Confirmation of the stereochemistry of spiroviolene

• Yao Kong,
• Yuanning Liu,
• Kaibiao Wang,
• Tao Wang,
• Chen Wang,
• Ben Ai,
• Hongli Jia,
• Guohui Pan,
• Min Yin and
• Zhengren Xu

Beilstein J. Org. Chem. 2024, 20, 852–858, doi:10.3762/bjoc.20.77

• deoxyconidiogenol (4, Scheme 1A) by several terpene cyclases from fungus (PcCS, PchDS, PrDS) [15][16], which involves a 1,11-10,14 cyclization of GGPP, followed by 1,2-alkyl shift and a 2,10-cyclization, to give the key C3 cationic intermediate IM-1. A key 1,2-hydride shift from C2 to C3, which was observed in the

• IM-7. A key 1,3-hydride shift of IM-7 from the β-face, followed by deprotonation of the formed C2-cation IM-8, would deliver the originally proposed structure 1' [6]. However, no related natural products that would be derived from the intermediates of this pathway have been found so far. A third

Palladium-catalyzed three-component radical-polar crossover carboamination of 1,3-dienes or allenes with diazo esters and amines

• Geng-Xin Liu,
• Xiao-Ting Jie,
• Ge-Jun Niu,
• Li-Sheng Yang,
• Xing-Lin Li,
• Jian Luo and
• Wen-Hao Hu

Beilstein J. Org. Chem. 2024, 20, 661–671, doi:10.3762/bjoc.20.59

• , hydride shift process, and photoinduced homolytic cleavage of the C–Pd bond, furnishing hybrid α-ester alkylpalladium radical I. In path b, upon irradiation with blue light, photoexcited Pd(0)Ln* reduces ethyl diazoacetate (1a) to Pd-radical species I by a proton-coupled electron transfer (PCET) process

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

Germacrene B – a central intermediate in sesquiterpene biosynthesis

• Houchao Xu and
• Jeroen S. Dickschat

Beilstein J. Org. Chem. 2023, 19, 186–203, doi:10.3762/bjoc.19.18

• that 11 can bind to the main protease Mpro of the SARS-CoV-2 virus that is involved in viral reproduction, but experimental tests supporting this finding are lacking [89]. Selina-5,7(11)-diene (20) can arise from I1 through 1,2-hydride shift to I1a and deprotonation (Scheme 7). This compound was first

• attack of water to I2. As mentioned above, this compound occurs in Cinnamomum camphora [86] and has later also been isolated from Laggera pterodonta ([α]D24 = +4, c 0.5, MeOH) [93]. Compound 38, (+)-eudesma-5,7(11)-diene, could potentially arise from I2 by 1,2-hydride shift to I2a and deprotonation, but

• likely precursor than I3, because I1 is the intermediate towards structurally related natural products such as the widespread compounds 9 and 10 and a common biosynthesis of 18 through the same intermediate can be assumed (Scheme 7). A 1,2-hydride shift to I3a and deprotonation could give rise to 50, a

Characterization of a new fusicoccane-type diterpene synthase and an associated P450 enzyme

• Jia-Hua Huang,
• Jian-Ming Lv,
• Liang-Yan Xiao,
• Qian Xu,
• Fu-Long Lin,
• Gao-Qian Wang,
• Guo-Dong Chen,
• Sheng-Ying Qin,
• Dan Hu and
• Hao Gao

Beilstein J. Org. Chem. 2022, 18, 1396–1402, doi:10.3762/bjoc.18.144

• ], MgMS [20], CotB2 [19], and CpCS [21] have been deciphered. All these enzymes undergo a common C1,11–C10,14-bicyclization to form a C15 carbocation, but differ a lot at the following C2,6 cyclization (Scheme 1B). CotB2 and CpCS trigger the C2,6 cyclization via a distant hydride shift, whereas PaFS

Anti-inflammatory aromadendrane- and cadinane-type sesquiterpenoids from the South China Sea sponge Acanthella cavernosa

• Shou-Mao Shen,
• Qing Yang,
• Yi Zang,
• Jia Li,
• Xueting Liu and
• Yue-Wei Guo

