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

• substructure hidden inside the natural product’s cage-like ring system, Kalesse’s group chose to construct this architecture first using a tandem Nazarov/ene cyclization [36]. The cis-pentalene was subsequently assembled via a Ti(III)-mediated epoxide–ketone coupling reaction. Starting from the known

• , deprotonation, and intramolecular addition to ketone. Treatment of the silacycle with MeMgCl cleaved the Si–O bond and subsequent intramolecular nucleophilic substitution of the chloride with the adjacent hydroxy group yielded TMS-epoxide 41. Protonic acid-mediated opening of the TMS-epoxide, accompanied by TES

• ). 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

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

• compound 19. This intermediate is converted to lactone 20 via base-promoted Grob fragmentation followed by acid-mediated MOM deprotection. Epoxidation of the C10–C11 double bond in 20, lactone hydrolysis-promoted epoxide ring opening, and inversion of the C10 hydroxy configuration, yield the key

• conditions induces the first intramolecular reductive cyclization, affording hemiacetal 27. This intermediate is then transformed via a one-pot sequence involving epoxidation, fragmentation, and re-epoxidation to give epoxide 29. A second intramolecular reductive cyclization of 29 under Li/NH3 forms the

• epoxidation of the tetrasubstituted alkene followed by Grieco elimination yielded diene 92. Subsequent oxidation of the hemiacetal, saponification of the lactone, intramolecular epoxide opening, and Hoveyda–Grubbs (II)-catalyzed RCM afforded tetracyclic compounds 94 and its transesterification product 93

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

• of cyclopentane derivatives, promising for the synthesis of iridoids and compounds, that stimulate the formation of receptors that prevent platelet aggregation [75]. The derivatives of the Diels–Alder adduct of LG and piperylene, keto epoxide 146 and its analogue 152 lacking the spiro-fused

• products of epoxide ring opening. It should be noted that the position of the epoxy ring in the 6-membered ring has a major influence on the composition of reaction products. Catalysts only affect the yield of the reaction. A striking confirmation of this is the work of Berteina-Raboin and co-workers [87

• in the formation of a cyclopentane derivative 193 in the presence of InCl3 or Bi(OTf)3. The action of the same Lewis acids on the angular epoxide 190, a regioisomer of epoxide 189, led to other products (Scheme 34). According to the authors [87], depending on the nature of the Lewis acid, the

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

• , employing a late-stage biomimetic Norrish−Yang cyclization to construct the highly compact cyclobutanone motif [21]. The task commenced with epoxide 2 (Scheme 2), which was accessible via a known five-step protocol from geranyl acetate (1). Compound 2 was advanced to 3 using a tandem cyclization developed

• intramolecular aldehyde α-alkylation using MacMillan's protocol, subsequently undergoing Shi's asymmetric epoxidation to give rise to epoxide 60 as a 3:1 mixture of diastereomers. These were not separated until step 8 due to poor separability at this stage. Concurrently, diosgenin was then processed through a

• – was prepared from (+)-pulegone (77) through a six-step manipulation involving epoxidation, epoxide opening with sodium thiophenolate and subsequent concomitant retro-aldol, sulfoxidation, a one pot α-alkylation with acrylonitrile proceeding to thermal syn-elimination of phenylsulfenic acid, ketone

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

• , derived from phenylthiol and geranyl bromide, coupled with chiral epoxide 6, prepared through Sharpless epoxidation and TBS protection of 2-methylprop-2-en-1-ol, under strong basic conditions to generate intermediate 7 to further reduce the sulfide moiety with sodium, furnishing diol 8 with the loss of

• , 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

• . Epoxidation of 131 followed by methylation generated epoxide 132. Construction of the lactone moiety commenced with the oxidative cleavage of the double bond, and the resulting carboxylic acid underwent intramolecular cyclization in the presence of BF3·Et2O to give lactone 133. Subsequent hydride reduction

• 139, epoxide 136 was first prepared from (R)-130 in two steps. Parikh–Doering oxidation of 136 followed by addition with Et2Zn in the presence of ligand 137 afforded alcohol 138, which was subsequently converted into amine 139 via a seven-step sequence. With the fragments 135 and 139 in hand

• monobenzoate 142 in 94% yield along with 4% yield of its diastereomer (dr = 24:1). Following a four-step conversion of 142 to epoxide 143, reductive cleavage produced a diol intermediate, which was subjected to chemoselective glycosylation with compound 144 to provide compound 145. After a four-step

Preparation of spirocyclic oxindoles by cyclisation of an oxime to a nitrone and dipolar cycloaddition

