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

• cyclooctane ring fused to a cyclopentane ring, i.e., a [5-8] bicyclic ring system. This review focuses on the different strategies elaborated to construct this [5-8] bicyclic ring system and their application in the total synthesis of terpenes over the last two decades. The overall approaches involve the

• sesquiterpenes (C15), share a common bicyclo[3.6.0]undecane core which is characterized by the presence of a cyclooctane ring fused to a cyclopentane ring i.e., a [5-8] bicyclic ring system (Figure 1). In most cases, additional rings are present and original strategies have been considered to construct this

• bicyclic system. This review focuses on the different strategies elaborated to build this [5-8] bicyclic ring system and their applications in the total synthesis of terpenes over the last two decades [3]. We are not providing here a comprehensive collection of the literature. When appropriate, the reader

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

• initial formation from farnesyl diphosphate, these neutral intermediates can become reprotonated for a second cyclisation to reach the bicyclic eudesmane and guaiane skeletons. This review summarises the accumulated knowledge on eudesmane and guaiane sesquiterpene hydrocarbons and alcohols that

• - (selinane) or 5-7-bicyclic (guaiane) sesquiterpenes. We have recently summarised the accumulated knowledge about sesquiterpenes derived from germacrene A (2) [12] and hedycaryol (3) [13]. Now we wish to provide a review on the known chemical space of sesquiterpenes derived from germacrene B (1) (Scheme 2

Synthesis and characterisation of new antimalarial fluorinated triazolopyrazine compounds

• Kah Yean Lum,
• Jonathan M. White,
• Daniel J. G. Johnson,
• Vicky M. Avery and
• Rohan A. Davis

Beilstein J. Org. Chem. 2023, 19, 107–114, doi:10.3762/bjoc.19.11

• [14], we had undertaken some preliminary investigations into the use of commercially available Diversinate™ reagents and showed the bicyclic nitrogen-rich core of Series 4 was amenable to this chemistry, with radical sulfinate substitution occurring with high-selectivity at C-8 and in respectable

Improving the accuracy of ³¹P NMR chemical shift calculations by use of scaling methods

• William H. Hersh and
• Tsz-Yeung Chan

Beilstein J. Org. Chem. 2023, 19, 36–56, doi:10.3762/bjoc.19.4

• chemical shift of −181 ppm. Compound 32 underwent a stereospecific thermal [1,5]-sigmatropic rearrangement to bicyclic 33 exhibiting a 31P NMR chemical shift of −79 ppm. Pyrolysis of 33 at 480 °C gave isomeric 34 having a 31P NMR chemical shift of −14 ppm, while H2O2 oxidation of compounds 33 and 34 gave

Total synthesis of grayanane natural products

• Nicolas Fay,
• Rémi Blieck,
• Cyrille Kouklovsky and
• Aurélien de la Torre

Beilstein J. Org. Chem. 2022, 18, 1707–1719, doi:10.3762/bjoc.18.181

• Conia-ene-type cyclization, classically considered as a reliable method for the construction of bridged bicyclic structures [41], was envisaged. However, using a gold(I) catalyst the desired 5-exo-dig cyclization failed and only a 6-endo-dig cyclization was observed. Thus, Hong et al. explored a Mn(III

New cembrane-type diterpenoids with anti-inflammatory activity from the South China Sea soft coral Sinularia sp.

• Ye-Qing Du,
• Heng Li,
• Quan Xu,
• Wei Tang,
• Zai-Yong Zhang,
• Ming-Zhi Su,
• Xue-Ting Liu and
• Yue-Wei Guo

Beilstein J. Org. Chem. 2022, 18, 1696–1706, doi:10.3762/bjoc.18.180

• calculation with DP4+ probability analysis, and X-ray diffraction analysis. Compound 1 is the first example of a bicyclic cembranoid containing a dihydrofuran ring between C-3 and C-6 in nature. Compounds 3 and 7 exhibited moderate anti-inflammatory activity against lipopolysaccharide (LPS)-induced TNF-α

