Synthesis of eunicellane-type bicycles embedding a 1,3-cyclohexadiene moiety

• Alex Frichert,
• Peter G. Jones and
• Thomas Lindel

Beilstein J. Org. Chem. 2018, 14, 2461–2467, doi:10.3762/bjoc.14.222

• the plant Vellozia magdalenae [6]. Recently, prehydropyrene (6) was discovered as biosynthetic intermediate towards the diterpene hydropyrene from the Gram-positive bacterium Streptomyces clavuligerus [7]. The six- and ten-membered rings of eunicellane diterpenoids can be either cis or trans fused

Volatiles from three genome sequenced fungi from the genus Aspergillus

• Jeroen S. Dickschat,
• Ersin Celik and
• Nelson L. Brock

Beilstein J. Org. Chem. 2018, 14, 900–910, doi:10.3762/bjoc.14.77

• homolog of the geosmin synthase is encoded in the genome of A. fischeri or of any other fungus. Furthermore, the diterpene pimara-8(14),15-diene (7) was one of the main compounds in the bouquet of A. fischeri. The biosynthesis of this compound is a two-step process that requires cyclisation of

• TS homologs (accession numbers GAA83682, GAA88217 and GAA91251, locus tags AKAW_01797, AKAW_06331 and AKAW_09365). The first enzyme GAA83682 shows close homology to the bifunctional ent-kaurene synthases from Fusarium and is likely involved in diterpene biosynthesis. The fact that no corresponding

• diterpene was observed may point to a low gene expression under laboratory culture conditions. It is currently not possible to conclude which of the other two TSs are involved in the biosynthesis of the observed sesquiterpenes from A. kawachii. Notably, both enzymes GAA88217 and GAA91251 are closely related

Recent developments in the asymmetric Reformatsky-type reaction

• Hélène Pellissier

Beilstein J. Org. Chem. 2018, 14, 325–344, doi:10.3762/bjoc.14.21

• constituted the key step of a nine-step total synthesis of the eastern fragment of jatrophane diterpene Pl-3, which is a complex natural product with high promising biological activities, such as antiproliferative activity and inhibition of the efflux-pump activity of multidrug resistance P-glycoprotein. The

• , cebulactam A1, and ansamacrolactams. In addition, novel total syntheses of prostaglandin E2, the cytotoxic agent epothilone D, and protein inhibitor ABT-737 along with formal syntheses of the protein inhibitor tedanolide C, the neprilysin inhibitor sacubitril, the antiproliferative agent jatrophane diterpene

• -mediated nitrile Reformatsky-type reaction [18]. Synthesis of apratoxin E and its C30 epimer through a Zn-mediated Reformatsky reaction. Fmoc = 9-fluorenylmethoxylcarbonyl [20]. Synthesis of the eastern fragment of jatrophane diterpene Pl-3 through a SmI2-mediated Reformatsky reaction [21]. First total

Volatiles from the tropical ascomycete Daldinia clavata (Hypoxylaceae, Xylariales)

• Tao Wang,
• Kathrin I. Mohr,
• Marc Stadler and
• Jeroen S. Dickschat

Beilstein J. Org. Chem. 2018, 14, 135–147, doi:10.3762/bjoc.14.9

• roqueforti [7][8][9], trichodiene (4) is the parent hydrocarbon of the trichothecene family of mycotoxins in various Trichothecium and Fusarium strains [10], and the diterpene ent-kaurene (5) is the precursor of gibberellins, a class of plant hormones that are produced in large amounts by the rice pathogen

Herpetopanone, a diterpene from Herpetosiphon aurantiacus discovered by isotope labeling

• Xinli Pan,
• Nicole Domin,
• Sebastian Schieferdecker,
• Hirokazu Kage,
• Martin Roth and
• Markus Nett

Beilstein J. Org. Chem. 2017, 13, 2458–2465, doi:10.3762/bjoc.13.242

• . aurantiacus 114-95T, we fed the strain with 13C-labeled glucose and, subsequently, searched for characteristic mass shifts in its metabolome. This approach led to the discovery of a new natural product, of which the isotope pattern is indicative for a diterpene originating from the methylerythritol phosphate

