Recent highlights in biosynthesis research using stable isotopes

• Jan Rinkel and
• Jeroen S. Dickschat

Beilstein J. Org. Chem. 2015, 11, 2493–2508, doi:10.3762/bjoc.11.271

• the phenolic oxygen at C-6 to close the macrocycle in 25. In this mechanism, the aromaticity of the phenol ring remains untouched. Intramolecular Diels–Alder reaction gives rise to the hexacyclic system 26, which would then be oxidized to pyrrocidine A (24) at C-2’. In contrast to route A, the

Diversity-oriented synthesis of analogues of the novel macrocyclic peptide FR-225497 through late stage functionalization

• Jyotiprasad Mukherjee,
• Suman Sil and
• Shital Kumar Chattopadhyay

Beilstein J. Org. Chem. 2015, 11, 2487–2492, doi:10.3762/bjoc.11.270

• -225497. Keywords: cross metathesis; cyclic peptides; diversity oriented synthesis; macrocycle; Introduction Diversity-oriented synthesis (DOS) has been established as an important paradigm in drug discovery [1][2][3][4][5][6][7]. Although the major focus is on the synthesis of small molecular libraries

Aggregation behaviour of amphiphilic cyclodextrins: the nucleation stage by atomistic molecular dynamics simulations

• Giuseppina Raffaini,
• Antonino Mazzaglia and
• Fabio Ganazzoli

Beilstein J. Org. Chem. 2015, 11, 2459–2473, doi:10.3762/bjoc.11.267

• diameters of the two rims. This shape is qualitatively displayed by the internal molecular cavity shown in Figure 1a, and quantitatively revealed by the similarity of the pair distribution function PDF of the glycosidic oxygens on the macrocycle and of the S atoms carrying the H chain as a function of their

• distance from the macrocycle centre of mass (c.o.m.), shown in Figure 2a. In particular, these distances roughly fluctuate around a similar average value, with a similar shoulder at larger separation. We further note for the later discussion that the surface accessible to the solvent (Figure 1a) amounts to

• chains in order to minimize the exposed surface. The PDF is again most useful to characterize the molecular shape induced by the environment. This feature can be seen in the PDF of the glycosidic oxygens of the macrocycle and of the S atoms plotted as before as a function of their distance from the

Beyond catalyst deactivation: cross-metathesis involving olefins containing N-heteroaromatics

• Kevin Lafaye,
• Cyril Bosset,
• Lionel Nicolas,
• Amandine Guérinot and
• Janine Cossy

Beilstein J. Org. Chem. 2015, 11, 2223–2241, doi:10.3762/bjoc.11.241

• -dihydroquinolizinium salts (Scheme 13) [50]. In their synthetic approach towards (R)-(+)-muscopyridine, Fürstner and Leitner have constructed the 13-membered ring macrocycle using a RCM applied to diene 34 [51]. In order to avoid the catalyst deactivation due to the presence of the pyridine moiety, the precursor 34

• synthesis of the tris-pyrrole macrocyclic pigment nonylprodigiosin [52]. A preliminary protonation of the tris-pyrrole followed by a RCM applied to 37 in the presence of the ruthenium catalyst 36 gave the macrocycle 38, which was then transformed into the saturated derivative 39 using the Wilkinson’s

• of 2,6-disubstituted pyridine 60 was treated with GI, the expected macrocycle 61 was obtained (51%) together with the dimeric cyclophane 62 (20%). The authors explained that the sulfone moieties facilitated the RCM by steering the alkenyl chains into a favorable conformation, but it also may be

Easy access to heterobimetallic complexes for medical imaging applications via microwave-enhanced cycloaddition

• Nicolas Desbois,
• Sandrine Pacquelet,
• Adrien Dubois,
• Clément Michelin and
• Claude P. Gros

Beilstein J. Org. Chem. 2015, 11, 2202–2208, doi:10.3762/bjoc.11.239

• of radiolabeled 111In–NOTA [26]. Unlike the corrole macrocycle, indium(III) porphyrins can be prepared [27]. We wish to report herein (Scheme 1) the convenient synthesis of various multimodal ligands. Those complexes, incorporating one porphyrin or one corrole moiety on one side and one DOTA or NOTA

