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We report an approach to the core of the manzamine alkaloid keramaphidin B that relies on the strain-promoted cycloaddition of an azacyclic allene with a pyrone trapping partner. The cycloaddition is tolerant of nitrile and primary amide functional groups and can be complemented with a subsequent retro-Diels-Alder step. These efforts demonstrate that strained cyclic allenes can be used to build significant structural complexity and should encourage further studies of these fleeting intermediates.

Asymmetric organocatalysis is a growing method for the synthesis of axially chiral tetrasubstituted allenes, the most challenging one among allene syntheses. In this method, chiral organocatalysts such as phase-transfer catalysts, peptides, disulfonimides, and binaphthyl/bispiro phosphoric acids have displayed remote control of regio- and stereoselectivity. Highly functionalized enantiopure allenes including those with an adjacent tertiary or quaternary stereocenter have been efficiently prepared with high levels of regio-, diastereo-, and enantioselectivity using this method. Several mechanistic pathways, including electrophilic addition to cumulenolate or zwitterionic enolate intermediates, alkynylogous Mukaiyama aldol reaction, nucleophilic addition to quinone methides, and dearomative addition to imino esters, were proposed. The method is necessary for providing access to axially chiral tetrasubstituted allenes, which can be utilized for the preparation of novel ligands, natural products, and organic materials, particularly those having complex structures. This review covers the enantioselective organocatalytic synthesis of these tetrasubstituted allenes and the mechanistic insights into the formation of the chiral axis up to July 2022.

The general enantioselective catalytic synthesis of axially chiral 1,3-disubstituted allenes from readily available racemic propargylic alcohol derivatives remains a long-standing challenge in organic synthesis. Here we report an efficient nickel-catalyzed asymmetric propargylic substitution reaction/Myers rearrangement of racemic propargylic carbonates that furnishes a series of enantioenriched 1,3-disubstituted allenes using newly designed N -sulfonylhydrazone reagents as efficient diazo surrogates. This reaction proved to be remarkably general with regard to substrate scope, affording a diverse range of 1,3-disubstituted allenic compounds in good yields with excellent enantioselectivities. Additionally, applications of this powerful strategy for the enantioselective synthesis of methyl ( S )-8-hydroxyocta-5,6-dienoate, ( S )-laballenic acid, ( S )-phlomic acid, and ( S )-Δ 9,10 -pentacosadiene are described, further highlighting the broad potential of these new reagents for the discovery of novel reactions.

The synthesized 1,5 diarylpenta-1,4-dien-3-one derivatives (compounds 1-6) as synthetic curcumin analogues were tested for their potential anticancer activity against human ovarian and lung adenocarcinoma cells. The absorption, distribution, metabolism, excretion, and toxicity (ADMET/pharmacokinetic) parameters of all the compounds were predicted by admetSAR software. The pharmacokinetics, pharmacodynamics and bioactivity scores properties based on Lipinski rule and Ghose filter, calculated with the help of Molinspiration and ChemDraw. Molecular docking evaluation of all the compounds was also performed by using AutoDock Vina and iGEMDOCK against three most common human anticancer targets; epidermal growth factor receptor (EGFR), heat shock protein (Hsp 90-α), and vascular endothelial growth factor receptor-2 (VEGFR2). The obtained results were compared with the reference compound 7 and drugs 8-10 (7: GO-035; 8: Quinazolin; 9: Naquotinib and 10: Ribofuranuronamide). Finding indicates, all the compounds were potentially interacting with VEGFR2 through the average -9.1 binding energy (BE) with closer contact <5.0 Å deep in the active site of the ligand-receptor complex. All the compounds showed excellent oral bioavailability, bioactivity score, and none of the compounds are virtually found to be toxic. Compounds 1-6 were also successfully characterized by the physical properties as well as spectroscopic techniques (FT-IR and 1 H-NMR). In vitro anti-proliferative activity was tested via MTT method against human ovarian carcinoma (PA-1) and human lung adenocarcinoma (A549) cells and further screened for apoptotic parameters such as nuclear fragmentation and ROS generation. Compound 4 exhibits good dose-dependent anti-proliferative activity (IC 50 73 and 79.7 µM) against human ovarian carcinoma and human lung adenocarcinoma, respectively.Communicated by Ramaswamy H. Sarma.

Polysubstituted allenes are useful synthetic intermediates in many applications, offering structural complexity, modularity, and their axial chirality in further transformations. While acyl and alkoxy-substituted allenes are known, there are currently few examples of allenes containing both functionalities and no reports of geminally substituted acyl/alkoxy allenes being isolated and characterized. Herein, we report the synthesis of tetrasubstituted allenes featuring a novel geminal acyl/alkoxy substitution. These unique "push-pull" allenes are bench-stable and exhibit interesting reactivity in several applications.

The Rh(III)-catalyzed chemo-, regio- and stereoselective carboamination of sulfonyl allenes has been realized by virtue of either N -phenoxy amides or N -enoxy imides simultaneously acting as the C- and N-sources, via redox-neutral tandem C-H activation/allene insertion/oxidative addition/C-N bond formation for the direct construction of allylamine derivatives equipped with an α-quaternary carbon center. This protocol features high atom-economy with good substrate compatibility and exhibits profound synthetic potential for late-stage C-H modification of complex molecules.

Conjugated dienes are versatile building blocks and prevalent substructures in synthetic chemistry. Herein, we report a method for the stereoselective hydroalkenylation of alkynes, utilizing readily available enol triflates. We leveraged an in situ -generated and geometrically pure vinyl-Cu(I) species to form the Z , Z - or Z , E -1,3-dienes in excellent stereoselectivity and yield. This approach allowed for the synthesis of highly substituted Z -dienes, including pentasubstituted 1,3-dienes, which are difficult to prepare by existing approaches.

