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

Experimental and theoretical investigations into the stability of cyclic aminals

• Edgar Sawatzky,
• Antonios Drakopoulos,
• Martin Rölz,
• Christoph Sotriffer,
• Bernd Engels and
• Michael Decker

Beilstein J. Org. Chem. 2016, 12, 2280–2292, doi:10.3762/bjoc.12.221

• chemistry, DNA intercalation, etc.) or in synthetic tetrahydroquinazolines as cholinesterase (ChE) inhibitors [15][16][17] as well as ChE inhibitors based on the scaffold of the naturally occurring alkaloid physostigmine from the calabar bean physostigma venenosum [18][19] (Figure 1). This is just a small

A chiral analog of the bicyclic guanidine TBD: synthesis, structure and Brønsted base catalysis

• Mariano Goldberg,
• Denis Sartakov,
• Jan W. Bats,
• Michael Bolte and
• Michael W. Göbel

Beilstein J. Org. Chem. 2016, 12, 1870–1876, doi:10.3762/bjoc.12.176

• natural products, have been used as chiral phase-transfer catalysts [12][13]. Bicyclic guanidines with five-membered rings are also known from the alkaloid isoalchornein [14][15]. In subsequent years, synthetic compounds (6–9) of this structural type have been developed as chiral Brønsted bases [16][17

Enantioselective addition of diphenyl phosphonate to ketimines derived from isatins catalyzed by binaphthyl-modified organocatalysts

• Hee Seung Jang,
• Yubin Kim and
• Dae Young Kim

Beilstein J. Org. Chem. 2016, 12, 1551–1556, doi:10.3762/bjoc.12.149

• attention, and numerous catalytic enantioselective methods using chiral catalysts have been reported [9][10][11][12][13]. Oxindole and its derivatives can be exploited as important synthons to synthesize various alkaloid natural products and biologically active compounds [14][15][16]. In particular, 3,3

Biosynthesis of oxygen and nitrogen-containing heterocycles in polyketides

• Franziska Hemmerling and
• Frank Hahn

Beilstein J. Org. Chem. 2016, 12, 1512–1550, doi:10.3762/bjoc.12.148

• mechanism is reminiscent of the formation of a tetrahydropyridine ring by the berberine bridge enzyme in plant alkaloid biosynthesis. It starts with S-adenosyl-L-methionine (SAM)-dependent methylation of the secondary hydroxy group in 81 by the O-methyltransferase Leu14 (Scheme 14a) [71][72][73][74

Towards the total synthesis of keramaphidin B

• Pavol Jakubec,
• Alistair J. M. Farley and
• Darren J. Dixon

Beilstein J. Org. Chem. 2016, 12, 1096–1100, doi:10.3762/bjoc.12.104

• addition; keramaphidin B; nitro-Mannich lactamisation cascade; Introduction Keramaphidin B (1) is a marine alkaloid first isolated by Kobayashi in 1994 from the Okinawan marine sponge Amphimedon sp and has been shown to be cytotoxic against KB human epidermoid carcinoma cells (IC50 0.28 μg/mL) and P388

Catalytic asymmetric synthesis of biologically important 3-hydroxyoxindoles: an update

• Bin Yu,
• Hui Xing,
• De-Quan Yu and
• Hong-Min Liu

Beilstein J. Org. Chem. 2016, 12, 1000–1039, doi:10.3762/bjoc.12.98

• , unprotected isatins failed to gave the desired products under the same conditions. As shown in the binding model, the catalyst activated the carbonyl groups through hydrogen bonds, while the allyltributyltin reagent attacked the 3-carbonyl group from the Si face, forming (R)-isomers. Cinchona alkaloid

• catalysts Cinchona alkaloids and their derivatives have been widely used as chiral catalysts in many reactions [44] and also show synthetic utilities in the synthesis of enantiomerically pure 3-substituted 3-hydroxyoxindoles. In 2013, Wu and co-workers reported the cinchona alkaloid (cat. 14)-catalyzed

• same group reported the organocatalytic asymmetric addition reactions of isatins with electron-rich aromatics sesamols using the cinchona alkaloid-derived thiourea catalyst (cat. 17) under mild conditions. In the presence of 10% catalyst, sesamols reacted with isatins smoothly in tert-butyl ether at

Asymmetric α-amination of 3-substituted oxindoles using chiral bifunctional phosphine catalysts

• Qiao-Wen Jin,
• Zhuo Chai,
• You-Ming Huang,
• Gang Zou and
• Gang Zhao

Beilstein J. Org. Chem. 2016, 12, 725–731, doi:10.3762/bjoc.12.72

• organocatalysis and metal catalysis for the construction of this type of structures. For example, Chen et al. reported the first organocatalytic enantioselective amination reaction of 2-oxindoles catalyzed by biscinchona alkaloid catalysts [8]. Zhou [9][10] and Barbas [11][12], have independently reported similar

