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

• an important class of compounds with significant biological activities. Spirocyclic derivatives are present in a variety of natural products. We describe here the formation of spirooxindoles using an intermolecular nitrone cycloaddition reaction. The nitrone dipole was prepared in situ by cyclisation

• -dipole, access to 1,3-amino-alcohol functionality is possible. This arrangement is present in many Alstonia alkaloids, and we envisaged using this cycloaddition chemistry to set up the bridged amine ring system found in these natural products. Bridged and spirocyclic ring systems are known to be

• approach. This generates the desired spirooxindole connected to a bicyclic amine, with functionality related to the natural products. It is likely that unactivated dipolarophiles could be successful in related intramolecular cycloadditions [18]. Hence this approach could allow access the spirooxindole and

Chiral phosphoric acid-catalyzed asymmetric synthesis of helically chiral, planarly chiral and inherently chiral molecules

• Wei Liu and
• Xiaoyu Yang

Beilstein J. Org. Chem. 2025, 21, 1864–1889, doi:10.3762/bjoc.21.145

• potential applications in catalytic asymmetric reactions have also been showcased. Planar chirality Planarly chiral cyclophanes, a unique class of macrocyclic compounds featuring planar chirality, can be found in various natural products and are widely utilized in asymmetric catalysis, host–guest chemistry

Systematic pore lipophilization to enhance the efficiency of an amine-based MOF catalyst in the solvent-free Knoevenagel reaction

• Pricilla Matseketsa,
• Margret Kumbirayi Ruwimbo Pagare and
• Tendai Gadzikwa

Beilstein J. Org. Chem. 2025, 21, 1854–1863, doi:10.3762/bjoc.21.144

• of carbonyl compounds, such as aldehydes or ketones, with active methylene compounds [37]. The resulting α,β-unsaturated carbonyl products can then be further elaborated to form natural products, therapeutic agents, polymers, pesticides, and insecticides [38], which have important applications in the

Formal synthesis of a selective estrogen receptor modulator with tetrahydrofluorenone structure using [3 + 2 + 1] cycloaddition of yne-vinylcyclopropanes and CO

• Jing Zhang,
• Guanyu Zhang,
• Hongxi Bai and
• Zhi-Xiang Yu

Beilstein J. Org. Chem. 2025, 21, 1639–1644, doi:10.3762/bjoc.21.127

• the [3.2.1] motif as the SERMs in Scheme 1 do. Lei used a [3 + 2 + 1] reaction [23][24][25][26][27][28], which was developed in our group and has been applied in synthesis, coupled with stoichiometric Pd-mediated Heck reaction, concisely reaching the framework of their target natural products. We

• position, which could be the key to Lei’s synthesis. Realizing the synthesis of VI would provide a practical strategy not only to our target here but also to other natural products with [3.2.1] framework such as songorine, beyerene, garryine and steviol shown in Scheme 3B. Results and Discussion Scheme 4

• reaction in synthesis. Reported biologically active tetrahydrofluorenone-SERMs molecules. Reported synthesis routes to SERMs molecule VI. Lei’s synthesis of natural products of ent-kaurane diterpenoids (A), and natural products songorine, beyerene, garryine and steviol (B). Retrosynthetic analysis for the

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

• used in the synthesis of a good number of target molecules, including complex natural products [32][33][34][35]. Typically, the LA binds the dienophile through a donor–acceptor interaction (usually involving a carbonyl group) which results in a significant stabilization of the dienophile’s LUMO. As a

• natural products such as (+)-steenkrotin A [64] or (±)-andrastin C [65], among others. In order to understand the factors leading to the observed reactivity enhancement, we first compared the parent carbonyl–ene reaction between 1-butene and acetaldehyde with the analogous processes catalyzed by different

Heterologous biosynthesis of cotylenol and concise synthesis of fusicoccane diterpenoids

• Ye Yuan,
• Zhenhua Guan,
• Xue-Jie Zhang,
• Nanyu Yao,
• Wenling Yuan,
• Yonghui Zhang,
• Ying Ye and
• Zheng Xiang

Beilstein J. Org. Chem. 2025, 21, 1489–1495, doi:10.3762/bjoc.21.111

• biosynthesis; P450 oxidation; synthesis; Introduction Fusicoccanes are a family of 5-8-5 tricyclic diterpenoid natural products that are produced by bacteria, fungi, algae, and plants (Figure 1a) [1][2][3][4][5][6][7]. Fusicoccanes possess a broad range of biological activities, including anticancer, anti

• enzymatic terpene cyclization and chemical synthesis [30][31][32][33]. Briefly, the carbon scaffolds are forged by terpene cyclases, followed by concise chemical transformations to yield the desired natural products. Here, we describe heterologous biosynthesis of cotylenol by engineering the biosynthetic

