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

• filtrate during this process and isolated as a diastereomeric mixture of 2.6:1. At first, the benzyl moieties of 66 were cleaved off and the diol was reprotected as acetonide to afford 67. The remaining secondary alcohol was PMB-protected and the olefin was oxidatively cleaved, before addition of a

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

• routes (Scheme 1) [14][15][18]. Intermediates 5–7 were prepared in a manner analogous to Smalley et al. [14]. The first step in the linker synthesis for Au–(CI-994) involved a monoprotection of nonanedioic acid with a benzyl group to give 5 which proceeded in moderate yield due to the formation of the

• dibenzylated by-product. Compound 5 was then coupled to the CI-994 intermediate 3 via HATU-mediated amide bond formation to produce 6 in good yield. Removal of the benzyl protecting group was performed by catalytic hydrogenation and acid 7 was obtained in near quantitative yield. Intermediate 7 was converted

• , 67%; e) TFA, DCM, 0 °C to rt, 20 h; (f) MP-carbonate resin, MeOH, rt, 3 h, 95%; g) benzyl bromide, 1,4-dioxane/DMF 1:1, 90 °C, 19 h, 45%; h) 3, 5, HATU, DIPEA, DMF, 0 °C to rt, 40 h, 59%; i) H2, 10% Pd/C, THF, rt, 19 h, 99%; j) N-hydroxysuccinimide, EDC, DMF, 0 °C to rt, 16 h, 90%; k) TFA, DCM, 0 °C

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

• 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

• conditions, followed by deprotection of the amino groups, and their conversion to urea moieties (Schemes 6–9). The propargylated calix[4]arenes 24–26 were reacted with benzyl azide in the presence of CuI activated with triethylamine (20 equiv per Cu, Scheme 6). Under these conditions all three reactions were

• . Synthesis of triazolated p-aminocalix[4]arenes 37–39 from the propargylated calixarene precursors 24–26. Conditions: i) benzyl azide, CuI, Et3N, toluene, rt. Synthesis of triazolated p-aminocalix[4]arenes 40 and 41 from the 2-azidoethylated calixarene precursors 35 and 36. Conditions: i) phenylacetylene

Dialkylaminoalkylation of β-ketosulfones via ring-opening of 3-sulfonylpyrrolidines

• Evgeny M. Buev,
• Alexander V. Pavlushin,
• Vladimir S. Moshkin and
• Vyacheslav Y. Sosnovskikh

Beilstein J. Org. Chem. 2026, 22, 383–389, doi:10.3762/bjoc.22.26

• -1-amines 4c–e,h were isolated in 40–69% yields (Scheme 2). Introduction of the m-nitro substituent led to partial resinification during the ring-cleavage step and significant decrease in the reaction outcome (products 4f,g). We have demonstrated that ethyl bromide, benzyl chloride, allyl bromide

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

• corresponding amide products 26 were obtained using only 10−4 mol % Pd(COD)Cl2 in combination with 1-benzyl-1H-1,2,3-triazole (L1). Based on kinetic curves, TEM images, catalyst poisoning experiments, MS identification of intermediates, and EPR spectra of the crude mixture, the authors proposed two kinetically

• electrophilic benzylating reagent (Scheme 7) [55]. DPT-BM functions as an O-benzylating reagent that generates benzyl cation equivalents upon dissolution in the solvent under non-acidic conditions. Thus, the reaction of an amide with DPT-BM is proposed to form a benzyl imidate salt J, which subsequently

• 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

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

• corresponding alkynylmagnesium bromides to nitrone 1 [20]. Radicals 2d and 2e were prepared in analogy to the known procedure using trimethylsilylacetylene and benzyl propargyl ether as the terminal alkynes (Scheme 1). Nitrone 1 was treated with a 10-fold excess of alkynylmagnesium bromide prepared in situ via

