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 While P(III)-based phosphoramidite and H-phosphonate chemistries are almost exclusively used on a solid support, the “outdated” P(V)-based phosphotriester chemistry still offers one major advantage for the synthesis on a soluble support; the omission of the oxidation step simplifies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

A new and expeditious synthesis of all enantiomerically pure stereoisomers of rosaprostol, an antiulcer drug

• Wiesława Perlikowska,
• Remigiusz Żurawiński and
• Marian Mikołajczyk

Beilstein J. Org. Chem. 2016, 12, 2234–2239, doi:10.3762/bjoc.12.215

• be prepared from optically inactive meso-tartaric acid through a two-step reaction sequence. It involves a complete desymmetrization during an acid-catalyzed reaction with (+)-camphor and methyl orthoformate and the subsequent treatment of the formed methyl diester with α-phosphonate carbanion

• above reaction is identical with the stereoisomer (−)-(1S,2R,5R)-1a prepared in our earlier work [23]. In summary, the rosaprostol stereoisomer (−)-1a was synthesized from the starting cyclopentanone phosphonate (+)-3 in four steps and 56% overall yield. As expected, the reduction of the carbonyl group

Stereo- and regioselectivity of the hetero-Diels–Alder reaction of nitroso derivatives with conjugated dienes

• Lucie Brulíková,
• Aidan Harrison,
• Marvin J. Miller and
• Jan Hlaváč

Beilstein J. Org. Chem. 2016, 12, 1949–1980, doi:10.3762/bjoc.12.184

• investigation. It was calculated that the hetero-Diels–Alder reaction between 29a and 1-diethoxyphosphonyl-1,3-butadiene (28) proceeds as a polar cycloaddition via a two-stage process involved in one step, in which the C4–N5 centers’ interaction governs the reaction [83]. The phosphonate moiety also drives the

• reaction towards one regioisomer because of the activating effect and steric hindrance of the phosphonate substituent onto the butadienyl moiety. The computed activation barriers for the cycloaddition of 28 to some representative nitroso compounds 29 were used to elucidate the structure–reactivity

Rearrangements of organic peroxides and related processes

• Ivan A. Yaremenko,
• Vera A. Vil’,
• Dmitry V. Demchuk and
• Alexander O. Terent’ev

Beilstein J. Org. Chem. 2016, 12, 1647–1748, doi:10.3762/bjoc.12.162

• 25, dicarboxylic acids 28, carboxylic acids 26, and keto carboxylic acids 27 (Scheme 7, Table 1) [223]. The oxidation of isophorone oxide (29) is an industrial process for the production of dimethylglutaric acid 30 (Scheme 8) [223]. Acyl phosphate 32 can be synthesized from acyl phosphonate 31 in

Enantioselective addition of diphenyl phosphonate to ketimines derived from isatins catalyzed by binaphthyl-modified organocatalysts

• Hee Seung Jang,
• Yubin Kim and
• Dae Young Kim

Beilstein J. Org. Chem. 2016, 12, 1551–1556, doi:10.3762/bjoc.12.149

• Hee Seung Jang Yubin Kim Dae Young Kim Department of Chemistry, Soonchunhyang University, Soonchunhyang-Ro 22, Asan, Chungnam 31538, Korea 10.3762/bjoc.12.149 Abstract Chiral binaphthyl-modified squaramide-catalyzed enantioselective addition of diphenyl phosphonate to ketimines derived from

• reaction time, and low temperature required for good enantioselectivity. Thus, new approaches for the organocatalytic enantioselective addition of diphenyl phosphonate to isatin imines are highly desired. In connection with our ongoing research program on the design and application in asymmetric catalysis

• phosphonate to ketimines derived from isatins catalyzed by binaphthyl-modified bifunctional organocatalysts (Figure 1). Results and Discussion To determine suitable reaction conditions for the organocatalytic enantioselective addition reaction of diphenyl phosphonate to ketimines derived from isatins, we

Beta-hydroxyphosphonate ribonucleoside analogues derived from 4-substituted-1,2,3-triazoles as IMP/GMP mimics: synthesis and biological evaluation

• Tai Nguyen Van,
• Audrey Hospital,
• Corinne Lionne,
• Lars P. Jordheim,
• Charles Dumontet,
• Christian Périgaud,
• Laurent Chaloin and
• Suzanne Peyrottes

Beilstein J. Org. Chem. 2016, 12, 1476–1486, doi:10.3762/bjoc.12.144

• : cancer; cN-II inhibitors; nucleotide; phosphonate; triazole; Introduction Nucleotidases are an important family of enzymes involved in the metabolism of nucleotides [1]. In particular, human cytosolic 5’-nucleotidase II (cN-II) catalyses the dephosphorylation of purine 5’-monophosphate derivatives to

