Total syntheses of highly oxidative Ryania diterpenoids facilitated by innovations in synthetic strategies

• Zhi-Qi Cao,
• Jin-Bao Qiao and
• Yu-Ming Zhao

Beilstein J. Org. Chem. 2025, 21, 2553–2570, doi:10.3762/bjoc.21.198

• )allylium tetrafluoroborate, which was then coupled to the C3 hydroxy group via Yamaguchi esterification. Global deprotection subsequently afforded ryanodine (1) in 10 steps, thus achieving this critical synthetic transformation. Although the interaction of ryanodine with intracellular calcium release

Isoorotamide-based peptide nucleic acid nucleobases with extended linkers aimed at distal base recognition of adenosine in double helical RNA

• Grant D. Walby,
• Brandon R. Tessier,
• Tristan L. Mabee,
• Jennah M. Hoke,
• Hallie M. Bleam,
• Angelina Giglio-Tos,
• Emily E. Harding,
• Vladislavs Baskevics,
• Martins Katkevics,
• Eriks Rozners and
• James A. MacKay

Beilstein J. Org. Chem. 2025, 21, 2513–2523, doi:10.3762/bjoc.21.193

• portion of the nucleobase (the isoorotamide) simply dissolved, or rotated away from the binding pocket, not forming the intended interaction with distal A base in silico (Figure 7A). In the case of Db2, the amide NH in the linker was apparently too far from the PNA backbone and did not form the intended

• stabilizing H-bond but rather formed a hydrogen bond with the U in the U–A base pair (ca. 2.2 Å, Figure 7B). This interaction resulted in pushing the entire residue towards the RNA backbone where the Io base could further bind to a phosphate which likely explains why Db2 shows the lowest triplex stability of

• , heterocycle of Db2 is rotated, placing its polar face towards solute and non-polar methyl group towards RNA. This results in the whole Db2 base being tilted, which breaks the intended stabilizing H-bond between the Db2 linker and the adjacent M. Db3 resulted in the best interaction in silico despite the low

Effect of a photoswitchable rotaxane on membrane permeabilization across lipid compositions

• Udyogi N. K. Conthagamage,
• Lilia Lopez,
• Zuliah A. Abdulsalam and
• Víctor García-López

Beilstein J. Org. Chem. 2025, 21, 2498–2512, doi:10.3762/bjoc.21.192

• occurred mainly within the first 10 minutes and then plateaued for the following hour, indicating that the initial interaction drives most of the perturbation. In contrast, 4-E continued to promote release over time, reflecting larger and sustained membrane disruption. Comparing isomers, the difference in

Synthesis of the tetracyclic skeleton of Aspidosperma alkaloids via PET-initiated cationic radical-derived interrupted [2 + 2]/retro-Mannich reaction

• Ru-Dong Liu,
• Jian-Yu Long,
• Zhi-Lin Song,
• Zhen Yang and
• Zhong-Chao Zhang

Beilstein J. Org. Chem. 2025, 21, 2470–2478, doi:10.3762/bjoc.21.189

• formation of IN1. The radical cation IN1 served as the reference point for DFT investigations. As illustrated in Figure 2a, facilitated by a favorable radical cation–π interaction [31], IN1 proceeds to the first radical addition transition state (TS1), with an energy barrier of 8.3 kcal/mol. This leads to

• ). Further geometrical adjustment and conformational restriction of the transient structure enable the N9 nonbonding p orbital to align parallel to the σ(C19–C3)* orbital (Figure 2f, TS2 → F-10 → F-40 → IN3), which reinforces the hyperconjugative interaction. Facilitated by the bond stretching and bond-angle

• bending of the transient structure with a pseudo bicyclo[2.2.0]hexane unit, the favorable hyperconjugative interaction ultimately leads to cleavage of the C19–C3 bond (TS2 → IN3) and release of the ring strain. DFT analysis hereby explains that the orbital symmetry involved in this process does not

The intramolecular stabilizing effects of O-benzoyl substituents as a driving force of the acid-promoted pyranoside-into-furanoside rearrangement

• Alexey G. Gerbst,
• Sofya P. Nikogosova,
• Darya A. Rastrepaeva,
• Dmitry A. Argunov,
• Vadim B. Krylov and
• Nikolay E. Nifantiev