• metalation of trimethylsilylacetylene or benzyl propargyl ether with ethylmagnesium bromide. After quenching, removal of the MOP protecting group, and oxidation by atmospheric oxygen the nitroxides 2d and 2e were isolated in 64% and 66% yields, respectively. Terminal alkynes can be converted into

• to the methylene groups of the propargyl and benzyl fragments, respectively, and a multiplet of phenyl group in the range of 7.30–7.40 ppm (5H). Successful aminomethylation of the ethynyl group was confirmed by the appearance of two singlets at 3.01 ppm (6H) and 4.28 ppm (2H), attributed to the

Spirobarbiturates with a pyrrolizidine moiety: synthesis, structure and biological evaluation

• Arthur A. Puzyrkov,
• Andrew S. Drachuk,
• Ekaterina A. Popova,
• Alexander V. Stepakov and
• Vitali M. Boitsov

Beilstein J. Org. Chem. 2026, 22, 274–288, doi:10.3762/bjoc.22.20

• barbiturates [25]. Other methods include the DBU-mediated stereospecific cyclopropanation of barbiturate-based olefins with benzyl chlorides, developed by Chang’s group for the synthesis of spirobarbiturate-cyclopropanes [26]. Another interesting structural fragment is the pyrrolizidine heterocycle, which is a

Arene activation via π-bond localization: concepts and opportunities

• Paul Meiners,
• Julian J. Melder and
• Tobias Morack

Beilstein J. Org. Chem. 2026, 22, 257–273, doi:10.3762/bjoc.22.19

• remains untapped in catalysis, with only a few isolated examples of redox-mediated ligand substitution hinting at its feasibility [47]. η3-Benzyl complexes as intermediates in dearomative redox catalysis Binding and structure Within the landscape of redox catalysis, η3-benzyl complexes have emerged as

• principal platforms. Distinct from their η3-allyl counterparts, which readily isomerize between σ (η1) and π (η3) coordination, the η3-benzyl motif demands partial disruption of aromatic stabilization – an energetic penalty that must be compensated by the metal–ligand interaction (Scheme 5A). This challenge

• the first-of-its-kind η3-benzyl complex [70]. The resulting compound exhibited a striking upfield shift of the five aromatic proton resonances (2–5 ppm), and its C(3)–C(7) bond lengths alternated between 142 pm and 133 pm – hallmarks of π-bond localization within the arene [71][72]. Another notable

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

• -dimethylhydantoin (DBDMH) as an alternative bromine source led to more consistent yields (57%) of the desired benzyl bromide (Scheme 4B). Systematic variation of the stoichiometric amount of DBDMH indicated that the yield of 4-bromo-2-nitrobenzylbromide (6) was optimized using 0.6 equiv or 1.2 equiv of available

• Scheme 5A, dimethyl sulfoxide (DMSO) did not react with the benzyl bromide and instead only returned the starting material. The addition of 1.2 equivalents of silver nitrate promoted the substitution of the benzyl bromide with DMSO to yield an alkoxysulfonium ion 8 [22]. Following substitution, the

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

• corresponding vic-bis(dithiane) derivatives 16a–d. In 2018, Milsmann et al. reported the dimerization of benzyl bromide using a zirconium complex as a photosensitizer (Scheme 4) [14]. Heating a zirconium precursor with the pincer-type ligand 17, which can be synthesized in three steps from commercially

• a photosensitizer, together with compound 22 as a sacrificial reductant, in the dimerization of benzyl bromide (19). The desired dimerized product 20 was obtained in 40% yield. This study highlights the potential of zirconium complexes as a photoredox catalyst, pointing to promising opportunities

• development of efficient synthetic methods for its construction remains in high demand. Benzyl chlorides, which are inexpensive and readily available, have attracted attention as promising feedstocks. Against this background, Ota and Yamaguchi et al. in 2025 reported the dimerization of benzyl chlorides using

Reactivity umpolung of the cycloheptatriene core in hexa(methoxycarbonyl)cycloheptatriene

