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The development of synthetic strategies for the preparation of bioisosteric compounds is a demanding undertaking in medicinal chemistry. Numerous strategies have been developed for the synthesis of bicyclo[1.1.1]pentanes (BCPs), bridge-substituted BCPs, and bicyclo[2.1.1]hexanes. However, progress on the synthesis of bicyclo[3.1.1]heptanes, which serve as meta-substituted arene bioisosteres, has not been previously explored. Herein, we disclose the first photoinduced [3σ + 2σ] cycloaddition for the synthesis of trisubstituted bicyclo[3.1.1]heptanes using bicyclo[1.1.0]butanes and cyclopropylamines. This transformation not only uses mild and operationally simple conditions but also provides unique meta-substituted arene bioisosteres. The applicability of this method is showcased by simple derivatization reactions.

The organocatalytic enantioselective Michael addition of functionalized prochiral cyclic hemiacetals and nitroolefins has been developed under cooperative enamine and hydrogen bond catalysis. The obtained chiral hemiacetal intermediates could be used in the subsequent diastereocontrolled cyclization/desymmetrization divergent process to access (1) 9-oxabicyclo[3.3.1]nonane or 8-oxabicyclo[3.2.1]octane frameworks via oxocarbenium ion-mediated Friedel-Crafts cyclization, and (2) 2,9-dioxabicyclo[3.3.1]nonane frameworks via intramolecular nucleophilic cyclization. Experimental results suggest that there is neighboring group participation controlling the diastereoselectivities of the desymmetrization process.

Among the valuable saturated bicyclic structures incorporated in newly developed bio-active compounds, bicyclo[2.1.1]hexanes are playing an increasingly important role, while being still underexplored from a synthetic accessibility point of view. Here, we disclose an efficient and modular approach toward new 1,2-disubstituted bicyclo[2.1.1]hexane modules. Our strategy is based on the use of photochemistry to access new building blocks via [2 + 2] cycloaddition. The system can readily be derivatized with numerous transformations, opening the gate to sp 3 -rich new chemical space.

Small-ring cage hydrocarbons are popular bioisosteres (molecular replacements) for commonly found para-substituted benzene rings in drug design 1 . The utility of these cage structures derives from their superior pharmacokinetic properties compared with their parent aromatics, including improved solubility and reduced susceptibility to metabolism 2,3 . A prime example is the bicyclo[1.1.1]pentane motif, which is mainly synthesized by ring-opening of the interbridgehead bond of the strained hydrocarbon [1.1.1]propellane with radicals or anions 4 . By contrast, scaffolds mimicking meta-substituted arenes are lacking because of the challenge of synthesizing saturated isosteres that accurately reproduce substituent vectors 5 . Here we show that bicyclo[3.1.1]heptanes (BCHeps), which are hydrocarbons for which the bridgehead substituents map precisely onto the geometry of meta-substituted benzenes, can be conveniently accessed from [3.1.1]propellane. We found that [3.1.1]propellane can be synthesized on a multigram scale, and readily undergoes a range of radical-based transformations to generate medicinally relevant carbon- and heteroatom-substituted BCHeps, including pharmaceutical analogues. Comparison of the absorption, distribution, metabolism and excretion (ADME) properties of these analogues reveals enhanced metabolic stability relative to their parent arene-containing drugs, validating the potential of this meta-arene analogue as an sp 3 -rich motif in drug design. Collectively, our results show that BCHeps can be prepared on useful scales using a variety of methods, offering a new surrogate for meta-substituted benzene rings for implementation in drug discovery programmes., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Acyl bicyclobutanes are shown to engage in strain-promoted cycloaddition reactions with a diverse array of triazolinedione reagents. The synthesis of an orthogonally protected urazole building block enabled the facile preparation of amino acid- and peptide-derived triazolinediones that undergo cycloaddition reactions to afford novel peptide conjugates. The additive-free and fully atom-economical nature of the transformation is a promising starting point for the generalization of this cycloaddition reaction for the functionalization of biomolecules.

Owing to its roles in human health and disease, the modification of nuclear, cytoplasmic, and mitochondrial proteins with O-linked N -acetylglucosamine residues (O-GlcNAc) has emerged as a topic of great interest. Despite the presence of O-GlcNAc on hundreds of proteins within cells, only two enzymes regulate this modification. One of these enzymes is O-GlcNAcase (OGA), a dimeric glycoside hydrolase that has a deep active site cleft in which diverse substrates are accommodated. Chemical tools to control OGA are emerging as essential resources for helping to decode the biochemical and cellular functions of the O-GlcNAc pathway. Here we describe rationally designed bicyclic thiazolidine inhibitors that exhibit superb selectivity and picomolar inhibition of human OGA. Structures of these inhibitors in complex with human OGA reveal the basis for their exceptional potency and show that they extend out of the enzyme active site cleft. Leveraging this structure, we create a high affinity chemoproteomic probe that enables simple one-step purification of endogenous OGA from brain and targeted proteomic mapping of its post-translational modifications. These data uncover a range of new modifications, including some that are less-known, such as O-ubiquitination and N-formylation. We expect that these inhibitors and chemoproteomics probes will prove useful as fundamental tools to decipher the mechanisms by which OGA is regulated and directed to its diverse cellular substrates. Moreover, the inhibitors and structures described here lay out a blueprint that will enable the creation of chemical probes and tools to interrogate OGA and other carbohydrate active enzymes.

Chiral sp 3 -rich bicyclo[3.3.1]nonane scaffolds 10-12 were synthesized as single diastereomers from aldehyde 9, which was prepared from 4,4-dimethoxycyclohexa-2,5-dienone through a copper-catalyzed enantioselective reduction. Three different types of intramolecular addition reactions were studied: SmI 2 -mediated reductive cyclization, base-promoted aldol reaction, and one-pot Mannich reaction. We succeeded in introducing three side-chains to scaffold 11 and construct an sp 3 -rich compound library in both enantiomeric variants by simply changing the chirality of the ligands. The biological evaluation revealed that all synthesized compounds exhibited a concentration-dependent inhibition of hypoxia-inducible factor-1 (HIF-1) transcriptional activity, with IC 50 values in the range of 17.2-31.7 µM, whereas their effects on cell viability were varied (IC 50  = 3.5 to > 100 µM). The most active compound 16f inhibits the accumulation of HIF-1α protein and mRNA in hypoxia, indicating that it has a mechanism of action distinctly different from other known compounds bearing the common bicyclo[3.3.1]nonane skeleton., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Amines containing bridged bicyclic carbon skeletons are desirable building blocks for medicinal chemistry. Herein, we report the conversion of bicyclo[1.1.1]pentan-1-amines to a wide range of polysubstituted bicyclo[3.1.1]heptan-1-amines through a photochemical, formal (4 + 2)-cycloaddition of an intermediate imine diradical. To our knowledge, this is the first reported method to convert the bicyclo[1.1.1]pentane skeleton to the bicyclo[3.1.1]heptane skeleton. Hydrolysis of the imine products gives complex, sp 3 -rich primary amine building blocks.

