Facile synthesis of 7-alkyl-1,2,3,4-tetrahydro-1,8-naphthyridines as arginine mimetics using a Horner–Wadsworth–Emmons-based approach

• Rhys A. Lippa,
• John A. Murphy and
• Tim N. Barrett

Beilstein J. Org. Chem. 2020, 16, 1617–1626, doi:10.3762/bjoc.16.134

• , exploiting the base stability of the phosphoramidate protecting group. A variety of bases were trialed at 0 °C for the initial N-phosphorylation, with 10 minutes allowed for complete deprotonation to occur (Table 1). Only minimal phosphorylation was observed when using potassium tert-butoxide (Table 1, entry

• proceeded well (91% isolated yield) in 2-MeTHF, which offers a preferred alternative if the reaction is performed on a larger scale due to better partitioning with water, stability, and sustainability of production [21]. Of the bases trialled, only s-BuLi was efficient in promoting C-phosphorylation

• . Optimisation of the use of this base was then investigated further (Table 2). An optimal deprotonation and phosphorylation was found to occur when an excess (3 equiv) of base was used at −42 °C (Table 2, entry 4), with a lithiation time of 20 min. The addition of TMEDA was detrimental to this conversion with a

Architecture and synthesis of P,N-heterocyclic phosphine ligands

• Wisdom A. Munzeiwa,
• Bernard Omondi and
• Vincent O. Nyamori

Beilstein J. Org. Chem. 2020, 16, 362–383, doi:10.3762/bjoc.16.35

• methodology was also faster than the metal-catalyzed phosphorylation route reported by the same authors. The use of multiply halogenated compounds opens up opportunities to synthesize multidentate ligands. Zhang et al. [64] reported on a sequential synthetic route of multichelate pyridylphosphines 15, 16 and

• phosphorylation with diphenylphosphine in the presence of potassium tert-butoxide and 18-crown-6. The use of silyl and dialkylamine as reagents Organosilyl, silylphosphine derivatives, along with dialkylamines can also be used as alternative substrates to halogen-based reagents. These compounds are more stable

• quenching the metalated triazole 66 with chlorophosphine. However, a separation of the triazole before phosphorylation makes purification of the final ligand easier [74]. The direct ortho-metalation of pyridyltriazole 69 and subsequent reaction with chlorophosphines gave the isomeric ligands 71 and 72 in

N-(1-Phenylethyl)aziridine-2-carboxylate esters in the synthesis of biologically relevant compounds

• Iwona E. Głowacka,
• Aleksandra Trocha,
• Andrzej E. Wróblewski and
• Dorota G. Piotrowska

Beilstein J. Org. Chem. 2019, 15, 1722–1757, doi:10.3762/bjoc.15.168

• group was acquired as shown earlier to provide (2S,3R)-92a and (2S,3R)-92b as N-Boc derivatives after N-debenzylation. Analogues (2S,3R)-89a (DS-SG-44) and (2S,3R)-89b (DS-SG-45) were formed after a regioselective phosphorylation and final treatment with bromotrimethylsilane. DS-SG-44 emerged as an

Synthesis of ([1,2,4]triazolo[4,3-a]pyridin-3-ylmethyl)phosphonates and their benzo derivatives via 5-exo-dig cyclization

• Aleksandr S. Krylov,
• Artem A. Petrosian,
• Julia L. Piterskaya,
• Nataly I. Svintsitskaya and
• Albina V. Dogadina

Beilstein J. Org. Chem. 2019, 15, 1563–1568, doi:10.3762/bjoc.15.159

• synthesized in a similar manner. The presence of a NO2 group in the starting hydrazinylpyridine induces a Dimroth-type rearrangement leading to 2-methylphosphonylated [1,2,4]triazolo[1,5-a]pyridines. Keywords: cyclization; fused-ring systems; nitrogen heterocycles; phosphorylation; rearrangement

Synthesis and fluorescent properties of N(9)-alkylated 2-amino-6-triazolylpurines and 7-deazapurines

