gem-Difluorovinyl and trifluorovinyl Michael acceptors in the synthesis of α,β-unsaturated fluorinated and nonfluorinated amides

• Monika Bilska-Markowska,
• Marcin Kaźmierczak,
• Wojciech Jankowski and
• Marcin Hoffmann

Beilstein J. Org. Chem. 2024, 20, 2946–2953, doi:10.3762/bjoc.20.247

• importantly, the application of 8 equiv of tert-BuLi induced the formation of N-methylation products (Scheme 6). Compounds 15a (15a’) and 16a (16a’) existed as two rotamers, in ratios of 1:1.15 and 1:1.76, respectively, with the predominant cisoid isomer. Transoid (trans 15a(16a)) isomers contained a larger

• -unsaturated amides. Formation of β-fluorinated and nonfluorinated α,β-unsaturated amides. Michael addition of 1a–d with tert-BuLi. Michael addition of 2a–d with tert-BuLi. Formation of N-methylation products. Optimization of reaction conditions. Supporting Information Supporting Information File 40: Detailed

N-Glycosides of indigo, indirubin, and isoindigo: blue, red, and yellow sugars and their cancerostatic activity

• Peter Langer

Beilstein J. Org. Chem. 2024, 20, 2840–2869, doi:10.3762/bjoc.20.240

• ). Dehydrogenation of the latter with DDQ afforded the anomerically pure indol-N-glycoside β-26a which upon benzylation and methylation gave products β-27a and β-27b, respectively. Iodination gave products β-28a and β-28b, however, due to the basic reaction conditions (I2, NaOH, DMF), ether rather than ester

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

• ) starting from the oxoester 3, which is conveniently available from propenylpiperidine (2) [27] and methyl acrylate [28]. The Wittig reagent 1-methylheptyltriphenylphosphonium iodide (5) was prepared by methylation of the Wittig salt of heptyl iodide (4). A Wittig reaction with 3 afforded an E/Z mixture of

• heated to 60 °C for 60 min and then excess MSTFA was removed with a stream of N2. The sample was taken up in CH2Cl2 and analyzed by GC–MS [42]. Methylation with TMSH: An extract (100 µL) in a 2 mL GC vial was mixed with 50 µL trimethylsulfonium hydroxide in methanol (TMSH, 0.25 M) and allowed to stand at

A review of recent advances in electrochemical and photoelectrochemical late-stage functionalization classified by anodic oxidation, cathodic reduction, and paired electrolysis

• Nian Li,
• Ruzal Sitdikov,
• Ajit Prabhakar Kale,
• Joost Steverlynck,
• Bo Li and
• Magnus Rueping

Beilstein J. Org. Chem. 2024, 20, 2500–2566, doi:10.3762/bjoc.20.214

• bioactive compounds such as caffeine and prothioconazole (Scheme 2a). Additionally, Lin, Terrett and Neurock's group [8] reported the electrochemical C(sp3)–H methylation of complex molecules. This strategy enabled the synthesis of the "magic methyl" product, a TRPA1 antagonist (Scheme 2b). C–H bond

Asymmetric organocatalytic synthesis of chiral homoallylic amines

• Nikolay S. Kondratyev and
• Andrei V. Malkov

Beilstein J. Org. Chem. 2024, 20, 2349–2377, doi:10.3762/bjoc.20.201

• synthesis, the deprotected derivatives such as 69 are desired for the synthesis of natural products. Therefore, an easy-to-perform two-step deprotection procedure was developed that is based on methylation of the phenolic hydroxy group with an excess of MeI in acetone at rt (68), followed by oxidative

Natural resorcylic lactones derived from alternariol

• Joachim Podlech

Beilstein J. Org. Chem. 2024, 20, 2171–2207, doi:10.3762/bjoc.20.187

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

• mammalian glycans rely on a group of “only” 10 monosaccharide units, they can be assembled, in linear or branched chains, through different glycosidic linkages and diverse spatial orientations, which can also undergo modifications, such as methylation, sulfation, and phosphorylation, resulting in a plethora

• able to add branching points and some sugar derivatisation, including methylation and acetylation. The user has also the possibility to choose the ring type and the anomeric configuration of each monosaccharide. Once the structure is complete, it is possible to download not only the generated .pdb

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

• (hetero)aryl-3-(methylthio)-2-propenones 94, are accessible through Claisen-type thioacylation of methylketones, followed by methylation. These intermediates serve as precursors for the concomitant cyclization with arylhydrazines in a consecutive multicomponent reaction to regioselectively give pyrazoles

