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Search for "agonist" in Full Text gives 74 result(s) in Beilstein Journal of Organic Chemistry.
Origami with small molecules: exploiting the C–F bond as a conformational tool
- Patrick Ryan,
- Ramsha Iftikhar and
- Luke Hunter
Beilstein J. Org. Chem. 2025, 21, 680–716, doi:10.3762/bjoc.21.54
- case (e.g., 107), suggesting that the NH···F interaction (i.e., II, Figure 12) is not a dominant one. The gauche preference of β-fluoroamides has been exploited to control the conformations of a variety of bioactive molecules [186]. For example, the activity of the GPR119 receptor agonist 108 (Figure
Graphical Abstract
Figure 1: Fundamental characteristics of the C–F bond.
Figure 2: Incorporation of fluorine at the end of an alkyl chain.
Figure 3: Incorporation of fluorine into the middle of a linear alkyl chain.
Figure 4: Incorporation of fluorine across much, or all, of a linear alkyl chain.
Figure 5: Incorporation of fluorine into cycloalkanes.
Figure 6: Conformational effects of introducing fluorine into an ether (geminal to oxygen).
Figure 7: Conformational effects of introducing fluorine into an ether (vicinal to oxygen).
Figure 8: Effects of introducing fluorine into alcohols (and their derivatives).
Figure 9: Controlling the ring pucker of sugars through fluorination.
Figure 10: Controlling bond rotations outside the sugar ring through fluorination.
Figure 11: Effects of incorporating fluorine into amines.
Figure 12: Effects of incorporating fluorine into amine derivatives, such as amides and sulfonamides.
Figure 13: Effects of incorporating fluorine into organocatalysts.
Figure 14: Effects of incorporating fluorine into carbonyl compounds, focusing on the “carbon side.”
Figure 15: Fluoroproline-containing peptides and proteins.
Figure 16: Further examples of fluorinated linear peptides (besides fluoroprolines). For clarity, sidechains a...
Figure 17: Fluorinated cyclic peptides.
Figure 18: Fluorine-derived conformational control in sulfur-containing compounds.
Multicomponent reactions driving the discovery and optimization of agents targeting central nervous system pathologies
- Lucía Campos-Prieto,
- Aitor García-Rey,
- Eddy Sotelo and
- Ana Mallo-Abreu
Beilstein J. Org. Chem. 2024, 20, 3151–3173, doi:10.3762/bjoc.20.261
- μM for cannabinoid receptors). Then, the most promising antagonist (14a; IC50 = 0.28 µM) was selected for a G-protein-dependent functional assay, where 14a acted as a weak GPR55 inverse agonist (EC50 = 0.9 µM). Depression and anxiety Benzodiazepines are widely used in treating a range of CNS
- a multicomponent approach. Bucherer–Bergs reaction: The dense presence of mGlu2/3 receptors in regions associated with psychiatric disorders suggests them as potential drug targets. One clinical candidate to treat psychiatric disorders was the mGluR2/3 agonist pomaglumetad methionil (POM). This drug
- findings illustrated that POM has the capability to restore normal dopamine neuron activity in situations of increased hippocampal activity. These results showed that a deep understanding of the mechanistic function of mGlu2/3, and particularly the agonist POM, is needed. Epilepsy Epilepsy is a disease
Graphical Abstract
Figure 1: Classical MCRs.
Figure 2: Different scaffolds that can be formed with the Ugi adduct.
Scheme 1: Oxoindole-β-lactam core produced in a U4C-3CR.
Figure 3: Most active oxoindole-β-lactam compounds developed by Brãndao et al. [33].
Scheme 2: Ugi-azide synthesis of benzofuran, pyrazole and tetrazole hybrids.
Figure 4: The most promising hybrids synthesized via the Ugi-azide multicomponent reaction reported by Kushwa...
Scheme 3: Four-component Ugi reaction for the synthesis of novel antioxidant compounds.
Figure 5: Most potent antioxidant compounds obtained through the Ugi four-component reaction developed by Pac...
Scheme 4: Four-component Ugi reaction to synthesize β-amiloyd aggregation inhibitors.
Figure 6: The most potential β-amiloyd aggregation inhibitors generated by Galante et al. [37].
Scheme 5: Four-component Ugi reaction to obtain FATH hybrids and the best candidate synthesized.
Scheme 6: Four-component Ugi reaction for the synthesis of FATMH hybrids and the best candidate synthesized.
Scheme 7: Petasis multicomponent reaction to produce pyrazine-based MTDLs.
Figure 7: Best pyrazine-based MTDLs synthesized by Madhav et al. [40].
Scheme 8: Synthesis of BCPOs employing a Knoevenagel-based multicomponent reaction and the best candidate syn...
Scheme 9: Hantzsch multicomponent reaction for the synthesis of DHPs as novel MTDLs.
Figure 8: Most active 1,4-dihydropyridines developed by Malek et al. [43].
Scheme 10: Chromone–donepezil hybrid MTDLs obtained via the Passerini reaction.
Figure 9: Best CDH-based MTDLs as AChE inhibitors synthesized by Malek et al. [46].
Scheme 11: Replacement of the nitrogen in lactams 11 with an oxygen in 12 to influence hydrogen-bond donating ...
Scheme 12: MCR 3 + 2 reaction to develop spirooxindole, spiroacenaphthylene, and bisbenzo[b]pyran compounds.
Figure 10: SIRT2 activity of best derivatives obtained by Hasaninejad et al. [49].
Scheme 13: Synthesis of ML192 analogs using the Gewald multicomponent reaction and the best candidate synthesi...
Scheme 14: Development of 1,5-benzodiazepines via Ugi/deprotection/cyclization (UDC) approach by Xu et al. [59].
Scheme 15: Synthesis of polysubstituted 1,4-benzodiazepin-3-ones using UDC strategy.
Scheme 16: Synthetic procedure to obtain 3-carboxamide-1,4-benzodiazepin-5-ones employing Ugi–reduction–cycliz...
Scheme 17: Ugi cross-coupling (U-4CRs) to synthesize triazolobenzodiazepines.
Scheme 18: Azido-Ugi four component reaction cyclization to obtain imidazotetrazolodiazepinones.
Scheme 19: Synthesis of oxazolo- and thiazolo[1,4]benzodiazepine-2,5-diones via Ugi/deprotection/cyclization a...
Scheme 20: General synthesis of 2,3-dichlorophenylpiperazine-derived compounds by the Ugi reaction and Ugi/dep...
Figure 11: Best DRD2 compounds synthesized using a multicomponent strategy.
Scheme 21: Bucherer–Bergs multicomponent reaction to obtain a key intermediate in the synthesis of pomaglumeta...
Scheme 22: Ugi reaction to synthesize racetam derivatives and example of two racetams synthesized by Cioc et a...
Natural resorcylic lactones derived from alternariol
- Joachim Podlech
Beilstein J. Org. Chem. 2024, 20, 2171–2207, doi:10.3762/bjoc.20.187
- aggregation, attracting interest for the treatment of Alzheimer’s disease [240], was a selective agonist of the farnesoid X receptor FXR (EC50: 3.2 µM) [241], and displayed remarkable neuroprotective effects against oxidative injuries by acting as potent activator of nuclear factor erythroid-derived 2-like 2
Graphical Abstract
Figure 1: Examples of compounds covered in this review categorized in six sub-classes (see text).
Figure 2: Examples of compounds not covered in this review.
Figure 3: Wrongly assigned and thus obsolete structures (details will be discussed in the respective chapters...
Figure 4: Alternariol with the correct IUPAC numbering and an occasionally used numbering based on the biphen...
Figure 5: Alternariol O-methyl ethers.
Figure 6: Alternariol O-glycosides.
Figure 7: Alternariol O-acetates and O-sulfates.
Figure 8: 2-Hydroxy- and 4-hydroxy-substituted alternariol and its O-methyl ethers.
Figure 9: Chloro- and amino-substituted alternariol and its O-methyl ethers.
Figure 10: Presumed alternariol derivatives with non-canonical substitution pattern.
Figure 11: Alternariol derivatives with the 1-methyl group hydroxylated.
Figure 12: Verrulactones: pseudo-dimeric derivatives of altertenuol and related compounds.
Figure 13: Biaryls formed by reductive lactone opening and/or by decarboxylation.
Figure 14: Altenuene and its diastereomers.
Figure 15: 9-O-Demethylated altenuene diastereomers.
Figure 16: Acetylated and methylated altenuene diastereomers.
Figure 17: Altenuene diastereomers modified with lactic acid, pyruvic acid, or acetone.
Figure 18: Neoaltenuene and related compounds.
Figure 19: Dehydroaltenusin and its derivatives.
Scheme 1: Equilibrium of dehydroaltenusin in polar solvents [278].
Figure 20: Further quinoid derivatives.
Figure 21: Dehydroaltenuenes.
Figure 22: Complex aggregates containing dehydroaltenuene substructures and related compounds.
Figure 23: Dihydroaltenuenes.
Figure 24: Altenuic acids and related compounds.
Figure 25: Cyclopentane- and cyclopentene-fused derivatives.
Figure 26: Cyclopentenone-fused derivatives.
Figure 27: Spiro-fused derivatives and a related ring-opened derivative.
Figure 28: Lactones-fused and lactone-substituted derivatives.
Scheme 2: Biosynthesis of alternariol [324].
Scheme 3: Biosynthesis of alternariol and its immediate successors with the genes involved in the respective ...
Scheme 4: Presumed formation of altenuene and its diastereomers and of botrallin.
Scheme 5: Presumed formation of altenuic acids and related compounds.
Scheme 6: A selection of plausible biosynthetic paths to cyclopenta-fused metabolites. (No stereochemistry is...
Scheme 7: Biomimetic synthesis of alternariol (1) by Harris and Hay [66].
Scheme 8: Total synthesis of alternariol (1) by Subba Rao et al. using a Diels–Alder approach [34].
Scheme 9: Total synthesis of alternariol (1) using a Suzuki strategy by Koch and Podlech [62], improved by Kim et...
Scheme 10: Total synthesis of alternariol (1) using an intramolecular biaryl coupling by Abe et al. [63].
Scheme 11: Total synthesis of altenuene (54) and isoaltenuene (55) by Podlech et al. [249].
Scheme 12: Total synthesis of neoaltenuene (69) by Podlech et al. [35].
Scheme 13: Total synthesis of TMC-264 (79) by Tatsuta et al. [185].
Scheme 14: Total synthesis of cephalosol (99) by Koert et al. [304].
2-Heteroarylethylamines in medicinal chemistry: a review of 2-phenethylamine satellite chemical space
- Carlos Nieto,
- Alejandro Manchado,
- Ángel García-González,
- David Díez and
- Narciso M. Garrido
Beilstein J. Org. Chem. 2024, 20, 1880–1893, doi:10.3762/bjoc.20.163
- improvement through inverse agonism at histamine receptor 3 (H3) using recombinant isoforms. This finding corrects their previous assumption of betahistidine acting as an antagonist. Inhibition of cAMP formation and [3H]arachidonic acid release concluded the inverse agonist role. Five-membered heteroaromatic
- envisaged by Heffernan et al. [40], including human TAAR1 agonist activity and structural evaluation via homology model development followed by molecular docking and molecular dynamics studies (Scheme 6). Structural features like sulfur location and ring opening of the aminoethyl section were investigated
- invertebrates as neurotransmitter, in the so called histaminergic synapses [50]. As a consequence, histamine has been used as a template to rationally design histamine receptor agonists/antagonists capable to modulate their extensive range of capabilities. (R)-α-Methylhistamine (51) is an H3 receptor agonist
Graphical Abstract
Scheme 1: Description of the 2-heteroarylethylamine scope of the present review featuring appropriate heteroa...