• Andrejs Šišuļins,
• Jonas Bucevičius,
• Yu-Ting Tseng,
• Irina Novosjolova,
• Kaspars Traskovskis,
• Ērika Bizdēna,
• Huan-Tsung Chang,
• Sigitas Tumkevičius and
• Māris Turks

Beilstein J. Org. Chem. 2019, 15, 474–489, doi:10.3762/bjoc.15.41

• and 7-deaza-7-ethenyl-2'-deoxyadenosine or 5-(azidomethyl)-2'-deoxyuridine, we can assume that nucleoside analogs bearing fluorophores of our type would be susceptible to metabolic phosphorylation and incorporation into DNA in the living cells. Further studies are required to develop the newly

Syntheses and chemical properties of β-nicotinamide riboside and its analogues and derivatives

• Mikhail V. Makarov and
• Marie E. Migaud

Beilstein J. Org. Chem. 2019, 15, 401–430, doi:10.3762/bjoc.15.36

• +Cl− by phosphorylation with phosphoryl chloride in a water/nitromethane solution. When its optical rotation was measured ( −24°) and compared to a standard solution of NMN generated from NAD+, it was concluded that the synthesized NR+Cl− consisted of a 4:1 mixture of β- and α-anomers (Scheme 1) [20

• is most commonly modified to generate the phosphorylated derivative of NR+, nicotinamide mononucleotide, NMN. The phosphorylation is achieved by reacting NR+ in its salt form with phosphorus oxychloride in trimethyl phosphate resulting, after hydrolysis, in NMN (Scheme 17). Lee et al. [27] carefully

• studied this reaction and found that the phosphorylation step should be conducted under strictly controlled temperature conditions in the range of −5 to 0 °C to prevent the undesired 5′-chlorination which occurs at higher temperatures, and to avoid slow reaction rates at lower temperatures. Lee et al. [27

Impact of Pseudomonas aeruginosa quorum sensing signaling molecules on adhesion and inflammatory markers in endothelial cells

• Carmen Curutiu,
• Florin Iordache,
• Veronica Lazar,
• Aurelia Magdalena Pisoschi,
• Aneta Pop,
• Mariana Carmen Chifiriuc and
• Alina Maria Hoban

Beilstein J. Org. Chem. 2018, 14, 2580–2588, doi:10.3762/bjoc.14.235

• intercellular adherence junctions (AJ) and tight junctions (TJ), interconnected with cytoskeletal proteins. 3O-C12-HSL induces breaks in the epithelial barrier, disrupting cell junction and enhanced permeability by alterations in the phosphorylation status of TJ and AJ proteins [12]. The transmembrane protein

Anomeric modification of carbohydrates using the Mitsunobu reaction

• Julia Hain,
• Patrick Rollin,
• Werner Klaffke and
• Thisbe K. Lindhorst

Beilstein J. Org. Chem. 2018, 14, 1619–1636, doi:10.3762/bjoc.14.138

• authors state that the observed pKa effect is either due to the influence of the acidity of the employed acid on the reaction mechanism or results from the proton-catalyzed change of the anomeric ratio of the starting material 30 in solution. Very recently, anomeric phosphorylation via a Mitsunobu

• ]. Correlation between pKa value of the employed acids (or alcohol) and the favoured anomeric configuration of the respective product. aCarried out at 0 °C; bcarried out at rt [27]. Synthesis of the β-mannosyl phosphates for the synthesis of HBP 43 by anomeric phosphorylation according to Mitsunobu [41][42

Recent applications of chiral calixarenes in asymmetric catalysis

• Mustafa Durmaz,
• Erkan Halay and
• Selahattin Bozkurt

Beilstein J. Org. Chem. 2018, 14, 1389–1412, doi:10.3762/bjoc.14.117

• selectivity was the chiral oxazoline unit and not the inherent chirality of calixarene skeleton. Asymmetric hydrogenation Starting with distally O-dialkylated calixarene precursors, a series of BINOL-derived calix[4]arene-diphosphite ligands 40a–g were synthesized by Liu and Sandoval through phosphorylation

