Total synthesis of panicein A₂

• Lili Yeung,
• Lisa I. Pilkington,
• Melissa M. Cadelis,
• Brent R. Copp and
• David Barker

Beilstein J. Org. Chem. 2015, 11, 1991–1996, doi:10.3762/bjoc.11.215

• of panicein A2 Firstly, aldehyde 10 was required; it was prepared through methylation followed by Vilsmeier–Haack reaction of 2,3,5-trimethylphenol (11), giving 10 in 51% yield over two steps (Scheme 1) [7]. Aldehyde 10 then underwent an aldol reaction according to the procedures of Samokhvalov et al

Fates of imine intermediates in radical cyclizations of N-sulfonylindoles and ene-sulfonamides

• Hanmo Zhang,
• E. Ben Hay,
• Stephen J. Geib and
• Dennis P. Curran

Beilstein J. Org. Chem. 2015, 11, 1649–1655, doi:10.3762/bjoc.11.181

• amination of N-tosylindole aldehyde 6 with 2-iodoaniline (66%), followed by methylation of the aniline nitrogen atom (91%). Substrate 10 with the ester on C2 of the indole was chosen to learn if a more stabilized radical intermediate would still eliminate the N-tosyl group. Reductive amination of 9, 2

Synthesis of icariin from kaempferol through regioselective methylation and para-Claisen–Cope rearrangement

• Qinggang Mei,
• Chun Wang,
• Zhigang Zhao,
• Weicheng Yuan and
• Guolin Zhang

Beilstein J. Org. Chem. 2015, 11, 1220–1225, doi:10.3762/bjoc.11.135

• , Southwest University for Nationalities, Chengdu 610041, China 10.3762/bjoc.11.135 Abstract The hemisynthesis of the naturally occurring bioactive flavonoid glycoside icariin (1) has been accomplished in eleven steps with 7% overall yield from kaempferol. The 4′-OH methylation of kaempferol, the 8

• a continuation of this program, herein we report a new approach to icaritin and then icariin through semi-synthesis from the commercially available natural product kaempferol. Our previously developed regioselective methylation of kaempferol [19], Europium(III)-catalyzed para-Claisen–Cope

• rearrangement and the bis-glycosylation are the key features of this linear synthesis. Previously, we succeeded in the selective methylation of 4′-OH in kaempferol. In this work, we focus on developing an efficient procedure for the selective prenylation of flavonols for facile access to icariin (1). Results

The synthesis of active pharmaceutical ingredients (APIs) using continuous flow chemistry

• Marcus Baumann and
• Ian R. Baxendale

Beilstein J. Org. Chem. 2015, 11, 1194–1219, doi:10.3762/bjoc.11.134

• which although commercially available was expensive and could be generated from 1,3-cyclohexadione (104). The sequence consisted of O-acetylation, a Steglich rearrangement, oxidation and a final methylation reaction. As the use of flow chemistry had already improved the O-acetylation during scale-up

• an iodine mediated aromatisation, followed by high temperature mono-methylation using dimethyl carbonate/dimethylimidazole as a more benign alternative to methyl iodide at scale. The subsequent Claisen condensation step between ketone 112 and diethyl oxalate (113) was reportedly hampered by product

Advances in the synthesis of functionalised pyrrolotetrathiafulvalenes

• Luke J. O’Driscoll,
• Sissel S. Andersen,
• Marta V. Solano,
• Dan Bendixen,
• Morten Jensen,
• Troels Duedal,
• Jess Lycoops,
• Cornelia van der Pol,
• Rebecca E. Sørensen,
• Karina R. Larsen,
• Kenneth Myntman,
• Christian Henriksen,
• Stinne W. Hansen and
• Jan O. Jeppesen

Beilstein J. Org. Chem. 2015, 11, 1112–1122, doi:10.3762/bjoc.11.125

• ) (EtO)3P, 120–135 °C, 1–4 h, 70–87%. Deprotection and methylation of cyanoethyl-protected thiol moieties on MPTTFs as reported by Jeppesen et al. [25]. Reagents and conditions: a) (i) 1 equiv CsOH·H2O, MeOH, THF, rt, 1 h, (ii) MeI, THF, rt, 30 min; b) (i) 1 equiv CsOH·H2O, MeOH, THF, rt, 1 h, (ii) MeI

