Synthesis of new bile acid-fused tetrazoles using the Schmidt reaction

• Dušan Đ. Škorić,
• Olivera R. Klisurić,
• Dimitar S. Jakimov,
• Marija N. Sakač and
• János J. Csanádi

Beilstein J. Org. Chem. 2021, 17, 2611–2620, doi:10.3762/bjoc.17.174

• acid (9) were selectively esterified in refluxing ethyl acetate with a catalytic amount of p-toluenesulfonic acid (pTsOH) [42]. Subsequent oxidation of the free OH groups afforded compounds 3 and 11 in high yields. Similarly, compound 7 was prepared in good overall yield from ethyl cholate (5) by

Silica gel and microwave-promoted synthesis of dihydropyrrolizines and tetrahydroindolizines from enaminones

• Robin Klintworth,
• Garreth L. Morgans,
• Stefania M. Scalzullo,
• Charles B. de Koning,
• Willem A. L. van Otterlo and
• Joseph P. Michael

Beilstein J. Org. Chem. 2021, 17, 2543–2552, doi:10.3762/bjoc.17.170

• such enaminones by the route shown in Scheme 4. Alkylation of piperidin-2-one (23) with ethyl bromoacetate followed by treatment of the resulting lactam [66][67] with Lawesson’s reagent in toluene at 80 °C gave the thione 24 in 83% overall yield. Reaction of 24 with phenacyl bromide and its 4-methoxy

Synthesis of new substituted 7,12-dihydro-6,12-methanodibenzo[c,f]azocine-5-carboxylic acids containing a tetracyclic tetrahydroisoquinoline core structure

• Agnieszka Grajewska,
• Maria Chrzanowska and
• Wiktoria Adamska

Beilstein J. Org. Chem. 2021, 17, 2511–2519, doi:10.3762/bjoc.17.168

• cyclization reaction was easily performed by treatment of 6a with 20% HCl for 24 h to give dihydromethanodibenzoazocine-5-carboxylic acid (7a, Scheme 5) in 72% yield by extraction of the neutralized reaction mixture. Compound 7a was obtained in two simple steps from 3a with an overall yield of 67%. Then the

• with 67% yield (53% overall yield from 3d), while the reaction carried out in 20% HCl led to a mixture of products, among which 7f was not detected (Scheme 5). It should be also mentioned that the amino acid 6g with a benzyloxy-substituted aromatic ring, obtained in the Petasis reaction of boronic acid

Targeting active site residues and structural anchoring positions in terpene synthases

• Anwei Hou and
• Jeroen S. Dickschat

Beilstein J. Org. Chem. 2021, 17, 2441–2449, doi:10.3762/bjoc.17.161

• . Future structural work on SmTS1 and its Q227D derivative is required to clarify this effect. The R242N substitution showed almost no consequences for total production (94 ± 17%) and yields of individual compounds, while for the F307W variant the overall yield dropped to 53 ± 6% with similar product

Synthesis of phenanthridines via a novel photochemically-mediated cyclization and application to the synthesis of triphaeridine

• Songeziwe Ntsimango,
• Kennedy J. Ngwira,
• Moira L. Bode and
• Charles B. de Koning

Beilstein J. Org. Chem. 2021, 17, 2340–2347, doi:10.3762/bjoc.17.152

• synthesis of trisphaeridine to afford the product in four linear steps in an overall yield of 6.5% from 1-bromo-2,4,5-trimethoxybenzene. Keywords: aromatic compounds; cyclization; iminyl radical; phenanthridines; radical cation; synthesis; UV irradiation; Introduction Phenanthridine derivatives have

• zinc in acetic acid which resulted in the synthesis of trisphaeridine (3) in five steps in a moderate overall yield of 6.5% commencing from 19. Conclusion In summary, a novel UV light-mediated method for the synthesis of phenanthridines from biaryl oximes has been discovered. A key highlight includes

Synthesis of O⁶-alkylated preQ₁ derivatives

• Laurin Flemmich,
• Sarah Moreno and
• Ronald Micura

Beilstein J. Org. Chem. 2021, 17, 2295–2301, doi:10.3762/bjoc.17.147

• ; overall yield: 30%. The synthesis of e6preQ1 (2a) and bn6preQ1 (2b) was performed in analogy to the route outlined in Scheme 4 with an overall yield of 23% and 34%, respectively. For details see the Supporting Information File 1. Supporting Information Supporting Information File 360: Synthetic

