Solid-phase-supported synthesis of morpholinoglycine oligonucleotide mimics

• Tatyana V. Abramova,
• Sergey S. Belov,
• Yulia V. Tarasenko and
• Vladimir N. Silnikov

Beilstein J. Org. Chem. 2014, 10, 1151–1158, doi:10.3762/bjoc.10.115

• positively charged centers in oligonucleotide analogues results in increased water solubility and higher thermal stability of complementary duplexes of such oligonucleotide mimics with nucleic acids [14][15]. Some conformationally restricted protonated PNA or pyrrolidine oligonucleotide mimics exhibit

Preparation of phosphines through C–P bond formation

• Iris Wauters,
• Wouter Debrouwer and
• Christian V. Stevens

Beilstein J. Org. Chem. 2014, 10, 1064–1096, doi:10.3762/bjoc.10.106

• reaction with chiral pyrrolidine 62 derivatives and acid (Scheme 16). Subsequent treatment with sodium borohydride forms the air-stable phosphine–borane product and also reduces the aldehyde. The method gives compounds 61 in high yields and enantioselectivities (ee up to 99%) for α,β-unsaturated aldehydes

Site-selective covalent functionalization at interior carbon atoms and on the rim of circumtrindene, a C₃₆H₁₂ open geodesic polyarene

• Hee Yeon Cho,
• Ronald B. M. Ansems and
• Lawrence T. Scott

Beilstein J. Org. Chem. 2014, 10, 956–968, doi:10.3762/bjoc.10.94

• ] cycloadditions, the reaction with azomethine ylides has found great popularity, because it leads to versatile pyrrolidine derivatives of C60. The sources of the ylide can be iminium salts, aziridines, oxazolidines or silylated iminium compounds. In 1993, Prato and coworkers developed the protocol that is now

• used most commonly [31][32]. In the first step, an N-substituted amino acid (e.g., N-methylglycine) reacts with an aldehyde or ketone to generate an azomethine ylides in situ. Trapping of the ylide by a fullerene provides a fullerene-pyrrolidine derivative (8), as illustrated in Scheme 1. In light of

• circumtrindene in refluxing benzene to give the pyrrolidine derivative 24 (Scheme 7). As in the Bingel–Hirsch reaction, the 1,3-dipole reacts exclusively with the 6:6-bond in circumtrindene that contains the most pyramidalized carbon atoms in the molecule. Considering the [3 + 2] cycloaddition processes in terms

Molecular architecture with carbohydrate functionalized β-peptides adopting 3₁₄-helical conformation

• Nitin J. Pawar,
• Navdeep S. Sidhu,
• George M. Sheldrick,
• Dilip D. Dhavale and
• Ulf Diederichsen

Beilstein J. Org. Chem. 2014, 10, 948–955, doi:10.3762/bjoc.10.93

• conformationally constrained and well-defined scaffold for sugar presentation on a 314-helix [18][19][20] as well as on a β-peptide 312-helical scaffold obtained by oligomerization of glycosylated pyrrolidine β-amino acids [35]. Glycopeptide or glycoprotein synthesis is challenged by different conditions required

Aza-Diels–Alder reaction between N-aryl-1-oxo-1H-isoindolium ions and tert-enamides: Steric effects on reaction outcome

• Amitabh Jha,
• Ting-Yi Chou,
• Zainab ALJaroudi,
• Bobby D. Ellis and
• T. Stanley Cameron

Beilstein J. Org. Chem. 2014, 10, 848–857, doi:10.3762/bjoc.10.81

• and strongly basic conditions [19]. Kang et al. achieved a highly enantioselective synthesis of an isoindolo[2,1-a]quinoline derivative by affecting an intramolecular ring closure on (E)-3-(2-(isoindolin-2-yl)phenyl)acrylaldehyde using camphorsulfonic acid and a chiral pyrrolidine organocatalyst [20

Copper–phenanthroline catalysts for regioselective synthesis of pyrrolo[3′,4′:3,4]pyrrolo[1,2-a]furoquinolines/phenanthrolines and of pyrrolo[1,2-a]phenanthrolines under mild conditions

• Rupankar Paira,
• Tarique Anwar,
• Maitreyee Banerjee,
• Yogesh P. Bharitkar,
• Shyamal Mondal,
• Sandip Kundu,
• Abhijit Hazra,
• Prakas R. Maulik and
• Nirup B. Mondal

Beilstein J. Org. Chem. 2014, 10, 692–700, doi:10.3762/bjoc.10.62

• [1][2][3][4][5][6][7][8][9]. These ylides, both stabilized or non-stabilized 1,3-dipoles, can easily enter the reaction independent of their stability and lead to the formation of a pyrrolidine core, a structural motif of immense interest from both chemical and pharmacological points of view [10]. In

