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

• : isocyanide; multicomponent reactions; one-pot reaction; oxidation; spiroindolenine; Ugi reaction; visible light; Introduction Diversity-oriented synthesis (DOS) is a successful approach to biologically active scaffolds directed to create an enormous exploratory space in pharmaceutical hit discovery [1][2

• construction of spirocyclic motifs is often associated with increased synthetic effort and number of synthetic steps. Hence, developing efficient strategies to access spirocyclic targets with structural diversity is highly desirable and valuable. Among the bioactive compounds containing spiro atoms, the spiro

• spiro-heterocyclic indolenines from readily available starting materials under mild conditions and in a diversity-oriented fashion remains desirable. In this contest, oxidative isocyanide-based multicomponent reactions (oxidative IMCRs) can be considered as a convenient tool [15]. Actually, the use of

5th International Symposium on Synthesis and Catalysis (ISySyCat2023)

• Anthony J. Burke and
• Elisabete P. Carreiro

Beilstein J. Org. Chem. 2024, 20, 2704–2707, doi:10.3762/bjoc.20.227

• reported that imidazole analogs behaved differently due to the ʟ-histidine unit representing a nonphenyl scaffold. Some important data on the bioisosteric modifications of 2-phenethylamine derivatives, focusing on their affinity and core aromatic diversity, were included. In another Review article

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

• -dimethyltetradec-5-enoic acid (F, Table 2). No differences between samples from males and females were detected. As discussed in the introduction, fatty acids are common constituents of the SGS of many snakes and show great structural diversity. Their typical chain length is between 2–26 carbons and they have been

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

• should allow us to introduce the molecular diversity on the anilino moiety in the last step through a palladium-catalyzed reaction (Scheme 1). Therefore, we prepared first the core structure 3 in two steps from the commercially available fluoronaphthalene 1. Metallation, followed by trapping with DMF

Machine learning-guided strategies for reaction conditions design and optimization

• Lung-Yi Chen and
• Yi-Pei Li

Beilstein J. Org. Chem. 2024, 20, 2476–2492, doi:10.3762/bjoc.20.212

• scarcity and diversity, as they need to cover a vast reaction space [26][27]. However, collecting data relevant to chemical reactions represents a significant challenge. While specific molecular properties can be precisely computed using existing simulation methods like quantum chemical calculations

• reduced the diversity of options available for experimentalists. Subsequent studies have attempted to overcome this challenge by proposing different solutions. Kwon et al. [145] used a variational autoencoder (VAE) architecture to sample different reaction conditions, while Chen et al. [42] designed a two

• databases, such as Reaxys, only record the highest-yield reaction conditions from a single publication. Therefore, the data might lack diversity in reaction conditions for a given reaction, unless the same reaction appears in multiple publications with different conditions. A variety of ML approaches have

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

• , anticancer, non-steroidal anti-inflammatory, antihypertensive, antipsychotic, anxiolytic and in other pharmaceuticals [3][4][5]. Therefore, considering the diversity of biological properties, development of reliable approaches for the synthesis of new nitrogen heterocyclic systems is a highly urgent goal

Hydrogen-bond activation enables aziridination of unactivated olefins with simple iminoiodinanes

• Phong Thai,
• Lauv Patel,
• Diyasha Manna and
• David C. Powers

Beilstein J. Org. Chem. 2024, 20, 2305–2312, doi:10.3762/bjoc.20.197

• the combination of synthetically tunable iodine-centered electrophilicity and the diversity of substrate functionalization mechanisms that can be accessed [1][2]. Large families of iodine(III)- and iodine(V)-based reagents have been developed – including iodobenzene diacetate (PhI(OAc)2, PIDA

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

• quality of the underlying dataset will determine the model’s predictive capabilities. To obtain high predictive accuracy for a broad range of problems, a data set is sought which covers the problem space comprehensively. This does not only encompass the chemical diversity of the included molecules, but

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

• exhibit poor performance during early project stages where the training data is limited and model exploitation might lead to analog identification with limited scaffold diversity. Here, we present ActiveDelta, an adaptive approach that leverages paired molecular representations to predict improvements

• , model exploitation can lead to analog identification, which can limit the acquired knowledge and the scaffold diversity of selected hits [1]. We previously showed that leveraging pairwise molecular representations as training data can support molecular optimization by directly training on and predicting

• networks even when combinatorially expanding datasets through pairing. Chemical diversity in molecular selection Beyond their ability to identify the most potent inhibitors, we sought to determine how these approaches sampled chemical space. When analyzing the scaffold diversity of hits (i.e., the number

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

From perfluoroalkyl aryl sulfoxides to ortho thioethers

• Yang Li,
• Guillaume Dagousset,
• Emmanuel Magnier and
• Bruce Pégot

Beilstein J. Org. Chem. 2024, 20, 2108–2113, doi:10.3762/bjoc.20.181

• % using hex-5-enenitrile. Conclusion In summary, fine-tuning of the experimental conditions gave us access to original ortho-cyanoalkylated aryl perfluoroalkylsulfur derivatives. We have also shown that structural diversity is possible by varying the substituents on the aromatic ring, the perfluoroalkyl

