Synthesis of 1-indolyl-3,5,8-substituted γ-carbolines: one-pot solvent-free protocol and biological evaluation

• Premansh Dudhe,
• Mena Asha Krishnan,
• Kratika Yadav,
• Diptendu Roy,
• Krishnan Venkatasubbaiah,
• Biswarup Pathak and
• Venkatesh Chelvam

Beilstein J. Org. Chem. 2021, 17, 1453–1463, doi:10.3762/bjoc.17.101

• -pyrido[3,4-b]indole (β-carboline) is the most naturally abundant, present for instance, in the alkaloid harmine, a well-known selective inhibitor of monoamine oxidase-A (MAO-A) [1]. On the contrary, 5H-pyrido[4,3-b]indoles (γ-carbolines) are comparatively less examined, although these heterocycles have

• shown promising biological activities in preclinical and clinical studies (Figure 1) [2][3][4][5][6]. The pyrimidine-γ-carboline alkaloid ingenine B (isolated from an Indonesian sponge) exhibits a pronounced cytotoxicity against a murine lymphoma cell line [7] and several isocanthine analogs are

• alkaloid ingenine B [20]. The iodine-catalyzed [3 + 3] cycloaddition of indolyl alcohol to enaminones [21] and the thiourea-catalyzed iso-Pictet–Spengler reaction of isotryptamine with aldehydes [22], are some noteworthy contributions to the field. A cascade or domino reaction is an interesting approach

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

• , his Introduzione allo Studio degli Alcaloidi con special riguardo agli alcaloidi vegetali ed alle ptomaine (An Introduction to Alkaloid Chemistry, and especially on those of plant origin and on ptomaines), first published in 1892, was translated four years later into German, and the popularity of this

• work is testified by Willstätter, who in his memoirs refers to Guareschi as “alkaloid chemist” [28]. Ptomaines (from the Greek πτωμα, cadaver) are anaerobic bacterial degradation products of proteins and choline-containing phospholipids. The formation of these is associated with putrefaction of animal

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

• derivative 57 in 72% combined yield (Scheme 18) [88]. In 2020, Pierce and co-workers developed a method for the synthesis of guanidinium alkaloid batzelladine D in enantiomeric and racemic form, along with a series of stereochemical analogues. The batzelladines are a family of polycyclic guanidinium

• )2] in DMF was the best to produce lactams 77. The synthetic interest of these functionalized lactams was demonstrated in the synthesis of alkaloid (−)-preussin (78) from the appropriate precursor 77 in three steps (Scheme 23). Similar strategies were employed to obtain similar heterocycles [99

• straightforward synthesis of the alkaloid (−)-pelletierine (112) was accomplished by the diastereoselectivity coupling of 3-oxobutanoic acid (110) and the N-tert-butanesulfinyl imine (RS)-109 derived from 5-bromopentanal (114). The base-promoted decarboxylative-Mannich coupling of these reagents led to β-amino

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

• , Yokohama University of Pharmacy, 601 Matano, Totsuka-ku, Yokohama 245-0066, Japan 10.3762/bjoc.17.62 Abstract The first total synthesis of the pyrrolo[2,3-c]quinoline alkaloid trigonoine B (1) was accomplished via a six-step sequence involving the construction of an N-substituted 4-aminopyrrolo[2,3-c

• structures of the compounds were elucidated through 1D and 2D NMR spectroscopy. It was determined that trigonoine A was a β-carboline alkaloid containing a 2,8-diazabicyclo[3.3.1]nonane ring system, while trigonoine B (1) was formed by a combination of 2,3-dihydroquinolin-4-one and 3H-pyrrolo[2,3-c]quinoline

• acquired physical and spectroscopic data of the herein synthesized compound 1 were consistent with those of the natural trigonoine B [1]. Thus, in this study, we successfully achieved the first total synthesis of trigonoine B (1). Conclusion The total synthesis of a pyrrolo[2,3-c]quinoline alkaloid

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

• Deniz Tozendemir Cihangir Tanyeli Department of Chemistry, Middle East Technical University, 06800 Ankara, Turkey 10.3762/bjoc.17.43 Abstract Cinchona alkaloid-derived organocatalysts are widely employed in various asymmetric transformations, yielding products with high enantiopurity. In this

• transition state model to explain the origin of the stereoinduction was proposed (Scheme 2), according to the Houk’s Brønsted acid hydrogen bonding model. Guo’s computational work in 2017 on the sulfa-Michael addition of thiols to enones in the presence of cinchona alkaloid-type organocatalysts showed that

