Enhancing structural diversity of terpenoids by multisubstrate terpene synthases

• Min Li and
• Hui Tao

Beilstein J. Org. Chem. 2024, 20, 959–972, doi:10.3762/bjoc.20.86

• converted into (poly)cyclic skeletons, including hemiterpenes, monoterpenes, sesquiterpenes, diterpenes, sesterterpenes, and triterpenes, by a large class of enzymes called terpene synthases (TSs) (Figure 1). The reactions of TSs are one of the most important factors contributing to terpene diversity, as

Functions of enzyme domains in 2-methylisoborneol biosynthesis and enzymatic synthesis of non-natural analogs

• Binbin Gu,
• Lin-Fu Liang and
• Jeroen S. Dickschat

Beilstein J. Org. Chem. 2023, 19, 1452–1459, doi:10.3762/bjoc.19.104

• versions of 2MIBSs exhibit a proline-rich N-terminal domain of unknown function that appears disordered in the crystal structure [28]. As a first aspect of this study, we have investigated the possible function of this N-terminal domain. 2MIBS is known to form several methylated monoterpenes as side

• products that have been identified by GC–MS analysis and the synthesis of reference compounds [30][31]. Notably, 2MIBS also shows some substrate flexibility and can convert GPP into monoterpenes in vitro, albeit with less efficiency as compared to the conversion of 2-Me-GPP [24]. On the other hand, single

Functional characterisation of twelve terpene synthases from actinobacteria

• Anuj K. Chhalodia,
• Houchao Xu,
• Georges B. Tabekoueng,
• Binbin Gu,
• Kizerbo A. Taizoumbe,
• Lukas Lauterbach and
• Jeroen S. Dickschat

Beilstein J. Org. Chem. 2023, 19, 1386–1398, doi:10.3762/bjoc.19.100

• identifying the investigated enzyme as Nocardia brevicatena epi-isozizaene synthase (NbEIZS). GGPP was not converted, but the incubation with GPP resulted in the production of a complex mixture of monoterpenes including myrcene (14), sylvestrene (15), γ-terpinene (16), cis-sabinene hydrate (17), terpinolene

• plasticisers. Total ion chromatograms of the products obtained with NbEIZS A) from FPP and B) from GPP, and C) structures of identified monoterpenes (only relative configurations are known). Peak numbers in B) refer to compound numbers in C). Total ion chromatogram of the products obtained with SfES. Peak

Enantioselective total synthesis of putative dihydrorosefuran, a monoterpene with an unique 2,5-dihydrofuran structure

• Irene Torres-García,
• Josefa L. López-Martínez,
• Rocío López-Domene,
• Manuel Muñoz-Dorado,
• Ignacio Rodríguez-García and
• Miriam Álvarez-Corral

Beilstein J. Org. Chem. 2022, 18, 1264–1269, doi:10.3762/bjoc.18.132

• . Keywords: Ag(I) cyclization; allenylation; CpTiCl2; 2,5-dihydrofurans; monoterpenes; Introduction Artemisia pallens is an aromatic plant from southern India whose essential oil, known as Davana oil, has shown increasing interest mainly for its use in some beverages, cakes, pastries, etc., as well as in

The stereochemical course of 2-methylisoborneol biosynthesis

• Binbin Gu,
• Anwei Hou and
• Jeroen S. Dickschat

Beilstein J. Org. Chem. 2022, 18, 818–824, doi:10.3762/bjoc.18.82

• by GC/MS analysis and synthesis of reference compounds [29], several of which also occur in Escherichia coli or yeast strains that were engineered for the biosynthesis of methylated monoterpenes derived from 2-Me-GPP [30][31]. About one decade ago, the crystal structures of GPPMT and 2MIBS have been

Targeting active site residues and structural anchoring positions in terpene synthases

• Anwei Hou and
• Jeroen S. Dickschat

Beilstein J. Org. Chem. 2021, 17, 2441–2449, doi:10.3762/bjoc.17.161

• isopentenyl diphosphate (IPP), that can be fused by oligoprenyl diphosphate synthases to yield geranyl diphosphate (GPP, C10) as the precursor to monoterpenes, farnesyl diphosphate (FPP, C15) as sesquiterpene precursor, geranylgeranyl diphosphate (GGPP, C20) towards diterpenes, and geranylfarnesyl diphosphate

Volatile emission and biosynthesis in endophytic fungi colonizing black poplar leaves

• Christin Walther,
• Pamela Baumann,
• Katrin Luck,
• Beate Rothe,
• Peter H. W. Biedermann,
• Jonathan Gershenzon,
• Tobias G. Köllner and
• Sybille B. Unsicker