Beilstein J. Org. Chem. 2022, 18, 916–925, doi:10.3762/bjoc.18.91

• isomerized to nerolidyl diphosphate (NPP), followed by the 6,7-bond formation to generate carbocation intermediate I (Scheme 1, II) [31]. Sequential 1,3-hydride shift and 1,6-cyclization occurred to afford cadinyl cation (J). Further 1,3-hydride shift and deprotonation on J resulted in cadina-1(6),4-diene (L

Regioselectivity of the S_EAr-based cyclizations and S_EAr-terminated annulations of 3,5-unsubstituted, 4-substituted indoles

• Jonali Das and
• Sajal Kumar Das

Beilstein J. Org. Chem. 2022, 18, 293–302, doi:10.3762/bjoc.18.33

• nine-membered rings 27 via triflic acid (TfOH)-catalyzed reaction of indole-derived phenylenediamine 25 with aldehydes 26 (Scheme 9) [19]. Mechanistically, the initially formed iminium ion I undergoes isomerization to iminium ion II through a 1,3-hydride shift process. Iminium ion III could then be

• generated via 1,6-hydride shift in both I and II. Finally, an intramolecular Mannich-type cyclization then furnishes products 27. The cascade protocol enjoys several advantageous synthetic features, including high step- and atom-economy, transition-metal-free and room temperature conditions. In all cases

The enzyme mechanism of patchoulol synthase

• Houchao Xu,
• Bernd Goldfuss,
• Gregor Schnakenburg and
• Jeroen S. Dickschat

Beilstein J. Org. Chem. 2022, 18, 13–24, doi:10.3762/bjoc.18.2

• cation (A), followed by direct cyclisation reactions to B and C, a 1,4-hydride shift to D and capture with water to yield 3 (Scheme 1A) [9]. This mechanism was supported by radioactive labelling experiments with [12,13-14C,1-3H]FPP and [12,13-14C,6-3H]FPP, whose enzymatic conversion with PTS into 3

• retainment of labelling was reported for all intermediates until 13, while a loss of tritium was observed for 14 with both substrates. From these experiments it was concluded that the hydrogen H6 must migrate into another position, as realised by the 1,4-hydride shift from C to D. The loss of 3H in the

• neutral intermediates 8 and 6 (Scheme 2C) [13]. In 2010, Faraldos et al. published a third mechanism that also starts with a cyclisation of FPP to A (Scheme 3A) [14]. Similar to Croteau’s mechanism, A is directly further cyclised to H, followed by a 1,3-hydride shift to J (equivalent to the 1,4-hydride

Pentannulation of N-heterocycles by a tandem gold-catalyzed [3,3]-rearrangement/Nazarov reaction of propargyl ester derivatives: a computational study on the crucial role of the nitrogen atom

• Giovanna Zanella,
• Martina Petrović,
• Dina Scarpi,
• Ernesto G. Occhiato and
• Enrique Gómez-Bengoa

Beilstein J. Org. Chem. 2020, 16, 3059–3068, doi:10.3762/bjoc.16.255

• hydrolysis. These steps can occur through different pathways; in particular, we considered a single-step intramolecular hydride shift with concomitant C–Au-bond breaking (Figure 5) or a base-mediated deprotonation, followed by Au–C-bond hydrolysis through protodeauration (Figure 6). In the former case, it

• emerged that the 1,2-hydrogen shift in TS7 is quite high in energy (ΔG‡ = 18.5 kcal⋅mol−1) relative to the previous barriers shown in Figure 2. This barrier is also much higher than the traditional 1,2-hydride shift in carbocations, which usually show barriers even under 10 kcal⋅mol−1. It has been

On the mass spectrometric fragmentations of the bacterial sesterterpenes sestermobaraenes A–C

• Anwei Hou and
• Jeroen S. Dickschat

Beilstein J. Org. Chem. 2020, 16, 2807–2819, doi:10.3762/bjoc.16.231

• rearrangement to a2•+ and a hydride shift to b2•+ (Scheme 3A). This hydride migration is in reverse order compared to a similar step along the cationic cyclisation cascade during the biosynthesis of 2 (Scheme S1 in Supporting Information File 1). The subsequent inductive ring opening to c2•+ and α-cleavage of