Beilstein J. Org. Chem. 2025, 21, 2456–2464, doi:10.3762/bjoc.21.187

• furanoside forms exhibit π–π interactions between the phenyl rings of some benzoate substituents. These are benzoates at O2 and O3 in the pyranoside and benzoates at O2 and O6 in the furanoside. Obviously the orientation of the C5–C6 in the furanoside greatly influences the possibility of such an interaction

• given in Table 1. Looking at the obtained conformations (Figure 5B), one can find that the same π–π interactions are present in the α-galactoside structures as in their β-isomers. However, there is a possibility of another interaction. This is the repulsion between the cis-oriented O-1 and O-2 atoms in

• rings. The internal C–C–C angles in them differ leading to more freedom for the side substituents in furanosides. This, in our opinion, means that the π–π interactions between the phenyl rings must increase in this case. However, a repulsive interaction that occurs between O-1 and O-2 oxygen atoms in

Transformation of the cyclohexane ring to the cyclopentane fragment of biologically active compounds

• Natalya Akhmetdinova,
• Ilgiz Biktagirov and
• Liliya Kh. Faizullina

Beilstein J. Org. Chem. 2025, 21, 2416–2446, doi:10.3762/bjoc.21.185

• have been little studied, and are of interest to synthetic chemists. Thus, the interaction of (−)-metaphanine (70) with ammonia in CH3OH at room temperature led to the in situ formation of imine 72, which, as a result of an intramolecular aza-benzilic acid-type rearrangement, was converted in more than

• 10 μg/mL). Sequential interaction of indole 219 with pyridinium p-toluenesulfonate (PPTS) and excess of Davis’ oxaziridine 222, an effective oxidizing agent for synthesis of spirooxindole alkaloids, led to epoxide 220. Labile oxirane 220, without isolation, was subjected to a semipinacol

• unseparated mixture of abeolupanes 245 and 246, in a ratio of 1.5–3:1, with a total yield of 89%. The interaction of compound 243 with BF3·Et2O in benzene at 70 °C gave a mixture of olefins 245 and 246 in a 1:2 ratio, with an overall yield of 88%. Similar transformations were carried out with methyl

The high potential of methyl laurate as a recyclable competitor to conventional toxic solvents in [3 + 2] cycloaddition reactions

• Ayhan Yıldırım and
• Mustafa Göker

Beilstein J. Org. Chem. 2025, 21, 2389–2415, doi:10.3762/bjoc.21.184

• have been predicted for nitrone, with a δT (the Hildebrand solubility parameter or the total Hildebrand parameter) of approximately 17. This finding indicates that methyl laurate is a suitable solvent for nitrone, which has a δT of around 20. On the other hand, the radius of interaction (Ra) is a

• critical factor in the assessment of solute solubility in a solvent, particularly in the context of HSPs [97][98]. It facilitates estimation of the extent of interaction between a solute and solvent, as determined by their respective solubility parameters. Consequently, the difference between the HSPs

• approximately ≈ 6.57 MPa1/2. The radius of interaction (Ro) for a typical small organic molecule, such as the nitrone, is estimated to be approximately 7.5 MPa1/2 which value is usually determined for solute molecules [97][99]. The relationship between Ra and Ro is denoted by the term relative energy difference

Conformational effects on iodide binding: a comparative study of flexible and rigid carbazole macrocyclic analogs

• Guang-Wei Zhang,
• Yong Zhang,
• Le Shi,
• Chuang Gao,
• Hong-Yu Li and
• Lei Xue

Beilstein J. Org. Chem. 2025, 21, 2369–2375, doi:10.3762/bjoc.21.181

• by the two structural analogs, we added a commercially available tetrabutylammonium salt (TBAI) to the body dissolved in CDCl3 (TBAI has a good solubility in CDCl3) and studied the interaction between the receptor and iodide ion by 1H NMR titration, UV–vis absorption spectroscopy and fluorescence

• groups inside the macrocycle and thus causes the NH peak to be shifted downfield. At the same time, after the addition of TBAI to the PBG solution, both proton signals c/d and e/f were shifted downfield, while protons a/b moved slightly to higher field, confirming the interaction between the anion and