Chemical syntheses and salient features of azulene-containing homo- and copolymers

• Vijayendra S. Shetti

Beilstein J. Org. Chem. 2021, 17, 2164–2185, doi:10.3762/bjoc.17.139

• called polyazulene (Scheme 2). The elemental analysis of this polymer revealed that it existed as a 71:29 mixture of polymer 3 or 3’ bearing a heptafulvene structure (true polyazulene) and cycloheptatrienyl trifluoroacetate 2. The temperature and reaction time determined the overall yield and the Mn of

Asymmetric organocatalyzed synthesis of coumarin derivatives

• Natália M. Moreira,
• Lorena S. R. Martelli and
• Arlene G. Corrêa

Beilstein J. Org. Chem. 2021, 17, 1952–1980, doi:10.3762/bjoc.17.128

• product 17 was obtained in 15 steps with 6% overall yield. Although chiral secondary amines have proved to be particularly useful catalysts, primary amines as organocatalysts in asymmetric synthesis have also played a significant role [36]. For instance, Kim et al. described the enantioselective Michael

• % ee (Scheme 37). Furthermore, the natural product was synthesized in seven steps with 14% overall yield. Conclusion Coumarin derivatives are important scaffolds for synthetic and medicinal chemistry. These structures have an interesting reactivity and can be used in diverse organic reactions, for

On the application of 3d metals for C–H activation toward bioactive compounds: The key step for the synthesis of silver bullets

• Renato L. Carvalho,
• Amanda S. de Miranda,
• Mateus P. Nunes,
• Roberto S. Gomes,
• Guilherme A. M. Jardim and
• Eufrânio N. da Silva Júnior

Beilstein J. Org. Chem. 2021, 17, 1849–1938, doi:10.3762/bjoc.17.126

• increasing the overall yield. The resulting eight-step synthesis could be scaled to produce more than 100 kg of compound 41 [109]. Based on what was presented so far, vanadium catalysis is mainly applied as one of the steps involved in a total synthesis that usually leads to the formation of a valuable

• free amine derivative was produced in 43% overall yield. The 2,8-dioxabicyclo[3.3.1]nonane skeleton is contained in biflavonoids and was shown to exhibit many medicinal activities like antiviral, anti-inflammatory and antitumor properties. The bicyclic compound 49 was aminated at the benzylic position

• oxonium species in the methylation step. Abiraterone acetate (53) is a drug used in cancer treatment [138]. The Mn-catalyzed methylation of an abiraterone analogue was achieved by replacing the fluorination step by mesylation in 15% of overall yield and only a single diastereoisomer was observed (Scheme

Development of N-F fluorinating agents and their fluorinations: Historical perspective

• Teruo Umemoto,
• Yuhao Yang and
• Gerald B. Hammond

Beilstein J. Org. Chem. 2021, 17, 1752–1813, doi:10.3762/bjoc.17.123

• silyl ether 5-8 to the fluorinated lactone 5-9 in a very satisfactory overall yield [32]. N-Fluoro-2,6-bis(CH2OAc)pyridinium triflate 5-4n [32], N-fluoro-2,6-bis(COOMe)pyridinium triflate 5-4y [30][32], and N-fluoro-2-cyano- and -2,6-dicyanopyridinium tetrafluoroborates [39] were useful reagents, too

Chemical synthesis of C6-tetrazole ᴅ-mannose building blocks and access to a bioisostere of mannuronic acid 1-phosphate

• Eleni Dimitriou and
• Gavin J. Miller

Beilstein J. Org. Chem. 2021, 17, 1527–1532, doi:10.3762/bjoc.17.110

• nitrogen protection (Scheme 3). A first attempt here involved the reaction of 5 with PMBCl in DMF, using K2CO3 alongside KI. Two separable regioisomers 11 and 12 were isolated in an acceptable 53% overall yield and in a ratio of N1-PMB/N2-PMB = 1.1:1 (Scheme 3). HMBC NMR of 11 and 12 clarified the position

• overall yield for the route increased from 9 to 21%. To demonstrate capability for anomeric linker attachment and conversion to a biologically relevant analogue of mannuronic acid 1-phosphate, 3-aminopropyl glycoside 20 and glycosyl 1-phosphate 21 were synthesised (Scheme 4). The mixture 18/19 was used

