(2R,1'S,2'R)- and (2S,1'S,2'R)-3-[2-Mono(di,tri)fluoromethylcyclopropyl]alanines and their incorporation into hormaomycin analogues

• Armin de Meijere,
• Sergei I. Kozhushkov,
• Dmitrii S. Yufit,
• Christian Grosse,
• Marcel Kaiser and
• Vitaly A. Raev

Beilstein J. Org. Chem. 2014, 10, 2844–2857, doi:10.3762/bjoc.10.302

• (fluoromethylcyclopropyl)alanine moieties have been synthesized and subjected to preliminary tests of their antibiotic activity. Keywords: amino acids; biosynthesis; building blocks; cyclopropanes; natural products; synthetic methods; Introduction The intermolecular signal metabolite hormaomycin (1, Figure 1) was first

Indium-mediated allylation in carbohydrate synthesis: A short and efficient approach towards higher 2-acetamido-2-deoxy sugars

• Christopher Albler,
• Ralph Hollaus,
• Hanspeter Kählig and
• Walther Schmid

Beilstein J. Org. Chem. 2014, 10, 2230–2234, doi:10.3762/bjoc.10.231

• -Cope rearrangement of N-galactosyl-N-homoallylamines [18]. Aminooctoses, on the other hand, are present in the aminoglycoside antibiotic apramycin [19], in the form of an aminooctodiose derivative. However, only few syntheses of this dipyranoid aminosugar [20][21] were reported so far. Thus, we were

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

• ]. Erythromycin (1, Figure 1), for example, is an archetypal macrolide due to its molecular structure as well as its antibiotic activity; it is used clinically to treat Gram positive bacterial infections. The mechanism of action of erythromycin is via inhibition of bacterial protein synthesis [3][4]. Sophorolipid

• antibacterial activity [7][8]. Over time, antibiotic use has created a selection pressure that has led to bacterial resistance and a subsequent need for continuous development of new antibiotics. Despite cumbersome syntheses, erythromycin analogs continue to be used as front line antibiotics while the clinical

Palladium-catalysed cyclisation of alkenols: Synthesis of oxaheterocycles as core intermediates of natural compounds

• Miroslav Palík,
• Jozef Kožíšek,
• Peter Koóš and
• Tibor Gracza

Beilstein J. Org. Chem. 2014, 10, 2077–2086, doi:10.3762/bjoc.10.216

• presence of BuLi and LiCl provided selectively 5-exo-trig cyclisation products with excellent 2,3-trans diastereoselectivity. Finally, we have also proposed a synthetic access to the dioxaheptane core of natural C15 acetogenins and dioxaoctane, a substructure of the macrolide-polyether antibiotic

Expeditive synthesis of trithiotriazine-cored glycoclusters and inhibition of Pseudomonas aeruginosa biofilm formation

• Meriem Smadhi,
• Sophie de Bentzmann,
• Anne Imberty,
• Marc Gingras,
• Raoudha Abderrahim and
• Peter G. Goekjian

Beilstein J. Org. Chem. 2014, 10, 1981–1990, doi:10.3762/bjoc.10.206

• good affinity for Pseudomonas aeruginosa lectin lecA. They are convenient biological probes for investigating the roles of lecA and lecB in biofilm formation. Keywords: antibiotic; biofilm; glycocluster; lectin; multivalency effect; multivalent glycosystems; Introduction Pseudomonas aeruginosa (PA

• particular due to the physical barrier created by surface-attached biofilms, thus limiting antibiotic penetration [4][5][6]. A challenging and useful task is therefore to develop novel strategies against PA colonies at this late stage of virulence. Among recent approaches, targeting biofilm formation or

Application of cyclic phosphonamide reagents in the total synthesis of natural products and biologically active molecules

• Thilo Focken and
• Stephen Hanessian

Beilstein J. Org. Chem. 2014, 10, 1848–1877, doi:10.3762/bjoc.10.195

• component of polyoxins A, F, H, and K, which exhibit antibiotic properties [72]. Originally, the stereochemistry of the exocyclic double bond of polyoximic acid was incorrectly assigned as E based on a low resolution nOe experiment (Figure 3). The total synthesis of polyoximic acid (9) by Hanessian and co

OligArch: A software tool to allow artificially expanded genetic information systems (AEGIS) to guide the autonomous self-assembly of long DNA constructs from multiple DNA single strands

• Kevin M. Bradley and
• Steven A. Benner

Beilstein J. Org. Chem. 2014, 10, 1826–1833, doi:10.3762/bjoc.10.192

• resistance to the antibiotic kanamycin. Acknowledgements We are indebted to the DARPA Foundries program (HR0011-12-C-0064) and, through Firebird Biomolecular Sciences LLC, the US Army (W911NF-12-C-0059) for partial support of this work. The basic research that made this work possible was funded by the