Beilstein J. Org. Chem. 2021, 17, 1698–1711, doi:10.3762/bjoc.17.118

• precursors GPP, FPP, and GGPP into the different terpene skeletons [42][43][44]. However, our knowledge on terpene synthases of endophytic fungi is scarce, specifically in comparison to the vast knowledge on these enzymes in plants and bacteria [44][45]. Typical monoterpenes like limonene and linalool (5

• respective enzymes accepted the substrate GPP and produced monoterpenes (Figure 2). CxTPS1 produced myrcene (9) and (E)-β-ocimene (10) in similar amounts. CxTPS2 produced (E)-β-ocimene (10) as the major product and minor amounts of myrcene (9), (Z)-β-ocimene (11), and linalool (5) (Figure 2). Only one

• ), and α-muurolene (8). However, monoterpenes were completely absent from the volatile bouquets of the endophytic species in our study. Weikl et al. who compared the volatiles released from Alternaria alternata and Fusarium oxysporum also did not detect any monoterpenes [41]. However, other studies on

A comprehensive review of flow chemistry techniques tailored to the flavours and fragrances industries

• Guido Gambacorta,
• James S. Sharley and
• Ian R. Baxendale

Beilstein J. Org. Chem. 2021, 17, 1181–1312, doi:10.3762/bjoc.17.90

Bacterial terpene biosynthesis: challenges and opportunities for pathway engineering

• Eric J. N. Helfrich,
• Geng-Min Lin,
• Christopher A. Voigt and
• Jon Clardy

Beilstein J. Org. Chem. 2019, 15, 2889–2906, doi:10.3762/bjoc.15.283

• plant sources, which led to the production of 12 novel oxidized labdane-related diterpenes [128]. Recently, commercially available monoterpenes were incubated with cell-free extracts from E. coli expressing well-studied bacterial CYPs, resulting in 27 previously unreported terpenoids (selected examples

• accumulation of FPP (Figure 11c) [143]. Alternatively, in vitro pathway reconstitution led to the successful production of several monoterpenes, circumnavigating toxicity to the heterologous hosts [144]. Several intermediates are also known to inhibit enzyme activities in the pathway. Novel pathways, such as

• -isozizaene (33) synthase mutants that produce different sesquiterpene skeletons. Substrate promiscuity and engineering of CYPs. a) Selected examples from using a CYP library to oxidize various monoterpenes. b) Rational engineering of P450BM3 for epoxidation of amorphadiene (21). F87A/A328L and R47L/Y51F

Emission and biosynthesis of volatile terpenoids from the plasmodial slime mold Physarum polycephalum

• Xinlu Chen,
• Tobias G. Köllner,
• Wangdan Xiong,
• Guo Wei and
• Feng Chen

Beilstein J. Org. Chem. 2019, 15, 2872–2880, doi:10.3762/bjoc.15.281

• synthases (TPSs) are pivotal enzymes for the production of diverse terpenes, including monoterpenes, sesquiterpenes, and diterpenes. In our recent studies, dictyostelid social amoebae, also known as cellular slime molds, were found to contain TPS genes for making volatile terpenes. For comparison, here we

• PpolyTPS4 were able to produce sesquiterpenes and monoterpenes from the respective substrates farnesyl diphosphate and geranyl diphosphate. By comparing the volatile profile of P. polycephalum plasmodia and the in vitro products of PpolyTPS1 and PpolyTPS4, it was concluded that most sesquiterpenoids emitted

• using geranyl diphosphate (GPP) and (E,E)-farnesyl diphosphate (FPP) as substrates. PpolyTPS2 and PpolyTPS3 did not show detectable terpene products with either GPP or FPP. In contrast, PpolyTPS1 could convert GPP into a mixture of cyclic and acyclic monoterpenes, including myrcene and linalool (1

Synthetic terpenoids in the world of fragrances: Iso E Super^® is the showcase

• Alexey Stepanyuk and
• Andreas Kirschning

Beilstein J. Org. Chem. 2019, 15, 2590–2602, doi:10.3762/bjoc.15.252

• for the bergamot oil monoterpenes limonene (6, 37%), γ-terpinene (7, 7%), β-pinene (8, 6%), linalool (9a, 9%) and linalyl acetate (9b, 30%) are key ingredients (Figure 1). The ratio of (R)-linalool and (R)-linalyl acetate (commonly >99.3% ee) is one of the quality indices as it affects the aroma of

