Regioselective alkylation of a versatile indazole: Electrophile scope and mechanistic insights from density functional theory calculations

• Pengcheng Lu,
• Luis Juarez,
• Paul A. Wiget,
• Weihe Zhang,
• Krishnan Raman and
• Pravin L. Kotian

Beilstein J. Org. Chem. 2024, 20, 1940–1954, doi:10.3762/bjoc.20.170

• -carboxylate (6) and the use of density functional theory (DFT) to evaluate their mechanisms. Over thirty N1- and N2-alkylated products were isolated in over 90% yield regardless of the conditions. DFT calculations suggest a chelation mechanism produces the N1-substituted products when cesium is present and

• other non-covalent interactions (NCIs) drive the N2-product formation. Methyl 1H-indazole-7-carboxylate (18) and 1H-indazole-3-carbonitrile (21) were also subjected to the reaction conditions and their mechanisms were evaluated. The N1- and N2-partial charges and Fukui indices were calculated for

• -3 as a bidentate ligand to the Na+ cation from NaH. The tight ion pair would direct alkylation under conditions A to N1. As this and other postulations exist, we explored the possible mechanisms of each reaction conditions computationally. All calculations were performed in implicit THF at the

Electrochemical radical cation aza-Wacker cyclizations

• Sota Adachi and
• Yohei Okada

Beilstein J. Org. Chem. 2024, 20, 1900–1905, doi:10.3762/bjoc.20.165

• cations that offer unique reactivities as intermediates in various bond-formation processes. Such intermediates can potentially take part in both radical and ionic bond formation; however, the mechanisms involved are complicated and not fully understood. Herein, we report electrochemical radical cation

• different, their creative use may pave the way for complementary bond formation. This merging is unique and such intermediates could potentially take part in both radical and ionic bond formation. However, the mechanisms involved can be complicated and are not fully understood. Alkenes and styrenes are

• expected to proceed via radical cations, there are several interpretations of the mechanisms involved, since radical and ionic cyclizations are both possible. In this context, electrochemical and photochemical aza-Wacker cyclizations have provided interesting models for mechanistic discussion (Scheme 2

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

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

• compounds. For example, the discovery of teixobactin [8] has paved the way for developing antibiotics with innovative mechanisms of action. Similarly, the discovery of halicin, a molecule identified through a machine learning-based approach, has shown promise as a broad-spectrum antimicrobial agent

• peptides, coupled with their successful production in E. coli [30], has driven research to consider them a source for new antibiotics, as supported by the present study. Identifying the genetic and biochemical mechanisms underlying the production of compounds is of utmost importance in developing effective

• Clostridia are the human and animal microbiota and soil for both anaerobic and aerotolerant organisms. We interpret a lack of effect on C. difficile, an intestinal clinical isolate, due to either the presence of resistance mechanisms or the fact that these peptides evolved to be active against soil

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

• intermolecular Diels–Alder reactions with 34 or other dienophiles, leading to a diverse array of bisorbicillinoids. Based on the crystal structure of TropB, a homologous enzyme of SorbC, Narayan and co-workers have intensively elucidated that the detailed mechanisms of the oxidative dearomatization catalyzed by

• crystallographic structures of MaDA (6JQH) and MaDA-3 (7E2V) provided insights into the mechanisms of different stereoselectivities in the Diels–Alder reactions [56]. In 2014, the same group led by Lei also reported the total synthesis of kuwanon J (59) and related natural products. In their earlier fully chemical

Oxidation of benzylic alcohols to carbonyls using N-heterocyclic stabilized λ³-iodanes

• Thomas J. Kuczmera,
• Pim Puylaert and
• Boris J. Nachtsheim

Beilstein J. Org. Chem. 2024, 20, 1677–1683, doi:10.3762/bjoc.20.149

• reagents offer a viable alternative to traditional aryl-λ5-iodane-based oxidants, although further studies are necessary to fully understand their reaction mechanisms. Experimental General procedure for oxidation of benzylic alcohols 1a (700 µmol, 201 mg, 1.40 equiv), benzylic alcohol (3, 500 µmol, 1.00

