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

• triflate 46, alkylation with sulfone 47 via treatment with butyllithium and hexamethylphosphoramide (HMPA) yielded the coupling product 48 as a mixture of diastereoisomers in 60% yield. Ultimately, single-electron reduction removed both the sulfone and benzyl groups of 48, furnishing (S)-α-tocotrienol (49

• transesterification. After substrates screening, diol 65 was selected and converted into monoester 66 in 95% yield with 98% ee using vinyl acetate and lipase PS from Pseudomonas cepacia. Four subsequent steps afforded sulfone 67, and the following alkylation with fragment 68 in the presence of butyllithium and HMPA

• removal of the benzyl group, chemoselective N-alkylation with fragment 196, and removal of the benzoyl group allowed the conversion of 195 into iodide 197. Sequential oxidation of the alcohol, HWE reaction, and reduction of the resulting ester then provided compound 198. In the presence of Pd(OAc)2, PPh3

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

• albumin was chosen as a model protein because of its well‐characterized structure and the presence of reactive sites that are known to be susceptible to alkylation. In standard aqueous media, the electrochemical oxidation of HSA can be observed via LSV as a broad wave, which is often attributed to the

• themselves exhibit no discernible redox activity in this potential range when tested in the absence of HSA. Consequently, any changes in the recorded voltammogram could be attributed to the interaction (alkylation) of albumin rather than to new electrochemical processes arising directly from the compounds

• (Figure 4). In many alkylation scenarios, crosslinking or other structural rearrangements can render previously oxidizable moieties inaccessible or shift the protein’s conformational state. This suppresses or altogether eliminates the characteristic oxidation wave of HSA. Based on established literature

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

• bromide 47, followed by Fmoc protection of 56, Boc deprotection of 57, reduction of the NO2 group to NO and intramolecular Mills coupling to form 35h. Removal of the Fmoc protecting group under basic conditions affords the unsubstituted product 35d which, after N-alkylation or acylation affords the

• indigo is a well-known commercial product, we will not focus on other synthetic pathways, which can be found in a review by Hecht and co-workers [65], and instead discuss the N-functionalisation (Scheme 24, bottom). N-Alkylation in 76 can be achieved with alkyl halides and base. There are different

[3 + 2] Cycloaddition of thioformylium methylide with various arylidene-azolones in the synthesis of 7-thia-3-azaspiro[4.4]nonan-4-ones

• Daniil I. Rudik,
• Irina V. Tiushina,
• Anatoly I. Sokolov,
• Alexander Yu. Smirnov,
• Alexander R. Romanenko,
• Alexander A. Korlyukov,
• Andrey A. Mikhaylov and
• Mikhail S. Baranov

Beilstein J. Org. Chem. 2025, 21, 1791–1798, doi:10.3762/bjoc.21.141

• methylide [20]. generality and overall yields of the [2 + 3] cycloaddition of thioformylium methylide with azolones was not as effective. Possible alkylation of pyridine derivatives 1,3 and 4g by initial compound I did not allow us to obtain the corresponding products. A similar problem was observed for

Photocatalysis and photochemistry in organic synthesis

• Timothy Noël and
• Bartholomäus Pieber

Beilstein J. Org. Chem. 2025, 21, 1645–1647, doi:10.3762/bjoc.21.128

• of alkenylboronic esters using energy transfer catalysis [26]. Gualandi and co-workers leveraged a combination of photoredox and HAT catalysis to realize the intramolecular nucleophilic amidation of alkenes with β-lactams [27]. Further, Luridiana and colleagues developed a method for the alkylation

High-pressure activation for the solvent- and catalyst-free syntheses of heterocycles, pharmaceuticals and esters

• Kelsey Plasse,
• Valerie Wright,
• Guoshu Xie,
• R. Bernadett Vlocskó,
• Alexander Lazarev and
• Béla Török

Beilstein J. Org. Chem. 2025, 21, 1374–1387, doi:10.3762/bjoc.21.102

• Mannich reactions [20], lipase-catalyzed esterification [21], nitro-aldol [22], Michael [23], and aza-Michael reactions [24][25], Diels–Alder reactions [26][27] and Friedel–Crafts alkylation of indoles [28]. Many high pressure reactions were applied in natural product synthesis [29]. The high pressure

