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

A m-quaterphenyl probe for absolute configurational assignments of primary and secondary amines

• Yuka Takeuchi,
• Mutsumi Kobayashi,
• Yuuka Gotoh,
• Mari Ikeda,
• Yoichi Habata,
• Tomohiko Shirai and
• Shunsuke Kuwahara

Beilstein J. Org. Chem. 2025, 21, 2211–2219, doi:10.3762/bjoc.21.168

• group are planar, while the methyl group is more sterically demanding in three-dimensional space, this conformational model is supported (Table S1 in Supporting Information File 1). Although intramolecular electronic interactions should also be considered, the twist of the phenyl chromophores can be

Synthesis of triazolo- and tetrazolo-fused 1,4-benzodiazepines via one-pot Ugi–azide and Cu-free click reactions

• Xiaoming Ma,
• Zijie Gao,
• Jiawei Niu,
• Wentao Shao,
• Shenghu Yan,
• Sai Zhang and
• Wei Zhang

Beilstein J. Org. Chem. 2025, 21, 2202–2210, doi:10.3762/bjoc.21.167

• /bjoc.21.167 Abstract A one-pot Ugi–azide reaction followed by intramolecular Cu-free azide–alkyne cycloaddition generates a polycyclic scaffold 7 bearing polycyclic triazole, tetrazole, and benzodiazepine rings. This method could be extended for obtaining a more complicated scaffold 8 containing a

• . After evaporation of the solvent MeOH, the residue was redissolved in 2 mL of MeCN and heated at 130 °C for 2 h in a sealed vial to give product 7a in 90% yield after purification via Cu-free intramolecular click reaction (Scheme 3C) [46]. This Cu-free intramolecular cyclization provides key practical

• , the reaction of 0.2 mmol each of 1a and 2a led to the formation of Int-I which then reacted with 0.2 mmol each of 9 and 4 to form 1,5-DS-T 5b which consequently underwent lactamization to form 6a followed by an intramolecular click reaction to afford highly condensed polycyclic product 8a in 92

Electrochemical cyclization of alkynes to construct five-membered nitrogen-heterocyclic rings

• Lifen Peng,
• Ting Wang,
• Zhiwen Yuan,
• Bin Li,
• Zilong Tang,
• Xirong Liu,
• Hui Li,
• Guofang Jiang,
• Chunling Zeng,
• Henry N. C. Wong and
• Xiao-Shui Peng

Beilstein J. Org. Chem. 2025, 21, 2173–2201, doi:10.3762/bjoc.21.166

• characteristics. Electrochemical construction of five-membered rings from alkynes attracted increasing attention due to the notable advantages of electrochemical transformations and facile access of alkynes. Indole skeletons were constructed successfully through electrochemical intramolecular coupling of ethynyl

• ]. Besides, electrochemical cyclization of alkynes is also an important access towards indoles. In 2016, Xu reported the electrochemical intramolecular coupling of urea derivatives to form substituted indoles (Scheme 1) [162]. Using [Cp2Fe] (5 mol %) as the redox catalyst, the intramolecular coupling of

• , A proceeded an intramolecular nucleophilic attack by N and deprotonation to finish 15a. The other possible pathway was radical route, in which PhSe• dimerized to reform 14a or added to C≡C bond in 13a to afford B. The subsequent anodic oxidation of B gave C, which underwent nucleophilic cyclization

C2 to C6 biobased carbonyl platforms for fine chemistry

• Jingjing Jiang,
• Muhammad Noman Haider Tariq,
• Florence Popowycz,
• Yanlong Gu and
• Yves Queneau

Beilstein J. Org. Chem. 2025, 21, 2103–2172, doi:10.3762/bjoc.21.165

• –Crafts alkylation products were then converted into an intermediate tryptaldehyde that underwent intramolecular olefination to form the targeted product [34]. Glycolic acid (GA) The growing impact of fossil fuel consumption has heightened the need for advancing renewable energy technologies. One

• and hydroxyketones. The catalyst could be recovered and reused five times without decreasing its selectivity and activity. Mechanistically, the reaction involves a Heyns-type rearrangement and subsequent intramolecular olefination (Scheme 22) [96]. Arandia et al. reported the application of the

