Computational model predicts protein binding sites of a luminescent ligand equipped with guanidiniocarbonyl-pyrrole groups

• Neda Rafieiolhosseini,
• Matthias Killa,
• Thorben Neumann,
• Niklas Tötsch,
• Jean-Noël Grad,
• Alexander Höing,
• Thies Dirksmeyer,
• Jochen Niemeyer,
• Christian Ottmann,
• Shirley K. Knauer,
• Michael Giese,
• Jens Voskuhl and
• Daniel Hoffmann

Beilstein J. Org. Chem. 2022, 18, 1322–1331, doi:10.3762/bjoc.18.137

• interactions with other proteins. Here, we use a computational approach to predict the binding sites of the designed hybrid compound featuring aggregation-induced emission luminophores as a potential supramolecular ligand for 14-3-3ζ in the presence and absence of C-Raf peptides. Our results suggest that the

• area above and below the central pore of the dimeric 14-3-3ζ protein is the most probable binding site for the ligand. Moreover, we predict that the position of the ligand is sensitive to the presence of phosphorylated C-Raf peptides. With a series of experiments, we confirmed the computational

• prediction of two C2 related, dominating binding sites on 14-3-3ζ that may bind to two of the supramolecular ligand molecules. Keywords: AIE luminophores; fluorescence emission; guanidiniocarbonyl-pyrrole; ligand binding; 14-3-3 protein; Introduction The 14-3-3 protein family was one of the first

Cytochrome P450 monooxygenase-mediated tailoring of triterpenoids and steroids in plants

• Karan Malhotra and
• Jakob Franke

Beilstein J. Org. Chem. 2022, 18, 1289–1310, doi:10.3762/bjoc.18.135

• system as well as a cysteine thiolate ligand from the protein backbone (Figure 1B). The generally accepted catalytic cycle for hydroxylations is shown in Figure 1C. In the resting state A, the central ferric ion is coordinated by six ligands, four from the porphyrin ring system, one cysteine thiolate

• group and an aqua ligand (water), resulting in an octahedral complex [17]. The oxidative reaction is initiated by displacement of the axial water molecule by the substrate (step 1), which pushes the Fe(III) ion out of the porphyrin plane in intermediate B [17]. This geometrical distortion promotes

Modular synthesis of 2-furyl carbinols from 3-benzyldimethylsilylfurfural platforms relying on oxygen-assisted C–Si bond functionalization

• Sebastien Curpanen,
• Per Reichert,
• Gabriele Lupidi,
• Giovanni Poli,
• Julie Oble and
• Alejandro Perez-Luna

Beilstein J. Org. Chem. 2022, 18, 1256–1263, doi:10.3762/bjoc.18.131

• , but the yield of product 21 remained the same (Table 1, entry 4). In spite of the satisfactory yield of 21, these conditions were synthetically impractical as we were unable to conveniently separate the final product from the phosphite ligand. The use of a ligand for copper revealed to be necessary

Derivatives of benzo-1,4-thiazine-3-carboxylic acid and the corresponding amino acid conjugates

• Péter Kisszékelyi,
• Tibor Peňaška,
• Klára Stankovianska,
• Mária Mečiarová and
• Radovan Šebesta

Beilstein J. Org. Chem. 2022, 18, 1195–1202, doi:10.3762/bjoc.18.124

• , entries 1 and 4). Application of ligand (S,S)-methyl-DUPHOS (L3) gave increased ee in the hydrogenation reaction, but the best result (90% ee) was achieved using 6 mol % Josiphos ligand L2 at 35 °C. Following the synthesis of 3-propylnorleucin methyl ester (16a), we carried on with the amine couplings

Heterogeneous metallaphotoredox catalysis in a continuous-flow packed-bed reactor

• Wei-Hsin Hsu,
• Susanne Reischauer,
• Peter H. Seeberger,
• Bartholomäus Pieber and
• Dario Cambié

Beilstein J. Org. Chem. 2022, 18, 1123–1130, doi:10.3762/bjoc.18.115

• nickel catalyst in a single material have been reported [23][25][26][27]. For example, some of us have shown that a bipyridine ligand decorated with two carbazole groups can be polymerized to afford a heterogeneous macroligand (poly-czbpy) that coordinates nickel and serves as an active catalyst for

• (from Vapourtec) [29][30][31][32]. To decrease the optical density of the bed, the column was loaded with a mixture of poly-5,5’-di(9H-carbazol-9-yl)-2,2’-bipyridine (poly-czbpy), glass beads and silica [33]. Once the column was ready, nickel was ligated to the polymerized ligand to afford the