• Beth L. Ritchie,
• Alexandra Longcake and
• Iain Coldham

Beilstein J. Org. Chem. 2025, 21, 1890–1896, doi:10.3762/bjoc.21.146

• that can be explored for its ability to undergo dipolar cycloaddition chemistry. Results and Discussion The oxindole core was prepared from isatin following known chemistry to give the spirocyclic epoxide 1 (Scheme 2) [28]. This was subjected to regioselective ring-opening with allyltrimethylsilane in

• g, 1.3 mmol) was added to epoxide 1 [28] (2.2 g, 12.7 mmol) and allyltrimethylsilane (6.1 mL, 38 mmol) in dry MeCN (90 mL) at 0 °C. After 1 h, saturated aqueous NaHCO3 (50 mL) was added, and the mixture was extracted with EtOAc (2 × 50 mL). The combined organic layers were washed with brine (20 mL

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

• epoxide-opening cyclisation for the oxetane formation (Scheme 11b) [45]. The highest yield was obtained for the PhSH/I2 10:1 activator under unusually mild conditions – the authors believed it is due to the oxa-bridge which facilitates the Lewis acid coordination. In 2001, Rousseau and colleagues reported

• , vinyl, ethynyl or sulphide are sufficient if a superbase such as LIDAKOR or LICKOR is used (Scheme 16) [54][55]. The reaction tends to be remarkably regioselective (in terms of the epoxide opening) and stereoselective, however, it should be treated with caution in case of allyl ethers as they can also

• opened by SnCl4 at −78 °C in a syn manner to give the corresponding chlorohydrins 122, which then upon treatment with BF3·OEt2 underwent the O–H insertion producing oxetanones 123 in good yields. The authors also found that increasing the temperature to rt during the epoxide opening afforded the

Recent advances in amidyl radical-mediated photocatalytic direct intermolecular hydrogen atom transfer

• Hao-Sen Wang,
• Lin Li,
• Xin Chen,
• Jian-Li Wu,
• Kai Sun,
• Xiao-Lan Chen,
• Ling-Bo Qu and
• Bing Yu

Beilstein J. Org. Chem. 2025, 21, 1306–1323, doi:10.3762/bjoc.21.100

• range of functionalized polyolefins, showcasing the applicability of this xanthylated polyolefin in various reactions, including trifluoromethylthiolation, polymer grafting, Michael addition, and epoxide opening. Amidyl radical from N–X bond cleavage Direct halogenation of C–H bonds is of significant

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

• prepared via PMB removal of compound 21, which, in turn, was obtained through desulfonylation of compound 22. Compound 22 originated from the condensation of epoxide 23a with sulfone 26, which was produced by desilylation of 25 followed by converting the resulting primary alcohol into a sulfone group

• . Intermediate 25 was prepared through TBDMS protection and desulfonylation of 24, itself derived from the condensation of epoxide 23b and sulfone 27. The precursor 27 was synthesized from Roche ester 29 via a sequence of steps, including reduction, three-carbon homologation, and enzymatic desymmetrization. An

• failure may have been due to the low reactivity of sulfones 27 and ent-27 under the reaction conditions. Additionally, treating ent-42 with excess tert-butyllithium to form the corresponding lithiated derivative and reacting it with epoxide 23a, both with or without BF3·OEt2, also led to unsatisfying

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

• bond of cyclopropenone to give a cyclic intermediate 316 (Scheme 74A) [125]. On the other hand, Wu and co-workers (2022) developed a Pd-catalyzed selective ring-opening of cyclopropenones and vinyl epoxide 318 to give the corresponding esters 319–321 in good yields via a π–allyl palladium intermediate

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

• a fragmentation process for the total synthesis of (−)-phlegmariurine B. A one-pot epoxidation/nucleophilic epoxide opening introduced both a hydroxy group and a chloride across the cyclopentene, producing 14 in 57% yield. After oxidation of alcohol 14 to ketone 15, the Mukaiyama hydration then

Cryptophycin unit B analogues

• Thomas Schachtsiek,
• Jona Voss,
• Maren Hamsen,
• Beate Neumann,
• Hans-Georg Stammler and
• Norbert Sewald

Beilstein J. Org. Chem. 2025, 21, 526–532, doi:10.3762/bjoc.21.40

• -phenyl position of unit A [9][10][11] or derivatisation of unit A’s epoxide moiety into a halohydrin (-glycinate) [5][12][13][14][15][16][17]. Cryptophycins modified at the α-position of unit C [18] and, most recently, various derivatives with modifications in unit D [19] were established as potent and

• obtained through Grubbs metathesis and subsequent acetonide cleavage in a superior yield of 76%. The finalising steps to obtain epoxides 26 and 2 (Scheme 3) were a diol–epoxide transformation [11][19][32], including firstly the formation of a cyclic orthoester, secondly the formation of a bromohydrin

