Organophosphorus chemistry: from model to application

• György Keglevich

Beilstein J. Org. Chem. 2023, 19, 89–90, doi:10.3762/bjoc.19.8

• related N-heterocycles to prepare the respective bisphosphonate derivatives that were transformed to the corresponding diphosphonic acids. The Pudovik addition is still an evergreen reaction as it leads to α-hydroxyphosphonates that are versatile intermediates in organophosphorus chemistry. Yang et al

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

• purity is obtained without the use of any chromatography, which is ideal for large-scale processes. Optimisation of the synthesis of phosphoramidate 13 and phosphonate 7 Having been shown to be a feasible intermediate, attention turned to improving the synthesis of bisphosphonate 7 via a two-step process

Synthesis, antiinflammatory activity, and molecular docking studies of bisphosphonic esters as potential MMP-8 and MMP-9 inhibitors

• Abimelek Cortes-Pacheco,
• María Adelina Jiménez-Arellanes,
• Francisco José Palacios-Can,
• José Antonio Valcarcel-Gamiño,
• Rodrigo Said Razo-Hernández,
• María del Carmen Juárez-Vázquez,
• Adolfo López-Torres and
• Oscar Abelardo Ramírez-Marroquín

Beilstein J. Org. Chem. 2020, 16, 1277–1287, doi:10.3762/bjoc.16.108

• of each bisphosphonate represented a minimum in the potential energy surface since all vibrational frequency values were positive. In Table 3, all the molecular properties obtained for the compounds are displayed. The chemical hardness (η) and softness (S) were calculated using Equation 1 and

• ligand efficiency (LE) of each bisphosphonate is shown; the ligand efficiency stands for the coefficient of the interaction energy by the number of atoms in the molecule (excluding hydrogen atoms). By the inspection of the results above, there is a correlation between the LE parameter in MMP-8 and the

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

• . Subsequent deprotection of the NMN acetonide 33 using trifluoroacetic acid in DCM/water mixture or HCl in methanol was followed by C18 reverse phase chromatography to afford NMN in 90% and 67%, respectively. Meyer and Hilz [86] reported the synthesis of the bisphosphonate analogue of β-NAD+ 36 using a

• synthetic sequence, the key reaction of which was a coupling of bisphosphonate 34 with isopropylidene-protected NR+ 29 under the Steglich esterification conditions in the presence of tri-n-octylamine, pyridine and DCC in DMF medium at 60 °C for 18 h (Scheme 19). Compound 36 was isolated in pure form by

• means of purification on a Dowex formate column and characterized by 1H NMR spectroscopy. The low isolated yield of the final β-NAD+ bisphosphonate derivative (13%) may be explained by the fact that isopro-NR+ used was a mixture of β/α anomers with respective ratio of 3:2 and that the coupling

Strong binding and fluorescence sensing of bisphosphonates by guanidinium-modified calix[5]arene

• Jie Gao,
• Zhe Zheng,
• Lin Shi,
• Si-Qi Wu,
• Hongwei Sun and
• Dong-Sheng Guo

Beilstein J. Org. Chem. 2018, 14, 1840–1845, doi:10.3762/bjoc.14.157

• BPs in buffer solution, and more importantly, in artificial urine. Calibration lines were therefore set up in untreated artificial urine, allowing for quantifying the concentrations of BPs in the biologically relevant low range. Keywords: bisphosphonate; calixarene; fluorescence sensing; macrocyclic

Synthetic mRNA capping

• Fabian Muttach,
• Nils Muthmann and
• Andrea Rentmeister

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

• translation in in vitro translation experiments. In a further step, tetraphosphates with methylene(bisphosphonate) moieties were prepared which improved binding to eIF4E and in some cases conferred enzymatic resistance against DcpS degradation [67]. N2-Triazole-containing monophosphate cap analogues were

Synthesis of medronic acid monoesters and their purification by high-performance countercurrent chromatography or by hydroxyapatite

• Elina Puljula,
• Jouko Vepsäläinen and
• Petri A. Turhanen

Beilstein J. Org. Chem. 2016, 12, 2145–2149, doi:10.3762/bjoc.12.204

• : bisphosphonate; bisphosphonate monoester; high performance counter current chromatography; hydroxyapatite; medronic acid; Introduction Bisphosphonates (BPs) have been used for decades in the treatment of bone-related diseases as well as for bone imaging. Nevertheless, several recent reports have demonstrated

Microwave-assisted synthesis of (aminomethylene)bisphosphine oxides and (aminomethylene)bisphosphonates by a three-component condensation

• Erika Bálint,
• Ádám Tajti,
• Anna Dzielak,
• Gerhard Hägele and
• György Keglevich