• -like macrocycle on the other side, have been easily linked by microwave azide–alkyne 1,3-dipolar cycloaddition. The preliminary relaxivity study of these heterobimetallic complexes was also investigated for potential MRI applications. Results and Discussion We first wish to report a “library” of azido

• 1656 cm−1, which clearly demonstrates the complexation of Ga3+ ions with the carboxylic acid groups of ligand 3. Another macrocycle commonly used in medical imaging studies is the NOTA ligand, which is usually preferred to DOTA to chelate e.g. Cu2+. Propargyl-NOTA(t-Bu)2 11 (commercially available) was

Supramolecular chemistry: from aromatic foldamers to solution-phase supramolecular organic frameworks

• Zhan-Ting Li

Beilstein J. Org. Chem. 2015, 11, 2057–2071, doi:10.3762/bjoc.11.222

• core [11]. Using this method, I could prepare bimacrocycle 3 in a short time. This macrocycle was used to template the formation of the so-called tetracationic “blue box” [12][13] from 4 and 5 to give rise to the unique pseudo[3]catenanes 6a and 6b (Scheme 2), together with a trace amount of [2

• ]catenane 6c with the tetracationic cyclophane holding one of the peripheral benzene rings [14]. The TTF unit in 6a and 6b adopted a stable cis or trans configuration, although typically the two configurations easily isomerize into each other in solution. Macrocycle 3 is a brown solid due to the existence

• difference by crystallizing a fluorine-bearing pentagon macrocycle [49][50][51]. No stacking was observed for the methoxy-derived pentagon macrocycle. In contrast, their fluorine-engaged pentagon macrocycle stacked strongly. Moreover, the macrocycle stacked in the 2D space to give rise to the mathematically

Preparation of conjugated dienoates with Bestmann ylide: Towards the synthesis of zampanolide and dactylolide using a facile linchpin approach

• Jingjing Wang,
• Samuel Z. Y. Ting and
• Joanne E. Harvey

Beilstein J. Org. Chem. 2015, 11, 1815–1822, doi:10.3762/bjoc.11.197

• . Although fragment syntheses vary, the late-stage fragment assembly of the dactylolide macrocycle has centred mostly around construction of the C1–C5 dienoate by Wittig-type olefination reactions followed by ester hydrolysis and esterification with the C19 hydroxy group, combined with metathesis to form the

• macrocycle, suitably functionalised for transformation to the natural products. This highly efficient method for connecting the C3–C8 and C16–C20 fragments through a C1–C2 linchpin in a single step contrasts with other routes that require multiple-step sequences including Wittig-type reaction, ester

Structure and conformational analysis of spiroketals from 6-O-methyl-9(E)-hydroxyiminoerythronolide A

• Ana Čikoš,
• Irena Ćaleta,
• Dinko Žiher,
• Mark B. Vine,
• Ivaylo J. Elenkov,
• Marko Dukši,
• Dubravka Gembarovski,
• Marina Ilijaš,
• Snježana Dragojević,
• Ivica Malnar and
• Sulejman Alihodžić

Beilstein J. Org. Chem. 2015, 11, 1447–1457, doi:10.3762/bjoc.11.157

• 2 which sparked our interest, not only because the spiroketal is a biologically relevant subunit whose incorporation into macrolide could yield interesting biological activity, but also because this unit provides unique rigidity to the 6-C to 12-C region of the macrocycle allowing for specific

Selected synthetic strategies to cyclophanes

• Sambasivarao Kotha,
• Mukesh E. Shirbhate and
• Gopalkrushna T. Waghule

Beilstein J. Org. Chem. 2015, 11, 1274–1331, doi:10.3762/bjoc.11.142

• area due to the cost and energy demanding purification process and the poor processibility of the fullerenes. To this end, Zhang and co-workers [140] reported the synthesis of the bisporphyrin macrocycle 144 with an adaptable cavity by using alkyne metathesis with high efficiency. Tamm and co-workers

