Synthesis of chiral 3-substituted 3-amino-2-oxindoles through enantioselective catalytic nucleophilic additions to isatin imines

• Hélène Pellissier

Beilstein J. Org. Chem. 2018, 14, 1349–1369, doi:10.3762/bjoc.14.114

• ]. An extensively used two-component variant of this reaction consists in using a preformed imine. Among chiral metal complexes, a wide variety of organocatalysts [26][27][28][29][30][31][32][33][34] has been used to promote asymmetric Mannich reactions. Among them, cinchona alkaloid 1 was employed in

• -dicarbonyl compounds 5 performed in the presence of chiral cinchona alkaloid-derived squaramide 6 [36]. A range of chiral 3-amino-2-oxindoles 7 was obtained under mild reaction conditions in high to quantitative yields (78–99%) and uniformly excellent enantioselectivities (90–99% ee) as shown in Scheme 2. In

• diastereoselectivity of 90% de was achieved in the reaction of 1-benzoylacetone (R2 = Me, R3 = Ph) which afforded the corresponding single diastereoisomeric product in 96% yield and 95% ee. In 2018, Tanyeli et al. reinvestigated this type of reactions in the presence of related cinchona alkaloid-derived squaramide

Novel unit B cryptophycin analogues as payloads for targeted therapy

• Eduard Figueras,
• Adina Borbély,
• Mohamed Ismail,
• Marcel Frese and
• Norbert Sewald

Beilstein J. Org. Chem. 2018, 14, 1281–1286, doi:10.3762/bjoc.14.109

• research group. Docking and modelling of cryptophycin derivatives There is no X-ray analysis of cryptophycin–tubulin complexes available to provide information on the binding site. Based on biochemical evidence, binding close to the vinca-alkaloid binding site of β-tubulin, the so called “peptide-site

Rhodium-catalyzed C–H functionalization of heteroarenes using indoleBX hypervalent iodine reagents

• Erwann Grenet,
• Ashis Das,
• Paola Caramenti and
• Jérôme Waser

Beilstein J. Org. Chem. 2018, 14, 1208–1214, doi:10.3762/bjoc.14.102

• -pyridinone ring is present in milrinone (1), used to treat heart failure, while a 4-pyridinone is part of mimosine (2), an alkaloid isolated from Mimosa pudica. A benzene-fused pyridinone – a quinolone – can be found in brexpiprazole (3), a drug used against schizophrenia. In addition, the indole core is

One hundred years of benzotropone chemistry

• Arif Dastan,
• Haydar Kilic and
• Nurullah Saracoglu

Beilstein J. Org. Chem. 2018, 14, 1120–1180, doi:10.3762/bjoc.14.98

• system (Scheme 1). Their dipolar resonance structures such as tropylium oxide form 1B and 2B have been reported to provide a Hückel sextet of electrons that is necessary for aromaticity (Scheme 1) [1][2][3][4][5][6][7][8][9]. The tropone core is the ubiquitous structural motif in the alkaloid colchicine

An overview of recent advances in duplex DNA recognition by small molecules

• Sayantan Bhaduri,
• Nihar Ranjan and
• Dev P. Arya

Beilstein J. Org. Chem. 2018, 14, 1051–1086, doi:10.3762/bjoc.14.93

• as a result of binding to minor groove DNA. Samanta et al. investigated a thorough structure–activity correlation between mahanine, an anticancer carbazole alkaloid, and its chemically modified analogs to test the role of various functional groups on its antiproliferative activity against 19 cancer

On the design principles of peptide–drug conjugates for targeted drug delivery to the malignant tumor site

• Eirinaios I. Vrettos,
• Gábor Mező and
• Andreas G. Tzakos

Beilstein J. Org. Chem. 2018, 14, 930–954, doi:10.3762/bjoc.14.80

• of other types of cancers (breast cancer, bladder cancer, Kaposi's sarcoma) in combination with other anti-cancer agents. Camptothecin (CPT): Camptothecin is a cytotoxic alkaloid collected from extraction of the bark and stem of the Chinese tree ‘Camptotheca acuminata’. It was first isolated and

