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

• extensive NMR studies and unambiguously confirmed by a four-step synthesis. In 1991, a more concise and elegant route to this antimicrobial metabolite was established by Schubert-Zsilavecz [11]. The reaction was initiated by heating paraformaldehyde (13) and sarcosine (14) in the presence of benzoquinone 16

• allows for a rapid access to a variety of members of the cytochalasin alkaloid family. The power of the intramolecular Diels–Alder strategy for the synthesis of the isoindolinone moiety was also recognized during the synthesis of aspergillin PZ (91) [73]. This secondary metabolite has a remarkable

• Zakarian reported another approach to the fully elaborated isoindolinone core of 204 [154]. Chlorizidine A (208) (Scheme 27), a cytotoxic metabolite from a marine Streptomyces species shows an unprecedented 5H-pyrrolo[2,1-a]isoindolinone ring system, which is connected to a dichlorinated pyrrolizine [155

Natural products in synthesis and biosynthesis

• Jeroen S. Dickschat

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

• fascinating as is spectacularly demonstrated by the prominent examples of maitotoxin [3], the largest non-polymer secondary metabolite known to date, or calicheamycin (Figure 1), which possibly holds the record in carrying the most diverse functional groups including an enediyne subunit, a deoxysugar, an

Activation of cryptic metabolite production through gene disruption: Dimethyl furan-2,4-dicarboxylate produced by Streptomyces sahachiroi

• Dinesh Simkhada,
• Huitu Zhang,
• Shogo Mori,
• Howard Williams and
• Coran M. H. Watanabe

Beilstein J. Org. Chem. 2013, 9, 1768–1773, doi:10.3762/bjoc.9.205

• previously identified and characterized compounds has become a serious impediment to the discovery of new bioactive natural products. Here, genetic knockout of an unusual non-ribosomal peptide synthetase (NRPS) C-PCP-C module, aziA2, is performed resulting in the accumulation of the secondary metabolite

• , dimethyl furan-2,4-dicarboxylate. The cryptic metabolite represents the first non-azinomycin related compound to be isolated and characterized from the soil bacterium, S. sahachiroi. The results from this study suggest that abolishing production of otherwise predominant natural products through genetic

• knockout may constitute a means to “activate” the production of novel secondary metabolites that would otherwise lay dormant within microbial genome sequences. Keywords: cryptic metabolite; dimethyl furan-2,4-dicarboxylate; genetic knockout; natural products; non-ribosomal peptide synthetase module

New tridecapeptides of the theonellapeptolide family from the Indonesian sponge Theonella swinhoei

• Annamaria Sinisi,
• Barbara Calcinai,
• Carlo Cerrano,
• Henny A. Dien,
• Angela Zampella,
• Claudio D’Amore,
• Barbara Renga,
• Stefano Fiorucci and
• Orazio Taglialatela-Scafati

Beilstein J. Org. Chem. 2013, 9, 1643–1651, doi:10.3762/bjoc.9.188

• , exhibited an extremely different secondary metabolite composition. In particular, this second specimen has been found to be rich in polypeptides and, from the CHCl3 phase of the organic extract, we have identified the major member of this class as theonellapeptolide Id (1) (Figure 1). In this paper we

Isotopically labeled sulfur compounds and synthetic selenium and tellurium analogues to study sulfur metabolism in marine bacteria

• Nelson L. Brock,
• Christian A. Citron,
• Claudia Zell,
• Martine Berger,
• Irene Wagner-Döbler,
• Jörn Petersen,
• Thorsten Brinkhoff,
• Meinhard Simon and
• Jeroen S. Dickschat

Beilstein J. Org. Chem. 2013, 9, 942–950, doi:10.3762/bjoc.9.108

• the Roseobacter clade raises the question about the nature of their sulfur sources. The most important organic sulfur metabolite in marine environments is dimethylsulfoniopropionate (DMSP), which is produced by a wide range of marine organisms and in especially large amounts by dinoflagellates [11

Synthesis and stability study of a new major metabolite of γ-hydroxybutyric acid

• Ida Nymann Petersen,
• Jesper Langgaard Kristensen,
• Christian Tortzen,
• Torben Breindahl and
• Daniel Sejer Pedersen

