Mechanistic investigations on multiproduct β-himachalene synthase from Cryptosporangium arvum

• Jan Rinkel and
• Jeroen S. Dickschat

Beilstein J. Org. Chem. 2019, 15, 1008–1019, doi:10.3762/bjoc.15.99

• Jan Rinkel Jeroen S. Dickschat Kekulé-Institute for Organic Chemistry and Biochemistry, University of Bonn, Gerhard-Domagk-Str. 1, 53121 Bonn, Germany 10.3762/bjoc.15.99 Abstract A bacterial terpene synthase from Cryptosporangium arvum was characterised as a multiproduct β-himachalene synthase

• or multiple compounds, are terpene synthases (TSs). These enzymes are able to guide complex cascade reactions from structurally simple oligoprenyl diphosphates to often complex, polycyclic products [4][5][6] circumventing the low selectivity observed for carbocationic reactions by a defined active

• . Whereas the latter diphosphate did not lead to any terpene product, the incubation with FPP showed a smooth conversion into several sesquiterpenes (Figure 1A) with compound 1 as the major peak after GC–MS analysis. However, also the incubations with GPP (Figure 1B) and GGPP (Figure 1C) led to several less

Stereochemical investigations on the biosynthesis of achiral (Z)-γ-bisabolene in Cryptosporangium arvum

• Jan Rinkel and
• Jeroen S. Dickschat

Beilstein J. Org. Chem. 2019, 15, 789–794, doi:10.3762/bjoc.15.75

• transformations are ubiquitous, which diminishes the hard border between achiral and chiral. One intriguing example for this kind of reactivity is represented by terpene synthases (TSs), arguably building up the class of natural products with the highest density of stereochemical information, the terpenes. By

• , Supporting Information File 1) and incubated with the common terpene precursors geranyl- (GPP, C10), farnesyl- (FPP, C15), geranylgeranyl- (GGPP, C20) and geranylfarnesyl (GFPP, C25) diphosphate. With hexane extraction and GC–MS analysis, only the incubation with FPP yielded a terpene product (Figure 2) that

• enantiomers of NPP, which is surprising in the light of the fact that these reactive tertiary allylic diphosphates were often found to result in a complex mixture of terpene cyclase products and Mg2+-catalysed spontaneous hydrolysis products for other TSs [29][30]. While the reaction with (R)-NPP leads to

Systematic synthetic study of four diastereomerically distinct limonene-1,2-diols and their corresponding cyclic carbonates

• Hiroshi Morikawa,
• Jun-ichi Yamaguchi,
• Shun-ichi Sugimura,
• Masato Minamoto,
• Yuuta Gorou,
• Hisatoyo Morinaga and
• Suguru Motokucho

Beilstein J. Org. Chem. 2019, 15, 130–136, doi:10.3762/bjoc.15.13

• Research, University of Yamanashi, 4-4-37, Takeda, Kofu, Yamanashi 400-8510, Japan Graduate School of Engineering, Nagasaki University, 1-14, Bunkyo-machi, Nagasaki-city 852-8521, Japan 10.3762/bjoc.15.13 Abstract In order to produce versatile and potentially functional terpene-based compounds, a (R

• their characteristic signals. Keywords: cyclic carbonate; diastereomer; diol; limonene; NMR; Introduction (R)-Limonene (LM) is a naturally occurring terpene, and therefore a very attractive and renewable resource [1]. Its derivatives have versatilely and widely been studied [1][2][3][4]. Otherwise

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

• encoded terpene synthases for each strain. Besides terpenes, a series of aromatic compounds and volatiles derived from fatty acid and branched amino acid metabolism were identified. Some of these compounds have not been described as fungal metabolites before. For the compound ethyl (E)-hept-4-enoate known

• ][30], but geosmin could not be observed as a volatile of A. fischeri. The bacterial geosmin synthase is a class I terpene synthase (TS) with two domains [31] that occurs in many actinomycetes, cyanobacteria and myxobacteria, but fungal geosmin biosynthesis must require a different enzyme, because no

• ). A phylogenetic analysis of 878 fungal terpene synthase homologs (Figure S1 in Supporting Information File 1) demonstrates that this enzyme is closely related to the bifunctional ent-copalyl diphosphate synthase/ent-kaurene synthase from Fusarium fujikuroi [33]. The N-terminal domain shows the DXDD

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

• Biology, Hans Knöll Institute, Beutenbergstr. 11a, 07745 Jena, Germany 10.3762/bjoc.13.242 Abstract The genome of the predatory bacterium Herpetosiphon aurantiacus 114-95T harbors a number of biosynthesis genes, including four terpene cyclase genes. To identify the terpenes biosynthesized from H