• cleavage of C22, C23, C24, or C25, as observed before for compounds 1 and 2. Especially noteworthy is the cleavage of the methylene carbon C25, which is explainable from 3•+ by a hydrogen rearrangement to a3•+, followed by a hydride shift to b3•+ and an α-fragmentation to c3+ (Scheme 5A). The alternative

• a multistep process (Scheme 6A). Starting from 3•+, a hydride shift to n3•+ and skeletal rearrangement lead to o3•+. A subsequent hydrogen rearrangement of this primary radical yields the tertiary radical p3•+ that can undergo an α-fragmentation to q3•+, followed by hydrogen rearrangement to r3

Recent advances in photocatalyzed reactions using well-defined copper(I) complexes

• Mingbing Zhong,
• Xavier Pannecoucke,
• Philippe Jubault and
• Thomas Poisson

Beilstein J. Org. Chem. 2020, 16, 451–481, doi:10.3762/bjoc.16.42

• oxidized copper complex oxidized the glycine ester, regenerating the catalyst, furnishing the N-centered radical cation. Then, the latter underwent a 1,2-hydride shift in the presence of the base (or the phthalimide anion) to form the α-amino radical that recombined with the alkyl radical formed in the

Understanding the role of active site residues in CotB2 catalysis using a cluster model

• Keren Raz,
• Ronja Driller,
• Thomas Brück,
• Bernhard Loll and
• Dan T. Major

Beilstein J. Org. Chem. 2020, 16, 50–59, doi:10.3762/bjoc.16.7

• electrophilic cyclizations to generate intermediate A. Intermediate A undergoes a 1,5-hydride shift, forming intermediate B. A subsequent cyclization forms intermediate C. Intermediate C generates intermediate E via one of two possible pathways: either a direct 1,3-hydride shift or an indirect pathway involving

• isotope labeling experiments combined with QM calculations. Intermediate G forms via a 1,5-hydride shift from C6 to C10 to generate a homoallylic cation, and the formation of intermediate H occurs due to cyclization to yield a cyclopropyl ring. Intermediate I forms due to isomeric formation of a

Current understanding and biotechnological application of the bacterial diterpene synthase CotB2

• Ronja Driller,
• Daniel Garbe,
• Norbert Mehlmer,
• Monika Fuchs,
• Keren Raz,
• Dan Thomas Major,
• Thomas Brück and
• Bernhard Loll

Beilstein J. Org. Chem. 2019, 15, 2355–2368, doi:10.3762/bjoc.15.228

• lead to different migration of the double bound and different hydroxylation pattern (Table 2 and Scheme 1). An exchange to leucine drastically changes the product to cembrane A (7) and 3,7,18-dolabellatriene 12 (Table 2 and Scheme 1) [36]. The cation migrates via a 1,5 hydride shift, as shown by

• Figure 7). F107 has been targeted by site-directed mutagenesis as well (Table 2 and Scheme 1) [30], leading to compounds R-cembrene A (7) and cyclooctat-1,7-diene (8). Now the cationic intermediate has two possibilities to react to G, either by a 1,3- and 1,5-hydride shift or by two 1,2-hydride shifts

• followed by a 1,5-hydride shift. The sequential 1,2-hydride shift (C to E) route was initially suggested by theoretical calculations, which supported the overall mechanism [33][34], and this was verified via isotope labeling [34]. Such series of two 1,2-hydride shifts have previously been demonstrated

Isolation and biosynthesis of an unsaturated fatty acid with unusual methylation pattern from a coral-associated bacterium Microbulbifer sp.

