Cu(OTf)₂-catalyzed multicomponent reactions

• Sara Colombo,
• Camilla Loro,
• Egle M. Beccalli,
• Gianluigi Broggini and
• Marta Papis

Beilstein J. Org. Chem. 2025, 21, 122–145, doi:10.3762/bjoc.21.7

• the triple bond furnishes the furo-ring and the final oxidation affords the tricyclic product 22. Substituted quinolines 23 were obtained in a convenient solvent-free multicomponent reaction starting from electron-rich or electron-poor anilines, alkyl or arylaldehydes and terminal alkynes, performing

• corresponding saturated compounds. Subsequent nucleophilic addition of the cyclic vinyl ether to the iminium salt generates an intermediate XXI susceptible of intramolecular electrophilic attack to give a tricyclic structure XXII. The final deprotonation provides the desired product 24. The multicomponent

Non-covalent organocatalyzed enantioselective cyclization reactions of α,β-unsaturated imines

• Sergio Torres-Oya and
• Mercedes Zurro

Beilstein J. Org. Chem. 2024, 20, 3221–3255, doi:10.3762/bjoc.20.268

• furnish the cycloaddition product 13a. In 2019, Xu’s group published a bifunctional squaramide-catalyzed inverse electron demand aza-Diels–Alder reaction of saccharin-derived 1-azadienes 14 and azlactones 15 [27]. This methodology enables chiral tricyclic derivatives 16 bearing a quaternary amino acid

• azlactones through H-bond interactions with the squaramide moiety. The activated complex undergoes a [4 + 2] cyclization, through the Si-face attack of the enolate to the 1-azadiene leading to intermediate A which undergoes tautomerization and protonation to yield the chiral tricyclic derivative 16. To

• further investigate the potential utility of this methodology, a gram scale experiment was conducted affording product 16f in a good yield and a slight decrease of the enantioselectivity. Additionally, a derivatization of product 16f by hydrogenation was carried out to yield the tricyclic piperidine 17

Efficacy of radical reactions of isocyanides with heteroatom radicals in organic synthesis

• Akiya Ogawa and
• Yuki Yamamoto

Beilstein J. Org. Chem. 2024, 20, 2114–2128, doi:10.3762/bjoc.20.182

• synthesize tricyclic pyridine derivatives in a single step (Scheme 22) [75]. Zhang and Yu et al. also developed a cyclization of 2-isocyanobiaryls using a photoredox system [76][77][78][79][80] in which carbon radicals were generated by a photoredox reaction of α-bromopropanoates under visible light

The Groebke–Blackburn–Bienaymé reaction in its maturity: innovation and improvements since its 21st birthday (2019–2023)

• Cristina Martini,
• Muhammad Idham Darussalam Mardjan and
• Andrea Basso

Beilstein J. Org. Chem. 2024, 20, 1839–1879, doi:10.3762/bjoc.20.162

• interesting strategy for the construction of new tricyclic systems (Scheme 29). Adducts 92 were prepared from 3-phenylpropiolaldehyde (90), benzylisocyanides 91 and 2-aminopyridines via a HClO4-promoted GBB reaction, then, under thermal conditions, in the presence of tetrabutylammonium bromide, an

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

• considered a remarkable example of utilizing the complementarity between chemical and enzymatic transformations (Scheme 1 and Scheme 2). The cotylenin and fusicoccin families comprise structurally related diterpene glucosides with a 5/8/5 fused tricyclic aglycon and a sugar moiety linked through the C9

• prenyltransferase (PT) domain located at the C-terminus of BscA (Scheme 2A). Subsequently, the terpene cyclase (TC) domain at the N-terminal of BscA generates fusicocca-2,10(14)-diene (6), which bears the common 5/8/5 fused tricyclic scaffold common to this natural products family. Sequential oxidative conversions

• tricyclic scaffold was produced through scalable chemical synthesis. Subsequently, in vitro enzymatic oxidative functionalizations were carried out during the oxidation stage. The exploration of Bsc9 homologs and directed evolution expanded the scope of substrates of the dioxygenase beyond the natural

Rapid construction of tricyclic tetrahydrocyclopenta[4,5]pyrrolo[2,3-b]pyridine via isocyanide-based multicomponent reaction

• Xiu-Yu Chen,
• Ying Han,
• Jing Sun and
• Chao-Guo Yan

Beilstein J. Org. Chem. 2024, 20, 1436–1443, doi:10.3762/bjoc.20.126

• ). The reaction in toluene, methylene dichloride or acetonitrile at room temperature afforded an unexpected tricyclic compound 4a in 12–18% yields (Table 1, entries 4–6). 1H NMR spectra clearly indicated that two molecules of dimethyl but-2-ynedioates took part in the reaction. The yields of the product