• reaction involves the enantioselective organocatalyzed transfer of boronic acid to HFO followed by an intramolecular diastereoselective Passerini-type reaction. Varying the boronic acid enabled to reach high yields (Scheme 39) [124]. The tautomeric transformation of HFO to cis-β-formylacrylic acid was

The application of desymmetric enantioselective reduction of cyclic 1,3-dicarbonyl compounds in the total synthesis of terpenoid and alkaloid natural products

• Dong-Xing Tan and
• Fu-She Han

Beilstein J. Org. Chem. 2025, 21, 2085–2102, doi:10.3762/bjoc.21.164

• steps, respectively. As shown in Scheme 6 [58], the Cu-catalyzed 1,4-conjugated addition of 71 [59] with vinylMgBr followed by intramolecular Claisen condensation furnished bicyclic diketone 72 on a gram scale. Notably, for such a bicyclic substrate, it is quite challenging to achieve desymmetric

• intramolecular Diels–Alder reaction generated tricyclo[3.2.1.02,7]-octene 113. A two-step transformation including HAT hydrogenation and acetal C–H oxidation with RuCl3/NaIO4, 113 was converted into ketoester 114. The TFA-mediated C13–C15 bond cleavage of 114 proceed smoothly to give ring-opening products, which

• transformations of 121 generated bromodiene 122. Next, the metal–halogen exchange/intermolecular addition of 122 with aldehyde (+)-123 and in situ PtCl2-promoted hydrolysis and hydration gave tricyclic product 124. The BnMe3NOH-mediated intramolecular Michael/aldol cascade reaction of 124 constructed the C/D

Bioinspired total syntheses of natural products: a personal adventure

• Zhengyi Qin,
• Yuting Yang,
• Nuran Yan,
• Xinyu Liang,
• Zhiyu Zhang,
• Yaxuan Duan,
• Huilin Li and
• Xuegong She

Beilstein J. Org. Chem. 2025, 21, 2048–2061, doi:10.3762/bjoc.21.160

• . By analyzing the structure, we supposed that there might exist an inversed pathway in which tabertinggine could be converted into the ibogamine aza-[2.2.2] bridged skeleton through intramolecular aza-Michael addition of the enone moiety to form the C21–N bond and a subsequent C16–N bond cleavage

• might undergo benzylic oxidations and intramolecular dehydration to access a diaryltetrahydrofuran (THF) skeleton. Then, oxidation of one aryl group through phenol oxidation would generate a putative cyclohexadienone intermediate to be further captured by the other phenol to access eupodienone through a

α-Ketoglutaric acid in Ugi reactions and Ugi/aza-Wittig tandem reactions

• Vladyslav O. Honcharov,
• Yana I. Sakhno,
• Olena H. Shvets,
• Vyacheslav E. Saraev,
• Svitlana V. Shishkina,
• Tetyana V. Shcherbakova and
• Valentyn A. Chebanov

Beilstein J. Org. Chem. 2025, 21, 2021–2029, doi:10.3762/bjoc.21.157

• in 33–93% yields (Scheme 3; Table 3). According to the literature [31][53], this reaction proceeds through the formation of an iminophosphorane intermediate (Scheme 3), the product of a Staudinger reaction, which, however, was not isolated because it easily undergoes intramolecular cyclization on a

Aryl iodane-induced cascade arylation–1,2-silyl shift–heterocyclization of propargylsilanes under copper catalysis

• Rasma Kroņkalne,
• Rūdolfs Beļaunieks,
• Armands Sebris,
• Anatoly Mishnev and
• Māris Turks

Beilstein J. Org. Chem. 2025, 21, 1984–1994, doi:10.3762/bjoc.21.154

• rearrangements via the 1,2-silyl shift, enabled by the β-cation-stabilizing properties of silyl groups [19][20]. This phenomenon has been successfully employed in 1,3-difunctionalization events in both intermolecular [21] and intramolecular fashion [22] (Scheme 1B). Thus far such propargylsilane rearrangements

• likely formed via the allylic cation intermediate Int-1 (Scheme 2), from where on two competing mechanistic pathways are possible. Deprotonation of the β-H and reductive elimination affords diene 10. Alternatively, an intramolecular cyclization leads to silylindenes 11. We were interested to see whether

• described by us recently, among other possible transformations [21][22]. Interestingly, the addition of O-nucleophiles to form 1,3-carbofunctionalization products, can only be achieved in an intramolecular fashion. In the presence of an excess (5 equiv) of external an O-nucleophile R–OX (alcohol, carboxylic

