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

• 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

Synthesis of a HDAC inhibitor–nanogold probe for cryo-EM visualization in class I HDAC co-repressor complexes

• Wiktoria A. Pytel,
• John W. R. Schwabe and
• James T. Hodgkinson

Beilstein J. Org. Chem. 2026, 22, 480–485, doi:10.3762/bjoc.22.35

• dibenzylated by-product. Compound 5 was then coupled to the CI-994 intermediate 3 via HATU-mediated amide bond formation to produce 6 in good yield. Removal of the benzyl protecting group was performed by catalytic hydrogenation and acid 7 was obtained in near quantitative yield. Intermediate 7 was converted

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

• ligands (Scheme 3) [44]. The resulting catalysts 18 demonstrated remarkable efficiency in the asymmetric transfer hydrogenation of quinoline derivatives. Along similar lines, Zhang and co-workers introduced an additional axial chirality element into a ligand framework, affording a pair of diastereomeric

• remote biaxial chiral ligands 21 (Scheme 4) [45]. These ligands were successfully applied in asymmetric hydrogenation, revealing dual asymmetric induction effects and enriching the design principles for chiral catalytic systems. In addition, Yan’s group developed an organocatalytic strategy for the

Cone p-aminocalix[4]arenes enriched with ‘clickable’ alkyne or azide functionalities

• Ilia Korniltsev,
• Vasily Bazhenov,
• Alexander Gorbunov,
• Dmitry Cheshkov,
• Stanislav Bezzubov,
• Vladimir Kovalev and
• Ivan Vatsouro

Beilstein J. Org. Chem. 2026, 22, 399–415, doi:10.3762/bjoc.22.28

• to be not bulky enough to protect the alkyne from a Raney-Ni-catalyzed reduction by gaseous hydrogen, as a trial hydrogenation of the nitrated/propargylated calix[4]arene 11 resulted in only trace amounts of the desired p-aminocalix[4]arene 18 among numerous other reaction products. Due to this, a

• hampering or preventing a catalytic hydrogenation of these compounds. On the other hand, in calixarenes 31 and 32, which are immediate products of the selective reduction of the nitro groups in compounds 29 and 30 under neutral or basic conditions, the free amino groups may be alkylated by a neighboring

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

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

• hydrogenation of the aromatic core of highly substituted benzocyclobutenes using simple Pd/C under ambient conditions [38]. The pronounced substituent effects on the hydrogenation rate highlight the key role of small-ring strain in this generally challenging transformation. Complementary to these strictly

• , increases π-bond localization, rendering phenylenes more susceptible to hydrogenation, metal complexation, ring opening, and cycloaddition reactions [39]. Building on these intriguing studies and the ongoing renaissance of strain-release-driven catalysis [40], harnessing small-ring strain to drive

• ; Figure 4B) [44][45][46]. Collectively, these changes alter the innate reactivity of the arene, steering η2-coordinated systems toward electrophilic addition, cycloaddition, and hydrogenation processes. While many transition metals can engage aromatic rings through η2-coordination, only a handful have

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

• saturation the aromatic ring facilitates synthetic chemists to efficiently synthesize natural products with complex three-dimensional structures. Recent advances in catalyst and ligand design have enabled unprecedented progress in the catalytic hydrogenation of (hetero)aromatic systems. Quinoline

• , isoquinoline, pyridine, and related substrates can now be reduced with high efficiency and stereoselectivity, providing efficient access to saturated and partially saturated architectures vital to synthetic chemistry. Furthermore, catalytic asymmetric aromatic hydrogenation has facilitated the asymmetric total

• synthesis of complex natural products and pharmaceutical agents. This review highlights recent advances in catalytic (hetero)arene hydrogenation, with a focus on its application in natural product synthesis. Keywords: aromatic rings; dearomatization; hydrogenation; natural products; total synthesis

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

• formation to give the cyclic acetal 33. This transformation was applicable to a range of oxetanes 30a–c bearing benzylic alcohol derivatives, each affording the corresponding cyclic acetals in good yields. In 2023, Ota and Yamaguchi et al. reported the hydrogenation of alkyl chlorides via halogen atom

• hydrogenation to give the corresponding alkanes in good yields. Secondary (34f–h) and tertiary alkyl chlorides (34i–k) also reacted smoothly. Moreover, the method was successfully applied to complex molecules, including valine (34l), caffeine (34m), and glucofuranoside (34n), giving the desired products in good

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

• installed another exo-methylene (in the future F-ring), which would later be reduced to the methyl group at C25. Staudinger reduction and two protecting group manipulations set the stage for the formation of the piperidine (F-ring) through a Mitsunobu reaction. Hydrogenation employing Wilkinson’s catalyst

• . Compound 44 could then be subjected to a Nazarov cyclization, which was performed in a photochemical fashion, to close ring C. Further reduction and hydrogenation in ring D and an acid-induced spirocyclization of Nazarov-product 45 concluded the synthesis of cyclopamine. Notably, this total synthesis of