The biologically important, FAD-containing acyl-coenzyme A (CoA) dehydrogenases (ACAD) usually catalyze the anti-1,2-elimination of a proton and a hydride of aliphatic CoA thioesters. Here, we report on the structure and function of an ACAD from anaerobic bacteria catalyzing the unprecedented 1,4-elimination at C3 and C6 of cyclohex-1-ene-1-carboxyl-CoA (Ch1CoA) to cyclohex-1,5-diene-1-carboxyl-CoA (Ch1,5CoA) and at C3 and C4 of the latter to benzoyl-CoA. Based on high-resolution Ch1CoA dehydrogenase crystal structures, the unorthodox reactivity is explained by the presence of a catalytic aspartate base (D91) at C3, and by eliminating the catalytic glutamate base at C1. Moreover, C6 of Ch1CoA and C4 of Ch1,5CoA are positioned towards FAD-N5 to favor the biologically relevant C3,C6- over the C3,C4-dehydrogenation activity. The C1,C2-dehydrogenation activity was regained by structure-inspired amino acid exchanges. The results provide the structural rationale for the extended catalytic repertoire of ACADs and offer previously unknown biocatalytic options for the synthesis of cyclic 1,3-diene building blocks., (© 2021 The Authors. ChemBioChem published by Wiley-VCH GmbH.)

A set of new substituted dienes were synthesized from betulinic acid by its oxidation to 30-oxobetulinic acid followed by the Wittig reaction. Cytotoxicity of all compounds was tested in vitro in eight cancer cell lines and two noncancer fibroblasts. Almost all dienes were more cytotoxic than betulinic acid. Compounds 4.22, 4.30, 4.33, 4.39 had IC 50 below 5 μmol/L; 4.22 and 4.39 were selected for studies of the mechanism of action. Cell cycle analysis revealed an increase in the number of apoptotic cells at 5 × IC 50 concentration, where activation of irreversible changes leading to cell death can be expected. Both 4.22 and 4.39 led to the accumulation of cells in the G0/G1 phase with partial inhibition of DNA/RNA synthesis at 1 × IC 50 and almost complete inhibition at 5 × IC 50 . Interestingly, compound 4.39 at 5 × IC 50 caused the accumulation of cells in the S phase. Higher concentrations of tested drugs probably inhibit more off-targets than lower concentrations. Mechanisms disrupting cellular metabolism can induce the accumulation of cells in the S phase. Both compounds 4.22 and 4.39 trigger selective apoptosis in cancer cells via intrinsic pathway, which we have demonstrated by changes in the expression of the crucial apoptosis-related protein. Pharmacological parameters of derivative 4.22 were superior to 4.39, therefore 4.22 was the finally selected candidate for the development of anticancer drug., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier Masson SAS. All rights reserved.)

The direct oxyamination of olefins is a compelling tool to rapidly access β-amino alcohols-a privileged motif ubiquitous in natural products, pharmaceuticals and agrochemicals. Although a variety of expedient methods are established for simple alkenes, selective amino oxygenation of 1,3-dienes is less explored. Within this context, methods for the oxyamination of 1,3-dienes that are selective for the internal position remain unprecedented. We herein report a modular three-component approach to perform an internal and highly diastereoselective amino oxygenation of 1,3-dienes catalyzed by a cationic heptamethylindenyl (Ind*) Rh(III) complex.

Aryl-substituted pyridine(diimine) iron complexes promote the catalytic [2 + 2] cycloadditions of alkenes and dienes to form vinylcyclobutanes as well as the oligomerization of butadiene to generate divinyl(oligocyclobutane), a microstructure of poly(butadiene) that is chemically recyclable. A systematic study on a series of iron butadiene complexes as well as their ruthenium congeners has provided insights into the essential features of the catalyst that promotes these cycloaddition reactions. Structural and computational studies on iron butadiene complexes identified that the structural rigidity of the tridentate pincer enables rare s-trans diene coordination. This geometry, in turn, promotes dissociation of one of the alkene arms of the diene, opening a coordination site for the incoming substrate to engage in oxidative cyclization. Studies on ruthenium congeners established that this step occurs without redox involvement of the pyridine(diimine) chelate. Cyclobutane formation occurs from a metallacyclic intermediate by reversible C(sp 3 )-C(sp 3 ) reductive coupling. A series of labeling experiments with pyridine(diimine) iron and ruthenium complexes support the favorability of accessing the +3 oxidation state to trigger C(sp 3 )-C(sp 3 ) reductive elimination, involving spin crossover from S = 0 to S = 1. The high density of states of iron and the redox-active pyridine(diimine) ligand facilitate this reactivity under thermal conditions. For the ruthenium congener, the pyridine(diimine) remains redox innocent and irradiation with blue light was required to promote the analogous reactivity. These structure-activity relationships highlight important design principles for the development of next generation catalysts for these cycloaddition reactions as well as the promotion of chemical recycling of cycloaddition polymers.

