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

Isosorbide and dimethyl carbonate: a green match

• Fabio Aricò and
• Pietro Tundo

Beilstein J. Org. Chem. 2016, 12, 2256–2266, doi:10.3762/bjoc.12.218

• double cyclisation reaction that requires 2 equiv of base for each tetrahydrofuran formed. The reaction mechanism is quite complex (Scheme 2) since it encompasses two carboxymethylation reactions (via BAc2) followed by two intramolecular cyclisations (via BAl2). In order to avoid the use of excess base

• amount of DBU used was, in the latter case (entry 6, Table 2) only 2.5 mol % for each tetrahydrofuranic cycle. The same synthetic approach can be also employed for the cyclisation of D-mannitol. The synthesis of isosorbide via DMC chemistry takes advantage of the enhanced reactivity of DMC in the

• intermediate, as well as the intramolecular cyclisation reaction (BAl2 mechanism). It is also noteworthy that in general alkylation reactions promoted by DMC chemistry are conducted at temperatures above 150 °C [24][25][26][27][28][29][30][31][32][33][34][35], but in this case study the intramolecular

Solvent-free synthesis of novel para-menthane-3,8-diol ester derivatives from citronellal using a polymer-supported scandium triflate catalyst

• Lubabalo Mafu,
• Ben Zeelie and
• Paul Watts

Beilstein J. Org. Chem. 2016, 12, 2046–2054, doi:10.3762/bjoc.12.193

• -diol (3) [1][2]. These chemical derivatives have a wide range of uses in pharmaceuticals, cosmetics, toothpastes, insect repellents, cleaning agents and other products [3]. The synthesis of menthol involves the acid-catalysed cyclisation of 1 to form isopulegol 4 as a stable intermediate. The latter is

• citronellal para-Menthane-3,8-diol (3) was synthesised according to our earlier developed procedure, which has not been reported in open literature. The synthesis procedure involves the acid-catalysed cyclisation of 1 in aqueous sulfuric acid (Scheme 2) at 100 °C. After which the oil simply separates from the

Scope and limitations of a DMF bio-alternative within Sonogashira cross-coupling and Cacchi-type annulation

• Kirsty L. Wilson,
• Alan R. Kennedy,
• Jane Murray,
• Ben Greatrex,
• Craig Jamieson and
• Allan J. B. Watson

Beilstein J. Org. Chem. 2016, 12, 2005–2011, doi:10.3762/bjoc.12.187

• annulation (Scheme 3) [42][43]. Specifically, employing ortho-amino (5) or ortho-hydroxyaryl iodides (6) in the Sonogashira process generated an alkyne intermediate that, upon increasing the reaction temperature from 30 °C to 60 °C, could undergo 5-endo-dig cyclisation to forge functionalised and

Practical synthetic strategies towards lipophilic 6-iodotetrahydroquinolines and -dihydroquinolines

• David R. Chisholm,
• Garr-Layy Zhou,
• Ehmke Pohl,
• Roy Valentine and
• Andrew Whiting

Beilstein J. Org. Chem. 2016, 12, 1851–1862, doi:10.3762/bjoc.12.174

• substituent, each with a different means of cyclisation. A versatile and stable quinolin-2-one intermediate was identified, which could be reduced to the corresponding THQ with borane reagents, or to the DHQ with diisobutylaluminium hydride via a novel elimination that is more favourable at higher

• temperatures. Coupling these strongly electron-donating scaffolds to electron-accepting moieties caused the resulting structures to exhibit strong fluorescence. Keywords: cyclisation; dihydroquinoline; elimination; reduction; tetrahydroquinoline; Introduction Tetrahydroquinolines (THQ) and dihydroquinolines

• the inexpensive 3,3-dimethylallyl bromide/chloride, followed by cyclisation mediated by Lewis acids, or under acidic conditions [5][6]. A second, analogous approach involves an initial acylation with the commercially available 3,3-dimethylacryloyl chloride, followed by Friedel–Crafts cyclisations that

