Synthesis of the reported structure of piperazirum using a nitro-Mannich reaction as the key stereochemical determining step

• James C. Anderson,
• Andreas S. Kalogirou,
• Michael J. Porter and
• Graham J. Tizzard

Beilstein J. Org. Chem. 2013, 9, 1737–1744, doi:10.3762/bjoc.9.200

• unambiguously assigned by single crystal X-ray diffraction but the spectroscopic data did not match those reported for the natural product. The structure of the natural product must therefore be revised. Keywords: alkaloid; aza-Henry; natural products; nitro-Mannich; piperazinone; stereoselective synthesis

• a novel bioactive alkaloid, piperazirum (2, Scheme 2), which to our knowledge had not been previously synthesised. Piperazirum was isolated from the leaf extract of Arum palaestinum Boiss and was shown to possess significant cytotoxicity against cultured tumor cell lines in vitro [46]. Its chemical

Organocatalyzed enantioselective desymmetrization of aziridines and epoxides

• Ping-An Wang

Beilstein J. Org. Chem. 2013, 9, 1677–1695, doi:10.3762/bjoc.9.192

• including cinchona alkaloid derivatives, chiral phosphoric acids, chiral amino alcohols, chiral thioureas, chiral guanidines, and chiral 1,2,3-triazolium chlorides. In this review, the research work of enantioselective desymmetrization of meso-aziridines is organized into sections according to the employed

• organocatalysts. Cinchona alkaloid derivatives The first organocatalytic enantioselective desymmetrization of meso-aziridines was discovered by Hou and co-workers in 2007 [40] with various arylthiols as nucleophiles in CCl4 at 0 °C in the presence of cinchonine-derived phase-transfer catalysts (PTCs, Figure 2, OC

• -1 to OC-6). The substituent on the bridgehead nitrogen of cinchona alkaloids has a great impact on the enantioselectivity of the reactions. The catalyst OC-2 with 9-anthracenylmethyl on the bridgehead nitrogen is more efficient than other cinchona alkaloid-derived catalysts for the desymmetrization

Bioinspired total synthesis of katsumadain A by organocatalytic enantioselective 1,4-conjugate addition

• Yongguang Wang,
• Ruiyang Bao,
• Shengdian Huang and
• Yefeng Tang

Beilstein J. Org. Chem. 2013, 9, 1601–1606, doi:10.3762/bjoc.9.182

• [19][20][21][22][23], the 9-amino-9-deoxyepicinchona alkaloid-promoted Michael addition is particularly attractive, mainly due to the availability of the catalyst and its superior reactivity towards the activation of the unsaturated ketone substrates through formation of the corresponding iminium

Selective copper(II) acetate and potassium iodide catalyzed oxidation of aminals to dihydroquinazoline and quinazolinone alkaloids

• Matthew T. Richers,
• Chenfei Zhao and
• Daniel Seidel

Beilstein J. Org. Chem. 2013, 9, 1194–1201, doi:10.3762/bjoc.9.135

• to affect the selective oxidation of ring-fused aminals to dihydroquinazolines and quinazolinones, respectively. These methods enable the facile preparation of a number of quinazoline alkaloid natural products and their analogues. Keywords: aminal; copper; oxygen; tert-butylhydroperoxide

• ; quinazoline alkaloid; Introduction Quinazoline alkaloids are a class of naturally occurring compounds with a range of medicinal properties and have been indicated for use as bronchodilators, vasodilators, anti-inflammatory agents and acetylcholinesterase inhibitors [1][2][3][4][5]. Many of the plants these

• preparation of novel materials for biological studies. Examples of naturally occurring quinazoline alkaloids. Different approaches to the synthesis of quinazoline alkaloid structures. Oxidation of other aminal systems. Optimization of conditions for deoxyvasicine (2) formation.a Scope of the copper-catalyzed

Exploration of an epoxidation–ring-opening strategy for the synthesis of lyconadin A and discovery of an unexpected Payne rearrangement

