Enantioselective Diels–Alder reaction of anthracene by chiral tritylium catalysis

• Qichao Zhang,
• Jian Lv and
• Sanzhong Luo

Beilstein J. Org. Chem. 2019, 15, 1304–1312, doi:10.3762/bjoc.15.129

• -coordinated phosphonate anion with balanced association ability with tritylium ions provided a new opportunity in pursuing chiral ion pair-type carbocation catalysis. The resulted asymmetric tritylium catalysis has enabled the so-far challenging Diels–Alder reactions of unsubstituted anthracene with good

Steroid diversification by multicomponent reactions

• Leslie Reguera,
• Cecilia I. Attorresi,
• Javier A. Ramírez and
• Daniel G. Rivera

Beilstein J. Org. Chem. 2019, 15, 1236–1256, doi:10.3762/bjoc.15.121

• to be conducted at reflux to obtain a good yield of Ugi-derived steroids, albeit the procedure generated a pair of diastereomers (epimeric at C-5) in almost equal amount. The stereoselectivity of the intramolecular MCR increased when a bulky isonitrile was used, e.g., diethyl phosphonate isocyanide

An improved synthesis of adefovir and related analogues

• David J. Jones,
• Eileen M. O’Leary and
• Timothy P. O’Sullivan

Beilstein J. Org. Chem. 2019, 15, 801–810, doi:10.3762/bjoc.15.77

• the versatility of our approach. Keywords: acyclic nucleoside phosphonate; adefovir; alkylation; antiviral; N-alkylation; purine; Introduction The acyclic nucleoside phosphonate adefovir (1) [1], administered as its dipivoxil prodrug form (2) [2], is used clinically for the treatment of infections

• form alcohol 4 and further base-mediated alkylation with tosylate 5 affords phosphonate ester intermediate 6. Subsequent dealkylation of 6 using trimethylsilyl bromide (TMSBr) gives adefovir (1). The related analogue tenofovir, developed as an anti-HIV agent, may be prepared in a similar manner [37][38

• a sticky resin on exposure to atmospheric moisture. This resin hinders the isolation of phosphonate 6 and stymies scale-up. Finally, several byproducts, including the ethyl ether of 4 and the hemi-dealkylated ester of 6, are produced during this reaction, further reducing the atom economy of this

Synthesis of the polyketide section of seragamide A and related cyclodepsipeptides via Negishi cross coupling

• Jan Hendrik Lang and
• Thomas Lindel

Beilstein J. Org. Chem. 2019, 15, 577–583, doi:10.3762/bjoc.15.53

• [39] proved to be superior to the more commonly employed n-BuLi/MeI reagent combination that led to the formation of a series of side products. We also attempted a Bestmann–Ohira reaction with in situ formation of the diazo phosphonate [40] that gave a slightly inferior yield after methylation of the

Aqueous olefin metathesis: recent developments and applications

• Valerio Sabatino and
• Thomas R. Ward

Beilstein J. Org. Chem. 2019, 15, 445–468, doi:10.3762/bjoc.15.39

• , entries 2, 7 and 12). Gebbink and co-workers anchored the HG-type catalyst 79 to cutinase, a serine hydrolase [75]. The phosphonate ester moiety acts as a suicide inhibitor forming an irreversible covalent bond to a serine residue present in the active site of the enzyme. Assembly of ArM 8 occurs at pH 5

Pd-Catalyzed microwave-assisted synthesis of phosphonated 13α-estrones as potential OATP2B1, 17β-HSD1 and/or STS inhibitors

• Rebeka Jójárt,
• Szabolcs Pécsy,
• György Keglevich,
• Mihály Szécsi,
• Réka Rigó,
• Csilla Özvegy-Laczka,
• Gábor Kecskeméti and
• Erzsébet Mernyák

Beilstein J. Org. Chem. 2018, 14, 2838–2845, doi:10.3762/bjoc.14.262

• the yields of the C–P couplings. Reactions with catalyst precursor Pd(OAc)2 gave the desired phosphonate 8a in moderate yields (Table 1, entries 1–8). Starting from 2-iodo compound 1I, dehalogenation, an unwanted side reaction occurred, in particular, at elevated temperature (Table 1, entries 3, 4, 7

