[²H₂₆]-1-epi-Cubenol, a completely deuterated natural product from Streptomyces griseus

• Christian A. Citron and
• Jeroen S. Dickschat

Beilstein J. Org. Chem. 2013, 9, 2841–2845, doi:10.3762/bjoc.9.319

• the homomonoterpene 1 proceeds by S-adenosylmethionine-dependent methylation of GPP followed by a cyclisation reaction [3][4][5]. For biosynthetic studies on secondary metabolites isotopically labelled precursors are frequently used. Historically, the usage of radiolabelled compounds was most

• ], and A-factor biosynthesis may be significantly delayed on DMM. It is unknown whether the biosynthesis of 1 is also A-factor controlled in S. griseus, but an alternative explanation for its abolished production is that the biosynthesis of 1 requires additional chemistry, i.e., a methylation step [3][4

Modulating NHC catalysis with fluorine

• Yannick P. Rey and
• Ryan Gilmour

Beilstein J. Org. Chem. 2013, 9, 2812–2820, doi:10.3762/bjoc.9.316

• yield (92%). A three step, one pot sequence consisting of methylation, treatment with phenylhydrazine and subsequent cyclisation furnished the triazolium salt 17 in 76% yield (3 steps). Finally, DAST-mediated TBDMS deprotection/deoxyfluorination completed the synthetic sequence to give 7 in 45% yield

Halogenated volatiles from the fungus Geniculosporium and the actinomycete Streptomyces chartreusis

• Tao Wang,
• Patrick Rabe,
• Christian A. Citron and
• Jeroen S. Dickschat

Beilstein J. Org. Chem. 2013, 9, 2767–2777, doi:10.3762/bjoc.9.311

• diazonium salt followed by a Sandmeyer reaction resulted in 4b (61% over two steps). The isomer 4c was efficiently prepared by double methylation of 2-chlororesorcinol (8) with potassium carbonate and methyl iodide in acetone (88%), while 4f was obtained by chlorination of dimethoxybenzene 9 with

• mixture of mono- and disubstitution products, but the target compounds 10f and 10g were obtained in better yields (29% and 17%). Derivative 10b was prepared from 3,5-dichlorocatechol (13) by methylation with potassium carbonate and methyl iodide in high yield (80%). Accordingly, methylation of 4,6

• -dichlororesorcinol (14) provided 10h in 80% yield, and methylation of 2,3-dichlorohydroquinone (16), prepared from benzoquinone (15) by treatment with SO2Cl2 under acidic conditions, generated 10i (13% via two steps). Reduction of 2,6-dichlorobenzoquinone with ascorbic acid to the corresponding hydroquinone 18

The total synthesis of D-chalcose and its C-3 epimer

• Jun Sun,
• Song Fan,
• Zhan Wang,
• Guoning Zhang,
• Kai Bao and
• Weige Zhang

Beilstein J. Org. Chem. 2013, 9, 2620–2624, doi:10.3762/bjoc.9.296

• for diacetate 14 was identical to the data reported for the natural product-derived D-chalcose diacetate [10]. A nearly identical synthetic procedure was used to transform 4′ into the C-3 epimer of chalcose (I′); this procedure began with a methylation to form 5′ (Scheme 7). The stereoselective

The myxocoumarins A and B from Stigmatella aurantiaca strain MYX-030

• Tobias A. M. Gulder,
• Snežana Neff,
• Traugott Schüz,
• Tammo Winkler,
• René Gees and
• Bettina Böhlendorf

Beilstein J. Org. Chem. 2013, 9, 2579–2585, doi:10.3762/bjoc.9.293

• O-methylation, glycosylation, prenylation, oxygenation and subsequent cyclization or dimerization events [34]. Nitrogen-bearing congeners are rather scarce, with the bacterial aminocoumarins, such as the gyrase inhibitor novobiocin, being the most well-known examples [35]. Despite the larger number