Scheme 2: 2-Aminoethylpyridine derivatives with therapeutic activity.
Scheme 3: 2-Aminoethylfuran derivatives with therapeutic activity.
Scheme 4: 2-Aminoethylthiophene derivatives with therapeutic activity, part 1.
Scheme 5: 2-Aminoethylthiophene derivatives with therapeutic activity, part 2.
Scheme 6: 2-Aminoethylthiophene derivatives with therapeutic activity, part 3.
Scheme 7: 2-Aminoethylpyrrole derivatives with therapeutic activity.
Scheme 8: Histamine metabolic pathway.
Scheme 9: 2-Aminoethylimidazole derivatives with therapeutic activity, part 1. Krel is referred as histamine ...
Scheme 10: Conformationally restricted 2-aminoethylimidazole derivatives with therapeutic activity, part 2.
Scheme 11: 2-Aminoethylimidazole derivatives with therapeutic activity, part 3.
Scheme 12: 2-Aminoethylimidazole derivatives with therapeutic activity, part 4.
Scheme 13: 2-Aminoethylpyrazole derivatives with therapeutic activity.
Scheme 14: 2-Aminoethylisoxazole derivatives with therapeutic activity.
Scheme 15: 2-Aminoethylthiazole derivatives with therapeutic activity.
Scheme 16: 2-Aminoethyloxadiazole derivatives with therapeutic activity.
Scheme 17: 2-Aminoethyltriazole derivatives with therapeutic activity.
Scheme 18: 2-Aminoethyloxadiazole derivatives with therapeutic activity.
HPW-Catalyzed environmentally benign approach to imidazo[1,2-a]pyridines
- Luan A. Martinho and
- Carlos Kleber Z. Andrade
Beilstein J. Org. Chem. 2024, 20, 628–637, doi:10.3762/bjoc.20.55
- 1 [13] and include alpidem (anxiety disorders), minodronic acid (osteoporosis), miroprofen (non-steroidal anti-inflammatory drug, NSAID), necopidem (insomnia), olprinone (acute heart failure), saripidem (type A GABA receptor agonist), zolimidine (gastroesophageal reflux disease), and zolpidem
Graphical Abstract
Figure 1: Selected examples of commercial drugs containing the imidazo[1,2-a]pyridine core [13].
Figure 2: Examples of application of HPW as catalyst in the synthesis of heterocyclic compounds through multi...
Scheme 1: a) Reported phosphomolybdic acid-catalyzed synthesis of imidazo[1,2-a]pyridines via GBB-3CR. b) Att...
Scheme 2: Substrate scope of the HPW-catalyzed GBB reactions using a range of aromatic/heteroaromatic aldehyd...
Scheme 3: Substrate scope of the HPW-catalyzed GBB reaction using aliphatic aldehydes. Reaction conditions: 2...
Scheme 4: Unsuccessful substrates for the HPW-catalyzed GBB-3CR for the synthesis of imidazo[1,2-a]pyridines.
Scheme 5: 10-Fold scale-up of the HPW-catalyzed GBB reaction (5.0 mmol) between 2-aminopyridine (1a), 4-nitro...
Scheme 6: Plausible reaction mechanism for the HPW-catalyzed GBB reaction.
Entry to new spiroheterocycles via tandem Rh(II)-catalyzed O–H insertion/base-promoted cyclization involving diazoarylidene succinimides
- Alexander Yanovich,
- Anastasia Vepreva,
- Ksenia Malkova,
- Grigory Kantin and
- Dmitry Dar’in
Beilstein J. Org. Chem. 2024, 20, 561–569, doi:10.3762/bjoc.20.48
- ], drospirenone (exhibits high affinity to progesterone receptors and is used as a birth control medication) [26][27], griseofulvin (an antifungal agent used to treat fungal infections of the fingernails and toes) [28], as well as oliceridine (a selective G protein-biased μ-opioid receptor agonist used for
Graphical Abstract
Scheme 1: DAS spirocyclizations reported earlier and the synthetic methodology investigated in this work.
Figure 1: Examples of biologically active compounds and natural products based on THF/THP spiro-conjugates wi...
Scheme 2: An initial example on Rh(II)-catalyzed O–H insertion/base-promoted cyclization involving diazo comp...
Scheme 3: Tandem Rh2(esp)2-catalyzed O–H insertion/base-promoted cyclization involving DAS 1 and various prop...
Scheme 4: Tandem Rh2(esp)2-catalyzed O–H insertion/base-promoted cyclization involving DAS 1 and allenic acid...
Scheme 5: Tandem Rh2(esp)2-catalyzed O–H insertion/base-promoted cyclization involving various DAS 1 and 3-br...
Scheme 6: Tandem Rh2(esp)2-catalyzed O–H insertion/base-promoted cyclization involving DAS 1 and 2-(bromometh...
Scheme 7: Examples where a target spirocyclic product was not observed.
Scheme 8: Plausible mechanism of the transformations studied.
Green and sustainable approaches for the Friedel–Crafts reaction between aldehydes and indoles
- Periklis X. Kolagkis,
- Eirini M. Galathri and
- Christoforos G. Kokotos
Beilstein J. Org. Chem. 2024, 20, 379–426, doi:10.3762/bjoc.20.36
- general extends to other types of cancers as well, such as prostate cancer by being an androgen receptor (AR) agonist in LNCaP prostate cancer cells [6]. DIM controls cell growth rates in AR-negative cells, while also targeting the mitochondria inducing apoptosis, which alleviates some of the symptoms of
Graphical Abstract
Scheme 1: Examples of BIMs used for their medicinal properties.
Scheme 2: Mechanisms for the synthesis of BIMs using protic or Lewis acids as catalysts.
Scheme 3: Synthesis of bis(indolyl)methanes using DBDMH.
Scheme 4: Competition experiments and synthesis of bis(indolyl)methanes using DBDMH.
Scheme 5: Proposed mechanism for formation of BIM of using DBDMH.
Scheme 6: Synthesis of bis(indolyl)methanes using I2.
Scheme 7: General reaction mechanism upon halogen bonding.
Scheme 8: Synthesis of bis(indolyl)methanes using I2, introduced by Ji.
Scheme 9: Synthesis of bis(indolyl)methanes using Br2 in CH3CN.
Scheme 10: Βidentate halogen-bond donors.
Scheme 11: Synthesis of bis(indolyl)methanes using bidentate halogen-bond donor 26.
Scheme 12: Proposed reaction mechanism.
Scheme 13: Synthesis of bis(indolyl)methanes using iodoalkyne as catalyst.
Scheme 14: Proposed reaction mechanism.
Scheme 15: Optimized reaction conditions used by Ramshini.
Scheme 16: Activation of the carbonyl group by HPA/TPI-Fe3O4.
Scheme 17: Synthesis of BIMs in the presence of nanoAg-Pt/SiO2-doped silicate.
Scheme 18: Mechanism of action proposed by Khalafi-Nezhad et al.
Scheme 19: Activation of the carbonyl group by the Cu–isatin Schiff base complex.
Scheme 20: Optimum reaction conditions published by Jain.
Scheme 21: Organocatalytic protocol utilizing nanoparticles introduced by Bankar.
Scheme 22: Activation of the carbonyl group by the AlCl3·6H2O-SDS-SiO2 complex.
Scheme 23: Optimal reaction conditions for the aforementioned nano-Fe3O4 based catalysts.
Scheme 24: Nanocatalytic protocol proposed by Kaur et al.
Scheme 25: Microwave approach introduced by Yuan.
Scheme 26: Microwave approach introduced by Zahran et al.
Scheme 27: Microwave irradiation protocol introduced by Bindu.
Scheme 28: Silica-supported microwave irradiation protocol.
Scheme 29: Proposed mechanism for formation of BIM by Nongkhlaw.
Scheme 30: Microwave-assisted synthesis of BIMs catalyzed by succinic acid.
Scheme 31: Proposed mechanism of action of MMO-4.
Scheme 32: Catalytic approach introduced by Muhammadpoor-Baltork et al.
Scheme 33: Reaction conditions used by Xiao-Ming.
Scheme 34: Ultrasonic irradiation-based protocol published by Saeednia.
Scheme 35: Pyruvic acid-mediated synthesis of BIMs proposed by Thopate.
Scheme 36: Synthesis of BIMs using [bmim]BF4 or [bmim]PF6 ionic liquids.
Scheme 37: Synthesis of BIMs utilizing In(OTf)3 in octylmethylimidazolium hexafluorophosphate as ionic liquid.
Scheme 38: FeCl3·6H2O-catalyzed synthesis of BIMs with use of ionic liquid.
Scheme 39: Synthesis of BIMs utilizing the [hmim]HSO4/EtOH catalytic system.
Scheme 40: Synthesis of BIMs utilizing acidic ionic liquid immobilized on silica gel (ILIS-SO2Cl).
Scheme 41: The [bmim][MeSO4]-catalyzed reaction of indole with various aldehydes.
Scheme 42: The role of [bmim][MeSO4] in catalyzing the reaction of indole with aldehydes.
Scheme 43: Synthesis of BIMs utilizing FeCl3-based ionic liquid ([BTBAC]Cl-FeCl3) as catalyst.
Scheme 44: Synthesis of BIMs using [Msim]Cl at room temperature.
Scheme 45: [Et3NH][H2PO4]-catalyzed synthesis of bis(indolyl)methanes.
Scheme 46: PILs-catalyzed synthesis of bis(indolyl)methanes.
Scheme 47: FSILs-mediated synthesis of bis(indolyl)methanes.
Scheme 48: Possible “release and catch” catalytic process.
Scheme 49: Synthesis of bis(indolyl)methanes by [DABCO-H][HSO4].
Scheme 50: Synthesis of bis(indolyl)methanes by [(THA)(SO4)].
Scheme 51: Synthesis of BBSI-Cl and BBSI-HSO4.
Scheme 52: Synthesis of BIMs in the presence of BBSI-Cl and BBSI-HSO4.
Scheme 53: Chemoselectivity of the present method.
Scheme 54: Synthesis of BIMs catalyzed by chitosan-supported ionic liquid.
Scheme 55: Proposed mechanism of action of CSIL.
Scheme 56: Optimization of the reaction in DESs.
Scheme 57: Synthesis of BIMs using ChCl/SnCl2 as DES.
Scheme 58: Synthesis of BIMs derivatives in presence of DES.
Scheme 59: BIMs synthesis in choline chloride/urea (CC/U).
Scheme 60: Flow chemistry-based synthesis of BIMs by Ley.
Scheme 61: Flow chemistry-based synthesis of BIMs proposed by Nam et al.
Scheme 62: Amino-catalyzed reaction of indole with propionaldehyde.
Scheme 63: Aminocatalytic synthesis of BIMs.
Scheme 64: Proposed mechanism for the aminocatalytic synthesis of BIMs.
Scheme 65: Enzymatic reaction of indole with aldehydes.
Scheme 66: Proposed mechanism for the synthesis of BIMs catalyzed by TLIM.
Scheme 67: Proposed reaction mechanism by Badsara.
Scheme 68: Mechanism proposed by D’Auria.
Scheme 69: Photoinduced thiourea catalysis.
Scheme 70: Proposed mechanism of photoacid activation.
Scheme 71: Proposed mechanism of action for CF3SO2Na.
Scheme 72: Proposed mechanism for the synthesis of BIMs by Mandawad.
Scheme 73: Proposed mechanism for the (a) acid generation and (b) synthesis of BIMs.
Scheme 74: a) Reaction conditions employed by Khaksar and b) activation of the carbonyl group by HFIP.