Antimicrobial resistance is a looming health crisis, and it is becoming increasingly clear that organic chemistry alone is not sufficient to continue to provide the world with novel and effective antibiotics. Recently there has been an increased number of reports describing promising antimicrobial properties of metal-containing compounds. Platinum complexes are well known in the field of inorganic medicinal chemistry for their tremendous success as anticancer agents. Here we report on the promising antibacterial properties of platinum cyclooctadiene (COD) complexes. Amongst the 15 compounds studied, the simplest compounds Pt(COD)X 2 (X=Cl, I, Pt1 and Pt2) showed excellent activity against a panel of Gram-positive bacteria including vancomycin and methicillin resistant Staphylococcus aureus. Additionally, the lead compounds show no toxicity against mammalian cells or haemolytic properties at the highest tested concentrations, indicating that the observed activity is specific against bacteria. Finally, these compounds showed no toxicity against Galleria mellonella at the highest measured concentrations. However, preliminary efficacy studies in the same animal model found no decrease in bacterial load upon treatment with Pt1 and Pt2. Serum exchange studies suggest that these compounds exhibit high serum binding which reduces their bioavailability in vivo, mandating alternative administration routes such as e. g. topical application., (© 2021 The Authors. ChemMedChem published by Wiley-VCH GmbH.)

An iron-catalyzed C-H functionalization of simple monosubstituted allenes is reported. An efficient protocol for this process was made possible by the use of a newly developed electron-rich and sterically hindered cationic cyclopentadienyliron dicarbonyl complex as the catalyst and N -sulfonyl hemiaminal ether reagents as precursors to iminium ion electrophiles. Under optimized conditions, the use of a mild, functional-group-tolerant base enabled the conversion of a range of monoalkyl allenes to their allenylic sulfonamido 1,1-disubstituted derivatives, a previously unreported and contrasteric regiochemical outcome for the C-H functionalization of electronically unbiased and directing-group-free allenes.

Herein, a highly regioselective alkylation of propargylic carbonates for trisubstituted allenes with alkyl 1,4-dihydropyridine derivatives (1,4-DHPs) is developed via a photoredox/nickel dual-catalyzed process, which represents the first direct approach to access alkylated allene products without alkyl organometallic reagents. This method features a broad substrate scope and mild conditions. A hypothetical mechanism with an alkyl radical and an allenyl Ni(III) species is proposed. Benzylation products were also obtained to be the complement building blocks for the potential synthesis of pharmaceuticals.

Herein we report the copper-catalyzed silylation of propargylic difluorides to generate axially chiral, tetrasubstituted monofluoroallenes in both good yields (27 examples >80%) and enantioselectivities (82-98% ee). Compared to previously reported synthetic routes to axially chiral allenes (ACAs) from prochiral substrates, a mechanistically distinct reaction has been developed: the enantiodiscrimination between enantiotopic fluorides to set an axial stereocenter. DFT calculations and vibrational circular dichroism (VCD) suggest that β-fluoride elimination from an alkenyl copper intermediate likely proceeds through a syn -β-fluoride elimination pathway rather than an anti -elimination pathway. The effects of the C1-symmetric Josiphos-derived ligand on reactivity and enantioselectivity were investigated. Not only does this report showcase that alkenyl copper species (like their alkyl counterparts) can undergo β-fluoride elimination, but this elimination can be achieved in an enantioselective fashion.

We report the first enantioselective addition of pyrazoles to 1,3-dienes. Secondary and tertiary allylic pyrazoles can be generated with excellent regioselectivity. Mechanistic studies support a pathway distinct from previous hydroaminations: a Pd 0 -catalyzed ligand-to-ligand hydrogen transfer (LLHT). This hydroamination tolerates a range of functional groups and advances the field of diene hydrofunctionalization., (© 2021 Wiley-VCH GmbH.)

Ketones are among the most widely used intermediates in organic synthesis, and their synthesis from inexpensive feedstocks could be quite impactful. Regio- and enantioselective hydroacylation reactions of dienes provide facile entry into useful ketone-bearing chiral motifs with an additional latent functionality (alkene) suitable for further elaboration. Three classes of dienes, 2- or 4-monosubstituted and 2,4-disubstituted 1,3-dienes, undergo cobalt(I)-catalyzed regio- and enantioselective hydroacylation, giving products with high enantiomeric ratios (er). These reactions are highly dependent on the ligands, and we have identified the most useful ligands and reaction conditions for each class of dienes. 2-Substituted and 2,4-disubstituted dienes predominantly undergo 1,2-addition, whereas 4-substituted terminal dienes give highly enantioselective 4,1- or 4,3-hydroacylation depending on the aldehyde, aliphatic aldehydes giving 4,1-addition and aromatic aldehydes giving 4,3-addition. Included among the substrates are feedstock dienes, isoprene (US$1.4/kg) and myrcene (US$129/kg), and several common aldehydes. We propose an oxidative dimerization mechanism that involves a Co(I)/Co(III) redox cycle that appears to be initiated by a cationic Co(I) intermediate. Studies of reactions using isolated neutral and cationic Co(I) complexes confirm the critical role of the cationic intermediates in these reactions. Enantioselective 1,2-hydroacylation of 2-trimethylsiloxy-1,3-diene reveals a hitherto undisclosed route to chiral siloxy-protected aldols. Finally, facile syntheses of the anti-inflammatory drug ( S )-Flobufen (2 steps, 92% yield, >99:1 er) and the food additive ( S )-Dihydrotagetone (1 step, 83% yield; 96:4 er) from isoprene illustrate the power of this method for the preparation of commercially relevant compounds.

