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

• , coenzyme A (CoA), phosphopantetheine, and thiophenol. The thiophenol thioesters exhibited the highest cyclization rates, suggesting that chemical reactivity precedes cofactor recognition [54]. Moreover, CDA3 TE had a broad substrate spectrum, even indicating activity to cyclize daptomycin and its analogs

SOMOphilic alkyne vs radical-polar crossover approaches: The full story of the azido-alkynylation of alkenes

• Julien Borrel and
• Jerome Waser

Beilstein J. Org. Chem. 2024, 20, 701–713, doi:10.3762/bjoc.20.64

• reactivity of the C-centered radical with Ph-EBX (2). Aliphatic alkenes, enamides, enol ethers and acrylates were tested in the reaction but did not lead to formation of the desired products (Scheme S1, Supporting Information File 1). In almost all cases >70% of the EBX reagent was left after 16 hours of

• solubility in DME, which might cause the low yield observed. Ynonetrifluoroborate 5d could not be introduced as nucleophile, probably due to its reduced reactivity caused by the electron-withdrawing acyl group. Unfortunately, although Molander previously reported the use of vinyl-trifluoroborate 11 to trap

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

• [9][10] are commonly employed for quinazoline modification (Scheme 1). Existing literature underscores the reactivity of the C4 position in aromatic nucleophilic substitutions of quinazolines I while achieving regioselective replacement at the C2 position poses challenges [11]. Modification of the C2

• reactivity in the SNAr reactions in comparison to polar solvents such as DMSO and DMF. This is explained by solvent hydrogen bond acidity and basicity descriptors α and β, for example, α(DMSO) = 0, β(DMSO) = 0.88, α(MeOH) = 0.43, β(MeOH) = 0.47. The rate constant of the SNAr process escalates with an

• substrates, but the step sulfoxide → sulfone was entirely slower and required stirring overnight (except for 8d (R = iC3H7)). With 2-chloro-6,7-dimethoxy-4-sulfonylquinazolines 8 in hand, we started to explore the reactivity in SNAr reactions (Scheme 5). Sulfonyl group dance reactions did not work in

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

• a highly emerging area of research and exhibit complementary reactivity to those well-developed carbene-mediated MCRs [30][31][32][33][34][35][36][37][38][39][40][41][42]. In the radical-mediated difunctionalization of alkenes, the carbon-centered radical species from a diazo compound can add to

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

• +@C60 has been the focus of intensive studies in chemistry, physics, and related interdisciplinary fields over the past 13 years [9]. A noteworthy discovery during these investigations is the significant enhancement of reactivity arising from the encapsulated Li+. Both experimental and theoretical

• approaches have diligently explored the details of reaction kinetics, quantitatively elucidating the impact of encapsulated Li+ on the reactivity of the outer fullerene cage as a specialized “encapsulated” Lewis acid catalyst [10][11]. While previous studies have revealed valuable insights, such as

• range of unsaturated substrates having a relatively lower HOMO level. With the previously uncovered reactivity of Li+@C60 in hand, we synthesized Li+@C60 derivatives in this study through the thermal [2 + 2] cycloaddition of styrene derivatives, which do not react with empty C60 through the same

HPW-Catalyzed environmentally benign approach to imidazo[1,2-a]pyridines

• Luan A. Martinho and
• Carlos Kleber Z. Andrade

Beilstein J. Org. Chem. 2024, 20, 628–637, doi:10.3762/bjoc.20.55

• reactivity of the imine formation [24]. The most common catalysts are those derived from triflate salts such as Sc(OTf)3 [25], Yb(OTf)3 [26], In(OTf)3 [27] and Gd(OTf)3 [28], and inorganic Brønsted or Lewis acids like HClO4 [29], ZrCl4 [30], InCl3 [31], BiCl3 [32], RuCl3 [33], NH4Cl [34], HCl [35], LaCl3

• obtained. Meta,para-substituted aromatic aldehydes showed a high reactivity with yields greater than 84% for products 4s–w. Notably, the use of tri-substituted aromatic aldehydes gave imidazo[1,2-a]pyridines 4x–z in moderate to excellent yields (35–99%), though the hydroxy substituent at the ortho position

• and methyl isocyanoacetate furnished the desired products (4ff–ii and 4jj–ll, respectively) in moderate yields (55–68%), possibly due to the lower reactivity of these isocyanides compared to tert-butyl and cyclohexyl isocyanides [54]. In the latter cases, transesterification of the ester group with

A laterally-fused N-heterocyclic carbene framework from polysubstituted aminoimidazo[5,1-b]oxazol-6-ium salts