Mannich base-connected syntheses mediated by ortho-quinone methides

• Petra Barta,
• Ferenc Fülöp and
• István Szatmári

Beilstein J. Org. Chem. 2018, 14, 560–575, doi:10.3762/bjoc.14.43

• unexpected side products. As mentioned above [71], Osyanin et al. reported the synthesis of Uvaria scheffleri alkaloid (±)-schefflone. In this publication, the dimerization of the o-QM resulting in intermediate 41 is a key step in the synthesis of the final natural trimer compound. Reactions with C=N

• polyheterocycles formed was also described. The [4 + 2] cycloadditions between cyclic imines and o-QMs derived from Mannich bases could also be successfully applied in the syntheses of natural alkaloid-like compounds 47. Osyanin et al. reported the preparation of rutaecarpine and evodiamine, the 14-oxa analogues

Nucleophilic fluoroalkylation/cyclization route to fluorinated phthalides

• Masanori Inaba,
• Tatsuya Sakai,
• Shun Shinada,
• Tsuyuka Sugiishi,
• Yuta Nishina,
• Norio Shibata and
• Hideki Amii

Beilstein J. Org. Chem. 2018, 14, 182–186, doi:10.3762/bjoc.14.12

• ). Previously, Shibata et al. reported a cinchona alkaloid/Me4NF-catalyzed nucleophilic enantioselective trifluoromethylation of carbonyl compounds [33][34][35]. Initially, we tried to conduct the reaction of 2-cyanobenzaldehyde (2) with CF3–SiMe3 in the presence of cinchona alkaloids 9/TMAF combination (Table

Aminomethylation/hydrogenolysis as an alternative to direct methylation of metalated isoquinolines – a novel total synthesis of the alkaloid 7-hydroxy-6-methoxy-1-methylisoquinoline

• Benedikt C. Melzer,
• Jan G. Felber and
• Franz Bracher

Beilstein J. Org. Chem. 2018, 14, 130–134, doi:10.3762/bjoc.14.8

• products and in drug development and hence, effective synthetic approaches are required. Here we present a novel method for the introduction of a methyl group at C1 of isoquinolines. This is exemplified by a new total synthesis of the alkaloid 7-hydroxy-6-methoxy-1-methylisoquinoline. Direct metalation of

• 7-benzyloxy-6-methoxyisoquinoline with Knochel–Hauser base, followed by cuprate-mediated methylation gives the target alkaloid directly, but separation from the educt is cumbersome. Quenching the metalated intermediate with Eschenmoser’s reagent gives an easy to clean tertiary benzylamine, which

• , after quaternization with iodomethane, is easily converted into the desired 1-methylisoquinoline by hydrogenolysis of both the benzylamine and benzyl ether groups. Keywords: alkaloid; aminomethylation; hydrogenolysis; isoquinoline; metalation; methylation; Introduction The isoquinoline ring system has

A concise flow synthesis of indole-3-carboxylic ester and its derivatisation to an auxin mimic

• Marcus Baumann,
• Ian R. Baxendale and
• Fabien Deplante

Beilstein J. Org. Chem. 2017, 13, 2549–2560, doi:10.3762/bjoc.13.251

• chemistry; heterocycle; hydrogenation; indole; multistep; Introduction Indoles are amongst the most important bioactive heterocyclic structures being commonly encountered in the amino acid tryptophan (1), the related neurotransmitter serotonin (2) as well as numerous complex alkaloid natural products and

A permutation approach to the assignment of the configuration to diastereomeric tetrads by comparison of experimental and ab initio calculated differences in NMR data

