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

• introduce another side chain, affording a diene intermediate. A subsequent ring-closing metathesis (RCM) reaction formed the cyclopentene ring, and one pot protection of both carbonyl groups with ethylene glycol provided bis-ketal 55. Notably, due to steric hindrance, only one carbonyl group could be

• protected prior to the RCM step. Oxidative cleavage of the cyclopentene followed by Pinnick oxidation of the resulting aldehyde to the carboxylic acid and esterification yielded ketoester 56. Dieckmann condensation of 56, esterification of the resulting enolate with 57, and subsequent one-pot partial

• transpositions [31]. Starting from (S)-carvone (67), reaction with allyl bromide introduced an allyl group to give 68, which was then converted to the bicyclic compound 69 via a ring-closing metathesis (RCM) reaction followed by one-pot epimerization at the α-position of the carbonyl group (Scheme 7

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

• -alkoxy bridgehead radical addition then installed an allyl fragment, and ring-closing metathesis (RCM) smoothly formed the C ring to complete the core skeleton. The total synthesis was finalized by installing the four remaining stereocenters (C2, C3, C9, and C10). The specific synthetic route is as

• reaction with allyltributylstannane, yielding compound 40. After isomerization of the C11 allyl double bond and introduction of a C6 isobutenyl group, the resulting diene 42 underwent RCM catalyzed by the Hoveyda–Grubbs catalyst to form the pentacyclic skeleton 43, thus completing the C ring of the natural

• 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

Rapid access to the core of malayamycin A by intramolecular dipolar cycloaddition

• Yilin Liu,
• Yuchen Yang,
• Chen Yang,
• Sha-Hua Huang,
• Jian Jin and
• Ran Hong

Beilstein J. Org. Chem. 2025, 21, 2542–2547, doi:10.3762/bjoc.21.196

• three contiguous stereogenic centers (Scheme 1A). The pyran ring was constructed by a RCM reaction [16]. Subsequent functionalization of the alkene to install the 1,2-cis-hydroxy amine required 6 steps from the sterically more demanding side. In continuing our recent interest in accessing unusual

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

• underwent the 1,2-addition of isopropenyllithium reagent (prepared from n-BuLi/tetraisopropenyltin (67) [55]) and DMP oxidation to afford ketone 68. A three-step transformation including RCM, Mukaiyama hydration, and esterification, 68 was converted to methyl oxalate 69. Irradiation of the reaction mixture

• could be acquired in 60% yield with 93% ee. Subsequently, the Grignard addition of the ketone in 120 provided diene intermediate, which was converted to bicyclic secondary alcohol 121 via RCM reaction/hydrogenation and dehydration/hydrogenation. Oxidation states adjustment and functional group

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

• . PPL-catalyzed desymmetrization of 10 with vinyl acetate yielded monoacetate (R)-11 in 41% yield (94% brsm) with 78% ee. Diene 12 was prepared from (R)-11 via a ten-step sequence. The following ring-closing metathesis (RCM) reaction catalyzed by Grubbs catalyst 13 converted 12 into the bicyclic

• 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

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

• being the major product (81% yield). Conversely, using 121b exclusively yielded the bis-acylated product 122b1 (59% yield), which was transformed into the mono-acylated compound 122b2 upon treatment with sodium methoxide. A final ring-closing metathesis (RCM) using a second-generation Grubbs catalyst (G

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

• ) [66]. Variations of this reaction include alkyne metathesis [67] and carbonyl metathesis [68]. Ring-closing metathesis (RCM) gave access to a series of dibenzo[b,f]heteropines, as reported by Matsuda and Sato [31] (Scheme 25). The authors synthesised a series of Si-, Sn-, Ge- and B-tethered dienes 118

• –Grubbs catalyst) catalysed ring-closing metathesis gave dibenzo[b,f]heteropines 122 in excellent yields (>80%). Unfortunately, the metathesis reaction required elevated temperatures (>100 °C) and dilute solutions to reduce unwanted self-metathesis competing with RCM. While excellent yields for

