Recent advances in organocatalytic asymmetric aza-Michael reactions of amines and amides

• Pratibha Sharma,
• Raakhi Gupta and
• Raj K. Bansal

Beilstein J. Org. Chem. 2021, 17, 2585–2610, doi:10.3762/bjoc.17.173

• asymmetric aza-MR. Thus, the review includes the examples wherein cinchona alkaloids, squaramides, chiral amines, phase-transfer catalysts and chiral bifunctional thioureas have been used, which activate the substrates through hydrogen bond formation. Most of these reactions are accompanied by high yields

• compounds; however, in order to comply with the requirements of a mini review, additions of amines and amides only will be included. 1. Non-covalent bonding organocatalytic aza-Michael reactions Organocatalysts catalyzing aza-MRs through mainly hydrogen bonding include cinchona alkaloids, squaramide

• derivatives, phase-transfer catalysts and bifunctional thiourea derivatives. 1.1 Reactions catalyzed by chiral cinchona alkaloid derivatives Cai et al. prepared and used a number of organocatalysts from Cinchona alkaloids for the aza-MR of aniline (1) with chalcone (2) to obtain the adducts 4 in poor to very

α-Ketol and α-iminol rearrangements in synthetic organic and biosynthetic reactions

• Scott Benz and
• Andrew S. Murkin

Beilstein J. Org. Chem. 2021, 17, 2570–2584, doi:10.3762/bjoc.17.172

• biosynthesis of delitschiapyrone A could occur non-enzymatically in nature by a similar process. The final example of a tandem reaction involving an α-ketol rearrangement in a total synthesis was employed by Chen et al. in the preparation of (±)-securinine (54) and (±)-allosecurinine (55), biological alkaloids

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

• ; tetrahydroindolizines; Introduction Partially or fully saturated variants of the pyrrolizine nucleus 1 are widely occurring motifs in natural products. The hexahydropyrrolizine (pyrrolizidine) system, for example, forms the nucleus of literally hundreds of alkaloids, many of which have gained notoriety owing to their

• hepatotoxicity and neurological effects on livestock and humans [1][2]. The less commonly encountered 2,3-dihydro-1H-pyrrolizine framework occurs in the butterfly metabolites danaidal (2) and hydroxydanaidal (3) [3], as well as in plant alkaloids such as loroquin (4) [4] and the recently characterized

• ] and procuramine (10) [13], have also attracted attention recently. Our continuing efforts to exploit enaminones as building blocks for the synthesis of alkaloids and other nitrogen-containing heterocycles have largely concentrated on targets containing indolizidine and quinolizidine backbones [14

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; multicomponent reactions; synthetic methods; tetrahydroisoquinoline; Introduction The tetrahydroisoquinoline moiety is the key structure in large number of natural and synthetic biologically important molecules. Among them, isoquinoline alkaloids constitute a large family of natural products

• exhibiting a huge range of structural diversity and biological activity [1][2][3]. Within this family several structural motifs can be identified, for instance, the isopavines, constrained alkaloids possessing the 1,2,3,4-tetrahydroisoquinoline skeleton incorporated into the double cyclized azabicyclo[3.2.2

• significance in the central nervous system but also as a building blocks for the synthesis of alkaloids [10][11]. The classical strategy for the synthesis of dihydromethanodibenzoazocines is based on the use of N,N-dibenzylaminoacetaldehydes [8][9] and less often α-dibenzylaminoketone [12][13] derivatives in

Efficient synthesis of polyfunctionalized carbazoles and pyrrolo[3,4-c]carbazoles via domino Diels–Alder reaction

• Ren-Jie Fang,
• Chen Yan,
• Jing Sun,
• Ying Han and
• Chao-Guo Yan

Beilstein J. Org. Chem. 2021, 17, 2425–2432, doi:10.3762/bjoc.17.159

• alkaloids and pharmacologically active compounds representing a broad spectrum of important bioactivities such as anticancer, antituberculosis, anti-protein kinase C, antipsychotic, and antioxidative activities [1][2][3][4][5]. For some examples, carprofen is a nonsteroidal anti-inflammatory pharmaceutical

Advances in mercury(II)-salt-mediated cyclization reactions of unsaturated bonds

• Sumana Mandal,
• Raju D. Chaudhari and
• Goutam Biswas

Beilstein J. Org. Chem. 2021, 17, 2348–2376, doi:10.3762/bjoc.17.153

• histrionicotoxin alkaloids 218 (Scheme 65) [127][128] and lepadoformine [129][130] were being successfully synthesized using this methodology for spirocyclic ring structure synthesis. The proposed mechanism proceeded initially with aminoketal formation by 6-exo-dig intramolecular oxymercuration, followed by