• 4a slightly increased to 29–45% yields when the reaction was carried out at elevated temperature in toluene, methylene dichloride or acetonitrile (Table 1, entries 7–10). When the reaction was carried out in refluxing acetonitrile, the tricyclic compound 4a can be obtained in 47% yield (Table 1

• -ynedioate usually gave the expected tricyclic products in good yields. However, the reaction with diethyl but-2-ynedioate afforded products 4p, 4r and 4t in moderate to lower yields. The 5,6- unsubstituted dihydropyridines with various substituents showed marginal effects on the yields. These results

Computation-guided scaffold exploration of 2E,6E-1,10-trans/cis-eunicellanes

• Zining Li,
• Sana Jindani,
• Volga Kojasoy,
• Teresa Ortega,
• Erin M. Marshall,
• Khalil A. Abboud,
• Sandra Loesgen,
• Dean J. Tantillo and
• Jeffrey D. Rudolf

Beilstein J. Org. Chem. 2024, 20, 1320–1326, doi:10.3762/bjoc.20.115

• collected NMR data of 1 in chloroform [5], but when we dissolved 2 in chloroform for NMR, it cyclized into two 6/6/6-tricyclic diterpenes (5 and 6) [7]. We discovered that 2 was much more sensitive to acid than 1 and eventually took advantage of its reactivity to determine its absolute configuration [7

• ]. Here, we sought to understand the molecular basis of chemical and thermal reactivities of these diterpene skeletons. We also took advantage of their intrinsic chemical properties to transform the eunicellanes in functionalized tricyclic skeletons of natural product importance. Results and Discussion

• Ring fusion configuration does not affect protonation-induced cyclization Our initial observation that albireticulene (2) was unstable in chloroform, resulting in two tricyclic isomers gersemienes A (5) and B (6) [7], while benditerpetriene (1) was stable [5], led us to investigate the protonation

Sustainable tandem acylation/Diels–Alder reaction toward versatile tricyclic epoxyisoindole-7-carboxylic acids in renewable green solvents

• Ayhan Yıldırım

Beilstein J. Org. Chem. 2024, 20, 1308–1319, doi:10.3762/bjoc.20.114

• second step of this reaction, regio- and stereochemically controlled intramolecular cyclization leads to the formation of versatile nitrogen-containing tricyclic systems. However, these useful organic transformations are usually carried out in highly toxic organic solvents such as benzene, toluene

• biocompatible solvents for IMDAF reactions. The corresponding tricyclic epoxyisoindole-7-carboxylic acids were obtained in less time and in higher yields than in reactions carried out in conventional toxic and volatile organic solvents. A challenge in the use of vegetable oils as solvents in organic

• maleamic acid precursors. Optimization of IMDAF cycloaddition using different solvents.a Synthesized tricyclic epoxyisoindole-7-carboxylic acidsa. Supporting Information Supporting Information File 88: Tables S1 and S2, Cartesian coordinates of the optimized structures and copies of NMR spectra.

Secondary metabolites of Diaporthe cameroonensis, isolated from the Cameroonian medicinal plant Trema guineensis

• Bel Youssouf G. Mountessou,
• Élodie Gisèle M. Anoumedem,
• Blondelle M. Kemkuignou,
• Yasmina Marin-Felix,
• Frank Surup,
• Marc Stadler and
• Simeon F. Kouam

Beilstein J. Org. Chem. 2023, 19, 1555–1561, doi:10.3762/bjoc.19.112

• derivative of alternariol, a heptaketide coumarin derivative with a fused tricyclic ring called dibenzo-α-pyrone [31][32]. Alternariol is one of the toxic metabolites isolated from Alternaria strains, that grow on various natural resources such as corn, rice, fruits, vegetables, oilseeds, juices, wins, and

Non-noble metal-catalyzed cross-dehydrogenation coupling (CDC) involving ether α-C(sp³)–H to construct C–C bonds

• Hui Yu and
• Feng Xu

Beilstein J. Org. Chem. 2023, 19, 1259–1288, doi:10.3762/bjoc.19.94

• tricyclic chromane nucleus from 8-hydroxyisochromanes and 1,3-dicarbonyl compounds in the presence of Cu(OTf)2 and T+BF4− (Scheme 7b) [57]. The strategy has a wide range of applications and is highly diastereoselective, making it an attractive strategy for synthesizing related natural products. The role of

