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

Chemical structure metagenomics of microbial natural products: surveying nonribosomal peptides and beyond

• Thomas Ma and
• John Chu

Beilstein J. Org. Chem. 2024, 20, 3050–3060, doi:10.3762/bjoc.20.253

• ; natural products; natural product discovery; nonribosomal peptides; Introduction Natural products present diverse structures to elicit a wide range of biological activities and are of paramount importance to both translational science and basic research. Despite not knowing the underlying active

• ingredient(s) and their mechanisms of action, humans have taken advantage of the therapeutic effects of herbal and microbial extracts for thousands of years [1]. We now know that natural products, genetically encoded secondary metabolites, are in most cases responsible for the desirable effects in these

• traditional medicine formulations [2]. Modern science has found that natural products are uniquely suited as the starting point for the development of new drugs [3][4]. They may serve as chemical probes and help confirm laboratory findings [5]; furthermore, entirely new physical and chemical principles are

gem-Difluorovinyl and trifluorovinyl Michael acceptors in the synthesis of α,β-unsaturated fluorinated and nonfluorinated amides

• Monika Bilska-Markowska,
• Marcin Kaźmierczak,
• Wojciech Jankowski and
• Marcin Hoffmann

Beilstein J. Org. Chem. 2024, 20, 2946–2953, doi:10.3762/bjoc.20.247

• nucleophiles to unsaturated compounds with electron-withdrawing groups, is a cornerstone in constructing carbon–carbon and carbon–heteroatom bonds [1]. It is instrumental in synthesizing natural products [2][3][4][5] and pharmaceuticals [6], underlining its significance in organic chemistry. Recent

• using organolithium reagents (Scheme 1), revealing new avenues in fluorinated unsaturated amide synthesis, which are present in numerous natural products, pharmaceuticals, and polymers [34][35][36][37][38]. The obtained α,β-unsaturated amides may represent promising structural motifs for further

4,6-Diaryl-5,5-difluoro-1,3-dioxanes as chiral dopants for liquid crystal compositions

• Maurice Médebielle,
• Peer Kirsch,
• Jérémy Merad,
• Carolina von Essen,
• Clemens Kühn and
• Andreas Ruhl

Beilstein J. Org. Chem. 2024, 20, 2940–2945, doi:10.3762/bjoc.20.246

• found in some natural products [34] with some fluorinated analogues [35][36], this motif is rarely found in LCs [37][38][39]. Based on these observations and literature data, we embarked in the synthesis and evaluation of enantiomerically pure acetals derived from anti-2,2-difluoro-1,3-diols as

Recent advances in transition-metal-free arylation reactions involving hypervalent iodine salts

• Ritu Mamgain,
• Kokila Sakthivel and
• Fateh V. Singh

Beilstein J. Org. Chem. 2024, 20, 2891–2920, doi:10.3762/bjoc.20.243

• biologically active compounds and natural products. Consequently, the synthesis of aryl sulfides has drawn increasing attention. Diaryliodonium salts have been reported to be utilized to arylate thiols in a number of publications in recent years [44][86][87]. In 2022, Sarkar et al. demonstrated a synthesis of

Synthesis of pyrrole-fused dibenzoxazepine/dibenzothiazepine/triazolobenzodiazepine derivatives via isocyanide-based multicomponent reactions

• Marzieh Norouzi,
• Mohammad Taghi Nazeri,
• Ahmad Shaabani and
• Behrouz Notash

Beilstein J. Org. Chem. 2024, 20, 2870–2882, doi:10.3762/bjoc.20.241

• compounds with antibiotic, antiviral, and anticancer properties that are found in many drugs and natural products [1][2][3][4][5][6]. Pyrroles' biological properties manifest when they are fused to other heterocycles [7][8][9][10][11][12]. Among them, seven-membered heterocycles of the benzodiazepine

N-Glycosides of indigo, indirubin, and isoindigo: blue, red, and yellow sugars and their cancerostatic activity

• Peter Langer

Beilstein J. Org. Chem. 2024, 20, 2840–2869, doi:10.3762/bjoc.20.240

• , indirubin, and isoindigo which can be regarded as blue, red, and yellow sugars, respectively. Review Indigo-N-glycosides (blue sugars) In 2002, Laatsch and Maskey reported the isolation of the akashins A, B and C, indigo-N-glycosides, from terrestric Streptomyces (Scheme 2) [17][18]. These natural products

• -glycososides 3-Alkylideneoxindoles are of considerable pharmacological relevance and occur in a variety of clinically used drugs and natural products [42][43][44][45]. The reaction of isatin-N-rhamnoside 16a with acetophenone (45a) afforded the desired 3-alkylideneoxindole-N-rhamnoside E-β-46a in good yield as

• an improved water solubility or ability to pass the cell membrane or by an improved recognition of the drug in the active site of the receptor. In contrast to indirubin-N-glycosides, indigo-N-glycosides are relatively unstable and not highly active against cancer, except for the natural products

Copper-catalyzed yne-allylic substitutions: concept and recent developments

• Shuang Yang and
• Xinqiang Fang

Beilstein J. Org. Chem. 2024, 20, 2739–2775, doi:10.3762/bjoc.20.232

• numerous natural products and pharmaceutical prospects. Given their significance, the pursuit of efficient and direct synthetic routes to access functionalized chiral coumarins has garnered substantial interest. While the literature is abundant with reports on coumarin-based propargylic and allylic

