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

• ; 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

Catalysing (organo-)catalysis: Trends in the application of machine learning to enantioselective organocatalysis

• Stefan P. Schmid,
• Leon Schlosser,
• Frank Glorius and
• Kjell Jorner

Beilstein J. Org. Chem. 2024, 20, 2280–2304, doi:10.3762/bjoc.20.196

• mechanical calculations is also increasing, such as a data set that considers propargylation reactions catalysed by bipyridine N,N’-dioxide-derived scaffolds, created by Wheeler and co-workers using their AARON toolkit [21][114][115][116]. Similar to experimental data, computational data sets also lead to

Deuterated reagents in multicomponent reactions to afford deuterium-labeled products

• Kevin Schofield,
• Shayna Maddern,
• Yueteng Zhang,
• Grace E. Mastin,
• Rachel Knight,
• Wei Wang,
• James Galligan and
• Christopher Hulme

Beilstein J. Org. Chem. 2024, 20, 2270–2279, doi:10.3762/bjoc.20.195

• ethyl acetoacetate with aldehyde and ammonia to give 1,4-dihydropyridine [53]. Such scaffolds are seen in several FDA-approved calcium channel blockers including nifedipine, nicardipine and nimodipine and three site-specific deuterated analogs of approved 1,4-dihydropyridines (DHPs) are presented

Finding the most potent compounds using active learning on molecular pairs

• Zachary Fralish and
• Daniel Reker

Beilstein J. Org. Chem. 2024, 20, 2152–2162, doi:10.3762/bjoc.20.185

• at identifying more potent inhibitors compared to the standard exploitative active learning implementations of Chemprop, XGBoost, and Random Forest. The ActiveDelta approach is also able to identify more chemically diverse inhibitors in terms of their Murcko scaffolds. Finally, deep models such as

• molecules based on their Murcko scaffolds, possibly due to the ability to learn property differences rather than exploiting analog identification. Finally, the acquired data enabled the Chemprop algorithm to predict the most promising compounds more accurately in challenging time-split test datasets. Taken

• of unique Murcko scaffolds in the set of molecules selected by the different approaches whose Ki values are within the top ten percentile of the most potent compounds in the complete learning set), AD-CP selected more distinct hit scaffolds than Chemprop (Figure 2E, p = 5e − 25 at 100 iterations) but

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

• reaction is the traditional method for synthesizing DHPM scaffolds, but it faces limitations in product diversity. To overcome these challenges, two main strategies have been developed. The first strategy involves modifying the conventional components of the Biginelli chemistry, while the second focuses on

Efficacy of radical reactions of isocyanides with heteroatom radicals in organic synthesis

• Akiya Ogawa and
• Yuki Yamamoto

Beilstein J. Org. Chem. 2024, 20, 2114–2128, doi:10.3762/bjoc.20.182

• yields the sequential addition products 9 in moderate to excellent yields (Scheme 5) [33]. The product can be used as a precursor for the carbapenem scaffold, one of the basic scaffolds of antibiotics. Thermal or photoirradiated decomposition of organotellurium compounds generates carbon radicals that

• via the radical addition of hetroatom radicals to 2-isocyanobiphenyl, another pathway to form phenanthridine scaffolds is the radical reaction of 2-aminobiaryls with free isocyanides. For example, oxidative generation of amino radicals from 2-aminobiaryls followed by intermolecular addition to

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

• Medicus (Figure 1) [9]. Therefore, in recent years, isoquinolinone derivatives have attracted considerable attention, and successful synthetic methods involving the isoquinolinone framework have been reported. A number of appealing methods for the synthesis of isoquinolinone scaffolds using transition

• metal reagents, including cobalt [10], copper [11], rhodium [12][13][14], palladium [15][16][17], silver [18], and gold [19] catalysts, have been reported. However, compared to the widespread use of metal catalysts, the synthesis of isoquinolinone scaffolds mediated by environmentally friendly

2-Heteroarylethylamines in medicinal chemistry: a review of 2-phenethylamine satellite chemical space

• Carlos Nieto,
• Alejandro Manchado,
• Ángel García-González,
• David Díez and
• Narciso M. Garrido