Quarternization of 3-azido-1-propyne oligomers obtained by copper(I)-catalyzed azide–alkyne cycloaddition polymerization

• Shun Nakano,
• Akihito Hashidzume and
• Takahiro Sato

Beilstein J. Org. Chem. 2015, 11, 1037–1042, doi:10.3762/bjoc.11.116

• region of the 13C NMR spectrum, the signals at 141.4, 135.2, 133.5, and 124.3 ppm are ascribable to the carbons in the 1,2,3-triazole ring. This observation indicates that the methylation occurred on both the 2- and 3-positions in 1,2,3-triazole under the present conditions, although the quarternization

• indicated that the methylation occurred on both the 2- and 3-positions in 1,2,3-triazole under the present conditions. The hydrodynamic radius RH of oligoAPMe of n = 11 and xq = 0.96 in DMSO-d6 dilute solutions was determined to be 0.95 nm by PGSE NMR to study the conformation of the quarternized oligomer

An intramolecular C–N cross-coupling of β-enaminones: a simple and efficient way to precursors of some alkaloids of Galipea officinalis

• Hana Doušová,
• Radim Horák,
• Zdeňka Růžičková and
• Petr Šimůnek

Beilstein J. Org. Chem. 2015, 11, 884–892, doi:10.3762/bjoc.11.99

• ]. As part of our ongoing interest in the preparation of polarized ethylenes and their application in organic synthesis, we have been attracted by the procedure published by Zhou [30]. Here, the authors used heterocyclic enaminone 1b as the reactant for an asymmetric reduction followed by N-methylation

Ruthenium-catalyzed C–H activation of thioxanthones

• Danny Wagner and
• Stefan Bräse

Beilstein J. Org. Chem. 2015, 11, 431–436, doi:10.3762/bjoc.11.49

• cleavage catalyzed by hot sulfuric acid. In this case, methylation (Me2SO4, K2CO3) of the hydroxythioxanthones 1c, 1e and 1g provided the required methyl ethers 1d, 1f and 1h, respectively in good yields (80, 85 and 95%), Scheme 1. Ru-catalyzed C–H activation Following the precedence for other carbonyl

Attempts to prepare an all-carbon indigoid system

• Şeref Yildizhan,
• Henning Hopf and
• Peter G. Jones

Beilstein J. Org. Chem. 2015, 11, 363–372, doi:10.3762/bjoc.11.42

• . Results and Discussion Our first attempt to prepare hydrocarbon 4 started from indene (6, Scheme 2). Epoxidation with m-chloroperbenzoic acid (MCPBA) according to a literature method [15] yielded the epoxide 7 in meager yields (Scheme 2). The methylation of 7 to 8 was achieved by the treatment with

Selective methylation of kaempferol via benzylation and deacetylation of kaempferol acetates

• Qinggang Mei,
• Chun Wang,
• Weicheng Yuan and
• Guolin Zhang

Beilstein J. Org. Chem. 2015, 11, 288–293, doi:10.3762/bjoc.11.33

• /bjoc.11.33 Abstract A strategy for selective mono-, di- and tri-O-methylation of kaempferol, predominantly on the basis of selective benzylation and controllable deacetylation of kaempferol acetates, was developed. From the selective deacetylation and benzylation of kaempferol tetraacetate (1), 3,4′,5

• ,-tri-O-acetylkaempferol (2) and 7-O-benzyl-3,4′5,-tri-O-acetylkaempferol (8) were obtained, respectively. By controllable deacetylation and followed selective or direct methylation of these two intermediates, eight O-methylated kaempferols were prepared with 51–77% total yields from kaempferol

