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

Synthesis of (−)-julocrotine and a diversity oriented Ugi-approach to analogues and probes

• Ricardo A. W. Neves Filho,
• Bernhard Westermann and
• Ludger A. Wessjohann

Beilstein J. Org. Chem. 2011, 7, 1504–1507, doi:10.3762/bjoc.7.175

• heterocyclic precursor as an amino input in Ugi four-component reactions (Ugi-4CR) [1]. Keywords: diversity oriented synthesis; julocrotine; leishmania; Mitsunobu reaction; Ugi reaction; Introduction Julocrotine (1) is a natural glutarimide alkaloid isolated from several plants of the genus Croton [2][3][4

• ], including Croton cuneatus Klotzsch, which is used by Amazonia natives in anti-inflammatory and analgesic medicines. The structure of this glutarimide-containing alkaloid was first proposed in 1960, based upon a series of degradative experiments, but only confirmed in 2008 by X-ray analysis [5][6][7]. Most

Directed aromatic functionalization in natural-product synthesis: Fredericamycin A, nothapodytine B, and topopyrones B and D

• Charles Dylan Turner and
• Marco A. Ciufolini

Beilstein J. Org. Chem. 2011, 7, 1475–1485, doi:10.3762/bjoc.7.171

• form of the alkaloid, mappicine [64], and indeed it can be converted into the latter by NaBH4 reduction of the ethyl ketone. A brief historical aside: The term “mappicine ketone” was apparently introduced by Kametani [65], who synthesized 36 in the course of investigations directed toward mappicine

Manganese dioxide mediated one-pot synthesis of methyl 9H-pyrido[3,4-b]indole-1-carboxylate: Concise synthesis of alangiobussinine

• Jessica Baiget,
• Sabin Llona-Minguez,
• Stuart Lang,
• Simon P. MacKay,
• Colin J. Suckling and
• Oliver B. Sutcliffe

Beilstein J. Org. Chem. 2011, 7, 1407–1411, doi:10.3762/bjoc.7.164

• process for the preparation of methyl 9H-pyrido[3,4-b]indole-1-carboxylate has subsequently been used as the key step in the synthesis of alangiobussinine and a closely related analogue. Keywords: alkaloid synthesis; carboline; heterocycle; oxidation; tandem reaction; Introduction Carbolines are an

• of β-carboline 6 as the key synthetic step in the first reported synthesis of alangiobussinine, although the synthesis of dihydroalangiobussinine [23] has been reported in low yield as a byproduct by Laronze and coworkers. Alangiobussinine (7, Figure 1) is an alkaloid that is isolated from the leaves

• occurring alkaloid, alangiobussinine (7) and its analogue 10. Structure of alangiobussinine (7). Proposed mechanism for the formation of 6. Preparation of compounds 7 and 10. Reagents and conditions: i) LiOH (10 equiv), MeOH–H2O, rt, overnight; ii) oxalyl chloride (5 equiv), DMF (0.01 equiv), CH2Cl2, rt, 6

Functionalization of heterocyclic compounds using polyfunctional magnesium and zinc reagents

• Paul Knochel,
• Matthias A. Schade,
• Sebastian Bernhardt,
• Georg Manolikakes,
• Albrecht Metzger,
• Fabian M. Piller,
• Christoph J. Rohbogner and
• Marc Mosrin

Beilstein J. Org. Chem. 2011, 7, 1261–1277, doi:10.3762/bjoc.7.147

• readily converted to the desired zinc reagents 31. The Pd-catalyzed cross-coupling of 31 with the iodoquinoline 32 and with S-Phos as ligand [15][16][17] provides the alkaloid papaverine (33) in 68% yield (Scheme 5) [13]. Ni-catalyzed cross-couplings can also be realized [14]. Thus, the reaction of the

The Eschenmoser coupling reaction under continuous-flow conditions

• Sukhdeep Singh,
• J. Michael Köhler,
• Andreas Schober and
• G. Alexander Groß

Beilstein J. Org. Chem. 2011, 7, 1164–1172, doi:10.3762/bjoc.7.135

• - [5], sedamine alkaloid- [6], sparteine- [7], mersicarpine- [8], batzelladine- [9], fuligocandin- [10] and vitamin B12-derivatives [11] were prepared with the aid of sulfide contraction steps. Pharmaceutically important substances, such as methylphenidat [12] or the marine neurotoxin hemibrevetoxin

A practical two-step procedure for the preparation of enantiopure pyridines: Multicomponent reactions of alkoxyallenes, nitriles and carboxylic acids followed by a cyclocondensation reaction

• Christian Eidamshaus,
• Roopender Kumar,
• Mrinal K. Bera and
• Hans-Ulrich Reissig

Beilstein J. Org. Chem. 2011, 7, 962–975, doi:10.3762/bjoc.7.108

• as pharmaceuticals that feature the pyridine nucleus [6][7][8][9][10]. Natural products that contain a pyridine ring include the 3-alkylpyridine alkaloid niphatesine C and the fuzanin family [11][12]. Moreover, the ability to form coordination compounds makes pyridines ideal ligands for transition

Intramolecular hydroamination of alkynic sulfonamides catalyzed by a gold–triethynylphosphine complex: Construction of azepine frameworks by 7-exo-dig cyclization

• Hideto Ito,
• Tomoya Harada,
• Hirohisa Ohmiya and
• Masaya Sawamura

Beilstein J. Org. Chem. 2011, 7, 951–959, doi:10.3762/bjoc.7.106

• in many biologically active natural products and pharmaceuticals, such as (−)-tuberosutemonin (1) [1][2][3][4][5][6], related Stemona alkaloids [7], Cephalotaxus alkaloid (−)-cephalotaxine (2) [8][9][10][11][12], and SB-462795 (3) (Figure 1) [13][14][15][16]. Among a number of different approaches

When gold can do what iodine cannot do: A critical comparison

• Sara Hummel and
• Stefan F. Kirsch

Beilstein J. Org. Chem. 2011, 7, 847–859, doi:10.3762/bjoc.7.97

• alkaloid cleistopholine (41) from the aminoquinone 40 was easily achieved after in-situ aromatization of the intermediate to yield the desired compound in 60% yield. Furthermore, Wang and co-workers investigated a totally analogous cycloisomerization sequence using iodine as the electrophile to activate

Metathesis access to monocyclic iminocyclitol-based therapeutic agents

• Ileana Dragutan,
• Valerian Dragutan,
• Carmen Mitan,
• Hermanus C.M. Vosloo,
• Lionel Delaude and
• Albert Demonceau

Beilstein J. Org. Chem. 2011, 7, 699–716, doi:10.3762/bjoc.7.81

• , nojirimycin (NJ, trivial name for 5-amino-5-deoxy-D-glucopyranose) (59), the first alkaloid discovered that mimicks a sugar (originally isolated from Streptomyces filtrate but also found in other bacterial cultures and plant sources), is a potent glycosidase inhibitor. In aqueous solution nojirimycin exists

Palladium- and copper-mediated N-aryl bond formation reactions for the synthesis of biological active compounds

• Carolin Fischer and
• Burkhard Koenig

Beilstein J. Org. Chem. 2011, 7, 59–74, doi:10.3762/bjoc.7.10

• demanding N-nucleophile at two positions. Murrazoline (23), a carbazole alkaloid isolated from the shrub Murraya, is used in folk medicine for the treatment of eczema, rheumatism and dropsy, as an analgesic, and in anaesthesia. It is known to be a potent platelet aggregation inhibitor. The double N