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

• been successfully done for this method. Similarly, Hou and co-workers (2022) also used CO2 to carry out an auto-tandem Cu-catalyzed carboxylation of styrenes via β-hydride elimination (208) (Scheme 60B) [104]. Impressively, several natural product-like compounds (e.g., 207) were successfully prepared

• -Markovnikov selectivity catalyzed by Au(III) in the presence of dimethylaminopyridine N-oxide (DMAPO) as oxidant. The reaction proceeds via Au–allenylidene species 307 (Scheme 73) [124]. Various cinnamic esters and amides with natural product-based alkoxy groups 301–304 and sulfoximines 305 and 306, a

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

• Chun-Yu Mi Jia-Yuan Zhai Xiao-Ming Zhang State Key Laboratory of Natural Product Chemistry & College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou 730000, P. R. China 10.3762/bjoc.21.81 Abstract Enamides are distinctive amphiphilic synthons that can be strategically

• 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

• review of these advancements up until 2015 has already been documented [16]. In this review, recent breakthroughs of these enamide cyclizations will be surveyed from the viewpoint of natural product synthesis. Leveraging the enamide–alkyne cycloisomerization cyclizations, Lycopodium alkaloids

Studies on the syntheses of β-carboline alkaloids brevicarine and brevicolline

• Benedek Batizi,
• Patrik Pollák,
• András Dancsó,
• Péter Keglevich,
• Gyula Simig,
• Balázs Volk and
• Mátyás Milen

Beilstein J. Org. Chem. 2025, 21, 955–963, doi:10.3762/bjoc.21.79

• group with methylhydrazine afforded butynylamine derivative 6. Cyclization of the latter to dihydropyrrole 7 and subsequent reduction resulted in compound 8, which was N-methylated to give racemic brevicolline ((±)-1). The natural product (S)-brevicolline ((S)-1) was finally obtained by chiral

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

• carbon monoxide were used as starting materials, and two natural product frameworks of phenanthridone and acridone alkaloids could be selectively obtained by controlling ligands. The reaction of o-iodoaniline with in situ-generated arynes under CO atmosphere under ligand-free conditions selectively

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

• emerges. The 1,3-C–F bonds tend to avoid a parallel alignment, due to dipolar repulsion (III, Figure 3) [30][31][32]. This phenomenon can be harnessed to control molecular conformations in a predictable way, and once again the stereochemistry is important. For example, compare the natural product

• if the hydroxy group is required for target binding. A series of (fluorinated) protease inhibitors illustrates this point (57 and 58, Figure 8) [108]. The non-fluorinated lead compound 57 is a natural product known as pepstatin; the backbone of 57 adopts a bent conformation when bound to the protease

• which the conformation can be controlled by fluorine, is the natural product balanol (99, Figure 11) [112][167][168][169][170][171][172]. Balanol is an ATP mimic that inhibits protein kinase Cε (PKCε), an enzyme that is implicated in cancer. However, compound 99 also inhibits off-target kinases

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

• (+)-lasiol was achieved through a highly selective SN2 substitution (SN2/SN2' = >99:1, dr = 98:2, 99% ee), while the preparation of (+)-13-norfaranal and (+)-faranal showcased the versatility of the methodology in constructing more complex terpene frameworks. These successful applications in natural product

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

• the natural product, cyanosafracin B (4), bearing a para-quinone moiety at the left end [14]. Considering the relationships between the aromatic ring structures and DNA alkylating ability, we envisioned a modular and flexibly modifiable synthetic approach that would allow for the initial installation

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

• total synthesis of the fungal natural product bulgarein. Keywords: acenaphthylene-fused heteroarenes; benzo[j]fluoranthenes; C–H arylation; fluoranthenes; heterocycles; Introduction An important subclass of polycyclic aromatic hydrocarbons (PAHs) [1] is comprised of fluoranthenes, which have been the

