Synthesis of a leopolic acid-inspired tetramic acid with antimicrobial activity against multidrug-resistant bacteria

• Luce Mattio,
• Loana Musso,
• Leonardo Scaglioni,
• Andrea Pinto,
• Piera Anna Martino and
• Sabrina Dallavalle

Beilstein J. Org. Chem. 2018, 14, 2482–2487, doi:10.3762/bjoc.14.224

• compounds 6a and 6b by condensation with monoethyl malonate and monobenzyl malonate, in the presence of DCC and DMAP, in 80% and 83% yield, respectively. Starting from intermediates 6a and 6b, treatment with a tetrabutylammonium fluoride solution in diethyl ether at room temperature induced the cyclisation

• decarboxylation, we planned to synthesize the alkyl-substituted tetramic core in one single step by Lacey–Dieckmann cyclisation of ethyl 2-(N-(4-methoxybenzyl)dodecanoylamino)acetate (9), although this compound does not contain an active methylene group. Thus, compound 5 was acylated with dodecanoyl chloride to

Applications of organocatalysed visible-light photoredox reactions for medicinal chemistry

• Michael K. Bogdos,
• Emmanuel Pinard and
• John A. Murphy

Beilstein J. Org. Chem. 2018, 14, 2035–2064, doi:10.3762/bjoc.14.179

• performing a visible light-driven oxidative cyclisation of arylamidines using Rose Bengal as the photocatalyst, in the presence of base and CBr4 as the oxidant (Scheme 25) [69]. The scope of the reaction is restricted to mono-substituted benzenes and lacks any carbonyl derivatives as ligands. The reaction

DFT calculations on the mechanism of copper-catalysed tandem arylation–cyclisation reactions of alkynes and diaryliodonium salts

• Tamás Károly Stenczel,
• Ádám Sinai,
• Zoltán Novák and
• András Stirling

Beilstein J. Org. Chem. 2018, 14, 1743–1749, doi:10.3762/bjoc.14.148

• the basis of the mechanism the origin of the stereoselectivity is ascribed to the interaction of the Cu ion with the oxazoline oxygen driving the ring-closure step selectively. Keywords: catalysis; DFT calculation; iodonium salts; reaction mechanism; tandem arylation–cyclisation; Introduction

• ][20][21][22][23][24][25][26][27][28]. In particular, the arylation–cyclisation reactions promoted by the highly electrophilic Cu(III)–aryl intermediates 3 can allow access to aryl-functionalised carbocyclic and heterocyclic molecules 8 with valuable functionalities [9][29][30][31][32][33][34][35][36

• before the C–O bond formation in the ring closing step (see Scheme 1). As an example of the catalytic arylation–cyclisation strategy, an efficient procedure to form substituted oxazoline derivatives from alkyl and aryl propargylamides has been developed. The process involves a 5-exo-dig cyclisation and

Fluorocyclisation via I(I)/I(III) catalysis: a concise route to fluorinated oxazolines

• Felix Scheidt,
• Christian Thiehoff,
• Gülay Yilmaz,
• Stephanie Meyer,
• Constantin G. Daniliuc,
• Gerald Kehr and
• Ryan Gilmour

Beilstein J. Org. Chem. 2018, 14, 1021–1027, doi:10.3762/bjoc.14.88

• ; cyclisation; fluorination; gauche effect; hypervalent iodine; oxazolines; Introduction Marine and terrestrial natural product bioprospecting has established a broad spectrum of structurally complex, bioactive metabolites containing the venerable 2-oxazoline unit [1][2]. This diversity is exemplified by the

• which contains a free phenol moiety, were also tolerated (69% and 65% yield, respectively), as was the highly deactivated pentafluorophenyl analogue 2j (48%). To briefly explore the effect of chain length on efficiency, the cyclisation of N-(but-3-en-1-yl)benzamide and N-(pent-4-en-1-yl)benzamide was

• explored (to generate 2k and 2l, respectively). Unsurprisingly, whilst the 6-membered ring formed in 42% yield, cyclisation to form the analogous 7-membered ring failed. It was, however, possible to generate heterocyclic species such as the 9-fluorenonyl-substituted oxazoline 2m (48%) and the furan 2n (59

