Multicomponent reactions driving the discovery and optimization of agents targeting central nervous system pathologies

• Lucía Campos-Prieto,
• Aitor García-Rey,
• Eddy Sotelo and
• Ana Mallo-Abreu

Beilstein J. Org. Chem. 2024, 20, 3151–3173, doi:10.3762/bjoc.20.261

• , inspired by natural alkaloids such as deoxyvasicinone and evodiamine with promising inhibition of ChEs and antioxidant and neuroprotective effects against glutamate-induced OS in HT-22 cells [41]. In 2016, Dgachi et al. [42] applied a Knoevenagel-based multicomponent approach to further explore the

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

• bioinformatic analysis. Their updated PRISM 4 pipeline outperformed antiSMASH5 and was able to predict the chemical structures of a wide variety of secondary metabolites [90]. Notably, the repertoire of PRISM 4 spans beyond NRPs and PKs and includes alkaloids, terpenoids, aminoglycosides, nucleosides, etc

• . Structure prediction of natural products other than NRPs and PKs has historically progressed slower. However, it was not due to a lack of data. Indeed, terpenoids and alkaloids are the two largest families of natural products in plants and also represent a sizable minority in microorganisms. The lagging

• information that are available for terpenoids and alkaloids biosynthesis. Data standardization (albeit a tedious and labor-intensive task) may be the final roadblock between AI and generalizable chemical structure metagenomics [91]. Conclusion and Outlook Microorganisms produce specialized metabolites to

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

• of 1-fluorobis(phenylsulfonyl)methane (FBSM) to α,β-unsaturated ketones with cinchona alkaloids [9]. Fluorinated Michael acceptors usually contain one fluorine atom or a trifluoromethyl group in the structure [10][11][12]. There are also known examples of gem-difluoroalkenes being used as Michael

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

• indole alkaloids. Here, we develop a novel approach for the one-pot multistep synthesis of different spiro[indole-isoquinolines]. The protocol proposed involves the visible light mediated oxidation of N-aryl tertiary amines using bromochloroform with the generation of a reactive iminium species, which

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

• -synthesized and posttranslationally modified peptides, polyketides, alkaloids, aromatics, and terpenoids. This generation of young investigators will continue to shape the field of natural products for years to come. We pass on our greatest thanks to all the contributors to this special thematic issue. We

Efficient modification of peroxydisulfate oxidation reactions of nitrogen-containing heterocycles 6-methyluracil and pyridine

• Alfiya R. Gimadieva,
• Yuliya Z. Khazimullina,
• Aigiza A. Gilimkhanova and
• Akhat G. Mustafin

Beilstein J. Org. Chem. 2024, 20, 2599–2607, doi:10.3762/bjoc.20.219

• , including drugs and alkaloids [8]. Several drugs are known to contain the 2-pyridone structure, such as the cardiotonic drugs milrinone (Figure 1c) and amrinone (Figure 1d) [9][10], as well as the antibiotic pilicide (Figure 1e) [11][12]. As described in [13] during preliminary experiments, it was

Photoredox-catalyzed intramolecular nucleophilic amidation of alkenes with β-lactams

• Valentina Giraldi,
• Giandomenico Magagnano,
• Daria Giacomini,
• Pier Giorgio Cozzi and
• Andrea Gualandi

Beilstein J. Org. Chem. 2024, 20, 2461–2468, doi:10.3762/bjoc.20.210

• investigated whether this protocol could be adapted to other lactams, allowing for a practical synthesis of bicyclic structures. The resulting bicyclic lactam substrate could serve as a foundation to access pyrroloisoquinoline alkaloids [50][51]. The model substrate 14 was synthesized in a two-step process

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

• ; rearrangement; Introduction Nitrogen-containing organic compounds (sometimes referred to as alkaloids due to their basic properties) are of critical importance in medicinal chemistry because of their unique binding properties to biomolecules [1]. Out of 55 drug candidates, approved by the FDA in 2023, 28 (51

• %) are nitrogen-containing organic compounds, with many featuring amino groups adjacent to a stereogenic centre. Some reports suggest that 75% of all FDA-approved compounds are alkaloids [2]. The industrial production of amines on a million-ton scale underscores the significance of methods for their

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

Novel oxidative routes to N-arylpyridoindazolium salts

• Oleg A. Levitskiy,
• Yuri K. Grishin and
• Tatiana V. Magdesieva

Beilstein J. Org. Chem. 2024, 20, 1906–1913, doi:10.3762/bjoc.20.166

• popular structural motif of many biologically active alkaloids and other molecules of therapeutic interest [1][2][3][4]. Polycyclic N-heteroaromatics also often exhibit intercalating properties [5][6][7][8][9]. Pyridoindazolium salts can be considered as one of the typical representatives of polyfused N

