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

• filtrate during this process and isolated as a diastereomeric mixture of 2.6:1. At first, the benzyl moieties of 66 were cleaved off and the diol was reprotected as acetonide to afford 67. The remaining secondary alcohol was PMB-protected and the olefin was oxidatively cleaved, before addition of a

• lithiated furanyl unit took place. The so-obtained 1:1 diastereomeric mixture of 68 was treated with (PhO)3PMeI in dimethylacetamide and formed an intermediate trans-olefin, which subsequently underwent an asymmetric Sharpless dihydroxylation. The acetonide was cleaved with AcOH and the addition of NBS

• using acetic anhydride. Oxidative cleavage of olefin 73, followed by treatment with ʟ-proline led to an intermediate β-aldehyde with inverted stereochemistry at the β-C (4:1 dr). Subsequent reduction with NaBH4 yielded alcohol 74. Piv-protection of the primary alcohol, reductive deprotection of the Bn

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

• reaction may find application as novel S-olefin ligands. In 2023, Amatore and co-workers developed an NHC-catalyzed method to acquire previously unknown axially chiral N-arylphthalimides 79 (Scheme 22) [61]. This system adopted a (4 + 2) oxidative annulation strategy. The products are generated through the

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

• the activation of the diphosphate group and ionisation) [25][37] and Class II (ionisation by olefin or epoxide protonation via a carboxylic acid in the active site) [26][38][39] and their reactions thus are mediated by carbocations and olefins, through careful preorganisation of the linear substrate

• framework and ring contraction (10b). From here, follow up oxidations and olefin isomerisation afford β-vetivone B (11), a constituent of aromatic vetiver oil. Finally, in the biosynthesis of the antibiotic pleuromutilin (13) [61][62][63] a similar ring contraction takes place (see Scheme 2C). Cyclisation

• is initiated via protonation of geranylgeranyl pyrophosphate (GGPP, 12) at the terminal olefin with CpPS (= Clitopilus passeckeranis pleuromutilin synthase), forming the decalin system 12a. A cascade of 1,2-shifts delivers the carbocation 12b which undergoes ring contraction and elimination to give

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

• , olefin hydrogenation, and DMP oxidation, provided diketone 125. The two carbonyl groups in 125 were then chemoselectively and stereoselectively reduced using rhodium as a catalyst to yield hydroxylated ketone 126. A further three-step transformation provided the catalytic hydrogenation precursor 127

• another synthesis work to revise the structure of huperzine N. Similar to their previous study, the synthesis started with a 1,3-dicarbonyl compound 154 to synthesize the hydrogenation precursor 155. A three-step process, including hydrogenation of the olefin, hydride reduction and methylation, afforded

• -type alkaloids [98]. That same year, Sherburn and co-workers described a complementary synthesis employing an aza-Diels–Alder cycloaddition followed by olefin hydrogenation [99]. Starting from pyridine and glutaryl chloride, tetracyclic intermediate 192 was efficiently generated in a single step

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

• Schwartz’s reagent (Scheme 1) [7][8]. When compound 2, bearing an alkyl halide and an olefin moiety, was treated with triethylborane and Schwartz’s reagent in tetrahydrofuran, a halogen atom transfer (XAT) occurred at the alkyl halide, generating alkyl radical 3. This radical subsequently underwent

• intramolecular addition to the olefin, affording the cyclized acetal product 4. The reaction proceeded efficiently across a range of substrates bearing various substituents at R¹–R⁴, delivering the desired cyclized products 4a–f in good yields. The proposed mechanism is illustrated in Scheme 1C. Initially

• , Schwartz’s reagent reacts with triethylborane to generate a low-valent zirconium complex 5. This complex abstracts the halogen atom from the alkyl halide, forming alkyl radical 8. The radical then cyclizes onto the olefin, and the resulting radical intermediate undergoes hydrogen atom transfer (HAT) from

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

• stereocontrolled olefin metathesis with molybdenum catalysts to access trisubstituted alkenes including alkenyl chlorides (Figure 3H) [39]. Two recent reviews by Lu [40] and Nishiwaki [41] provide overviews of current developments in the hydrochlorination of alkynes, highlighting emerging catalytic strategies