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

• methodology followed by NaBH4 reduction. This structure with three condensed rings can be seen as a new class of unnatural, chiral alkaloid scaffolds, potentially exhibiting pharmacological activity (Scheme 3) [40]. Various unsuccessful attempts were made to deprotect compound 3e. Unexpectedly, however, one of

• couplings and NOE effects shown. Our previous efforts in the field of functionalization of sugar-derived lactams. Preliminary experiment in search of a procedure for the synthesis of 2-(1H-tetrazol-5-yl)-iminosugars. Synthesis of a new class of alkaloid scaffold using the presented methodology. Synthesis of a

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

• ), 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

• ] and [3.2.2] (Figure 1). The homotropane alkaloid (−)-adaline (1) was isolated from ladybird Adalia bipunctata [17] and Cryptolaemus moutrouzieri secretions [18]. A methyl analog, (+)-euphococcinine (2), has been found in vegetable and animal kingdoms. The compound was first isolated from the

• Australian coastal plant Euphorbia atoto [19], and it is also present in the defense secretion of ladybirds Cryptolaemus montrouzieri [18] and Epilachna varivestis [16]. Also, (+)-N-methyleuphococcinine (3) has been identified as a trace homotropane alkaloid isolated from the spruce tree Picea pungens [20

Synthesis, crystal structures and properties of carbazole-based [6]helicenes fused with an azine ring

• Daria I. Tonkoglazova,
• Anna V. Gulevskaya,
• Konstantin A. Chistyakov and
• Olga I. Askalepova

Beilstein J. Org. Chem. 2021, 17, 11–21, doi:10.3762/bjoc.17.2

• last, carbazole-based heterohelicenes were found in nature, for example, purpurone [55] isolated from the marine sponge Iotrochota sp. and having an inhibitory effect on the ATP-citrate lyase, and the marine alkaloid ningalin D produced by Didemnum sp., Dictyodendrins [56] isolated from Dictyodendrilla

An atom-economical addition of methyl azaarenes with aromatic aldehydes via benzylic C(sp³)–H bond functionalization under solvent- and catalyst-free conditions

• Divya Rohini Yennamaneni,
• Vasu Amrutham,
• Krishna Sai Gajula,
• Rammurthy Banothu,
• Murali Boosa and
• Narender Nama

Beilstein J. Org. Chem. 2020, 16, 3093–3103, doi:10.3762/bjoc.16.259

• diversity, these compounds constitute a motif in various natural alkaloid products, such as chimanine and those derived from lobelia, sedum, etc. These compounds act as anti-HIV and anti-asthma drugs [9][10][11]. Mainly, 2-substituted quinolines and their analogues exhibits magnificent bioactivity [12][13

Synthesis and investigation of quadruplex-DNA-binding, 9-O-substituted berberine derivatives

• Jonas Becher,
• Daria V. Berdnikova,
• Heiko Ihmels and
• Christopher Stremmel

Beilstein J. Org. Chem. 2020, 16, 2795–2806, doi:10.3762/bjoc.16.230

• successfully developed as G4-DNA ligands [17], the natural product berberine (1a) has attracted special attention. Berberine (1a) is an isoquinoline alkaloid with an exceptionally wide range of biological activities [23][24]. It has been shown that berberine (1a) and its derivatives act, for example, as anti

3-Acetoxy-fatty acid isoprenyl esters from androconia of the ithomiine butterfly Ithomia salapia

• Florian Mann,
• Daiane Szczerbowski,
• Lisa de Silva,
• Melanie McClure,
• Marianne Elias and
• Stefan Schulz

Beilstein J. Org. Chem. 2020, 16, 2776–2787, doi:10.3762/bjoc.16.228

• contained ithomiolide A (3), a pyrrolizidine alkaloid derived γ-lactone, I. s. derasa carried the sesquiterpene α-elemol (8) in the androconia. These differences might be important for the reproductive isolation of the two subspecies, in line with previously reported low gene exchange between the two

• various plants [9]. These alkaloids are transformed into the alkaloid and pheromone precursor lycopsamine (1, Scheme 1) [10][11][12] that can then be converted either into necine base derived compounds such as methyl hydroxydanaidoate (2), or into necic acids derived ones, e.g., ithomiolide A (3) [10][11