Diarylpentanoid (DAP), an analog that was structurally modified from a naturally occurring curcumin, has shown to enhance anticancer efficacy compared to its parent compound in various cancers. This study aims to determine the cytotoxicity, antiproliferative, and apoptotic activity of diarylpentanoid MS13 on two subtypes of non-small cell lung cancer (NSCLC) cells: squamous cell carcinoma (NCI-H520) and adenocarcinoma (NCI-H23). Gene expression analysis was performed using Nanostring PanCancer Pathways Panel to determine significant signaling pathways and targeted genes in these treated cells. Cytotoxicity screening revealed that MS13 exhibited greater inhibitory effect in NCI-H520 and NCI-H23 cells compared to curcumin. MS13 induced anti-proliferative activity in both cells in a dose- and time-dependent manner. Morphological analysis revealed that a significant number of MS13-treated cells exhibited apoptosis. A significant increase in caspase-3 activity and decrease in Bcl-2 protein concentration was noted in both MS13-treated cells in a time- and dose-dependent manner. A total of 77 and 47 differential expressed genes (DEGs) were regulated in MS13 treated-NCI-H520 and NCI-H23 cells, respectively. Among the DEGs, 22 were mutually expressed in both NCI-H520 and NCI-H23 cells in response to MS13 treatment. The top DEGs modulated by MS13 in NCI-H520-DUSP4, CDKN1A, GADD45G, NGFR, and EPHA2-and NCI-H23 cells-HGF, MET, COL5A2, MCM7, and GNG4-were highly associated with PI3K, cell cycle-apoptosis, and MAPK signaling pathways. In conclusion, MS13 may induce antiproliferation and apoptosis activity in squamous cell carcinoma and adenocarcinoma of NSCLC cells by modulating DEGs associated with PI3K-AKT, cell cycle-apoptosis, and MAPK pathways. Therefore, our present findings could provide an insight into the anticancer activity of MS13 and merits further investigation as a potential anticancer agent for NSCLC cancer therapy.

We report Pd-catalyzed annulations of in situ generated strained cyclic allenes. This methodology employs aryl halides and cyclic allene precursors as the reaction partners in order to generate fused heterocyclic products. The annulation proceeds via the formation of two new bonds and an sp 3 center. Moreover, both diastereo- and enantioselective variants of this methodology are validated, with the latter ultimately enabling the rapid enantioselective synthesis of a complex hexacyclic product. Studies leveraging transition metal catalysis to intercept cyclic allenes represent a departure from the more common, historical modes of cyclic allene trapping that rely on nucleophiles or cycloaddition partners. As such, this study is expected to fuel the development of reactions that strategically merge transition metal catalysis and transient strained intermediate chemistry for the synthesis of complex scaffolds.

The first catalytic enantioselective ruthenium-catalyzed carbonyl reductive couplings of allene pronucleophiles is described. Using an iodide-modified ruthenium-BINAP-catalyst and O -benzhydryl alkoxyallene 1a , carbonyl (α-alkoxy)allylation occurs from the alcohol or aldehyde oxidation level to form enantiomerically enriched syn - sec,tert -diols. Internal chelation directs intervention of ( Z )-σ-alkoxyallylruthenium isomers, which engage in stereospecific carbonyl addition.

A new application of vacuum-ultraviolet circular dichroism (VUVCD), which enables the measurement of CD spectra in the vacuum-ultraviolet region (140-200 nm), for the assignment of the absolute configurations of bromoallenes is described. Bromoallene moieties are found in natural products obtained from many marine organisms. To date, the absolute configuration of bromoallenes has been assigned almost exclusively with Lowe's rule, which is based on specific rotation. However, exceptions to Lowe's rule have been reported arising from the presence of other substituents with large specific rotations. For the unambiguous assignment of the absolute configuration of the bromoallene moiety with its characteristic absorption wavelength at 180-190 nm due to the π-π* transition, VUVCD was applied to four pairs of bromoallene diastereomers prepared by modifying the synthetic scheme of omaezallene. The VUVCD spectra clearly showed positive or negative Cotton effects around 180-190 nm according to the configuration of the bromoallene employed, revealing the potential of VUVCD for determining absolute stereochemistry.

A series of novel penta-1,4-diene-3-one derivatives containing quinazoline and oxime ether moieties were designed and synthesized. Their anticancer activities were evaluated by MTT assay, the results showed that most compounds exhibited extremely inhibitory effects against hepatoma SMMC-7721 cells. In particular, compounds Q2 and Q8 displayed the more potent inhibitory activity with IC 50 values of 0.64 and 0.63 μM, which were better than that of gemcitabine (1.40 μM). Further mechanism studies indicated that compounds Q2, Q8, Q13 and Q19 could control the migration of SMMC-7721 cells effectively, and inhibit the proliferation of cancer cells by inhibiting the DNA replication. Western-blot results showed that compounds Q2 and Q8 induced irreversible apoptosis of SMMC-7721 cells by regulating the expression level of apoptose-related proteins. Those studies demonstrated that the penta-1,4-diene-3-one derivatives containing quinazoline and oxime ether fragments merited further research as potential anticancer agents., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

The site- and regio-selectivity of thermal, uncatalysed 1,3-dipolar cycloadditions between arylazides and mono- or tetra-substituted allenes with different electronic features have been investigated by both conceptual (reactivity indices) and computational (M08-HX, ωB97X-D, and B3LYP) DFT approaches. Both approaches show that these cycloadditions follow a nonpolar one-step mechanism. The experimental site- and regio-selectivity of arylazides towards methoxycarbonyl- and sulfonyl-allenes as well as tetramethyl- and tetrafluoro-allenes was calculated by DFT transition state calculations, achieving semiquantitative agreement to both previous and novel experimental findings. From the mechanistic standpoint, 1 H-NMR evidence of a methylene-1,2,3-triazoline intermediate reinforces the reliability of the computational scheme.

