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

• dependence [95]. On the other hand, simple benzyl cations can undergo more controlled (3 + 2) annulations, as is illustrated by the long-known Friedel–Crafts-type acid-catalyzed cascade reaction of styrene leading to the cyclic styrene dimer 86 (Scheme 13c) [96][97]. This (3 + 2) cycloaddition reactivity of

• which is likely formed directly from the allyl cation/vinylthionium-type intermediate 112. In 2016, Liu and co-workers extended this interesting reactivity mode to a cascade polyyne cyclization of 1,3-dithiolane 114 to 1,4-dithiane 115 (Scheme 18b) [111]. These authors also investigated mechanistic

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

• activation/annulation cascade of readily available enaminones with iodonium ylides towards the convenient synthesis of isocoumarins. This coupling system proceeds in useful chemical yields (up to 93%) via a cascade C–H activation, Rh-carbenoid migratory insertion and acid-promoted intramolecular annulation

• to couple iodonium ylides with enaminones in a Rh(III)-catalyzed C–H activation/annulation cascade reaction for the rapid construction of isocoumarins (Scheme 1c). Results and Discussion Our initial experiment was performed with enaminone 1a and iodonium ylide 1b in the presence of [Cp*RhCl2]2 (5 mol

• obtained by using [{Ru(p-cymene)Cl2}]2 as a catalyst (Table 1, entry 10). With the optimal conditions in hand, we then investigated the scope of this Rh-catalyzed C–H activation/annulation cascade reaction. As shown in Scheme 2, a range of functionalized enaminones were compatible with this Rh-catalytic

NaI/PPh₃-catalyzed visible-light-mediated decarboxylative radical cascade cyclization of N-arylacrylamides for the efficient synthesis of quaternary oxindoles

• Dan Liu,
• Yue Zhao and
• Frederic W. Patureau

Beilstein J. Org. Chem. 2023, 19, 57–65, doi:10.3762/bjoc.19.5

• Dan Liu Yue Zhao Frederic W. Patureau Institute of Organic Chemistry, RWTH Aachen University, Landoltweg 1, 52074 Aachen, Germany 10.3762/bjoc.19.5 Abstract A practical NaI/PPh3-catalyzed decarboxylative radical cascade cyclization of N-arylacrylamides with redox-active esters is described, which

• afforded various functionalized oxindoles featuring a C3 quaternary stereogenic center. Mechanistic experiments suggest a radical mechanism. Keywords: decarboxylative cascade cyclization; iodide catalysis; metal-free photocatalysis; oxindole; phosphine catalysis; Introduction Radical-initiated cascade

• reactions constitute a powerful synthetic approach to construct multiple C–C or C–X bonds in one pot. As such, these tend to allow facile access to many complex natural molecules and drugs [1][2][3][4][5][6]. Recently, radical-initiated cascade cyclizations involving acrylamides have attracted considerable

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

• a semipinacol rearrangement leading to 95, followed by subsequent cyclization to natural products guignardone A (96) and C (97). This process involved 1,2-allyl migration and C–O bond formation through a semipinacol rearrangement and a cyclodehydration cascade reaction (Scheme 8). Following the same

• discoveries, namely a photoredox-catalytic nitrogen-centered radical cascade [72], which has resulted in the impressive collective total synthesis of 33 alkaloids of three different classes of indole natural products (please see the inset of Scheme 11 for concise representation). Specifically, this included

• (–)-eburnaminol (132), (+)-larutenine (133), (–)-terengganensine B (134), and (–)-strempeliopine (136), as well as the asymmetric formal total synthesis of (–)-terengganensine A (not shown, Scheme 11). The requisite common synthetic intermediate 129 for the cascade was accessed by an acid-promoted condensation of

Inline purification in continuous flow synthesis – opportunities and challenges

• Jorge García-Lacuna and
• Marcus Baumann

Beilstein J. Org. Chem. 2022, 18, 1720–1740, doi:10.3762/bjoc.18.182

• of alcohols using a phase transfer catalyst (PTC) [55]. In a scale-up run, a three-stage counter-current cascade was used downstream of the first separation to remove the PTC (Scheme 4). In this scenario more than 90% of the phase transfer catalyst was separated from the phase containing the desired

