Chemoenzymatic synthesis of the cardenolide rhodexin A and its aglycone sarmentogenin

• Fuzhen Song,
• Mengmeng Zheng,
• Dongkai Wang,
• Xudong Qu and
• Qianghui Zhou

Beilstein J. Org. Chem. 2025, 21, 2637–2644, doi:10.3762/bjoc.21.204

• – sarmentogenin and ʟ-rhamnose connected by the C3–O bond. In the steroidal skeleton, both the A/B and C/D rings are cis fused, which is different from common steroids. Besides, the steroidal skeleton is moderately oxidized at the C3, C11, and C14 positions. The introduction of the hydroxy groups and the

• C14 β-OH group. The revised synthetic route is described in Scheme 2. At first, 4 was subjected to a Pd/C-catalyzed hydrogenation to afford the desired A/B-cis fused intermediate 7 along with its C5 epimer as a 2:1 separable mixture in a quantitative yield. By treating 7 with the Bestmann ylide

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

• ) and G (7) using a pseudoprolinic acid strategy to induce cis-amide bond formation, followed by desulfurization [19]. Despite achieving cyclization, this route involves intricate procedures, expensive starting materials, and has limited applicability to other segetalins. Given the limitations of

Recent advances in total synthesis of illisimonin A

• Juan Huang and
• Ming Yang

Beilstein J. Org. Chem. 2025, 21, 2571–2583, doi:10.3762/bjoc.21.199

• directly, the team adopted a strategy involving rearrangement from the more accessible cis-pentalene isomer. They first assembled the cis-pentalene core through an elegant intramolecular Diels–Alder (IMDA) reaction. Subsequently, the conversion from cis to trans-pentalene was achieved via a semipinacol

• , obtained as a 1.7:1 mixture of diastereomers after protection of one of the carbonyl groups in 19 as enol ether with BOMCl. A silyl-tethered intramolecular Diels–Alder reaction of the in situ generated 22 constructed the tricyclo[5.2.1.01,5]decane core bearing a cis-pentalene unit, yielding compound 23

• rearrangement of 28 enabled the rearrangement of cis-pentalene to trans-pentalene, delivering intermediate 29, which possesses the same carbon skeleton as the natural product. Further oxidation of the primary alcohol to a carboxylic acid, accompanied by TBS deprotection, afforded hemiketal 30. Finally, a White

Rapid access to the core of malayamycin A by intramolecular dipolar cycloaddition

• Yilin Liu,
• Yuchen Yang,
• Chen Yang,
• Sha-Hua Huang,
• Jian Jin and
• Ran Hong

Beilstein J. Org. Chem. 2025, 21, 2542–2547, doi:10.3762/bjoc.21.196

• three contiguous stereogenic centers (Scheme 1A). The pyran ring was constructed by a RCM reaction [16]. Subsequent functionalization of the alkene to install the 1,2-cis-hydroxy amine required 6 steps from the sterically more demanding side. In continuing our recent interest in accessing unusual

• intermediate 5 will be converted into the final target after installation of the urea and uracil motifs. Accordingly, a nitrone-based latent functionality approach [28] would be tunable from fully substituted tetrahydrofuran-derived nitrone 7. The cis-1,2-hydroxy amine could be derived from oxazoline 6 through

• malayamycin A and other related uracil nucleosides via a dipolar cycloaddition. The latent functionality strategy employing oxazoline to reveal the cis-1,2-hydroxyamine moiety proves to be feasible, circumventing the lengthy route for alkene functionalization required in previous syntheses. Although the

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

• construction of the tetracyclic core of Aspidosperma alkaloids. Our method involves an Ir-catalyzed PET reaction of K for the stereoselective formation of the cis-configured BC bicyclic core with an all-carbon quaternary center [25][26]. Computational studies suggest that the observed tandem PET reaction of K