• ) in MeCN (2.5 mL), respectively, were stirred at 60 °C for 2.5 h and quenched with Me2S (1.40 mmol). Possible reaction mechanisms via the formation of a) a Cl(I) species and b) the formation of an alkoxyiodane IIb. Both are initialized by the activated iodane I-OH, which was observed as c) I-OMe

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

• oxygen-independent coproporphyrinogen-III oxidase (CPO). B) Catalytic mechanisms of rSAM-mediated methylation are depicted exemplary for class B (TsrM) and class C (TbtI) RiPP MTs. The three-dimensional structures of the rSAM C-MTs TsrM with bound cobalamin and [4Fe-4S] cluster (PDB ID: 6WTE (https

Divergent role of PIDA and PIFA in the AlX₃ (X = Cl, Br) halogenation of 2-naphthol: a mechanistic study

• Kevin A. Juárez-Ornelas,
• Manuel Solís-Hernández,
• Pedro Navarro-Santos,
• J. Oscar C. Jiménez-Halla and
• César R. Solorio-Alvarado

Beilstein J. Org. Chem. 2024, 20, 1580–1589, doi:10.3762/bjoc.20.141

• energy than our proposed species. The reaction mechanisms are described in detail in this work and were found to be in excellent agreement with the experimental yield. These initial results confirmed that our proposed mechanism was energetically favored and therefore more plausible compared to

• reactions, we explored different pathways of the reaction mechanisms for the ortho-halogenation using 2-naphthol as a model substrate (Scheme 2). In such a way, we found a reaction pathway that was energetically favored. Based on our successful procedure for chlorination, we also developed an efficient

• TS2 is energetically less favored (ΔG‡ = 16.2 kcal/mol, see Supporting Information File 1 for details of the explored chlorination and bromination mechanisms). Additionally, for this mechanism, we identified that the formation of TS4 has the highest energy barrier (ΔG‡ = 20.2 kcal/mol), becoming a

Benzylic C(sp³)–H fluorination

• Alexander P. Atkins,
• Alice C. Dean and
• Alastair J. J. Lennox

Beilstein J. Org. Chem. 2024, 20, 1527–1547, doi:10.3762/bjoc.20.137

• publications by the Doyle and Musacchio groups in 2021 and 2022 demonstrated the effective use of photochemical oxidative radical-polar crossover mechanisms to achieve this. The Doyle group reported the use of an iridium-catalysed system in this context with Et3N·3HF as the fluoride source (Figure 32) [83

Photoswitchable glycoligands targeting Pseudomonas aeruginosa LecA

• Yu Fan,
• Ahmed El Rhaz,
• Stéphane Maisonneuve,
• Emilie Gillon,
• Maha Fatthalla,
• Franck Le Bideau,
• Guillaume Laurent,
• Samir Messaoudi,
• Anne Imberty and
• Juan Xie

Beilstein J. Org. Chem. 2024, 20, 1486–1496, doi:10.3762/bjoc.20.132

• the leading cause of morbidity and mortality in cystic fibrosis and immunocompromised patients and as one of the leading causes of nosocomial infections [1]. Due to the existence of numerous molecular mechanisms conferring resistance to multiple classes of antibiotics, therapeutic options are

• -isomer is twice better than for its Z-counterpart for the S-linked compound 3 and three times better for the O-glycoside 1. Even though the other compounds do not exhibit significant variations of affinities between E- and Z-isomers, a closer look at the thermodynamic values indicates that the mechanisms

Bioinformatic prediction of the stereoselectivity of modular polyketide synthase: an update of the sequence motifs in ketoreductase domain

• Changjun Xiang,
• Shunyu Yao,
• Ruoyu Wang and
• Lihan Zhang

Beilstein J. Org. Chem. 2024, 20, 1476–1485, doi:10.3762/bjoc.20.131

• stereochemical outcomes of KRs. These updated fingerprint motifs for stereochemical prediction not only enhance our understanding of the enzymatic mechanisms governing stereocontrol but also facilitate accurate stereochemical prediction and genome mining of polyketides derived from modular cis-AT PKSs. Keywords

