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

• pyrrolizidine alkaloids with diverse biological activity [6][7][8]. An analysis of experimental and review articles showed that (3 + 2) cycloaddition reactions are carried out, in most cases, using two main strategies for obtaining azomethine ylides, depending on the amino acid derivative used: a free amino

• multicomponent one-pot (3 + 2) cycloaddition reactions involving azomethine ylides from isatins and amino acids [21][35]. The main feature of this review is that we have attempted to consider all currently known systems for generating azomethine ylides based on carbonyl compounds and amino acid derivatives (or

• and effective for the preparation of racemic cycloadducts [69][70][71]. Of interest are also non-catalytic reactions of 1,3-dipolar cycloaddition of azomethine ylides, which are formed in situ from the corresponding aldehydes and amino acid esters. In 2011, Shi and Gan proposed a stereoselective

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

• fails to yield hits [9]. While the term peptidomimetics has been used to describe a variety of molecular classes, including modified peptides and molecular scaffolds for display of amino acid side-chains, this Perspective focuses on non-peptidic small molecules with the appropriate shape and

• translation (also known as RaPID, random non-standard peptides integrated discovery [4]). Key interactions that comprise the pharmacophores were experimentally determined by alanine scanning and other amino acid substitutions to explore SAR, coupled with analysis of co-crystal structures obtained for the

• 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

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

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

• ) calcium ion with amino acid side chains – that might also be in part be responsible for the lack of tweezer binding to Lys-121 – but also represents a new binding mode for the tweezer moiety. The (hydrated) Ca2+ ion is apparently too large to enter the cavity of the tweezer ring, in contrast to larger Cs

• 2b on K-121 leaves more room for stabilizing packing effects. Lys-122 is also located in the vicinity of the H3-T3ph binding site; although it forms a protein contact with Asn-118, there is plenty of room around it in the crystal structure (Figure 4). However, to target this amino acid, the linker

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

• )-235 and (S)-235), which epimerized upon the addition of ᴅ-proline. The subsequent stereoselective aldol reaction with tetrahydrothiopyran-4-one went significantly slower than the epimerization and was directed as well by the amino acid. Therefore, 236 was produced diastereoselectively via dynamic

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

• compounds, selenoproteins, incorporating selenocysteine, the 21st amino acid, are of special importance due to their essential role in various biochemical processes [16][17]. Inspired by natural biosynthetic pathways, synthetic chemists have developed novel low-molecular-weight organoselenium compounds

• significant negative character that enables it to form a hydrogen bonding interaction with the active site amino acid residue of the proteins. MEP analysis of compounds 7 and 8 The molecular electrostatic potential (MEP) maps of compounds 7 and 8 are depicted in Figure 6a and 6b, respectively. The MEP

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

• benzoates 59, 185, and 51 in essentially quantitative yields. A key advantage of this protocol is its applicability to amino acid- and peptide-derived amides. Complex alcohols were successfully employed, producing the corresponding esters 186–192 in high yields without any detectable racemization or

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

• and α-amino acids, which includes a stage of decarboxylation of the intermediate lactone. It is worth noting that generating azomethine ylides via decarboxylation of α-amino acid derivatives is a common practice in synthetic chemistry [44][45][46]. It was shown in our recent works that spirocyclopropa

• sensitive to water presence in the system. It is worth noting that in all cases, a side reaction was observed between alloxan (1) and α-amino acid 2, leading to the formation of murexide via Strecker degradation (Scheme S1, Supporting Information File 1) [53]. This side reaction resulted in decreased yields

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

• intermolecular interactions in biological environments. This study clarifies the electronic origin of DFMO’s gauche effect and provides insight into how local electronic factors determine the structure of fluorinated amino acid derivatives. Keywords: conformational analysis; difluoromethylornithine; gauche

• balance shifts, since strong intermolecular interactions – especially hydrogen bonding with amino acid residues – favor a type-II geometry as the predominant bioconformation. Nevertheless, when different conformers engage in comparable intermolecular interactions, intramolecular effects such as the gauche

• amino acid residues and water molecules, while the ligand is delineated by a contour line to distinguish it from the binding cavity. Lowest-energy type-I, type-II, and type-III conformers of the zwitterionic form of (S)-DFMO. Color labels: H = blue, C = pink, N = orange, O = red, F = yellow. DFT

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

• helical chiral entities was reported by Wang and co-workers. They reported an organocatalyzed asymmetric synthesis of phosphorus-containing chiral helicenes enabled by dynamic kinetic resolution using copper and peptide-mimetic phosphonium salts, i.e. amino acid-derived phosphonium iodide and bromide as