Beilstein J. Org. Chem. 2016, 12, 1493–1502, doi:10.3762/bjoc.12.146

• condensation of butylamine, triethyl orthoformate with 2 equivalents of diethyl phosphite was studied at 125 °C. After a 2 h’s reaction time, the conversion was 91%, and beside the expected (aminomethylene)bisphosphonate 3a formed in 81%, the N-ethylated by-product 4a was formed in 19% (Table 3, entry 1

• , entries 5–8), and the corresponding (cyclohexylaminomethylene)bisphosphonate 3b was obtained in a yield of 68% after column chromatography (Table 3, entry 6). Finally, the three-component condensation of aniline, triethyl orthoformate and diethyl phosphite was studied (Table 3, entries 9–11). Applying 2

• (dialkylaminomethylene)bisphosphine oxides. Synthesis of tetramethyl (phenylaminomethylene)bisphosphonate. Synthesis of (dialkylaminomethylene)bisphosphonates. Synthesis of alkylamino- and (phenylaminomethylene)bisphosphine oxides 1a–d. Synthesis of (dialkylaminomethylene)bisphosphine oxides 2a–g. The reactions of

Towards potential nanoparticle contrast agents: Synthesis of new functionalized PEG bisphosphonates

• Souad Kachbi-Khelfallah,
• Maelle Monteil,
• Margery Cortes-Clerget,
• Evelyne Migianu-Griffoni,
• Jean-Luc Pirat,
• Olivier Gager,
• Julia Deschamp and
• Marc Lecouvey

Beilstein J. Org. Chem. 2016, 12, 1366–1371, doi:10.3762/bjoc.12.130

• is a procedure developed in our laboratory to introduce the bisphosphonate from acyl chloride and tris(trimethylsilyl)phosphite in one step. Keywords: bisphosphonate; Fe2O3 nanoparticle; polyethylene glycol derivatives; surface ligand synthesis; Introduction Numerous researchers are interested in

• bifunctional molecules substituted by amines, thiols, carboxylates, sulfonates, phosphonates or bisphosphonates [5][6][7]. Particularly, a strong interaction between the NPs and the phosphonic moiety was observed and more interestingly the best results were obtained with bisphosphonate products [8][9]. For the

• (trimethylsilyl) phosphite to the acyl chloride derivatives 8 and 9a,b yielded the corresponding silylated PEG-HMBP. The formation of silylated bisphosphonate was monitored by 31P NMR. After evaporation of volatile compounds under vacuum the silylated PEG-HMBP was hydrolyzed with methanol at room temperature for

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

• -2-ylphosphonates showed cysteine protease inhibition activities. 2.2.9 Heterocyclic bisphosphonates: A modified Kabachnik–Fields reaction of the substituted amine 135 with triethyl orthoformate followed by reaction with sodium diethylphosphite afforded bisphosphonate intermediate 136 that was

• converted to the heterocyclic bisphosphonate 137 through an intramolecular cyclization (Scheme 29) [55]. The sequenced reaction of the amine with triethyl orthoformate followed by the addition of sodium diethylphosphite dissolved in toluene considerably increased the yields of bisphosphonates. In this way

Organophosphorus chemistry

• Paul R. Hanson

Beilstein J. Org. Chem. 2014, 10, 2087–2088, doi:10.3762/bjoc.10.217

• phosphanylidenecarbenes and phosphoryl azides, and bisphosphonate ethers as promising inhibitors of geranylgeranyl diphosphate synthase (GGDPS). The articles and reviews capture the emerging potential of organophosphorus compounds and exciting opportunities in the field, and hopefully, will inspire and motivate

Synthesis of isoprenoid bisphosphonate ethers through C–P bond formations: Potential inhibitors of geranylgeranyl diphosphate synthase

• Xiang Zhou,
• Jacqueline E. Reilly,
• Kathleen A. Loerch,
• Raymond J. Hohl and
• David F. Wiemer

Beilstein J. Org. Chem. 2014, 10, 1645–1650, doi:10.3762/bjoc.10.171

• City, Iowa 52242-1294, USA 10.3762/bjoc.10.171 Abstract A set of bisphosphonate ethers has been prepared through sequential phosphonylation and alkylation of monophosphonate ethers. After formation of the corresponding phosphonic acid salts, these compounds were tested for their ability to inhibit the

• no activity against FDPS even at a 10 μM concentration. Keywords: bisphosphonate; isoprenoid biosynthesis; organophosphorous; phosphonate formation; Introduction Several enzymes of the isoprenoid biosynthesis pathways are the targets of widely prescribed drugs. For example, hydroxymethylglutaryl