Synthesis of imidazo[4,5-e][1,3]thiazino[2,3-c][1,2,4]triazines via a base-induced rearrangement of functionalized imidazo[4,5-e]thiazolo[2,3-c][1,2,4]triazines

• Dmitry B. Vinogradov,
• Alexei N. Izmest’ev,
• Angelina N. Kravchenko,
• Yuri A. Strelenko and
• Galina A. Gazieva

Beilstein J. Org. Chem. 2023, 19, 1047–1054, doi:10.3762/bjoc.19.80

• ][1,2,4]triazine or imidazo[4,5-e]thiazolo[2,3-c][1,2,4]triazine and the expansion of the thiazolidine ring to a thiazine core. The methodology proved to be effective for the preparation of a series of target compounds with different substituents in the tricyclic fragment. Examples of natural and

Photoredox catalysis enabling decarboxylative radical cyclization of γ,γ-dimethylallyltryptophan (DMAT) derivatives: formal synthesis of 6,7-secoagroclavine

• Alessio Regni,
• Francesca Bartoccini and
• Giovanni Piersanti

Beilstein J. Org. Chem. 2023, 19, 918–927, doi:10.3762/bjoc.19.70

• -dimethylallyltryptophan (DMAT) derivatives containing unactivated alkene moieties has been developed, providing green and efficient access to various six-, seven-, and eight-membered ring 3,4-fused tricyclic indoles. This type of cyclization, which was hitherto very difficult to comprehend in ergot biosynthesis and to

• no desired cyclized product was observed, an interesting aspect of this reaction was the access of an attractive, unusual, and highly functionalized 3,4-fused eight-membered tricyclic indole, whose ring closure would not have been possible or at least very difficult in the ground state [87][88][89

• functionalized 3,4-fused tricyclic indoles with medium-sized rings (seven and eight), which have been largely neglected in previous studies, can be synthesized by this new protocol. Notably, the reaction has been successfully applied in the formal synthesis of (±)-6,7-secoagroclavine, a key intermediate for a

Pyridine C(sp²)–H bond functionalization under transition-metal and rare earth metal catalysis

• Haritha Sindhe,
• Malladi Mounika Reddy,
• Karthikeyan Rajkumar,
• Akshay Kamble,
• Amardeep Singh,
• Anand Kumar and
• Satyasheel Sharma

Beilstein J. Org. Chem. 2023, 19, 820–863, doi:10.3762/bjoc.19.62

• tricyclic imidazonaphthyridinone derivative having antibacterial properties, with low catalyst loading (0.1 mol %) (Scheme 20b). Later, in 2014, the same authors, using an amide as directing group (DG), developed a protocol for the regioselective C3-alkenylation of pyridines through syn-addition of alkynes

Eschenmoser coupling reactions starting from primary thioamides. When do they work and when not?

• Lukáš Marek,
• Jiří Váňa,
• Jan Svoboda and
• Jiří Hanusek

Beilstein J. Org. Chem. 2023, 19, 808–819, doi:10.3762/bjoc.19.61

• (9a) or decomposition (Scheme 3 and Table 1). Table 1 shows that in both polar aprotic solvents without base and thiophile (entries 1 and 4) only tricyclic 5,5-dimethyl-2-phenyl-4,5-dihydrothiazolo[4,5-c]isoquinoline (8a) was formed probably through unstable intermediate (7a). Compound 7a can be

• also briefly investigated, but the corresponding salt 6b was not isolated. The reaction in DMF without any additive (16 h, rt) also led to tricyclic 5,5-dimethyl-2-methyl-4,5-dihydrothiazolo[4,5-c]isoquinoline (8b) but its isolated yield was only 40% in addition to thioacetamide (19%) and unidentified

• give the zwitterionic intermediates 6a,b'' necessary for successful ECR. On the other hand, without any base only thiazoles 7a,b are formed probably from isomeric forms 6a,b' of the starting salts 6a,b. In contrast to the tricyclic intermediate 16 formed from oxindole α-thioiminium salt (15), which in

Strategies in the synthesis of dibenzo[b,f]heteropines

• David I. H. Maier,
• Barend C. B. Bezuidenhoudt and
• Charlene Marais

Beilstein J. Org. Chem. 2023, 19, 700–718, doi:10.3762/bjoc.19.51

• ) [8][9][10]. Commercial pharmaceutical agents based on dibenzo[b,f]azepine (1a), or the 10,11-dihydro derivative thereof (2a), include imipramine (3) and clomipramine (4) (tricyclic antidepressants) [11][12][13][14], opipramol (5) (generalized anxiety disorder) [15] and carbamazepine (6) (seizure

