Chemo-enzymatic total synthesis: current approaches toward the integration of chemical and enzymatic transformations

• Ryo Tanifuji and
• Hiroki Oguri

Beilstein J. Org. Chem. 2024, 20, 1693–1712, doi:10.3762/bjoc.20.151

• on a decagram scale in five steps from (+)-limonene oxide (13), involving epoxide manipulation, oxidative cleavage, and intramolecular aldol condensation. Similarly, the right-half fragment, allyl chloride 16, was synthesized from limonene in five steps. Site-selective hydrogenation, oxidative

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

• properties (Figure 4c) [45]. Notably, one tetrahydrofuranoterpenoid 59 is also formed as a major product in the BcBoT2 reaction, despite the low sequence similarity between these sesqui-TSs, which could be explained by similar active-site conformations to stabilize prenyl substrates. Similarly, limonene

• synthases, limonene synthase (CLS) and 5-epi-aristolochene synthase (TEAS). Noncanonical substrates for mechanism studies and their conversion to new terpenoids. a) New terpenoids from FPP analogs by β-himachalene synthase (HcS), (Z)-γ-bisabolene synthase (BbS), and germacrene A synthase (SmTS6). b

Advancements in hydrochlorination of alkenes

• Daniel S. Müller

Beilstein J. Org. Chem. 2024, 20, 787–814, doi:10.3762/bjoc.20.72

• no reaction was observed with p-chloro-substituted styrene (product 52). Geraniol chloride reacted rapidly but only with the more electron-rich double bond (product 49). 1-Methylcyclohex-1-ene was conveniently transformed into chloride 50 within 20 minutes at 0 °C. Limonene was fully hydrochlorinated

• hours reaction time, changed to the thermodynamic ratio of 23:77 of cis-30/trans-30. The reaction appears to be very robust in terms of scale as illustrated by several examples shown in Scheme 12. More recently, de Mattos applied the Kropp procedure to the delicate monohydrochlorination of limonene on a

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

• homolog spiroalbatene synthase from Allokutzneria albata [42]. Test incubations with GPP resulted in the formation of acyclic products besides minor amounts of limonene, while GGPP and GFPP were not converted by both enzymes. With FPP both enzymes resulted in the formation of a sesquiterpene hydrocarbon

Photoredox catalysis harvesting multiple photon or electrochemical energies

• Mattia Lepori,
• Simon Schmid and
• Joshua P. Barham

Beilstein J. Org. Chem. 2023, 19, 1055–1145, doi:10.3762/bjoc.19.81

Strategies to access the [5-8] bicyclic core encountered in the sesquiterpene, diterpene and sesterterpene series

• Cécile Alleman,
• Charlène Gadais,
• Laurent Legentil and
• François-Hugues Porée

Beilstein J. Org. Chem. 2023, 19, 245–281, doi:10.3762/bjoc.19.23

• cyclopentane intermediate accessed from (S)-limonene [64]. Several cyclopentane precursors were prepared to investigate the importance of the alkene functionalization on the cyclization. Thus, the reaction proceeded in the presence of silylated allylic alcohol 131, producing 132 albeit in low yield. The

• allowed the functionalization for each natural product. Their general method consisted in using an intramolecular Pauson–Khand reaction catalyzed by a rhodium complex from an allene-yne substrate to build the eight-membered ring, which was quite challenging. Starting from commercial (R)-limonene (51), Li

Isolation and biosynthesis of daturamycins from Streptomyces sp. KIB-H1544

• Yin Chen,
• Jinqiu Ren,
• Ruimin Yang,
• Jie Li,
• Sheng-Xiong Huang and
• Yijun Yan

Beilstein J. Org. Chem. 2022, 18, 1009–1016, doi:10.3762/bjoc.18.101

• S. sp. KIB-H1544, we conducted the following experiments. Firstly, the genome of S. sp. KIB-H1544 was sequenced, and bioinformatic analysis yields the three-genes cluster (NCBI accession number: ON973849) encoded by datA (peptide synthetase), datB (NAD-dependent dehydratase), and datC (limonene-1,2

