Total synthesis of natural products based on hydrogenation of aromatic rings

• Haoxiang Wu and
• Xiangbing Qi

Beilstein J. Org. Chem. 2026, 22, 88–122, doi:10.3762/bjoc.22.4

• 18, 20 to piperidine compounds using [CpRhCl2]2 as a metal catalyst and formic acid as a hydrogen source (Scheme 3) [45]. Different with other previous studies, this method allows for substituents at the 3-position of pyridine, enabling the rapid preparation of chiral piperidine compounds. It should

• tetrahydroquinolines by using dihydrogen or formic acid as the hydrogen source. In 2021 and 2024, Liu and co-workers demonstrated that with [NNP-Mn] catalysts, the hydrogenation of quinoline and its derivatives can proceed with high regio- and stereoselectivity [54][55] (Scheme 5). In 2022, Stoltz and co-workers

• range, the reaction was scaled up to the gram scale with high yield and high enantioselectivity. Recently, Du and co-workers reported a transition-metal-free asymmetric transfer hydrogenation reaction (Scheme 6) [58]. Under a hydrogen atmosphere, using chiral phosphoric acid and achiral borane as

Advances in Zr-mediated radical transformations and applications to total synthesis

• Hiroshige Ogawa and
• Hugh Nakamura

Beilstein J. Org. Chem. 2026, 22, 71–87, doi:10.3762/bjoc.22.3

• iodide 10n failed to give the desired products. In substrate 10o containing both iodide and bromide, selective activation of the alkyl iodide was observed, affording the coupled product in 96% yield. Furthermore, the reaction proceeded smoothly in the presence of alcohols 10p–q and carboxylic acid 10r

Synthesis and applications of alkenyl chlorides (vinyl chlorides): a review

• Daniel S. Müller

Beilstein J. Org. Chem. 2026, 22, 1–63, doi:10.3762/bjoc.22.1

• first synthesis of alkenyl chlorides from acyl chlorides was reported by Moughamir and Mestdagh in 1999 (Scheme 18A) [71]. They observed that strongly acidic solvents, including trifluoroacetic acid and methanesulfonic acid, provided the corresponding products in good yields with excellent

• stereoselectivity, exclusively yielding the Z-isomer. Nonan-2-one required activation with the stronger methanesulfonic acid and gave a 91:9 regioisomeric mixture of 91 to 92. 1-Tetralone provided the corresponding product 61 in only 7% yield; the acid additive was not specified in this case. The authors were

• unable to efficiently separate 61 from side product 94, which was likely formed via addition of acetyl chloride to 61 followed by conversion of the ketone to the alkenyl chloride. Regarding the mechanism (Scheme 18B), acid-catalyzed enolization of the ketone is proposed (enol I), followed by acetylation

One-pot synthesis of ethylmaltol from maltol

• Immanuel Plangger,
• Marcel Jenny,
• Gregor Plangger and
• Thomas Magauer

Beilstein J. Org. Chem. 2025, 21, 2755–2760, doi:10.3762/bjoc.21.212

• to 100 ppm depending on the application [1][2][3]. Numerous syntheses of ethylmaltol (1) have been developed, most of which can be categorized into two distinct approaches based on the respective starting materials (Scheme 1b): In the first case, a 4-pyrone such as kojic acid (3), readily available

• through fermentation, or a synthetic intermediate derived thereof is being utilized. For example, the 1969 Pfizer patent describes the oxidation of kojic acid (3) with molecular oxygen to comenic acid, which is then decarboxylated to yield pyromeconic acid. An aldol addition with acetaldehyde followed by

• from corncob to access pyromeconic acid [6]. The second group of synthetic strategies takes advantage of furfural (4), which originates from the acid-catalyzed dehydration of agricultural biomass. It is then converted with an ethyl Grignard compound to alcohol 5 [7]. From alcohol 5, oxidation state

Sustainable electrochemical synthesis of aliphatic nitro-NNO-azoxy compounds employing ammonium dinitramide and their in vitro evaluation as potential nitric oxide donors and fungicides

• Alexander S. Budnikov,
• Nikita E. Leonov,
• Michael S. Klenov,
• Andrey A. Kulikov,
• Igor B. Krylov,
• Timofey A. Kudryashev,
• Aleksandr M. Churakov,
• Alexander O. Terent’ev and
• Vladimir A. Tartakovsky