• Brad M. Loertscher,
• Yu Zhang and
• Steven L. Castle

Beilstein J. Org. Chem. 2013, 9, 1179–1184, doi:10.3762/bjoc.9.132

• Brad M. Loertscher Yu Zhang Steven L. Castle Department of Chemistry and Biochemistry, Brigham Young University, C100 BNSN, Provo, UT, 84602, USA 10.3762/bjoc.9.132 Abstract In the context of synthetic efforts targeting the alkaloid lyconadin A, scalemic epoxide 25 was prepared by a highly

• for synthesis. Herein, we provide an account of our studies directed toward the construction of this alkaloid. Specifically, we describe our efforts to prepare advanced intermediates that could be employed in the aforementioned pyridone annulation and tandem radical cyclization processes. In the

• location of the trityl ether in 26, they do provide compelling evidence that the carbon backbone of this compound is correct as drawn and is produced by a Payne rearrangement of some type. Conclusion In the context of synthetic efforts targeting the polycyclic alkaloid lyconadin A, we prepared scalemic

Establishing the concept of aza-[3 + 3] annulations using enones as a key expansion of this unified strategy in alkaloid synthesis

• Aleksey I. Gerasyuto,
• Zhi-Xiong Ma,
• Grant S. Buchanan and
• Richard P. Hsung

Beilstein J. Org. Chem. 2013, 9, 1170–1178, doi:10.3762/bjoc.9.131

• synthesis; catalysis; enones; intramolecular aza-[3 + 3] annulation; N-heterocycles; natural product; vinylogous amides; Introduction Throughout the past decade, we have been developing an aza-[3 + 3] annulation reaction as a general and unified strategy in alkaloid synthesis [1][2][3][4][5][6][7][8][9][10

• of isomerization and hydrolysis (Figure 1) [34][35][36][37]. The prevalence of six-membered nitrogen heterocyclic motifs in alkaloids renders the development of this aza-[3 + 3] annulation into a powerful strategy a unique opportunity in the field of alkaloid synthesis [1][2][3][4][8][9][10][11][12

• acidic conditions, thereby implying that the observed ratio of 12 and 14 represents a thermodynamic one in favor of the more stable isopropyleine [48]. With these experimental findings, Mueller and Thompson concluded that the alkaloid isolated by Tursch and co-workers [46][47] was in fact a mixture of

Tandem dinucleophilic cyclization of cyclohexane-1,3-diones with pyridinium salts

• Mostafa Kiamehr,
• Firouz Matloubi Moghaddam,
• Satenik Mkrtchyan,
• Volodymyr Semeniuchenko,
• Linda Supe,
• Alexander Villinger,
• Peter Langer and
• Viktor O. Iaroshenko

Beilstein J. Org. Chem. 2013, 9, 1119–1126, doi:10.3762/bjoc.9.124

• containing an annulated pyridinium core, such as quinolinium and isoquinolinium salts, are of considerable importance as building blocks for the synthesis of various alkaloid frameworks [10][25][26][27][28][29][30][31][32][33][34][35]. During the past decade the reaction of dinucleophiles with

• addition of acid due to decomposition [36]. Additionally, we have shown a broad application of the quinolinium [44][45][46][47][48] and isoquinolinium [49] salts for the synthesis of a wide variety of alkaloid-like frameworks. Results and Discussion Reaction optimization During the course of the above

Formal synthesis of (−)-agelastatin A: an iron(II)-mediated cyclization strategy

• Daisuke Shigeoka,
• Takuma Kamon and
• Takehiko Yoshimitsu

Beilstein J. Org. Chem. 2013, 9, 860–865, doi:10.3762/bjoc.9.99

• intermediate for the synthesis of (−)-agelastatin A (AA, 1), a potent antiproliferative alkaloid. The present synthetic endeavour offered an insight into the mechanism underlying the iron(II)-mediated aminohalogenation of N-tosyloxycarbamate, in which the radical properties of the N–iron intermediates in the

• redox states were operative. Keywords: agelastatin; aminohalogenation; iron(II); free radical; natural product synthesis; Introduction Marine organisms often produce bioactive substances that potentially serve as attractive resources for drug discovery. (−)-Agelastatin A (AA, 1), a cytotoxic alkaloid