• a/b and c/d both moved slightly to higher field. This indicates that there is a slight difference in the interaction between NH protons and iodine ions of the two structural analogs. Structural analysis showed that since the two single bonds are rotationally restricted, all its accessible

Rotaxanes with integrated photoswitches: design principles, functional behavior, and emerging applications

• Jullyane Emi Matsushima,
• Khushbu,
• Zuliah Abdulsalam,
• Udyogi Navodya Kulathilaka Conthagamage and
• Víctor García-López

Beilstein J. Org. Chem. 2025, 21, 2345–2366, doi:10.3762/bjoc.21.179

• the macrocycle interaction with the axle. In a different approach, the authors demonstrated that the macrocycle can shuttle along an axle by incorporating two acridane photoswitches at both ends. However, upon light activation, the macrocycle stops shuttling and remains in the middle of the axle

• –guest interaction induces a chiral signal, while the azobenzene chromophore imparts photoswitching properties to the molecule. Furthermore, solvent-mediated hydrogen-bonding interactions tailored within the inner cyclodextrin cavity, combined with photocontrolled isomerization of the azo moiety, enable

• the axle and allowed geometrical changes to occur, thereby modifying the nature and strength of the interaction between the macrocycle and the recognition sites [63][64]. Later, a new rotaxane was reported, which generates a strong induced circular dichroism response when the macrocycle is hydrogen

Insoluble methylene-bridged glycoluril dimers as sequestrants for dyes

• Suvenika Perera,
• Peter Y. Zavalij and
• Lyle Isaacs

Beilstein J. Org. Chem. 2025, 21, 2302–2314, doi:10.3762/bjoc.21.176

• , it is not possible to use 1H NMR to assess the geometry of the interaction between H2 or G2W1 with methylene blue or methylene violet, respectively. Determination of the adsorption capacity. Next, we wanted to learn more about the capacity of H2 and G2W1 for the removal of methylene blue and

Pathway economy in cyclization of 1,n-enynes

• Hezhen Han,
• Wenjie Mao,
• Bin Lin,
• Maosheng Cheng,
• Lu Yang and
• Yongxiang Liu

Beilstein J. Org. Chem. 2025, 21, 2260–2282, doi:10.3762/bjoc.21.173

• acted as nucleophile, the stable imine–gold–aryl cation–π–π interaction precluded rearrangement and promoted the capture of imine to form spiro[indoline-3,3'-pyridine] derivatives 67. The Ph3PAuCl/AgNTf2-catalyzed cyclization of N-propargyl-tethered amide enynes efficiently afforded four distinct

Research towards selective inhibition of the CLK3 kinase

• Vinay Kumar Singh,
• Frédéric Justaud,
• Dabbugoddu Brahmaiah,
• Nangunoori Sampath Kumar,
• Blandine Baratte,
• Thomas Robert,
• Stéphane Bach,
• Chada Raji Reddy,
• Nicolas Levoin and
• René L. Grée

Beilstein J. Org. Chem. 2025, 21, 2250–2259, doi:10.3762/bjoc.21.172

• decided to prepare also the same molecules with hydrogen instead of the chlorine in meta position of the anilino group. Our previous work on DB18 suggested indeed that the chlorine atom is implicated in intramolecular halogen–π interaction, ending in a conformational constraint and ligand rigidity [24

• addition of the terminal acid significantly reinforces the interaction of our new molecules with CLK3, probably through a salt bridge with lysine 241. Logically, the corresponding esters are found to be inactive. Finally, in order to complete our profiling of VS-77, we then measured its activity against

• also evidenced by the better affinity for DYRK1A of the acidic molecules as compared to their ester analogues. Therefore, this new interaction could explain the higher affinity of VS-77 toward Hs_DYRK1A, as compared to DB-18. Conclusion In the present work, we disclosed a new strategy to improve the

Discovery of cytotoxic indolo[1,2-c]quinazoline derivatives through scaffold-based design

• Daniil V. Khabarov,
• Valeria A. Litvinova,
• Lyubov G. Dezhenkova,
• Dmitry N. Kaluzhny,
• Alexander S. Tikhomirov and
• Andrey E. Shchekotikhin