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

• -aminoimidazole moiety can be found in different alkaloids isolated from sponges and exhibits useful bioactive properties. The methodology employed by the authors to assemble C4/C5-functionalized 2-aminoimidazoles 49 exploited a Mannich condensation followed by an iodoxybenzoic acid (IBX) and N-iodophthalimide

Harnessing unprotected deactivated amines and arylglyoxals in the Ugi reaction for the synthesis of fused complex nitrogen heterocycles

• Javier Gómez-Ayuso,
• Pablo Pertejo,
• Tomás Hermosilla,
• Israel Carreira-Barral,
• Roberto Quesada and
• María García-Valverde

Beilstein J. Org. Chem. 2024, 20, 1758–1766, doi:10.3762/bjoc.20.154

• piperazinoquinazoline derivatives, a core found in fungal metabolites [25][26], systems with promising antitumour activity [27], as well as dipyrrolopiperazinone derivatives, substructure found in some alkaloids such as dibromophakellin or the palau’amine [28], which possess immunosuppressive and cytotoxic properties

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

• families, known as bistetrahydroisoquinoline (THIQ) alkaloids, share a highly functionalized pentacyclic scaffold with different aromatic ring oxidation states and sidechain structures [90][91][92][93]. The biosynthetic mechanism of 5 has been extensively studied by gene disruption and reconstruction of in

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

• classes of natural products isolated from Microbulbifer to date include alkaloids [15], fatty acid and polyketides [16][17], and non-ribosomally synthesized peptides [3][4][7]. These findings validate the potential for secondary metabolite discovery from Microbulbifer genus. This review will cover the

• from this bacterium by comparison of their 1H NMR and MS data with those reported in literature (Figure 7). Alkaloids Three new alkanoyl imidazoles 21–23 (Figure 8) were isolated from a culture extract of a Microbulbifer bacterium isolated from a scleractinian coral [15]. Their structures were

• of 32 natural products, including NRPSs, PKS, parabens, and alkaloids, have been isolated and identified from Microbulbifer bacteria. Based on the growing genomic data, it is unquestionable that the Microbulbifer genus is an untapped resource for natural products. The number of molecules described

Regio- and stereochemical stability induced by anomeric and gauche effects in difluorinated pyrrolidines

• Ana Flávia Candida Silva,
• Francisco A. Martins and
• Matheus P. Freitas

Beilstein J. Org. Chem. 2024, 20, 1572–1579, doi:10.3762/bjoc.20.140

• Lewis interactions from a natural bond orbital perspective. Keywords: anomeric effect; fluoropyrrolidine; gauche effect; stereochemistry; Introduction The pyrrolidine ring structure is prevalent in numerous natural alkaloids and is an important feature of the proline and hydroxyproline residues that

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

• 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

• ]. These RiPP natural products encompass a wide range of structural scaffolds including cyclopeptide alkaloids that contain a phenolic ether-linkage and the lyciumin-type peptides that are composed of a crosslink between the Trp-indole-N and the carbon in another amino acid side chain or peptide backbone

• (HMM) for split burpitide precursor peptides. Using this approach, we assembled 700 transcriptomes and used predicted precursor peptide diversity for target discovery of new cyclopeptide alkaloids. Additionally, metabolomic analysis revealed the tissue distribution of these molecules across select

Towards an asymmetric β-selective addition of azlactones to allenoates

• Behzad Nasiri,
• Ghaffar Pasdar,
• Paul Zebrowski,
• Katharina Röser,
• David Naderer and
• Mario Waser

Beilstein J. Org. Chem. 2024, 20, 1504–1509, doi:10.3762/bjoc.20.134

• these catalysts (Table 1, entries 1–4, other cinchona alkaloid-based ammonium salt derivatives as well as free base cinchona alkaloids were tested too but did not allow for any improvement). Using the established and commercially available Maruoka catalysts B1 and B2 [39] next turned out to be more

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

• -β-lactone core 73 (Scheme 21). An expedient use of the Cannizzaro reaction was exemplified in the noteworthy enantioselective synthesis towards the indole alkaloids 16-epivellosimine, (+)-polyneuridine, and (+)-macusine A as reported by Cook and coworkers [89]. This was effectively worked out from ᴅ

• intramolecular Cannizzaro reaction. Spiro-β-lactone-γ-lactam part of oxazolomycins via aldol crossed-Cannizzaro reaction. Synthesis of indole alkaloids via aldol crossed-Cannizzaro reaction. Aldol and crossed-Cannizzaro reaction towards the synthesis of ertuliflozin. Synthesis of cyclooctadieneones using a

Synthesis and optical properties of bis- and tris-alkynyl-2-trifluoromethylquinolines

• Stefan Jopp,
• Franziska Spruner von Mertz,
• Peter Ehlers,
• Alexander Villinger and
• Peter Langer

Beilstein J. Org. Chem. 2024, 20, 1246–1255, doi:10.3762/bjoc.20.107

• which can be found in several natural and synthetic products and many of them show interesting pharmacological properties [1][2][3]. Quinine, for example, is a widely known natural product which was first isolated from the cinchona tree besides many other quinoline-containing cinchona alkaloids [4]. It