Medicinal chemists have continuously shown interest in new curcuminoid derivatives, diarylpentadienones, owing to their enhanced stability feature and easy preparation using a one-pot synthesis. Thus far, methods such as Claisen-Schmidt condensation and Julia- Kocienski olefination have been utilised for the synthesis of these compounds. Diarylpentadienones possess a high potential as a chemical source for designing and developing new and effective drugs for the treatment of diseases, including inflammation, cancer, and malaria. In brief, this review article focuses on the broad pharmacological applications and the summary of the structure-activity relationship of molecules, which can be employed to further explore the structure of diarylpentadienone. The current methodological developments towards the synthesis of diarylpentadienones are also discussed., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

A series of aminated- (1-9) and sulfonamide-containing diarylpentadienones (10-18) were synthesized, structurally characterized, and evaluated for their in vitro anti-diabetic potential on α-glucosidase and DPP-4 enzymes. It was found that all the new molecules were non-associated PAINS compounds. The sulfonamide-containing series (compounds 10-18) selectively inhibited α-glucosidase over DPP-4, in which compound 18 demonstrated the highest activity with an IC 50 value of 5.69 ± 0.5 µM through a competitive inhibition mechanism. Structure-activity relationship (SAR) studies concluded that the introduction of the trifluoromethylbenzene sulfonamide moiety was essential for the suppression of α-glucosidase. The most active compound 18, was then further tested for in vivo toxicities using the zebrafish animal model, with no toxic effects detected in the normal embryonic development, blood vessel formation, and apoptosis of zebrafish. Docking simulation studies were also carried out to better understand the binding interactions of compound 18 towards the homology modeled α -glucosidase and the human lysosomal α -glucosidase enzymes. The overall results suggest that the new sulfonamide-containing diarylpentadienones, compound 18, could be a promising candidate in the search for a new α-glucosidase inhibitor, and can serve as a basis for further studies involving hit-to-lead optimization, in vivo efficacy and safety assessment in an animal model and mechanism of action for the treatment of T2DM patients., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Strained cyclic organic molecules, such as arynes, cyclic alkynes and cyclic allenes, have intrigued chemists for more than a century with their unusual structures and high chemical reactivity 1 . The considerable ring strain (30-50 kilocalories per mole) 2,3 that characterizes these transient intermediates imparts high reactivity in many reactions, including cycloadditions and nucleophilic trappings, often generating structurally complex products 4 . Although strategies to control absolute stereochemistry in these reactions have been reported using stoichiometric chiral reagents 5,6 , catalytic asymmetric variants to generate enantioenriched products have remained difficult to achieve. Here we report the interception of racemic cyclic allene intermediates in a catalytic asymmetric reaction and provide evidence for two distinct mechanisms that control absolute stereochemistry in such transformations: kinetic differentiation of allene enantiomers and desymmetrization of intermediate π-allylnickel complexes. Computational studies implicate a catalytic mechanism involving initial kinetic differentiation of the cyclic allene enantiomers through stereoselective olefin insertion, loss of the resultant stereochemical information, and subsequent introduction of absolute stereochemistry through desymmetrization of an intermediate π-allylnickel complex. These results reveal reactivity that is available to cyclic allenes beyond the traditional cycloadditions and nucleophilic trappings previously reported, thus expanding the types of product accessible from this class of intermediates. Additionally, our computational studies suggest two potential strategies for stereocontrol in reactions of cyclic allenes. Combined, these results lay the foundation for the development of catalytic asymmetric reactions involving these classically avoided strained intermediates.

Two complementary regiodivergent [(P,N)Ni]-catalyzed hydroalkylations of branched dienes are reported. When amides are employed as unstabilized C(sp 3 ) nucleophiles, a highly regioselective 1,4-addition process is favored. The addition products are obtained in high yield and with excellent stereocontrol of the internal olefin. With use of a chiral ligand and imides as carbon nucleophiles, a 3,4-addition protocol was developed, enabling construction of two contiguous tertiary stereocenters in a single step with moderate to high levels of diastereocontrol and excellent enantiocontrol. Both methods operate under mild reaction conditions, display a broad scope, and show excellent functional group tolerance. The synthetic potential of the 3,4-hydroalkylation reaction was established via a series of postcatalytic modifications.

The tetrazine/ trans -cyclooctene (TCO) inverse electron-demand Diels-Alder (IEDDA) reaction is the fastest bioorthogonal "click" ligation process reported to date. In this context, TCO reagents have found widespread applications; however, their availability and structural diversity is still somewhat limited due to challenges connected with their synthesis and structural modification. To address this issue, we developed a novel strategy for the conjugation of TCO derivatives to a biomolecule, which allows for the creation of greater structural diversity from a single precursor molecule, i.e., trans,trans -1,5-cyclooctadiene [( E , E )-COD] 1 , whose preparation requires standard laboratory equipment and readily available reagents. This two-step strategy relies on the use of new bifunctional TCO linkers ( 5a - 11a ) for IEDDA reactions, which can be synthesized via 1,3-dipolar cycloaddition of ( E , E )-COD 1 with different azido spacers ( 5 - 11 ) carrying an electrophilic function (NHS-ester, N -succinimidyl carbonate, p -nitrophenyl-carbonate, maleimide) in the ω-position. Following bioconjugation of these electrophilic linkers to the nucleophilic residue (cysteine or lysine) of a protein (step 1), the resulting TCO-decorated constructs can be subjected to a IEDDA reaction with tetrazines functionalized with fluorescent or near-infrared (NIR) tags (step 2). We successfully used this strategy to label bovine serum albumin with the TCO linker 8a and subsequently reacted it in a cell lysate with the fluorescein-isothiocyanate (FITC)-derived tetrazine 12 . The same strategy was then used to label the bacterial wall of Gram-positive Staphylococcus aureus , showing the potential of these linkers for live-cell imaging. Finally, we determined the impact of structural differences of the linkers upon the stability of the bioorthogonal constructs. The compounds for stability studies were prepared by conjugation of TCO linkers 6a , 8a , and 10a to mAbs, such as Rituximab and Obinutuzumab, and subsequent labeling with a reactive Cy3-functionalized tetrazine.