• Przemysław J. Boratyński

Beilstein J. Org. Chem. 2017, 13, 2478–2485, doi:10.3762/bjoc.13.245

• four diastereomers can help to assign their relative configurations. This method was exercised on a set of diastereomeric Cinchona alkaloid derivatives, where 13C NMR data always identified the proper configuration. The presented approach is also an attempt to quantify the assignment by exclusion

Conjugated nitrosoalkenes as Michael acceptors in carbon–carbon bond forming reactions: a review and perspective

• Yaroslav D. Boyko,
• Valentin S. Dorokhov,
• Alexey Yu. Sukhorukov and
• Sema L. Ioffe

Beilstein J. Org. Chem. 2017, 13, 2214–2234, doi:10.3762/bjoc.13.220

• Ottenheijm in the total synthesis of an analogue of the tryptophan-containing natural alkaloid neoechinulin B (indole 77) [67][68] (Scheme 28). At the initial stage, N-methylindole was alkylated with ethyl bromopyruvate oxime and sodium carbonate to give adduct 78, which was then transformed into N

Chiral phase-transfer catalysis in the asymmetric α-heterofunctionalization of prochiral nucleophiles

• Johannes Schörgenhumer,
• Maximilian Tiffner and
• Mario Waser

Beilstein J. Org. Chem. 2017, 13, 1753–1769, doi:10.3762/bjoc.13.170

• ][16][17][18][19][20]. Following the pioneering reports of Wynberg et al. [25] and Merck scientists [26] who employed cinchona alkaloid-derived quaternary ammonium salts for asymmetric epoxidations [25] and the α-methylation of a phenylindanone derivative [26] in the late 1970s, early 1980s already

• nucleophiles dates back to 2002, when Kim and Park described the first use of cinchona alkaloid-based quaternary ammonium salts A (i.e., derivative A1) for the enantioselective α-fluorination of β-ketoesters 1 by using N-fluorobenzenesulfonimide (NFSI, 2) as the fluoride-transfer reagent [73] (Scheme 2). By

• fluorination reaction [78]. The groups of Duan and Lin have also very heavily been engaged in the systematic design of highly active bifunctional cinchona alkaloid-based ammonium salt catalysts that contain an additional H-bonding donor [43][44]. Very impressively, they succeeded in synthesizing and testing

Oxidative dehydrogenation of C–C and C–N bonds: A convenient approach to access diverse (dihydro)heteroaromatic compounds

• Santanu Hati,
• Ulrike Holzgrabe and
• Subhabrata Sen

Beilstein J. Org. Chem. 2017, 13, 1670–1692, doi:10.3762/bjoc.13.162

• conditions were not well tolerated by few sensitive groups, most of the β-carbolines were successfully prepared utilizing this procedure, including the alkaloid harmine with 99% yield. The final product precipitates at the end of the reaction and hence required minimum purification. Organocatalytic aerobic

A novel approach to oxoisoaporphine alkaloids via regioselective metalation of alkoxy isoquinolines

• Benedikt C. Melzer and
• Franz Bracher

Beilstein J. Org. Chem. 2017, 13, 1564–1571, doi:10.3762/bjoc.13.156

• the synthesis of the alkaloid bianfugecine (6, Scheme 4), which contains only one methoxy group at ring B. Until now, only one partial synthesis of this alkaloid is described in the literature. Kunitomo et al. [30] obtained alkaloid 6 by hydrogenolytic demethoxylation of alkaloid menisporphine (2

• ) with H2/PtO2 in acetic acid. Unfortunately, upon cyclization of the carboxylic acid 11c, obtained by acidic hydrolysis of ester 10c, with Eaton’s reagent alkaloid 6 could be isolated in only very poor yield (7%). Other established cyclization methods starting from methyl ester 10c were tested in order

• and N-2 of the isoquinoline moiety, thus is kept away from C-8’. In contrast, we found in previous investigations on the synthesis of the pyridoacridone alkaloid demethyldeoxyamphimendine [21], that an ester group located at a comparable position (suitable for forming a chelate in cooperation with a