• extraction of antioxidants from olive leaf waste [130], and of patchoulol from green algal cells [49]. In the last case, nanofiltration is coupled to an inline phase separation to both concentrate the compound and reuse the solvent. In another scenario, a two-stage membrane cascade was used as a purification

Total synthesis of grayanane natural products

• Nicolas Fay,
• Rémi Blieck,
• Cyrille Kouklovsky and
• Aurélien de la Torre

Beilstein J. Org. Chem. 2022, 18, 1707–1719, doi:10.3762/bjoc.18.181

• involves the construction of a tetracyclic structure where rings A and B had the correct arrangement, while rings C and D form a bicyclo[2.2.2]octane structure [31]. The correct bicyclo[3.2.1]octane structure was obtained after a key reductive epoxide opening/Dowd–Beckwith rearrangement cascade. The

• reagent and DMDO could induce an epoxidation on the strained olefin. From intermediate 40, the key reductive epoxide opening/Dowd–Beckwith rearrangement cascade could be performed in the presence of an in situ-generated Ti(III) catalyst. The main side-product of this reaction was due to a simple reductive

• bromide coupling. While both Ding and Luo propose a 1,2-shift relying on epoxide ring-opening as key step, each group proposes a different disconnection. For Ding, the rearrangement forms bond C13–C16 through a Ti(III)-mediated reductive epoxide opening/Dowd–Beckwith rearrangement cascade. This allows to

Navigating and expanding the roadmap of natural product genome mining tools

• Friederike Biermann,
• Sebastian L. Wenski and
• Eric J. N. Helfrich

Beilstein J. Org. Chem. 2022, 18, 1656–1671, doi:10.3762/bjoc.18.178

• , terpene cyclases generate the oftentimes multicyclic, hydrocarbon scaffold via a carbocation-mediated cascade reaction [30]. Terpene cyclases are obligatory components of canonical terpene pathways and are used to identify terpene BGCs (Figure 3B) [30][31]. RiPPs, on the other hand, lack genes that are

Synthesis of (−)-halichonic acid and (−)-halichonic acid B

• Keith P. Reber and
• Emma L. Niner

Beilstein J. Org. Chem. 2022, 18, 1629–1635, doi:10.3762/bjoc.18.174

• acids. Keywords: alkaloid; amino acid; aza-Prins reaction; cascade reaction; natural product; Introduction Marine sponges produce a large number of structurally diverse natural products, including many that exhibit biological activity [1][2][3]. In 2019, Tsukamoto and co-workers isolated the

Synthetic study toward the diterpenoid aberrarone

• Liang Shi,
• Zhiyu Gao,
• Yiqing Li,
• Yuanhao Dai,
• Yu Liu,
• Lili Shi and
• Hong-Dong Hao

Beilstein J. Org. Chem. 2022, 18, 1625–1628, doi:10.3762/bjoc.18.173

• were reported [30][31] and more recently, Carreira and co-workers reported [32] the first total synthesis of aberrarone through an impressive cascade reaction including a gold-catalyzed Nazarov cyclization, a cyclopropanation followed by intramolecular aldol reaction to forge the A, B and D rings

One-pot double annulations to confer diastereoselective spirooxindolepyrrolothiazoles

• Juan Lu,
• Bin Yao,
• Desheng Zhan,
• Zhuo Sun,
• Yun Ji and
• Xiaofeng Zhang

Beilstein J. Org. Chem. 2022, 18, 1607–1616, doi:10.3762/bjoc.18.171

• oxindoles. High synthetic efficiency, operational simplification and reaction process economy using EtOH as solvent, and only releasing CO2 and H2O as side products confer this approach favorable in green chemistry metrics analysis. Keywords: azomethine ylides; cascade; double annulations; N,S-acetalation

