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

• 119. The addition of propargyl bromide led to racemic 120. By the use of a flow setup involving a column packed with Amano lipase, an enzyme from the bacterium Pseudomonas fluorescens, a kinetic resolution of 120 was performed leading to the continuous production of acetate 121 and free alcohol 122

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

• CoREST complex that encompasses HDAC1/2, the co-repressor of REST (CoREST) and the lysine-specific demethylase 1 (LSD1). Cryo-EM and small angle X-ray scattering revealed that the CoREST complex exists as a bi-lobed structure [10]. Enzyme kinetics studies showed that HDAC1 and LSD1 do not act

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

• and stabilizes a catalytically inactive form of the enzyme [11][12]. The BPTES scaffold has undergone significant medicinal chemistry development resulting in CB-839/telaglenastat, which is being evaluated in clinical trials in combination with other anticancer agents [13]. Compound 968 is a third

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

• effects [14], сoagulation enzyme factor (FXa) inhibition [15] and antidepressant properties [16]. Considering the approaches to the synthesis of γ-aminosulfones, we focused our attention on the implementation of an aminoalkylation as a powerful and versatile tool for the synthesis of aliphatic amines [17

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

• skeleton terpenoids can be broken down to several stages. First, a linear polyolefin precursor containing multiples of C5 will be assembled. In general, the cyclisation precursor will interact with a cyclase or synthase enzyme and form a “primary reactive species” which undergoes programmed termination to

• 12c. From here, a second cyclisation towards 12d, 1,5-hydride shift to secondary carbocation 12e and follow-up oxidative decoration of 12f affords the pleuromutilin molecule 13. A more recently unveiled example of a specific cyclase enzyme effecting a change in ring size during polyene cyclisation was

• 4→5 ring expansion which is depicted in Scheme 9 [77]. Intermediate 27 is obtained like shown before (see above, Scheme 4 and Scheme 6), through the enzyme cattleyene synthase (CyS). Next, a concerted ring expansion/ring contraction and additional 2,10-cyclisation delivers the macrocyclic cation 27a

Conformational analysis of difluoromethylornithine: factors influencing its gas-phase and bioactive conformations

• Matheus P. Freitas

Beilstein J. Org. Chem. 2026, 22, 237–243, doi:10.3762/bjoc.22.17

• as a potent inhibitor of ornithine decarboxylase, the key enzyme that catalyzes the first step in polyamine biosynthesis [6]. This inhibition underlies both its therapeutic utility and its importance as a biochemical probe. From a structural standpoint, DFMO provides an intriguing case study for

• intrinsic stereoelectronic preferences but also by intermolecular interactions within the ornithine decarboxylase active site. Therefore, the conformational behavior of DFMO arises from a delicate balance between the fluorine gauche effect and the intermolecular interactions that stabilize the ligand–enzyme

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

• dehydrogenase type 1 (11-β-HSD-1), a key enzyme that alleviates insulin resistance by lowering cortisol production. Compound 157 emerged as a promising 11-β-HSD-1 inhibitor candidate. In 2016, researchers from Boehringer Ingelheim Pharmaceuticals and the University of Pennsylvania reported a concise and

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

• ) studies. Conversely, the “biomimetic synthesis” strategy mimics nature’s enzyme-catalyzed pathways to construct target molecules in the laboratory, offering milder reaction conditions and more concise synthetic steps, while demonstrating excellent atom economy and step economy [5][6][7]. These powerful

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

• as agonists of the GPR35 receptor [22], further underscoring the value of the TT scaffold in enzyme- and receptor-targeted drug discovery. Given the established practical significance of thieno[3,2-b]thiophene compounds, the construction of molecules featuring the TT core remains a key objective in

Enantioselective radical chemistry: a bright future ahead

• Anna C. Renner,
• Sagar S. Thorat,
• Hariharaputhiran Subramanian and
• Mukund P. Sibi

Beilstein J. Org. Chem. 2025, 21, 2283–2296, doi:10.3762/bjoc.21.174

• , transition-metal catalysis, and enzyme catalysis. Progress in enantioselective reactions using these approaches is discussed with the help of one or two examples in each category to highlight the outstanding achievements in the past three decades. Other modes of catalysis relying on hydrogen-bonding [13][14