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

• synthesized and screened in asymmetric Mannich reaction. The reaction of aromatic imines with malonates in the presence of amino acid-derived catalysts gave Mannich adducts in very high enantiomeric purities (up to 98% ee). It is proposed that a network of hydrogen and halogen bonds with Lewis bases, together

• between the catalyst and the reagents. The chirality of the catalysts is derived from either amino acid or amino alcohols (including cinchona alkaloid derivatives). There are three exceptional structures: catalysts A-H and E-H, which are the hydrogen analogues of the corresponding iodine-containing

• % ee, Table 1, entry 6). Aminoindane-based catalysts C and D were inefficient and stereomeric purity of the products were not determined (Table 1, entries 7 and 8). The next group of catalysts consists of amino acid derivatives. The most selective was tert-leucine-based catalyst E affording the Mannich

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

• conditions that would be incompatible with the presence of an amino acid appendage at C-3. 7-Prenylindole has been prepared from N-Boc-indoline in the presence of sec-BuLi, TMEDA, and prenyl bromide at −78 °C, followed by oxidation with MnO2 [51]. We deemed it necessary to explore alternative synthetic

• amino acid reagent that could be removed under non-acidic conditions after the cross-coupling reaction. To this end, we prepared iodo N-Fmoc-ᴅ-alanyl anthranilamide methyl ester 29 from ᴅ-serine. Treatment of prenylindoles 14–17 with iodine and KOH followed by acetylation afforded the corresponding

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

• (Caryophyllaceae), are head-to-tail cyclic oligopeptides comprising 5–9 amino acid residues [5][6][7][8][9][10][11][12][13]. These natural products exhibit a significant diversity of pharmacological activities [14][15][16], including estrogen-like activity (1, 2, 7, 8), antitumor effects (5), and antimicrobial

• electrospray ionization mass spectrometry (HRESIMS) data for all compounds matched the calculated exact masses for their respective molecular formulas. NMR spectroscopic analysis in appropriate deuterated solvents (e.g., DMSO-d6, D2O) fully corroborated the amino acid sequence and cyclic connectivity

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

• -oxidized analog and complanadines D and E are partially reduced analogs. In addition, natural analogs such as lycoplatyrine A (6), isolated as a mixture of diastereomers, were discovered as derivatives of lycodine and an amino acid [11]. Biosynthetically, lysine was proposed to be the starting point of

Research towards selective inhibition of the CLK3 kinase

• Vinay Kumar Singh,
• Frédéric Justaud,
• Dabbugoddu Brahmaiah,
• Nangunoori Sampath Kumar,
• Blandine Baratte,
• Thomas Robert,
• Stéphane Bach,
• Chada Raji Reddy,
• Nicolas Levoin and
• René L. Grée

Beilstein J. Org. Chem. 2025, 21, 2250–2259, doi:10.3762/bjoc.21.172

• [22]. But because our goal is to enhance activity for CLK3, we cannot take advantage of this amino acid variation, and we had to investigate for other differences between CLKs. Here, we report our strategy and first efforts towards this end, starting from compound DB18 which is highly potent and

• , examination of the structure of CLK3 shows that this key lysine 241 is very close to the entry of the ATP binding site (Figure 1B). Lysine 241 could be considered as an opportunity to design new molecules with an improved affinity to CLK3, by adding specific interactions with this amino acid bearing a primary

A m-quaterphenyl probe for absolute configurational assignments of primary and secondary amines

• Yuka Takeuchi,
• Mutsumi Kobayashi,
• Yuuka Gotoh,
• Mari Ikeda,
• Yoichi Habata,
• Tomohiko Shirai and
• Shunsuke Kuwahara

Beilstein J. Org. Chem. 2025, 21, 2211–2219, doi:10.3762/bjoc.21.168

• Shibazono, Narashino, Chiba 275-0023, Japan Research Center for Materials with Integrated Properties, Toho University, 2-2-1 Miyama, Funabashi, Chiba 274-8510, Japan 10.3762/bjoc.21.168 Abstract We report a method for determining the absolute configurations of chiral amino alcohols, amino acid esters, and

• amines. In this work, we report that the method was applied to chiral amino alcohols and amino acid esters. We also applied the method to chiral secondary amines, for which it is generally difficult to determine the absolute configuration due to the conformational complexity of their derivatives [33]. By

• comparing the observed and calculated sign of the CD Cotton effect, their absolute configurations were determined. Results and Discussion The probe 1 was prepared as described previously [41]. Probe 1–primary amine conjugates 2a–e were prepared by the reaction of 1 with chiral amino alcohols and amino acid

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

Further elaboration of the stereodivergent approach to chaetominine-type alkaloids: synthesis of the reported structures of aspera chaetominines A and B and revised structure of aspera chaetominine B