• resemblance to cadinane-type sesquiterpenes from plants, but is structurally entirely unprecedented in bacteria. Based on its molecular architecture, a possible biosynthetic pathway is postulated. Keywords: genome mining; herpetopanone; Herpetosiphon; isotope labeling; terpene; Introduction Terpenoids

• numerous bacterial terpene cyclase genes [2][3]. Both in vitro and in vivo approaches involving recombinant enzymes are commonly pursued for their functional characterization [4]. Care must be taken, however, in interpreting the results of these analyses, as the products of terpene cyclases are often

Are boat transition states likely to occur in Cope rearrangements? A DFT study of the biogenesis of germacranes

• José Enrique Barquera-Lozada and
• Gabriel Cuevas

Beilstein J. Org. Chem. 2017, 13, 1969–1976, doi:10.3762/bjoc.13.192

• choice for pericyclic reactions studies [20][56]. In particular, third generation hybrid functionals have improved the description of the potential energy surface and produce very reliable results [57][58][59][60]. Our studies in terpene biogenesis show that these hybrid functionals competes successfully

Pd(OAc)₂/Ph₃P-catalyzed dimerization of isoprene and synthesis of monoterpenic heterocycles

• Dominik Kellner,
• Maximilian Weger,
• Andrea Gini and
• Olga García Mancheño

Beilstein J. Org. Chem. 2017, 13, 1807–1815, doi:10.3762/bjoc.13.175

• increase of the reactivity (86% yield), delivering the TT-linear terpene as the main product in a 16:1 ratio of 2-TT vs other dimeric isomers 2, along with Diels–Alder-generated cyclic monoterpene byproducts (Table 1, entry 4). Interestingly, the dimerization did not take place at temperatures below 90 °C

• - and N-heterocycles The different dimers of isoprene can be transformed into a large number of derivatives such as terpene-alcohols or ethers [38]. Moreover, some isoprene dimers have been submitted to Diels–Alder reactions with olefins such as maleic acid anhydride or methacrolein to form products

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

• 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

• , revealing that the expression of one and the same terpene synthase in different heterologous hosts may yield different terpene products. Keywords: biosynthesis; Chitinophaga pinensis; Nicotiana benthamiana; structure elucidation; terpenes; Introduction Terpene synthases convert a handful of simple linear

• and achiral oligoprenyl diphosphates in just one enzymatic step into a remarkable diversity of usually polycyclic structurally complex lipophilic terpenes with multiple stereogenic centres. In their active sites type I terpene synthases contain the highly conserved aspartate-rich motif DDXX(X)(D,E

Correction: Dynamic behavior of rearranging carbocations – implications for terpene biosynthesis

• Stephanie R. Hare and
• Dean J. Tantillo

Beilstein J. Org. Chem. 2017, 13, 1669–1669, doi:10.3762/bjoc.13.161

• Stephanie R. Hare Dean J. Tantillo Department of Chemistry, University of California–Davis, 1 Shields Avenue, Davis, CA 95616, USA 10.3762/bjoc.13.161 Keywords: carbocation; density functional theory; dynamics; mechanism; terpene; The originally published Figure 6 had several mis-drawn

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

• with recombinant terpene biosynthesis modules, they are very suitable hosts for heterologous production of high value terpenes. Yet, in contrast to the number of extracted and characterized terpenes, little is known about the specific biosynthetic enzymes that are involved especially in the formation

• of highly functionalized compounds. Novel approaches discussed in this review include metabolic engineering as well as site-directed mutagenesis to expand the natural terpene landscape. Focusing mainly on the validation of successful integration of engineered biosynthetic pathways into optimized

• 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

Lipids: fatty acids and derivatives, polyketides and isoprenoids

• Jeroen S. Dickschat

Beilstein J. Org. Chem. 2017, 13, 793–794, doi:10.3762/bjoc.13.78

• fundamentally different biosynthetic origin from fatty acids since they are made via terpene biosynthetic pathways. Nevertheless, steroids are highly apolar yet may contain a polar headgroup such as a 3-hydroxy function (as in lanosterol). Besides membrane formation, the highly apolar character of lipids has

A detailed view on 1,8-cineol biosynthesis by Streptomyces clavuligerus

• Jan Rinkel,
• Patrick Rabe,
• Laura zur Horst and
• Jeroen S. Dickschat

Beilstein J. Org. Chem. 2016, 12, 2317–2324, doi:10.3762/bjoc.12.225

• and achiral precursors such as geranyl diphosphate (GPP, monoterpenes), farnesyl diphosphate (FPP, sesquiterpenes) and geranylgeranyl diphosphate (GGPP, diterpenes). Terpene cyclases (type I) contain a trinuclear (Mg2+)3 cluster in their active site that is stabilised by binding to several highly

