A comprehensive review of flow chemistry techniques tailored to the flavours and fragrances industries

• Guido Gambacorta,
• James S. Sharley and
• Ian R. Baxendale

Beilstein J. Org. Chem. 2021, 17, 1181–1312, doi:10.3762/bjoc.17.90

• , an immunoactivating natural product (substrate 37) [97][98]. In 2015, the diastereoselective synthesis of (E,S)-3-hydroxy-7-tritylthio-4-heptenoic acid 43, a key component of cyclodepsipeptide histone deacetylase (HDAC) inhibitors, was achieved in flow (Scheme 4) [99]. Acetyloxazolidinone 41 was used

N-tert-Butanesulfinyl imines in the asymmetric synthesis of nitrogen-containing heterocycles

• Joseane A. Mendes,
• Paulo R. R. Costa,
• Miguel Yus,
• Francisco Foubelo and
• Camilla D. Buarque

Beilstein J. Org. Chem. 2021, 17, 1096–1140, doi:10.3762/bjoc.17.86

• alkaloids that were isolated in the mid-1990s from the Caribbean sponge bataella sp. From a biological point of view, the batzelladines have received attention due to their reported activity as inhibitors of HIV gp120-human CD4 binding. Chiral N-tert-butanesulfinyl aldimine (SS)-58 was used as a precursor

• -hydroxypipecolic acid 145 was reported recently by Zhang and Sun. Compound 145 is an intermediate for the synthesis of β-lactamase inhibitors. A key step in this synthesis was the hydrocyanation of chiral sulfinyl imine 141, prepared from commercially available and inexpensive ʟ-glyceraldehyde acetal, with

Synthetic accesses to biguanide compounds

• Oleksandr Grytsai,
• Cyril Ronco and
• Rachid Benhida

Beilstein J. Org. Chem. 2021, 17, 1001–1040, doi:10.3762/bjoc.17.82

• synthesis has been recently reported by Loesche et al. [43]. The reaction between piperazine and different N-aryl-N’-cyanoguanidines in methanol at 120 °C afforded low to moderate yields for potential new cholinesterase inhibitors (Scheme 17A). Another example of microwave conditions has been provided by

Application of the Meerwein reaction of 1,4-benzoquinone to a metal-free synthesis of benzofuropyridine analogues

• Rashmi Singh,
• Tomas Horsten,
• Rashmi Prakash,
• Swapan Dey and
• Wim Dehaen

Beilstein J. Org. Chem. 2021, 17, 977–982, doi:10.3762/bjoc.17.79

• cancer cell lines [12][13]. Fluoroquinophenoxazines 2 have been used as telomerase inhibitors in anticancer research [14]. Furthermore, benzofuroisoindoles 3 were part of a kinase inhibitor study [15]. Photobiologically active psoralene (linear furocoumarin) dibenzofurans 1 and angular furanocoumarin

• ][21]. These compounds are presumably multitargeting drugs because of the diverse applications as insulin-like growth factor 1 receptor (IGF-1R) inhibitors [22], selective GSK-3β inhibitors important in Alzheimer's disease [23][24], and cyclin-dependent kinase (CDK) inhibitors [25][26][27]. Lastly, the

Microwave-assisted multicomponent reactions in heterocyclic chemistry and mechanistic aspects

• Shivani Gulati,
• Stephy Elza John and
• Nagula Shankaraiah

Beilstein J. Org. Chem. 2021, 17, 819–865, doi:10.3762/bjoc.17.71

• ] reported the potential of naphthopyrans as non-purine xanthine oxidase inhibitors. They explored a silicated fluoroboric acid-catalyzed three-component cycloaddition involving acyclic 1,3-diketones 54, β-naphthol (55) and aldehyde 5 for the synthesis of substituted naphthopyrans 56 under microwave

• irradiation under solvent-free conditions. The library of compounds proved to be active as xanthine oxidase inhibitors with the most potent molecule showcasing IC50 = 4 μM (Scheme 21). 5 Pyrroles Pyrroles are five-membered heterocycles consisting of four carbon atoms and a nitrogen atom. The pyrrole ring is

• phenanthroline. 6 Pyrimidines/fused pyrimidines 6.1 Pyrimidines Pyrimidines are six-membered aromatic heterocycles containing two nitrogen atoms at positions 1 and 3. These are an important class of compounds depicting a wide range of biological activities such as COX inhibitors, anti-inflammatory, anticancer