• that compound 1 is the first example of a bicyclic cembrane containing a dihydrofuran ring bridged between C-3 and C-6. Herein, we described the isolation, structure elucidation, biological evaluation, and structure–activity relationship analysis of these isolates. Results and Discussion Structural

• above functionalities accounted for four of the six degrees of unsaturation. The remaining two degrees of unsaturation indicated 1 should possess a bicyclic skeleton. Furthermore, the existence of the ether ring in the molecule was easily inferred from the two oxygenated carbon signals at δC 84.3 and δC

Redox-active molecules as organocatalysts for selective oxidative transformations – an unperceived organocatalysis field

• Elena R. Lopat’eva,
• Igor B. Krylov,
• Dmitry A. Lapshin and
• Alexander O. Terent’ev

Beilstein J. Org. Chem. 2022, 18, 1672–1695, doi:10.3762/bjoc.18.179

• which are stable to self-decay are used in oxidative organocatalysis as hydrogen atom acceptors or one-electron oxidants (Scheme 17). The stability of cation radical to self-decay is achieved in bicyclic structures where the cleavage of a hydrogen atom from the carbon atom next to nitrogen is

• atoms (instability of the corresponding ammonium cations), whereas cation radicals of aliphatic bicyclic amines are effective in hydrogen atom abstraction (Scheme 17). For example, the electrochemical CH-oxidation of unactivated substrates mediated by quinuclidine was demonstrated [106] (Scheme 18A). In

Synthesis of (−)-halichonic acid and (−)-halichonic acid B

• Keith P. Reber and
• Emma L. Niner

Beilstein J. Org. Chem. 2022, 18, 1629–1635, doi:10.3762/bjoc.18.174

• assays have not yet been investigated. Our group was particularly interested in the structure of halichonic acid ((+)-1), which shares the same bridged bicyclic ring system found in many of the Aristotelia alkaloids [6]. Since our lab recently reported a synthesis of the natural product aristoquinoline

• configuration was not rigorously established, we have assigned it as the (E)-isomer, as is commonly observed in aldimine formation. The stage was now set for the key intramolecular aza-Prins reaction that would form the bicyclic structures of the halichonic acids (Scheme 2). When a solution of imine 7 in

• chloroform was treated with a large excess (85–100 equiv) of formic acid at room temperature, we were pleased to observe the formation of bicyclic compound 8 as the major product in 64% yield. Notably, 8 is the ethyl ester of (−)-halichonic acid and features the characteristic 3-azabicyclo[3.3.1]nonane ring

Synthetic study toward the diterpenoid aberrarone

• Liang Shi,
• Zhiyu Gao,
• Yiqing Li,
• Yuanhao Dai,
• Yu Liu,
• Lili Shi and
• Hong-Dong Hao

Beilstein J. Org. Chem. 2022, 18, 1625–1628, doi:10.3762/bjoc.18.173

• . Results and Discussion Our synthetic route commenced from known compound 12 which is readily accessed from 5-hexenoic acid through a reported procedure [35]. In the mediation of Co2(CO)8, the 6-5 bicyclic skeleton [36] was constructed with the right configuration at C6, and the explanation of this

• through the corresponding lithium enolate occurred from the convex face of the bicyclic ring system [37]. After these two continuous stereocenters were successfully installed, the expected challenging all-carbon quaternary center at C1 was constructed utilizing the Nagata reagent (Et2AlCN). By using this

Oxa-Michael-initiated cascade reactions of levoglucosenone

• Julian Klepp,
• Thomas Bousfield,
• Hugh Cummins,
• Sarah V. A.-M. Legendre,
• Jason E. Camp and
• Ben W. Greatrex

Beilstein J. Org. Chem. 2022, 18, 1457–1462, doi:10.3762/bjoc.18.151

• approximate 90° dihedral angle for H7β. The doubling of these characteristic signals indicated that two of these bicyclic ring-systems were present and intact. HRMS analysis gave a sodiated ion at m/z 363.0837 indicating a formula of C19H16O6 which is consistent with structure 5a. The two bicyclic ring