Beilstein J. Org. Chem. 2025, 21, 2062–2071, doi:10.3762/bjoc.21.161

• new indolo[1,2-c]quinazoline derivatives to interact with nucleic acids. Since not all compounds exhibited intrinsic fluorescence, we initially performed a screening using the fluorescent intercalator displacement (FID) assay. Only compounds 7a–c showed a positive response and interaction with DNA

• (Figure S1 in Supporting Information File 1). The interaction of compounds 7a–c with duplex DNA was then investigated by fluorescence titration, measuring the quenching of ligand fluorescence upon binding to the nucleic acid. Fluorimetric titration studies confirmed the interaction of 7a–c with double

• -stranded calf thymus DNA, as evidenced by ligand fluorescence quenching (Figure 2). Elongation of the linker in the carboxamide residue is accompanied by weaker DNA complexation (Table 4). The interaction of the compounds with DNA was found to be largely dependent on electrostatic forces. Reducing the

Asymmetric total synthesis of tricyclic prostaglandin D2 metabolite methyl ester via oxidative radical cyclization

• Miao Xiao,
• Liuyang Pu,
• Qiaoli Shang,
• Lei Zhu and
• Jun Huang

Beilstein J. Org. Chem. 2025, 21, 1964–1972, doi:10.3762/bjoc.21.152

• a single diastereomer (Table 1, entry 4). To explain this diastereoselectivity, we hypothesize that the C–O bond, which occupies an axial position in the proposed transition state TS-1, could avert an additional hyperconjugative interaction (σ*C-O/π) that renders the reacting C=C bond electron

Synthesis, biological and electrochemical evaluation of glycidyl esters of phosphorus acids as potential anticancer drugs

• Almaz A. Zagidullin,
• Emil R. Bulatov,
• Mikhail N. Khrizanforov,
• Damir R. Davletshin,
• Elvina M. Gilyazova,
• Ivan A. Strelkov and
• Vasily A. Miluykov

Beilstein J. Org. Chem. 2025, 21, 1909–1916, doi:10.3762/bjoc.21.148

• . Electrochemical studies Alkylating agents are widely recognized for their ability to form covalent bonds with biological macromolecules (proteins, DNA). The literature discusses the interaction of small molecules with proteins, highlighting how linear sweep voltammetry (LSV) can be used to understand these

• themselves exhibit no discernible redox activity in this potential range when tested in the absence of HSA. Consequently, any changes in the recorded voltammogram could be attributed to the interaction (alkylation) of albumin rather than to new electrochemical processes arising directly from the compounds

Photoswitches beyond azobenzene: a beginner’s guide

• Michela Marcon,
• Christoph Haag and
• Burkhard König

Beilstein J. Org. Chem. 2025, 21, 1808–1853, doi:10.3762/bjoc.21.143

• of T-shaped 8a and 9a the Z-isomer was more thermally stable thanks to the weak interaction between the hydrogen and the π-system. However, the high symmetry weakens the intensity of the nπ* absorption band, which is the excitation band for the Z–E isomerisation, resulting in a lower E-PSS. Basic

• , giving better PSSs) and improved the half-lives without interfering too much with the absorption of the E-indigo (Figure 14). Diarylated indigos like 60g showed the presence of the Z-isomer in the dark, possibly due to the stabilisation energy given by the π–π interaction between the aryl rings (Figure

• (Scheme 33) [110]. The direct consequence of the planar 104 is the enhanced conjugation, which gives a red-shift in the absorption and favours the rotation mechanism (as seen in Scheme 32). The forced steric interaction of the aryl ring with the hydrazone moiety destabilises 105-E even further, decreasing

Research progress on calixarene/pillararene-based controlled drug release systems

• Liu-Huan Yi,
• Jian Qin,
• Si-Ran Lu,
• Liu-Pan Yang,
• Li-Li Wang and
• Huan Yao

Beilstein J. Org. Chem. 2025, 21, 1757–1785, doi:10.3762/bjoc.21.139

• hydrophobic alkyl chain core. The assembly driving force directly relies on the host–guest interaction between WP6 and FC. Further studies have shown that by regulating the deprotonation/protonation state of the WP6 carboxyl groups through pH control, the reversible dissociation and reassembly of the vesicle

