Continuous-flow synthesis of primary amines: Metal-free reduction of aliphatic and aromatic nitro derivatives with trichlorosilane

• Riccardo Porta,
• Alessandra Puglisi,
• Giacomo Colombo,
• Sergio Rossi and
• Maurizio Benaglia

Beilstein J. Org. Chem. 2016, 12, 2614–2619, doi:10.3762/bjoc.12.257

• [29]. The corresponding amide 6 is a direct precursor of the GABA receptor agonist Baclofen (Scheme 5). Nitro compound 5 was continuously reduced in a 5 mL reactor and, after work-up under neutral conditions, chiral lactam 6 was isolated in 48% yield. Finally we explored the possibility of performing

The direct oxidative diene cyclization and related reactions in natural product synthesis

• Juliane Adrian,
• Leona J. Gross and
• Christian B. W. Stark

Beilstein J. Org. Chem. 2016, 12, 2104–2123, doi:10.3762/bjoc.12.200

• by Sakai et al. together with the already known and closely related dysiherbaine [42]. Neodysiherbaine A (14) is a neurologically active compound that acts as a glutamate receptor agonist and shows epileptogenic properties. Contiguous to the isolation, the first synthesis has been carried out by the

Discovery of an inhibitor of the production of the Pseudomonas aeruginosa virulence factor pyocyanin in wild-type cells

• Bernardas Morkunas,
• Balint Gal,
• Warren R. J. D. Galloway,
• James T. Hodgkinson,
• Brett M. Ibbeson,
• Yaw Sing Tan,
• Martin Welch and
• David R. Spring

Beilstein J. Org. Chem. 2016, 12, 1428–1433, doi:10.3762/bjoc.12.137

• . Interestingly, this data suggests that 4 may have slight agonist activity at low concentrations. This type of behaviour has previously been observed for AHL-based modulators of quorum sensing. Many such compounds have been identified that can both slightly activate and inhibit a quorum sensing circuit depending

• pyocyanin inhibitors in P.aeruginosa are not directly inhibiting LasR but have an alternate mode of action(s), this hypothesis should not be completely ruled out. This may be especially relevant for compounds such as 4, which are clearly structurally distinct from OdDHL, the natural LasR agonist [12]. In

Catalytic asymmetric synthesis of biologically important 3-hydroxyoxindoles: an update

• Bin Yu,
• Hui Xing,
• De-Quan Yu and
• Hong-Min Liu

Beilstein J. Org. Chem. 2016, 12, 1000–1039, doi:10.3762/bjoc.12.98

• currently being used for the treatment of growth hormone deficiency as a potent and orally active GHSR agonist [10]. YK-4-279 can potently inhibit the growth of Ewing’s sarcoma by blocking the interaction between the oncogenic protein EWS-FLI1 and RNA helicase A (RHA) [11]. Interestingly, only (S)-YK-4-279

Base metal-catalyzed benzylic oxidation of (aryl)(heteroaryl)methanes with molecular oxygen

• Hans Sterckx,
• Johan De Houwer,
• Carl Mensch,
• Wouter Herrebout,
• Kourosch Abbaspour Tehrani and
• Bert U. W. Maes

Beilstein J. Org. Chem. 2016, 12, 144–153, doi:10.3762/bjoc.12.16

• acid as a promotor [25]. The resulting ketones are very valuable as they are intermediates in the synthesis of a variety of pharmaceuticals such as the antimalarial Mefloquine (Lariam®), the antihistamine Acrivastine, the β2-adrenergic agonist Rimiterol and the anxiolytic Bromazepam [26]. Furthermore

Copper-catalyzed intermolecular oxyamination of olefins using carboxylic acids and O-benzoylhydroxylamines

• Brett N. Hemric and
• Qiu Wang

Beilstein J. Org. Chem. 2016, 12, 22–28, doi:10.3762/bjoc.12.4

• -adrenergic receptor agonist [3]; lumefantrine, an antimalarial drug [4]; ifenprodil, an N-methyl-D-aspartate (NMDA) antagonist [5]; and tebuconazole, a commercial fungicide [6]. With the importance of 1,2-oxyamino motifs as privileged pharmacophores, the development of facile and efficient access to this

