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

Novel synthesis of pseudopeptides bearing a difluoromethyl group by Ugi reaction and desulfanylation

• Jingjing Wu,
• Hui Li and
• Song Cao

Beilstein J. Org. Chem. 2011, 7, 1070–1074, doi:10.3762/bjoc.7.123

• reported of the preparation and bioassay of pseudopeptides and peptidomimetics bearing difluoromethyl groups. For example, compound I can act as bradykinin B1 antagonist or inverse agonist and can be used in the prevention of inflammation and pain [19]. Compound II is an inhibitor of microsomal

An overview of the key routes to the best selling 5-membered ring heterocyclic pharmaceuticals

• Marcus Baumann,
• Ian R. Baxendale,
• Steven V. Ley and
• Nikzad Nikbin

Beilstein J. Org. Chem. 2011, 7, 442–495, doi:10.3762/bjoc.7.57

• structure, mutation studies have shown that the AT2 antagonists such as losartan bind to an active site located within the membrane-bound part of the receptor, which is different to that of the peptide agonist. Further studies led to the discovery of valsartan, where the imidazole ring of losartan is

• , and is part of the imidazopyridine class of pharmaceuticals. It is an agonist for the target receptor of γ-aminobutyric acid (GABA), an inhibitory neurotransmitter. Zolpidem binds to GABA receptors at the same site as typical benzodiazepines. This drug is preferred to benzodiazepines for long term use

• , Arimidex) and 5-HT1 agonist triptan drugs such as rizatriptan (76, Maxalt) which are prescribed for migraine headaches. The large scale syntheses of all these compounds use the commercially available 1,2,4-triazolyl sodium salt 258 in an alkylation reaction with the corresponding benzyl bromide derivative

Palladium- and copper-mediated N-aryl bond formation reactions for the synthesis of biological active compounds

• Carolin Fischer and
• Burkhard Koenig

Beilstein J. Org. Chem. 2011, 7, 59–74, doi:10.3762/bjoc.7.10

• A-366833, a selective α4β2 neural nicotinic receptor agonist. A new route to oxcarbazepine. Synthesis of key intermediates for norepinephrine transporter (NET) inhibitors. N-Annulation yielding substituted indole for the synthesis of demethylasterriquinone A1. Palladium-catalysed double N-arylation

Transition- metal/Lewis acid free synthesis of acyl benzothiophenes via C-C bond forming reaction

• Sarbani Pal,
• Mohammad Ashrafuddin Khan,
• P. Bindu and
• P. K. Dubey

Beilstein J. Org. Chem. 2007, 3, No. 35, doi:10.1186/1860-5397-3-35

• , Raloxifene, [2-(4-hydroxyphenyl)-6-hydroxybenzo[b]thien-3-yl] [4-[2-(1-piperidinyl)ethoxy]phenyl]-methanone hydrochloride (A, Figure 1), is representative of a class of compounds known as selective estrogen receptor modulators[1] (SERMs) that possess estrogen agonist-like actions on bone tissues and serum

8-epi-Salvinorin B: crystal structure and affinity at the κ opioid receptor

• Thomas A. Munro,
• Katharine K. Duncan,
• Richard J. Staples,
• Wei Xu,
• Lee-Yuan Liu-Chen,
• Cécile Béguin,
• William A. Carlezon Jr. and
• Bruce M. Cohen

Beilstein J. Org. Chem. 2007, 3, No. 1, doi:10.1186/1860-5397-3-1

• hallucinogenic sage Salvia divinorum,[1] is a potent and selective κ opioid receptor (KOR) agonist.[2] Because it is the first known non-nitrogenous compound to have biologically significant actions at mammalian opioid receptors, 1a enables new approaches to studies of endogenous opioid receptor systems. KOR