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

• proposed mechanism to 21 involved the formation of an electron-deficient, resonance-stabilized radical species, followed by intramolecular alkylation of the unactivated alkene to generate radical 29 via a diastereoselective 5-exo-trig cyclization step. Radical intermediate 29 was trapped by 2,4,6

Enantioselective desymmetrization strategy of prochiral 1,3-diols in natural product synthesis

• Lihua Wei,
• Rui Yang,
• Zhifeng Shi and
• Zhiqiang Ma

Beilstein J. Org. Chem. 2025, 21, 1932–1963, doi:10.3762/bjoc.21.151

• intramolecular cyclization of 16 generated benzofuran 17 in 83% yield. After protecting the phenolic hydroxy group of 17, cross-metathesis (CM) with allylic alcohol 18 catalyzed by 13 furnished intermediate 19. Desilylation of 19 produced heliannuol G (20) and heliannuol H (21), with the structure of 21

• in intramolecular [7-exo] and [8-endo] cyclization, furnishing the 7-membered cyclic ether 40 and 8-membered cyclic ether 41, respectively. Finally, MOM deprotection produced (−)-heliannuol D (42) and (+)-heliannuol A (43). In 2002, Chênevert and co-workers completed the total synthesis of (S)-α

• suppress potential intramolecular acyl migration. To further improve the optical purity of monoester 53, a Pseudomonas aeruginosa lipase-mediated kinetic resolution was performed with ethoxyvinyl butyrate 54, ultimately achieving monoester 53 with 97% ee in 60% yield and the diester 53a. With

Stereoselective electrochemical intramolecular imino-pinacol reaction: a straightforward entry to enantiopure piperazines

• Margherita Gazzotti,
• Fabrizio Medici,
• Valerio Chiroli,
• Laura Raimondi,
• Sergio Rossi and
• Maurizio Benaglia

Beilstein J. Org. Chem. 2025, 21, 1897–1908, doi:10.3762/bjoc.21.147

• Margherita Gazzotti Fabrizio Medici Valerio Chiroli Laura Raimondi Sergio Rossi Maurizio Benaglia Dipartimento di Chimica, Università degli Studi di Milano, via Golgi 19, IT-20133 Milano, Italy 10.3762/bjoc.21.147 Abstract The stereoselective electroreductive intramolecular coupling of chiral

• for different N-benzyl benzaldimines in moderate to good yields. In 1991, Shono’s research group described the electroreductive intramolecular coupling of aromatic diimines, carried out in DMF in the presence of methanesulfonic acid in a divided cell equipped with a lead cathode, a carbon rod anode

• , and a ceramic diaphragm [44]. This method was found to be effective for synthesizing trans-2,3-diarylpiperazines through the intramolecular reductive coupling of 1,2-diimines and seven- and eight-membered heterocycles which were obtained in moderate to good yields via the cyclization of 1,3- and 1,4

Preparation of spirocyclic oxindoles by cyclisation of an oxime to a nitrone and dipolar cycloaddition

• Beth L. Ritchie,
• Alexandra Longcake and
• Iain Coldham

Beilstein J. Org. Chem. 2025, 21, 1890–1896, doi:10.3762/bjoc.21.146

• -containing compounds makes use of intramolecular 1,3-dipolar cycloaddition reactions [15], including examples with nitrone ylides [16][17][18][19][20][21][22]. Our research group has exploited this approach for the synthesis of alkaloids such as myrioxazine A and aspidospermidine [23][24]. With a nitrone 1,3

• approach. This generates the desired spirooxindole connected to a bicyclic amine, with functionality related to the natural products. It is likely that unactivated dipolarophiles could be successful in related intramolecular cycloadditions [18]. Hence this approach could allow access the spirooxindole and

Chiral phosphoric acid-catalyzed asymmetric synthesis of helically chiral, planarly chiral and inherently chiral molecules

• Wei Liu and
• Xiaoyu Yang

Beilstein J. Org. Chem. 2025, 21, 1864–1889, doi:10.3762/bjoc.21.145

• planarly chiral paracyclophanes [39]. Commenced with a macrocyclization precursor 36 featuring both a hydroxy group and an allenamide moiety, the CPA-catalyzed asymmetric intramolecular addition led to the successful construction of planarly chiral macrocycles 37 (Scheme 10). This method demonstrated broad

