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

• rearrangement and Lewis acid-promoted acetal–ene reaction provided the tetracyclic skeleton 101. With 101 in hands, a 6 step transformation afforded the alkyne 102 in an overall yield of 45%. After obtaining 102, the authors used a free radical reaction to initiate a one-step 6-exo-trig cyclization

• chloride, and radical reduction. Subsequently, reduction of the cyanide group with DIBAL-H and a Wittig reaction afford alkene 114 in 82% yield. Sodium metal was then used as a single-electron reducing agent to provide the second cycloaddition precursor 115, which was converted to the enamine. The enamine

• ]. Starting from pyridine derivatives 129, they obtained the key intermediate 131 via a Simmon–Smith reaction and a bimetallic-mediated photocatalytic radical coupling reaction. Intermediate 132 was then constructed by Friedel–Crafts alkylation using diethylaluminum chloride as a Lewis acid. The pyridine ring

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

• Hiroshige Ogawa Hugh Nakamura The Hong Kong University of Science and Technology (HKUST), Clear Water Bay, New Territories, Hong Kong SAR, China 10.3762/bjoc.22.3 Abstract Radical reactions, which have been reported in large numbers in recent years, have exerted major influence across fields

• and discovery of two-electron ionic transformations dominated the early stages. Over time, pericyclic reactions exemplified by the Woodward–Hoffmann rules and one-electron radical processes became prominent research topics. Today, many of these classical transformations have been further refined to

• afford reactions that are cheaper, safer, and less toxic. In this context, we focus on mild radical reactions mediated by zirconium (Zr), which has recently attracted attention because of its low toxicity and ease of handling. We discuss the utility of Zr in such radical processes and consider prospects

Reactivity umpolung of the cycloheptatriene core in hexa(methoxycarbonyl)cycloheptatriene

• Dmitry N. Platonov,
• Alexander Yu. Belyy,
• Rinat F. Salikov,
• Kirill S. Erokhin and
• Yury V. Tomilov

Beilstein J. Org. Chem. 2026, 22, 64–70, doi:10.3762/bjoc.22.2

• isomer of anion 2 we analyzed the structure of its highest occupied molecular orbital (HOMO) and the distribution of the electrophilic Fukui function (f–) [28] – the difference in electron density between the anion and the derived radical by abstraction of one electron (Figure 2). Both approaches

• possibility of i-halogenation via a chain radical mechanism (Scheme 3). The initiation stage includes an oxidation of anion 2 into the corresponding radical 13 which in turn reacts with halogens to form products 4a,b and a halogen atom which can also oxidize the anion. Quantum chemical calculations revealed

• negative free energy changes for all the stages of this reaction. A chlorination experiment with 2,2,6,6-tetramethylpiperidinyloxyl revealed a trace amount of a trap product detected by high-resolution mass spectrometry to support the radical mechanism. However, this does not exclude the possibility of a

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

• Scheme 28D, involving initial generation of a nitrogen-centered radical 165, which undergoes intramolecular addition to the pendant allene to form a vinyl radical intermediate 166. Subsequent interception of 166 by an N–Cl bond furnishes alkenyl chloride 164. 1.4 Reaction of alkenyl metals with chlorine

Sustainable electrochemical synthesis of aliphatic nitro-NNO-azoxy compounds employing ammonium dinitramide and their in vitro evaluation as potential nitric oxide donors and fungicides

• Alexander S. Budnikov,
• Nikita E. Leonov,
• Michael S. Klenov,
• Andrey A. Kulikov,
• Igor B. Krylov,
• Timofey A. Kudryashev,
• Aleksandr M. Churakov,
• Alexander O. Terent’ev and
• Vladimir A. Tartakovsky

Beilstein J. Org. Chem. 2025, 21, 2739–2754, doi:10.3762/bjoc.21.211

• electrochemical cell distinguishes electroorganic synthesis from traditional organic chemistry methods. Particular attention is paid to the generation of radical intermediates via the oxidation or reduction of radical precursors [40][41][42][43][44][45][46][47][48][49]. In this regard, the anodic oxidation of

• approaches focus mainly on intramolecular radical cyclizations [42][54][55][56][57][58][59][60][61][62][63], while intermolecular [1][64][65][66][67][68] N–N coupling remains a poorly studied area. In addition to the preparation of azo compounds [69][70], intermolecular N–N coupling reactions are of