• -hydroxy-11-octadecenoate; Y: methyl 3-hydroxyoctadecanoate; E: (E)-isomer of (R)-25. The enantiomer (S,E)-25 elutes together with (R,Z)-25, indicated by the broader base of this peak in B compared to C. Pyrrolizidine alkaloid lycopsamine (1) and the putative pheromone compounds methyl hydroxydanaidoate (2

Controlling the stereochemistry in 2-oxo-aldehyde-derived Ugi adducts through the cinchona alkaloid-promoted electrophilic fluorination

• Yuqing Wang,
• Gaigai Wang,
• Anatoly A. Peshkov,
• Ruwei Yao,
• Muhammad Hasan,
• Manzoor Zaman,
• Chao Liu,
• Stepan Kashtanov,
• Olga P. Pereshivko and
• Vsevolod A. Peshkov

Beilstein J. Org. Chem. 2020, 16, 1963–1973, doi:10.3762/bjoc.16.163

• alkaloid-promoted electrophilic fluorination producing enantioenriched post-Ugi adducts fluorinated at the peptidyl position. Keywords: cinchona alkaloids; electrophilic fluorination; enantioselective synthesis; 2-oxo-aldehydes; Ugi reaction; Introduction Multicomponent reactions (MCRs) [1][2][3][4][5][6

• carbonyl compounds promoted by cinchona alkaloid derivatives developed independently by Shibata, Takeuchi and co-workers [65][66] and by the group of Cahard [67][68][69][70]. The method proved to be applicable to a broad range of substrates under a variety of conditions [71][72][73][74][75][76][77][78] and

• , a cinchona alkaloid derivative was allowed to react with an electrophilic fluorinating agent to afford an N-fluoroammonium salt of the cinchona alkaloid via transfer fluorination. In the second step, the Ugi adduct 8a was added to this in situ generated N-fluorocinchona intermediate to afford the

Et₃N/DMSO-supported one-pot synthesis of highly fluorescent β-carboline-linked benzothiophenones via sulfur insertion and estimation of the photophysical properties

• Dharmender Singh,
• Vipin Kumar and
• Virender Singh

Beilstein J. Org. Chem. 2020, 16, 1740–1753, doi:10.3762/bjoc.16.146

• [42][43][44][45][46]. In our research endeavors, we have been involved in the exploration of the synthetic potential of 1-formyl-9H-β-carboline (an alkaloid, kumujian C) [47] for preparing chemical libraries of β-carboline-substituted [48][49][50][51][52][53][54] and N-fused heterocycles [55][56

• a one-pot metal-free approach for the first time. The transformation could be executed from β-carboline-based 2-nitrochalcones via a one-pot, two-step procedure starting from 1(3)-formyl-β-carbolines (a framework represented by alkaloid kumujian C). The combination of Et3N and DMSO played a vital

Pauson–Khand reaction of fluorinated compounds

• Jorge Escorihuela,
• Daniel M. Sedgwick,
• Alberto Llobat,
• Mercedes Medio-Simón,
• Pablo Barrio and
• Santos Fustero

Beilstein J. Org. Chem. 2020, 16, 1662–1682, doi:10.3762/bjoc.16.138

• quantities of cobalt present in the reaction mixture. The same group also studied the intramolecular PKR of chiral fluorine-containing N-tethered 1,7-enynes 48 for the stereoselective construction of enantioenriched bicyclic alkaloid analogues 49, containing a fluorine atom in the bridge position [61]. For

Synthesis of new dihydroberberine and tetrahydroberberine analogues and evaluation of their antiproliferative activity on NCI-H1975 cells

• Giacomo Mari,
• Lucia De Crescentini,
• Serena Benedetti,
• Francesco Palma,
• Stefania Santeusanio and
• Fabio Mantellini

Beilstein J. Org. Chem. 2020, 16, 1606–1616, doi:10.3762/bjoc.16.133

• Molecular Biology, Department of Biomolecular Sciences, University of Urbino “Carlo Bo”, Via Saffi 2, 61029 Urbino, Italy 10.3762/bjoc.16.133 Abstract Dihydroberberine (DHBER), the partially reduced form of the alkaloid berberine (BER), is known to exhibit important biological activities. Despite this fact

• various inflammatory diseases. The main component of this rhizome is berberine (BER), an alkaloid with numerous pharmacological properties, which include anticancer and anti-inflammatory activities [1]. However, the low bioavailability, poor solubility, and moderate nucleic acid binding affinity