Mechanochemistry of nucleosides, nucleotides and related materials

• Olga Eguaogie,
• Joseph S. Vyle,
• Patrick F. Conlon,
• Manuela A. Gîlea and
• Yipei Liang

Beilstein J. Org. Chem. 2018, 14, 955–970, doi:10.3762/bjoc.14.81

• absence of any observable intramolecular cyclisation of the unprotected purine nucleoside derivatives typical of solution-phase reactions using such substrates. More variable yields were obtained using potassium selenocyanate which required grinding in the presence of DMF to promote the reaction with

• adenosine or thymidine derivatives (Scheme 8). No reaction of 5′-chloro-5′-deoxyadenosine was observed. Under these conditions, cyclisation of 5′-tosyladenosine was inferred although rapid and clean reaction of 5′-iodo-5′-deoxyguanosine was apparent in the absence of added solvent – the product from this

Volatiles from three genome sequenced fungi from the genus Aspergillus

• Jeroen S. Dickschat,
• Ersin Celik and
• Nelson L. Brock

Beilstein J. Org. Chem. 2018, 14, 900–910, doi:10.3762/bjoc.14.77

• homolog of the geosmin synthase is encoded in the genome of A. fischeri or of any other fungus. Furthermore, the diterpene pimara-8(14),15-diene (7) was one of the main compounds in the bouquet of A. fischeri. The biosynthesis of this compound is a two-step process that requires cyclisation of

• geranylgeranyl diphosphate (GGPP) to copalyl diphosphate (CPP) by a class II TS, followed by a second cyclisation event by a class I TS [32]. These reactions are likely catalysed by the only corresponding two-domain enzyme encoded in the A. fischeri genome (accession number XP_001264196, locus tag NFIA_009790

• -sesquiphellandrene (8), ar-curcumene (9), β-bisabolene (10), (E)-γ-bisabolene (11), trans-α-bergamotene (12), δ-cuprenene (13), and cuparene (14). All these sesquiterpenes arise through a 1,6-cyclisation of farnesyl diphosphate (FPP, via nerolidyl diphosphate, NPP) to the bisabolyl cation (A, Scheme 2). A mixture of

Sequential Ugi reaction/base-induced ring closing/IAAC protocol toward triazolobenzodiazepine-fused diketopiperazines and hydantoins

• Robby Vroemans,
• Fante Bamba,
• Jonas Winters,
• Joice Thomas,
• Jeroen Jacobs,
• Luc Van Meervelt,
• Jubi John and
• Wim Dehaen

Beilstein J. Org. Chem. 2018, 14, 626–633, doi:10.3762/bjoc.14.49

• hours at room temperature, afforded the expected Ugi adduct 5a in 96% yield. The synthesis of fused heterocycles from the Ugi adduct 5a was attempted via two routes (Scheme 3). The first route involved the base-induced cyclisation of 5a at the amide end by treatment with KOH from which the

• commenced with the intramolecular azide–alkyne cycloaddition of 5a which furnished the triazole-fused benzodiazepine 8 in 72% yield after 3 hours. The triazolobenzodiazepine 8 was then subjected to base-induced cyclisation with KOH which failed to afford the expected tetracyclic compound 7a. We believe that

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

• . Cyclisation of chiral benzamides (R)-7a–e and (R)-8 led to isoindolinones (2R)-4a–e, (2R)-5 in good yields and average to good diastereoselectivities (Scheme 3). In some cases, purification by flash chromatography afforded products 4b, 4c and 5 in higher diastereomeric purity. In order to access to the

CF₃SO₂X (X = Na, Cl) as reagents for trifluoromethylation, trifluoromethylsulfenyl-, -sulfinyl- and -sulfonylation and chlorination. Part 2: Use of CF₃SO₂Cl

• Hélène Chachignon,
• Hélène Guyon and
• Dominique Cahard

Beilstein J. Org. Chem. 2017, 13, 2800–2818, doi:10.3762/bjoc.13.273

• most widely described type of reactions in which CF3SO2Cl and molecules carrying a C=C double bond are involved are actually cascade reactions that include a cyclisation or a group migration step. In this context, the acrylamide motif was a notably popular object of research, and served in several

