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

• starting materials [32]. This synthesis features a pentafulvene-based intramolecular [6 + 2] cycloaddition [41][42] and a nitroso-Diels–Alder reaction [43] as key steps. The route began with the esterification of pentafulvenol 82 to give β-ketoester 83, which was subsequently converted to the sterically

• and the installation of the C1 methyl group, then afforded compound 96. However, subjecting 96 to the singlet oxygen cycloaddition again led to rearrangement, producing diketones 98 and 99. The solution was found by employing a nitroso-Diels–Alder reaction with dienophile 87, which provided a stable

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

• of the non-naturally produced ryanodol (4) and its dehydrated derivative, anhydroryanodol (10) [30] (Scheme 2). Given the highly complex fused-ring system and the stereochemical challenges posed by multiple chiral centers, the author utilized the Diels–Alder reaction, a prominent representative of

• pericyclic reactions [31][32][33][34][35][36][37][38][39][40][41][42][43][44], to control the formation of the crucial C5 chiral center precisely. Subsequent oxidative cleavage of the carbon–carbon double bond introduced in the Diels–Alder reaction, followed by an intramolecular aldol reaction, efficiently

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

• hydroxyketone 207 using the Diels–Alder reaction and the ring contraction reaction of epoxyketone 208. After treatment with TMSOTf in dichloromethane at −78 °C, epoxyketone 208 was subjected to selective cleavage of the epoxide, followed by а 1,2-shift of the carbonyl group and the formation of the ring

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

• close the second six-membered carbocycle to deliver 48 in 73% yield. The Diels–Alder reaction and Heck reaction quickly set up the tetracyclic skeleton for subsequent peripheral modifications. First, the ketone functionality of 48 was reduced to a methylene group via a sequence of Luche reduction and

• -oxide directed C–H arylation to forge the C2–C3’ linkage, but the approaches to prepare the C–H arylation precursors they employed differ completely. In the Tsukano synthesis, a Diels–Alder reaction and an intramolecular Heck reaction were used to build the key ring systems of complanadine A. In the Dai

• diastereomers) via either a creative “degradation” of the piperidine ring or cross-coupling reactions at the pyridine C3 position [29]. The Tsukano total synthesis – 2013 In 2013, Tsukano and co-workers reported their total synthesis of complanadines A and B (Scheme 4). Their synthesis utilizes a Diels–Alder

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

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

• -catalyzed intermolecular Diels–Alder reaction of 106 with methacrolein 107 afforded the common intermediate 108 in high yield. Sequential Grignard reagent addition and acid-promoted ethoxy elimination provided the separable planar diene 109 (dr = 1:1), which underwent a Mn-catalyzed HAT hydrogenation to

• intramolecular Diels–Alder reaction generated tricyclo[3.2.1.02,7]-octene 113. A two-step transformation including HAT hydrogenation and acetal C–H oxidation with RuCl3/NaIO4, 113 was converted into ketoester 114. The TFA-mediated C13–C15 bond cleavage of 114 proceed smoothly to give ring-opening products, which

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

• bioinspired synthetic approach [44]. Initially, we prepared a bicyclic precursor similar with toussaintine C to react with α-phellandrene to mimic the bioinspired Diels–Alder reaction, which, however, showed no reactivity due to the strong steric hindrance. To decrease the steric effect, we finally used

• simple 1,4-benzoquinone to act as the dienophile, and the expected Diels–Alder reaction proceeded smoothly to provide the endo adducts 48a and 48b, in which 48b was the major product dominated by the isopropyl steric effect. Isomers 48a and 48b were separable and determined through X-ray diffraction

• supports the proposed biogenetic pathway, and the endo-selective stereochemical outcome of the Diels–Alder reaction in the bioinspired synthesis fully matched with the proposed approach in nature. Conclusion The biomimetic or bioinspired total synthesis of natural product has gone a long way from more than

Preparation of a furfural-derived enantioenriched vinyloxazoline building block and exploring its reactivity

• Madara Darzina,
• Anna Lielpetere and
• Aigars Jirgensons

Beilstein J. Org. Chem. 2025, 21, 1737–1741, doi:10.3762/bjoc.21.136

• reactions. Out of these, the aza-Diels–Alder reaction with TsNCO was successful, leading to a highly diastereoselective formation of an oxazolo[3,2-c]pyrimidine derivative. Keywords: aza-Diels–Alder reaction; electrosynthesis; furfural; valinol; vinyloxazoline; Introduction The utilization of biomass as