• activity [13][14][15][16][17][18][19], and an increased DNA and RNA binding efficacy [4][6][9], due to its aromatic interactions with the biological macromolecules [20]. Another interesting and promising derivative is dihydroberberine (DHBER), the reduced form of BER. The enaminic function of this alkaloid

Photocatalyzed syntheses of phenanthrenes and their aza-analogues. A review

• Alessandra Del Tito,
• Havall Othman Abdulla,
• Davide Ravelli,
• Stefano Protti and
• Maurizio Fagnoni

Beilstein J. Org. Chem. 2020, 16, 1476–1488, doi:10.3762/bjoc.16.123

• method was applied to the two-step synthesis of the alkaloid trisphaeridine (15.3) on a gram-scale quantity (Scheme 15) [78]. O-2,4-Dinitrophenyloximes were competent substrates for the photocatalyzed generation of iminyl radicals. In this case, the reaction was photoorganocatalyzed by eosin Y and took

• heteroarylalkynes. Synthesis of noravicine (14.2a) and nornitidine (14.2b) alkaloids. Gram-scale synthesis of the alkaloid trisphaeridine (15.3). Synthesis of phenanthridines starting from vinyl azides. Synthesis of pyrido[4,3,2-gh]phenanthridines 17.5a–d through the radical trifluoromethylthiolation of N-(o

Synthesis of pyrrolidinedione-fused hexahydropyrrolo[2,1-a]isoquinolines via three-component [3 + 2] cycloaddition followed by one-pot N-allylation and intramolecular Heck reactions

• Xiaoming Ma,
• Suzhi Meng,
• Xiaofeng Zhang,
• Qiang Zhang,
• Shenghu Yan,
• Yue Zhang and
• Wei Zhang

Beilstein J. Org. Chem. 2020, 16, 1225–1233, doi:10.3762/bjoc.16.106

• ; Introduction Pyrrolo[2,1-a]isoquinoline and hexahydropyrrolo[2,1-a]isoquinoline are privileged heterocyclic rings existing in many natural products and synthetic compounds possessing antitumor, antibacterial, antiviral, antioxidizing, and other biological activities (Figure 1) [1][2]. For example, the alkaloid

Copper-catalysed alkylation of heterocyclic acceptors with organometallic reagents

• Yafei Guo and
• Syuzanna R. Harutyunyan

Beilstein J. Org. Chem. 2020, 16, 1006–1021, doi:10.3762/bjoc.16.90

• this reaction, in most cases providing the products with a high enantioselectivity and a moderate yield. An exception was found with diisopropylzinc, for which only 56% ee could be obtained. The methodology was also successfully applied to the total synthesis of the natural alkaloid (R)-coniine

Combining enyne metathesis with long-established organic transformations: a powerful strategy for the sustainable synthesis of bioactive molecules

• Valerian Dragutan,
• Ileana Dragutan,
• Albert Demonceau and
• Lionel Delaude

Beilstein J. Org. Chem. 2020, 16, 738–755, doi:10.3762/bjoc.16.68

• metathesis steps applying the second-generation Hoveyda–Grubbs Ru catalyst, while, unexpectedly, the second-generation Grubbs ruthenium catalyst was less active and gave rise to some side-products. (−)-Galanthamine An important alkaloid active in the treatment of mild to moderate Alzheimer's disease and

• (+)-3-epi-kempene-2 (14c). Importantly, the tandem metathesis of the dienyne precursor could also be performed in good yield (82%) with the Grubbs first-generation Ru catalyst (10 mol %). (+)-Lycoflexine alkaloid In 2010, Ramharter and Mulzer [83] prepared an intricate tricyclic intermediate useful for

• the total synthesis of the alkaloid (+)-lycoflexine (15). In this strategy, first a protected dienyne precursor was prepared that, by an enyne tandem ring-closing metathesis induced by the Grubbs second-generation Ru catalyst, produced a tricyclic diene in 52% yield. Next, a selective hydrogenation of

Pigmentosins from Gibellula sp. as antibiofilm agents and a new glycosylated asperfuran from Cordyceps javanica

• Soleiman E. Helaly,
• Wilawan Kuephadungphan,
• Patima Phainuphong,
• Mahmoud A. A. Ibrahim,
• Kanoksri Tasanathai,
• Suchada Mongkolsamrit,
• Janet Jennifer Luangsa-ard,
• Souwalak Phongpaichit,
• Vatcharin Rukachaisirikul and
• Marc Stadler