• complexated catalyst (Ni@poly-czbpy). Based on previous batch optimizations we aimed for a ligand/metal ratio of 2:1 to ensure no unligated nickel is present as it negatively impacts the selectivity. By recirculating a solution of NiCl2∙glyme (4.3 mM) through the reactor for three hours (flow rate: 0.5 mL/min

Scope of tetrazolo[1,5-a]quinoxalines in CuAAC reactions for the synthesis of triazoloquinoxalines, imidazoloquinoxalines, and rhenium complexes thereof

• Laura Holzhauer,
• Chloé Liagre,
• Olaf Fuhr,
• Nicole Jung and
• Stefan Bräse

Beilstein J. Org. Chem. 2022, 18, 1088–1099, doi:10.3762/bjoc.18.111

• of a metal complex with an inverse triazoloquinoxaline ligand [12]. Imidazo[1,2-a]quinoxalines have been reported to possess anticancer and antitumor properties [27][28] and show activity as adenosine receptor antagonists [29] as well as PDE4 inhibitors [30]. The reaction of ring-fused tetrazoles to

• residues on the triazole moiety (14a, 14k and 14j*) were selected. Moreover, the two substituted ligands 15a and 15d were employed to obtain novel substituted rhenium triazoloquinoxaline complexes and the TIQ compound 25b was tested for use as a ligand in rhenium tricarbonyl complexes. The complexes were

• -triazoloquinoxaline ligand in a distorted octahedral coordination geometry in all cases. The obtained data for the alkyl-chain complex 27a corresponds to similar published results [12]. For complex 29, single crystals were formed from slow evaporation of a methylene chloride solution under ambient conditions. The

Synthesis of N-phenyl- and N-thiazolyl-1H-indazoles by copper-catalyzed intramolecular N-arylation of ortho-chlorinated arylhydrazones

• Yara Cristina Marchioro Barbosa,
• Guilherme Caneppele Paveglio,
• Claudio Martin Pereira de Pereira,
• Sidnei Moura,
• Cristiane Storck Schwalm,
• Gleison Antonio Casagrande and
• Lucas Pizzuti

Beilstein J. Org. Chem. 2022, 18, 1079–1087, doi:10.3762/bjoc.18.110

• . Results and Discussion First, optimization of the reaction conditions was conducted using substrate 1a as a model according to Table 1. The molar ratio of 1a, the catalyst, the base, and the ligand used in Table 1, entry 1 was adapted from the literature [25]. The reaction mixture was stirred for 5 h at

• show the presence of the product 2a, but it showed the presence of 91% of the starting hydrazone (Table 1, entry 8). To evaluate the effect of the base, K3PO4 or Cs2CO3 was used, but the yield was lower than 60% (Table 1, entries 9 and 10). The influence of the catalyst/ligand molar ratio (Table 1

• ligand (Table 1, entry 22), but the product could not be detected by TLC analysis. In order to compare the efficiency of the optimized conditions with the one-pot approach, a reaction was carried out starting from o-chlorobenzaldehyde and phenylhydrazine under the conditions shown in Table 1, entry 3

Facile and diastereoselective arylation of the privileged 1,4-dihydroisoquinolin-3(2H)-one scaffold

• Dmitry Dar’in,
• Grigory Kantin,
• Alexander Bunev and
• Mikhail Krasavin

Beilstein J. Org. Chem. 2022, 18, 1070–1078, doi:10.3762/bjoc.18.109

• associated biological activities and relevance to the naturally occurring alkaloids [1], 1,4-dihydro-3(2H)-isoquinolones (1,4-DHIQs) undoubtedly represent a privileged scaffold [2] for drug design considering such diversely bioactive compounds documented in the literature as ligand for serotonin 5-HT1A

Anti-inflammatory aromadendrane- and cadinane-type sesquiterpenoids from the South China Sea sponge Acanthella cavernosa

• Shou-Mao Shen,
• Qing Yang,
• Yi Zang,
• Jia Li,
• Xueting Liu and
• Yue-Wei Guo

Beilstein J. Org. Chem. 2022, 18, 916–925, doi:10.3762/bjoc.18.91

• tumor necrosis factor-α (TNF-α) and C–C motif chemokine ligand 2 (CCL2) were investigated in lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages, using NF-κB inhibitor BAY-11-7082 as the positive control. Compound 3 displayed promising dose-dependent anti-inflammatory activity with the inhibition

Synthesis of novel alkynyl imidazopyridinyl selenides: copper-catalyzed tandem selenation of selenium with 2-arylimidazo[1,2-a]pyridines and terminal alkynes