We herein describe a new approach for the efficient and asymmetric construction of the tricyclic core of eurifoloid A, which possesses a unique and highly strained bicyclo[4.4.1] ring system. A rhodium-catalyzed intramolecular [3 + 2] dipolar cycloaddition was developed to install synthetically challenging bridged bicyclo[4.3.1] ring systems. The reported chemistry shows the feasibility of constructing the eurifoloid A framework using a diastereoselective intramolecular [3 + 2] cycloaddition and a ring enlargement.

Conformationally restricted bicyclic KOR agonists 10 with an endo -configured amino moiety were synthesized to analyze the bioactive conformation of conformationally flexible KOR agonists such as 2-5. A seven-step synthesis starting with ( S )-configured 4-oxopiperidine-2-carboxylate 13 was developed. cis - and trans -configured diesters 12 were obtained in a 3 : 1 ratio via hydrogenation of the α,β-unsaturated ester 14. After establishment of the bicyclic scaffold, a diastereoselective reductive amination of ketone 11 provided exclusively the endo -configured bicyclic amines 10a,b. The 3 : 1 mixtures of enantiomers were separated by chiral HPLC, respectively, leading to enantiomerically pure KOR agonists (1 S ,5 S ,7 R )-10a,b and (1 R ,5 R ,7 S )-10a,b ( ent -10a,b). The KOR affinity was determined in receptor binding studies with the radioligand [ 3 H]U-69 593. The high KOR affinity of endo -configured amines 10a ( K i = 7 nM) and 10b ( K i = 13 nM) indicates that the dihedral angle of the KOR pharmacophoric element N(pyrrolidine)-C-C-N(phenylacetyl) of 42° is close to the bioactive conformation of more flexible KOR agonists. It should be noted that changing the configuration of potent and selective KOR agonists 10a and 10b led to potent and selective σ 1 ligands ( e.g. ent -10a K i ( σ 1 ) = 10 nM).

A convenient fluorometrical test method to identify skin sensitizers in chemico was developed using reactivity with glutathione (GSH), a low molecular weight endogenous substance. Following incubation of test chemicals with GSH, the remaining GSH was quantitated fluorometrically by using monobromobimane (mBBr), a thiol-detecting agent, for determining % depletion of this endogenous substance by test chemicals. The experimental conditions optimized were: (1) reactivity of thiol compounds including GSH with mBBr, (2) effects of vehicles on reactivity, (3) molar ratios of GSH to test chemicals, and (4) reactivity of endogenous substance with test substances under different incubation times. When an optimized condition with DMSO as a vehicle for test chemicals and in 1:60 ratio for 24 hr at 4°C was applied to classify 48 well-known skin sensitizers and non-sensitizers, the predictive capacity was as follows: 88.2% sensitivity, 78.6% specificity, and 85.4% accuracy with 95.8% consistency of three trials when 10.3% depletion of GSH was used as a cutoff value. Because the present method employed relatively simple GSH as an acceptor for sensitizers and/or a relatively convenient fluorometric detection system in 96-well plates for a high throughput test, it would be a useful test tool for screening skin sensitization potential of test chemicals.

Omphalane diterpenoids usually contain a cyclohexane-fused bicyclo[3.2.1]octane scaffold embedded with two continuous quaternary carbon centers, which pose considerable challenges to synthetic chemists. Herein, we reported the first total synthesis of omphalic acid with high stereochemical control, featuring an intermolecular Diels-Alder cycloaddition, ring reorganization through Criegee oxidative cleavage and programmed aldol condensations, conformationally controlled hydrogenation, and Pd-catalyzed carboxylation. The absolute configuration of omphalic acid was defined for the first time via the asymmetric total synthesis facilitated by a derivatization resolution protocol.

A novel norditerpenoid, sinusiaetone A ( 1 ), featuring an uncommon bicyclo[11.3.0]hexadecane carbon skeleton, and four polyoxygenated cembranoids ( 2-5 ) were isolated from the Hainan soft coral Sinularia siaesensis . Their structures were established by spectroscopic analysis, X-ray diffraction, quantum chemical computational approaches, and/or a modified Mosher's method. A plausible biosynthetic pathway of 1 and its biogenetic relationship with 2-5 were proposed. New compounds 1-3 displayed an interesting inhibitory activity against lipopolysaccharide-induced inflammation in BV-2 microglial cells.

Inflammation as a host's excessive immune response to stimulation, is involved in the development of numerous diseases. To discover novel anti-inflammatory agents and based on our previous synthetic work on marine natural product Chrysamide B, it and a series of derivatives were synthesized and evaluated for their anti-inflammatory activity on inhibition of LPS-induced NO production. Then the preliminary structure-activity relationships were conducted. Among them, Chrysamide B is the most potent anti-inflammatory agent with low cytotoxicity and strong inhibition on the production of NO (IC 50  = 0.010 μM) and the activity of iNOS (IC 50  = 0.082 μM) in LPS-stimulated RAW 264.7 cells. Primary studies suggested that the mechanism of action may be that it interfered the formation of active dimeric iNOS but not affected transcription and translation. Furthermore, its good performance of anti-inflammatory effect on LPS-induced multiple inflammatory cytokines production, carrageenan-induced paw edema, and endotoxin-induced septic mice, was observed. We believe that these findings would provide an idea for the further modification and research of these analogs in the future., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Seiridiasteriscane A is an asteriscane-type sesquiterpenoid bearing a trans-fused bicyclo[6.3.0]undecane skeleton. Although its biosynthesis has been proposed to involve a semipinacol rearrangement of a putative intermediary acetate bearing a bicyclo[7.2.0]undecane ring system (presumably derived from coisolated pestalotiopsin M) followed by epimerization of the resulting cis-fused seiridiasteriscane B, such a type of semipinacol rearrangement has never been reported so far. Our model study revealed that a 1-hydroxybicyclo[7.2.0]undecan-2-yl acetate underwent a smooth and stereospecific semipinacol rearrangement with the assistance of Et2AlCl to give the corresponding bicyclo[6.3.0]undecane-9-one. In addition, the resulting cis-fused 5,8-bicyclic ketone was partially epimerized to the corresponding trans-fused ketone by prolonged adsorption onto a silica gel plate. These results may support a recently proposed biosynthetic pathway of seiridiasteriscane A., (© The Author(s) 2021. Published by Oxford University Press on behalf of Japan Society for Bioscience, Biotechnology, and Agrochemistry.)