Mechanochemistry of nucleosides, nucleotides and related materials

• Olga Eguaogie,
• Joseph S. Vyle,
• Patrick F. Conlon,
• Manuela A. Gîlea and
• Yipei Liang

Beilstein J. Org. Chem. 2018, 14, 955–970, doi:10.3762/bjoc.14.81

• mills [46][47]. Reaction scales up to 40 g were described and the conditions developed enabled exclusive formation of the β-anomer of nicotinamide riboside (NR) in the absence of toxic bromide salts. Preparation and reactions of nucleotides and their analogues Phosphorylation of NR on gram-scales using

• in a MBM. Thiolate displacement reactions of nucleoside derivatives in a MBM. Selenocyanate displacement reactions of nucleoside derivatives in a MBM. Nucleobase glycosidation reactions and subsequent deacetylation performed in a MBM. Regioselective phosphorylation of nicotinamide riboside in a MBM

On the design principles of peptide–drug conjugates for targeted drug delivery to the malignant tumor site

• Eirinaios I. Vrettos,
• Gábor Mező and
• Andreas G. Tzakos

Beilstein J. Org. Chem. 2018, 14, 930–954, doi:10.3762/bjoc.14.80

• Heinrich Warburg in the early 1900s, who was awarded the Nobel Prize in 1931. He proposed that malignant tumor growth relies on aerobic glycolysis, in contrast to normal cells that generate energy by mitochondrial oxidative phosphorylation. The fact that cells converted pyruvate to lactate, even in the

Aminosugar-based immunomodulator lipid A: synthetic approaches

• Alla Zamyatina

Beilstein J. Org. Chem. 2018, 14, 25–53, doi:10.3762/bjoc.14.3

• content of LPS comprises a complex mixture of structural homologs varying in the acylation pattern, the length of the (R)-3-hydroxyacyl- and (R)-3-acyloxyacyl long-chain residues and in the phosphorylation status of the β(1→6)-linked diglucosamine backbone. The structural heterogeneity of the lipid A

• lengths usually comprising 12–16 carbon atoms [16][17]. The endotoxic activity of lipid A depends on numerous factors such as acylation and phosphorylation pattern [18], the length of lipid chains, and the tertiary 3D structure of the MD-2 bound βGlcN(1→6)GlcN backbone [19][20]. The most profoundly

• purity. To obtain clear structure–activity relationships data on lipid A–TLR4 interaction as well as unambiguous correlation of the lipid A acylation and phosphorylation pattern to its capacity in induction of different (i.e., MyD88-dependent and TRIF-dependent) signaling pathways, numerous well-defined

Synthetic mRNA capping

• Fabian Muttach,
• Nils Muthmann and
• Andrea Rentmeister

Beilstein J. Org. Chem. 2017, 13, 2819–2832, doi:10.3762/bjoc.13.274

• diphosphate (GDP, 15) and guanosine monophosphate (GMP, 16, Figure 4B), which are both accessible by phosphorylation of guanosine [54]. Methylation of GDP gives m7GDP (17) with high yield and regioselectivity [55]. The key step in cap analogue synthesis is the formation of the triphosphate linkage. Multiple

The chemistry and biology of mycolactones

• Matthias Gehringer and
• Karl-Heinz Altmann

Beilstein J. Org. Chem. 2017, 13, 1596–1660, doi:10.3762/bjoc.13.159

• different downstream signaling cascades. As the core component of these complexes, mTOR exhibits protein kinase activity and phosphorylates a variety of downstream meditators. One of the principal substrates of the mTORC2 complex is the serine/threonine kinase Akt, which gets activated upon phosphorylation