Synthesis of odorants in flow and their applications in perfumery

• Merlin Kleoff,
• Paul Kiler and
• Philipp Heretsch

Beilstein J. Org. Chem. 2022, 18, 754–768, doi:10.3762/bjoc.18.76

• ” (substantivity of many hours), or a “base note” (substantivity of days up to weeks) [2][20]. Typically, fresh and citric odorants, e.g., limonene, are top notes, while warm and sweet odorants such as vanillin are base notes [21]. However, these classical categories have been partially overcome by synthetic

A resorcin[4]arene hexameric capsule as a supramolecular catalyst in elimination and isomerization reactions

• Tommaso Lorenzetto,
• Fabrizio Fabris and
• Alessandro Scarso

Beilstein J. Org. Chem. 2022, 18, 337–349, doi:10.3762/bjoc.18.38

• series of reactions like the carbonyl–ene cyclization of (S)-citronellal preferentially to isopulegol, the water elimination from 1,1-diphenylethanol, the isomerization of α-pinene and β-pinene preferentially to limonene and minor amounts of camphene. The role of the supramolecular catalyst consists in

• to react less rapidly than β-pinene. The reaction of α-pinene was monitored following the disappearing of the resonance of the vinylic hydrogen atom at 5.23 ppm. Concomitant formation of a new resonance at 5.43 attributed to limonene and at 4.52 for camphene was observed. In the presence of 10 mol

• % of 16 substrate conversion after 24 h at 60 °C corresponded to 75%, leading to double amounts of limonene with respect to camphene (Figure 3C and Table 3 entries 1 and 2). All the control experiments with the cavity of the capsule occupied by the competitive guest 3, or with 2 or acetic acid as

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

Methodologies for the synthesis of quaternary carbon centers via hydroalkylation of unactivated olefins: twenty years of advances

• Thiago S. Silva and
• Fernando Coelho

Beilstein J. Org. Chem. 2021, 17, 1565–1590, doi:10.3762/bjoc.17.112

• ). Natural products like α and β-pinene that contain an olefinic moiety were also used as substrates, and these afforded ring-opened products like 89e, thereby corroborating a radical mechanism hypothesis [111]. Enantiopure substrates, like limonene oxide (88f) and the proline derivative 88h, afforded the

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

A new and efficient methodology for olefin epoxidation catalyzed by supported cobalt nanoparticles

• Lucía Rossi-Fernández,
• Viviana Dorn and
• Gabriel Radivoy

Beilstein J. Org. Chem. 2021, 17, 519–526, doi:10.3762/bjoc.17.46

• other hand, among the peroxide-free oxidation processes, a Co3O4/SBA-16 catalyst for the epoxidation of limonene in AcOEt [43] and a Co/HAP catalyst in DCM as the solvent [44] have been very recently reported. Both of these catalytic systems gave good conversions to the desired epoxides and allowed the

• the diene (±)-limonene (1k, Table 2, entry 11) took place mainly on the endocyclic C=C double bond with good selectivity, although with a relatively modest conversion. On the contrary, for cyclohexene (1l, Table 2, entry 12) the main oxidation product was found to be the corresponding allylic ketone

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

• , PpolyTPS1 possessed monoterpene synthase activity in vitro and produced a mixture of monoterpenes. One of the PpolyTPS1 monoterpene products, linalool (1), could be detected in the headspace of P. polycephalum, but the other monoterpene products including myrcene, limonene, (Z)-β-ocimene, and (E)-β-ocimene

• ; 3, unidentified sesquiterpene 3; 5, α-muurolene. C) GC chromatogram monoterpenes produced by recombinant PoplyTPS1 incubated with GPP. 1, linalool; 11, myrcene; 12, limonene; 13, (Z)-β-ocimene; 14, (E)-β-ocimene. Phylogenetic analysis of PpolyTPSs with TPSs from dictyostelid social amoebae

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

• , a composition of coumarin, oak moss, geranium and bergamot, commercially launched by Houbigant [4]. The major constituents of geranium oil include myrcene (1), menthone (2), α-pinene (3), geraniol (4a), geranyl acetate (4b), geranyl butyrate (4c), citronellol (5), limonene (6) and linalool (9a). As

• 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

• monoterpene ether 1,8-cineole (14) and camphene (21) can be isolated from the Siberian fir needle oil. Cymbopogon oils provide among other components borneol (16b), geranyl acetate (4b) and citronellol (5). Besides limonene (6), (−)-carvone (17) is one of the main constituents in caraway oil and dill seed oil