• nitrogen-based heterocycles, such as multicomponent reactions (MCRs) [18][19][20][21][22][23], one-pot cascade reactions [24][25][26][27][28][29][30][31][32] as good examples of PASE synthesis. We have reported a series of multicomponent reactions, like Groebke–Blackburn–Bienayme for making BET inhibitors

• UMB32 and UMB136 [33][34]. Zhang developed 4-aminoquinolines for the synthesis of fluorinated analogues of acetylcholinesterase (AChE) inhibitors [35] in cascade reactions, such as one-step syntheses of quinolines. Quinolin-4-ols involving histone acetyltransferases (HAT) inhibitors [36][37], as well as

Oxa-Michael-initiated cascade reactions of levoglucosenone

• Julian Klepp,
• Thomas Bousfield,
• Hugh Cummins,
• Sarah V. A.-M. Legendre,
• Jason E. Camp and
• Ben W. Greatrex

Beilstein J. Org. Chem. 2022, 18, 1457–1462, doi:10.3762/bjoc.18.151

• , United Kingdom 10.3762/bjoc.18.151 Abstract The reactions of aromatic aldehydes and levoglucosenone promoted by methoxide gives bridged α,β-unsaturated ketones, formed by a series of oxa-Michael-initiated cascade reactions in yields of up to 91% (14 examples). A complex series of equilibria operate

• during the reaction, and the formation of the bridged species is thermodynamically favored, except in the case of 5-methylfurfural and pyrrole-2-carboxaldehyde. This is the first report detailing this type of aldol/Michael cascade involving oxa-Michael initiation. Keywords: cascade reactions; green

• oxymethylene bridge [8][9][10]. Many selective nucleophilic additions are known, and the reaction has been applied to the synthesis of disaccharides [11], the pheromone eldanolide [12], and flavoring compounds such as whiskey lactone [13]. The use of heteronucleophiles can also be used to initiate cascade

Cytochrome P450 monooxygenase-mediated tailoring of triterpenoids and steroids in plants

• Karan Malhotra and
• Jakob Franke

Beilstein J. Org. Chem. 2022, 18, 1289–1310, doi:10.3762/bjoc.18.135

• polycyclic skeletons of triterpenoids and steroids are created by oxidosqualene cyclases (OSCs) from the universal substrate 2,3-oxidosqualene [5]. As different folding modes (chair–boat–chair vs chair–chair–chair) and different ring sizes can occur during this cyclisation cascade, resulting triterpene and

Make or break: the thermodynamic equilibrium of polyphosphate kinase-catalysed reactions

• Michael Keppler,
• Sandra Moser,
• Henning J. Jessen,
• Christoph Held and
• Jennifer N. Andexer

Beilstein J. Org. Chem. 2022, 18, 1278–1288, doi:10.3762/bjoc.18.134

• linear cascade to produce the desired NTP. Figure 3b shows the reaction sequence from 5-fluorouridine-5’-monophosphate to the triphosphate in an enzymatic synthesis of an unnatural uridine nucleotide [42]. In these type of setup, the yield of the overall reaction is strongly determined by the position of

• the thermodynamic equilibrium of the last reaction step [22][23][42][43][44][45]. To efficiently implement such a reaction sequence, detailed kinetic and thermodynamic information has to be available to identify bottlenecks and improve the turnover of such cascade systems [25]. In the present study

• ). As discussed before, the conversion of a nucleotide diphosphate to the corresponding triphosphate is normally the last step in the biomimetic synthesis of NTPs, and might have a substantial influence on the yield of the whole cascade. A biomimetic cascade published by Whitesides and co-workers for

Enzymes in biosynthesis

• Jeroen S. Dickschat

Beilstein J. Org. Chem. 2022, 18, 1131–1132, doi:10.3762/bjoc.18.116

• proceed through multistep cationic cascade reactions and usually produce a polycyclic terpene hydrocarbon or alcohol with multiple stereogenic centers. While these transformations require only a single enzyme, polyketide and nonribosomal peptide biosyntheses are catalyzed by megasynthases that follow an

