Investigations of amination reactions on an antimalarial 1,2,4-triazolo[4,3-a]pyrazine scaffold

• Henry S. T. Smith,
• Ben Giuliani,
• Kanchana Wijesekera,
• Kah Yean Lum,
• Sandra Duffy,
• Aaron Lock,
• Jonathan M. White,
• Vicky M. Avery and
• Rohan A. Davis

Beilstein J. Org. Chem. 2025, 21, 1126–1134, doi:10.3762/bjoc.21.90

• scaffold for aminations with 14 commercially available primary amines. Reacting scaffold 1 with excess primary amine at room temperature for 16 h generated the desired amine analogues in respectable yields (18–87%) and high purity (≥95%) following chromatography workup. The structures of the 14 previously

• undescribed amine analogues 2–15 were fully characterised following 1D/2D NMR, UV, and HRMS data analyses. X-ray crystallographic analysis of crystals obtained from the aminated products 2, 7, 10, and 15 are also reported here. The new library of amine-substituted triazolopyrazines was screened against the

• primary research focus surrounds a fourth series of antimalarial 1,2,4-triazolo[4,3-a]pyrazine analogues [5] identified from screening a Pfizer compound library, which was conducted by Discovery Biology (Griffith University). The OSM series 4 database contains hundreds of unique 1,2,4-triazolo[4,3-a

Recent total synthesis of natural products leveraging a strategy of enamide cyclization

• Chun-Yu Mi,
• Jia-Yuan Zhai and
• Xiao-Ming Zhang

Beilstein J. Org. Chem. 2025, 21, 999–1009, doi:10.3762/bjoc.21.81

• nucleophilic addition or substitution, the resulting iminium ions often undergo direct hydrolysis, preventing further use in a cascade nucleophilic addition. As a result, enamines are not ideal partners in tandem reactions for the synthesis of nitrogen-containing products. As analogues to enamines, the

Studies on the syntheses of β-carboline alkaloids brevicarine and brevicolline

• Benedek Batizi,
• Patrik Pollák,
• András Dancsó,
• Péter Keglevich,
• Gyula Simig,
• Balázs Volk and
• Mátyás Milen

Beilstein J. Org. Chem. 2025, 21, 955–963, doi:10.3762/bjoc.21.79

• synthesized several new, potentially pharmacologically active β-carboline derivatives structurally close to the alkaloids brevicarine and brevicolline. These derivatives (25–28, 30–32) can also serve as versatile starting materials for the synthesis of new alkaloid analogues and other C(4)-substituted β

Synthesis and photoinduced switching properties of C₇-heteroatom containing push–pull norbornadiene derivatives

• Daniel Krappmann and
• Andreas Hirsch

Beilstein J. Org. Chem. 2025, 21, 807–816, doi:10.3762/bjoc.21.64

• explored. For instance, incorporation of a C2H4 moiety into the bridge led to the formation of [2.2.2]-bicyclooctadiene derivatives with increased storage capacities but significantly reduced half-lifes compared to analogues NBD derivatives [23][24]. Additionally, introduction of one or more heteroatoms at

• a subsequent Suzuki cross-coupling reaction with (4-(diphenylamino)phenyl)boronic acid was performed. The reaction conditions were adapted from prior experiments with C-NBD1 [40] and further refined for the heterocyclic analogues. Optimal results were achieved using K2CO3, Pd(OAc)2 and RuPhos with

• characterized using UV–vis and NMR spectroscopy, as well as high-resolution mass spectrometry. An overview of the synthetic and spectroscopic data for all derivatives is provided in Table 1, while the specific spectroscopic properties of the individual QC analogues can be found in Supporting Information File 1

Copper-catalyzed domino cyclization of anilines and cyclobutanone oxime: a scalable and versatile route to spirotetrahydroquinoline derivatives

• Qingqing Jiang,
• Xinyi Lei,
• Pan Gao and
• Yu Yuan

Beilstein J. Org. Chem. 2025, 21, 749–754, doi:10.3762/bjoc.21.58

• moderate to good yields. Subsequently, we investigated the scope of cyclobutanones and their analogues in the domino cyclization to access structurally diverse spirotetrahydroquinoline derivatives (Scheme 2). Heterocyclic analogues incorporating oxygen or sulfur atoms within the four-membered ring proved