• . Keywords: benzylation; deacetylation; kaempferol; methylation; regioselectivity; Introduction Kaempferol [2-(4-hydroxyphenyl)-3,5,7-trihydroxychromen-4-one] (Figure 1) and its derivatives are widely distributed in plants such as beans, broccoli, strawberries, teas, and propolis [1][2]. They are well known

Natural phenolic metabolites with anti-angiogenic properties – a review from the chemical point of view

• Qiu Sun,
• Jörg Heilmann and
• Burkhard König

Beilstein J. Org. Chem. 2015, 11, 249–264, doi:10.3762/bjoc.11.28

• an attempt to increase its bioavailability and stability, the structure of resveratrol was modified by methylation of the phenol groups [44] and by introduction of other groups on the phenyl ring (compounds 9–15, Figure 4) [45]. trans-3,4,4’,5-Tetramethoxystilbene (DMU-212) has improved

NAA-modified DNA oligonucleotides with zwitterionic backbones: stereoselective synthesis of A–T phosphoramidite building blocks

• Boris Schmidtgall,
• Claudia Höbartner and
• Christian Ducho

Beilstein J. Org. Chem. 2015, 11, 50–60, doi:10.3762/bjoc.11.8

• ., methylation, with the liberated formaldehyde. Our method to prevent this side reaction was to include an excess of n-butylamine as an additive in the reaction mixture of the hydrogenolysis step. This way, the formaldehyde methylated the added n-butylamine, furnishing a reasonably volatile byproduct [38][48

Conjugates of methylated cyclodextrin derivatives and hydroxyethyl starch (HES): Synthesis, cytotoxicity and inclusion of anaesthetic actives

• Lisa Markenstein,
• Antje Appelt-Menzel,
• Marco Metzger and
• Gerhard Wenz

Beilstein J. Org. Chem. 2014, 10, 3087–3096, doi:10.3762/bjoc.10.325

• hand, methylation of β-CD leads to excellent solubilities in water and high binding potentials, but causes even higher toxicity compared to native β-CD. Among the methyl derivatives of β-CD the heptakis-2,6-di-O-methyl derivative, abbreviated as DIMEB [15], showed very high binding potentials [16] and

• base following the procedure of Szejtli et al. published for the methylation of native β-CD [15] (Scheme 1). The product 1a showed a quite narrow distribution of methyl substituents as revealed by the ESIMS showing signals corresponding to β-CD-N3 derivatives with 14 to 18 methyl groups (Figure 1

• in O-2 and O-6 position, respectively [40]. Nearly no signal was found corresponding to methyl groups in O-3 position. If the according methylation was instead performed with NaOH as the base it proceeded much faster and with a high chance of over-methylation. Careful control of the reaction time

Synthetic strategies for the fluorescent labeling of epichlorohydrin-branched cyclodextrin polymers

• Milo Malanga,
• Mihály Bálint,
• István Puskás,
• Kata Tuza,
• Tamás Sohajda,
• László Jicsinszky,
• Lajos Szente and
• Éva Fenyvesi

Beilstein J. Org. Chem. 2014, 10, 3007–3018, doi:10.3762/bjoc.10.319

• conditions were then used for the methylation of the polymer. The methylation in DMSO and KOH is effective at very mild conditions. As the process is a random reaction, the branching agent is methylated as well. By comparing the HSQC-DEPT spectrum of the methylated β-CD (Supporting Information File 1, Figure

• File 1, Figure S14). The signal at (3.47, 57.01) ppm (Figure 4, EPI-OCH3) which is only present in the methylated polymer belongs to the methyl group attached to the branching agent. The methylation of the branching agent affects the determination of the total amount of methyl groups calculated by 1H

• NMR since all the signals overlap in the region between 3.0–4.5 ppm (Supporting Information File 1, Figure S12). For the evaluation of the amount of methyl groups in compound 4 the CD content of the starting β-CD polymer (CD content ca. 70%) must be taken into consideration. The methylation process is