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

• 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

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

• C7, forming synthon 60. Destruction of this tetrahedral intermediate with migration of the aryl group promoted the formation of intermediate 61, decarboxylation of which led to the cis-substituted product 62. The resulting ketone 62 was the key synthon in the synthesis of (−)-taiwaniaquinone H (11

• Dotson et al. [84] for cis/trans salts 159 (Scheme 30). The authors noted that photochemical experiments carried out in benzene solutions with benzylic esters cis-159 or trans-159 gave complex product mixtures. To achieve higher conversion, a photochemical reaction was carried out in the crystalline

• in the stabilization of cationic reaction intermediates [91][92]. Yokoshima and co-workers [93][94] developed an elegant approach to the total synthesis of the alkaloid huperzine Q (206) in racemic form (Scheme 37). In the process of synthesis, a cis-hydrindane core was prepared from the known

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

• purification techniques [62][63][64]. Synthesis of pyrrolo-isoxazolidines utilizing nitrosoarenes via the multicomponent strategy is indeed feasible [65][66]. In a similar manner, Chakraborty obtained diastereomer products, primarily in cis configuration, from the cycloaddition reaction of a fluoro or a furyl

• ]. The 28:72 exo/endo (cis/trans) isomer ratio (Table 1, entry 9), obtained in this cycloaddition reaction indicates that the endo transition state is more stable, and that the thermodynamically more stable trans isomer is the major product in the reaction proceeding diastereoselectively through this

• -H6a and cis-H6a) is shown in Figure 10 for the compound 3a. Conversely, when these two reagents were heated in toluene, the ratio of cis/trans diastereoisomers was observed to be 1:1 [107], indicating that a remarkable diastereoselectivity can be achieved when methyl laurate is used as a solvent. The

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

• or upon irradiation with light at 280 nm. Azobenzene Azobenzene is one of the most widely utilized photoresponsive units in the design and synthesis of photoswitchable rotaxanes. These photoswitches undergo trans–cis isomerization and are classified as T-type, due to the thermal reversibility of the

• stilbene photoswitchable unit on the axle and an α-cyclodextrin macrocycle, where different wavelengths were required to induce isomerization of each photoswitch. Furthermore, after converting both units from trans to cis, the cyclodextrin was trapped in the middle of the axle. This reversible, light

• unhindered macrocycle movement, enabling effective K+ ion transport. Upon photoisomerization, the cis isomer restricts the macrocycle’s motion and slows ion transport (Figure 6). Importantly, this switching is reversible, permitting precise light-triggered control of ion transport. Such photoswitchable 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

• products and pharmaceutical agents. In 2013, Chan and co-workers reported a ligand-controlled cycloisomerization of 1,7-enyne esters affording the selective synthesis of cis-tetrahydropyridinones and δ-diketones (Scheme 16) [24]. When NHC-ligated gold catalysts were employed, a cascade sequence comprising

• 1,3-acyloxy migration, 6-exo-trig cyclization, and 1,5-acyl migration proceeded, affording δ-diketone-substituted cis-1,2,3,6-tetrahydropyridine derivatives 75 (Scheme 16, path a). The phosphine-ligated catalysts promoted an alternative pathway cascade involving 1,3-acyloxy migration, 6-exo-trig

• cyclization, and hydrolysis, exclusively producing cis-tetrahydropyridin-4-one derivatives 77 (Scheme 16, path b). Mechanistic studies revealed that intermediate 74 could be stabilized by NHC ligands to facilitate 1,5-acyl migration, whereas phosphine ligands could accelerate proton dissociation in

Thiadiazino-indole, thiadiazino-carbazole and benzothiadiazino-carbazole dioxides: synthesis, physicochemical and early ADME characterization of representatives of new tri-, tetra- and pentacyclic ring systems and their intermediates

• Gyöngyvér Pusztai,
• László Poszávácz,
• Anna Vincze,
• András Marton,
• Ahmed Qasim Abdulhussein,
• Judit Halász,
• András Dancsó,
• Gyula Simig,
• György Tibor Balogh and
• Balázs Volk

