Site-specific labelling of native peptides and proteins: chemical and enzymatic strategies

• Antonio Angelastro,
• Jonathan Bargh,
• Subhajit Guria,
• Victor Laserna and
• Louis Luk

Beilstein J. Org. Chem. 2026, 22, 857–881, doi:10.3762/bjoc.22.67

• to form amide bonds via trans-thioesterification, though often under denaturing conditions (Scheme 1c) [9]. Intein-mediated ligation is a recombinant alternative but often requires linker sequences. Newer reagents such as 2-cyanobenzothiazole 2 (CBT) react with N-terminal cysteine to form luciferin

• and glutamine (or other small primary amides) is another frequently used enzyme for bioconjugation. The primary amide in glutamine is converted into an acyl intermediate that is subsequently attacked by amine nucleophiles such as lysine ε-amines and glycine α-amines. Although MTG can modify Gln295 on

• . [141] provide a comprehensive summary of recent advances in engineering amide-bond-forming enzymes for modifications, including asparaginyl endopeptidase (AEP), omniligase and other emerging biocatalysts. Comparative Analysis, Outlook and Future Directions In Table 1, we compile a bird’s-eye overview

The trans-influence in gold chemistry from a catalytic perspective

• Manfred Bochmann

Beilstein J. Org. Chem. 2026, 22, 838–856, doi:10.3762/bjoc.22.66

• complexes. Both terminal and internal alkynes could be inserted, with a wide variety of functional groups including alkyl, aryl, OH, COOH, amide and aldehyde substituents, but not DMAD. The excellent stereo- and regiochemical selectivity could be explained by a bimolecular mechanism, as confirmed by DFT

Synthesis and structural elucidation of a novel bis-spirooxindole from isatin and ethylenediamine

• Irene Moreno-Gutiérrez,
• Josefa L. López-Martínez,
• Sonia Berenguel-Gómez,
• Irene Torres-García,
• Duane Choquesillo-Lazarte,
• Manuel Muñoz-Dorado,
• Miriam Álvarez-Corral and
• Ignacio Rodríguez-García

Beilstein J. Org. Chem. 2026, 22, 813–820, doi:10.3762/bjoc.22.63

• retained the four-signal pattern of isatin (H4', H5', H6', H7'), slightly shifted by the new structural environment. In the 13C NMR spectrum, the amide carbonyl appeared at δ 176.5 ppm, while a key quaternary carbon at δ 61.0 ppm (C3‘) – formerly the C-3 isatin carbonyl carbon – confirmed the formation of

Design, synthesis, and biological evaluation of FXR/ASK1 dual-target modulators

• Xi Zhang,
• Jingyan Wang,
• Ziqiang Zhao,
• Caiyi Wang,
• Zenghui Ye,
• Wei-Yuan Ma,
• Jian-Xing Xu and
• Fengzhi Zhang

Beilstein J. Org. Chem. 2026, 22, 771–781, doi:10.3762/bjoc.22.59

• systems or the phenyl ring at the 3-position of the isoxazole to enhance hydrophilicity and improve pharmacokinetic properties [42]. Co-crystallization of GS-4997 with ASK1 unveiled key stabilizing interactions in the active site. Specifically, the amide carbonyl forms a hydrogen bond with the backbone

• amide of Val 757, and concurrently, a triazole nitrogen engages in a hydrogen bond with the amine moiety of Lys 709 [43]. By merging the key pharmacophores of the two drugs and systematically optimizing the resulting bipharmacophoric structure, we ultimately obtained balanced dual-target modulators

Preparation of 3-(alkylamino)imidazo[1,2-a]pyridine-2-carbaldehydes via Kornblum oxidation and unexpected ring-opening reactions of the corresponding alcohols under oxidative conditions

• Sandile J. Mkhize,
• Memory Zimuwandeyi,
• Manuel A. Fernandes,
• Amanda L. Rousseau and
• Moira L. Bode

Beilstein J. Org. Chem. 2026, 22, 763–770, doi:10.3762/bjoc.22.58

• ester 13b into the corresponding amide using AlCl3 were not promising and therefore the hydrolysis of this ester to corresponding carboxylic acid 14 was tested. Using KOH in MeOH at 35–40 °C for the ester hydrolysis reaction resulted in decarboxylated compound 12b being isolated as the sole product in

Synthesis of heterocycles based on azomethine ylides from α-amino acids (or amines) and carbonyl compounds

• Ekaterina V. Berezhnaya,
• Alexander I. Ponyaev,
• Vitali M. Boitsov and
• Alexander V. Stepakov