• brassicicene biosynthesis-related gene cluster (BGC) in Alternaria brassicicola and Pseudocercospora fijiensis [34][35]. The 5-8-5 tricyclic scaffold is transformed into various fusicoccane natural products catalyzed by P450s, dioxygenases, dehydrogenases, and reductases. Therefore, we propose to harness the

N-Salicyl-amino acid derivatives with antiparasitic activity from Pseudomonas sp. UIAU-6B

• Joy E. Rajakulendran,
• Emmanuel Tope Oluwabusola,
• Michela Cerone,
• Terry K. Smith,
• Olusoji O. Adebisi,
• Adefolalu Adedotun,
• Gagan Preet,
• Sylvia Soldatou,
• Hai Deng,
• Rainer Ebel and
• Marcel Jaspars

Beilstein J. Org. Chem. 2025, 21, 1388–1396, doi:10.3762/bjoc.21.103

• human system. In this study, we isolated two previously undescribed N-salicyl-amino acids as natural products (1 and 2) and other two new derivatives (3 and 4) from the organic extract of a culture broth in a modified starch–glucose–glycerol (SGG) medium of Pseudomonas sp. UIAU-6B. The structure of the

• new natural products, pseudomonins D–G (1–4) isolated alongside other three known compounds, pseudomonine (5), pseudomonin B (6) and salicylic acid (7), were elucidated based on high-resolution mass spectrometry, 1D and 2D NMR analyses. The absolute configurations of the threonine residue in compounds

• Pseudomonas are huge producers of bioactive natural products with a vast array of structural and functional molecular diversity. This reflects in the bacteria’s genome which ranges in size from 4.6 to 7.1 megabases with 4237 to 6396 predicted genes [1]. Natural products play a major role in the live of these

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

• of ring-opening and ring-expansion reactions, and finally total syntheses of selected oxetane-containing natural products. The literature review primarily covers reports made after the year 2015, but a few older contributions that were considered relevant are also discussed. Keywords: medicinal

• chemistry; natural products; oxetane; reactivity; synthesis; Introduction Oxetanes are 4-membered heterocyclic compounds containing one oxygen atom whose discovery dates back to the 1870s when the first synthesis of the parent, unsubstituted oxetane was reported by Reboul [1]. Over the next 100 years, it

• vitro [19]. As for natural occurrence of oxetanes, they are relatively uncommon, and an extensive review has recently been published by Dembitsky which explored the structural features and biological activities of oxetane-containing natural products [20]. Some of the most famous examples are taxol [21

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

• C(sp3)–H in polyolefins addressed by amidyl radical under visible light. Site-selective C(sp3)–H bromination implemented by amidyl radical under visible light. Site-selective chlorination of C(sp3)–H in natural products implemented by amidyl radical under visible light. Alkylation of C(sp3)–H

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

• a marine or hypersaline environment natural products library to identify potent drugs, a putatively novel metabolite co-produced with borrelidin was discovered, expanding the potential for new borrelidin derivatives. This led to the formation of the so-called “borrelidin family” (Table 1), with

• synthesis of polydeoxypropionate based on iridium-catalyzed asymmetric hydrogenation of α-substituted acrylic acid [40]. This method was subsequently applied to the synthesis of a promising vaccine candidate (+)-phthioceranic acid, as well as key intermediates for two natural products, ionomycin and

Investigations of amination reactions on an antimalarial 1,2,4-triazolo[4,3-a]pyrazine scaffold

• Henry S. T. Smith,
• Ben Giuliani,
• Kanchana Wijesekera,
• Kah Yean Lum,
• Sandra Duffy,
• Aaron Lock,
• Jonathan M. White,
• Vicky M. Avery and
• Rohan A. Davis

Beilstein J. Org. Chem. 2025, 21, 1126–1134, doi:10.3762/bjoc.21.90

• -position of the pyrazine ring [10][11]. During small-scale late-stage functionalisation of natural products, we have observed that amination or amidation with primary amines often involves less of a kinetic barrier than might otherwise be expected [12][13][14]. The use of readily available liquid amines in

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

• -catalyzed ring-opening reactions, e.g., by using PPh3. For instance, Reddy and co-workers (2024) utilized PPh3 to catalyze the esterification of diphenylcyclopropenone (309) with a series of natural products of the coumarin family to give the corresponding esters 311, 343, and 344 in good yields via the

• Meldrum’s acid (361), aldehyde 360, and an amine to prepare the corresponding cinnamamides 362–364, natural products of the piperamide family. The multicomponent reaction involves consecutive acetone and CO2 release via 365 and 366 (Scheme 80A) [135]. A multigram scale operation has been achieved smoothly

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

• particular emphasis on their pivotal role as a strategy in the total synthesis of natural products. Keywords: alkaloid; cyclization; enamide; natural product; total synthesis; Introduction The use of enamines as surrogates for enols in nucleophilic reactions has been well-documented for decades since their