A protecting group-free synthesis of the Colorado potato beetle pheromone

• Zhongtao Wu,
• Manuel Jäger,
• Jeffrey Buter and
• Adriaan J. Minnaard

Beilstein J. Org. Chem. 2013, 9, 2374–2377, doi:10.3762/bjoc.9.273

• , oxidation and stereoselective methylation using organometallic reagents are the key steps, affording (S)-1 in high enantiomeric purity and in gram quantities. In all these approaches, however, protection of the primary hydroxy group of the 1,2,3-triol substructure is required for the selective oxidation of

Towards stereochemical control: A short formal enantioselective total synthesis of pumiliotoxins 251D and 237A

• Jie Zhang,
• Hong-Kui Zhang and
• Pei-Qiang Huang

Beilstein J. Org. Chem. 2013, 9, 2358–2366, doi:10.3762/bjoc.9.271

• ; ring closure; trans-methylation; Introduction Pumiliotoxins (PTXs, 1, Figure 1) such as pumiliotoxin 251D (2) are a subclass of indolizidine alkaloids isolated from the skin secretion of neotropical frogs. A total of 19 members have been isolated and partially characterized [1]. Pumiliotoxins are

• minor diastereomer. Similar results have been reported by Nubbemeyer [27] and Li [8]. In view of the fruitless efforts of Nubbemeyer [27] and Li [8] in inversing the diastereoselectivity of the methylation reaction of keto-lactam 7, an alternative approach was envisaged. To develop a diastereoselective

• approach to (8S,8aS)-5, it would be helpful to analyze the plausible stereochemical course of the methylation of keto-lactam 7. The observed unusual stereoselective cis-methylation implicates a preferential axial attack of the methylmagnesium iodide to the bicyclic keto-lactam 7 (Scheme 2). Although the

An overview of the synthetic routes to the best selling drugs containing 6-membered heterocycles

• Marcus Baumann and
• Ian R. Baxendale

Beilstein J. Org. Chem. 2013, 9, 2265–2319, doi:10.3762/bjoc.9.265

• metabolism via oxidation or methylation pathways forming the corresponding pyridinium ions [9][10]. Although many of these metabolites are potentially highly toxic to humans they are conveniently and quickly excreted from the body via the kidneys. With a good understanding of the pharmacokinetics and

Structure of 1,5-benzodiazepinones in the solid state and in solution: Effect of the fluorination in the six-membered ring

• Marta Pérez-Torralba,
• Rosa M. Claramunt,
• M. Ángeles García,
• Concepción López,
• M. Carmen Torralba,
• M. Rosario Torres,
• Ibon Alkorta and
• José Elguero

Beilstein J. Org. Chem. 2013, 9, 2156–2167, doi:10.3762/bjoc.9.253

• to compound 1 indicate a greater deformation in the seven-membered ring owing to the presence of the N-methyl substituent. The N-methylation prevents the dimerization by hydrogen bonding leading to a very different packing. Therefore, the most significant intermolecular interaction is the F–F contact

• ) > b (18 kJ mol−1 in average), the other tautomers having considerably higher energies. Always tautomer b is destabilized by N-methylation (in average, 8.4 kJ mol−1) probably due to a steric effect; the conjugated tautomer b tends to be planar and this is indeed the case for 1H-derivatives 1b, 3b and

• -2-one) [27]. When using calculated values it is possible to analyze the main effects on the barriers that in the present case are three: i) N-methylation; ii) 6,7,8,9-tetrafluorination; iii) the substituent at position 4 (CH3 or C6H5). This last effect is negligible, the other two interact, then a

Non-cross-linked polystyrene-supported 2-imidazolidinone chiral auxiliary: synthesis and application in asymmetric alkylation reactions

• Quynh Pham Bao Nguyen and
• Taek Hyeon Kim

Beilstein J. Org. Chem. 2013, 9, 2113–2119, doi:10.3762/bjoc.9.248

• polystyrene (NCPS)-supported 2-phenylimino-2-oxazolidine, which facilitated the synthesis of several chiral amides in excellent stereoselectivity (>96% ee). However, the sterically undemanding methylation has not been investigated [20]. Recently, we introduced 2-imidazolidinone [26][27], a versatile auxiliary