• synthesising the tethers and RCM products are reported, the method does not currently allow for the synthesis of unsymmetrical compounds. 3.6 Alkyne–aldehyde metathesis Bera et al. [69] reported on the synthesis of a series of 10-acyldibenzo[b,f]oxepines 125 by alkyne–aldehyde metathesis catalysed by iron(III

Synthesis of medium and large phostams, phostones, and phostines

• Jiaxi Xu

Beilstein J. Org. Chem. 2023, 19, 687–699, doi:10.3762/bjoc.19.50

• applied for the synthesis of seven to fourteen-membered phostam, phostone, and phostine derivatives. 1.1 Synthesis via C–C bond formation Most medium and large phostams, phostones, and phostines were prepared via C–C bond formation, especially via ring-closing metathesis (RCM). 1.1.1 Synthesis via C–C

• bond formation through RCM reaction: Ring-closing metathesis (RCM) is an efficient strategy for the construction of common to large cyclic compounds via the formation of a C=C bond [26], which can be further reduced to a C–C bond. To prepare phostam-derived antitumor agents, ethyl N-allyl-N-(but-3-en-1

• hydroxylamine (Scheme 1) [23]. The RCM reaction is a powerful strategy for the synthesis of P-stereogenic 3,4,7-trihydro-1,2-azaphosphepine 2-oxide and 1,3,4,5,8-pentahydro-1,2-azaphosphocine 2-oxide derivatives, unsaturated seven- and eight-membered phostams, which can be further reduced to saturated 1,2

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

• synthesis of five- and six-membered rings can be readily achieved through ring-closing metathesis (RCM), but the synthesis of eight-membered rings has been carried out later [13][14]. In this part, we will focus on the use of RCM to achieve total syntheses of natural products or to access the carbon

• skeleton of natural products, and more particularly to construct the cyclooctane ring that is part in these motifs. 1.1 Ring-closing metathesis (RCM) Among all metathesis reactions available in the chemist’s toolbox, ring-closing metathesis (RCM) is nowadays one of the most popular and has been used

• the eight-membered ring by RCM (Scheme 1). Optimization of the reaction parameters (temperature, solvent, concentration, and catalyst amount) was carried out with G-I catalyst. Indeed, the authors noticed that high temperatures improved the reaction conversion, and dichloromethane seemed to furnish

Synthetic strategies for the preparation of γ-phostams: 1,2-azaphospholidine 2-oxides and 1,2-azaphospholine 2-oxides

• Jiaxi Xu

Beilstein J. Org. Chem. 2022, 18, 889–915, doi:10.3762/bjoc.18.90

• -oxides 56a in 23% and 93 in 63% yields, respectively, showing the limited scope of the synthetic method (Scheme 17) [39]. Ring-closing metathesis (RCM) is an efficient strategy for the construction of cyclic compounds via the formation of a C=C bond [40][41], which can be reduced to the C–C bond. 2

• -Allylamino-1,5-dihydro-1,2-azaphosphole 2-oxide derivatives 95 were prepared in 13–76% yield from N,N’-diallyl-vinylphosphonodiamides 94 via the Grubbs ruthenium-catalyzed RCM. N,N’-Dicinnamyl-N,N’-dimethyl-vinylphosphonodiamide (94a) (R = R’ = H) generated the 2-(N-methyl-N-cinnamylamino)-1,5-dihydro-1,2

• -azaphosphole 2-oxide (95a) in the lowest yield. The (E)-prop-1-enylphosphonodiamide 96 also underwent the RCM well. However, N,N’-dicinnamyl-vinylphosphonodiamides 94b,c (R’ = H, Me, R = Ph) always generated the corresponding N,N’-dicinnamyl-styrylphosphonodiamides 98 in 12–17% yields as byproducts via the RCM