• chlorides (not shown) [185][186]. 1.8 Alkenyl chloride synthesis via olefin metathesis Johnson and co-workers investigated complex 287, which forms as a product of an initial metathesis cycle in the cross-metathesis (CM) with alkenyl chlorides (Scheme 55) [187][188]. The authors observed that complex 287

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

• product 11 in 37% yield (Scheme 2). Despite the modest yield, product 11 was transformed to the corresponding tertiary alcohol 12. Removal of the N-Piv group and dehydration with the Burgess reagent [35] led to an inseparable mixture of olefins slightly in favor of the exo-olefin isomer. Dehydration in

• -substituted indoles as well as to the corresponding allylindoles. In the latter case, a Grubbs olefin cross-metathesis reaction with 2-butene would indirectly introduce the prenyl appendage [43][44][45]. The synthesis of 7-prenylindole from 2-iodoaniline in 4 steps was reported in 1996 [46][47]. Subsequently

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

• sequence of redox manipulations and acetylation, olefin 90 was transformed into 3,18-diacetate 92. The degradation of the superfluous side chain was realized by acidic cleavage of the spiroketal moiety, followed by redox manipulations. A seven-step sequence afforded methyl ketone 93 [20]. The F-ring was

• afford cyclization of the E-ring. The obtained pyridinium species was directly reduced to reveal the piperidine moiety. The observed selectivity for hydrogenation from the α-side was attributed to the steric hindrance of the C20 axial tertiary TMS ether. The survival of the olefin in the D-ring was

Chemoenzymatic synthesis of the cardenolide rhodexin A and its aglycone sarmentogenin

• Fuzhen Song,
• Mengmeng Zheng,
• Dongkai Wang,
• Xudong Qu and
• Qianghui Zhou

Beilstein J. Org. Chem. 2025, 21, 2637–2644, doi:10.3762/bjoc.21.204

• donor, through a late-stage glycosylation. The aglycon 2 can be derived from the Δ14 olefin intermediate 3 via Mukaiyama hydration and several functional group transformations. In turn, 3 would be generated from the key C14α-hydroxylated intermediate 4 via an elimination process. For the synthesis of 4

• reagent [20], the key intermediate 8 bearing a butenolide motif was obtained in 76% yield. Next, with the aid of the strong Lewis acid Bi(OTf)3, the regioselective elimination of 8 was achieved to produce the Δ14 olefin intermediate 9 in 86% yield. Afterwards, we evaluated the reactivity of 9 towards

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

• hydroxy group could be responsible for this reversal in selectivity. Dai’s asymmetric synthesis of (−)-illisimonin A In 2025, Dai and co-workers accomplished an asymmetric total synthesis of (−)-illisimonin A in 16 steps from (S)-carvone (67) using a pattern-recognition strategy and five sequential olefin

• the same pot to give 72. Isomerization of the allylic methyl ether to an enol methyl ether was achieved using Crabtree’s catalyst in refluxing THF. Subsequent ketalization with the primary alcohol yielded the bridged ketal 73. A Schenck ene reaction on 73 induced the second olefin isomerization

• , generating an allylic alcohol that was acetylated in situ to provide 74. An Ireland–Claisen rearrangement facilitated the third olefin transposition, concurrently forming an all-carbon quaternary center at C9 and affording carboxylic acid 75. The fourth olefin transposition was achieved via a palladium

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

• the simultaneous construction of four quaternary carbon centers (C1, C4, C5, and C12) and the core AB bicyclic skeleton, markedly improving synthetic efficiency. Subsequent oxidative desymmetrization of the C14–C15 olefin in (±)-33 established the sterically hindered C11 quaternary carbon center. An α

• successfully accomplished via an epoxide ring-opening/tandem lactonization/olefin hydration sequence. In total, 12 consecutive redox manipulations (7 oxidations and 5 reductions) established all stereocenters, with subsequent functional group transformations completing the total synthesis of garajonone (8