Beilstein J. Org. Chem. 2024, 20, 1880–1893, doi:10.3762/bjoc.20.163

• outline which structural motifs are included in this work and which ones are discarded (Scheme 1). In detail, this review encompasses bioactive compounds which satisfy: flexible, open chain-substituted 5/6-membered heteroaromatic scaffolds with decorations, condensed heteroaromatic or polycyclic systems

• specific heteroaromatic subsection indicates no biologically relevant data has been reported up to date. Review 2‑Heteroarylethylamine scaffolds of biological importance Six-membered heteroaromatic rings Pyridines: IL4I1, interleukin-4 induced gene 1, encodes ʟ-phenylalanine oxidase IL4I1 present in the

• observed for this family of tetrazole scaffolds. Conclusion The present review focuses on an examination of the expanded 2-phenethylamine chemical space, highlighting heteroaromatic structures with reported pharmacological profiles. The close inspection of each of the phenyl and other heteroaryl ring

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

• achieved during the last five years, and classifies them into five categories: synthetic methods, building blocks, scaffolds, biological activities and physical properties. Keywords: Groebke–Blackburn–Bienaymé reaction; multicomponent reactions; heterocycles; imidazo[1,2-a]pyridines; isocyanides

• on biological activities or photophysical properties (i.e., fluorescence) of GBB adducts. Another advantage is that, by replacing the amidine component (classically 2-aminopyridines) with other heterocycles, different scaffolds are obtained, and this is extremely efficient in diversity-oriented

• synthesis (DOS) where a single methodology should generate diverse scaffolds. This comprehensive review focuses on all these aspects, and has been divided into five chapters, describing, respectively: a) efforts to develop new and milder reaction conditions; b) the use of new building blocks; c) the

Synthesis and characterization of 1,2,3,4-naphthalene and anthracene diimides

• Adam D. Bass,
• Daniela Castellanos,
• Xavier A. Calicdan and
• Dennis D. Cao

Beilstein J. Org. Chem. 2024, 20, 1767–1772, doi:10.3762/bjoc.20.155

• Adam D. Bass Daniela Castellanos Xavier A. Calicdan Dennis D. Cao Chemistry Department, Macalester College, 1600 Grand Avenue, Saint Paul, Minnesota 55105, United States 10.3762/bjoc.20.155 Abstract We report the synthesis and characterization of naphthalene and anthracene scaffolds end-capped by

• described isomers and expand the toolbox of electron-deficient aromatic compounds available to organic materials chemists. Keywords: electron acceptors; organic materials; polycyclic aromatic hydrocarbons; Introduction Aromatic diimides are ubiquitous molecular scaffolds that have served as the basis for

• -) derivatization of aromatic scaffolds because it can be exploited to stabilize the longer (hetero)acenes. In contrast to cata-benzannulation, cata-imide-annulation does not perturb aromaticity patterns and further introduces inductive stabilization of frontier MO levels, which has enabled the production of n-type

Syntheses and medicinal chemistry of spiro heterocyclic steroids

• Laura L. Romero-Hernández,
• Ana Isabel Ahuja-Casarín,
• Penélope Merino-Montiel,
• Sara Montiel-Smith,
• José Luis Vega-Báez and
• Jesús Sandoval-Ramírez

Beilstein J. Org. Chem. 2024, 20, 1713–1745, doi:10.3762/bjoc.20.152

• the future design of more potent and selective drugs. Keywords: biological activity; drug development; heterocycle; spiro steroid; synthetic transformations; Introduction Small-ring heterocycles constitute valuable scaffolds in medicinal chemistry for generating biologically active derivatives

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

• using an enzyme or at what stage in a synthesis the enzyme is employed: 1) regio- and stereoselective late-stage functionalization of core scaffolds, 2) in situ generation of highly reactive intermediates, and 3) the one-step construction of macrocyclic or fused multicyclic scaffolds via regio- and

• 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

• -enzymatic synthesis, featuring the late-stage enzymatic oxidation of chemically synthesized intricate scaffolds are attracting increasing attention. A collaboration between Stoltz and Arnold led to the pioneering accomplishment in the total synthesis of nigelladine A by exploiting P450 enzymes engineered

Generation of multimillion chemical space based on the parallel Groebke–Blackburn–Bienaymé reaction

• Evgen V. Govor,
• Vasyl Naumchyk,
• Ihor Nestorak,
• Dmytro S. Radchenko,
• Dmytro Dudenko,
• Yurii S. Moroz,
• Olexiy D. Kachkovsky and
• Oleksandr O. Grygorenko

