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

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

• ; photocatalyst; sunlight; Introduction The furan ring moiety is present in several natural products [1] and serves as a key precursor to 1,4-dicarbonyls [2], cyclopentanones [3], and carboxylic acids [4], in synthetic organic chemistry. Furfuryl alcohols, a family of 2-substituted furan molecules, are

Hypervalent iodine-mediated cyclization of bishomoallylamides to prolinols

• Smaher E. Butt,
• Konrad Kepski,
• Jean-Marc Sotiropoulos and
• Wesley J. Moran

Beilstein J. Org. Chem. 2024, 20, 2455–2460, doi:10.3762/bjoc.20.209

• many organocatalysts [3][4][5], natural products (e.g., the potent α-glucosidase inhibitor (−)-codonopsinol B) [6][7], and pharmaceutical drug molecules such as saxagliptin and ramipril (Figure 1) [8]. Accordingly, the development of methods to access substituted prolines and pyrrolidines is an

Asymmetric organocatalytic synthesis of chiral homoallylic amines

• Nikolay S. Kondratyev and
• Andrei V. Malkov

Beilstein J. Org. Chem. 2024, 20, 2349–2377, doi:10.3762/bjoc.20.201

• as a key methodology in the synthesis of alkaloids and natural products with 4-, 5- and 6-membered cyclic amine motifs. Initially reliant on stoichiometric reagents, synthetic chemists predominantly used N-substituted chiral imines, organometallic chiral reagents and achiral reagents with an

• process and the rich toolkit of advanced organic synthesis [5]. Homoallylic amines occupy a significant niche in alkaloid synthesis as they frequently appear as key intermediates in syntheses of the various nitrogen-containing natural products [6][7][8][9][10][11][12][13][14]. Additionally, they can be

• synthesis, the deprotected derivatives such as 69 are desired for the synthesis of natural products. Therefore, an easy-to-perform two-step deprotection procedure was developed that is based on methylation of the phenolic hydroxy group with an excess of MeI in acetone at rt (68), followed by oxidative

Tandem diazotization/cyclization approach for the synthesis of a fused 1,2,3-triazinone-furazan/furoxan heterocyclic system

• Yuri A. Sidunets,
• Valeriya G. Melekhina and
• Leonid L. Fershtat

Beilstein J. Org. Chem. 2024, 20, 2342–2348, doi:10.3762/bjoc.20.200

• thermostable components of functional organic materials. Keywords: molecular hybridization; nitric oxide; nitrogen heterocycles; 1,2,5-oxadiazoles; 1,2,3-triazin-4-one; Introduction Nitrogen heterocycles are a significant and broad class of organic substances included in the structure of various natural

• products and pharmacologically active molecules. For example, nucleic acids, proteins and enzymes, hormones and vitamins, essential for the functioning of a living organism, also contain nitrogen frameworks [1][2]. Besides that, nitrogen-containing compounds are widely used in medicine as antibiotics

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

• Andreas Wiest Pavel Kielkowski LMU Munich, Department of Chemistry, Butenandtstr. 5-13, 81377 Munich, Germany 10.3762/bjoc.20.199 Abstract Identification of interactions between proteins and natural products or similar active small molecules is crucial for understanding of their mechanism of

• ; Introduction Natural products (NPs) have been pivotal for the development of modern medicine accompanying humans from the prehistorical age [1]. In the last century, NPs became the main source of the active scaffolds for the pharmaceutical industry with focus on principle of one compound, one target, and one

• field have the potential to facilitate this advancement. Overall chemical proteomics strategy to identify protein targets of natural products (NPs) and similar active small compounds. The example protein (blue) is an AlphaFold v2.0-generated prediction of bovine serum albumin (BSA) [23][24]. A) Design

Selective hydrolysis of α-oxo ketene N,S-acetals in water: switchable aqueous synthesis of β-keto thioesters and β-keto amides

• Haifeng Yu,
• Wanting Zhang,
• Xuejing Cui,
• Zida Liu,
• Xifu Zhang and
• Xiaobo Zhao

Beilstein J. Org. Chem. 2024, 20, 2225–2233, doi:10.3762/bjoc.20.190

• structural characters and multiple good reactivities [1][2][3][4]. Both β-keto thioesters [5][6][7][8][9][10][11][12] and β-keto amides [13][14][15][16][17][18][19][20][21][22] have served as useful synthetic intermediates for the synthesis of a range of potent natural products. Therefore, much effort has

Heterocycle-guided synthesis of m-hetarylanilines via three-component benzannulation

• Andrey R. Galeev,
• Maksim V. Dmitriev,
• Alexander S. Novikov and
• Andrey N. Maslivets

Beilstein J. Org. Chem. 2024, 20, 2208–2216, doi:10.3762/bjoc.20.188

• (Figure 1). On the other hand, 3,5-diarylanilines can be regarded as meta-terphenyls which are of great interest for material and coordination chemistry [5][6][7][8][9][10][11][12][13][14][15][16]. Moreover, compounds with diverse bioactivities and natural products contain the meta-terphenyl moiety as a

