Using generative AI to transform peptide hits into small molecule leads

• Joshua Mills and
• Yu Heng Lau

Beilstein J. Org. Chem. 2026, 22, 672–679, doi:10.3762/bjoc.22.51

• protein partners that form functional complexes [1][2][3]. Furthermore, powerful high-throughput library screening technologies such as mRNA and phage display have revolutionised our ability to identify novel peptide binders, frequently generating binders with nanomolar affinity directly from screening

• bound complexes, including computational analysis of the amino acid interactions (SiteMap [16]) and hydration in the binding pocket (grid inhomogeneous solvation theory [17] in AmberTools [18]). The pharmacophores were then used as the basis for virtual screening with docking (Glide [19][20]) to obtain

• ) experiment in 2020 [24]. Since then, numerous models with advanced functionality have been released (Table 1), including AlphaFold3 which incorporates diffusion-based components, providing a range of options for predicting the structure of protein targets (including protein complexes and interactions with

Photoorganocatalytic trifluoromethylation of (het)arenes in green conditions

• Egor N. Boronin,
• Svetlana E. Kaurkina,
• Milena M. Svetlakova,
• Anton S. Bolshakov,
• Maxim V. Arsenyev,
• Vasilii F. Otvagin,
• Alexey Yu. Fedorov,
• Timothy Noël and
• Alexander V. Nyuchev

Beilstein J. Org. Chem. 2026, 22, 662–671, doi:10.3762/bjoc.22.50

• -based complexes to other transition metals and organic photocatalysts, as well as diverse CF3 sources. The major limitations of these methodologies include the high cost of catalysts and trifluoromethylating reagents, along with the use of toxic species such as transition-metal complexes and hazardous

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

• optimization often prioritizes the linker fragment, as its length and composition are critical determinants of target selectivity [39]. Recent evidence underscores the pivotal role of the linker in promoting the assembly of "positive cooperative" ternary complexes [40], wherein the linker participates in

• in recent years [12]. The selectivity of PROTACs toward CDK4/6 over other highly homologous CDKs can be attributed to their event-driven pharmacology and the formation of stable ternary complexes that exploit subtle structural differences among the family members [54]. Unlike traditional kinase

• VHL ligand are connected via a conformation-restricting macrocyclic linker. Although this seems to be a minor change, the comparison of these two studies reveals that compound 36 is able to cooperatively form ternary complexes with the BD2 domains of BRD4, BRD2, and BRD3. The cooperativity factor α, a

Hydrogen production from formic acid catalyzed by NHC–Cu complexes

• Orlando Santoro and
• Catherine S. J. Cazin

Beilstein J. Org. Chem. 2026, 22, 620–627, doi:10.3762/bjoc.22.48

• ]. Finally, a Cu(I)–formato complex able to promote FA dehydrogenation in the absence of any additive was very recently reported by Berthet, Cantat and co-workers [48]. During the past decades, NHC–Cu complexes have shown to be efficient catalysts in a plethora of reactions. Indeed, they guarantee better

• performances than copper salts, even with lower catalyst loading and under milder conditions [49][50][51]. Based on this background, the first potential formic acid dehydrogenation catalyzed by NHC–Cu complexes (Figure 1) was investigated. Results and Discussion We have shown that the reaction of [Cu(OH)(IPr

• ), almost 2 equivalents of gas were produced from 1 equivalent of formic acid within 3 hours. It has to be noted that, since all reactions were conducted in solution, all copper complexes must be considered as monomeric. In fact, dimeric Cu–H and Cu–formato are generally observed only in the solid state [53

Kinetic resolution of racemic planar-chiral vinylcymantrenes by molybdenum-catalyzed asymmetric metathesis dimerization

• Haruna Imazu,
• Hitoshi Izu,
• Yasuhiro Ohki and
• Masamichi Ogasawara

Beilstein J. Org. Chem. 2026, 22, 568–574, doi:10.3762/bjoc.22.42

• metathesis chemistry, and various chiral metal-alkylidene catalysts have been prepared over the past two decades [6][7][8][9]. Since 2002, our group and others have been interested in utilizing the olefin metathesis reaction for the modulation of various transition-metal complexes [10][11][12][13] thanks to

• the excellent tolerance of the Mo-/Ru-metathesis catalysts toward the organometallic substrates. The olefin metathesis protocols could be extended to the asymmetric synthesis of diverse planar-chiral transition metal complexes either by the kinetic resolution of the racemic substrates [14][15][16] or