• Andrew D. Gillie,
• Matthew G. Wakeling,
• Bethan L. Greene,
• Louise Male and
• Paul W. Davies

Beilstein J. Org. Chem. 2024, 20, 621–627, doi:10.3762/bjoc.20.54

• provide scope to influence the reactivity profile of their resulting metal complexes through steric shielding, direct stabilising interactions with the metal, or by proximal effects to reactive species. Given the sensitivity of metal catalysis to even subtle steric and electronic changes in the ligand

• seen with imidazolidines (cf. for IPr TEP[Ir] = 2050.2 cm−1) [34]. A benchmarking exercise was then performed looking at the reactivity of 13 compared against reaction of symmetrical IPrAuCl across a range of known gold-mediated transformations of alkynes featuring intermolecular attack [35

• ) complex is catalytically competent across several transformations with excellent conversions at 1 mol % loading and with broadly comparable reactivity to IPrAuCl. Having validated the AImOx motif as a viable ligand platform for development, further elaboration and applications will be reported in due

Entry to new spiroheterocycles via tandem Rh(II)-catalyzed O–H insertion/base-promoted cyclization involving diazoarylidene succinimides

• Alexander Yanovich,
• Anastasia Vepreva,
• Ksenia Malkova,
• Grigory Kantin and
• Dmitry Dar’in

Beilstein J. Org. Chem. 2024, 20, 561–569, doi:10.3762/bjoc.20.48

• obtained when unsubstituted propiolic acid was used as OH-substrate (2g). The reasons for this result may be due to the increased reactivity of the terminal triple bond of the propiolic moiety, which favors the participation of the OH-insertion intermediate in side processes. However, we were unable to

• by the higher reactivity of benzyl bromide and the lower conformational mobility of the side chain with the ortho-phenylene link. As a result, new spirocyclic compounds 5 were obtained in high (5a,b) or moderate (5c) yields. With some other bromo-substituted OH substrates, we obtained O–H insertion

Synthesis and biological profile of 2,3-dihydro[1,3]thiazolo[4,5-b]pyridines, a novel class of acyl-ACP thioesterase inhibitors

• Jens Frackenpohl,
• David M. Barber,
• Guido Bojack,
• Birgit Bollenbach-Wahl,
• Ralf Braun,
• Rahel Getachew,
• Sabine Hohmann,
• Kwang-Yoon Ko,
• Karoline Kurowski,
• Bernd Laber,
• Rebecca L. Mattison,
• Thomas Müller,
• Anna M. Reingruber,
• Dirk Schmutzler and
• Andrea Svejda

Beilstein J. Org. Chem. 2024, 20, 540–551, doi:10.3762/bjoc.20.46

• introducing a nonaromatic motif via preparation of the novel 2,3-dihydro[1,3]thiazolo[4,5-b]pyridines 7. Results and Discussion Although the 2,3-dihydro[1,3]thiazolo[4,5-b]pyridine scaffold looks relatively simple at a first glance, it displays a very different reactivity compared to the parent naphthyridine

Switchable molecular tweezers: design and applications

• Pablo Msellem,
• Maksym Dekthiarenko,
• Nihal Hadj Seyd and
• Guillaume Vives

Beilstein J. Org. Chem. 2024, 20, 504–539, doi:10.3762/bjoc.20.45

• cooperative catalytic effect of the two Cr(III) units. Control experiments without K+, or in the presence of competitive crown ether presented a reduced conversion rate and enantioselectivity, proving the conformation change in the reactivity of the system. Anion responsive tweezers The main types of anion

Ligand effects, solvent cooperation, and large kinetic solvent deuterium isotope effects in gold(I)-catalyzed intramolecular alkene hydroamination

• Ruichen Lan,
• Brock Yager,
• Yoonsun Jee,
• Cynthia S. Day and
• Amanda C. Jones

Beilstein J. Org. Chem. 2024, 20, 479–496, doi:10.3762/bjoc.20.43

• observed rate was outside of one standard deviation from the average of 3 trials, confirming the overall reactivity trend. In hindsight, the ligand effect here may be expected to be small since the bisbiphenyl scaffold contains 2 of 3 identical substituents. Nevertheless, these comparisons confirm the

• meaningful determination of an actual ligand effect on reactivity (see Supporting Information File 1, Figures S25 and S26). These experiments indicate that with highly reactive catalysts, productive reactions can take place despite a drop in concentration of non-decomposed catalyst. The true reactivity of