• Mio Matsumura,
• Kaho Tsukada,
• Kiwa Sugimoto,
• Yuki Murata and
• Shuji Yasuike

Beilstein J. Org. Chem. 2022, 18, 863–871, doi:10.3762/bjoc.18.87

• intermediate A to form a π-complex B, and a ligand exchange reaction from B occurs to produce intermediate D, together with the elimination of selenol C. The selenol C is oxidized to diselenide 2. Finally, the intermediate D undergoes a reductive elimination to form the desired product 4, with the regeneration

Palladium-catalyzed solid-state borylation of aryl halides using mechanochemistry

• Koji Kubota,
• Emiru Baba,
• Tamae Seo,
• Tatsuo Ishiyama and
• Hajime Ito

Beilstein J. Org. Chem. 2022, 18, 855–862, doi:10.3762/bjoc.18.86

• halides in a test tube [15]. They found that a Pd(dba)2/DPEphos catalytic system was effective for aryl bromides, and aryl chlorides reacted more efficiently when XPhos was used as the ligand [15]. Although their achievements are remarkable, this protocol is only applicable to liquid substrates, which can

• ). When the reaction was stopped after 5 min, only a 26% yield of 3a was obtained (Table 1, entry 2). The use of 1,1'-bis(diphenylphosphino)ferrocene (dppf), which is the optimal ligand under the original conditions for the solution-based protocol [8], provided only trace amounts of 3a (1%, Table 1, entry

Structural basis for endoperoxide-forming oxygenases

• Takahiro Mori and
• Ikuro Abe

Beilstein J. Org. Chem. 2022, 18, 707–721, doi:10.3762/bjoc.18.71

• Fe(III)-OH species can be exchanged with the solvent water [76]. Therefore, the fact that almost all of the oxygen atoms in the Fe(III)-OH species exchanged with the solvent in the enzyme reaction of NvfI suggested the presence of a long-lived C3' radical and the hydroxy ligand during the reaction

Mechanochemical halogenation of unsymmetrically substituted azobenzenes

• Dajana Barišić,
• Mario Pajić,
• Ivan Halasz,
• Darko Babić and
• Manda Ćurić

Beilstein J. Org. Chem. 2022, 18, 680–687, doi:10.3762/bjoc.18.69

• ; N-halosuccinimide; palladium(II); Introduction Electrophilic aromatic substitution [1][2][3] and ligand-directed transition-metal-catalyzed reactions [4][5][6][7][8] are among the most widely used synthetic approaches for the preparation of halogenated arenes. They are important precursors in cross

Heteroleptic metallosupramolecular aggregates/complexation for supramolecular catalysis

• Prodip Howlader and
• Michael Schmittel

Beilstein J. Org. Chem. 2022, 18, 597–630, doi:10.3762/bjoc.18.62

• from supramolecular protocols in catalysis [9]. Metal–ligand-based 2D and 3D self-assembled architectures have been extensively studied over the past decades [15][16][17][18][19][20][21]. While in the early years, the focus has been on the exploration of structural features, more recent advancements

• have led to a multitude of extremely useful functional applications (molecular recognition, ion sensing, catalysis, etc.) [9][22]. Since most of these structures are homoleptic in nature, i.e., they are constructed from a single type of ligand [4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19

• multicomponent ATP synthase motor [23], a more detailed and refined configuration of purposeful machinery [24]. For the preparation of heteroleptic aggregates, one must differentiate between dynamic (rapidly exchanging) and kinetically inert heteroleptic metal–ligand interactions. While the inert heteroleptic

BINOL as a chiral element in mechanically interlocked molecules

• Matthias Krajnc and
• Jochen Niemeyer

Beilstein J. Org. Chem. 2022, 18, 508–523, doi:10.3762/bjoc.18.53

• ]. The template complex (S)-3 was assembled by mixing the macrocycle (S)-1 (containing both a phenanthroline ligand and a BINOL unit) with [Cu(CH3CN4)]PF6 and the acyclic phenanthroline precursor 2. Then, the BINOL-based diiodide (S)-4 and Cs2CO3 were added successively over 18 hours. This resulted in

Menadione: a platform and a target to valuable compounds synthesis

• Acácio S. de Souza,
• Ruan Carlos B. Ribeiro,
• Dora C. S. Costa,
• Fernanda P. Pauli,
• David R. Pinho,
• Matheus G. de Moraes,
• Fernando de C. da Silva,
• Luana da S. M. Forezi and
• Vitor F. Ferreira