Total synthesis of ent-pavettamine

• Memory Zimuwandeyi,
• Manuel A. Fernandes,
• Amanda L. Rousseau and
• Moira L. Bode

Beilstein J. Org. Chem. 2021, 17, 1440–1446, doi:10.3762/bjoc.17.99

• developing a route for the synthesis of enantiomer 2 by modification of the established protocol used for the synthesis of 1. The plan was that the alternative strategy would lead to an improvement in the overall yield whilst eliminating some of the troublesome steps. Results and Discussion The synthetic

• , using our previously published methodology in an overall yield of 8% over 8 steps (Scheme 1) [1]. An alternative strategy for the synthesis of 4 was developed so as to avoid a cumbersome continuous extraction step of a triol associated with the established method, in addition to improving the overall

• that the new route doubled the overall yield to 16% for a similar number of steps. The specific optical rotation for 4 of +28.1° in acetone was comparable to that obtained previously [1]. Single crystal X-ray analysis of compound 4 (Figure 3), further confirmed the identity and stereochemistry of the

A comprehensive review of flow chemistry techniques tailored to the flavours and fragrances industries

• Guido Gambacorta,
• James S. Sharley and
• Ian R. Baxendale

Beilstein J. Org. Chem. 2021, 17, 1181–1312, doi:10.3762/bjoc.17.90

• synthesis of coumarin (90) was also reported, which involved an intramolecular aldol-type condensation of the acetylated intermediate 89 derived from salicylaldehyde (88, Scheme 18) [125]. The initial O-acetylation step was telescoped directly into the next reactor; the two-step process gave an overall

• yield of 91% under optimal conditions. Beneficially as all components were liquids the need for a solvent was completely avoided; from a green chemistry standpoint this is highly attractive and the intrinsic low melting points of many fragrance ingredients and precursors lend themselves to continuous

N-tert-Butanesulfinyl imines in the asymmetric synthesis of nitrogen-containing heterocycles

• Joseane A. Mendes,
• Paulo R. R. Costa,
• Miguel Yus,
• Francisco Foubelo and
• Camilla D. Buarque

Beilstein J. Org. Chem. 2021, 17, 1096–1140, doi:10.3762/bjoc.17.86

• N-methylation led to (−)-angustureine (107) in high overall yield (Scheme 31). The same methodology was applied to the synthesis of (−)-cuspareine (108), starting in this case from enantiomeric imine (RS)-104b, and using 2-(3,4-dimethoxyphenyl)ethylmagnesium bromide as Grignard reagent. A

• , which after desulfination and N-methylation led to expected (+)-sedamine (125) in 30% overall yield from ketone derivative 124. The stereoselective synthesis of trans-5-hydroxy-6-substituted-2-piperidinones was also reported by the group of Wei, taking advantage of the addition of Grignard reagents to N

• the Grignard reagent in this synthesis, with a 18% overall yield after seven steps from aldimine ent-126 (Scheme 35) [125]. The reaction of chiral α-siloxyl imine (SS)-126 with enolates derived from methyl ketones 131 was also investigated. The enolate was formed with LDA at −78 °C and reacted at the

Metal-free glycosylation with glycosyl fluorides in liquid SO₂

• Krista Gulbe,
• Jevgeņija Lugiņina,
• Edijs Jansons,
• Artis Kinens and
• Māris Turks

Beilstein J. Org. Chem. 2021, 17, 964–976, doi:10.3762/bjoc.17.78

• halides α-1a–c gave O-mannoside 3a as the major product in 58 to 71% yield, while overall yield of products 3a,c varied from 77% for α-1b to quant. for α-1a (Table S1, Supporting Information File 1). Pivaloyl-protected mannosyl fluoride α-1a was further applied for the synthesis of various O-, S- and C

Total synthesis of pyrrolo[2,3-c]quinoline alkaloid: trigonoine B

• Takashi Nishiyama,
• Erina Hamada,
• Daishi Ishii,
• Yuuto Kihara,
• Nanase Choshi,
• Natsumi Nakanishi,
• Mari Murakami,
• Kimiko Taninaka,
• Noriyuki Hatae and
• Tominari Choshi

