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

• and further treated with Lindlar catalyst and DIBAL-H to afford the alkene and aldehyde motifs of 195, respectively. Oxime formation and oxidation yielded an intermediate nitrile oxide, which underwent an intramolecular [3 + 2]-cycloaddition with the adjacent ethene substituent towards isoxazoline 196

• assemble 226 as an E/Z mixture. Hydrogenation of alkene 226 and treatment with allyltrimethylsilane were used to form 228. The ester moiety of 228 was reduced and the Bz-group was cleaved simultaneously to afford the respective diol (229), then TIPS-protection of the primary alcohol unit enabled the

• the secondary alcohol, hydroboration–oxidation of the terminal alkene and treatment with DMP produced aldehyde 261. The second building block (265) was synthesized via stereoselective Noyori reduction of 262 [105], followed by TMS cleavage and Bz-protection of the free alcohol unit (Scheme 30). Both

Synthesis and stereochemical analysis of dynamic planar chiral oxa[7]orthocyclophene

• Yukiho Hashimoto,
• Yuuya Kawasaki,
• Kazunobu Igawa and
• Katsuhiko Tomooka

Beilstein J. Org. Chem. 2026, 22, 436–442, doi:10.3762/bjoc.22.30

• ][3][4][5][6][7][8][9][10], we previously synthesized hetera[7]orthocyclophenes 1 having a heteroatom-embedded ansa-chain (X = O or NR) and an (E)-alkene moiety (Figure 1) [6][9], and found that the orthocyclophenes exhibit dynamic planar chirality in a wide range of stereochemical stability depending

• on the differences of the heteroatom and substituents on the (E)-alkene moiety [11][12]. The half-lives of the optical activity optt1/2 of 1aa (X = O, Y = H) and 1ba (X = NTs, Y = H) were 380 h and 56.7 h at 25 °C, respectively, indicating that the stereochemical stability of the oxygen-containing

• -substituted oxacyclophene 1ad We planned to construct the nine-membered cyclic ether skeleton of 1ad in the final step by an intramolecular Williamson etherification of haloalcohol 2 (Scheme 1). The iodine-substituted Z-alkene moiety of 2 was planned to be introduced through a trans-selective hydroiodination

Dialkylaminoalkylation of β-ketosulfones via ring-opening of 3-sulfonylpyrrolidines

• Evgeny M. Buev,
• Alexander V. Pavlushin,
• Vladimir S. Moshkin and
• Vyacheslav Y. Sosnovskikh

Beilstein J. Org. Chem. 2026, 22, 383–389, doi:10.3762/bjoc.22.26

• consists in the simultaneous generation of two reactive intermediates: terminal alkene A and N-methylazomethine ylide B, and final [3 + 2] cycloaddition. It was found that the latter approach depends on CH-acidity of the active methylene compounds and performs well with the acidic substrates in the range

Ring contraction and ring expansion reactions in terpenoid biosynthesis and their application to total synthesis

• Nicolas Kratena,
• Nicolas Heinzig and
• Peter Gärtner

Beilstein J. Org. Chem. 2026, 22, 289–343, doi:10.3762/bjoc.22.21

• ring expansion, and additional 5-ring cyclisation by the pendant alkene a new tricyclic carbocation 14c is formed. From here a 1,2-alkyl shift delivers the 7,6,6-ring system of lydicene (15) [66]. Alternatively, a 1,5-hydride shift affords the secondary carbocation 14d which undergoes ring contraction

• ) and B (78) the tricyclic precursor 79 was invoked (see Scheme 22B) [129]. This compound could undergo oxidation at the alkene (and C-1) to give intermediate 80, which after oxidative cleavage affords the enolate of diketone 82 which can undergo transannular aldol addition to give either product 77 or

• liphagal (104) [150]. Oxidation of the alkene in 102 may give rise to an oxidised species, such as 105, which is able to undergo Meinwald rearrangement to the ring-expanded ketone 106. From here, epimerisation of the C-8 methyl group and acetalisation to 106a followed by elimination delivers the final

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

• springboards to three-dimensional molecular architectures largely untapped (Figure 2A) [13]. Enforcing localization of the arene π-system achieves precisely this: it activates the arene through induction of an alkene-like character, thereby presenting a twofold opportunity: (1) to advance dearomative chemistry

