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

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

• substituted saccharides. The vast diversity among CEs is organized into 16 different families [123]. Members of the CE6 family are typical serine-type esterases. A cold-adapted CE6 enzyme, CEST, was cloned and expressed in E. coli from Microbulbifer thermotolerans DAU221 with a temperature optimum of 15 °C

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

• purposes [1][2][3][4][5][6]. Isonitrile-based multicomponent reactions, such as the Groebke–Blackburn–Bienaymé (GBB) reaction, is an important tool in chemical synthesis providing easy access to a huge compound diversity and complexity [7][8][9][10][11][12][13][14][15][16][17]. Essentially, the GBB

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

• N–H bond was the most stable conformer, allowing for an intramolecular F∙∙∙H hydrogen bond. However, 3-fluoropyrrolidine displayed extensive conformational diversity (ΔG0 among conformers ≤1.6 kcal⋅mol−1) as the intramolecular interactions were not sufficiently stabilizing to dictate a dominant

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

• (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

• peptides for split burpitide pathways, we developed a custom HMM (see Supporting Information File 1, Figure S1). This approach gave us the speed, sensitivity, and customization needed to identify diverse sequences. We targeted a diversity of plants from every available order in Streptophyta for a total of

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

• by harsh reaction conditions, which reduces functional group compatibility and product diversity. As such, the development of practical methods for the preparation of alkylnitriles from readily available starting materials are particularly valuable in synthetic and medicinal applications [15][16][17

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

• of diversity-oriented synthesis of N-heterocycles via sequential multicomponent approaches, we envisioned that α-aminoacetals could act as bifunctional building blocks along with 1,2-diaza-1,3-diene (DD) coupling partners [22][23], in obtaining functionalized N-aminohydrazones as key intermediates

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

• with remarkable atom economy, cost and time-effective and mainly diminishing waste production is a conscientious boost for structural diversity and sustainability [1][2][3]. The well-known Passerini, Ugi, Mannich, Biginelli, Hantzsch and Strecker reactions are some examples of the classic MCRs

Introduction of peripheral nitrogen atoms to cyclo-meta-phenylenes

• Koki Ikemoto and
• Hiroyuki Isobe

Beilstein J. Org. Chem. 2024, 20, 1207–1212, doi:10.3762/bjoc.20.103

• were installed in an outward-radiated manner, which expands the structural diversity to exploit the chemistry at the periphery of [n]CMP (Figure 1b). Through the use of Suzuki–Miyaura coupling for macrocyclisation, pyridinyl and phenylene rings were assembled in an alternating fashion, which afforded

Enhancing structural diversity of terpenoids by multisubstrate terpene synthases

• Min Li and
• Hui Tao

Beilstein J. Org. Chem. 2024, 20, 959–972, doi:10.3762/bjoc.20.86

• TaiKang Center for Life and Medical Sciences, Wuhan University, Wuhan, Hubei 430071, China 10.3762/bjoc.20.86 Abstract Terpenoids are one of the largest class of natural products with diverse structures and activities. This enormous diversity is embedded in enzymes called terpene synthases (TSs), which

• -methyltransferases, or engineered lepidopteran mevalonate pathways. The substrate promiscuity of TSs not only expands the structural diversity of terpenes but also highlights their potential for the discovery of novel terpenoids via combinatorial biosynthesis. In this review, we focus on the current knowledge on

• broad range of bioactivities [2][3]. Despite their stunning diversity, all terpenes are biosynthetically derived from two general isomeric C5 building blocks, dimethylallyl diphosphate (DMAPP, 1) and isopentenyl diphosphate (IPP, 2), via the mevalonate (MVA) or methylerythritol 4-phosphate (MEP

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

• of the de novo approach and furthermore provides an extra efficiency, complexity and diversity in the same number of steps (Figure S1, Supporting Information File 1). Also, it offers a flexibility of placement of the tetrazole moiety in the scaffold and enables additional facile post-modifications