• pathway. After large-scale fermentation of H. aurantiacus 114-95T, the putative diterpene was isolated in sufficient quantity to enable NMR-based structure elucidation. The compound, for which the name herpetopanone is proposed, features a rare octahydro-1H-indenyl skeleton. Herpetopanone bears

• originated from the MEV pathway (Figure 1). The possible number of labeled carbon atoms was compatible, however, with an octaketide origin or with a diterpene from the MEP pathway. We then recorded the high resolution (HR) mass of the unlabeled compound and determined its molecular formula as C20H36O4

18-Hydroxydolabella-3,7-diene synthase – a diterpene synthase from Chitinophaga pinensis

• Jeroen S. Dickschat,
• Jan Rinkel,
• Patrick Rabe,
• Arman Beyraghdar Kashkooli and
• Harro J. Bouwmeester

Beilstein J. Org. Chem. 2017, 13, 1770–1780, doi:10.3762/bjoc.13.171

• Wageningen, The Netherlands, Swammerdam Institute for Life Sciences, University of Amsterdam, Sciencepark 904, 1098 XH Amsterdam, The Netherlands 10.3762/bjoc.13.171 Abstract The product obtained in vitro from a diterpene synthase encoded in the genome of the bacterium Chitinophaga pinensis, an enzyme

• previously reported to have germacrene A synthase activity during heterologous expression in Escherichia coli, was identified by extensive NMR-spectroscopic methods as 18-hydroxydolabella-3,7-diene. The absolute configuration of this diterpene alcohol and the stereochemical course of the terpene synthase

• reaction were addressed by isotopic labelling experiments. Heterologous expression of the diterpene synthase in Nicotiana benthamiana resulted in the production of 18-hydroxydolabella-3,7-diene also in planta, while the results from the heterologous expression in E. coli were shown to be reproducible

An improved preparation of phorbol from croton oil

• Alberto Pagani,
• Simone Gaeta,
• Andrei I. Savchenko,
• Craig M. Williams and
• Giovanni Appendino

Beilstein J. Org. Chem. 2017, 13, 1361–1367, doi:10.3762/bjoc.13.133

• diterpene pentaol, named phorbol (Figure 1, 1a) after the plant family to whom C. tiglium belongs (Euphorbiaceae) [5]. The early studies left their mark in organic chemistry in the well-known names of crotonic and tiglic acids, although, paradoxically, croton oil does not contain crotonic acid, that is only

• phorbol, making it possible to selectively partition them. In this way, the preparation of the diterpene polyol fraction was telescoped to only five operational steps (treatment of croton oil with sodium methylate, extraction with petroleum ether, evaporation, partition between THF and brine, and

• of a colorless powder. The major diterpene polyols from croton oil [phorbol (1a), 4α-phorbol (2), 4-deoxy-4α-phorbol (3a)] and their derivatives. Supporting Information Supporting Information File 168: ESI-HRMS and 1H and 13C NMR spectra of compounds 1d and 1e. Acknowledgements We acknowledge

Opportunities and challenges for the sustainable production of structurally complex diterpenoids in recombinant microbial systems

• Katarina Kemper,
• Max Hirte,
• Markus Reinbold,
• Monika Fuchs and
• Thomas Brück

Beilstein J. Org. Chem. 2017, 13, 845–854, doi:10.3762/bjoc.13.85

• terpene producing Escherichia coli, this review shall give an insight in recent progresses regarding manipulation of mostly diterpene synthases. Keywords: enzyme engineering; heterologous production in E. coli; metabolic pathway optimization; modular biosynthesis; plant diterpenes; Introduction

• localization of diterpene biosynthesis in the plastids [31]. Metabolic engineering of plants to produce diterpenes remains challenging due to the required direction of biosynthetic enzymes into the specific organelles [32] and feedback inhibition of the 1-deoxy-D-xylulose-5-phosphate synthase (DXS) that can