• -based natural product, which was discovered to induce topoisomerase I-mediated DNA cleavage [16][17]. For the construction of the fluoranthene skeleton, a broad range of synthetic strategies including C–H arylation [18][19][20][21][22], Diels–Alder [7][8][23][24][25] and [2 + 2 + 2] cycloadditions [26

• [54]. It was also shown by the authors that compound 18 could be efficiently converted to the fungal natural product bulgarein (5) in only two steps. Our synthesis started with the mono-iodination of 1,8-dimethoxynaphthalene (20), which was prepared in single step from the commercially available 1,8

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

• . 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

• ], therefore it is no surprise that sponges are highly sought after for novel bioactive metabolites and have been a major focus of marine natural product drug discovery for over 70 years. The identification of ianthelliformisamines A–C from the Australian marine sponge Suberea ianthelliformis, which displayed

• undertook the first total synthesis of this natural product, which was successfully achieved in only three steps and respectable yield. All newly identified metabolites were subsequently assessed for their ability to inhibit the growth of planktonic P. aeruginosa PAO1 and formation of biofilms. Results and

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

• Thomas Ma John Chu Department of Chemistry, National Taiwan University, Taipei City 10617, Taiwan 10.3762/bjoc.20.253 Abstract Bioactivity-guided fractionation (BGF) has historically been a fruitful natural product discovery workflow. However, it is plagued by increasing rediscovery rates in

• recent years and new methods capable of exploring the natural product chemical space more broadly and more efficiently is in urgent need. Chemical structure metagenomics as one such method is the theme of this Perspective. It emphasizes a chemical-structure-centered viewpoint toward natural product

• research. Key to chemical structure metagenomics is the ability to predict the structure of a natural product based on its biosynthetic gene sequences, which facilitated the discovery of numerous new bioactive molecules and helped uncover oversampled/underexplored niches of decades of BGF based discovery

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

• photophysical materials. While unsubstituted (parent) indigo (1a) is not a natural product, Tyrian purple (also known as Shellfish purple) is present in nature and represents, besides indigo, an important indigo derivative used as a dye for thousands of years [4]. Several types of cancers, Alzheimer's disease

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

• present this collection of 19 Full Research Papers, three Letters, and nine Review articles from our colleagues around the world. Topics covered include natural product discovery efforts from a variety of organisms, genome and transcriptome mining and bioinformatics of natural products, biosynthetic gene

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

• investigated by direct inlet atmospheric solids analysis probe-atmospheric mass spectrometry (ASAP-APCI-MS), which allows the detection of secondary metabolites up to a molecular mass of 1,500 Da, but no additional compounds were detected. A more detailed description of the use of this method in natural

• product research has recently been published by our team [41]. Conclusion 4,6-Dimethylalk-5-enoic acids are important components of the scent gland secretion of Protobothrops mangshanensis. Since NMR analysis was not possible due to the low amounts present, the compounds were identified only with the help

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

• undivided cell using a boron-doped diamond (BDD) anode and a platinum cathode at constant current, resulting in 1,4-dicarbonyls with yields up to 91% and enantiomeric excesses (ee) greater than 99%. This methodology was demonstrated in the LSF of two complex natural product derivatives: a β-ionone

Visible-light-mediated flow protocol for Achmatowicz rearrangement

• Joachyutharayalu Oja,
• Sanjeev Kumar and
• Srihari Pabbaraja

Beilstein J. Org. Chem. 2024, 20, 2493–2499, doi:10.3762/bjoc.20.213

• as sun light, as a greener approach and easily available biomass-derived furfuryl alcohols as starting materials. The flow platform with the developed protocol was utilized successfully to make several dihyropyranones that may find wide applications in medicinal and materials chemistry and natural

• product synthesis. Scope of the integrated continuous photo-flow (visible light)-induced Achmatowicz rearrangement reaction. Reaction conditions: Stock solution (A) comprise of 2/K2S2O8/Ru(bpy)3Cl·6H2O/ACN/DMSO/H2O in a molar ratio of 1:1:0.005:70:54:408; yields are based on isolated yields. Proposed