• -hydroxy-7-azabenzotriazole; HATU = 1-[bis(dimethylamino)methyliumyl]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate. Three-step diol–epoxide transformation starting from diols 24 and 25. a) (MeO)3CH, pyridinium p-toluenesulfonate, CH2Cl2, rt, 3 h; b) AcBr, CH2Cl2, rt, 3–4 h; c) K2CO3

Advances in the use of metal-free tetrapyrrolic macrocycles as catalysts

• Mandeep K. Chahal

Beilstein J. Org. Chem. 2024, 20, 3085–3112, doi:10.3762/bjoc.20.257

• , with TBAI as a co-catalyst, up to 74% yields (Table 1). The inactivity of porphyrin 18 was attributed to the inaccessibility of the inner core imine due to its planar structure. The mechanism of the epoxide ring-opening reaction was elucidated by DFT calculations, which suggested that the macrocycle

• adopts a 1,3-alternate conformation and binds simultaneously to the epoxide O-atom and iodide anion via (NH···O and NH···I) hydrogen-bonding interactions. The TBA countercation is bound to the O-atom of the epoxide ring with hydrogen bonds and is situated away from the I− anion. This crucial transition

• state stabilizes the anionic species generated during the reaction pathway and facilitates a backside attack of I− on the epoxide thus resulting in the initial ring opening (Figure 4b). Apart from acting as an organocatalyst, calix[4]pyrrole 11 has been used for the promotion of cuprous chloride

Computational design for enantioselective CO₂ capture: asymmetric frustrated Lewis pairs in epoxide transformations

• Maxime Ferrer,
• Iñigo Iribarren,
• Tim Renningholtz,
• Ibon Alkorta and
• Cristina Trujillo

Beilstein J. Org. Chem. 2024, 20, 2668–2681, doi:10.3762/bjoc.20.224

• strategy to mitigate rising atmospheric carbon dioxide levels. Despite extensive research on the CO2 insertion into epoxides to form cyclic carbonates, the stereochemical implications of this reaction have been largely overlooked, despite the prevalence of racemic epoxide solutions. This study introduces

• strategically modifying LB substituents to induce asymmetry, a stereoselective catalytic scaffold was developed, favouring one enantiomer from both epoxide enantiomers. This work advances the in silico design of FLPs, highlighting their potential as asymmetric CCU catalysts with implications for optimising

• catalyst efficiency and selectivity in sustainable chemistry applications. Keywords: asymmetric catalysis; carbon dioxide; CO2; epoxide; frustrated Lewis pairs (FLPs); volcano plot; Introduction The field of frustrated Lewis pairs (FLPs) has flourished since their seminal discovery in 2006 by Stephan and

Facile preparation of fluorine-containing 2,3-epoxypropanoates and their epoxy ring-opening reactions with various nucleophiles

• Yutaro Miyashita,
• Sae Someya,
• Tomoko Kawasaki-Takasuka,
• Tomohiro Agou and
• Takashi Yamazaki

Beilstein J. Org. Chem. 2024, 20, 2421–2433, doi:10.3762/bjoc.20.206

• shorter period possibly because of its significantly high electrophilicity by the attachment of three strongly electron-withdrawing moieties. Reactions of (E)-3-Rf-2,3-epoxypropanoates 2 with amines, thiols, and metal halides Because the epoxide ring opening is known to occur in an SN2 fashion, compounds

Natural resorcylic lactones derived from alternariol

• Joachim Podlech

Beilstein J. Org. Chem. 2024, 20, 2171–2207, doi:10.3762/bjoc.20.187

Syntheses and medicinal chemistry of spiro heterocyclic steroids

• Laura L. Romero-Hernández,
• Ana Isabel Ahuja-Casarín,
• Penélope Merino-Montiel,
• Sara Montiel-Smith,
• José Luis Vega-Báez and
• Jesús Sandoval-Ramírez

Beilstein J. Org. Chem. 2024, 20, 1713–1745, doi:10.3762/bjoc.20.152

• -Montiel recently reported a straightforward method to obtain the spiromorpholinone cycle on estrone. Initially, estrone was benzylated at C-3 and subjected to a Corey–Chaykovsky reaction using trimethylsulfonium iodide and potassium tert-butoxide, to produce diastereoselectively the epoxide 145. The

• epoxide was then opened by treatment with sodium azide and boric acid, yielding the azide derivative 146 in 87% from estrone. A subsequent reduction of the azide with LiAlH4 provided the aminoalcohol derivative 147 in 64% yield. Then, a chloroacetamido moiety was formed at the amino function in 51% yield

• nucleophilic and can lead to the formation of five- or six-membered rings, the authors proposed that the thione group of ii was tautomerized to an iminothiol, from which the sulfur atom attacked the most electrophilic site of the epoxide (which was activated by protonation), producing the spiro-1,3,4