Beilstein J. Org. Chem. 2022, 18, 381–419, doi:10.3762/bjoc.18.43

• (Scheme 24). Tang and co-workers described the synthesis of thiosemicarbazone 80 from menadione (10) through a condensation reaction with thiosemicarbazide (79), which was used as a ligand in the synthesis of metal complexes using different transition metals, in refluxing ethanol (Scheme 25) [125

Borylated norbornadiene derivatives: Synthesis and application in Pd-catalyzed Suzuki–Miyaura coupling reactions

• Robin Schulte and
• Heiko Ihmels

Beilstein J. Org. Chem. 2022, 18, 368–373, doi:10.3762/bjoc.18.41

• , the approach presented herein avoids the use of the significantly more expensive reagents such as the arylboronic acid derivatives and the (t-Bu)3P ligand. To add to that, the latter is also highly air sensitive and thus requires special handling, but it is essential for a reasonably efficient Pd

Amamistatins isolated from Nocardia altamirensis

• Till Steinmetz,
• Wolf Hiller and
• Markus Nett

Beilstein J. Org. Chem. 2022, 18, 360–367, doi:10.3762/bjoc.18.40

• metallic ions depends on the presence of suitable ligand groups. Hydroxamates, 2,3-dihydroxybenzoates, and α-hydroxycarboxylates make excellent bidentate ligand groups, as their negatively charged oxygen atoms can maintain strong interactions with ferric iron [3]. But there are also many siderophores

• featuring ligand groups with nitrogen or sulfur as donor atoms [4]. The siderophore–iron complexes are recognized by highly selective microbial transporters. Following their translocation into the cell, the bound iron is released via a reductive or hydrolytic mechanism [2] Members of the genus Nocardia are

• structural features of these molecules. Amamistatin B (5) exhibits three bidentate ligand groups and can thus form an octahedral complex with ferric iron. The removal of one of these groups (e.g., the hydroxamate function at the ε terminus of the lysine residue) already leads to a considerable loss of iron

A resorcin[4]arene hexameric capsule as a supramolecular catalyst in elimination and isomerization reactions

• Tommaso Lorenzetto,
• Fabrizio Fabris and
• Alessandro Scarso

Beilstein J. Org. Chem. 2022, 18, 337–349, doi:10.3762/bjoc.18.38

• structures endowed with catalytic features are full covalent units (e.g., cyclodextrins, cucurbiturils, pillararenes and other derivatives) whose synthesis can be sometimes time consuming. Alternatively, supramolecular catalysts can be obtained through self-assembling units [18][19], metal-ligand components

• tetrahedral polyanionic metal-ligand capsule as supramolecular catalyst, observing lower catalytic activity and product distribution favoring isopulegol but also with large amounts of neoisopulegol and neoisoisopulegol (52%, 32% and 11%, respectively) [51]. More favorable selectivity towards isopulegol was

• obtained by the same group with a larger tetrahedral capsule using pyrene in place of naphthalene units observing isopulegol, neoisopulegol and neoisoisopulegol with 71%, 24% and 4% selectivity [52]. The comparison between the metal-ligand tetrahedral capsules and the H-bonded 16 shows a common trend of

Site-selective reactions mediated by molecular containers

• Rui Wang and
• Yang Yu

Beilstein J. Org. Chem. 2022, 18, 309–324, doi:10.3762/bjoc.18.35

• environment inside the container. The containers include supramolecular structures self-assembled through metal/ligand interactions or hydrogen bonding and open-ended covalent structures such as cyclodextrins and cavitands. Challenges and prospects for the future are also provided. Keywords: confinement

• accommodated in the cavity of A through π–π stacking interactions between the naphthalene ring of 3 and a triazine ligand of A from the X-ray crystallographic analysis. In the control experiment, without host A, only 44% yield of the conventional 9,10-adduct 4 was produced without any 1,4-adduct product

Unexpected chiral vicinal tetrasubstituted diamines via borylcopper-mediated homocoupling of isatin imines

• Marco Manenti,
• Leonardo Lo Presti,
• Giorgio Molteni and
• Alessandra Silvani

Beilstein J. Org. Chem. 2022, 18, 303–308, doi:10.3762/bjoc.18.34

• of water to the minimum necessary to solubilize the copper sulfate. Thus, performing the reaction in toluene/water 100:1, ketimine hydrolysis was almost entirely prevented and the yield of compound 2a raised to 52% (Table 1, entry 6). With regard to the ligand (Table 1, entries 7 and 8), PPh3 behaved

Regioselectivity of the S_EAr-based cyclizations and S_EAr-terminated annulations of 3,5-unsubstituted, 4-substituted indoles