Scheme 75: Activation of the carbonyl group by the PPy@CH2Br through the formation of a halogen bond.
Scheme 76: Reaction conditions utilized by Mhaldar et al.
Scheme 77: a) Reaction conditions employed by López and b) activation of the carbonyl group by thiourea.
Scheme 78: Infrared irradiation approach introduced by Luna-Mora and his research group.
Scheme 79: Synthesis of BIMs with the use of the Fe–Zn BMOF.
Synthesis of tetrahydrofuro[3,2-c]pyridines via Pictet–Spengler reaction
- Elena Y. Mendogralo and
- Maxim G. Uchuskin
Beilstein J. Org. Chem. 2023, 19, 991–997, doi:10.3762/bjoc.19.74
- -opioid receptor agonist and exhibits excellent antinociceptive activity [2]. Lactam C possesses potent antituberculosis activity and excellent selectivity to Mycobacterium tuberculosis strain H37Rv [3]. Araliopsine (D) was isolated from the fruits of Zanthoxylum simulans [4]. Benzofuran E is a potent and
Graphical Abstract
Figure 1: Examples of natural and bioactive hydrogenated furo[3,2-c]pyridines.
Scheme 1: The described approaches to tetrahydrofuro[3,2-c]pyridines and our work.
Scheme 2: The synthesis of tetrahydrofuro[3,2-c]pyridines 4. Conditions: athe reaction was performed at 1 mmo...
Scheme 3: The acid-catalyzed reversible transformation of tetrahydrofuro[3,2-c]pyridine 4a and 3-(2-oxopropyl...
Scheme 4: Synthesis of tetrahydropyrrolo[3,2-c]pyridine 6a.
Scheme 5: Reactivity of tetrahydrofuro[3,2-c]pyridine 4a.
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
- the last two decades owing to their applicability in biological and pharmaceutical fields [9][10]. For example, butyl (2-phenylethynyl)selenide (I, Figure 1) has an antinociceptive effect on the formalin test in mice [11], selanyl acetylenic retinoids II show an RAR agonist activity [12], and bis
Graphical Abstract
Figure 1: Biologically active selenides having alkynyl or imidazopyridinyl groups.
Figure 2: (a) ORTEP drawing of 4aa and (b) its stacking structure.
Scheme 1: Control reactions.
Figure 3: Proposed mechanism.
Scheme 2: Transformation from 4aa.
Regioselectivity of the SEAr-based cyclizations and SEAr-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
- stereochemistry in the Ir-catalyzed allylic substitution reactions. In 2016, Billingsley and co-workers disclosed the total synthesis of (−)-indolactam V (6), a nanomolar agonist of protein kinase C (Scheme 3) [12]. The authors applied an intramolecular SEAr reaction of 4-substituted indole derivative to
Graphical Abstract
Scheme 1: SEAr-based, CAr–C bond-forming cyclization or annulation of: (A) substituted arenes/heteroarenes an...
Scheme 2: Indole C3 regioselective intramolecular alkylation of indolyl allyl carbonates.
Scheme 3: Indole C3 regioselective Michael-type cyclization in the total synthesis of (−)-indolactam V.
Scheme 4: Synthesis of azepino[4,3,2-cd]indoles via indole C3 regioselective aza-Michael addition/cyclization...
Scheme 5: Indole C3 regioselective Pictet−Spengler reaction of 2-(1H-indol-4-yl)ethanamines.
Scheme 6: Indole C3 regioselective hydroindolation of cis-β-(α′,α′-dimethyl)-4′-methindolylstyrenes.
Scheme 7: Indole C3 regioselective cyclization leading to the formation of polycyclic azepino[5,4,3-cd]indole...
Scheme 8: Synthesis of azepino[3,4,5-cd]indoles via iridium-catalyzed asymmetric [4 + 3] cycloaddition of rac...
Scheme 9: Aldimine condensation/1,6-hydride transfer/Mannich-type cyclization cascade of indole-derived pheny...
Scheme 10: Indole C5 regioselective intramolecular FC acylation of 4-substituted indoles.
Scheme 11: Catalyst-dependent regioselectivity switching in the cyclization of ethyl 2-diazo-4-(4-indolyl)-3-o...
Scheme 12: Indole C5 regioselective cyclization of α-carbonyl sulfoxonium ylides.
Scheme 13: Indole C5 regioselective cyclization of an indole-tethered donor–acceptor cyclopropane.
Scheme 14: Indole C5 regioselective epoxide–arene cyclization.
On the application of 3d metals for C–H activation toward bioactive compounds: The key step for the synthesis of silver bullets
- Renato L. Carvalho,
- Amanda S. de Miranda,
- Mateus P. Nunes,
- Roberto S. Gomes,
- Guilherme A. M. Jardim and
- Eufrânio N. da Silva Júnior
Beilstein J. Org. Chem. 2021, 17, 1849–1938, doi:10.3762/bjoc.17.126
- retinoic acid receptor agonist analogue 63 and an estrone acetate derivative 64 (Scheme 22D). A seminal work involving manganese-catalyzed C–H organic electrosynthesis and photoredox catalysis was reported in the same year by Lei and co-workers, also regarding the azidation of alkyl scaffolds (Scheme 23A
Graphical Abstract
Scheme 1: Schematic overview of transition metals studied in C–H activation processes.
Scheme 2: (A) Known biological activities related to benzimidazole-based compounds; (B and C) an example of a...
Scheme 3: (A) Known biological activities related to quinoline-based compounds; (B and C) an example of a sca...
Scheme 4: (A) Known biological activities related to sulfur-containing compounds; (B and C) an example of a s...
Scheme 5: (A) Known biological activities related to aminoindane derivatives; (B and C) an example of a scand...
Scheme 6: (A) Known biological activities related to norbornane derivatives; (B and C) an example of a scandi...
Scheme 7: (A) Known biological activities related to aniline derivatives; (B and C) an example of a titanium-...
Scheme 8: (A) Known biological activities related to cyclohexylamine derivatives; (B) an example of an intram...
Scheme 9: (A) Known biologically active benzophenone derivatives; (B and C) photocatalytic oxidation of benzy...
Scheme 10: (A) Known bioactive fluorine-containing compounds; (B and C) vanadium-mediated C(sp3)–H fluorinatio...
Scheme 11: (A) Known biologically active Lythraceae alkaloids; (B) synthesis of (±)-decinine (30).
Scheme 12: (A) Synthesis of (R)- and (S)-boehmeriasin (31); (B) synthesis of phenanthroindolizidines by vanadi...
Scheme 13: (A) Known bioactive BINOL derivatives; (B and C) vanadium-mediated oxidative coupling of 2-naphthol...
Scheme 14: (A) Known antiplasmodial imidazopyridazines; (B) practical synthesis of 41.
Scheme 15: (A) Gold-catalyzed drug-release mechanism using 2-alkynylbenzamides; (B and C) chromium-mediated al...
Scheme 16: (A) Examples of anti-inflammatory benzaldehyde derivatives; (B and C) chromium-mediated difunctiona...
Scheme 17: (A and B) Manganese-catalyzed chemoselective intramolecular C(sp3)–H amination; (C) late-stage modi...
Scheme 18: (A and B) Manganese-catalyzed C(sp3)–H amination; (C) late-stage modification of a leelamine deriva...
Scheme 19: (A) Known bioactive compounds containing substituted N-heterocycles; (B and C) manganese-catalyzed ...
Scheme 20: (A) Known indoles that present GPR40 full agonist activity; (B and C) manganese-catalyzed C–H alkyl...
Scheme 21: (A) Examples of known biaryl-containing drugs; (B and C) manganese-catalyzed C–H arylation through ...
Scheme 22: (A) Known zidovudine derivatives with potent anti-HIV properties; (B and C) manganese-catalyzed C–H...
Scheme 23: (A and B) Manganese-catalyzed C–H organic photo-electrosynthesis; (C) late-stage modification.
Scheme 24: (A) Example of a known antibacterial silylated dendrimer; (B and C) manganese-catalyzed C–H silylat...
Scheme 25: (A and B) Fe-based small molecule catalyst applied for selective aliphatic C–H oxidations; (C) late...
Scheme 26: (A) Examples of naturally occurring gracilioethers; (B) the first total synthesis of gracilioether ...
Scheme 27: (A and B) Selective aliphatic C–H oxidation of amino acids; (C) late-stage modification of proline-...
Scheme 28: (A) Examples of Illicium sesquiterpenes; (B) first chemical synthesis of (+)-pseudoanisatin (80) in...
Scheme 29: (A and B) Fe-catalyzed deuteration; (C) late-stage modification of pharmaceuticals.
Scheme 30: (A and B) Biomimetic Fe-catalyzed aerobic oxidation of methylarenes to benzaldehydes (PMHS, polymet...
Scheme 31: (A) Known tetrahydroquinolines with potential biological activities; (B and C) redox-selective Fe c...
Scheme 32: (A) Known drugs containing a benzofuran unit; (B and C) Fe/Cu-catalyzed tandem O-arylation to acces...
Scheme 33: (A) Known azaindolines that act as M4 muscarinic acetylcholine receptor agonists; (B and C) intramo...
Scheme 34: (A) Known indolinones with anticholinesterase activity; (B and C) oxidative C(sp3)–H cross coupling...
Scheme 35: (A and B) Cobalt-catalyzed C–H alkenylation of C-3-peptide-containing indoles; (C) derivatization b...
Scheme 36: (A) Cobalt-Cp*-catalyzed C–H methylation of known drugs; (B and C) scope of the o-methylated deriva...
Scheme 37: (A) Known lasalocid A analogues; (B and C) three-component cobalt-catalyzed C–H bond addition; (D) ...
Scheme 38: (A and B) Cobalt-catalyzed C(sp2)–H amidation of thiostrepton.
Scheme 39: (A) Known 4H-benzo[d][1,3]oxazin-4-one derivatives with hypolipidemic activity; (B and C) cobalt-ca...
Scheme 40: (A and B) Cobalt-catalyzed C–H arylation of pyrrole derivatives; (C) application for the synthesis ...
Scheme 41: (A) Known 2-phenoxypyridine derivatives with potent herbicidal activity; (B and C) cobalt-catalyzed...
Scheme 42: (A) Natural cinnamic acid derivatives; (B and C) cobalt-catalyzed C–H carboxylation of terminal alk...
Scheme 43: (A and B) Cobalt-catalyzed C–H borylation; (C) application to the synthesis of flurbiprofen.
Scheme 44: (A) Benzothiazoles known to present anticonvulsant activities; (B and C) cobalt/ruthenium-catalyzed...
Scheme 45: (A and B) Cobalt-catalyzed oxygenation of methylene groups towards ketone synthesis; (C) synthesis ...
Scheme 46: (A) Known anticancer tetralone derivatives; (B and C) cobalt-catalyzed C–H difluoroalkylation of ar...
Scheme 47: (A and B) Cobalt-catalyzed C–H thiolation; (C) application in the synthesis of quetiapine (153).
Scheme 48: (A) Known benzoxazole derivatives with anticancer, antifungal, and antibacterial activities; (B and...
Scheme 49: (A and B) Cobalt-catalyzed C–H carbonylation of naphthylamides; (C) BET inhibitors 158 and 159 tota...
Scheme 50: (A) Known bioactive pyrrolo[1,2-a]quinoxalin-4(5H)-one derivatives; (B and C) cobalt-catalyzed C–H ...
Scheme 51: (A) Known antibacterial cyclic sulfonamides; (B and C) cobalt-catalyzed C–H amination of propargyli...
Scheme 52: (A and B) Cobalt-catalyzed intramolecular 1,5-C(sp3)–H amination; (C) late-stage functionalization ...
