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

• , obtained as a 1.7:1 mixture of diastereomers after protection of one of the carbonyl groups in 19 as enol ether with BOMCl. A silyl-tethered intramolecular Diels–Alder reaction of the in situ generated 22 constructed the tricyclo[5.2.1.01,5]decane core bearing a cis-pentalene unit, yielding compound 23

• ). Chemoselective epoxidation of the enone double bond in 69 yielded epoxide 70. A Wittig reaction of 70 with (methoxymethyl)triphenylphosphonium chloride and t-BuOK generated a methyl enol ether, which was unstable in the presence of the epoxide. During aqueous workup, simultaneous hydrolysis of the enol ether and

• encumbered tricyclic lactone 84 via an intramolecular [6 + 2] cycloaddition (Scheme 8). Attempts to achieve an asymmetric version of the cycloaddition were unsuccessful. Treatment of the lactone with MeMgBr, followed by mesylation and elimination of the resulting hemiacetal, afforded enol ether 85. Reaction

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

• desired methyl group at its α-position to afford 51 in racemic form. This seemingly straightforward α-methylation turned out to be quite challenging. Tsukano and co-workers eventually utilized a two-step sequence to solve this problem, namely, TMS enol ether formation followed by trapping the enol ether

• 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

• -chloroperoxybenzoic acid) induced epoxidation, which was then followed by a Meinwald rearrangement to accomplish aldehyde 7. From 7, a sequence involving silyl enol ether formation, Simmons−Smith cyclopropanation, and acid-mediated regioselective ring-opening installed the C8 quaternary methyl group in 10. Subsequent

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

• converted into the silyl enol ether 12 and treated with Selectfluor, fluorinated ketone 13 was formed as the major product after aqueous workup (Scheme 2). When the solution of 13 was concentrated following flash column chromatography, rapid decomposition was observed, which may explain failures with many

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

• reaction proceeded via 5-endo-dig cyclization. This pathway involved enol ether attack on the gold-activated alkyne, leading to the formation of oxonium intermediate 2. Subsequently, nucleophilic addition of methanol culminated in the formation of indene motif 5 (Scheme 2, path a). When methanol served

• nitrogen atom was substituted with strong electron-withdrawing groups, a nucleophilic attack to gold(I)-activated alkyne generated intermediate 38, with subsequent 6-endo-trig cyclization affording benzo[a]carbazole 39 (Scheme 9, path a). Conversely, the activated alkyne was attacked by enol ether to yield

• identical reaction conditions. In 2016, the Liu group achieved unconventional Au(I)-catalyzed 6-endo-trig cyclization by modulating the angle strain of the enol ether (Scheme 29) [41]. In previous studies [42], propargylic vinyl ethers 140 underwent Au(I)-catalyzed propargyl-Claisen rearrangement to form an

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

• the A- and D-rings of 96, respectively, delivering the methyl enol ether 98. Finally, allylic oxidation [76], α-methylation and reduction of 98 followed by hydrolysis accomplished the first total synthsis of (−)-conidiogenone F (21). After achieving the aforementioned success, the authors continued to

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

• , 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

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

• , including (−)-ψ-akuammigine (Scheme 33) [81]. The synthesis commenced with dibenzoate 274, which underwent a Pd-catalyzed Trost desymmetrization using sulfonamide 275 and ligand 276. Deprotection of the resulting adduct furnished alcohol 277, which was subsequently converted to silyl enol ether 278 in two

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

• by trans-hydrostannation [50] of the corresponding alkyne precursors, so this report potentially introduced a new method for oxetane synthesis through an intramolecular Chan–Lam-type coupling. Due to the high reactivity of the exocyclic enol ether induced by the ring strain, 2-alkylidene

• substrate scope revealed that the reaction stereoselectivity is highly dependent on the structure of the ketoester component and tends to be unpredictable. 1.3.2 Formal cycloadditions: These stepwise processes typically take place between an enolate or enol ether and a carbonyl under Lewis acid or base

Synthesis of β-ketophosphonates through aerobic copper(II)-mediated phosphorylation of enol acetates

• Alexander S. Budnikov,
• Igor B. Krylov,
• Fedor K. Monin,
• Valentina M. Merkulova,
• Alexey I. Ilovaisky,
• Liu Yan,
• Bing Yu and
• Alexander O. Terent’ev

Beilstein J. Org. Chem. 2025, 21, 1192–1200, doi:10.3762/bjoc.21.96

• from diisopropyl H-phosphonate (2a) was confirmed by HRMS analysis of the crude reaction mixture. Finally, vinyl azide 4a and silyl enol ether 4b were introduced into standard reaction conditions (Scheme 4, reaction 3). However, no phosphorylation product 3a was observed. On the basis of the obtained