• tandem trifluoromethylation/cyclisation processes. Dolbier and co-workers first proposed the use of N-arylacrylamides 3 to access trifluoromethylated 3,3-disubstituted 2-oxindoles 4 under photocatalytic conditions (Scheme 4) [11]. In the presence of Ru(phen)3Cl2 (phen = phenanthroline), a variety of N

• reaction [15]. Another cyclisation pattern was observed for other benzylacrylamide derivatives: indeed, in the case of the N-benzylmethacrylamide derivative 11, the formation of an azaspiro[4,5]decyl system through a dearomitising spirocyclisation was observed (Scheme 11) [16]. Other motifs than

CF₃SO₂X (X = Na, Cl) as reagents for trifluoromethylation, trifluoromethylsulfenyl-, -sulfinyl- and -sulfonylation. Part 1: Use of CF₃SO₂Na

• Hélène Guyon,
• Hélène Chachignon and
• Dominique Cahard

Beilstein J. Org. Chem. 2017, 13, 2764–2799, doi:10.3762/bjoc.13.272

• 27, which was reduced into 28 prior to be converted into nitrogen heterocycles via [1,3]-hydride shift and cyclisation steps (Scheme 12). The reaction was regioselective and had a broad scope. This application of alkene trifluoromethylation provided a convenient entry to trifluoromethylated nitrogen

• oxidised to Ag(II) by the persulfate anion; then, CF3SO2– was oxidised to CF3SO2• that generated CF3• by release of SO2. Addition of the CF3 radical to the alkene led to the radical intermediate 50, which underwent intramolecular cyclisation into 51. The sulfate radical anion then oxidised intermediate 51

• with PhI•OAc. Addition of the CF3 radical to the alkene followed by intramolecular cyclisation mediated by PhI•OAc gave the desired oxindole with release of PhI and AcOH (Scheme 28) [49]. For another metal-free trifluoromethylation/cyclisation of N-arylacrylamides by means of a different oxidant, Liu

A concise flow synthesis of indole-3-carboxylic ester and its derivatisation to an auxin mimic

• Marcus Baumann,
• Ian R. Baxendale and
• Fabien Deplante

Beilstein J. Org. Chem. 2017, 13, 2549–2560, doi:10.3762/bjoc.13.251

• subjected to heterogeneous hydrogenation conditions to produce the indole product 12 through a reductive cyclisation sequence. From the corresponding ester functionalised indole 12 we anticipated that condensation with hydrazine would furnish the corresponding acyl hydrazine 13 which could be cyclised to

• -toxic byproducts (base·HCl, H2O) and uses industrially favourable hydrogenation protocols in the key cyclisation step. To commence the study we first conducted a comprehensive screening program to determine flow compatible conditions for the formation of compound 11 optimising for solvent, base

• we determined that when EtOAc was used as the solvent and diluted with EtOH in the presence of acetic acid as an additive this allowed for the successful reductive cyclisation to the indole. As a result we investigated the scaled synthesis of intermediate 11 in EtOAc. Having had previous success with

Synthesis and supramolecular properties of regioisomers of mononaphthylallyl derivatives of γ-cyclodextrin

• Markéta Bláhová,
• Sergey K. Filippov,
• Lubomír Kováčik,
• Jiří Horský,
• Simona Hybelbauerová,
• Zdenka Syrová,
• Tomáš Křížek and
• Jindřich Jindřich

Beilstein J. Org. Chem. 2017, 13, 2509–2520, doi:10.3762/bjoc.13.248

• consequently, longer oligomers can be expected for it. The fraction of suprapolymer with polymerization degree n is then given for negligible cyclisation as where θ is the degree of occupation, i.e., the probability that the particular group, either naphthyl or CD, is in a bound state. θ is determined by the

18-Hydroxydolabella-3,7-diene synthase – a diterpene synthase from Chitinophaga pinensis

• Jeroen S. Dickschat,
• Jan Rinkel,
• Patrick Rabe,
• Arman Beyraghdar Kashkooli and
• Harro J. Bouwmeester