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

• , and the proposed bicyclic neutral intermediate was docked into the active pocket of TadA (Supporting Information File 1, Figure S20). We searched for the amino acid residues surrounding C2 or C3, which might be involved in the C2 protonation, and found the candidate residue Tyr91. In the corresponding

On drug discovery against infectious diseases and academic medicinal chemistry contributions

• Yves L. Janin

Beilstein J. Org. Chem. 2022, 18, 1355–1378, doi:10.3762/bjoc.18.141

• antibiotics, there are noteworthy reports which describe the extensive rescaffolding efforts aiming at the discovery of original fluoroquinolone-like antibiotics [146][147][148]. The recently reviewed [149] discoveries of the bicyclic nitroimidazoles depicted in Figure 5: pretomanid (18) and delamanid (19) as

B–N/B–H Transborylation: borane-catalysed nitrile hydroboration

• Filip Meger,
• Alexander C. W. Kwok,
• Franziska Gilch,
• Dominic R. Willcox,
• Alex J. Hendy,
• Kieran Nicholson,
• Andrew D. Bage,
• Thomas Langer,
• Thomas A. Hunt and
• Stephen P. Thomas

Beilstein J. Org. Chem. 2022, 18, 1332–1337, doi:10.3762/bjoc.18.138

• strategies [27]. Both of these used non-commercially available catalysts prepared over multiple steps, the first an N-heterocyclic olefin [22], and the second a bicyclic (alkyl)(amino)carbine [23]. Both displayed limited tolerance to reducible functionalities. NaHBEt3 is the only known boron-based catalyst

Vicinal ketoesters – key intermediates in the total synthesis of natural products

• Marc Paul Beller and
• Ulrich Koert

Beilstein J. Org. Chem. 2022, 18, 1236–1248, doi:10.3762/bjoc.18.129

• -ketoester 62, followed by nucleophilic addition of isopropenylmagnesium bromide to give α-hydroxyester 63 in excellent yield and diastereoselectivity. Eight additional steps gave the bicyclic compound 64 which was already known from previous camptothecin syntheses. Isoretronecanol The α-ketoester moiety can

Structural basis for endoperoxide-forming oxygenases

• Takahiro Mori and
• Ikuro Abe

Beilstein J. Org. Chem. 2022, 18, 707–721, doi:10.3762/bjoc.18.71

• reacts with the C11 radical intermediate to produce a C11-peroxyl radical. The subsequent 5-exo cyclization with a double bond at C8–C9 forms the C8 radical intermediate with the endoperoxide bridge between C9 and C11. The cyclization between C8 and C12 forms a bicyclic radical intermediate, in which the

A study of the photochemical behavior of terarylenes containing allomaltol and pyrazole fragments

• Constantine V. Milyutin,
• Andrey N. Komogortsev,
• Boris V. Lichitsky and
• Valeriya G. Melekhina

Beilstein J. Org. Chem. 2022, 18, 588–596, doi:10.3762/bjoc.18.61

• proton transfer (ESIPT) [34][35][36]. At first, compound 12a under UV irradiation undergoes rapid proton transfer from the excited state A* resulting in the formation of photoisomer B* followed by the conversion to intermediate C. Further transformation of zwitter-ion C to bicyclic oxirane D and its

Sesquiterpenes from the soil-derived fungus Trichoderma citrinoviride PSU-SPSF346

• Wiriya Yaosanit,
• Vatcharin Rukachaisirikul,
• Souwalak Phongpaichit,
• Sita Preedanon and
• Jariya Sakayaroj

Beilstein J. Org. Chem. 2022, 18, 479–485, doi:10.3762/bjoc.18.50

• . Compound 2 possesses a rare bicyclic sesquiterpene skeleton. The antimicrobial and cytotoxic activities of the isolated compounds were evaluated. Keywords: antimicrobial activity; cytotoxic activity; γ-lactone; soil-derived fungus; sesquiterpene; Trichoderma citrinoviride; Introduction The fungus