Beilstein J. Org. Chem. 2025, 21, 2739–2754, doi:10.3762/bjoc.21.211

• a mixture of acetic anhydride (3.4 mL, 36.0 mmol) and 100% nitric acid (0.6 mL, 13.2 mmol) at 0 °C, and the mixture was stirred at this temperature for 30 min. Then the reaction mixture was poured into ice-water (50 mL) and extracted with CH2Cl2 (3 × 20 mL). The combined organic phase was washed

Total synthesis of asperdinones B, C, D, E and terezine D

• Ravi Devarajappa and
• Stephen Hanessian

Beilstein J. Org. Chem. 2025, 21, 2730–2738, doi:10.3762/bjoc.21.210

• Bock in 1987 [16]. It is of interest that although the biosynthesis of 3-indolylbenzoquinone-2,5-dione ent-5 is initiated with ʟ-tryptophan and anthranilic acid [17], the resulting natural products 1–4 possess a (3R) configuration. This is because of an epimerization mediated by the non-ribosomal

• amorphous powder. Viswanathan [25] and Chen [28] reported a C-2 prenylation of tryptophan methyl ester mediated by acid salts and Lewis acids, respectively. A prenylation at C-4 in bis-N-Boc-tryptophan methyl ester has been achieved by Chein utilizing optimized Suzuki coupling conditions [29]. Results and

• conditions that would be incompatible with the presence of an amino acid appendage at C-3. 7-Prenylindole has been prepared from N-Boc-indoline in the presence of sec-BuLi, TMEDA, and prenyl bromide at −78 °C, followed by oxidation with MnO2 [51]. We deemed it necessary to explore alternative synthetic

Competitive cyclization of ethyl trifluoroacetoacetate and methyl ketones with 1,3-diamino-2-propanol into hydrogenated oxazolo- and pyrimido-condensed pyridones

• Svetlana O. Kushch,
• Marina V. Goryaeva,
• Yanina V. Burgart,
• Marina A. Ezhikova,
• Mikhail I. Kodess,
• Pavel A. Slepukhin,
• Alexandrina S. Volobueva,
• Vladimir V. Zarubaev and
• Victor I. Saloutin

Beilstein J. Org. Chem. 2025, 21, 2716–2729, doi:10.3762/bjoc.21.209

• -trifluoroacetoacetate and methyl ketones enables the synthesis to be carried out for octahydropyrido[1,2-a]pyrimidin-6-ones and hexahydrooxazolo[3,2-a]pyridin-5-ones, the preferential formation of which depends on the substituent in the methyl ketone component. Dual acid–base catalysis of the reactions with alkyl

• -1-yl)ethane-1,2-dione [57], or 4-(4-phenyl-2-(trifluoromethyl)oxazolidin-2-yl)butanoic acid under acidic conditions [58], and condensation of 6,6,6-trifluoro-5-oxohexanoic acid with (S)-(+)-phenylglycine [59]. The data on the multicomponent synthesis of fluoroalkyl-containing pyrido[1,2-a

• composition of the products, increasing the content of the trans,cis-form 4atc to 20%. The use of 1,4-dioxane with acetic acid catalysis at different molar ratios (Table 1, entries 7, 8) led to the formation of a large fraction of unidentified by-products (42–61%), whereas the base catalysis with

Tandem hydrothiocyanation/cyclization of CF₃-iminopropargyl alcohols with NaSCN in the presence of AcOH

• Ruslan S. Shulgin,
• Ol’ga G. Volostnykh,
• Anton V. Stepanov,
• Igor’ A. Ushakov,
• Alexander V. Vashchenko and
• Olesya A. Shemyakina

Beilstein J. Org. Chem. 2025, 21, 2694–2702, doi:10.3762/bjoc.21.207

• acid at the triple bond – vinyl thiocyanates. This protocol features simple operating, readily prepared starting materials and occurs under relatively mild conditions. Keywords: CF3-alkynyl imines; hydrothiocyanation; isothiazolium thiocyanates; propargyl alcohols; sodium thiocyanate; Introduction

• ionic liquid- [16] or lactic acid-catalyzed [17] reactions of alkynoates, KSCN and water under ultrasound conditions as well as by the reactions of alkynoates, KSCN and water using deep eutectic solvents [18]. Reddy and co-workers [19] proposed an approach to thiocyano enones through the

