Cobalt- and rhodium-catalyzed carboxylation using carbon dioxide as the C1 source

• Tetsuaki Fujihara and
• Yasushi Tsuji

Beilstein J. Org. Chem. 2018, 14, 2435–2460, doi:10.3762/bjoc.14.221

• , respectively. The reaction of unsymmetrical 1-phenyl-1-hexyne with 18a afforded 19d-H and 19d-Et regioselectively. In addition, an alkyne with a thiophene ring regioselectively produced the desired product 19e-Me after methylation with MeI. It is noteworthy that an alkynoate was also converted into the

A novel and practical asymmetric synthesis of eptazocine hydrobromide

• Ruipeng Li,
• Zhenren Liu,
• Liang Chen,
• Jing Pan,
• Kuaile Lin and
• Weicheng Zhou

Beilstein J. Org. Chem. 2018, 14, 2340–2347, doi:10.3762/bjoc.14.209

• improved the reaction yield (Table 3, entries 4 and 5). The reductive methylation of 14 under Eschweiler–Clarke conditions (HCOOH/formalin/reflux) furnished 15 in quantitative yield. The latter was reduced by NaBH4 in methanol at room temperature, and then dehydration and hydrogenation with H2/Pd/C in

Studies towards the synthesis of hyperireflexolide A

• G. Hari Mangeswara Rao

Beilstein J. Org. Chem. 2018, 14, 2106–2111, doi:10.3762/bjoc.14.185

• cyclopentane 5, a functionalized key intermediate, is presented. Compound 5 is involved in hydrolysis, α-allylation at C-8 and α-methylation at C-10 stereoselectively from the convex face. Then it is subjected to cross metathesis to give α,β-unsaturated ketone 11 as precursor in the total synthesis of

• subjected to methylation using 1.1 equiv of K2CO3 in the presence of methyl iodide (MeI). The α-methylated β-ketoester 8 was obtained in good yield. In the 1H NMR, 8 showed a signal at 3.70 ppm as doublet for C-10 (ring junction) proton confirming the selective methylation at C-8. Further, installation of

• afforded α-allylated γ-lactone-fused β-ketoester 4 in 88% yield. In the 1H NMR a signal appeared at 3.64 ppm as doublet for ring junction (C-10) proton confirmed that selective allylation occurred at C-8. Compound 4 was then subjected to methylation at C-10 using K2CO3 and MeI to obtain the requisite γ

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

Volatiles from the xylarialean fungus Hypoxylon invadens

• Jeroen S. Dickschat,
• Tao Wang and
• Marc Stadler

Beilstein J. Org. Chem. 2018, 14, 734–746, doi:10.3762/bjoc.14.62

• hydroxy-methylbenzaldehydes were converted into the corresponding methoxy derivatives by methylation with potassium carbonate and methyl iodide. The GC–MS analysis of all the obtained methylation products unequivocally established the identity of 17 and 2-methoxy-4-methylbenzaldehyde by the same retention

• derivative to the corresponding aldehyde 12 that upon O-methylation (green), likely with S-adenosylmethionine, would result in 17. The alternative oxidation of 12 by a Baeyer–Villiger monooxygenase could result in the insertion of an oxygen (blue) to yield the formate ester 21, followed by ester hydrolysis

• reported from the fungi Nodulisporium sp. [18][28], Sporothrix sp. [31], and Leptographium wageneri [32]. The compound comprises the bis-methylation product of 1,8-dihydroxynaphthalene, an important precursor of melanin-type pigments in fungi [33], while 20 has been reported to inhibit melanin biosynthesis

An air-stable bisboron complex: a practical bidentate Lewis acid catalyst

• Longcheng Hong,
• Sebastian Ahles,
• Andreas H. Heindl,
• Gastelle Tiétcha,
• Andrey Petrov,
• Zhenpin Lu,
• Christian Logemann and
• Hermann A. Wegner