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

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

• )-limonene-derived diol and its corresponding five-membered cyclic carbonate were prepared. The diol (cyclic carbonate) comprises four diastereomers based on the stereochemical configuration of the diol (and cyclic carbonate) moiety. By choosing the appropriate starting compounds (trans- and cis-limonene

• 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

• , syntheses of five-membered cyclic carbonates (5CCs) have been intensively investigated [5][6][7] in terms of utilisation of CO2 and the further reactions to produce functional chemicals such as oxazolizin-2-ones [8] and polyurethanes [9]. For (R)-limonene-derived 5CC (LM5CC), four diastereomers are

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

• reduction of non-cyclizing cyclohexane systems that were synthesized from limonene oxide. The title compounds and their synthetic precursors are prone to aromatization on contact with air oxygen. Attempted synthesis of cyclohexene-containing eunicellane bicycles by elimination of water from tertiary alkynyl

•  3). For the synthesis of 25, we started from the known limonene oxide-derived diol 20 [24] that was hydrogenated, oxidized, and silylated at the tertiary alcohol moiety (81%). Reaction of deprotonated 21 with ethyl cyanoformate afforded cyanohydrin 22 by attack of liberated cyanide at the carbonyl

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

• , including limonene (3) and pinene (44), and the octalins 5 and 6, in this species accompanied by geosmin (45) (Figure 1, Table 3 and Scheme 5). Furthermore, daucene (19) was observed in small amounts, which further supports the functional assignment of the enzyme XP_001265719 from A. fischeri for the

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

• 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

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

• -pinene or limonene [78]. At present, 27.4 g/L of amorphadiene is the highest published titer for any reported terpenoid produced in E. coli. This result is of particular industrial relevance as amorphadiene constitutes the sesquiterpenoid scaffold of the antimalarial drug artemisinin [79]. In comparison

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

• interesting molecular properties. Particularly obvious is their often characteristic aroma that contributes to the typical flavour of many essential oils from plants. This is exemplified by the monoterpene α-pinene that occurs in form of both enantiomers in pine trees, while (R)-(+)-limonene is found in

Stereoselective synthesis of hernandulcin, peroxylippidulcine A, lippidulcines A, B and C and taste evaluation

• Marco G. Rigamonti and
• Francesco G. Gatti

Beilstein J. Org. Chem. 2015, 11, 2117–2124, doi:10.3762/bjoc.11.228

• double bonds of (+)-limonene or (−)-isopulegol with m-chloroperbenzoic acid (MCPBA) to introduce the stereogenic center at the C(2’) position. Unfortunately both methods were only modestly stereoselective and resulted in mixtures of the respective epoxides. These results implied a not simple column

Hydrogenation of unactivated enamines to tertiary amines: rhodium complexes of fluorinated phosphines give marked improvements in catalytic activity

• Sergey Tin,
• Tamara Fanjul and
• Matthew L. Clarke

Beilstein J. Org. Chem. 2015, 11, 622–627, doi:10.3762/bjoc.11.70

• tetrasubstituted enamines. The use of the sustainable and environmentally benign solvent (R)-limonene for the reaction is also reported with the amine isolated by acid extraction. Keywords: alkenes; homogeneous catalysis; hydrogenation; renewable solvents; tertiary amines; Introduction A potentially very direct

• solvent (MeOH) was chosen (Table 2). The electronic effect still holds in MeOH as a solvent, although it is less pronounced, and the best rate of conversion is found in toluene. Another solvent explored in this study was (R)-limonene. This solvent is now being used as a green alternative to hexane in the

• hydrogenation of enamines, as was shown above, enamine hydrogenation benefits from electron-poor ligands, so the hope was that the enamine hydrogenation would be competitive over limonene hydrogenation. In addition, this solvent enables us to study the relative reactivities of these C=C bonds, as well as

Stereoselective cathodic synthesis of 8-substituted (1R,3R,4S)-menthylamines

• Carolin Edinger,
• Jörn Kulisch and
• Siegfried R. Waldvogel

Beilstein J. Org. Chem. 2015, 11, 294–301, doi:10.3762/bjoc.11.34

• fraction of starting materials for the synthesis of these compounds is still provided by the chiral pool. Usually, optically active alcohols or amino acids serve as starting material for such amine syntheses [14]. Naturally occurring terpenes such as carene [15], limonene [16], pinene [17][18] or camphor