• should reduce cellular levels of GGPP and thus diminish protein geranylgeranylation, one might expect that inhibitors of this enzyme would interfere with essential cell signaling pathways and demonstrate antiproliferative activity. Several years ago we reported the synthesis of digeranyl bisphosphonate

Phosphinate-containing heterocycles: A mini-review

• Olivier Berger and
• Jean-Luc Montchamp

Beilstein J. Org. Chem. 2014, 10, 732–740, doi:10.3762/bjoc.10.67

• have synthesized a few phosphindoles. The first phosphindole 6 was simply obtained in 84% yield by reacting an α,ω-bisphosphonate derivative 5 with n-butyllithium in a phospha-Dieckmann condensation (Scheme 3) [17]. Cyclohexyl 2-(biphenyl)-H-phosphinate 7 was cyclized using 2 mol % of Pd(OAc)2 in

Synthesis and quantitative structure–activity relationship study of substituted imidazophosphor ester based tetrazolo[1,5-b]pyridazines as antinociceptive/anti-inflammatory agents

• Wafaa M. Abdou,
• Neven A. Ganoub and
• Eman Sabry

Beilstein J. Org. Chem. 2013, 9, 1730–1736, doi:10.3762/bjoc.9.199

• of our continued interest in the development of convenient synthetic approaches to β-enamino- and α-aminophosphonates with anti-inflammatory properties [13][14][15][16][17][18][19][20], we recently successfully synthesized a series of mono- and bisphosphonate-based tetrazolo[1,5-a]quinolines with

Methylidynetrisphosphonates: Promising C₁ building block for the design of phosphate mimetics

• Vadim D. Romanenko and
• Valery P. Kukhar

Beilstein J. Org. Chem. 2013, 9, 991–1001, doi:10.3762/bjoc.9.114

• addition. The reaction sequence leads to N-phosphorylated bisphosphonates 5 instead of the desired trisphosphonates (Scheme 3) [23][24]. Synthesis via anionic methylenebisphosphonates The anionic bisphosphonate [CH(PO3Et2)2]− proved unreactive with diethyl chlorophosphate, ClP(O)(OEt2)2, but

• phosphinylation of the bisphosphonate anion with diethyl chlorophosphite, ClP(OEt)2, followed by in situ oxidation with atmospheric oxygen of the presumed phosphinate intermediate to the trisphosphonate 6 was successful (Scheme 4) [25]. An improved version of this method includes oxidation of the phosphinate

• intermediate with hydrogen peroxide in tetrahydrofuran [26]. Mixed ethyl/isopropyl trisphosphonate ester 9 has been prepared by treatment of the bisphosphonate 7 with diethyl chlorophosphite and sodium hexamethyldisilazane, and subsequent oxidation of the phosphinate intermediate 8 with iodine in pyridine–THF

Preparation of mixed trialkyl alkylcarbonate derivatives of etidronic acid via an unusual route

• Petri A. Turhanen,
• Janne Weisell and
• Jouko J. Vepsäläinen

Beilstein J. Org. Chem. 2012, 8, 2019–2024, doi:10.3762/bjoc.8.228

• mechanism is discussed to explain these methyl substitutions. These unusual reactions also clarify why it is difficult to prepare alkylcarbonate prodrugs from bisphosphonates. The compounds prepared were analysed by spectroscopic techniques. Keywords: alkyl carbonate; bisphosphonate; etidronate; ester

• tetraester derivative 4 was also isolated. The observed results from this study explain some of the difficulties encountered in preparing carbonate prodrugs of bisphosphonates similar to etidronate. On the other hand, the Hewitt reaction observed here enabled the preparation of more complex bisphosphonate

Multistep organic synthesis of modular photosystems

• Naomi Sakai and
• Stefan Matile

Beilstein J. Org. Chem. 2012, 8, 897–904, doi:10.3762/bjoc.8.102

• diphosphonates [20][21] for tetravalent anchoring on the ITO surface. The geminal diphosphonates 7 were synthesized from methylene bis(phosphonic dichloride) 8 (Scheme 1) [20][21]. Conversion with benzyl alcohol and pyridine as a base yielded tetrabenzyl methylene bisphosphonate 9. Activation with sodium hydride

Regioselective ester cleavage during the preparation of bisphosphonate methacrylate monomers

• Kamel Chougrani,
• Gilles Niel,
• Bernard Boutevin and
• Ghislain David

Beilstein J. Org. Chem. 2011, 7, 364–368, doi:10.3762/bjoc.7.46

• Kamel Chougrani Gilles Niel Bernard Boutevin Ghislain David Institut Charles Gerhardt, UMR 5253 CNRS, Ecole Nationale Supérieure de Chimie, 8, rue de l'Ecole Normale, 34296 Montpellier Cedex 5, France 10.3762/bjoc.7.46 Abstract New functional monomers bearing a methacrylate, a bisphosphonate