• the essence of bergamot [5]. Nowadays, these historically important oils, rich in monoterpenes, are complemented by other essential oils from flowers, roots, fruit, wood, and moss [6], e.g., lavender and petitgrain oils are rich in linalyl acetate (9b) and lemon oil in γ-terpinene (7) and β-pinene (8

• versatile monoterpenes to be used as starting material for generating products in various industries. These include polymers, insect repellents, vitamins, flavours and fragrances [16]. Commercially, it is obtained from turpentine, a side product in paper manufacturing. Its main constituents are α-pinene (3

Chiral terpene auxiliaries V: Synthesis of new chiral γ-hydroxyphosphine oxides derived from α-pinene

• Anna Kmieciak and
• Marek P. Krzemiński

Beilstein J. Org. Chem. 2019, 15, 2493–2499, doi:10.3762/bjoc.15.242

• site providing a trans relationship between the hydroxy and the phosphine substituents. Keywords: isopinocamphone; monoterpenes; phosphines; [2,3]-sigmatropic rearrangement; verbanone; Introduction Chiral phosphorus compounds, despite many years of research, still enjoy unflagging interest of many

Phylogenomic analyses and distribution of terpene synthases among Streptomyces

• Lara Martín-Sánchez,
• Kumar Saurabh Singh,
• Mariana Avalos,
• Gilles P. van Wezel,
• Jeroen S. Dickschat and
• Paolina Garbeva

Beilstein J. Org. Chem. 2019, 15, 1181–1193, doi:10.3762/bjoc.15.115

• depends on the precursors that these synthases can accommodate: geranyl diphosphate (monoterpenes, C10), farnesyl diphosphate (sesquiterpenes, C15) and geranylgeranyl diphosphate (diterpenes, C20). The biological function of terpenes is best studied for plants where they play important roles in

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

• configuration (Figure S5, Supporting Information File 1). GC analysis on a homochiral stationary phase was used to assign the absolute configurations of the observed chiral monoterpenes (R)-(+)-limonene (10), (R)-(+)-α-terpineol (11), (+)-α-pinene (13) and (S)-(+)-linalool (15) as shown in Figure 2 by

• an enantiomeric mixture of monoterpenes are also known, e g., from Pinus taeda [33]. However, the major enantiomer of each cyclised monoterpene product described herein was found to be derived from (R)-A. Compound 17 was isolated from a large scale incubation of the TS with GGPP and identified by NMR

• 17 is a simple 1,14-cyclisation product, and all cyclised monoterpenes are derived from the extensively studied terpinyl cation [35][36], this work focusses on elucidating the more interesting sesquiterpene cyclase mechanism of HcS. Most sesquiterpene products 1–6 of HcS including the main product 1

Volatiles from the hypoxylaceous fungi Hypoxylon griseobrunneum and Hypoxylon macrocarpum

• Jan Rinkel,
• Alexander Babczyk,
• Tao Wang,
• Marc Stadler and
• Jeroen S. Dickschat

Beilstein J. Org. Chem. 2018, 14, 2974–2990, doi:10.3762/bjoc.14.277

• elucidation commercially available standards of 9–11 were used, while a synthesis of 12 was performed in our earlier study [24]. Furthermore, a group of monoterpenes and the sesquiterpene alcohol pogostol (19) that was previously reported from other fungi [29][30] were observed. Monoterpenes were comprised of

Iodine(III)-mediated halogenations of acyclic monoterpenoids

• Laure Peilleron,
• Tatyana D. Grayfer,
• Joëlle Dubois,
• Robert H. Dodd and
• Kevin Cariou

Beilstein J. Org. Chem. 2018, 14, 1103–1111, doi:10.3762/bjoc.14.96

• trisubstituted double bond occurred with excellent selectivity and moderate to good yields. Keywords: halogenation; hypervalent iodine; monoterpenes; Introduction In nature, mostly in marine environments, halogenated compounds are produced by means of various enzymes that rely on widely available halides as

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

• terpenes, including traces of the widespread monoterpenes limonene (3) and linalool (4). The C12 compounds (8S*,9R*,10S*)-8,10-dimethyl-1-octalin (5) and (8S*,10R*)-8,10-dimethyl-1(9)-octalin (6) are intermediates of the biosynthesis of the earthy odorant geosmin that is itself a degraded sesquiterpene [29

• quenching of cation J with water (box in Scheme 2), suggesting that this enzyme is responsible for the biosynthesis of 15 in A. fischeri. Therefore, the enzyme XP_001265719 is likely responsible for the biosynthesis of 19 and its byproducts. The biosynthetic origin of the observed traces of monoterpenes is