• direct anodic oxidation of dinitramide anion with the formation of N-centered radical A. Monitoring of the reaction potential during electrolysis under standard conditions using a reference electrode revealed that the measured potential ranged from 2.2 V (at the start of the reaction) to 2.4 V (at the

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

Visible-light-driven NHC and organophotoredox dual catalysis for the synthesis of carbonyl compounds

• Vasudevan Dhayalan

Beilstein J. Org. Chem. 2025, 21, 2584–2603, doi:10.3762/bjoc.21.200

• Vasudevan Dhayalan Department of Chemistry, National Institute of Technology Puducherry, Karaikal-609609, Puducherry, India 10.3762/bjoc.21.200 Abstract Over the past two decades, organocatalyzed visible-light-mediated radical chemistry has significantly influenced modern synthetic organic

• chemistry. In particular, dual catalysis combining N-heterocyclic carbenes (NHCs) with organophotocatalysts (e.g., 4CzIPN, eosin Y, rhodamine, 3DPAFIPN, Mes-Acr-Me+ClO4−) has emerged as a powerful photocatalytic strategy for efficiently constructing a wide variety of carbonyl compounds via radical cross

• ; NHC; organic photocatalyst; radicals; visible-light; Introduction Over the last ten years, NHC-catalyzed visible-light-promoted radical chemistry has been extensively developed for the cost-effective and practical synthesis of bioactive intermediates, pharmaceuticals, drugs, and natural products [1

Recent advances in total synthesis of illisimonin A

• Juan Huang and
• Ming Yang

Beilstein J. Org. Chem. 2025, 21, 2571–2583, doi:10.3762/bjoc.21.199

• deprotection, afforded enal 42. To avoid the chemoselectivity issues in the subsequent allylic oxidation and radical cyclization steps, enal 42 was converted to 43 by reduction of the aldehyde and protection of the resultant diol with Ph2SiCl2. Allylic oxidation of 43 with 44 [37] afforded the enone in 22

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

• -ryanodol, cinnzeylanol, and cinncassiols A,B In 2014, the Inoue group at the University of Tokyo reported a synthetic strategy for ryanodol (4) that leveraged substrate symmetry design, employing intramolecular radical coupling and olefin metathesis as key steps [46] (Scheme 4). Recognizing an embedded

• -alkoxy bridgehead radical addition then installed an allyl fragment, and ring-closing metathesis (RCM) smoothly formed the C ring to complete the core skeleton. The total synthesis was finalized by installing the four remaining stereocenters (C2, C3, C9, and C10). The specific synthetic route is as

• hemiacetalization to construct the oxa[3.2.1]-bridged ring system, thereby forming the D and E rings. Subsequently, the introduction of a tertiary hydroxy thiocarbonate at C11 afforded compound 38. Under thermal conditions, 38 underwent smooth introduction of an allyl fragment via intermolecular radical addition

Ni-promoted reductive cyclization cascade enables a total synthesis of (+)-aglacin B

• Si-Chen Yao,
• Jing-Si Cao,
• Jian Xiao,
• Ya-Wen Wang and
• Yu Peng

Beilstein J. Org. Chem. 2025, 21, 2548–2552, doi:10.3762/bjoc.21.197

• (2) and C (3), featuring a visible light-catalyzed radical cation cascade for the formation of the C8–C8′ and C2–C7′ bonds [6]. Subsequently, they improved the reaction conditions to achieve the racemic synthesis of aglacins A (1) and E (4) as well [7]. In 2021, the Gao group described the total

• relies on a non-photocatalysis approach. Results and Discussion Retrosynthetic analysis of (+)-aglacin B Based on the retrosynthetic analysis shown in Scheme 1, both C8′–C8 and C7–C1 bonds in (+)-aglacin B (2) could be constructed in one-step from the β-bromo acetal 5 by a Ni-promoted tandem radical

Synthesis of the tetracyclic skeleton of Aspidosperma alkaloids via PET-initiated cationic radical-derived interrupted [2 + 2]/retro-Mannich reaction