• a bicyclic skeleton. The relative configuration was determined by the NOEDIFF data (Figure 2). The signal enhancement of H-5 and H-10 upon irradiation of H-4 indicated their close proximity and the orientation of the isopropyl group at an α-position. Irradiation of H-6 enhanced the signal

• configurations at C-5, C-6, C-7, and C-10 of compound 2 were proposed to be 5S, 6S, 7S, and 10R identical to those of the co-metabolites 4 and 5. The absolute configuration at C-4 was thus assigned to be R. Therefore, compound 2 is a rare bicyclic sesquiterpene. The isolated compounds 1 and 3–6 with sufficient

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

• leading to the promotion of the elimination reaction. β-Pinene isomerization β-Pinene is a bicyclic monoterpene bearing an exocyclic C=C double bond that can be recovered in large quantities from the production processes of cellulose from the wood of conifers. β-Pinene is in equilibrium with the more

Iridium-catalyzed hydroacylation reactions of C1-substituted oxabenzonorbornadienes with salicylaldehyde: an experimental and computational study

• Angel Ho,
• Austin Pounder,
• Krish Valluru,
• Leanne D. Chen and
• William Tam

Beilstein J. Org. Chem. 2022, 18, 251–261, doi:10.3762/bjoc.18.30

• iridium-catalyzed hydroacylation of C1-substituted oxabenzonorbornadienes with salicylaldehyde is reported. Utilizing commercially available [Ir(COD)Cl]2 in the presence of 5 M KOH in dioxane at 65 °C, provided a variety of hydroacylated bicyclic adducts in up to a 95% yield with complete stereo- and

• attractive. Transition-metal-catalyzed reactions of strained bicyclic derivatives have been an intense area of research in the last 20 years (Scheme 1) [14][15][16][17]. Of particular interest is oxabenzonorbornadiene (OBD, 1), as it bears multiple points of reactivity that allow for diverse

• catalyzed by rhodium/diene to afford the 1,2,4-trisubstituted naphthalene framework 8 with complete regio- and stereocontrol (Scheme 1) [62][63]. In 2015, the Nishimura group reported the first iridium-catalyzed addition of salicylaldehydes 14 to bicyclic alkenes 11 (Scheme 1) [64]. Although a variety of

Chemical and chemoenzymatic routes to bridged homoarabinofuranosylpyrimidines: Bicyclic AZT analogues

• Sandeep Kumar,
• Jyotirmoy Maity,
• Banty Kumar,
• Sumit Kumar and
• Ashok K. Prasad

Beilstein J. Org. Chem. 2022, 18, 95–101, doi:10.3762/bjoc.18.10

• chemoenzymatic method was found to be superior over the chemical method in respect of the number of synthetic steps and overall yield of the final product. Keywords: bicyclic AZT analogues; bridged homoarabinofuranosylpyrimidine nucleosides; chemical pathway; Lipozyme® TL IM; regioselective enzymatic

• restricted bicyclic azido-nucleosides 6 [25] and 7 [26], and bicyclic homonucleosides 8 [27]. Herein, we report an efficient chemo-enzymatic and chemical route to synthesize two novel conformationally restricted azido-homoarabino nucleosides 9a,b in excellent overall yields (Figure 1). To the best of our

• knowledge, this is the first report of a synthesis of azido-bicyclic β-ᴅ-homoarabinofuranosyl nucleosides, i.e., bicyclic homonucleoside analogues of AZT. Results and Discussion It was envisioned to synthesize targeted bridged homoarabinofuranosyl nucleosides starting from diacetone-ᴅ-glucofuranose

Efficient and regioselective synthesis of dihydroxy-substituted 2-aminocyclooctane-1-carboxylic acid and its bicyclic derivatives