Beilstein J. Org. Chem. 2024, 20, 1604–1613, doi:10.3762/bjoc.20.143

• , extended Bemis–Murcko scaffolds were generated by cutting off the side chains of the molecules and retaining ring systems and linkers between them. After removal of duplicates, Tanimoto similarity coefficients were calculated for each pair of the molecules in the compared databases (T = 1 and 0 for similar

• space were found in the ChEMBL database, and some of them had high potency against various biological targets. Marketed drugs comprising imidazo[1,2-a]azine scaffolds. Yields of library members 4 synthesized using both Sc(OTf)3 and TsOH as the catalysts. Amino heterocycles 1{1–27} demonstrating poor

• yellow. Distribution of maximal values among pairwise-calculated Tanimoto similarities T (MFP2 fingerprints [46]) of extended Bemis–Murcko scaffolds for the generated chemical space members (5.60 Mln. scaffolds) to the extended Bemis–Murcko scaffolds of A) ChEMBL compounds (v. 33); B) PubChem compounds

Supramolecular assemblies of amphiphilic donor–acceptor Stenhouse adducts as macroscopic soft scaffolds

• Ka-Lung Hung,
• Leong-Hung Cheung,
• Yikun Ren,
• Ming-Hin Chau,
• Yan-Yi Lam,
• Takashi Kajitani and
• Franco King-Chi Leung

Beilstein J. Org. Chem. 2024, 20, 1590–1603, doi:10.3762/bjoc.20.142

• revealed by X-ray diffraction analysis. Upon visible-light irradiation, significant transformations of the DA geometry enabled transformations of the supramolecular assemblies on a microscopic scale, subsequently disassembling macroscopic soft scaffolds of DAs. The current work shows promising use for the

• fabrication of visible-light-controlled macroscopic scaffolds, offering the next generation of biomedical materials with visible-light-controlled microenvironments and future soft-robotic systems. Keywords: donor–acceptor Stenhouse adduct; photoresponsive molecular amphiphile; supramolecular transformation

• are available. UV-light-driven supramolecular transformations on a macroscopic length scale were pioneered by Leung and Feringa [42][43]. Besides, we recently reported the first indigo amphiphiles in fabrication of macroscopic soft scaffolds with photoshrinking properties as a smart functional cell

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

• ]. 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

Primary amine-catalyzed enantioselective 1,4-Michael addition reaction of pyrazolin-5-ones to α,β-unsaturated ketones

• Pooja Goyal,
• Akhil K. Dubey,
• Raghunath Chowdhury and
• Amey Wadawale

Beilstein J. Org. Chem. 2024, 20, 1518–1526, doi:10.3762/bjoc.20.136

• fascinating but at the same time challenging. Pyrazoles [4][5][6][7], benzofurans [34], and indoles [35][36] are popular scaffolds as they are prevalent in many bioactive molecules. Compounds bearing both pyrazole and indole moieties or pyrazole and benzofuran moieties (Figure 1) are highly attractive since

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

• . Spirobiindane-based salts C emerged as promising alternative for quaternary ammonium salt scaffolds recently [40][41] and were also the catalysts of choice in our recently developed β-selective allenoate addition of isoxazolidinones 2 (compare with Scheme 1B [18]). Unfortunately, these catalysts were found to

Electrophotochemical metal-catalyzed synthesis of alkylnitriles from simple aliphatic carboxylic acids

• Yukang Wang,
• Yan Yao and
• Niankai Fu

Beilstein J. Org. Chem. 2024, 20, 1497–1503, doi:10.3762/bjoc.20.133

• readily converted into a myriad of functional groups including carbonyls, amines, imines, and a variety of heterocyclic scaffolds with well-established procedures [4][5][6][7][8][9]. In particular, tertiary nitriles are common structural motifs in many bioactive compounds and are widely used as

Challenge N- versus O-six-membered annulation: FeCl₃-catalyzed synthesis of heterocyclic N,O-aminals

• Giacomo Mari,
• Lucia De Crescentini,
• Gianfranco Favi,
• Fabio Mantellini,
• Diego Olivieri and
• Stefania Santeusanio

