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

• Field (AEIF), which are calculated for each CPA substituent (R) by observing the electrostatic potential of a quarternary ammonium ion with the substituent of interest (NMe3R+). The authors performed unsupervised clustering on an in silico library to select a ‘Universal Training Set’ (UTS) consisting of

• implementations were chosen to tackle this problem. In 2022, Denmark and co-workers [132] (Figure 12) investigated a disulfonimide-catalysed atroposelective iodination with the intention of finding a general reaction procedure. After constructing an in silico library consisting of 1,478 catalysts, a universal

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

• (D-MPNN) Chemprop [20]. For our evaluation with tree-based models, we selected XGBoost [21] with readily available GPU acceleration [26]. Standard, single-molecule machine learning models were implemented using the single-molecule mode of Chemprop [12][27], XGBoost from the XGBoost library [22], and

Computational toolbox for the analysis of protein–glycan interactions

• Ferran Nieto-Fabregat,
• Maria Pia Lenza,
• Angela Marseglia,
• Cristina Di Carluccio,
• Antonio Molinaro,
• Alba Silipo and
• Roberta Marchetti

Beilstein J. Org. Chem. 2024, 20, 2084–2107, doi:10.3762/bjoc.20.180

Negishi-coupling-enabled synthesis of α-heteroaryl-α-amino acid building blocks for DNA-encoded chemical library applications

• Matteo Gasparetto,
• Balázs Fődi and
• Gellért Sipos

Beilstein J. Org. Chem. 2024, 20, 1922–1932, doi:10.3762/bjoc.20.168

• ; flow chemistry; Negishi; on-DNA chemistry; Introduction DNA-encoded chemical library (DEL) technology is a powerful tool for hit identification [1][2]. DELs are chemically synthesized libraries in which every member is covalently attached to a unique DNA sequence serving as a molecular “barcode” [3

• complexity of DELs, there is only limited opportunity to track the efficiency of individual reactions during library synthesis. Therefore, BBs need to pass validation before being used in library synthesis settings. For these bifunctional amino esters, we performed a three-step validation where they were

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

• reactions, if we exclude a 96-member library of GBB adducts reported very recently by Dömling et al. [9]. In this case, however, Sc(OTf)3 was used as the catalyst and the choice for ethylene glycol was dictated by the need to have a polar solvent with a high boiling temperature. Shankar et al., however

• . Brunschweiger et al. employed the compartmentation strategy to overcome synthetic problems related to the preparation of a DNA-encoded GBB library [17]. DNA-encoded libraries (DELs) are widely used in screening projects, allowing the synthesis of a huge number of compounds as pools, and the identification of

• cyclophanyl-imidazole-based library of ligands. The synthesis of ligands based on the [2.2]paracyclophane (PCP) moiety, thanks to its structural features and inherent planar chirality upon selective substitution, has been recently reviewed by the same author [46]. Starting from 4-formylcyclophane 37, a GBB

Hetero-polycyclic aromatic systems: A data-driven investigation of structure–property relationships

• Sabyasachi Chakraborty,
• Eduardo Mayo Yanes and
• Renana Gershoni-Poranne

Beilstein J. Org. Chem. 2024, 20, 1817–1830, doi:10.3762/bjoc.20.160

• , and contain nitrogen, boron, oxygen, and sulfur atoms. Using these building blocks, we generated a chemical library of cata-condensed hetero-PASs (cc-hPASs) ranging in size from 3- to 10-ring systems, by combining the rings according to the annulation types shown in Figure 1B. The number, type, and

• some of the building blocks contained in the COMPAS-2 library can only annulate linearly (specifically, cyclobutadiene, pyrazine, 1,4-diborinine, 1,4-dihydro-1,4-diborinine), this dataset shows a greater density of structures close to the “rod” vertex and along the “rod/disc” edge of the PMI plot

• distribution of the COMPAS-1 molecules (light blue) is contained within the distribution of the COMPAS-2 molecules (purple). In other words, the expansion of the building block library widens the property distributions towards both higher and lower energies, providing access to functional molecules with

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

• clinical strains isolated from patients in Mexico: S. epidermidis MIQ43 (multidrug-resistant clinical sample) (internal code from the MicroIQ laboratory library), and P. aeruginosa MIQPA25 [54] (multidrug-resistant clinical sample isolated from cystic fibrosis patients), and C. difficile R20291. All

Ugi bisamides based on pyrrolyl-β-chlorovinylaldehyde and their unusual transformations