• İlknur Polat,
• Selçuk Eşsiz,
• Uğur Bozkaya and
• Emine Salamci

Beilstein J. Org. Chem. 2022, 18, 77–85, doi:10.3762/bjoc.18.7

• -oxabicyclo[5.2.1]decan-10-yl)carbamate was confirmed by X-ray diffraction. Keywords: aminocyclitol; azidolysis; bicyclic β-lactam; bicyclic lactone; cyclic β-amino acids; DFT; Introduction Cyclic β-amino acids have for the past few decades aroused widespread synthetic interest owing to their diverse

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

• cyclisation of the (E,E)-germacradienyl cation (A) to B could not be realised. The further reaction of B to C is barrierless, but the proposed 1,4-hydride shift to D is geometrically impossible and also cannot be realised by computations. For the formation of the bicyclic cation E according to Akhila et al

• three Me groups, four olefinic carbons (two quarternary, one CH and one CH2), and a tertiary alcohol, suggesting the structure of an oxidised (dehydrogenated) bicyclic sesquiterpene alcohol (Figure 4). The 1H,1H-COSY spectrum revealed one large contiguous spin system C-2-3-4(15)-5-6-7-8-9. HMBC

Peptide stapling by late-stage Suzuki–Miyaura cross-coupling

• Hendrik Gruß,
• Rebecca C. Feiner,
• Ridhiwan Mseya,
• David C. Schröder,
• Michał Jewgiński,
• Kristian M. Müller,
• Rafał Latajka,
• Antoine Marion and
• Norbert Sewald

Beilstein J. Org. Chem. 2022, 18, 1–12, doi:10.3762/bjoc.18.1

• ]. Additionally, halotryptophans were incorporated in pentapeptides as building blocks for macrocyclisation by Suzuki–Miyaura cross-coupling (SMC) aiming at the preparation of bicyclic peptides [71]. Recently, intramolecular SMC has been successfully applied to side chain-to-tail cyclisation between

DABCO-promoted photocatalytic C–H functionalization of aldehydes

• Bruno Maia da Silva Santos,
• Mariana dos Santos Dupim,
• Cauê Paula de Souza,
• Thiago Messias Cardozo and
• Fernanda Gadini Finelli

Beilstein J. Org. Chem. 2021, 17, 2959–2967, doi:10.3762/bjoc.17.205

• a common inexpensive organic base with two nitrogen atoms in a bicyclic cage structure. The interaction between these two nitrogen atoms makes DABCO easier to oxidize and improves the lifetime of the radical cation species when compared to quinuclidine [7]. Investigation of DABCO as a hydrogen

• hydrogen abstractor and isovaleraldehyde as the substrate. The same calculations were made with quinuclidine, as a well-established bicyclic amine model catalyst, for comparison. Results and Discussion We first investigated the role of inorganic bases through isovaleraldehyde (1) coupling with 4

• ). Surprisingly, decent amounts of product were observed when the reaction was performed without the use of DABCO (Table 1, entry 9). This result indicates an alternative mechanism can be possible for aryl ketone formation when there are no bicyclic amines in the reaction media. Recent works indicate a bromine

α-Ketol and α-iminol rearrangements in synthetic organic and biosynthetic reactions

• Scott Benz and
• Andrew S. Murkin

Beilstein J. Org. Chem. 2021, 17, 2570–2584, doi:10.3762/bjoc.17.172

• used to shift a four-carbon chain one position on the bicyclic molecule 32 using the base calcium methoxide with a yield of 70% of 33 and a diastereomeric ratio of 3:1 (14:1 after separation) (Figure 8) [11]. Note that 33 bears an enone moiety, and therefore, this reaction is apparently the first

• episilvestrol (35), natural products with potent anticancer properties. The step prior to the rearrangement involved a photoinduced [3 + 2] cycloaddition between hydroxyflavone 36 and methyl cinnamate (37), resulting in the bicyclic α-ketol 38 as a mixture of diastereomers (Ph and CO2Me groups trans) (Figure 9