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

• , several conditions to cleave the N–O bond in 11 or 12 had not yielded any successful outcome. Therefore, we turned to adjust the synthetic sequence to switch the oxidation states at C2 and C3 (Scheme 4). It should be noted that compound 16 [38] was obtained as a stereoisomeric mixture of olefin, resulting

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

• form three possible products: ketone 191, olefin 192, and cyclopentane 193 (Scheme 33). At the first stage, the epoxy ring was opened to form intermediate A. According to the authors [87], there are three possible ways of carbocation stabilization. The 1,2-shift of a proton at C3 to C4 led to the

Synthetic study toward vibralactone

• Liang Shi,
• Jiayi Song,
• Yiqing Li,
• Jia-Chen Li,
• Shuqi Li,
• Li Ren,
• Zhi-Yun Liu and
• Hong-Dong Hao

Beilstein J. Org. Chem. 2025, 21, 2376–2382, doi:10.3762/bjoc.21.182

• -lactone with an all-carbon quaternary center and two trisubstituted olefin moieties. It is therefore not surprising that this compound has attracted considerable interest from both the chemical biology and synthetic chemistry communities. Sieber and co-workers disclosed that vibralactone can target ClpP1

Rotaxanes with integrated photoswitches: design principles, functional behavior, and emerging applications

• Jullyane Emi Matsushima,
• Khushbu,
• Zuliah Abdulsalam,
• Udyogi Navodya Kulathilaka Conthagamage and
• Víctor García-López

Beilstein J. Org. Chem. 2025, 21, 2345–2366, doi:10.3762/bjoc.21.179

• in-situ generation of toxic 1O2. Fumaramide Fumaramide is a bisamide photoswitch with a thermally stable trans-olefin, which, upon UV light irradiation, undergoes trans-to-cis isomerization, affording the corresponding maleamide (Figure 2). These photoswitches are distinct due to their ability to

• -counterfeiting applications. Stilbene and stiff-stilbene Stilbene photoswitches consist of a central olefin with a phenyl group at each end. Upon light irradiation, they undergo trans-to-cis isomerization, with the reverse isomerization triggered photochemically at a different wavelength or thermally (Figure 2

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

• Scheme 5, the Dai synthesis starts with compound 58 which can be prepared from (+)-pulegone in three steps or via an organocatalyzed tandem sequence in one step. The terminal olefin of 58 was then converted to a primary azide via an anti-Markovnikov hydroazidation reaction with a combination of 59 and

• TMSN3 recently developed by Xu and co-workers [34]. Mukaiyama conjugate addition between 60 and 61 promoted by Tf2NH followed by a one-pot enol ether hydrolysis gave 62 as a mixture of inconsequential stereoisomers. Subsequent oxidative cleavage of the terminal olefin of 62 using ozonolysis followed by

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

• moderate diastereoselectivity; this was followed by Mn(III)-catalyzed metal-hydride hydrogen atom (MHAT) transfer to reduce the endocyclic olefin, forming 41 as a single diastereomer. Subsequent transformations – including a Wittig reaction, demethylation, and oxidation of the resulting phenol to a p

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

• mechanism involving single-electron oxidation of an enamine intermediate, addition of the resulting radical to the olefin, single-electron oxidation of the adduct to form a carbocationic intermediate, and intramolecular nucleophilic attack on the carbocation to form the pyrrolidine ring. The reaction

• tolerated a range of substituents on the olefin, giving the products with high enantioselectivity. Reactions of chiral β-methyl-substituted aldehydes 11 and 12 with indene (13) yielded tricyclic products with good diastereoselectivity and particularly high optical purity (99% ee). Organo-SOMO catalysis was

• , a relatively electrophilic radical could readily add to a nearby electron-rich olefin, and the resulting nucleophilic radical could add to an electron-poor olefin (e.g., substituted with a cyano group). In one example, polyene 15 underwent cyclization to afford hexacyclic product 17 with 93% ee in a

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

• 93 (Scheme 20, path a). However, the indoloazocines 97 was afforded by Au(III)-catalyzed 8-endo-dig cyclization via intermediated 96 (Scheme 20, path b). Interestingly, prolonged reaction time under Au(I) catalysis facilitated the formation of olefin intermediate 98, which then underwent further Au(I