Synthesis of spiroindolenines through a one-pot multistep process mediated by visible light

• Francesco Gambuti,
• Jacopo Pizzorno,
• Chiara Lambruschini,
• Renata Riva and
• Lisa Moni

Beilstein J. Org. Chem. 2024, 20, 2722–2731, doi:10.3762/bjoc.20.230

• -indolenines, specially the spiro-heterocyclic indolenines, can be considered as a privileged scaffold, present in several natural products with interesting biological activities, as depicted in Figure 1 [4][5][6][7]. Among the known methods of synthesizing spiro-heterocyclic indolenines, the dearomative

• ), 103.5 (CH Ar), 75.9 (Cq spiro), 55.4 (OCH3), 52.1 (Cq t-Bu), 47.9 (CH2), 30.9 (CH2), 28.5 (3 CH3 of t-Bu); HRMS (ESI+) (m/z) [M + H]+: calcd for C27H30N3O, 412.238; found, 412.2395. Selected natural products containing spiro-indolenines. Time profile of the reaction of N-Ph-THIQ, 3,5-dimethoxyaniline

Young investigators in natural products chemistry, biosynthesis, and enzymology

• Jeffrey D. Rudolf,
• Lena Barra and
• Takayoshi Awakawa

Beilstein J. Org. Chem. 2024, 20, 2720–2721, doi:10.3762/bjoc.20.229

• , Japan 10.3762/bjoc.20.229 There is just something about natural products. When staring at these structurally complex molecules produced by diverse organisms on our planet, one may wonder why a particular natural product is made, how it is made, how I can make it, or how I can use it. The isolation and

• structural elucidation of a single natural product can inspire a wide array of scientific disciplines. Natural products, first as bioactive metabolites in traditional medicines and now as isolated or (bio)synthesized metabolites, are one of the most important sources of therapeutics historically and today

• . Their privileged structures have led organic and bioorganic chemists to develop methods to construct them. Our fundamental knowledge in enzymology is continually expanded by enzymes involved in natural products biosynthesis, as their production requires evolved enzymes to perform chemical reactions

Synthesis of benzo[f]quinazoline-1,3(2H,4H)-diones

• Ruben Manuel Figueira de Abreu,
• Peter Ehlers and
• Peter Langer

Beilstein J. Org. Chem. 2024, 20, 2708–2719, doi:10.3762/bjoc.20.228

• other compounds with medicinal or photophysical properties [52][53][54][55]. Compounds A are related to the class of natural products known as coumestans, while B resembles flavins. While the medical potential of coumestans is still the subject of current research, interesting photocatalytic properties

The scent gland composition of the Mangshan pit viper, Protobothrops mangshanensis

• Jonas Holste,
• Paul Weldon,
• Donald Boyer and
• Stefan Schulz

Beilstein J. Org. Chem. 2024, 20, 2644–2654, doi:10.3762/bjoc.20.222

• -configuration for all compounds except Em, where both diastereomers were present in approximately equal amounts. We conclude that (E)-4,6-dimethyldodec-5-enoic acid is D, accompanied by D’, which is the (Z)-diastereomer. As shown, the spectra of natural products A–C, E, and F are very similar to D, except for

Synthesis and cytotoxicity studies of novel N-arylbenzo[h]quinazolin-2-amines

• Battini Veeraiah,
• Kishore Ramineni,
• Dabbugoddu Brahmaiah,
• Nangunoori Sampath Kumar,
• Hélène Solhi,
• Rémy Le Guevel,
• Chada Raji Reddy,
• Frédéric Justaud and
• René Grée

Beilstein J. Org. Chem. 2024, 20, 2592–2598, doi:10.3762/bjoc.20.218

• Chemveda Life Sciences for providing laboratory facility for carrying out these research experiments. This work has been performed also as part of the Indo-French “Joint Laboratory for Natural Products and Synthesis towards Affordable Health”. We thank CSIR, CNRS, IICT and University of Rennes for their

A review of recent advances in electrochemical and photoelectrochemical late-stage functionalization classified by anodic oxidation, cathodic reduction, and paired electrolysis

• Nian Li,
• Ruzal Sitdikov,
• Ajit Prabhakar Kale,
• Joost Steverlynck,
• Bo Li and
• Magnus Rueping

Beilstein J. Org. Chem. 2024, 20, 2500–2566, doi:10.3762/bjoc.20.214

• pharmaceutical drugs and natural products. We classify these advancements into three types: anodic oxidation, cathodic reduction, and paired electrolysis (Figure 1). This review considers direct electrolysis (oxidation or reduction), mediator-induced electrolysis, and metal-catalyzed and photocatalyzed

• anode and a foamed Ni cathode, at a constant current of 12 mA in DMSO at room temperature under atmospheric conditions. The reaction has been applied to more than 80 examples, including the late-stage functionalization of natural products and pharmaceuticals, as well as the synthesis and radiosynthesis

• functionalized pyrimido[5,4-b]indoles due to its high functional group tolerance. Multiple examples were demonstrated with indole 1H-carboxamides linked to drug molecules or natural products at the R2 position. Additionally, an alkyl azide at the R2 position and an iodide at the R1 position were tolerated