Diastereoselective synthesis of nitroso acetals from (S,E)-γ-aminated nitroalkenes via multicomponent [4 + 2]/[3 + 2] cycloadditions promoted by LiCl or LiClO₄

• Leandro Lara de Carvalho,
• Robert Alan Burrow and
• Vera Lúcia Patrocinio Pereira

Beilstein J. Org. Chem. 2013, 9, 838–845, doi:10.3762/bjoc.9.96

• -dipolarophiles to furnish nitroso acetals of type 4 in an inter- or intramolecular fashion [1][2][3][8][9]. These nitroso acetals can be transformed into functionalized pyrrolizidin-3-ones and in sequence into alkaloid nuclei [1][3][10][11]. The majority of the tandem nitroalkene cycloadditions require the

Synthesis of skeletally diverse alkaloid-like molecules: exploitation of metathesis substrates assembled from triplets of building blocks

• Sushil K. Maurya,
• Mark Dow,
• Stuart Warriner and
• Adam Nelson

Beilstein J. Org. Chem. 2013, 9, 775–785, doi:10.3762/bjoc.9.88

Inter- and intramolecular enantioselective carbolithiation reactions

• Asier Gómez-SanJuan,
• Nuria Sotomayor and
• Esther Lete

Beilstein J. Org. Chem. 2013, 9, 313–322, doi:10.3762/bjoc.9.36

• chiral ligands for lithium, thus opening new opportunities for their application in asymmetric synthesis. The naturally occurring alkaloid (−)-sparteine, which has been until recently inexpensive and commercially available, is the most widely used chiral ligand in enantioselective carbolithiation

• retention of configuration affords a new organolithium, which can be reacted with electrophiles to afford pyrrolizidines with no loss of optical purity. Scheme 12a shows the application to the synthesis of the pyrrolizidine alkaloid (+)-pseudoheliotridane (33) [43]. The reaction can be extended to the

Engineering of indole-based tethered biheterocyclic alkaloid meridianin into β-carboline-derived tetracyclic polyheterocycles via amino functionalization/6-endo cationic π-cyclization

• Piyush K. Agarwal,
• Meena D. Dathi,
• Mohammad Saifuddin and
• Bijoy Kundu

Beilstein J. Org. Chem. 2012, 8, 1901–1908, doi:10.3762/bjoc.8.220

• -based alkaloid meridianins into annulated indole-based polyheterocycles as novel chemprobes. For the synthesis of meridianin-inspired indole-based annulated polyheterocycles, we proposed to transform tethered biheterocycles into β-carboline-based polyheterocycles, a new prototype hitherto not reported

• inhibition [48] to inhibition of cGMP-dependent processes [49][50]. In this communication, we report engineering of naturally occurring tethered indole-based biheterocyclic alkaloid meridianins into β-carboline-derived tetracyclic polyheterocycles by amino functionalization of the pyrimidine ring followed by

Determination of the relative configuration of tropinone and granatanone aldols by using TBDMS ethers

• Ryszard Lazny,
• Aneta Nodzewska,
• Katarzyna Sidorowicz and
• Przemyslaw Kalicki

Beilstein J. Org. Chem. 2012, 8, 1877–1883, doi:10.3762/bjoc.8.216

• of cocaine (ent-cocaine) [2], knightinol [3], alkaloid KD-B [3] and ferrugine [4][5]. Stereoselective syntheses of nortropinone aldols [6][7] and N-protected nortropinone aldols [5][8][9], which can open access to other N-substituted analogues, have also been described. The known diastereomerically

Organocatalytic tandem Michael addition reactions: A powerful access to the enantioselective synthesis of functionalized chromenes, thiochromenes and 1,2-dihydroquinolines