Beilstein J. Org. Chem. 2019, 15, 2968–2981, doi:10.3762/bjoc.15.293

• were found to produce the same compound. So far, pigmentosin A (1) was reported only from lichenized fungi [20][21], and thus this is the first report of this compound stemming from another group of fungi. Recently, we have reported on the two new β-carboline alkaloid derivatives gibellamines A and B

A review of asymmetric synthetic organic electrochemistry and electrocatalysis: concepts, applications, recent developments and future directions

• Munmun Ghosh,
• Valmik S. Shinde and
• Magnus Rueping

Beilstein J. Org. Chem. 2019, 15, 2710–2746, doi:10.3762/bjoc.15.264

• cathode in an undivided cell in the presence of cinchonidine alkaloid as the source of chirality [30]. They modified the electrolysis conditions using a mixture of CH3CN/H2O and tetraethylammonium iodide as the supporting electrolyte and achieved a slight improvement in the enantiomeric excess (Scheme 7

• , conditions B). Based on a strychnine alkaloid-induced asymmetric electroreduction, Kopilov, Kariv and Miller showed that 4- and 2-acetylpyridines (1 and 25) could be reduced to the corresponding pyridylethanols (2 and 26, respectively) in presence of a catalytic amount of the alkaloid on a mercury cathode

• . Notably, the highest optical yields were achieved using strychnine (Scheme 8) [31]. Similarly, by applying modified electrolytic conditions, in 1993, Schoo and Schäfer increased the enantioselectivity of the alkaloid-catalyzed enantioselective electroreduction of 4-methylcoumarin (8) relative to that

Functionalization of 4-bromobenzo[c][2,7]naphthyridine via regioselective direct ring metalation. A novel approach to analogues of pyridoacridine alkaloids

• Benedikt C. Melzer,
• Alois Plodek and
• Franz Bracher

Beilstein J. Org. Chem. 2019, 15, 2304–2310, doi:10.3762/bjoc.15.222

• manner of a radical reaction [27][28][29]. Starting with alcohol 12b, a putative precursor of the alkaloid kuanoniamine A (3), the three described cyclization methodologies were tested starting directly from alcohol 12b as well as from ketone 21, obtained by oxidation of 12b. The intramolecular biaryl

• synthesis via an Heck-type palladium-catalysed reaction according to the method of Harayama [30] (Pd(II)acetate/tri(o-tolyl)phosphine/K2CO3) did not lead to the expected alkaloid 3. Also the radical procedure published by Markgraf et al. [31] using AIBN and Bu3SnH and a photochemical cyclization protocol we

A metal-free approach for the synthesis of amides/esters with pyridinium salts of phenacyl bromides via oxidative C–C bond cleavage

• Kesari Lakshmi Manasa,
• Yellaiah Tangella,
• Namballa Hari Krishna and
• Mallika Alvala

Beilstein J. Org. Chem. 2019, 15, 1864–1871, doi:10.3762/bjoc.15.182

• benzylamines, where electron-donating substituents resulted in comparably higher yields than the electron-withdrawing substituents. An alkaloid amine like tryptamine was well reacted and produced the corresponding amide 3f in a good yield. It is worth mentioning that a sterically bulkier amine like 1

N-(1-Phenylethyl)aziridine-2-carboxylate esters in the synthesis of biologically relevant compounds

• Iwona E. Głowacka,
• Aleksandra Trocha,
• Andrzej E. Wróblewski and
• Dorota G. Piotrowska

Beilstein J. Org. Chem. 2019, 15, 1722–1757, doi:10.3762/bjoc.15.168

• )-24 was obtained. On the other hand, alkylation of 2,6-dimethylphenol with the tosylate (2S,1'R)-25 proceeded regioselectively to give (2S,1'R)-26, a precursor to (S)-24. (−)-Cathinone ((S)-27) is an alkaloid acting as a central nervous system stimulant found in leaves of Catha edulis. It was

Synthesis of 9-O-arylated berberines via copper-catalyzed C_Ar–O coupling reactions

• Qiaoqiao Teng,
• Xinhui Zhu,
• Qianqian Guo,
• Weihua Jiang,
• Jiang Liu and
• Qi Meng

Beilstein J. Org. Chem. 2019, 15, 1575–1580, doi:10.3762/bjoc.15.161

• natural alkaloid extracted from ranunculaceae, rutaceae and berberidaceae, which features a tetracyclic isoquinoline core unit. It was widely used as antibacterial agent [1] and has shown myriad therapeutic potencies in tumor cell suppression [2][3] and various chronic disease management [4]. In most