• by the desymmetrization of the Cs-symmetric substrates [17][18][19] by the use of an appropriate chiral catalyst (see the drawing in Table 1 for the structures of the representative chiral molybdenum precatalysts used in this study) [20][21][22][23]. Planar-chiral transition-metal complexes have been

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

• region of histone H3 (green). The boxed region is enlarged in the right panel. Several of the residues lining the interface between survivin and histone H3 are shown. Survivin complexes with peptide tweezers: Fluorescence polarization measurements of wild type and mutated survivin (top) and modeling of

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

• and have found diverse applications across both biomedical and industrial fields [25][26]. Hydroxamic acids are also well known for their strong chelating ability toward uranyl, forming stable complexes through the synergistic coordination of the carbonyl and hydroxylamine groups [27]. Uranium is a

• aqueous solution, hexavalent uranium, the most dominant oxidation state, exists predominantly as the linear uranyl ion UO22+. In this ion, two oxo ligands occupy axial positions while the equatorial plane accommodates four to six donor atoms [74][75]. Complexes of UO22+ often adopt either a pseudoplanar

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

• LE1 7RH, UK 10.3762/bjoc.22.35 Abstract Class I histone deacetylases (HDACs 1–3) serve as catalytic subunits within seven multiprotein co-repressor complexes, each of which has distinct functions in the cell. We report the synthesis of a HDAC inhibitor–nanogold probe, derived from the class I HDAC

• inhibitor CI-994, for cryo-electron microscopy (cryo-EM) visualization of the HDAC catalytic domain within class I HDAC co-repressor complexes. The nanogold probe retained HDAC inhibitory activity comparable to CI-994 against the HDAC1-LSD1-CoREST complex in vitro. In cryo-EM studies, 2D class averages

• III [3]. HDAC1, HDAC2, and HDAC3 of the class I HDACs exist in multiprotein co-repressor complexes in vivo [4]. HDAC1 and HDAC2 exist interchangeably in the CoREST, MIDAC, SIN3, NuRD, MIER, and RERE complexes, while HDAC3 exists in the SMRT/NCoR complex [4]. The protein complex partners govern 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

• -containing five-membered rings with iridium complexes and examined the influence of different alcohol protecting groups on the monoalkyne substrates. The reaction proceeded in generally high yields (>70%) with satisfactory enantioselectivity. Building on this work, Shibata and Tsuchikama developed a one-pot

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

• derived from propargylated and 2-azidoethylated precursors possess drastically different complexation abilities towards transition-metal cations [81][82][83][84] including the formation of unique inherently dinuclear iridium(III) complexes with cone calix[4]arenes having pairs of 2-(4-aryltriazol-1-yl

Design, synthesis and biological evaluation of 2,5-diaryloxazolo[4,5-d]pyrimidin-7-ylamines as selective cytotoxic agents against HeLa cells

• Maryna V. Kachaeva,
• Agnieszka B. Olejniczak,
• Marta Denel-Bobrowska,
• Victor V. Zhirnov,
• Yevheniia S. Velihina,
• Stepan G. Pilyo and
• Volodymyr S. Brovarets

Beilstein J. Org. Chem. 2026, 22, 390–398, doi:10.3762/bjoc.22.27

• regulation of the cell life cycle [8]. On the contrary, oxazolo[4,5-d]pyrimidines represent a poorly studied class of compounds because of limited access to this scaffold [9]. An in silico study showed that both isomeric forms of oxazolopyrimidines can form stable complexes due to hydrogen bonds between a

• lone electron pair at the nitrogen atoms and protonated amino acids of proteins. However, oxazolo[5,4-d]pyrimidine forms more stable complexes, which is in good agreement with in vitro studies [10]. We have already shown the anticancer potential of 7-N-derivatives of 2,5-diaryl[1,3]oxazolo[4,5-d

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

• % yield. Mechanistically, WCl6 coordinates with Phen to generate the active tungsten species [G]. In cooperation with TMSCl as a Lewis acid, the catalyst activates the amide toward nucleophilic attack by forming an electron-deficient intermediate H that readily undergoes substitution. Palladium complexes

• dianion activates the amide carbonyl, thereby facilitating nucleophilic attack and subsequent transamidation. Boron complexes, among the most commonly used non-metallic Lewis acids, are effective activators for amide C–N bond cleavage, as demonstrated in the esterification developed by Dou et al. (Scheme