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

• of novel synthetic strategies. It has expanded the scope of available synthetic methods and contributed to the synthesis of complex molecules with high efficiency and selectivity. Ongoing research in this field continues to explore new catalysts, photosensitizers, and reaction mechanisms to further

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

• (1) [6]. In 1, the C2–C3 and C6–C7 alkenes are E-configured, with the latter alkene configuration being conserved in all known eunicellane cyclization mechanisms. The first trans-eunicellane synthase, AlbS from the biosynthesis of albireticulone in Streptomyces albireticuli [10], was also identified

• chemically-induced cationic cyclization mechanisms, we performed quantum chemical calculations [mPW1PW91/6–31+G(d/p)/SMD(chloroform)] [13][14][15][16][17][18][19][20] to obtain the relative free energies of the cationic intermediates and transition states that interconvert them, as well as the relative free

Cofactor-independent C–C bond cleavage reactions catalyzed by the AlpJ family of oxygenases in atypical angucycline biosynthesis

• Jinmin Gao,
• Liyuan Li,
• Shijie Shen,
• Guomin Ai,
• Bin Wang,
• Fang Guo,
• Tongjian Yang,
• Hui Han,
• Zhengren Xu,
• Guohui Pan and
• Keqiang Fan

Beilstein J. Org. Chem. 2024, 20, 1198–1206, doi:10.3762/bjoc.20.102

• monomeric structure of AlpJ shares similarities with the dimeric cofactor-independent anthrone oxygenases, such as ActVA-Orf6 [13], the structural intricacies governing the accommodation of these two distinct mechanisms warrant further investigation. The current findings indicate that both 8 and 1 can serve

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

Light on the sustainable preparation of aryl-cored dibromides

• Fabrizio Roncaglia,
• Alberto Ughetti,
• Nicola Porcelli,
• Biagio Anderlini,
• Andrea Severini and
• Luca Rigamonti

Beilstein J. Org. Chem. 2024, 20, 1076–1087, doi:10.3762/bjoc.20.95

• ion in aqueous acidic media (Equation 1) [43]. Its practical implementation is surprisingly simple as standard aqueous HBr and H2O2 solutions are effective. The generated bromine can be involved in different chemical mechanisms, such as an Ar-SE (Equation 2) [44] or a radical substitution on activated

Carbonylative synthesis and functionalization of indoles

• Alex De Salvo,
• Raffaella Mancuso and
• Xiao-Feng Wu

Beilstein J. Org. Chem. 2024, 20, 973–1000, doi:10.3762/bjoc.20.87

• )/TMSCl in the presence of CO. The reaction, again, ends with an N-cyclization giving the N-aroylindoles with fair to good isolated yields. The reaction mechanisms are reported in Scheme 23. Synthesis of indoles by Rh-catalyzed carbonylation reactions In the past, Tang and co-workers, demonstrated that

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

• often results in multiple terpene products from a single prenyl substrate. In addition to their distinct mechanisms, the two major classes of TSs are classified according to their sequences, structures, and functions. For instance, class I TSs often have conserved sequence motifs, DDXXD and NSE/DTE

• . Classically, these prenyl analogs have been used as co-crystallization ligands [38], inhibitors of specific TSs [39], and tools to study the reaction mechanisms of cyclization cascades [40][41] which have been comprehensively addressed in important previous reviews [8][13]. Currently, noncanonical prenyl

• unusual terpenoid skeletons and new value-added terpenoids. In addition to expanding the repertoire of terpenoids, the biotransformation of noncanonical prenyl substrates by TSs provides insights into the mechanisms of cyclization reactions. β-Himachalene synthase (HcS) and (Z)-γ-bisabolene synthase (BbS

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

• spiroviolene and related natural products. Heterologous production of spiroviolene using the isopentenol utilization pathway. A) Gas chromatogram of the EtOAc extract of the fermentation broth. B) EI mass spectrum of spiroviolene. Possible cyclization mechanisms for spiroviolene (1) and related natural

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

• , share the drimanyl scaffold, their biosynthetic pathways, particularly the terpene cyclases synthesizing the drimanyl structures, show substantial divergence from DMT pathways [21][30][31][32]. This fundamental difference in biosynthetic mechanisms serves to categorize DMSs and drimentines into distinct