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

• traced back to 3-oxetanone. In 2018, Bull and co-workers disclosed the first lithium-catalysed thiol alkylation using electron-rich 3-aryloxetan-3-ols 142 (Scheme 35) [84]. This protocol is completely chemoselective as no ring-opening was observed and the resulting oxetane sulphides 143 were obtained in

• 2020, Bull et al. published a short synthesis of 3-aryloxetan-3-carboxylic acids 152 employing a Friedel–Crafts alkylation (which builds on their previous alkylation of phenols [87]) and a selective furan oxidative cleavage (Scheme 37) [88]. The oxidation protocol uses a catalytic amount of a high

• 178 from 3-aryloxetan-3-ols through a tandem Friedel–Crafts alkylation/intramolecular ring opening (Scheme 45) [87]. The reaction was mostly high yielding and best results were obtained for electron-rich para-substituted phenols, while substituents in the ortho/meta-positions diverted the

Recent advances in amidyl radical-mediated photocatalytic direct intermolecular hydrogen atom transfer

• Hao-Sen Wang,
• Lin Li,
• Xin Chen,
• Jian-Li Wu,
• Kai Sun,
• Xiao-Lan Chen,
• Ling-Bo Qu and
• Bing Yu

Beilstein J. Org. Chem. 2025, 21, 1306–1323, doi:10.3762/bjoc.21.100

• transformation. Representative photocatalysts discussed in this review. Alkylation of C(sp3)–H catalyzed by amidyl radical under visible light. Direct heteroarylation of C(sp3)–H catalyzed by amidyl radical under visible light. Alkylation of C(sp3)–H catalyzed by amidyl radical and metal-free photocatalyst under

• visible light. Alkylation of C(sp3)–H, Si–H, and Ge–H catalyzed by amidyl radical under visible light. Direct heteroarylation of C(sp3)–H catalyzed by synergistic promotion of amidyl radical and photocatalyst, under visible light. Direct B–H functionalization of icosahedral carboranes catalyzed by amidyl

• C(sp3)–H in polyolefins addressed by amidyl radical under visible light. Site-selective C(sp3)–H bromination implemented by amidyl radical under visible light. Site-selective chlorination of C(sp3)–H in natural products implemented by amidyl radical under visible light. Alkylation of C(sp3)–H

Recent advances in oxidative radical difunctionalization of N-arylacrylamides enabled by carbon radical reagents

• Jiangfei Chen,
• Yi-Lin Qu,
• Ming Yuan,
• Xiang-Mei Wu,
• Heng-Pei Jiang,
• Ying Fu and
• Shengrong Guo

Beilstein J. Org. Chem. 2025, 21, 1207–1271, doi:10.3762/bjoc.21.98

• . Control experiments confirmed the necessity of both AIBN and DTBP, with higher temperatures favoring the desired cyclization over side reactions. In 2021, a novel excited-state palladium-catalyzed alkylation/annulation reaction was developed to achieve reaction of unactivated alkyl chlorides, facilitating

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

Pd-Catalyzed asymmetric allylic amination with isatin using a P,olefin-type chiral ligand with C–N bond axial chirality

• Natsume Akimoto,
• Kaho Takaya,
• Yoshio Kasashima,
• Kohei Watanabe,
• Yasushi Yoshida and
• Takashi Mino

Beilstein J. Org. Chem. 2025, 21, 1018–1023, doi:10.3762/bjoc.21.83

• synthesis of spirocyclic compounds [1][2][3]. The nucleophilicity of isatin at the nitrogen atom allows it to participate in reactions such as alkylation [4], arylation [5], and aza-Michael addition [6][7][8]. However, the products obtained from these reactions are primarily achiral or racemic, and only a

Recent total synthesis of natural products leveraging a strategy of enamide cyclization

• Chun-Yu Mi,
• Jia-Yuan Zhai and
• Xiao-Ming Zhang

Beilstein J. Org. Chem. 2025, 21, 999–1009, doi:10.3762/bjoc.21.81

• cephalotaxine, cephalezomine H, (−)-cephalotaxine, (−)-cephalotine B, (−)-fortuneicyclidin A, (−)-fortuneicyclidin B, and (−)-cephalocyclidin A. Unlike enamines, tertiary enamides can participate in cyclization reactions initial as nucleophiles, and upon protonation, alkenylation, or alkylation, the resultant