An improved preparation of phorbol from croton oil

• Alberto Pagani,
• Simone Gaeta,
• Andrei I. Savchenko,
• Craig M. Williams and
• Giovanni Appendino

Beilstein J. Org. Chem. 2017, 13, 1361–1367, doi:10.3762/bjoc.13.133

• reported by Pelletier and Caventou, the founding fathers of alkaloid chemistry, in 1818 [4], but the nature of its irritant principles remained obscure and controversial until 1930, when Flaschenträger unambiguously characterized the inflammatory fraction of the oil as a mixture of esters of a crystalline

Construction of highly enantioenriched spirocyclopentaneoxindoles containing four consecutive stereocenters via thiourea-catalyzed asymmetric Michael–Henry cascade reactions

• Yonglei Du,
• Jian Li,
• Kerong Chen,
• Chenglin Wu,
• Yu Zhou and
• Hong Liu

Beilstein J. Org. Chem. 2017, 13, 1342–1349, doi:10.3762/bjoc.13.131

• strategies with chiral transition metals [27][28][29][30][31][32][33], organocatalysts such as secondary amines [34][35][36], nucleophilic phosphines [26][37][38][39][40][41][42][43][44], tertiary amines [45], N-heterocyclic carbenes (NHCs) [46][47][48], and cinchona alkaloid derivatives [25][28][49][50

• variety of organocatalysts (a–f) were investigated in CH2Cl2 at −20 °C for 12 h to evaluate their ability to promote the transformation (Table 1, entries 1–6). When cinchona alkaloid-derived catalyst a and quinine-derived amine catalyst b were tested, however, poor yields or ee values were obtained

Characterization of non-heme iron aliphatic halogenase WelO5* from Hapalosiphon welwitschii IC-52-3: Identification of a minimal protein sequence motif that confers enzymatic chlorination specificity in the biosynthesis of welwitindolelinones

• Qin Zhu and
• Xinyu Liu

Beilstein J. Org. Chem. 2017, 13, 1168–1173, doi:10.3762/bjoc.13.115

• -52-3 has an enhanced substrate specificity towards 12-epi-hapalindole C (1) in comparison to WelO5 in H. welwitschii UTEX B1830. This allowed us to define the origin of the varied chlorinated versus dechlorinated alkaloid structural diversity between the two welwitindolinone producers. Furthermore

• engineering and evolution of these proteins for biocatalyst application. Keywords: alkaloid biogenesis; biosynthetic divergency; C–H activation; halogenase; non-heme iron enzyme; Introduction Carbon–halogen (C–X) bonds are prevalent structural motifs in modern agrochemicals, pharmaceuticals and bioactive

• ], analogous oxidative functionalizations with halogens via C–H activations remain challenging that need to be addressed [9][10][11]. Recently, during the systematic investigation of hapalindole-type alkaloid biogenesis [12][13][14][15][16][17][18][19], we discovered a family of Fe/2OG-dependent halogenases

A strategic approach to [6,6]-bicyclic lactones: application towards the CD fragment of DHβE

• Tue Heesgaard Jepsen,
• Emil Glibstrup,
• François Crestey,
• Anders A. Jensen and
• Jesper Langgaard Kristensen

Beilstein J. Org. Chem. 2017, 13, 988–994, doi:10.3762/bjoc.13.98

• effective synthetic protocol to access [6,6]-bicyclic lactone moieties through a regio- and stereoselective intramolecular Mizoroki–Heck cross-coupling reaction followed by a 6π-electrocyclization. This method enabled the first synthesis of the elusive CD fragment of the Erythrina alkaloid DHβE. Preliminary

• challenging [6,6]-bicyclic lactone fragment in general through an expedient regio- and stereoselective Mizoroki–Heck cyclization approach. This method enabled the synthesis of the elusive and volatile CD fragments ([6,6]-bicyclic lactones 9 and 26) of the Erythrina alkaloid DHβE. This allowed the