Biothiols are extremely powerful antioxidants that protect cells against the effects of oxidative stress. They are also considered relevant disease biomarkers, specifically risk factors for cardiovascular disease. In this paper, a new procedure for the simultaneous determination of human serum albumin and low-molecular-weight thiols in plasma is described. The method is based on the pre-column derivatization of analytes with a thiol-specific fluorescence labeling reagent, monobromobimane, followed by separation and quantification through reversed-phase high-performance liquid chromatography with fluorescence detection (excitation, 378 nm; emission, 492 nm). Prior to the derivatization step, the oxidized thiols are converted to their reduced forms by reductive cleavage with sodium borohydride. Linearity in the detector response for total thiols was observed in the following ranges: 1.76-30.0 mg mL -1 for human serum albumin, 0.29-5.0 nmol mL -1 for α-lipoic acid, 1.16-35 nmol mL -1 for glutathione, 9.83-450.0 nmol mL -1 for cysteine, 0.55-40.0 nmol mL -1 for homocysteine, 0.34-50.0 nmol mL -1 for N-acetyl-L-cysteine, and 1.45-45.0 nmol mL -1 for cysteinylglycine. Recovery values of 85.16-119.48% were recorded for all the analytes. The developed method is sensitive, repeatable, and linear within the expected ranges of total thiols. The devised procedure can be applied to plasma samples to monitor biochemical processes in various pathophysiological states.

Marine natural products derived from special or extreme environment provide an important source for the development of anti-tumor drugs due to their special skeletons and functional groups. In this study, based on our previous work on the total synthesis and structure revision of the novel marine natural product Chrysamide B, a group of its derivatives were designed, synthesized, and subsequently of which the anti-cancer activity, structure-activity relationships and cellular mechanism were explored for the first time. Compared with Chrysamide B, better anti-cancer performance of some derivatives against five human cancer cell lines (SGC-7901, MGC-803, HepG2, HCT-116, MCF-7) was observed, especially for compound b-9 on MGC-803 and SGC-7901 cells with the IC 50 values of 7.88 ± 0.81 and 10.08 ± 1.08 μM, respectively. Subsequently, cellular mechanism study suggested that compound b-9 treatment could inhibit the cellular proliferation, reduce the migration and invasion ability of cells, and induce mitochondrial-dependent apoptosis in gastric cancer MGC-803 and SGC-7901 cells. Furthermore, the mitochondrial-dependent apoptosis induced by compound b-9 is related with the JAK2/STAT3/Bcl-2 signaling pathway. To conclude, our results offer a new structure for the discovery of anti-tumor lead compounds from marine natural products., (Copyright © 2021 Elsevier Inc. All rights reserved.)

The first photoinduced synthesis of polyfunctionalized 3-aza[n.1.0]bicycles from readily available ene-ynamides and 2,6-lutidine N-oxide using an organic acridinium photocatalyst is reported. Applying a photocatalytic strategy to the reactive distonic cation vinyl radical intermediate from ynamide, a series of bio-valuable 3-azabicycles, including diverse 3-azabicyclio[4.1.0]heptanes and 3-azabicyclo[5.1.0]octanes that are challenging to accomplish using traditional methods, have been successfully synthesized in good to high yields under mild and metal-free conditions. Mechanistic studies are consistent with the photocatalyzed single-electron oxidation of ene-ynamide and the intermediacy of a putative cationic vinyl radical in this transformation. Importantly, this strategy provides new access to the development of photocatalytic vinyl radical cascades for the synthesis of structurally sophisticated substrates.

A three-component method is described for the preparation of syn -1,2-disubstituted bridged bicyclic compounds. The reaction was demonstrated for readily available aromatic and heteroaromatic C-H bond substrates with tertiary and secondary amide, lactam, pyrazole, and triazole directing groups and a variety of bridged bicyclic alkenes, including norbornene, benzonorbornadiene, oxygen- and nitrogen-bridged analogs, and an unsaturated tropinone. A broad dioxazolone scope was also observed. The use of a chiral Cp-derived Rh III catalyst enables asymmetric synthesis of products.

We report that oxo- or aza-bridged alkylidenemalononitrile-cycloheptenes undergo a [3,3] ring rearrangement to yield cyclopenta-fused dihydro-furans or pyrroles. Described herein are the origins of the serendipitous discovery, scope studies, and representative functional group interconversion chemistry.

A series of novel nopol derivatives bearing the 1,3,4-thiadiazole-thiourea moiety were designed and synthesized by multi-step reactions in search of potent natural product-based antifungal agents. Their structures were confirmed by FT-IR, NMR, ESI-MS, and elemental analysis. Antifungal activity of the target compounds was preliminarily evaluated by in vitro methods against Fusarium oxysporum f. sp. cucumerinum , Cercospora arachidicola , Physalospora piricola , Alternaria solani , Gibberella zeae , Rhizoeotnia solani , Bipolaris maydis , and Colleterichum orbicalare at 50 µg/mL. All the target compounds exhibited better antifungal activity against P. piricola , C. arachidicola , and A. solani . Compound 6j (R = m , p -Cl Ph) showed the best broad-spectrum antifungal activity against all the tested fungi. Compounds 6c (R = m -Me Ph), 6q (R = i -Pr), and 6i (R = p -Cl Ph) had inhibition rates of 86.1%, 86.1%, and 80.2%, respectively, against P. piricola , much better than that of the positive control chlorothalonil. Moreover, compounds 6h (R = m -Cl Ph) and 6n (R = o -CF 3 Ph) held inhibition rates of 80.6% and 79.0% against C. arachidicola and G. zeae , respectively, much better than that of the commercial fungicide chlorothalonil. In order to design more effective antifungal compounds against A. solani , analysis of the three-dimensional quantitative structure-activity relationship (3D-QSAR) was carried out using the CoMFA method, and a reasonable and effective 3D-QSAR model ( r 2 = 0.992, q 2 = 0.753) has been established. Furthermore, some intriguing structure-activity relationships were found and are discussed by theoretical calculation.

