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

• -oxidation (Scheme 4, above). For the assembly of 33, only the hydrolysis of previously reported 32 [75] with Me3SnOH and thioesterification using EtSH and DCC were necessary (Scheme 4, below). Both fragments (31 and 33) were fused together via NHK coupling to furnish 34 in 86% yield. The addition of SrCO3

• . 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

Synthesis of a HDAC inhibitor–nanogold probe for cryo-EM visualization in class I HDAC co-repressor complexes

• Wiktoria A. Pytel,
• John W. R. Schwabe and
• James T. Hodgkinson

Beilstein J. Org. Chem. 2026, 22, 480–485, doi:10.3762/bjoc.22.35

• domain within the CoREST complex. Keywords: CI-994; co-repressor complex; CoREST; cryo-EM; gold nanoparticle; HDAC; Introduction Histone deacetylase (HDAC) enzymes catalyze the hydrolysis of acetyl groups from N-acetylated lysine residues in histone proteins. HDACs are also capable of the deacetylation

• of non-histone proteins [1], and the hydrolysis of other acyl functional groups [2]. The human genome encodes 18 histone deacetylases (HDACs), which are divided into two main groups based on their catalytic mechanisms [3]. Eleven HDACs are zinc-dependent enzymes, while the remaining seven, known as

Structural reassignment of compound 968, an allosteric glutaminase inhibitor

• Lindsey A. Albertelli,
• Sainabou Jallow,
• Chun Li and
• Scott M. Ulrich

Beilstein J. Org. Chem. 2026, 22, 455–460, doi:10.3762/bjoc.22.33

• . Glutaminases catalyze the hydrolysis of glutamine to glutamate, which supports the biosynthesis of amino acids, lipids, and glutathione and can also be oxidatively deaminated to α-ketoglutarate and enter the citric acid cycle. The “glutamine addiction” of cancer cells has made glutaminase an attractive

• glutaminase enzymes GLS1 and GLS2 catalyze the hydrolysis of glutamine to glutamate and ammonia. Compound 968 is a dual inhibitor of GLS1 and GLS2. The cycloaddition reaction between an arylaldehyde (shown here is the specific aldehyde that produces compound 968), dimedone, and 2-naphthylamine was originally

Recent advances in the cleavage of non-activated amides

• Eun-Sol Choi and
• Hyo-Jun Lee

Beilstein J. Org. Chem. 2026, 22, 352–369, doi:10.3762/bjoc.22.23

• for the hydrolysis of amides (Scheme 3) [47]. In the presence of a catalytic amount of Nb2O5, N,N-dialkylamides 3 and 4 and anilides 5 and 10 were efficiently converted into the corresponding carboxylic acids 9 in high yields, and the Nb2O5 catalyst could be successfully recycled. The authors proposed

• undergoes hydrolysis to afford the benzyl ester 30. Under the optimized conditions, primary, secondary, and tertiary amides 12, 31–33 were successfully converted to benzyl esters in high yields. Notably, loss of enantiopurity of chiral amide 33 was not observed during esterification. Sulfuryl fluoride

• electrophilic activation of pyrrolidine-derived amides with Tf2O and 2-bromopyridine generates a keteniminium ion O, which undergoes nucleophilic addition to form an enamine intermediate P. Subsequent electrophilic α-fluorination followed by hydrolysis produces the α-fluoroester products. Notably, the C2-chiral

Synthesis of tricyclic fused pyrrolidine nitroxides from 2-alkynylpyrrolidine-1-oxyls

• Mark M. Gulman,
• Yuliya F. Polienko,
• Sofia Yu. Trakhininа,
• Yuri V. Gatilov,
• Tatyana V. Rybalova,
• Sergey A. Dobrynin and
• Igor A. Kirilyuk

Beilstein J. Org. Chem. 2026, 22, 344–351, doi:10.3762/bjoc.22.22

• acetoxy groups and reduction of the nitroxyl fragment to the corresponding hydroxylamine. Primary products were stirred with a solution of NaOH in methanol under aerobic conditions to achieve complete hydrolysis and regeneration of the nitroxide group. Pyrazole 9a was isolated with an overall yield of 33

Ring contraction and ring expansion reactions in terpenoid biosynthesis and their application to total synthesis

• Nicolas Kratena,
• Nicolas Heinzig and
• Peter Gärtner

Beilstein J. Org. Chem. 2026, 22, 289–343, doi:10.3762/bjoc.22.21

A mild and atom-efficient four-component cascade strategy for the construction of biologically relevant 4-hydroxyquinolin-2(1H)-one derivatives