Synthesis and bioactivity of analogues of the marine antibiotic tropodithietic acid

• Patrick Rabe,
• Tim A. Klapschinski,
• Nelson L. Brock,
• Christian A. Citron,
• Paul D’Alvise,
• Lone Gram and
• Jeroen S. Dickschat

Beilstein J. Org. Chem. 2014, 10, 1796–1801, doi:10.3762/bjoc.10.188

• of Denmark, Matematiktorvet bldg. 301, 2800 Kongens Lyngby, Denmark 10.3762/bjoc.10.188 Abstract Tropodithietic acid (TDA) is a structurally unique sulfur-containing antibiotic from the Roseobacter clade bacterium Phaeobacter inhibens DSM 17395 and a few other related species. We have synthesised

• several structural analogues of TDA and used them in bioactivity tests against Staphylococcus aureus and Vibrio anguillarum for a structure–activity relationship (SAR) study, revealing that the sulfur-free analogue of TDA, tropone-2-carboxylic acid, has an antibiotic activity that is even stronger than

• (TDA, 1a) is an antibiotic produced by the marine bacterium Phaeobacter inhibens. It has an unusual structure that is made up by a dithiet moiety fused to tropone-2-carboxylic acid (Figure 1) [1]. In Phaeobacter the compound is accompanied by hydroxy-TDA 2, while its tautomer thiotropocin (1b) was

Synthesis of rigid p-terphenyl-linked carbohydrate mimetics

• Maja Kandziora and
• Hans-Ulrich Reissig

Beilstein J. Org. Chem. 2014, 10, 1749–1758, doi:10.3762/bjoc.10.182

• compounds with β-D-talose configuration that are rarely found in nature, an exception being the antibiotic amino glycoside hygromycin B [37]. Aminopyran 17b correlates to β-D-idopyranose; iduronic acid is a component of sulfated glycosamine glycans such as chrondroitin sulfate and heparan sulfate [38]. The

Multicomponent reactions in nucleoside chemistry

• Mariola Koszytkowska-Stawińska and
• Włodzimierz Buchowicz

Beilstein J. Org. Chem. 2014, 10, 1706–1732, doi:10.3762/bjoc.10.179

• -nucleoside substrates, the ones dealing with the construction of a non-natural nucleobase predominated (18 examples). Interestingly, a combinatorial solid-phase approach has not been extensively exploited (2 examples). The findings concerning the syntheses of nucleoside antibiotic analogs or 1'-aza-analogs

Streptopyridines, volatile pyridine alkaloids produced by Streptomyces sp. FORM5

• Ulrike Groenhagen,
• Michael Maczka,
• Jeroen S. Dickschat and
• Stefan Schulz

Beilstein J. Org. Chem. 2014, 10, 1421–1432, doi:10.3762/bjoc.10.146

• Ulrike Groenhagen Michael Maczka Jeroen S. Dickschat Stefan Schulz Institut für Organische Chemie, Technische Universität Braunschweig, Hagenring 30, 38106 Braunschweig, Germany 10.3762/bjoc.10.146 Abstract Streptomyces sp. FORM5 is a bacterium that is known to produce the antibiotic streptazolin

• that are accompanied by a broad range of headspace constituents that occur in many actinomycetes. Volatiles might be of ecological importance for the producing organism, and, as biosynthetic intermediates or shunt products, they can be useful as indicators of antibiotic production in a bacterium

• similar structure has the antibiotic nigrifactin (26), a hexaketide produced by S. nigrifaciens, differing only in the length of the side chain [25]. Piperideine 24 lacks a N–H and might get lost during work-up of the E-extract, contrary to the other alkylpiperidines. It can be detected as trace component

Heronapyrrole D: A case of co-inspiration of natural product biosynthesis, total synthesis and biodiscovery

• Jens Schmidt,
• Zeinab Khalil,
• Robert J. Capon and
• Christian B. W. Stark

Beilstein J. Org. Chem. 2014, 10, 1228–1232, doi:10.3762/bjoc.10.121

• initiate a cyclization cascade [1][3][8] that would provide the bis-tetrahydrofuran heronapyrrole C (Scheme 1), via a mechanism that closely resembles polyether antibiotic biosynthesis [12][13][14][15][16][17]. This biosynthetic hypothesis raises the possibility that Streptomyces sp. (CMB-M0423) may

Olefin cross metathesis based de novo synthesis of a partially protected L-amicetose and a fully protected L-cinerulose derivative