• decatungstate (TBADT) and chiral amine 33 was able to catalyze the reaction between benzodioxoles 32 and cyclic β,β-disubstituted enones 31. Cyclic ketones 34 bearing all-carbon quaternary stereocenters at the β-position were obtained in good yields and high enantioselectivity. Enzyme-catalyzed radical

• individually or synergistically with other catalytic systems. Enzymatic catalysis can pose challenges including enzyme engineering, reaction scale-up, etc. but is optimal in terms of the toxicity profile of the reaction conditions. Biomolecules such as enzymes are attractive candidates for efficient and

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

• " (FLS), an enzyme able to catalyze the formose process. Various teams investigated the kinetics of the reaction and the entire carbon uptake allowing to select the best computationally modified enzyme profile depending on the formaldehyde amount and guiding future efforts to improve this pathway (Scheme

The application of desymmetric enantioselective reduction of cyclic 1,3-dicarbonyl compounds in the total synthesis of terpenoid and alkaloid natural products

• Dong-Xing Tan and
• Fu-She Han

Beilstein J. Org. Chem. 2025, 21, 2085–2102, doi:10.3762/bjoc.21.164

• cyclic prochiral dicarbonyl substrates. In addition, various approaches could be used for the desymmetrization reactions such as enzyme catalytic-, organocatalyst-, and transition-metal-catalyzed reductions [5][6][7]. Advance about the synthesis of several terpenoid and alkaloid natural products (1–5

• ][26][27][28][29][30]. In 2018, the group of Han accomplished the total synthesis of (+)-cyrneine A (7), (−)-cyrneine B (9), (−)-glaucopine C (10), and (+)-allocyathin B2 (8) by a collective manner [31]. In their synthetic route, an enzyme-catalyzed desymmetric enantioselective reduction of 1,3

• ], the enzyme-catalyzed desymmetric enantioselective reduction of 28, afforded hydroxyketone 54 in 65% yield with >99% ee and 8–9:1 dr on multigram scale [34]. Functional group transformations of 54 in four steps produced sterically hindered allyl triflate 55. By employing the palladacycle catalyst 45

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

• high enantioselectivity. However, since an enzymatic reaction generally produces only one of the two enantiomers, extensive enzyme screening is often required to access the desired enantiomer. Among various types of enzymes, lipases have proven to be efficient for the desymmetrization of 1,3-diols

• confirmed by X-ray crystallographic analysis. Comparative analysis of the 1H NMR data with authentic samples of the natural heliannuol G and heliannuol H enabled structural revision of these compounds, correcting prior misassignments in the literature [31][32]. Through enzyme-catalyzed asymmetric

• followed by desilylation to afford (−)-rasfonin (109). In 2009, Davies and co-workers disclosed the asymmetric synthesis of (+)-pilocarpine and (+)-isopilocarpine using an enzyme-catalyzed acetylation with Pseudomonas fluorescens lipase (PFL) (Scheme 16) [48]. Treatment of diol 110 with PFL and vinyl

Rhodium-catalysed connective synthesis of diverse reactive probes bearing S(VI) electrophilic warheads

• Scott Rice,
• Julian Chesti,
• William R. T. Mosedale,
• Megan H. Wright,
• Stephen P. Marsden,
• Terry K. Smith and
• Adam Nelson

Beilstein J. Org. Chem. 2025, 21, 1924–1931, doi:10.3762/bjoc.21.150

• the synthesis of structurally diverse reactive probes bearing S(VI) electrophiles. Proteome-wide screens have shown that S(VI) electrophiles predominantly target lysine and tyrosine [12], although other residues (e.g. serine) may also be targeted within enzyme active sites [13]. It was envisaged that

Systematic pore lipophilization to enhance the efficiency of an amine-based MOF catalyst in the solvent-free Knoevenagel reaction

• Pricilla Matseketsa,
• Margret Kumbirayi Ruwimbo Pagare and
• Tendai Gadzikwa

Beilstein J. Org. Chem. 2025, 21, 1854–1863, doi:10.3762/bjoc.21.144

• groups. This selective functionalization yielded MOFs in which the catalytically active amines are confined within highly lipophilic pores, reminiscent of many enzyme active sites. We determined that systematically increasing the lipophilicity of the pores results in a commensurate increase of catalyst