Synthesis and late stage modifications of Cyl derivatives

• Phil Servatius and
• Uli Kazmaier

Beilstein J. Org. Chem. 2022, 18, 174–181, doi:10.3762/bjoc.18.19

• compound, we decided to use the Cyl-1 amino acid backbone and introduce a double unsaturated side chain (Scheme 1). In principle, selective modifications at the two different double bonds (internal and terminal) should be possible. Ring-closing metathesis (RCM) should generate an allylglycine unit, which

Peptide stapling by late-stage Suzuki–Miyaura cross-coupling

• Hendrik Gruß,
• Rebecca C. Feiner,
• Ridhiwan Mseya,
• David C. Schröder,
• Michał Jewgiński,
• Kristian M. Müller,
• Rafał Latajka,
• Antoine Marion and
• Norbert Sewald

Beilstein J. Org. Chem. 2022, 18, 1–12, doi:10.3762/bjoc.18.1

• stapling and the most prominent methodology was developed by the groups of Grubbs and Verdine using ring-closing metathesis (RCM) [4][5][6]. The optimised protocol for these so-called hydrocarbon-stapled peptides uses α-methyl-, α-alkenylglycines in a distance of i, i + 3/i + 4 for one helix turn or i, i

• partner β-catenin. The N-terminal FITC-labelled RCM-stapled peptide fStAx-3 was synthesised as tracer for this study and its dissociation constant was determined to be 63 ± 6 nM in a direct fluorescence polarisation assay, which is in agreement with previously reported data [77]. Noteworthy, the isomer

A study on selective transformation of norbornadiene into fluorinated cyclopentane-fused isoxazolines

• Zsanett Benke,
• Attila M. Remete and
• Loránd Kiss

Beilstein J. Org. Chem. 2021, 17, 2051–2066, doi:10.3762/bjoc.17.132

• ; organofluorine chemistry; selectivity; Introduction Olefin metathesis is considered to be a powerful synthetic tool for the creation of olefin bonds [1]. Several types of metathesis reactions, such as ring-opening metathesis (ROM), cross-metathesis (CM), ring-closing metathesis (RCM) or ring-opening/cross

Design, synthesis and photophysical properties of novel star-shaped truxene-based heterocycles utilizing ring-closing metathesis, Clauson–Kaas, Van Leusen and Ullmann-type reactions as key tools

• Shakeel Alvi and
• Rashid Ali

Beilstein J. Org. Chem. 2021, 17, 1374–1384, doi:10.3762/bjoc.17.96

• -closing metathesis (RCM), Clauson–Kaas and Ullmann-type coupling reactions as key steps. Moreover, we have also assembled some other interesting heterocyclic systems possessing oxazole, imidazole, benzimidazole, and benzoxazole in the framework of truxene. Additionally, the preliminary photophysical

• required C3-symmetric tripyrroltruxene 6 by means of RCM in the presence of Grubbs′ first generation catalyst (G-I, 9) followed by self-aromatization without the involvement of any oxidizing agent. Compound 3 was produced from the hexabutylated truxene system 2 involving nitration, reduction and N

• to the pyrrole-based C3-symmetric truxene derivative 6. Synthesis of tripyrrolotruxene 6 via cyclotrimerization and RCM as crucial steps. Synthesis of star-shaped molecule 6 utilizing the Clauson–Kaas pyrrole strategy. Synthesis of truxene derivative 6 involving Ullmann-type cross-coupling reaction

A comprehensive review of flow chemistry techniques tailored to the flavours and fragrances industries

• Guido Gambacorta,
• James S. Sharley and
• Ian R. Baxendale

Beilstein J. Org. Chem. 2021, 17, 1181–1312, doi:10.3762/bjoc.17.90

Prins cyclization-mediated stereoselective synthesis of tetrahydropyrans and dihydropyrans: an inspection of twenty years

• Asha Budakoti,
• Pradip Kumar Mondal,
• Prachi Verma and
• Jagadish Khamrai

Beilstein J. Org. Chem. 2021, 17, 932–963, doi:10.3762/bjoc.17.77

• metathesis (RCM) [16], halo etherification [17], reductive etherification [18][19], and metal-mediated cyclization [20][21], etc. are the most frequent strategies utilized for THP ring construction (Scheme 1). Amongst all, the Prins reaction has proven as a powerful technique in the stereoselective synthesis