• enamides as nucleophiles, rendering them more stable than enamines. This stability is reflected in their frequent occurrence in natural products [4]. As a result, research on the synthetic applications of enamides has historically lagged behind that of enamines [5][6]. Beyond their use in hydrogenation

• , these methods offer promising strategies for the total synthesis of complex natural products. Review Aza-Prins cyclization – total synthesis of (−)-dihydrolycopodine and (−)-lycopodine Cyclizations of enamides can proceed via several distinct pathways. If protonation of the enamide occurs first, 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

• oxidative truncation of apotirucallane or apoeuphane precursors coupled with subsequent β-furan annulation [1][2][3][4][5][6], constitute an architecturally sophisticated family of natural products. Based on their specific skeletal rearrangements, limonoids can be systematically categorized into four

Recent advances in controllable/divergent synthesis

• Jilei Cao,
• Leiyang Bai and
• Xuefeng Jiang

Beilstein J. Org. Chem. 2025, 21, 890–914, doi:10.3762/bjoc.21.73

• enantiocontrol. Metal control Over the past decade, the relentless pursuit of precision in natural products and pharmaceutical synthesis has driven remarkable advances in catalytic methodologies, particularly in the realm of catalyst-controlled chemoselective transformations [11][25][26][27][28][29]. In 2023

• successfully applied in the synthesis of complex natural products, pharmaceuticals, and functional materials, often streamlining multistep sequences and minimizing protecting-group strategies [50][51]. In 2016, Li and co-workers developed divergent coupling conditions for iminamides 77 with receptor-type diazo

Chitosan-supported CuI-catalyzed cascade reaction of 2-halobenzoic acids and amidines for the synthesis of quinazolinones

• Xuhong Zhao,
• Weishuang Li,
• Mengli Yang,
• Bojie Li,
• Yaoyao Zhang,
• Lizhen Huang and
• Lei Zhu

Beilstein J. Org. Chem. 2025, 21, 839–844, doi:10.3762/bjoc.21.67

• catalytic efficiency (up to 99% yield). Keywords: chitosan-supported CuI catalyst; cyclization reaction; mild conditions; quinazolinone; Introduction Quinazolinones are not only a key core of nitrogen-containing benzo heterocyclic compounds found in many natural products and bioactive molecules [1][2][3

4-(1-Methylamino)ethylidene-1,5-disubstituted pyrrolidine-2,3-diones: synthesis, anti-inflammatory effect and in silico approaches

• Nguyen Tran Nguyen,
• Vo Viet Dai,
• Luc Van Meervelt,
• Do Thi Thao and
• Nguyen Minh Thong

Beilstein J. Org. Chem. 2025, 21, 817–829, doi:10.3762/bjoc.21.65

• ), electronegativity (χ), hardness (η), and softness (S). The calculations were based on established formulas, as described in literature [49]. Natural products and synthetic medicinal compounds containing a 2-pyrrolidinone subunit. The molecular structure of 5a, showing the atom-labelling scheme and displacement

Regioselective formal hydrocyanation of allenes: synthesis of β,γ-unsaturated nitriles with α-all-carbon quaternary centers

• Seeun Lim,
• Teresa Kim and
• Yunmi Lee

Beilstein J. Org. Chem. 2025, 21, 800–806, doi:10.3762/bjoc.21.63

• catalysis; hydrocyanation; regioselectivity; tosyl cyanide; Introduction Acyclic nitriles that incorporate α-all-carbon quaternary centers are highly valuable structural motifs typically found in natural products, biologically active compounds, and synthetic pharmaceuticals [1][2][3][4][5]. These compounds

Origami with small molecules: exploiting the C–F bond as a conformational tool

• Patrick Ryan,
• Ramsha Iftikhar and
• Luke Hunter

Beilstein J. Org. Chem. 2025, 21, 680–716, doi:10.3762/bjoc.21.54

• mimics that of 2-benzyl-2,3-dihydrobenzofuran (overlaid in Figure 4), a structural motif that is commonly found within bioactive natural products. Having seen that the conformations of multivicinal fluoroalkanes can be altered by changing the stereochemistry, it follows that other physical properties can

• ]. This molecule is a ring-expanded analogue of proline, and derivatives of it are found within several natural products and drugs. The pucker of the six-membered ring of 96 is quite important for bioactivity, because different puckers project the carboxyl substituent in different orientations (equatorial

Recent advances in allylation of chiral secondary alkylcopper species

• Minjae Kim,
• Gwanggyun Kim,
• Doyoon Kim,
• Jun Hee Lee and
• Seung Hwan Cho

Beilstein J. Org. Chem. 2025, 21, 639–658, doi:10.3762/bjoc.21.51

• arrangements. The ability to precisely control multiple contiguous stereogenic centers would significantly expand the synthetic utility of such transformations, particularly in the synthesis of complex molecules such as natural products and pharmaceuticals [60]. Furthermore, future efforts could also focus on

