amides in a transformation that was compatible with a variety of functional groups and maintained the integrity of a stereocenter α to carbonyl. This methodology was applied to α-amino esters and N -BOC dipeptide esters and also to the synthesis of rufinamide, an antiepileptic drug.

An efficient electrochemical flow process for the selective oxidation of sulfides to sulfoxides and sulfones and of sulfoxides to N -cyanosulfoximines has been developed. In total, 69 examples of sulfoxides, sulfones, and N -cyanosulfoximines have been synthesized in good to excellent yields and with high current efficiencies. The synthesis was assisted and facilitated through a supporting electrolyte-free, fully automated electrochemical protocol that highlights the advantages of flow electrolysis.

High Resolution Image Download MS PowerPoint Slide We have quantum chemically studied the Lewis acid-catalyzed epoxide ring-opening reaction of cyclohexene epoxide by MeZH (Z = O, S, and NH) using relativistic dispersion-corrected density functional theory. We found that the reaction barrier of the Lewis acid-catalyzed epoxide ring-opening reactions decreases upon ascending in group 1 along the series Cs + > Rb + > K + > Na + > Li + > H + . Our activation strain and Kohn–Sham molecular orbital analyses reveal that the enhanced reactivity of the Lewis acid-catalyzed ring-opening reaction is caused by the reduced steric (Pauli) repulsion between the filled orbitals of the epoxide and the nucleophile, as the Lewis acid polarizes the filled orbitals of the epoxide more efficiently away from the incoming nucleophile. Furthermore, we established that the regioselectivity of these ring-opening reactions is, aside from the “classical” strain control, also dictated by a hitherto unknown mechanism, namely, the steric (Pauli) repulsion between the nucleophile and the substrate, which could be…

An efficient and practical strategy was developed to synthesize 1,3,4-triaryl-6-trifluoromethylpyridones from CF 3 -imidoyl sulfoxonium ylides and cyclopropenones in good to excellent yields. This stepwise [3 + 3] annulation reaction was carried out under transition-metal-, additive-, and solvent-free conditions, generating 1 equiv of dimethyl sulfoxide as byproduct and tolerating a series of functional groups.

2019, 58, 16923), taking advantage of the strong Lewis acidity of the catalyst. This species was found to be more effective than an analogous iodine-based halogen bond organocatalyst. Herein, we present a detailed mechanistic and kinetic analysis of these catalytic cycles including the influence of the solvent (and the performance of different intrinsic solvation models). While the chalcogen bonding interaction is fundamental to activate the C-C bond formation, we found that the presence of a two-water molecular bridge is critical to allow the following, otherwise high-energy proton transfer step. Even though the iodine-based halogen bonding interaction is stronger than the tellurium-based chalcogen bonding one, which makes the former a stronger Lewis acid and hence in principle a more efficient catalyst, solvation effects explain the smaller energy span of the latter.

Four new indole diterpenoids, ascandinines A–D ( 1 – 4 ), were isolated from an Antarctic sponge-derived fungus Aspergillus candidus HDN15-152. Their structures, including absolute configurations, were established based on NMR data, computational calculations, and biosynthetic considerations. Ascandinine A ( 1 ) possesses an unprecedented 2-oxabicyclo[2.2.2]octan-3-ol motif embedded in a pentacyclic ring system, while compounds 2 – 4 represent a rare type of indole diterpenoid featuring the 6/5/5/6/6/6/6-fused ring system. Compound 3 displayed anti-influenza virus A (H1N1) activity with an IC 50 value of 26 μM, while compound 4 showed cytotoxicity against HL-60 cells with an IC 50 value of 7.8 μM.

An efficient diastereoselective route is developed to get access to novel spiropyrrolo[1,2- a ]isoquinoline-oxindole skeletons by a one-pot three -component [3 + 2] cycloaddition reaction of ( Z )-5-arylidene-1,3-thiazolidine-2,4-diones, isatin derivatives, and 1,2,3,4-tetrahydroisoquinoline (THIQ). Interestingly, the regioselectivity of the reaction is both temperature- and solvent-dependent, allowing the synthesis of two regioisomeric endo -dispiropyrrolo[2,1- a ]isoquinolineoxindoles in excellent yield. Unprecedentedly, each isomeric dispiropyrrolo[2,1- a ]isoquinolineoxindole endured retro- 1,3-dipolar cycloaddition/recycloaddition reactions under thermal or catalytic conditions to regenerate the corresponding regioisomeric counterpart. In addition, DFT calculations were performed at the M062X/6-31++g(d,p) level of theory to unravel the origin of the reversal of regioselectivity and endo- stereoselectivity of the title 1,3-dipolar cycloaddition reactions. Upon treatment of Isatin, THIQ with ( Z )-4-arylidene-5-thioxo-thiazolidin-2-ones as dipolarophiles, unusual rhodanine…

The syntheses of dyes and fluorophores have significant commercial importance. In recent years, mechanochemistry has emerged as a green and sustainable alternative for the synthesis of conventional dyes, new fluorophores, and also synthetic modification of known dyes for their use as chemosensors. The dyestuffs based on BODIPYs, rhodamine, fluorescein, perylenedimides, coumarins, benzothiazoles, etc. were synthesized or derivatized by grinding or milling. The synopsis aims to pay key attention to their synthesis and the applications as chemosensors will be briefly covered.

