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

Intermolecular addition reactions of N-alkyl-N-chlorosulfonamides to unsaturated compounds

• Gerold Heuger and
• Richard Göttlich

Beilstein J. Org. Chem. 2015, 11, 1226–1234, doi:10.3762/bjoc.11.136

• cyclisation of various unsaturated N-hetero-substituted amines and amides via radicals [1][2][3] and other mechanistic pathways [4][5][6][7][8]. Although reported by other groups [9][10][11] in our hands an efficient intermolecular addition reaction of N-hetero substituted amines via radicals was not possible

• has been achieved by Zhang [22] using copper or palladium catalysts and proceeds via radicals and fluoropalladation, respectively. Cyclisation reactions of unsaturated sulfonamides which proceed via amidyl radicals have been described by Li [23] and by Oshima [24]. Chemler [25][26] discusses radical

The synthesis of active pharmaceutical ingredients (APIs) using continuous flow chemistry

• Marcus Baumann and
• Ian R. Baxendale

Beilstein J. Org. Chem. 2015, 11, 1194–1219, doi:10.3762/bjoc.11.134

• syntheses of two lead compounds reported earlier by AstraZeneca. The first one details the flow synthesis of a potent 5HT1B antagonist (28) that was assembled through a five step continuous synthesis including a SNAr reaction, heterogeneous hydrogenation, Michael addition–cyclisation and final amide

• intermediate passes into a tube-in-tube reactor, where carboxylation takes place furnishing the lithium carboxylate 129. Excess carbon dioxide is subsequently removed using a degassing tube before reacting species 129 with a further stream of n-BuLi to induce cyclisation to dibenzosuberone (130) in a short

Hydrogenation of unactivated enamines to tertiary amines: rhodium complexes of fluorinated phosphines give marked improvements in catalytic activity

• Sergey Tin,
• Tamara Fanjul and
• Matthew L. Clarke

Beilstein J. Org. Chem. 2015, 11, 622–627, doi:10.3762/bjoc.11.70

• regioselectivity in enantioselective hydroformylation of alkyl- and arylalkenes [23][24], we reconsidered this cyclisation reaction using the new catalyst (Scheme 2). We were pleased to find that the selectivity is increased to 78%. Since the desired product is achiral, there is no need to use enantiopure BOBPHOS

Sequence-specific RNA cleavage by PNA conjugates of the metal-free artificial ribonuclease tris(2-aminobenzimidazole)

• Friederike Danneberg,
• Alice Ghidini,
• Plamena Dogandzhiyski,
• Elisabeth Kalden,
• Roger Strömberg and
• Michael W. Göbel

Beilstein J. Org. Chem. 2015, 11, 493–498, doi:10.3762/bjoc.11.55

• thiocarbonyldiimidazole and methyl 3,4-diaminobenzoate (Scheme 2). The cyclisation to form the first benzimidazole unit was then achieved by reacting thiourea 3 with Mukaiyama’s reagent in the presence of NEt3 at rt yielding 88% of 4. Although the yield is slightly lower compared to the cyclisation with HgO (97% yield

Further exploration of the heterocyclic diversity accessible from the allylation chemistry of indigo

• Alireza Shakoori,
• John B. Bremner,
• Mohammed K. Abdel-Hamid,
• Anthony C. Willis,
• Rachada Haritakun and
• Paul A. Keller

Beilstein J. Org. Chem. 2015, 11, 481–492, doi:10.3762/bjoc.11.54

• 9 and 10, while no such product was evident from the reaction with the larger cinnamyl bromide. Minor byproducts isolated were the corresponding N-monoallylated indigos (7–15%). These heterocycles arise from the cyclisation of one allyl unit onto a carbonyl, leading to the tertiary alcohol. They are

• derivatives of the azepino[1,2-a:3,4-b']diindolone skeleton have been reported previously, albeit in a different oxidation state and with notably different substitution patterns [5] (Figure 2), they were only obtained as very minor diastereomeric products (ca 1% yields) from acid-catalysed cyclisation studies

• and moisture. This is the first example of the synthesis of this bridged heterocyclic skeleton. The formation of 22 is an excellent example of the ‘gem-dimethyl effect’ [9] whereby the presence of that moiety enhances cyclisation [10]. This explains the formation of 22 and the lack analogous cyclised

The reactions of 2-ethoxymethylidene-3-oxo esters and their analogues with 5-aminotetrazole as a way to novel azaheterocycles

• Marina V. Goryaeva,
• Yanina V. Burgart,
• Marina A. Ezhikova,
• Mikhail I. Kodess and
• Viktor I. Saloutin

Beilstein J. Org. Chem. 2015, 11, 385–391, doi:10.3762/bjoc.11.44

• -benzoyl-3-ethoxyprop-2-enoate reacted with 5-aminotetrazole by two reaction routes to form ethyl 2-benzoyl-3-(1H-tetrazol-5-ylamino)prop-2-enoate and ethyl 7-(1-ethoxy-1,3-dioxo-3-phenylpropan-2-yl)-5-phenyl-4,7-dihydrotetrazolo[1,5-a]pyrimidine-6-carboxylate. Keywords: 5-aminotetrazole; cyclisation

Anionic sigmatropic-electrocyclic-Chugaev cascades: accessing 12-aryl-5-(methylthiocarbonylthio)tetracenes and a related anthra[2,3-b]thiophene

• Laurence Burroughs,
• John Ritchie,
• Mkhethwa Ngwenya,
• Dilfaraz Khan,
• William Lewis and
• Simon Woodward

Beilstein J. Org. Chem. 2015, 11, 273–279, doi:10.3762/bjoc.11.31

• (47%), 7c (56%), 7f (44%) and 7g (38%). The decreasing yields suggest that meta substitution promotes the 6π cyclisation while para electronic affects are minor and unhelpful according to the observed trend. Increasing the reaction temperature, in attempts to facilitate E2 elimination, was generally

Synthesis of the furo[2,3-b]chromene ring system of hyperaspindols A and B

• Danielle L. Paterson and
• David Barker

Beilstein J. Org. Chem. 2015, 11, 265–270, doi:10.3762/bjoc.11.29

• it to determine the complete relative stereochemistry of the natural products. Results and Discussion The proposed route to furo[2,3-b]chromene 7 was based around the preparation of benzylic ketone 8 which was hoped to under acidic conditions would undergo cyclisation to give 7 (Figure 2). We have