Non-metal-templated approaches to bis(borane) derivatives of macrocyclic dibridgehead diphosphines via alkene metathesis

• Tobias Fiedler,
• Michał Barbasiewicz,
• Michael Stollenz and
• John A. Gladysz

Beilstein J. Org. Chem. 2018, 14, 2354–2365, doi:10.3762/bjoc.14.211

• tethered by a methylene chain, in two steps in 66–68% overall yields from diethyl phosphonate ((O=)PH(OEt)2), Grignard reagents BrMg(CH2)mCH=CH2, base (NaH), and appropriate α,ω-dibromides Br(CH2)nBr [25]. Following metathesis and hydrogenation, these afford dibridgehead diphosphine oxides 15 and 16 in 14

Investigation of the electrophilic reactivity of the biologically active marine sesquiterpenoid onchidal and model compounds

• Melissa M. Cadelis and
• Brent R. Copp

Beilstein J. Org. Chem. 2018, 14, 2229–2235, doi:10.3762/bjoc.14.197

• enol acetate 17. Reagents and conditions: a) phosphonate 19 (1.3 equiv), LiOH·H2O (1.5 equiv), THF, 4 h, 15% (25), 1.5% (26); b) LiAlH4 (2.5 equiv), Et2O, 0 °C, 1 h, 61% (27), 71% (28); c) DMP (2.5 equiv), CH2Cl2, 4 h, 49% (15), 73% (16); d) Ac2O (2 equiv), pyridine (4 equiv), overnight, 43% (17

Visible light-mediated difluoroalkylation of electron-deficient alkenes

• Vyacheslav I. Supranovich,
• Vitalij V. Levin,
• Marina I. Struchkova,
• Jinbo Hu and
• Alexander D. Dilman

Beilstein J. Org. Chem. 2018, 14, 1637–1641, doi:10.3762/bjoc.14.139

• were coupled with alkenes 2 (Figure 1). Esters and amides of acrylic acid, acrylonitrile, and vinyl phosphonate used in a small excess (1.2 equiv) were successfully fluoroalkylated. For vinyl(phenyl)sulfone, significant amounts of hydrodeiodination product RfH was formed, likely because of the

Oligonucleotide analogues with cationic backbone linkages

• Melissa Meng and
• Christian Ducho

Beilstein J. Org. Chem. 2018, 14, 1293–1308, doi:10.3762/bjoc.14.111

• oligonucleotide analogues was performed on solid support using H-phosphonate chemistry (Scheme 1). Thus, solid phase-linked thymidine 12 was coupled with 5'-dimethoxytrityl-(DMTr)-protected thymidine 3'-H-phosphonate 13 to give dimeric H-phosphonate 14, which was then acidically DMTr-deprotected to furnish 15

• review. Fathi et al. have established the aminoethylphosphonate linkage 19 (i.e., a phosphonate analogue of amidate 7) [47], and Rahman, Obika and co-workers have described cationic phosphorothioates of type 20 [48] (Figure 4). The preparation of phosphonate linkage 19 was achieved in diastereomerically

• accessible by means of chemical synthesis, which is either based on the application of H-phosphonate (for i) or phosphoramidite-based (for iv) DNA synthesis, or on a massively modified version of DNA synthesis (for ii and iii), or on solid phase-supported peptide synthesis (for iv). Studies on the properties

Electrochemically modified Corey–Fuchs reaction for the synthesis of arylalkynes. The case of 2-(2,2-dibromovinyl)naphthalene

• Fabiana Pandolfi,
• Isabella Chiarotto and
• Marta Feroci

Beilstein J. Org. Chem. 2018, 14, 891–899, doi:10.3762/bjoc.14.76

• dihalides or vinyl bromides using sodium in ammonia or strong bases [8]. Alternatively, the compounds are accessible by homologation of aldehydes following the Bestmann modification of the Seyferth–Gilbert reaction, using in situ generated dimethyl (diazomethyl)phosphonate [9][10]. Moreover, the aldehyde