• rapamycin, the mTOR pathway was contemplated as a potential molecular target. To put this hypothesis to test, the effect of mycolactone treatment on the phosphorylation of the mTORC1-targeted ribosomal protein S6 (rpS6) and the mTORC2-targeted kinase Akt was investigated in L929 fibroblast and Jurkat T

• cells. Strikingly, mycolactone treatment abolished both, S6 and Akt phosphorylation. Since mycolactone A/B did not directly interfere with the kinase activity of mTOR and caused a time-dependent gradual loss of mTORC1/2 signaling capacity, it was hypothesized that mycolactone interferes with the mTOR

Chemical systems, chemical contiguity and the emergence of life

• Terrence P. Kee and
• Pierre-Alain Monnard

Beilstein J. Org. Chem. 2017, 13, 1551–1563, doi:10.3762/bjoc.13.155

• of catalysts, which affords a barrier to these species having been instrumental in the origins of life [7]. However, the reactivity of pyrophosphites (P with a +3 oxidation state) [46][47] is large enough to concomitantly permit phosphorylation reactions to activate small chemicals, as such as amino

Grip on complexity in chemical reaction networks

• Albert S. Y. Wong and
• Wilhelm T. S. Huck

Beilstein J. Org. Chem. 2017, 13, 1486–1497, doi:10.3762/bjoc.13.147

• being simple enough (i.e., analytically solvable) and are therefore well-suited for approaches viewed in the framework of rates of chemical reactions. Figure 1a shows more detail on how a simple phosphorylation and dephosphorylation system can influence the rates of its own formation creating either a

G-Protein coupled receptors: answers from simulations

• Timothy Clark

Beilstein J. Org. Chem. 2017, 13, 1071–1078, doi:10.3762/bjoc.13.106

• . GPCRs are normally deactivated by β-arrestin, as shown in Figure 4. After activation and dissociation of the β/γ subunit, IL3 and the C-terminus of the GPCR are phosphorylated at serine and threonine residues (Figure 4a). This phosphorylation allows the recruitment of β-arrestin (Figure 4b), which can

Aggregation behaviour of a single-chain, phenylene-modified bolalipid and its miscibility with classical phospholipids

• Simon Drescher,
• Vasil M. Garamus,
• Christopher J. Garvey,
• Annette Meister and
• Alfred Blume

Beilstein J. Org. Chem. 2017, 13, 995–1007, doi:10.3762/bjoc.13.99

• synthesised from the corresponding diol (HO-C18pPhC18-OH) by established phosphorylation and quarternisation reactions described previously [38]. The long-chain, phenylene-modified 1,ω-diol in turn was prepared using a bis-Sonogashira cross-coupling reaction [37] with PdCl2(PPh3)2 as catalyst and tetra-n

Derivatives of the triaminoguanidinium ion, 5. Acylation of triaminoguanidines leading to symmetrical tris(acylamino)guanidines and mesoionic 1,2,4-triazolium-3-aminides

• Jan Szabo,
• Julian Greiner and
• Gerhard Maas

Beilstein J. Org. Chem. 2017, 13, 579–588, doi:10.3762/bjoc.13.57

• biological activities have been reported for some of the other types of mesoionic heterocycles. For example, antitumor [27][28][29], antileishmanial [30] and trypanocidal [31] activities, as well as reduction of the phosphorylation efficiency of rat liver mitochondria [32], have been described for 1,3,4

Revaluation of biomass-derived furfuryl alcohol derivatives for the synthesis of carbocyclic nucleoside phosphonate analogues

• Bemba Sidi Mohamed,
• Christian Périgaud and
• Christophe Mathé

Beilstein J. Org. Chem. 2017, 13, 251–256, doi:10.3762/bjoc.13.28

• . However, none of them showed significant antiviral or cytotoxic activities. The absence of biological activity may be attributed to various factors, such as inability to enter cells or to behave as substrates for intracellular enzymes catalyzing phosphorylation, as well as a lack of inhibition of viral

