gem-Difluorination of carbon–carbon triple bonds using Brønsted acid/Bu₄NBF₄ or electrogenerated acid

• Mizuki Yamaguchi,
• Hiroki Shimao,
• Kengo Hamasaki,
• Keiji Nishiwaki,
• Shigenori Kashimura and
• Kouichi Matsumoto

Beilstein J. Org. Chem. 2024, 20, 2261–2269, doi:10.3762/bjoc.20.194

• use the optimized conditions in entry 2, because reducing the amount of Bu4NBF4, for example, to 5 equiv is important from the viewpoint of eco-friendly chemical synthesis. The reaction time of 16 h also seems to be suitable for the investigation. Thus, the combination of Tf2NH and Bu4NBF4 might

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

• screening and rapid optimization [46][47]. Homogenous heating and mixing in flow reactors can lead to higher reaction rates and yields. In terms of photochemistry, continuous flow setups provide enhanced light irradiation as well [48][49]. These advantages make flow chemistry a powerful tool for chemical

• synthesis and industrial applications [50][51]. To assess the advantage of moving from batch to flow, the production of compounds 2b and 2i was carried out with the telescoped approach. Despite the difference in the yield being minimal, the rate of the transformation showed a significant improvement under

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

• approach" merging efficient enzymatic synthesis – traditionally employed in the biosynthesis of natural products by microorganisms and plants – with precise chemical synthesis conducted by chemists. Chemo-enzymatic total syntheses reported recently fall into three main categories based on the purpose for

• tricyclic scaffold was produced through scalable chemical synthesis. Subsequently, in vitro enzymatic oxidative functionalizations were carried out during the oxidation stage. The exploration of Bsc9 homologs and directed evolution expanded the scope of substrates of the dioxygenase beyond the natural

• biosynthetic intermediate 8 to its analogs 21, enabling the chemo-enzymatic total synthesis of 1. The chemical synthesis commenced with the preparation of two fragments and their subsequent coupling to assemble the core 5/8/5 tricyclic scaffold (Scheme 3A). The left-half fragment, aldehyde 14, was synthesized

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

• three main routes for the synthesis of methylated peptides: chemical synthesis [33][34], in vitro ribosomal synthesis [35], and enzymatic synthesis. Chemical synthesis. Three main categories of reactions are commonly used: reductive amination, reductive ring openings, and the use of methylating agents

• peptide methylation. Biocatalysis provides an efficient and sustainable alternative to chemical synthesis strategies. Both NRPS and RiPP biosynthetic machineries can be used for cell-based or in vitro strategies [53]. Especially well suited as biocatalysts are MTs from RiPP pathways, as they demonstrate

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

Electrocatalytic hydrogenation of cyanoarenes, nitroarenes, quinolines, and pyridines under mild conditions with a proton-exchange membrane reactor

• Koichi Mitsudo,
• Atsushi Osaki,
• Haruka Inoue,
• Eisuke Sato,
• Naoki Shida,
• Mahito Atobe and
• Seiji Suga

Beilstein J. Org. Chem. 2024, 20, 1560–1571, doi:10.3762/bjoc.20.139

• ; quinoline; Introduction Nitrogen-containing molecules are important bioactive compounds and intermediates in chemical synthesis. Therefore, the chemical transformations of nitrogen-containing compounds have been widely studied in the field of organic synthesis [1][2][3][4]. For instance, the reduction of

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

• product structures were experimentally determined, such as by crystallography, nuclear magnetic resonance (NMR) analysis or by chemical synthesis, were obtained for further analysis. The modules in PKSs were categorized as α-module (containing KS-AT-ACP tridomain), β-module (KS-AT-KR-ACP), γ-module (KS-AT

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

• Mithu Roy Bitan Sardar Itu Mallick Dipankar Srimani Department of Chemistry, Indian Institute of Technology-Guwahati, Kamrup, Assam 781039, India 10.3762/bjoc.20.119 Abstract Alkyl and acyl radicals play a critical role in the advancement of chemical synthesis. The generation of acyl and alkyl

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

• germacrene A and hedycaryol and how this might affect product distribution in chemical synthesis and biosynthesis. Additionally, we compare the effect of the choice of DFT functional and basis set on the results. Methods The structures of all studied intermediate carbocations originating from germacrene A

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

• complexity of chemical synthesis towards novel drugs has almost doubled from eight chemical steps to an average of 14 in 2021 [1]. Therefore, the need for robust reactions compatible with many functional groups in complex molecules is an integral part in contemporary medicinal chemistry and drug development

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

• -inflammatory properties, hepatorenal protection, and anticancer activity. They are often used as coloring and seasoning agents. Due to the limited content of crocins in plants and the high cost of chemical synthesis, the supply of crocins is insufficient to meet current demand. The biosynthetic pathways for

• cell suspension culture, heterologous biosynthesis, and total synthesis [16][17]. Crocins can be obtained from plant cell culture, but the production is prone to epigenetic silencing and toxic intermediates. The chemical synthesis of crocins is challenging due to the presence of numerous chiral centers

