Formation of an unexpected 3,3-diphenyl-3H-indazole through a facile intramolecular [2 + 3] cycloaddition of the diazo intermediate

• Andrew T. King,
• Hugh G. Hiscocks,
• Lidia Matesic,
• Mohan Bhadbhade,
• Roger Bishop and
• Alison T. Ung

Beilstein J. Org. Chem. 2019, 15, 1347–1354, doi:10.3762/bjoc.15.134

• our compound 5. The formation of compound 8 can be explained by the rearrangement of 7 through a hydrogen-shift to form the diazo intermediate 9 which underwent a concerted [2 + 3] intramolecular cyclisation to 3,3-diphenyl-3H-indazole 8 (Scheme 2). The process was facilitated by the presence of a

• method a or b, respectively. The results confirm our initial hypothesis that the cyclisation occurred through the diazo species 9 (Scheme 2) and the Cu2+ plays no part in the reaction process. Conclusion The formation of the unexpected product 8 from 5 under anhydrous diazotisation conditions has led to

Phylogenomic analyses and distribution of terpene synthases among Streptomyces

• Lara Martín-Sánchez,
• Kumar Saurabh Singh,
• Mariana Avalos,
• Gilles P. van Wezel,
• Jeroen S. Dickschat and
• Paolina Garbeva

Beilstein J. Org. Chem. 2019, 15, 1181–1193, doi:10.3762/bjoc.15.115

• gray and dark gray circles). The 2-MIB synthases are present in members of all the three clades from the whole genome phylogenetic tree (Figure 1), but are most abundant in members of the clade depicted in red. These terpene synthases catalyse a unique cyclisation reaction utilizing the modified

• substrate 2-methyl-GPP to form 2-MIB (2) [25][26]. An S-adenosylmethionine (SAM) dependent methyl transferase is responsible for the methylation of GPP into 2-methyl-GPP (14, Scheme 2). Its isomerisation to 15 allows for a cyclisation via the cationic intermediates B and C to 2. Genes encoding for SAM

• enantiomers of the corresponding alcohols (R)- and (S)-albaflavenol (16ab) and the epoxide 4β,5β-epoxy-2-epi-zizaan-6β-ol (18) are known oxidation products that are all made by a cytochrome P450 monooxygenase [10][29] that is genetically clustered with the epi-isozizaene synthase for the cyclisation of FPP to

Mechanistic investigations on multiproduct β-himachalene synthase from Cryptosporangium arvum

• Jan Rinkel and
• Jeroen S. Dickschat

Beilstein J. Org. Chem. 2019, 15, 1008–1019, doi:10.3762/bjoc.15.99

• diphosphate. In-depth mechanistic investigations using isotopically labelled precursors regarding the stereochemical course of both 1,11-cyclisation and 1,3-hydride shift furnished a detailed catalytic model suggesting the molecular basis of the observed low product selectivity. The enzyme’s synthetic

• TSs is largely unknown [12]. In this study, we present the characterisation of a bacterial TS with a reduced selectivity both for substrates and for products together with the challenging investigation of its cyclisation mechanism by labelling experiments. Results and Discussion A bacterial β

• and 15 in the incubation with GPP and 18 in the experiment with GGPP, this TS from C. arvum is characterised as a multiproduct (+)-β-himachalene synthase (HcS) possessing additional mono- and diterpene cyclase activity. The structures of its minor products reveal the cyclisation mechanism of HcS Since

An improved synthesis of adefovir and related analogues

• David J. Jones,
• Eileen M. O’Leary and
• Timothy P. O’Sullivan

Beilstein J. Org. Chem. 2019, 15, 801–810, doi:10.3762/bjoc.15.77

• were unable to access 2 (Scheme 7). Instead, the major product isolated in both cases was novel heterocycle 35. It is likely that cleavage of one of the pivaloxymethyl groups, followed by intramolecular cyclisation, results in the formation of 35. Microwave heating of 33 in the presence of DBU also

Stereochemical investigations on the biosynthesis of achiral (Z)-γ-bisabolene in Cryptosporangium arvum

• Jan Rinkel and
• Jeroen S. Dickschat

Beilstein J. Org. Chem. 2019, 15, 789–794, doi:10.3762/bjoc.15.75

• Jan Rinkel Jeroen S. Dickschat Kekulé-Institute for Organic Chemistry and Biochemistry, University of Bonn, Gerhard-Domagk-Str. 1, 53121 Bonn, Germany 10.3762/bjoc.15.75 Abstract A newly identified bacterial (Z)-γ-bisabolene synthase was used for investigating the cyclisation mechanism of the

• recombinant enzyme, which resolved in an exclusive cyclisation of (R)-NPP, while (S)-NPP that is non-natural to the (Z)-γ-bisabolene synthase was specifically converted into (E)-β-farnesene. A hypothetical enzyme mechanistic model that explains these observations is presented. Keywords: biosynthesis

• stereochemical imprint of a TS on achiral products is not directly visible, there still can be a chiral cyclisation cascade behind these terpenes. This is true as well for examples featuring a mirror plane like the monoterpene 1,8-cineol (eucalyptol, 3), for which the absolute configuration of the intermediary

Efficient synthesis of 4-substituted-ortho-phthalaldehyde analogues: toward the emergence of new building blocks

• Clémence Moitessier,
• Ahmad Rifai,
• Pierre-Edouard Danjou,
• Isabelle Mallard and
• Francine Cazier-Dennin

