Chemoenzymatic synthesis of the cardenolide rhodexin A and its aglycone sarmentogenin

• Fuzhen Song,
• Mengmeng Zheng,
• Dongkai Wang,
• Xudong Qu and
• Qianghui Zhou

Beilstein J. Org. Chem. 2025, 21, 2637–2644, doi:10.3762/bjoc.21.204

• -electron demand Diels–Alder (IEDDA) reaction was utilized to successfully construct the BCD tricyclic structure with the correct configuration of the four contiguous stereocenters in just one step. However, the requirement of a series of protecting group manipulations undermined the step-economy and

Visible-light-driven NHC and organophotoredox dual catalysis for the synthesis of carbonyl compounds

• Vasudevan Dhayalan

Beilstein J. Org. Chem. 2025, 21, 2584–2603, doi:10.3762/bjoc.21.200

• , Michael additions, cycloadditions, domino reactions, cascade annulations, Diels–Alder reactions, and Michael–Stetter reactions, to name a few [31][32][33][34][35]. Notably, previous reports have demonstrated that the utility of chiral N-heterocyclic carbene (NHC) catalysts permits contracting asymmetric C

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

• directly, the team adopted a strategy involving rearrangement from the more accessible cis-pentalene isomer. They first assembled the cis-pentalene core through an elegant intramolecular Diels–Alder (IMDA) reaction. Subsequently, the conversion from cis to trans-pentalene was achieved via a semipinacol

• , 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

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

Ni-promoted reductive cyclization cascade enables a total synthesis of (+)-aglacin B

• Si-Chen Yao,
• Jing-Si Cao,
• Jian Xiao,
• Ya-Wen Wang and
• Yu Peng

Beilstein J. Org. Chem. 2025, 21, 2548–2552, doi:10.3762/bjoc.21.197

• synthesis of both enantiomers of aglacins A (1), B (2), and E (4) by asymmetric photoenolization/Diels–Alder reactions as the key steps for the construction of the C7–C8 and C7′–C8′ bonds [8]. During the past decade, we had developed nickel-catalyzed or -promoted reductive coupling/cyclization reactions for

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

• interesting transformation of a cyclohexene fragment into the cyclopentane fragment in Diels–Alder adducts of levoglucosenone (LG) and 1,3-dienes is presented in [16]. Diels–Alder adducts of LG and 1,3-dienes, containing in their structure fragments of cyclohexene and a carbohydrate residue, are attractive

• explained to some extent by their structural diversity. Figure 1 shows the general formula of iridoids. The authors [16] have established regiocontrol of the effect of the 1,6-anhydro bridge on the Dieckmann condensation of dicarboxylic acid diester 16, obtained in four steps from 13, the Diels–Alder adduct

• method for the synthesis of cyclopentane derivatives through oxidative cleavage of the double bond in Diels–Alder adducts of LG with 1,3-butadiene and piperylene (3E-penta-1,3-diene), followed by an intramolecular aldol condensation of the resulting dialdehydes was described in [19]. The dicarbonyl

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

• 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

• a thermal Diels–Alder cycloaddition, which afforded a mixture of stereo- (endo/exo) and regioisomers, among which the desired product 46 was obtained in 45% yield as a racemic mixture. After triflation of the free hydroxy group of 46 to provide 47, an intramolecular Heck reaction was employed to

• 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

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

• distinct from those generated through thermal Diels–Alder cycloaddition of (Z)-100. However, when [ReCl(CO)5] was used as the catalyst, a regioselective C–H bond insertion pathway was observed for substrate (E)-100, leading to the formation of tricyclic products 104 and 105 (Scheme 21, path b). This

• strategy employed transition metal-catalyzed carbene intermediates to mediate stereoselective cyclization, affording bicyclo[4.3.0]nonane derivatives with configurations distinct from Diels–Alder adducts. In 2013, Alami and co-workers demonstrated catalyst-dependent cycloisomerization of aromatic enynes

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

• bicyclic alkanes, used as fuel additives, by hydrodeoxygenation catalyzed by iridium/rhenium oxide supported on silica [182]. Conversion of furfural to amines: The synthesis of m-xylylenediamine from furfural and acrylonitrile through a Diels–Alder/aromatization sequence was developed by Wischet and Jérôme

• [183]. 2-(Furan-2-yl)-1,3-dioxolane with higher reactivity was generated through the acetalization of furfural with ethylene glycol, and converted to Diels–Alder cycloadducts in the presence of acrylonitrile at 60 °C. Treatment of the Diels–Alder adduct in basic conditions allowed the rearomatization

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

• (Scheme 7a). Biogenetically, sarglamides A–C are generated directly from α-phellandrene and toussaintine C through stereodivergent Diels–Alder reactions, since the indolidinoid natural product toussaintine C is known and symbiotic with sarglamides. More importantly, a solid evidence to support this

• proposal is that toussaintine C was isolated as a racemic mixture, and sarglamides A and B are derived from one enantiomer of toussaintine C while sarglamides C–E are derived from the other one. The Diels–Alder cycloadditions are basically proceeded through endo-selectivity. The isopropyl group in α