• Dmitrii A. Grishin,
• Kseniia I. Sharkovskaia,
• Ilya G. Kolmakov,
• Daria A. Ipatova,
• Rostislav A. Petrov,
• Nikolai D. Dagaev,
• Dmitry A. Skvortsov,
• Maria G. Khrenova,
• Valeriy V. Andreychev,
• Sergei A. Evteev,
• Yan A. Ivanenkov,
• Roman L. Antipin,
• Olga А. Dontsova and
• Elena K. Beloglazkina

Beilstein J. Org. Chem. 2026, 22, 244–256, doi:10.3762/bjoc.22.18

• conditions. Subsequent transformations afford isopropyl and cyclohexyl analogues via hydrolysis–esterification. A preliminary biological evaluation revealed low cytotoxicity and modest antibacterial activity against Escherichia coli ΔtolC strains. This sustainable synthetic approach constitutes the first

• NaCN, wet DMSO, 160 °C) failed to yield the target product. Acidic and alkaline hydrolysis followed by decarboxylation also proved unsuccessful (Scheme 4E). Subsequently, following the second retrosynthetic approach (Scheme 2), compounds 2b and 2c were reacted with 3,4-dimethoxybenzaldehyde via Michael

• cyclohexyl esters directly via the four-component reaction, an alternative synthetic route was employed (Scheme 7). The corresponding acids 11a–c, derived from hydrolysis of methyl esters 10a–c and ethyl esters 9a–c with 5 M aqueous alkali in refluxing THF, were isolated in high yields (85–97%). Subsequent

Synthesis of diaryl phosphates using phytic acid as a phosphorus source

• Kazuya Asao,
• Seika Matsumoto,
• Haruka Mori,
• Riku Yoshimura,
• Takeshi Sasaki,
• Naoya Hirata,
• Yasuyuki Hayakawa and
• Shin-ichi Kawaguchi

Beilstein J. Org. Chem. 2026, 22, 213–223, doi:10.3762/bjoc.22.15

• hydrolysis of phytic acid without phytases is extremely difficult because of its hydrolysis resistance, and only a few studies have considered the utilization of phytic acid as a phosphorus source [6]. In recent years, industrial applications of phytic acid have been investigated for its potential

• groups [49][50][51][52], and thus phosphate esters easily undergo transesterification or hydrolysis reactions. Considering these factors, we assumed that shifting the reaction equilibrium of compounds derived from phenols containing strong electron-withdrawing groups toward phosphate diester formation

• S2 in Supporting Information File 1, phytic acid decomposed immediately after the oil bath temperature increased to 200 °C and released phosphoric acid into the reaction mixture. We assume that two types of phytic acid degradation occurred. One is a simple hydrolysis of the phosphate ester bond, and

Base-promoted deacylation of 2-acetyl-2,5-dihydrothiophenes and their oxygen-mediated hydroxylation

• Vladimir G. Ilkin,
• Margarita Likhacheva,
• Igor V. Trushkov,
• Tetyana V. Beryozkina,
• Vera S. Berseneva,
• Vladimir T. Abaev,
• Wim Dehaen and
• Vasiliy A. Bakulev

Beilstein J. Org. Chem. 2026, 22, 192–204, doi:10.3762/bjoc.22.13

• migration in the formed tetrahedral intermediate to afford formate ester; c) hydrolysis of the latter to form phenols [28]. The development of methods for the construction of heterocycles and their modification is an important area of organic synthesis [29]. Although the Dakin oxidation has become a

A new synthesis of Tyrian purple (6,6’-dibromoindigo) and its corresponding sulfonate salts

• Holly Helmers,
• Mark Horton,
• Julie Concepcion,
• Jeffrey Bjorklund and
• Nicholas C. Boaz

Beilstein J. Org. Chem. 2026, 22, 167–174, doi:10.3762/bjoc.22.10

• expense of waste treatment raise issues [8][9][11][12]. Others have produced the desired aldehyde by formation and subsequent hydrolysis of a nitrone, a route which requires four distinct steps, making it less desirable [13][14][15][16][17]. While there have been several syntheses of 1 using 3 as a key

• synthesis that does not require the use of chromium(VI) and, therefore, does not generate chromium waste that is costly to dispose of [23]. The literature reports that the oxidation of 3 to 4 can be performed using a high-valent chromium oxidation, followed by hydrolysis of the formed benzylidene diacetate