• diterpenes (geranylgeranyl diphosphate, GGPP) [35]. Terpene synthases Interestingly, plant metabolism can convert the universal aliphatic diterpene precursor GGPP into thousands of different terpene structures with high structural complexity and elaborately functional decorations [41]. While the structural

Secondary metabolome and its defensive role in the aeolidoidean Phyllodesmium longicirrum, (Gastropoda, Heterobranchia, Nudibranchia)

• Alexander Bogdanov,
• Cora Hertzer,
• Stefan Kehraus,
• Samuel Nietzer,
• Sven Rohde,
• Peter J. Schupp,
• Heike Wägele and
• Gabriele M. König

Beilstein J. Org. Chem. 2017, 13, 502–519, doi:10.3762/bjoc.13.50

• ) and 136.9 (C-8), 127.0 (C-11) and 135.4 (C-12) pointed towards three carbon–carbon double bonds. Together with two carbonyls (at C-2 and C-18) one RDE accountable to a ring remained, and suggested a cembrane-class diterpene. The proton resonances could be unambiguously assigned to those of directly

• mg), 3 (1.0 mg) and 4 (1.5 mg). The new cembranoid diterpene 5 was isolated after RP–HPLC separation of VLC fraction 8 (MeOH/H2O 90:10, Phenomenex Luna column, 2 mL/min). Seven fractions (8.1–8.7) were obtained, fraction

A non-canonical peptide synthetase adenylates 3-methyl-2-oxovaleric acid for auriculamide biosynthesis

• Daniel Braga,
• Dirk Hoffmeister and
• Markus Nett

Beilstein J. Org. Chem. 2016, 12, 2766–2770, doi:10.3762/bjoc.12.274

• gene clusters complete the total set involved in the biosynthesis of natural products. Contrasting the high number of biosyntheses deduced from genomic data, knowledge on the actual natural products is limited. Recently, the dipeptide auriculamide (1, Figure 1), and the diterpene O-methylkolavelool

Three new trixane glycosides obtained from the leaves of Jungia sellowii Less. using centrifugal partition chromatography

• Luíse Azevedo,
• Larissa Faqueti,
• Marina Kritsanida,
• Antonia Efstathiou,
• Despina Smirlis,
• Gilberto C. Franchi Jr,
• Grégory Genta-Jouve,
• Sylvie Michel,
• Louis P. Sandjo,
• Raphaël Grougnet and
• Maique W. Biavatti

Beilstein J. Org. Chem. 2016, 12, 674–683, doi:10.3762/bjoc.12.68

• iridoid derivatives [31], and diterpene glycosides [32]. This technique was for the first time used with Jungia extracts. Elucidation of the compounds Compound 1 was obtained as colorless gum. The molecular formula C21H30O8 was determined from its ESI–HRMS spectrum which gave the cationic ion peak [M + H

Antibiotics from predatory bacteria

• Juliane Korp,
• María S. Vela Gurovic and
• Markus Nett

Beilstein J. Org. Chem. 2016, 12, 594–607, doi:10.3762/bjoc.12.58

• associated pathway, (+)-O-methylkolavelool was identified as a metabolic product. Subsequent GC–MS analyses confirmed that this previously unknown diterpene is actually produced by the predatory bacterium [128]. From genomic data, it is evident that the genus Herpetosiphon harbors a significant potential for

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

• made in vitro by usage of enzymes. This approach was used for investigating the structure of miltiradiene (33, Figure 7), a diterpene from Selaginella moellendorffii, starting from uniformly labeled mevalonate [59]. Despite the tools for structure elucidation, labeled compounds continue to offer

• , the first structurally characterized bacterial diterpene cyclase [66]. After identification of the biosynthetic gene cluster, a mechanism involving a deprotonation–reprotonation sequence and two 1,2-hydride shifts was proposed [67]. However, a simple feeding experiment performed with a S. albus

Aspergiloid I, an unprecedented spirolactone norditerpenoid from the plant-derived endophytic fungus Aspergillus sp. YXf3