The stereochemical course of 2-methylisoborneol biosynthesis

• Binbin Gu,
• Anwei Hou and
• Jeroen S. Dickschat

Beilstein J. Org. Chem. 2022, 18, 818–824, doi:10.3762/bjoc.18.82

• ), followed by a conformational change through rotation around the C2–C3 bond and cyclization to the 2-methyl-α-terpinyl cation (A). A second cyclization to B and attack of water results in 2-methylisoborneol (1) [8]. The stereochemical details of this cyclization cascade were first suggested by Cane, with

DDQ in mechanochemical C–N coupling reactions

• Shyamal Kanti Bera,
• Rosalin Bhanja and
• Prasenjit Mal

Beilstein J. Org. Chem. 2022, 18, 639–646, doi:10.3762/bjoc.18.64

• practice by applying the strategies like domino, cascade, or tandem [11][12][13]. These environmentally friendly approaches set forth the journey of facilitating sustainable systems by using mechanochemical methods to access small organic compounds [3]. Due to the high reduction potential of the quinone

Chemistry of polyhalogenated nitrobutadienes, 17: Efficient synthesis of persubstituted chloroquinolinyl-1H-pyrazoles and evaluation of their antimalarial, anti-SARS-CoV-2, antibacterial, and cytotoxic activities

• Viktor A. Zapol’skii,
• Isabell Berneburg,
• Ursula Bilitewski,
• Melissa Dillenberger,
• Katja Becker,
• Stefan Jungwirth,
• Aditya Shekhar,
• Bastian Krueger and
• Dieter E. Kaufmann

Beilstein J. Org. Chem. 2022, 18, 524–532, doi:10.3762/bjoc.18.54

• in moderate yields (58–69%). A conceivable mechanistic pathway for the reaction cascade to pyrazoles 3 is shown in Scheme 2. Initially, a first molecule of the strong nucleophile 7-chloro-4-hydrazinylquinoline is assumed to react with the nitrodiazolylvinyl subunit of 2 to give butene A. 1,2

• poor leaving group quality of the formal alkoxide. A conceivable mechanistic pathway for the reaction cascade to pyrazole 7 is shown in Scheme 6. Initially, a nucleophilic attack of the NH2 group of 7-chloro-4-hydrazinylquinoline on the C2 position of the oxazolidine ring of 6 leads to the formation of

Tosylhydrazine-promoted self-conjugate reduction–Michael/aldol reaction of 3-phenacylideneoxindoles towards dispirocyclopentanebisoxindole derivatives

• Sayan Pramanik and
• Chhanda Mukhopadhyay

Beilstein J. Org. Chem. 2022, 18, 469–478, doi:10.3762/bjoc.18.49

• generation of new cascade reactions to construct carbo- and heterocyclic moieties [27][28], we aimed to synthesize dispirocyclopentanebisoxindoles in one pot operation using a new protocol. Chemical hydrogenation of double bonded compounds like α,β-unsaturated ketones, approaching to saturated ketones, is an

Regioselectivity of the S_EAr-based cyclizations and S_EAr-terminated annulations of 3,5-unsubstituted, 4-substituted indoles

• Jonali Das and
• Sajal Kumar Das

Beilstein J. Org. Chem. 2022, 18, 293–302, doi:10.3762/bjoc.18.33

• generated via 1,6-hydride shift in both I and II. Finally, an intramolecular Mannich-type cyclization then furnishes products 27. The cascade protocol enjoys several advantageous synthetic features, including high step- and atom-economy, transition-metal-free and room temperature conditions. In all cases

• cyclization leading to the formation of polycyclic azepino[5,4,3-cd]indoles. Synthesis of azepino[3,4,5-cd]indoles via iridium-catalyzed asymmetric [4 + 3] cycloaddition of racemic 4-indolyl allylic alcohols with azomethine ylides. Aldimine condensation/1,6-hydride transfer/Mannich-type cyclization cascade of