• with yields ranging from 18 to 60.5% yield relative to starting 3 [8][9][11][12]. Chromium-free oxidation of 3 to 4 has been reported via the condensation of 3 with an alkyl nitrate to yield an oxime. Subsequent hydrolysis of the oxime yields the desired aldehyde 4, but only in low yield [6][7

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

• % yield over two steps [76]. Alkylation with MeI furnished pyridinium 91, which was hydrogenated in two steps with NaBH3CN to the fully saturated piperidine 92. Acidic removal of the benzoyl group triggered auto-oxidation to the indole, and subsequent hydrolysis of methyl ester delivered the target

• , including hydroxylation of aryl halide, partial lactam reduction with cyanide trapping, and oxidation of the phenol, enabled the total synthesis of jorunnamycin A in 15 steps. The acetylation of the hydroxy group in jorunnamycin A followed by cyano hydrolysis led to the total synthesis of another natural

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

• can subsequently undergo hydrolysis in the presence of trace water to furnish the corresponding ketone (see Scheme 27, formation of ketone 167) [92]. Furthermore, Melloni were the first to demonstrate that highly hindered internal alkynes resist double HCl addition (Scheme 25) [93]. In cases where a

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

• hydrolysis of 9e furnished ethylmaltol (1) in 95% yield. Screening of different bases for the methylation step of 8e revealed LiHMDS to be superior to NaHMDS. Various tert-butoxide bases as well as 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) were ineffective for deprotonation (see Supporting Information File 1

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

• (22), an atypical antidepressant drug on the market [21][22][23][24][25], by hydrolysis of esters 20a and 21a (Scheme 3). Treatment of chloro derivative 19 with various alcohols afforded ethers 23, while its reaction with 2-(morpholin-4-yl)ethanethiol resulted in thioether 24 (Scheme 4). The structure

• ): reduction of 8 with NaBH4, followed by chlorination of alcohol 36 with SOCl2 and substitution of chloro derivative 37 with various amines resulted in compounds 38a–c. Tianeptine analogue 38d was obtained by hydrolysis of ester 38c. The synthesis of the new regioisomeric tetracyclic compounds containing the

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

• triflate formation followed by a palladium-catalyzed coupling reaction with AlMe3. The carbonyl group at C8, required for the subsequent aldol reaction, was introduced by enolate oxidation followed by Jones oxidation. Hydrolysis of the ketal at C11 afforded ketoester 64. A TBD (1,5,7-triazabicyclo[4.4.0

• ). Chemoselective epoxidation of the enone double bond in 69 yielded epoxide 70. A Wittig reaction of 70 with (methoxymethyl)triphenylphosphonium chloride and t-BuOK generated a methyl enol ether, which was unstable in the presence of the epoxide. During aqueous workup, simultaneous hydrolysis of the enol ether and

• intramolecular Diels–Alder reaction, affording 102 and 103 in 91% yield with a 1:6 ratio. The major product 103 was selected to investigate the tandem retro-Claisen/aldol reaction. Hydrolysis of the enol methyl ether in 103 under acidic conditions delivered triketone 104. Subsequent treatment of 104 with aqueous

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

• limitations in technical capabilities at the time, its absolute configuration remained undetermined. Over the subsequent two decades, its hydrolysis product ryanodol (4) and several structurally related analogs were isolated sequentially [9][10][11][12][13][14]. The absolute configurations of both 1 and 4

• the correct relative configuration undergoes hydrolysis of its spirocyclic lactone moiety under basic conditions to yield 13, establishing the critical C5 chiral center. Under acidic conditions, intermediate 13 undergoes ketal deprotection followed by successive intramolecular aldol reactions

• 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

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

• from the use of crotyl bromide as a mixture of geometric isomers. After installation of the crotyl group, hydrolysis of the acetonide group and oxidative cleavage of diol 16, oxime 17 was prepared through the condensation of the aldehyde with hydroxylamine in overall 59% yield. Upon oxidation with

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

• % of the final desired monomer 8 was also isolated in the coupling step, presumably due to hydrolysis of the allyl ester in the iron reduction step. The remaining allyl ester 7 was deallylated via Pd(PPh3)4 to afford the monomer 8 in 51% yield. Db2 Synthesis Db2 was prepared through a convergent

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

• reactions, probably involving ester hydrolysis or alkylating agent decomposition, can be avoided by omitting the external base. In addition, Na2S2O4 was investigated as a reductant in a DMF/water 9:1 (v/v) mixture at room temperature (Table 2, entry 6). In the presence of both K2CO3 and the alkylating agent