• Bernd Schmidt and
• Sylvia Hauke

Beilstein J. Org. Chem. 2014, 10, 1023–1031, doi:10.3762/bjoc.10.102

• ][8] and display both antibiotic and cytotoxic activity [9]. They have a polycyclic xanthone aglycone in common, which is glycosylated at the C14–OH group. In Figure 1 the structure of kigamicin B, which carries a D-amicetose disaccharide unit, is shown as a representative example. Another antitumor

• antibiotic is aclacinomycin A, which has been used clinically under the name aclarubicin. It is an anthracycline [10] bearing a trisaccharide side chain consisting of L-rhodosamin, 2,6-didesoxy-L-lyxose, and L-cinerulose attached to the aglycon aclavinon [11][12]. It was found to be a potent antineoplastic

A novel family of (1-aminoalkyl)(trifluoromethyl)- and -(difluoromethyl)phosphinic acids – analogues of α-amino acids

• Natalia V. Pavlenko,
• Tatiana I. Oos,
• Yurii L. Yagupolskii,
• Igor I. Gerus,
• Uwe Doeller and
• Lothar Willms

Beilstein J. Org. Chem. 2014, 10, 722–731, doi:10.3762/bjoc.10.66

• , bearing side chain C–F linkages are well documented in a review [10]. The isolation of phosphinothricin, a naturally occurring phosphorus analogue of glutamic acid and the discovery of its antibiotic, fungicidal and herbicidal properties [11] has led to an increased activity in the study of

Isocyanide-based multicomponent reactions towards cyclic constrained peptidomimetics

• Gijs Koopmanschap,
• Eelco Ruijter and
• Romano V.A. Orru

Beilstein J. Org. Chem. 2014, 10, 544–598, doi:10.3762/bjoc.10.50

• expected compound 109 (Scheme 34). Thiazoles In several natural products, the thiazole ring can be found as a backbone linker, probably resulting from easy cyclization/oxidation of cysteine residues. These compounds show interesting antifungal and antibiotic [95][96], algicidal [97], and antitumor [98][99

Intermediates in monensin biosynthesis: A late step in biosynthesis of the polyether ionophore monensin is crucial for the integrity of cation binding

• Wolfgang Hüttel,
• Jonathan B. Spencer and
• Peter F. Leadlay

Beilstein J. Org. Chem. 2014, 10, 361–368, doi:10.3762/bjoc.10.34

• important and extensive group of natural products including a large number of antibiotic ionophores [1][2][3][4][5] as well as remarkable marine toxins such as the brevetoxins [6][7]. The antibiotic polyethers adopt a characteristic conformation in which multiple oxygen atoms provide ligands for a centrally

• accounts for its lower effectiveness as an ionophore antibiotic [7]. Otherwise, both show a highly rigid structure in which the sodium cation is enveloped by the polyether and coordinated by four oxygen atoms in ether rings (O-6, O-7, O-8 and O-9), and by the oxygen atoms (O-5 and O-11, respectively) of

• surrounding the sodium ion. It has previously been shown that chemical modifications at the C-25 and/or C-26 hydroxy groups of monensin A lower both cation binding and antibiotic activity [35][36], presumably by the same mechanism. However, not all derivatives at C-26 behave in the same way: both natural and

Halogenated volatiles from the fungus Geniculosporium and the actinomycete Streptomyces chartreusis

• Tao Wang,
• Patrick Rabe,
• Christian A. Citron and
• Jeroen S. Dickschat

Beilstein J. Org. Chem. 2013, 9, 2767–2777, doi:10.3762/bjoc.9.311

• ) [25] or the trichlorinated phenols 20–22 (Figure 5) [26]. The biological function of 4b and 10b in Geniculosporium is unknown, but the antibiotic activity of the related compound drosophilin A towards bacteria is well known [27]. A iodinated volatile from Streptomyces chartreusis During the course of

Multigramme synthesis and asymmetric dihydroxylation of a 4-fluorobut-2E-enoate

• James A. B. Laurenson,
• John A. Parkinson,
• Jonathan M. Percy,
• Giuseppe Rinaudo and
• Ricard Roig

Beilstein J. Org. Chem. 2013, 9, 2660–2668, doi:10.3762/bjoc.9.301

• . Modifications of this type are sometimes accepted by sugar-processing enzymes such as the kinases and transferases involved in oligosaccharide assembly, or in antibiotic biosynthesis. Mechanistic insights, and new routes to hybrid natural products represent the rewards of this endeavour [1][2][3][4][5][6][7][8

IBD-mediated oxidative cyclization of pyrimidinylhydrazones and concurrent Dimroth rearrangement: Synthesis of [1,2,4]triazolo[1,5-c]pyrimidine derivatives