• Dmitry N. Platonov,
• Alexander Yu. Belyy,
• Rinat F. Salikov,
• Kirill S. Erokhin and
• Yury V. Tomilov

Beilstein J. Org. Chem. 2026, 22, 64–70, doi:10.3762/bjoc.22.2

• halogenation reactions. The reactions with methyl iodide and propargyl bromide resulted in equilibrium mixtures of α-alkylated cycloheptatrienes 5d,e and the corresponding norcaradienes 6d,e. At the same time, benzyl bromide afforded pure norcaradiene 6f in a good yield. Apparently, the formation of a pure

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

• mixtures of E- and Z-isomers (Scheme 40C). Notably, in these less-selective cases, excess alkyne was required to achieve synthetically useful yields. For example, compound 221 was obtained in only 15% yield when phenylacetylene and benzyl chloride were employed in a 1:1 molar ratio. Mayr and co-workers

• hydrocarbon precursors using DDQ, followed by interception with alkynes, was reported by Shi and co-workers (Scheme 47) [154]. However, the authors did not clarify whether the corresponding benzyl chloride was formed in the absence of the alkyne trapping agent (trapping of cationic intermediate by chloride

• Rodriguez subsequently reported a slightly modified procedure in 2017 (Scheme 67) [209]. In 2008, Charette reported that treatment of benzyl bromides with “NaICHCl” furnished the corresponding styrenyl chlorides in good yields and with high E-selectivity (Scheme 68) [210]. Pace and co-workers recently

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

• structure of 2c was confirmed by single-crystal X-ray analysis. The benzyl moiety was also tolerated, and the corresponding product 2e was obtained in 57% yield. 2,2-Dimethyl-5-nitro-5-nitroso-1,3-dioxane (1f) was successfully employed under the reaction conditions, leading to the formation of product 2f in

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

• attributed to the hindrance by the axial benzyl ether group on one side, and the C7 axial TBS ether group on the other. Removal of the silyl groups at C7 and C20 with CsF was followed by dihydroxylation of the C14,15-double bond, and the major product 105 was determined to be the desired α-diol by 1H–1H

• -NOESY and DFT calculations. The tertiary amine was masked as the hydrochloride salt with concomitant ketal deprotection, which was followed by hydrogenation to remove the benzyl protecting group to obtain (±)-4-methylenegermine hydrochloride (17·HCl) in 31 steps (LLS from commercial materials) and an

• -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

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

• -photocatalyst, leading to various β-aryl keto ester derivatives 20 in good to excellent yields. The key steps of the reactions undergo radical–radical cross-coupling with the alkyl ester radical E and benzyl radical B to afford the desired keto-esters 20 in up to 88% yield. This catalytic process displayed good

• catalyst. The anticipated meta-acylation product 32 was achieved through highly selective C(sp3)–C(sp3)-radical–radical cross-coupling between the cyclohexadienyl radical C and the benzyl radical species F, formed via single-electron reduction. This photochemical method overturns the traditional ortho and

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

• trans-esterification to give lactone 78. The resulting tertiary alcohol was protected as its benzyl ether to afford 79. A two-step oxidation protocol, analogous to Yang’s method, introduced the C8 carbonyl group, yielding 80. The final ring was closed via an intramolecular aldol reaction following

• Yang’s conditions [30], assembling the trans-pentalene to give 81. Finally, deprotection of the benzyl ether delivered (−)-illisimonin A (1). Lu’s gram-scale synthesis of illisimonin A In 2025, the Lu group reported a gram-scale total synthesis of illisimonin A in 15 steps from commercially available

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

• . While its mechanism remains incompletely understood, this additive’s unique efficacy in such transformations is unprecedented. Subsequent steps involved hydroxylation of the double bond and the protection of the vicinal diol as a dimethyl ketal giving ester 100. Oxidative dehydrogenation, benzyl