• -6 is a good substrate for an aza-Diels–Alder reaction with tosylisocyanate (TsNCO) providing the oxazolo[3,2-c]pyrimidine derivative 7 as the only detectable diastereomer (Scheme 6) [22][23][24]. Oxazolo[3,2-c]pyrimidines are substructures in several pharmaceutically relevant compounds such as

• potent gonadotropin-releasing hormone receptor antagonists with potential application as anticancer drugs [25] and as nucleoside analogs with antiviral potency [26]. According to the reaction mechanism proposed by Elliott et al., the aza-Diels–Alder reaction of vinyloxazoline S-6 with TsNCO is a step

Transition-state aromaticity and its relationship with reactivity in pericyclic reactions

• Israel Fernández

Beilstein J. Org. Chem. 2025, 21, 1613–1626, doi:10.3762/bjoc.21.125

• rationalization of the effect of the LA in the Diels–Alder reaction therefore does not consider a possible influence of the aromaticity of the transition state on the barrier heights. For this reason, and to understand the ultimate origin of the faster rates observed in the LA-catalyzed Diels–Alder reactions, we

Synthesis and photoinduced switching properties of C₇-heteroatom containing push–pull norbornadiene derivatives

• Daniel Krappmann and
• Andreas Hirsch

Beilstein J. Org. Chem. 2025, 21, 807–816, doi:10.3762/bjoc.21.64

• . Starting with 1-((bromoethynyl)sulfonyl)-4-methylbenzene, which was previously prepared and characterized [40][41], Diels–Alder reaction with either cyclopentadiene, furan or Boc-protected pyrrol, resulted in the NBD precursors C-NBD1, O-NBD1 and N-NBD1, respectively [31][42]. With these precursors in hand

• were observed. However, purification was not possible. Furthermore, an alternative commonly used synthetic strategy involving the Diels–Alder reaction of a pre-functionalized push–pull acetylene with furan or pyrrol derivatives proved unsuccessful [4][43]. All synthesized NBD derivatives were

Synthesis of HBC fluorophores with an electrophilic handle for covalent attachment to Pepper RNA

• Raphael Bereiter and
• Ronald Micura

Beilstein J. Org. Chem. 2025, 21, 727–735, doi:10.3762/bjoc.21.56

• intention was to provide an RNA pulldown tool where the RNA of interest tagged with the Pepper aptamer becomes covalently attached to the fluorophore, which in turn can be biotinylated via a catalyst-free inverse-electron-demand Diels–Alder reaction (IEDDA) [11]. Thereby, the entire process is easily

Semisynthetic derivatives of massarilactone D with cytotoxic and nematicidal activities

• Rémy B. Teponno,
• Sara R. Noumeur and
• Marc Stadler

Beilstein J. Org. Chem. 2025, 21, 607–615, doi:10.3762/bjoc.21.48

• oxa-Diels–Alder reaction between two methacryloyl chloride molecules could have taken place to yield 6-chloro-3,4-dihydro-2,5-dimethyl-2H-pyran-2-carbonyl chloride as previously described [18] before esterification of the hydroxy group at C-7. Compounds 3 (6% yield) and 4 (90% yield) were obtained

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

• such as an aza-Prins cyclization [23] and aza-Diels–Alder reaction [24], where MMS serves as direct source of the methylene (-CH2-) group (Scheme 5b). In both cases, the resulting reactive species (MMS or formaldehyde) can participate as electrophilic component in several MCRs as C1 building block

• –Alder reaction between an imine and an alkene (Scheme 6). Very successfully, the multicomponent version of the Povarov reaction using aldehydes, anilines, and alkenes has been explored in a three-component cascade reaction to quinolines [28][29][30][31] (Scheme 6). Furthermore, protocols have been

• this context, quinoline and its derivatives are privileged structures in several natural products and biologically active compounds, rendering this scaffold an important synthetic target. An attractive strategy to afford tetrahydroquinolines and quinolines is the Povarov reaction, a type of aza-Diels