• Chittaranjan Bhanja,
• Satyaban Jena,
• Sabita Nayak and
• Seetaram Mohapatra

Beilstein J. Org. Chem. 2012, 8, 1668–1694, doi:10.3762/bjoc.8.191

• unprecedented asymmetric domino thio-Michael–Michael process, involving dynamic kinetic resolution, was reported by Wang et al. [72] using cinchona alkaloid amine-thiourea XXXIb as catalyst at a low catalytic loading of 2 mol %. Reaction of 3-(2-mercaptophenyl)-2-propenoic acid ethyl esters 50 with α,β

• α,β-unsaturated oxazolidinones, as presented by Wang and co-workers. Domino Michael–aldol reaction of 2-mercaptobenzaldehydes with maleimides catalyzed by cinchona alkaloid thiourea, as reported by Wang’s group. Domino thio-Michael–aldol reaction between 2-mercaptoacetophenone and enals developed by

• Córdova and co-workers. Enantioselective tandem Michael–Henry reaction of 2-mercaptobenzaldehyde with β-nitrostyrenes reported by Zhao. Enantioselective tandem Michael–Knoevenagel reaction between 2-mercaptobenzaldehydes and benzylidenemalonates, as developed by the Zhao group. Cinchona alkaloid thiourea

Organocatalytic asymmetric Michael addition of unprotected 3-substituted oxindoles to 1,4-naphthoquinone

• Jin-Sheng Yu,
• Feng Zhou,
• Yun-Lin Liu and
• Jian Zhou

Beilstein J. Org. Chem. 2012, 8, 1360–1365, doi:10.3762/bjoc.8.157

• [26][27]. To construct the C3 quaternary stereogenic carbon center, we have designed a novel cinchona alkaloid-based phosphoramide bifunctional catalyst to realize a highly enantioselective Michael addition of both unprotected 3-alkyl- and 3-aryloxindoles to nitroolefins [28]. Based on these results

• -phenyloxindole 1a and 1,4-naphthoquinone (2a), with ethyl acetate (EtOAc) as the solvent at 0 °C (Table 1, Figure 1). A variety of bifunctional cinchona alkaloid-derived catalysts 5–9 were first tried, aiming to facilitate the reaction by the dual activation of both reaction partners, with H-bonding donor moiety

• reactivity and enantioselectivity of this reaction is now in progress in our lab. Cinchona alkaloid-derived catalysts screened for condition optimization (Table 1). A one-pot synthesis of enantioenriched 3,3-diaryloxindoles. Condition optimization for the reaction of 1a and 2a. Substrate scope of unprotected

Asymmetric organocatalytic decarboxylative Mannich reaction using β-keto acids: A new protocol for the synthesis of chiral β-amino ketones

• Chunhui Jiang,
• Fangrui Zhong and
• Yixin Lu

Beilstein J. Org. Chem. 2012, 8, 1279–1283, doi:10.3762/bjoc.8.144

• tosylimine 1a and β-keto acid 2a in the presence of a range of bifunctional catalysts (Table 1). We first evaluated the catalytic effects of several cinchona alkaloid derivatives. Commercially available cinchonidine (CD-1) led to the formation of the product with disappointing enantioselectivity (Table 1

• , entry 1). Quinine-derived sulfonamide [40], β-isocupreidine (β-ICD) [41][42] and biscinchona alkaloid (DHQ)2AQN were all found to be poor catalysts (Table 1, entries 2–4). On the other hand, cinchona alkaloid derived bifunctional thiourea tertiary amine catalysts afforded much improved results (Table 1

Recyclable fluorous cinchona alkaloid ester as a chiral promoter for asymmetric fluorination of β-ketoesters

• Wen-Bin Yi,
• Xin Huang,
• Zijuan Zhang,
• Dian-Rong Zhu,
• Chun Cai and
• Wei Zhang

Beilstein J. Org. Chem. 2012, 8, 1233–1240, doi:10.3762/bjoc.8.138

• , Boston, MA 02125, USA 10.3762/bjoc.8.138 Abstract A fluorous cinchona alkaloid ester has been developed as a chiral promoter for the asymmetric fluorination of β-ketoesters. It has comparable reactivity and selectivity to the nonfluorous versions of cinchona alkaloids and can be easily recovered from