The synthesis of active pharmaceutical ingredients (APIs) using continuous flow chemistry

• Marcus Baumann and
• Ian R. Baxendale

Beilstein J. Org. Chem. 2015, 11, 1194–1219, doi:10.3762/bjoc.11.134

• second study, the flow synthesis of the selective δ-opioid receptor agonist 33 was discussed (Scheme 6) [57]. Again, a strategy of integrating each of the three synthetic steps with a sequenced cascade of scavenger agents to perform the aspects of work-up and purification was used. The report also

Diastereoselective and enantioselective conjugate addition reactions utilizing α,β-unsaturated amides and lactams

• Katherine M. Byrd

Beilstein J. Org. Chem. 2015, 11, 530–562, doi:10.3762/bjoc.11.60

• enantioselectivities than phosphine ligands in rhodium-catalyzed asymmetric reactions [152][153]. Scheme 16 shows the rhodium-catalyzed asymmetric 1,4-arylation that was developed by Lin and co-workers and the subsequent transformation to the GABAB receptor agonist, (R)-(−)-baclofen. Much of the work that has been

• agonist AMG 837 [199]. Shibasaki and co-workers expanded their application of soft Lewis acid/hard Brønsted base cooperative catalysis to the asymmetric vinylogous conjugate addition of α,β-unsaturated butyrolactones to α,β-unsaturated thioamides [200]. This reaction provides a method for producing

Natural phenolic metabolites with anti-angiogenic properties – a review from the chemical point of view

• Qiu Sun,
• Jörg Heilmann and
• Burkhard König

Beilstein J. Org. Chem. 2015, 11, 249–264, doi:10.3762/bjoc.11.28

• the regulation of cell functions, including cell proliferation and cell transformation. Later, genistein was also found to act as an oestrogen receptor agonist [80]. The anti-angiogenic potential of genistein was first reported by Fotsis et al. in 1993 [81]. Then, further studies showed that genistein

Preparation of neuroprotective condensed 1,4-benzoxazepines by regio- and diastereoselective domino Knoevenagel–[1,5]-hydride shift cyclization reaction

• László Tóth,
• Yan Fu,
• Hai Yan Zhang,
• Attila Mándi,
• Katalin E. Kövér,
• Tünde-Zita Illyés,
• Attila Kiss-Szikszai,
• Balázs Balogh,
• Tibor Kurtán,
• Sándor Antus and
• Péter Mátyus

Beilstein J. Org. Chem. 2014, 10, 2594–2602, doi:10.3762/bjoc.10.272

• unit and its analogues are found in several pharmacologically active derivatives such as the selective 5-HT1A agonist SUN 8399 (1) [1], the neuroprotective piclozotan (2) [2][3], the antihistaminic rocastine (3) [4][5], and the antihelmintic 4 [6] (Figure 1). We report herein the preparation of two

Application of cyclic phosphonamide reagents in the total synthesis of natural products and biologically active molecules

• Thilo Focken and
• Stephen Hanessian

Beilstein J. Org. Chem. 2014, 10, 1848–1877, doi:10.3762/bjoc.10.195

• (14) [28], and mGluR agonist DCG-IV (18) [57], as discussed later in this review. Studies for the synthesis of ottelione A and B [58] also employed this cyclopropanation methodology using a mixture of 47a and 47b. The discussion of the latter natural products is not included in this review, as

• acids 55 (Scheme 7) [59]. The synthesis of an mGluR agonist was achieved using chloromethyl phosphonamide 28d [60][61], as discussed later in this review. Replacing Michael acceptors with oximes in the reaction with chloroallyl phosphonamide 47a leads to the stereoselective formation of cis-aziridines

• mGluR agonist DCG-IV (162) (Figure 9) as a potent anticonvulsant and neuroprotective agent [123] had sparked interest in more efficient routes for its synthesis. Pellicciari and Marinozzi developed an asymmetric synthesis of DCG-IV (162) based on Hanessian’s cyclopropanation protocol (Scheme 20) [57

A novel family of (1-aminoalkyl)(trifluoromethyl)- and -(difluoromethyl)phosphinic acids – analogues of α-amino acids