Scheme 53: (A and B) Cobalt-catalyzed C–H/C–H cross-coupling between benzamides and oximes; (C) late-state syn...
Scheme 54: (A) Known anticancer natural isoquinoline derivatives; (B and C) cobalt-catalyzed C(sp2)–H annulati...
Scheme 55: (A) Enantioselective intramolecular nickel-catalyzed C–H activation; (B) bioactive obtained motifs;...
Scheme 56: (A and B) Nickel-catalyzed α-C(sp3)–H arylation of ketones; (C) application of the method using kno...
Scheme 57: (A and B) Nickel-catalyzed C(sp3)–H acylation of pyrrolidine derivatives; (C) exploring the use of ...
Scheme 58: (A) Nickel-catalyzed C(sp3)–H arylation of dioxolane; (B) library of products obtained from biologi...
Scheme 59: (A) Intramolecular enantioselective nickel-catalyzed C–H cycloalkylation; (B) product examples, inc...
Scheme 60: (A and B) Nickel-catalyzed C–H deoxy-arylation of azole derivatives; (C) late-stage functionalizati...
Scheme 61: (A and B) Nickel-catalyzed decarbonylative C–H arylation of azole derivatives; (C) application of t...
Scheme 62: (A and B) Another important example of nickel-catalyzed C–H arylation of azole derivatives; (C) app...
Scheme 63: (A and B) Another notable example of a nickel-catalyzed C–H arylation of azole derivatives; (C) lat...
Scheme 64: (A and B) Nickel-based metalorganic framework (MOF-74-Ni)-catalyzed C–H arylation of azole derivati...
Scheme 65: (A) Known commercially available benzothiophene-based drugs; (B and C) nickel-catalyzed C–H arylati...
Scheme 66: (A) Known natural tetrahydrofuran-containing substances; (B and C) nickel-catalyzed photoredox C(sp3...
Scheme 67: (A and B) Another notable example of a nickel-catalyzed photoredox C(sp3)–H alkylation/arylation; (...
Scheme 68: (A) Electrochemical/nickel-catalyzed C–H alkoxylation; (B) achieved scope, including three using na...
Scheme 69: (A) Enantioselective photoredox/nickel catalyzed C(sp3)–H arylation; (B) achieved scope, including ...
Scheme 70: (A) Known commercially available trifluoromethylated drugs; (B and C) nickel-catalyzed C–H trifluor...
Scheme 71: (A and B) Stereoselective nickel-catalyzed C–H difluoroalkylation; (C) late-stage functionalization...
Scheme 72: (A) Cu-mediated ortho-amination of oxalamides; (B) achieved scope, including derivatives obtained f...
Scheme 73: (A) Electro-oxidative copper-mediated amination of 8-aminoquinoline-derived amides; (B) achieved sc...
Scheme 74: (A and B) Cu(I)-mediated C–H amination with oximes; (C) derivatization using telmisartan (241) as s...
Scheme 75: (A and B) Cu-mediated amination of aryl amides using ammonia; (C) late-stage modification of proben...
Scheme 76: (A and B) Synthesis of purine nucleoside analogues using copper-mediated C(sp2)–H activation.
Scheme 77: (A) Copper-mediated annulation of acrylamide; (B) achieved scope, including the synthesis of the co...
Scheme 78: (A) Known bioactive compounds containing a naphthyl aryl ether motif; (B and C) copper-mediated eth...
Scheme 79: (A and B) Cu-mediated alkylation of N-oxide-heteroarenes; (C) late-stage modification.
Scheme 80: (A) Cu-mediated cross-dehydrogenative coupling of polyfluoroarenes and alkanes; (B) scope from know...
Scheme 81: (A) Known anticancer acrylonitrile compounds; (B and C) Copper-mediated cyanation of unactivated al...
Scheme 82: (A) Cu-mediated radiofluorination of 8-aminoquinoline-derived aryl amides; (B) achieved scope, incl...
Scheme 83: (A) Examples of natural β-carbolines; (B and C) an example of a zinc-catalyzed C–H functionalizatio...
Scheme 84: (A) Examples of anticancer α-aminophosphonic acid derivatives; (B and C) an example of a zinc-catal...
Sustainable manganese catalysis for late-stage C–H functionalization of bioactive structural motifs
- Jongwoo Son
Beilstein J. Org. Chem. 2021, 17, 1733–1751, doi:10.3762/bjoc.17.122
- , citalopram (17b), an antidepressant, was also reacted under amination conditions involving HBF4, affording product 19b in good yield and excellent diastereoselectivity (dr > 20:1). Other multiple benzylic C–H bond-containing molecules, including a dopamine receptor agonist analogue 17c as well as derivatives
Graphical Abstract
Scheme 1: Mn-catalyzed late-stage fluorination of sclareolide (1) and complex steroid 3.
Figure 1: Proposed reaction mechanism of C–H fluorination by a manganese porphyrin catalyst.
Scheme 2: Late-stage radiofluorination of biologically active complex molecules.
Figure 2: Proposed mechanism of C–H radiofluorination.
Scheme 3: Late-stage C–H azidation of bioactive molecules. a1.5 mol % of Mn(TMP)Cl (5) was used. bMethyl acet...
Figure 3: Proposed reaction mechanism of manganese-catalyzed C–H azidation.
Scheme 4: Mn-catalyzed late-stage C–H azidation of bioactive molecules via electrophotocatalysis. a2.5 mol % ...
Figure 4: Proposed reaction mechanism of electrophotocatalytic azidation.
Scheme 5: Manganaelectro-catalyzed late-stage azidation of bioactive molecules.
Figure 5: Proposed reaction pathway of manganaelectro-catalyzed late-stage C–H azidation.
Scheme 6: Mn-catalyzed late-stage amination of bioactive molecules. a3 Å MS were used. Protonation with HBF4⋅...
Figure 6: Proposed mechanism of manganese-catalyzed C–H amination.
Scheme 7: Mn-catalyzed C–H methylation of heterocyclic scaffolds commonly found in small-molecule drugs. aDAS...
Scheme 8: Examples of late-stage C–H methylation of bioactive molecules. aDAST activation. bFor insoluble sub...
Scheme 9: A) Mn-catalyzed late-stage C–H alkynylation of peptides. B) Intramolecular late-stage alkynylative ...
Figure 7: Proposed reaction mechanism of Mn(I)-catalyzed C–H alkynylation.
Scheme 10: Late-stage Mn-catalyzed C–H allylation of peptides and bioactive motifs.
Scheme 11: Intramolecular C–H allylative cyclic peptide formation.
Scheme 12: Late-stage C–H glycosylation of tryptophan analogues.
Scheme 13: Late-stage C–H glycosylation of tryptophan-containing peptides.
Scheme 14: Late-stage C–H alkenylation of tryptophan-containing peptides.
Scheme 15: A) Late-stage C–H macrocyclization of tryptophan-containing peptides and B) traceless removal of py...
Iodine-catalyzed electrophilic substitution of indoles: Synthesis of (un)symmetrical diindolylmethanes with a quaternary carbon center
- Thanigaimalai Pillaiyar,
- Masoud Sedaghati,
- Andhika B. Mahardhika,
- Lukas L. Wendt and
- Christa E. Müller
Beilstein J. Org. Chem. 2021, 17, 1464–1475, doi:10.3762/bjoc.17.102
- constitutive activity [41]. Compound 3e reduced the basal activity of CB1 receptors (Supporting Information File 1, Figure S2A) but not that of CB2 receptors indicating that this compound acts as an inverse agonist (EC50 0.786 ± 0.233 µM) at CB1 receptors (Supporting Information File 1, Figure S2B). This
- effect was less pronounced for 3ad. Non-transfected cells used as controls also did not show any effect after treatment with 3ad (Supporting Information File 1, Figure S2C). DIM was previously shown to be weak inverse agonist at CB1 receptors which is consistent with our current findings for DIM
Graphical Abstract
Figure 1: Diindolylmethanes and reported biological activities.
Figure 2: Synthetic strategies toward trifluoromethylated unsymmetrical quaternary DIMs.
Figure 3: Reactions performed to study the scope of the method.
Figure 4: Gram-scale synthesis of unsymmetrical DIMs 3a and 3ad.
Figure 5: Plausible reaction mechanism for the synthesis of fluoromethylated unsymmetrical DIMs, shown for co...
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
Graphical Abstract
Figure 1: Representative shares of the global F&F market (2018) segmented on their applications [1].
Figure 2: General structure of an international fragrance company [2].
Figure 3: The Michael Edwards fragrance wheel.
Figure 4: Examples of oriental (1–3), woody (4–7), fresh (8–10), and floral (11 and 12) notes.
Figure 5: A basic depiction of batch vs flow.
Scheme 1: Examples of reactions for which flow processing outperforms batch.
Scheme 2: Some industrially important aldol-based transformations.
Scheme 3: Biphasic continuous aldol reactions of acetone and various aldehydes.
Scheme 4: Aldol synthesis of 43 in flow using LiHMDS as the base.
Scheme 5: A semi-continuous synthesis of doravirine (49) involving a key aldol reaction.
Scheme 6: Enantioselective aldol reaction using 5-(pyrrolidin-2-yl)tetrazole (51) as catalyst in a microreact...
Scheme 7: Gröger's example of asymmetric aldol reaction in aqueous media.
Figure 6: Immobilised reagent column reactor types.
Scheme 8: Photoinduced thiol–ene coupling preparation of silica-supported 5-(pyrrolidin-2-yl)tetrazole 63 and...
Scheme 9: Continuous-flow approach for enantioselective aldol reactions using the supported catalyst 67.
Scheme 10: Ötvös’ employment of a solid-supported peptide aldol catalyst in flow.
Scheme 11: The use of proline tetrazole packed in a column for aldol reaction between cyclohexanone (65) and 2...
Scheme 12: Schematic diagram of an aminosilane-grafted Si-Zr-Ti/PAI-HF reactor for continuous-flow aldol and n...
Scheme 13: Continuous-flow condensation for the synthesis of the intermediate 76 to nabumetone (77) and Microi...
Scheme 14: Synthesis of ψ-Ionone (80) in continuous-flow via aldol condensation between citral (79) and aceton...
Scheme 15: Synthesis of β-methyl-ionones (83) from citral (79) in flow. The steps are separately described, an...
Scheme 16: Continuous-flow synthesis of 85 from 84 described by Gavriilidis et al.
Scheme 17: Continuous-flow scCO2 apparatus for the synthesis of 2-methylpentanal (87) and the self-condensed u...
Scheme 18: Chen’s two-step flow synthesis of coumarin (90).
Scheme 19: Pechmann condensation for the synthesis of 7-hydroxyxcoumarin (93) in flow. The setup extended to c...
Scheme 20: Synthesis of the dihydrojasmonate 35 exploiting nitro derivative proposed by Ballini et al.
Scheme 21: Silica-supported amines as heterogeneous catalyst for nitroaldol condensation in flow.
Scheme 22: Flow apparatus for the nitroaldol condensation of p-hydroxybenzaldehyde (102) to nitrostyrene 103 a...
Scheme 23: Nitroaldol reaction of 64 to 105 employing a quaternary ammonium functionalised PANF.
Scheme 24: Enantioselective nitroaldol condensation for the synthesis of 108 under flow conditions.
Scheme 25: Enatioselective synthesis of 1,2-aminoalcohol 110 via a copper-catalysed nitroaldol condensation.
Scheme 26: Examples of Knoevenagel condensations applied for fragrance components.
Scheme 27: Flow apparatus for Knoevenagel condensation described in 1989 by Venturello et al.
Scheme 28: Knoevenagel reaction using a coated multichannel membrane microreactor.