• Amit Raj Sharma,
• Enjuro Harunari,
• Tao Zhou,
• Agus Trianto and
• Yasuhiro Igarashi

Beilstein J. Org. Chem. 2019, 15, 2327–2332, doi:10.3762/bjoc.15.225

• methyltransferase, followed by 1,2-hydride shift and deprotonation, and a subsequent reduction of the exo-methylene intermediate gives rise to a methyl group (Scheme 2) [18]. The presence of the exo-methylene intermediate was experimentally proved but the enzyme responsible for the double bond reduction has not

Harnessing enzyme plasticity for the synthesis of oxygenated sesquiterpenoids

• Melodi Demiray,
• David J. Miller and
• Rudolf K. Allemann

Beilstein J. Org. Chem. 2019, 15, 2184–2190, doi:10.3762/bjoc.15.215

• closure to form the bisabolyl cation (6). A [1,3]-hydride shift to form carbocation 7 and 1,10-ring closure yield the amorphyl cation (8). Finally, deprotonation generates amorpha-4,11-diene (3) [8][9]. Several sesquiterpene synthases including ADS accept FDP analogues containing a variety of heteroatoms

• bisabolyl cation and the amorphane skeleton. Rather the active site conformations of 11 and cation 22 appear to enable a 1,11-cyclisation to 23. A subsequent [1,3]-hydride shift to cation 24 and deprotonation from C15 lead to 8-methoxy-γ-humulene (20, Scheme 3A). Alternatively, the nucleophilic 8-methoxy

• group could react at C10 to induce a fast 1,11-cyclisation, forming cation 25, which effectively competes with the isomerization of 11 to 8-methoxy-NDP. A subsequent [1,3]-hydride shift leads to 24 (Scheme 3A). Direct deprotonation of 22 at C15 forms the minor reaction product (E)-8-methoxy-β-farnesene

Analysis of sesquiterpene hydrocarbons in grape berry exocarp (Vitis vinifera L.) using in vivo-labeling and comprehensive two-dimensional gas chromatography–mass spectrometry (GC×GC–MS)

• Philipp P. Könen and
• Matthias Wüst

Beilstein J. Org. Chem. 2019, 15, 1945–1961, doi:10.3762/bjoc.15.190

• [5][32]. In 1999 Schmidt et al. were able to show that the enantiomers of germacrene D are formed via two different H-transfer pathways in Solidago canadensis. (S)-(−)-Germacrene D is generated by a cyclization reaction, that includes a 1,3-hydride shift as opposed to the cyclization reaction of (R

• cyclization takes place only from (S)-(−)-germacrene D, from which the absolute configuration of these substances can be derived. While the detected labeling patterns in our feeding experiments are in full agreement with the 1,3-hydride shift pathway, the cloning and functional characterization of the

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

• diphosphate. In-depth mechanistic investigations using isotopically labelled precursors regarding the stereochemical course of both 1,11-cyclisation and 1,3-hydride shift furnished a detailed catalytic model suggesting the molecular basis of the observed low product selectivity. The enzyme’s synthetic

• secondary cation D, which either stabilises by 2,10-ring closure to give the caryophyllenyl cation E that can be deprotonated at the methyl group to yield 9-epi-(E)-β-caryophyllene (7), or D undergoes a 1,3-hydride shift to the allylic cation F. Deprotonation leads to γ-humulene (8), but a 1,6-ring closure

• gives access to B. The second shown option, path B, assumes a 1,6-ring closure of (R)-NPP to the bisabolyl cation G. Proceeding with a 1,2-hydride shift to H, the key step is a 1,6-proton shift to give the tertiary cation I. This idea is derived from a very similar proton transfer starting from the

Quinolines from the cyclocondensation of isatoic anhydride with ethyl acetoacetate: preparation of ethyl 4-hydroxy-2-methylquinoline-3-carboxylate and derivatives

• Nicholas G. Jentsch,
• Jared D. Hume,
• Emily B. Crull,
• Samer M. Beauti,
• Amy H. Pham,
• Julie A. Pigza,
• Jacques J. Kessl and
• Matthew G. Donahue

Beilstein J. Org. Chem. 2018, 14, 2529–2536, doi:10.3762/bjoc.14.229

• intramolecular 6-exo-trig cyclization and subsequent proton transfer to the aminal oxygen D. Elimination of the 2-hydroxy group from D then affords the 4-quinolone E that tautomerizes via [1,5]-hydride shift to form quinoline 10. Given the success of employing ethyl acetoacetate in the quinoline

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

• sesquiterpenes arising via cation A with the main product trichodiene was previously reported from Fusarium [34]. The compounds 10 and 11 are directly formed from this cation by deprotonation. A 1,3-hydride shift to B and deprotonation yields 8 and γ-curcumene (C). Instead of the latter compound its autoxidation