• Jonali Das and
• Sajal Kumar Das

Beilstein J. Org. Chem. 2022, 18, 293–302, doi:10.3762/bjoc.18.33

• [Pd(C3H5)Cl]2 and ligand L1 (Scheme 2) [11]. The reaction, that could also be considered as Friedel–Crafts type, intramolecular allylic alkylation, delivered nine-membered ring bearing 3,4-fused indoles 2 in moderate to good yields. In the asymmetric version of the reaction catalyzed by [Ir(cod)Cl]2

• (4 mol %) and ligand L2, the ring closure also took place regioselectively at the indole C3 position, albeit the products 3 were embedded with a seven-membered ring instead of a nine-membered one. The absolute configuration of products 3 was proposed to be S, based on the general rule of

• diastereo- and enantioselectivities (up to >20:1 dr and >99% ee) (Scheme 8) [18]. The optimized reaction conditions for the annulation reaction were as follows: [Ir(cod)Cl]2 (4 mol %), Carreira’s P/olefin ligand (S)-L3 (16 mol %), Zn(OTf)2 (100 mol %), and 4 Å MS in CH2Cl2 at rt. The synthetic protocol

Recent developments and trends in the iron- and cobalt-catalyzed Sonogashira reactions

• Surendran Amrutha,
• Sankaran Radhika and
• Gopinathan Anilkumar

Beilstein J. Org. Chem. 2022, 18, 262–285, doi:10.3762/bjoc.18.31

• ligand 2,2’-bipyridyl (Scheme 1). The reaction utilizes KOH as the base, since it provides the suitable deprotection of arylynols 3 during the synthesis of the terminal arylalkynes. The optimized conditions revealed that 10 mol % of Fe catalyst/ligand at 140 °C for 48 h afforded the maximum yields of the

• steric effects. Anilkumar and co-workers reported an iron-catalyzed Sonogashira coupling of aryl iodides with terminal alkynes in the presence of a catalytic system made up of the greenest solvent, water, in the presence of 10 mol % FeCl3·6H2O and 20 mol % 1,10-phenanthroline as ligand under aerobic

• , but their efficiencies were found to be lower than that of 1,10-phenanthroline. Metal impurities in FeCl3·6H2O were detected by using ICP mass spectrometry. Lipshutz and co-workers prepared nanoparticles from inexpensive iron(III) chloride containing reusable palladium in ppm level and XPhoS as ligand

Iridium-catalyzed hydroacylation reactions of C1-substituted oxabenzonorbornadienes with salicylaldehyde: an experimental and computational study

• Angel Ho,
• Austin Pounder,
• Krish Valluru,
• Leanne D. Chen and
• William Tam

Beilstein J. Org. Chem. 2022, 18, 251–261, doi:10.3762/bjoc.18.30

• dummy ligand present on the active iridium species, tetrabutylammonium salts were added (Table 1, entries 4 and 5); however, these were not as efficient in the reaction. Other iridium sources (Table 1, entries 2 and 3) proved to be not as effective in promoting the reaction, with Vaska’s complex failing

• its derivatives were used in all calculations rather than the experimentally used precatalyst [Ir(COD)Cl]2, as ligand exchange with the hydroxide ions present likely generates the [Ir(COD)OH]2 species in solution. Upon monomerization of [Ir(COD)OH]2, either through solvolysis or coordination of the

• over endo-η2-coordination, as the less congested convex face would impose reduced steric requirements. There are two potential isomeric intermediates following η2-coordination to the exo-face of MeOBD concerning the relative orientation of the COD ligand, acyl group, and C1-substituent on the

Diametric calix[6]arene-based phosphine gold(I) cavitands

• Gabriele Giovanardi,
• Andrea Secchi,
• Arturo Arduini and
• Gianpiero Cera

Beilstein J. Org. Chem. 2022, 18, 190–196, doi:10.3762/bjoc.18.21

• phosphine ligand implanted on the aromatic ring (entry 5, Table 1). Interestingly, this effect was substantially improved with the use of the calix[6]arene-based complex C(AuCl)2 (entry 6, Table 1). Overall, the ortho-substituted macrocycle C(AuCl)2 displayed an enhanced selectivity, with respect to the

• ’, 69%); ii) (Me2S)AuCl in DCM, 0 °C to rt (A’(AuCl), 94%; B’(AuCl), 92%; C’(AuCl), 96%). Ligand effect in gold(I)-catalyzed cycloisomerization of 1a. Supporting Information Supporting Information File 18: Experimental procedures, characterization data of compounds and copies of NMR spectra