Base-free enantioselective S_N2 alkylation of 2-oxindoles via bifunctional phase-transfer catalysis

• Mili Litvajova,
• Emiliano Sorrentino,
• Brendan Twamley and
• Stephen J. Connon

Beilstein J. Org. Chem. 2021, 17, 2287–2294, doi:10.3762/bjoc.17.146

• synthesis of a potent CRTH2 receptor antagonist. Keywords: alkylation; base-free; cinchona alkaloids; CRTH2 antagonist; hydrogen-bonding; oxindole; phase-transfer catalysis; Introduction The 2-oxindole scaffold is an important motif present in a myriad of natural products. Among 2-oxidole derivatives, 3,3

A study on selective transformation of norbornadiene into fluorinated cyclopentane-fused isoxazolines

• Zsanett Benke,
• Attila M. Remete and
• Loránd Kiss

Beilstein J. Org. Chem. 2021, 17, 2051–2066, doi:10.3762/bjoc.17.132

• of natural products (especially macrocycles) [12], alkaloids [13], amino acids and functionalized biomolecules such as peptides [14][15][16][17][18][19][20] or various drugs [21]. Due to the ring strain, bicyclic systems and derivatives, such as norbornadiene derivatives can easily be converted

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

• ammonium salts derived from cinchona alkaloids [28]. Therefore, the asymmetric synthesis of coumarin derivatives is herein presented according to the activation mode, i.e., via covalent or non-covalent bonding. Furthermore, the use of bifunctional catalysts and multicatalysis are discussed as well

• of 2-hydroxycinnamaldehydes is important for the success of the employed catalytic system. Finally, but not least, the phase-transfer chiral organocatalysts have also been highly explored [72][73]. Most of the PTCs are based on the skeletons of cinchona alkaloids and chiral binaphthyls, though, more

Regioselective N-alkylation of the 1H-indazole scaffold; ring substituent and N-alkylating reagent effects on regioisomeric distribution

• Ryan M. Alam and
• John J. Keating

Beilstein J. Org. Chem. 2021, 17, 1939–1951, doi:10.3762/bjoc.17.127

• occurring indazoles have been reported in the literature [2][3][4], such as the alkaloids nigellicine (1) and nigellidine (2), there are a myriad of synthetic indazole derivatives known that display a broad range of biological activities. For example, several N-1 and N-2-substituted indazoles are currently

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

• synthesis of the bioactive natural macrolactone (±)-decinine (30) (Scheme 11B) [96]. These compounds (26–29) derive from the class of Lythraceae alkaloids (Scheme 11A), extracted from Heimia salicifolia, and present valuable pharmacological properties, such as antisyphilitic, sudoritic, antipyretic

Natural products in the predatory defence of the filamentous fungal pathogen Aspergillus fumigatus

• Jana M. Boysen,
• Nauman Saeed and
• Falk Hillmann

Beilstein J. Org. Chem. 2021, 17, 1814–1827, doi:10.3762/bjoc.17.124

• molecules like non-ribosomal peptides (NRP), polyketides (PK), terpenes or indole alkaloids [10][11]. The vast majority of fungal BGCs is found in the genomes of members of the Basidiomycota and Ascomycota including the genus Penicillium in which the first BGC was identified in 1990 [12][13][14

• bisnaphthopyrones like aurofusarin but also Aspergillus and Penicilllium species produce these metabolites which show antifeedant effects on a wide variety of arthropods [24]. Some fungal compounds can have deleterious effects on humans, livestock or crops, like the ergot alkaloids, e.g., ergotamine (4) present in

• therapeutic potential of ergot alkaloids as early as 1582 and used it for abortion or to aid childbirth. The ecological significance of ergot alkaloids remains unclear, but they are assumed to be a feeding deterrent due to their toxicity and bad taste [25][26][27][28]. To trigger the synthesis of new SMs a

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

• reported by Banks when quinuclidine was N-fluorinated with Selectfluor [62] (Scheme 67). Subsequently, in 2001, Shibata et al. presented full details of their studies including the definitive identification of N-fluorinated cinchona alkaloids by X-ray crystallography analysis and further applications [96