β-Lactamase inhibition profile of new amidine-substituted diazabicyclooctanes

• Zafar Iqbal,
• Lijuan Zhai,
• Yuanyu Gao,
• Dong Tang,
• Xueqin Ma,
• Jinbo Ji,
• Jian Sun,
• Jingwen Ji,
• Yuanbai Liu,
• Rui Jiang,
• Yangxiu Mu,
• Lili He,
• Haikang Yang and
• Zhixiang Yang

Beilstein J. Org. Chem. 2021, 17, 711–718, doi:10.3762/bjoc.17.60

• -lactamase inhibitors. As part of our efforts, we have synthesized a series of DBO derivatives A1–23 containing amidine substituents at the C2 position of the bicyclic ring. These compounds, alone and in combination with meropenem, were tested against ten bacterial strains for their antibacterial activity in

• MIC from <0.125 mg/L to 2 mg/L, and is comparable to avibactam against both E. coli strains with a MIC value of <0.125 mg/L. Keywords: amidine; antibacterial activity; β-lactamase inhibitors; diazabicyclooctane; synthesis; Introduction Survival stress posed by antimicrobial agents triggers multiple

• , sulbactam and tazobactam [13] evolved as the BLIs of class A, B and few of class D β-lactamases [14]. These inhibitors were advantageous to clavulanic acid due to their lack of chromosomal induction of AmpC but found susceptible to a few of class A enzymes such as TEM type [10] and CTX-M (ESBL), identified

Stereoselective syntheses of 3-aminocyclooctanetriols and halocyclooctanetriols

• Emine Salamci and
• Yunus Zozik

Beilstein J. Org. Chem. 2021, 17, 705–710, doi:10.3762/bjoc.17.59

• have become important structural components for drug development with a modifying action as inhibitors of glycosidases [4][5][6][7][8][9][10]. Aminocyclitols are amino polyhydroxy cycloalkanes [2] formally derived from cyclitols [11][12][13][14][15], which are polyhydroxylated cycloalkanes, via

• of the most important conduramines 4 is valienamine (3) [17], which is found as a building block in several aminoglycoside antibiotics [2]. Furthermore, conduramines 4 and their derivatives are used as both inhibitors of glycosidases and useful intermediates in organic synthesis [18]. Halocyclitols

• inhibitors of α-glycosidases [11][19]. Recent reviews report on the latest synthetic methodologies for aminocyclitols and related compounds [1][2][3][16]. Many methods have been previously reported for the synthesis of aminocyclitols containing five- and six-membered rings, along with their diverse

Amino- and polyaminophthalazin-1(2H)-ones: synthesis, coordination properties, and biological activity

• Zbigniew Malinowski,
• Emilia Fornal,
• Agata Sumara,
• Renata Kontek,
• Karol Bukowski,
• Beata Pasternak,
• Dariusz Sroczyński,
• Joachim Kusz,
• Magdalena Małecka and
• Monika Nowak

Beilstein J. Org. Chem. 2021, 17, 558–568, doi:10.3762/bjoc.17.50

• analogs are an interesting group of pharmacologically active heterocycles [1][2], many of which possess, e.g., antimicrobial [3][4], antifungal [5], antidepressant [6][7], and antihistaminic [8][9][10] properties. Amino- and amidophthalazine derivatives have been examined, e.g., as inhibitors of PGE2

• ][14] and PDE-10 [15] for a potential use in the treatment of chronic pain and neurodegenerative or psychiatric disorders. Some of these derivatives are known to possess anti-inflammatory (p38 MAP kinase inhibitors, Figure 1) [16], cardiotonic [17], and anticancer (Aurora-A kinase inhibitors

Synthesis of (Z)-3-[amino(phenyl)methylidene]-1,3-dihydro-2H-indol-2-ones using an Eschenmoser coupling reaction

• Lukáš Marek,
• Lukáš Kolman,
• Jiří Váňa,
• Jan Svoboda and
• Jiří Hanusek

Beilstein J. Org. Chem. 2021, 17, 527–539, doi:10.3762/bjoc.17.47

• of all products was confirmed by NMR techniques. Keywords: 3-bromooxindoles; Eschenmoser coupling reaction; thioamides; tyrosin kinase inhibitors; (Z)-3-[amino(phenyl)methylidene]-1,3-dihydro-2H-indol-2-ones; Introduction 3-(Aminomethylidene)-1,3-dihydro-2H-indol-2-ones (3-(aminomethylidene

Synthetic strategies of phosphonodepsipeptides

• Jiaxi Xu

Beilstein J. Org. Chem. 2021, 17, 461–484, doi:10.3762/bjoc.17.41

• and phosphonate-linked analogues of naturally occurring peptides. They are more stable than phosphonopeptides and have been widely applied as enzyme inhibitors, haptens for the production of antibodies, biological agents, and prodrugs. The synthetic strategies towards phosphonodepsipeptides are