• cyclization to isothiazolones (Scheme 1). Silver- [20] and gold-catalyzed [21] hydrothiocyanations of haloalkynes with thiocyanate salts in acetic acid to give Z-vinyl thiocyanates were reported. The reaction between alkynic hydrazones and KSCN in AcOH/MeCN delivered N-iminoisothiazolium ylides [22] (Scheme 1

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

• . Compound 44 could then be subjected to a Nazarov cyclization, which was performed in a photochemical fashion, to close ring C. Further reduction and hydrogenation in ring D and an acid-induced spirocyclization of Nazarov-product 45 concluded the synthesis of cyclopamine. Notably, this total synthesis of

• moiety was introduced as a precursor to an aldehyde, which was obtained by reduction of 46 to 47. For the right-hand fragment (ring D, E, and F), an asymmetric hydrogenation of α-substituted acrylic acid 48 was performed, followed by redox manipulations to give aldehyde 49 over 3 steps in 95% and an

• selectively, and, through acid-catalyzed cyclization, the spiro-E-ring was fused. Elimination of the alcohol moiety at C13 installed the double bond in the correct position at C12–C13. Final Fmoc-deprotection furnished cyclopamine (6). In summary, the Zhu/Gao group disclosed the total synthesis of cyclopamine

Synthesis of new tetra- and pentacyclic, methylenedioxy- and ethylenedioxy-substituted derivatives of the dibenzo[c,f][1,2]thiazepine ring system

• Gábor Berecz,
• András Dancsó,
• Mária Tóthné Lauritz,
• Loránd Kiss,
• Gyula Simig and
• Balázs Volk

Beilstein J. Org. Chem. 2025, 21, 2645–2656, doi:10.3762/bjoc.21.205

• followed by basic hydrolysis afforded carboxylic acids 14 and 15. Ring closure of the latter compounds to tetracyclic derivatives 6 and 7 was carried out in one pot by SnCl4-catalyzed Friedel–Crafts cyclization of the acid chlorides obtained via reaction of 14 and 15 with phosphorus pentachloride. In the

• regioselectivity. Reduction of 51 with NaBH4 and subsequent chlorination of alcohol 52 with SOCl2 gave chloro derivative 53, which was treated with amines to afford compounds 54a–e. 7-Aminoheptanoic acid ester derivative 54e was hydrolyzed to tianeptine analogue 54f. Conclusion As continuation of our efforts to

• to 0–5 °C, and SnCl4 (47.28 g, 182 mmol, 21.2 mL) was added to the reaction mixture. The red suspension obtained was stirred at 0–5 °C for 1 h, then at room temperature for 2 h. It was poured onto a mixture of crushed ice (1500 g) and conc. hydrochloric acid (200 mL). It was stirred while warming to

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

• reagent [20], the key intermediate 8 bearing a butenolide motif was obtained in 76% yield. Next, with the aid of the strong Lewis acid Bi(OTf)3, the regioselective elimination of 8 was achieved to produce the Δ14 olefin intermediate 9 in 86% yield. Afterwards, we evaluated the reactivity of 9 towards

Thiazolidinones: novel insights from microwave synthesis, computational studies, and potentially bioactive hybrids

• Luan A. Martinho,
• Victor H. J. G. Praciano,
• Guilherme D. R. Matos,
• Claudia C. Gatto and
• Carlos Kleber Z. Andrade

Beilstein J. Org. Chem. 2025, 21, 2618–2636, doi:10.3762/bjoc.21.203

• [52], acetic acid [53], or solvent-free processes [54]. Ionic liquids, such as [Bu4N][OH] [55], [bmim][OH] [56], and [Et3NH][HSO4] [57], and deep eutectic solvents (DES) [58] have been introduced to improve efficiency. Traditional methods for synthesizing these compounds, however, face several

• ) [63]. Glacial acetic acid (AcOH) was initially selected as a hydrophilic (polar) protic solvent due to its high dipole moment, which makes it ideal for microwave reactions, as well as its ability to facilitate simple work-up procedures by simple addition of water [64]. Using sodium acetate (NaOAc) as

• mechanism involving the participation of ethylenediamine (EDA) is shown in Scheme 4. Initially, the basic EDA is protonated by acetic acid (AcOH), forming ethylenediamine diacetate (EDDA) in situ. The use of EDDA has been reported as a highly efficient catalyst for the synthesis of 5-arylidene-2,4