Studies on the syntheses of β-carboline alkaloids brevicarine and brevicolline

• Benedek Batizi,
• Patrik Pollák,
• András Dancsó,
• Péter Keglevich,
• Gyula Simig,
• Balázs Volk and
• Mátyás Milen

Beilstein J. Org. Chem. 2025, 21, 955–963, doi:10.3762/bjoc.21.79

• hydrogenation of the C=C double bond in the side chain gave brevicarine (2). The first total synthesis of brevicarine is shown in Scheme 3 [2][20][21]. Condensation of indole (11) with 1-methylpiperidone (12) gave compound 13 [22]. N-Alkylation of 13 with benzyl bromide, followed by treatment of the quaternary

• -monomethylation of the primary amino group of compound 25 by alkylation with methyl iodide or by Eschweiler–Clarke reductive amination with formaldehyde and formic acid were unsuccessful, because the dimethylated byproduct was also formed, even when one equivalent alkylating agent was used. Finally, our efforts

Cu–Bpin-mediated dimerization of 4,4-dichloro-2-butenoic acid derivatives enables the synthesis of densely functionalized cyclopropanes

• Patricia Gómez-Roibás,
• Andrea Chaves-Pouso and
• Martín Fañanás-Mastral

Beilstein J. Org. Chem. 2025, 21, 877–883, doi:10.3762/bjoc.21.71

• organoboron compound with CuOt-Bu and subsequent SN2’-selective allylic alkylation of 1. The densely functionalized structure of these dimerization products offers a versatile synthetic handle for further chemoselective functionalization. Considering the presence of two enolizable esters together with the

Synthesis of HBC fluorophores with an electrophilic handle for covalent attachment to Pepper RNA

• Raphael Bereiter and
• Ronald Micura

Beilstein J. Org. Chem. 2025, 21, 727–735, doi:10.3762/bjoc.21.56

• have shown that this feature can be exploited to construct a covalent bond between the fluorophore and the RNA by replacing the N-hydroxyethyl group of the dye with an electrophilic handle, resulting in efficient RNA alkylation at the N7 of G41 [11]. Synthesis and evaluation of Pepper dyes with an

• electrophilic handle In analogy to the reported synthesis of HBC [7], we first developed a route to generate a series of HBC derivatives with N-(bromoalkyl) handles of different lengths (Scheme 2), with the intention of optimizing the RNA alkylation reaction for high yields. The synthesis starts with a

• containing potassium and magnesium ions at a physiological pH of 7.0 for 5 hours. Analysis of the reaction mixture by anion-exchange HPLC revealed that the bromopropyl handle (C3 homolog 8) gave the highest yield of covalently tethered HBC-RNA complex (50%). Significantly less RNA alkylation yield was

Asymmetric synthesis of fluorinated derivatives of aromatic and γ-branched amino acids via a chiral Ni(II) complex

• Maurizio Iannuzzi,
• Thomas Hohmann,
• Michael Dyrks,
• Kilian Haoues,
• Katarzyna Salamon-Krokosz and
• Beate Koksch

Beilstein J. Org. Chem. 2025, 21, 659–669, doi:10.3762/bjoc.21.52

• hectogram range, is a major strength of this method. In this context, Han et al. could show that the trifluorinated variant of α-aminobutyric acid, trifluoroethylglycine (TfeGly), can be synthesized on a 100 g scale with great enantiomeric purity [8]. The critical step here is the alkylation of the Ni(II

• , base, solvent, and reagent equivalents to optimize the alkylation reaction for both bromides 4 and 5 (Table 1 and Table 2). For Ni(II) complex of [2.3.5.6F]TfMePhe (6), firstly we screened different inorganic and organic bases (Table 1, entries 1–3) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) was

• fluorinated alkyl iodide precursor 10, the corresponding alkylation reaction with the Ni(II) complex 1 was conducted under previously optimized conditions for the synthesis of Fmoc-TfIle [13] in terms of base (NaH) and solvent (DMF) and thoroughly screened in terms of base equivalents, concentration and