Beilstein J. Org. Chem. 2026, 22, 705–741, doi:10.3762/bjoc.22.55

• the catalytic precursor and chiral bis-ferrocenyl amide phosphine (FAP) (L1) as ligand [36] (Scheme 2). The obtained results demonstrated the high efficiency of the Ag(I)-FAP catalytic system for this transformation. In particular, most α-(arylimino)esters yielded cycloaddition products 3 in excellent

Advantages of PROTACs in achieving selective degradation of homologous protein families

• Luxi Yang,
• Xinfei Mao,
• Jingyi Zhang,
• Jing Shu,
• Wenhai Huang,
• Xiaowu Dong,
• Yinqiao Chen and
• Mingfei Wu

Beilstein J. Org. Chem. 2026, 22, 628–661, doi:10.3762/bjoc.22.49

• to explore the influence of the direction of VHL recruitment of PROTACs on selectivity (termed the “amide series” and “phenyl series” individually). Simultaneously, they used four linkers of different lengths to connect the E3 ligand and the POI ligand to explore the influence of linker fragments on

• molecular selectivity (Figure 10). As for the “amide series”, the authors discovered that in MDA-MB-231 human breast cancer cells, the 10-atom and 11-atom linker PROTACs (SJF-6693 (26) and SJF-6690 (27)) were not selective and degraded both p38α and p38δ nonspecifically with DC50 < 100 nM (Figure 11

Towards the targeted protein degradation of CK2: design and synthesis of CAM4066-based PROTACs

• Sophie Day-Riley,
• Sona Krajcovicova,
• Aryaman Raj Sokhal,
• Jan L. Venne,
• Paul Brear,
• Marko Hyvönen,
• Benjamin C. Whitehurst,
• Jason S. Carroll and
• David R. Spring

Beilstein J. Org. Chem. 2026, 22, 611–619, doi:10.3762/bjoc.22.47

• revealed a small solvent-accessible channel adjacent to the amide linking the ATP- and αD-binding fragments (Figure 1). This channel represented a promising region from which to project a linker, as it was oriented toward solvent and spatially removed from residues critical for 1 binding to CK2α. The amide

• closest to this opening was therefore identified as the optimal site for structural modification. To allow more flexible functionalisation, the linking region was redesigned to introduce a secondary amine adjacent to the original amide position. This amine maintained the length and orientation of the

Molecular tweezer–peptide conjugates disrupt the protein–protein interaction between survivin and histone H3 essential in mitosis

• Catherine Gsell,
• Philipp Rebmann,
• Karina Opara,
• Christine Beuck,
• Peter Bayer,
• David Bier,
• Ingrid R. Vetter and
• Thomas Schrader

Beilstein J. Org. Chem. 2026, 22, 557–567, doi:10.3762/bjoc.22.41

• as a barrier for the rearrangement of survivin’s side chains and the interaction diagram reveals contacts to all nine accessible acidic amino acids on the protein surface [14]. The new tweezer H3 conjugate 2a has a C4 spacer between the Lys-4 amide and the azide, very close to 1 with its C3 spacer

Synthesis and uranyl(VI) extraction performance of a calix[4]pyrrole–tetrahydroxamic acid receptor

• Sara Karnib,
• Rana Baydoun,
• Wissam Zaidan,
• Nancy AlHaddad,
• Omar El Samad,
• Bilal Nsouli,
• Francine Cazier-Dennin and
• Pierre-Edouard Danjou

Beilstein J. Org. Chem. 2026, 22, 486–494, doi:10.3762/bjoc.22.36

• the hydroxamic acid moieties, in agreement with previous reports (Supporting Information File 1, Figure S3) [57]. Additionally, two pairs of singlets at 8.97, 9.32 and 10.20, 10.93 ppm (2H total) were assigned to the hydroxy (–OH) and amide (–NH) protons of the hydroxamic acid groups (Supporting

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

• 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

Synthesis and anti-cancer activity of naphthalimide–organylselanyl conjugates

• Rajkumar Ravi and
• Selvakumar Karuthapandi

Beilstein J. Org. Chem. 2026, 22, 416–435, doi:10.3762/bjoc.22.29

• interactions: van der Waals (Gly772), hydrogen bonding and carbon–hydrogen bonding (Met769), π–donor (Thr766), π–σ (Leu820), π–sulfur (Met742), amide–π (Phe771), alkyl (Leu694), and π–alkyl interactions (Val702, Ala719, Lys721, Leu764). In contrast, compound 8 formed eight interactions: van der Waals (Pro770

• ), hydrogen bonding (Met769), carbon–hydrogen bonding (Thr766), π–anion (Asp831), π–σ (Leu694), amide–π (Met769), alkyl (His781), and π–alkyl (Val702, Ala719, Leu768, Leu820). These results confirm that both ligands are well accommodated within the binding pocket of EGFR tyrosine kinase, with compound 7