New tandem Ugi/intramolecular Diels–Alder reaction based on vinylfuran and 1,3-butadienylfuran derivatives

• Yuriy I. Horak,
• Roman Z. Lytvyn,
• Andrii R. Vakhula,
• Yuriy V. Homza,
• Nazariy T. Pokhodylo and
• Mykola D. Obushak

Beilstein J. Org. Chem. 2025, 21, 444–450, doi:10.3762/bjoc.21.31

• yields. The studied tandem Ugi and intramolecular Diels–Alder reactions allow high substituent variation in the named isoindoles. Keywords: 1,3-butadienylfuran; furo[2,3-f]isoindole; intramolecular Diels–Alder reaction; isoindole; one-pot; Ugi reaction; vinylfuran; Introduction Energy-saving and

• present work, the new tandem sequence involving an Ugi reaction and Diels–Alder [4 + 2] cycloaddition based on vinylfuran, 1,3-butadienylfuran derivatives was designed and studied. Results and Discussion To carry out an intramolecular Diels–Alder reaction, we tested (E)-3-(furan-2-yl)acrylaldehyde (1a) in

• agree with our previous results on tandem acylation/Diels–Alder reactions [31][32][33] and lead us to conclude that the final Diels–Alder reaction products are formed as the exo-adducts. Moreover, since we do not observe other stereoisomers we speculate that the Ugi and Diels–Alder reactions occur under

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

• formed. This reaction only occurs close to the photocatalyst or sensitizer fixed at the intracellular target, for example at tubulin. An intramolecular Diels–Alder reaction followed by nitrogen extrusion

Three-component reactions of conjugated dienes, CH acids and formaldehyde under diffusion mixing conditions

• Dmitry E. Shybanov,
• Maxim E. Kukushkin,
• Eugene V. Babaev,
• Nikolai V. Zyk and
• Elena K. Beloglazkina

Beilstein J. Org. Chem. 2025, 21, 262–269, doi:10.3762/bjoc.21.18

• adducts of the Diels–Alder (i.e., I) and the hetero-Diels–Alder reaction (i.e., II), or adducts resulting from the addition of a second equivalent of CH acid to the crotonic condensation product (i.e., III). Apparently ʟ-proline played an essential role as catalyst in this three-component reaction. Using

• and 8, the reaction also produced hetero-Diels–Alder reaction adducts 6 and 9. For these, CH–O 1H NMR signals in the region of 4.9–5.4 ppm were characteristic. It is worth noting that the individual isolated compounds 8 and particularly 9 were unstable when stored in solution, and boiling adduct 8 or

• participation of the C=C bond. Apparently, the ratio of the adducts of the Diels–Alder (i.e., I) and the hetero-Diels–Alder reaction (i.e., II) was strongly influenced by steric factors; a decreased steric hindrance in the initial CH acid derivatives led to a more selective formation of the structures I. This

Cu(OTf)₂-catalyzed multicomponent reactions

• Sara Colombo,
• Camilla Loro,
• Egle M. Beccalli,
• Gianluigi Broggini and
• Marta Papis

Beilstein J. Org. Chem. 2025, 21, 122–145, doi:10.3762/bjoc.21.7

• is plausible to assume as the key step for ring formation an aza-Diels–Alder reaction between the alkyne and the imine generated by dehydration between the aldehyde and aniline. The catalyst promotes the formation of the imine XI, while the high regioselectivity is ascribable to the favored

Non-covalent organocatalyzed enantioselective cyclization reactions of α,β-unsaturated imines

• Sergio Torres-Oya and
• Mercedes Zurro

Beilstein J. Org. Chem. 2024, 20, 3221–3255, doi:10.3762/bjoc.20.268

• imines; asymmetric organocatalysis; cyclization; N-heterocycles; inverse electron demand aza-Diels–Alder reaction; Introduction Nitrogen-containing heterocycles are abundant scaffolds present in natural products, biologically active compounds, pharmaceuticals, synthetic agrochemicals, and functional

• , they can be attacked by a nucleophile and undergo a 1,2-addition or conjugate addition leading to the production of allylic amines or aliphatic imines, respectively. They can also behave as C4 synthons in cycloaddition reactions such as the aza-Diels–Alder reaction, giving access to nitrogen-containing