Come-back of phenanthridine and phenanthridinium derivatives in the 21st century

• Lidija-Marija Tumir,
• Marijana Radić Stojković and
• Ivo Piantanida

Beilstein J. Org. Chem. 2014, 10, 2930–2954, doi:10.3762/bjoc.10.312

• intercalator able to differentiate between A–U(T) and G–C base pairs by sign of opposite fluorimetric response. An introduction of the permanent positive charge by methylation of the heterocyclic nitrogen changed the binding mode of the conjugates with shorter linkers from minor groove binding to intercalation

• ), but this recognition was completely lost upon introduction of a permanent positive charge by methylation of phenanthridine-N5 13 [71]. Intriguingly, N5-methylated phenanthridine–adenine conjugate 13 exhibited preferred binding to peculiar protonated poly AH+ double stranded helix (Scheme 23) [71

Synthesis of uniform cyclodextrin thioethers to transport hydrophobic drugs

• Lisa F. Becker,
• Dennis H. Schwarz and
• Gerhard Wenz

Beilstein J. Org. Chem. 2014, 10, 2920–2927, doi:10.3762/bjoc.10.310

• full methylation of all secondary hydroxy groups of β-CD causes a significant drop of binding potential, while substitution at the primary site does not alter the binding potential or even increases it [20]. Especially substitution of all primary hydroxy groups by thioether groups gives rise to

Total synthesis of the proposed structure of astakolactin

• Takayuki Tonoi,
• Keisuke Mameda,
• Moe Fujishiro,
• Yutaka Yoshinaga and
• Isamu Shiina

Beilstein J. Org. Chem. 2014, 10, 2421–2427, doi:10.3762/bjoc.10.252

• constructed via an aldol reaction with ethyl acetate, followed by anti-selective methylation [32][33]. The trisubstituted alkene moiety of the prenyl chain of 3 could be stereoselectively constructed via a Johnson orthoester–Claisen rearrangement of 4 [34][35][36], which would be generated from compound 5

• ethyl acetate to afford the adduct 19. Diastereoselective methylation of the ester enolate moiety of 19 with MeI afforded only the anti-product 20 [32][33], which was then subjected to the deprotection of the TBDPS group with HF·pyridine, followed by cleavage of the ethyl ester group in 21 to give the

Photorelease of phosphates: Mild methods for protecting phosphate derivatives

• Sanjeewa N. Senadheera,
• Abraham L. Yousef and
• Richard S. Givens

Beilstein J. Org. Chem. 2014, 10, 2038–2054, doi:10.3762/bjoc.10.212

• a photo-Favorskii rearrangement with quantum yields of 0.028 for 1,4-HNA DEP and 0.0076 for 1,4-MNA DEP. The lower quantum efficiency of 1,4-MNA in MeOH is fully in accord with a similar methylation of the hydroxy group of pHP DEP, emphasizing the role of the phenolic OH on the reaction and

Supercritical carbon dioxide: a solvent like no other

• Jocelyn Peach and
• Julian Eastoe

Beilstein J. Org. Chem. 2014, 10, 1878–1895, doi:10.3762/bjoc.10.196

• through intelligent surfactant design and synthesis. Several structural aspects have thus far been identified as increasing CO2-philicity of hydrocarbon surfactants, including the degree of surfactant tail branching and methylation [49], where increased tail branching and methylation led to increased

A complete series of 6-deoxy-monosubstituted tetraalkylammonium derivatives of α-, β-, and γ-cyclodextrin with 1, 2, and 3 permanent positive charges

• Martin Popr,
• Simona Hybelbauerová and
• Jindřich Jindřich

Beilstein J. Org. Chem. 2014, 10, 1390–1396, doi:10.3762/bjoc.10.142

• mono-Ts-CD with neat N,N,N’-trimethylethane-1,2-diamine or N,N,N’-trimethylpropane-1,3-diamine and subsequent methylation by CH3I in good yields. Finally, analogues bearing a moiety with three tetraalkylammonium sites were synthesized by reacting mono-Ts-CD with bis(3-aminopropyl)amine and subsequent