Beilstein J. Org. Chem. 2017, 13, 1770–1780, doi:10.3762/bjoc.13.171

• diphosphate and the pyrophosphate sensor, a highly conserved arginine located 43 amino acids upstream of the NSE triad, and the RY dimer, a highly conserved motif at the C-terminus. The substrate is ionised by extrusion of diphosphate, yielding a highly reactive allyl cation that can react in a cyclisation

• -hydroxydolabella-3,7-diene synthase (HdS). The proposed cyclisation mechanism from GGPP to 3 is likely a concerted one-step process with 1,11- and 10,14-cyclisation and concomittant attack of water at C15 (Scheme 2). We have recently shown that the absolute configurations of terpenes can be determined by enzymatic

• labelling of C2 (Figure 2). Consistently, the substrate (S)-(1-13C,1-2H)GGPP gave a product with specific incorporation of the deuterium label into the 2β position. Assuming inversion of configuration at C1 for the cyclisation of GGPP to 3 as reported for several other terpene synthases [13][20][21][22

Oxidative dehydrogenation of C–C and C–N bonds: A convenient approach to access diverse (dihydro)heteroaromatic compounds

• Santanu Hati,
• Ulrike Holzgrabe and
• Subhabrata Sen

Beilstein J. Org. Chem. 2017, 13, 1670–1692, doi:10.3762/bjoc.13.162

• cyclisation and oxidative dehydrogenation in the presence of barium manganate to produce benzimidazoles, benzoxazoles and benzothiazoles 54, respectively in appropriate solvent at ambient or lower temperature (Scheme 16). Catalytic approaches As a normal evolution of any synthetic approaches, oxidative

Switchable highly regioselective synthesis of 3,4-dihydroquinoxalin-2(1H)ones from o-phenylenediamines and aroylpyruvates

• Juraj Dobiaš,
• Marek Ondruš,
• Gabriela Addová and
• Andrej Boháč

Beilstein J. Org. Chem. 2017, 13, 1350–1360, doi:10.3762/bjoc.13.132

• products 22 and 23 [24] (Scheme 3). The proposed mechanism was based on the isolation of the 4-nitrodiaminobenzene imine intermediate which possessed reduced reactivity for intramolecular cyclisation. This type of reaction was exploited in the literature several times for the synthesis of quinoxalin-2(1H

Synthesis of alkynyl-substituted camphor derivatives and their use in the preparation of paclitaxel-related compounds

• M. Fernanda N. N. Carvalho,
• Rudolf Herrmann and
• Gabriele Wagner

Beilstein J. Org. Chem. 2017, 13, 1230–1238, doi:10.3762/bjoc.13.122

• analogous to the one observed previously with the bis-phenylalkynyl compound [27] as a starting material. Cyclisation of the alkynes and a three-carbon ring enlargement lead in a single step to a rare bicyclic carbon framework that bears some similarity to that of the anticancer drug paclitaxel. Remarkably

• alkyne cyclisation but the ring expansion has not yet taken place. The sulfonamide reduction and formation of the ketone are just about to occur, as the oxygen atom involved is on its way of being transferred from the sulphur onto the carbon atom. The structure of 23 was established by two-dimensional 1H

From chemical metabolism to life: the origin of the genetic coding process

• Antoine Danchin

Beilstein J. Org. Chem. 2017, 13, 1119–1135, doi:10.3762/bjoc.13.111

• attachment groups and first units involved in energy exchanges [26]. Alternating drying steps followed by rains or floods resulted in the condensation of phosphate moieties on many primeval compounds. These include serine as serine phosphate and aspartate protected against cyclisation as aspartyl phosphate

Continuous N-alkylation reactions of amino alcohols using γ-Al₂O₃ and supercritical CO₂: unexpected formation of cyclic ureas and urethanes by reaction with CO₂

• Emilia S. Streng,
• Darren S. Lee,
• Michael W. George and
• Martyn Poliakoff

Beilstein J. Org. Chem. 2017, 13, 329–337, doi:10.3762/bjoc.13.36

• led to an increase in the rate of cyclisation and methylation which then allowed for faster flow rates to be used under this operating temperature whilst still maintaining the same yield of 2b (Table 1, entry 1). Hence, three times the amount of material could be processed in the same time using this