• than the corresponding phosphonopeptides because the phosphonate bond is more inert than a phopshonamidate bond. Phosphonodepsipeptides are widely used as enzyme inhibitors [6][7][8][9][10], haptens for inducing catalytic antibodies [11][12], and produgs [8][9][13]. They have potential applications as

• and selective hydrolysis. Synthesis of α-phosphonodepsipeptides In 1987, a series of phosphonodepsidipeptides 10 was synthesized as phosphorus analogues of peptides and evaluated as inhibitors of leucine aminopeptidase from porcine kidney and two compounds, i.e., 10e and 10h (R = isobutyl, benzyl

Synthesis of trifluoromethyl ketones by nucleophilic trifluoromethylation of esters under a fluoroform/KHMDS/triglyme system

• Yamato Fujihira,
• Yumeng Liang,
• Makoto Ono,
• Kazuki Hirano,
• Takumi Kagawa and
• Norio Shibata

Beilstein J. Org. Chem. 2021, 17, 431–438, doi:10.3762/bjoc.17.39

• TFMK moiety is a proven effective metal chelator in various enzyme inhibitors (Figure 1b) [58][59][60][61][62][63][64][65]. Several useful methods exist for preparing trifluoromethyl ketones [66][67], such as the direct trifluoromethylation of esters by the Ruppert–Prakash reagent (Me3SiCF3) [68][69

Hydrazides in the reaction with hydroxypyrrolines: less nucleophilicity – more diversity

• Dmitrii A. Shabalin,
• Evgeniya E. Ivanova,
• Igor A. Ushakov,
• Elena Yu. Schmidt and
• Boris A. Trofimov

Beilstein J. Org. Chem. 2021, 17, 319–324, doi:10.3762/bjoc.17.29

• fragments of influenza neuraminidase inhibitors [1], nonsteroidal progesterone receptor regulators [2][3], anti-inflammatory [4], antihypertensive and spasmolytic [5][6][7] agents (Figure 1). It is due to their prospects in drug design that a search for effective synthetic protocols to construct partially

¹⁹F NMR as a tool in chemical biology

• Diana Gimenez,
• Aoife Phelan,
• Cormac D. Murphy and
• Steven L. Cobb

Beilstein J. Org. Chem. 2021, 17, 293–318, doi:10.3762/bjoc.17.28

• reviewed in detail by Dalvit and Vulpetti [41][42]. The main advantages of these methods for lead compound screening is that they offer a platform not only for the rapid high-throughput screening of multiple protein small ligands, but also for the direct screening of functional inhibitors of much larger

• inhibitors in situ using 19F NMR spectroscopy (Figure 6). For this, the activity of the membrane-bound FAAH enzyme was evaluated by monitoring the hydrolysis of a fluorinated anandamide analogue ARN1203, a previously reported FAAH substrate, to arachidonic acid and 1-amino-3-fluoropropanol in the presence

• and absence of a broad range of known FAAH inhibitors with widely different potencies. The results clearly showed that the proposed n-FABS method was successful in detecting strong inhibitors of FAAH activity in cells. Also, it allowed the accurate quantification of the corresponding IC50 values, all

Novel library synthesis of 3,4-disubstituted pyridin-2(1H)-ones via cleavage of pyridine-2-oxy-7-azabenzotriazole ethers under ionic hydrogenation conditions at room temperature

• Romain Pierre,
• Anne Brethon,
• Sylvain A. Jacques,
• Aurélie Blond,
• Sandrine Chambon,
• Sandrine Talano,
• Catherine Raffin,
• Branislav Musicki,
• Claire Bouix-Peter,
• Loic Tomas,
• Gilles Ouvry,
• Rémy Morgentin,
• Laurent F. Hennequin and
• Craig S. Harris

Beilstein J. Org. Chem. 2021, 17, 156–165, doi:10.3762/bjoc.17.16

• present (Scheme 6). Conclusion In conclusion, we have developed novel, complementary multi-parallel synthetic routes permitting the exploitation of the C-3 then C-4 vectors or vice versa to deliver our library of novel 3,4-disubstituted pyridin-2(1H)-one kinase inhibitors starting from readily-available 2

Ultrasound-assisted Strecker synthesis of novel 2-(hetero)aryl-2-(arylamino)acetonitrile derivatives