Allostreptopyrroles A–E, β-alkylpyrrole derivatives from an actinomycete Allostreptomyces sp. RD068384

• Marwa Elsbaey,
• Naoya Oku,
• Mohamed S. A. Abdel-Mottaleb and
• Yasuhiro Igarashi

Beilstein J. Org. Chem. 2024, 20, 1981–1987, doi:10.3762/bjoc.20.174

• , 332.1832; found, 332.1838. Methylation of 1 Allostreptopyrrole A (1, 2.0 mg, 0.007 mmol) and K2CO3 (4.4 mg, 0.032 mmol) were stirred in dry DMF (0.5 mL) at 50 °C for 10 min. Methyl iodide (19 μL, 0.32 mmol) was added and the mixture was stirred at this temperature for 12 h [29]. Reaction completion was

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

• , introduce hydroxy groups at C8 and C16 to produce FD-8β,16-diol (7), and BscE-catalyzed O-methylation generates the putative intermediate 8. The subsequent oxidative allylic rearrangement (8→9), catalyzed by the nonheme iron(II) and 2-oxoglutarate (Fe(II)/2OG)-dependent dioxygenase BscD, was a key step

• pentacyclic core scaffold of 5. Overall, the single NRPS module SfmC is responsible for the construction of the highly functionalized scaffold 93 from the two simple amino acid derivatives 86 and 88. After NRPS-catalyzed scaffold assembly, SfmM1-mediated N-methylation at N12, and subsequent SfmO2/O4-promoted

• chemo-enzymatic total synthesis of jorunnamycin A (103). SfmC-catalyzed enzymatic conversion followed by cyanation and N-methylation also converted substrate analog 101 to the corresponding pentacyclic tertiary amine 102 in 18% overall yield based on peptidyl aldehyde 101. Subsequent simple chemical

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

• allowing methylation at various positions. The different possible acceptor regions in ribosomally synthesised peptides are described in this article. Furthermore, we will discuss the potential application of these methyltransferases as powerful biocatalytic tools in the synthesis of modified peptides and

• other bioactive compounds. By providing an overview of the various methylation options available, this review is intended to emphasise the biocatalytic potential of RiPP methyltransferases and their impact on the field of natural product chemistry. Keywords: biocatalysis; methylation; post

• contrast to ribosomal peptide biosynthesis, many non-proteinogenic amino acids can be incorporated as building blocks. However, RiPP pathways are more flexible and they represent interesting biotechnological production routes. In this review, we will focus on post-translational methylation reactions. A

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

• interactions in the marine environment may be broadly shared [132]. Further examples of shared natural products are delineated below. Aliphatic and aromatic hydrocarbons (2Z,4E)-3-Methyl-2,4-decadienoic acid (25, Figure 9), an unsaturated fatty acid with unusual methylation pattern was isolated and identified

Synthesis of 2-benzyl N-substituted anilines via imine condensation–isoaromatization of (E)-2-arylidene-3-cyclohexenones and primary amines

• Lu Li,
• Na Li,
• Xiao-Tian Mo,
• Ming-Wei Yuan,
• Lin Jiang and
• Ming-Long Yuan

Beilstein J. Org. Chem. 2024, 20, 1468–1475, doi:10.3762/bjoc.20.130

• could be easily carried out by catalytic hydrogenation to produce 6 (Scheme 6a). On the other hand, 4ax could smoothly undergo N-methylation with MeI to give product 7 in quantitative yield (Scheme 6b). Conclusion In conclusion, we have developed an efficient method to rapidly synthesize 2-benzyl-N

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 several alcohols and primary amines in the presence of t-BuOK (0.75 equiv) in toluene at 80 °C for 24–48 h and selectively produced the N-alkylated products with good yields (Scheme 3). More interestingly, the first non-noble-metal catalyzed the most challenging N-methylation of amines with

• generation of manganese PNP pincer complexes for the N-methylation of aromatic amines with methanol [35]. Various primary anilines were methylated selectively with good yields using Mn2 (2 mol %) and t-BuOK (0.5 equiv) as a base at 100 °C for 16 h (Scheme 4). Compared to their previous report, the N

• -methylation of amines with methanol was achieved with lower catalyst and base loading. Sortais et al. reported an elegant example of a manganese-catalyzed N-methylation of primary amines with methanol using catalytic amounts of base. They synthesized a novel Mn(I) complex bearing a bis(diaminopyridine