A chiral LC–MS strategy for stereochemical assignment of natural products sharing a 3-methylpent-4-en-2-ol moiety in their terminal structures

• Rei Suo,
• Raku Irie,
• Hinako Nakayama,
• Yuta Ishimaru,
• Yuya Akama,
• Masato Oikawa and
• Shiro Itoi

Beilstein J. Org. Chem. 2025, 21, 2243–2249, doi:10.3762/bjoc.21.171

• Discussion Our degradation strategy of natural products bearing an MPO moiety includes (1) acylation of hydroxy group, (2) oxidative cleavage of olefin to generate 3-acyloxy-2-methylbutanoic acid, and (3) its methyl esterification (Scheme 1A). We initially investigated derivatization strategies to enable LC

Bioinspired total syntheses of natural products: a personal adventure

• Zhengyi Qin,
• Yuting Yang,
• Nuran Yan,
• Xinyu Liang,
• Zhiyu Zhang,
• Yaxuan Duan,
• Huilin Li and
• Xuegong She

Beilstein J. Org. Chem. 2025, 21, 2048–2061, doi:10.3762/bjoc.21.160

• aldehyde 3. This linear aldehyde would be activated by an acid to trigger a key Prins cyclization with the trisubstituted olefin through reaction model 3 and generate a putative tertiary carbocation to be trapped by the chiral alcohol, providing bicycle 4 stereoselectively. Finally, the last olefin would

• approach. This key reaction mimics the plausible biosynthetic pathway and demonstrates great efficiency and sole diastereoselectivity, showcasing the plausibility of the biosynthetic proposal. Further redox manipulations of the last olefin and deprotection ultimately provided chabranol. To clearly confirm

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

• by the anomeric effect [23] in the tricyclic scaffold. Compound 13 could be produced from olefin 14 via cross-metathesis. The regio- and diastereoselective connection of C8 and C12 in compound 14 could be realized through a transition-metal-mediated oxidative radical cyclization through TS-1 from β

• , compounds 14 and 20 were evaluated for the cross-metathesis of the olefin moiety in 14. No reaction occurred and the desired product was not detected (not shown), presumably because of the steric hindrance from the TBS group. Following the removal of the silyl group, cyclopentanol 19 underwent the cross

• controlled by the stereoelectronic effect of the axial hydroxy group at C11 (Scheme 4) [28]. First, β-keto ester 21 was synthesized (Scheme 5). Cross-metathesis of allylic alcohol 18 and olefin 28 with the assistance of the Hoveyda–Grubbs second-generation catalyst delivered the desired product 27 in 68

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

• into alcohol 170 in nine steps. Subsequent epoxidation of olefin in 170 followed by acid-mediated cyclization provided compound 171 bearing a tetrahydrofuran ring. An eight-step transformation then yielded compound 172. Next, epoxidation of olefin of 172 with Shi’s dioxirane (generated from ketone 173

Chiral phosphoric acid-catalyzed asymmetric synthesis of helically chiral, planarly chiral and inherently chiral molecules

• Wei Liu and
• Xiaoyu Yang

Beilstein J. Org. Chem. 2025, 21, 1864–1889, doi:10.3762/bjoc.21.145

• conducted a thorough evaluation of the stability of the helical chirality across the synthesized quinohelicenes, indicating a high racemization barrier. In 2024, our group further extended the CPA-catalyzed sequential Povarov reaction and aromatization strategy by using 2-vinylphenols 14 as the olefin

Preparation of a furfural-derived enantioenriched vinyloxazoline building block and exploring its reactivity

• Madara Darzina,
• Anna Lielpetere and
• Aigars Jirgensons

Beilstein J. Org. Chem. 2025, 21, 1737–1741, doi:10.3762/bjoc.21.136

• chiral HPLC. This confirmed that no erosion of enantiomeric purity had happened during the deprotection stage. With the enantioenriched vinyloxazoline S-6 in hand, we explored the reaction scope involving its electron-deficient double bond. Unfortunately, the olefin appeared unreactive or gave a mixture