Beilstein J. Org. Chem. 2024, 20, 1412–1420, doi:10.3762/bjoc.20.123

• Abstract A new class of heterocyclic N,O-aminal and hemiaminal scaffolds was successfully obtained by means of a three-component reaction (3-CR) of 1,2-diaza-1,3-dienes (DDs), α-aminoacetals and iso(thio)cyanates. These stable imine surrogates are generated from key-substituted (thio)hydantoin

Synthesis of substituted triazole–pyrazole hybrids using triazenylpyrazole precursors

• Simone Gräßle,
• Laura Holzhauer,
• Nicolai Wippert,
• Olaf Fuhr,
• Martin Nieger,
• Nicole Jung and
• Stefan Bräse

Beilstein J. Org. Chem. 2024, 20, 1396–1404, doi:10.3762/bjoc.20.121

• addition, the compatibility of the method with solid-phase synthesis is shown exemplarily. Keywords: azide; click reaction; CuAAC; pyrazole; triazene; triazole; Introduction Nitrogen-containing heterocycles are central scaffolds in medicinal chemistry and are incorporated in most small-molecule drugs [1

• ][2]. We are interested in feasible strategies to synthesize nitrogen-rich heterocyclic scaffolds that can extend the currently available libraries with new drug-like molecules. Our past work on pyrazoles [3][4][5][6] and triazoles [7][8][9][10][11] motivated us to search for suitable and versatile

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

• scaffolds Burroughs et al. developed an intramolecular Cannizzaro-based cascade synthesis for the construction of 8-membered cycloocta-2,5-dienones [91]. The initial formation of the organolithium species 82 formed by acetylide addition to the ortho-substituted bromoaldehyde 81, was subjected to halogen

Generation of alkyl and acyl radicals by visible-light photoredox catalysis: direct activation of C–O bonds in organic transformations

• Mithu Roy,
• Bitan Sardar,
• Itu Mallick and
• Dipankar Srimani

Beilstein J. Org. Chem. 2024, 20, 1348–1375, doi:10.3762/bjoc.20.119

• the SET transfer process of PPh3 and quenching of photoexcited *[Ir(dF(CF3)ppy)2(bpy)]PF6 by PPh3. Fluorinated organic compounds are widely used in pharmaceuticals and pesticides. Therefore, it is crucial to diversify organic scaffolds by addition of fluorinated groups or by defluorination. In 2020

Computation-guided scaffold exploration of 2E,6E-1,10-trans/cis-eunicellanes

• Zining Li,
• Sana Jindani,
• Volga Kojasoy,
• Teresa Ortega,
• Erin M. Marshall,
• Khalil A. Abboud,
• Sandra Loesgen,
• Dean J. Tantillo and
• Jeffrey D. Rudolf

Beilstein J. Org. Chem. 2024, 20, 1320–1326, doi:10.3762/bjoc.20.115

• recent discovery of the aridacins, which transforms a 2E-cis-eunicellane into a 6/7/5-tricyclic diterpene via a cytochrome P450 [12]. Coincidentally, these reactive skeletons also provide chemists the ability to access synthetically challenging scaffolds with simple electrophilic cyclizations. With

Phenotellurazine redox catalysts: elements of design for radical cross-dehydrogenative coupling reactions

• Alina Paffen,
• Christopher Cremer and
• Frederic W. Patureau

Beilstein J. Org. Chem. 2024, 20, 1292–1297, doi:10.3762/bjoc.20.112

• , which exploit the redox flexibility of tellurium, especially in the context of phenotellurazine scaffolds. Notably, we showed that phenotellurazine PTeZ1 could significantly catalyze the cross-dehydrogenative phenothiazination of phenols bearing challenging electron-withdrawing substituents under a

The Ugi4CR as effective tool to access promising anticancer isatin-based α-acetamide carboxamide oxindole hybrids

• Carolina S. Marques,
• Aday González-Bakker and
• José M. Padrón

Beilstein J. Org. Chem. 2024, 20, 1213–1220, doi:10.3762/bjoc.20.104

• chemists regarding process formation of new bonds and synthesis of new scaffolds. In drug discovery and development, medicinal chemists struggle everyday towards the creation of new synthetic methods, driven by the increasing complexity of the molecules and taking into consideration economic and social

• . Generally, the biological results point out the relevance of these isatin hybrids as privileged scaffolds for the development of new therapeutically relevant substances. Conclusion Two new families of α-acetamide carboxamide oxindole and isatin hybrids were synthesized efficiently using the sustainable and