• with the pentafluorobenzyl ester auxiliary, ester 210 was synthesized in a multistep process and then subjected to olefin metathesis to deliver the macrocycle using the Blechert catalyst 17. The treatment of the pentafluorophenyl benzyl ester 210 with catalyst 17 in toluene afforded the rigid

• macrocycle 211 (39%, Scheme 33). Kotha and Shirbhate [169] have reported the longithorone framework by using RCM as a key step. Dibromo compound 212 was reacted with monoalkylated ethyl acetoacetate 213 in the presence of NaH to deliver bis-alkyated product 214, followed by an oxidation the quinone

Hybrid macrocycle formation and spiro annulation on cis-syn-cis-tricyclo[6.3.0.0^2,6]undeca-3,11-dione and its congeners via ring-closing metathesis

• Sambasivarao Kotha,
• Ajay Kumar Chinnam and
• Rashid Ali

Beilstein J. Org. Chem. 2015, 11, 1123–1128, doi:10.3762/bjoc.11.126

• based macrocycle 6 involving Fischer indolization and ring-closing metathesis (RCM). Various spiro-polyquinane derivatives have been assembled via RCM as a key step. Keywords: aza-polyquiananes; Fischer indolization; macrocycles; ring-closing metathesis; spiropolyquinanes; Introduction Design and

• hydrogenation sequence to deliver the saturated bis-spiro-polyquinane 16d in good yield (Table 1). Conclusion In summary, we have developed a protocol for the synthesis of a diindole-based hybrid macrocycle through Fischer indolization of the triquinane 2 followed by bis-N-allylation and RCM. The allylation-RCM

Tuning the size of a redox-active tetrathiafulvalene-based self-assembled ring

• Sébastien Bivaud,
• Sébastien Goeb,
• Vincent Croué,
• Magali Allain,
• Flavia Pop and
• Marc Sallé

Beilstein J. Org. Chem. 2015, 11, 966–971, doi:10.3762/bjoc.11.108

• adjusted to tune the macrocycle size and shape. Complexation of ligand L1 with precursor Pd(en)(OTf)2 (en = 1,2-ethylenediamine) was carried out in DMSO at 40 °C and monitored by 1H NMR. In 30 min, the reaction converged into a unique symmetrical discrete species that could be isolated in more than 90

Discrete multiporphyrin pseudorotaxane assemblies from di- and tetravalent porphyrin building blocks

• Mirko Lohse,
• Larissa K. S. von Krbek,
• Sebastian Radunz,
• Suresh Moorthy,
• Christoph A. Schalley and
• Stefan Hecht

Beilstein J. Org. Chem. 2015, 11, 748–762, doi:10.3762/bjoc.11.85

• to the macrocycle indicates that the porphyrin core is protonated (three BArF anions per divalent guest A2; five BArF anions per tetravalent guest A4). Based on the assumption that protonation of the porphyrin core, which is rather remote to the primary binding sites, does not influence the

Inclusion of trans-resveratrol in methylated cyclodextrins: synthesis and solid-state structures

• Lee Trollope,
• Dyanne L. Cruickshank,
• Terence Noonan,
• Susan A. Bourne,
• Milena Sorrenti,
• Laura Catenacci and
• Mino R. Caira

Beilstein J. Org. Chem. 2014, 10, 3136–3151, doi:10.3762/bjoc.10.331

• longer axis of each macrocycle being approximately parallel to the planes of the respective included 4-hydroxyphenyl rings. In addition, the crystallographically independent TMA host molecules adopt somewhat different conformations given the fact that their contents differ, owing to the disorder

• ° (Figure 4a). As is usually observed, the primary methoxy groups of the host TMB are generally directed towards the centre of the macrocycle, and effectively close the primary side, presenting a bowl-shaped surface to the RSV molecule. Instead, the secondary side of the host molecule is open and a portion

