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

• cyclization proved to be suitable, but only moderately yielding, procedures. Further, this pathway, with the exception of the coupling reaction between 167 and 171, involves only simple and mild transformations using standard reagents. As mentioned above, 186 served as an intermediate for the total synthesis

• thereafter, Nasam and co-workers developed a novel synthesis of 1`s fragment 272 using multiple asymmetric catalytic transformations (Schemes 29–31) [102]. 256 was synthesized from trans-crotonic acid and served as a starting material for the first building block (261, Scheme 29). Hosomi–Sakurai allylation

• sequence of 12 steps, which only included the use of cheap materials and preparatively simple transformations. Therefore, if the overall yield can be increased even further, this synthesis represents a useful alternative to existing pathways. Conclusion In summary, numerous advancements were made in the

Recent advances in the stereoselective synthesis of distal biaxially chiral molecules

• Fanxing Zhou,
• Chen Zhang,
• Lingyu Sun,
• Yiyun Fang,
• Siming Zheng,
• Lina Hu,
• Mengyang Shen,
• Zhen Zhao,
• Wei Xu,
• Yunqiang Sun and
• Zi-Qiang Rong

Beilstein J. Org. Chem. 2026, 22, 461–479, doi:10.3762/bjoc.22.34

• induce axial chirality. In this approach, the initial formation of one or more stereogenic centers establishes a defined three-dimensional framework, which subsequently guides the generation of one or more chiral axes through cyclization, oxidative aromatization, or related transformations. This central

Concept-driven strategies in target-oriented synthesis

• David Yu-Kai Chen,
• Chao Li and
• Yefeng Tang

Beilstein J. Org. Chem. 2026, 22, 451–454, doi:10.3762/bjoc.22.32

• (vibralactone, Zhi-Yun Liu, Hong-Dong Hao et al.), interrupted [2 + 2]/retro-Mannich (aspidosperma alkaloids, Zhen Yang, Zhong-Chao Zhang et al.), dipolar cycloaddition (malayamycin A, Sha-Hua Huang, Jian Jin, Ran Hong, et al.), Zr-mediated radical transformations (review, Hugh Nakamura and co-worker)]. The

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

• tetraureacalix[4]arenes was obtained. Examination of the 1H NMR spectra of the tetraureas in CDCl3 showed that in most cases triazole heterocycles do not intervene the formation of homo- and heterodimeric capsules by these compounds. Thus, considering the synthetic value of CuAAC and amine transformations, p

• herein report on the synthesis approaches to a series of cone p-aminocalix[4]arenes having propargyl or 2-azidoethyl groups at the narrow rims (Figure 1). The newly synthesized compounds may be thus treated as novel building blocks in calixarene chemistry capable of step-wise orthogonal transformations

• compatible with propargyl or 2-azidoethyl functionalities residing at the calixarene narrow rims, these ‘simple’ transformations are not applicable to the available propargylated/2-azidoethylated p-tert-butyl- or p-H-calix[4]arenes. Therefore, the multistep reaction sequences presented below have been

Electrosynthetic access to unsymmetrical oxaza[8]helicenes with high chiral stability and strong circularly polarized luminescence (CPL)

• Tin Zar Aye,
• Rubal Sharma,
• Muthu Karuppasamy,
• Daiya Suzuki,
• Haruka Nakajima,
• Yoshitane Imai,
• Mitsuhiro Arisawa,
• Mohamed S. H. Salem and
• Shinobu Takizawa

Beilstein J. Org. Chem. 2026, 22, 372–382, doi:10.3762/bjoc.22.25

• characteristic transformations of the organosulfur functionality [32][33]. In 2024, Badani, Karnik, and co-workers accessed one member of this class, 7,12-dioxa[8]helicene I, through a sequence featuring photochemical E–Z isomerization, electrocyclization, and oxidative aromatization [34]. In parallel, Liu and

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

• ]. Such activation has enabled a wide array of transformations, including metal-catalyzed cross-couplings via oxidative addition into the amide C–N bond (Scheme 1c) [32][33][34][35][36], and transition-metal-free acyl substitutions facilitated by improved leaving-group ability [37][38][39][40]. Although

• -promoted transformations enhanced by alkali-metal counter-cation effects, and (iii) installation of activating groups on the nitrogen to enable chemoselective cleavage under tailored conditions. These approaches collectively offer promising avenues for the efficient transformation of non-activated amides