Beilstein J. Org. Chem. 2018, 14, 618–625, doi:10.3762/bjoc.14.48

• optimized procedure, BBr3 was used to replace BCl3 and the dimerization reaction can be carried out in a normal Schlenk tube without any solvent. The methylation reagent, AlMe3 can be added in situ followed by the complexation with pyridazine. The one-pot procedure is also applicable to the synthesis of

Diastereoselective auxiliary- and catalyst-controlled intramolecular aza-Michael reaction for the elaboration of enantioenriched 3-substituted isoindolinones. Application to the synthesis of a new pazinaclone analogue

• Romain Sallio,
• Stéphane Lebrun,
• Frédéric Capet,
• Francine Agbossou-Niedercorn,
• Christophe Michon and
• Eric Deniau

Beilstein J. Org. Chem. 2018, 14, 593–602, doi:10.3762/bjoc.14.46

• with a tert-butyl increased significantly the diastereoselectivity of the reaction with 62% de (Table 2, entry 3). No de improvements resulted from the use of catalysts 18d,e which were modified by methylation or allylation of the cinchoninium alcohol fragment (Table 2, entries 4 and 5). While using

Copper-catalyzed asymmetric methylation of fluoroalkylated pyruvates with dimethylzinc

• Kohsuke Aikawa,
• Kohei Yabuuchi,
• Kota Torii and
• Koichi Mikami

Beilstein J. Org. Chem. 2018, 14, 576–582, doi:10.3762/bjoc.14.44

• Kohsuke Aikawa Kohei Yabuuchi Kota Torii Koichi Mikami Department of Chemical Science and Engineering, School of Materials and Chemical Technology, Tokyo Institute of Technology, O-okayama, Meguro-ku, Tokyo 152-8552, Japan 10.3762/bjoc.14.44 Abstract The catalytic asymmetric methylation of

• fluoroalkylated pyruvates is shown with dimethylzinc as a methylating reagent in the presence of a copper catalyst bearing a chiral phosphine ligand. This is the first catalytic asymmetric methylation to synthesize various α-fluoroalkylated tertiary alcohols with CF3, CF2H, CF2Br, and n-CnF2n+1 (n = 2, 3, 8

• ) groups in good-to-high yields and enantioselectivities. Axial backbones and substituents on phosphorus atoms of chiral phosphine ligands critically influence the enantioselectivity. Moreover, the methylation of simple perfluoroalkylated ketones is found to be facilitated by only chiral phosphines without

Investigations towards the stereoselective organocatalyzed Michael addition of dimethyl malonate to a racemic nitroalkene: possible route to the 4-methylpregabalin core structure

• Denisa Vargová,
• Rastislav Baran and
• Radovan Šebesta

Beilstein J. Org. Chem. 2018, 14, 553–559, doi:10.3762/bjoc.14.42

• 4-methylpregabalin from ethyl 3-methylbutanoate using an organocatalytic Michael addition as the stereoinduction step. Results and Discussion The starting material for the Michael addition was synthesized from ethyl 3-methylbutanoate (2). This straightforward sequence comprised methylation

• , reduction, nitro-aldol reaction, and dehydration (Scheme 1). Methylation of the ester 2 in the alpha position proceeded easily with LDA as a base and methyl iodide as an alkylating agent. The ester functionality was then reduced with DIBAL in dichloromethane to afford aldehyde 4 in 90% yield. A base

Volatiles from the tropical ascomycete Daldinia clavata (Hypoxylaceae, Xylariales)

• Tao Wang,
• Kathrin I. Mohr,
• Marc Stadler and
• Jeroen S. Dickschat

Beilstein J. Org. Chem. 2018, 14, 135–147, doi:10.3762/bjoc.14.9

• -SACP. This may be followed by SAM-dependent C-methylation by a methyl transferase domain (MT). The stereochemical course for this reaction can be inferred from the 4R-configuration of the final product 11a, if indeed an iterative PKS is involved that should have the same stereochemical course for the