Aim: To synthesize novel antiproliferative agents. Results & methodology: A variety of 1,4-pentadien-3-one derivatives bearing quinoxaline scaffolds was designed and synthesized and their antiproliferative activities were evaluated. Notably, compounds N3 and N4 exhibited markedly greater antiproliferative activities against SMMC-7721 cells in vitro compared with the well-known antitumor drug gemcitabine. The mechanistic investigation showed that compounds N3 and N4 induced SMMC-7721 cell apoptosis by regulating the expression levels of apoptosis-related proteins. In addition, the molecular docking model further revealed that compound N3 could be a potential peroxisome proliferator-activated receptor inhibitor. Conclusion: These compounds might serve as bioactive fragments and lead compounds for developing more potent apoptosis inducers.

Additions of acids to 1,3-dienes are conventionally understood as involving discrete intermediates that undergo an ordinary competition between subsequent pathways to form the observed products. The combined experimental, computational, and dynamic trajectory study here suggests that this view is incorrect, and that solvation dynamics plays a critical role in the mechanism. While implicit solvent models were inadequate, QM/QM' trajectories in explicit solvent provide an accurate prediction of the experimental selectivity in the addition of HCl to 1,3-pentadiene. Trajectories initiated from a protonation saddle point on the potential of mean force surface are predominantly unproductive due to a gating effect of solvation that allows diene protonation only when the incipient ion pair is neither too solvent-stabilized nor too little. Protonation then leads to relatively unsolvated ion pairs, and a majority of these collapse rapidly to the 1,2-product, without barrier and without achieving equilibrium solvation as intermediates. The remainder decay slowly, at a rate consistent with equilibrium solvation as true intermediates, affording a mixture of addition products. Overall, an accurate description of the nature and pathway selectivity of the ion pair intermediates in carbocation reactions must allow for species lacking equilibrium solvation. Potential reinterpretations of a series of historically notable observations in carbocation reactions are discussed.

A critically important process in catalysis is the formation of an active catalyst from the combination of a metal precursor and a ligand, as the efficacy of this reaction governs the amount of active catalyst. This Review is a comprehensive overview of reactions catalyzed by nickel and an added bidentate phosphine, focusing on the steps transforming the combination of precatalyst and ligand into an active catalyst and the potential effects of this transformation on nickel catalysis. Reactions covered include common cross-coupling reactions, such as Suzuki, Heck, Kumada, and Negishi couplings, addition reactions, cycloadditions, C-H functionalizations, polymerizations, hydrogenations, and reductive couplings, among others. Overall, the most widely used nickel precatalyst with free bidentate phosphines is Ni(cod) 2 , which accounts for ∼50% of the reports surveyed, distantly followed by Ni(acac) 2 and Ni(OAc) 2 , which account for ∼10% each. By compiling the reports of these reactions, we have calculated statistics of the usage and efficacy of each ligand with Ni(cod) 2 and other nickel sources. The most common bidentate phosphines are simple, relatively inexpensive ligands, such as DPPE, DCPE, DPPP, and DPPB, along with others with more complex backbones, such as DPPF and Xantphos. The use of expensive chiral phosphines is more scattered, but the most common ligands include BINAP, Me-Duphos, Josiphos, and related analogs.

A photoinduced palladium-catalyzed 1,2-carbofunctionalization of conjugated dienes has been developed. This mild modular approach, which does not require employment of exogeneous photosensitizers and external oxidants, allows for efficient and highly regio- and stereoselective synthesis of a broad range of allylic amines from readily available 1,3-dienes, alkyl iodides, and amines. Employment of O- and C-nucleophiles toward oxyalkylation and dialkylation products was also demonstrated. A putative π-allyl palladium radical-polar crossover path is proposed as a key event in this three-component coupling process. The utility of this protocol is highlighted by its application for derivatization of several amine-containing drugs.

DNA-encoded libraries of small molecules are being explored extensively for the identification of binders in early drug-discovery efforts. Combinatorial syntheses of such libraries require water- and DNA-compatible reactions, and the paucity of these reactions currently limit the chemical features of resulting barcoded products. The present work introduces strain-promoted cycloadditions of cyclic allenes under mild conditions to DNA-encoded library synthesis. Owing to distinct cycloaddition modes of these reactive intermediates with activated olefins, 1,3-dipoles, and dienes, the process generates diverse molecular architectures from a single precursor. The resulting DNA-barcoded compounds exhibit unprecedented ring and topographic features, related to elements found to be powerful in phenotypic screening.

3d transition metals-catalyzed C-H bond functionalizations represent nowadays an important tool in organic synthesis, appearing as the most promising alternative to cross-coupling reactions. Among 3d transition metals, iron found widespread application due to its availability and benign nature, and it was established as an efficient catalyst in organic synthesis. In this context, the use of ortho -orientating directing groups (DGs) turned out to be necessary for promoting selective iron-catalyzed C-H functionalization reactions. Very recently, triazoles DGs were demonstrated to be more than an excellent alternative to the commonly employed 8-aminoquinoline (AQ) DG, as a result of their modular synthesis as well as the mild reaction conditions applied for their removal. In addition, their tunable geometry and electronics allowed for new unprecedented reactivities in iron-catalyzed C-H activation methodologies that will be summarized within this review.

