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

Synthetic approach to borrelidin fragments: focus on key intermediates

• Yudhi Dwi Kurniawan,
• Zetryana Puteri Tachrim,
• Teni Ernawati,
• Faris Hermawan,
• Ima Nurasiyah and
• Muhammad Alfin Sulmantara

Beilstein J. Org. Chem. 2025, 21, 1135–1160, doi:10.3762/bjoc.21.91

• synthesis of polydeoxypropionate based on iridium-catalyzed asymmetric hydrogenation of α-substituted acrylic acid [40]. This method was subsequently applied to the synthesis of a promising vaccine candidate (+)-phthioceranic acid, as well as key intermediates for two natural products, ionomycin and

• borrelidin (C3–C11). The synthesis involved three main steps: (1) carboxymethylation using Meldrum’s acid, (2) alkenylation with Eschenmoser’s salt, and (3) asymmetric hydrogenation catalyzed by iridium complex (Ra)-50 or (Sa)-50. The authors began their investigation by performing the hydrogenation of α

• reacting it with Eschenmoser’s salt, followed by hydrolysis with lithium hydroxide. The resulting unsaturated acid 54, isolated in 92% yield, underwent asymmetric hydrogenation using both (Ra)-50 and (Sa)-50 catalysts. This step provided the respective compounds 55 and 56 in excellent high yield and

A versatile route towards 6-arylpipecolic acids

• Erich Gebel,
• Cornelia Göcke,
• Carolin Gruner and
• Norbert Sewald

Beilstein J. Org. Chem. 2025, 21, 1104–1115, doi:10.3762/bjoc.21.88

• accordance with coupling constants and resulting dihedral angles. Keywords: conformational restraints; dihedral angle NMR; half-chair conformation; modified amino acids; pipecolic acid; stereoselective hydrogenation; Suzuki–Miyaura cross-coupling; Introduction Non-proteinogenic amino acids play an

• coupled with yields ranging from 50 to 90% (Scheme 3). Once the cross-coupling has been performed, the next step included establishing the piperidine motif through hydrogenation or reduction of the N-formyl enamine thereby introducing a second stereocenter in C6 position. We decided to use two approaches

• , heterogeneous catalytic hydrogenation of the enamine with palladium on carbon was chosen. While the hydride reduction of the acyliminium intermediate gave a nearly 1:1 diastereomer ratio, a 9:1 ratio was obtained for the catalytic hydrogenation (Scheme 4). While the hydride reduction of the N-acyliminium

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

• construction, alkyne hydrogenation, ylide and carbene reaction, metathesis, E/Z isomerization, and other methods, including Cα and Cβ functionalizations. Preparing various functional group-tethered aromatic groups can be achieved by directly installing an aromatic group via cross-coupling reactions and other

• ]. 3 Double-bond functionalization 3.1 Double-bond constructions 3.1.1 Conjugated alkyne hydrogenation: Mei and co-workers (2019) developed a Pd-catalyzed partial hydrogenation of conjugated alkynes in the presence of water as the hydrogen source and Mn as the reductant to give the corresponding

• catalyze the partial hydrogenation of the conjugated alkyne 374, also using water as the hydrogen source to give trans-methyl cinnamate (44). The reaction also proceeds via a palladium–hydride species (Scheme 81B) [138]. The method has been smoothly conducted in a gram scale operation. More sustainable

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

• enamides as nucleophiles, rendering them more stable than enamines. This stability is reflected in their frequent occurrence in natural products [4]. As a result, research on the synthetic applications of enamides has historically lagged behind that of enamines [5][6]. Beyond their use in hydrogenation

• aldol condensation of 5 provided the tetracyclic α,β-unsaturated enone 6 in 57% yield. Subsequent catalytic hydrogenation using Pd/C conditions delivered the hydrogen to the alkene from the less hindered face, producing ketone 7 with high diastereoselectivity. Final reduction of both the amide and

