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

Silica gel and microwave-promoted synthesis of dihydropyrrolizines and tetrahydroindolizines from enaminones

• Robin Klintworth,
• Garreth L. Morgans,
• Stefania M. Scalzullo,
• Charles B. de Koning,
• Willem A. L. van Otterlo and
• Joseph P. Michael

Beilstein J. Org. Chem. 2021, 17, 2543–2552, doi:10.3762/bjoc.17.170

• . Yields of the bicyclic products were generally above 75%. The analogous microwave-assisted reaction to produce ethyl 2-aryl-5,6,7,8-tetrahydroindolizine-3-carboxylates from (E)-ethyl 2-[2-(2-oxo-2-arylethylidene)piperidin-1-yl]acetates failed in nonpolar solvents, but occurred in ethanol at lower

Advances in mercury(II)-salt-mediated cyclization reactions of unsaturated bonds

• Sumana Mandal,
• Raju D. Chaudhari and
• Goutam Biswas

Beilstein J. Org. Chem. 2021, 17, 2348–2376, doi:10.3762/bjoc.17.153

• [46]. A similar type of reaction methodology was employed for the formation of a bicyclic nucleoside analog. 4'-C-vinylribofuranoside derivative 21 on treatment with Hg(TFA)2 followed by reduction with NaBH4 leads to the formation of bicyclic nucleoside derivative 22 (Scheme 10) [49]. Pyrrolidine and

• depending on the reaction conditions (Scheme 13) [53][58]. Cyclization of 4-cycloocten-1-ol (35) with Hg(OAc)2 resulted in formation of two types of fused bicyclic products, 9-oxabicyclo[3.3.1]nonane (36) and 9-oxabicyclo[4.2.1]nonane (37) (Scheme 14) [59][60]. It was observed that the regioselective

• -amino alcohol 38 leading to the formation of (1R,2R,6R)-9-benzyl-9-azabicyclo[4.2.1]nonan-2-ol (39). The bicyclic derivative 39 through the number of consequent reactions formed a highly potent (+)/(−)-pyrido[3,4-b]homotropane (40), a bridged nicotinoid (Scheme 15) [61]. Similarly, precursor 41 at room

Photoredox catalysis in nickel-catalyzed C–H functionalization

• Lusina Mantry,
• Rajaram Maayuri,
• Vikash Kumar and
• Parthasarathy Gandeepan

Beilstein J. Org. Chem. 2021, 17, 2209–2259, doi:10.3762/bjoc.17.143

• efficient HAT photocatalyst to perform the desired C–H abstraction (Scheme 10) [62]. The catalytic reaction required near-ultraviolet light irradiation (Kessil 34 W 390 nm LEDs) and the exclusion of both oxygen and water to the success of the reaction. A variety of cyclic, acyclic, and bicyclic aliphatic

A study on selective transformation of norbornadiene into fluorinated cyclopentane-fused isoxazolines

• Zsanett Benke,
• Attila M. Remete and
• Loránd Kiss

Beilstein J. Org. Chem. 2021, 17, 2051–2066, doi:10.3762/bjoc.17.132

• Abstract This work presents an examination of the selective functionalization of norbornadiene through nitrile oxide 1,3-dipolar cycloaddition/ring-opening metathesis (ROM)/cross-metathesis (CM) protocols. Functionalization of commercially available norbornadiene provided novel bicyclic scaffolds with

• of natural products (especially macrocycles) [12], alkaloids [13], amino acids and functionalized biomolecules such as peptides [14][15][16][17][18][19][20] or various drugs [21]. Due to the ring strain, bicyclic systems and derivatives, such as norbornadiene derivatives can easily be converted

• view of chemodifferentiation. The reactions were performed with various olefin metathesis catalysts to find the most optimal conditions (Figure 1). The starting divinyl-substituted bicyclic isoxazolines were synthesized according to literature methods, as shown in Figure 2, utilizing nitrile oxide

Asymmetric organocatalyzed synthesis of coumarin derivatives

• Natália M. Moreira,
• Lorena S. R. Martelli and
• Arlene G. Corrêa

Beilstein J. Org. Chem. 2021, 17, 1952–1980, doi:10.3762/bjoc.17.128

• , respectively, has proved to be the most effective for the promotion of the conjugate addition of 4-hydroxycoumarins 1 to 2-hydroxycinnamaldehydes 109, leading to chiral bridged bicyclic acetal products 110 with high ee (Scheme 35). The mechanistic study performed showed that possibly the phenolic hydroxy group

Regioselective N-alkylation of the 1H-indazole scaffold; ring substituent and N-alkylating reagent effects on regioisomeric distribution

• Ryan M. Alam and
• John J. Keating

Beilstein J. Org. Chem. 2021, 17, 1939–1951, doi:10.3762/bjoc.17.127

• electrophiles, while maintaining a high degree of N-1 regioselectivity. Keywords: indazole; N-alkylation; regioselective; sodium hydride; tetrahydrofuran; Introduction Indazole (benzo[c]pyrazole) is an aromatic bicyclic heterocycle and can be viewed as a (bio)isostere of indole [1]. While only a few naturally

• -alkylation, varying reaction conditions, such as the choice of base [17][21], acid [22], solvent, and/or N-alkylating reagent may also facilitate regioselective indazole N-alkylation [23][24][25]. Bookser et al. have investigated the N-alkylation of related bicyclic azolo-fused-ring heterocycles, including

On the application of 3d metals for C–H activation toward bioactive compounds: The key step for the synthesis of silver bullets

• Renato L. Carvalho,
• Amanda S. de Miranda,
• Mateus P. Nunes,
• Roberto S. Gomes,
• Guilherme A. M. Jardim and
• Eufrânio N. da Silva Júnior

Beilstein J. Org. Chem. 2021, 17, 1849–1938, doi:10.3762/bjoc.17.126

• ). These bicyclic structures may present unique biological activities including neuroprotective properties (15), as it was recently reported by Joubert and co-workers [58], as well as acting as agonists of nicotinic receptors (16) [59], representing an alternative option for the treatment of cigarette

• free amine derivative was produced in 43% overall yield. The 2,8-dioxabicyclo[3.3.1]nonane skeleton is contained in biflavonoids and was shown to exhibit many medicinal activities like antiviral, anti-inflammatory and antitumor properties. The bicyclic compound 49 was aminated at the benzylic position