• from a single parent framework. Additionally, we can introduce new functionality into a MOF without changing the framework topology, thus minimizing the number of variables to consider as we study the influence of a particular property on catalytic performance. Perhaps more importantly for enzyme

• catalysis have focused on lipophilization to prevent water-based catalyst decomposition, with only a few investigating how lipophilic pores surfaces can increase catalyst efficiency [32][33], despite enzymes employing such a strategy. The lipophilicity of enzyme active sites tends to improve reaction rates

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

• release systems based on host–guest selective recognition, self-assembly, and nano-valves by the use of of calixarenes and pillararenes from five perspectives: pH, light, enzyme, hypoxia, and multi-stimuli combination responses. Furthermore, the article projects the future clinical application prospects

• in pH, light, and enzyme activity, the binding affinity between the guest and host molecules can be altered, thereby achieving controlled drug release and targeted delivery. (2) Drugs are loaded into self-assembled host–guest systems [29][30][31][32]. The chemical structure or properties of the host

• accessibility, structural adaptability, and responsiveness to external stimuli (pH, light, enzyme, hypoxia) facilitate sustained drug release, side effect mitigation, and therapeutic efficacy, making them increasingly prominent in drug carrier research. In recent years, the diversity of supramolecular

Synthesis of β-ketophosphonates through aerobic copper(II)-mediated phosphorylation of enol acetates

• Alexander S. Budnikov,
• Igor B. Krylov,
• Fedor K. Monin,
• Valentina M. Merkulova,
• Alexey I. Ilovaisky,
• Liu Yan,
• Bing Yu and
• Alexander O. Terent’ev

Beilstein J. Org. Chem. 2025, 21, 1192–1200, doi:10.3762/bjoc.21.96

• -inflammatory [21][22] as well as enzyme inhibition activities [23][24][25][26]. Traditionally, β-ketophosphonates were prepared via Arbuzov reaction [27], acylation of alkylphosphonates [28], and hydration of alkynylphosphonates [29][30][31]. However, these methods have several drawbacks, including low atom

Synthetic approach to borrelidin fragments: focus on key intermediates

• Yudhi Dwi Kurniawan,
• Zetryana Puteri Tachrim,
• Teni Ernawati,
• Faris Hermawan,
• Ima Nurasiyah and
• Muhammad Alfin Sulmantara

Beilstein J. Org. Chem. 2025, 21, 1135–1160, doi:10.3762/bjoc.21.91

• . Hydroxylation at the (ω-1) position was achieved using the NADH-dependent mutated enzyme variant CYP102A1 3 mDS, a p450 monooxygenase derived from Bacillus megaterium CYP102A1. After chromatographic purification, alcohol 89 was obtained in a 34% yield with a diastereomeric ratio of 82:18. This alcohol was

A versatile route towards 6-arylpipecolic acids

• Erich Gebel,
• Cornelia Göcke,
• Carolin Gruner and
• Norbert Sewald

Beilstein J. Org. Chem. 2025, 21, 1104–1115, doi:10.3762/bjoc.21.88

• important role as building blocks for peptide synthesis [1][2][3][4][5], as organocatalysts [6][7][8][9][10] and as enzyme inhibitors [4][11][12][13]. The incorporation of such amino acids into peptides can, for example, influence peptide conformation, the binding affinity to receptors [14], as well as

Recent advances in synthetic approaches for bioactive cinnamic acid derivatives

• Betty A. Kustiana,
• Galuh Widiyarti and
• Teni Ernawati

Beilstein J. Org. Chem. 2025, 21, 1031–1086, doi:10.3762/bjoc.21.85

• a naturally occurring plant metabolite frequently found in honey, fruits, and vegetables [1]. Cinnamic acid is biosynthesized through a shikimate pathway, catalyzed by the phenylalanine ammonia-lyase (PAL) enzyme. Generally, cinnamic acid derivatives possess a wide range of bioactivities, such as

Dicarboxylate recognition based on ultracycle hosts through cooperative hydrogen bonding and anion–π interactions

• Wen-Hui Mi,
• Teng-Yu Huang,
• Xu-Dong Wang,
• Yu-Fei Ao,
• Qi-Qiang Wang and
• De-Xian Wang

Beilstein J. Org. Chem. 2025, 21, 884–889, doi:10.3762/bjoc.21.72

• cellular metabolism; they regulate the activity of numerous enzyme receptors, and serve as intermediates in the synthesis of more complex biomolecules [21]. However, excessive consumption or production, as well as insufficient clearance of dicarboxylates, can lead to various health problems [22