• -fluoro salts of cinchona alkaloids through the reaction of the alkaloids with Selectfluor [97]. Following the precedent from Banks’s fluorine-transfer reaction from Selectfluor to the N-site of quinuclidine [62], Cahard et al. isolated four N-fluorocinchona alkaloid salts, F-CD-BF4 30-1, F-CN-BF4 30-2, F

Iodine-catalyzed electrophilic substitution of indoles: Synthesis of (un)symmetrical diindolylmethanes with a quaternary carbon center

• Thanigaimalai Pillaiyar,
• Masoud Sedaghati,
• Andhika B. Mahardhika,
• Lukas L. Wendt and
• Christa E. Müller

Beilstein J. Org. Chem. 2021, 17, 1464–1475, doi:10.3762/bjoc.17.102

• affinity; cannabinoid receptors; diindolylmethane; unsymmetrical 3,3'-diindolylmethane; Introduction Diindolylmethanes (DIMs) represent an important class of indole alkaloids, that are constituents of pharmaceuticals [1][2][3][4][5][6][7] and agrochemicals [8][9]. DIM derivatives possess a variety of

Design, synthesis and photophysical properties of novel star-shaped truxene-based heterocycles utilizing ring-closing metathesis, Clauson–Kaas, Van Leusen and Ullmann-type reactions as key tools

• Shakeel Alvi and
• Rashid Ali

Beilstein J. Org. Chem. 2021, 17, 1374–1384, doi:10.3762/bjoc.17.96

• medicinally active as well as smart functional materials possessing the pyrrole as a fundamental subunit [28][29][30]. Additionally, 3,4-disubstituted pyrrole derivatives are versatile building blocks for the production of diverse bioactive molecules like co-enzyme, alkaloids, porphyrins and other related

Icilio Guareschi and his amazing “1897 reaction”

• Gian Cesare Tron,
• Alberto Minassi,
• Giovanni Sorba,
• Mara Fausone and
• Giovanni Appendino

Beilstein J. Org. Chem. 2021, 17, 1335–1351, doi:10.3762/bjoc.17.93

• of 47. In Turin, Guareschi pursued an amazing range of research topics. The one of ptomaines (alcaloidi cadaverici, cadaverous alkaloids) and the chemistry of naphthalene led to considerable fame for Guareschi because of both his original contributions and his comprehensive reviews of the area. Thus

• considered a major cause of food poisoning, a huge problem throughout the 19th century that, as we now know, is rather associated with bacterial activity. The surprising popularity of ptomaines as research topic was also due to the forensic relevance. Thus, ptomaines yield positive test results for alkaloids

• Guareschi” [42]. Triacetonamine bears a certain similarity to tropinone (9), the heterocyclic core of tropane alkaloids, and the one-pot preparation from acetone and ammonia reminds of, and anticipates by two decades, the Robinson synthesis of tropinone and the Willstätter synthesis of the corresponding 2

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

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

• Orgánica (ISO), Universidad de Alicante, Apdo. 99, 03080 Alicante, Spain 10.3762/bjoc.17.86 Abstract The synthesis of nitrogen-containing heterocycles, including natural alkaloids and other compounds presenting different types of biological activities have proved to be successful employing chiral sulfinyl

• widespread use of these imines as precursors of chiral compounds with a nitrogen atom bonded to a stereogenic center. The amine derivatives, resulting after removal of the tert-butanesulfinyl group, can be transformed into enantioenriched nitrogen-containing heterocycles [6][7] including natural alkaloids [8

• -butanesulfonamide and applications in some nucleophilic additions, the next sections will describe the synthesis of several alkaloids according to the size of the heterocycles. We regret in advance that some contributions are excluded in order to maintain a concise format. Review Asymmetric synthesis of aziridines

Synthesis of 10-O-aryl-substituted berberine derivatives by Chan–Evans–Lam coupling and investigation of their DNA-binding properties

• Peter Jonas Wickhorst,
• Mathilda Blachnik,
• Denisa Lagumdzija and
• Heiko Ihmels

Beilstein J. Org. Chem. 2021, 17, 991–1000, doi:10.3762/bjoc.17.81

• -DNA by terminal stacking. Keywords: berberine alkaloids; Cu-mediated coupling reactions; DNA recognition; nucleic acids; quadruplex DNA; Introduction Berberine (1a) is the most prominent member of the protoberberine family, i.e., a group of tetracyclic isoquinolinium alkaloids [1]. Like many members