Mono- and multilayers of molecular spoked carbazole wheels on graphite

• Stefan-S. Jester,
• A. Vikas Aggarwal,
• Daniel Kalle and
• Sigurd Höger

Beilstein J. Org. Chem. 2014, 10, 2783–2788, doi:10.3762/bjoc.10.295

• -persistent macrocycle with an intraannular spoke/hub system) and its synthetic precursor are investigated by scanning tunneling microscopy (STM) at the liquid/solid interface of 1-octanoic acid and highly oriented pyrolytic graphite. The submolecularly resolved STM images reveal that the molecules indeed

Self-assembled monolayers of shape-persistent macrocycles on graphite: interior design and conformational polymorphism

• Joscha Vollmeyer,
• Friederike Eberhagen,
• Sigurd Höger and
• Stefan-S. Jester

Beilstein J. Org. Chem. 2014, 10, 2774–2782, doi:10.3762/bjoc.10.294

• macrocycle distances are mainly determined by their size and symmetry. This is an excellent example that the graphite acts as a template for the macrocycle organization independent from their specific interior. Keywords: conformational polymorphism; self-assembled monolayers; shape-persistent macrocycles

• supramolecular surface patterning is highly oriented pyrolytic graphite (HOPG) which provides large atomically flat terraces between step edges and a sufficient adsorbate mobility, required for the self-assembly process that leads to the 2D crystal formation. For a more detailed understanding of the macrocycle

• –HOPG and macrocycle–macrocycle interactions, the following key aspects must be considered: (i) how the extraannular alkyl side chains of the adsorbed macrocycles pack, and whether this can be compared to the packing of linear hydrocarbons on HOPG, (ii) how the specific attachment of the extraannular

Formal total syntheses of classic natural product target molecules via palladium-catalyzed enantioselective alkylation

• Yiyang Liu,
• Marc Liniger,
• Ryan M. McFadden,
• Jenny L. Roizen,
• Jacquie Malette,
• Corey M. Reeves,
• Douglas C. Behenna,
• Masaki Seto,
• Jimin Kim,
• Justin T. Mohr,
• Scott C. Virgil and
• Brian M. Stoltz

Beilstein J. Org. Chem. 2014, 10, 2501–2512, doi:10.3762/bjoc.10.261

• indole alkaloid isolated from the Aspidosperma quebracho tree bark [60]. It has been found to possess adrenergic blocking activities for a variety of urogenital tissues [85]. Structurally, it features a tetracycle including an indole nucleus, a 9-membered macrocycle, and an all-carbon quaternary

• enantioselective total synthesis of quebrachamine (Scheme 12) [92]. In their planning, disconnection at the macrocycle led to amide 52, which was prepared from 3,3-disubstituted piperidine 53. The all-carbon quaternary stereocenter in 53 was installed by double alkylation of lactam 55, using an auxiliary to

A versatile δ-aminolevulinic acid (ΑLA)-cyclodextrin bimodal conjugate-prodrug for PDT applications with the help of intracellular chemistry

• Chrysie Aggelidou,
• Theodossis A. Theodossiou,
• Antonio Ricardo Gonçalves,
• Mariza Lampropoulou and
• Konstantina Yannakopoulou

Beilstein J. Org. Chem. 2014, 10, 2414–2420, doi:10.3762/bjoc.10.251

• prodrug 2, bearing ~3 δ-aminolevulinic acid moieties per β-CD macrocycle. The dual nature of the system was exemplified by the intracellular formation of PpIX using “intracellular chemical synthesis”. At the same time 2 was able to carry inside the cytoplasm a model guest molecule. The possibility that

De novo macrolide–glycolipid macrolactone hybrids: Synthesis, structure and antibiotic activity of carbohydrate-fused macrocycles

• Richard T. Desmond,
• Anniefer N. Magpusao,
• Chris Lorenc,
• Jeremy B. Alverson,
• Nigel Priestley and
• Mark W. Peczuh

Beilstein J. Org. Chem. 2014, 10, 2215–2221, doi:10.3762/bjoc.10.229

• . Glycosylation of an available hydroxy group on the macrocycle gave a hybrid macrolide with features common to erythromycin and sophorlipid macrolactone. Weak antibiotic activity (MICs <100 μg/mL) was observed for several of the compounds. Keywords: antibiotic; carbohydrate; exo-anomeric effect; macrolide