• cinchona alkaloids for catalytic Diels–Alder reactions [23][24]. Introduced in this paper is a new fluorous cinchona alkaloid ester for flourination of β-ketoesters. It is part of our recent effort on the development of recyclable fluorous reagents and organocatalysts for asymmetric synthesis [25][26][27

• organocatalysts and reagents can be readily recovered by F-SPE [19][20]. In the current work, upon completion of the fluorination reaction, a base such as aqueous NaOH or KOH was added to the reaction mixture to convert the cinchona alkaloid/Selectfluor complex to free cinchona alkaloid. The organic phase was

Parallel and four-step synthesis of natural-product-inspired scaffolds through modular assembly and divergent cyclization

• Hiroki Oguri,
• Haruki Mizoguchi,
• Hideaki Oikawa,
• Aki Ishiyama,
• Masato Iwatsuki,
• Kazuhiko Otoguro and
• Satoshi Ōmura

Beilstein J. Org. Chem. 2012, 8, 930–940, doi:10.3762/bjoc.8.105

• process to access indole-alkaloid-like scaffolds utilizing a piperidine-based manifold 1, was developed in 2005 [18]. By exploiting lactam, carboxylic acid and β-ketocarbonyl functional groups on 1, α-diazoketocarbonyl and indole groups were installed to produce a set of tetraketide-like precursors, 2 and

• controlled manner. With the intention to produce screening collections, we then devised a second-generation strategy applicable for a parallel synthetic protocol. This approach allows unified four-step access to a series of indole-alkaloid-like scaffolds. Some of these results were previously reported as a

Unprecedented deoxygenation at C-7 of the ansamitocin core during mutasynthetic biotransformations

• Tobias Knobloch,
• Gerald Dräger,
• Wera Collisi,
• Florenz Sasse and
• Andreas Kirschning

Beilstein J. Org. Chem. 2012, 8, 861–869, doi:10.3762/bjoc.8.96

• to β-tubulin monomers at a site overlapping the vinca alkaloid binding site [9]. Recently, we disclosed several mutasynthetic studies aimed at the production of derivatives of ansamitocins 3–5 [10][11][12] as well as of geldanamycin (6), utilizing mutant strains of Actinosynnema pretiosum, the

Two-directional synthesis as a tool for diversity-oriented synthesis: Synthesis of alkaloid scaffolds

• Kieron M. G. O’Connell,
• Monica Díaz-Gavilán,
• Warren R. J. D. Galloway and
• David R. Spring

Beilstein J. Org. Chem. 2012, 8, 850–860, doi:10.3762/bjoc.8.95

• particular reference to the synthesis of polycyclic alkaloid scaffolds. Keywords: alkaloids; cascade reactions; chemical diversity; diversity-oriented synthesis; Lewis acid catalysis; two-directional synthesis; Introduction Diversity-oriented synthesis (DOS) aims to prepare structurally diverse compound

• synthesis of myrrhine compares favourably with previously reported syntheses [26][27][28], achieving the feat in eight steps and 7% overall yield. Alternative starting materials The evident efficiency of two-directional synthesis in a DOS context, as exemplified by our synthesis of these alkaloid scaffolds

• formation of bicyclic compounds by the folding up of doubly substituted precursors, and it proved to be a very effective strategy for the synthesis of natural-product-like alkaloid scaffolds. Our work so far in this area has focused mainly on the synthesis of fused bicyclic compounds; however, we hope in

Synthesis and characterization of Sant-75 derivatives as Hedgehog-pathway inhibitors

• Chao Che,
• Song Li,
• Bo Yang,
• Shengchang Xin,
• Zhixiong Yu,
• Taofeng Shao,
• Chuanye Tao,
• Shuo Lin and
• Zhen Yang

Beilstein J. Org. Chem. 2012, 8, 841–849, doi:10.3762/bjoc.8.94

• human diseases, intense efforts have been invested to identify therapeutic inhibitors acting on the Smo protein. Cyclopamine (Figure 1), a natural alkaloid isolated from Veratrum californicum [12][13], was disclosed as the first small molecule inhibitor of the Hh pathway through direct interaction with