Beilstein J. Org. Chem. 2013, 9, 641–646, doi:10.3762/bjoc.9.72

• to detect for forensic scientists due to rapid metabolism to endogenous levels of GHB. We recently discovered a new major metabolite, 2, of GHB (1) that could potentially extend the analytical detection window for GHB intoxications. Herein we disclose synthetic procedures based on a Koenigs–Knorr

• analytical methods. Using NMR we show that GHB glucuronide 2 is highly stable towards aqueous hydrolysis within the pH range normally observed for urine even at elevated temperature. Keywords: analytical chemistry; cabohydrate chemistry; forensic chemistry; glucuronide; γ-hydroxybutyric acid; metabolite

• detection window [5]. By analogy with ethanol, we hypothesised the existence of a GHB glucuronide, and recently discovered that GHB glucuronide 2 is indeed a major metabolite of GHB (Figure 1) [6]. The presence of GHB glucuronide 2 is likely to have important implications for future analysis of GHB in

Thioester derivatives of the natural product psammaplin A as potent histone deacetylase inhibitors

• Matthias G. J. Baud,
• Thomas Leiser,
• Vanessa Petrucci,
• Mekala Gunaratnam,
• Stephen Neidle,
• Franz-Josef Meyer-Almes and
• Matthew J. Fuchter

Beilstein J. Org. Chem. 2013, 9, 81–88, doi:10.3762/bjoc.9.11

• represents the first example of a disulfide and oxime containing metabolite isolated from a marine sponge. Since its initial report by Crews and co-workers as a potent HDAC inhibitor [16], psammaplin A has provided inspiration for the development of new HDAC inhibitors with novel structures [19]. Recently

Chemical–biological characterization of a cruzain inhibitor reveals a second target and a mammalian off-target

• Jonathan W. Choy,
• Clifford Bryant,
• Claudia M. Calvet,
• Patricia S. Doyle,
• Shamila S. Gunatilleke,
• Siegfried S. F. Leung,
• Kenny K. H. Ang,
• Steven Chen,
• Jiri Gut,
• Juan A. Oses-Prieto,
• Jonathan B. Johnston,
• Michelle R. Arkin,
• Alma L. Burlingame,
• Jack Taunton,
• Matthew P. Jacobson,
• James M. McKerrow,
• Larissa M. Podust and
• Adam R. Renslo

Beilstein J. Org. Chem. 2013, 9, 15–25, doi:10.3762/bjoc.9.3

• metabolite. Whatever the explanation, reversible inhibition of CYP enzymes (as with 4) is clearly preferable to irreversible inhibition from a drug-safety perspective. Inhibition of TcCYP51 in live parasites We next sought to better define the relative importance of TcCYP51 and cruzain inhibition in the

Algicidal lactones from the marine Roseobacter clade bacterium Ruegeria pomeroyi

• Ramona Riclea,
• Julia Gleitzmann,
• Hilke Bruns,
• Corina Junker,
• Barbara Schulz and
• Jeroen S. Dickschat

Beilstein J. Org. Chem. 2012, 8, 941–950, doi:10.3762/bjoc.8.106

• symbionts [3][4] or associated with molluscs [5]; and can form biofilms [6]. Particularly interesting from an ecological point of view is their association with marine algae, such as dinoflagellates and coccolithophores, which produce large amounts of the sulfur metabolite dimethylsulfoniopropionate (1

• bioavailability of metal ions by the formation of metal–MeSH complexes [7] and can be used for the biosynthesis of various sulfur-containing secondary metabolites [20]. A sulfur-containing metabolite, for which the direct sulfur precursor has not been determined yet, is the antibiotic tropodithietic acid (TDA, 2

Unprecedented deoxygenation at C-7 of the ansamitocin core during mutasynthetic biotransformations

• Tobias Knobloch,
• Gerald Dräger,
• Wera Collisi,
• Florenz Sasse and
• Andreas Kirschning

Beilstein J. Org. Chem. 2012, 8, 861–869, doi:10.3762/bjoc.8.96

• unusual is metabolite 16, which is yet another example of a case in which deoxygenation at C-7 has taken place. In summary, deoxygenation may occur when the AHBA-blocked mutant A. pretiosum HGF073 or the acyl transferase Asm19-blocked mutant A. pretiosum HGF059 are employed, whereas the reduction process

Identification and isolation of insecticidal oxazoles from Pseudomonas spp.