Manganese-catalyzed C–C and C–N bond formation with alcohols via borrowing hydrogen or hydrogen auto-transfer

• Mohd Farhan Ansari,
• Atul Kumar Maurya,
• Abhishek Kumar and
• Saravanakumar Elangovan

Beilstein J. Org. Chem. 2024, 20, 1111–1166, doi:10.3762/bjoc.20.98

• interrupted BH approach using Mn26 (3 mol %) and t-BuOK (50 mol %) in toluene at 130 °C for 24 h (Scheme 67). Fascinatingly, this process was used to synthesize pharmacologically active compounds like vibrindole A and turbomycin B alkaloids and natural products like gramine and dipterine analogues. Discrete

Methodology for awakening the potential secondary metabolic capacity in actinomycetes

• Shun Saito and
• Midori A. Arai

Beilstein J. Org. Chem. 2024, 20, 753–766, doi:10.3762/bjoc.20.69

• ribosomal S12 protein mutation results in increased expression of translation factors, which leads to enhanced protein synthesis in secondary metabolism [47]. Liu et al. reported activation of the production of bohemamines 11–13, bacterial alkaloids containing a pyrrolizidine core with two unusual methyl

Chemical and biosynthetic potential of Penicillium shentong XL-F41

• Ran Zou,
• Xin Li,
• Xiaochen Chen,
• Yue-Wei Guo and
• Baofu Xu

Beilstein J. Org. Chem. 2024, 20, 597–606, doi:10.3762/bjoc.20.52

• investigations, accompanied by fermentation media optimization, of a newly isolated fungus, Penicillium shentong XL-F41, led to the isolation of twelve compounds. Among these are two novel indole terpene alkaloids, shentonins A and B (1 and 2), and a new fatty acid 3. Shentonin A (1) is distinguished by an

• polyketides, alkaloids, sterol derivatives, terpenoids, and macrolides, with polyketides and alkaloids comprising 40% and 32% of the total, respectively. Alkaloids are a diverse group of compounds with multiple pharmacological activities, including anti-inflammatory, antibacterial, antiviral, insecticidal

• , and anticancer properties [6][7]. Historically, most alkaloids were isolated from higher plants, with a significant number found in the Apocynaceae family. Notable examples such as vinblastine, vinorelbine, vincristine, and vindesine have gained prominence as effective anticancer drugs [6][7][8][9][10

Entry to new spiroheterocycles via tandem Rh(II)-catalyzed O–H insertion/base-promoted cyclization involving diazoarylidene succinimides

• Alexander Yanovich,
• Anastasia Vepreva,
• Ksenia Malkova,
• Grigory Kantin and
• Dmitry Dar’in

Beilstein J. Org. Chem. 2024, 20, 561–569, doi:10.3762/bjoc.20.48

• antagonist 7 [33], and aldosterone synthase inhibitor 8 [34]) as well as natural products (e.g., new alkaloids deoxytryptoquivaline and deoxynortryptoquivaline from fungus Aspergillus clavatonanicus identified as natural cardiomyocyte-protective agents against cold ischemic injury [35] and possible natural

Pseudallenes A and B, new sulfur-containing ovalicin sesquiterpenoid derivatives with antimicrobial activity from the deep-sea cold seep sediment-derived fungus Pseudallescheria boydii CS-793

• Zhen Ying,
• Xiao-Ming Li,
• Sui-Qun Yang,
• Hong-Lei Li,
• Xin Li,
• Bin-Gui Wang and
• Ling-Hong Meng

Beilstein J. Org. Chem. 2024, 20, 470–478, doi:10.3762/bjoc.20.42

• alkaloids containing an unprecedented spiro[bicyclo[2.2.2]octane-diketopiperazine] skeleton, chevalinulins A and B, and the first cytochalasin homodimer containing a thioether bridge, verruculoid A, were identified from deep-sea cold seeps-derived fungi and were described to have potent proangiogenic and

• our attention. Several meroterpenoids, alkaloids, polyketides, and sesquiterpenoids from the species displayed various biological properties including anti-inflammatory, antimicrobial, and cytotoxic activities [7][8][9]. In the present work, two rare new examples of sulfur-containing ovalicin

Photoinduced in situ generation of DNA-targeting ligands: DNA-binding and DNA-photodamaging properties of benzo[c]quinolizinium ions

• Julika Schlosser,
• Olga Fedorova,
• Yuri Fedorov and
• Heiko Ihmels

Beilstein J. Org. Chem. 2024, 20, 101–117, doi:10.3762/bjoc.20.11

• structurally related alkaloids berberine [61][62][63][64][65] and coralyne [36][66][67] have been shown already to act as efficient photosensitizers for DNA damage. To the best of our knowledge, however, benzo[c]quinolizinium derivatives have not been investigated with respect to their DNA-photodamaging