• chiral CA named chiral azo-calix[4]arene derivative (FC4AD) (Figure 10) [117]. Its interaction with enantiomers of aminoindanol in solution was investigated. It was found that FC4AD has high selective binding and release for (1R,2S)-1-amino-2-indanol, forming a 1:1 complex. S-phenethylamine was used as a

• inherent in non-covalent interactions. Building on biocompatibility studies, they also developed an enzyme-responsive supramolecular vesicle for treating Alzheimer's disease. This vesicle is assembled via the host–guest interaction between SC4A and myristoyl choline (Figure 13) [119]. The host–guest

Unique halogen–π association detected in single crystals of C–N atropisomeric N-(2-halophenyl)quinolin-2-one derivatives and the thione analogue

• Mai Uchibori,
• Nanami Murate,
• Kanako Shima,
• Tatsunori Sakagami,
• Ko Kanehisa,
• Gary James Richards,
• Akiko Hori and
• Osamu Kitagawa

Beilstein J. Org. Chem. 2025, 21, 1748–1756, doi:10.3762/bjoc.21.138

• , Shibaura Institute of Technology, 307 Fukasaku, Minuma-ku, Saitama 337-8570, Japan 10.3762/bjoc.21.138 Abstract In single crystals of C–N atropisomeric N-(2-halophenyl)quinolin-2-one and the thione analogue, a unique association based on a halogen–π interaction was detected. In racemic and optically pure

• -electron on the quinolinone benzene ring, while that in optically pure forms is caused by an n–π* interaction between a lone electron pair on the halogen atom and a π* orbital of the quinolinone. In contrast to the formation of the homochiral layered polymer in quinolinones, in racemic N-(2-bromophenyl

• )quinoline-2-thione, heterochiral layered polymers, in which (P)- and (M)-atropisomers were alternately connected, were formed through an n–π* interaction between a lone electron pair on the bromine atom and a π* orbital of the quinoline-2-thione. Keywords: atropisomers; C–N bond; halogen bond; quinolinones

Thermodynamics and polarity-driven properties of fluorinated cyclopropanes

• Matheus P. Freitas

Beilstein J. Org. Chem. 2025, 21, 1742–1747, doi:10.3762/bjoc.21.137

• stabilizing due to the presence of two anomeric-like interactions, nF → σ*CF [16]. According to a natural bond orbital (NBO) analysis, this electron delocalization accounts for a stabilization energy of 14.3 kcal mol−1 per interaction in compound 1.1. Similar stabilization values are observed in other

• electron delocalization effects. Among the difluorocyclopropanes, the stability order is 1.1 > 1.2-t. > 1.2-c., highlighting the destabilizing influence of 1,2-syn-diaxial repulsion in the 1.2-c. isomer. A similar interaction is observed in cis-1,3-difluorocyclobutane, where the diaxial conformer is

• 2.70 Å, this interaction is consistent with electrostatic hydrogen bonding. Consequently, similar to the behavior observed in the crystalline form of all-cis-1,2,3,4,5,6-hexafluorocyclohexane [10], 1.2.3-c.c. is expected to self-assemble in the condensed phase. Given the "Janus"-face-like structure of

Preparation of a furfural-derived enantioenriched vinyloxazoline building block and exploring its reactivity

• Madara Darzina,
• Anna Lielpetere and
• Aigars Jirgensons

Beilstein J. Org. Chem. 2025, 21, 1737–1741, doi:10.3762/bjoc.21.136

• attack to the double bond in intermediate A is kinetically preferred from the face forming the R-configured carbon of the C–N bond as a result of a minimized steric interaction of the oxygen in zwitterion with iPr substituent of oxazoline. Conclusion Unsaturated ester obtained by Torii-type ester

Continuous-flow-enabled intensification in nitration processes: a review of technological developments and practical applications over the past decade

• Feng Zhou,
• Chuansong Duanmu,
• Yanxing Li,
• Jin Li,
• Haiqing Xu,
• Pan Wang and
• Kai Zhu

Beilstein J. Org. Chem. 2025, 21, 1678–1699, doi:10.3762/bjoc.21.132

• compound production, fundamentally involving the interaction between organic substrates and nitrating reagents. The intrinsic kinetics of nitration processes are governed by the synergistic interplay between the substrate’s molecular architecture and nitrating reagent reactivity. Distinct substrate