Plasmodium falciparum causes the deadliest form of malaria. Adequate redox control is crucial for this protozoan parasite to overcome oxidative and nitrosative challenges, thus enabling its survival. Sulfenylation is an oxidative post-translational modification, which acts as a molecular on/off switch, regulating protein activity. To obtain a better understanding of which proteins are redox regulated in malaria parasites, we established an optimized affinity capture protocol coupled with mass spectrometry analysis for identification of in vivo sulfenylated proteins. The non-dimedone based probe BCN-Bio1 shows reaction rates over 100-times that of commonly used dimedone-based probes, allowing for a rapid trapping of sulfenylated proteins. Mass spectrometry analysis of BCN-Bio1 labeled proteins revealed the first insight into the Plasmodium falciparum trophozoite sulfenylome, identifying 102 proteins containing 152 sulfenylation sites. Comparison with Plasmodium proteins modified by S-glutathionylation and S-nitrosation showed a high overlap, suggesting a common core of proteins undergoing redox regulation by multiple mechanisms. Furthermore, parasite proteins which were identified as targets for sulfenylation were also identified as being sulfenylated in other organisms, especially proteins of the glycolytic cycle. This study suggests that a number of Plasmodium proteins are subject to redox regulation and it provides a basis for further investigations into the exact structural and biochemical basis of regulation, and a deeper understanding of cross-talk between post-translational modifications., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Tetracyclic diterpenoids (C 20 ) mainly refer to the plant terpenoids bearing biogenetically related carbon skeletons derived from copalyl diphosphates ( ent -CPP and syn -CPP). This large family contains over 1600 known members that can be categorized into 11 major structural types. Among them, more than three-quarters share a bridged bicyclo[3.2.1]octane subunit, which is also an important branching point in biosynthesis en route to the other types of bicyclic scaffolds, such as bicyclo[2.2.2]-, bicyclo[3.3.0]-, and tricyclo[3.2.1.0]octanes. Combined with the significance of its stereochemical importance in biological activity, the assembly of the bicyclo[3.2.1]octane skeletons is critical to the success of the whole synthesis blueprint toward tetracyclic diterpenoids. Although a number of inspiring methodologies have been disclosed, general approaches by the incorporation of innovative cascade reactions permitting access to diverse structural types of tetracyclic diterpenoids remain limited and in urgent demand.Because of the long-standing interest in the synthesis of bridged diterpenoids, we have recently developed two complementary types of oxidative dearomatization induced (ODI) cascade approaches to the rapid and efficient construction of bicyclo[3.2.1]octane skeletons. In this Account, we summarize our original synthesis design, methodology development, and the application of these two strategies in tetracyclic diterpenoid synthesis during the past few years in our laboratory.First, we detail our preliminary investigation of the ODI-[5 + 2] cycloaddition/pinacol rearrangement cascade reaction, which showed a wide scope of vinylphenol substrates and led to cyclopentane and cyclohexane-fused bicyclo[3.2.1]octanes in good yields with excellent dr values. Next, we describe the utilization of this ODI-[5 + 2] cascade reaction which resulted in the asymmetric total syntheses of four highly oxygenated ent -kauranoids. The strategy concerning accurate stereochemical control in the ODI-[5 + 2] cycloaddition was then successfully transplanted to the total syntheses of three stemaranoids, thus providing a straightforward and diastereoselective route to C9-ethano-bridged tetracyclic diterpenoids. To access more complex diterpenoid rhodomollanol A, we exploited two additional biomimetic rearrangements, namely, the retro- Dieckmann fragmentation/vinylogous Dieckmann cyclization cascade and the photo-Nazarov cyclization/intramolecular cycloetherification cascade. Taken together with the ODI-[5 + 2] cascade, the asymmetric total synthesis of the target molecule was realized, which shed light on the biogenetic pathway of the unprecedented rhodomollane-type carbon framework. Finally, we describe an ODI-Diels-Alder/Beckwith-Dowd cascade approach as a valuable supplement to the ODI-[5 + 2] cascade for the fabrication of cycloheptane-fused bicyclo[3.2.1]octane skeletons. Its versatility was also demonstrated by the total syntheses of two challenging grayanane diterpenoids. In view of the high functional-group compatibility and scalability, we anticipate that the two novel cascade approaches will find further use in the field of complex natural product synthesis.

Malaria remains a significant cause of morbidity and mortality in Sub-Saharan Africa and South Asia. While clinical antimalarials are efficacious when administered according to local guidelines, resistance to every class of antimalarials is a persistent problem. There is a constant need for new antimalarial therapeutics that complement parasite control strategies to combat malaria, especially in the tropics. In this work, nopol-based quinoline derivatives were investigated for their inhibitory activity against Plasmodium falciparum , one of the parasites that cause malaria. The nopyl-quinolin-8-yl amides ( 2 - 4 ) were moderately active against the asexual blood stage of chloroquine-sensitive strain Pf 3D7 but inactive against chloroquine-resistant strains Pf K1 and Pf NF54. The nopyl-quinolin-4-yl amides and nopyl-quinolin-4-yl-acetates analogs were generally less active on all three strains. Interesting, the presence of a chloro substituent at C7 of the quinoline ring of amide 8 resulted in sub-micromolar EC 50 in the Pf K1 strain. However, 8 was more than two orders of magnitude less active against Pf 3D7 and Pf NF54. Overall, the nopyl-quinolin-8-yl amides appear to share similar antimalarial profile (asexual blood-stage) with previously reported 8-aminoquinolines like primaquine. Future work will focus on investigating the moderately active and selective nopyl-quinolin-8-yl amides on the gametocyte or liver stages of Plasmodium falciparum and Plasmodium vivax .