• Florian Grundmann,
• Veronika Dill,
• Andrea Dowling,
• Aunchalee Thanwisai,
• Edna Bode,
• Narisara Chantratita,
• Richard ffrench-Constant and
• Helge B. Bode

Beilstein J. Org. Chem. 2012, 8, 749–752, doi:10.3762/bjoc.8.85

• intermediates were also investigated revealing interesting biological activities for several compounds despite their overall simple structures. Keywords: insecticidal activity; labradorin; oxazole; Pseudomonas; secondary metabolite; Findings During our search for novel natural products from entomopathogenic

Volatile organic compounds produced by the phytopathogenic bacterium Xanthomonas campestris pv. vesicatoria 85-10

• Teresa Weise,
• Marco Kai,
• Anja Gummesson,
• Armin Troeger,
• Stephan von Reuß,
• Silvia Piepenborn,
• Francine Kosterka,
• Martin Sklorz,
• Ralf Zimmermann,
• Wittko Francke and
• Birgit Piechulla

Beilstein J. Org. Chem. 2012, 8, 579–596, doi:10.3762/bjoc.8.65

• volatile compounds emitted by X. c. pv. vesicatoria 85-10, shows a close biogenetic relation to 11-methyldodec-2Z-enoic acid (compound V in Scheme 2), which has been described earlier as a metabolite produced by Xanthomonas [13]. Possible biogenetic pathways to the two compounds are shown in Scheme 2

Mutational analysis of a phenazine biosynthetic gene cluster in Streptomyces anulatus 9663

• Orwah Saleh,
• Katrin Flinspach,
• Lucia Westrich,
• Andreas Kulik,
• Bertolt Gust,
• Hans-Peter Fiedler and
• Lutz Heide

Beilstein J. Org. Chem. 2012, 8, 501–513, doi:10.3762/bjoc.8.57

• endophenazine B as a minor product (Figure 1) [11]. In the present study, we carried out inactivation experiments of genes on cosmid ppzOS04, followed by heterologous expression of the modified clusters and chemical analysis of secondary metabolite formation. This allowed us to investigate the function of

• quantitative differences in production reliably. We decided to use cultivation in 24 square deep-well plates (EnzyScreen BV, The Netherlands). Previous studies have shown that this greatly reduces the variability of secondary metabolite production in comparison to cultivation in Erlenmeyer flasks [14]. In

• shown to increase the production of certain antibiotics [14]. Of each mutant obtained in this study, usually three independent clones were isolated, and secondary metabolite production was determined in three parallel cultivations for each clone. The variability of production between different clones

Aldol elaboration of 4,5,6,7-tetrahydroisoxazolo[4,3-c]pyridin-4-ones, masked precursors to acylpyridones

• Raymond C. F. Jones,
• Abdul K. Choudhury,
• James N. Iley,
• Mark E. Light,
• Georgia Loizou and
• Terence A. Pillainayagam

Beilstein J. Org. Chem. 2012, 8, 308–312, doi:10.3762/bjoc.8.33

• -tetrahydroisoxazolo[4,3-c]pyridin-4-one (8a) [19]. Ilicicolin H as an example of a 3-decalinoyl-4-hydroxypyridin-2-one metabolite. Aldol reactions of tetrahydroisoxazolopyridone 6. Reagents: (i) LDA–TMEDA, RCHO, THF, −20 °C; (ii) toluene, reflux, PTSA. Retrosynthetic analysis of a model 3-decalinyl-4,5,6,7

Conserved and species-specific oxylipin pathways in the wound-activated chemical defense of the noninvasive red alga Gracilaria chilensis and the invasive Gracilaria vermiculophylla

• Martin Rempt,
• Florian Weinberger,
• Katharina Grosser and
• Georg Pohnert

Beilstein J. Org. Chem. 2012, 8, 283–289, doi:10.3762/bjoc.8.30

• the up-regulated metabolites, arachidonic acid derived hydroxylated and dihydroxylated fatty acids are most prominent, with 7,8-dihydroxyeicosatetraenoic acid (7,8-di-HETE (3)) being the most active metabolite in the chemical defense against epiphytism. Recent work indicates that the invasive G

• an additional signal of an arachidonic acid derived metabolite with a characteristic UV spectrum of a conjugated tetraene. Purification yielded about 2.3 mg of an unstable metabolite, which was submitted to MS, 1D and 2D-NMR analysis. The molecular formula C20H28O2 was determined by HRMS–ESI ([M + Na