Recent advances in allylation of chiral secondary alkylcopper species

• Minjae Kim,
• Gwanggyun Kim,
• Doyoon Kim,
• Jun Hee Lee and
• Seung Hwan Cho

Beilstein J. Org. Chem. 2025, 21, 639–658, doi:10.3762/bjoc.21.51

• asymmetric allylic alkylation (AAA) has been remarkable since its initial development in 1995, when Bäckvall and van Koten first reported moderate enantioselectivity using Grignard reagents with allylic acetates [21][22]. This discovery triggered extensive research endeavors, significantly expanding the

• largely depends on the choice of the nucleophilic organometallic species (Scheme 2). For example, the asymmetric copper-catalyzed allylic alkylation utilizing organometallic species 5 bearing a primary carbon–metal bond predominantly constructs the stereogenic center derived from electrophiles. The

• low configurational stability of the chiral secondary organometallic 9 and organocopper species 10 [38]. Therefore, the development of a more broadly applicable catalytic system that could accomplish copper-catalyzed stereoselective allylic alkylation with chiral secondary nucleophiles represents a

Entry to 2-aminoprolines via electrochemical decarboxylative amidation of N‑acetylamino malonic acid monoesters

• Olesja Koleda,
• Janis Sadauskis,
• Darja Antonenko,
• Edvards Janis Treijs,
• Raivis Davis Steberis and
• Edgars Suna

Beilstein J. Org. Chem. 2025, 21, 630–638, doi:10.3762/bjoc.21.50

• also suitable as nucleophiles for the cyclization into 2-aminoproline and 2-aminopipecolic acid derivatives 6 (Figure 2, reaction 3). The starting disubstituted malonic esters are readily available by C-alkylation of inexpensive and readily available diethyl acetamidomalonate, followed by

• in three steps (62% overall yield) from commercially available diethyl acetamidomalonate by an alkylation/hydrolysis/Boc-cleavage sequence (Scheme 1). The development of decarboxylative amidation commenced by examining the published conditions for anodic decarboxylation/etherification [4

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

• sulfhydryls can be conjugated by several means, including alkylation with α-halo carbonyls (in which case Lys may compete), and Michael additions (e.g., to maleimide, which is reversible and therefore may lead to incomplete conversion). The Michael adducts also present chemical instability in plasma and

Total synthesis of (±)-simonsol C using dearomatization as key reaction under acidic conditions

• Xiao-Yang Bi,
• Xiao-Shuai Yang,
• Shan-Shan Chen,
• Jia-Jun Sui,
• Zhao-Nan Cai,
• Yong-Ming Chuan and
• Hong-Bo Qin

Beilstein J. Org. Chem. 2025, 21, 601–606, doi:10.3762/bjoc.21.47

• ] and has been used in syntheses of natural products containing aryl quaternary carbon centers [9][10]. Unlike the intramolecular alkylation strategy of a phenol derivative, which can only be applied in basic dearomatization reactions, our approach using an α-iodophenol ether as precursor of the

• oxy-Michael addition from dienone 15. The 6/6/6 tricyclic structure in 15 can be constructed through dearomatization of compound 16, which in turn can be readily synthesized through consecutive alkylation steps starting from magnolol (11). Additionally, using magnolol as the starting material brings

• DIPEA, affording compound 17 with an 89% yield [11]. For the following alkylation step with tert-butyl bromoacetate, three bases were tested: potassium carbonate, cesium carbonate, and sodium hydride. Considering the targeted alkylation of a phenolic hydroxy group and the pKa requirements of this

Cryptophycin unit B analogues

• Thomas Schachtsiek,
• Jona Voss,
• Maren Hamsen,
• Beate Neumann,
• Hans-Georg Stammler and
• Norbert Sewald

Beilstein J. Org. Chem. 2025, 21, 526–532, doi:10.3762/bjoc.21.40

• of N-alkylation on the non-chlorinated unit B derivatives. Results and Discussion For the synthesis of unit B derivatives with amino groups instead of the naturally occurring methoxy group ᴅ-phenylalanine served as the fundamental substrate (Scheme 1). Nitration [23] followed by methyl ester