Acyclic cucurbit[n]uril bearing alkyl sulfate ionic groups

• Christian Akakpo,
• Peter Y. Zavalij and
• Lyle Isaacs

Beilstein J. Org. Chem. 2025, 21, 717–726, doi:10.3762/bjoc.21.55

• acyclic CB[n] are not macrocycles, they are preorganized into a C-shaped geometry by virtue of their polycyclic chemical structure and display binding affinities approaching those of macrocyclic CB[n]. M1 and analogues display outstanding biocompatibility and have been used for a number of in vivo

Origami with small molecules: exploiting the C–F bond as a conformational tool

• Patrick Ryan,
• Ramsha Iftikhar and
• Luke Hunter

Beilstein J. Org. Chem. 2025, 21, 680–716, doi:10.3762/bjoc.21.54

• analogues 18 and 19 (Figure 3) [30][33]. Compound 18 contains a 1,3,5-trifluoroalkane moiety with syn,syn-stereochemistry, and it is found to adopt a bent alkyl chain which is necessary for the avoidance of parallel 1,3-difluoro alignments [30]. Compound 19 also contains a 1,3,5-trifluoroalkane moiety, but

• be altered, too [44]. For example, consider compounds 26 and 27 (Figure 4), which are fluorinated analogues of the multiple sclerosis drug gilenya (25) [45]. The syn,anti-fluorinated stereoisomer 26 has a much higher water solubility than gilenya (25), attributable to the presence of new polar bonds

• orthogonal in 47 [84], leading to different overall molecular shapes for compounds 46 and 47. Another illustration of this phenomenon is seen with the macrocycles 48 and 49, which are simplified analogues of a known BACE-1 inhibitor [85]. In the non-fluorinated macrocycle 48, the aryl ether moiety features a

Semisynthetic derivatives of massarilactone D with cytotoxic and nematicidal activities

• Rémy B. Teponno,
• Sara R. Noumeur and
• Marc Stadler

Beilstein J. Org. Chem. 2025, 21, 607–615, doi:10.3762/bjoc.21.48

• activity of this polyketide. Seven analogues of massarilactone D, compounds 2–8, were synthetized through acylation modifications aimed at enhancing the compound’s interactions with biological targets (Scheme 1). These acylated analogues were subsequently screened for their cytotoxicity against a panel of

• then elucidated as massarilactone D 4,7-di-O-crotonyl. Cytotoxic and nematicidal activities The antiproliferative properties of massarilactone D and the newly synthesized analogues were evaluated against the murine fibroblasts L929, human cervix carcinoma KB3-1, human lung carcinoma A549, human

Study of the interaction of 2H-furo[3,2-b]pyran-2-ones with nitrogen-containing nucleophiles

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

Beilstein J. Org. Chem. 2025, 21, 556–563, doi:10.3762/bjoc.21.44

• isolation of intermediate salt 3a. Indeed, the reflux of starting compound 1a with amine 2a in AcOH for 24 h led to formation of product 4a with 62% yield. Using various furanones 1 and amines we attempted to synthesize analogues of compound 4a based on the above procedure. It was found that the presence of

Binding of tryptophan and tryptophan-containing peptides in water by a glucose naphtho crown ether

• Gianpaolo Gallo and
• Bartosz Lewandowski

Beilstein J. Org. Chem. 2025, 21, 541–546, doi:10.3762/bjoc.21.42

• , Table 2). The binding affinity of 1 towards peptide 4 is around 1.5 times higher than for the free amino acid (entry 3, Table 2). The acetylated analogues of peptides 2 and 3 – compounds 5 and 6, are bound by 1 notably weaker, with 1.8× and 1.3× lower affinities respectively (entries 4 and 5, Table 2

• as well indicated by the lower binding affinity of 1 to the acetylated analogues of peptides 2 and 3. In the case of peptide 4, acetylation of its N-terminus did not affect the stability of the complex with receptor 1. This suggests that 1 interacts with the N-terminal ammonium in 4 to a much lesser

Cryptophycin unit B analogues

• Thomas Schachtsiek,
• Jona Voss,
• Maren Hamsen,
• Beate Neumann,
• Hans-Georg Stammler and
• Norbert Sewald

Beilstein J. Org. Chem. 2025, 21, 526–532, doi:10.3762/bjoc.21.40

• relationship (SAR) studies between derivatisations of all four units (A to D) (Figure 1A) of cryptophycin-52 analogues with functional groups [8]. While many modifications of cryptophycin decrease the cytotoxicity drastically, some viable attachment points for conjugation were found, mainly including the para