• Natalia V. Pavlenko,
• Tatiana I. Oos,
• Yurii L. Yagupolskii,
• Igor I. Gerus,
• Uwe Doeller and
• Lothar Willms

Beilstein J. Org. Chem. 2014, 10, 722–731, doi:10.3762/bjoc.10.66

• (trifluoromethyl)- or (difluoromethyl)phosphonyl moiety instead of the carboxylate function. To the best of our knowledge there is only one report on the application of ethyl (difluoromethyl)phosphinate CHF2(H)P(O)(OEt) in the synthesis of a (difluoromethyl)phosphinic acid analogue of GABA, as a potent agonist of

Studies toward bivalent κ opioids derived from salvinorin A: heteromethylation of the furan ring reduces affinity

• Thomas A. Munro,
• Wei Xu,
• Douglas M. Ho,
• Lee-Yuan Liu-Chen and
• Bruce M. Cohen

Beilstein J. Org. Chem. 2013, 9, 2916–2924, doi:10.3762/bjoc.9.328

• showed no affinity for any opioid receptor. Follow-up testing in the [35S]GTPγS functional assay demonstrated that 4 was an agonist less potent than 1 at κ-OR, but giving an equal maximal response (Table 1). (2-Hydroxyethoxy)methyl ether 6 showed high affinity for κ-OR, but not for µ- or δ-OR (Ki > 1 μM

• . Given our interest in the development of κ-opioid antagonists [35], we tested for negative modulation. To maximize the physiological relevance of the assays, we used the endogenous agonist dynorphin A. In addition to 2–5, we retested a number of derivatives of 1 we had previously found to exhibit

An overview of the synthetic routes to the best selling drugs containing 6-membered heterocycles

• Marcus Baumann and
• Ian R. Baxendale

Beilstein J. Org. Chem. 2013, 9, 2265–2319, doi:10.3762/bjoc.9.265

Synthesis and characterization of novel bioactive 1,2,4-oxadiazole natural product analogs bearing the N-phenylmaleimide and N-phenylsuccinimide moieties

• Catalin V. Maftei,
• Elena Fodor,
• Peter G. Jones,
• M. Heiko Franz,
• Gerhard Kelter,
• Heiner Fiebig and
• Ion Neda

Beilstein J. Org. Chem. 2013, 9, 2202–2215, doi:10.3762/bjoc.9.259

• oxadiazole core is quisqualic acid (Figure 1). This metabolite was obtained from the seeds of Quisqualis indica and Q. fructus [5][6] and is a strong agonist for AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptors and group I metabotropic glutamate receptors [7]. Furthermore, 1,2,4

Synthesis of the calcilytic ligand NPS 2143

• Henrik Johansson,
• Thomas Cailly,
• Alex Rojas Bie Thomsen,
• Hans Bräuner-Osborne and
• Daniel Sejer Pedersen

Beilstein J. Org. Chem. 2013, 9, 1383–1387, doi:10.3762/bjoc.9.154

• -aminobutyric acid type B (GABAB) receptors, three taste (TR) receptors, the GPRC6A receptor, the calcium-sensing receptor (CaSR), and seven orphan receptors [4]. Class C GPCRs have proven viable as drug targets, exemplified by the marketed GABAB agonist baclofen, and by cinacalcet (1), a positive allosteric

• have been characterised carefully and the optical purity of (R)-3 was deemed excellent by chiral HPLC (er > 99:1). Moreover, the pharmacological profile of (R)-3 was consistent with that reported in the literature. Marketed calcium-sensing receptor agonist cinacalcet (1), and CaSR antagonists Calhex

Recent progress in the discovery of small molecules for the treatment of amyotrophic lateral sclerosis (ALS)

• Allison S. Limpert,
• Margrith E. Mattmann and
• Nicholas D. P. Cosford

Beilstein J. Org. Chem. 2013, 9, 717–732, doi:10.3762/bjoc.9.82

• in animal models of ALS and in the study of other diseases where glutamate toxicity plays an essential role. In addition to dysregulation of glutamate levels in ALS patients, recent studies have also detected elevated levels of D-serine (Figure 3), an activator/co-agonist of the N-methyl-D-aspartate