• the cyclization rate of alkene urea 1a with JPhosAu(NCCH3)SbF6 (5) in CH2Cl2 (Table 7, Figure 5). In this case an initial boost in reactivity was observed with 5 and 25 μL of CH3OD, followed by a drop-off in reactivity at 55 μL (even slower than in pure CH2Cl2). In all three experiments, rapid H/D

Synthesis of 2,2-difluoro-1,3-diketone and 2,2-difluoro-1,3-ketoester derivatives using fluorine gas

• Alexander S. Hampton,
• David R. W. Hodgson,
• Graham McDougald,
• Linhua Wang and
• Graham Sandford

Beilstein J. Org. Chem. 2024, 20, 460–469, doi:10.3762/bjoc.20.41

• the difluorination of 1a with fluorine gas as a model process to assess how direct fluorination reactions could be achieved using reaction additives. The lack of reactivity of 1a towards one equiv of fluorine gas when compared with strong reactivity towards Selectfluor suggested the use of a cationic

(E,Z)-1,1,1,4,4,4-Hexafluorobut-2-enes: hydrofluoroolefins halogenation/dehydrohalogenation cascade to reach new fluorinated allene

• Nataliia V. Kirij,
• Andrey A. Filatov,
• Yurii L. Yagupolskii,
• Sheng Peng and
• Lee Sprague

Beilstein J. Org. Chem. 2024, 20, 452–459, doi:10.3762/bjoc.20.40

• reactivity we performed the reaction with iodine. All experiments were carried out in THF, N-methylpyrrolidone and sulfolane with iodine in the presence of a source of fluoride ion. The best result was observed when the reaction was carried out in dry sulfolane with a two-fold excess of iodine and 1.5-fold

• information about their reactivity in the literature. Therefore, we became interested in exploring the synthetic potential of halo-bistrifluoromethyl-containing olefins 3, 6 and 7, which are readily available and can be synthesized in the laboratory in appreciable amounts. Fluorinated organic compounds are

• . Although olefin 3 has been available for many decades, only one paper describes its lithiation with methyllithium and the subsequent reaction of the lithium compound with trifluoroacetophenone [27]. We began our research on the reactivity of the bromobutenes 3a,b with isopropylmagnesium chloride (iPrMgCl

Mono or double Pd-catalyzed C–H bond functionalization for the annulative π-extension of 1,8-dibromonaphthalene: a one pot access to fluoranthene derivatives

• Nahed Ketata,
• Linhao Liu,
• Ridha Ben Salem and
• Henri Doucet

Beilstein J. Org. Chem. 2024, 20, 427–435, doi:10.3762/bjoc.20.37

• appropriate positions should enable them to be introduced regioselectively at the desired fluoranthene position, due to the greater reactivity of some of the C–H bonds in Pd-catalyzed direct arylations. First, we used 1,4-difluorobenzene under optimized reaction conditions, – i.e., 5 mol % PdCl(C3H5)(dppb

• ]thiophenes [25]. In these reactions, the C–H bonds at the C2 and C3 positions of the thienyl unit were functionalized. In order to obtain acenaphtho[1,2-c]thiophenes and related compounds that are not easily accessible [33][34][35][36][37][38], we investigated the reactivity of three 5-membered heteroarenes

• in 63% yield without cleavage of the C–Cl bond. The use of 3-substituted arylboronic acids is also possible. The reaction of 3-nitrophenylboronic acid gave product 24 in 58% yield. Access to products 25 and 26 by activating two C–H bonds is not possible due to the higher reactivity of the C–H bond

Green and sustainable approaches for the Friedel–Crafts reaction between aldehydes and indoles

• Periklis X. Kolagkis,
• Eirini M. Galathri and
• Christoforos G. Kokotos

Beilstein J. Org. Chem. 2024, 20, 379–426, doi:10.3762/bjoc.20.36

• mixture was heated at 50 °C. The generality of this approach was also excellent with substituted ketones, aldehydes and indoles, all forming the respective BIMs in yields ranging from 65–98% with ketones displaying the lowest reactivity, requiring up to 12 h for reaction completion. Thus, this protocol is

• to prove the generality of this protocol. Non-activated aldehydes (not bearing an electron-withdrawing group) and heteroaromatic aldehydes showed a lower reactivity and 30 mol % of catalyst 29 was required to achieve high yields (81–95%). In contrast, activated or aliphatic aldehydes afforded

• efficiency would not diminish even after 3 cycles [99]. Several substituted indoles, aldehydes and ketones reacted in good yields (74–98%), with ketones requiring longer reaction rates of 3 hours, due to their lower reactivity. The electron-donating or withdrawing effects of the substituents of the benzene