A metal-free, photocatalyst-free, photochemical system was developed for the direct alkylation of thiophenols via electron donor–acceptor (EDA) complexes ( K EDA = 145 M –1 ) between two reactants, N -hydroxyphthalimide esters as acceptors and thiophenol anions as donors, in the presence of a tertiary amine. The EDA complexes in the reaction system have a broad range of visible-light absorption (400–650 nm) and can trigger the reaction effectively under sunlight.

The chemical investigation of the South China Sea soft coral Sinularia humilis has resulted in the isolation of a library of diverse diterpenoids, including four new cembranoids, namely, humilisins A–D ( 1 – 4 ), two new uncommon diterpenoids possessing a tetradecahydrocyclopenta[3′,4′]cyclobuta[1′,2′:4,5]cyclonona[1,2- b ]oxirene ring system, namely, humilisins E and F ( 5 and 6 ), and eight known related compounds ( 7 – 14 ). Humilisin A ( 1 ) is the first cembranoid with an ether linkage between C-3 and C-7. The structures and absolute configurations of 1 – 8 were determined by extensive spectroscopic data analyses, chemical reactions, and a series of quantum chemical calculations including quantum mechanical–nuclear magnetic resonance (QM-NMR), time-dependent density functional theory–electronic circular dichroism (TDDFT-ECD), and optical rotatory dispersion (ORD) methods. In bioassay, compound 6 displayed anti-inflammatory activity in lipopolysaccharide (LPS)-stimulated BV-2 microglia cells.

A manganese-catalyzed N -alkylation reaction of amines with alcohols via hydrogen autotransfer strategy has been demonstrated. The developed practical catalytic system including an inexpensive, nontoxic, commercially available MnCl 2 or MnBr(CO) 5 as the metal salt and triphenylphosphine as a ligand provides access to diverse aromatic, heteroaromatic, and aliphatic secondary amines in moderate-to-high yields. In addition, this operationally simple protocol is scalable to the gram level and suitable for synthesizing heterocycles such as indole and resveratrol-derived amines known to be active for Alzheimer’s disease.

High Resolution Image Download MS PowerPoint Slide We have quantum chemically investigated how solvation influences the competition between the S N 2 and E2 pathways of the model F – + C 2 H 5 Cl reaction. The system is solvated in a stepwise manner by going from the gas phase, then via microsolvation of one to three explicit solvent molecules, then last to bulk solvation using relativistic density functional theory at (COSMO)-ZORA-OLYP/QZ4P. We explain how and why the mechanistic pathway of the system shifts from E2 in the gas phase to S N 2 upon strong solvation of the Lewis base (i.e., nucleophile/protophile). The E2 pathway is preferred under weak solvation of the system by dichloromethane, whereas a switch in reactivity from E2 to S N 2 is observed under strong solvation by water. Our activation strain and Kohn–Sham molecular orbital analyses reveal that solvation of the Lewis base has a significant impact on the strength of the Lewis base. We show how strong solvation furnishes a weaker Lewis base that is unable to overcome the high characteristic distortivity associated with…

Lipases are ubiquitously used in chemo-enzymatic synthesis and industrial applications. Nevertheless, the modulation of the activity of lipases by organic solvents still is not fully understood at the molecular level. We systematically investigated the activity and structure of lipase A from Bacillus subtilis in binary water–organic solvent mixtures of dimethyl sulfoxide (DMSO), acetonitrile (ACN), and isopropyl alcohol (IPA) using activity assays, fluorescence spectroscopy, molecular dynamics (MD) simulations, and FRET/MD analysis. The enzymatic activity strongly depended on the type and amount of organic solvent in the reaction media. Whereas IPA and ACN reduced the activity of the enzyme, small concentrations of DMSO led to lipase activation via an uncompetitive mechanism. DMSO molecules did not directly interfere with the binding of the substrate in the active site, contrary to what is known for other solvents and enzymes. We propose that the His156-Asp133 interaction, the binding of organic molecules to the active site, and the water accessibility of the substrate are key…