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

• be oxidized to ketone, which gives chabranol. According to this biosynthetic proposal, we thought that the Prins-triggered double cyclization would serve as a powerful method to construct the bicycle in one step, and moreover, the proposed Prins-based double cyclization needs further supporting

• , Wittig reaction with MOMPPh3Cl and LDA gave the putative methyl enol ether, which could be directly converted into 1,3-dithiane 12 with propane-1,3-dithiol. Nucleophilic addition to chiral epoxide 13 and oxidative hydrolysis of 1,3-dithiane to ketone delivered chiral β-hydroxyketone 14. Evans−Tishchenko

• reduction of ketone using SmI2 and propionaldehyde provided 15 diastereoselectively. Friedel–Crafts cyclization using trimethyl orthoformate and TMSOTf provided the cyclic acetal moiety to be oxidized with PDC, delivering the isocoumarin skeleton in 16. Chemoselective removal of the ester with the lactone

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

• catalytic photoenolization/Diels–Alder (PEDA) reaction [14][15]. In this process, the NHC fragment present in the acylazolium species influences the absorption wavelength and fundamental photochemical reactivity of the C=O bond, enabling a “ketone-like” photoreaction from otherwise unsuitable carboxylic

• 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

• as a single diastereomer. Subsequently, one-pot transesterification and palladium-catalyzed decarboxylative allylation delivered compound 25 in 72% yield. Next, we expected that we could perform a chemo- and diastereoselective reduction of the ketone to introduce the hydroxy group at C9 in a single

• step. However, the diastereoselective reduction of the ketone in 25 was challenging because the ketone was embedded in the concave face, which was more sterically hindered than the convex face. Common reductants, such as NaBH4, DIBAL-H, and LiAlH(Ot-Bu)3, provided product 32 with the opposite

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

• norlignans hyperione A and ent-hyperione B was reported by the Deska group (Scheme 4) [33]. The synthesis commenced with a two-step conversion of ketone 22 to alkyne 23. Pd-catalyzed Tsuji-type reaction with zinc reagent 24, followed by acetonide hydrolysis, furnished allenic diol 25. Treating allenic diol

• enantioenriched monoester 53 in hand, the synthesis proceeded toward fredericamycin A (60) (Scheme 9). Dione 55, which was prepared from 53 in six steps, underwent addition with alkyne 56 followed by acylation of the resulting hydroxy group with compound 57 to yield ketone 58. A subsequent seven-step

• the cyclohexanone ring into 120, and the resulting hydroxy group was protected to give ketone 121. The γ-lactam moiety of compound 122 was then constructed in subsequent 12 steps. SmI2-mediated intermolecular Reformatsky-type reaction with aldehyde 123 yielded compound 124. Finally, salinosporamide A

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

• and polycyclic ketone 2, they achieved the efficient asymmetric synthesis of various helically chiral azahelicenes 3 (Scheme 1). To address the inherent length-scale challenges of molecular helicene frameworks, the authors designed and synthesized novel CPAs bearing extended π-substituents at the

• stereoselectivity for the more sterically demanding aza[5]helicene 3c and aza[7]helicenes 3d–f. Furthermore, the authors expanded this methodology to a double Fischer indolization reaction between hydrazine 1i and ketone 2i, which yielded diaza[8]helicene 4 with moderate yield and high enantioselectivity after

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

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

• ) ketone, which could be converted to the corresponding bis(4-hydroxybenzyl) ketone (25c) by heating at 200 °C for 15 min to 3 h in the presence of pyridinium chloride [22][24]. Herein, we also show that the EDC-mediated coupling of 4-(benzyloxy)phenylacetic acid readily yields 25b, which may be

• , 38.7, 28.3 ppm; HRESIMS (m/z): [M + Na]+ calcd for C29H32N2NaO5, 511.2203; found, 511.2222. 1,3-Di(1H-indol-3-yl)propan-2-one (1): The ketone 23 (200 mg, 0.4 mmol, 1 equiv) was dissolved in DCM (6 mL) in a 25 mL round bottom flask equipped with a magnetic stirrer. Trifluoroacetic acid (3 mL) was then

• anhydrous Na2SO4 and concentrated under reduced pressure to afford 2-(1-benzyl-1H-indol-3-yl)acetic acid [36]. The resulting product was then used to synthesize ketone 25d following the general procedure. The crude product was purified by chromatography on silica gel (hexane/EtOAc; 90:10) to afford 25d as a