• Emese Gal,
• Luiza Gaina,
• Hermina Petkes,
• Alexandra Pop,
• Castelia Cristea,
• Gabriel Barta,
• Dan Cristian Vodnar and
• Luminiţa Silaghi-Dumitrescu

Beilstein J. Org. Chem. 2020, 16, 2929–2936, doi:10.3762/bjoc.16.242

• biological properties exhibiting enzymatic activity as potent and selective protease inhibitors, fungicidal and herbicidal activity [17], we designed an efficient, simple, and ecofriendly synthetic procedure for the preparation of new synthetic compounds containing joint phenothiazine/ferrocene and α-amino

Three-component reactions of aromatic amines, 1,3-dicarbonyl compounds, and α-bromoacetaldehyde acetal to access N-(hetero)aryl-4,5-unsubstituted pyrroles

• Wenbo Huang,
• Kaimei Wang,
• Ping Liu,
• Minghao Li,
• Shaoyong Ke and
• Yanlong Gu

Beilstein J. Org. Chem. 2020, 16, 2920–2928, doi:10.3762/bjoc.16.241

• with aniline (1a) or amantadine in the presence of HATU or EDCI to form the multisubstituted pyrrole-3-carboxamide derivatives 4x and 4y (Scheme 4). These skeletons have been proven to be promising inhibitors for the production of cytokines [47]. A plausible mechanism for the model reaction was

Synthesis of purines and adenines containing the hexafluoroisopropyl group

• Viacheslav Petrov,
• Rebecca J. Dooley,
• Alexander A. Marchione,
• Elizabeth L. Diaz,
• Brittany S. Clem and
• William Marshall

Beilstein J. Org. Chem. 2020, 16, 2739–2748, doi:10.3762/bjoc.16.224

• number of important drugs used in different therapeutic areas contain the benzimidazole ring […], such as proton pump inhibitors (omeprazole), antihypertensives (candesartan, telmisartan), antihistaminics (astemizole), antihelmintics (albendazole, mebendazole), as well as several other kinds of still

NMR Spectroscopy of supramolecular chemistry on protein surfaces

• Peter Bayer,
• Anja Matena and
• Christine Beuck

Beilstein J. Org. Chem. 2020, 16, 2505–2522, doi:10.3762/bjoc.16.203

• interaction between the 14-3-3 protein and its phosphorylated cargo proteins [42][44][45]. Another ligand with just one GCP unit targets the central pore of the 14-3-3 dimer [43]. Unfortunately, these systems have not yet been studied by NMR. However, several other 14-3-3 inhibitors and stabilizers serve as

• signal intensities (tau bound by 14-3-3 compared to free tau) show a decrease for tau residues that are part of the 14-3-3 binding epitopes due to line broadening. In the presence of chimeric inhibitors, in which a small molecule was fused to a 14-3-3 binding peptide, the inhibitors target the unlabeled

• protein in unlabeled minimal media by simply adding the isotope-labeled amino acid, without the need for auxotrophic strains or metabolic enzyme inhibitors [108]. The assignment of all Lys residues, beyond the assignments available from classic uniform 15N- and 13C-labeling, was achieved by specific 15N

Synthesis of 1,4-benzothiazinones from acylpyruvic acids or furan-2,3-diones and o-aminothiophenol

• Ekaterina E. Stepanova,
• Maksim V. Dmitriev and
• Andrey N. Maslivets

Beilstein J. Org. Chem. 2020, 16, 2322–2331, doi:10.3762/bjoc.16.193

• use. Particularly, some enaminones I and II were found to show antioxidant [3], antimycotic [7][8], antimycobacterial [9][10], anti-Alzheimer’s disease (JNK3 inhibitors) [11], platelet aggregation inhibitory [12], antimicrobial [7] and analgesic [13] activities. Enaminones II were reported as

Lipophilicity trends upon fluorination of isopropyl, cyclopropyl and 3-oxetanyl groups

• Benjamin Jeffries,
• Zhong Wang,
• Robert I. Troup,
• Anaïs Goupille,
• Jean-Yves Le Questel,
• Charlene Fallan,
• James S. Scott,
• Elisabetta Chiarparin,
• Jérôme Graton and
• Bruno Linclau

Beilstein J. Org. Chem. 2020, 16, 2141–2150, doi:10.3762/bjoc.16.182

• give analogue 7b reduced the lipophilicity. Interestingly, while the nonfluorinated 7a and 7c diastereomers have different logD7.4 values, this is not the case for their fluorinated analogues 7b and 7d. Oxazine derivative 8 featured in the development of centrally active β-secretase (BACE1) inhibitors