Mechanistic investigations on six bacterial terpene cyclases

• Patrick Rabe,
• Thomas Schmitz and
• Jeroen S. Dickschat

Beilstein J. Org. Chem. 2016, 12, 1839–1850, doi:10.3762/bjoc.12.173

• containing water or deuterium oxide allowed for detailed insights into the cyclisation mechanisms of the bacterial terpene cyclases. Keywords: absolute configuration; biosynthesis; enzyme mechanisms; structure elucidation; terpenes; Introduction Terpenes are structurally fascinating natural products with

• highest identity with pentalenene synthases (39% identical residues with pentalenene synthase from Streptomyces exfoliatus UC5319) [11]. Intriguingly, both compounds are made from FPP via an initial 1,11-cyclisation. The cyclisation mechanisms of the bacterial terpene cyclases were investigated by

• isotopic labelling experiments. The proposed biosynthesis of 7-epi-α-eudesmol (4) starts with a 1,10-cyclisation of FPP to the (E,E)-germacradienyl cation (B) which is attacked by water to form hedycaryol (4a). Its reprotonation at C-1 initiates a second cyclisation to cation C that undergoes deprotonation

Biosynthesis of oxygen and nitrogen-containing heterocycles in polyketides

• Franziska Hemmerling and
• Frank Hahn

Beilstein J. Org. Chem. 2016, 12, 1512–1550, doi:10.3762/bjoc.12.148

• cyclisation modes triggers the interest on the responsible enzymes. Due to the relevance of heterocycles, understanding the enzymology of heterocycle formation is also an important milestone on the way to using the enzymes as chemoenzymatic tools in natural product synthesis and medicinal chemistry [6][7

• ) domains as well as ketoreductase (KR), dehydratase (DH), enoyl reductase (ER) and thioesterase (TE) domains [6][8]. The PKS intermediates remain tethered to the megaenzyme via a thioester linkage during the whole process. Among these domains, only TE domains participate in cyclisation reactions as part of

• 1.1.1 and 1.2.1), during the cleavage of the fully elongated precursor from the PKS (as for example for tetronates, tetramates and pyridinones, see chapters 1.7.1, 2.2.1 and 2.1.3) or during post-PKS tailoring (as for example during oxidative cyclisation in aureothin biosynthesis, see chapter 1.2.2

The hydrolysis of geminal ethers: a kinetic appraisal of orthoesters and ketals

• Sonia L. Repetto,
• James F. Costello,
• Craig P. Butts,
• Joseph K. W. Lam and
• Norman M. Ratcliffe

Beilstein J. Org. Chem. 2016, 12, 1467–1475, doi:10.3762/bjoc.12.143

• former affords a leaving group covalently tethered to a cation which renders the overall rate apparently slow, perhaps through a favoured re-cyclisation. It is noteworthy that the hydroxonium catalytic coefficient for the hydrolysis – albeit measured in water – of a similar yet acyclic ketal (i.e., 2,2

Discovery of an inhibitor of the production of the Pseudomonas aeruginosa virulence factor pyocyanin in wild-type cells

• Bernardas Morkunas,
• Balint Gal,
• Warren R. J. D. Galloway,
• James T. Hodgkinson,
• Brett M. Ibbeson,
• Yaw Sing Tan,
• Martin Welch and
• David R. Spring

Beilstein J. Org. Chem. 2016, 12, 1428–1433, doi:10.3762/bjoc.12.137

• intramolecular cyclisation of an analogous β-ketoamide in sulphuric acid [27], or pallidum catalysed intramolecular cyclisation of an acetylene derivative under acidic conditions [28]. The 4-alkylquinolin-2(1H)-one molecular scaffold of compound 4 is clearly distinct from that of AHLs; to the best of our

The EIMS fragmentation mechanisms of the sesquiterpenes corvol ethers A and B, epi-cubebol and isodauc-8-en-11-ol