• Ru-Dong Liu,
• Jian-Yu Long,
• Zhi-Lin Song,
• Zhen Yang and
• Zhong-Chao Zhang

Beilstein J. Org. Chem. 2025, 21, 2470–2478, doi:10.3762/bjoc.21.189

• of new reactions and strategies. In this work, a PET-initiated cationic radical-derived interrupted [2 + 2]/retro-Mannich reaction of N-substituted cyclobutenone provided a facile approach to the direct construction of the ABCE tetracyclic framework of Aspidosperma alkaloids. DFT calculations showed

• formation of unique radical intermediates [9][10]. We previously demonstrated the Ir-catalyzed [2 + 2] cyclization/retro-Mannich reaction of a tryptamine-substituted cyclopentenone F, which led to the formation of indoline J (Figure 1b) [15]. Unlike other reported methods [16][17][18], the PET reaction of F

• generates the cationic radical G, which initiates formation of H, which has a strained bicyclo [3.2.0]heptane core. Strain release of H triggers a downstream radical-driven retro-Mannich reaction, which ultimately results in the formation of J via reductive quenching of intermediate I. As part of our

Transformation of the cyclohexane ring to the cyclopentane fragment of biologically active compounds

• Natalya Akhmetdinova,
• Ilgiz Biktagirov and
• Liliya Kh. Faizullina

Beilstein J. Org. Chem. 2025, 21, 2416–2446, doi:10.3762/bjoc.21.185

• ] described the first total syntheses of racemic meroterpenes (±)-andrastin D (106), (±)-preterrenoid (107), (±)-terrenoid (108), and (±)-terretonin L (109) using a Co-catalyzed homoallyl-type rearrangement/hydrogen atom transfer (HAT) as ring contraction strategy. Radical hydrochlorination of olefin 110 [57

• (±)-terretonin L (109) as the main product with a yield of 46%. Radical hydrochlorination of olefin 110 under more powerful oxidizing conditions (Co(II) catalyst 113, N-fluoropyridinium salt (F+) 114), resulted in the formation of cyclopentenone derivative 112 with a yield of 90%. Demethylation of the latter led

An Fe(II)-catalyzed synthesis of spiro[indoline-3,2'-pyrrolidine] derivatives

• Elizaveta V. Gradova,
• Nikita A. Ozhegov,
• Roman O. Shcherbakov,
• Alexander G. Tkachenko,
• Larisa Y. Nesterova,
• Elena Y. Mendogralo and
• Maxim G. Uchuskin

Beilstein J. Org. Chem. 2025, 21, 2383–2388, doi:10.3762/bjoc.21.183

• bond cleavage to generate an N-imidoyl radical intermediate that undergoes intramolecular cyclization to yield the spirocyclic product (Scheme 1, path g) [14]. Notably, iron is known to exhibit similar behavior in single-electron transfer (SET) processes [15][16][17]. In fact, we previously

• . Third, the introduction of an ortho-methyl substituent on the ketone moiety (3m) likewise suppressed product formation, likely due to steric hindrance interfering with cyclization at the C3 position of the indole ring. Based on literature precedents [15][16], we propose a mechanism involving a radical

• pathway (Scheme 4). Initial Fe(II)-mediated reductive cleavage of the N–O bond in the ketoxime acetate generates an iminyl radical. This is followed by a 5-exo-trig cyclization to form a carbon-centered radical. Final single-electron oxidation by Fe(III) delivers the desired spirocyclic product. All

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

• . With optically active 51 in hand, its extra ketone functionality was reduced via thioacetalization (51 → 52) and radical reduction (52 → 53) to provide 53, a diverging point to access C–H arylation partners 54 and 55. mCPBA oxidation of 53 afforded pyridine N-oxide 54. The Ir-catalyzed C–H borylation

Recent advances in Norrish–Yang cyclization and dicarbonyl photoredox reactions for natural product synthesis

• Peng-Xi Luo,
• Jin-Xuan Yang,
• Shao-Min Fu and
• Bo Liu

Beilstein J. Org. Chem. 2025, 21, 2315–2333, doi:10.3762/bjoc.21.177

• intermediate is also capable of cyclization through radical coupling to form cyclobutanol D, a process systematically expanded upon by Yang's group at the University of Chicago [4], which later became known as the Norrish–Yang cyclization. In recent years, dicarbonyls, specifically 1,2-diketones, α-keto esters

