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

Recent advances in electrochemical copper catalysis for modern organic synthesis

• Yemin Kim and
• Won Jun Jang

Beilstein J. Org. Chem. 2025, 21, 155–178, doi:10.3762/bjoc.21.9

• functionalization of highly complex and diverse molecules, such as those of pharmaceuticals and natural products, has provided new retrosynthetic disconnections for complex compounds, contributing to improved resource efficiency [41][42][43][44][45][46]. Recently, the merging of C–H activation and electrochemistry

• enantioenriched nitrile products 89 and a reduced Cu(I) complex 94, which is reoxidized through anodic oxidation. The 1,2-diamine moiety is present in numerous natural products and bioactive compounds. In 2022, Xu et al. reported the Cu-catalyzed electrocatalytic diazidation of olefins with ppm-level catalyst

• 2022, Xu and co-workers established a site- and enantioselective cyanation of benzylic C(sp³)–H bonds using an electro-photochemical strategy (Figure 7) [55]. The reaction conditions show a broad substrate tolerance, and the late-stage functionalization of complex molecules derived from natural

Synthesis of acenaphthylene-fused heteroarenes and polyoxygenated benzo[j]fluoranthenes via a Pd-catalyzed Suzuki–Miyaura/C–H arylation cascade

• Merve Yence,
• Dilgam Ahmadli,
• Damla Surmeli,
• Umut Mert Karacaoğlu,
• Sujit Pal and
• Yunus Emre Türkmen

Beilstein J. Org. Chem. 2024, 20, 3290–3298, doi:10.3762/bjoc.20.273

• access polyoxygenated benzo[j]fluoranthenes, which are all structurally relevant to benzo[j]fluoranthene-based fungal natural products. The effectiveness of our strategy was demonstrated via a concise, four-step synthesis of the tetramethoxybenzo[j]fluoranthene derivative 18, which represents a formal

• heteroatoms or other heterocycles to obtain heterocyclic fluoranthene analogues offers numerous opportunities for structural and functional diversifications. For instance, azafluoranthenes such as triclisine (1) or imeluteine (2) constitute a common structural motif encountered in natural products isolated

• ) ligand 4 were reported by Cowley and co-workers in 2010 [14]. In addition to heterocyclic fluoranthene analogues, highly oxygenated benzo[j]fluoranthenes are commonly encountered fungal natural products with important biological activities [15]. Bulgarein (5) is an example of such a benzo[j]fluoranthene

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

Ceratinadin G, a new psammaplysin derivative possessing a cyano group from a sponge of the genus Pseudoceratina

• Shin-ichiro Kurimoto,
• Kouta Inoue,
• Taito Ohno and
• Takaaki Kubota

Beilstein J. Org. Chem. 2024, 20, 3215–3220, doi:10.3762/bjoc.20.267

• cytotoxicity against L1210 murine leukemia cells and KB epidermoid carcinoma cells. Keywords: ceratinadin; cytotoxicity; marine sponge; psammaplysin; Pseudoceratina sp.; Introduction Marine sponges are widely recognized as a rich source of unique bioactive natural products. For instance, marine sponges

Discovery of ianthelliformisamines D–G from the sponge Suberea ianthelliformis and the total synthesis of ianthelliformisamine D

• Sasha Hayes,
• Yaoying Lu,
• Bernd H. A. Rehm and
• Rohan A. Davis

Beilstein J. Org. Chem. 2024, 20, 3205–3214, doi:10.3762/bjoc.20.266

• aeruginosa biofilm inhibitors and antibiotic enhancers. Large-scale extraction and isolation studies resulted in the discovery of four new and minor natural products, ianthelliformisamines D–G (4–7) and the known steroid, aplysterol (8). Compounds 4–7 were fully characterised following 1D/2D NMR, MS and UV

• data analyses. All compounds were assessed for their inhibition on planktonic growth of P. aeruginosa PAO1 in addition to their ability to inhibit the formation of biofilms. None of the tested natural products inhibited planktonic growth or biofilm formation of PAO1 when screened at 50 µM

• . Ianthelliformisamine D (4) contains a rare N-(3-aminopropyl)-2-pyrrolidone moiety only found in <30 natural products. Owing to the novelty of compound 4, we undertook the first total synthesis of this natural product, which was achieved in three steps. Keywords: ianthelliformisamine; marine sponge; natural products