• Patrick Rabe and
• Jeroen S. Dickschat

Beilstein J. Org. Chem. 2016, 12, 1380–1394, doi:10.3762/bjoc.12.132

• carry a labelling (>99% 13C) in specific positions that can easily be located, if the cyclisation mechanism of the terpene cyclase is known. Furthermore, 13C NMR spectroscopy can be used to experimentally locate the labelling if the cyclisation mechanism is unidentified. As we have shown in two previous

• be a valuable source of information for many questions in natural product chemistry [23]. Many recent examples have shown how isotopic labelling experiments can unravel the complex and sometimes surprising cyclisation cascades that are catalysed by terpene cyclases in the conversion of simple linear

Cyclisation mechanisms in the biosynthesis of ribosomally synthesised and post-translationally modified peptides

• Andrew W. Truman

Beilstein J. Org. Chem. 2016, 12, 1250–1268, doi:10.3762/bjoc.12.120

• amount of RiPP chemical diversity is generated from cyclisation reactions, and the current mechanistic understanding of these reactions will be discussed here. These cyclisations involve a diverse array of chemical reactions, including 1,4-nucleophilic additions, [4 + 2] cycloadditions, ATP-dependent

• heterocyclisation to form thiazolines or oxazolines, and radical-mediated reactions between unactivated carbons. Future prospects for RiPP pathway discovery and characterisation will also be highlighted. Keywords: biosynthesis; cyclisation; enzymes; peptides; RiPPs; Introduction Nature employs a number of routes

• predictably than molecules made from multi-domain megasynthases such as polyketides and non-ribosomal peptides. Cyclisation is a common post-translational modification in RiPP pathways and includes a multitude of transformations. These modifications are usually essential for the proper biological activity of

Muraymycin nucleoside-peptide antibiotics: uridine-derived natural products as lead structures for the development of novel antibacterial agents

• Daniel Wiegmann,
• Stefan Koppermann,
• Marius Wirth,
• Giuliana Niro,
• Kristin Leyerer and
• Christian Ducho

Beilstein J. Org. Chem. 2016, 12, 769–795, doi:10.3762/bjoc.12.77

• diastereoselectively converted with a Grignard reagent into the amine 53 as a key step of the synthesis [78]. Cbz protection followed by ozonolysis with subsequent reductive amination and hydrogenolysis led to the 1,3-diamine 54. The cyclisation to the guanidine functionality was achieved with the novel

A practical way to synthesize chiral fluoro-containing polyhydro-2H-chromenes from monoterpenoids

• Oksana S. Mikhalchenko,
• Dina V. Korchagina,
• Konstantin P. Volcho and
• Nariman F. Salakhutdinov

Beilstein J. Org. Chem. 2016, 12, 648–653, doi:10.3762/bjoc.12.64

• was 7% (Table 2). Thus, we found for the first time the conditions enabling production of chiral fluoro-containing heterocyclic compounds from a monoterpenoid using the halo-Prins cyclisation. It should also be noted that preparative isolation of compounds of type 7a is complicated by the presence of

• as fluorine sources. Presumably, the reaction starts with the Prins cyclisation resulting in the formation of cation 10. There are then several mechanistic pathways, some or all of them may be in operation: a) cation 10 may undergo stereoselective trap by [F−] to form fluoride epimers 8; b) cation 10

Recent advances in N-heterocyclic carbene (NHC)-catalysed benzoin reactions

• Rajeev S. Menon,
• Akkattu T. Biju and
• Vijay Nair

Beilstein J. Org. Chem. 2016, 12, 444–461, doi:10.3762/bjoc.12.47

• reaction conditions. An intramolecular cross-benzoin condensation between aldehyde and ketone moieties was developed by Suzuki in 2003. The isoxazole-fused cyclohexanone 51 endowed with an aryl aldehyde underwent a smooth cross-benzoin cyclisation in the presence of the thiazolium catalyst 19 and DBU

• -derived triazolium precatalyst 54 promoted enantioselective intramolecular benzoin reactions of N-tethered keto-aldehydes effectively. The substrates for the cyclisation are easily accessible and dihydroquinolinone systems possessing a quaternary stereocentre are produced in high yields and