• indicate the major presence of a fully deprotected and trifluoroacetylated seco-cryptophycin, most likely a TFA ester of one of the free hydroxy groups, a finding which might reason the comparably low yields (21–25%) of structurally similar unit B analogues reported earlier [21]. Contrary, diol 25 was

• amines still show nanomolar activity against the MDR cell line KB-V1 (Table 1) with resistance factors FR (being the ratio between IC50 (KB-V1) and IC50 (KB-3-1)) of 25 (1) and 34 (2), thus being comparably much more potent against KB-V1 cells than for example the unit D analogues (FR ≈ 103) [19

Electrochemical synthesis of cyclic biaryl λ³-bromanes from 2,2’-dibromobiphenyls

• Andrejs Savkins and
• Igors Sokolovs

Beilstein J. Org. Chem. 2025, 21, 451–457, doi:10.3762/bjoc.21.32

• -substituted 1d could be also obtained under the developed conditions. Unsymmetrically substituted 4e and monosubstituted dibromides 4f,g demonstrated reactivity similar to that of their symmetrical analogues 4b,c with exception of the mono-MeO-substituted dibromide 4h. Notably, the presence of two stabilizing

Beyond symmetric self-assembly and effective molarity: unlocking functional enzyme mimics with robust organic cages

• Keith G. Andrews

Beilstein J. Org. Chem. 2025, 21, 421–443, doi:10.3762/bjoc.21.30

• preorganization to catalyze new reactions, better stabilize transition states, or provide new selectivities. The study of discrete, soluble cavities in solution before translation to lattice analogues might prove a fruitful avenue. Covalent organic cages Covalent organic cages [235] are any discrete assembly, at

• ) mimic by Otte [44]. (A) Design and development of soluble, functionalized, robust organic cages. (B) Examples of modular structural changes and properties. Ester hydrolysis of cages 2e–4e gives the diacid analogues 2–4. (A) There are 13 metastable conformers (symmetry-corrected) for cage 1 due to

Unraveling aromaticity: the dual worlds of pyrazole, pyrazoline, and 3D carborane

• Zahra Noori,
• Miquel Solà,
• Clara Viñas,
• Francesc Teixidor and
• Jordi Poater

Beilstein J. Org. Chem. 2025, 21, 412–420, doi:10.3762/bjoc.21.29

• of the N–N bond in pyrazole might help preserve its aromaticity. To explore this, we performed quantum chemical analyses on a range of o-carborane-fused pyrazoles and pyrazolines and compared them with their fully planar indazole and indazoline analogues. Aromaticity or non-aromaticity can be

Streamlined modular synthesis of saframycin substructure via copper-catalyzed three-component assembly and gold-promoted 6-endo cyclization

• Asahi Kanno,
• Ryo Tanifuji,
• Satoshi Yoshida,
• Sota Sato,
• Saori Maki-Yonekura,
• Kiyofumi Takaba,
• Jungmin Kang,
• Kensuke Tono,
• Koji Yonekura and
• Hiroki Oguri

Beilstein J. Org. Chem. 2025, 21, 226–233, doi:10.3762/bjoc.21.14

• avenues for the development of fluorescent probes based on the bis-THIQ alkaloidal scaffold. Further efforts to develop a concise and modular synthetic process for saframycins are currently underway. Representative bis-tetrahydroisoquinoline (THIQ) alkaloids and their analogues. Oxygen atoms on both the A

Heteroannulations of cyanoacetamide-based MCR scaffolds utilizing formamide

• Marios Zingiridis,
• Danae Papachristodoulou,
• Despoina Menegaki,
• Konstantinos G. Froudas and
• Constantinos G. Neochoritis

Beilstein J. Org. Chem. 2025, 21, 217–225, doi:10.3762/bjoc.21.13

• under the umbrella of C1 chemistry was to provide a straightforward access to the privileged scaffold of fused heteroannulated pyrimidones, which demonstrate a broad range of biological activities [28][29][30][31][32][33][34][35], including use as emissive nucleoside analogues [36][37][38]. Moreover

Dioxazolones as electrophilic amide sources in copper-catalyzed and -mediated transformations