Scheme 29: Continuous-flow apparatus for Knoevenagel condensation employing sugar cane bagasse as support deve...
Scheme 30: Knoevenagel reaction for the synthesis of 131–135 in flow using an amine-functionalised silica gel. ...
Scheme 31: Continuous-flow synthesis of compound 137, a key intermediate for the synthesis of pregabalin (138)...
Scheme 32: Continuous solvent-free apparatus applied for the synthesis of compounds 140–143 using a TSE. Throu...
Scheme 33: Lewis et al. developed a spinning disc reactor for Darzens condensation of 144 and a ketone to furn...
Scheme 34: Some key industrial applications of conjugate additions in the F&F industry.
Scheme 35: Continuous-flow synthesis of 4-(2-hydroxyethyl)thiomorpholine 1,1-dioxide (156) via double conjugat...
Scheme 36: Continuous-flow system for Michael addition using CsF on alumina as the catalyst.
Scheme 37: Calcium chloride-catalysed asymmetric Michael addition using an immobilised chiral ligand.
Scheme 38: Continuous multistep synthesis for the preparation of (R)-rolipram (173). Si-NH2: primary amine-fun...
Scheme 39: Continuous-flow Michael addition using ion exchange resin Amberlyst® A26.
Scheme 40: Preparation of the heterogeneous catalyst 181 developed by Paixão et al. exploiting Ugi multicompon...
Scheme 41: Continuous-flow system developed by the Paixão’s group for the preparation of Michael asymmetric ad...
Scheme 42: Continuous-flow synthesis of nitroaldols catalysed by supported catalyst 184 developed by Wennemers...
Scheme 43: Heterogenous polystyrene-supported catalysts developed by Pericàs and co-workers.
Scheme 44: PANF-supported pyrrolidine catalyst for the conjugate addition of cyclohexanone (65) and trans-β-ni...
Scheme 45: Synthesis of (−)-paroxetine precursor 195 developed by Ötvös, Pericàs, and Kappe.
Scheme 46: Continuous-flow approach for the 5-step synthesis of (−)-oseltamivir (201) as devised by Hayashi an...
Scheme 47: Continuous-flow enzyme-catalysed Michael addition.
Scheme 48: Continuous-flow copper-catalysed 1,4 conjugate addition of Grignard reagents to enones. Reprinted w...
Scheme 49: A collection of commonly encountered hydrogenation reactions.
Figure 7: The ThalesNano H-Cube® continuous-flow hydrogenator.
Scheme 50: Chemoselective reduction of an α,β-unsaturated ketone using the H-Cube® reactor.
Scheme 51: Incorporation of Lindlar’s catalyst into the H-Cube® reactor for the reduction of an alkyne.
Scheme 52: Continuous-flow semi-hydrogenation of alkyne 208 to 209 using SACs with H-Cube® system.
Figure 8: The standard setups for tube-in-tube gas–liquid reactor units.
Scheme 53: Homogeneous hydrogenation of olefins using a tube-in-tube reactor setup.
Scheme 54: Recyclable heterogeneous flow hydrogenation system.
Scheme 55: Leadbeater’s reverse tube-in-tube hydrogenation system for olefin reductions.
Scheme 56: a) Hydrogenation using a Pd-immobilised microchannel reactor (MCR) and b) a representation of the i...
Scheme 57: Hydrogenation of alkyne 238 exploiting segmented flow in a Pd-immobilised capillary reactor.
Scheme 58: Continuous hydrogenation system for the preparation of cyrene (241) from (−)-levoglucosenone (240).
Scheme 59: Continuous hydrogenation system based on CSMs developed by Hornung et al.
Scheme 60: Chemoselective reduction of carbonyls (ketones over aldehydes) in flow.
Scheme 61: Continuous system for the semi-hydrogenation of 256 and 258, developed by Galarneau et al.
Scheme 62: Continuous synthesis of biodiesel fuel 261 from lignin-derived furfural acetone (260).
Scheme 63: Continuous synthesis of γ-valerolacetone (263) via CTH developed by Pineda et al.
Scheme 64: Continuous hydrogenation of lignin-derived biomass (products 265, 266, and 267) using a sustainable...
Scheme 65: Ru/C or Rh/C-catalysed hydrogenation of arene in flow as developed by Sajiki et al.
Scheme 66: Polysilane-immobilized Rh–Pt-catalysed hydrogenation of arenes in flow by Kobayashi et al.
Scheme 67: High-pressure in-line mixing of H2 for the asymmetric reduction of 278 at pilot scale with a 73 L p...
Figure 9: Picture of the PFR employed at Eli Lilly & Co. for the continuous hydrogenation of 278 [287]. Reprinted ...
Scheme 68: Continuous-flow asymmetric hydrogenation using Oppolzer's sultam 280 as chiral auxiliary.
Scheme 69: Some examples of industrially important oxidation reactions in the F&F industry. CFL: compact fluor...
Scheme 70: Gold-catalysed heterogeneous oxidation of alcohols in flow.
Scheme 71: Uozumi’s ARP-Pt flow oxidation protocol.
Scheme 72: High-throughput screening of aldehyde oxidation in flow using an in-line GC.
Scheme 73: Permanganate-mediated Nef oxidation of nitroalkanes in flow with the use of in-line sonication to p...
Scheme 74: Continuous-flow aerobic anti-Markovnikov Wacker oxidation.
Scheme 75: Continuous-flow oxidation of 2-benzylpyridine (312) using air as the oxidant.
Scheme 76: Continuous-flow photo-oxygenation of monoterpenes.
Scheme 77: A tubular reactor design for flow photo-oxygenation.
Scheme 78: Glucose oxidase (GOx)-mediated continuous oxidation of glucose using compressed air and the FFMR re...
Scheme 79: Schematic continuous-flow sodium hypochlorite/TEMPO oxidation of alcohols.
Scheme 80: Oxidation using immobilised TEMPO (344) was developed by McQuade et al.
Scheme 81: General protocol for the bleach/catalytic TBAB oxidation of aldehydes and alcohols.
Scheme 82: Continuous-flow PTC-assisted oxidation using hydrogen peroxide. The process was easily scaled up by...
Scheme 83: Continuous-flow epoxidation of cyclohexene (348) and in situ preparation of m-CPBA.
Scheme 84: Continuous-flow epoxidation using DMDO as oxidant.
Scheme 85: Mukayama aerobic epoxidation optimised in flow mode by the Favre-Réguillon group.
Scheme 86: Continuous-flow asymmetric epoxidation of derivatives of 359 exploiting a biomimetic iron catalyst.
Scheme 87: Continuous-flow enzymatic epoxidation of alkenes developed by Watts et al.
Scheme 88: Engineered multichannel microreactor for continuous-flow ozonolysis of 366.
Scheme 89: Continuous-flow synthesis of the vitamin D precursor 368 using multichannel microreactors. MFC: mas...
Scheme 90: Continuous ozonolysis setup used by Kappe et al. for the synthesis of various substrates employing ...
Scheme 91: Continuous-flow apparatus for ozonolysis as developed by Ley et al.
Scheme 92: Continuous-flow ozonolysis for synthesis of vanillin (2) using a film-shear flow reactor.
Scheme 93: Examples of preparative methods for ajoene (386) and allicin (388).
Scheme 94: Continuous-flow oxidation of thioanisole (389) using styrene-based polymer-supported peroxytungstat...
Scheme 95: Continuous oxidation of thiosulfinates using Oxone®-packed reactor.
Scheme 96: Continuous-flow electrochemical oxidation of thioethers.
Scheme 97: Continuous-flow oxidation of 400 to cinnamophenone (235).
Scheme 98: Continuous-flow synthesis of dehydrated material 401 via oxidation of methyl dihydrojasmonate (33).
Scheme 99: Some industrially important transformations involving Grignard reagents.
Scheme 100: Grachev et al. apparatus for continuous preparation of Grignard reagents.
Scheme 101: Example of fluidized Mg bed reactor with NMR spectrometer as on-line monitoring system.
Scheme 102: Continuous-flow synthesis of Grignard reagents and subsequent quenching reaction.
Figure 10: Membrane-based, liquid–liquid separator with integrated pressure control [52]. Adapted with permission ...
Scheme 103: Continuous-flow synthesis of 458, an intermediate to fluconazole (459).
Scheme 104: Continuous-flow synthesis of ketones starting from benzoyl chlorides.
Scheme 105: A Grignard alkylation combining CSTR and PFR technologies with in-line infrared reaction monitoring....
Scheme 106: Continuous-flow preparation of 469 from Grignard addition of methylmagnesium bromide.
Scheme 107: Continuous-flow synthesis of Grignard reagents 471.
Scheme 108: Preparation of the Grignard reagent 471 using CSTR and the continuous process for synthesis of the ...
Scheme 109: Continuous process for carboxylation of Grignard reagents in flow using tube-in-tube technology.
Scheme 110: Continuous synthesis of propargylic alcohols via ethynyl-Grignard reagent.
Scheme 111: Silica-supported catalysed enantioselective arylation of aldehydes using Grignard reagents in flow ...
Scheme 112: Acid-catalysed rearrangement of citral and dehydrolinalool derivatives.
Scheme 113: Continuous stilbene isomerisation with continuous recycling of photoredox catalyst.
Scheme 114: Continuous-flow synthesis of compound 494 as developed by Ley et al.
Scheme 115: Selected industrial applications of DA reaction.
Scheme 116: Multistep flow synthesis of the spirocyclic structure 505 via employing DA cycloaddition.
Scheme 117: Continuous-flow DA reaction developed in a plater flow reactor for the preparation of the adduct 508...
Scheme 118: Continuous-flow DA reaction using a silica-supported imidazolidinone organocatalyst.
Scheme 119: Batch vs flow for the DA reaction of (cyclohexa-1,5-dien-1-yloxy)trimethylsilane (513) with acrylon...
Scheme 120: Continuous-flow DA reaction between 510 and 515 using a shell-core droplet system.
Scheme 121: Continuous-flow synthesis of bicyclic systems from benzyne precursors.
Scheme 122: Continuous-flow synthesis of bicyclic scaffolds 527 and 528 for further development of potential ph...
Scheme 123: Continuous-flow inverse-electron hetero-DA reaction to pyridine derivatives such as 531.
Scheme 124: Comparison between batch and flow for the synthesis of pyrimidinones 532–536 via retro-DA reaction ...
Scheme 125: Continuous-flow coupled with ultrasonic system for preparation of ʟ-ascorbic acid derivatives 539 d...
Scheme 126: Two-step continuous-flow synthesis of triazole 543.
Scheme 127: Continuous-flow preparation of triazoles via CuAAC employing 546-based heterogeneous catalyst.
Scheme 128: Continuous-flow synthesis of compounds 558 through A3-coupling and 560 via AgAAC both employing the...
Scheme 129: Continuous-flow photoinduced [2 + 2] cycloaddition for the preparation of bicyclic derivatives of 5...
Scheme 130: Continuous-flow [2 + 2] and [5 + 2] cycloaddition on large scale employing a flow reactor developed...
Scheme 131: Continuous-flow preparation of the tricyclic structures 573 and 574 starting from pyrrole 570 via [...
Scheme 132: Continuous-flow [2 + 2] photocyclization of cinnamates.
Scheme 133: Continuous-flow preparation of cyclobutane 580 on a 5-plates photoreactor.
Scheme 134: Continuous-flow [2 + 2] photocycloaddition under white LED lamp using heterogeneous PCN as photocat...
Figure 11: Picture of the parallel tube flow reactor (PTFR) "The Firefly" developed by Booker-Milburn et al. a...