• installation of the stereocentre in intermediate A corresponding to C-6 of 11a. The next chain extension with malonyl-SCoA and methylation proceeds with the same stereochemical courses as discussed above, but stops after action of the KR to yield intermediate B in which all the stereocentres that occur in 11a

• are already defined. A third extension with malonyl-SCoA and methylation gives rise to intermediate C that can be released, e.g., by a thioesterase to the β-keto acid D, followed by spontaneous decarboxylation to 11a. Two structurally related molecules to 11a have been reported from endophytic

Aminomethylation/hydrogenolysis as an alternative to direct methylation of metalated isoquinolines – a novel total synthesis of the alkaloid 7-hydroxy-6-methoxy-1-methylisoquinoline

• Benedikt C. Melzer,
• Jan G. Felber and
• Franz Bracher

Beilstein J. Org. Chem. 2018, 14, 130–134, doi:10.3762/bjoc.14.8

• 7-benzyloxy-6-methoxyisoquinoline with Knochel–Hauser base, followed by cuprate-mediated methylation gives the target alkaloid directly, but separation from the educt is cumbersome. Quenching the metalated intermediate with Eschenmoser’s reagent gives an easy to clean tertiary benzylamine, which

• , after quaternization with iodomethane, is easily converted into the desired 1-methylisoquinoline by hydrogenolysis of both the benzylamine and benzyl ether groups. Keywords: alkaloid; aminomethylation; hydrogenolysis; isoquinoline; metalation; methylation; Introduction The isoquinoline ring system has

• of the direct methylation of electron-deficient N-heterocycles have been reviewed [9]. In a project aimed at the synthesis of tri- and tetracylic alkaloids containing the isoquinoline scaffold, we were interested in isoquinoline building blocks which bear a methyl group at C1, since this group should

Fluorescent nucleobase analogues for base–base FRET in nucleic acids: synthesis, photophysics and applications

• Mattias Bood,
• Sangamesh Sarangamath,
• Moa S. Wranne,
• Morten Grøtli and
• L. Marcus Wilhelmsson

Beilstein J. Org. Chem. 2018, 14, 114–129, doi:10.3762/bjoc.14.7

• conformations depending on conditions. Z-DNA, a GC-repeat rich, thermodynamically less preferred, left-handed helical conformation that is favored by cytosine methylation is known to form in vivo under negative supercoiling or high salt concentrations [64][65][66][67][68]. Circular dichroism is traditionally

Synthetic mRNA capping

• Fabian Muttach,
• Nils Muthmann and
• Andrea Rentmeister

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

• triphosphorylated viral RNAs from cellular RNAs [12]. The antiviral response is among others mediated by the cytosolic receptor RIG-I which is activated by short single and double-stranded triphosphorylated RNAs and MDA-5. MDA-5 recognizes long triphosphorylated RNAs and RNAs lacking the 2′-OH methylation at the

• subsequent methylation of the 2′-hydroxy group of the adjacent second and third ribose, respectively [34]. These capping enzymes – e.g., from Vaccinia virus – can be harnessed for the production of capped RNA in vitro by adding them and their respective cosubstrates to the IVT reaction, as described by

• diphosphate (GDP, 15) and guanosine monophosphate (GMP, 16, Figure 4B), which are both accessible by phosphorylation of guanosine [54]. Methylation of GDP gives m7GDP (17) with high yield and regioselectivity [55]. The key step in cap analogue synthesis is the formation of the triphosphate linkage. Multiple

Vinylphosphonium and 2-aminovinylphosphonium salts – preparation and applications in organic synthesis