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

• macrocyclizations (Scheme 1c). NAC thioester and other related mimics (such as coenzyme A (CoA), phosphopantetheine, and thiophenol) span the gap between the chemical synthesis and biosynthesis languages and expand the substrate promiscuity of TE domains. This bridge makes the in vitro TE-catalyzed macrocyclization

• contrast to Kang’s chemical synthesis route, this biotransformation provided a more efficient and productive strategy for the desoaminylation of macrolide aglycones. Combining in vitro and in vivo enzymatic reactions together, this chemoenzymatic platform exhibits the potential to access a broader range of

Regioselective quinazoline C2 modifications through the azide–tetrazole tautomeric equilibrium

• Dāgs Dāvis Līpiņš,
• Andris Jeminejs,
• Una Ušacka,
• Anatoly Mishnev,
• Māris Turks and
• Irina Novosjolova

Beilstein J. Org. Chem. 2024, 20, 675–683, doi:10.3762/bjoc.20.61

• of 4-azido-6,7-dimethoxy-2-sulfonylquinazoline derivatives 12 were proven by chemical synthesis of the regioisomers 15 (Scheme 7) and X-ray analysis of 12a (Scheme 6). 6,7-Dimethoxy-2,4-diazidoquinazoline (13) was synthesized from commercially available dichloroquinazoline 7 in 93% yield. Further

Photochromic derivatives of indigo: historical overview of development, challenges and applications

• Gökhan Kaplan,
• Zeynel Seferoğlu and
• Daria V. Berdnikova

Beilstein J. Org. Chem. 2024, 20, 228–242, doi:10.3762/bjoc.20.23

• for 6000 years [1]. Initially, indigo has been extracted from the plant species, for example Indigofera tinctoria and Polygonum tinctorium in Asia and America, Isatis tinctoria or dyer’s woad in Europe [2] before the chemical synthesis of indigo was achieved by the German chemist Adolf von Baeyer [3

• ]. As an alternative to the chemical synthesis of indigo, environmentally friendly biological approaches towards constructing the indigo scaffold are also being developed for nearly a century [5][6][7][8]. The biosynthetic methods include production of indigo by microorganisms and enzymatic synthesis

Optimizations of lipid II synthesis: an essential glycolipid precursor in bacterial cell wall synthesis and a validated antibiotic target

• Milandip Karak,
• Cian R. Cloonan,
• Brad R. Baker,
• Rachel V. K. Cochrane and
• Stephen A. Cochrane

Beilstein J. Org. Chem. 2024, 20, 220–227, doi:10.3762/bjoc.20.22

• bacteria. Accessing this valuable cell wall precursor is important both for studying cell wall synthesis and for studying/identifying novel antimicrobial compounds. Herein, we describe optimizations to the modular chemical synthesis of lipid II and unnatural analogues. In particular, the glycosylation step

• ramoplanin [2]. It is also the target for a host of other antimicrobials (mostly non-ribosomal peptides), including the tridecaptins [3], nisin [4], teixobactin [5], clovibactin [6], malacidin [7], and cilagicin [8]. Despite significant progress in the chemical synthesis of lipid II and its analogues, the

• , the chemical, chemoenzymatic, or biochemical synthesis of lipid II and its variants has been achieved by several research groups [10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27]. Nonetheless, considering the current state of knowledge, the chemical synthesis approach emerges as

Long oligodeoxynucleotides: chemical synthesis, isolation via catching-by-polymerization, verification via sequencing, and gene expression demonstration

• Yipeng Yin,
• Reed Arneson,
• Alexander Apostle,
• Adikari M. D. N. Eriyagama,
• Komal Chillar,
• Emma Burke,
• Martina Jahfetson,
• Yinan Yuan and
• Shiyue Fang

Beilstein J. Org. Chem. 2023, 19, 1957–1965, doi:10.3762/bjoc.19.146

• ligation from shorter 20 to 60 nt ODNs produced by automated de novo chemical synthesis. While these methods have made many projects in areas such as synthetic biology and protein engineering possible, they have various drawbacks. For example, they cannot produce genes and genomes with long repeats and

• have difficulty to produce sequences containing stable secondary structures. Here, we report a direct de novo chemical synthesis of 400 nt ODNs, and their isolation from the complex reaction mixture using the catching-by-polymerization (CBP) method. To determine the authenticity of the ODNs, 399 and

• to address all the aforementioned problems, such as generating sequences having highly stable secondary structures [18]. In this paper, we report a method to access long ODNs involving automated direct de novo chemical synthesis and isolation of full-length sequences using the catching-by

Photoredox catalysis enabling decarboxylative radical cyclization of γ,γ-dimethylallyltryptophan (DMAT) derivatives: formal synthesis of 6,7-secoagroclavine

• Alessio Regni,
• Francesca Bartoccini and
• Giovanni Piersanti

Beilstein J. Org. Chem. 2023, 19, 918–927, doi:10.3762/bjoc.19.70

• requires a multistep process in conventional chemical synthesis [39][40][41]. Among the various widely available and abundant substrates for photocatalyzed reactions, natural and unnatural α-amino acids play a very important role, given their paramount importance across several chemistry fields as well as