Beilstein J. Org. Chem. 2021, 17, 730–736, doi:10.3762/bjoc.17.62

• ]quinoline framework via electrocyclization of 2-(pyrrol-3-yl)benzene containing a carbodiimide moiety as a 2-azahexatriene system. The employed six-step sequence afforded trigonoine B (1) in 9.2% overall yield. The described route could be employed for the preparation of various N-substituted 4

• , trigonoine B (1), was achieved for the first time through the electrocyclization of 2-(pyrrol-3-yl)benzene bearing a carbodiimide moiety as a 2-azahexatriene system. The employed six-step sequence afforded the desired product 1 in 9.2% overall yield. Notably, the developed synthetic route could be used for

Synthesis of (Z)-3-[amino(phenyl)methylidene]-1,3-dihydro-2H-indol-2-ones using an Eschenmoser coupling reaction

• Lukáš Marek,
• Lukáš Kolman,
• Jiří Váňa,
• Jan Svoboda and
• Jiří Hanusek

Beilstein J. Org. Chem. 2021, 17, 527–539, doi:10.3762/bjoc.17.47

• Eschenmoser coupling reaction can be found in the recent literature [38][39][40]. In our case, the 3-bromooxindoles 1a–e worked very well but they are accessible from commercially available isatins only through a three-step synthesis in an acceptable overall yield 51–76% (see Table 6 in the Experimental). In

• reference [14]). As a result, a good overall yield of 65% was achieved over three steps starting from N-methylisatin. For comparison, the four-step synthesis starting from N-methylisatin and giving 11 through 3-bromo-N-methyloxindole (1a’), has an overall yield of only 48%. Moreover, no formation of the

• starting 3-bromooxindoles 1a–e are available from the corresponding isatins by a three-step synthesis (overall yield 51–76%), the total yields related to these commercially available and cheap starting compounds are better or at least competitive to the methods described in Scheme 1 of which several have

Synthesis of N-perfluoroalkyl-3,4-disubstituted pyrroles by rhodium-catalyzed transannulation of N-fluoroalkyl-1,2,3-triazoles with terminal alkynes

• Olga Bakhanovich,
• Viktor Khutorianskyi,
• Vladimir Motornov and
• Petr Beier

Beilstein J. Org. Chem. 2021, 17, 504–510, doi:10.3762/bjoc.17.44

• an electrophile, the crude product 2a was treated with butyllithium, followed by the reaction with carbon dioxide to afford pyrrole carboxylic acid 6 in a good overall yield (Scheme 5). The trifluoromethyl group on the nitrogen was not affected by these highly basic reaction conditions. The mechanism

CF₃-substituted carbocations: underexploited intermediates with great potential in modern synthetic chemistry

• Anthony J. Fernandes,
• Armen Panossian,
• Bastien Michelet,
• Agnès Martin-Mingot,
• Frédéric R. Leroux and
• Sébastien Thibaudeau

Beilstein J. Org. Chem. 2021, 17, 343–378, doi:10.3762/bjoc.17.32

Synthesis of legonmycins A and B, C(7a)-hydroxylated bacterial pyrrolizidines

• Wilfred J. M. Lewis,
• David M. Shaw and
• Jeremy Robertson

Beilstein J. Org. Chem. 2021, 17, 334–342, doi:10.3762/bjoc.17.31

• , equating to 44% overall yield from proline derivative 16). Rf 0.10 (ethyl acetate/methanol 9:1); 1H NMR (400 MHz, CDCl3) δ [the resonances vary with sample concentration and source of CDCl3] 1.56–1.65 (m, 1H) overlaying 1.60 (s, 3H), 1.94–2.04 (m, 2H), 2.10–2.29 (m, 1H), 3.08–3.15 (m, 1H), 3.17–3.23 (m, 1H

Regioselective chemoenzymatic syntheses of ferulate conjugates as chromogenic substrates for feruloyl esterases

• Olga Gherbovet,
• Fernando Ferreira,
• Apolline Clément,
• Mélanie Ragon,
• Julien Durand,
• Sophie Bozonnet,
• Michael J. O'Donohue and
• Régis Fauré

Beilstein J. Org. Chem. 2021, 17, 325–333, doi:10.3762/bjoc.17.30

• ferulate to the primary hydroxy group of α‐ʟ‐arabinofuranosides. Moreover, a novel feruloylated 4-nitrocatechol-1-yl-substituted butanetriol analog, containing a cleavable hydroxylated linker, was also synthesized in 32% overall yield in 3 steps (convergent synthesis). The latter route combined the