Inhibition of peptide aggregation by means of enzymatic phosphorylation

• Kristin Folmert,
• Malgorzata Broncel,
• Hans v. Berlepsch,
• Christopher H. Ullrich,
• Mary-Ann Siegert and
• Beate Koksch

Beilstein J. Org. Chem. 2016, 12, 2462–2470, doi:10.3762/bjoc.12.240

• , Umweltservice, Bahntechnikerring 74, 14774 Kirchmöser, Germany Department of Organic Chemistry, Technische Universität Berlin, Strasse des 17. Juni 124, 10623 Berlin, Germany 10.3762/bjoc.12.240 Abstract As is the case in numerous natural processes, enzymatic phosphorylation can be used in the laboratory to

• influence the conformational populations of proteins. In nature, this information is used for signal transduction or energy transfer, but has also been shown to play an important role in many diseases like tauopathies or diabetes. With the goal of determining the effect of phosphorylation on amyloid fibril

• recognition motif for PKA (cAMP-dependent protein kinase) that enables enzymatic phosphorylation. We have analyzed the pathway of amyloid formation and the influence of enzymatic phosphorylation on the different states along the conformational transition from random-coil to β-sheet-rich oligomers to

A detailed view on 1,8-cineol biosynthesis by Streptomyces clavuligerus

• Jan Rinkel,
• Patrick Rabe,
• Laura zur Horst and
• Jeroen S. Dickschat

Beilstein J. Org. Chem. 2016, 12, 2317–2324, doi:10.3762/bjoc.12.225

• organic layers were dried over MgSO4 and the solvent was removed under reduced pressure. The crude product was used for phosphorylation. In a second flask, to a solution of (n-Bu4)3HP2O7 (97 mg, 0.11 mmol, 1.5 equiv) in dry CH3CN (1.0 mL) the crude product of the allyl bromide (1.0 equiv) was added and

Biosynthesis of oxygen and nitrogen-containing heterocycles in polyketides

• Franziska Hemmerling and
• Frank Hahn

Beilstein J. Org. Chem. 2016, 12, 1512–1550, doi:10.3762/bjoc.12.148

Multicomponent reactions: A simple and efficient route to heterocyclic phosphonates

• Mohammad Haji

Beilstein J. Org. Chem. 2016, 12, 1269–1301, doi:10.3762/bjoc.12.121

• heterocyclic phosphonates: (a) the direct electrophilic or nucleophilic phosphorylation of the heterocyclic systems and (b) the ring closure of phosphoryl-functionalized substrates through cyclization or cycloaddition reactions [14][15][16][17][18][19]. Multicomponent reactions (MCRs) constitute one of the

• heterocyclic phosphonates through modification of the products obtained by the Kabachnik–Fields reaction. 2.1 Phosphorylation of the parent heterocycles through a traditional Kabachnik–Fields reaction Heterocycloalkanones may be used as carbonyl components in the Kabachnik–Fields reaction to give cyclic α

• 1,2-dihydropyridine-3-phosphonate 259. Yavari et al. have described the phosphorylation of benzothiazole (263) and isoquinoline (246) through a one-pot three-component reaction with activated acetylenes 260 and diphenyl phosphonate (261) under solvent-free conditions at room temperature (Scheme 54

Cyclisation mechanisms in the biosynthesis of ribosomally synthesised and post-translationally modified peptides

• Andrew W. Truman

Beilstein J. Org. Chem. 2016, 12, 1250–1268, doi:10.3762/bjoc.12.120

• cyclisation reactions are catalysed by bifunctional lanthionine synthetases for classes II–IV [47][49][54]. Furthermore, dehydration in each of these classes has been shown to proceed via phosphorylation of the amino acid side chain rather than by glutamylation [54]. Class II synthetases (“LanM”) have an N

• central kinase domain catalyses phosphorylation and an N-terminal lyase domain catalyses elimination [58]. Both class III and IV synthetases have C-terminal LanC-like cyclase domains, but class III enzymes lack the three conserved residues that bind zinc in the other classes [57], which is surprising