• neuroblastoma-spinal cord (NSC)-34 cells, a motor neuron cell line [19]. Since D-serine serves as a co-agonist at the glycine site of the NMDA glutamate receptor, increases in D-serine are likely to contribute to glutamate excitotoxicity in ALS patients. These data suggest that reducing D-serine levels through

• animals [66]. Additional work from this group identified the dopamine D2 receptor agonist, bromocriptine (32), as an NAIP upregulating compound that reduced oxidative stress through the upregulation of antioxidant proteins, such as activating transcription factor 3 (ATF3) and HO-1 [68]. In vivo studies

N-Heterocyclic carbene–palladium catalysts for the direct arylation of pyrrole derivatives with aryl chlorides

• Ismail Özdemir,
• Nevin Gürbüz,
• Nazan Kaloğlu,
• Öznur Doğan,
• Murat Kaloğlu,
• Christian Bruneau and
• Henri Doucet

Beilstein J. Org. Chem. 2013, 9, 303–312, doi:10.3762/bjoc.9.35

• important research area in organic synthesis as such motives are known to be present in several bioactive molecules, such as Atorvastatin, which is used for lowering blood cholesterol, Fendosal, which is an anti-inflammatory agent, or Tanaproget, which is a progesterone-receptor agonist (Figure 1). The

Development of peptidomimetic ligands of Pro-Leu-Gly-NH₂ as allosteric modulators of the dopamine D₂ receptor

• Swapna Bhagwanth,
• Ram K. Mishra and
• Rodney L. Johnson

Beilstein J. Org. Chem. 2013, 9, 204–214, doi:10.3762/bjoc.9.24

• β-turn that is mimicked is dictated by the chirality of C-3. Lactams 1, 2, 4–6, and 9 (Figure 2) were active in enhancing the binding of the dopamine receptor agonist 2-amino-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene (ADTN) to dopamine receptors, while 3, 7, and 8 were inactive [19][20]. The

• positive ψ2 value is consistent with the positive ψ2 value required of an ideal type II β-turn [22]. In the series of lactam PLG peptidomimetics shown in Figure 2, peptidomimetic 2 was found to be the most potent in enhancing the binding of the dopamine receptor agonist ADTN to isolated dopamine receptors

• high-affinity state, which couples to the G-proteins [23]. Studies carried out in cell lines transfected with human dopamine receptor subtypes have shown that PLG and 2 enhance agonist binding to the D2S, D2L and D4 dopamine receptor subtypes, whereas the D1 and D3 receptor subtypes are unaffected [24

Intramolecular carbolithiation of N-allyl-ynamides: an efficient entry to 1,4-dihydropyridines and pyridines – application to a formal synthesis of sarizotan

• Wafa Gati,
• Mohamed M. Rammah,
• Mohamed B. Rammah and
• Gwilherm Evano

Beilstein J. Org. Chem. 2012, 8, 2214–2222, doi:10.3762/bjoc.8.250

• of the 3,5-disubstituted pyridine core of the antidyskinetic drug, 5-HT1A receptor agonist, dopamine D2 receptor ligand sarizotan 19 (Scheme 6). The pyridinyl-chroman sarizotan (also called EMD-128130) was originally developed by Merck KGaA in the late 1990’s [44] and was found to be a dual selective

• 5-HT1A receptor agonist and D2 receptor antagonist displaying a strong efficacy in the reduction of dyskinesia resulting from long-term antiparkinsonian treatment with levodopa [45][46][47][48][49][50]. Although its development was stopped by Merck KGaA in 2006 after analysis of data from Phase III

• starting N-allyl-ynamides. Intramolecular carbolithiation of N-allyl-ynamides to 1,4-dihydropyridines and pyridines. 2,3-Disubstituted pyridines by trapping of the intermediate metallated 1,4-dihydropyridine. Formal synthesis of the anti-dyskinesia agent, 5-HT1A receptor agonist, dopamine D2 receptor