• etherification entails the palladium or copper-catalysed formation of a carbon–heteroatom bond. Despite significant successes and facile access to the core tricyclic motif, access to dibenzo[b,f]heteropines with disparately substituted aromatic rings fused to the heterocyclic ring and varied substitution

• ]oxepine 54 and -azepine 55 derivatives via (i) Heck reaction and (ii) Buchwald–Hartwig-type etherification or amination. Double Buchwald–Hartwig amination and thioetherification in the synthesis of tricyclic azepines 60 and thiepines 52. Double Buchwald–Hartwig amination towards substituted

Enolates ambushed – asymmetric tandem conjugate addition and subsequent enolate trapping with conventional and less traditional electrophiles

• Péter Kisszékelyi and
• Radovan Šebesta

Beilstein J. Org. Chem. 2023, 19, 593–634, doi:10.3762/bjoc.19.44

• war against resistant bacteria strains. The tricyclic diterpene fungal metabolite (+)-pleuromutilin was isolated in 1951 [104]. Since then it has served as a starting point for developing new antibiotics, including semisynthetic derivatives effective against Gram-positive or even both types of

• in the first step by the phosphoramidite ligand L39 (92% ee, dr 1:1) (Scheme 60). Recently, Liu and co-workers reported the stereoselective synthesis of the tricyclic core of dodecahydrodibenzo[b,d]furan skeleton containing 12-epi-JBIR-23 and -24 [111]. Besides their intriguing complex structures

• :1). Additional transformation of compound 230 following an A–AB–ABC synthetic strategy resulted in the desired complex tricyclic skeleton opening the door for the total synthesis of 12-epi-JBIR-23/24 (Scheme 61). The sulfated β-glycoside peyssonnoside A was isolated only recently from the red algae

Transition-metal-catalyzed domino reactions of strained bicyclic alkenes

• Austin Pounder,
• Eric Neufeld,
• Peter Myler and
• William Tam

Beilstein J. Org. Chem. 2023, 19, 487–540, doi:10.3762/bjoc.19.38

• substituents on the nitrogens and sterically more hindered tricyclic adducts. Mechanistically, the authors proposed the reaction begins with a transmetalation of 2-cyanophenylboronic acid with the Rh(I) species resulting in 143. Upon association of 143 with the diazabicyclic alkene 132a a syn exo-addition

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

• ), respectively (Figure 1). Both families share the same core structure bearing a fused [5-8-5] tricyclic skeleton and they vary within their decorative functional groups. Over the years, many different syntheses to access compounds from the fusicoccan and ophiobolin family have been reported, with two strategies

• to the final [5-8-5] tricyclic core: The synthesis of the core bicyclic structure 12 of ophiobolin M (13) isolated from the fungus Cochliobolus heterostrophus and cycloaraneosene (14) firstly isolated in 1975 from the fungus Sordaria araneosa, was undertaken by Williams et al. in 2002 [15]. Compound

• 14 shares the common [5-8-5] tricyclic framework emblematic of the fusicoccan series, albeit cycloaraneosene (14) does not have any heteroatom (Scheme 1) [16]. Focusing on the B–C bicyclic fragment, they used diene 10, readily available from cyclopentane-1,3-dione (9), as the precursor for installing

Catalytic aza-Nazarov cyclization reactions to access α-methylene-γ-lactam heterocycles

• Bilge Banu Yagci,
• Selin Ezgi Donmez,
• Onur Şahin and
• Yunus Emre Türkmen

Beilstein J. Org. Chem. 2023, 19, 66–77, doi:10.3762/bjoc.19.6

• cyclization of 3,4-dihydroisoquinolines with α,β-unsaturated acyl chlorides gives tricyclic lactam products 7 in up to 79% yield with full diastereocontrol (dr = >99:1). The use of acyclic imines in a similar catalytic aza-Nazarov reaction with 20 mol % of AgOTf results in the formation of α-methylene-γ

• the synthesis of tricyclic α-methylene-γ-lactams 7 as single diastereomers and in good to high yields through the use of a catalytic amount of AgOTf (silver trifluoromethanesulfonate) as an anion-exchange agent (Scheme 1d) [35]. In this transformation, treatment of 3,4-dihydroisoquinolines 5 with acyl