The aminoindanol core as a key scaffold in bifunctional organocatalysts

• Isaac G. Sonsona,
• Eugenia Marqués-López and
• Raquel P. Herrera

Beilstein J. Org. Chem. 2016, 12, 505–523, doi:10.3762/bjoc.12.50

• in the chiral induction of the process. The authors proposed the transition state TS14, where the NH groups and the OH group of the squaramide would coordinate to the nitroalkene 3 through hydrogen-bonding interactions with the nitro group. Simultaneously, the amine in the cinchona alkaloid would

(Thio)urea-mediated synthesis of functionalized six-membered rings with multiple chiral centers

• Giorgos Koutoulogenis,
• Nikolaos Kaplaneris and
• Christoforos G. Kokotos

Beilstein J. Org. Chem. 2016, 12, 462–495, doi:10.3762/bjoc.12.48

• stereochemistry of the carbon bearing the R2 group. Very recently, Wang and co-workers used a cinchona alkaloid-based bifunctional thiourea 103 as the catalyst of choice to an organocatalytic domino process. This domino reaction involded a Michael cyclization–tautomerization reaction sequence between isatylidene

Cupreines and cupreidines: an established class of bifunctional cinchona organocatalysts

• Laura A. Bryant,
• Rossana Fanelli and
• Alexander J. A. Cobb

Beilstein J. Org. Chem. 2016, 12, 429–443, doi:10.3762/bjoc.12.46

• their derivatives in asymmetric organocatalysis over the last five years or so [13][14]. The review is organized by reaction type, beginning with the Morita–Baylis–Hillman process – one of the first reactions to utilize 6’-OH-cinchona alkaloid derivatives in asymmetric organocatalysis. The focus will

• produced, as is often the case with cinchona alkaloid catalyzed processes. However, the role of the 6’-OH was clearly important when directly compared with the equivalent 6’-OiPr catalysts 66 and 68 (Scheme 16). Jørgensen and co-workers have used another anthracenyl-modified hydrocupreidine HCPD-70 in an

• with cupreine, cupreidine, β-isoquinidine and β-isocupreidine derivatives. The original 6’-OH cinchona alkaloid organocatalytic MBH process, showing how the free 6’-OH is essential for coordination to the substrate. Use of β-ICPD in an aza-MBH reaction. (a) The isatin motif is a common feature for MBH

Study on the synthesis of the cyclopenta[f]indole core of raputindole A

• Nils Marsch,
• Mario Kock and
• Thomas Lindel

Beilstein J. Org. Chem. 2016, 12, 334–342, doi:10.3762/bjoc.12.36

• and coworkers for benzyl ether cleavage in the presence of Boc-protected amines when studying the late stages of the total synthesis of the trisindole alkaloid yatakemycin [44]. As an alternative, the 3,4-dimethoxybenzyl (DMB) protecting group was installed (13). We favored the DMB over the related

• alkaloid raputindole A (1) from the Amazonian tree Raputia simulans. Investigated synthetic precursors B–E of the cyclopenta[f]indole moiety (A) of raputindole A (1), all to be assembled from 6-iodoindole (2). 6-Iodoindole (2) serves twice as starting material towards indole-6-yl-substituted enone 8

Enantioselective additions of copper acetylides to cyclic iminium and oxocarbenium ions

• Jixin Liu,
• Srimoyee Dasgupta and
• Mary P. Watson

Beilstein J. Org. Chem. 2015, 11, 2696–2706, doi:10.3762/bjoc.11.290

• 13 to deliver (S)-homolaudanosine, a natural product from an alkaloid family with neurologic activity, in high yield and enantiopurity. They also demonstrated that this alkynylation is amenable to solid phase synthesis; alkyne 14 was prepared by alkynylation of an isoquinolinium ion linked to a

Bifunctional phase-transfer catalysis in the asymmetric synthesis of biologically active isoindolinones

• Antonia Di Mola,
• Maximilian Tiffner,
• Francesco Scorzelli,
• Laura Palombi,
• Rosanna Filosa,
• Paolo De Caprariis,
• Mario Waser and
• Antonio Massa

Beilstein J. Org. Chem. 2015, 11, 2591–2599, doi:10.3762/bjoc.11.279

• elaborations en route to the targets of medicinal interest (Figure 1). A high yield (usually >95%) and a maximum level of enantioselectivity of 74% ee were obtained but only in the presence of large amounts of cinchona alkaloid-based thiourea-containing organocatalysts (15 mol %) and after an unacceptably long

• reaction time (72 h) [21][22]. Readily available chiral ammonium salts (e.g., cinchona alkaloid-based or commercially available Maruoka catalysts) were also investigated, but the enantioselectivity was lower, reaching a maximum of 46% ee [23]. Gratifyingly, a very efficient heterochiral crystallization