• of a research program on phosphonate derivatives of nucleosides as mimics of 5’-monophosphate nucleosides, we explored the SAR of various beta-hydroxyphosphonate analogues. Such derivatives have been extensively studied and exhibited Ki values in the same range as the known natural substrates (IMP

• hydrophilic pocket (Ser251 and Lys215) where the hydroxy groups of the sugar interact and a phosphonate binding site close to the magnesium ion located in the substrate binding site. Thus, as few cytosine-containing analogues were equipotent in terms of cN-II inhibition to their purine counterparts (Figure 1

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

• ligands. The use of phosphonate ligands to modify the nanoparticle surface drew a lot of attention in the last years for the design of highly functional hybrid materials. Here, we report a methodology to synthesize bisphosphonates having functionalized PEG side chains with different lengths. The key step

Selective bromochlorination of a homoallylic alcohol for the total synthesis of (−)-anverene

• Frederick J. Seidl and
• Noah Z. Burns

Beilstein J. Org. Chem. 2016, 12, 1361–1365, doi:10.3762/bjoc.12.129

• reduced with dimethyl phosphonate [16][17]. While the mechanism of this Hirao reduction is not fully understood, the reaction was exquisitely mild and proceeded with high chemoselectivity for the geminal dihalide, delivering (−)-anverene (1) in high yield as a 7:1 mixture of E/Z isomers. Following

• mol % Ti(OiPr)4, 10 mol % (S,R)-4, 0.025 M hexanes, −15 °C, 42 h; g) Dess–Martin periodinane (1.2 equiv), NaHCO3 (5 equiv), CH2Cl2, 0 °C to rt; h) CBr4 (2 equiv), PPh3 (4 equiv), CH2Cl2, 0 °C, 10 min; i) Et3N (5 equiv), dimethyl phosphonate (4 equiv), DMF, rt, 5 min. Optimization of a selective

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

• compounds bearing a phosphonate group on the ring is given. Keywords: multicomponent reactions; organophosphorus chemistry; phosphorus reagents; phosphorylated heterocycles; Introduction Heterocyclic rings are found in many naturally occurring compounds and they compose the core structures of many

• were resistant to this reaction. The trimethylchlorosilane-mediated one-pot reaction of diethyl (3,3,3-trifluoropropyl-2-oxo)phosphonate (8) with aryl aldehydes 9 and urea under Biginelli conditions has been presented by Timoshenko et al. (Scheme 3) [27]. The resulting 4-hydroxytetrahydropyrimidin-2

• better yields than in protic solvents. When diethyl (2-oxopropyl)phosphonate and 4-nitrobenzaldehyde were treated in the presence of 50 mol % TsOH in acetonitrile, 5-phosphonato-3,4-dihydropyrimidin-2-one 18 was obtained in excellent yield (Scheme 5). 2 Kabachnik−Fields reaction and its post-condensation

Synthesis, fluorescence properties and the promising cytotoxicity of pyrene–derived aminophosphonates

• Jarosław Lewkowski,
• Maria Rodriguez Moya,
• Anna Wrona-Piotrowicz,
• Janusz Zakrzewski,
• Renata Kontek and
• Gabriela Gajek

Beilstein J. Org. Chem. 2016, 12, 1229–1235, doi:10.3762/bjoc.12.117

• biological imaging. Investigation of cytotoxic effects of studied compounds The cytotoxic effects of dimethyl aminophosphonates 3Aa, 3Ab, 3Ac, 3Ad, 3Ai and dimethyl [hydroxy(pyren-1-yl)methyl]phosphonate (5A) were investigated with two human colorectal carcinoma cell lines: HT29 and HCT116 and also on the

One-pot synthesis of enantiomerically pure N-protected allylic amines from N-protected α-amino esters

• Gastón Silveira-Dorta,
• Sergio J. Álvarez-Méndez,
• Víctor S. Martín and
• José M. Padrón

Beilstein J. Org. Chem. 2016, 12, 957–962, doi:10.3762/bjoc.12.94

• , and N-Ac and N-Boc glutamic acid dialkyl esters, this time using a stabilized phosphonate ester [18]. This strategy was used later on in the synthesis of aminopeptidase A inhibitors [19]. Similarly, N-methylproline methyl ester was reacted in a similar one-pot fashion during the synthesis of nine

Muraymycin nucleoside-peptide antibiotics: uridine-derived natural products as lead structures for the development of novel antibacterial agents

• Daniel Wiegmann,
• Stefan Koppermann,
• Marius Wirth,
• Giuliana Niro,
• Kristin Leyerer and
• Christian Ducho

Beilstein J. Org. Chem. 2016, 12, 769–795, doi:10.3762/bjoc.12.77

• )-selective Wittig–Horner reaction with phosphonate 66 [111] in order to obtain the didehydro amino acid 67. The next important step of this route was an asymmetric catalytic hydrogenation [112][113] with the chiral Rh(I)–DuPHOS catalyst 68 to prepare the (6'S)-configured product 69 [109][110]. Subsequent