Scheme 135: Continuous-flow acid-catalysed [2 + 2] cycloaddition between silyl enol ethers and acrylic esters.
Scheme 136: Continuous synthesis of lactam 602 using glass column reactors.
Scheme 137: In situ generation of ketenes for the Staudinger lactam synthesis developed by Ley and Hafner.
Scheme 138: Application of [2 + 2 + 2] cycloadditions in flow employed by Ley et al.
Scheme 139: Examples of FC reactions applied in F&F industry.
Scheme 140: Continuous-flow synthesis of ibuprofen developed by McQuade et al.
Scheme 141: The FC acylation step of Jamison’s three-step ibuprofen synthesis.
Scheme 142: Synthesis of naphthalene derivative 629 via FC acylation in microreactors.
Scheme 143: Flow system for rapid screening of catalysts and reaction conditions developed by Weber et al.
Scheme 144: Continuous-flow system developed by Buorne, Muller et al. for DSD optimisation of the FC acylation ...
Scheme 145: Continuous-flow FC acylation of alkynes to yield β-chlorovinyl ketones such as 638.
Scheme 146: Continuous-flow synthesis of tonalide (619) developed by Wang et al.
Scheme 147: Continuous-flow preparation of acylated arene such as 290 employing Zr4+-β-zeolite developed by Kob...
Scheme 148: Flow system applied on an Aza-FC reaction catalysed by the thiourea catalyst 648.
Scheme 149: Continuous hydroformylation in scCO2.
Scheme 150: Two-step flow synthesis of aldehyde 655 through a sequential Heck reaction and subsequent hydroform...
Scheme 151: Single-droplet (above) and continuous (below) flow reactors developed by Abolhasani et al. for the ...
Scheme 152: Continuous hydroformylation of 1-dodecene (655) using a PFR-CSTR system developed by Sundmacher et ...
Scheme 153: Continuous-flow synthesis of the aldehyde 660 developed by Eli Lilly & Co. [32]. Adapted with permissio...
Scheme 154: Continuous asymmetric hydroformylation employing heterogenous catalst supported on carbon-based sup...
Scheme 155: Examples of acetylation in F&F industry: synthesis of bornyl (S,R,S-664) and isobornyl (S,S,S-664) ...
Scheme 156: Continuous-flow preparation of bornyl acetate (S,R,S-664) employing the oscillating flow reactor.
Scheme 157: Continuous-flow synthesis of geranyl acetate (666) from acetylation of geraniol (343) developed by ...
Scheme 158: 12-Ttungstosilicic acid-supported silica monolith-catalysed acetylation in flow.
Scheme 159: Continuous-flow preparation of cyclopentenone 676.
Scheme 160: Two-stage synthesis of coumarin (90) via acetylation of salicylaldehyde (88).
Scheme 161: Intensification process for acetylation of 5-methoxytryptamine (677) to melatonin (678) developed b...
Scheme 162: Examples of macrocyclic musky odorants both natural (679–681) and synthetic (682 and 683).
Scheme 163: Flow setup combined with microwave for the synthesis of macrocycle 686 via RCM.
Scheme 164: Continuous synthesis of 2,5-dihydro-1H-pyrroles via ring-closing metathesis.
Scheme 165: Continuous-flow metathesis of 485 developed by Leadbeater et al.
Figure 12: Comparison between RCM performed using different routes for the preparation of 696. On the left the...
Scheme 166: Continuous-flow RCM of 697 employed the solid-supported catalyst 698 developed by Grela, Kirschning...
Scheme 167: Continuous-flow RORCM of cyclooctene employing the silica-absorbed catalyst 700.
Scheme 168: Continuous-flow self-metathesis of methyl oleate (703) employing SILP catalyst 704.
Scheme 169: Flow apparatus for the RCM of 697 using a nanofiltration membrane for the recovery and reuse of the...
Scheme 170: Comparison of loadings between RCMs performed with different routes for the synthesis of 709.
Stereoselective synthesis and transformation of pinane-based 2-amino-1,3-diols
- Ákos Bajtel,
- Mounir Raji,
- Matti Haukka,
- Ferenc Fülöp and
- Zsolt Szakonyi
Beilstein J. Org. Chem. 2021, 17, 983–990, doi:10.3762/bjoc.17.80
- very good agonist for the S1P1 receptor (Figure 1). Sphingosine 1-phosphate (S1P, 4), in turn, performed critical regulator functions in many physiological and pathological treatments, such as Alzheimer’s disease [8][9], cancer [10][11][12][13], multiple sclerosis [14], and inflammation [15]. Due to
Graphical Abstract
Figure 1: Biologically active 2-amino-1,3-diols.
Scheme 1: Stereoselective synthesis of the pinane-fused oxazolidin-2-one 9.
Figure 2: NOESY experiments and X-ray structure elucidation of oxazolidin-2-one 9.
Scheme 2: Stereoselective synthesis of the pinane spiro-fused oxazolidin-2-one 12.
Scheme 3: Parallel synthesis of 2-amino-1,3-diols.
Scheme 4: Synthesis of N-benzyl-2-amino-1,3-diol 16.
Scheme 5: Synthesis of 2-amino-1,3-diols.
Figure 3: NOESY experiments and X-ray structure proofment of the structure of oxazolidine 17.
Scheme 6: Synthesis of 2-phenyliminooxazolidines.
Figure 4: Proposed pathway for the ring–ring tautomerism.
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
- -β2AR, changes in the NMR signals monitored within different helices of the protein revealed that agonist binding primarily shifted the equilibrium towards the G protein-specific active state of helix VI. In contrast, β-arrestin-biased ligands predominantly affected the conformation of specifically
Graphical Abstract
Figure 1: Selected examples of 19F-labelled amino acid analogues used as probes in chemical biology.
Figure 2: (a) Sequences of the antimicrobial peptide MSI-78 and pFtBSer-containing analogs and cartoon repres...
Figure 3: (a) Chemical structures of a selection of trifluoromethyl tags. (b) Comparative analysis showing th...
Figure 4: (a) First bromodomain of Brd4 with all three tryptophan residues displayed in blue and labelled by ...
Figure 5: (a) Enzymatic hydroxylation of GBBNF in the presence of hBBOX (b) 19F NMR spectra showing the conve...
Figure 6: (a) In-cell enzymatic hydrolysis of the fluorinated anandamide analogue ARN1203 catalyzed by hFAAH....
Figure 7: (a) X-ray crystal structure of CAM highlighting the location the phenylalanine residues replaced by...
Figure 8: 19F PREs of 4-F, 5-F, 6-F, 7-FTrp49 containing MTSL-modified S52CCV-N. The 19F NMR resonances of ox...
Figure 9: 19F NMR as a direct probe of Ud NS1A ED homodimerization. Schematic representation showing the loca...
Figure 10: (a) Representative spectrum of a 182 μM sample of Aβ1-40-tfM35 at varying times indicating the majo...
Figure 11: Illustration of the conformational switch induced by SDS in 4-tfmF-labelled α-Syn. Also shown are t...
Figure 12: (a) Structural models of the Myc‐Max (left), Myc‐Max‐DNA (middle) and Myc‐Max‐BRCA1 complexes (righ...
Figure 13: (a) Side (left) and bottom (right) views of the pentameric apo ELIC X-ray structure (PDB ID: 3RQU) ...
Figure 14: (a) General structure of a selection of recently developed 19F-labelled nucleotides for their use a...
Figure 15: Monitoring biotransformation of the fluorinated pesticide cyhalothrin by the fungus C. elegans. The...
Figure 16: Following the biodegradation of emerging fluorinated pollutants by 19F NMR. The spectra are from cu...
Figure 17: Discovery of new fluorinated natural products by 19F NMR. The spectrum is of the culture supernatan...
Figure 18: Application of 19F NMR to investigate the biosynthesis of nucleocidin. The spectra are from culture...
Figure 19: Detection of new fluorofengycins (indicated by arrows) in culture supernatants of Bacillus sp. CS93...
Figure 20: Measurement of β-galactosidase activity in MCF7 cancer cells expressing lacZ using 19F NMR. The deg...
Figure 21: Detection of ions using 19F NMR. (a) Structure of TF-BAPTA and its 19F iCEST spectra in the presenc...
Figure 22: (a) The ONOO−-mediated decarbonylation of 5-fluoroisatin and 6-fluoroisatin. The selectivity of (b)...
The preparation and properties of 1,1-difluorocyclopropane derivatives
- Kymbat S. Adekenova,
- Peter B. Wyatt and
- Sergazy M. Adekenov
Beilstein J. Org. Chem. 2021, 17, 245–272, doi:10.3762/bjoc.17.25
Graphical Abstract
Scheme 1: Synthesis of 1,1-difluoro-2,3-dimethylcyclopropane (2).
Scheme 2: Cyclopropanation via dehydrohalogenation of chlorodifluoromethane.
Scheme 3: Difluorocyclopropanation of methylstyrene 7 using dibromodifluoromethane and zinc.
Scheme 4: Synthesis of difluorocyclopropanes from the reaction of dibromodifluoromethane and triphenylphosphi...
Scheme 5: Generation of difluorocarbene in a catalytic two-phase system and its addition to tetramethylethyle...
Scheme 6: The reaction of methylstyrene 7 with chlorodifluoromethane (11) in the presence of a tetraarylarson...
Scheme 7: Pyrolysis of sodium chlorodifluoroacetate (12) in refluxing diglyme in the presence of alkene 13.
Scheme 8: Synthesis of boron-substituted gem-difluorocyclopropanes 16.
Scheme 9: Addition of sodium bromodifluoroacetate (17) to alkenes.
Scheme 10: Addition of sodium bromodifluoroacetate (17) to silyloxy-substituted cyclopropanes 20.
Scheme 11: Synthesis of difluorinated nucleosides.
Scheme 12: Addition of butyl acrylate (26) to difluorocarbene generated from TFDA (25).
Scheme 13: Addition of difluorocarbene to propargyl esters 27 and conversion of the difluorocyclopropenes 28 t...
Scheme 14: The generation of difluorocyclopropanes using MDFA 30.
Scheme 15: gem-Difluorocyclopropanation of styrene (32) using difluorocarbene generated from TMSCF3 (31) under...
Scheme 16: Synthesis of a gem-difluorocyclopropane derivative using HFPO (41) as a source of difluorocarbene.
Scheme 17: Cyclopropanation of (Z)-2-butene in the presence of difluorodiazirine (44).
Scheme 18: The cyclopropanation of 1-octene (46) using Seyferth's reagent (45) as a source of difluorocarbene.
Scheme 19: Alternative approaches for the difluorocarbene synthesis from trimethyl(trifluoromethyl)tin (48).
Scheme 20: Difluorocyclopropanation of cyclohexene (49).
Scheme 21: Synthesis of difluorocyclopropane derivative 53 using bis(trifluoromethyl)cadmium (51) as the diflu...
Scheme 22: Addition of difluorocarbene generated from tris(trifluoromethyl)bismuth (54).
Scheme 23: Addition of a stable (trifluoromethyl)zinc reagent to styrenes.
Scheme 24: The preparation of 2,2-difluorocyclopropanecarboxylic acids of type 58.
Scheme 25: Difluorocyclopropanation via Michael cyclization.
Scheme 26: Difluorocyclopropanation using N-acylimidazolidinone 60.
Scheme 27: Difluorocyclopropanation through the cyclization of phenylacetonitrile (61) and 1,2-dibromo-1,1-dif...
Scheme 28: gem-Difluoroolefins 64 for the synthesis of functionalized cyclopropanes 65.
Scheme 29: Preparation of aminocyclopropanes 70.
Scheme 30: Synthesis of fluorinated methylenecyclopropane 74 via selenoxide elimination.