• aromaticity and unveiling the latent double-bond character within the aromatic ring. This dramatically increases reactivity, enabling alkene-like transformations with aromatic molecules that are inaccessible by conventional synthetic methods, thereby complementing traditional arene chemistry. Other modes of

• distortion enforces an alkene-like double-bond character at the junction, accompanied by enhanced reactivity unusual for aromatic systems [24][25]. In contrast to the breadth of structural and theoretical studies, synthetic utilization remains underexplored, despite the growing evidence that strain-induced

Synthesis of diaryl phosphates using phytic acid as a phosphorus source

• Kazuya Asao,
• Seika Matsumoto,
• Haruka Mori,
• Riku Yoshimura,
• Takeshi Sasaki,
• Naoya Hirata,
• Yasuyuki Hayakawa and
• Shin-ichi Kawaguchi

Beilstein J. Org. Chem. 2026, 22, 213–223, doi:10.3762/bjoc.22.15

• the other mechanism is based on an E2 reaction, which involves the elimination of phosphoric acid accompanied by alkene formation. The phosphoric acid ester of a secondary alcohol releases phosphoric acid and alkenes through thermal degradation, which has been previously observed using isosorbide

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

• 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

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

• compound loss or degradation at the purification step. 1.2 Exchange reactions This chapter deals with exchange reactions, meaning that a given substituent on the alkene is formally exchanged for chlorine. The reactions are very different from each other in terms of mechanism and for a full discussion the

• alkenyl chloride 156 was isolated only in trace amounts, alongside isomerized alkene 157 and dichloride 158. Notably, only the sterically hindered tert-butyl-substituted alkyne afforded the desired product 155 in high yields, whereas hydrochlorination of 4-octyne proved inefficient to deliver compound 159

• access cyclohexenyl chlorides via chloride trapping of alkenyl cation intermediates (Scheme 48B) [157]. Comparable yields were obtained when either alkene or alcohol precursors were employed, consistent with the formation of a common cationic intermediate. The method proved limited to six-membered ring

Mechanistic insights into hydroxy(tosyloxy)iodobenzene-mediated ditosyloxylation of chalcones: a DFT study

• Jai Parkash,
• Sangeeta Saini,
• Vaishali Saini,
• Omkar Bains and
• Raj Kamal

Beilstein J. Org. Chem. 2025, 21, 2703–2715, doi:10.3762/bjoc.21.208

• ) compounds in polar nucleophilic or non-nucleophilic solvents [10][11][12][20][29][30][31][32][33][34][35][36]. Fujita discusses typical pathways of alkene oxidation with hypervalent iodine in great detail including the stereochemical course of reaction involving a cyclic iodonium ion [30]. In the literature

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

• the hydroxy moiety in C12 was performed, followed by Grignard addition of ethynylmagnesium bromide and then hydrocyanation to result in vinyl nitrile 57 over five steps. The key Wagner–Meerwein-type rearrangement occurred in 68% yield furnishing epoxide 58. Hydrogenation of the alkene moiety as well

• 63. The D-ring was saturated and the remaining alkene epoxidized – a strategy that we have observed in cyclopamine synthesis before. The sequence needed several protecting group manipulations. Therefore, epoxide 64 was synthesized in eleven steps from ketone 62. The key spirocyclization was performed

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

• of single-electron NHC catalysis by incorporating oxidatively generated aryloxymethyl radicals A as a key intermediate. A variety of γ-aryloxy ketones 12 were successfully prepared in the presence of NHC (15 mol %), photocatalyst (2 mol %), using 467 nm LED and a combination of alkene 11, amide 9

• for 18 h (Scheme 6) [56]. Gao, Ye, and co-workers reported the iminoacylation of alkenes 17 via photoredox NHC dual catalysis in the presence of NHC (20 mol %), photocatalyst (5 mol %), with Na2CO3 (1.2 equiv) using a 36 W blue LED. In this method, the alkene-attached iminyl radicals A and the NHC

• -attached ketyl radical B are generated under photoredox NHC catalysis under visible-light irradiation. The 5-exo-trig radical cyclization of the alkene-tethered iminyl radicals A furnished a dihydropyrrole-derived radical coupled with the NHC group attached ketyl radical B. This approach features readily

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

• [5.2.1.01,5]decane core with a cis-pentalene unit. The product was further processed into rearrangement precursor 46 (as an inseparable mixture, dr = 1:1.6) by TBS protection of the primary alcohol and epoxidation of the alkene with m-CPBA. Unlike Rychnovsky’s substrate, epoxy alcohol 46 underwent