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

• addition of the acyl chloride to excess 9 was important to avoid forming bis-acylation of the phenylenediamine. The carboxylic acid 13 was formed using a microwave-promoted ring opening of glutaric anhydride (11) and benzyl-protected PNA backbone 12 [38]. A series of optimizations was performed in a

• perform equally well using conventional heating methods. Aniline 10 and carboxylic acid 13 were combined under standard (HBTU) amide coupling conditions to afford benzyl ester 14 in 52% yield. Compound 14 was subsequently debenzylated via hydrogenolysis to afford the target Db2 monomer 15 in 77% yield

• -nitroaniline into benzyl acrylate to afford compound 17 in 57% yield (Scheme 3). Aniline 17 then was subjected to a three-step Boc protection, nitro reduction, and coupling with isoorotic acid derivative 6 that afforded 18 in 39% yield over 3 steps. The benzyl ester was then cleaved under hydrogenolysis

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

• benzyl halides and other electrophiles were used under optimal reaction conditions to obtain various 3-(alkylthio)thiophene-2,5-dicarboxylates. Among them, compounds 4b–g, bearing benzylthio substituents, were prepared using different benzyl-type alkylating agents. It was found that the reaction

• (77% yield). For product 4b, methyl 4-(bromomethyl)benzoate was employed as the alkylating agent. In all other cases, benzyl chlorides were used for the alkylation. The alkylation with chloroacetonitrile afforded 3-(cyanomethyl)thio derivative 5a in 48% yield, shown in parenthesis in Scheme 6, while

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

• the formation of benzyl radical IN2, which has a boat-like seven-membered ring. This structural feature may facilitate formation of the C19–C12 bond, even in the presence of critical steric hindrance between the C5 quaternary carbon and the indole moiety. Further DFT investigation proved challenging

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

• glycosyl trifluoroacetimidates are more stable and hence easier to purify and store, whereas the more activated benzyl-protected analog 3 is unstable and decomposes in contact with silica unless the silica had been deactivated with triethylamine in the eluent. It was furthermore found that the best yields

• synthesis of several glycosyl haloacetimidates and benzyl fluoroacetimidates, with different substituent patterns. The method allows for a larger substrate scope of halonitriles than earlier methods and is easily facilitated by low cost commercially available equipment. Examples of methods for the synthesis

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

• the furanoside form. Thus it is possible to determine preliminary that the current PIF-rearrangement is regulated by thermodynamics in case of methyl-aglycons and by mechanistic restrictions in case of the phenyl-aglycon. Abbreviations Bz: benzoate; Bn: benzyl; TIPS: triisopropylsilyl; TBDPS: tert

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

• (BnOH, 2,4,6-collidine, 160 °C). The desired benzyl ester 126 was isolated as single diastereomer with a yield of 56% yield. Reduction of 126 with LiAlH4 followed by oxidation with Dess–Martin periodinane (DMP) led to the synthesis of a key aldehyde 127, with a yield of 75% in two steps. The target

• phase. Benzyl esters were cleaved, and the resulting carboxylic acids were converted into corresponding benzylammonium salts by addition of two equivalents of benzylamine. Subsequent irradiation of these salts in the form of a crystalline suspension in hexane led to ring-contraction products with a 95

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

• alkyne-nitrile partner, the undesired regioisomer (2,2’-bipyridyl product) was obtained as the major product. Switching the alkyne-nitrile partner from 19, bearing a benzyl group, to the formyl-substituted partner 23, combined with addition of 8 equivalents of PPh3, successfully inverted the

• 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

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

• involved at the ethyne moiety like substituted phenyl (30b–e), benzodioxole (30f), naphthyl (30g), thienyl (30h), pyridinyl (30i), furyl (30j), benzofuranyl (30k), alkyl (30l, 30m), cycloalkyl (30n–p) and trimethylsilyl (30r). This reaction was also compatible with benzyl ester (30s), propynyl ester (30t