• ], have investigated compounds that blend features of macrolides and glycolipid lactones. These natural product-like compounds fuse the carbohydrate ring to the macrocycle rather than connecting them through a glycosidic linkage. Compounds 3 and 4 in Figure 1 illustrate one approach that has been reported

• . Here oxygens at the C6 and C4 positions of a pyranose provide two linkage points between the macrocycle and the carbohydrate. Atoms of the carbohydrate are integral to the structure of the macrocycle to form a 13-membered ring in 3 and an 18-membered ring in 4. In addition to the number of atoms in the

The effect of permodified cyclodextrins encapsulation on the photophysical properties of a polyfluorene with randomly distributed electron-donor and rotaxane electron-acceptor units

• Aurica Farcas,
• Ana-Maria Resmerita,
• Pierre-Henri Aubert,
• Flavian Farcas,
• Iuliana Stoica and
• Anton Airinei

Beilstein J. Org. Chem. 2014, 10, 2145–2156, doi:10.3762/bjoc.10.222

• macrocycle molecules has been employed as an alternative approach to achieve the control of aggregation and to improve the photophysical and morphological characteristics [13]. In the past years, it has been demonstrated that the encapsulation of conjugated polymer into macrocycle cavities leads to an

• polyrotaxanes exhibited a thermal decomposition temperature around 412 °C, whereas the thermal decomposition temperature of reference 4 was around 414 °C at 5% weight loss (Figure 4 and Table 1). It is noteworthy that the polyrotaxane formation increases the thermal stability of the macrocycle molecules

Macrocyclic bis(ureas) as ligands for anion complexation

• Claudia Kretschmer,
• Gertrud Dittmann and
• Johannes Beck

Beilstein J. Org. Chem. 2014, 10, 1834–1839, doi:10.3762/bjoc.10.193

• isocyanates lead to indoloquinolinones. The crystal structure of the N-methylated congener of 3 has been determined [15]. Thermal treatment of 2 does not lead to fragmentation or sublimation of volatile material as observed for 1. Macrocycle 2 is soluble in dimethylformamide (DMF) or dimethyl sulfoxide (DMSO

• the cavity of the macrocycle (Figure 2). The ligand is strongly tilted. The four N−H∙∙∙Br bonds, however, show uniform lengths (H1−Br, 2.72; H2−Br, 2.74; H3−Br, 2.75; H4−Br, 2.71 Å; N−H∙∙∙O angles 149–169°). The representation with space filling radii shows that the halide anion fits well into the bis

• 578.2 clearly indicate the masses of the neat macrocycle 2 and the complex [NO3·2]. Signals originating from higher masses at 640.13 (2 with two molecules nitrate) or 1094.31 (two molecules of 2 with one molecule nitrate) could not be detected. So the 1:1 binding mode seems the most plausible ratio

Sacrolide A, a new antimicrobial and cytotoxic oxylipin macrolide from the edible cyanobacterium Aphanothece sacrum

• Naoya Oku,
• Miyako Matsumoto,
• Kohsuke Yonejima,
• Keijiroh Tansei and
• Yasuhiro Igarashi

Beilstein J. Org. Chem. 2014, 10, 1808–1816, doi:10.3762/bjoc.10.190

• (-H22-H23-H24-H25-H26-H27-H28-H9(-O-)-H10=H11-) were bidirectionally opened by a methylene and a double bond at the termini and should constitute a body of the macrocycle core. The connectivity of the two fragments was verified by HMBC correlations from H10 (δH 6.93), H11 (δH 6.56), H13 (δH 5.23), and

Clicked and long spaced galactosyl- and lactosylcalix[4]arenes: new multivalent galectin-3 ligands

• Silvia Bernardi,
• Paola Fezzardi,
• Gabriele Rispoli,
• Stefania E. Sestito,
• Francesco Peri,
• Francesco Sansone and
• Alessandro Casnati

Beilstein J. Org. Chem. 2014, 10, 1672–1680, doi:10.3762/bjoc.10.175

• macrocycle, we decided to exploit the easily available and highly versatile p-aminocalixarene 6 prepared according to literature procedures [25]. The coupling reaction between amino-calix[4]arene 6 and 4-pentynoic acid (7) in the presence of dicyclohexylcarbodiimide (DCC) led to compound 8 in 44% yield. Due