Stereoselective, nitro-Mannich/lactamisation cascades for the direct synthesis of heavily decorated 5-nitropiperidin-2-ones and related heterocycles

• Pavol Jakubec,
• Dane M. Cockfield,
• Madeleine Helliwell,
• James Raftery and
• Darren J. Dixon

Beilstein J. Org. Chem. 2012, 8, 567–578, doi:10.3762/bjoc.8.64

• [60], in the construction of architecturally complex polycyclic alkaloid structures [61] and more recently as a key complexity building step in the total synthesis of nakadomarin A [62][63][64][65]. Herein we wish to report our full findings in this synthetically powerful cyclisation cascade. The

• -Mannich/lactamisation cascade to be of use in alkaloid natural-product synthesis (or even simple stereoselective piperidine synthesis), controlled, reductive manipulation of both the nitro group and the lactam carbonyl were required. Although Nef-type oxidation followed by exhaustive reduction of the

• in the synthesis of architecturally complex multicyclic alkaloid structures. The first applications of the developed methodology were disclosed recently as the total syntheses of paroxetine [60] and nakadomarin A [61][62][63][64][65] were successfully finished by employing the strategy as a

Synthesis of fused tricyclic amines unsubstituted at the ring-junction positions by a cascade condensation, cyclization, cycloaddition then decarbonylation strategy

• Iain Coldham,
• Adam J. M. Burrell,
• Hélène D. S. Guerrand,
• Luke Watson,
• Nathaniel G. Martin and
• Niall Oram

Beilstein J. Org. Chem. 2012, 8, 107–111, doi:10.3762/bjoc.8.11

• an aldehyde – which could be removed to give the tricyclic amine products that are unsubstituted at the ring junction positions – or was converted into an alkene, which allowed the formation of the core ring system of the alkaloids scandine and meloscine. Keywords: alkaloid; azomethine ylide

• chemistry for the construction of the core ring system found in alkaloid natural products. Wittig reaction with aldehyde 16 should be possible to provide the core ring system found in the alkaloids meloscine and scandine [26][27][28][29][30]. However, we chose to investigate a shorter reaction sequence

Natural product biosyntheses in cyanobacteria: A treasure trove of unique enzymes

• Jan-Christoph Kehr,
• Douglas Gatte Picchi and
• Elke Dittmann

Beilstein J. Org. Chem. 2011, 7, 1622–1635, doi:10.3762/bjoc.7.191

• bioactivity-guided screening techniques towards cytotoxic, multidrug-resistance reversal, antiprotease, antifungal and antiviral activities [5]. Many bioactive metabolites possess a peptide or a macrolide structure, or a combination of both types [6][7][8]. Other metabolites belong to the alkaloid class of

• product is released from the enzyme complex. Cylindrospermopsin Cylindrospermopsin (4) is a hepatotoxin produced by different genera of freshwater cyanobacteria, including Cylindrospermopsis raciborskii, Aphanizomenon ovalisporum and Aphanizomenon flos-aquae. The polyketide-derived alkaloid inhibits

• neurotoxins produced by cyanobacteria. A gene cluster for the alkaloid was first described for the strain Oscillatoria sp. PCC 6506 [36]. Analysis of the gene cluster and feeding studies suggested a biosynthetic scheme starting from L-proline and involving three polyketide synthases, with (S)-1-pyrolline-5

Chiral recognition of ephedrine: Hydrophilic polymers bearing β-cyclodextrin moieties as chiral sensitive host molecules

• Sabrina Gingter and
• Helmut Ritter

Beilstein J. Org. Chem. 2011, 7, 1516–1519, doi:10.3762/bjoc.7.177

• pharmaceutically active (+)- and (−)-ephedrine. Ephedrine is an alkaloid that functions as a decongestant, stimulant and appetite suppressant. Ephedrine is an aromatic amine and belongs to the group of amphetamines. We chose ephedrine as a model compound for the present investigation, as it exhibits chirality and