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

• -catalyzed dimerization of isoprene is a practical approach of synthesizing monoterpenes. Though several highly selective methods have been reported, most of them still required pressure or costly ligands for attaining the active system and desired selectivity. Herein, we present a simple and economical

• formed: tail-to-tail, head-to-tail, tail-to-head and head-to-head (Figure 1). In addition to the linear dimeric products, cyclic monoterpenes such as limonene can also be formed as byproducts. A number of transition metal complexes can be used as catalysts in the dimerization of isoprene. In one hand

• amount to 0.02 mol % of Pd(OAc)2, since only traces of the desired dimers 2 were obtained (Table 1, entry 18). Under these conditions, the main products detected were cyclic monoterpenes, which were only obtained in a low 7% yield. After having identified the optimal reaction conditions for the

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

• recombinant enzyme from C. pinensis, showing no formation of monoterpenes from GPP (A) and no formation of sesquiterpenes from FPP (B), but formation of a single diterpene alcohol 3 from GGPP (C) with the mass spectrum depicted in (D). Asterisks indicate non-terpenoid contaminants such as plasticisers

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

• , GPP, the universal precursor for all monoterpenes [40]. Subsequent cis-addition of further IPP-units to geranyl diphosphate by farnesyl diphosphate synthase (FPPS) and geranylgeranyl diphosphate synthase (GGPPS) yield in the respective precursors for sesquiterpenes (farnesyl diphosphate, FPP) and

• introduction of heterologous genes for terpene production lead to unpredictable metabolic feedback reactions that currently can only be counteracted by empirical approaches. Monoterpenes, for example, can have toxic effects on microorganisms, though E. coli seems to be more tolerant towards products like α

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 flow reactor setup for photochemistry of biphasic gas/liquid reactions

• Josef Schachtner,
• Patrick Bayer and
• Axel Jacobi von Wangelin

Beilstein J. Org. Chem. 2016, 12, 1798–1811, doi:10.3762/bjoc.12.170

• photooxidations of citronellol [35][40][41][42], indanes [43], monoterpenes [36], furans [42], furfurals [44], thiols [37] and amines [45] as well as the syntheses of ascaridol [46] and artemisinin [47]. Related microreactor setups were applied to biphasic gas/liquid mixtures in the photochlorination of

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

• the actinobacterium Micromonospora aurantiaca [9] and more than 30 blastmycinones, a class of γ-lactones that depend on the antimycin biosynthetic gene cluster in several streptomycetes [10]. We have also recently developed structural proposals for a series of methylated monoterpenes from the 2

• , contain several methyl groups, and possibly one or more olefinic double bonds, an alcohol or ether function. Their much higher structural complexity compared to, e.g., FAMEs and monoterpenes renders a prediction of the fragmentation behaviour of unknown compounds in mass spectrometry and consequently the

Selective bromochlorination of a homoallylic alcohol for the total synthesis of (−)-anverene

• Frederick J. Seidl and
• Noah Z. Burns

Beilstein J. Org. Chem. 2016, 12, 1361–1365, doi:10.3762/bjoc.12.129

• ]. (−)-Anverene (1) is a member of a large and synthetically challenging family of polyhalogenated acyclic monoterpenes, for which few stereoselective synthetic approaches exist [11]. Results and Discussion In considering a retrosynthesis of anverene (1) we initially identified prenol bromochlorotriflate 2

Efficient syntheses of climate relevant isoprene nitrates and (1R,5S)-(−)-myrtenol nitrate

• Sean P. Bew,
• Glyn D. Hiatt-Gipson,
• Graham P. Mills and
• Claire E. Reeves

Beilstein J. Org. Chem. 2016, 12, 1081–1095, doi:10.3762/bjoc.12.103

• [2], however, many other different types of biogenic volatile organic compounds (BVOCs) are also generated and released. These include monoterpenes, e.g., 1,8-cineole, borneol, β-phellandrene, 2-carene, camphene, sabinene and citral; sesquiterpenes, e.g., α-copaene, β-cubebene, α-cedrene, β-selinene

• “ [12]. Organic nitrates are important in locations where biogenic hydrocarbon emissions mix with anthropogenic NOx sources. It is generally accepted that transport models should include representation of organic aerosols derived from the reaction of monoterpenes with nitrate radicals. With this in mind

• Pye et al. recently developed a system to study the formation and subsequent aerosol-phase partitioning of organic nitrates derived from both isoprene and monoterpenes. Their studies indicated the concentrations of organic aerosol and gas-phase organic nitrates increased when particulate organic