New advances in asymmetric organocatalysis

• Radovan Šebesta

Beilstein J. Org. Chem. 2022, 18, 240–242, doi:10.3762/bjoc.18.28

• within the area. Organocatalytic reactions are highly suitable components of cascade transformations as exemplified by the seminal work of Enders [13]. Besides traditional enamine and iminium activation of carbonyl compounds other activation modes were uncovered which significantly broadened the

Asymmetric organocatalytic Michael addition of cyclopentane-1,2-dione to alkylidene oxindole

• Estelle Silm,
• Ivar Järving and
• Tõnis Kanger

Beilstein J. Org. Chem. 2022, 18, 167–173, doi:10.3762/bjoc.18.18

• molecular complexity. There are many examples of the organocatalytic synthesis of fused cycles starting from the cyclohexane-1,3-dione. For example, Rueping et al. demonstrated that the cyclohexane-1,3-dione undergoes a cascade reaction with α,β-unsaturated aldehydes [4] and they later employed the method

• substituted cyclopentane diones were uninvestigated until 2014 when we showed that CPD undergoes a Michael addition with nitrostyrenes [22]. Subsequently, different cascade reactions for CPD have been developed: with highly reactive (E)-2-oxobut-3-enoates [23], α,β-unsaturated aldehydes [24] and alkylidene

Chemical and chemoenzymatic routes to bridged homoarabinofuranosylpyrimidines: Bicyclic AZT analogues

• Sandeep Kumar,
• Jyotirmoy Maity,
• Banty Kumar,
• Sumit Kumar and
• Ashok K. Prasad

Beilstein J. Org. Chem. 2022, 18, 95–101, doi:10.3762/bjoc.18.10

• pyridine to afford dimesylated nucleosides 16a,b in 93 and 94% yields, respectively. The reaction of nucleosides 16a,b with NaOH in dioxane/water (1:1) underwent a cascade reaction pathway to form 9a,b in 82 and 84% yields, respectively (Scheme 4). The overall yields for the synthesis of nucleosides 9a,b

1,2-Naphthoquinone-4-sulfonic acid salts in organic synthesis

• Ruan Carlos B. Ribeiro,
• Patricia G. Ferreira,
• Amanda de A. Borges,
• Luana da S. M. Forezi,
• Fernando de Carvalho da Silva and
• Vitor F. Ferreira

Beilstein J. Org. Chem. 2022, 18, 53–69, doi:10.3762/bjoc.18.5

• -naphthoquinones 35 and β-lapachone (11) for hCE1 (Scheme 9). It is important to note that 35 can be obtained from other reagents, such as 2-naphthol, in a cascade of reactions involving oxidation to 1,2-naphthoquinones followed by Michael addition to the olefin and reoxidation [85]. In addition, Yang and co

Bifunctional thiourea-catalyzed asymmetric [3 + 2] annulation reactions of 2-isothiocyanato-1-indanones with barbiturate-based olefins

• Jiang-Song Zhai and
• Da-Ming Du

Beilstein J. Org. Chem. 2022, 18, 25–36, doi:10.3762/bjoc.18.3

• cascade reagent with the indane framework, namely, 2-isothiocyanato-1-indanone (Scheme 1a) [15], but research on its participation in the construction of chiral compounds has been relatively low [16][17]. On the other hand, as a kind of vital spiroheterocyclic derivatives, spirobarbiturates show a wide

A two-phase bromination process using tetraalkylammonium hydroxide for the practical synthesis of α-bromolactones from lactones

• Yuki Yamamoto,
• Akihiro Tabuchi,
• Kazumi Hosono,
• Takanori Ochi,
• Kento Yamazaki,
• Shintaro Kodama,
• Akihiro Nomoto and
• Akiya Ogawa

Beilstein J. Org. Chem. 2021, 17, 2906–2914, doi:10.3762/bjoc.17.198

• . Finally, the residue was purified by distillation to give pure product 3b in 64% yield (1.05 g). Cascade synthesis of 5 via two-phase ring closing of 3b and following substitution with benzenethiol 4 in the presence of K2CO3 (Scheme 4). To a 100 mL flask were added 2b (4.0 mmol), CH3CN (4 mL), H2O (16 mL