• the reactivity of a thiophene-fused dihydropyridine as a cyclic imine. The tricyclic α-methylene-γ-lactam product 19k was obtained in 40% yield and as single diastereomer. It should be noted that due to the low solubility of the imine substrate in CH3CN, this reaction was carried out in CH2Cl2 at 23

Two-step continuous-flow synthesis of 6-membered cyclic iodonium salts via anodic oxidation

• Julian Spils,
• Thomas Wirth and
• Boris J. Nachtsheim

Beilstein J. Org. Chem. 2023, 19, 27–32, doi:10.3762/bjoc.19.2

• also been investigated as useful building blocks for the synthesis of larger diaryl-based molecules, (hetero)aromatic tricyclic systems, or new aryl-moieties [24][25]. Most methods that generate DIS utilize iodoarenes as starting materials [26][27]. In these one-pot procedures, iodoarenes react with

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

• reported in 1972 the synthesis of grayanotoxin II from a degradation product 1 obtained in a few steps from grayanotoxin II itself (Scheme 2) [18]. Later on in 1976 [19], the same authors reported the synthesis of intermediate 1 from the known phenanthrene derivative 2 [20]. The tricyclic compound 2 was

• had previously reported a similar rearrangement for the synthesis of a grayanane-type skeleton [21]. Further methylation and protecting group interconversions lead to an advanced tricyclic structure 5, which could be further elaborated into relay intermediate 1. Although Matsumoto’s approach does not

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

• the 6-5-5 tricyclic skeleton includes the mediation of Nagata reagent for constructing the C1 all-carbon quaternary centers and gold-catalyzed cyclopentenone synthesis through C–H insertion. Keywords: aberrarone; C–H insertion; gold; Pauson–Khand; total synthesis; Introduction Marine natural

• . Impressed by the structural features and biological profiles, our group embarked a project on the total synthesis of this natural product. Herein, we report our stereoselective synthesis of its 6-5-5 tricyclic skeleton. Our retrosynthetic analysis is shown in Scheme 1. For the formation of the D ring with

• constructing the D ring is currently undergoing. Conclusion In summary, we have developed an approach to assemble the tricyclic skeleton of aberrarone through stereoselective methylation, conjugate addition and gold-catalyzed C–H insertion from the readily accessed cyclopentenone. Further work to access

One-pot synthesis of 2-arylated and 2-alkylated benzoxazoles and benzimidazoles based on triphenylbismuth dichloride-promoted desulfurization of thioamides

• Arisu Koyanagi,
• Yuki Murata,
• Shiori Hayakawa,
• Mio Matsumura and
• Shuji Yasuike

Beilstein J. Org. Chem. 2022, 18, 1479–1487, doi:10.3762/bjoc.18.155

• furnished the tricyclic compound 8v in 84% yield. In contrast, the reaction with 3-amino-2-anthracenol resulted in a low yield of the tetracyclic compound 8w due to the low solubility of aminoanthracenol. The reaction of 2a with 2-aminothiophenol instead of 2-aminophenol proceeded smoothly, and the

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

• their abundant structural architectures [1]. Fusicoccane (FC)-type terpenoids are a subgroup of diterpenoids possessing a unique 5-8-5 tricyclic skeleton, which can be produced by plants, fungi and bacteria [2]. This type of diterpenoids, represented by fusicoccin A and cotylenin A, can serve as

• ionization mass spectrometry (HRESIMS), the molecular formula of 1 was deduced as C20H32, indicating that 1 has five degrees of unsaturation. The 13C NMR spectrum showed that there are four olefinic carbons (δC 153.2, 137.4, 125.1, 118.6) in 1. We thus reasoned that 1 features a tricyclic system

Cytochrome P450 monooxygenase-mediated tailoring of triterpenoids and steroids in plants

• Karan Malhotra and
• Jakob Franke

Beilstein J. Org. Chem. 2022, 18, 1289–1310, doi:10.3762/bjoc.18.135

• modification of monocyclic marnerol and tricyclic thalianol (12) in Arabidopsis [27][41]. Marneral synthase (MRN1) produces two oxidation products, one is marneral (aldehyde) and the other marnerol (alcohol). Arabidopsis CYP71A16 hydroxylates the allylic methyl side-chain of monocyclic marneral/marnerol to 23

• -hydroxymarneral/23-hydroxymarnerol. Modification of thalianol (12) involves CYPs from two clans. Genes encoding CYP708A2 (clan 85) and CYP705A5 (clan 71) are physically clustered with the thalianol synthase (THAS) gene, encoding the corresponding oxidosqualene cyclase. CYP708A2 oxidises the tricyclic thalianol