• envisioned the use of multicomponent reactions in both steps. The use of MCRs provides the benefits of simplicity, speed, complexity, and diversity with the minimum number of steps and with an environmentally friendly nature. First, we focused on the use of the Passerini-tetrazole reaction for the synthesis

• pathways in terms of economy, sustainability, generalizability, step-count, reaction simplicity, and yields. With these tetrazole building blocks in hand, we next aimed to investigate the scope and limitations by assembling smaller compound libraries with a high degree of complexity and skeletal diversity

Enantioselective synthesis of β-aryl-γ-lactam derivatives via Heck–Matsuda desymmetrization of N-protected 2,5-dihydro-1H-pyrroles

• Arnaldo G. de Oliveira Jr.,
• Martí F. Wang,
• Rafaela C. Carmona,
• Danilo M. Lustosa,
• Sergei A. Gorbatov and
• Carlos R. D. Correia

Beilstein J. Org. Chem. 2024, 20, 940–949, doi:10.3762/bjoc.20.84

• herein an enantioselective palladium-catalyzed Heck–Matsuda reaction for the desymmetrization of N-protected 2,5-dihydro-1H-pyrroles with aryldiazonium salts, using the chiral N,N-ligand (S)-PyraBox. This strategy has allowed straightforward access to a diversity of 4-aryl-γ-lactams via Heck arylation

Confirmation of the stereochemistry of spiroviolene

• Yao Kong,
• Yuanning Liu,
• Kaibiao Wang,
• Tao Wang,
• Chen Wang,
• Ben Ai,
• Hongli Jia,
• Guohui Pan,
• Min Yin and
• Zhengren Xu

Beilstein J. Org. Chem. 2024, 20, 852–858, doi:10.3762/bjoc.20.77

• cyclization mechanism of spiroviolene. Keywords: boron migration; diterpene; spiroviolene; stereochemistry; Introduction Terpenes represent one of the most fascinating families of natural products due to their structural complexity and diversity, as well as their indispensable biological functions that

Ortho-ester-substituted diaryliodonium salts enabled regioselective arylocyclization of naphthols toward 3,4-benzocoumarins

• Ke Jiang,
• Cheng Pan,
• Limin Wang,
• Hao-Yang Wang and
• Jianwei Han

Beilstein J. Org. Chem. 2024, 20, 841–851, doi:10.3762/bjoc.20.76

• the low yield of 3al. We subsequently turned our attention to explore the effect of structural diversity of the ortho-ester-substituted diaryliodonium salts. Firstly, a family of substituted diaryliodonium salts were synthesized in a one-pot procedure. These ortho-substituted diaryliodonium salts were

Discovery and biosynthesis of bacterial drimane-type sesquiterpenoids from Streptomyces clavuligerus

• Dongxu Zhang,
• Wenyu Du,
• Xingming Pan,
• Xiaoxu Lin,
• Fang-Ru Li,
• Qingling Wang,
• Qian Yang,
• Hui-Min Xu and
• Liao-Bin Dong

Beilstein J. Org. Chem. 2024, 20, 815–822, doi:10.3762/bjoc.20.73

• analogs. This discovery not only broadens the known chemical diversity of DMTs from bacteria, but also provides new insights into DMT biosynthesis in bacteria. Keywords: bacterial terpenoid; cytochrome P450s; drimane-type sesquiterpenoid; Streptomyces clavuligerus; terpenoid biosynthesis; Introduction

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

• polyketides; thioesterase; Introduction Nonribosomal peptides, polyketides, and their hybrids exhibit significant diversity and a broad spectrum of bioactivities [1][2][3]. Particularly, macrocycles from these three categories of natural products are vital resources for developing pharmaceuticals and drug

• responsible for the structural diversity of natural products, both NRPS and PKS contain thioesterase (TE) domains in the final elongation module, which contribute to terminating biosynthesis [13][14]. Typically, TE domains cleave the thioester bond between the last PCP or ACP domain and the intermediate of