• acidification, however, the reaction afforded mixtures of the desired products and the corresponding carboxylic acids due to partial hydrolysis of the ester groups. This behavior was observed during cyclization of substrates 4a and 5a. In the case of substrate 6b, treatment with NaOMe resulted primarily in the

Palladium-catalyzed regioselective C1-selective nitration of carbazoles

• Vikash Kumar,
• Jyothis Dharaniyedath,
• Aiswarya T P,
• Sk Ariyan,
• Chitrothu Venkatesh and
• Parthasarathy Gandeepan

Beilstein J. Org. Chem. 2025, 21, 2479–2488, doi:10.3762/bjoc.21.190

• NH-unsubstituted carbazole bearing a nitro group by removing the pyridyl directing group [58]. Treatment of compound 2a with methyl triflate, followed by hydrolysis with sodium hydroxide, successfully delivered the deprotected carbazole 3 in 53% yield (Scheme 4b). Next, we demonstrated the reduction

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

• with a yield of 53% yield. The excess of base (t-BuOK) caused simultaneous decarboxylation and hydrolysis of ester 37, forming the new nortriterpenoid 39 with a pentacyclic ring A (Scheme 7). In the work of Rath et al. [32], a similar method was proposed for the interconversion of cycles in the

Synthetic study toward vibralactone

• Liang Shi,
• Jiayi Song,
• Yiqing Li,
• Jia-Chen Li,
• Shuqi Li,
• Li Ren,
• Zhi-Yun Liu and
• Hong-Dong Hao

Beilstein J. Org. Chem. 2025, 21, 2376–2382, doi:10.3762/bjoc.21.182

• ketal moiety was removed and the resulting intermediate underwent Wittig olefination to yield vinyl chloride 20. Subsequent hydrolysis and intramolecular esterification furnished intermediate 21, which was then subjected to C–H insertion [42][43][44]. To our disappointment, this ring closure still did

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

• , followed by acetylation of the resulting propargylic alcohol afforded 17 which was further advanced to 18 via copper-catalyzed selective displacement of the propargyl acetate with benzylamine and hydrolysis of the primary acetate. The primary alcohol of 18 was activated with PPh3/CCl4, triggering an

• regioselectivity and gave the desired cycloadduct 24 as the major product in 56% yield. From here on, removal of the TMS group with TBAF, followed by hydrogenolytic removal of the benzyl group and acidic hydrolysis of the formyl group, completed Siegel’s total synthesis of complanadine A. In addition, this

• underwent ketone release and amine-ketone condensation to form iminium ion 27. Under the same acidic conditions, enamide 26 underwent hydrolysis and tautomerization to form enol 28. Conjugate addition of enol 28 to iminium ion 27 gave 29 for the subsequent intramolecular Mannich cyclization to deliver 30

Recent advances in Norrish–Yang cyclization and dicarbonyl photoredox reactions for natural product synthesis

• Peng-Xi Luo,
• Jin-Xuan Yang,
• Shao-Min Fu and
• Bo Liu

Beilstein J. Org. Chem. 2025, 21, 2315–2333, doi:10.3762/bjoc.21.177

• southern furan moiety of 69. Finally, hydrolysis of the carbonate followed by oxidation of the resulting diol completed the Norrish–Yang cyclization precursor gracilisoid A (49). Irradiation of 49 under anaerobic conditions with a CFL, followed by treatment with silica gel, successfully generated a pair of

Halogenated butyrolactones from the biomass-derived synthon levoglucosenone

• Johannes Puschnig,
• Martyn Jevric and
• Ben W. Greatrex

Beilstein J. Org. Chem. 2025, 21, 2297–2301, doi:10.3762/bjoc.21.175

• sofosbuvir (2). Fluorination at C2 in the nucleoside results in metabolic stability and resistance to hydrolysis as it destabilizes the formation of a C1 oxocarbenium ion [5][6]. Trifluoromethylated γ-butyrolactones also find applications as antiviral agents, for example, lactone 4 which has activity against

• transfer all three chlorine atoms [32], dichlorinated ketone 10a was obtained in 88% yield following acidic workup. Similarly, treatment of enamine 9a with 3.0 equivalents of N-bromosuccinimide and acidic hydrolysis gave dibrominated material 10b in excellent yield. This procedure is attractive due to the

• the intermediate formate ester. Fluorination of enamine 9a with Selectfluor (SF) resulted only in hydrolysis with conditions adapted from Peng and Shreeves work [28]; and likewise, the base-promoted (KOt-Bu, LHMDS) fluorination of ketone 6 with Selectfluor was unsuccessful. However, when ketone 6 was