Synthesis and optical resolution of 4,5-diaminohomoadamantane: a promising scaffold for chiral ligands and bioactive compounds

• Polina A. Man’kova,
• Vadim A. Shiryaev,
• Olga S. Podlipnova,
• Marat M. Khisyamov,
• Dmitry S. Nikerov,
• Alexander N. Reznikov and
• Yuri N. Klimochkin

Beilstein J. Org. Chem. 2026, 22, 1013–1022, doi:10.3762/bjoc.22.80

• easily when the aziridine bears an electron-withdrawing group at the N-atom, we synthesized N-substituted aziridines 10–12 by reactions of 9 with Boc2O, TsCl, and Tf2O, respectively (Scheme 3). Compounds 10–12 were studied in the aziridine ring-opening reaction with sodium azide. Typically, N-Boc

• -substituted aziridines easily give the corresponding ring-opened products [77][88][89], however in our case only the starting compound 10 was isolated. In the reaction of tosylated compound 11 with sodium azide in the presence of ammonium chloride, trans- and cis-diastereomers of 13a,b were obtained (Scheme 4

Site-specific labelling of native peptides and proteins: chemical and enzymatic strategies

• Antonio Angelastro,
• Jonathan Bargh,
• Subhajit Guria,
• Victor Laserna and
• Louis Luk

Beilstein J. Org. Chem. 2026, 22, 857–881, doi:10.3762/bjoc.22.67

• branches: metabolic and in vitro glycoengineering. Metabolic glycoengineering introduces a non-natural sugar precursor, such as Ac4GlcNAz (34), Ac4ManNAz (35) and Ac4GalNAz (36, Scheme 12b) into living cells. These analogues enter the cellular glycosylation pathway, thereby incorporating azide motifs into

• native glycans for chemical attachment through bioorthogonal chemistry (e.g. strain-promoted azide–alkyne cycloaddition/SPAAC) [114][115][116][117][118][119]. While this strategy enables visualisation and derivatisation of native glycoproteins in their natural environment, metabolic labelling rarely

Towards the targeted protein degradation of CK2: design and synthesis of CAM4066-based PROTACs

• Sophie Day-Riley,
• Sona Krajcovicova,
• Aryaman Raj Sokhal,
• Jan L. Venne,
• Paul Brear,
• Marko Hyvönen,
• Benjamin C. Whitehurst,
• Jason S. Carroll and
• David R. Spring

Beilstein J. Org. Chem. 2026, 22, 611–619, doi:10.3762/bjoc.22.47

• complex. The azide–alkyne-derived triazole linkage may also impose a rigid orientation not compatible with CK2’s topology. Moreover, PROTACs typically display reduced cellular permeability owing to their high molecular weight and polar surface area [12]. This is particularly relevant given that CAM4066

Molecular tweezer–peptide conjugates disrupt the protein–protein interaction between survivin and histone H3 essential in mitosis

• Catherine Gsell,
• Philipp Rebmann,
• Karina Opara,
• Christine Beuck,
• Peter Bayer,
• David Bier,
• Ingrid R. Vetter and
• Thomas Schrader

Beilstein J. Org. Chem. 2026, 22, 557–567, doi:10.3762/bjoc.22.41

• as a barrier for the rearrangement of survivin’s side chains and the interaction diagram reveals contacts to all nine accessible acidic amino acids on the protein surface [14]. The new tweezer H3 conjugate 2a has a C4 spacer between the Lys-4 amide and the azide, very close to 1 with its C3 spacer

Experimental and DFT studies on the regioselective methanolysis of 5-azido-9-oxabicyclo[6.1.0]nonan-4-yl 4-nitrobenzoate isomers

• İlknur Polat,
• Selçuk Eşsiz and
• Emine Salamci

Beilstein J. Org. Chem. 2026, 22, 547–556, doi:10.3762/bjoc.22.40

• process, highlighting its precision and efficiency. Keywords: azides; 8-azidocyclooct-4-en-1-yl 4-nitrobenzoate; DFT; epoxycyclooctane azide; methanolysis; Introduction Organic azides are very important precursors for the preparation and synthesis of various nitrogen-containing compounds, as well as

• -ray analysis (Figure 2) [25]. X-ray analysis of azido compound 10 confirmed the trans configuration of the azide group with chloride and the cis configuration with the acetate. Our suggested mechanism for the ring-opening of the epoxides 9 with HCl(g) in MeOH proceeded as described in Scheme 3. As