• Anna Kuźnik,
• Roman Mazurkiewicz and
• Beata Fryczkowska

Beilstein J. Org. Chem. 2017, 13, 2710–2738, doi:10.3762/bjoc.13.269

• phosphorus ylides from vinylphosphonium salts. Intramolecular Wittig reaction with the use of vinylphosphonium salts. Alkylation of diphenylvinylphosphine with methyl or benzyl iodide. Methylation of isopropenyldiphenylphosphine with methyl iodide. Alkylation of phosphines with allyl halide derivatives and

Hydrolysis, polarity, and conformational impact of C-terminal partially fluorinated ethyl esters in peptide models

• Vladimir Kubyshkin and
• Nediljko Budisa

Beilstein J. Org. Chem. 2017, 13, 2442–2457, doi:10.3762/bjoc.13.241

• three hexaproline peptides 8a–c, while some increase of the negative band amplitude was only observed for the methanol samples. Overall, this model suggests a small conformational impact from the C-terminal 2,2-difluoroethylation or methylation as compared to the parent peptide 8a. These findings

Synthesis and photophysical properties of novel benzophospholo[3,2-b]indole derivatives

• Mio Matsumura,
• Mizuki Yamada,
• Atsuya Muranaka,
• Misae Kanai,
• Naoki Kakusawa,
• Daisuke Hashizume,
• Masanobu Uchiyama and
• Shuji Yasuike

Beilstein J. Org. Chem. 2017, 13, 2304–2309, doi:10.3762/bjoc.13.226

• electron-accepting properties. This red shift related to methylation of a phosphorus atom is in line with other earlier studies [10][18][33]. The fluorescence intensity of 7 (Ф = 67%) was as strong as that of phosphine oxide 4. The gold and boron complexes (8 and 9, respectively) showed contrasting

Synthesis of benzannelated sultams by intramolecular Pd-catalyzed arylation of tertiary sulfonamides

• Valentin A. Rassadin,
• Mirko Scholz,
• Anastasiia A. Klochkova,
• Armin de Meijere and
• Victor V. Sokolov

Beilstein J. Org. Chem. 2017, 13, 1932–1939, doi:10.3762/bjoc.13.187

• methyl iodide (Scheme 2). Unfortunately, this apparently simple transformation yielded a mixture of C-, N- and C,N-methylation products due to similar reactivities of the C- and N-nucleophilic centers in 3a. At best, the tertiary sulfonamide 5 was isolated in 32% yield. In contrast to the behavior of 3a

Chiral phase-transfer catalysis in the asymmetric α-heterofunctionalization of prochiral nucleophiles

• Johannes Schörgenhumer,
• Maximilian Tiffner and
• Mario Waser

Beilstein J. Org. Chem. 2017, 13, 1753–1769, doi:10.3762/bjoc.13.170

• ][16][17][18][19][20]. Following the pioneering reports of Wynberg et al. [25] and Merck scientists [26] who employed cinchona alkaloid-derived quaternary ammonium salts for asymmetric epoxidations [25] and the α-methylation of a phenylindanone derivative [26] in the late 1970s, early 1980s already

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

A novel approach to oxoisoaporphine alkaloids via regioselective metalation of alkoxy isoquinolines

• Benedikt C. Melzer and
• Franz Bracher

Beilstein J. Org. Chem. 2017, 13, 1564–1571, doi:10.3762/bjoc.13.156

• using polyphosphoric acid (Scheme 1). In the course of this cyclization, the methoxy group at C-6 is typically hydrolized to the phenol, subsequent O-methylation gives the 6-methoxy derivatives menisporphine (2) and dauriporphine (3). Recently, Zhang et al. [20] described an alternative approach

• methylation protocol, we explored diazomethane, but no conversion was observed at all. Finally, all of the synthesized alkaloids were tested for their cytotoxic potential in a MTT assay on the HL-60 cell line. Except for menisporphine (2) and bianfugecine (6, both IC50 values > 50 µM), all of the described