Phosphodiester models for cleavage of nucleic acids

• Satu Mikkola,
• Tuomas Lönnberg and
• Harri Lönnberg

Beilstein J. Org. Chem. 2018, 14, 803–837, doi:10.3762/bjoc.14.68

Preparation of trinucleotide phosphoramidites as synthons for the synthesis of gene libraries

• Ruth Suchsland,
• Bettina Appel and
• Sabine Müller

Beilstein J. Org. Chem. 2018, 14, 397–406, doi:10.3762/bjoc.14.28

• proceed by either phosphite triester chemistry or phosphotriester chemistry with the latter being the more robust method. Also H-phosphonate chemistry has been used for assembling short oligomers in solution [34], although not with the aim of generating trinucleotide synthons for gene synthesis. 2

• released by a transesterification mechanism [35]. The 3'-start nucleoside is bound to one of the primary hydroxy groups of CPG-linked glycerol via an H-phosphonate linkage (Figure 5B). The removal of the TBDMS group from the remaining primary alcohol of glycerol induces the spontaneous cleavage of the H

• -phosphonate and the release of the oligomer with the free 3'-OH group leaving all other protecting groups intact. This strategy has been shown to be compatible with phosphoramidite chemistry and β-cyanoethyl protection of the internucleotide phosphates [33]. A more recent report describes the preparation of a

Aminosugar-based immunomodulator lipid A: synthetic approaches

• Alla Zamyatina

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

Phosphonic acid: preparation and applications

• Charlotte M. Sevrain,
• Mathieu Berchel,
• Hélène Couthon and
• Paul-Alain Jaffrès

Beilstein J. Org. Chem. 2017, 13, 2186–2213, doi:10.3762/bjoc.13.219

• that can be used for the synthesis of phosphonic acids from dialkyl or diaryl phosphonate, from dichlorophosphine or dichlorophosphine oxide, from phosphonodiamide, or by oxidation of phosphinic acid. Direct methods that make use of phosphorous acid (H3PO3) and that produce a phosphonic acid functional

• the best methods to prepare phosphonic acids. Keywords: bromotrimethylsilane; hydrolysis; McKenna’s reaction; phosphonate; phosphonic acid; Review 1. Introduction Phosphonic acid is a functional group featuring two hydroxy moieties, one P=O double bond and one P–C bond. This functional group was

• K26 6) [45] or the anti-osteoporosis compounds alendronate (7) [46] and zoledronate (8) [47] (Figure 3A). In some cases, the bio-active phosphonic acid is generated in vivo from a phosphonate pro-drug [48] as exemplified by the formation of 10 from 9 which permits to improve the pharmacokinetic

Mechanochemical synthesis of small organic molecules

• Tapas Kumar Achar,
• Anima Bose and
• Prasenjit Mal

Beilstein J. Org. Chem. 2017, 13, 1907–1931, doi:10.3762/bjoc.13.186

• this protocol. Different organophosphorus compounds including phosphine oxides, phosphinate ester, and phosphonate diester underwent C–P bond formation to give 22–94% of yield (Scheme 42). This method was also found to be applicable in gram scale synthesis with excellent yield. Mechanistically they

Synthesis of benzothiophene and indole derivatives through metal-free propargyl–allene rearrangement and allyl migration

• Jinzhong Yao,
• Yajie Xie,
• Lianpeng Zhang,
• Yujin Li and
• Hongwei Zhou

Beilstein J. Org. Chem. 2017, 13, 1866–1870, doi:10.3762/bjoc.13.181

• , which were versatile synthetic intermediates [37][38]. The N-methyl-N-allylpropargyl alcohol 3 was treated with (EtO)2PCl under alkaline conditions, then underwent a propargyl phosphite/allenyl phosphonate rearrangement and an intramolecular nucleophilic attack to form the indole moiety, followed by