Azo-dimethylaminopyridine-functionalized Ni(II)-porphyrin as a photoswitchable nucleophilic catalyst

• Jannis Ludwig,
• Julian Helberg,
• Hendrik Zipse and
• Rainer Herges

Beilstein J. Org. Chem. 2020, 16, 2119–2126, doi:10.3762/bjoc.16.179

• , spiropyranes, and stilbenes [2]. Diarylethenes were reported in the context of photoswitchable catalysis as inhibitors of the Karstedt´s catalyst [3] and for pKa modulation in acid–base-controlled processes [4]. Molecular motors for stereodivergent anion binding catalysis [5], azopeptides for the acetylation

Muyocopronones A and B: azaphilones from the endophytic fungus Muyocopron laterale

• Ken-ichi Nakashima,
• Junko Tomida,
• Tomoe Tsuboi,
• Yoshiaki Kawamura and
• Makoto Inoue

Beilstein J. Org. Chem. 2020, 16, 2100–2107, doi:10.3762/bjoc.16.177

• (Dothideomycetes) were reported as intercellular adhesion molecule-1 (ICAM1) expression inhibitors in a patent literature [28]. Therefore, the presence of the 2,4-dimethyl-3-hydroxyhexanoate moiety may be a potential chemical marker for Dothideomycetes, although this is difficult to conclude due to the fact that

Convenient access to pyrrolidin-3-ylphosphonic acids and tetrahydro-2H-pyran-3-ylphosphonates with multiple contiguous stereocenters from nonracemic adducts of a Ni(II)-catalyzed Michael reaction

• Alexander N. Reznikov,
• Dmitry S. Nikerov,
• Anastasiya E. Sibiryakova,
• Victor B. Rybakov,
• Evgeniy V. Golovin and
• Yuri N. Klimochkin

Beilstein J. Org. Chem. 2020, 16, 2073–2079, doi:10.3762/bjoc.16.174

• Micromonospora [5]. Dipeptide analogs with phosphonoproline 2 and piperidine-2-phosphonic acid 3 are potent inhibitors of dipeptidyl peptidase IV [6][7]. Oxygen-containing heterocycles containing a phosphoryl group are also of interest in the development of new drugs. It is known that phosphorylated carbohydrate

• analogues 4 and 5 are neuraminidase inhibitors (Figure 1) [8][9]. These circumstances create an interest in discovering synthetic routes for obtaining nonracemic phosphoryl-substituted heterocycles. Thus, in recent years, effective methods for the asymmetric synthesis of chiral phosphonates containing

Automated high-content imaging for cellular uptake, from the Schmuck cation to the latest cyclic oligochalcogenides

• Rémi Martinent,
• Javier López-Andarias,
• Dimitri Moreau,
• Yangyang Cheng,
• Naomi Sakai and
• Stefan Matile

Beilstein J. Org. Chem. 2020, 16, 2007–2016, doi:10.3762/bjoc.16.167

• recorded for microtiter plates with hundreds to thousands of wells. This standard HT screening provides access to quantitatively reliable curves for the dependence on the concentration, incubation time, activators, inhibitors, and so on within a reasonable time. High-content screening (HCS) combines this

Synthesis, docking study and biological evaluation of ᴅ-fructofuranosyl and ᴅ-tagatofuranosyl sulfones as potential inhibitors of the mycobacterial galactan synthesis targeting the galactofuranosyltransferase GlfT2

• Marek Baráth,
• Jana Jakubčinová,
• Zuzana Konyariková,
• Stanislav Kozmon,
• Katarína Mikušová and
• Maroš Bella

Beilstein J. Org. Chem. 2020, 16, 1853–1862, doi:10.3762/bjoc.16.152

• site of GlfT2, none of these compounds serve as efficient inhibitors of the enzymes involved in the mycobacterial galactan biosynthesis. Keywords: GlfT2; molecular modeling; mycobacterium tuberculosis; synthesis; transition state inhibitors; Introduction Tuberculosis (TB) is one of the most prevalent

• silico based design of possible GlfT2 inhibitors that mimic the TS structure. The galactofuranosyltransferase GlfT2 is a bisubstrate enzyme with a single catalytic domain and its catalytic reaction transition state shares some structural similarities with the previously modeled N

• -acetylglucosaminyltransferase I (GnT-I) reaction transition state [11]. Previously, we have designed 2-thiohexofuranoside skeletons bearing a phosphate group in position 1 by molecular modeling as potential transition state inhibitors of human glycosyltransferase I (GnT-I) [12], the bisubstrate enzyme requiring a metal co