• the primary hydroxy group compare favorably with the previously reported overall yield (46 and 47%, respectively, in three steps) [15][16][17][29], which relate to the selective enzymatic O-5-deacetylation and esterification of the primary hydroxy group and a final deprotection of the 2,3-O-acetyl

• in a high yield of 94%. Accordingly, the synthesis of the chromogenic ferulate 12 was achieved in 32% overall yield in 3 steps from commercial reactants (convergent synthesis using a slight excess of the synthesized vinyl ferulate 2) and without the requirement to perform a final deprotection. As

Diels–Alder reaction of β-fluoro-β-nitrostyrenes with cyclic dienes

• Savva A. Ponomarev,
• Roman V. Larkovich,
• Alexander S. Aldoshin,
• Andrey A. Tabolin,
• Sema L. Ioffe,
• Jonathan Groß,
• Till Opatz and
• Valentine G. Nenajdenko

Beilstein J. Org. Chem. 2021, 17, 283–292, doi:10.3762/bjoc.17.27

• and stereoisomers, respectively) 3d in 40% overall yield. Two pairs of regioisomers were partially separated by column chromatography with sufficiently slow elution and analyzed by 1H NMR spectroscopy. The structure assignment was made as depicted in Scheme 5. The structures of two pairs of

Direct synthesis of anomeric tetrazolyl iminosugars from sugar-derived lactams

• Michał M. Więcław and
• Bartłomiej Furman

Beilstein J. Org. Chem. 2021, 17, 115–123, doi:10.3762/bjoc.17.12

• highest yield and diastereoselectivity, thus were chosen as optimal (Table 1, entry 9.). We also tried to isolate the imine after the reduction step and carry out the second step in a solvent commonly used for the Ugi–azide reaction alone. For this, we observed a significant decrease in overall yield and

Progress in the total synthesis of inthomycins

• Bidyut Kumar Senapati

Beilstein J. Org. Chem. 2021, 17, 58–82, doi:10.3762/bjoc.17.7

• step due to its high instability. Finally, the Stille cross-coupling reaction between vinylstannane 24 and dienyl iodide (rac)-20 using PdCl2(CN)2 and triethylamine in DMF produced racemic inthomycin A (or phthoxazolin A) (rac)-1 in 22% yield (Scheme 1). Although the overall yield of this route was

• derivative (rac)-63 was subjected to undergo acetylation, acid chloride formation, and quenching with ammonium hydroxide to produce amide derivative (rac)-64 in 70% yield. Finally, saponification of acetate (rac)-64 using lithium hydroxide gave racemic inthomycin A ((rac)-1) in 14% overall yield (Scheme 5

• triene (+)-146c was successfully converted into an 8:1 mixture of inthomycin C ((−)-3) and another minor isomer in good overall yield after the final step (Scheme 26). The spectroscopic data and specific rotation values of the three inthomycins A–C ((+)-1, (+)-2, and (−)-3) were consistent with those

Recent progress in the synthesis of homotropane alkaloids adaline, euphococcinine and N-methyleuphococcinine

• Dimas J. P. Lima,
• Antonio E. G. Santana,
• Michael A. Birkett and
• Ricardo S. Porto

Beilstein J. Org. Chem. 2021, 17, 28–41, doi:10.3762/bjoc.17.4

• tricyclic adduct (+)-23b, a precursor to (−)-adaline (1). This methodology, based on the synthesis of optically active β-sulfinyl nitrones, was proved to be efficient in the synthesis of (+)-euphococcinine (2) in 7 steps from piperidine (17), in an overall yield of 2.1%. Specific rotation for (+)-2 was [α

• ]D24 +7.43 (c 0.350, MeOH); {lit. [α]D +7.5 (c 2.0, MeOH), [26]}. The (−)-adaline precursor (+)-23b was also accessed from 17 in 5 steps, in an overall yield of 7.3%. Inspired by Gössinger’s work, Murahashi et al. prepared a nitrone from a cyclic amine. However, the route was improved by the

• from 30 not only led to the formation of the bicyclic system but also resulted in the loss of the chiral auxiliary, providing (+)-euphococcinine (2). Meyer's approach led to (+)-euphococcinine (2) in 5 steps from lactam 26 in an overall yield of 51.2%. The spectral analysis (1H and 13C NMR, IR, MS) was