Classical terpenoid biosynthesis involves the cyclization of the linear prenyl pyrophosphate precursors geranyl-, farnesyl-, or geranylgeranyl pyrophosphate (GPP, FPP, GGPP) and their isomers, to produce a huge number of natural compounds. Recently, it was shown for the first time that the biosynthesis of the unique homo-sesquiterpene sodorifen by Serratia plymuthica 4Rx13 involves a methylated and cyclized intermediate as the substrate of the sodorifen synthase. To further support the proposed biosynthetic pathway, we now identified the cyclic prenyl pyrophosphate intermediate pre-sodorifen pyrophosphate (PSPP). Its absolute configuration (6R,7S,9S) was determined by comparison of calculated and experimental CD-spectra of its hydrolysis product and matches with those predicted by semi-empirical quantum calculations of the reaction mechanism. In silico modeling of the reaction mechanism of the FPP C-methyltransferase (FPPMT) revealed a S N 2 mechanism for the methyl transfer followed by a cyclization cascade. The cyclization of FPP to PSPP is guided by a catalytic dyad of H191 and Y39 and involves an unprecedented cyclopropyl intermediate. W46, W306, F56, and L239 form the hydrophobic binding pocket and E42 and H45 complex a magnesium cation that interacts with the diphosphate moiety of FPP. Six additional amino acids turned out to be essential for product formation and the importance of these amino acids was subsequently confirmed by site-directed mutagenesis. Our results reveal the reaction mechanism involved in methyltransferase-catalyzed cyclization and demonstrate that this coupling of C-methylation and cyclization of FPP by the FPPMT represents an alternative route of terpene biosynthesis that could increase the terpenoid diversity and structural space.

Through structural modification of an oxalamide derived chemotype, a novel class of highly potent, orally bioavailable IDO1-specific inhibitors was identified. Representative compound 18 inhibited human IDO1 with IC 50 values of 3.9 nM and 52 nM in a cellular and human whole blood assay, respectively. In vitro assessment of the ADME properties of 18 demonstrated very high metabolic stability. Pharmacokinetic profiling in mice showed a significantly reduced clearance compared to the oxalamides. In a mouse pharmacodynamic model 18 nearly completely suppressed lipopolysaccharide-induced kynurenine production. Hepatocyte data of 18 suggest the human clearance to be in a similar range to linrodostat (1)., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Cholesteryl ester transfer protein (CETP) inhibitors reduce the transfer of cholesteryl esters from the high-density lipoprotein (HDL-C) to apolipoprotein such as VLDL/LDL, with exchange of triglycerides. Thus, this inhibition increases the HDL-C levels, which is believed to lower the risk for heart disease and stroke. We report here a series of CETP inhibitors based on the cyclic, bicyclic urea and sulfamide cores. These CETP inhibitors exemplified by 15, 31, and 45 demonstrated in vitro potency in inhibiting the CETP transfer activity, and 15, 31 showing in vivo efficacy to increase HDL-C levels in cynomolgus-CETP transgenic mice. The synthesis and biological evaluations of these CETP inhibitors are described., (Copyright © 2020. Published by Elsevier Ltd.)

We have been interested in the reactivities of small-ring compounds and have reported reactions that proceed through cyclopropane intermediates starting from coumarin derivatives bearing an electron-withdrawing group at the 3-position or 2-oxo-2H-pyran-3-carboxylate derivatives and dimethylsulfoxonium methylide. This time, the reaction between 3-oxa-2-oxobicyclo[4.2.0]oct-4-ene-1-carboxylate and dimethylsulfoxonium methylide has been investigated. 3a,4,5,7a-Tetrahydro-7-hydroxybenzofuran-6-carboxylate and/or 2-hydroxybicyclo[4.1.0]hept-2-ene-3-carboxylate were obtained. The compounds were characterized using various spectral and X-ray crystallographic techniques. A plausible reaction mechanism has been discussed. This reaction was applied to some 3-oxa-2-oxobicyclo[4.2.0]oct-4-ene-1-carboxylate derivatives to clarify the generality.

Novel innovative catalytic systems such as hydrogen-bond donors and thiourea hybrid catalysts have been developed for the asymmetric synthesis of biologically important pharmaceuticals and natural products. Benzothiadiazines possess a stronger hydrogen-bond donor ability compared to thioureas and exhibit remarkable catalytic performance for the activation of α,β-unsaturated amides. Hybrid thioureas (bearing an arylboronic acid and an ammonium salt) efficiently promote the hetero-Michael addition to α,β-unsaturated carboxylic acids and the O-alkylation of keto enols with 5-chlorofuran-2(5H)-one. These hybrid catalysts enable the first total synthesis of non-racemic avenaol, a noncanonical strigolactone, as well as the asymmetric synthesis of several pharmaceuticals. In addition, this study discovers unique chemical phenomena (i.e., the dual role of benzoic acid as a boron ligand and a proton shuttle, the chirality switch of products by solvent used, and the dynamic kinetic resolution of a racemic electrophile in an S N 2-type reaction).

'precision medicine' is characterized by the selection of targeted drugs based on genetic characteristics of tumor from patients, and no longer selected basis on the type of cancer tissue. Among them, clinical trials on neurotrophin receptor tyrosine kinase genes (NTRK) have proven that great anti-cancer effects can be achieved in different cancer patients. In this paper, a novel total of twenty compounds in two categories have been designed and synthesized. Results of Kinase activity tests showed that I-9 (TRKA IC 50  = 1.3 nM, TRKA G595R IC 50  = 6.1 nM), and I-10 (TRKA IC 50  = 1.1 nM, TRKA G595R IC 50  = 5.3 nM) have significant inhibitory activity, and results of cell viability tests showed that I-9 and I-10 can maintain a great inhibitory effect in the Ba/F3-LMNA-NTRK1 cell line(IC 50  = 81.1 nM and 41.7 nM, respectively), and in Ba/F3-LMNA-NTRK1-G595R cell line, I-9 and I-10 have better cell activity (IC 50 was 495.3 nM, 336.6 nM, respectively) compared with the positive control drug LOXO-101. These results indicate that I-9 and I-10 are potential TRK inhibitors that can overcome drug resistance for further investigation., (Copyright © 2020. Published by Elsevier Ltd.)

The thiol-selective fluorescent imaging agent, dibromobimane, has been repurposed to crosslink cysteine- and homocysteine-containing peptides, with the resulting bimane linker acting as both a structural constraint and a fluorescent tag. Macrocyclisation was conducted on nine short peptides containing two cysteines and/or homocysteines, both on-resin and in buffered aqueous solution, to give macrocycles ranging in size from 16 (i,i+2) to 31 (i,i+7) atoms. The structures were defined by CD, NMR structure calculations by using Xplor-NIH, NMR secondary shift and J HαNH analyses to reveal helical structure in the i,i+4 (1, 2), and i,i+3 (5) constrained peptides. Cellular-uptake studies were conducted with three of the macrocycles. Subsequent confocal imaging revealed punctate fluorescence within the cytosol indicative of peptides trapped in endocytic vesicles. These studies demonstrate that dibromobimane is an effective tool for defining secondary structure within short peptides, whilst simultaneously introducing a fluorescent tag suitable for common cell-based experiments., (© 2020 Wiley-VCH GmbH.)