• ]+ calcd for 323.1986; found, 323.1982). 1H–1H COSY allowed us to follow the entire spin system of the metabolite, including 10 olefinic protons, 7 CH2, 1 CH3 and 1 CH groups (Scheme 1, spectra are shown in Supporting Information File 1). In combination with HMBC data all hydrogen and carbon signals were

Advances in synthetic approach to and antifungal activity of triazoles

• Kumari Shalini,
• Nitin Kumar,
• Sushma Drabu and
• Pramod Kumar Sharma

Beilstein J. Org. Chem. 2011, 7, 668–677, doi:10.3762/bjoc.7.79

• , and is excreted in an inactive form via liver and kidneys. Fluconazole is 94% absorbed and its oral bioavailability is not affected by food or gastric pH. It is excreted unchanged in urine with t1/2 = 25–30 h. Itraconazole is largely metabolized in liver by cytochrome P450 3A4, an active metabolite is

An overview of the key routes to the best selling 5-membered ring heterocyclic pharmaceuticals

• Marcus Baumann,
• Ian R. Baxendale,
• Steven V. Ley and
• Nikzad Nikbin

Beilstein J. Org. Chem. 2011, 7, 442–495, doi:10.3762/bjoc.7.57

• atorvastatin which has a five times greater potency then the initial lead, the fungal metabolite compactin (5, Figure 2). Although it was possible to construct such fully substituted pyrrole rings by ZnCl2-catalysed condensation reactions between a functionalised enamine 6 and simple benzoin (7), this method

Synthesis of (3R,5R)-harzialactone A and its (3R,5S)-isomer

• Gowravaram Sabitha,
• Rangavajjula Srinivas,
• Sukant K. Das and
• Jhillu S. Yadav

Beilstein J. Org. Chem. 2010, 6, No. 8, doi:10.3762/bjoc.6.8

• and biologically active secondary metabolites [1]. (+)-Harzialactone A (1), a marine metabolite isolated from the culture broth of a strain of Trichoderma harzianum OUPS-N115 by Numata and co-workers, exhibited antitumor and cytotoxic activities against cultured P388 cells [2]. The absolute

Synthesis of phosphonate and phostone analogues of ribose-1-phosphates

• Pitak Nasomjai,
• David O'Hagan and
• Alexandra M. Z. Slawin

Beilstein J. Org. Chem. 2009, 5, No. 37, doi:10.3762/bjoc.5.37

• phosphonate 8a was obtained (Figure 2) which confirmed its structure and stereochemical relationship to intermediate ribose-1-phosphate metabolite 5. Clearly, phosphonate 8a formed a 1:1 salt with the amine. Additionally, 23a and 22a were treated in separate reactions with acetic anhydride in dry pyridine [13

Mitomycins syntheses: a recent update

• Jean-Christophe Andrez

Beilstein J. Org. Chem. 2009, 5, No. 33, doi:10.3762/bjoc.5.33

• unique activity was thought to originate from their ability to transform in vivo to generate the active metabolite. This was followed by decades of investigations to understand in detail their singular mode of action. It was found that the aziridine played a crucial role, allowing an irreversible bis

A divergent asymmetric approach to aza-spiropyran derivative and (1S,8aR)-1-hydroxyindolizidine

• Jian-Feng Zheng,
• Wen Chen,
• Su-Yu Huang,
• Jian-Liang Ye and
• Pei-Qiang Huang

Beilstein J. Org. Chem. 2007, 3, No. 41, doi:10.1186/1860-5397-3-41

• toward DNA repair-deficient yeast mutants;[7] azaspiracids are marine phycotoxins isolated from cultivated mussels in Killary harbor, Ireland;[8] and chlorofusin A is a novel fungal metabolite showing the potential as a lead in cancer therapy.[9] In addition, aza-spiropyrans C, being able to equilibrate

Multiple hydride reduction pathways in isoflavonoids

• Auli K. Salakka,
• Tuija H. Jokela and
• Kristiina Wähälä

Beilstein J. Org. Chem. 2006, 2, No. 16, doi:10.1186/1860-5397-2-16

• of isoflavones [10][16][17][18][19][20]. Deoxybenzoins (5) and propenols (6) Isoflavanones undergo a facile retro-Michael-type ring opening [21][55] under basic conditions to give the propenone intermediate 14 (Figure 2), sometimes considered [56] to be an independent isoflavone metabolite but