4-(1-Methylamino)ethylidene-1,5-disubstituted pyrrolidine-2,3-diones: synthesis, anti-inflammatory effect and in silico approaches

• Nguyen Tran Nguyen,
• Vo Viet Dai,
• Luc Van Meervelt,
• Do Thi Thao and
• Nguyen Minh Thong

Beilstein J. Org. Chem. 2025, 21, 817–829, doi:10.3762/bjoc.21.65

• response, respiratory, vasodilation, apoptosis, tumor growth, and cardiovascular system [1][2]. Nitric oxide (NO) is released as product of the NADPH and oxygen-dependent oxidation of ʟ-arginine to ʟ-citrulline under the catalysis of the enzyme nitric oxide synthase (NOS) [3]. There are three distinct

• interactions of these derivatives with the enzyme inducible nitric oxide synthase (iNOS), compared to dexamethasone used as a reference. Furthermore, ADMET (absorption, distribution, metabolism, excretion, and toxicity) predictions were performed to assess their drug-likeness and pharmacokinetic properties

• clear that overproduction of nitric oxide (NO) by the iNOS enzyme causes inflammation-related diseases. Moreover, large quantities of nitric oxide (NO) are released when RAW 264.7 cells are stimulated by lipopolysaccharides (LPS) [5][26]. Consequently, nitric oxide (NO) production in LPS-stimulated

Origami with small molecules: exploiting the C–F bond as a conformational tool

• Patrick Ryan,
• Ramsha Iftikhar and
• Luke Hunter

Beilstein J. Org. Chem. 2025, 21, 680–716, doi:10.3762/bjoc.21.54

• enzyme, and the hydroxy group of 57 interacts with catalytic aspartate residues in the active site. The fluorinated pepstatin analogue 58 was predicted to be pre-organised into the bent conformation and hence be a more potent inhibitor than 57. Compound 58 was indeed found to be more potent than 57

• important [145][146][147]. For example, the diastereoisomeric monofluorophosphonates 83 and 84 were compared in their ability to bind to a phosphosugar-processing enzyme. Epimer 84 was found to bind with 100-fold higher affinity than epimer 83, and this was attributed to a lower-energy binding conformation

• which the conformation can be controlled by fluorine, is the natural product balanol (99, Figure 11) [112][167][168][169][170][171][172]. Balanol is an ATP mimic that inhibits protein kinase Cε (PKCε), an enzyme that is implicated in cancer. However, compound 99 also inhibits off-target kinases

Photocatalyzed elaboration of antibody-based bioconjugates

• Marine Le Stum,
• Eugénie Romero and
• Gary A. Molander

Beilstein J. Org. Chem. 2025, 21, 616–629, doi:10.3762/bjoc.21.49

• decision-making [6][7]. Antibody–oligonucleotide conjugates, antibody–enzyme conjugates, antibody–polymer conjugates, antibody–nanomaterial conjugates, antibody–catalyst conjugates, and antibodies involved in protein degradation also play critical roles in biomedical research and therapies [2]. In whatever

Synthesis of electrophile-tethered preQ₁ analogs for covalent attachment to preQ₁ RNA

• Laurin Flemmich and
• Ronald Micura

Beilstein J. Org. Chem. 2025, 21, 483–489, doi:10.3762/bjoc.21.35

• as riboswitches [6][7][8] or the queuosine biosynthetic enzyme machinery [9][10][11]. Recently, even the self-methylation activity of a preQ1 riboswitch has been discovered with a methylated preQ1 derivative acting as a ribozyme cofactor [12]. Moreover, these analogs have found utility in several

• biotechnological applications, including the identification of queuosinylation sites in cellular RNA [13], RNA and DNA labeling [14][15], and mRNA photocaging [16]. The latter applications rely on the promiscuity of the tRNA-modifying enzyme tRNA-guanine transglycosylase (TGT), which can incorporate functionalized

• preQ1 congeners into oligonucleotide strands at specific recognition sites. In addition, the potential of modified preQ1 for protein enzyme-independent RNA labeling has also been demonstrated [12][17]. In a recent study [4], sequence-specific RNA–small molecule crosslinking (Scheme 1B) was achieved in