Mechanisms for radical reactions initiating from N-hydroxyphthalimide esters

• Carlos R. Azpilcueta-Nicolas and
• Jean-Philip Lumb

Beilstein J. Org. Chem. 2024, 20, 346–378, doi:10.3762/bjoc.20.35

• Carlos R. Azpilcueta-Nicolas Jean-Philip Lumb Department of Chemistry, McGill University, 801 Sherbrooke Street West, Montreal, Quebec H3A 0B8, Canada 10.3762/bjoc.20.35 Abstract Due to their ease of preparation, stability, and diverse reactivity, N-hydroxyphthalimide (NHPI) esters have found

• of parameters with which to control reactivity. In this perspective, we provide an overview of the different mechanisms for radical reactions involving NHPI esters, with an emphasis on recent applications in radical additions, cyclizations and decarboxylative cross-coupling reactions. Within these

• , leading to their strategic incorporation as "synthons" in modern organic chemistry, with complementary reactivity to more common polar reaction manifolds [12][13][14][15]. The utility of radicals has also been expanded through the recent development of transformations involving radical-polar crossover

Synthesis of π-conjugated polycyclic compounds by late-stage extrusion of chalcogen fragments

• Aissam Okba,
• Pablo Simón Marqués,
• Kyohei Matsuo,
• Naoki Aratani,
• Hiroko Yamada,
• Gwénaël Rapenne and
• Claire Kammerer

Beilstein J. Org. Chem. 2024, 20, 287–305, doi:10.3762/bjoc.20.30

• , and this reactivity pattern was exploited as early as in the 1950s to generate in a controlled way polycyclic aromatic compounds from isolable heteropine precursors. By way of example, the phenanthrene derivative 2 was obtained by heating the dibenzo[b,f]thiepine precursor 1 in the presence of copper

• thiepine precursor 3a exhibited a mass decrease at 300 °C in agreement with the expected elimination of sulfur to yield almost quantitatively the corresponding PBI 6a. Its sulfoxide analogue 4a exhibited higher thermal reactivity, with the loss of SO identified at lower temperature (225 °C). As a proof of

• helical S- and Se-doped seco-HBCs 28b and 28c were thus obtained as racemic mixtures in three steps from dibenzoheteropines 23b and 23c in 45% and 18% overall yield, respectively. To evaluate the impact of the heteroatom oxidation state on reactivity, the sulfur and selenium oxides were next prepared via

Unveiling the regioselectivity of rhodium(I)-catalyzed [2 + 2 + 2] cycloaddition reactions for open-cage C₇₀ production

• Cristina Castanyer,
• Anna Pla-Quintana,
• Anna Roglans,
• Albert Artigas and
• Miquel Solà

Beilstein J. Org. Chem. 2024, 20, 272–279, doi:10.3762/bjoc.20.28

• to be able to produce meaningful changes in the reactivity of the cage [28][29][30][31][32]. In 2018, our group reported a catalytic process to transform C60 in bis(fulleroid) derivatives [33][34][35]. This transformation encompassed a partially intermolecular Rh-catalyzed [2 + 2 + 2] cycloaddition

Nucleophilic functionalization of thianthrenium salts under basic conditions

• Xinting Fan,
• Duo Zhang,
• Xiangchuan Xiu,
• Bin Xu,
• Yu Yuan,
• Feng Chen and
• Pan Gao

Beilstein J. Org. Chem. 2024, 20, 257–263, doi:10.3762/bjoc.20.26

• -metal-catalyzed cross-coupling [32][33] and aminofunctionalization [34] of alkenes were achieved, benefiting from the unique reactivity of organothianthrenium species that are generated through the reaction of alkenes and thianthrene sulfoxide (TT=O) or thianthrene (TT) (Scheme 1b). Alcohols are widely

Catalytic multi-step domino and one-pot reactions

• Svetlana B. Tsogoeva

Beilstein J. Org. Chem. 2024, 20, 254–256, doi:10.3762/bjoc.20.25

• of transannular cycloadditions of cycloalkenone hydrazones catalyzed by BINOL-derived phosphoric acid are reported in the Full Research Paper by Vicario, Merino, and co-workers [10]. Their methodologies can now be used to predict the reactivity of different substrates in other cycloaddition reactions

Substitution reactions in the acenaphthene analog of quino[7,8-h]quinoline and an unusual synthesis of the corresponding acenaphthylenes by tele-elimination