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

• methyltransferase (IPPMT) from Streptomyces monomycini. Notably, polymethylated C41, C42, and C43 carotenoids were produced by combining the endogenous terpene biosynthesis pathway and IPPMT, demonstrating the potential of this approach to expand the terpene structural space [52]. In addition to methylation of the

• coelicolor [55] (Figure 8a). Further structure-based engineering of BezA successfully repurposed it to catalyze the unprecedented C6-methylation of FPP by a single residue substitution in its substrate-binding pocket [55]. Moreover, efforts have also been made to engineer the TSs to modulate their product

• selectivity with the noncanonical prenyl substrates. To enable the biotechnological synthesis of irregular terpenes, the product selectivity of 2-methylenebornane synthase from Pseudomonas fluorescenes was altered using a semi-rational engineering approach [56]. In contrast to GPP methylation, modification of

(Bio)isosteres of ortho- and meta-substituted benzenes

• H. Erik Diepers and
• Johannes C. L. Walker

Beilstein J. Org. Chem. 2024, 20, 859–890, doi:10.3762/bjoc.20.78

• methylation of the intermediate diacid. As for the 1,2-cubanes, the authors were able to derivatise this general building block into a range of other 1,3-cubanes via metallophotoredox catalysis using acid 167 and redox active esters 168 and 169 (Scheme 17B) [51]. Arylation (to 170), amination (to 171) and

Introduction of a human- and keyboard-friendly N-glycan nomenclature

• Friedrich Altmann,
• Johannes Helm,
• Martin Pabst and
• Johannes Stadlmann

Beilstein J. Org. Chem. 2024, 20, 607–620, doi:10.3762/bjoc.20.53

• -vertebrates contain numerous “unusual” and remarkable structural features such as methylation, sulfation, and zwitterionic non-sugar substituents, again glucuronic acid and often unusual architectures such as substituted core-fucose just as an example [44][52]. While the methylated moss glycans are accessible

Pseudallenes A and B, new sulfur-containing ovalicin sesquiterpenoid derivatives with antimicrobial activity from the deep-sea cold seep sediment-derived fungus Pseudallescheria boydii CS-793

• Zhen Ying,
• Xiao-Ming Li,
• Sui-Qun Yang,
• Hong-Lei Li,
• Xin Li,
• Bin-Gui Wang and
• Ling-Hong Meng

Beilstein J. Org. Chem. 2024, 20, 470–478, doi:10.3762/bjoc.20.42

• II, which could be transferred to III by cyclization and epoxidation. Oxidation and methylation of intermediate III would produce IV. Compounds 1–4 could be obtained by nucleophilic attack at C-8 with the hydroxy or thiol group from IV via intermediate V, followed by oxidation and cyclization

Benzoimidazolium-derived dimeric and hydride n-dopants for organic electron-transport materials: impact of substitution on structures, electrochemistry, and reactivity

• Swagat K. Mohapatra,
• Khaled Al Kurdi,
• Samik Jhulki,
• Georgii Bogdanov,
• John Bacsa,
• Maxwell Conte,
• Tatiana V. Timofeeva,
• Seth R. Marder and
• Stephen Barlow

Beilstein J. Org. Chem. 2023, 19, 1651–1663, doi:10.3762/bjoc.19.121

• , for example through hydride abstraction by Ph3C+ [13]. Alternatively, they can also be obtained by condensation of N,N'-dimethylphenylene-1,2-diamine derivatives with acid chlorides, YCOCl, or through the methylation of 2-substituted benzoimidazoles [24], which in turn can be obtained from

Synthesis and biological evaluation of Argemone mexicana-inspired antimicrobials

• Jessica Villegas,
• Bryce C. Ball,
• Katelyn M. Shouse,
• Caleb W. VanArragon,
• Ashley N. Wasserman,
• Hannah E. Bhakta,
• Allen G. Oliver,
• Danielle A. Orozco-Nunnelly and
• Jeffrey M. Pruet

Beilstein J. Org. Chem. 2023, 19, 1511–1524, doi:10.3762/bjoc.19.108

• of two substituted arylboronic acids, followed by N-methylation, and final ring-closure via Bischler–Napieralski conditions [45][47][48]. These steps provided chelerythrine variants C1–C4, with structural variability stemming from the initial substituted tetralone (R1/R2) and/or the arylboronic acid