Natural resorcylic lactones derived from alternariol

• Joachim Podlech

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

• 9-O-methyl ether, altenusin, dehydroaltenusin, altertenuol, and altenuene) were frequently found and isolated as fungal contaminants in food and feed and have been investigated in significant detail, further metabolites, which were much more rarely found as natural products, similarly show

• . Derivatives formed through metabolization in the human body (or in animals) are only covered if the respective metabolites were similarly identified as natural products. A thorough survey of the literature revealed (at now) 127 natural products to be classified as natural resorcylic lactones derived from

• 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

O,S,Se-containing Biginelli products based on cyclic β-ketosulfone and their postfunctionalization

• Kateryna V. Dil and
• Vitalii A. Palchykov

Beilstein J. Org. Chem. 2024, 20, 2143–2151, doi:10.3762/bjoc.20.184

• organic and medicinal chemists. DHPMs are found in a variety of marine-sourced alkaloids, which are essential for creating biologically active natural products [10]. Some of the DHPM derivatives are also known as functional polymers, adhesives, and fabric dyes [8][12]. In recent decades, the scope of the

Diastereoselective synthesis of highly substituted cyclohexanones and tetrahydrochromene-4-ones via conjugate addition of curcumins to arylidenemalonates

• Deepa Nair,
• Abhishek Tiwari,
• Banamali Laha and
• Irishi N. N. Namboothiri

Beilstein J. Org. Chem. 2024, 20, 2016–2023, doi:10.3762/bjoc.20.177

• considerable interest in the stereoselective synthesis of the cyclohexanone skeleton as it constitutes the core structure in many natural products and pharmaceutical drugs [1][2]. Garsubellin A with a cyclohexanone skeleton is a potent inducer of choline acetyltransferase (ChAT) and could be used for the

Harnessing the versatility of hydrazones through electrosynthetic oxidative transformations

• Aurélie Claraz

Beilstein J. Org. Chem. 2024, 20, 1988–2004, doi:10.3762/bjoc.20.175

• as pivotal element during the total synthesis of natural products. Therefore, the development of mild and efficient methods to access this motif from readily available starting materials is a never-ending quest. With the aim to propose an alternative to the classical olefination of carbonyls through

Allostreptopyrroles A–E, β-alkylpyrrole derivatives from an actinomycete Allostreptomyces sp. RD068384

• Marwa Elsbaey,
• Naoya Oku,
• Mohamed S. A. Abdel-Mottaleb and
• Yasuhiro Igarashi

Beilstein J. Org. Chem. 2024, 20, 1981–1987, doi:10.3762/bjoc.20.174

• many marine natural products [6][7], pyrroles substituted with long hydrocarbon chains (pyrrole lipids) are seldomly isolated, and their presence is limited to certain marine organisms [8]. A series of 3-alkylpyrrole-2-carbaldehydes/carboxylic acid/methylcarboxylate was reported from the marine sponge

• of this specific composition have not been reported. The pyrrole-2-carboxyl skeleton is a recurring framework in pyrrolic natural products including microbial pyrrolostatin and aminocoumarin antibiotics [2], plant-derived brachystemidines [26], and lamellarins from marine invertebrates [6] (Figure

Regioselective alkylation of a versatile indazole: Electrophile scope and mechanistic insights from density functional theory calculations

• Pengcheng Lu,
• Luis Juarez,
• Paul A. Wiget,
• Weihe Zhang,
• Krishnan Raman and
• Pravin L. Kotian

Beilstein J. Org. Chem. 2024, 20, 1940–1954, doi:10.3762/bjoc.20.170

• heterocycles with interesting biological and medicinal properties. Indazole, also called benzpyrazole, is a heterocyclic organic compound commonly found as a structural motif in natural products, pharmaceuticals, agrochemicals, and bioactive compounds [1][2][3][4][5][6]. Indazole-containing compounds possess a

Solvent-dependent chemoselective synthesis of different isoquinolinones mediated by the hypervalent iodine(III) reagent PISA

• Ze-Nan Hu,
• Yan-Hui Wang,
• Jia-Bing Wu,
• Ze Chen,
• Dou Hong and
• Chi Zhang

Beilstein J. Org. Chem. 2024, 20, 1914–1921, doi:10.3762/bjoc.20.167

• is an important heterocyclic framework in natural products and biologically active molecules, and the efficient synthesis of this structural motif has received much attention in recent years. Herein, we report a (phenyliodonio)sulfamate (PISA)-mediated, solvent-dependent synthesis of different

• ); isoquinolinone; solvent-dependence; Introduction Isoquinolinone is an important heterocyclic structure found in many natural products and biologically active compounds, including pharmaceuticals [1]. For instance, lycoricidine, found in the medicinal plant Lycoris radiata, may inhibit the MCPyV LT protein