Nucleic acids through condensation of nucleosides and phosphorous acid in the presence of sulfur

• Tuomas Lönnberg

Beilstein J. Org. Chem. 2016, 12, 670–673, doi:10.3762/bjoc.12.67

• elemental sulfur. Desulfurization and subsequent digestion of the products by P1 nuclease revealed that nearly 80% of the internucleosidic linkages thus formed were of the canonical 3´,5´-type. Keywords: H-phosphonate; nucleic acid; polymerization; phosphite; sulfurization; Introduction Arguably the most

• phosphorous acid are hydrolytically stable compounds that are readily formed upon concentration of aqueous solutions of alcohols and phosphite salts [12]. The monoesters may react further to H-phosphonate diesters but this is an equilibrium process that under aqueous conditions favors the starting materials

• [13]. Oxidation of the H-phosphonate diester products, however, converts them to the stable phosphodiester counterparts. It is interesting to note that this reaction is faster for H-phosphonate diesters than for the respective monoesters or phosphorous acid itself [12], providing the driving force for

The aminoindanol core as a key scaffold in bifunctional organocatalysts

• Isaac G. Sonsona,
• Eugenia Marqués-López and
• Raquel P. Herrera

Beilstein J. Org. Chem. 2016, 12, 505–523, doi:10.3762/bjoc.12.50

• the acyl phosphonate 24a, in dichloromethane at room temperature, with subsequent addition of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and methanol to give the corresponding ester derivative 25a (Scheme 10a) [39]. The use of the analog squaramide 23 afforded the product with slightly lower selectivity

Interactions of cyclodextrins and their derivatives with toxic organophosphorus compounds

• Sophie Letort,
• Sébastien Balieu,
• William Erb,
• Géraldine Gouhier and
• François Estour

Beilstein J. Org. Chem. 2016, 12, 204–228, doi:10.3762/bjoc.12.23

• phosphonate group for the three methylfluorophosphonates do not result in fundamental changes of the dissociation constants. However, the rather slow hydrolysis rate of P(R)-sarin can be explained by the space arrangement of this stereoisomer into the β-CD cavity. Sarin is the smallest of the three

Hydroquinone–pyrrole dyads with varied linkers

• Hao Huang,
• Christoffer Karlsson,
• Maria Strømme,
• Martin Sjödin and
• Adolf Gogoll

Beilstein J. Org. Chem. 2016, 12, 89–96, doi:10.3762/bjoc.12.10

• material for the corresponding phosphonate. However, neither n-BuLi nor t-BuOK used as base succeeded to give the desired product. Acetylene linker: Synthesis of 3-((2,5-dimethoxyphenyl)ethynyl)-1H-pyrrole (3d) The synthesis strategy for the ethynyl-linked compound 3d was straightforward, using a

Friedel–Crafts-type reaction of pyrene with diethyl 1-(isothiocyanato)alkylphosphonates. Efficient synthesis of highly fluorescent diethyl 1-(pyrene-1-carboxamido)alkylphosphonates and 1-(pyrene-1-carboxamido)methylphosphonic acid

• Anna Wrona-Piotrowicz,
• Janusz Zakrzewski,
• Anna Gajda,
• Tadeusz Gajda,
• Anna Makal,
• Arnaud Brosseau and
• Rémi Métivier

Beilstein J. Org. Chem. 2015, 11, 2451–2458, doi:10.3762/bjoc.11.266

• Oxone®. 1-(Pyrene-1-carboxamido)methylphosphonic acid was obtained in a 87% yield by treating the corresponding diethyl phosphonate with Me3Si-Br in methanol. All of the synthesized amidophosphonates were emissive in solution and in the solid state. The presence of a phosphonato group brought about an

• approximately two-fold increase in solution fluorescence quantum yield in comparison with that of a model N-alkyl pyrene-1-carboxamide. This effect was tentatively explained by stiffening of the amidophosphonate lateral chain which was caused by the interaction (intramolecular hydrogen bond) of phosphonate and

• = 0.25) was assigned to π–π aggregates, the presence of which was revealed by single-crystal X-ray diffraction analysis. Keywords: amide; fluorescence; isothiocyanate; phosphonate; pyrene; thioamide; X-ray structure; Introduction Friedel–Crafts-type reaction of arenes with isothiocyanates constitutes a

Recent applications of ring-rearrangement metathesis in organic synthesis

• Sambasivarao Kotha,
• Milind Meshram,
• Priti Khedkar,
• Shaibal Banerjee and
• Deepak Deodhar

Beilstein J. Org. Chem. 2015, 11, 1833–1864, doi:10.3762/bjoc.11.199

• structurally diverse small molecules starting with solid-supported phosphonate 213. In this regard, they have shown the use of a RRM protocol to prepare the bicyclic product 218 as well as tricyclic product 217. To this end, the phosphonate ester 213 reacted with a wide variety of aldehydes 214 such as aryl