• methylation. The majority of the presented reactions are very straightforward with a simple work-up, which avoids the need of chromatographic separation. Thus, these reactions are suitable for the multigram-scale production of monosubstituted cationic CDs. Keywords: cationic; cyclodextrins; monosubstitution

• step, the installed triamine was quaternized by methylation with MeI. To achieve a full conversion, the use of a sterically hindered base was necessary. First, we attempted to methylate intermediate 27 containing a diethylenetriamine moiety. Different bases (K2CO3, 2,6-lutidine, 2,4,6-collidine and DBU

Heronapyrrole D: A case of co-inspiration of natural product biosynthesis, total synthesis and biodiscovery

• Jens Schmidt,
• Zeinab Khalil,
• Robert J. Capon and
• Christian B. W. Stark

Beilstein J. Org. Chem. 2014, 10, 1228–1232, doi:10.3762/bjoc.10.121

• the farnesyl residue (for atom numbering see Scheme 1), followed by regio- and stereoselective nucleophilic addition of water (and methylation) would deliver heronapyrroles A and B. Similarly, regio- and stereoselective nucleophilic addition of water to a tris-epoxy farnesyl intermediate 4 could

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

• refluxing THF to produce another phosphindole 8 in 48% yield (Scheme 4) [18]. A phosphindol-3-one 11 was prepared in 54% yield from butylphosphinate 9 by first methylation using DBU and iodomethane followed by a cross-coupling with ethyl 2-bromobenzoate (10) and then a Dieckmann-like condensation using

Synthesis of complex intermediates for the study of a dehydratase from borrelidin biosynthesis

• Frank Hahn,
• Nadine Kandziora,
• Steffen Friedrich and
• Peter F. Leadlay

Beilstein J. Org. Chem. 2014, 10, 634–640, doi:10.3762/bjoc.10.55

• Dess–Martin oxidation, Pinnick oxidation and methylation. Methyl ester 12 was obtained in 10 steps with a good overall yield of 20%. Olefin cross metathesis of alkene 12 with crotonaldehyde in the presence of a second generation Grubbs catalyst required only a short filter column to isolate α,β

• assay mixture, the latter will be transformed into their corresponding methyl esters by saponification and following methylation with trimethylsilyldiazomethane. The fully protected E-isomer 10a was obtained in 18% yield by a Horner–Wadsworth–Emmons reaction with phosphonate 25 or, alternatively, in 64

Intermediates in monensin biosynthesis: A late step in biosynthesis of the polyether ionophore monensin is crucial for the integrity of cation binding

• Wolfgang Hüttel,
• Jonathan B. Spencer and
• Peter F. Leadlay

Beilstein J. Org. Chem. 2014, 10, 361–368, doi:10.3762/bjoc.10.34

• steps in monensin biosynthesis, namely hydroxylation catalysed by the P450 monooxygenase MonD and O-methylation catalysed by the methyl-transferase MonE. The corresponding genes were deleted in-frame in a monensin-overproducing strain of Streptomyces cinnamonensis. The mutants produced the expected

• MonE, are hydroxylation at C-26 and O-methylation of the hydroxy group at C-3. Although hydroxylation is shown as preceding methylation in Scheme 1, the preferred order of these events has not been established. The final catalysed step in biosynthesis is the release of mature monensins A and B from the

• strain. These results lend support to the idea that the preferred order of events is hydroxylation at C-26 catalysed by MonD, followed by O-methylation at the hydroxy group borne at C-3 catalysed by MonE, as shown in Scheme 1. The amount of dehydroxymonensin A isolated from the MonE mutant was

Recent applications of the divinylcyclopropane–cycloheptadiene rearrangement in organic synthesis

• Sebastian Krüger and
• Tanja Gaich

Beilstein J. Org. Chem. 2014, 10, 163–193, doi:10.3762/bjoc.10.14

• carbon dioxide [74][75] resulted in the formation of carboxylic acid 75. Birch reduction with concomitant methylation [76][77] followed by selective hydrogenation and reduction of the carboxylic acid resulted in the formation of alcohol 76. Installation of the remaining quarternary carbon center was