• a RY dimer [9]. The substrate is ionised by diphosphate abstraction and the resulting allyl cation undergoes a domino reaction via a series of cationic intermediates and a final deprotonation or attack of water to yield a terpene hydrocarbon or alcohol. This reaction cascade proceeds in a

• involved in the stabilisation of cationic intermediates, e.g., by cation–π interactions [8][9][10]. The overall process usually generates an enantiomerically pure (poly)cyclic terpene with several stereogenic centres. A large variety of carbon skeletons is accessible, e g., more than 120 skeletons each

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

• sustainability perspective, but clearly it is necessary to develop protocols that are as environmentally friendly and sustainable as possible. The terpene, citronellal (3,7-dimethyl-6-octenal, 1) is widely used as a feedstock material in the synthesis of fine chemicals such as menthol (2) and para-menthane-3,8

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

• terpene cyclases were characterised by one- and two-dimensional NMR spectroscopic methods, allowing for a full structure elucidation. The absolute configurations of four terpenes were determined based on their optical rotary powers. Incubation experiments with 13C-labelled isotopomers of FPP in buffers

• 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

• terpene cyclases from bacterial genomes. Altogether, a number of ca. 1000 terpene cyclase genes are found in the genomes of sequenced bacteria [10], and about 50 bacterial terpene cyclases have so far been characterised for their products [11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27

Rearrangements of organic peroxides and related processes

• Ivan A. Yaremenko,
• Vera A. Vil’,
• Dmitry V. Demchuk and
• Alexander O. Terent’ev

Beilstein J. Org. Chem. 2016, 12, 1647–1748, doi:10.3762/bjoc.12.162

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

• bacterial terpene cyclases corvol ether synthase from Kitasatospora setae, the epi-cubebol synthase from Streptosporangium roseum, and the isodauc-8-en-11-ol synthase from Streptomyces venezuelae. The enzyme products were analysed by GC–MS and GC–QTOF MS2 and the obtained data were used to delineate the

• -methylisoborneol biosynthetic pathway by comparing the mass spectra of the methylated compounds to their non-methylated analogs [11]. Higher terpenes such as sesqui- and diterpenes, as being produced by terpene cyclases from oligoprenyl diphosphates, are usually (poly)cyclic compounds with different ring sizes

• , introduction of labelling into the various positions of the compound of interest may require a different synthetic strategy for each individual target isotopomer. Most of these studies made use of deuterium labellings that can frequently be introduced into reactive positions of a (functionalised) terpene

Marine-derived myxobacteria of the suborder Nannocystineae: An underexplored source of structurally intriguing and biologically active metabolites

• Antonio Dávila-Céspedes,
• Peter Hufendiek,
• Max Crüsemann,
• Till F. Schäberle and
• Gabriele M. König

Beilstein J. Org. Chem. 2016, 12, 969–984, doi:10.3762/bjoc.12.96

• our group revealed that this organism displays, analogous to the previously discussed example M. xanthus strain DK1622, a plethora of cryptic gene clusters, e.g., five NRPS, four hybrid PKS-NRPS, one PKS-NRPS-lantipeptide, three lantipeptide and numerous bacteriocin- and terpene-encoding gene loci. A

• terpene biosynthesis gene clusters. The genus Haliangium Haliangium ochraceum sp. nov. (initially termed H. luteum, DSM 14365T) and H. tepidum sp. nov. (DSM 14436T) were isolated from seaweed and sea grass, respectively, with both samples being obtained from a sandy beach in Miura, Japan by Fudou et al

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

• been used in a semi-empirical mode [20] as a replacement of vacuum liquid chromatography (VLC) or reversed-phase medium pressure liquid chromatography (MPLC), permitting specially the isolation of several terpene glycosides [27], such as a geranyl disaccharide [28], natural [29][30], semisynthetic

Dynamic behavior of rearranging carbocations – implications for terpene biosynthesis

• Stephanie R. Hare and
• Dean J. Tantillo

Beilstein J. Org. Chem. 2016, 12, 377–390, doi:10.3762/bjoc.12.41

• transformations. Cautions for analyzing both experimental and theoretical data on carbocation rearrangements are included throughout. Keywords: carbocation; density functional theory; dynamics; mechanism; terpene; Review Introduction to terpene forming carbocation rearrangements Terpene natural products display

• . Ultimately these carbocations are either trapped by a nucleophile (e.g., water, diphosphate) or deprotonated to form alkenes. The details of terpene-forming carbocation cyclization/rearrangement processes have been of interest for decades [1][2][3][4][5][6]. Although much has been learned, new observations

• tendencies, i.e., the dynamical behavior of carbocations in the absence of an enzyme, tend to be reflected in product distributions for enzyme-promoted reactions. Consequently, the problem of elucidating the role of terpene synthase enzymes in terpene formation has been redefined. In addition, these studies