• investigated. As shown in Table 3, benzyl bromide, allyl iodide and methyl iodide reacted very well to give the alkylated products 7 in moderate to good yields and excellent de values of >99% (Supporting Information File 1). Especially, the diastereocontrol of asymmetric methylation in this case was better

• diastereoselectivity (>99% de) without using any special strategy. To the best of our knowledge, no studies have reported successful diastereocontrol by using other polymer-supported chiral auxiliaries in asymmetric alkylation reactions, especially in the methylation case [13][14][15][16][17][18][19][20][21][22][23

The chemistry of isoindole natural products

• Klaus Speck and
• Thomas Magauer

Beilstein J. Org. Chem. 2013, 9, 2048–2078, doi:10.3762/bjoc.9.243

• after methylation, 26 is obtained [27]. As already mentioned before, indolocarbazoles are characterized by their excellent biological activities and unusual architecture and hence drawing an enormous interest from the synthetic organic chemistry community. This led to several syntheses of the natural

• –Spengler reaction of dopamine (99) with 4-hydroxyphenylacetaldehyde (100), both derived from L-tyrosine (98) (Scheme 11). After oxidation and O-methylation, which is carried out by S-adenosylmethionine (SAM), (S)-reticuline (101) is obtained. Oxidation of the N-methyl group to the iminium ion and

• cyclization gives the tetracyclic carbon skeleton, which upon further methylation and oxidation furnishes berberine (92) [80]. Prechilenine (102), itself isolated as its O-methyl ether is formed via oxidation [78]. A base-catalyzed semipinacol-type rearrangement yields 93 [76]. Chilenine (93) can be further

A practical synthesis of long-chain iso-fatty acids (iso-C₁₂–C₁₉) and related natural products

• Mark B. Richardson and
• Spencer J. Williams

Beilstein J. Org. Chem. 2013, 9, 1807–1812, doi:10.3762/bjoc.9.210

• determined. Conversion of iso-C17 acid 6 to the N-acyloxazolidinone 28 was achieved using pivalyl chloride/LiCl [62] and (S)-4-benzyloxazolidinone. Diastereoselective methylation [63] of the chelated Z-enolate, derived from deprotonation of 28, using NaHMDS, followed by addition of iodomethane, yielded 29 as

Total synthesis of ochnaflavone

• Monica M. Ndoile and
• Fanie R. van Heerden

Beilstein J. Org. Chem. 2013, 9, 1346–1351, doi:10.3762/bjoc.9.152

• formation of the chalcone by an aldol condensation reaction with a suitably substituted acetophenone. Selective methylation of 2,4,6-trihydroxyacetophenone with methyl iodide yielded 2'-hydroxy-4',6'-dimethoxyacetophenone (5) in moderate yield. The Claisen–Schmidt condensation of 5 with diaryl ether 4 under

Establishing the concept of aza-[3 + 3] annulations using enones as a key expansion of this unified strategy in alkaloid synthesis

• Aleksey I. Gerasyuto,
• Zhi-Xiong Ma,
• Grant S. Buchanan and
• Richard P. Hsung

Beilstein J. Org. Chem. 2013, 9, 1170–1178, doi:10.3762/bjoc.9.131

• (Scheme 5). Grignard addition to the glutarimide Mg-salt 20 followed by reduction of the Mg salt 21 afforded lactam 22 as an inseparable 1:1 mixture of two diastereomers in 77% overall yield [68][69][70]. Vinylogous amide 23 was prepared by O-methylation of lactam 22 with freshly distilled MeOTf followed

Amyloid-β probes: Review of structure–activity and brain-kinetics relationships

• Todd J. Eckroat,
• Abdelrahman S. Mayhoub and
• Sylvie Garneau-Tsodikova

Beilstein J. Org. Chem. 2013, 9, 1012–1044, doi:10.3762/bjoc.9.116

• . Subsequent nitro reduction, reductive methylation, methyl ether cleavage, and pegylation gave the nonlabeled precursors 39a–c. The [18F]-label was introduced by using the standard [K/K222]18F in DMSO and acetonitrile reaction conditions (Scheme 3B) [16]. The [Re]- and [99mTc]-labeled flavone complexes 30a