• macrocycle arms to the saccharide units. On the basis of the comparison between the efficiency of the conjugation steps bringing to glycoconjugates 9 and 13 (yields >80% in both cases) and contrary to the observation by Marra et al. [37], we could not collect any evidence for an autocatalytic effect in the

Improving the reactivity of phenylacetylene macrocycles toward topochemical polymerization by side chains modification

• Simon Rondeau-Gagné,
• Jules Roméo Néabo,
• Maxime Daigle,
• Katy Cantin and
• Jean-François Morin

Beilstein J. Org. Chem. 2014, 10, 1613–1619, doi:10.3762/bjoc.10.167

• -assembly of two new phenylacetylene macrocycle (PAM) organogelators were performed. Polar 2-hydroxyethoxy side chains were incorporated in the inner part of the macrocycles to modify the assembly mode in the gel state. With this modification, it was possible to increase the reactivity of the macrocycles in

• alkyne protective group, the half-macrocycle 5 was obtained by Castro–Stephens–Sonogashira coupling with previously reported 3,5-diiodooctylbenzene [39] in good yields despite of the possible polymerization side reaction (54% yield). TMS-protected alkynes were, then, installed on the half-macrocycle to

• approach was used for PAM3. Starting from previously synthesized compound 3, the half-macrocycle 9 was obtained by standard Castro–Stephens–Sonogashira coupling with dialkyne 8 in good yield (59%). It is noteworthy that compound 8 was obtained from oxidative deprotection of compound 7. After installing TMS

Homochiral BINOL-based macrocycles with π-electron-rich, electron-withdrawing or extended spacing units as receptors for C₆₀

• Marco Caricato,
• Silvia Díez González,
• Idoia Arandia Ariño and
• Dario Pasini

Beilstein J. Org. Chem. 2014, 10, 1308–1316, doi:10.3762/bjoc.10.132

• shape, involving both cyclic π-electron rich and π-electron deficient substrates [23][25]. The calculated thermodynamic binding constants are reported in Table 3. In the case of macrocycle 4d, a 1:1 binding isotherm could be efficiently employed to fit the titration data, strongly indicating that a 1:1

• the Hill equation [42] gave an average binding constant of 1600 M−1, thus confirming a higher affinity for the π-electron rich thiophene-derived spacer units. The Hill coefficient [43][44] suggests the presence of concomitant 1:1 and 1:2 C60:macrocycle complexes in solution. Even more interestingly

• concentration dissolved in solution A, so that the guest always remains at the same, constant concentration. In the case of a 1:1 binding isotherm (Figure 4, bottom), by employing a nonlinear fitting curve program, the plot of A against the macrocycle concentration x was fitted by Equation 1, thus affording the

Substitution effect and effect of axle’s flexibility at (pseudo-)rotaxanes

• Friedrich Malberg,
• Jan Gerit Brandenburg,
• Werner Reckien,
• Oldamur Hollóczki,
• Stefan Grimme and
• Barbara Kirchner

Beilstein J. Org. Chem. 2014, 10, 1299–1307, doi:10.3762/bjoc.10.131

• ][2][3]. They are mechanically interlocked molecules consisting of a macrocycle, called “wheel”, threaded on a linear chain, termed “axle”, see Figure 1 for examples. Typically, the axle has at least one recognition site – often hydrogen bond donors or acceptors [4][5] – for the wheel, because most

• macrocycle with isophtalamide units building up twofold hydrogen bonds to an acceptor axle. The Schalley group often used a similar hydrogen bond motif for the design of molecular shuttles with the Vögtle–Hunter tetralactam macrocycle next to several other combinations [13][14][15]. Fernandes et al. recently

• combination provides reliable results for both the gas phase and the solid state as shown in a number of publications by us [49][50][51] and other groups [45][52]. Structures under study The hereby considered pseuodorotaxanes (Figure 1) consist of an amide axle inside the cavity of a macrocycle, which