• activation assisted by alkali metal counter cations Although strong bases can promote nucleophilic transformations of amides, such reactions have traditionally required harsh conditions [69][70]. Recently, however, the role of alkali metal counter cations in facilitating acyl substitution has been recognized

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

• secured. Organic synthetic chemistry can help to fill gaps or evaluate, support or revise initially implausible proposed biogenesis routes by attempting to mimic these transformations (= bioinspired or biomimetic synthesis) [11][12][13][14][15][16][17][18]. In general, the biogenesis of unique carbon

• Moving on from these carefully characterised biosynthetic transformations, where often single steps were carried out with specific enzymes or isotope-labelled substrates to prove origin, we now move to the much larger body of speculative biosynthetic relationships. From macrocyclic lathyrane frameworks

• previous studies, no detailed studies on the transformations connecting all these families have been performed thus far [133][134][135][136]. Novel Euphorbia diterpenoids recently isolated by Wang, Zheng and Yu in 2024 (see Scheme 23A) could be considered “missing links” offering an explanation as to how

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

• transformations for the synthesis of complex, three-dimensional molecular architectures with tailored physicochemical properties. Despite notable advances in dearomative methodologies over the past decades, the selective and controlled disruption of the aromatic core continues to represent a fundamental challenge

• disrupting the aromatic core, such as electrophilic and nucleophilic aromatic substitutions, transition metal-catalyzed cross-couplings [11], and C–H functionalizations [12]. Taken together with their natural abundance, these transformations have established arenes and heteroarenes as versatile synthetic

• aromaticity and unveiling the latent double-bond character within the aromatic ring. This dramatically increases reactivity, enabling alkene-like transformations with aromatic molecules that are inaccessible by conventional synthetic methods, thereby complementing traditional arene chemistry. Other modes of

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

• acids followed by sequential Michael-type addition and subsequent cascade transformations. This versatile one-pot protocol delivers structurally diverse open-chain 3-arylpropanoate esters in moderate to good yields (46–69%), while cyclic pyranoquinolinones are formed under kinetically controlled

• 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

Screwing the helical chirality through terminal peri-functionalization

• Devesh Chandra,
• Sachin and
• Upendra Sharma

Beilstein J. Org. Chem. 2026, 22, 205–212, doi:10.3762/bjoc.22.14

• substitution pattern along the plane of symmetry, is known as planar chirality, as seen in metallocene and cyclophanes. Molecules containing planar chirality have greater relevance in materials science and stereoselective transformations [12][13]. The fourth branch of the chiral tree is helical chirality. A

• further transformed into representative derivatives. Notably, the reaction performed well in the scale-up demonstration and the post-synthetic transformations proceeded smoothly without hampering the enantiomeric excess (Scheme 2). Another report applying peri-C–H functionalization for the synthesis of

• enantiomeric excess and diastereomeric ratio (Scheme 3). The developed protocol was also tested for up-scale synthesis and post-synthetic transformations. Notably, the reaction worked well at a 4.0 mmol scale providing product 8g in quantitative yield and >99% ee. This product was further reduced to the

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

• , Leuven B-3001, Belgium 10.3762/bjoc.22.13 Abstract Solvent-dependent transformations of polysubstituted 2-acetyl-2,5-dihydrothiophenes to the corresponding 2-hydroxy- or deacetylated derivatives are described. The treatment of a methanolic solution of the dihydrothiophene substrates with sodium

• methoxide afforded the deacylated products. Conversely, the treatment with sodium ethoxide in an oxygen saturated ethanolic solution produced 2-hydroxy substituted 2,5-dihydrothiophenes. Keywords: 2-acetyl-2,5-dihydrothiophenes; deacylation; 2-hydroxy-2,5-dihydrothiophenes; transformations; Introduction

• Oxidative transformations are an important area of modern organic synthesis [1], producing a broad range of valuable synthetic products for the industry. A variety of catalytic reactions were developed for the oxidative conversions of unsaturated compounds [2][3][4][5], alcohols [6][7], alkanes [8][9][10

Circumventing Mukaiyama oxidation: selective S–O bond formation via sulfenamide–alcohol coupling

• Guoling Huang,
• Huarui Zhu,
• Shuting Zhou,
• Wanlin Zheng,
• Fangpeng Liang,
• Zhibo Zhao,
• Yifei Chen and
• Xunbo Lu