Catalytic asymmetric reactions of isocyanides for constructing non-central chirality

• Jia-Yu Liao

Beilstein J. Org. Chem. 2025, 21, 1648–1660, doi:10.3762/bjoc.21.129

• L6 as the chiral catalyst, atropisomeric 3-arylpyrroles 34 were generated in 43–98% yield with 82–96% ee. Notably, two by-products 35 and 36 were observed during the reaction, resulting from the aldol reaction of isocyanoacetates with the ketone moiety in 33. The authors have also demonstrated that

• 34f could be used as the starting material to prepare the axially chiral olefin-oxazole 37, which might be a potentially useful ligand in asymmetric catalysis. A possible stereochemical model was proposed as well, involving synergistic activation of both the alkynyl ketone and isocyanoacetate by the

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

General method for the synthesis of enaminones via photocatalysis

• Paula Pérez-Ramos,
• Raquel G. Soengas and
• Humberto Rodríguez-Solla

Beilstein J. Org. Chem. 2025, 21, 1535–1543, doi:10.3762/bjoc.21.116

• condensation of 1,3-dicarbonyl compounds with amines [30]. While this approach is simple and straightforward, it often leads to a mixture of constitutional isomers in which the two different α-positions of the ketone have been functionalized. Therefore, the development of novel methods for the synthesis of

Heterologous biosynthesis of cotylenol and concise synthesis of fusicoccane diterpenoids

• Ye Yuan,
• Zhenhua Guan,
• Xue-Jie Zhang,
• Nanyu Yao,
• Wenling Yuan,
• Yonghui Zhang,
• Ying Ye and
• Zheng Xiang

Beilstein J. Org. Chem. 2025, 21, 1489–1495, doi:10.3762/bjoc.21.111

• (7) and R (8) (Scheme 1). The secondary hydroxy group of brassicicene I was selectively TBS-protected in the presence of TBSOTf and 2,6-lutidine to give compound 13 in 93% yield. Then, compound 13 underwent oxidative rearrangement with PCC to afford ketone 14 in 61% yield. Under Luche reduction

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

• /Williamson etherification sequence (Scheme 8) [43]. In this case, however, the radicals were generated by irradiation of α-acetyloxy iodides 36, formed by treating the corresponding ketone precursors with acetyl iodide in the presence of catalytic Zn(OTf)2. The radical addition employed electron-rich alkenes

• by the same research group [65][66], the Ir catalyst initially interacts through hydrogen bonds with the quinolone substrate 84, and then upon irradiation, energy transfer occurs to the unbound ketone which enantioselectively reacts with the bound quinolone. Unfortunately, investigations of the

• diastereomeric ratios favouring the trans-isomer, however, a reversed diastereoselectivity was observed for ortho-substituted aryls due to steric factors. The investigation of the substrate scope revealed that while the reaction shuts down in the absence of the trifluoromethyl group in the ketone component, it

Recent advances and future challenges in the bottom-up synthesis of azulene-embedded nanographenes

• Bartłomiej Pigulski

Beilstein J. Org. Chem. 2025, 21, 1272–1305, doi:10.3762/bjoc.21.99

• . Dehydrogenation played a pivotal role as a key step also in the synthesis of larger π-scaffolds. For example, Murata and co-workers reported the synthesis of an azulene containing isomer of benzo[a]pyrene 9 (Scheme 2) [33]. Reduction of ketone 7 using LiAlH4 resulted in alcohol 8 which was subsequently

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

• the significant role of asymmetric catalysis in their strategy, utilizing a copper-catalyzed asymmetric 1,4-addition and a ruthenium-catalyzed asymmetric ketone hydrogenation. Fragment 61 was synthesized in 15% overall yield across 19 steps, while fragment 62b was achieved in 32% yield over 11 steps

• the late stage coupling with 137 was prepared from the known lactone 138 (Scheme 21). Following a literature procedure, compound 139 was obtained from lactone 138 and subsequently treated with CrO3 to yield ketone 140 in 90% yield [55]. The ketone moiety of this compound was then reacted with a Wittig

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

• with nucleophilic cinnamonitrile 149 to give benzocyclooctene 150 via iodonium intermediate 151 (Scheme 46) [86]. 2.2 Oxidative acylations Cinnamic ester or amide preparation could also be achieved by oxidizing cinnamyl alcohol, aldehyde, imine, and ketone as an alternative to the traditional O/N