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

• -culture of microorganisms and animal cells, were outlined. The mechanisms by which these silent secondary metabolites are produced should be specific to each method. Elucidation of these mechanisms will directly lead to the development of new silent gene activation methods. In these approaches, there are

Research progress on the pharmacological activity, biosynthetic pathways, and biosynthesis of crocins

• Zhongwei Hua,
• Nan Liu and
• Xiaohui Yan

Beilstein J. Org. Chem. 2024, 20, 741–752, doi:10.3762/bjoc.20.68

• , and epileptic disorders [26][27]. Four mechanisms have been reported for the treatment of Alzheimer's disease with crocins. Crocins function as antioxidants that slow down the progression of the disease by increasing the ʟ-glutathione (GSH) level and reducing the presence of reactive oxygen species

• broad pharmacological properties. They are promising drugs for treating cardiovascular and liver diseases. Despite numerous pharmacological properties, the exact mechanisms of action of crocins remain elusive. The therapeutic potential of crocins is impeded by the limited bioavailability and rapid

• , including common substituents of the crocetin skeleton. The pharmacological activity and mechanisms of action of crocins. Crocin biosynthetic pathways in C. sativus and G. jasminoides. Enzyme abbreviations are as follows: lycopene β-cyclase (LCYB), β-carotene hydrolase (BHY), carotenoid cleavage dioxygenase

Substrate specificity of a ketosynthase domain involved in bacillaene biosynthesis

• Zhiyong Yin and
• Jeroen S. Dickschat

Beilstein J. Org. Chem. 2024, 20, 734–740, doi:10.3762/bjoc.20.67

• glutamate decarboxylase, and incubated with BaeJ-KS2. Substrate binding was demonstrated through 13C NMR analysis of the products against the background of various control experiments. Keywords: bacillaene; biosynthesis; enzyme mechanisms; isotopes; trans-AT polyketide synthases; Introduction Polyketides

Palladium-catalyzed three-component radical-polar crossover carboamination of 1,3-dienes or allenes with diazo esters and amines

• Geng-Xin Liu,
• Xiao-Ting Jie,
• Ge-Jun Niu,
• Li-Sheng Yang,
• Xing-Lin Li,
• Jian Luo and
• Wen-Hao Hu

Beilstein J. Org. Chem. 2024, 20, 661–671, doi:10.3762/bjoc.20.59

• (TEMPO) and the corresponding radical-trapping product A could be confirmed by HRMS of both reaction mixtures, unambiguously supporting radical mechanisms (Scheme 4a). The reaction with styrene was conducted under standard conditions, but no product X could be detected, indicating the cationic

• amine and the traces amount of water in this reaction system may serve as proton sources for the formation of hybrid α-ester alkylpalladium radical. On the basis of above mechanistic studies and previous reports [47][48][49][50][52][58], the following plausible mechanisms are proposed for the palladium

• ) Radical trapping experiments with TEMPO. b) Exclusion of possible intermediate. c) Subjecting the product Z-6i to the standard conditions. d) The control reaction with HPd(PPh3)2Cl. e) UV–visible absorption analysis. Proposed mechanisms for the carboamination of 1,3-dienes or allenes with diazo esters and

Enhanced reactivity of Li⁺@C₆₀ toward thermal [2 + 2] cycloaddition by encapsulated Li⁺ Lewis acid

• Hiroshi Ueno,
• Yu Yamazaki,
• Hiroshi Okada,
• Fuminori Misaizu,
• Ken Kokubo and
• Hidehiro Sakurai

Beilstein J. Org. Chem. 2024, 20, 653–660, doi:10.3762/bjoc.20.58

• +) reference couple. Working electrode: Pt, counter electrode: Pt, reference electrode: Ag/Ag+ in acetonitrile, solvent: o-dichlorobenzene, supporting electrolyte: 50 mM TBAPF6. Reaction mechanisms of thermal and photoinduced [2 + 2] cycloaddition on C60 [19][22][23]. Thermal [2 + 2] reaction of Li+@C60 TFSI