• acid substrates 43 which, upon treatment with ynamide 44, yielded the vinyl acetate intermediate INT-A (Scheme 13). Subsequently, the one-pot CPA-catalyzed intramolecular esterification of this intermediate afforded the planarly chiral macrocycles 45 with good yield and high enantioselectivity

• macrocyclization strategy [53]. Starting from the linear precursor 60 bearing two triazine moieties, the intramolecular SNAr reaction catalyzed by CPA 13 (30 mol %) led to macrocyclization, which produced the inherently chiral N3,O-calix[2]arene[2]triazines 61 with high enantioselectivity, albeit in moderate yield

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

• the time within 50% of the metastable isomer is thermally converted to the stable one [3]. It depends on the photoswitch class, solvent, substitution pattern, and temperature. For some photoswitch classes, proton exchange and intramolecular hydrogen bonds are known to accelerate the thermal relaxation

• bromide 47, followed by Fmoc protection of 56, Boc deprotection of 57, reduction of the NO2 group to NO and intramolecular Mills coupling to form 35h. Removal of the Fmoc protecting group under basic conditions affords the unsubstituted product 35d which, after N-alkylation or acylation affords the

• Wiedbrauk and Dube [93]. Double-bond-substituted hemithioindigos 93 are synthesised by functionalising 87 with an aliphatic or aromatic 88 and subsequent intramolecular aldol reaction to 90. Treatment with SOCl2 and with the aromatic nucleophile or a cross-coupling partner of choice affords 93 (Scheme 27

Fe-catalyzed efficient synthesis of 2,4- and 4-substituted quinolines via C(sp²)–C(sp²) bond scission of styrenes

• Prafull A. Jagtap,
• Manish M. Petkar,
• Vaishnavi R. Sawant and
• Bhalchandra M. Bhanage

Beilstein J. Org. Chem. 2025, 21, 1799–1807, doi:10.3762/bjoc.21.142

• cycloaddition, tandem annulation, intramolecular cyclization, and cross-coupling reactions are commonly employed under thermal conditions, utilizing metal catalysts based on Pd, Ru, Au, Cu, and Fe to access a wide array of substituted quinoline frameworks [29][30][31][32][33][34][35][36][37][38]. Conversely, in

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

• bromine atom and the π*-orbital of the quinoline-2-thione ring, rather than through π-type halogen bonding. Various C–N atropisomeric compounds and their intermolecular interactions in single crystals. Intramolecular associations detected in crystals of rac-1a and rac-1b. Intramolecular association

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

• its ability to form ion complexes and self-assemble into a stacking arrangement [12][13][14]. Therefore, understanding the energetics and polarity of fluorinated cyclopropanes is crucial for elucidating the intramolecular forces that govern the stability of molecular structures. Moreover, these

• preclude its synthesis, as the all-cis-1,2,3-trifluorocyclopropane framework has been successfully prepared in earlier studies [17]. To better understand the intramolecular interactions that govern the stability of fluorinated cyclopropanes, the sets of di-, tri-, and tetrafluorinated cyclopropane isomers

• intramolecular forces in fluorinated systems but also provide a molecular framework for the design of advanced applications. Fluorinated cyclopropanes exhibit considerable potential in pharmaceuticals, where polarity influences drug solubility and activity, and in material sciences, particularly for the

Convenient alternative synthesis of the Malassezia-derived virulence factor malassezione and related compounds

• Karu Ramesh and
• Stephen L. Bearne

Beilstein J. Org. Chem. 2025, 21, 1730–1736, doi:10.3762/bjoc.21.135

• -protected malassezione, which upon deprotection yields malassezione in an overall yield of ca. 20%. This is an improvement over the preparation of the isonitrile followed by an Fe hydride initiated isonitrile–olefin intramolecular coupling reaction, which generated malassezione with an overall yield of ca

• [20], or, more recently, (iii) prepared via an Fe hydride initiated isonitrile–olefin intramolecular coupling reaction (Scheme 1A) [18]. The reported synthetic route relies on an initial 4-step preparation of the isonitrile precursor, which was accomplished in an overall yield of ca. 14%. The

• . 20% (4 steps) relative to an overall yield of ca. 5% via the preparation of the isonitrile followed by the Fe hydride initiated isonitrile–olefin intramolecular coupling reaction [18]. Protection of the indole nitrogens with the Boc group was preferable to the use of benzyl protecting groups since