Menthyl esterification allows chiral resolution for the synthesis of artificial glutamate analogs

• Kenji Morokuma,
• Shuntaro Tsukamoto,
• Kyosuke Mori,
• Kei Miyako,
• Ryuichi Sakai,
• Raku Irie and
• Masato Oikawa

Beilstein J. Org. Chem. 2021, 17, 540–550, doi:10.3762/bjoc.17.48

• ). Enantiospecific synthesis of TKM-38 For the enantiospecific synthesis of TKM-38, which uniquely bears an eight-membered azacycle as the ring C, we explored 1) the amino-protecting group and 2) the conditions for the cyclization of the medium-sized ring by ring-closing metathesis (RCM). Finally, the established

• . The predominant generation of triene (rac)-15 obviously indicated that the ROM reaction proceeded regioselectively, as also observed in our previous study [6]. With triene (rac)-15 in hand, the cyclization of the eight-membered ring was furthermore attempted by RCM. Gratifyingly, after several trial

• conversion of oxanorbornene (rac)-13 to heterotricycle (rac)-16 through the eight-membered-ring formation would be owing to the cis-relationships of the pentenyl and vinyl groups on the ring B of (rac)-15, which allows the proximal arrangement of the reacting sites in the RCM. The N-Boc derivatization of

Recent progress in the synthesis of homotropane alkaloids adaline, euphococcinine and N-methyleuphococcinine

• Dimas J. P. Lima,
• Antonio E. G. Santana,
• Michael A. Birkett and
• Ricardo S. Porto

Beilstein J. Org. Chem. 2021, 17, 28–41, doi:10.3762/bjoc.17.4

• , activated by lithium ion in a tricyclic N,O-acetal (−)-46, and an olefin metathesis (RCM) of a dialkenylpiperidine (−)-50 for the construction of an azabicyclononane system [48]. The synthetic sequence described by the authors is shown in Scheme 6. The lactam present in 43 was opened by treatment with

Ring-closing metathesis of prochiral oxaenediynes to racemic 4-alkenyl-2-alkynyl-3,6-dihydro-2H-pyrans

• Viola Kolaříková,
• Markéta Rybáčková,
• Martin Svoboda and
• Jaroslav Kvíčala

Beilstein J. Org. Chem. 2020, 16, 2757–2768, doi:10.3762/bjoc.16.226

• reactions of unsaturated compounds, e.g., alkene and enyne cross metathesis (CM [1] and EYCM [2][3][4]), alkene and enyne ring-closing metathesis (RCM and RCEYM) [5][6], ring-opening metathetic polymerization (ROMP) [7], etc., the CM and RCM are the most popular in organic synthesis [8]. Furthermore, the

• for other catalytic reactions, e.g., for the Pauson–Khand reaction [14]. In the enantioselective RCM, prochiral trienes have been most often employed, leading to chiral cycloalkenes. The Schrock molybdenum precatalysts [15][16][17] proved to be more effective than the Grubbs or Collins ruthenium

• precatalysts [18][19][20] in the enantioselective RCM, however, the high air and moisture sensitivity makes their use less practical. The choice of the catalyst is one of the key elements in both cross and ring-closing enyne metathesis and the other is the substrate structure. Both of these factors determine

Design and synthesis of a bis-macrocyclic host and guests as building blocks for small molecular knots

• Elizabeth A. Margolis,
• Rebecca J. Keyes,
• Stephen D. Lockey IV and
• Edward E. Fenlon

Beilstein J. Org. Chem. 2020, 16, 2314–2321, doi:10.3762/bjoc.16.192

• [13][17][18][19][20]. The first-generation TLC approach for the synthesis of molecular knots involved a single knot precursor compound that had two macrocycles and two long tails [13][21]. Solvophobic effects [22][23] were used to promote the tail threading step, ring-closing olefin metathesis (RCM