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

• on a decagram scale in five steps from (+)-limonene oxide (13), involving epoxide manipulation, oxidative cleavage, and intramolecular aldol condensation. Similarly, the right-half fragment, allyl chloride 16, was synthesized from limonene in five steps. Site-selective hydrogenation, oxidative

Generation of multimillion chemical space based on the parallel Groebke–Blackburn–Bienaymé reaction

• Evgen V. Govor,
• Vasyl Naumchyk,
• Ihor Nestorak,
• Dmytro S. Radchenko,
• Dmytro Dudenko,
• Yurii S. Moroz,
• Olexiy D. Kachkovsky and
• Oleksandr O. Grygorenko

Beilstein J. Org. Chem. 2024, 20, 1604–1613, doi:10.3762/bjoc.20.143

• ), which is another confirmation of the GBB space uniqueness. Notably, 432 members of the generated GBB chemical space were already present in the ChEMBL database [42]. Among them, potent nonacidic farnesoid X receptor (FXR) modulators [48], 5-lipooxygenase (5-LO) inhibitors [49], soluble epoxide hydrolase

Computation-guided scaffold exploration of 2E,6E-1,10-trans/cis-eunicellanes

• Zining Li,
• Sana Jindani,
• Volga Kojasoy,
• Teresa Ortega,
• Erin M. Marshall,
• Khalil A. Abboud,
• Sandra Loesgen,
• Dean J. Tantillo and
• Jeffrey D. Rudolf

Beilstein J. Org. Chem. 2024, 20, 1320–1326, doi:10.3762/bjoc.20.115

• -epoxide 9, which readily crystallized (Figure 2A and Figures S5–S10, Table S1 in Supporting Information File 1). Similarly, the 6,7-epoxy derivatives of klysimplexin R (3) and microeunicellene (4) were recently synthesized and isolated [11][21]; 3 cyclized to the 6/6/6-scaffold after the addition of acid

• epoxide 9, but the similar reaction with 2 yields gersemienol 8. Isolation yields are provided. (B and C) Results of DFT calculations on the protonation-induced cyclizations of 1 and 2. The energies of the cationic intermediates (italicized values) are not on the same energy scale as for the substrates

Bismuth(III) triflate: an economical and environmentally friendly catalyst for the Nazarov reaction

• Manoel T. Rodrigues Jr.,
• Aline S. B. de Oliveira,
• Ralph C. Gomes,
• Amanda Soares Hirata,
• Lucas A. Zeoly,
• Hugo Santos,
• João Arantes,
• Catarina Sofia Mateus Reis-Silva,
• João Agostinho Machado-Neto,
• Leticia Veras Costa-Lotufo and
• Fernando Coelho

Beilstein J. Org. Chem. 2024, 20, 1167–1178, doi:10.3762/bjoc.20.99

• synthesis has been reported for several transformations, such as epoxide opening [56], ketal formation and deprotection [57][58], Mannich reaction [59], intramolecular Sakurai cyclization [60], alcohol oxidation [61], aromatic hydrocarbon nitration [62], imine allylation [63], Knoevenagel condensation [64

• ], Reformatsky reaction [65], azalactone synthesis [66], nitro reduction [67][68], epoxide rearrangement, thiourea guanylation, and others [69][70]. In this article, we describe a simple and direct protocol for the preparation of indanones through a classical Nazarov reaction catalyzed by bismuth(III) triflate

Enhancing structural diversity of terpenoids by multisubstrate terpene synthases

• Min Li and
• Hui Tao

Beilstein J. Org. Chem. 2024, 20, 959–972, doi:10.3762/bjoc.20.86

• depyrophosphorylation, whereas class II TSs utilize a general acid (a key Asp residue) to protonate the terminal C=C bond or epoxide group to yield a tertiary carbocation. The highly reactive carbocation is then converted to different carbocation intermediates, facilitated by the hydrophobic pocket of the TSs, which

(Bio)isosteres of ortho- and meta-substituted benzenes

• H. Erik Diepers and
• Johannes C. L. Walker

Beilstein J. Org. Chem. 2024, 20, 859–890, doi:10.3762/bjoc.20.78

• ], they were able to access cubane 166 on gram scale. Synthesis of enone 176 was achieved by a Wharton transposition sequence [66]. The enone 173 was epoxidised yielding epoxide 174, which could be converted into the allylic alcohol 175 by the Wharton reaction. Enone 176 could then be obtained by

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

• presence of transition metal catalysts [11][12][13][14]. Currently, this motif is synthesized by sequential introduction of the two functional groups [11][12][13]. Addition of a lithium acetylide to an epoxide affords the corresponding homopropargylic alcohol which can then undergo a sequence of mesylation