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

• interaction with host proteins [5][6]. Notably, the complexity of the glycome far surpasses that of the genome, transcriptome, and proteome, not only due to the structural and conformational diversity of glycans, whose synthesis is not template driven, but also due to their dynamic nature [5][6]. Although

• in bacteria, which are able to use most of the mammalian sugar units to construct their glycoconjugates but, in addition, can also use a wide variety of particular, and potentially endless, monosaccharides that are instead not present in eukaryotes (Figure 2). This huge diversity and complexity

• only by their chemical composition but also by their conformation. As mentioned above, glycans are characterised by a huge conformational diversity (see Figure 1): even individual furanoid or pyranoid monosaccharides can assume various shapes and in longer glycans the relative orientation of the

Multicomponent syntheses of pyrazoles via (3 + 2)-cyclocondensation and (3 + 2)-cycloaddition key steps

• Ignaz Betcke,
• Alissa C. Götzinger,
• Maryna M. Kornet and
• Thomas J. J. Müller

Beilstein J. Org. Chem. 2024, 20, 2024–2077, doi:10.3762/bjoc.20.178

• coordination of the magnesium ions and subsequent hydrazine inactivation. The diversity-oriented nature of this consecutive four-component synthesis was used to synthesize 17 different donor/acceptor-substituted pyrazoles 108 in moderate to good yields (Scheme 39) [136]. The synthesis of bispyrazoles was also

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

• ]. The success of this technology ultimately relies on the quality and diversity of the libraries. DEL synthesis must employ DNA-compatible reactions; hence it operates under a limited set of conditions [4][5]. DELs are typically produced via split-and-pool combinatorial chemistry methods. Using

• bifunctional building blocks (BBs) can quickly increase the diversity of these molecular libraries [6]. Hence, DEL practitioners constantly seek access to novel building blocks [7]. Amino acids (AAs) are vital motifs in the domain of biochemistry, serving as the foundational unit for peptides and proteins

• -amino acids as primary diversity elements [10]. The pursuit of achieving the efficient synthesis of α-amino acids has been an ongoing challenge since 1850, marked by the initial report of the Strecker condensation [11]. The Strecker synthesis and the related Bucherer−Bergs hydantoin formation remains

Access to 2-oxoazetidine-3-carboxylic acid derivatives via thermal microwave-assisted Wolff rearrangement of 3-diazotetramic acids in the presence of nucleophiles

• Ivan Lyutin,
• Vasilisa Krivovicheva,
• Grigory Kantin and
• Dmitry Dar’in

Beilstein J. Org. Chem. 2024, 20, 1894–1899, doi:10.3762/bjoc.20.164

• well as a wide range of nucleophiles provides access to a structural diversity of medically relevant 2-oxoazetidine-3-carboxylic acid amides and esters. Keywords: β-lactams; diazotetramic acids; nucleophiles; spirocycles; thermolysis; Wolff rearrangement; Introduction The importance of the β-lactam

• were carried out using microwave activation. We then introduced various aromatic and aliphatic amines as well as alcohols and mercaptans into the reaction. In order to demonstrate the structural diversity of the compounds obtained, a wide range of diazotetramic acids 1 of different structures was used

• -diastereomeric β-lactam products. The use of variously substituted diazotetramic acids, including their spirocyclic derivatives, provides access to a new structural diversity of medically relevant β-lactam derivatives. The possibility of transforming the obtained benzyl esters into 2-oxoazetidine-3-carboxylic

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

• tumor bed of a vast diversity of human tumor types. As phenylalanine is the preferred substrate of IL4I1 catalytic activity, Presset et al. [6] reported novel phenylalanine derivatives as a strategy to inhibit IL4I1 activity, as this enzyme has a preference for hydrophobic amino acids. Among them

• -phenethylamine derivatives evaluating affinity and aromatic core diversity. Description of the 2-heteroarylethylamine scope of the present review featuring appropriate heteroaromatic systems (A = O, N, S). 2-Aminoethylpyridine derivatives with therapeutic activity. 2-Aminoethylfuran derivatives with therapeutic

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

• 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

• (41–67%). Multicomponent polymerizations are simple and efficient methods to construct a library of polymers with great structural complexity and diversity, including fused-heterocyclic polymers[64]. Tang et al. [65] reported the transition-metal-free multicomponent polymerization of dialdehydes 96a–c

• economy (water was the only byproduct) and thermal stability as well as remarkable fluorescence properties. Multicomponent reaction can be also employed to prepare crystalline porous materials namely covalent organic frameworks (COFs). The structural diversity and functionality of COFs were assembled from