• Zhi Kai Guo,
• Rong Wang,
• Wei Huang,
• Xiao Nian Li,
• Rong Jiang,
• Ren Xiang Tan and
• Hui Ming Ge

Beilstein J. Org. Chem. 2014, 10, 2677–2682, doi:10.3762/bjoc.10.282

• . Here the hypothetical pimarane compound 2, the hemiketal lactone ring-opening product of aspergiloid E, was proposed as the most probable biosynthetic intermediate. As shown in Scheme 1, we suggest the biosynthesis of 1 starts from the classical diterpene precursor geranylgeranyl diphosphate [14], and

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

• family Dictyotaceae and from the sea hare [74][75]. Paquette and co-workers reported the first and only total synthesis of this diterpene (Figure 4) [41][42]. The cyclooctanoid core of the target was envisioned to be formed by a Claisen rearrangement of intermediate 81. The latter and most of its

Recent applications of the divinylcyclopropane–cycloheptadiene rearrangement in organic synthesis

• Sebastian Krüger and
• Tanja Gaich

Beilstein J. Org. Chem. 2014, 10, 163–193, doi:10.3762/bjoc.10.14

• synthesis of the diterpene scopadulcic acid B (79, see Scheme 10), isolated from the Paraguayan plant Scoparia dulcis [66]. Starting from 2-iodobenzaldehyde (65) allyl-Grignard addition took place followed by TBS-protection of the resulting alcohol. The installed double bond was subjected to hydroboration

• diterpene 5-epi-vibsanin E (115), from the plant Viburnum awabuki (see Scheme 14) [104]. Starting from triene 108 cyclopropanation was achieved using vinyldiazo compound 101. The fomal [4 + 3]-cycloaddition proceeded through cis-divinylcyclopropane 109 to yield rearranged cycloheptadiene 110. Desilylation

Novel supramolecular affinity materials based on (−)-isosteviol as molecular templates

• Christina Lohoelter,
• Malte Brutschy,
• Daniel Lubczyk and
• Siegfried R. Waldvogel

Beilstein J. Org. Chem. 2013, 9, 2821–2833, doi:10.3762/bjoc.9.317

• of a single substrate [23][24]. Due to the concave arrangement of both functional groups, exhibiting a distance of the two carbonyl carbon atoms of about 7 Å, naturally occurring diterpene (−)-isosteviol 1 [25] came into focus as building block for the construction of such receptor geometries (Figure

End game strategies towards the total synthesis of vibsanin E, 3-hydroxyvibsanin E, furanovibsanin A, and 3-O-methylfuranovibsanin A

• Brett D. Schwartz,
• Craig M. Williams and
• Paul V. Bernhardt

Beilstein J. Org. Chem. 2008, 4, No. 34, doi:10.3762/bjoc.4.34

• some literature methods called upon for the attempted total synthesis of this family of natural products were gained. A collection of the structural diversity seen in the vibsanin type diterpene family. Vibsanin type diterpene synthetic targets. ORTEP diagrams of compounds 24 and 23 (30% probability

Sordarin, an antifungal agent with a unique mode of action

• Huan Liang

Beilstein J. Org. Chem. 2008, 4, No. 31, doi:10.3762/bjoc.4.31

• Huan Liang Department of Chemistry, The University of British Columbia, 2036 Main Mall, Vancouver, BC V6T 1Z1, Canada 10.3762/bjoc.4.31 Abstract The sordarin family of compounds, characterized by a unique tetracyclic diterpene core including a norbornene system, inhibits protein synthesis in

• total syntheses (by the Kato, Mander and Narasaka groups), modifications of the glycosyl unit, and changes to the diterpene core (Cuevas and Ciufolini models) will also be discussed in this review. Keywords: antifungal; bioactivity; sordaricin; sordarin; total synthesis; Introduction For

• sordarin [17] in 2004 and 2006, respectively. Both Kato’s and Mander’s syntheses employed intramolecular Diels-Alder cyclizations to construct the norbornene-like framework, while an intramolecular Pd catalyzed Tsuji-Trost reaction was utilized by the Narasaka group to build the diterpene core. Kato’s