• Alexander V. Tsygankov,
• Vladyslav O. Vereshchak,
• Tetiana O. Savluk,
• Serhiy M. Desenko,
• Valeriia V. Ananieva,
• Oleksandr V. Buravov,
• Yana I. Sakhno,
• Svitlana V. Shishkina and
• Valentyn A. Chebanov

Beilstein J. Org. Chem. 2024, 20, 1773–1784, doi:10.3762/bjoc.20.156

• University, Svobody sq., 4, 61022, Kharkiv, Ukraine 10.3762/bjoc.20.156 Abstract By one-pot four- and three-component Ugi reactions involving convertible isocyanides and unexplored pyrrole-containing β-chlorovinylaldehyde, a small library of 20 bisamides with unusual behavior in post-Ugi transformations was

• -4CR reaction and post-transformation of the corresponding bisamide 8c. Plausible transformation sequence of the formation of amides 10 and ketobisamides 12. Library of Ugi bisamides 5–8 containing a β-chlorovinyl fragment. Post-Ugi transformations of bisamides 5–8 under different conditions

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

• , such as a one-pot four-component synthesis and the use of ionic liquids as solvents [30]. Kanchithalaivan et al. [31] reported a library of 16-spiro pyrrolo[1,2-c][1,3]thiazoles of trans-androsterone and DHEA (49a and 49b, respectively). The syntheses were achieved through the 1,3-dipolar cycloaddition

• tolylhydrazonoyl chloride derivative 54 [35]. The reaction conducted in the presence of silver acetate at room temperature, achieved yields of 78–81% of the 16-spiropyrazolines 55a,b (Scheme 17). 6-Spiroimidazoline steroids In 2015, Dar’s group reported a small library of spiroimidazo[1,2-a]pyridines obtained

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

• -adapted CE was isolated from a fosmid genomic library of Microbulbifer thermotolerans DAU221 with a similar catalytic triad and expressed in E. coli [56]. Other enzymes Chondroitinases (ChSases) are enzymes that digest chondroitin sulfate chains to generate disaccharides. They can be classified into

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

• involving the use of Sc(OTf)3 and TsOH as the catalysts were tested on a broad substrate scope, and prevalence of the first method was clearly demonstrated. Furthermore, the scope and limitations of the procedure were established. A model 790-member library was obtained with 85% synthesis success rate

• allowed obtaining the target library member in pure form) on a large set of starting materials. Through the article, the compound numbering system common for the works on combinatorial chemistry was used: the starting materials used for the library generation were marked as 1{i}, 2{j}, and 3{k}, whereas

• the corresponding library members were denoted as 4{i,j,k}. Results and Discussion Library synthesis Preliminary experiments on the parallel GBB reaction were performed with heterocyclic amines 1{1–430}, aldehydes 2{1–583}, and isonitriles 3{1–73} available from our stock (based on our previous in

Predicting bond dissociation energies of cyclic hypervalent halogen reagents using DFT calculations and graph attention network model

• Yingbo Shao,
• Zhiyuan Ren,
• Zhihui Han,
• Li Chen,
• Yao Li and
• Xiao-Song Xue

Beilstein J. Org. Chem. 2024, 20, 1444–1452, doi:10.3762/bjoc.20.127

• the core framework, incorporating ten selected atomic descriptors as local information within the graph structure. Effective molecular transformations into molecular graphs (Figure 4b) were achieved using the RDKit and Deep Graph Library [87]. The dataset was randomly divided into training and testing

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

• the triazole unit via a copper-catalyzed azide–alkyne cycloaddition. The developed methodology was used to synthesize a library of over fifty new multi-substituted pyrazole–triazole hybrids. We also demonstrate a one-pot strategy that renders the isolation of potentially hazardous azides obsolete. In

• suitable for single-crystal X-ray diffraction could be obtained and confirmed the product structure with the presumed regioisomer (Scheme 3). A library of over 50 triazole products 21aa–vg was successfully synthesized with yields ranging from 28% to quantitative, combining four different pyrazole-carbon

• pyrazoles, as the corresponding azides analogous to 19j–v could not be obtained from immobilized triazene precursors. Conclusion A synthesis route to access substituted triazole–pyrazole hybrids from triazenylpyrazoles has been established and applied to obtain a library of over 50 new triazole–pyrazole

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

• , we highlight the reputation of this reaction approach to access number and scaffold diversity of a library of isatin-based α-acetamide carboxamide oxindole hybrids, promising anticancer agents, in a mild and fast sustainable reaction process. The library was tested against six human solid tumor cell