• cryptophycins 1 and 2 showed high cytotoxicity with 313 pM (1) and 6.36 nM (2) and outstandingly low resistance factors. Furthermore, the new cryptophycin 1 confirms the correlation between degree of alkylation and cytotoxicity of m-chloro-p-amino unit B derivatives. Since MDR is responsible for over 90% of

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

• novel compound DPQ1. Keywords: deazapurines; heterocycles; pyrrolopyrimidines; queuosine; riboswitches; ribozymes; RNA alkylation; RNA labelling; Introduction Pre-queuosine 1 (preQ1) is a biosynthetic precursor of the hypermodified nucleoside queuosine (Q) that is found in the wobble position of

Photomechanochemistry: harnessing mechanical forces to enhance photochemical reactions

• Francesco Mele,
• Ana M. Constantin,
• Andrea Porcheddu,
• Raimondo Maggi,
• Giovanni Maestri,
• Nicola Della Ca’ and
• Luca Capaldo

Beilstein J. Org. Chem. 2025, 21, 458–472, doi:10.3762/bjoc.21.33

• reactions: A) atom-transfer-radical addition, B) pinacol coupling, C) decarboxylative alkylation, D) [2 + 2] cycloaddition. The photo in Scheme 11 was reproduced from [77] (© 2024 F. Millward et al., published by Wiley-VCH GmbH, distributed under the terms of the Creative Commons Attribution 4.0

Synthesis, characterization, antimicrobial, cytotoxic and carbonic anhydrase inhibition activities of multifunctional pyrazolo-1,2-benzothiazine acetamides

• Ayesha Saeed,
• Shahana Ehsan,
• Muhammad Zia-ur-Rehman,
• Erin M. Marshall,
• Sandra Loesgen,
• Abdus Saleem,
• Simone Giovannuzzi and
• Claudiu T. Supuran

Beilstein J. Org. Chem. 2025, 21, 348–357, doi:10.3762/bjoc.21.25

• ) products and with alkylating agents 6i–n to give the N- and O-alkylated (dialkylated) products. The alkylation of compound 5 was controlled by the molar quantities of alkylating agents and base present. Thus, compound 5 was N-alkylated using equimolar quantities of the alkylating agents 6a–h to give the

• susceptible to alkylation than the OH group. However, under more basic conditions and using the alkylating agent in excess can lead to a dialkylated product. It has already been established that N-alkylation takes place before O-alkylation because the nitrogen atom is a softer nucleophile as compared to the

• oxygen atom [50]. Preferential N-alkylation (over O-alkylation) of 1,2-benzothiazine scaffolds has also been carried out by Ahmad and co-workers in 2014 and Szczęśniak-Sięga and companions in 2018 [37][51]. Structure elucidation of all the synthesized derivatives was carried out using 1H, 13C NMR, and

Streamlined modular synthesis of saframycin substructure via copper-catalyzed three-component assembly and gold-promoted 6-endo cyclization

• Asahi Kanno,
• Ryo Tanifuji,
• Satoshi Yoshida,
• Sota Sato,
• Saori Maki-Yonekura,
• Kiyofumi Takaba,
• Jungmin Kang,
• Kensuke Tono,
• Koji Yonekura and
• Hiroki Oguri

Beilstein J. Org. Chem. 2025, 21, 226–233, doi:10.3762/bjoc.21.14

• antitumor activity, triggered by DNA alkylation [6][7][8]. The aminonitrile/hemiaminal at C21 generates an iminium cation while releasing a cyanide or a hydroxy group under physiological conditions. This iminium cation facilitates nucleophilic attack by guanine residues in the minor groove of the GC-rich

• three base pairs, predominantly 5’-GGC-3’ and 5’-GGG-3’ [12][13]. Notably, a bis-phenol type unnatural analog 3, composed of the C5 deoxy A-ring bearing a phenolic hydroxy group at C8, presumably as a HB donor upon interaction with nucleic acids, exhibits superior DNA alkylation capability compared to

• - and E- rings serve as hydrogen bond (HB) donors/acceptors to facilitate DNA alkylation at C21. UV–vis absorption (gray solid line), the emission spectrum (blue solid line), and the corresponding excitation spectrum (blue dashed line) of the imidate 18 in CHCl3 (c = 100 μM). aQuantum yield (Φfl