• reaction of 87 was employed, generating both the kinetic product 88 and the desired thermodynamic product 89. Heating 88 promoted a retro-Diels–Alder/Diels–Alder equilibrium, favoring the more stable isomer 89. Palladium-catalyzed hydrogenation of the 1,2-disubstituted alkene in 89, followed by Mo(CO)6

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

• , provided compound 78. Finally, a sequence comprising terminal alkene reduction, epoxidation of the tetrasubstituted alkene, and LiDBB-promoted intramolecular reductive cyclization and deprotection completed the asymmetric total synthesis of (+)-ryanodine (1) in 17 steps. Notably, the additive used in the

• , terminal alkene reduction, and intramolecular reductive cyclization culminated in the completion of the first asymmetric total synthesis of (+)-20-deoxyspiganthine (2) in 19 steps. Micalizio’s formal total synthesis of ryanodol (4) In 2020, the Micalizio group at the University of California, San Diego

• epoxidation of the tetrasubstituted alkene followed by Grieco elimination yielded diene 92. Subsequent oxidation of the hemiacetal, saponification of the lactone, intramolecular epoxide opening, and Hoveyda–Grubbs (II)-catalyzed RCM afforded tetracyclic compounds 94 and its transesterification product 93

Rapid access to the core of malayamycin A by intramolecular dipolar cycloaddition

• Yilin Liu,
• Yuchen Yang,
• Chen Yang,
• Sha-Hua Huang,
• Jian Jin and
• Ran Hong

Beilstein J. Org. Chem. 2025, 21, 2542–2547, doi:10.3762/bjoc.21.196

• functionality strategy employing oxazoline to unmask the 1,2-hydroxyamine moiety proves feasible, eliminating the need for alkene functionalization required in previous endeavours. This current strategy provides a reliable platform for accessing diverse uracil nucleosides and their derivatives, facilitating the

• three contiguous stereogenic centers (Scheme 1A). The pyran ring was constructed by a RCM reaction [16]. Subsequent functionalization of the alkene to install the 1,2-cis-hydroxy amine required 6 steps from the sterically more demanding side. In continuing our recent interest in accessing unusual

• position. Therefore, dihydroxylation [37] readily converted alkene 11 to diol 12 as a mixture of inseparable isomers. Without purification, oxidative cleavage with NaIO4 resulted in a compound with strong UV absorption, which was eventually identified as enone 14 (Scheme 3). It is assumed that the

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

• leads to ketene D, which can undergo cycloaddition with an alkene to yield E. This fragmentation pathway dominates under various conditions (e.g., transition-metal catalysis, nucleophilic addition) and is driven by ring-strain release [11]. PET, an alternative to direct excitation and EnT, enables the

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

• , followed by diastereoselective α-alkylation, produced 38. A Wittig reaction and subsequent deketalization converted the ketone in 38 to the terminal alkene 39, allowing for subsequent sequential chemoselective hydrogenations: first, hydrogenation of the exo-olefin using Wilkinson’s catalyst proceeded with

• known two-step sequence to 61, followed by Mitsunobu reaction, ester reduction, thioether oxidation, and silylation of the primary alcohol to furnish sulfone 64. The two key fragments – aldehyde 60 and sulfone 64 – were merged via Julia–Kocienski olefination to construct alkene 65. Treatment of 65 with

• (C6F5)3B triggered a Meinwald rearrangement, generating aldehyde 66. Nucleophilic addition, oxidation of the resulting alcohol, and base-promoted epimerization at C6 of 67' delivered 67. Subsequent dihydroxylation of the alkene in 67 and protection of the resulting 1,2-diol as a cyclic carbonate

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

• low, the synthesis of 7c via this method represents a substantial improvement on previous approaches to this material [24]. The Baeyer–Villiger oxidation of 7c was uneventful and the fluorinated alkene 17 was isolated in 50% yield. The α-trifluoromethylation of ketones and aldehydes can be performed

• cascade to give enone 21 in 42% yield. Baeyer–Villiger oxidation of this highly activated alkene promoted an epoxidation/Baeyer–Villiger oxidation cascade to yield lactone 22 in 67% yield (dr 2:1). The low diastereoselectivity suggested that the epoxidation happened subsequent to the ring contraction, as