Amidoallyl cations are appealing three-carbon synthons for the preparation of complex amine-containing carbocycles; however, methods to generate and utilize these reactive species are limited and underexplored compared to those for oxallyl cations. Here we disclose a bioinspired strain-driven ring opening of bicyclic methyleneaziridines to 2-amidopentadienyl cation intermediates that readily engage in Nazarov cyclizations. Advantages of this strategy include ease of generation and improved reactivity compared to 3-pentadienyl cations, control over the ultimate position of the alkene, the potential for high dr between vicinal stereocenters, and the ability to further elaborate the products to fully substituted aminocyclopentanes. Experimental and computational studies support a dual role for the Rh 2 L n complex as both a nitrene transfer catalyst and a Lewis acid promoter, insight that provides a framework for the future development of asymmetric 2-imino-Nazarov cyclizations.

Enantiopure ( P ) 4 - and ( M ) 4 -configured alleno-acetylenic cage (AAC) receptors offer a highly defined interior for the complexation and structure elucidation of small molecule fragments of the stereochemically complex chlorosulfolipid danicalipin A. Solution (NMR), solid state (X-ray), and theoretical investigations of the formed host-guest complexes provide insight into the conformational preferences of 14 achiral and chiral derivatives of the danicalipin A chlorohydrin core in a confined, mostly hydrophobic environment, extending previously reported studies in polar solvents. The conserved binding mode of the guests permits deciphering the effect of functional group replacements on Gibbs binding energies Δ G . A strong contribution of conformational energies toward the binding affinities is revealed, which explains why the denser packing of larger apolar domains of the guests does not necessarily lead to higher association. Enantioselective binding of chiral guests, with energetic differences ΔΔ G 293 K up to 0.7 kcal mol -1 between diastereoisomeric complexes, is explained by hydrogen- and halogen-bonding, as well as dispersion interactions. Calorimetric studies (ITC) show that the stronger binding of one enantiomer is accompanied by an increased gain in enthalpy Δ H but at the cost of a larger entropic penalty T Δ S stemming from tighter binding.

Some important pro-inflammatory cytokines such as interleukin-6, tumor necrosis factor-α and nitric oxide are thought to play key roles in the destruction of cartilage and bone tissue in joints affected by rheumatoid arthritis. In the present study, a series of new myricetin-pentadienone hybrids were designed and synthesized. Majority of them effectively inhibited the expressions liposaccharide-induced secretion of IL-6, TNF-α and NO in RAW264.7. The most prominent compound 5o could significantly decrease production of above inflammatory factors with IC 50 values of 5.22 µM, 8.22 µM and 9.31 µM, respectively. Preliminary mechanism studies indicated that it could inhibit the expression of thioredoxin reductase, resulting in inhibiting of cell signaling pathway nuclear factor (N-κB) and mitogen-activated protein kinases. Significantly, compound 5o was found to effectively inhibit Freund's complete adjuvant induced rat adjuvant arthritis in vivo., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Inc. All rights reserved.)

We describe a strategy for the enantio- and diastereoselective synthesis of homoallylic α-trifluoromethyl amines by the catalytic hydroalkylation of terminal dienes. Trifluoromethyl-substituted isatin-derived azadienolate nucleophiles undergo γ-selective alkylation with a Pd-DTBM-SEGPHOS catalyst, which additionally promotes regioselective addition to the diene and delivers products in up to 86% yield, 10:1 dr, and 97.5:2.5 er.

Pd-phosphinooxazoline (Pd-PHOX)-catalyzed asymmetric hydroalkylation of 1,3-dienes with azlactones was successfully developed for the first time, affording various enantioenriched α-quaternary α-amino acid derivatives bearing contiguous quaternary and tertiary stereogenic centers in good yields with exclusive regioselectivity and excellent stereoselective control (up to 92% yield, >20:1 dr, and >99% ee). The scale-up catalytic asymmetric hydroalkylation was performed well without loss of reactivity and stereoselectivities, which exhibited great potential application. The synthetic utility of the current methodology was demonstrated through product transformations to access other biologically important compounds such as chiral β-amino alcohol and α-quaternary cyclic α-amino acid derivatives.

Natural products are useful sources in the search for biochemical probes and drug leads because of their unique biological activities. However, synthetic studies or functional analyses of polycyclic complex natural products or conjugated lipids (e.g., glycolipids) are often hampered because of their synthesis and handling are challenging. On the basis of rational designs, synthetic studies, and chemical modifications, natural products need to be optimized to more potent compounds with improved activities, selectivities and/or physical properties. We have been synthesizing natural products and their derivatives for the elucidation of their biological mechanisms and discovery of drug leads. This review describes three topics for developing functional compounds derived from natural products for prospective involvement in pharmaceutical research: 1) direct construction of the ergot alkaloid scaffold by palladium catalyzed domino cyclization of amino allenes; 2) identification of novel sphingosine kinase inhibitors through a structure-activity relationship study of jaspine B; and 3) design, synthesis and biological evaluation of novel CD1d glycolipid ligands containing modified lipid moieties.

Species of kalanchoe are rich in bioactive compounds and are widely used in folk medicine; however, these plants are not well known from the point of view of aroma. Two species, Kalanchoe pinnata and Kalanchoe daigremontiana, were examined after six months and two years of growth and their vitamin C content, succulence, and aroma composition were determined. The efficiency of juice extraction was highest (72%) for the leaves of K. daigremontiana after six months of growth. The concentration of vitamin C was highest in juices from two-year-old plants and much higher in the juice of K. pinnata (81 mg/100 g). SPME/GC/MS analysis identified 32 aroma components, considering those with the spectrum similarity over 75%. The main components were furan-2-ethyl, hexanal, 2-hexenal, 2,4-hexadienal, 1-octen-3-ol, nonanal. The quantitative relations of these compounds were somewhat different in the two species. The most dominant component, 2-hexenal, is responsible for the green-like aroma noted by the sensory panel.