Scheme 31: Reductive dehalogenation of (1R,3R)-75.
Scheme 32: Synthesis of chiral monoacetates by lipase catalysis.
Scheme 33: Transformation of (±)-trans-81 using Rhodococcus sp. AJ270.
Scheme 34: Transformation of (±)-trans-83 using Rhodococcus sp. AJ270.
Scheme 35: Hydrogenation of difluorocyclopropenes through enantioselective hydrocupration.
Scheme 36: Enantioselective transfer hydrogenation of difluorocyclopropenes with a Ru-based catalyst.
Scheme 37: The thermal transformation of trans-1,2-dichloro-3,3-difluorocyclopropane (84).
Scheme 38: cis–trans-Epimerization of 1,1-difluoro-2,3-dimethylcyclopropane.
Scheme 39: 2,2-Difluorotrimethylene diradical intermediate.
Scheme 40: Ring opening of stereoisomers 88 and 89.
Scheme 41: [1,3]-Rearrangement of alkenylcyclopropanes 90–92.
Scheme 42: Thermolytic rearrangement of 2,2-difluoro-1-vinylcyclopropane (90).
Scheme 43: Thermal rearrangement for ethyl 3-(2,2-difluoro)-3-phenylcyclopropyl)acrylates 93 and 95.
Scheme 44: Possible pathways of the ring opening of 1,1-difluoro-2-vinylcyclopropane.
Scheme 45: Equilibrium between 1,1-difluoro-2-methylenecyclopropane (96) and (difluoromethylene)cyclopropane 97...
Scheme 46: Ring opening of substituted 1,1-difluoro-2,2-dimethyl-3-methylenecyclopropane 98.
Scheme 47: 1,1-Difluorospiropentane rearrangement.
Scheme 48: Acetolysis of (2,2-difluorocyclopropyl)methyl tosylate (104) and (1,1-difluoro-2-methylcyclopropyl)...
Scheme 49: Ring opening of gem-difluorocyclopropyl ketones 106 and 108 by thiolate nucleophiles.
Scheme 50: Hydrolysis of gem-difluorocyclopropyl acetals 110.
Scheme 51: Ring-opening reaction of 2,2-difluorocyclopropyl ketones 113 in the presence of ionic liquid as a s...
Scheme 52: Ring opening of gem-difluorocyclopropyl ketones 113a by MgI2-initiated reaction with diarylimines 1...
Scheme 53: Ring-opening reaction of gem-difluorocyclopropylstannanes 117.
Scheme 54: Preparation of 1-fluorovinyl vinyl ketone 123 and the synthesis of 2-fluorocyclopentenone 124. TBAT...
Scheme 55: Iodine atom-transfer ring opening of 1,1-difluoro-2-(1-iodoalkyl)cyclopropanes 125a–c.
Scheme 56: Ring opening of bromomethyl gem-difluorocyclopropanes 130 and formation of gem-difluoromethylene-co...
Scheme 57: Ring-opening aerobic oxidation reaction of gem-difluorocyclopropanes 132.
Scheme 58: Dibrominative ring-opening functionalization of gem-difluorocyclopropanes 134.
Scheme 59: The selective formation of (E,E)- and (E,Z)-fluorodienals 136 and 137 from difluorocyclopropyl acet...
Scheme 60: Proposed mechanism for the reaction of difluoro(methylene)cyclopropane 139 with Br2.
Scheme 61: Thermal rearrangement of F2MCP 139 and iodine by CuI catalysis.
Scheme 62: Synthesis of 2-fluoropyrroles 142.
Scheme 63: Ring opening of gem-difluorocyclopropyl ketones 143 mediated by BX3.
Scheme 64: Lewis acid-promoted ring-opening reaction of 2,2-difluorocyclopropanecarbonyl chloride (148).
Scheme 65: Ring-opening reaction of the gem-difluorocyclopropyl ketone 106 by methanolic KOH.
Scheme 66: Hydrogenolysis of 1,1-difluoro-3-methyl-2-phenylcyclopropane (151).
Scheme 67: Synthesis of monofluoroalkenes 157.
Scheme 68: The stereoselective Ag-catalyzed defluorinative ring-opening diarylation of 1-trimethylsiloxy-2,2-d...
Scheme 69: Synthesis of 2-fluorinated allylic compounds 162.
Scheme 70: Pd-catalyzed cross-coupling reactions of gem-difluorinated cyclopropanes 161.
Scheme 71: The (Z)-selective Pd-catalyzed ring-opening sulfonylation of 2-(2,2-difluorocyclopropyl)naphthalene...
Figure 1: Structures of zosuquidar hydrochloride and PF-06700841.
Scheme 72: Synthesis of methylene-gem-difluorocyclopropane analogs of nucleosides.
Figure 2: Anthracene-difluorocyclopropane hybrid derivatives.
Figure 3: Further examples of difluorcyclopropanes in modern drug discovery.
Synthesis of aryl 2-bromo-2-chloro-1,1-difluoroethyl ethers through the base-mediated reaction between phenols and halothane
- Yukiko Karuo,
- Ayaka Kametani,
- Atsushi Tarui,
- Kazuyuki Sato,
- Kentaro Kawai and
- Masaaki Omote
Beilstein J. Org. Chem. 2021, 17, 89–96, doi:10.3762/bjoc.17.9
- as monofluorinated and trifluoromethylated arenes or aliphatics [1][2][3][4]. Recent progress in difluoromethylene chemistry successfully led to the finding of bioactive compounds such as pantoprazole, a proton pump inhibitor [5], and AFP-07, a prostaglandin I2 receptor-selective agonist [6][7][8
Graphical Abstract
Figure 1: Medical compounds having a difluoromethyl group.
Scheme 1: Methods for the synthesis of ethers containing fluorine substituents.
Scheme 2: The previous work reported by Yagupol’skii et al.
Scheme 3: Intramolecular 1,4-addition of 2o.
Scheme 4: Proposed reaction mechanism.
Synthesis of esters of diaminotruxillic bis-amino acids by Pd-mediated photocycloaddition of analogs of the Kaede protein chromophore
- Esteban P. Urriolabeitia,
- Pablo Sánchez,
- Alexandra Pop,
- Cristian Silvestru,
- Eduardo Laga,
- Ana I. Jiménez and
- Carlos Cativiela
Beilstein J. Org. Chem. 2020, 16, 1111–1123, doi:10.3762/bjoc.16.98
- activity, not only as antinociceptive drugs but also in the treatment of type 2 diabetes mellitus. In fact, recent results have shown that these compounds are the only non-peptidic agonists of the GLP-1R (glucagon-like peptide 1 receptor) and they have a higher stability than any other agonist prepared to
Graphical Abstract
Figure 1: (a) General scheme for truxillic acid derivatives; (b) general scheme for symmetric 1,3-diaminotrux...
Figure 2: (a) (Z)-4-Arylidene-2-aryl-5(4H)-oxazolones used for the synthesis of 1,3-diaminotruxillic derivati...
Figure 3: (Z)-4-Arylidene-2((E)-styryl)-5(4H)-oxazolones 2a–j used in this work and overall reaction scheme.
Figure 4: Molecular drawing of the oxazolone 2c.
Scheme 1: Ortho-palladation of oxazolones 2 by treatment with Pd(OAc)2 and different structures obtained for ...
Scheme 2: [2 + 2] Photocycloaddition of cyclopalladated complexes 3 in solution to give the dinuclear cyclobu...
Figure 5: Molecular drawing of cyclobutane ortho-palladated 4a. Ellipsoids are shown at the 50% probability l...
Scheme 3: Release of the 1,3-diaminotruxillic bis-amino ester derivatives 5 by methoxycarbonylation of the Pd...
Palladium-catalyzed regio- and stereoselective synthesis of aryl and 3-indolyl-substituted 4-methylene-3,4-dihydroisoquinolin-1(2H)-ones
- Valeria Nori,
- Antonio Arcadi,
- Armando Carlone,
- Fabio Marinelli and
- Marco Chiarini
Beilstein J. Org. Chem. 2020, 16, 1084–1091, doi:10.3762/bjoc.16.95
- active small molecules that exhibit antihypertensive activity [7][8]. Moreover, these heterocycles can be used as 5-HT3 antagonists [9], rho kinase inhibitors [10], thymidylate synthetase inhibitors [11], PARP-1 inhibitors [12], melatonin MT1 and MT2 receptor agonist [13], and fascin-targeted
Graphical Abstract
Scheme 1: Planned approach to tetrasubstituted-4-methylene-3,4-dihydroisoquinolin-1(2H)-ones 4 and 6.
Scheme 2: Preparation of the starting N-propargyl-2-iodobenzamides 2.
Scheme 3: Substrate scope of the reaction of N-propargyl-2-iodobenzamide 2a with arylboronic acids 3b–i.
Scheme 4: Substrate scope of the reaction of N-propargyl-2-iodobenzamides 2c–f with arylboronic acids 3a–c/j.
Scheme 5: Reaction of N-propargyl-2-iodobenzamides 2b,f with the 2-alkynyltrifluoroacetanilides 5a–c.
Fluorinated phenylalanines: synthesis and pharmaceutical applications
- Laila F. Awad and
- Mohammed Salah Ayoup
Beilstein J. Org. Chem. 2020, 16, 1022–1050, doi:10.3762/bjoc.16.91
- emerged as a promising approach for treatment. (R)-2,5-Difluorophenylalanine is a required building block for the synthesis of LY2497282 [50][124] (Figure 9). 5.2.5. Ulimorelin: Ulimorelin (187) is a small cyclic peptide containing ᴅ-4-FPhe. Ulimorelin acts as a selective agonist of the ghrelin/growth
Graphical Abstract
Figure 1: Categories I–V of fluorinated phenylalanines.
Scheme 1: Synthesis of fluorinated phenylalanines via Jackson’s method.
Scheme 2: Synthesis of all-cis-tetrafluorocyclohexylphenylalanines.
Scheme 3: Synthesis of ʟ-4-[sulfono(difluoromethyl)]phenylalanine (nPt: neopentyl, TCE: trichloroethyl).
Scheme 4: Synthesis of ʟ-4-[sulfono(difluoromethyl)]phenylalanine derivatives 17.
Scheme 5: Synthesis of fluorinated Phe analogues from Cbz-protected aminomalonates.
Scheme 6: Synthesis of tetrafluorophenylalanine analogues via the 3-methyl-4-imidazolidinone auxiliary 25.
Scheme 7: Synthesis of tetrafluoro-Phe derivatives via chiral auxiliary 31.
Scheme 8: Synthesis of 2,5-difluoro-Phe and 2,4,5-trifluoro-Phe via Schöllkopf reagent 34.
Scheme 9: Synthesis of 2-fluoro- and 2,6-difluoro Fmoc-Phe derivatives starting from chiral auxiliary 39.
Scheme 10: Synthesis of 2-[18F]FPhe via chiral auxiliary 43.
Scheme 11: Synthesis of FPhe 49a via photooxidative cyanation.
Scheme 12: Synthesis of FPhe derivatives via Erlenmeyer azalactone synthesis.
Scheme 13: Synthesis of (R)- and (S)-2,5-difluoro Phe via the azalactone method.
Scheme 14: Synthesis of 3-bromo-4-fluoro-(S)-Phe (65).
Scheme 15: Synthesis of [18F]FPhe via radiofluorination of phenylalanine with [18F]F2 or [18F]AcOF.
Scheme 16: Synthesis of 4-borono-2-[18F]FPhe.
Scheme 17: Synthesis of protected 4-[18F]FPhe via arylstannane derivatives.
Scheme 18: Synthesis of FPhe derivatives via intermediate imine formation.