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

• -trig cyclization and HAT furnished the enantioenriched products with up to 97:3 er. In addition to intramolecular radical reactions, intermolecular radical transformations have also been achieved using photoenzymatic catalysis, such as the addition of fluoroalkyl radicals to alkene substrates [36] and

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

• dichloromethane (DCM), gold(I)-catalyzed alkyne activation initiated 6-endo-dig cyclization of the conjugated alkene. Subsequent alkyl migration formed four-membered ring intermediate 9, which underwent fragmentation and rearrangement to yield phenanthrene derivative 10 (Scheme 3, path a). When tetrahydrofuran

• dihydrochromenone skeleton 24 (Scheme 6, path a). When DMSO was employed instead, the strongly coordinating solvent diverted the reaction towards 5-exo-dig cyclization, furnishing a Z-configured tetrasubstituted alkene product 26 (Scheme 6, path b). The isocoumarin-fused dihydrochromenones prepared by this strategy

• delivered tricyclic indole derivative 59 featuring an exocyclic Z-alkene (Scheme 13, path a). When the terminal substituent of the alkyne was an aryl group, C3-selective cyclization was triggered under BiCl3 catalysis to generate tricyclic iminium 60. Subsequent aryl-assisted Mannich cyclization efficiently

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

• operation including azide–alkene dipolar cycloaddition, irradiation of the resulting triazoline to aziridine 80 and in situ ring opening followed by deacetylation achieved the first total synthesis of (−)-hunterine A (14). On the other hand, aza-Cope/Mannich reaction of 78 produced imine intermediate 81

• underwent dehydration with Martin′s sulfurane to afford the known intermediate 115 [83] and terminal alkene 116 (C12–C13 bond-cleaved byproduct). Thus, the formal total synthesis of (−)-platencin (24) was achieved. On the other hand, epoxidation of 113 followed by acid-mediated regioselective ring-opening

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

• used as a powerful method for synthesizing complex natural products [20][21]. We envisaged that the A-ring in 4 could be constructed from the alkene-substituted β-keto ester precursor A via a bioinspired oxidative radical cyclization (Scheme 1D). Herein, we report the full details of our efforts to

• connection of C8 and C12 in compound 21 could be realized through a photoredox-catalyzed radical cyclization of unactivated alkene-substituted β-ketoester 27. This reaction was expected to involve a 5-exo-trig radical cyclization via transition state TS-3 [38], in which the diastereoselectivity could be

• proposed mechanism to 21 involved the formation of an electron-deficient, resonance-stabilized radical species, followed by intramolecular alkylation of the unactivated alkene to generate radical 29 via a diastereoselective 5-exo-trig cyclization step. Radical intermediate 29 was trapped by 2,4,6

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

• reaction can also be used to prepare precursors for the Ullman–Goldberg coupling (Scheme 12B and 12C); however, in the presence of halogens, an alternative reduction pathway of the alkene with tosylhydrazine and NaOAc must be used [55]. Hetereodiazocines 35b and 35c are synthesised by coupling of o

Fe-catalyzed efficient synthesis of 2,4- and 4-substituted quinolines via C(sp²)–C(sp²) bond scission of styrenes

• Prafull A. Jagtap,
• Manish M. Petkar,
• Vaishnavi R. Sawant and
• Bhalchandra M. Bhanage

Beilstein J. Org. Chem. 2025, 21, 1799–1807, doi:10.3762/bjoc.21.142

• the FeIII species. An alternative mechanism involving a concerted [4 + 2] cycloaddition between the aza-butadiene moiety in II and the alkene, leading to intermediate IV, cannot be ruled out. Conclusion In summary, we have successfully developed a highly efficient method for the oxidative C–C bond

Influence of the cation in hypophosphite-mediated catalyst-free reductive amination

• Natalia Lebedeva,
• Fedor Kliuev,
• Olesya Zvereva,
• Klim Biriukov,
• Evgeniya Podyacheva,
• Maria Godovikova,
• Oleg I. Afanasyev and
• Denis Chusov

Beilstein J. Org. Chem. 2025, 21, 1661–1670, doi:10.3762/bjoc.21.130

• an important role in medicinal and pharmaceutical chemistry [23][24][25] (Scheme 1a). Sodium hypophosphite exhibited good chemoselectivity – it selectively reduced imines while leaving other functional groups intact, e.g., nitro (NO₂), cyano (CN), alkene (C=C), and benzyloxy (OBn) groups. In contrast