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

Synthesis of oligonucleotides on a soluble support

• Harri Lönnberg

Beilstein J. Org. Chem. 2017, 13, 1368–1387, doi:10.3762/bjoc.13.134

• byproducts after each coupling, oxidation and deprotection step. The techniques applied so far include precipitation, extraction, chromatography and nanofiltration. As regards coupling, all conventional chemistries, viz. phosphoramidite, H-phosphonate and phosphotriester strategies, have been attempted

• . While P(III)-based phosphoramidite and H-phosphonate chemistries are almost exclusively used on a solid support, the “outdated” P(V)-based phosphotriester chemistry still offers one major advantage for the synthesis on a soluble support; the omission of the oxidation step simplifies the coupling cycle

• protected nucleoside 3´-(2-cyanoethyl-N,N-dialkylphosphoramidite)s (1 in Scheme 1) or 3´-(H-phosphonate)s are usually preferred as building blocks [3] (2 in Scheme 1). The attacking 5´-OH apart, all other nucleophilic functionalities must be kept protected during the coupling. The primary amino groups of

Total syntheses of the archazolids: an emerging class of novel anticancer drugs

• Stephan Scheeff and
• Dirk Menche

Beilstein J. Org. Chem. 2017, 13, 1085–1098, doi:10.3762/bjoc.13.108

• the molecule could not be suppressed and required a tedious HPLC separation at this stage. After attachment of the phosphonate 7, aldehyde 35 was obtained by removal of the PMB group and oxidation of the primary alcohol. The moderate yields of this sequence are mainly due to side reactions in the

• alcohol 49 in 76% over 2 steps [83]. Before TBS protection the Weinreb amide was generated and then conversed into the phosphonate 50 as a precursor for a Horner–Wadsworth–Emmons reaction. The olefination led to unsaturated ketone 52 in 79% yield. For the final fragment synthesis the ketone was reduced

• with phosphonate 61 in an excellent yield of 93% over 4 steps. After reduction of ester 62 to the corresponding aldehyde (by a method that was not specified by the authors) phosphorane 63 was used to generate the respective Z-vinyl iodide in 85% yield as an 8:1 (Z,Z):(Z,E) mixture [91] which was later

Transition-metal-catalyzed synthesis of phenols and aryl thiols

• Yajun Liu,
• Shasha Liu and
• Yan Xiao

Beilstein J. Org. Chem. 2017, 13, 589–611, doi:10.3762/bjoc.13.58

• , Yang and co-workers reported the first phosphonate-directed hydroxylation of arenes for the synthesis of 2’-phosphorylbiphenyl-2-ol [73]. The reaction was catalyzed by Pd(TFA)2 in the presence of PhI(OAc)2 as oxidant (Scheme 44). Screening for directing groups found a series of dialkyl and diaryl

• phosphonates were compatible with the hydroxylation condtions, while monoalkyl phosphonate gave the phosphoryl lactone as product. Exploration of substrate scope showed that both electron-donating groups (such as Me, OMe) and electron-withdrawing groups (such as F, Cl, Br, CF3) are tolerable. 1.2.2.3 Phenol as

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

• compounds were evaluated for their activity against a large number of viruses. However, none of them showed significant antiviral activity or cytotoxicity. Keywords: analogue; antiviral; carbocyclic; nucleoside; phosphonate; Introduction Biomass is a valuable resource in search of renewable organic carbon

• afforded the carbocyclic phosphonate (+/−)-10. Subsequently, the phosphonoester protecting groups were cleaved in the presence of TMSCl and NaI in a CH3CN/DMF mixture to give (+/−)-12 in 61% yield. The treatment of (+/−)-9 with K2CO3 in methanol at room temperature gave compound (+/−)-11 which upon

• upon reaction with water as an incoming nucleophile, afforded compound (+/−)-15 with a higher substituted double bond. After deprotection of the phosphonate diester groups, structural assignments of (+/−)-16 were based upon 1H and 13C NMR spectra and correlation experiments, which showed some