Beilstein J. Org. Chem. 2025, 21, 2220–2233, doi:10.3762/bjoc.21.169

• hydrazino derivatives 5a,b with ketones 6a–e in the presence of bismuth nitrate pentahydrate catalyst in refluxing methanol with good to excellent yields (method A, step 1). As regards cis–trans isomerism, compounds (E)-7a and (E)-7f were isolated in high yields (94% and 84%, respectively), however, in 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

• 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

• reported by Strizhov et al. [125]. The liable equilibrium transformation requires precisely pH-controlled conditions. In neutral medium, the furanone is in the form of its cis tautomer, while upon a slight increase in the pH, its cyclic original tautomer undergoes a ring opening with the formation of

• acid, fumaric acid and ʟ-aspartic acid by biocatalysis in 91%, 79%, 94%, 97% yield, respectively, in the presence of enzymes such as maleate hydratase, maleate cis–trans isomerase, fumarase, or ʟ-aspartase [155]. C5 biobased carbonyl platforms Furfural Furfural is a versatile biobased C5 platform

Further elaboration of the stereodivergent approach to chaetominine-type alkaloids: synthesis of the reported structures of aspera chaetominines A and B and revised structure of aspera chaetominine B

• Jin-Fang Lü,
• Jiang-Feng Wu,
• Jian-Liang Ye and
• Pei-Qiang Huang

Beilstein J. Org. Chem. 2025, 21, 2072–2081, doi:10.3762/bjoc.21.162

• , we have communicated the revision of the structure of versiquinazoline H to 11. During and after the latter work, we undertook further investigation on the last step of our approach to chaetominine-type alkaloids, namely, the lactamization reaction for synthesizing 3,14-cis-chaetominines and the DMDO

• chaetominine B. Conclusion In summary, we have elaborated our epoxidation-triggered diastereodivergent approach to chaetominine-type alkaloids. As shown by the synthesis of (–)-isochaetominine A, the previously six-step total synthesis of 3,14-cis diastereomeric isochaetominines could be completed in five

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

• form a cis-substituted tetrahydrofuran (THF) moiety fused to the lactone with higher oxidation states. Notably, the phenyl ring contains three oxygen substituents in the form of alcohol and methoxy groups at different positions. Biosynthetically, the THF ring was supposed to be formed through a

• transformation was successfully achieved by using PhI(OAc)2 as oxidant, providing 7-O-demethylmonocerin, containing the cis-substituted THF ring with sole diastereoselectivity. Site-selective mono-methylation gave rise to monocerin. The bioinspired approach successfully found applications in the total synthesis

Solar thermal fuels: azobenzene as a cyclic photon–heat transduction platform

• Jie Yan,
• Shaodong Sun,
• Minghao Wang and
• Si Wu

Beilstein J. Org. Chem. 2025, 21, 2036–2047, doi:10.3762/bjoc.21.159

• temperature and the Tm of the isomerized cis-azobenzene is below room temperature, while others require solvent-assisted charging mechanisms [70][71]. This structural and functional diversity makes them particularly valuable for solar thermal storage applications. Feng et al. incorporated fluorinated

• comparisons highlight future directions for cross-material integration. The reversible trans–cis isomerization of azobenzene makes it an ideal model system for studying solar thermal fuels, as it enables both solar energy storage and heat release. While significant advances have been made, critical challenges

• , and hinders practical deployment. Third, azobenzene groups release energy through a process involving thermal relaxation or thermally induced cis–trans isomerization. Temperature critically governs the efficiency and kinetics of this process: elevated temperatures accelerate uncontrolled instantaneous