Beilstein J. Org. Chem. 2026, 22, 158–166, doi:10.3762/bjoc.22.9

• , such transformations remain synthetically challenging. This is primarily due to the well-known Mukaiyama-type oxidation, wherein sulfenamides serve as redox catalysts for NBS- or NCS-mediated oxidations of alcohols to aldehydes or ketones (Scheme 1b, top) [38][39][40][41][42]. Under such oxidative

Asymmetric Mannich reaction of aromatic imines with malonates in the presence of multifunctional catalysts

• Kadri Kriis,
• Harry Martõnov,
• Annette Miller,
• Mia Peterson,
• Ivar Järving and
• Tõnis Kanger

Beilstein J. Org. Chem. 2026, 22, 151–157, doi:10.3762/bjoc.22.8

• efficient in Mannich reactions, as demonstrated by our studies [18] and those of others [19][20][21]. Halogen bonding has also been introduced to further broaden the field of noncovalent interactions. Despite the limited number of asymmetric transformations driven solely by halogen-bond activation [22

Highly electrophilic, gem- and spiro-activated trichloromethylnitrocyclopropanes: synthesis and structure

• Ilia A. Pilipenko,
• Mikhail V. Grigoriev,
• Olga Yu. Ozerova,
• Igor A. Litvinov,
• Darya V. Spiridonova,
• Aleksander V. Vasilyev and
• Sergey V. Makarenko

Beilstein J. Org. Chem. 2026, 22, 123–130, doi:10.3762/bjoc.22.5

• biologically active properties. Thus, barbamide exhibits molluscicidal activity [7], and sintokamide A is active against prostate cancer [8] (Figure 1). As derivatives of strained and unique structure and properties [9][10] cyclopropanes are of interest for entering into various transformations along the path

• -3,3,3-trichloropropene (1) [40] in reactions with nucleophiles, including those following the formation of cyclic products in tandem transformations [41][42][43][44], methods for obtaining cyclopropane structures based on it are not known. In this way, it seemed desirable to synthesize vicinal

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

• , which perfomed as a key substrate for the aerobic oxidation. The formation of the tetracyclic 3-spirooxindole structure 137 was achieved through a transition-metal-free intramolecular cross-dehydrogenative coupling. With 137 in hand, a sequence of transformations including ketone reduction with NaBH4

• into the zwitterionic salt 166, extensive screening revealed that iridium catalysis with MeO-BoQPhos afforded the highest stereoselectivity. This approach furnished the reduced product 167 in high yield. After five further transformations (overall yield: 67%), the final coupling with a benzimidazole

• mechanistic hypothesis. Based on this stereochemical control, the Stoltz team successfully obtained the asymmetric hydrogenation product 176, which spontaneously underwent intramolecular cyclization to furnish the bridged cyclic compound 177. With compound 177 in hand, a series of three transformations

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

• and discovery of two-electron ionic transformations dominated the early stages. Over time, pericyclic reactions exemplified by the Woodward–Hoffmann rules and one-electron radical processes became prominent research topics. Today, many of these classical transformations have been further refined to

• and accelerating the whole process. Zr-mediated catalytic radical reactions In recent years, numerous chemical transformations employing photoredox catalysts in combination with catalytic amounts of zirconium complexes have been reported. In this section, representative examples of such reactions are

• for further development in this area. In 2022, Ota and Yamaguchi et al. reported the zirconocene-catalyzed ring-opening of epoxides using Cp₂Zr(OTf)2·THF (Scheme 5) [4]. Traditionally, such transformations are carried out with low-valent titanium catalysts, which typically proceed via more substituted

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

• recognized. This review provides a comprehensive overview of the synthesis and application of alkenyl chlorides, with a focus on developments over the past four decades. By organizing this growing body of work, I aim to highlight key advances and help guide the design of new transformations involving this

• (Figure 3I). It should be noted that the review by Petrone and Lautens also covers some hydrochlorination chemistry. A concise three-page overview of alkenyl chloride synthesis appeared in 1995 in a book chapter “Comprehensive Organic Functional Group Transformations” by C. J. Urch [42]. Lastly, Cao and

• and classification of these transformations – excluding decarboxylative processes – is provided in Figure 4. Each class is discussed in detail in chapter 1. However, several transformations do not fit cleanly into the defined categories and are therefore discussed under miscellaneous reactions

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

• applications in organic synthesis as precursors for free radicals in selective transformations [5][6][7][8][9][10][11] and polymerization initiators [12], energetic materials [13][14][15], NO donors [16][17], and organic light-emitting diodes (OLEDs) [18]. Despite the wide diversity of their applications