Scheme 19: Synthesis of FPhe derivatives via Knoevenagel condensation.
Scheme 20: Synthesis of FPhe derivatives 88a,b from aspartic acid derivatives.
Scheme 21: Synthesis of 2-(2-fluoroethyl)phenylalanine derivatives 93 and 95.
Scheme 22: Synthesis of FPhe derivatives via Zn2+ complexes.
Scheme 23: Synthesis of FPhe derivatives via Ni2+ complexes.
Scheme 24: Synthesis of 3,4,5-trifluorophenylalanine hydrochloride (109).
Scheme 25: Synthesis of FPhe derivatives via phenylalanine aminomutase (PAM).
Scheme 26: Synthesis of (R)-2,5-difluorophenylalanine 115.
Scheme 27: Synthesis of β-fluorophenylalanine via 2-amino-1,3-diol derivatives.
Scheme 28: Synthesis of β-fluorophenylalanine derivatives via the oxazolidinone chiral auxiliary 122.
Scheme 29: Synthesis of β-fluorophenylalanine from pyruvate hemiketal 130.
Scheme 30: Synthesis of β-fluorophenylalanine (136) via fluorination of β-hydroxyphenylalanine (137).
Scheme 31: Synthesis of β-fluorophenylalanine from aziridine derivatives.
Scheme 32: Synthesis of β-fluorophenylalanine 136 via direct fluorination of pyruvate esters.
Scheme 33: Synthesis of β-fluorophenylalanine via fluorination of ethyl 3-phenylpyruvate enol using DAST.
Scheme 34: Synthesis of β-fluorophenylalanine derivatives using photosensitizer TCB.
Scheme 35: Synthesis of β-fluorophenylalanine derivatives using Selectflour and dibenzosuberenone.
Scheme 36: Synthesis of protected β-fluorophenylalanine via aziridinium intermediate 150.
Scheme 37: Synthesis of β-fluorophenylalanine derivatives via fluorination of α-hydroxy-β-aminophenylalanine d...
Scheme 38: Synthesis of β-fluorophenylalanine derivatives from α- or β-hydroxy esters 152a and 155.
Scheme 39: Synthesis of a series of β-fluoro-Phe derivatives via Pd-catalyzed direct fluorination of β-methyle...
Scheme 40: Synthesis of series of β-fluorinated Phe derivatives using quinoline-based ligand 162 in the Pd-cat...
Scheme 41: Synthesis of β,β-difluorophenylalanine derivatives from 2,2-difluoroacetaldehyde derivatives 164a,b....
Scheme 42: Synthesis of β,β-difluorophenylalanine derivatives via an imine chiral auxiliary.
Scheme 43: Synthesis of α-fluorophenylalanine derivatives via direct fluorination of protected Phe 174.
Figure 2: Structures of PET radiotracers of 18FPhe derivatives.
Figure 3: Structures of melfufen (179) and melphalan (180) anticancer drugs.
Figure 4: Structure of gastrazole (JB95008, 181), a CCK2 receptor antagonist.
Figure 5: Dual CCK1/CCK2 antagonist 182.
Figure 6: Structure of sitagliptin (183), an antidiabetic drug.
Figure 7: Structure of retaglpitin (184) and antidiabetic drug.
Figure 8: Structure of evogliptin (185), an antidiabetic drug.
Figure 9: Structure of LY2497282 (186) a DPP-4 inhibitor for the treatment of type II diabetes.
Figure 10: Structure of ulimorelin (187).
Figure 11: Structure of GLP1R (188).
Figure 12: Structures of Nav1.7 blockers 189 and 190.
Two antibacterial and PPARα/γ-agonistic unsaturated keto fatty acids from a coral-associated actinomycete of the genus Micrococcus
- Amit Raj Sharma,
- Enjuro Harunari,
- Naoya Oku,
- Nobuyasu Matsuura,
- Agus Trianto and
- Yasuhiro Igarashi
Beilstein J. Org. Chem. 2020, 16, 297–304, doi:10.3762/bjoc.16.29
- cytotoxicity against murine leukemia P388 cells at 100 µM. Additionally, compounds 1 and 2 were evaluated for agonist activity to peroxisome proliferator-activated receptors (PPARs) because similar oxo fatty acids are known to act as PPAR agonists [42]. PPARs are ligand-activated transcription factors playing
- physiological functions in energy metabolism, PPARs are the molecular targets of metabolic disorders [48]. To assess the PPAR isoform specificity of 1 and 2, three reporter cell lines expressing luciferase genes in response to PPARα, PPARβ/δ, and PPARγ agonists were used [49]. The agonist activity was
- β/δ agonist activities were observed for 1 at the lower concentration of 6.25 μM, but the activity at 6.25 μM was almost equivalent to the activity level of the vehicle DMSO. We thus considered that 1 had no significant activity at 6.25 μM. Overall, 1 was lesser potent than 2, indicating that the
Graphical Abstract
Figure 1: Structures of (6E,8Z)- and (6E,8E)-5-oxo-6,8-tetradecadienoic acids (1 and 2).
Figure 2: COSY and key HMBC correlations for 1 and 2.
Figure 3: Spin system simulation for the C8–C9 double bond of 2.
Figure 4: Natural keto fatty acids of various origins.
Figure 5: PPAR activation by 1 and 2.
Chemical tuning of photoswitchable azobenzenes: a photopharmacological case study using nicotinic transmission
- Lorenzo Sansalone,
- Jun Zhao,
- Matthew T. Richers and
- Graham C. R. Ellis-Davies
Beilstein J. Org. Chem. 2019, 15, 2812–2821, doi:10.3762/bjoc.15.274
- biologically inert, irradiation with violet light effectively "uncaged" agonist activity, but in a photoreversible manner. Since the neurotransmitter acetylcholine has fully saturated heteroatom valences, our photoswitchable 4FABTA probe could be useful for physiological studies of this neurotransmitter
- )AChR. The structural difference between the native acetylcholine and nicotine are striking, and their diversity reflects the complexity of structure–activity relationships of ligands for nicotinic acetylcholine receptors. For example, the drug homocholine phenyl ether (HoChPE) is an agonist of the
- and health of cells. Next we examined if 1 could serve as a photoswitchable antagonist of nicotinic acetylcholine receptors having α4β2E61C mutant as predicted from previous results [16]. After labeling HEK293 cells as described above, we recorded the currents evoked by puffing the agonist carbachol
Graphical Abstract
Figure 1: Fluoro-AB derivatives and spectra. Structures of 4FAB-diamides [13] cis and trans configurations, and t...
Scheme 1: Synthesis of 4FABTA. a) Reagents and conditions: (a) 3-Butynol, PdCl2(PPh3)2, CuI, THF, rt, 93%; (b...
Figure 2: Photochemistry of 4FABTA (2), and thermodynamic stability in physiological buffer. a) Trans–cis pho...
Figure 3: Reaction of t-4FABTA (1) with thiols, and thermal stability of initial conjugate. a) Chemical react...
Figure 4: Testing photo-antagonism of 1 with genetically tagged nicotinic acetylcholine receptors. Currents f...
Figure 5: Photopharmacology with 4FABTA (2). Currents from neurons in the medial habenula in acutely isolated...
A toolbox of molecular photoswitches to modulate the CXCR3 chemokine receptor with light
- Xavier Gómez-Santacana,
- Sabrina M. de Munnik,
- Tamara A. M. Mocking,
- Niels J. Hauwert,
- Shanliang Sun,
- Prashanna Vijayachandran,
- Iwan J. P. de Esch,
- Henry F. Vischer,
- Maikel Wijtmans and
- Rob Leurs
Beilstein J. Org. Chem. 2019, 15, 2509–2523, doi:10.3762/bjoc.15.244
- , exemplified by partial agonist 1c and equal full agonists 1d and 1e (VUF11418, Figure 2A). A tentative explanation for this efficacy switch includes a variation of the dihedral angle of the biaryl moiety, an increase of the electron density in the biaryl unit and/or a postulated halogen bond of the halogen
- alignment between trans-2a and the agonist 1e (Figure 2B), since the planar azobenzene is partially overlapping with the biaryl moiety. However, the two aromatic rings of both compounds can evidently not be in exactly the same plane because the azobenzene moiety is planar while the tilting of the dihedral
- angle of the biaryl moiety of 1e was speculated to be associated with its agonist activity (vide supra) [24]. The alignment of the cis-isomer of 2a with agonist 1e is very different. The outer aromatic ring of cis-2a goes out of plane and is now occupying the space that is also occupied by the iodine
Graphical Abstract
Figure 1: Design of the CXCR3 efficacy photowitchable ligands. A,B) Schematic representation of a GPCR photoc...
Figure 2: Conformational alignment of a biaryl CXCR3 agonist with a designed azobenzene analogue. A) 2D struc...
Scheme 1: Synthetic strategies for compounds 2a–e, 3a–e, 4a–d, 4f–i and 5b,c (Y = H, Cl). Reagents and condit...
Scheme 2: Synthetic strategies for compounds 3f–h, 4e, 6b, and 6d (Y = H, F, Cl, Br). Reagents and conditions...
Figure 3: Comparison of compounds belonging to the subseries 3 or 4 with a halogen substitution on the ortho-...
Scheme 3: Synthetic strategy for compound 6e. Reagents and conditions: (a) i) K2CO3 (2.0 equiv), DMF, µW, 65 ...
Scheme 4: Synthetic strategies for compounds 6f–h (Y = OMe, OiPr, SMe). Reagents and conditions: (a) NaOMe or...
Figure 4: Properties of subseries 3e, 4d, 6b and 6d-h. (A) UV–vis absorption spectra of (top) trans-isomers o...
Design, synthesis and biological evaluation of immunostimulating mannosylated desmuramyl peptides
- Rosana Ribić,
- Ranko Stojković,
- Lidija Milković,
- Mariastefania Antica,
- Marko Cigler and
- Srđanka Tomić
Beilstein J. Org. Chem. 2019, 15, 1805–1814, doi:10.3762/bjoc.15.174
- antigens and regulate the immune reaction by specific binding to CLRs. Therefore, compounds with expressed CRL agonist or antagonist properties could also be considered as potential agents for cancer immunotherapy [49][50]. Mannosylated liposomes with incorporated MDP have proved to be effective carriers
Graphical Abstract
Figure 1: Peptidoglycan fragments with immunostimulating properties.
Figure 2: Immunostimulating mannosylated desmuramyl peptide (ManAdTP).
Figure 3: General structure of: a) glycolyl and b) (R)-hydroxyisobutyryl derivatives.
Scheme 1: Synthesis of desmuramyl peptides modified at N-terminus. Reagents and conditions: a) TFA/DCM 1:2, r...
Scheme 2: Synthesis of C-modified desmuramyl peptides. Reagents and conditions: a) H2, 10% Pd/C, MeOH, 38 psi...
Scheme 3: Synthesis of the mannose precursor. Reagents and conditions: a) Zn(OAc)2·H2O, abs. MeOH, rt, 20 h, ...
Scheme 4: Synthesis of mannosylated peptides with hydroxyisobutyryl linker. Reagents and conditions: a) EDC·H...
Scheme 5: Synthesis of mannosylated peptides with glycolyl linker. Reagents and conditions: a) EDC·HCl, HOBt·H...
Figure 4: The effect of mannosyl desmuramyl peptides on production of anti-OVA IgG in BALB/c mice immunized w...
Figure 5: The effect of mannosylated desmuramyl peptides on production of anti-OVA IgG subtypes, anti-OVA IgG...
Figure 6: The ratio of anti-OVA IgG1 and anti-OVA IgG2a (IgG1/IgG2a) in BALB/c mice. For each mouse serum IgG...