Synthesis of Xenia diterpenoids and related metabolites isolated from marine organisms

• Tatjana Huber,
• Lara Weisheit and
• Thomas Magauer

Beilstein J. Org. Chem. 2015, 11, 2521–2539, doi:10.3762/bjoc.11.273

• structurally related caryophyllene sesquiterpenes [25]. Xenia diterpenoids are believed to originate from the common diterpenoid precursor geranylgeranyl pyrophosphate (GGPP, 28), which is assembled from the two terpene units, isoprenyl pyrophosphate (IPP, 26) and dimethylallyl pyrophosphate (DMAPP, 27) [26

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

• prominent example of the deoxyxylulose phosphate way in terpene biosynthesis [7][8]. Thus, a critical analysis of labeling experiments is required and may hint towards undiscovered metabolic pathways or enzyme functions [9]. As demonstrated in this article, the isotopic labeling technique continues to be an

• skeletons (Figure 6). The fascination of terpene biosynthesis arises from the complexity and variety of carbon scaffolds, terpene cyclases are able to build up using few linear oligoprenyl diphosphate precursors. This promotes investigations using isotopically labeled compounds both on acetate- and

• made accessible, 13C,13C-COSY experiments are possible that allow for a comparably easy structure elucidation even for minimal amounts of material. As recently demonstrated for hypodoratoxide (31) from Hypomyces odoratus DSM 11934, such labeled products can be obtained by feeding of terpene precursors

Recent advances in the electrochemical construction of heterocycles

• Robert Francke

Beilstein J. Org. Chem. 2014, 10, 2858–2873, doi:10.3762/bjoc.10.303

• [65]. These structures consist of a terpene element and a benzodihydropyran unit and feature antiviral activity. First, quinomethane intermediate 53 is formed upon indirect anodic oxidation of 52, which reacts with α-phellandrene at room temperature to give compound 54. Alternatively, 53 can be

Thermal and oxidative stability of the Ocimum basilicum L. essential oil/β-cyclodextrin supramolecular system

• Daniel I. Hădărugă,
• Nicoleta G. Hădărugă,
• Corina I. Costescu,
• Ioan David and
• Alexandra T. Gruia

Beilstein J. Org. Chem. 2014, 10, 2809–2820, doi:10.3762/bjoc.10.298

• , linalool or caryophyllene, with allergenic and skin sensitization properties [29]. The formation of these harmful oxi-derivatives is supported by the access of oxygen/air to the reaction site of the terpene molecule. This reaction could be significantly reduced by molecular encapsulation of the bioactive

• of 4.1% to 3.3%. In the recovered oil, reduced concentrations of 1.55% to 1.3%, and 2.1% to 1.75% were observed (see Table 1). Furthermore, all terpene epoxides (even those found in lower relative concentrations) were encapsulated in very low concentrations in the β-CD complexes in comparison with

Total synthesis of the proposed structure of astakolactin

• Takayuki Tonoi,
• Keisuke Mameda,
• Moe Fujishiro,
• Yutaka Yoshinaga and
• Isamu Shiina

Beilstein J. Org. Chem. 2014, 10, 2421–2427, doi:10.3762/bjoc.10.252

• stereochemistry in 62% yield. Finally, determination of the exact structure of astakolactin was attempted by comparing the 1H and 13C NMR spectra of the synthetic compounds 1 and 1’ with those reported for astakolactin (Figure 2 and Figure 3). The chemical shifts for the terpene chain of the synthetic compound 1

Selective allylic hydroxylation of acyclic terpenoids by CYP154E1 from Thermobifida fusca YX

• Anna M. Bogazkaya,
• Clemens J. von Bühler,
• Sebastian Kriening,
• Alexandrine Busch,
• Alexander Seifert,
• Jürgen Pleiss,
• Sabine Laschat and
• Vlada B. Urlacher

Beilstein J. Org. Chem. 2014, 10, 1347–1353, doi:10.3762/bjoc.10.137

• minimal CYP102A1 library of only 24 variants was constructed and screened with four terpene substrates [20]. 11 variants demonstrated either a strong shift or improved regio- or chemoselectivity during oxidation of at least one substrate as compared to CYP102A1 wild type. This library was the starting

• hindrance were selected. Terpene substrates (grey background) and their oxidised derivatives. a) Ac2O, pyridine, room temperature, 24 h; b) SeO2, t-BuOOH, CH2Cl2, 0 °C, 5 h; c) K2CO3, MeOH, room temperature, 2.5 h; d) MPPA, NaOH, H2O, room temperature, 5 h (MPPA = magnesium monoperoxyphthalate). a) SeO2, t