• shown, the syn-face of the epoxide isomers 9a and 9b with the benzoate in 9a and the azide in 9b is more blocked than the anti-face. Therefore, the sterically hindering effect of these groups is observed in the syn-face. We assume that the chloride anion prefers to first attack the epoxide ring of

Modern synthetic pathways towards eribulin and its subunits

• Sebastian Dominik Graf

Beilstein J. Org. Chem. 2026, 22, 495–526, doi:10.3762/bjoc.22.37

• . Hydrolytic kinetic resolution of 209 afforded enantioenriched epoxide (S)-209, which was opened regioselectively with lithium acetylide. The allylation and [3 + 2]-cycloaddition with tosyl azide led to 212. Treatment with Rh2(OAc)4 induced a [2,3]-Wittig rearrangement and subsequent hydrolysis afforded 213

Cone p-aminocalix[4]arenes enriched with ‘clickable’ alkyne or azide functionalities

• Ilia Korniltsev,
• Vasily Bazhenov,
• Alexander Gorbunov,
• Dmitry Cheshkov,
• Stanislav Bezzubov,
• Vladimir Kovalev and
• Ivan Vatsouro

Beilstein J. Org. Chem. 2026, 22, 399–415, doi:10.3762/bjoc.22.28

• were ipso-nitrated followed by reduction of the nitro groups. To prepare 2-azidoethylated macrocycles, the ipso-nitration/reduction sequence was applied to p-tert-butylcalix[4]arenes containing 2-tosyloxyethyl groups at the narrow rims followed by replacement of the tosyloxy groups with azide ones. In

• excess benzyl azide or phenylacetylene, taken as representatives, under copper(I) catalysis, resulting in the narrow-rim triazolated macrocycles. By removing the Boc protecting groups and involving the free amino groups in reactions with p-tolyl isocyanate, a series of narrow-rim triazolated

• -aminocalix[4]arenes enriched with alkyne or azide functionalities can be readily used as multifunctional platforms to obtain even higher functionalized macrocycles. As an example, they can be used for the preparation of sophisticated supramolecular assemblies with homo- or heterodimeric calixarene cores and

Recent advancements in the synthesis of Veratrum alkaloids

• Morwenna Mögel,
• David Berger and
• Philipp Heretsch

Beilstein J. Org. Chem. 2025, 21, 2657–2693, doi:10.3762/bjoc.21.206

• -valerolactone). This was followed by an azide-Mitsunobu reaction and auxiliary removal with LiOBn to yield β-azido ester 115. Staudinger reduction of the azide moiety with PPh3 was accompanied by spontaneous cyclization to the lactam. The benzyl ester was converted to the aldehyde (2 steps), followed by

Efficient solid-phase synthesis and structural characterization of segetalins A–H, J and K

• Liangyu Liu,
• Wanqiu Lu,
• Quanping Guo and
• Zhaoqing Xu

Beilstein J. Org. Chem. 2025, 21, 2612–2617, doi:10.3762/bjoc.21.202

• synthetic approaches have encountered significant challenges. Sonnet et al. reported the first total synthesis of segetalin A (1) via Sasrin resin-based SPPS, followed by cyclization under highly dilute conditions (10−4 M) with diphenylphosphoryl azide (DPPA) [17]. While successful, this approach suffers

Pentacyclic aromatic heterocycles from Pd-catalyzed annulation of 1,5-diaryl-1,2,3-triazoles

• Kaylen D. Lathrum,
• Emily M. Hanneken,
• Katelyn R. Grzelak and
• James T. Fletcher

Beilstein J. Org. Chem. 2025, 21, 2524–2534, doi:10.3762/bjoc.21.194

• where the attachment of alkyne and azide functional groups was reversed, as summarized in Table 2. The azide analogs 19–24 [25][28][31][43] used in this study were prepared from commercially available amines using the Sandmeyer reaction (Table S2, Supporting Information File 1). Reaction of each azide

• prepared using non-brominated azide and alkyne reactants (Figure 4). Although 1,4-disubstituted-1,2,3-triazoles possessing quinoline and isoquinoline subunits are known [25][26][27][28][29][30][31][32][33][34][35][36][37][38][39][40][41][42][43][44], no prior examples of analogous 1,5-regioisomers have

• been reported. 1,5-Diaryl-1,2,3-triazole control compounds 37–42 were prepared via tandem deprotection/click reactions of TMS-protected alkynes with phenyl azide in yields similar to bromophenyl annulation precursors 7–12 and 25–30. Compounds 43–48, inverting the diaryltriazole connectivity, were