• Seungmin Lee,
• Minsuk Kim,
• Hyewon Han and
• Jongwoo Son

Beilstein J. Org. Chem. 2025, 21, 200–216, doi:10.3762/bjoc.21.12

• -triazole analogues 6. Both dioxazolones 4 and N-iminoquinolinium ylides 5 demonstrated excellent tolerance in this transformation. Notably, electron-rich dioxazolones exhibited slightly higher reactivity. The proposed catalytic cycle for the copper-catalyzed synthesis of 1,2,4-triazole derivatives is

• -catalyzed synthesis of 1,2,4-triazole analogues from dioxazolones and N-iminoquinolinium ylides. Proposed reaction mechanism for the copper(I)-catalyzed synthesis of N-acyl amidines. Proposed reaction pathway for the copper-mediated synthesis of N-arylamides from dioxazolones. Proposed reaction pathway for

Facile one-pot reduction of β-nitrostyrenes to phenethylamines using sodium borohydride and copper(II) chloride

• Laura D’Andrea and
• Simon Jademyr

Beilstein J. Org. Chem. 2025, 21, 39–46, doi:10.3762/bjoc.21.4

• limited, since a NaBH4/transition metal salt system is mostly used to reduce nitroarenes [23][24][25][26]. One of the reported methods takes advantage of titanium(IV) isopropoxide as a catalyst to prepare varied β-phenethylamine analogues. Despite its simplicity, the reaction time is quite prolonged (from

• to synthesize phenethyl- and phenylisopropylamines from the corresponding nitroalkenes [15][17]. Representatively substituted β-nitrostyrene analogues were reduced via this method at 80 ˚C, including 2,5-dimethoxy-β-methyl-β-nitrostyrene (3a), precursor of amphetamines, and 2,5-dimethoxy-β

• crucial role in the synthesis of phenethylamine analogues via this method. Dithering before the addition of the copper solution leads to the formation of Micheal adducts, which decrease the product yields. This phenomenon is due to the nature of β-nitrostyrenes, displaying considerable delocalization

Chemical glycobiology

• Elisa Fadda,
• Rachel Hevey,
• Benjamin Schumann and
• Ulrika Westerlind

Beilstein J. Org. Chem. 2025, 21, 8–9, doi:10.3762/bjoc.21.2

• glycan assembly [9]. Target-directed synthetic strategies are being developed by Reihill et al. [10] and Karak et al. [11], exploring the syntheses of the linker-displaying, sulfated TF disaccharide and lipid II analogues, respectively. The direct application of synthetic glycans is shown by Fan et al

Synthesis of acenaphthylene-fused heteroarenes and polyoxygenated benzo[j]fluoranthenes via a Pd-catalyzed Suzuki–Miyaura/C–H arylation cascade

• Merve Yence,
• Dilgam Ahmadli,
• Damla Surmeli,
• Umut Mert Karacaoğlu,
• Sujit Pal and
• Yunus Emre Türkmen

Beilstein J. Org. Chem. 2024, 20, 3290–3298, doi:10.3762/bjoc.20.273

• %). This cascade involves an initial Suzuki–Miyaura cross-coupling reaction between 1,8-dihalonaphthalenes and heteroarylboronic acids or esters, followed by an intramolecular C–H arylation under the same conditions to yield the final heterocyclic fluoranthene analogues. The method was further employed to

• heteroatoms or other heterocycles to obtain heterocyclic fluoranthene analogues offers numerous opportunities for structural and functional diversifications. For instance, azafluoranthenes such as triclisine (1) or imeluteine (2) constitute a common structural motif encountered in natural products isolated

• ) ligand 4 were reported by Cowley and co-workers in 2010 [14]. In addition to heterocyclic fluoranthene analogues, highly oxygenated benzo[j]fluoranthenes are commonly encountered fungal natural products with important biological activities [15]. Bulgarein (5) is an example of such a benzo[j]fluoranthene

Discovery of ianthelliformisamines D–G from the sponge Suberea ianthelliformis and the total synthesis of ianthelliformisamine D

• Sasha Hayes,
• Yaoying Lu,
• Bernd H. A. Rehm and
• Rohan A. Davis

Beilstein J. Org. Chem. 2024, 20, 3205–3214, doi:10.3762/bjoc.20.266

• activity against both Pseudomonas aeruginosa and Staphylococcus aureus, has contributed to a surge in the interest of polyamines as new antibacterial leads [6]. To date the total synthesis of ianthelliformisamines A–C (1–3) has been described [7] and numerous synthetically related analogues have been