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

• (Caryophyllaceae), are head-to-tail cyclic oligopeptides comprising 5–9 amino acid residues [5][6][7][8][9][10][11][12][13]. These natural products exhibit a significant diversity of pharmacological activities [14][15][16], including estrogen-like activity (1, 2, 7, 8), antitumor effects (5), and antimicrobial

• ) 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

• electrospray ionization mass spectrometry (HRESIMS) data for all compounds matched the calculated exact masses for their respective molecular formulas. NMR spectroscopic analysis in appropriate deuterated solvents (e.g., DMSO-d6, D2O) fully corroborated the amino acid sequence and cyclic connectivity

Silica gel with covalently attached bambusuril macrocycle for dicyanoaurate sorption from water

• Michaela Šusterová and
• Vladimír Šindelář

Beilstein J. Org. Chem. 2025, 21, 2604–2611, doi:10.3762/bjoc.21.201

• . Additionally, a new absorption band at 1558 cm−1 was observed in the spectra of SG-NHCO-BU1 further confirming covalent attachment of BU1 through an amide bond. In the case of SG-BU1, a C=O vibrational band is observed at 1705 cm−1, which corresponds to the vibration of the C=O of BU1 carboxylic acid groups

Visible-light-driven NHC and organophotoredox dual catalysis for the synthesis of carbonyl compounds

• Vasudevan Dhayalan

Beilstein J. Org. Chem. 2025, 21, 2584–2603, doi:10.3762/bjoc.21.200

• Lewis acid-mediated traditional Friedel–Crafts acylation of 2-methoxynaphthalene typically proceeds at the ortho positions relative to the methoxy group due to the electron-rich nature of these sites, while the meta position remains deactivated under the ionic mechanism. Notably, the present work

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

• then converted to vinyl iodide 26 via hydrazine formation followed by iodination using Barton’s method. Subsequent Bouvealt aldehyde synthesis and in situ reduction delivered allylic alcohol 27. Epoxidation of 27 with m-CPBA afforded the rearrangement precursor 28. Protonic acid-promoted semipinacol

• 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

• , deprotonation, and intramolecular addition to ketone. Treatment of the silacycle with MeMgCl cleaved the Si–O bond and subsequent intramolecular nucleophilic substitution of the chloride with the adjacent hydroxy group yielded TMS-epoxide 41. Protonic acid-mediated opening of the TMS-epoxide, accompanied by TES

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

• compound 19. This intermediate is converted to lactone 20 via base-promoted Grob fragmentation followed by acid-mediated MOM deprotection. Epoxidation of the C10–C11 double bond in 20, lactone hydrolysis-promoted epoxide ring opening, and inversion of the C10 hydroxy configuration, yield the key

• secondary hydroxy group, successfully achieving the conversion of ryanodol (4) to 3-epi-ryanodol (5) and 3-epi-ryanodine (30) [45]. The specific synthetic route is as follows (Scheme 3): Beginning with ryanodol (4), an acid-promoted fragmentation yields anhydroryanodol (10). Subjecting compound 10 to Li/NH3

• natural product. Similarly, starting from 57, installation of an allyl group at C2, followed by oxidative cleavage, reduction, and deprotection, provided cinncassiol B (7). Subjecting this compound to an acid-promoted fragmentation reaction then completed the total synthesis of cinncassiol A (9

Ni-promoted reductive cyclization cascade enables a total synthesis of (+)-aglacin B

• Si-Chen Yao,
• Jing-Si Cao,
• Jian Xiao,
• Ya-Wen Wang and
• Yu Peng

Beilstein J. Org. Chem. 2025, 21, 2548–2552, doi:10.3762/bjoc.21.197

• ] by flash column chromatography in 30% yield. The stereocontrolled formation of aryltetralin 13 could be attributed to an adoption of a pseudo-half-chair conformation 5a. Finally, the final step towards the total synthesis of (+)-aglacin B (2) was achieved by treatment with BF3·Et2O as the Lewis acid

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

• 19 was moderate because the anomeric carbon at C7 is associated with an acid-sensitive acetonide group. The structural determination of the major product 19a was accomplished by comprehensive NMR spectroscopy and further unambiguously confirmed by X-ray analysis (see Supporting Information File 1 for

Synthesis and characterization of a isothiouronium-calix[4]arene derivative: self-assembly and anticancer activity