• Jin-Fang Lü,
• Jiang-Feng Wu,
• Jian-Liang Ye and
• Pei-Qiang Huang

Beilstein J. Org. Chem. 2025, 21, 2072–2081, doi:10.3762/bjoc.21.162

• compound 14, an intermediate in our synthesis of (–)-isochaetominine A (4) [63]. Indeed, EDCI/HOBt-mediated lactamization of 14 derived amino acid (not shown) via debenzylation increased the yield of (–)-isochaetominine A (4) from 75% to 91% (Scheme 1). Thus, overall yield of the total synthesis of

• (–)-isochaetominine A (4) increased to 30.8% over five steps. Similarly, EDCI/HOBt-mediated lactamization of amino acid (not shown) derived from 15 [63] via debenzylation produced the known (–)-2,3,14-tris-epi-isochaetominine C (16) with a significantly increased 92% yield. The epoxidation-triggered stereodivergent

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

• ][3]. Established sets of reactive probes are typically armed with electrophilic warheads that have the potential to target nucleophilic amino acid side chains. Most reactive probe sets bear cysteine-directed warheads [3][4][5][6][7], although sets have also been designed to target a wider range of

Synthesis, biological and electrochemical evaluation of glycidyl esters of phosphorus acids as potential anticancer drugs

• Almaz A. Zagidullin,
• Emil R. Bulatov,
• Mikhail N. Khrizanforov,
• Damir R. Davletshin,
• Elvina M. Gilyazova,
• Ivan A. Strelkov and
• Vasily A. Miluykov

Beilstein J. Org. Chem. 2025, 21, 1909–1916, doi:10.3762/bjoc.21.148

• oxidation of amide and other amino acid side‐chain fragments. By tracking changes in this oxidation signal upon addition of an alkylating agent, we can infer whether the agent has effectively reacted with (and thus structurally altered) the protein. As illustrated by the black trace in the LSV plot, pure

• . When these agents alkylate the HSA amino acid residues (particularly reactive sites like lysine, cysteine, serine NH2, SH, OH-side chains, and possibly other nucleophilic groups), the resulting covalent modification can disrupt the electroactive centers responsible for the protein’s oxidation peaks

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

• efficiency. Keywords: metal-organic frameworks; post-synthesis modification; supramolecular catalysis; Introduction Most enzymatic reactions take place in multifunctional cavities in which multiple amino acid residues work cooperatively to orient and activate reactants [1][2][3]. These residues may also

• by increasing the binding affinity for the lipophilic reactants and by decreasing the energy required to desolvate acid/base amino acid catalysts [34][35]. Lipophilicity has also been found to be beneficial in condensation reactions as the removed water molecules are repelled by the hydrophobic

Photoswitches beyond azobenzene: a beginner’s guide

• Michela Marcon,
• Christoph Haag and
• Burkhard König

Beilstein J. Org. Chem. 2025, 21, 1808–1853, doi:10.3762/bjoc.21.143

N-Salicyl-amino acid derivatives with antiparasitic activity from Pseudomonas sp. UIAU-6B

• Joy E. Rajakulendran,
• Emmanuel Tope Oluwabusola,
• Michela Cerone,
• Terry K. Smith,
• Olusoji O. Adebisi,
• Adefolalu Adedotun,
• Gagan Preet,
• Sylvia Soldatou,
• Hai Deng,
• Rainer Ebel and
• Marcel Jaspars

Beilstein J. Org. Chem. 2025, 21, 1388–1396, doi:10.3762/bjoc.21.103

• by HPLC with a wavelength monitored at 340 nm of the derivatized amino acid residuals in the hydrolysate and threonine standards (see Supporting Information File 1, Figure S24). Compound 3 was isolated as a yellow oil. Its molecular formula of C11H11NO4 (Δ: −0.3 ppm, calcd. for C11H10NO4, 220.0615

Oxetanes: formation, reactivity and total syntheses of natural products

• Peter Gabko,
• Martin Kalník and
• Maroš Bella

Beilstein J. Org. Chem. 2025, 21, 1324–1373, doi:10.3762/bjoc.21.101

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

• Erich Gebel Cornelia Gocke Carolin Gruner Norbert Sewald Department of Chemistry, Organic and Bioorganic Chemistry, Bielefeld University, Universitätsstraße 25, D-33615 Bielefeld, Germany 10.3762/bjoc.21.88 Abstract Pipecolic acid is known as a non-proteinogenic amino acid with a secondary amine

• aryl modifications in C6 position by utilising the chiral pool of a non-proteinogenic amino acid in combination with transition metal-catalysed cross-coupling reactions. Moreover, we present an in-depth NMR analysis of the key intermediate steps, which illustrates the conformational constraints in