• several different alcohols by flowing a starting mixture of 1 with the alcohol as the solvent (Table 2, entries 2–4). As might be expected, the cyclisation to N-alkylated piperidines was observed for the primary alcohols. The yield of the corresponding N-alkylated piperidine falls as the longer chain

• alcohols were run in the absence of scCO2 the yields of the corresponding N-alkylated products were lower and more piperidine 2a was observed. These results suggest that the rate of intermolecular alkylation is faster in scCO2, while the rate of intramolecular cyclisation is not significantly affected by

Nucleophilic displacement reactions of 5′-derivatised nucleosides in a vibration ball mill

• Olga Eguaogie,
• Patrick F. Conlon,
• Francesco Ravalico,
• Jamie S. T. Sweet,
• Thomas B. Elder,
• Louis P. Conway,
• Marc E. Lennon,
• David R. W. Hodgson and
• Joseph S. Vyle

Beilstein J. Org. Chem. 2017, 13, 87–92, doi:10.3762/bjoc.13.11

• ′-tosylates in five to 60 minutes. Under these conditions, commonly-encountered nucleoside cyclisation byproducts (especially of purine nucleosides) were not observed. Liquid-assisted grinding of the same 5'-iodide and 5′-tosylate substrates with potassium selenocyanate in the presence of DMF produced the

• reactions require the use of high-boiling, dipolar aprotic solvents and anionic nucleophiles under anhydrous conditions at elevated temperatures (up to 150 °C). Competing intramolecular cyclisation reactions between both purine and pyrimidine nucleobases and (especially) the 5′-position of the (deoxy

• liquid [13][14][15]. Recently, Jicsinszky et al. described using a planetary ball mill to perform substitution reactions of 6I-O-(p-toluenesulfonyl)-β-cyclodextrin (Ts-β-CD) with azide, halide or thiolate nucleophiles and thereby avoided intramolecular cyclisation (commonly found under solution-phase

Biochemical and structural characterisation of the second oxidative crosslinking step during the biosynthesis of the glycopeptide antibiotic A47934

• Veronika Ulrich,
• Clara Brieke and
• Max J. Cryle

Beilstein J. Org. Chem. 2016, 12, 2849–2864, doi:10.3762/bjoc.12.284

• , which is generated by the actions of cytochrome P450 (Oxy) enzymes that affect the crosslinking of aromatic side chains of amino acid residues contained within the GPA heptapeptide precursor. Given the crucial role peptide cyclisation plays in GPA activity, the characterisation of this process is of

• great importance in understanding the biosynthesis of these important antibiotics. Here, we report the cyclisation activity and crystal structure of StaF, the D-O-E ring forming Oxy enzyme from A47934 biosynthesis. Our results show that the specificity of StaF is reduced when compared to Oxy enzymes

• that this is due to the ability of the StaF/X-domain complex to allow substrate reorganisation after initial complex formation has occurred. These results highlight the importance of testing different peptide/protein carrier constructs for in vitro GPA cyclisation assays and show that different Oxy

New syntheses of (±)-tashiromine and (±)-epitashiromine via enaminone intermediates

• Darren L. Riley,
• Joseph P. Michael and
• Charles B. de Koning

Beilstein J. Org. Chem. 2016, 12, 2609–2613, doi:10.3762/bjoc.12.256

• [3] (Figure 1). To date this natural product and its unnatural epimer 2 have been the targets of numerous enantioselective and racemic syntheses [4][5][6][7][8][9]. Typical approaches to accessing the alkaloid’s indolizidine skeleton have included a key cyclisation onto the nitrogen atom of either a

• electrophilic substituents are attached to the nitrogen, alkylating or acylating cyclisation onto the enamine carbon site leads to the formation of bicyclic systems with nitrogen located at the bridgehead. Our approach to the synthesis of indolizidines is thus unusual in that it entails the formation of the C-7

• planned reaction sequence was the alkylating cyclisation of the liberated alcohols 8a–c to produce the indolizidine nucleus (Scheme 2). The cyclisation was achieved by initially treating these deprotected enaminones with imidazole and triphenylphosphine at ambient temperature in acetonitrile followed by