Synthesis and conformational analysis of pyran inter-halide analogues of ᴅ-talose

• Olivier Lessard,
• Mathilde Grosset-Magagne,
• Paul A. Johnson and
• Denis Giguère

Beilstein J. Org. Chem. 2024, 20, 2442–2454, doi:10.3762/bjoc.20.208

• chiral halides: F, Cl, Br, I) [19]. Only a handful of natural product syntheses have been reported [20][21], despite the promising biological activity of these unique inter-halides [22]. For our part, we recently reported the synthesis of contiguous inter-halide-bearing stereocenters using a Chiron

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

• trifunctional linker AzKTB (Figure 14) was introduced by Wright et al. to study protein N-myristoylation and was later used for the identification of the natural product callyspongynic acid and zerumbone protein targets [117][121][122]. The AzKTB linker integrates biotin for affinity enrichment with a TAMRA

Natural resorcylic lactones derived from alternariol

• Joachim Podlech

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

• natural product F [32]) will not be discussed (with scarce exceptions, when the respective compounds are most likely derived from alternariol or from related natural products). Compounds, which have not been isolated as natural products, but are synthetic derivatives [33] (e.g., G) of natural products, or

• : Total synthesis and comparison of the NMR spectra revealed that this natural product is identical with altertenuol [41], whose structure was correctly given previously [42]. Furthermore, the originally proposed structures [43] of graphislactones E and F were corrected after total synthesis and

• altertenuol, but is in fact a different natural product. The originally proposed structure of altenuisol turned out to be wrong; it is in fact identical with the structure of altertenuol and the name ‘altenuisol’ is thus obsolete (although it is still frequently used in the community) [41]. The occasionally

The Groebke–Blackburn–Bienaymé reaction in its maturity: innovation and improvements since its 21st birthday (2019–2023)

• Cristina Martini,
• Muhammad Idham Darussalam Mardjan and
• Andrea Basso

Beilstein J. Org. Chem. 2024, 20, 1839–1879, doi:10.3762/bjoc.20.162

• molecules, with the possibility of generating pseudo-natural compound libraries: Cortés-García et al. [44] applied this strategy to vouacapane. The authors developed a two-step reaction for the synthesis of fused vouacapane-azoles 36. Starting from the 6-β-acetoxyvouacapane (34), a natural product isolated

Chemo-enzymatic total synthesis: current approaches toward the integration of chemical and enzymatic transformations

• Ryo Tanifuji and
• Hiroki Oguri

Beilstein J. Org. Chem. 2024, 20, 1693–1712, doi:10.3762/bjoc.20.151

• comprehensive understanding of the chemo-enzymatic synthetic approach, we refer the reader to recent excellent reviews that provide multiple perspectives on the topic [1][2][3][4][5][6][7][8][9][10]. Review Late-stage oxidative transformations of natural product scaffolds: cotylenol and brassicicenes Chemo

• natural product family sharing the highly substituted methyl cyclohexene moiety, Lei and co-workers synthesized analogs of biosynthetic intermediates 44 and 48, and subjected them to the established chemo-enzymatic synthetic process (Scheme 6A) [56]. MaDA exhibited a relatively broad substrate tolerance

• . Iterative Pictet–Spengler cyclizations: saframycin A and jorunnamycin A Saframycin A (5) was isolated from Streptomyces lavendulae, and a number of related alkaloid families such as safracins and renieramycins have been identified from both soil and marine microorganisms [89][90]. These natural product

Methyltransferases from RiPP pathways: shaping the landscape of natural product chemistry

• Maria-Paula Schröder,
• Isabel P.-M. Pfeiffer and
• Silja Mordhorst

Beilstein J. Org. Chem. 2024, 20, 1652–1670, doi:10.3762/bjoc.20.147

• other bioactive compounds. By providing an overview of the various methylation options available, this review is intended to emphasise the biocatalytic potential of RiPP methyltransferases and their impact on the field of natural product chemistry. Keywords: biocatalysis; methylation; post