• Co/Cu nanoparticle-co-decorated nitrogen-doped carbon catalyst (CoCu@NCn) which was used to catalyze the oxidative esterification of cinnamyl alcohol (157) without the need of a base additive (Scheme 51B) [26]. 2.2.2 Aldehyde/ketone oxidation: By employing non-precious transition metals, Wei and co

• and a catalytic amount of Bu4NI to synthesize bisamide 178. The reaction proceeds through intermediates 179–181 (Scheme 57) [100]. In addition, the method has been successfully scaled up to a gram scale. Han and co-workers (2021) converted ketone 182 into methyl cinnamate (44) catalyzed by Zn(II

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

• 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

• ketone groups completed the total synthesis of (−)-dihydrolycopodine, which could then be further oxidized to (−)-lycopodine. The entire synthetic route hinges upon the development of a sterically congested aza-Prins cyclization, enabled by the presence of the enamide and its neighboring alkyne. Building

• the reduction of amide-generated ketone 12 after a subsequent Dess–Martin oxidation. Upon treatment of 12 with Co(acac)2 and PhSiH3 in iPrOH at 80 °C, the Mukaiyama hydration of enamide delivered hemiaminal 13. Despite the incorrect configuration of the newly formed hydroxy group, it is considered

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

• ammonium derivative 14 with the potassium salt of compound 15 resulted in the ring-opened derivative 16. Removal of the benzylthiocarbonyl moiety, then Beckmann rearrangement of the oxime obtained from ketone 17 and subsequent cyclization gave β-carboline derivative 18, which was dehydrogenated and

A convergent synthetic approach to the tetracyclic core framework of khayanolide-type limonoids

• Zhiyang Zhang,
• Jialei Hu,
• Hanfeng Ding,
• Li Zhang and
• Peirong Rao

Beilstein J. Org. Chem. 2025, 21, 926–934, doi:10.3762/bjoc.21.75

• bicyclic ketone 21, which was prepared from (+)-Hajos–Parrish ketone in 49% yield over two steps (Scheme 3) [40][41][42][43]. Ensuring silyl enol etherification of the ketone at C29 coupled with IBX-mediated Nicolaou oxidation [44] furnished the corresponding enone in 72% yield (90% brsm). The methyl group

• reactivity of those two alcohols toward oxidation allowed for the selective conversion of desired alcohol to ketone 24 using PCC, producing a 50% overall yield, while the recovered undesired alcohol could be reverted to 21 by Swern oxidation. Direct enol triflation (Et3N/Tf2O, NaH/PhNTf2, DTBMP/Tf2O, etc

Cu–Bpin-mediated dimerization of 4,4-dichloro-2-butenoic acid derivatives enables the synthesis of densely functionalized cyclopropanes

• Patricia Gómez-Roibás,
• Andrea Chaves-Pouso and
• Martín Fañanás-Mastral

Beilstein J. Org. Chem. 2025, 21, 877–883, doi:10.3762/bjoc.21.71

• transformation could be efficiently applied to the dimerization of other 4,4-dichloro-2-butenoates and 4,4-dichloro-2-butenamides. The corresponding products 8 and 9 were obtained in good yield and excellent diastereoselectivity (Scheme 2). In sharp contrast, the use of gem-dichlorides bearing a ketone group did

4-(1-Methylamino)ethylidene-1,5-disubstituted pyrrolidine-2,3-diones: synthesis, anti-inflammatory effect and in silico approaches

• Nguyen Tran Nguyen,
• Vo Viet Dai,
• Luc Van Meervelt,
• Do Thi Thao and
• Nguyen Minh Thong

Beilstein J. Org. Chem. 2025, 21, 817–829, doi:10.3762/bjoc.21.65

• -hybridized carbon atom directly bonded to the nitrogen atom of the secondary amino group of compound 5a. In the structure of each pyrrolidine-2,3-dione derivative 3a–e, there is an α,β-unsaturated ketone moiety in which the π systems of the C=C and C=O bonds could overlap each other to yield an extended