• Caifei Tang,
• Zhiming Li and
• Quanrui Wang

Beilstein J. Org. Chem. 2013, 9, 2629–2634, doi:10.3762/bjoc.9.298

• therapy of syndromes that may be influenced by immunomodulators [5][6]. Interestingly, the first [1,2,4]triazolo[1,5-a]pyrimidine antibiotic essramycin has been isolated from natural sources (Figure 1) [7]. It has also been revealed that compounds carrying a [1,2,4]triazolo[1,5-c]pyrimidine nucleus behave

The regulation and biosynthesis of antimycins

• Ryan F. Seipke and
• Matthew I. Hutchings

Beilstein J. Org. Chem. 2013, 9, 2556–2563, doi:10.3762/bjoc.9.290

• antAB and antCDE is a transcriptional activator that is encoded outside of the ant gene cluster and is absent from the heterologous host strains (Seipke and Hutchings, unpublished results). Regulation of antibiotic gene clusters by ECF σ factors has only been reported in two rare actinomycete strains

An overview of the synthetic routes to the best selling drugs containing 6-membered heterocycles

• Marcus Baumann and
• Ian R. Baxendale

Beilstein J. Org. Chem. 2013, 9, 2265–2319, doi:10.3762/bjoc.9.265

• ). Nalidixic acid is a prototype quinolone antibiotic that has been used extensively as an effective treatment against both gram positive and gram negative bacteria. In general, quinolone antibiotics act by interfering with the enzymes DNA-gyrase and/or topoisomerase of bacteria [55]. Moxifloxacin (1.102

• fluoroquinolone product 1.117 (Scheme 21). A final intermolecular SNAr reaction then introduces the methylpiperazine unit and thus completes the synthesis of this antibiotic compound [62]. Alternatively, an elaborated benzoxazine substrate 1.118 may be prepared via another linear sequence starting from phenol

The chemistry of isoindole natural products

• Klaus Speck and
• Thomas Magauer

Beilstein J. Org. Chem. 2013, 9, 2048–2078, doi:10.3762/bjoc.9.243

• natural product and synthetic precursor of 193 shows strong antibiotic activity against methicillin-resistant Staphylococcus aureus (MRSA, MIC = 84 nM) and vancomycin-resistant Enterococcus (VRE, MIC = 178 nM) [148]. The structural similarity between pestalachloride A (193) and pestalone (192), which both

An approach towards azafuranomycin analogs by gold-catalyzed cycloisomerization of allenes: synthesis of (αS,2R)-(2,5-dihydro-1H-pyrrol-2-yl)glycine

• Jörg Erdsack and
• Norbert Krause

Beilstein J. Org. Chem. 2013, 9, 1936–1942, doi:10.3762/bjoc.9.229

• ; amino acids; cuprates; furanomycin; gold catalysis; Introduction In 1967, Katagiri et al. reported the isolation of a novel antibiotic from the culture broth of the fungus Streptomyces threomyceticus [1]. The compound acts as a competitive antagonist for isoleucine in vitro and hampers the growth of

• were published [2][5][6][7][8] as well as numerous reports dedicated to derivatives and stereoisomers [9][10][11][12][13][14][15][16][17][18][19][20]. Examination of structure–activity relationship (SAR) revealed a loss of antibiotic activity upon shifting of the methyl group to different positions

Synthesis and antibacterial activity of monocyclic 3-carboxamide tetramic acids

• Yong-Chul Jeong and
• Mark G. Moloney

Beilstein J. Org. Chem. 2013, 9, 1899–1906, doi:10.3762/bjoc.9.224

• rapid construction, and the evaluation of their antibacterial activity is reported. Keywords: acylation; antibacterial; drug discovery; natural products; tetramate; Introduction The discovery of new antibiotic families with novel modes of action is a promising way to overcome resistant or virulent

• bacteria, since novel modes of action might be expected to slow target-based endogenous resistance [1]. In this regard, natural products play a major role by providing a biologically validated starting point [2]. Recently discovered antibiotic lead compounds of major interest include platensimycin (a FabF

• , tautomeric behaviour and antibiotic activity of related monocyclic 3-carboxamide tetramic acid systems 2 and 3 (Schemes 1–3), the results of which are outlined below. In system 2, the N(1) and C(5) substituents were chosen in order to probe the effect of the length of the N-alkyl chain on antibiotic activity

Natural products in synthesis and biosynthesis

• Jeroen S. Dickschat

Beilstein J. Org. Chem. 2013, 9, 1897–1898, doi:10.3762/bjoc.9.223

• rapid spreading of antibiotic resistances and the comeback of some infectious diseases already claimed to be eliminated should sharpen our minds for the beneficial roles of natural products in medicine as well as their responsible use. This should be a strong appeal upon the responsibility of both