• -translational modifications; ribosomal peptides; SAM-dependent enzymes; Introduction In the complex landscape of natural product biosynthesis, ribosomally synthesised and post-translationally modified peptides (RiPPs) stand out as a fascinating class of compounds with both structural diversity and unique

• encoded in the same BGC as the precursor peptide install post-translational modifications in the core peptide. Finally, a protease releases the modified core peptide, creating the mature natural product [2]. The transfer of a methyl group is a common post-translational modification in RiPP biosynthesis

Polymer degrading marine Microbulbifer bacteria: an un(der)utilized source of chemical and biocatalytic novelty

• Weimao Zhong and
• Vinayak Agarwal

Beilstein J. Org. Chem. 2024, 20, 1635–1651, doi:10.3762/bjoc.20.146

• commonly detected in the commensal marine microbiomes. These bacteria have been recognized for their ability to degrade polysaccharides and other polymeric materials. Increasingly, Microbulbifer genomes indicate these bacteria to be an untapped reservoir for novel natural product discovery and biosynthetic

• barriers to natural product discovery; high rediscovery rates, reliance on largely serendipitous response in bioactivity assays, and the resources and expertise required for their structure determination being the primary impediments [1][2]. With this background, accessing biological sources that have not

• yet been extensively mined for natural product discovery is a promising route, one which, at the very least, promises to ameliorate the problem of continued rediscovery of known natural products. This review outlines the recent progress that has been realized using bacteria of the genus Microbulbifer

Mining raw plant transcriptomic data for new cyclopeptide alkaloids

• Draco Kriger,
• Michael A. Pasquale,
• Brigitte G. Ampolini and
• Jonathan R. Chekan

Beilstein J. Org. Chem. 2024, 20, 1548–1559, doi:10.3762/bjoc.20.138

• biosynthetic enzymes. Ultimately proteolysis releases the modified core peptide as the mature RiPP natural product [5][6]. In the case of the newly described burpitide family of RiPPs, the defining feature is the presence of amino acid side-chain crosslinks installed by a copper-dependent burpitide cyclase [4

• . ameranicus using UHPLC-HRMS/MS. Finally, we generated a global natural product social (GNPS) network to show the correlation between metabolites from these different plant species (Figure 5) [29]. Cyclopeptides in Ceanothus americanus The GNPS network showed the presence of multiple features from C

Selectfluor and alcohol-mediated synthesis of bicyclic oxyfluorination compounds by Wagner–Meerwein rearrangement

• Ziya Dağalan,
• Muhammed Hanifi Çelikoğlu,
• Saffet Çelik,
• Ramazan Koçak and
• Bilal Nişancı

Beilstein J. Org. Chem. 2024, 20, 1462–1467, doi:10.3762/bjoc.20.129

• study, benzonorbornadiene (1a) and the chiral natural product (+)-camphene (1b) were used as bicyclic alkenes. Safe, easily soluble, easy to use, stable solid, reactive and commercial available selectfluor [18][27][28] was selected for electrophilic fluorination source. Water and various alcohols were

• (Scheme 1). The configurations of fluoroalkoxy compounds 3a–j were confirmed by the COSY 2D-NMR spectrum of compound 3a (Supporting Information File 1). Additionally, (+)-camphene (1b), a chiral natural product, was used as another alkene for fluoroalkoxy reactions. From (+)-camphene (1b), fluoroalkoxy

Synthetic applications of the Cannizzaro reaction

• Bhaskar Chatterjee,
• Dhananjoy Mondal and
• Smritilekha Bera

Beilstein J. Org. Chem. 2024, 20, 1376–1395, doi:10.3762/bjoc.20.120

• [87]. The sequence of transformations commencing from the aldehyde 64 afforded the desymmetrized biaryl derivative 66 and proceeded towards the final natural product 67 (Scheme 20). Applying crossed-Cannizzaro reaction: Mondal and coauthors demonstrated an efficient application of the aldol/crossed