• reactions with various chiral cycloallylic phosphates 17, which consistently yielded the corresponding SN2' products 18 with high stereoselectivity. The synthetic utility and broad applicability of this methodology was prominently demonstrated through the total synthesis of biologically important natural

• products. The high stereochemical selectivity of both SN2 and SN2' pathways enabled the efficient construction of complex molecular frameworks. Notably, this approach facilitated the enantioselective synthesis of three ant pheromones: (+)-lasiol, (+)-13-norfaranal, and (+)-faranal. The synthesis of

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

• nematicidal activity with LD90 and LD50 of 100 and 12.5 µg/mL, respectively. Since the parent compound was not active, the present study supports the fact that the acylation reaction can improve bioactivities of some natural products. Keywords: acylation reaction; cytotoxic activity; massarilactone D

• negative impact on the environment and human health. Prolonged and widespread applications of these substances have also increased the development of nematode resistance to pesticides [2][3][4]. However, advancements in natural products chemistry have shown that chemical modifications of certain natural

• cytotoxic activity of natural products by increasing the hydrophobicity, enhancing cell membrane permeability and binding affinity with intracellular targets [26]. Structure–activity relationships analysis of both hemisynthetic products 2 and 3 revealed a shared conjugated methylene olefinic function that

Total synthesis of (±)-simonsol C using dearomatization as key reaction under acidic conditions

• Xiao-Yang Bi,
• Xiao-Shuai Yang,
• Shan-Shan Chen,
• Jia-Jun Sui,
• Zhao-Nan Cai,
• Yong-Ming Chuan and
• Hong-Bo Qin

Beilstein J. Org. Chem. 2025, 21, 601–606, doi:10.3762/bjoc.21.47

• synapse growth and inhibits acetylcholinesterase. (±)-Simonsol C (Figure 1) has received considerable attention due to the presence of an aryl- and allyl-containing quaternary carbon center, which is common in natural products such as galanthamine and morphine. To construct the quaternary carbon in

• ] and has been used in syntheses of natural products containing aryl quaternary carbon centers [9][10]. Unlike the intramolecular alkylation strategy of a phenol derivative, which can only be applied in basic dearomatization reactions, our approach using an α-iodophenol ether as precursor of the

• route to date. The structural motif of an all-carbon quaternary center containing an aryl group is common in many natural products, such as galanthamine and morphine. Our current strategy provides an alternative approach for the synthesis of aryl-containing quaternary carbon centers, which could be

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

• 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

• in MCR reactions applied to the synthesis of propargylamines and aminophosphonates. We will discuss the reaction conditions, mechanisms, and scope. Synthesis of propargylamines Propargylamines are essential building blocks for the synthesis of natural products or biologically active compounds in

Streamlined modular synthesis of saframycin substructure via copper-catalyzed three-component assembly and gold-promoted 6-endo cyclization

• Asahi Kanno,
• Ryo Tanifuji,
• Satoshi Yoshida,
• Sota Sato,
• Saori Maki-Yonekura,
• Kiyofumi Takaba,
• Jungmin Kang,
• Kensuke Tono,
• Koji Yonekura and
• Hiroki Oguri

Beilstein J. Org. Chem. 2025, 21, 226–233, doi:10.3762/bjoc.21.14

• Strecker reaction and cyclization to form the 2,3-diaminobenzofuran moiety, and gold(I)-promoted cascade sequence via 6-endo hydroamination, spontaneous dehydrogenative oxidation followed by ring opening. Carbon numbering was assigned in accordance with natural products. The structure of 16 was determined

Dioxazolones as electrophilic amide sources in copper-catalyzed and -mediated transformations

• Seungmin Lee,
• Minsuk Kim,
• Hyewon Han and
• Jongwoo Son

Beilstein J. Org. Chem. 2025, 21, 200–216, doi:10.3762/bjoc.21.12

• leads to the formation of the N-acyl amidine product 10. 1.4 N-Arylation of dioxazolones Amides bearing N-substituents are key structural motifs in a wide range of polymers [82], natural products [83], and pharmaceuticals [84][85]. Conventional synthetic routes for N-arylamides typically involve the

• yields (16a–c). Moreover, alkyl groups were tolerated during the formation of N-acyl iminophosphoranes (16d, 16f). It is noteworthy that dioxazolones derived from bioactive motifs, such as peptides, natural products, and commercially available drugs were also compatible with this transformation

• late-stage functionalizations of complex scaffolds such as peptides, drug molecules, and natural products containing unprotected free OH and NH groups are anticipated. Proposed reaction pathway for the copper-catalyzed synthesis of δ-lactams from dioxazolones. Proposed reaction mechanism for the copper