Automating multistep flow synthesis: approach and challenges in integrating chemistry, machines and logic

• Chinmay A. Shukla and
• Amol A. Kulkarni

Beilstein J. Org. Chem. 2017, 13, 960–987, doi:10.3762/bjoc.13.97

• (±)-oxomaritidine (gas–liquid–solid reaction) Baxendale et al. have developed a multistep synthesis for (±)-oxomaritidine, a cytotoxic alkaloid of the amaryllidaceae family of natural products [9] (Scheme 4). The process involved seven reaction steps out of which the first two reactions were carried out in parallel

Nucleophilic and electrophilic cyclization of N-alkyne-substituted pyrrole derivatives: Synthesis of pyrrolopyrazinone, pyrrolotriazinone, and pyrrolooxazinone moieties

• Işıl Yenice,
• Sinan Basceken and
• Metin Balci

Beilstein J. Org. Chem. 2017, 13, 825–834, doi:10.3762/bjoc.13.83

• , nannozinone B (5, Figure 2), containing a pyrrolopyrazinone moiety was isolated from a myxobacterium, Nannocystis pusilla [11]. The alkaloid peramine (6, Figure 2), isolated from endophyte-infected perennial ryegrass, has feeding deterrent activity against insects [12][13]. An efficient and straightforward

Phosphazene-catalyzed desymmetrization of cyclohexadienones by dithiane addition

• Matthew A. Horwitz,
• Elisabetta Massolo and
• Jeffrey S. Johnson

Beilstein J. Org. Chem. 2017, 13, 762–767, doi:10.3762/bjoc.13.75

• ] nucleophiles using bifunctional cinchona alkaloid catalysts. The Sasai and Enders groups used a phosphinothiourea to enable a Rauhut–Currier reaction to form bicyclic enones [16]. The Tian and Lin group used alkyne-tethered cyclohexadienones in an arylrhodation/conjugate addition sequence that

Studies directed toward the exploitation of vicinal diols in the synthesis of (+)-nebivolol intermediates

• Runjun Devi and
• Sajal Kumar Das

Beilstein J. Org. Chem. 2017, 13, 571–578, doi:10.3762/bjoc.13.56

• number of cinchona alkaloid-derived ligands which allow the dihydroxylation of alkenes of almost all substitution patterns with high enantioselectivity. Noteworthy is that the SAD is not limited to only E-allylic alcohols in its choice of substrates as is the SAE process. Moreover, the SAD is much more

The reductive decyanation reaction: an overview and recent developments

• Jean-Marc R. Mattalia

Beilstein J. Org. Chem. 2017, 13, 267–284, doi:10.3762/bjoc.13.30

• (15i–k). A series of aliphatic α-iminonitriles also gave good results (15n,o). Notably the labile dimethylacetal group tolerates this two-step transformation (15m). Using this protocol, the authors described a total synthesis of (±)-isoretronecanol (19), a pyrrolizidine alkaloid (Scheme 9). In this

New syntheses of (±)-tashiromine and (±)-epitashiromine via enaminone intermediates

• Darren L. Riley,
• Joseph P. Michael and
• Charles B. de Koning

Beilstein J. Org. Chem. 2016, 12, 2609–2613, doi:10.3762/bjoc.12.256

• of the naturally occurring indolizidine alkaloid (±)-tashiromine and its unnatural epimer (±)-epitashiromine are demonstrated through the use of enaminone chemistry. The impact of various electron-withdrawing substituents at the C-8 position of the indolizidine core on the preparation of the bicyclic

• system is described. Keywords: alkaloid; enaminone; epitashiromine; indolizidine; tashiromine; Introduction Tashiromine (1) is a monosubstituted indolizidine alkaloid originally isolated from the Asian deciduous shrub Maackia tashiroi [1] and subsequently from the genera Poecilanthe [2] and Crotalaria