Native to the Asia-Pacific region and widely applied in traditional Chinese medicine, the genus Daphniphyllum has produced over 330 known Daphniphyllum alkaloids. Investigations into these alkaloids have shown an exceptional range of interesting bioactivities. Challenging and caged polycyclic architectures and the promising biological profiles make Daphniphyllum alkaloids intriguing synthetic targets. Based on their backbones, these alkaloids can be categorized into 13-35 structurally distinct subfamilies. In addition to our work, almost 30 impressive total syntheses of Daphniphyllum alkaloids from seven subfamilies, namely, daphniphylline-type, secodaphniphylline-type, daphnilactone A-type, bukittinggine-type, daphmanidin A-type, calyciphylline A-type, and calyciphylline B-type alkaloids, have been reported by 11 research groups. However, many Daphniphyllum alkaloid subfamilies remain inaccessible by chemical synthesis.In this Account, we summarize our recent endeavors in the total synthesis of Daphniphyllum alkaloids commencing from simple chiral bicyclic synthons. Daphniphyllum alkaloids with diversified skeletons from four different subfamilies, namely, calyciphylline A-type, daphnezomine A-type, bukittinggine-type, and yuzurimine-type alkaloids, have been achieved. Furthermore, the tricyclic core structure of daphniglaucin C-type alkaloids daphnimacropodines was also synthesized. First, we describe a 14-step synthesis of calyciphylline A-type alkaloid (-)-himalensine A, which features a mild Cu-mediated nitrile hydration, an intramolecular Heck reaction to assemble the pivotal 2-azabicyclo[3.3.1]nonane moiety, and a Meinwald rearrangement to introduce the critical oxidative state into the skeleton. We then introduce the synthesis of daphnezomine A-type alkaloid dapholdhamine B, which possesses a unique aza-adamantane core. This target molecule was fabricated using key reactions including Huang's amide-activation-annulation. An unexpected radical detosylation during the synthesis of dapholdhamine B further inspired an ambitious radical cyclization cascade strategy, which eventually led to an efficient total synthesis of bukittinggine-type alkaloid (-)-caldaphnidine O. This highly chemo-, regio-, and stereoselective radical reaction cascade also shed light on the synthetic strategy of other alkaloids with caged structures. We next describe the first total synthesis of yuzurimine-type alkaloid (+)-caldaphnidine J. The key steps in our approach include a Pd-catalyzed regioselective hydroformylation and a novel Swern oxidation/ketene dithioacetal Prins reaction cascade. The work has achieved the first synthesis of a member of the largest subfamily of Daphniphyllum alkaloids. Finally, we show our efforts toward the total synthesis of daphniglaucin C-type alkaloids. Overall, we hope that the interesting strategies and synthetic methods demonstrated in our efforts could inspire a wide variety of additional applications to natural product synthesis.

Thirteen new diterpenoid compounds, named agallolides A-M (1-13), including ten ent-atisanes, were isolated from the stems and twigs of the Chinese semi-mangrove plant, Excoecaria agallocha. Most notably, agallolides A (1) and B (2) are two rearranged ent-atisanes featuring a unique 6/6/5/7 tetracyclic carbon skeleton. Agallolides C-J (3-10) are ent-atisanes, among which agallolide C (3) represents the first example of 3,4-seco-17-nor-ent-atisane. Agallolides K (11) and L (12) are two ent-isopimaranes, whereas agallolide M (13) is a rare 3,4-seco-ent-trachylobane. The structures of these diterpenoid compounds were established by HR-ESIMS and extensive 1D and 2D NMR investigations. The absolute configurations of agallolide A (1) and agallolides I-K (9-11) were further confirmed by single-crystal X-ray diffraction analyses with Cu Kα radiation. The plausible biogenetic pathways for agallolides A (1), B (2), and I (9) were proposed. Agallolides I (9) and J (10) exhibited NF-κB inhibitory activity with inhibition rates of 23.4% and 19.4%, respectively, at the concentration of 100.0 µM., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Expanding the repertoire of electrophiles with unique reactivity features would facilitate the development of covalent inhibitors with desirable reactivity profiles. We herein introduce bicyclo[1.1.0]butane (BCB) carboxylic amide as a new class of thiol-reactive electrophiles for selective and irreversible inhibition of targeted proteins. We first streamlined the synthetic routes to generate a variety of BCB amides. The strain-driven nucleophilic addition to BCB amides proceeded chemoselectively with cysteine thiols under neutral aqueous conditions, the rate of which was significantly slower than that of acrylamide. This reactivity profile of BCB amide was successfully exploited to develop covalent ligands targeting Bruton's tyrosine kinase (BTK). By tuning BCB amide reactivity and optimizing its disposition on the ligand, we obtained a selective covalent inhibitor of BTK. The in-gel activity-based protein profiling and mass spectrometry-based chemical proteomics revealed that the selected BCB amide had a higher target selectivity for BTK in human cells than did a Michael acceptor probe. Further chemical proteomic study revealed that BTK probes bearing different classes of electrophiles exhibited distinct off-target profiles. This result suggests that incorporation of BCB amide as a cysteine-directed electrophile could expand the capability to develop covalent inhibitors with the desired proteome reactivity profile.

The replacement of one chemical motif with another that is broadly similar is a common method in medicinal chemistry to modulate the physical and biological properties of a molecule (i.e., bioisosterism). In recent years, bioisosteres such as cubane and bicyclo[1.1.1]pentane (BCP) have been used as highly effective phenyl mimics. Herein, we show the successful incorporation of a range of phenyl bioisosteres during the open-source optimization of an antimalarial series. Cubane ( 19 ) and closo -carborane ( 23 ) analogues exhibited improved in vitro potency against Plasmodium falciparum compared to the parent phenyl compound; however, these changes resulted in a reduction in metabolic stability; unusually, enzyme-mediated oxidation was found to take place on the cubane core. A BCP analogue ( 22 ) was found to be equipotent to its parent phenyl compound and showed significantly improved metabolic properties. While these results demonstrate the utility of these atypical bioisosteres when used in a medicinal chemistry program, the search to find a suitable bioisostere may well require the preparation of many candidates, in our case, 32 compounds.