• function and, for most, an internal carboxylate group, were prepared for incorporation into copolymers with adhesive or anticorrosive properties. Methanolysis of some trimethylsilyl bisphosphonate esters not only deprotects the desired bisphosphonate function but also regioselectively cleaves the alkyl

• use of phosphonate-type methacrylates for the same purpose [8][9]. In the domain of polymer-based materials exhibiting specific properties, bifunctional monomers bearing a methacrylate function and a bisphosphonate function are recognized as useful building blocks for dental materials [11][12][18][19

RAFT polymers for protein recognition

• Alan F. Tominey,
• Julia Liese,
• Sun Wei,
• Klaus Kowski,
• Thomas Schrader and
• Arno Kraft

Beilstein J. Org. Chem. 2010, 6, No. 66, doi:10.3762/bjoc.6.66

• protein affinities [8], accompanied in a number of cases with promising protein selectivities [9]. These linear polymers were all prepared by free radical copolymerization in DMF followed by deprotection of the binding monomers in polymer-analogous transformations. Thus, a polymerized bisphosphonate

• tetramethyl ester was subjected to LiBr-assisted nucleophilic cleavage to furnish the free bisphosphonate dianion binding site. This procedure has two major drawbacks. First, if the functional groups on the polymer backbone become restricted in their accessability, the final deprotection step will suffer from

• from earlier work with linear polymers and microgels [9][15][16]: Sodium methacrylate (2) (S), polymerizable tetrazolate 3 (T) and bisphosphonate 4 (B). These anionic comonomers were directly copolymerized with NIPAM and a hydrophobic acrylamide. The latter carried cyclohexyl (CH), benzyl (BN) or octyl

Molecular recognition of organic ammonium ions in solution using synthetic receptors

• Andreas Späth and
• Burkhard König

Beilstein J. Org. Chem. 2010, 6, No. 32, doi:10.3762/bjoc.6.32

Synthesis of imidazol- 1-yl-acetic acid hydrochloride: A key intermediate for zoledronic acid

• Santosh Kumar Singh,
• Narendra Manne,
• Purna Chandra Ray and
• Manojit Pal

Beilstein J. Org. Chem. 2008, 4, No. 42, doi:10.3762/bjoc.4.42

• then utilized to prepare zoledronic acid. Keywords: ester; N-alkylation; imidazol-1-yl-acetic acid hydrochloride; zoledronic acid; Introduction Zoledronic acid (Z, Figure 1) [1][2][3][4][5][6][7] is a third-generation bisphosphonate (or diphosphonate) derivative characterized by a side chain that

Unexpected degradation of the bisphosphonate P-C-P bridge under mild conditions

• Petri A. Turhanen and
• Jouko J. Vepsäläinen

Beilstein J. Org. Chem. 2008, 4, No. 7, doi:10.1186/1860-5397-4-7

• Petri A. Turhanen Jouko J. Vepsalainen University of Kuopio, Department of Biosciences, Laboratory of Chemistry, PO Box 1627, FIN-70211, Kuopio, Finland 10.1186/1860-5397-4-7 Abstract Unexpected degradation of the P-C-P bridge from novel bisphosphonate derivative 1a and known etidronate trimethyl

• ) partial transesterification of bisphosphonate 1a before degradation of P-C-P bridge, 2) partial esterification of phosphonate group after the carbonate groups (R3) decomposition from compound 1a (this is proposed to occur rapidly after the addition of 40% NaOH) and before the degradation of P-C-P bridge

• (40% NaOH in H2O), MeOH, 30 min, rt. Proposed reaction mechanism for 1b decomposition. Proposed reaction mechanism for 1a decomposition. Supporting Information Supporting Information File 34: Unexpected degradation of bisphosphonate P-C-P bridge under mild conditions. Experimental procedures, full

Synthesis of novel (1-alkanoyloxy- 4-alkanoylaminobutylidene)-1,1-bisphosphonic acid derivatives

• Petri A. Turhanen and
• Jouko J. Vepsäläinen

Beilstein J. Org. Chem. 2006, 2, No. 2, doi:10.1186/1860-5397-2-2

• washing the residue with diethyl ether after the reaction mixture was evaporated to dryness. If needed, after drying the products were dissolved in a small volume of water and stirred for 40 minutes at room temperature for hydrolyzing any of formed bisphosphonate dimers which were obtained as determined