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

• ]. Their synthesis commenced with compound 150, which was converted into triol 151 in two steps. Treatment of triol 151 with catalyst 128 furnished monobenzoate 152 in 96% yield and 97% de. Subsequently, monobenzoate 152 was transformed into diene 153 in five steps. The cis-3,6-disubstituted dihydropyran

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

• stereoisomer has the ring-junction NC–H bond, the imide carbonyls, and the oxindole carbonyl all cis to one another across the two newly formed rings. This must arise from a preference for an exo transition state that places the incoming maleimide away from the oxindole carbonyl. The cascade chemistry allows

• of the dipolar cycloaddition process. In contrast, the dipolarophile dimethyl maleate gave predominantly one stereoisomer of the cycloadduct 8 (ratio of isomers 95:5) (Scheme 5). The stereochemistry of the major isomer was assigned from NOESY analysis, that indicated the methyl ester groups were cis

• to one another and cis to the ring junction NC–H. The relative stereochemistry of the oxindole quaternary stereocentre was less obvious from this method, but the coupling constants of the aliphatic ring protons in the 1H NMR spectrum had similar values to those in the adduct 5a, suggesting that the

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

• ) single bond N–N. The hydrazone pathway in protic solvents could be ruled out in cases when the energy of the s-cis-hydrazone was superior to the energy of the other two transition states. For further substituent effects on azoheteroarenes, we refer the readers to the following reports by Venkataramani

[3 + 2] Cycloaddition of thioformylium methylide with various arylidene-azolones in the synthesis of 7-thia-3-azaspiro[4.4]nonan-4-ones

• Daniil I. Rudik,
• Irina V. Tiushina,
• Anatoly I. Sokolov,
• Alexander Yu. Smirnov,
• Alexander R. Romanenko,
• Alexander A. Korlyukov,
• Andrey A. Mikhaylov and
• Mikhail S. Baranov

Beilstein J. Org. Chem. 2025, 21, 1791–1798, doi:10.3762/bjoc.21.141

• single either cis or trans stereoisomers, dependent on the heterocycle core used. Keywords: arylidene-azolones; cycloaddition; nitrogen heterocycles; sulfur heterocycles; thioformylium methylide; Introduction Spirocyclic derivatives of heterocycles occupy an important place in modern organic and

• relative configuration (cis or trans) of the substituents. Therefore, the structures of the obtained compounds were determined by single crystal X-ray analysis (Figure 1). Thus, all the obtained derivatives of oxo-rhodanine 6, rhodanine 8 and imidazolone 9 had a cis configuration, while the derivatives of

• thermodynamically stable cis- and trans- isomers were also obtained in the reaction with azomethine ylides [20]. Finally, we performed preliminary derivatization studies of the obtained spiro-tetrahydrothiophenes. Compounds 7 and 9 demonstrated remarkable stability under both acidic and basic hydrolysis conditions

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

• -affinity host–guest interactions between PA5 and these groups (mainly through phosphonate-quaternary ammonium ion pairing) [90]. Azobenzene guest molecules can achieve dual functions (on and off) as ligands through photo-induced cis-trans isomerization. Using pillar[6]arene as the ion channel, the host

• employed as an external trigger for supramolecular systems. Azobenzene can regulate geometry, shape, and interfacial curvature under ultraviolet or visible light irradiation. It undergoes cis–trans isomerization, which can trigger alterations in bioactivity or assembly configurations. Methods for creating

• to particular light wavelengths, displays reversible switching between its trans and cis forms, a molecular behavior well-documented in light-responsive systems. Initially, Azo-SMX, bearing an azobenzene unit, exists in a trans form and creates a stable complex with the PA5 component within the

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

• conversion of cyclopropane and methyl fluoride into mono-, di-, tri-, tetra-, penta-, and hexafluorinated cyclopropanes is exothermic, except for the all-cis-1,2,3-trifluorocyclopropane (1.2.3-c.c.). Compounds featuring geminal fluorines are particularly stabilized due to anomeric-like nF → σ*CF interactions