• methylation, methyl ether cleavage, pegylation and radiolabeling. Several synthetic procedures have been described for the preparation of 46a and its precursors in an effort to optimize yield [21][41][42]. The best reported yield and purity was obtained by mixing the mesylate precursor with the fluorinating

• agent in a modified PET-MF-2V-IT-1 synthesizer and by purifying using plus C18 Sep-Pak cartridges [41]. In the preparation of [11C]44d, the [11C]-methylation of 4-amino-4'-hydroxystilbene was carried out using the “LOOP” method, in which trapping and reaction of [11C]CH3OTf with the appropriate stilbene

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

• group and the formation of bisphosphonic acid 39. Even with Me3SiBr/H2O, transsilylation and solvolysis under mild conditions afforded only the dephosphonylated product (Scheme 20) [43]. The result of the methylation of trisphosphonate 1a depends on the reagent: treatment of 1a with methyl p

• benzyl azide. The use of the transsilylation reaction for the synthesis of trisphosphonate salts 37. Synthesis of the sodium salt of the acid-labile trisphosphonic acid 38. Acidic hydrolysis of trisphosphonate ester 1a. Methylation of trisphosphonate 1a. Synthesis of the free methylidynetrisphosphonic

Isotopically labeled sulfur compounds and synthetic selenium and tellurium analogues to study sulfur metabolism in marine bacteria

• Nelson L. Brock,
• Christian A. Citron,
• Claudia Zell,
• Martine Berger,
• Irene Wagner-Döbler,
• Jörn Petersen,
• Thorsten Brinkhoff,
• Meinhard Simon and
• Jeroen S. Dickschat

Beilstein J. Org. Chem. 2013, 9, 942–950, doi:10.3762/bjoc.9.108

• methaneselenol-derived volatiles via reduction and methylation. The pathway of selenate/selenite reduction, however, proved to be strictly separated from sulfate reduction. Keywords: dimethylsulfoniopropionate; Roseobacter clade; selenium metabolism; sulfur metabolism; volatiles; Introduction The Roseobacter

• genome only encodes DddP as a single DMSP lyase, while no conclusions can be drawn on the participation of DddW. Exploring the source of methanethiol Two possible sources for MeSH production from MB2216 medium are sulfate via reduction to sulfide and methylation, or methionine via γ-lysis. The

• ]methionine demonstrated that methionine γ-lysis is an important pathway for MeSH production in P. gallaeciensis. Sulfate reduction and methylation was not observed in feeding experiments with 34S-labeled sulfate or thiosulfate, likely because sulfate reduction was not active under the experimental growth

Carbolithiation of N-alkenyl ureas and N-alkenyl carbamates

• Julien Lefranc,
• Alberto Minassi and
• Jonathan Clayden

Beilstein J. Org. Chem. 2013, 9, 628–632, doi:10.3762/bjoc.9.70

• products 4 was likewise confirmed by methylation (NaH, MeI) of 6d to provide a single diastereoisomer of urea 4g in 60% yield, which was spectroscopically identical with the compound obtained by treating urea E-3g with iPrLi (Table 2, entry 9). Again, the stereochemical outcome is consistent with syn

One-pot tandem cyclization of enantiopure asymmetric cis-2,5-disubstituted pyrrolidines: Facile access to chiral 10-heteroazatriquinanes

• Ping-An Wang,
• Sheng-Yong Zhang and
• Henri B. Kagan

Beilstein J. Org. Chem. 2013, 9, 265–269, doi:10.3762/bjoc.9.32

• CH2Cl2, suitable for X-ray diffraction analysis. It was found that the ring-closing reaction took place during the heating process following N-methylation to provide the rigid 1-oxo-3-aza-10-azaquinane skeleton 7b as its ammonium salt. Compound 7b contains four stereogenic centers, and their

• configurations are assigned to be 2R, 5S, 8R and 10R (chiral N atom) based on its starting material 4b (Figure 4). Actually, HC(OCH3)3 as an efficient reagent for C-, N-, and O-methylation has been reported [21][22][23][24], but the mechanism of these methylations is elusive. The other chiral ammonium salt 7a