• using 5-amino-1-benzyl-3,3-dimethoxyindolin-2-one (1) [12] and benzyl isocyanide (4), as amine and isocyanide components, respectively. Different carboxylic acids 2 and aldehydes/ketones 3 were evaluated using ZnF2 as catalyst (10 mol %) and MeOH as the solvent (Scheme 2 and Figure 2). A library of α

• conditions (120 ºC, 30 minutes) (Scheme 3). Resourcefulness of the Ugi4CR and preliminary SAR studies [16] lead us to synthesize a third library of oxindole derivatives, using trifluoroacetic acid (TFA), under mild reaction conditions, to afford the corresponding α-acetamide carboxamide isatin hybrids 8 from

Stability trends in carbocation intermediates stemming from germacrene A and hedycaryol

• Naziha Tarannam,
• Prashant Kumar Gupta,
• Shani Zev and
• Dan Thomas Major

Beilstein J. Org. Chem. 2024, 20, 1189–1197, doi:10.3762/bjoc.20.101

• and hedycaryol were prepared from their corresponding SMILES string using the RDKit library [30]. Electronic structure calculations on these carbocations were performed using the hybrid DFT functional M06-2X [31] and with the range-separated hybrid meta-GGA functional ωB97M-V [32] with the 6-31+G(d,p

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

• the manganese catalyst, a catalytic amount of t-BuONa (10 mol %) and an open reflux system (120 °C in toluene) under argon flow were required. Utilizing this unique method, many aromatic, aliphatic, and acyclic alcohols were cross-coupled, furnishing a library of disubstituted alcohols and ketones in

Structure–property relationships in dicyanopyrazinoquinoxalines and their hydrogen-bonding-capable dihydropyrazinoquinoxalinedione derivatives

• Tural N. Akhmedov,
• Ajeet Kumar,
• Daken J. Starkenburg,
• Kyle J. Chesney,
• Khalil A. Abboud,
• Novruz G. Akhmedov,
• Jiangeng Xue and
• Ronald K. Castellano

Beilstein J. Org. Chem. 2024, 20, 1037–1052, doi:10.3762/bjoc.20.92

• . Primary motivation for our effort comes from the work of Yamashita et al. who explored the OFET behavior of a library of electron-deficient dicyanopyrazinoquinoxaline (DCPQ) compounds [25]. The computations predicted low-lying LUMO levels, around −4.0 eV. However, the molecules exhibited poor n-type FET

• lactam form would mirror our prior work with phthalhydrazide (PH) and is also consistent with the work later reported by Takeda et al. We additionally envisioned that the DCPQs would serve as valuable comparators as the H-bonding capable DPQDs were studied. Reported here is the synthesis of a library of

A Diels–Alder probe for discovery of natural products containing furan moieties

• Alyssa S. Eggly,
• Namuunzul Otgontseren,
• Carson B. Roberts,
• Amir Y. Alwali,
• Haylie E. Hennigan and
• Elizabeth I. Parkinson

Beilstein J. Org. Chem. 2024, 20, 1001–1010, doi:10.3762/bjoc.20.88

• aim to use these same conditions in cell extracts to probe for small molecules that may be unstable or volatile at higher temperatures. To test the chemical probe and determine the substrate scope of the reaction, we tested a small library of furans (Table 1). After each reaction was run, the samples

• known natural products. To do this, the five naturally occurring MMFs (1–5) were synthesized by following a previous route [22]. In addition to the naturally occurring MMFs, a library of derivatives (Figure 3B) was also tested to determine if changes in the alkyl chain would affect conversion. These

• alternative alkyl chains likely exist in other bacterial strains. Lastly, the probe was tested with flufuran (23) to show that it can also identify a natural product that is not an MMF. The maleimide probe was tested with the natural MMF molecules and the library of MMF derivatives in the same fashion as

Innovative synthesis of drug-like molecules using tetrazole as core building blocks

• Jingyao Li,
• Ajay L. Chandgude,
• Qiang Zheng and
• Alexander Dömling

Beilstein J. Org. Chem. 2024, 20, 950–958, doi:10.3762/bjoc.20.85

• the Passerini and Ugi reactions amenable to convenient, efficient, simple, and fast synthesis of diverse scaffolds library to afford variously functionalized tetrazole-based drug-like molecules. In order to achieve the synthesis of novel tetrazole building blocks and their use in organic synthesis we