Formaldehyde surrogates in multicomponent reactions

• Cecilia I. Attorresi,
• Javier A. Ramírez and
• Bernhard Westermann

Beilstein J. Org. Chem. 2025, 21, 564–595, doi:10.3762/bjoc.21.45

• , methyl aryl ketones, and DMSO under iron(III) catalysis and using K2S2O8 for its activation [39]. The proposed mechanism is very close to those described above, with the methyl aryl ketone taking part of the reaction in place of the styrene component in the Povarov cyclization. In this case, the imine

• reacts with the enolate of the ketone, which is stabilized by coordination with Fe(III), resulting in the formation of the C–C bond. A further oxidative aromatization process affords compound I. Compared to the protocol developed by Zhang et al. [24], the reaction is less regioselective, as Troger’s base

• which, after MMS formation, this reactive species is subsequently captured by the stabilized Cu(II) enolate of the ketone, to provide an α,β-unsaturated ketone intermediate F. This compound condenses with the aniline component to give an imine G that follows a cyclization and aromatization cascade

Vinylogous functionalization of 4-alkylidene-5-aminopyrazoles with methyl trifluoropyruvates

• Judit Hostalet-Romero,
• Laura Carceller-Ferrer,
• Gonzalo Blay,
• Amparo Sanz-Marco,
• José R. Pedro and
• Carlos Vila

Beilstein J. Org. Chem. 2025, 21, 533–540, doi:10.3762/bjoc.21.41

• 3aa–ca in good yields (47–69%). On the other hand, the reaction with tetrahydro-4H-pyran-4-one (1d) occurred with a significant decrease in yield, dropping to 11%. The yield is also affected by the number of carbon atoms of the starting cyclic ketone 1. In the case of structure 3ea, which involves 2

• -indanone, the decrease in yield is not very pronounced. However, when cyclopentanone (1f) or cycloheptanone (1g) are used, the yields dropped significantly to 5% and 6%, respectively. Next, maintaining cyclohexanone as a cyclic ketone, a series of compounds 3 were synthesized by modifying the 5

• -butyl group is present in the C-3 position of the pyrazole as in the case of substrate 2e, the reaction did not take place, likely due to a considerable increase in steric hindrance. We also attempted to synthesize 4-(alkenyl)-5-aminopyrazoles using an acyclic ketone, such as acetone, but unfortunately

Organocatalytic kinetic resolution of 1,5-dicarbonyl compounds through a retro-Michael reaction

• James Guevara-Pulido,
• Fernando González-Pérez,
• José M. Andrés and
• Rafael Pedrosa

Beilstein J. Org. Chem. 2025, 21, 473–482, doi:10.3762/bjoc.21.34

• olefins with a wide range of nucleophiles, with many organocatalyzed asymmetric examples highlighted in the literature [23][24]. We have observed that the enantioenriched 1,5-dicarbonyl Michael adducts, synthesized via organocatalyzed reaction of cinnamaldehyde with benzyl phenyl ketone, undergo

• , enantioselectivity increased until a specific time, and after that, the enantiomeric ratio decreased (compare entries 1–3 and 21–23 in Table 1). The interesting result is that the major enantiomer in the enantioenriched mixture is now the opposite of the one obtained when the ketone and the α,β-unsaturated aldehyde

• reacts more quickly than the anti-(3S,4R)-1, forming the enamine E (Scheme 4) that participates in the retro-Michael reaction, producing the starting ketone and the enal and enantio-enriching the reaction mixture in anti-(3S,4R)-1. Subsequently, toluene was chosen as the solvent due to its ability to

Red light excitation: illuminating photocatalysis in a new spectrum

• Lucas Fortier,
• Corentin Lefebvre and
• Norbert Hoffmann

Beilstein J. Org. Chem. 2025, 21, 296–326, doi:10.3762/bjoc.21.22

• has been quantitatively reduced to the corresponding methyl ketone within one hour under red-light irradiation. The optimized reaction conditions proposed by the authors have demonstrated the superiority of thiaporphyrins over conventional metal-based systems like Ru(bpy)3Cl2. When tested, one of the

Molecular diversity of the reactions of MBH carbonates of isatins and various nucleophiles

• Zi-Ying Xiao,
• Jing Sun and
• Chao-Guo Yan

Beilstein J. Org. Chem. 2025, 21, 286–295, doi:10.3762/bjoc.21.21

• an indole motif with a ketone and a γ-lactam moiety occur in numerous natural substances [1][2][3][4]. Isatins have many interesting aspects in organic reactions and potential applications. The versatile reactivity of isatins used both as an electrophiles and nucleophiles and their easy availability