• transformations that may have additional energy barriers (not estimated). Assessment of the NO release from compounds 2a–i, 3f, and 4f. Current synthetic approaches to aliphatic nitro-NNO-azoxy compounds and the summary of the present work achievements. Scope of the discovered electrochemical nitro-NNO

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

• to be obtained in one stage using commercially available reagents [1][2][3]. Their ambident properties make 3-oxo esters convenient reagents for the use in multicomponent syntheses, with the Hantzsch [4][5] and Biginelli [6][7][8] reactions being the best known. In the transformations, 3-oxo esters

• the mechanistic aspects of these transformations. Our team has discovered a new multicomponent synthesis that is based on autocatalyzed reactions of ethyl trifluoroacetoacetate and other polyfluoroalkyl-3-oxo esters with α-methylenecarbonyl compounds and amines [9]. This approach is appropriate only

• octahydropyrido[1,2-a]pyrimidinones 4bcс (δF 80.00 ppm) and 4btс (δF 79.50 ppm) were obtained in a mixture at a ratio of 4:1 (Scheme 2). The transformations with 2-hexanone (2c) led to the formation of two diastereomers of 4cct (δF 80.09 ppm) and 4ccc (δF 80.00 ppm), two diastereomers of 5ctc (δF 79.65 ppm) and

Mechanistic insights into hydroxy(tosyloxy)iodobenzene-mediated ditosyloxylation of chalcones: a DFT study

• Jai Parkash,
• Sangeeta Saini,
• Vaishali Saini,
• Omkar Bains and
• Raj Kamal

Beilstein J. Org. Chem. 2025, 21, 2703–2715, doi:10.3762/bjoc.21.208

• -substituents; α,β-unsaturated carbonyl compounds; Introduction Hypervalent iodine compounds exhibit a range of bonding patterns which making these compounds powerful reagents or catalysts for a number of organic transformations [1][2][3][4] – oxidation of alcohols [5], epoxidation of alkenes [6], oxidative

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

• The hydrofunctionalization of alkynes is one of the most effective and convenient ways of synthesizing polysubstituted alkenes [1][2][3][4][5]. Such reactions can also afford more complex products, provided that the vinyl intermediates formed during the reaction undergo further transformations [6][7

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

• group in the sequence to temporarily mask that specific group and its reactivity. The latter are considered undesirable transformations, since they do not contribute to advancing the complexity of the synthetic intermediate toward the target and should therefore be avoided, or at least minimized in use

• and as a semisynthesis, poses some non-strategic redox transformations (orange) and protecting manipulations (red) especially in the beginning and in the endgame of the synthesis. Nevertheless, several transformations are desirable green transformations, although it is noticeably more difficult to

• the semisynthesis of Liu/Qin [26] 15 years later. The only non-green transformations displayed at the start were a protecting group installation (red) and a condensation (yellow), which was needed for the C–H activation (light green). All other transformations connect either C–C or C–heteroatom bonds

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

• donor, through a late-stage glycosylation. The aglycon 2 can be derived from the Δ14 olefin intermediate 3 via Mukaiyama hydration and several functional group transformations. In turn, 3 would be generated from the key C14α-hydroxylated intermediate 4 via an elimination process. For the synthesis of 4

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

• transformations. The EDA-catalyzed Knoevenagel condensation reactions performed well even when a 10-fold increase in scale was applied (Supporting Information File 1, Scheme S1). The overall reaction profile was very much alike the smaller scales, affording the products in excellent yields (96–97%). A proposed

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

• ]. The use of visible light as an energy source has significantly expanded the scope of organic molecule activation and its application in organic synthesis or medicinal chemistry [12], thereby driving the fast development of various photocatalytic transformations. Among these advances, dual catalysis

• asymmetric reactions and are functional transformations in synthetic organic chemistry. Especially, 1,2,3-triazole-based NHCs are generally more reactive and stronger σ-donors than imidazole or thiazole analogues. Triazolium NHC enhances their ability to stabilize reactive radical intermediates or acyl anion

• transformations. Previous reports displayed various research groups successfully designed and prepared a variety of triazolium-based NHCs, eventually leading to the development of chiral NHC scaffolds by Knight and Leeper [17], followed by the remarkable contributions of Bode [18], Rovis [19], Glorius [20