• 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

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

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

• hetisine-type diterpenoids (+)-18-benzoyldavisinol and (+)-davisinol [82] (Scheme 34). Using diester 286 as a starting material, phenol 287 was prepared in six steps. Subsequent oxidative dearomatization-induced Diels–Alder cycloaddition with PhI(OAc)2, delivered endo-cycloadduct 288 with high

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

• this end, selected representative examples ranging from fundamental processes such as Diels–Alder or Alder–ene reactions to double-group transfer reactions or 1,3-dipolar cycloadditions involving metal complexes are presented. It is found that while more synchronous processes tend to exhibit greater

• transition structure of the Diels–Alder cycloaddition reaction between butadiene and ethylene “…Very qualitatively, we may say that whereas in the initial state the mobile electrons are those characteristics of an ethylene and a butadiene structure, in the TS they simulate the behavior of a benzene molecule

• the aromaticity of the transition state and the activation barriers of different pericyclic reactions spanning from the parent Diels–Alder reactions to higher-order cycloadditions or even transition-metal-mediated transformations [22][23][24][25][26][27][28][29]. By selecting illustrative examples, in

Copper catalysis: a constantly evolving field

• Elena Fernández and
• Jaesook Yun

Beilstein J. Org. Chem. 2025, 21, 1477–1479, doi:10.3762/bjoc.21.109

• reactions, are separately debated. In addition, mechanistic insights into the reaction of heteropolycyclic systems, cycloadditions, and aza-Diels–Alder reactions are provided. This is important because multicomponent, one-pot reactions have gained interest as potentially more economic, efficient, and

High-pressure activation for the solvent- and catalyst-free syntheses of heterocycles, pharmaceuticals and esters

• Kelsey Plasse,
• Valerie Wright,
• Guoshu Xie,
• R. Bernadett Vlocskó,
• Alexander Lazarev and
• Béla Török

Beilstein J. Org. Chem. 2025, 21, 1374–1387, doi:10.3762/bjoc.21.102

• Mannich reactions [20], lipase-catalyzed esterification [21], nitro-aldol [22], Michael [23], and aza-Michael reactions [24][25], Diels–Alder reactions [26][27] and Friedel–Crafts alkylation of indoles [28]. Many high pressure reactions were applied in natural product synthesis [29]. The high pressure

A multicomponent reaction-initiated synthesis of imidazopyridine-fused isoquinolinones

• Ashutosh Nath,
• John Mark Awad and
• Wei Zhang

Beilstein J. Org. Chem. 2025, 21, 1161–1169, doi:10.3762/bjoc.21.92

• Ashutosh Nath John Mark Awad Wei Zhang Department of Chemistry, University of Massachusetts Boston, 100 Morrissey Boulevard, Boston, MA 02125, USA 10.3762/bjoc.21.92 Abstract A new synthetic route initiated with Groebke–Blackburn–Bienaymé (GBB) followed by N-acylation, intramolecular Diels–Alder

• –Bienaymé (GBB); imidazopyridine; intramolecular Diels–Alder (IMDA); isoquinolinone; multicomponent reaction (MCR); re-aromatization; Introduction Multicomponent reactions (MCRs) have intrinsic green chemistry advantages of synthetic efficiency and operational simplicity. Performing post-condensational

• dienophile, characteristic of Diels–Alder processes. The incorporation of a bromine atom at the 5-position of the diene (+0.306, −0.041, 6j) complicates the situation. As an electronegative element, Br exerts an inductive electron-withdrawing influence to enhance the electron shortage of the diene. This

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

• compound and MMS, undergoes an aza-Diels–Alder cyclization with the alkyne, and after oxidation and aromatization steps generates quinoline II. Unfortunately, under these gentle and greener conditions, aliphatic alkynes remain unreacted, compared to the metal-catalyzed version developed by Xu et al. [37

• 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

• reaction and Diels–Alder [4 + 2] cycloaddition based on vinylfuran and 1,3-butadienylfuran derivatives was designed and studied. It was found that in the case of 3-(furan-2-yl)acrylaldehyde, a one-pot Ugi reaction and intramolecular Diels–Alder vinylarene (IMDAV) reaction leads to the formation of the

• 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

• , form heterolignans, which are synthetic derivatives of naturally occurring lignans [22][23][24][25]. This has gained significant attention in drug discovery [26]. Several synthetic routes, such as tandem Pummerer/Diels–Alder or Wittig/Diels–Alder approaches, have been developed for heterolignan

Beyond symmetric self-assembly and effective molarity: unlocking functional enzyme mimics with robust organic cages

• Keith G. Andrews

Beilstein J. Org. Chem. 2025, 21, 421–443, doi:10.3762/bjoc.21.30

• ]. Lattices can also contain defects, which may affect catalytic activity unpredictably [228]. Nonetheless, macroscale structures, like those that arise from the stacking in 2D COFs, can contribute to catalysis, for instance dense arrays of aligned C–H bonds can provide CH–π interactions in Diels–Alder

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