• moiety was introduced as a precursor to an aldehyde, which was obtained by reduction of 46 to 47. For the right-hand fragment (ring D, E, and F), an asymmetric hydrogenation of α-substituted acrylic acid 48 was performed, followed by redox manipulations to give aldehyde 49 over 3 steps in 95% and an

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

• reactive C17 side chain including an α-hydroxycarbonyl group, a set of side reactions (e.g., reduction of the C20 carbonyl, hydrogenation of Δ4 and Δ14 double bonds, etc.) occurred under the Mukaiyama hydration conditions [30][31]. Therefore, it was necessary to alter the side chain before installing the

• C14 β-OH group. The revised synthetic route is described in Scheme 2. At first, 4 was subjected to a Pd/C-catalyzed hydrogenation to afford the desired A/B-cis fused intermediate 7 along with its C5 epimer as a 2:1 separable mixture in a quantitative yield. By treating 7 with the Bestmann ylide

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

• 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

• group installed the tertiary alcohol at C1, yielding intermediate 92. The α-hydroxy lactone was constructed through RuO4-mediated oxidation, forming the pentacyclic core. Finally, debenzylation of the resulting pentacyclic compound under palladium-catalyzed hydrogenation provided (±)-illisimonin A

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

• alkylation with aldehyde 102, producing 103, which was then protected as its OMOM ether to yield 104. One-pot hydrogenation of quinone 104 afforded the corresponding hydroquinone, which, upon subsequent methylation, furnished 105. Removal of the MOM group from 105 followed by oxidation of the resulting

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

• valuable chemical used in the feed and food industry, is produced by petrochemical processes. Its synthesis from biobased lactic acid (LA) offers an access from renewable resources. However, this conversion is difficult due to the high activation energy required for the hydrogenation reaction removing the

• catalysts including Ni/CeO2-γAl2O3, spinal NiAl2O4 and Ni/La2O3-αAl2O3, at 230 °C and 3.2 MPa. Using a chiral catalyst composed of [RuCl2(benzene)]2 and SunPhos, an effective asymmetric hydrogenation of α-hydroxy ketones was reported, yielding chiral terminal 1,2-diols in up to 99% ee. This Ru-catalyzed

• asymmetric hydrogenation process of α-hydroxy ketones opens up a new pathway for the production of chiral terminal 1,2-diols (Scheme 23) [98]. Kini and Mathews reported the synthesis of novel oxazole derivatives such as 6-(substituted benzylidene)-2-methylthiazolo[2,3-b]oxazol-5(6H)-one by reacting 1

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

• of 57 to phenolic intermediate followed by the construction of the B ring generated tricyclic core 59. Subsequently, dihydroxylation of the doubled bond in the central six-membered ring using OsO4/NMO gave diol, which was then subjected to acetylation of the two hydroxy groups and hydrogenation of C5

• on the reported method for asymmetric transfer hydrogenation of commercially available cyclopentadione 62 [54], the authors adapted an efficient method for the desymmetric enantioselective reduction of 62 using commercially available (R,R)-Ts-DENEB (63) as the catalyst and formic acid as the hydrogen

• , protection of the resultant primary alcohol, and hydrogenation afforded ketone 65. The LaCl3·LiCl-promoted addition of 65 with Grignard reagent followed by TES protection of the resulting secondary alcohol, regioselective deprotection of the TES group and in situ oxidation provided aldehyde 66. Next, 66

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

• underwent dehydroxylation protocol involving base-promoted mesylate elimination and catalytic hydrogenation reactions, providing 31a. Reduction of lactam and ester in one pot with LiAlH4 and acid-promoted hydrolysis of ketal protection to ketone furnished 32a. Finally, oxidation of the primary alcohol to

Measuring the stereogenic remoteness in non-central chirality: a stereocontrol connectivity index for asymmetric reactions

• Ivan Keng Wee On,
• Yu Kun Choo,
• Sambhav Baid and
• Ye Zhu

Beilstein J. Org. Chem. 2025, 21, 1995–2006, doi:10.3762/bjoc.21.155

• index (Scheme 2). A detailed process for assigning the index is shown in Scheme 2A for asymmetric hydrogenation of 2-butanone [1]. The atoms involved in bond cleavage and bond formation are highlighted in orange color. The atoms responsible for assignment of the stereochemical configuration of the

• products are highlighted in grey color. The shortest connecting bonds between them are colored red. Accordingly, the asymmetric hydrogenation of 2-butanone is designated as [20] process because there are two connecting bonds between the stereogenic carbon and the stereochemical differentiation atoms, and

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

• -metathesis reaction smoothly in the presence of the Hoveyda–Grubbs second-generation catalyst to afford the enone 13 in 63% yield with the desired trans-configuration. Enone 13 was then subjected to the Pd/C-catalyzed hydrogenation to give the thermodynamically favored bicyclic hemiketal 21 in 92% yield as