• . Selected natural products, pharmaceuticals, and biologically active compounds having an isoquinolinone scaffold. Chemoselective and PISA-mediated, solvent-controlled synthesis of different isoquinolinone derivatives 2 and 3. Substrate scope for the synthesis of 4-substituted isoquinolinones 2. Reaction

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

• avoid opening of the furan ring. The authors explored the substrate scope by using different isocyanides and 2-aminoazines, obtaining 6 potentially bioactive pseudo natural products 35 in low to moderate yield (21–67%). Bräse et al. [45] reported the possibility of exploiting the GBB-3CR to synthesize a

Discovery of antimicrobial peptides clostrisin and cellulosin from Clostridium: insights into their structures, co-localized biosynthetic gene clusters, and antibiotic activity

• Moisés Alejandro Alejo Hernandez,
• Katia Pamela Villavicencio Sánchez,
• Rosendo Sánchez Morales,
• Karla Georgina Hernández-Magro Gil,
• David Silverio Moreno-Gutiérrez,
• Eddie Guillermo Sanchez-Rueda,
• Yanet Teresa-Cruz,
• Brian Choi,
• Armando Hernández Garcia,
• Alba Romero-Rodríguez,
• Oscar Juárez,
• Siseth Martínez-Caballero,
• Mario Figueroa and
• Corina-Diana Ceapă

Beilstein J. Org. Chem. 2024, 20, 1800–1816, doi:10.3762/bjoc.20.159

• associated bioactive peptides. Keywords: antimicrobials; genome mining; lantibiotics; lanthipeptides; multi-drug resistant bacteria; natural products; Introduction Antimicrobial resistance (AMR) is a significant public health challenge. Only in 2019, there were 4.95 million deaths associated with AMR [1

• are derived from bacterial natural products (NPs), which have proven to be a valuable source of antimicrobial agents. During the latter part of the 20th century, the discovery of NPs was hindered by the limitation of traditional methods, which often led to the rediscovery of previously identified NPs

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

• biosynthetic enzymatic transformations with chemical conversions. This review focuses on the total synthesis of natural products and classifies the enzymatic reactions into three categories. The total synthesis of five natural products: cotylenol, trichodimerol, chalcomoracin, tylactone, and saframycin A, as

• approach" merging efficient enzymatic synthesis – traditionally employed in the biosynthesis of natural products by microorganisms and plants – with precise chemical synthesis conducted by chemists. Chemo-enzymatic total syntheses reported recently fall into three main categories based on the purpose for

• stereoselective cyclization reactions. This review aims to provide an overview of these approaches and parallel comparisons with original biosynthetic pathways by highlighting five examples of chemo-enzymatic total syntheses of natural products reported since 2017. The examples are the synthesis of cotylenol (1

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

• within the context of ribosomally synthesised and post-translationally modified peptide (RiPP) natural products. Methyltransferases play a pivotal role in the biosynthesis of diverse natural products with unique chemical structures and bioactivities. They are highly chemo-, regio-, and stereoselective

• bioactivities [1]. RiPP natural products are typically encoded in a biosynthetic gene cluster (BGC) and produced following defined biosynthetic rules. Initially, a precursor peptide encompassing a core peptide, a leader part and/or a follower part, is synthesised at the ribosome. Next, distinct maturases

• resulting natural products with a spectrum of chemical complexity, contributing to the broad range of biological activities exhibited by RiPPs. Bioactivities attributed to RiPPs include a wide range of effects, such as antibiotic, antifungal, antiviral, antiparasitic, antitumour, analgesic, anti

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

• novelty. In this review, we summarize the distribution of Microbulbifer bacteria, activities of the various polymer degrading enzymes that these bacteria produce, and an up-to-date summary of the natural products that have been isolated from Microbulbifer strains. We argue that these bacteria have been

• hiding in plain sight, and contemporary efforts into their genome and metabolome mining are going to lead to a proliferation of Microbulbifer-derived natural products in the future. We also describe, where possible, the ecological interactions of these bacteria in marine microbiomes. Keywords: bacteria

• ; hydrolases; marine natural products; Introduction Microbial natural products represent an important reservoir for drug discovery and along with their (semi)synthetic derivatives, constitute a major component of the contemporary pharmaceutical arsenal. Their thusly validated utility is juxtaposed against the

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

• discovering diverse natural products from bacteria and fungi. In plants, this approach is often more limited due to the lack of available annotated genomes and transcriptomes combined with a less consistent clustering of biosynthetic genes. The recently identified burpitide class of ribosomally synthesized

• and post-translationally modified peptide (RiPP) natural products offer a valuable opportunity for bioinformatics-guided discovery in plants due to their short biosynthetic pathways and gene encoded substrates. Using a high-throughput approach to assemble and analyze 700 publicly available raw

• transcriptomic data sets, we uncover the potential distribution of split burpitide precursor peptides in Streptophyta. Metabolomic analysis of target plants confirms our bioinformatic predictions of new cyclopeptide alkaloids from both known and new sources. Keywords: burpitides; natural products; plants; RiPPs