Asymmetric tandem conjugate addition and reaction with carbocations on acylimidazole Michael acceptors

• Brigita Mudráková,
• Renata Marcia de Figueiredo,
• Jean-Marc Campagne and
• Radovan Šebesta

Beilstein J. Org. Chem. 2023, 19, 881–888, doi:10.3762/bjoc.19.65

• solubility in water. Among exceptional properties belongs to easy post-transformation of acylimidazoles to common carbonyl analogs. These tunable properties allow the use of acylimidazoles in chemical biology research, which includes chemical synthesis of proteins/peptides, structure analysis, and functional

Palladium-catalyzed enantioselective three-component synthesis of α-arylglycine derivatives from glyoxylic acid, sulfonamides and aryltrifluoroborates

• Bastian Jakob,
• Nico Schneider,
• Luca Gengenbach and
• Georg Manolikakes

Beilstein J. Org. Chem. 2023, 19, 719–726, doi:10.3762/bjoc.19.52

• , e.g., the antiplatelet drug clopidogrel [7] or the β-lactam antibiotic amoxicillin [8] (Figure 1). Therefore, the chemical synthesis of α-aryglycines has received considerable attention. Among the different methods introduced over time, multicomponent reactions utilizing an in situ generated reactive

Synthesis of medium and large phostams, phostones, and phostines

• Jiaxi Xu

Beilstein J. Org. Chem. 2023, 19, 687–699, doi:10.3762/bjoc.19.50

• chemical synthesis of macrocyclic lactones which are the key structural motifs in some biologically active compounds, 14-methyl-2-phenoxy-1-oxa-2-phosphacyclotetradecane 2-oxide (74) was synthesized as the hapten from phenyl hydrogen (12-hydroxytridecyl)phosphonate (73) via Mitsunobu reaction. The

1,4-Dithianes: attractive C2-building blocks for the synthesis of complex molecular architectures

• Bram Ryckaert,
• Ellen Demeyere,
• Frederick Degroote,
• Hilde Janssens and
• Johan M. Winne

Beilstein J. Org. Chem. 2023, 19, 115–132, doi:10.3762/bjoc.19.12

• mixtures of the desired and undesired positional alkene isomer could be obtained. We believe an outstanding challenge in the field of chemical synthesis is to find mild and catalytic deprotection chemistries for dithiane-type systems, be they reductive, hydrolytic or oxidative. In particular, a more

Practical synthesis of isocoumarins via Rh(III)-catalyzed C–H activation/annulation cascade

• Qian-Ci Gao,
• Yi-Fei Li,
• Jun Xuan and
• Xiao-Qiang Hu

Beilstein J. Org. Chem. 2023, 19, 100–106, doi:10.3762/bjoc.19.10

• and diverse functionalization of the isocoumarin products highlight the tremendous synthetic potential of this methodology in chemical synthesis and drug discovery. Experimental A 10 mL screw-cap vial was charged with enaminone 1 (0.2 mmol), iodonium ylide 2 (0.6 mmol), [Cp*RhCl2]2 (6.2 mg, 5 mol

Combining the best of both worlds: radical-based divergent total synthesis

• Kyriaki Gennaiou,
• Antonios Kelesidis,
• Maria Kourgiantaki and
• Alexandros L. Zografos

Beilstein J. Org. Chem. 2023, 19, 1–26, doi:10.3762/bjoc.19.1

• chemoselective manner [3]. The development of persistent radicals [4] as synthons in chemical synthesis, coupled with the advancements in generating and manipulating transient radicals [5] as cross-coupling partners in an array of chemical reactions, gives access to a wide variety of “new” retrosynthetic

Synthesis of the biologically important dideuterium-labelled adenosine triphosphate analogue ApppI(d₂)

• Petri A. Turhanen

Beilstein J. Org. Chem. 2022, 18, 1466–1470, doi:10.3762/bjoc.18.153

• Petri A. Turhanen University of Eastern Finland, School of Pharmacy, Biocenter Kuopio, P.O. Box 1627, FIN-70211, Kuopio, Finland 10.3762/bjoc.18.153 Abstract The chemical synthesis of the dideuterium-labelled ATP analogue 1-adenosin-5’-yl-3-(3-methylbut-3-en-1,1-d2-1-ol) triphosphoric acid

Dissecting Mechanochemistry III

• Lars Borchardt and
• José G. Hernández

Beilstein J. Org. Chem. 2022, 18, 1454–1456, doi:10.3762/bjoc.18.150

• chemical synthesis [1][2]. Within this period, the Beilstein Journal of Organic Chemistry has organized two Thematic Issues (i.e., Mechanochemistry and Mechanochemistry II) to facilitate the open dissemination of the best research in the field of synthetic organic mechanochemistry. The great success of

• activation to advance chemical synthesis on various fronts. Therefore, we hope you enjoy reading the variety of manuscripts in this Thematic Issues as much as we enjoyed editing it, which was only possible thanks to the impeccable assistance by the Editorial Team of the Beilstein-Institut. Lars Borchardt and