Benzobicyclon is a systemic herbicide that was officially registered in China in 2018. The environmental behaviors of benzobicyclon hydrolysate (BH), the main metabolite and active product of benzobicyclon, remain poorly understood in paddy fields. Here, agricultural soil samples were collected from paddy fields in Jiangxi (Ferralsols), Shandong (Alisols), Hebei (Luvisols), Heilongjiang (Phaeozems), Zhejiang (Anthrosols), Sichuan (Gleysols), Hainan (Plinthosols), and Hubei (Lixisols) across China. The equilibrium oscillation method was used to study the adsorption-desorption behaviors of BH in the eight soils. The relationships between BH adsorption and soil physicochemical properties, environmental factors (temperature and initial solution pH), and other external conditions (addition of humic acid, biochar, and metal ions) were quantified. The adsorption-desorption parameters of BH in all soils were well fitted by the Freundlich model. The adsorption constant of BH varied between 0.066 and 4.728. The BH adsorption capacity decreased in the following order: Phaeozems > Alisols > Ferralsols > Lixisols > Plinthosols > Anthrosols > Luvisols > Gleysols. The Freundlich adsorption and desorption constants of BH were linearly positively correlated with soil clay content (R 2  = 0.711 and 0.709; P = 0.009 and 0.009, respectively), organic carbon content (R 2  = 0.684 and 0.672; P = 0.011 and 0.013, respectively), and organic matter content (R 2  = 0.698 and 0.683; P = 0.010 and 0.011, respectively); however, their linear relationships with soil cation exchange capacity were not significant (R 2  = 0.192 and 0.192; P = 0.278 and 0.278, respectively). The adsorption and desorption constants of BH had negative, albeit not significant, correlations with soil pH (R 2  = 0.104 and 0.100; P = 0.437 and 0.445, respectively). The adsorption of BH by soil occurred spontaneously and was mainly based on physical adsorption. Either low or high temperature reduced the ability of the soil to adsorb BH. The addition of humic acid to the soil increased BH adsorption, while the addition of biochar increased the solution pH, resulting in decreased BH adsorption. Cation type and ionic strength also had strong effects on BH adsorption. With the exception of Phaeozems, BH exhibited intermediate or high mobility in the agricultural soils and thus poses risks to surface water and groundwater., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Cycloaddition reactions provide an expeditious route to construct ring systems in a highly convergent and stereoselective manner. For a typical cycloaddition reaction to occur, however, the installation of multiple reactive functional groups (π-bonds, leaving group, etc.) is required within the substrates, compromising the overall efficiency or scope of the cycloaddition reaction. Here, we report a palladium-catalyzed [3 + 2] reaction that utilizes twofold C(sp 3 )-H activation to generate the three-carbon unit for formal cycloaddition. The initial β-C(sp 3 )-H activation of aliphatic amide, followed by maleimide insertion, triggers a relayed, second C(sp 3 )-H activation to complete a formal [3 + 2] cycloaddition. The key to success was the use of weakly coordinating amide as the directing group, as previous studies have shown that Heck or alkylation pathways are preferred when stronger-coordinating directing groups are used with maleimide coupling partners. To promote the amide-directed C(sp 3 )-H activation step, the use of pyridine-3-sulfonic acid ligands is crucial. This method is compatible with a wide range of amide substrates, including lactams, which lead to spiro-bicyclic products. The [3 + 2] product is also shown to undergo a reductive desymmetrization process to access chiral cyclopentane bearing multiple stereocenters with excellent enantioselectivity.

We established a methodology for initiating cross-linking of antibodies selectively on the cell surface through intermolecular copper-free click reactions facilitated by increased effective concentrations of antibodies binding to target antigens. Upon cross-linking of tetrazine- and bicyclononyne-modified trastuzumab on the surface of HER2-overexpressing cells, increased antibody uptake and activation of intracellular signaling were observed. Our findings demonstrate that the cross-linking reaction can significantly alter the biophysical properties of proteins, activating their unique functionalities on targeted cells to realize an increased cargo delivery and synthetic manipulation of cellular signaling.

Enallenes can be readily converted into two families of 3.2.0 (hetero)bicycles with high diastereoselectivities through the combination of visible light with a suitable Ir(III) complex (1 mol %). Two complementary pathways, namely, a photocycloaddition versus a radical chain, can then take place. Both manifolds grant complete regiocontrol of the allene difunctionalization. This is accompanied by an original 1,3-group shift using sulfonyl allenamides that deliver a congested tetrasubstituted headbridging carbon in the corresponding product.

We designed and synthesized conformationally rigid histamine analogues with a bicyclo[3.1.0]hexane scaffold. All the compounds were selectively bound to the H 3 receptor subtype over the H 4 receptor subtype. Notably, compound 7 showed potent binding affinity and over 100-fold selectivity for the H 3 receptors ( K i = 5.6 nM for H 3 and 602 nM for H 4 ). These results suggest that the conformationally rigid bicyclo[3.1.0]hexane structure can be a useful scaffold for developing potent ligands selective for the target biomolecules.

A simple but previously undescribed macrolide with unprecedented bicyclo 5/9 ring system, namely, cladocladosin A (1), along with two new sulfur-containing macrolides, namely, thiocladospolides F and G (2 and 3), were characterized from the mangrove-derived endophytic fungus Cladosporium cladosporioides MA-299. The structures of these compounds were established on the basis of spectroscopic interpretation, and the absolute configurations of compounds 1-3 were determined by X-ray crystallographic analysis, Mosher's method, and by a biogenetic point of view. The possible biogenetic pathway for compounds 1-3 as well as their congeners thiocladospolides A-D and pandangolide 3 was proposed, providing a role in distinguishing the position of sulfur substitution in thiomacrolides. Compounds 1-3 were evaluated for antimicrobial activities against human-, aquatic-, and plant-pathogenic microbes., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Synthesis of bridged scaffolds via Type II cyclization constitutes substantial challenges due to the intrinsic ring strain accumulated in reaction transition states. Catalytic enantioselective Type II-cyclization methods are even rarer. Here, we describe a detailed study of developing a Rh(I)-catalyzed enantioselective intramolecular Type II cyclization of alkynes via C-C activation of cyclobutanones. This method offers a rapid approach to access a wide range of functionalized [3.3.1]-bridged bicycles along with an exocyclic olefin and an all-carbon quaternary stereocenter. Excellent enantioselectivity has been achieved using a combination of cationic rhodium(I) and DTBM-segphos. Attributed to the redox neutral and strong acid/base-free reaction conditions, high chemoselectivity has also been observed. For the oxygen-tethered substrates, the reaction can proceed at room temperature. In addition, partial kinetic resolution has been achieved for substrates with existing stereocenters, forging interesting chiral tricyclic scaffolds. The methylalkyne-derived substrates gave unexpected dimeric structures in good yield with excellent enantioselectivity and complete diastereoselectivity. Furthermore, the bridged bicyclic products can be diversely functionalized through simple transformations. Finally, mechanistic studies reveal a surprising reaction pathway that involves forming a metal-stabilized anti -Bredt olefin intermediate.