Beilstein J. Org. Chem. 2019, 15, 721–726, doi:10.3762/bjoc.15.67

• cyclisation in a basic medium of 2 then occurred to generate 4,5-dihydroisobenzofuran-5-ol (3) [19]. At this step, Cao et al. [17] have chosen the direct oxidation of 4,5-dihydroisobenzofuran-5-ol (3) to obtain 4-HO-OPA by using 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) as an oxidant. However, the yield

Catalysis of linear alkene metathesis by Grubbs-type ruthenium alkylidene complexes containing hemilabile α,α-diphenyl-(monosubstituted-pyridin-2-yl)methanolato ligands

• Tegene T. Tole,
• Johan H. L. Jordaan and
• Hermanus C. M. Vosloo

Beilstein J. Org. Chem. 2019, 15, 194–209, doi:10.3762/bjoc.15.19

• alia the cyclisation of hex-5-enyl undec-10-enoate to oxacyclohexadec-11-en-2-one (50% at 60 °C in toluene) and the ROMP of dicyclopentadiene. They were also able to immobilise these Grubbs 1-type precatalysts using dendritic pyridinyl alcohols [8]. These complexes catalysed the RCM reaction (at 80 °C

Volatiles from the hypoxylaceous fungi Hypoxylon griseobrunneum and Hypoxylon macrocarpum

• Jan Rinkel,
• Alexander Babczyk,
• Tao Wang,
• Marc Stadler and
• Jeroen S. Dickschat

Beilstein J. Org. Chem. 2018, 14, 2974–2990, doi:10.3762/bjoc.14.277

• acetate, two non-reducing elongations with malonyl-SCoA, the first without and the second with C-methylation, followed by another elongation with reduction of the 3-oxo group and cyclisation yields the aromatic system of 25 and 26. Hydrolytic cleavage from the ACP and two methylations of the phenol and

Unprecedented nucleophile-promoted 1,7-S or Se shift reactions under Pummerer reaction conditions of 4-alkenyl-3-sulfinylmethylpyrroles

• Takashi Go,
• Akane Morimatsu,
• Hiroaki Wasada,
• Genzoh Tanabe,
• Osamu Muraoka,
• Yoshiharu Sawada and
• Mitsuhiro Yoshimatsu

Beilstein J. Org. Chem. 2018, 14, 2722–2729, doi:10.3762/bjoc.14.250

• -carboxamides that produces pyrrolo[2,3-c]- and [2,3-d]azepinones [30][31]. However, this reaction is not suitable for the synthesis of pyrrolo[3,2-c]azepines in viewpoint of the difficulties in preparing the starting materials. We previously reported that the hydroamination/cyclisation reaction of sulfanyl-1,6

• cyclisation reactions. Results and Discussion We prepared sulfoxides as substrates for the Pummerer reactions according to the aforementioned method [32][33]; subsequently, oxidation with mCPBA was performed (Scheme 2). Both the allylic sulfides 4a–f and their sulfoxides 5a–f were obtained in good to high

• yields. Corresponding pyrroloselenides 6a–f were prepared by applying a similar synthetic sequence; however, the selenoxides could not be obtained by implementing the usual reaction conditions. The structure of the products derived from the amination–cyclisation reaction of sulfanyl 1,6-diyne 1a was

Synthesis and biological evaluation of 1,2-disubstituted 4-quinolone analogues of Pseudonocardia sp. natural products

• Stephen M. Geddis,
• Teodora Coroama,
• Suzanne Forrest,
• James T. Hodgkinson,
• Martin Welch and
• David R. Spring

Beilstein J. Org. Chem. 2018, 14, 2680–2688, doi:10.3762/bjoc.14.245

• primary amines 12, which following metal-catalysed cyclisation would give 1,2-disubstituted quinolones 14. Upon the successful synthesis of analogues of the form 14, biological evaluation of these and the natural products 1, 4 and 5–7 (synthesised during our previous study [11]) would then be possible. In

• flash column chromatography, which may account for the slightly lower yields in these cases (13ad and 13ae). With the compounds 13 now in hand, their cyclisation to the desired analogues 14 was explored. However, whilst the conditions which had proved successful in the total synthesis of natural

• to moderate (Scheme 4), sufficient quantities were obtained to facilitate biological screening. It appeared that bulkier N-substituents (e.g., 14ae) resulted in lower yields than less bulky derivatives (e.g., 14bf), underlining the importance of steric factors during cyclisation. Interestingly, the

Synthesis of functionalised β-keto amides by aminoacylation/domino fragmentation of β-enamino amides

• Pavel Yanev and
• Plamen Angelov

Beilstein J. Org. Chem. 2018, 14, 2602–2606, doi:10.3762/bjoc.14.238

• only upon heating in TFA solution, but then the cyclisation mode is completely different and leads to enaminotetramic derivatives 10 instead of pyrrolin-4-ones 6 [34]. Another drawback caused by the acidic deprotection conditions was the loss of chiral integrity. When the deprotection of 3 was

• for compounds 5 (87:13–80:20) were obtained with TFA/CH2Cl2 (1:4) and 15 min deprotection time, without any change in the yields indicated in Table 1. Experiments with more dilute TFA required longer deprotection time, which in turn gave advantage to the unwanted cyclisation to pyrrolinones 6 and

• -ketoamides 11 The longer chain in compounds 4 precludes the favourable 5-exo-trig process discussed earlier (Scheme 3) and accordingly there was no competing formation of cyclic side products. A different type of unwanted cyclisation occurred with the GABA derivatives 4b,c,f,j (n = 2) but here the competing

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