From bead to flask: Synthesis of a complex β-amido-amide for probe-development studies

• Kevin S. Martin,
• Cristian Soldi,
• Kellan N. Candee,
• Hiromi I. Wettersten,
• Robert H. Weiss and
• Jared T. Shaw

Beilstein J. Org. Chem. 2013, 9, 260–264, doi:10.3762/bjoc.9.31

• (11), malonic acid and ammonium acetate under reflux proceeded smoothly, as previously described, to furnish β-amino acid 21 in 73% yield [18]. Methylation of 21 (80%) followed by nitration of 22 (67%), boc protection of 23 and SNAr displacement of the fluoride in 24 with amine 8 (71% over two steps

Synthesis of 5-(ethylsulfonyl)-2-methoxyaniline: An important pharmacological fragment of VEGFR2 and other inhibitors

• Miroslav Murár,
• Gabriela Addová and
• Andrej Boháč

Beilstein J. Org. Chem. 2013, 9, 173–179, doi:10.3762/bjoc.9.20

• three simple synthetic steps (N-acetylation, O-methylation, N-acetyl deprotection). Later on 2-amino-4-(ethylsulfonyl)phenol was discontinued from current commercial sources. Compound 5 is still available in small 1 g quantities but at a price that was unfavourable (e.g., as part of the AldrichCPR

The β-cyclodextrin/benzene complex and its hydrogen bonds – a theoretical study using molecular dynamics, quantum mechanics and COSMO-RS

• Jutta Erika Helga Köhler and
• Nicole Grczelschak-Mick

Beilstein J. Org. Chem. 2013, 9, 118–134, doi:10.3762/bjoc.9.15

• solvation-free-energy differences was used to distinguish amylose helices from cellulose sheets by analysing the different reactivity of oxygen atoms O2, O3 and O6 of the sugar units with and without methylation, in line with experimental data [13]. Cyclodextrin-complex formation with substituted benzenes

Glycosylation efficiencies on different solid supports using a hydrogenolysis-labile linker

• Mayeul Collot,
• Steffen Eller,
• Markus Weishaupt and
• Peter H. Seeberger

Beilstein J. Org. Chem. 2013, 9, 97–105, doi:10.3762/bjoc.9.13

• /ethyl acetate (3:2), N-methylation and N-formylation were observed (Supporting Information File 1). Considering prior evidence that methanol can generate formaldehyde in the presence of Pd(0) by an oxidative addition mechanism [43][44] and the observation that apolar solvents cause N-formylation during

Polar reactions of acyclic conjugated bisallenes

• Reiner Stamm and
• Henning Hopf

Beilstein J. Org. Chem. 2013, 9, 36–48, doi:10.3762/bjoc.9.5

• with 5J = 2.8 Hz for the remaining allenic proton in the 1H NMR spectrum and by two singlets at δ 202.5 and 202.8 ppm for the central allene carbon atoms in the 13C NMR spectrum. When the methylation is carried out after 3 equiv of n-butyllithium have been added, small amounts of a dimethyl product

• : the monomethylation product 5 was subjected to the metalation/methylation sequence again and yielded pure 7 in very good yield (86%). This hydrocarbon, symmetric and hence relatively high-melting again (mp 72–75 °C), is a known compound [11]; however, in our hands its spectroscopic properties differed

Synthesis of a derivative of α-D-Glcp(1->2)-D-Galf suitable for further glycosylation and of α-D-Glcp(1->2)-D-Gal, a disaccharide fragment obtained from varianose

• Carla Marino,
• Carlos Lima,
• Karina Mariño and
• Rosa M. de Lederkremer

Beilstein J. Org. Chem. 2012, 8, 2142–2148, doi:10.3762/bjoc.8.241

• HPAEC–PAD Varianose was isolated from a culture of Penicillium varians [3] and its identity was proved by methylation and GLC–MS analysis. D-Galactose, D-mannose and D-glucose in the ratio 70:15:15 and the corresponding diagnostic peaks for the methylated sugars were observed, as previously described [4