• . Generally, cis-C–F bonds are less favored than their trans counterparts, not primarily because of steric repulsion, but due to reduced stabilizing electron-delocalization interactions. Among the series, 1.2.3-c.c. stands out as the most polar compound, enabling unique stacking interactions between its

• applications. The all-cis-1,2,3-trifluorocyclopropane (1.2.3-c.c.) is expected to be the most polar compound within the series of fluorinated cyclopropanes, as the C–F bonds are aligned in the same direction. Similarly, all-cis-1,2,3,4,5,6-hexafluorocyclohexane is both the most polar and the least stable

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

• material S-3d but provided a mixture of cis- and trans-amides cis-S-5 and trans-S-5 (Scheme 3). The use of PdCl2(S-BINAP) complex as a precatalyst resulted in a longer reaction time and an exclusive formation of amide trans-S-5 with isomerized double bond (Scheme 4). The amide trans-R-5 was prepared

• . Cleavage of the N-Alloc group leading to a mixture of isomers cis-S-5 and trans-S-5. Cleavage of the N-Alloc group with PdCl2(S-BINAP) leading to trans-S-5 and trans-R-5. Cyclization of amides trans-S-5 and trans-R-5 to oxazolines S-6 and R-6. aza-Diels–Alder reaction of vinyloxazoline S-6 with TsNCO. The

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

• synthesis of neotrehalosamines related to the sugar moiety of the nucleoside antibiotic tunicamycin was performed using benzoylated 2-(benzoyloxyimino)-protected GlcN bromide donor 5, which enabled 1,2-cis stereochemical control through the non-participating C-2 benzoyloxyimino group, leading to the

• group, glycosylations with low-nucleophilicity β-lactol acceptors still resulted in notable amounts of 1,2-cis-linked disaccharides. To mitigate this, incorporation of a 4,6-O-benzylidene group proved advantageous, as it is known to significantly decrease the relative reactivity value (RRV) of

• synthesis of α,α-1,1-thioglycosides. 1,2-cis-Glycosyl thiols with different sugar configurations were obtained from 2-substituted (mostly 2-acetylated) hexopyranose or 6-deoxyhexopyranose glycals and thioacetic acid under UV irradiation (λmax = 365 nm) using a synergistic photosensitizer–photoinitiator pair

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

• [81]. From a mechanistic point of view, this process involves the initial formation of a bent-allene intermediate, which leads to the final reaction product via hydrogen shifts (Scheme 2) [82]. The so-called Bergman cyclization of cis-3-hexene-1,5-diynes [83][84], which is suggested to proceed through

• an in-plane aromatic transition state, is analogous to the first step of this transformation, known as Hopf cyclization. Indeed, our calculations [85] indicate that the parent Hopf cyclization involving cis-hexa-1,3-diene-5-yne occurs in a concerted manner through a transition state that features in

• -plane aromaticity in view of the computed NICS(3, +1) value of −12.0 ppm and diatropic induced ring current (Figure 7a). Interestingly, the analogous reaction involving cis-pent-2-en-4-yn-1-imine, where the terminal CH=CH2 group in the parent system was replaced by an imine CH=NH group, proceeds with a

Azobenzene protonation as a tool for temperature sensing

• Antti Siiskonen,
• Sami Vesamäki and
• Arri Priimagi

Beilstein J. Org. Chem. 2025, 21, 1528–1534, doi:10.3762/bjoc.21.115

• azobenzene core by introducing different functional groups to the phenyl rings. For these reasons, azobenzenes can be sensitized to various stimuli and easily integrated into different types of materials. While cis–trans isomerization is the most prominent property of interest for azobenzenes, there are also

• different azo compounds [23][24][25]. More recent work has harnessed protonation to enable red-light switching [12][13][26] and to control the stability of the cis-isomer [27][28][29]. These studies have focused on how protonation affects isomerization, with less attention given on how external stimuli