• ]. In contrast to the direct radical coupling in Norrish–Yang cyclization, the distal biradical F, formed from quinone E through a pathway analogous to that of C in the photoredox process, subsequently undergoes intramolecular SET to generate a zwitterion G. This intermediate is then trapped by the

• dysideanone B (35) was completed from 46 via oxidative ethoxylation. The diversity of the key photoreaction stems from three factors: (1) the ability of the excited quinone moiety in 44 to abstract hydrogen atoms from distinct positions; (2) delocalization of the semiquinone radical; (3) the involvement of a

Halogenated butyrolactones from the biomass-derived synthon levoglucosenone

• Johannes Puschnig,
• Martyn Jevric and
• Ben W. Greatrex

Beilstein J. Org. Chem. 2025, 21, 2297–2301, doi:10.3762/bjoc.21.175

• traces of the desired product. Methods for the installation of a CF3-group on enones are limited, although approaches have been applied to quinones, uracils, flavones or arylenones via radical pathways [39][40][41][42]. As per the fluorination reactions, we envisaged that a leaving group in the β

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

• Anna C. Renner Sagar S. Thorat Hariharaputhiran Subramanian Mukund P. Sibi Department of Chemistry and Biochemistry, North Dakota State University, Fargo, North Dakota, 58105-5516, USA 10.3762/bjoc.21.174 Abstract This perspective is focused on enantioselective free radical reactions. It

• describes several important catalytic asymmetric strategies applied to enantioselective radical reactions, including chiral Lewis acid catalysis, organocatalysis, photoredox catalysis, chiral transition-metal catalysis and photoenzymatic catalysis. The application of electrochemistry to asymmetric radical

• transformations is also discussed. Keywords: chiral Lewis acid; electrochemistry; enantioselective radical reaction; organocatalysis; photoenzymatic catalysis; photoredox; Introduction Asymmetric catalysis plays an integral role in the enantioselective synthesis of organic compounds. A wide variety of

Pathway economy in cyclization of 1,n-enynes

• Hezhen Han,
• Wenjie Mao,
• Bin Lin,
• Maosheng Cheng,
• Lu Yang and
• Yongxiang Liu

Beilstein J. Org. Chem. 2025, 21, 2260–2282, doi:10.3762/bjoc.21.173

• radical initiated intramolecular cascade cyclization of 1,n-enynes to provide structurally diverse heterocycles (Scheme 4) [11]. Solvent selection dictated divergent reaction pathways under I2/TBHP oxidation. When an acetonitrile/water mixed solvent was used, iodine radical addition to the alkyne

• preferentially initiated 6-endo-trig cyclization, affording iodinated homoallylic alcohol piperidines 15 (Scheme 4, path a). Conversely, cyclopropane-annulated pyrrolidines 17 were constructed using methanol as solvent through hydroxyl radical-mediated 5-exo-trig cyclization pathway (Scheme 4, path b). This

• intellectually rewarding synthetic methodologies, with far-reaching implications for both fundamental science and industrial applications. Economical synthesis and pathway economy. Au(I)-catalyzed cascade cyclization paths of 1,5-enynes. Au(I)-catalyzed cyclization paths of 1,7-enynes. I2/TBHP-mediated radical

Electrochemical cyclization of alkynes to construct five-membered nitrogen-heterocyclic rings

• Lifen Peng,
• Ting Wang,
• Zhiwen Yuan,
• Bin Li,
• Zilong Tang,
• Xirong Liu,
• Hui Li,
• Guofang Jiang,
• Chunling Zeng,
• Henry N. C. Wong and
• Xiao-Shui Peng

Beilstein J. Org. Chem. 2025, 21, 2173–2201, doi:10.3762/bjoc.21.166

• ][94]. Electrochemical transformations used renewable and clean electricity as a source of electrons and electron holes to generate radical species, showing several superiorities such as safety, economy, high selectivity, scalability, mild reaction conditions, powerful efficiency, environment-friendly

• synthesis of cyclic compounds have emerged. The electrochemical functionalization of alkynes was highlighted by Ahmed in 2019 [109], Zhang described radical annulation of 1,n-enynes under photo/electrochemical reaction conditions in 2023 [110], the electrochemical formation of heterocycles was summarized by