The synthesis of α-aryl-α-aminophosphonates and α-aryl-α-aminophosphine oxides by the microwave-assisted Pudovik reaction

• Erika Bálint,
• Ádám Tajti,
• Anna Ádám,
• István Csontos,
• Konstantin Karaghiosoff,
• Mátyás Czugler,
• Péter Ábrányi-Balogh and
• György Keglevich

Beilstein J. Org. Chem. 2017, 13, 76–86, doi:10.3762/bjoc.13.10

• (Table 1). The products were α-aminophosphonates 2a–d and α-aminophosphine oxide 2e. The addition of 1 equivalent of dimethyl phosphite (DMP) to imine 1a at 80 °C was almost complete after 30 min, and dimethyl ((butylamino)(phenyl)methyl)phosphonate (2a) could be isolated in a yield of 73% (Table 1

• conditions, the reaction of dibenzyl phosphite (DBnP) was also clear-cut and afforded dibenzyl ((butylamino)(phenyl)methyl)phosphonate (2d) in 69% yield (Table 1, entry 10). Finally, diphenylphosphine oxide (DPPO) was added to imine 1a. After 10 min irradiation at 100 °C, complete conversion was observed and

• , no quantitative conversion could be achieved (Table 2, entry 2). There was need for 1.5 equivalents of DMP to attain a conversion of 99%. In this case, dimethyl ((cyclohexylamino)(phenyl)methyl)phosphonate (4a) was isolated in a yield of 87% (Table 2, entry 3). The comparative thermal experiment led

First DMAP-mediated direct conversion of Morita–Baylis–Hillman alcohols into γ-ketoallylphosphonates: Synthesis of γ-aminoallylphosphonates

• Marwa Ayadi,
• Haitham Elleuch,
• Emmanuel Vrancken and
• Farhat Rezgui

Beilstein J. Org. Chem. 2016, 12, 2906–2915, doi:10.3762/bjoc.12.290

• conditions, is described herein for the first time. Subsequently, a highly regioselective Luche reduction of the primary phosphonate 2a (R = H) gave the corresponding γ-hydroxyallylphosphonate 5 that further reacted with tosylamines in the presence of diiodine (15 mol %) as a catalyst, affording the

• interesting antimicrobial and antimalarial properties [8][9], as well as useful substrates for the synthesis of valuable organic compounds [10][11][12]. Historically, the Michaelis−Arbuzov rearrangement [13] is the most widely and generally high yielding strategy for phosphonate synthesis. The current three

• , without any additive, provided, after thermal Arbuzov rearrangement, a variety of diethyl allylphosphonates (Scheme 1, reaction 3) [18]. Moreover, the asymmetric allylic substitution of MBH carbonates with diphenyl phosphonate using chiral thiourea phosphite as catalyst, afforded the related

Benzothiadiazole oligoene fatty acids: fluorescent dyes with large Stokes shifts

• Lukas J. Patalag and
• Daniel B. Werz

Beilstein J. Org. Chem. 2016, 12, 2739–2747, doi:10.3762/bjoc.12.270

• same length, but of more extended conjugation we made use of the Horner–Wadsworth–Emmons (HWE) reaction. Phosphonate 4 was reacted with the respective aldehyde 1. In a facile three-step one-pot process the emerging α,β-unsaturated ester 5 was immediately converted to the alcohol 6 in 87% yield in the

• conjugated double bonds was accessed by a similar route that differs only in the type of the phosphonate being employed as starting material. Since three double bonds are required a tailor-made α,β-unsaturated phosphonate 8 was used, which we already employed successfully in former oligoene syntheses [15

• phosphonate 8 (189 mg, 0.792 mmol, 1.3 equiv) in THF (5 mL) was added n-butyllithium (2.5 M, 0.32 mL, 0.792 mmol, 1.3 equiv) at 0 °C. Stirring was continued at this temperature for 15 min. A solution of aldehyde 1 (100 mg, 0.609 mmol, 1 equiv) in THF (2 mL) was added dropwise at 0 °C and strirring continued