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

• cyclopentane ring, dihydroxylation, and oxidation of the diol to a diketone, produced intermediate 25 in its enol form. From this common intermediate, regioselective etherification at the less hindered position formed an enol ether. Final reduction of both the amide and the ketone using alane completed the

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

• .) of 24 led only to epimerization at C10 or slow decomposition of the starting material (see Supporting Information File 1, Table S1). Pleasingly, treating 24 with HMDS and TMSI regioselectively generated the expected TMS enol ether [46], which underwent a Li/Si exchange in the presence of MeLi

Mechanochemical difluoromethylations of ketones

• Jinbo Ke,
• Pit van Bonn and
• Carsten Bolm

Beilstein J. Org. Chem. 2024, 20, 2799–2805, doi:10.3762/bjoc.20.235

• efficiently converted to the target products under solvent-free conditions. The reactions proceed at room temperature and are complete within 90 minutes, demonstrating both efficiency and experimental simplicity. Keywords: ball milling; difluorocarbene; difluoromethylations; difluoromethyl enol ether

• standard reaction conditions with difluorocarbene precursor TMSCF2Br (2, 2.0 equiv), activator KFHF (4.0 equiv), and grinding auxiliary CsCl (4.0 equiv), difluoromethyl enol ether 3a was obtained after 90 min reaction time at 25 Hz in 74% yield, determined by quantitative 1H NMR spectroscopy (Table 1

• ketone 1g provided the corresponding product 3g in 56% yield. Difluoromethyl enol ether 3h with three methyl groups was obtained in 56% yield and column chromatography allowed to isolate it in 42% yield. 2-Acetonaphthone was successfully converted to 3i in 66% yield. Besides aryl ketones, arylalkyl

Chemo-enzymatic total synthesis: current approaches toward the integration of chemical and enzymatic transformations

• Ryo Tanifuji and
• Hiroki Oguri

Beilstein J. Org. Chem. 2024, 20, 1693–1712, doi:10.3762/bjoc.20.151

• oxidation with the incorporation of a ketone at the C13 position yielded brassicicene A (23). After conversion of 23 into the corresponding silyl enol ether, Rubottom oxidation allowed completion of the total synthesis of brassicicene R (24). As an effort to explore the biomimetic rearrangement, analogous

Domino reactions of chromones with activated carbonyl compounds

• Peter Langer

Beilstein J. Org. Chem. 2024, 20, 1256–1269, doi:10.3762/bjoc.20.108

• two silyl enol ether moieties, can be regarded as masked dianions or electroneutral equivalents of 1,3-dicarbonyl dianions and react with the same regioselectivity [13][14][15][16][17][18][19][20][21][22]. Both free and masked dianions were studied extensively in my group for many years. 1,3-Bis

• (silyloxy)-1,3-butadienes are highly moisture sensitive compounds which can be prepared from the corresponding 1,3-dicarbonyl dianions in two steps. For example, diene 6a is available by silylation of 2 to give silyl enol ether 5 which is subsequently deprotonated by LDA and treated with

Skeletal rearrangement of 6,8-dioxabicyclo[3.2.1]octan-4-ols promoted by thionyl chloride or Appel conditions

• Martyn Jevric,
• Julian Klepp,
• Johannes Puschnig,
• Oscar Lamb,
• Christopher J. Sumby and
• Ben W. Greatrex

Beilstein J. Org. Chem. 2024, 20, 823–829, doi:10.3762/bjoc.20.74

• mixture of ketone 9e and the O-alkylated enol ether by-product, which was then reduced using NaBH4 to give alcohol 10e with 98:2 selectivity. Similarly, the reaction of 4-methoxybenzyl bromide and 2 gave ketone 9f in 35% yield without chromatography, and when reduced resulted in only a single alcohol

SOMOphilic alkyne vs radical-polar crossover approaches: The full story of the azido-alkynylation of alkenes

• Julien Borrel and
• Jerome Waser

Beilstein J. Org. Chem. 2024, 20, 701–713, doi:10.3762/bjoc.20.64

• diasteroisomer was determined to be trans. Diyne 4l could be accessed in 44% yield from the exclusive 1,2-functionalization of the corresponding ene-yne. Crude NMR of the reaction did not show the presence of an allene product which could have been formed by a 1,4-functionalization. Enol ether could also be

• a simple enol ether was reactive in the transformation, we attempted to use glucal 1l but no conversion was observed. Enamide 1m could be azido-alkynylated in low yield and the product was inseparable from impurities. When dehydroalanine 1n was used in the reaction no product was formed and only

Ligand effects, solvent cooperation, and large kinetic solvent deuterium isotope effects in gold(I)-catalyzed intramolecular alkene hydroamination

• Ruichen Lan,
• Brock Yager,
• Yoonsun Jee,
• Cynthia S. Day and
• Amanda C. Jones