• . The well described, excellent functional group compatibility and versatility of MCRs along with their promising impact on medicinal chemistry and drug discovery for the library generation prompted us to further use the tetrazole building blocks in MCRs [31][32]. Building on our previous interest in

• the Passerini reaction involving atypical substrates, we aimed to investigate the unprecedented use of the tetrazole building block as an oxo component in the Passerini reaction to build a library that would possess drug-like molecules and could be easily screened for biological activity and

Activity assays of NnlA homologs suggest the natural product N-nitroglycine is degraded by diverse bacteria

• Kara A. Strickland,
• Brenda Martinez Rodriguez,
• Ashley A. Holland,
• Shelby Wagner,
• Michelle Luna-Alva,
• David E. Graham and
• Jonathan D. Caranto

Beilstein J. Org. Chem. 2024, 20, 830–840, doi:10.3762/bjoc.20.75

• ]. The discovery of the nnlA gene resulted from screening a JS1663 genomic library by monitoring for E. coli transformants that produced nitrite (NO2−) in the presence of NNG. Analysis of the mass balance via in vitro experiments showed that NnlA degraded NNG into NO2−, ammonium (NH4+), and glyoxylate

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

• have been no exhaustive analyses of high-temperature culture of actinomycetes. Thus, Saito et al. decided to test on a large scale whether high-temperature culture of actinomycetes can activate silent genes. First, an in-house library of 3,160 strains of actinomycetes widely isolated from Japanese soil

Chemoenzymatic synthesis of macrocyclic peptides and polyketides via thioesterase-catalyzed macrocyclization

• Senze Qiao,
• Zhongyu Cheng and
• Fuzhuo Li

Beilstein J. Org. Chem. 2024, 20, 721–733, doi:10.3762/bjoc.20.66

• possible and provides a potential to construct the analogs library of these bioactive macrocycles for further biological investigations. This review presents representative examples of chemoenzymatic approaches for macrocyclic peptides, polyketides, and their hybrids employing TE domains, and particular

• -like hexapeptides and also working on the cyclization of penta- and tetrapeptides [64]. The findings illustrated that PBP-type discrete TEs would become potent tools for the construction of a noncanonical macrocyclic peptides library. Macrocyclic polyketides and PKS/NRPS hybrids In contrast to the

New variochelins from soil-isolated Variovorax sp. H002

• Jabal Rahmat Haedar,
• Aya Yoshimura and
• Toshiyuki Wakimoto

Beilstein J. Org. Chem. 2024, 20, 692–700, doi:10.3762/bjoc.20.63

• sequencing. For the short-lead sequencing, the library was prepared using 100 ng of the gDNA with an MGIEasy FS DNA Library Prep Set (MGI), following the manufacturer’s protocol. The gDNA was fragmented enzymatically to approximately 400 bp. As a result of sequencing (150 bp × 2) and quality filtering (Q

• library preparation with a Ligation Sequencing Kit (SQK-LSK 109), following the 1D genomic DNA by ligation protocol. The library was applied to a MinION flowcell (FLO MIN106 R9.41revD) operated by the MinKNOW (20.06.9) software, and then processed by Guppy basecaller (4.0.11) in the high accuracy mode. As

Metal-catalyzed coupling/carbonylative cyclizations for accessing dibenzodiazepinones: an expedient route to clozapine and other drugs

• Amina Moutayakine and
• Anthony J. Burke

Beilstein J. Org. Chem. 2024, 20, 193–204, doi:10.3762/bjoc.20.19

• via a cross-coupling reaction with NH3 [13]. The reaction was undertaken in the presence of a catalytic amount of a palladium catalyst and afforded a library of dibenzodiazepinones in good to excellent yields (Scheme 1a). In 2013, Zhang et al. developed a synthetic route leading to structurally

GlAIcomics: a deep neural network classifier for spectroscopy-augmented mass spectrometric glycans data

• Thomas Barillot,
• Baptiste Schindler,
• Baptiste Moge,
• Elisa Fadda,
• Franck Lépine and
• Isabelle Compagnon

Beilstein J. Org. Chem. 2023, 19, 1825–1831, doi:10.3762/bjoc.19.134

• each monosaccharide unit is measured, and subsequently identified by comparison with a library of reference spectra of synthetic monosaccharide standards. In the early days of MS–IR spectroscopy, ca. one hour was necessary to record the IR fingerprint of a single molecule and the identification was

• made by visual inspection, which was shortly automated by introducing a score derived from the convolution between the spectrum of the analyte of interest and the library of reference spectra. Despite the advantage of being automated, this later approach remains biased: for each molecular species, a