• metalation of amide 12. Synthesis of 1-arylnaphthalene analogues 15 and 16. Outcome of a D2O quenching experiment after metalation of amide 16 with LDA. Synthesis of the alkaloids menisporphine (2) and dauriporphine (3) by O-methylation of the alkaloids 6-O-demethylmenisporphine (4) and dauriporphinoline (5

Phenylsilane as an effective desulfinylation reagent

• Wanda H. Midura,
• Aneta Rzewnicka and
• Jerzy A. Krysiak

Beilstein J. Org. Chem. 2017, 13, 1513–1517, doi:10.3762/bjoc.13.150

• phenylsilane utilizing the procedure described above and afforded phenylacetate 8 as the only product. Methylation of 9 afforded product 10 with full stereoselectivity as the only diastereomer although the configuration of this center was not determined. Also in this case treatment with PhSiH3/KOH caused a

A speedy route to sterically encumbered, benzene-fused derivatives of privileged, naturally occurring hexahydropyrrolo[1,2-b]isoquinoline

• Olga Bakulina,
• Alexander Ivanov,
• Vitalii Suslonov,
• Dmitry Dar’in and
• Mikhail Krasavin

Beilstein J. Org. Chem. 2017, 13, 1413–1424, doi:10.3762/bjoc.13.138

• product could be recovered from the filtrate in the form of respective methyl esters after O-methylation and chromatographic separation (see Experimental section): syn-10a' (7%), anti-10a' (12%), syn-10b' (13%). In those cases when the carboxylic acid precipitate contained a significant proportion of the

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

• auxiliary proved demanding. The Menche group realized that a transformation to a Weinreb amide may be realized in an effective manner by an in situ activation of 24 with iPrMgCl [75], followed by a methylation of the free hydroxy group and introduction of the methyl ketone. This procedure proved superior to

• with sodium borohydride to generate all three required stereogenic centers for this fragment with excellent diasteroselectivity. Final methylation of the free alcohol was followed by conversion of the vinyl iodide into the desired stannane to get fragment 39 which was used directly for coupling

• . Notably, they had to switch the halide/organometallic functionality of each building block after an unsuccessful coupling between the stannane synthesized by reduction and methylation of ketone 67 and the iodine derived from fragment 62. They assume that the steric hindrance of the methyl group in C10

Transition-metal-free one-pot synthesis of alkynyl selenides from terminal alkynes under aerobic and sustainable conditions

• Adrián A. Heredia and
• Alicia B. Peñéñory

Beilstein J. Org. Chem. 2017, 13, 910–918, doi:10.3762/bjoc.13.92

• inert gas atmosphere the phenyl selenide anion remains unoxidized and can be trapped by methylation. Furthermore, under the current reaction conditions no reduction of Se–Se bonds by the used base t-BuOK as proposed in the literature takes place (Scheme 5B) [44]. To account for the results obtained we

DMAP-assisted sulfonylation as an efficient step for the methylation of primary amine motifs on solid support

• Johnny N. Naoum,
• Koushik Chandra,
• Dorit Shemesh,
• R. Benny Gerber,
• Chaim Gilon and
• Mattan Hurevich

Beilstein J. Org. Chem. 2017, 13, 806–816, doi:10.3762/bjoc.13.81

• 10.3762/bjoc.13.81 Abstract Several multistep strategies were developed to ensure single methylation of amines on solid support. These strategies rely on the introduction of the o-NBS protecting/activating group as a key step. We found that the state-of-the-art strategies fail for the methylation of

• an explanation by showing that the energy barrier of the DMAP intermediate is significantly lower than the one of the collidine. We demonstrate that using DMAP as a sole additive in the sulfonylation step results in an overall effective and regioselective N-methylation. The method presented herein

• proved highly efficient in solid-phase synthesis of a somatostatin analogue bearing three Nα-methylation sites that could not be synthesized using the previously described state-of-the-art methods. Keywords: N-methylation; nucleophilic addition; solid phase; somatostatin; sulfonylation; Introduction