Recent highlights in biosynthesis research using stable isotopes

• Jan Rinkel and
• Jeroen S. Dickschat

Beilstein J. Org. Chem. 2015, 11, 2493–2508, doi:10.3762/bjoc.11.271

• mechanism. An interesting feeding experiment was performed for the elucidation of both absolute configuration and biosynthesis of the polyketid alkaloid coelimycin P1 (8, Scheme 2). The compound was isolated from Streptomyces coelicolor M145 after genetically engineered increase of the metabolic flux and is

Bromotyrosine-derived alkaloids from the Caribbean sponge Aplysina lacunosa

• Qun Göthel,
• Thanchanok Sirirak and
• Matthias Köck

Beilstein J. Org. Chem. 2015, 11, 2334–2342, doi:10.3762/bjoc.11.254

• . Bromotyrosine alkaloid (21) isolated from the sponge Verongula sp. NMR data (600 MHz, DMSO-d6) of 14-debromo-11-deoxyfistularin-3 (1) and 11-deoxyfistularin-3 (8). 13C NMR data (600 MHz, DMSO-d6) of the central benzene ring of the isolated compounds 1 and 4. NMR data (600 MHz, DMSO-d6) of aplysinin A (2

Beyond catalyst deactivation: cross-metathesis involving olefins containing N-heteroaromatics

• Kevin Lafaye,
• Cyril Bosset,
• Lionel Nicolas,
• Amandine Guérinot and
• Janine Cossy

Beilstein J. Org. Chem. 2015, 11, 2223–2241, doi:10.3762/bjoc.11.241

• temperature (Scheme 11) [48]. This method was used to prepare polycyclic scaffolds that can be encountered in diverse alkaloid natural products such as coralyne and berberine (Scheme 12) [49]. Similarly, enyne ring-closing metathesis reactions were performed to access a variety of vinyl-3,4

The marine sponge Agelas citrina as a source of the new pyrrole–imidazole alkaloids citrinamines A–D and N-methylagelongine

• Christine Cychon,
• Ellen Lichte and
• Matthias Köck

Beilstein J. Org. Chem. 2015, 11, 2029–2037, doi:10.3762/bjoc.11.220

• alkaloids (PIAs), the citrinamines A–D (1–4) and the bromopyrrole alkaloid N-methylagelongine (5). All citrinamines are dimers of hymenidin (6) which was also isolated from this sponge as the major metabolite. Citrinamines A (1) and B (2) are derivatives of the PIA dimer mauritiamine (7), whereas

• (10) [8][9][10] (Figure 1). Additionally, five new compounds, four with a dimeric PIA structure (1–4) and the N-methyl analogue (5) of the bromopyrrole alkaloid agelongine (12) [11], were isolated. Herein, we describe the isolation and structure elucidation of citrinamines A (1), B (2), and N

• the marine sponge Agelas citrina revealed four new compounds of the pyrrole–imidazole alkaloid (PIA) family. Citrinamines A (1) and B (2) are closely related to mauritiamine (7) which can be seen as the most less complex dimeric PIA (the first published one) in which the monomeric units are only

Asymmetric 1,4-bis(ethynyl)bicyclo[2.2.2]octane rotators via monocarbinol functionalization. Ready access to polyrotors

• Cyprien Lemouchi and
• Patrick Batail

Beilstein J. Org. Chem. 2015, 11, 1881–1885, doi:10.3762/bjoc.11.202

• obtainment of 14 (Scheme 4), a new class of extended alkaloid ligands similar to isonicotinic acid (of much smaller spatial extension) which was obtained recently in a synthesis of a simple Li(I) salt with an extended framework by Abrahams, Robson and co-workers [21]. Compound 13 was prepared either from 5

• potential in the development of molecular machines that can perform mechanical functions can now be systematically studied. Synthesis of the asymmetric rotor 1. Synthesis of dirotors 6 and 10. Synthesis of the tertiary amide 12. Synthesis of the extended alkaloid ligand 14. Supporting Information

Recent applications of ring-rearrangement metathesis in organic synthesis

• Sambasivarao Kotha,
• Milind Meshram,
• Priti Khedkar,
• Shaibal Banerjee and
• Deepak Deodhar

Beilstein J. Org. Chem. 2015, 11, 1833–1864, doi:10.3762/bjoc.11.199

• (Scheme 6). The erythrina alkaloids are known to exhibit sedative, hypotensive and neuromuscular activity. This alkaloid skeleton consists of a tetracyclic spiroamine framework and synthetic chemists consider it as a challenging target. Simpkins and co-workers [11] have used the RRM sequence tactically to

• spiropiperidine alkaloid nitramine was proved to be efficient by this methodology (Scheme 13). In 2004, Ni and Ma [18] have described the synthesis of bicyclic compounds 75 and 76 by adopting a metathesis protocol with catalysts 1 and 2 in good yields, but the product ratio is catalyst-dependent. In this context

• derivative 104 were obtained in a 22:78 ratio (Scheme 21). Aubé and co-workers [26] have accomplished the asymmetric synthesis of the dendrobatid alkaloid 251F by employing a RRM as the key step. The required building block 108a has been synthesized from enone 107 via a RRM protocol. When enone 107 was