• from A by a 1,2-hydride shift to the homobisabolyl cation I, cyclisation to J, and deprotonation. The second group of biosynthetically related sesquiterpenes is composed of daucene (19), the main component in the headspace extracts from A. fischeri, and its congeners dauca-4(11),8-diene (17

• ), isodaucene (18), and trans-dauca-8,11-diene (20). The biosynthesis of these compounds requires isomerisation of FPP to NPP, followed by cyclisation to K that results in 17 and 18 by deprotonation (Scheme 3). A 1,2-hydride shift to L and loss of a proton explains the main product 19. For compound 20 a

CF₃SO₂X (X = Na, Cl) as reagents for trifluoromethylation, trifluoromethylsulfenyl-, -sulfinyl- and -sulfonylation. Part 1: Use of CF₃SO₂Na

• Hélène Guyon,
• Hélène Chachignon and
• Dominique Cahard

Beilstein J. Org. Chem. 2017, 13, 2764–2799, doi:10.3762/bjoc.13.272

• 27, which was reduced into 28 prior to be converted into nitrogen heterocycles via [1,3]-hydride shift and cyclisation steps (Scheme 12). The reaction was regioselective and had a broad scope. This application of alkene trifluoromethylation provided a convenient entry to trifluoromethylated nitrogen

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

• configuration, thereby facilitating an intramolecular cyclization to a cyclodeca-1,5-diene by electrophilic attack of the allylic carbocation onto the corresponding double bond. A 1,3-hydride shift by Wagner–Meerwein rearrangement followed by another cyclization would then give rise to an octahydronaphthalene

Synthesis of ergostane-type brassinosteroids with modifications in ring A

• Vladimir N. Zhabinskii,
• Darya A. Osiyuk,
• Yuri V. Ermolovich,
• Natalia M. Chaschina,
• Tatsiana S. Dalidovich,
• Miroslav Strnad and
• Vladimir A. Khripach

Beilstein J. Org. Chem. 2017, 13, 2326–2331, doi:10.3762/bjoc.13.229

• stereospecific C(3) → C(2)-hydride shift/elimination process [30]. So, tosylation of the diol 14 occurred regioselectively at the equatorial C-2 hydroxy group to give monotosylate 30, which upon heating in pyridine, yielded compound 31 (Scheme 6). Its treatment with KOH in methanol led to 24-epi-3

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

• deprotonation with occasional hydration at the C8 position of the carbocation intermediate which yields hydroxylated diphosphate products [62]. MvCPS1, however, catalyzes a C9–C8 hydride shift preceding hydration resulting in the labdane-type diterpene precursor for the antidiabetic marrubiin [63]. Double

Nucleophilic and electrophilic cyclization of N-alkyne-substituted pyrrole derivatives: Synthesis of pyrrolopyrazinone, pyrrolotriazinone, and pyrrolooxazinone moieties

• Işıl Yenice,
• Sinan Basceken and
• Metin Balci

Beilstein J. Org. Chem. 2017, 13, 825–834, doi:10.3762/bjoc.13.83

• form the corresponding products by attack of lone pair electrons of the internal nitrogen or terminal nitrogen atoms, respectively. The 6-endo-dig cyclization follows only a proton shift to yield pyrrolopyrazinone skeleton 12, while 6-exo-dig follows first a proton shift and then an [1,3]-hydride shift

Selective and eco-friendly procedures for the synthesis of benzimidazole derivatives. The role of the Er(OTf)₃ catalyst in the reaction selectivity

• Natividad Herrera Cano,
• Jorge G. Uranga,
• Mónica Nardi,
• Antonio Procopio,
• Daniel A. Wunderlin and
• Ana N. Santiago

Beilstein J. Org. Chem. 2016, 12, 2410–2419, doi:10.3762/bjoc.12.235

• effective electrophilic activating agent for the formation of the bisimine and promotes the subsequent steps (intramolecular nucleophilic attack and the following 1,3-hydride shift), finally affording the 1,2-disubstituted imidazoles (b). In contrast, path ii is a non-catalyzed reaction. In path ii, when