• construction of carbon–carbon bonds [5][6][7][8][9][10]. The hetero-Diels–Alder reaction is therefore an attractive strategy for the synthesis of heterocyclic compounds. It involves the reaction of dienes or dienophiles which possess a heteroatom in their structure. In this reaction, the HOMO of the diene and

Germanyl triazoles as a platform for CuAAC diversification and chemoselective orthogonal cross-coupling

• John M. Halford-McGuff,
• Thomas M. Richardson,
• Aidan P. McKay,
• Frederik Peschke,
• Glenn A. Burley and
• Allan J. B. Watson

Beilstein J. Org. Chem. 2024, 20, 3198–3204, doi:10.3762/bjoc.20.265

• established as a powerful approach for molecule synthesis. Strategies within click chemistry include several widely used reactions such as the (hetero-)Diels–Alder reaction [1][2], alkene hydrothiolation [3], and an array of amide-bond-forming chemistries [4]. However, by virtue of the access to alkyne and

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

• hetero-Diels–Alder reaction of Danishefsky's diene 6 with p-nitrobenzaldehyde (7, Figure 2). The reaction can provide three products depending on the reaction conditions; either a Mukaiyama aldol (8) or products of Diels–Alder cycloaddition (9 and 10). Out of the three screened catalysts, only calix[4

• catalysis of Diels–Alder reaction in aqueous environment catalyzed by TPPS3 53 supramolecular aggregates [67]. The Diels–Alder reaction between cinnamaldehyde (55) and cyclopentadiene (56) proceeds via iminium activation by the zwitterionic hetero-aggregates derived from TPPS3 molecules 53 and a cyclic

• interactions between phenyl groups and cyclopentadiene. Due to the presence of both types of moieties on the aggregate surface, the two reacting species can get into proximity and form the desired product (Figure 10b). Later, an analogous system was used for catalysis of an asymmetrical Diels–Alder reaction

Improved deconvolution of natural products’ protein targets using diagnostic ions from chemical proteomics linkers

• Andreas Wiest and
• Pavel Kielkowski

Beilstein J. Org. Chem. 2024, 20, 2323–2341, doi:10.3762/bjoc.20.199

• bearing an affinity or reporter tag. To carry out this bioorthogonal reaction well-known chemistries were developed including traceless Staudinger ligation, Cu-catalyzed azide–alkyne cycloaddition (CuAAC), strain-promoted azide–alkyne cycloaddition (SPAAC), inverse electron-demand Diels–Alder reaction

Catalysing (organo-)catalysis: Trends in the application of machine learning to enantioselective organocatalysis

• Stefan P. Schmid,
• Leon Schlosser,
• Frank Glorius and
• Kjell Jorner

Beilstein J. Org. Chem. 2024, 20, 2280–2304, doi:10.3762/bjoc.20.196

Natural resorcylic lactones derived from alternariol

• Joachim Podlech

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

1,2-Difluoroethylene (HFO-1132): synthesis and chemistry

• Liubov V. Sokolenko,
• Taras M. Sokolenko and
• Yurii L. Yagupolskii

Beilstein J. Org. Chem. 2024, 20, 1955–1966, doi:10.3762/bjoc.20.171

• -phase photolysis at −80 °C from 1,2-difluoroethylene and diazomethane (Scheme 19). Unfortunately, the product yield was not reported. Diels–Alder reaction of (E)- and (Z)-1,2-difluoroethylenes with hexachlorocyclopentadiene was studied by Ihrid and Smith [99]. It was shown that (Z)-1,2-difluoroethylene

• -difluoroethylene. Cyclopropanation of 1,2-difluoroethylene. Diels–Alder reaction of 1,2-difluoroethylene and hexachlorocyclopentadiene. Cycloaddition reaction of 1,2-difluoroethylene and fluorinated ketones. Cycloaddition reaction of 1,2-difluoroethylene and perfluorinated aldehydes. Photochemical cycloaddition of

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

• microwaved, a Diels–Alder reaction occurred, yielding the spiro product 41. The reaction conditions were also applied to 17-ethynyl-17-hydroxysteroids derived from mestranol and desogestrel obtaining similar results. The one-pot RCEYM/Diels–Alder reaction was only applied to mestranol and lynestrenol