Synthetic approaches to bowl-shaped π-conjugated sumanene and its congeners

• Shakeel Alvi and
• Rashid Ali

Beilstein J. Org. Chem. 2020, 16, 2212–2259, doi:10.3762/bjoc.16.186

• catalyst 15 to yield the trimerized products 12 (syn) and 13 (anti) in respectable yields (Scheme 2). The alkene-bridge exchange of 12 (syn) was accomplished by tandem ring-opening and ring-closing metathesis (ROM–RCM) in the presence of Grubbs’ first generation (G-I) catalyst to generate a C3-symmetric

• % yield. Next, the methyl substituents were introduced at the position of the carbonyl groups of 23 to generate the methyl-substituted olefin derivative 25 via alkenyl phosphates 24 by means of three-fold cross-coupling reaction with methylmagnesium iodide in THF. Finally, during the tandem ROM–RCM, they

• noticed that the G-I catalyst provided a mixture of ring-opened products, therefore, the ring-closing step was then carried out using Grubbs’ second generation (G-II) catalyst. Hence, the tandem ROM–RCM step was made successful using both G-I and G-II catalysts in ethylene atmosphere to afford the C3

Combining enyne metathesis with long-established organic transformations: a powerful strategy for the sustainable synthesis of bioactive molecules

• Valerian Dragutan,
• Ileana Dragutan,
• Albert Demonceau and
• Lionel Delaude

Beilstein J. Org. Chem. 2020, 16, 738–755, doi:10.3762/bjoc.16.68

• metathesis (RCM) [67][68]. Starting from 3-cyanocyclohex-2-enone, the authors obtained a versatile intermediate able to provide the appropriate dienyne precursors (A–C, Scheme 4) by multicomponent Grignard addition-alkylations. Through divergent cyclizations involving a chemoselective enyne metathesis

• in the pyrrolidine ring catalyzed by RhCl3·H2O, followed by debenzylation, amidation, and aminal generation using the Stille protocol [77]. (–)‐Clavukerin A and related sesquiterpenes Applying original organocatalytic/metal-catalyzed tactics, Metz et al. [78] reported a tandem dienyne RCM for the

Recent advances in Cu-catalyzed C(sp³)–Si and C(sp³)–B bond formation

• Balaram S. Takale,
• Ruchita R. Thakore,
• Elham Etemadi-Davan and
• Bruce H. Lipshutz

Beilstein J. Org. Chem. 2020, 16, 691–737, doi:10.3762/bjoc.16.67

• alcohol due to decomposition. Nonetheless, several products could be transformed into molecules of greater complexity. For example, cyclopropanation could be achieved to give 269. Additionally, TBS protection of 268 followed by ring closing metathesis (RCM) led to the interesting 6-membered silacycle 270

Combination of multicomponent KA² and Pauson–Khand reactions: short synthesis of spirocyclic pyrrolocyclopentenones

• Riccardo Innocenti,
• Elena Lenci,
• Gloria Menchi and
• Andrea Trabocchi

Beilstein J. Org. Chem. 2020, 16, 200–211, doi:10.3762/bjoc.16.23

• [39][40], consisting of a [2 + 2 + 1] cycloaddition between an olefin, alkyne, and carbon monoxide. This reaction has been also applied in cascade approaches [41], and in combination with RCM [42], Diels–Alder [43] and Staudinger [44] reactions to produce novel structurally complex chemical entities

1,2,3-Triazolium macrocycles in supramolecular chemistry

• Mastaneh Safarnejad Shad,
• Pulikkal Veettil Santhini and
• Wim Dehaen

Beilstein J. Org. Chem. 2019, 15, 2142–2155, doi:10.3762/bjoc.15.211

• -catalyzed RCM clipping mechanical bond forming methodology [48]. The 1H NMR spectroscopy in CDCl3 (293 K, 500 MHz) and the fluorescence titration experiments which were done in acetonitrile have demonstrated that the synthesized 1,2,3-triazolium macrocycle 6 was able to bind and sense several anions but the