Construction of bis-, tris- and tetrahydrazones by addition of azoalkenes to amines and ammonia

• Artem N. Semakin,
• Aleksandr O. Kokuev,
• Yulia V. Nelyubina,
• Alexey Yu. Sukhorukov,
• Petr A. Zhmurov,
• Sema L. Ioffe and
• Vladimir A. Tartakovsky

Beilstein J. Org. Chem. 2016, 12, 2471–2477, doi:10.3762/bjoc.12.241

• -hydrazone ligand 10. Cyclisation of 11b into 1,4,6,10-tetraazaadamantane derivative. Reaction of α-halogen-substituted hydrazones 1 with benzylamine. Synthesis of trishydrazones 11. Supporting Information Supporting Information File 493: Experimental procedures, characterization data for new compounds

Useful access to enantiomerically pure protected inositols from carbohydrates: the aldohexos-5-uloses route

• Felicia D’Andrea,
• Giorgio Catelani,
• Lorenzo Guazzelli and
• Venerando Pistarà

Beilstein J. Org. Chem. 2016, 12, 2343–2350, doi:10.3762/bjoc.12.227

• intramolecular aldol condensation was also performed on aldohexos-5-uloses of the L-lyxo and D-xylo series bearing a methyl protection on position 4 or a benzyl protection on position 3 (compounds 4 [35] and 10 [38], respectively). The stereo-outcome and the yields confirmed the cyclisation results obtained for

Enduracididine, a rare amino acid component of peptide antibiotics: Natural products and synthesis

• Darcy J. Atkinson,
• Briar J. Naysmith,
• Daniel P. Furkert and
• Margaret A. Brimble

Beilstein J. Org. Chem. 2016, 12, 2325–2342, doi:10.3762/bjoc.12.226

• enzyme mppR is a pyruvate aldose that catalyses the dehydration/cyclisation of 20 to give cyclic guanidine 21 [52], where transamination by mppQ gives enduracididine (1). Further transformation to L-β-hydroxyenduracididine (5) is then catalysed by mppO [52][53]. Synthetic investigations Synthesis of

• protecting group manipulation and installation of the guanidine using S-methylisothiourea 33 (Scheme 5). Mitsunobu cyclisation followed by deprotection and oxidation afforded the azido acids 38 and 39 in 40% yield over 8 steps from amino azides 36 and 37. Synthesis of β-hydroxyenduracididine by Nieuwenhze et

• the guanidine group using isothiourea 33 before cyclisation was effected using Mitsunobu conditions. After a six-step conversion of alkene 44 to nosyl intermediate 42, the synthesis diverged to access both C-2 diastereomers. Displacement of nosylate 42 with sodium azide followed by reduction and amine

A detailed view on 1,8-cineol biosynthesis by Streptomyces clavuligerus

• Jan Rinkel,
• Patrick Rabe,
• Laura zur Horst and
• Jeroen S. Dickschat

Beilstein J. Org. Chem. 2016, 12, 2317–2324, doi:10.3762/bjoc.12.225

• Jan Rinkel Patrick Rabe Laura zur Horst Jeroen S. Dickschat Kekulé-Institute of Organic Chemistry and Biochemistry, University of Bonn, Gerhard-Domagk-Straße 1, 53121 Bonn, Germany 10.3762/bjoc.12.225 Abstract The stereochemical course of the cyclisation reaction catalysed by the bacterial 1,8

• -cineol synthase from Streptomyces clavuligerus was investigated using stereospecifically deuterated substrates. In contrast to the well investigated plant enzyme from Salvia officinalis, the reaction proceeds via (S)-linalyl diphosphate and the (S)-terpinyl cation, while the final cyclisation reaction is

• monooxygenases and acyl transferases [12][13]. Very few cases are known in which terpene cyclases generate an achiral product as exemplified by the monoterpene 1,8-cineol (eucalyptol, 1) and the sesquiterpenes germacrene B (2) and α-humulene (3) (Figure 1). A direct 1,6-cyclisation of the monoterpene precursor