Investigation on the reactivity of α-azidochalcones with carboxylic acids: Formation of α-amido-1,3-diketones and highly substituted 2-(trifluoromethyl)oxazoles

• Kandasamy Rajaguru,
• Arumugam Mariappan,
• Rajendran Suresh,
• Periasamy Manivannan and
• Shanmugam Muthusubramanian

Beilstein J. Org. Chem. 2015, 11, 2021–2028, doi:10.3762/bjoc.11.219

• to excellent yield. Compounds 7a and 7b have been characterized by one and two-dimensional NMR spectroscopy (see Supporting Information File 1). It can be noticed that the cyclisation could have happened in two different ways yielding either 7 or 7' (Figure 4). The fact that the compound formed is 7

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

• isolated from Reniera fulva and R. mucosa [2][3]. It has been postulated that the biosynthesis of paniceins centres around the cyclisation of a farnesyl precursor 6 [4] to an abscisane derivative 7 followed by a 1,2-methyl migration and subsequent oxidation to give panicein A (1) [1][3]. Subsequent

• proposed that panicein A2 (5) could be synthesised from the cyclisation and subsequent deprotection of propargyl ether 8. Ether 8 could be formed through the addition of the appropriate phenol to acetylenic alcohol 9, which itself can be derived from aldehyde 10 (Figure 3). Results and Discussion Synthesis

• produced (Scheme 4). The reaction was then attempted with the acetyl-protected propargyl ether 8. Gratifyingly, cyclised product 21 was obtained in a 46% yield, based on returned starting material. To investigate the effect of an alternative protecting group on the cyclisation reaction, TBDMS ether 22 was

Polythiophene and oligothiophene systems modified by TTF electroactive units for organic electronics

• Alexander L. Kanibolotsky,
• Neil J. Findlay and
• Peter J. Skabara

Beilstein J. Org. Chem. 2015, 11, 1749–1766, doi:10.3762/bjoc.11.191

• ) can be constructed by building up either of its two rings, involving cyclisation of a suitable precursor already containing one existing heterocycle. The construction of the 1,3-dithiole-2-thione unit of 17 can be completed using 3,4-dibromothiophene (18) as a starting material [56], or by oxidation

• of dihydroderivative 19 obtained from 4,6-dihydrothieno[3,4-d][1,2,3]thiadiazole (20) [57][58]. However, the most reliable method for the synthesis of 4,6-dihydrothieno[3,4-d][1,3]dithiole-2-thione (19) is cyclisation of 4,5-bis(bromomethyl)-1,3-dithiole-2-thione (21) [59] (synthetic pathway A). For

• 4,6-diaryl substituted thienodithiole-2-ones, e.g., 4,6-di(thiophen-2-yl)thieno[3,4-d][1,3]dithiol-2-one (15c), construction of the thiophene directly onto the dithiole ring seems to be the only strategy, which can be readily achieved by reductive cyclisation of diketone 22 [60] (synthetic pathway B

Pyridinoacridine alkaloids of marine origin: NMR and MS spectral data, synthesis, biosynthesis and biological activity

• Louis P. Sandjo,
• Victor Kuete and
• Maique W. Biavatti

Beilstein J. Org. Chem. 2015, 11, 1667–1699, doi:10.3762/bjoc.11.183

• conditions to give the natural product and its regioisomer (Scheme 2) [59]. The Diels–Alder cyclisation seems to be the key step for sebastianine A synthesis with a very low yield. Recently, the same cycloaddition was successfully performed on related compounds by attaching a bromine atom on the

• , while in method B, the cyclisation was performed in a radical mechanism manner. Whereas the radical condition afforded a low yield of the expected product, the Stille coupling seems to be a better solution. Synthesis of demethyldeoxyamphimedine (9) The synthesis of demethyldeoxyamphimedine was

• using phosphoryl bromide. Another organozinc substrate was coupled to the obtained intermediate by a Negishi cross-coupling and cyclisation occurred to give the expected secondary metabolite (Scheme 8) [68]. The yield of the last step in the preparation of 9 could be improved by using the synthetic