Beilstein J. Org. Chem. 2024, 20, 479–496, doi:10.3762/bjoc.20.43

• behaves accordingly here [66]. Specific gold–oxygen interactions are typically not invoked in mechanistic discussions, though a gold alcohol complex has been proposed in silyl enol ether protonation [67]. Equilibrium studies by Maier et al. indicate that methanol is more weakly coordinating than alkynes

Mechanisms for radical reactions initiating from N-hydroxyphthalimide esters

• Carlos R. Azpilcueta-Nicolas and
• Jean-Philip Lumb

Beilstein J. Org. Chem. 2024, 20, 346–378, doi:10.3762/bjoc.20.35

• , Shang and Fu initially demonstrated this approach by utilizing catalytic amounts of triphenylphosphine (PPh3) and sodium iodide (NaI) [67]. Upon formation of EDA complex 80, radical addition to silyl enol ether 81 was promoted under blue light irradiation, affording acetophenone product 82 (Scheme 16A

Radical chemistry in polymer science: an overview and recent advances

• Zixiao Wang,
• Feichen Cui,
• Yang Sui and
• Jiajun Yan

Beilstein J. Org. Chem. 2023, 19, 1580–1603, doi:10.3762/bjoc.19.116

• necessary. MF-ROMP, also termed photo-ROMP, is a novel technique to polymerize cyclic olefins. It begins with the reductive quenching of an photoexcited photocatalyst (PC) at an enol ether initiator to produce a radical cation carrier [90]. Then, the carrier undergoes cyclic addition with a cyclic olefin

• (Scheme 12B). Boydston and co-workers [91], systematically studied various pyrylium and thiopyrylium PCs (Scheme 13). It is necessary for these PCs having a high excited-state redox potential to oxidize the enol ether initiators. A range of enol ether initiators that has been successfully applied in metal

Strategies in the synthesis of dibenzo[b,f]heteropines

• David I. H. Maier,
• Barend C. B. Bezuidenhoudt and
• Charlene Marais

Beilstein J. Org. Chem. 2023, 19, 700–718, doi:10.3762/bjoc.19.51

• ). Carbamoylation of 151 gives the intermediate oxcarbazepine 152, whereafter hydrolysis of the methyl enol ether affords oxcarbazepine (153) [32][56]. 6.2.2 Ring functionalisation: Weng et al. [80] reported the synthesis of dihydrodibenzo[b,f]azepine (2a)-based pincer ligands for Rh and Ir metal complexes. The

Enolates ambushed – asymmetric tandem conjugate addition and subsequent enolate trapping with conventional and less traditional electrophiles

• Péter Kisszékelyi and
• Radovan Šebesta

Beilstein J. Org. Chem. 2023, 19, 593–634, doi:10.3762/bjoc.19.44

Strategies to access the [5-8] bicyclic core encountered in the sesquiterpene, diterpene and sesterterpene series

• Cécile Alleman,
• Charlène Gadais,
• Laurent Legentil and
• François-Hugues Porée

Beilstein J. Org. Chem. 2023, 19, 245–281, doi:10.3762/bjoc.19.23

• exo Diels–Alder cycloaddition, which resulted in compound 159. The enol ether was oxidized by ceric ammonium nitrate (CAN) to deliver intermediate 160, which was further subjected to an iron-catalyzed hydrogen atom transfer generating tricyclic intermediate 161. Further functionalization permitted the

Total synthesis of grayanane natural products

• Nicolas Fay,
• Rémi Blieck,
• Cyrille Kouklovsky and
• Aurélien de la Torre

Beilstein J. Org. Chem. 2022, 18, 1707–1719, doi:10.3762/bjoc.18.181

• of enol-ether formation/Grignard addition lead to intermediate 43, from which simple acidic treatment led to rhodomollein XXII, while α-oxidation in the presence of rhenium oxide followed by acidic work-up afforded rhodomollein XX. Interestingly, Ding’s synthesis constitutes an efficient approach (22

• into dimethylacetal 45 by Vilsmeier reaction followed by aldehyde protection in 54% yield over two steps. A Mukaiyama aldol reaction between trimethylsilyl enol ether 46 and dimethylacetal 45 followed by Sakurai cyclization provided an inseparable mixture of C9 epimers (dr = 2:1). A catalyst

A novel spirocyclic scaffold accessed via tandem Claisen rearrangement/intramolecular oxa-Michael addition

• Anastasia Vepreva,
• Alexander Yanovich,
• Dmitry Dar’in,
• Grigory Kantin,
• Alexander Bunev and
• Mikhail Krasavin

Beilstein J. Org. Chem. 2022, 18, 1649–1655, doi:10.3762/bjoc.18.177

• spirocyclization of DAS with the formation of minor enol ether product 3a and its Claisen rearrangement. (b) Synthetic strategy investigated in this work. Initial attempt at Rh(II)-catalyzed O–H insertion/Claisen rearrangement. Rh2(esp)2-catalyzed O–H insertion reactions between various DAS 1 and phenols. Two-step