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

• commercially available lithium bis(trimethylsilyl)amide (LiHMDS), but the latter was found inconvenient for routine syntheses due to high moisture sensitivity which prevented reproducibility of the reaction conditions. To overcome this difficulty, the LiHMDS solution was instead prepared in situ by reacting

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

• Eun-Sol Choi Hyo-Jun Lee Department of Chemistry, Kunsan National University, Gunsan 54150, Republic of Korea 10.3762/bjoc.22.23 Abstract The amide bond is one of the most fundamental and widely utilized functional groups in organic chemistry, central to the structures of pharmaceuticals

• of conventional, non-activated amides remains far more difficult. This review summarizes recent advances over the past decade in the activation and cleavage of non-activated amide C–N bonds for their conversion into diverse carboxylic acid derivatives. Key strategies covered include transition-metal

• catalysis, electrophilic activation, strong base-counter-cation systems, and N-based activating groups that enable chemoselective bond cleavage. Together, these developments provide powerful tools for amide functionalization and offer new opportunities for efficient, practical, and selective syntheses

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

• contacts: the barbiturate ring forms hydrogen bonds with water molecules through C=O···H–O and N–H···O–H interactions; the amide group of the barbiturate ring is engaged in a C=O···H–N hydrogen bond with the carbonyl oxygen of the maleimide fragment; additionally, a C=O···H–CH2 contact is observed between

• the hydrogen atom of the maleimide methyl group and the carbonyl oxygen of an adjacent maleimide ring. The crystal structure of compound 4b exists as a solvate. The oxygen atom of a water molecule forms a hydrogen bond with the amide hydrogen of the barbiturate fragment (N–H···O–H = 2.783 Å), while

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

• , is likely due to the electronic effects within pyranoquinoline. As an enol ester conjugated with an amide and an aromatic ring, electron-withdrawing groups decrease electron density on the enol OH, while aliphatic substituents (methyl, ethyl) increase electron density on the alcohol oxygen. This

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

• ). Therefore, the reaction is most likely not proceeding via a free radical mechanism. To clarify the influence of the amide group on the developed transformations, dihydrothiophene 4g bearing a sulfonylimine group instead of an amide was treated with sodium methoxide in methanol or with sodium ethoxide in

• amide group plays an important role in these transformations. In addition, analysis of the reaction mixture obtained in ethanolic solution was performed after evaporation of the ethanol. HRMS analysis showed the presence of two peaks with m/z values 400.1704 (retention time 7.952‒7.963) and 400.1700

• double bond, sulfur and amide group. The difference in the stability of these types of anions results in their distinct reactivity. Conclusion We have reported the solvent dependent transformation of dihydrothiophenes 1 under mild conditions. It was found that, in ethanolic solution in the presence of

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

• good to excellent yields (up to 99%), suggesting broad functional group compatibility. The protocol also demonstrated excellent compatibility with structurally and electronically distinct amide substrates. The sterically hindered 2-naphthylamide-derived sulfenamide afforded the desired product 3h’ in

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

• malonate. We have previously shown the importance of an acidic amide proton in asymmetric Mannich reactions [18]. The majority of the catalysts are also potential halogen-bond donors containing tetrafluoroiodophenyl or iodophenyl moieties, which enable the formation of additional noncovalent interactions

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

• the cyano group to an amide (162) under acidic conditions, which then allowed successful Pd/C-mediated hydrogenation to 163. Subsequent dehydration with POCl3 and chiral resolution using ᴅ-DBTA provided the optically enriched compound 165 (Scheme 22). While this approach rendered catalytic

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

• ). The developed dimerization protocol proved scalable to 100 g scale, affording 40 g of the desired dimer 61b in 47% yield. Subsequent removal of the two Boc groups with TMSI, followed by HATU-mediated amide coupling with various amino acids 65–67, furnished the diketopiperazine precursors 68–70

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

• commenced our investigation with acetylation of maltol (2) using acetic anhydride to afford ester 8a. Unfortunately, the acetate group proved labile upon treatment of 8a with lithium bis(trimethylsilyl)amide (LiHMDS), resulting exclusively in deprotection to give maltol (2, Table 2, entry 1). Turning to the

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

• (6) and ent-asperdinone E, now using an N-Boc protecting group (Scheme 8). Treatment of 3-iodoindole 39 with the iodozinc reagent prepared from N-Boc-ʟ-alanine methyl ester ((R)-35) under Negishi coupling conditions afforded 40 in excellent yield. Cleavage of the N-Boc group and amide formation with

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

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

• ) 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