• new leads against Pseudomonas aeruginosa and supported by numerous reports of favourable activity for ianthelliformisamines A–C [7][12] and their synthetic analogues [8][9][10], we investigated the planktonic and biofilm activity of the new natural products 4–7 in addition to the known metabolite

• , aplysterol (8) [13]. Our biological assessment of compounds 4–8 showed no inhibition of planktonic growth or biofilm formation for P. aeruginosa when screened at 50 µM. Previously reported antibacterial assessment of ianthelliformisamines A–C (1–3) and their synthetic analogues has generated structure

Synthesis of extended fluorinated tripeptides based on the tetrahydropyridazine scaffold

• Thierry Milcent,
• Pascal Retailleau,
• Benoit Crousse and
• Sandrine Ongeri

Beilstein J. Org. Chem. 2024, 20, 3174–3181, doi:10.3762/bjoc.20.262

• feature results will be further confirmed by the insertion of these cyclic β-dehydropiperazic acids in longer peptide sequences. Examples of bioactive tetrahydropyridazine derivatives. Linear and cyclic peptides incorporating the dehydropiperazic acid moiety. Piperazic acid and analogues and target

Advances in the use of metal-free tetrapyrrolic macrocycles as catalysts

• Mandeep K. Chahal

Beilstein J. Org. Chem. 2024, 20, 3085–3112, doi:10.3762/bjoc.20.257

• free-base) macrocycles have not been explored as much in terms of catalysis, even though they are starting compounds for the preparation of their metallated analogues that are commonly used as catalysts. In contrast with a calix[4]pyrrole macrocycle with four NHs (from four pyrrole units), a metal-free

• one remaining –NH group is catalytically active while both tri- and tetraalkylated analogues 40 and 41, without an –NH unit, are not. Further, the authors performed 1H NMR experiments with a different substrate:macrocycle ratio and suggested a bifunctional reaction mechanism involving both inner amine

• ones with secondary amine side arm (48d, 48g, h) were catalytically active for Michael additions, providing 60–71% yields (Table 3), whereas tetraalkylated analogues (49a–g) and dialkylated OxPs without a secondary amine side arm (48a–c, 48e and 48i) were not. Based on these results, the authors have

Extension of the π-system of monoaryl-substituted norbornadienes with acetylene bridges: influence on the photochemical conversion and storage of light energy

• Robin Schulte,
• Dustin Schade,
• Thomas Paululat,
• Till J. B. Zähringer,
• Christoph Kerzig and
• Heiko Ihmels

Beilstein J. Org. Chem. 2024, 20, 3061–3068, doi:10.3762/bjoc.20.254

• and the analogues 1c and 1e without an alkyne linker [29][30][34]. As the only exception, the m-substituted derivative 1k has a higher quantum yield than its analog 1b, which is, however, still lower than the one of the cyano-substituted norbornadiene 1c [30][34]. In addition, substitution at the 2

• quadricyclanes from 3.0 h to 7.8 h, which are essentially in the same range as the ones of analogues with an acceptor-substituent in the 3-position of the norbornadiene [34]. Notably, the quadricyclane derivatives with sterically more demanding substituents in the 2-position of the norbornadiene unit, such as 1e

• , showed longer half-lives. Therefore, compounds 1h–l,n have significanty lower half-lives than the corresponding analogues without an alkyne linker [29][30]. Conclusion In summary, a small series of mono-, bis-, and tris-norbornadiene derivatives with alkynylbenzene and alkynylnaphthalene core units was

Tunable full-color dual-state (solution and solid) emission of push–pull molecules containing the 1-pyrindane moiety

• Anastasia I. Ershova,
• Sergey V. Fedoseev,
• Konstantin V. Lipin,
• Mikhail Yu. Ievlev,
• Oleg E. Nasakin and
• Oleg V. Ershov

Beilstein J. Org. Chem. 2024, 20, 3016–3025, doi:10.3762/bjoc.20.251

• dimethylene bridge in arylidene derivatives of pyrindane 1 led to an increase in the emission quantum yield and caused an appearance of solid-state photoluminescence, in contrast to the previously synthesized analogues (stilbazoles A, Figure 1) without such a bridge (Tables S3 and S4, Supporting Information