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

• highlighted. Collectively, these concepts create a roadmap for the development of new strategies that harness π-bond localization to expand the synthetic utility of aromatic compounds. Keywords: arene activation; arene functionalization; dearomatization; metal–arene π-complexes; strained molecules

• following sections therefore focus on the selective disruption of aromaticity through the formation of transition metal–arene π-complexes. Transient and reversible coordination of transition metals to aromatic π-systems is a key feature of many catalytic transformations, with the oxidative addition of

• palladium to aryl halides serving as a prominent example [41]. In addition to such fleeting intermediates, recent decades have seen the emergence of numerous well-defined metal–arene complexes, sufficiently stable to enable systematic exploration of their rich and versatile organic chemistry. η2

Design and synthesis of an axially chiral platinum(II) complex and its CPL properties in PMMA matrix

• Daiki Tauchi,
• Sota Ogura,
• Misa Sakura,
• Kazunori Tsubaki and
• Masashi Hasegawa

Beilstein J. Org. Chem. 2026, 22, 143–150, doi:10.3762/bjoc.22.7

• Luminescent materials based on metal complexes have been extensively studied due to their high phosphorescence efficiency, making them promising candidates for applications in organic light-emitting diodes (OLEDs) [1][2][3][4][5], sensors [6][7][8][9], and bioimaging materials [10][11]. Among these materials

• , pincer-type platinum(II) complexes have attracted particular attention, owing to the structural robustness imparted by tridentate chelating ligands and their excellent luminescent properties [12][13][14][15][16][17]. These complexes have been widely investigated, not only for practical application but

• also from the perspective of fundamental chemistry. In recent years, the design and synthesis of luminescent pincer-type platinum(II) metal complexes incorporating chirality, as well as the study of their physicochemical properties, have gained significant interest [18][19][20][21][22]. Such efforts

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

• limitations in terms of substrate scope, stereoselectivity, and scalability, leaving ample room for innovation in catalyst design and mechanistic understanding. Fan and co-workers have long been dedicated to the asymmetric catalysis of chiral diamine ruthenium complexes. In 2020, they reported the efficient

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

• Yamaguchi published a review on radical reactions catalyzed by zirconium complexes [6]. Their review provides a comprehensive summary, particularly of photo-redox reactions involving zirconium catalysis. In the present review, we focus on three aspects: 1) Zr-mediated stoichiometric radical reactions 2) Zr

• -mediated stoichiometric radical reactions Traditionally, the use of Zr complexes in organic reactions had been limited to two-electron processes; however, the first example of a Zr-mediated radical reaction was reported by Oshima et al. in 2001. They reported an intramolecular radical cyclization using

• 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

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

• chlorides was also utilized in the total synthesis of (S)-jamaicamide C and laingolide B (not shown) [121][122]. Schwartz’s work on alkenylzirconium complexes revealed high-yielding, stereoretentive transformations under similar conditions (Scheme 29H) [123]. In a complementary study, Srebnik showed that

Silica gel with covalently attached bambusuril macrocycle for dicyanoaurate sorption from water

• Michaela Šusterová and
• Vladimír Šindelář

Beilstein J. Org. Chem. 2025, 21, 2604–2611, doi:10.3762/bjoc.21.201

• that 1.3/1.4 equivalents of BU1 on the material are required to bind a single dicyanoaurate anion. A similar macrocycle-to-anion ratio was previously determined for the SG-BnBU material. In contrast, water-soluble BU and dicyanoaurate have been reported to form complexes of 1:1 stoichiometry

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

• were ineffective in improving the reaction outcome (Table 1, entry 6). Other palladium complexes promoted the formation of 2a but with diminished efficiency (Table 1, entries 7 and 8). Varying the amount of AgNO3 did also not lead to a better yield (Table 1, entry 9), and alternative nitro sources also

Conformational effects on iodide binding: a comparative study of flexible and rigid carbazole macrocyclic analogs

• Guang-Wei Zhang,
• Yong Zhang,
• Le Shi,
• Chuang Gao,
• Hong-Yu Li and
• Lei Xue