• , probably due to the formation of a more acidic cationic gold complex. Following this annulation, reduction of the amide in 20, catalytic hydrogenation of the alkene and the N-benzyl group, and subsequent nitrogen acylation yielded chloride 21 in a 42% total yield, setting the stage for the Witkop

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

• debenzylated to brevicarine (2), isolated as a dihydrochloride salt. Müller et al. accomplished an alternative synthesis of brevicarine (2, Scheme 4) [23]. Compound 21 was obtained by treatment of nitrovinylindole 19 with N-methylpyrrole (20). Catalytic hydrogenation of the pyrrole ring and the nitro group of

• ester 29 gave pyrrolo-β-carboline 30 in excellent yield (Scheme 7). Our attempts for the selective saturation of the pyrrole ring of 30 by catalytic reduction were unsuccessful. When the hydrogenation was carried out under mild conditions (ambient temperature, 15 bar H2) in the presence of PtO2.H2O

Silver(I) triflate-catalyzed post-Ugi synthesis of pyrazolodiazepines

• Muhammad Hasan,
• Anatoly A. Peshkov,
• Syed Anis Ali Shah,
• Andrey Belyaev,
• Chang-Keun Lim,
• Shunyi Wang and
• Vsevolod A. Peshkov

Beilstein J. Org. Chem. 2025, 21, 915–925, doi:10.3762/bjoc.21.74

• scaffolds (Scheme 6) [64][65]. First, we attempted heterogeneous hydrogenation of the alkene functionality in compound 16a under 1 atm hydrogen pressure using Pd/C as a catalyst. Although the reaction proved sluggish, we were able to drive it to completion over a prolonged reaction time of 14 days

Regioselective formal hydrocyanation of allenes: synthesis of β,γ-unsaturated nitriles with α-all-carbon quaternary centers

• Seeun Lim,
• Teresa Kim and
• Yunmi Lee

Beilstein J. Org. Chem. 2025, 21, 800–806, doi:10.3762/bjoc.21.63

• % yield under basic conditions using sodium hydroxide and tert-butanol. The reduction of nitrile 3q with lithium aluminum hydride generated amine 7 in an 85% yield, whereas the selective hydrogenation of the alkene moiety of 3q using a Pd/C catalyst in a H2 gas environment smoothly produced product 8 in a

Development and mechanistic studies of calcium–BINOL phosphate-catalyzed hydrocyanation of hydrazones

• Carola Tortora,
• Christian A. Fischer,
• Sascha Kohlbauer,
• Alexandru Zamfir,
• Gerd M. Ballmann,
• Jürgen Pahl,
• Sjoerd Harder and
• Svetlana B. Tsogoeva

Beilstein J. Org. Chem. 2025, 21, 755–765, doi:10.3762/bjoc.21.59

• rearrangement under mild conditions [6], and the Nazarov-type electrocyclization of alkenyl aryl carbinols [7]. Exploiting the ease with which calcium forms hydrides, hydrogenation of aldimines, transfer hydrogenation of alkenes, and even deuteration of benzene by an SNAr mechanism, have been recently achieved

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

• reductive amination to form the hydroxyalkyl handles, which were further converted to the haloalkyl or mesyloxyalkyl-modified target compounds. In addition, we report hydrogenation conditions for preQ0 and DPQ0 that allow for cleaner and faster access to preQ1 compared to existing routes and provide the

• -diaminopyrimidin-4(3H)-one to afford preQ0 (7), as originally reported by Townsend et al. [30]. The next step, namely the reduction of the nitrile moiety by hydrogenation is critical and notoriously difficult due to the low reactivity of this group in preQ0 [26]. We solved this problem by applying strongly acidic

• protic conditions [31] together with a 7-fold increase in hydrogenation pressure (30 bar); this resulted in an almost quantitative conversion and pure preQ1 (1) in the form of its dihydrochloride salt which was isolated after a simple filtration step. Using the same approach, we were able to prepare the