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

• in two steps [70]. The intermediate tricyclic ketone 137 was converted to the corresponding α-diazoketone through treatment with 2,4,6-triisopropylbenzenesulfonyl azide (trisylN3), KOH, tetrabutylammonium bromide (TBAB), and 18-crown-6. Concurrent cleavage of the benzoyl group under basic conditions

Comparative analysis of complanadine A total syntheses

• Reem Al-Ahmad and
• Mingji Dai

Beilstein J. Org. Chem. 2025, 21, 2334–2344, doi:10.3762/bjoc.21.178

• Barton–McCombie deoxygenation. The extra ethyl carboxylate was removed via a sequence of LiOH hydrolysis and a Curtius rearrangement using DPPA to form the corresponding acyl azide. Ketone 50 was produced in 98% yield over two steps. The newly formed ketone functionality enabled the introduction of the

• Scheme 5, the Dai synthesis starts with compound 58 which can be prepared from (+)-pulegone in three steps or via an organocatalyzed tandem sequence in one step. The terminal olefin of 58 was then converted to a primary azide via an anti-Markovnikov hydroazidation reaction with a combination of 59 and

• Paal–Knorr pyrrole synthesis delivered 63, which was unstable and spontaneously cyclized to provide 64. Compound 64 was then advanced to tetracyclic intermediate 67 in a one-pot tandem process, which initiated with Staudinger azide reduction with PPh3 to form a primary amine. After reversible

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

• anilinoquinazoline 3a. Deprotection of the methoxy group by BBr3 gave phenol 4a which was propargylated to intermediate 5a. A final click-type reaction [27][28][29][30][31] with azide 6 gave the first target intermediate 7a. The second key intermediate 7b was prepared in a very similar manner, but starting from 3

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

• piperazinone ring. Keywords: benzodiazepine; click reaction; multicomponent reaction; one-pot; piperazinone; polycyclic; triazole; tetrazole; Ugi–azide reaction; Introduction Triazole, tetrazole, and benzodiazepine are privileged heterocyclic rings commonly found in drug molecules and functional materials [1

• methods for the synthesis of tetrazoles [25][26][27][28], the Ugi–azide reaction is a good approach for constructing 1,5-disubstituted-tetrazoles (1,5-DS-T) [29][30][31]. This scaffold can be subsequently linked to 1,2,3-triazole [32], 4H-chromen-4-one [33], pyrrolo[3,4-b]indolizine [34], and other

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

• of carbamates as well [271]. Notably, the above approach provided imidazopyridines in high yields under aqueous solution without any metal catalysts. Early in 2008, an electrochemical copper(I)-catalyzed azide–alkyne cycloaddition (CuAAC) to access 1,2,3-triazole was realized by Finn [272]. But the

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

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

• 77 and subsequent deprotection produced tertiary alcohol 78. Starting from this common intermediate, on the one hand, through successive manipulations by diazotization and in situ azide substitution, AgNO3-mediated aza-Cope/Mannich [62] reaction delivered ketone 79. Subsequently, a three-step

• operation including azide–alkene dipolar cycloaddition, irradiation of the resulting triazoline to aziridine 80 and in situ ring opening followed by deacetylation achieved the first total synthesis of (−)-hunterine A (14). On the other hand, aza-Cope/Mannich reaction of 78 produced imine intermediate 81

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

• for the preparation of benzodiazepinone derivatives, which showed promising psychotropic effects [20][21][22][23][24], using a tandem combination of Ugi/azide–alkyne cycloaddition reactions. From this point of view, azido amines are promising reagents for use in the Ugi reaction, opening up the

• further purification after filtration. The use of starting components containing highly reactive groups, for example, an azide group, in the Ugi reaction provides opportunities for various post-cyclizations to obtain nitrogen-containing heterocyclic systems with potential biological activity [18]. To

• this case a carboxyl proton. In order to avoid the step of isolation of the intermediate azide derivatives 8, we also studied a one-pot method for the synthesis of compounds 9. For this KGA 1, aldehydes 2a,b, azidoanilines 7b,c, and tert-butyl isocyanide (4) were stirred in methanol at 45 °C for 24

Rhodium-catalysed connective synthesis of diverse reactive probes bearing S(VI) electrophilic warheads

• Scott Rice,
• Julian Chesti,
• William R. T. Mosedale,
• Megan H. Wright,
• Stephen P. Marsden,
• Terry K. Smith and
• Adam Nelson