Xylarilongipins A (1) and B (2), two diterpenes each with an unusual cage-like bicyclo[2.2.2]octane moiety, along with their biosynthetic precursor hymatoxin L (3), were isolated from the culture broth of the fungicolous fungus Xylaria longipes HFG1018 inhabiting in the medicinal fungus Fomitopsis betulinus. The structures and absolute configurations of the three compounds were established by extensive spectroscopic analysis and single-crystal X-ray diffraction analysis. Xylarilongipin A (1) displayed moderate inhibitory activity against the cell proliferation of concanavalin A-induced T lymphocytes and lipopolysaccharide-induced B lymphocytes with IC50 values of 13.6 and 22.4 μM, respectively. Additionally, the biosynthetic pathways for compounds 1-3 are discussed. This work not only corroborates the structure of the 9,16-cyclo-(18-nor-)isopimarane skeleton by single-crystal X-ray diffraction analysis for the first time, but also provides new insights into the biosynthetic origin of the unusual diterpene skeletons.

The first total synthesis of the Euphorbia diterpenoid pepluanol B in both racemic and enantioenriched form involves 20 steps from a known bicyclic diol. This synthesis features an unprecedented bromo-epoxidation to control the eight-membered-ring conformation. In addition, salient reactions for the construction of the tetracyclic backbone include a sterically challenging aldol reaction to establish the quaternary center, a ring closing metathesis (RCM) to forge the eight-membered ring, and a diastereoselective cyclopropanation to assemble the embedded cyclopropane motif., (© 2020 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Bicyclo[1.1.0]butanes (BCBs) are highly strained carbocycles that have emerged as versatile synthetic tools, particularly for the construction of functionalized small molecules. This work reports two efficient pathways for the rapid preparation of over 20 structurally diverse BCB ketones, encompassing simple alkyl and aryl derivatives, as well as unprecedented amino acid, dipeptide, bioisostere, and bifunctional linchpin reagents currently inaccessible using literature methods. Analogues are readily forged in two steps and in high yields from simple carboxylic acids or through unsymmetrical ketone synthesis beginning with a convenient carbonyl dication equivalent. The utility of this novel toolbox of strained electrophiles for the selective modification of proteinogenic nucleophiles is highlighted., (© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Studies on the substrate selectivity of recombinant ferrous-iron- and 2-oxoglutarate-dependent proline hydroxylases (PHs) reveal that they can catalyse the production of dihydroxylated 5-, 6-, and 7-membered ring products, and can accept bicyclic substrates. Ring-substituted substrate analogues (such hydroxylated and fluorinated prolines) are accepted in some cases. The results highlight the considerable, as yet largely untapped, potential for amino acid hydroxylases and other 2OG oxygenases in biocatalysis., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Regioselectivity for intramolecular Diels-Alder (IMDA) reactions of 6-acetoxy-6-alkenylcyclohexa-2,4-dien-1-ones that were formed by oxidation of 2-alkenylphenols with lead tetraacetate in acetic acid were studied. Bridged regioselectivity was observed in the IMDA reactions of 6-acetoxy-6-alkenylcyclohexa-2,4-dien-1-ones having a dienophile part which could conjugate with an aromatic group. Bridged seven- and eight-membered rings and bicyclo[2.2.2]octane skeletons were constructed by the present IMDA reactions. Density functional theory (DFT) calculations suggested that conjugation of the dienophile with neighboring aromatic groups lowered the highest occupied molecular orbital-lowest unoccupied molecular orbital (HOMO-LUMO) energy gap and preceded bridged [4 + 2] adducts.

In this study, the impact of one or two hydroxy moieties at the benzo[7]annulene scaffold on the GluN2B affinity and cytoprotective activity was analyzed. The key intermediate for the synthesis of OH-substituted benzo[7]annulenamines 11-13 and 17 was the epoxyketone 8. Reductive epoxide opening of 8 resulted with high regioselectivity in the 5-hydroxyketone 9 (Pd(OAc) 2 , HCO 2 H, phosphane ligand) or the 6-hydroxyketone 10 (H 2 , Pd/C), whereas hydrolysis in aqueous dioxane led to the dihydroxyketone 14. Reductive amination of these ketones with primary amines and NaBH(OAc) 3 afforded the benzo[7]annulenamines 11-13 and 17. In receptor binding studies 5-OH derivatives 11 and 12 showed higher GluN2B affinity than 6-OH derivatives 13, which in turn were more active than 5,6-di-OH derivative 17a. The same order was found for the cytoprotective activity of the ligands. The tertiary amine 12a with one OH moiety in 5-position represents the most promising GluN2B negative allosteric modulator with a binding affinity of K i  = 49 nM and a cytoprotective activity of IC 50  = 580 nM. In the binding pocket 12a shows a crucial H-bond between the benzylic OH moiety and the backbone carbonyl O-atom of Ser132 (GluN1b). It was concluded that a 5-OH moiety is essential for the inhibition of the NMDA receptor associated ion channel, whereas a OH moiety in 6-position is detrimental for binding and inhibition. An OH or CH 2 OH moiety at 2-position results in binding at the ifenprodil binding site, but very weak ion channel inhibition., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Oxidopyrylium ylides are useful intermediates in synthetic organic chemistry because of their capability of forming structurally complex cycloadducts. They can also self-dimerize via [5 + 3] cycloaddition, which is an oft-reported side reaction that can negatively impact [5 + 2] cycloadduct yields and efficiency. In select instances, these dimers can be synthesized and used as the source of oxidopyrylium ylide, although the generality of this process remains unclear. Thus, how the substitution pattern governs both dimerization and cycloaddition reactions is of fundamental interest to probe factors to regulate them. The following manuscript details our findings that maltol-derived oxidopyrylium ylides (i.e., with ortho methyl substitution relative to oxide) can be trapped prior to dimerization more efficiently than the regioisomeric allomaltol-derived ylide (i.e., with a para methyl substitution relative to oxide). Density functional theory studies provide evidence in support of a sterically (kinetically) controlled mechanism, whereby gauche interactions between appendages of the approaching maltol-derived ylides are privileged by higher barriers for dimerization and thus are readily intercepted by dipolarophiles via [5 + 2] cycloadditions.