Microwave-assisted multicomponent reactions in heterocyclic chemistry and mechanistic aspects

• Shivani Gulati,
• Stephy Elza John and
• Nagula Shankaraiah

Beilstein J. Org. Chem. 2021, 17, 819–865, doi:10.3762/bjoc.17.71

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

• -aminopyrroloquinolines with various biological activities. Keywords: 2-azahexatiriene system; carbodiimide; electrocyclization; pyrrolo[2,3-c]quinoline; trigonoine B; Introduction In 2011, two novel alkaloids, namely trigonoine A and B, were isolated from the leaves of Trigonostemon lii by Hao and co-workers [1]. The

• rearranged from a β-carboline skeleton (Figure 1). Additionally, the antihepatitis B virus (HBV) activity of the alkaloids was evaluated in vitro using an HBV-transfected HepG2 cell line. The antihuman immunodeficiency virus (HIV) properties were also investigated to determine whether trigonoine A and B

α,γ-Dioxygenated amides via tandem Brook rearrangement/radical oxygenation reactions and their application to syntheses of γ-lactams

• Mikhail K. Klychnikov,
• Radek Pohl,
• Ivana Císařová and
• Ullrich Jahn

Beilstein J. Org. Chem. 2021, 17, 688–704, doi:10.3762/bjoc.17.58

• ] are central fragments in various natural products, which are often synthesized from lactams by reduction. This makes them important building blocks in the total syntheses of alkaloids and their non-natural analogs [17][18][19][20][21]. However, the γ-lactam substructure itself is a central fragment of

• numerous bioactive alkaloids, such as pyrrocidine B (I) [22], fusarin C (II) [23], fusarisetin A (III) [24], pseurotin A (IV) [25], (−)-salinosporamide A (V) [26], parvistemoline (VI) [27], glochidine (VII) [28], and other alkaloids [29][30][31][32][33][34] (Figure 1). Moreover, functionalized synthetic γ

• /EtOAc 10:1 to 1:1) to give keto lactam 13. Selected alkaloids containing the pyrrolidone motif. X-ray crystal structure of the major (2R,4S)-alkoxyamine hydrochloride derived from 9j. Displacement ellipsoids at 30% probability level and a disordered CHCl3 solvent molecule is not shown for clarity. X-ray

The synthesis of chiral β-naphthyl-β-sulfanyl ketones via enantioselective sulfa-Michael reaction in the presence of a bifunctional cinchona/sulfonamide organocatalyst

• Deniz Tözendemir and
• Cihangir Tanyeli

Beilstein J. Org. Chem. 2021, 17, 494–503, doi:10.3762/bjoc.17.43

• %) catalyst loading. Selected enantiomerically enriched sulfa-Michael addition products were subjected to oxidation to obtain the corresponding sulfones. Keywords: asymmetric synthesis; bifunctional catalysis; cinchona alkaloids; organocatalysis; sulfa-Michael reaction; Introduction Derivatives of the

• naturally occurring cinchona alkaloids have shown remarkable performance as organocatalysts for stereoselective synthesis in the past decade [1][2][3][4][5][6]. Among them, quinine-derived organocatalysts make a noteworthy appearance in the formation of new stereogenic centres, which can serve as valuable

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

• pyrrolizidines; cyanoketones; legonmycin; vinylogous ureas; Introduction At least 40 members of the large class of pyrrolizidine alkaloids [1][2][3][4] have so far been characterized from bacterial cultures. Of these ‘bacterial pyrrolizidines’, those of the vinylogous urea type are particularly intriguing from

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

• , West Common, Harpenden, AL5 2JQ, United Kingdon 10.3762/bjoc.17.4 Abstract The 9-azabicyclo[3.3.1]nonane ring system is present in several insect- and plant-derived alkaloids. (−)-Adaline (1) and (+)-euphococcinine (2), found in secretions of Coccinelid beetles, and (+)-N-methyleuphococcinine (3

• ), isolated from the Colorado blue spruce Picea pungens, are members of this alkaloid family. Their unique bicyclic system with a quaternary stereocenter, and the potent biological activity exerted by these homotropane alkaloids, make them attractive synthetic targets. This work aims briefly to review the

• variety of defensive alkaloids that makes them unpleasant for various predators [1]. Over 50 alkaloids have been characterized from ladybirds until now, including perhydroazaphenalenes, aliphatic and aromatic amines, piperidines, pyrrolidines, azamacrolides, dimeric alkaloids and homotropanes [2]. The