Approaches to stereoselective 1,1'-glycosylation

• Daniele Zucchetta and
• Alla Zamyatina

Beilstein J. Org. Chem. 2025, 21, 1700–1718, doi:10.3762/bjoc.21.133

• sucrose derivatives in plants [79][80][81]. In this case, the carboxymethyl group in the 2-thioethyl fructofuranoside was locked by an intramolecular bridge formed by the TIPDS group to the C4–OH [1,4-O-(1,1,3,3-tetraisopropyldisiloxane-1,3-diyl) bridge], resulting in a β-directing fructofuranosyl donor

• well known for their strong 1,2-trans-stereodirecting effect [44][90][91]. On the other hand, the use of N-Troc and N-Fmoc as protecting groups in GlcN-based lactol acceptors offers the advantage of stabilizing the α-configuration via an intramolecular hydrogen bond between the axial anomeric hydroxy

• unconventional approaches, including intramolecular aglycon delivery (IAD), are particularly impressive [114]. As the synthesis of α,α-1,1'-linked disaccharides has already been systematically reviewed [36], particularly with respect to the synthesis of trehalose-containing lipids of mycobacteria [37], this

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

Photocatalysis and photochemistry in organic synthesis

• Timothy Noël and
• Bartholomäus Pieber

Beilstein J. Org. Chem. 2025, 21, 1645–1647, doi:10.3762/bjoc.21.128

• ], hydrogen atom transfer [22], halogen atom transfer [23], and energy transfer catalysis [24][25] – have been established as powerful additions to the arsenal of photon-driven reactions. Three articles in this thematic issue exemplify this: The Molloy group developed an intramolecular [2 + 2]-cycloaddition

• of alkenylboronic esters using energy transfer catalysis [26]. Gualandi and co-workers leveraged a combination of photoredox and HAT catalysis to realize the intramolecular nucleophilic amidation of alkenes with β-lactams [27]. Further, Luridiana and colleagues developed a method for the alkylation

Formal synthesis of a selective estrogen receptor modulator with tetrahydrofluorenone structure using [3 + 2 + 1] cycloaddition of yne-vinylcyclopropanes and CO

• Jing Zhang,
• Guanyu Zhang,
• Hongxi Bai and
• Zhi-Xiang Yu

Beilstein J. Org. Chem. 2025, 21, 1639–1644, doi:10.3762/bjoc.21.127

• annulation to construct the C ring (cyclohexenone ring), and an intramolecular SN2 reaction to build the D ring (five-membered ring) [15][16][17][18]. In 2013, Wallace and co-workers disclosed the second route for this molecule (Scheme 2B) [19], in which the five-membered ring B was formed by utilizing

• is the retrosynthetic analysis for the key intermediate 1, which can reach the final compound VI via chlorination and demethylation [19]. Target molecule 1 can be accessed by decarboxylation reaction from compound 13, prepared by an intramolecular Heck reaction between the β-ketoester and the vinyl

Transition-state aromaticity and its relationship with reactivity in pericyclic reactions

• Israel Fernández

Beilstein J. Org. Chem. 2025, 21, 1613–1626, doi:10.3762/bjoc.21.125

• reaction coordinate, and particularly, at the transition state region. This results from the formation of a stabilizing, intramolecular CH3–OH···O=CH2 hydrogen bond at the initial stages of the process which brings together both reactants, significantly enhancing the orbital interactions (mainly HOMO–LUMO

• this case, as the reactions are intramolecular, the ASM terms are referred to the initial reactants and are computed by considering the interaction between E=CH• and •CH=CH–C≡CH radicals. As shown in Figure 8, although the change in the interaction (ΔΔEint) between the fragments is stronger for the

Synthesis of optically active folded cyclic dimers and trimers

• Ena Kumamoto,
• Kana Ogawa,
• Kazunori Okamoto and
• Yasuhiro Morisaki

Beilstein J. Org. Chem. 2025, 21, 1603–1612, doi:10.3762/bjoc.21.124

• ]paracyclophanes via Wurtz-type intramolecular cyclization [3]. [2.2]Paracyclophane has a molecular structure in which two benzene rings are stacked face-to-face with ethylene chains at the para positions. Various studies have been conducted on their reactivities and physical properties derived from their unique