Beilstein J. Org. Chem. 2025, 21, 1924–1931, doi:10.3762/bjoc.21.150

• isoindoline – were reacted with 2,2,6-trimethyl-4H-1,3-dioxin-4-one to give the corresponding β-ketoamides 4. Treatment of the β-ketoamides 4 with 4-acetamidobenzenesulfonyl azide (p-ABSA) and triethylamine gave the α-diazo-β-ketoamides 5. Subsequent KOH-mediated deacetylation yielded the corresponding α

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

• -triazoles 28 can be obtained by click chemistry (Scheme 6B) via one-pot deprotection of 26 and Cu(I)-catalysed reaction with an azide [43][44]. Heteroarylimines 31a,b can be easily obtained by condensation of a (hetero)aromatic aldehyde 30a,b with a (hetero)aromatic amine 29a,b [36][37][38] (Scheme 7). The

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

• triazaphospholes (Scheme 3) which can be further transformed into protio- and iodotriazaphospholes [101]. We first compared these metal cyaphide/azide cycloadditions with the analogous non-metallic process involving t-BuC≡P as dipolarophile [102][103]. Interestingly, we found that, although in all cases the

• electropositive magnesium atom whereas the stronger orbital interactions derive from a more stabilizing direct π(C≡P)→π*(azide) molecular orbital interaction coupled with a stronger reverse π(azide)→π*(C≡P) interaction. Conclusion Through selected representative examples, in this perspective article the interplay

Facile synthesis of hydantoin/1,2,4-oxadiazoline spiro-compounds via 1,3-dipolar cycloaddition of nitrile oxides to 5-iminohydantoins

• Juliana V. Petrova,
• Varvara T. Tkachenko,
• Victor A. Tafeenko,
• Anna S. Pestretsova,
• Vadim S. Pokrovsky,
• Maxim E. Kukushkin and
• Elena K. Beloglazkina

Beilstein J. Org. Chem. 2025, 21, 1552–1560, doi:10.3762/bjoc.21.118

• '-disubstituted ureas were initially reacted with oxalyl chloride to form imidazolidinetriones 1a,b, which were then added to an iminophosphorane formed in situ from an aryl azide and triphenylphosphine. As a result of the aza-Wittig reaction, 5-iminohydantoins 2a–i were then used as dipolarophiles in the 32CA

Azide–alkyne cycloaddition (click) reaction in biomass-derived solvent Cyrene^TM under one-pot conditions

• Zoltán Medgyesi and
• László T. Mika

Beilstein J. Org. Chem. 2025, 21, 1544–1551, doi:10.3762/bjoc.21.117

• CyreneTM, as a biomass-originated polar aprotic solvent, could be utilized as an alternative reaction medium for one-pot copper(I)-catalyzed azide–alkyne cycloaddition (click or CuAAC) reactions, for the synthesis of various 1,2,3-triazoles under mild conditions. Nineteen products involving N-substituted-4

• methods, the copper(I)-catalyzed azide–alkyne cycloaddition (CuAAC) reaction, the so-called click reaction [7], has received substantial attention for the selective synthesis of various 1,2,3-triazoles that are of utmost importance in the synthesis of biologically active compounds such as active

• -triazoles in a less toxic and recyclable medium could further control and reduce the environmental impacts of this synthetically very important transformation. Herein, we report a study on the copper(I)-catalyzed azide–alkyne cycloaddition (CuAAC) reaction in CyreneTM under mild conditions. Results and

Copper catalysis: a constantly evolving field

• Elena Fernández and
• Jaesook Yun

Beilstein J. Org. Chem. 2025, 21, 1477–1479, doi:10.3762/bjoc.21.109

• , Burley, Watson, and co-workers present a new synthesis of germyl triazoles from germyl alkynes through a copper-catalyzed azide–alkyne cycloaddition (CuAAC) reaction [6]. The resulting Ge-substituted triazoles could be further diversified. For example, through chemoselective transition-metal-catalyzed

Synthesis of β-ketophosphonates through aerobic copper(II)-mediated phosphorylation of enol acetates

• Alexander S. Budnikov,
• Igor B. Krylov,
• Fedor K. Monin,
• Valentina M. Merkulova,
• Alexey I. Ilovaisky,
• Liu Yan,
• Bing Yu and
• Alexander O. Terent’ev

Beilstein J. Org. Chem. 2025, 21, 1192–1200, doi:10.3762/bjoc.21.96

• from diisopropyl H-phosphonate (2a) was confirmed by HRMS analysis of the crude reaction mixture. Finally, vinyl azide 4a and silyl enol ether 4b were introduced into standard reaction conditions (Scheme 4, reaction 3). However, no phosphorylation product 3a was observed. On the basis of the obtained