• Ekaterina V. Kolupaeva,
• Narek A. Dzhangiryan,
• Alexander F. Pozharskii,
• Oleg P. Demidov and
• Valery A. Ozeryanskii

Beilstein J. Org. Chem. 2024, 20, 243–253, doi:10.3762/bjoc.20.24

• make molecule 5 (and derivatives) more rigid and flat when compared to compound 3 but it will also affect its reactivity and the sites of functionalization. This work is devoted to the clarification of this circumstance with substitution and elimination reactions chosen as the key transformations. The

Metal-catalyzed coupling/carbonylative cyclizations for accessing dibenzodiazepinones: an expedient route to clozapine and other drugs

• Amina Moutayakine and
• Anthony J. Burke

Beilstein J. Org. Chem. 2024, 20, 193–204, doi:10.3762/bjoc.20.19

• . The reactivity of Co2CO8 as CO surrogate was also explored, in this case the reaction afforded the DBDAP product 4a in 55% yield (entry 6, Table 3). Molybdenum hexacarbonyl (Mo(CO)6), was shown to be a powerful CO surrogate in this carbonylative intramolecular cyclization. The efficacy of Mo(CO)6 is

Comparison of glycosyl donors: a supramer approach

• Anna V. Orlova,
• Nelly N. Malysheva,
• Maria V. Panova,
• Nikita M. Podvalnyy,
• Michael G. Medvedev and
• Leonid O. Kononov

Beilstein J. Org. Chem. 2024, 20, 181–192, doi:10.3762/bjoc.20.18

• (trifluoroacetyl vs chloroacetyl), at different concentrations (0.05 and 0.15 mol·L−1) led to mutually excluding conclusions concerning their relative reactivity and selectivity, which prevented us from revealing a possible influence of remote protective groups at O-9 on glycosylation outcome. According to the

• and straightforward as it is usually considered. Keywords: concentration; glycosylation; protecting groups; reactivity; sialic acids; stereoselectivity; Introduction Glycoconjugates containing sialic acid occur on the surface of all cell types in a variety of organisms. They participate in a broad

• critical [57][62] concentrations that separate the concentration ranges, where supramers of similar structures hence chemical properties exist, from other concentration ranges, where supramers that are organized differently and have modified chemical properties (reactivity, selectivity) are present [35

Copper-promoted C5-selective bromination of 8-aminoquinoline amides with alkyl bromides

• Changdong Shao,
• Chen Ma,
• Li Li,
• Jingyi Liu,
• Yanan Shen,
• Chen Chen,
• Qionglin Yang,
• Tianyi Xu,
• Zhengsong Hu,
• Yuhe Kan and
• Tingting Zhang

Beilstein J. Org. Chem. 2024, 20, 155–161, doi:10.3762/bjoc.20.14

• such as 2d, 2e, and 2f performed well, affording the brominated product 3aa in excellent yields (90–99%). However, transformations of amide 1a to the brominated product 3aa employing unactivated alkyl bromides (2g–i) as reaction partners proceeded with low efficiency (0–53%). Notably, the reactivity of

• primary alkyl bromides is higher than that of secondary alkyl bromides, while the reactivity of tertiary alkyl bromides is the lowest (2a–c, 2g–i). Finally, dibromomethane (2j) proceeded well in the reaction, furnishing 3aa in 65% yield. As showcased in Scheme 4, this methodology is also applicable to

Perspectives on push–pull chromophores derived from click-type [2 + 2] cycloaddition–retroelectrocyclization reactions of electron-rich alkynes and electron-deficient alkenes

• Michio Yamada

Beilstein J. Org. Chem. 2024, 20, 125–154, doi:10.3762/bjoc.20.13

• [4][5][7]. Notably, the N,N-dimethylanilino (DMA) moiety activates the reactivity of the neighboring alkyne moiety so strongly that the [2 + 2] CA–RE reactions with electron-deficient olefins proceed seamlessly [15][16] even when the terminus of the alkyne moiety is substituted by a cyano group [17

• the DA reaction, leading to the efficient generation of the anthracenyl TCBD 19. Concerning [2 + 2] CA–RE reactions, studies have shown that alkynes exhibiting angular distortion exhibit high reactivity toward electron-deficient alkenes independent of the presence or absence of electron-donating

• substituents on the alkynes. The remarkable reactivity displayed by angle-strained alkynes makes them highly valuable tools in biorthogonal chemistry [107][108][109]. The reaction between dibenzo-fused cyclooctyne 20 and TCNE was observed to occur at room temperature, quantitatively yielding 22, wherein the