Beilstein J. Org. Chem. 2025, 21, 2369–2375, doi:10.3762/bjoc.21.181

• iodine ions, which is consistent with the conclusions reached by our NMR titration. The binding constants of the complexes (K), KPBG = (1.387 ± 0.02363) × 105 M−1, KWDG= (6.089 ± 0.3320) × 103 M−1 were measured (Tables S1 and S2 in Supporting Information File 1), indicating that both acceptors had strong

• than the formation of new excited state complexes. As the I− content continued to increase, the fluorescence emission intensity of PBG continued to decrease at 354 nm and 364 nm. Similarly, the fluorescence emission intensity of WDG at 356 nm and 369 nm decreases as the I− content increases

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

• enantioenriched catalysts ranging from chiral organometallic complexes to organocatalysts (small organic molecules) have been designed, synthesized, and successfully used in several organic transformations [1][2][3]. Despite these advances, catalytic methods involving radical intermediates were very rare until

• occurred in an anti fashion. Products were obtained with up to 97% ee via catalysis by complexes of magnesium or copper(II) with ligand L1. The absolute stereochemistry of the product could be controlled by a simple change from copper(II) to magnesium Lewis acids while using the same chiral ligand, thus

• different transition-metal complexes have been employed in metalloradical catalysis, including porphyrin complexes of cobalt(II) [55][56] and iron(III) [57][58]. Both cobalt in oxidation state +2 and iron in oxidation state +3 can be viewed as persistent metalloradicals. Zhang and co-workers reported a

Pd-catalyzed dehydrogenative arylation of arylhydrazines to access non-symmetric azobenzenes, including tetra-ortho derivatives

• Loris Geminiani,
• Kathrin Junge,
• Matthias Beller and
• Jean-François Soulé

Beilstein J. Org. Chem. 2025, 21, 2234–2242, doi:10.3762/bjoc.21.170

• )–aryl intermediate (B). Subsequently, ligand exchange occurs, generating hydrazido complexes C and C'. When bulky substituents are present on the phosphine ligand and/or (both) coupling partner(s) has ortho-substituent(s), the hydrazido complex C, chelating on the terminal nitrogen, is preferentially

Solar thermal fuels: azobenzene as a cyclic photon–heat transduction platform

• Jie Yan,
• Shaodong Sun,
• Minghao Wang and
• Si Wu

Beilstein J. Org. Chem. 2025, 21, 2036–2047, doi:10.3762/bjoc.21.159

• ], norbornadiene–quadricyclane (NBD–QC) complexes [17][18][19][20][21][22][23], dihydroazulene–vinylheptadiene (DHA-VHF) systems [24][25][26][27][28][29][30], and azobenzene derivatives [31][32][33][34] (Figure 2). In addition, other reversible photoisomers exhibit potential for development as solar thermal fuels

Photochemical reduction of acylimidazolium salts

• Michael Jakob,
• Nick Bechler,
• Hassan Abdelwahab,
• Fabian Weber,
• Janos Wasternack,
• Leonardo Kleebauer,
• Jan P. Götze and
• Matthew N. Hopkinson

Beilstein J. Org. Chem. 2025, 21, 1973–1983, doi:10.3762/bjoc.21.153

• transition-metal complexes such as the Grubbs’ second-generation metathesis catalyst, NHCs are now also well-established as organocatalysts. With the first application pre-dating the unambiguous characterization of a free NHC by nearly 50 years, NHCs can facilitate numerous synthetically attractive

• efficiency observed upon switching from blue to UV-A light irradiation. Nevertheless, alternative scenarios involving the potential formation of excited donor–acceptor (EDA) complexes between benzoylazolium species 1 and DIPEA were considered. Measurements of the UV–vis spectra in the presence of the amine

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

• been developed, employing enzymes, metal complexes, or organocatalysts to convert prochiral or meso precursors into chiral motifs. Different from other strategies constructing chiral centers by formation of a new chemical bond at the central carbon, enantioselective desymmetrization is achieved through

• desymmetrization of 1,3-diols in 2003 [56]. Subsequent advances included Cu-based complexes developed by Kang and co-workers [57][58], first applied in total synthesis in 2008. In this section, examples of transition-metal-catalyzed acylations of prochiral 1,3-diols in total synthesis are discussed, including Cu

• -catalyzed acylation Zn-based complexes are another class of effective catalysts used in desymmetrization of 1,3-diols, as reported by Trost and co-worker in 2003 [56]. In 2013, Trost et al. developed the synthesis of (−)-18-epi-peloruside A (Scheme 26) [68], and converted diol 204 into enantioenriched