A facile three-component route to powerful 5-aryldeazaalloxazine photocatalysts

• Ivana Weisheitelová,
• Radek Cibulka,
• Marek Sikorski and
• Tetiana Pavlovska

Beilstein J. Org. Chem. 2024, 20, 1831–1838, doi:10.3762/bjoc.20.161

• -type syntheses, MCRs have become helpful tools for more efficient preparation of chemical libraries with higher molecular diversity and complexity in fewer steps and less time [28][29]. Considering the limitations of existing methods, as well as the applications of 5-aryldeazaalloxazines 2, and in the

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

• heteroatoms boron, nitrogen, oxygen, and sulfur and ranging in size from four-membered to six-membered rings. Compared to the parent polycyclic aromatic hydrocarbons (PAHs), PASs containing heterocycles offer greater structural diversity as well as a much broader range of optoelectronic properties. Such

• between COMPAS-1 and COMPAS-2 To obtain a better overview of the COMPAS-2 chemical space and to study the effects of including these new components, we first compare the cc-PBHs in COMPAS-1 to the cc-hPASs in COMPAS-2, in terms of their shape diversity and molecular properties. As mentioned above, COMPAS

• demonstrates that increasing the diversity of conjugated cyclic building blocks does not have a notable impact on the relative distribution of molecular shapes. In contrast to their relatively high geometric similarity, the molecular properties of the two datasets vary substantially. We compared the

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

• substantial threat to global public health, demanding urgent attention and action. This study focuses on lanthipeptides, ribosomally encoded peptides that display significant structural diversity and hold promising potential as antibiotics. Genome mining was employed to locate biosynthetic gene clusters (BGCs

• catalyze the formation of Dha-Cys or Dhb-Cys [21]. Moreover, lanPt encodes a membrane protein with two ABC transporter domains and a C39 peptidase domain. The protein cleaves the leader peptide to generate mature lanthipeptides and exports them to the extracellular environment [22]. The diversity of

• . While some strains exhibit resistance due to changes in the cell wall, biofilm formation, or the expression of resistance proteins such as ABC transporters or proteases [28], specific mutations in nisin have rendered previously resistant strains susceptible [29]. The structural diversity of these

Oxidative fluorination with Selectfluor: A convenient procedure for preparing hypervalent iodine(V) fluorides

• Samuel M. G. Dearman,
• Xiang Li,
• Yang Li,
• Kuldip Singh and
• Alison M. Stuart

Beilstein J. Org. Chem. 2024, 20, 1785–1793, doi:10.3762/bjoc.20.157

• ring to stabilise the iodine(V) centre. Both sidearms were also changed to amides because the NR group is a point of diversity which could be used to modulate the sterics and electronics of these novel hypervalent iodine(V) compounds. Initially, we applied Togni’s oxidative fluorination protocol to

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

• compounds [1][2][3][4][5][6] to expand and systematically explore the chemical space within the concepts of molecular diversity chemistry (diversity oriented synthesis) [6] and biologically oriented synthesis [7]. Among the multicomponent processes, the four-component Ugi reaction (Ugi-4CR) [8][9][10][11

• other isocyanide MCRs is effective and one promising direction to increase the diversity of new peptidomimetics is the use of, for example, α,β-unsaturated aldehydes including those containing a halogen atom in the β-position, in the Ugi-4CR reaction [1][39]. As our previous studies have shown

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

• ]oxazinan)-6'-one derivatives with two types of molecular diversity as part of their efforts to produce inhibitors of 17β-HSDs [61]. The first type of diversity was achieved by introducing different amino acids through the opening of the oxirane ring on compound 127. After lactonization of compounds 128

• reactions. To increase the molecular diversity at the morpholine ring, tertiary amines were formed by nucleophilic substitution. A final removal of the cyclic ketal group in aq sulfuric acid provided spiromorpholinone derivatives 134a–e, 136a–e, and 138 (Scheme 37). Spiromorpholinones were evaluated as

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

• diversity, the research group achieved the synthesis of various dearomatized compounds, and the total synthesis of a member of the sorbicillinoid family. Enantioselective intermolecular Diels–Alder reaction to assemble core scaffolds: chalcomoracin and kuwanons Chalcomoracin (3) and kuwanons bearing a

• diversity-oriented synthesis. Targeted natural products and key enzymatic transformations in the chemo-enzymatic total syntheses featured in this review. Enzymatically formed bonds or units are highlighted in yellow. Biosynthetic pathway to brassicicenes in Pseudocercospora fijiensis [14]. (A) Cyclization

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

• -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

• [RMSD: 8.152 Å (109 to 109 atoms)], demonstrating the structural diversity among O-MTs (Figure 5). Streptomyces bottropensis produces various bottromycins, including bottromycin A2 (Figure 4) [79]. The precursor peptide consists of an N-terminal core and a rare C-terminal follower region. The

• acceptor molecules such as the polyketide rapamycin [31] or DNA [143]. The use of RiPP MTs with SAM supply or SAM regeneration systems has the potential to greatly increase chemical diversity of RiPP natural products. The addition of alternative alkyl groups onto peptide substrates could further expand the