A convenient and applicable approach to the construction of diverse functionalized (2-furyl)methylthioether derivatives via base-promoted S-H insertion of conjugated enynones with thiophenols or thiols has been developed. This reaction features readily available starting materials, high atom economy, broad substrate scope, and versatile operation. Moreover, the synthetic utility of this method has been demonstrated by the efficient synthesis of the CNKSPR1 inhibitor precursor and late-stage functionalization of glutathione.

Allenyl esters activated by titanium(IV) underwent additions to a wide range of aldehydes in high regio- and diastereoselectivities leading to products containing an all-carbon quaternary center bearing an α-vinyl group that was installed with high selectivity for the Z -geometry. An aldol product was also converted to an indanone offering a new route to this important compound class. Product triple diastereoselectivity has been rationalized using a concerted transition-state model.

We report the catalytic enantio- and diastereoselective preparation of aminocyclopropanes by the cyclopropanation of terminal and ( Z )-internal 2-azadienes with donor/acceptor carbenes derived from α-diazoesters. The resulting cyclopropanes bear quaternary carbon stereogenic centers vicinal to the amino-substituted carbon and are formed as a single diastereomer in up to 99:1 er and 97% yield with 0.5 mol % of Rh 2 (DOSP) 4 and only 1.5 equiv of the diazo reagent. Transformations with internal azadienes afford cyclopropanes with three contiguous stereogenic centers.

The first catalytic enantioselective carbonyl (α-amino)allylations are described. Phthalimido-allene 1 and primary alcohols 2a - 2z , 2a' - 2c' engage in hydrogen auto-transfer-mediated carbonyl reductive coupling by way of (α-amino)allyliridium-aldehyde pairs to form vicinal amino alcohols 3a - 3z , 3a' - 3c' with high levels of regio-, anti -diastereo-, and enantioselectivity. Reaction progress kinetic analysis and isotopic labeling studies corroborate a catalytic cycle involving turnover-limiting alcohol dehydrogenation followed by rapid allene hydrometalation.

The general enantioselective synthesis of axially chiral disubstituted allenes from prochiral starting materials remains a long-standing challenge in organic synthesis. Here, we report an efficient enantio- and chemoselective copper hydride catalyzed semireduction of conjugated enynes to furnish 1,3-disubstituted allenes using water as the proton source. This protocol is sufficiently mild to accommodate an assortment of functional groups including keto, ester, amino, halo, and hydroxyl groups. Additionally, applications of this method for the selective synthesis of monodeuterated allenes and chiral 2,5-dihydropyrroles are described.

An efficient Co III -catalyzed three-component strategy to prepare homoallylic alcohols containing acyclic quaternary centers is disclosed. This transformation enables the introduction of two C-C σ bonds through C-H bond activation and sequential addition to internally substituted dienes and a wide range of aldehydes and activated ketones. Isoprene and other internally monosubstituted dienes are effective inputs, with the reaction proceeding with high diastereoselectivity for those substrate combinations that result in more than one stereogenic center. Moreover, the opposite relative stereochemistry can be achieved by employing 1,2-disubstituted dienes. A mechanism for the transformation is proposed based upon the relative stereochemistry of the products and studies with isotopically labeled starting materials., (© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

A vital trait in insects is their cuticular hydrocarbon (CHC) profile, which protects the insect against desiccation and serves in chemical communication. Due to these functions, CHC profiles are shaped by both climatic conditions and biotic interactions. Here, we investigated CHC differentiation in the neotropical parabiotic ant species Crematogaster levior and Camponotus femoratus, which mutualistically share a nest. Both consist of two cryptic species each (Cr. levior A and B and Ca. femoratus PAT and PS) that differ genetically and possess strongly different CHC profiles. We characterized and compared CHC profiles of the four cryptic species in detail. Our results suggest that Cr. levior A, Ca. femoratus PAT and Ca. femoratus PS adapted their CHC profiles to the parabiotic lifestyle by producing longer-chain CHCs. At the same time, they changed their major CHC classes, and produce more alkadienes and methyl-branched alkenes compared to Cr. levior B or non-parabiotic species. The CHC profiles of Cr. levior B were more similar to related, non-parabiotic species of the Orthocrema clade than Cr. levior A, and the chain lengths of B were similar to the reconstructed ancestral state. Signals of both the parabiotic partner (biotic conditions) and climate (abiotic conditions) were found in the CHC profiles of all four cryptic species. Our data suggest that mutualisms shaped the CHC profiles of the studied species, in particular chain length and CHC class composition. Beside this, signals of the parabiotic partners indicate potential impacts of biotic interactions, via chemical mimicry or chemical camouflage.

Aim: Enamino 3-benzazecine compounds, incorporating the C6-C8 allene system, were synthesized and evaluated in vitro as inhibitors of P-glycoprotein (P-gp) and/or multidrug resistance-associated protein 1 (MRP1), two efflux pumps mainly connected with multidrug resistance (MDR) in cancer cells. Results & methodology: Most of the synthesized compounds were selective P-gp inhibitors in Calcein-AM uptake assay. Structure-activity relationships (SARs) pointed out that CO 2 Me derivatives are more potent than acetyl derivatives, and 10,11-dimethoxy compounds are five to tenfold more potent inhibitors than the respective unsubstituted compounds, and that the P-gp inhibition potency is mainly related to volume parameters. Conclusion: Nanomolar P-gp inhibitors, such as 23 (IC 50  = 4.2 nM), restored the antiproliferative activity of doxorubicin in multidrug-resistant cells. The observed activities showed that 3-benzazecine-based compounds may be promising MDR reversers.