• ] generated [Cp2Fe]+ along with cathodic reduction of MeOH to H2 and MeO− acting as a base. Deprotonation of 1a using MeO− produced the anion A, which underwent single-electron transfer (SET) with [Cp2Fe]+ to give the nitrogen-centered radical B with regeneration of [Cp2Fe] [164][165][166][167][168][169][170

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

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

• and aldehyde 37, which was prepared with 9 steps from commercially available (+)-citronellol, underwent a Reformatsky-type radical addition under the conditions of Et3B/air/Bu3SnH to deliver aldol product [16]. Dehydration of the secondary alcohol gave (E)-38. The HAT radical cyclization [17] of 38 in

Multicomponent reactions IV

• Thomas J. J. Müller and
• Valentyn A. Chebanov

Beilstein J. Org. Chem. 2025, 21, 2082–2084, doi:10.3762/bjoc.21.163

• a strong emphasis on heterocycle synthesis. Beyond traditional condensation-based approaches, mechanistically innovative crossovers – linking metal catalysis with radical chemistry and, more recently, with photo(redox) catalysis – are opening entirely new avenues for MCR development. Finally, seven

Understanding the origin of stereoselectivity in the photochemical denitrogenation of 2,3-diazabicyclo[2.2.1]heptene and its derivatives with non-adiabatic molecular dynamics

• Leticia A. Gomes and
• Steven A. Lopez

Beilstein J. Org. Chem. 2025, 21, 2007–2020, doi:10.3762/bjoc.21.156

• with experimental observations. They argued that the DZ intermediate reacts before thermal equilibration. The formation of inverted housane occurs via the pseudo-axial-to-equatorial inversion of DZ. From the axial DZ, the puckered-DR (puc-DR in Scheme 3) radical could be formed resulting in retained

• housane. From the equatorial DZ (eq-DZ in Scheme 3), the inverted housane can be formed through a homolytic substitution (SH2) process or can be formed via a planar DR (pl-DR in Scheme 3) radical which affords retained and inverted housane [82]. In 2020, Rollins and co-workers also investigated the

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

• research has demonstrated that NHCs are also capable of stabilizing radical or excited-state species [12][13]. In 2020, our group reported the concept of photo-NHC catalysis where direct excitation of acylazolium intermediates generated from o-toluoyl fluoride substrates with UV-A light resulted in a novel

• -electron reduction delivering the same stabilized radical C. Beginning with a seminal report by di Rocco and Rovis in 2012 [21], the combination of NHC and photoredox catalysis has recently been the subject of intense research activity [22][23][24][25][26][27][28][29][30]. Employing the latter reductive

• manifold with carboxylic acid derivatives, numerous coupling processes affording ketone products have been developed. Since the initial report from Scheidt and co-workers using 4-alkyl-substituted Hantzsch esters as coupling partners [31][32][33][34][35][36], several alkyl radical sources have been

Asymmetric total synthesis of tricyclic prostaglandin D2 metabolite methyl ester via oxidative radical cyclization

• Miao Xiao,
• Liuyang Pu,
• Qiaoli Shang,
• Lei Zhu and
• Jun Huang

Beilstein J. Org. Chem. 2025, 21, 1964–1972, doi:10.3762/bjoc.21.152

• available has prevented its practical use, and synthesis methods for tricyclic-PGDM methyl ester are required. Based on the utilization of oxidative radical cyclization for the stereoselective construction of the cyclopentanol subunit with three consecutive stereocenters, we describe an asymmetric total

• synthesis of tricyclic-PGDM methyl ester in 9 steps and 8% overall yield. Keywords: asymmetric total synthesis; oxidative radical cyclization; tricyclic prostaglandin D2 metabolite methyl ester; Introduction Prostaglandins (PGs), a family of hormone-like lipid compounds, are ubiquitous natural products

• total synthesis of 4 and is required to explore alternative synthetic strategies for PGs and analogues [17]. Biosynthetically, 4 is proposed to arise via a 5-exo-trig biogenetic radical-mediated cyclization (Scheme 1C) [18][19]. Over the past five decades, the Snider oxidative radical reaction has been