• Giuseppe Granata,
• Loredana Ferreri,
• Claudia Giovanna Leotta,
• Giovanni Mario Pitari and
• Grazia Maria Letizia Consoli

Beilstein J. Org. Chem. 2025, 21, 2535–2541, doi:10.3762/bjoc.21.195

• chains were tethered to the calixarene hydroxy groups (lower rim) by reaction with dodecyl iodide in the presence of NaH. At the upper rim of this derivative, four formyl groups were introduced by reaction with hexamethylenetetramine in trifluoroacetic acid. The formyl groups were reduced to alcohol

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

• acid (RNA) impacts many biological processes; however, the complexities of its many roles are not completely understood. Therefore, designing tools for molecular recognition is of paramount importance. Peptide nucleic acids (PNA) show promise as a tool for selective recognition of double helical

• oligonucleotides (TFOs) [8]. TFOs are utilized in both RNA and DNA recognition [9][10][11][12] and a particular type of TFO, peptide nucleic acid (PNA), has emerged as a promising probe for recognizing ncRNA [13][14][15][16]. The Nielsen lab first designed PNA with the N-(2-aminoethyl)glycine backbone for the

• functionalized. We noted that isoorotic acid offered an opportune core from which to prepare extended nucleobase monomers through amide bond formation (Figure 3a) [34]. Secondly, the work began with the initial goal to find an extended nucleobase scaffold capable of strong binding to A and then reverse its point

Assembly strategy for thieno[3,2-b]thiophenes via a disulfide intermediate derived from 3-nitrothiophene-2,5-dicarboxylate

• Roman A. Irgashev

Beilstein J. Org. Chem. 2025, 21, 2489–2497, doi:10.3762/bjoc.21.191

• formation of carboxylic acid 9bA, isolated in 71% yield (Scheme 7). In addition, an attempt to cyclize 6b in the presence of DBU without a solvent at 110 °C led to significant destruction of the substrate and product 9b was obtained with a yield of about 20%. Cyclization of substrate 4a with NaH in toluene

Ex-situ generation of gaseous nitriles in two-chamber glassware for facile haloacetimidate synthesis

• Nikolai B. Akselvoll,
• Jonas T. Larsen and
• Christian M. Pedersen

Beilstein J. Org. Chem. 2025, 21, 2465–2469, doi:10.3762/bjoc.21.188

• was the p-methoxy derivative 11 which, as expected, was more reactive and hence more difficult to purify due to decomposition on silica gel. The p-methoxybenzyl trifluoroacetimidate (9) has been shown to be an effective regent for the acid-catalyzed benzylation of alcohols [12][30]. Conclusion In

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

• (Figure 1) [19]. The introduction of an alkyl or aryl substituent in the anomeric center prevents free interconversion between pyranose and furanose forms; however, this transformation can still occur under specific conditions, typically in the presence of an acid catalyst. Even under such conditions, the

• furanose form through steric and electrostatic effects. In our previous work [24], we investigated the energetic aspects of the pyranoside-into-furanoside (PIF) rearrangement that proceeded under acid-promoted sulfation and whose mechanism was studied by us previously [25] along with the mechanism of

• , transformation of galactopyranosides to galactofuranosides under the action of TsOH in methanol [29] and silica-supported perchloric acid [30] is known. However, in both these cases di-O-isopropylidene ketals were used that underwent removal upon the isomerization leading to the loss of the aglycon. Recently, we

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

• , terpenoids, alkaloids, steroids and carbanucleosides. The spectrum of biological activities of the listed classes is wide and unique in efficacy. Natural prostaglandins are polyoxygenated derivatives of a hypothetical twenty-atom prostanoic acid, the C8–C12 atoms of which are contained in a cyclopentane ring

• . as a method for ring contraction of the cyclohexene ring to produce cytostatic taiwaniaquinoids [13][14][15]. Compound 4, derived from (–)-abietic acid, was subjected to an oxidative cleavage reaction to produce ketoaldehyde 5. Subsequent intramolecular aldol cyclization using 1,8-diazobicyclo[5.4.0

• explained to some extent by their structural diversity. Figure 1 shows the general formula of iridoids. The authors [16] have established regiocontrol of the effect of the 1,6-anhydro bridge on the Dieckmann condensation of dicarboxylic acid diester 16, obtained in four steps from 13, the Diels–Alder adduct