Structural analysis of stereoselective galactose pyruvylation toward the synthesis of bacterial capsular polysaccharides

• Tsun-Yi Chiang,
• Mei-Huei Lin,
• Chun-Wei Chang,
• Jinq-Chyi Lee and
• Cheng-Chung Wang

Beilstein J. Org. Chem. 2025, 21, 1671–1677, doi:10.3762/bjoc.21.131

• modifications of bacterial polysaccharides, and the interaction of 4,6-O-pyruvylated pyranoses with lectins depends on the stereochemistry of the pyruvate ketal. Moreover, this chemical modification is crucial, as the distinct R or S diastereochemistry at the ketal center directly influences its biological

• , pyruvate ketals are attached to the O4 and O6 positions of galactose, incorporating a negatively charged carboxyl group. The diastereoselectivity and negative charge of pyruvate ketals have a key role in their biological interaction, such as influencing immunological specificity and patterns of

Influence of the cation in hypophosphite-mediated catalyst-free reductive amination

• Natalia Lebedeva,
• Fedor Kliuev,
• Olesya Zvereva,
• Klim Biriukov,
• Evgeniya Podyacheva,
• Maria Godovikova,
• Oleg I. Afanasyev and
• Denis Chusov

Beilstein J. Org. Chem. 2025, 21, 1661–1670, doi:10.3762/bjoc.21.130

• has shown clear influence of the cation in the hypophosphite salt on the effectiveness of the reductive amination. The acidity of the reaction media was a key factor affecting the equilibrium in the interaction between carbonyl compounds and amines. Intermediately acidic media is the optimal for the

• media. Finally, the combination of H3PO2 and KH2PO2 1:1 with the ratio of H2PO2− to amine 1:2 is optimal balance between solubility of reductant, acidity of the medium and stability of the reducing system providing the highest efficiency of the interaction. Under optimized reaction conditions, the

• absence of an external hydrogen source. The alternative pathway to form a hemiaminal could not include the interaction of an acid with amine or aldehyde, nevertheless, the non-catalytic path had ΔEa = 32.1 kcal/mol (TS2→3'') which meant that hemiaminal definitely emerged faster via the amine protonation

Catalytic asymmetric reactions of isocyanides for constructing non-central chirality

• Jia-Yu Liao

Beilstein J. Org. Chem. 2025, 21, 1648–1660, doi:10.3762/bjoc.21.129

• condensation between 27 and the aldehyde afforded INT-A, which was activated by the CPA catalyst through hydrogen bonding interaction. The nucleophilic addition of isocyanide to Int-A produced INT-B bearing a stereogenic center. Subsequently, INT-B underwent intramolecular cyclization to generate axially

• explanations for such a diastereodivergence. Specifically, L9 functions as a monodentate ligand, and the stronger ligand–substrate hydrogen-bonding interaction and smaller distortion of the ligand resulted in endo-cycloadducts (L9-TS). In contrast, Trost ligand L10 serves as a bidentate ligand, and the smaller

On the aromaticity and photophysics of 1-arylbenzo[a]imidazo[5,1,2-cd]indolizines as bicolor fluorescent molecules for barium tagging in the study of double-beta decay of ¹³⁶Xe

• Eric Iván Velazco-Cabral,
• Fernando Auria-Luna,
• Juan Molina-Canteras,
• Miguel A. Vázquez,
• Iván Rivilla and
• Fernando P. Cossío

Beilstein J. Org. Chem. 2025, 21, 1627–1638, doi:10.3762/bjoc.21.126

• describe better the excitation process in the free state, whereas interaction of the sensor with Ba2+ requires the M06L functional. TDDFT analysis of the emission spectra shows larger errors, which have been corrected by means of a structural model. The bicolor behavior is rationalized based on the

• interactions. Finally, a spacer (denoted as X and Y in Figure 2) and a linker (denoted as Z) to anchor the sensor to a suitable surface via a covalent interaction are required. Ideally, different configurations and conformations of the fluorophore in the free and chelated states would result in a bicolor

• energies computed at 298.17 K. We also extended this study to the interaction between complexes 15a–d and benzene (14) and computed the corresponding complexation energies as In addition, Figure 4 includes the chief geometric parameters of the different complexes, as well as the corresponding free energy