Tricyclic flavonoids with 1,3-dithiolium substructure

• Lucian G. Bahrin,
• Peter G. Jones and
• Henning Hopf

Beilstein J. Org. Chem. 2012, 8, 1999–2003, doi:10.3762/bjoc.8.226

• led to the synthesis of derivative 1, a selective estrogen receptor β agonist (SERBA-1, Figure 1) [5]. Studies that focus on the structure–activity relationship were reported [6][7]. It was shown that a cyclopentane ring at the 3,4-carbon positions (labeled C, Figure 1) leads to a substantial rise in

trans-2-(2,5-Dimethoxy-4-iodophenyl)cyclopropylamine and trans-2-(2,5-dimethoxy-4-bromophenyl)cyclopropylamine as potent agonists for the 5-HT₂ receptor family

• Adam Pigott,
• Stewart Frescas,
• John D. McCorvy,
• Xi-Ping Huang,
• Bryan L. Roth and
• David E. Nichols

Beilstein J. Org. Chem. 2012, 8, 1705–1709, doi:10.3762/bjoc.8.194

• than for DOI itself. Keywords: cyclopropanation; diazomethane; hallucinogen; 5-HT2A agonist; receptor probe; trans-2-phenylcyclopropylamines; Introduction Among the molecules that have proven very valuable to neuroscientists studying brain serotonin systems is the substituted phenethylamine

• derivative 2,5-dimethoxy-4-iodoamphetamine (DOI, 1a, Figure 1), a potent but nonspecific agonist ligand for serotonin 5-HT2A and 5-HT2C receptors. It is relatively inexpensive and has been widely used throughout the neuroscience community to study behaviors mediated by 5-HT2 family receptors. Indeed, as of

Synthesis of compounds related to the anti-migraine drug eletriptan hydrobromide

• Suri Babu Madasu,
• Nagaji Ambabhai Vekariya,
• M. N. V. D. Hari Kiran,
• Badarinadh Gupta,
• Aminul Islam,
• Paul S. Douglas and
• Korupolu Raghu Babu

Beilstein J. Org. Chem. 2012, 8, 1400–1405, doi:10.3762/bjoc.8.162

• Chemistry Department, AU College of Engineering, Andhra University, Visakhapatnam-530003, Andhra Pradesh, India 10.3762/bjoc.8.162 Abstract Eletriptan hydrobromide (1) is a selective serotonin (5-HT1) agonist, used for the acute treatment of the headache phase of migraine attacks. During the manufacture of

• , Figure 1) is a second-generation drug serotonin (5-HT1) agonist [4][5] used in the management of sensations of tightness, pain, pressure and heaviness in the precordium, throat and jaws. Eletriptan is more lipophilic than other triptans and absorbed more quickly than sumatriptan in the intestinal

Control over molecular motion using the cis–trans photoisomerization of the azo group

• Estíbaliz Merino and
• María Ribagorda

Beilstein J. Org. Chem. 2012, 8, 1071–1090, doi:10.3762/bjoc.8.119

• , azobenzene and glutamate derivative (MAG) was used as a photochromic agonist of an ionotropic glutamate receptor (iGluR) (Figure 5a) [89][90][91]. The chromophore consists of a terminal maleimide unit, which is associated covalently to the protein via a cysteine residue, a central azobenzene unit and a

Synthesis and characterization of Sant-75 derivatives as Hedgehog-pathway inhibitors

• Chao Che,
• Song Li,
• Bo Yang,
• Shengchang Xin,
• Zhixiong Yu,
• Taofeng Shao,
• Chuanye Tao,
• Shuo Lin and
• Zhen Yang

Beilstein J. Org. Chem. 2012, 8, 841–849, doi:10.3762/bjoc.8.94

• carcinoma. In addition, a number of man-made inhibitors with a Smo binding affinity have been identified and reported [2][28][29][30][31][32][33][34], and some of them have entered phase I development. SAG is a synthetic Hh pathway agonist that directly targets Smo in a manner that antagonizes cyclopamine

• action, and thus it may serve as an interesting scaffold for drug development [35][36]. Recently, we have identified a Smo antagonist Sant-75 through zebrafish-based screening of a SAG-derived chemical library [37]. Interestingly, this antagonist differs from agonist SAG only in the chain length of the