Functions of enzyme domains in 2-methylisoborneol biosynthesis and enzymatic synthesis of non-natural analogs

• Binbin Gu,
• Lin-Fu Liang and
• Jeroen S. Dickschat

Beilstein J. Org. Chem. 2023, 19, 1452–1459, doi:10.3762/bjoc.19.104

• model was proposed that proceeds through the S-adenosylmethionine (SAM) dependent methylation of geranyl diphosphate (GPP) to 2-methyl-GPP (2-Me-GPP), followed by a terpene cyclisation to 1 (Scheme 1A) [10]. The cyclisation cascade requires isomerisation to (R)-2-methyllinalyl diphosphate [22], followed

• , the pathway to 1 can be reconstituted in vitro using the methyltransferase humMT from Micromonospora humi for the methylation of dimethylallyl diphosphate (DMAPP) to 2-methylisopentenyl diphosphate (2-Me-IPP) [25], followed by coupling with DMAPP to 2-Me-GPP and terpene cyclisation using farnesyl

• ) Enzyme precipitation after 12 h in elution buffer at 4 °C. The biosynthesis of 2-methylisoborneol (1). A) SAM-dependent methylation of GPP to 2-Me-GPP by GPPMT and terpene cyclisation to 1 by 2MIBS. B) Non-natural formation using the enzymes humMT for the methylation of DMAPP to 2-Me-IPP, FPPS for the

α-(Aminomethyl)acrylates as acceptors in radical–polar crossover 1,4-additions of dialkylzincs: insights into enolate formation and trapping

• Angel Palillero-Cisneros,
• Paola G. Gordillo-Guerra,
• Fernando García-Alvarez,
• Olivier Jackowski,
• Franck Ferreira,
• Fabrice Chemla,
• Joel L. Terán and
• Alejandro Perez-Luna

Beilstein J. Org. Chem. 2023, 19, 1443–1451, doi:10.3762/bjoc.19.103

• chiral induction. It should be mentioned here that our attempts to trap the intermediate enolate with a carbon electrophile other than carbonyl acceptors (i.e., iodomethane) were not successful and protodemetalation of the enolate outcompeted methylation. Conclusion In conclusion, we have demonstrated

Synthesis of ether lipids: natural compounds and analogues

• Marco Antônio G. B. Gomes,
• Alicia Bauduin,
• Chloé Le Roux,
• Romain Fouinneteau,
• Wilfried Berthe,
• Mathieu Berchel,
• Hélène Couthon and
• Paul-Alain Jaffrès

Beilstein J. Org. Chem. 2023, 19, 1299–1369, doi:10.3762/bjoc.19.96

• building unit. The synthesis of this intermediate was prepared as a racemic (Figure 24) or stereocontrolled form. One strategy to prepare rac-AMG starts from 24.1 (24.1 can be prepared from glycerol) [120][121]. Methylation of 24.1 is readily achieved by the deprotonation of the secondary alcohol with NaH

• followed by the methylation with iodomethane. Then, the cleavage of the acetal occurs by reaction with BH3·THF to give 24.3. Then, the primary alcohol was alkylated with the lipid chain (e.g., C16H33) to produce 24.4. Finally, the benzyl protecting group was removed by catalytic hydrogenolysis to produce

• mono-unsaturated lipid chain [142]. This synthesis starts from ᴅ-mannitol that was protected with 4-methoxybenzaldehyde to produce 32.1 (Figure 32) [143]. Then, the methylation of the two alcohol functions produced 32.2. A regioselective reductive cleavage of the acetal was achieved by using either

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

• -catalyzed radical decarboxylative cyclization. Synthesis of compound 5. Photoredox-catalyzed radical decarboxylative cyclization of 5. Synthesis of tryptophan derivatives 8 and 10. Methylation of 11 and the formal total synthesis of (±)-6,7-secoagroclavine. Photoredox-catalyzed radical decarboxylative

Transition-metal-catalyzed domino reactions of strained bicyclic alkenes

• Austin Pounder,
• Eric Neufeld,
• Peter Myler and
• William Tam

Beilstein J. Org. Chem. 2023, 19, 487–540, doi:10.3762/bjoc.19.38

• amides was quite wide, including different EWGs and EDGs, as well as heterocycles, ortho-substitution was not tolerated. The authors applied the methodology for the synthesis of biologically important benzo[c]phenanthridine derivatives 117. Through methylation and subsequent aromatization of the