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

• sequence including oxidation and subsequent hydrogenation. The Huang group reported their synthesis of (+)-brazilin and its racemic form in 2022 (Scheme 5) [34]. They first evaluated the feasibility of the Prins/Friedel–Crafts tandem reaction in the construction of the 6/6/5/6 tetracyclic skeleton

• between 80 and 81 gave diester 82. Through a ten-step sequence including an aza-Michael reaction, diester 82 was converted into diketone 83, which was further transformed into (−)-petrosin (84) via RCM reaction and hydrogenation. For the synthesis of (+)-petrosin (86) (Scheme 13b), a similar strategy was

• -step sequence to give lactone 114. Finally, hydrogenation of 114 provided (+)-pilocarpine (115) and (+)-isopilocarpine (116) in a ratio of 72:28. Treatment of the mixture with HNO3 followed by recrystallization afforded the nitrate salt of 115 (115·HNO3) in 70% yield from 114. In 2008, the Ōmura group

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

• ,R)-27a with high enantioselectivity. In 2025, Cai, Ji and co-workers reported a practical approach for the kinetic resolution of racemic aza[6]helicenes through CPA-catalyzed asymmetric transfer hydrogenation [31]. Commencing with the readily available racemic pyrido[6]helicene 29, the CPA-catalyzed

• asymmetric transfer hydrogenation employing Hantzsch ester HEH-1 as the reductant afforded both helically chiral tetrahydroquinoline derivatives (M)-30 and the recovered aza[6]helicene starting material (P)-29 with good to high enantioselectivity, achieving an s-factor of up to 121 (Scheme 8). Moreover, by

• resolution of helical polycyclic phenols via CPA-catalyzed enantioselective aminative dearomatization reaction. Kinetic resolution of azahelicenes via CPA-catalyzed transfer hydrogenation. Asymmetric synthesis of planarly chiral macrocycles via CPA-catalyzed electrophilic aromatic amination. Enantioselective

Thermodynamics and polarity-driven properties of fluorinated cyclopropanes

• Matheus P. Freitas

Beilstein J. Org. Chem. 2025, 21, 1742–1747, doi:10.3762/bjoc.21.137

• isomer among the 1,2,3,4,5,6-hexafluorocyclohexanes [10]. Although it was initially synthesized via a multistep reaction, it is now readily obtainable through the catalytic hydrogenation of hexafluorobenzene [11]. Its Janus-face-like structure has demonstrated unprecedented potential, particularly due to

Convenient alternative synthesis of the Malassezia-derived virulence factor malassezione and related compounds

• Karu Ramesh and
• Stephen L. Bearne

Beilstein J. Org. Chem. 2025, 21, 1730–1736, doi:10.3762/bjoc.21.135

• removal of the benzyl groups by hydrogenation was problematic (vide infra). The NMR spectral characteristics of the resulting material were identical to those reported for malassezione either isolated from cultures [11][20] or prepared from the isonitrile [18]. To further demonstrate the utility of the

• intent of using the benzyl group to protect the indole nitrogen rather than the Boc group. However, Pd-catalyzed hydrogenation of 25d led to a mixture of products, of which some were consistent with reduction of the indole ring. With respect to the scalability of the synthesis, the reactions can be

Formal synthesis of a selective estrogen receptor modulator with tetrahydrofluorenone structure using [3 + 2 + 1] cycloaddition of yne-vinylcyclopropanes and CO

• Jing Zhang,
• Guanyu Zhang,
• Hongxi Bai and
• Zhi-Xiang Yu

Beilstein J. Org. Chem. 2025, 21, 1639–1644, doi:10.3762/bjoc.21.127

• asymmetric Lu [3 + 2] cycloaddition reaction [20][21] between indanone and allenyl ketone. Then hydrogenation and Robinson annulation delivered the core of the target molecule. Some other excellent synthetic routes for tetrahydrofluorenone derivates have been developed [12][13][14][15][16][17][18][19] but

• not known). A hydrogenation reaction to reduce the C=C bond in 11 was then successfully applied, delivering product 12 in 80% yield (5 mol % RhCl(PPh3)3 catalyst and 1 atm hydrogen atmosphere were used). Next, we tested whether Krapcho decarboxylation reaction can convert 12 into 1 in one step

Azide–alkyne cycloaddition (click) reaction in biomass-derived solvent Cyrene^TM under one-pot conditions

• Zoltán Medgyesi and
• László T. Mika

Beilstein J. Org. Chem. 2025, 21, 1544–1551, doi:10.3762/bjoc.21.117

• (1R,5S)-7,8-dioxabicyclo-[3.2.1]octan-2-one, CAS: 53716-82-8) or CyreneTM (Scheme 1) has received increasing interest over the last few years. It can be produced from cellulose-containing feedstocks, through pyrolysis and a selective hydrogenation of levoglucosenone (Scheme 1). Regarding the market

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

• the phenomena [17]. In addition, due to the availability of commercially accessible instruments, the applications of HHP in synthetic chemistry have expanded in the past decades. The studied reactions include hydrogenation [18], the addition of enamines to Michael acceptors [19], enantioselective

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