• structure of 10a was deduced from the appearance of a new doublet of doublets at δ 5.50 and δ 6.20. Another doublet at δ 3.90 and a new multiplet at δ 3.50 also indicated the success of the reaction, as these signals could be attributed to the new pyrrolidine core. Besides, the cluster in the aromatic

• region (δ 6.60–8.50) indicated the presence of 19 aromatic protons in the cycloadduct 10a. This interpretation was also well supported by the 13C NMR of 10a. Peaks for the four sp3-methine carbons of the newly formed pyrrolidine motif appeared at δ 47.2, 47.4, 61.0 and 66.5 as expected. Two methine

Isocyanide-based multicomponent reactions towards cyclic constrained peptidomimetics

• Gijs Koopmanschap,
• Eelco Ruijter and
• Romano V.A. Orru

Beilstein J. Org. Chem. 2014, 10, 544–598, doi:10.3762/bjoc.10.50

• , oxazoles, thiazoles and triazoles incorporated into peptide structures will be described. Pyrrolidines 2-substituted pyrrolidine-based dipeptide mimics were obtained from an Ugi-4CR followed by a Pd-catalyzed Sn2 cyclization as described by Banfi et al. [51] . Herein, the Ugi reaction provided a small

• library of acyclic products (Scheme 11), in which the isocyanide input 30 was derived from the corresponding amine via an N-formylation/dehydration sequence [52]. An additional palladium-catalyzed cyclization gave the pyrrolidine mimics 32 in excellent yields and modest to good selectivities (de 8–78

• %). In addition, the mild conditions tolerate a wide range of Ugi-substrates, resulting in a broad range of different pyrrolidine mimics 32. A more straightforward method [53] includes a single Joullié-Ugi 3CR using previously described alkyl substituted cyclic imines [54] giving the cyclic constraint

Concise, stereodivergent and highly stereoselective synthesis of cis- and trans-2-substituted 3-hydroxypiperidines – development of a phosphite-driven cyclodehydration

• Peter H. Huy,
• Julia C. Westphal and
• Ari M. P. Koskinen

Beilstein J. Org. Chem. 2014, 10, 369–383, doi:10.3762/bjoc.10.35

• ring expansions of 2-(α-hydroxyalkyl)pyrrolidines deduced to proline. 3. Based on the ring expansion of Cossy and Pardo [37], O´Brien [39] realized the synthesis of L-733,060 (80% ee). The 2-(α-hydroxyalkyl)pyrrolidine precursor was prepared from a protected pyrrolidine through sparteine-mediated

• : Pyrrolidine 13a was formed in 80% yield after hydrolysis of the phosphate and in 81% yield after extraction of triethylphosphate with EtOAc (×5) while keeping the product 13a as the hydrochloride salt in the aqueous phase (Table 3, entries 1 and 2). Surprisingly, with the higher homologue 12b the piperidine

Additive-assisted regioselective 1,3-dipolar cycloaddition of azomethine ylides with benzylideneacetone

• Chuqin Peng,
• Jiwei Ren,
• Jun-An Xiao,
• Honggang Zhang,
• Hua Yang and
• Yiming Luo

Beilstein J. Org. Chem. 2014, 10, 352–360, doi:10.3762/bjoc.10.33

• prepare a series of novel spiropyrrolidine-oxindoles – 4′-acetyl-3′,5′-diarylspiro[indoline-3,2′-pyrrolidin]-2-ones and 3′-acetyl-4′,5′-diarylspiro[indoline-3,2′-pyrrolidine]-2-ones in good yields of up to 94% and with good regioselectivities. Regioselectivities are reversible by the addition of water or

• -constructed pyrrolidine. However, unsaturated ketones with α-hydrogens such as benzylideneacetone, which have attracted great interest due to their synthetic potential [40][41][42], have not been exhaustively studied as suitable dipolarophiles for 1,3-dipolar cycloadditions of azomethine ylides to prepare

Tuning the interactions between electron spins in fullerene-based triad systems

• Maria A. Lebedeva,
• Thomas W. Chamberlain,
• E. Stephen Davies,
• Bradley E. Thomas,
• Martin Schröder and
• Andrei N. Khlobystov

Beilstein J. Org. Chem. 2014, 10, 332–343, doi:10.3762/bjoc.10.31

• the nature of the fullerene cages resulting in the preparation of six fullerene–linker–fullerene (triad) compounds (Figure 1). The fullerenes were functionalised via Prato reaction chemistry forming a pyrrolidine ring across the [6.6] bond of the cage [21]. The resulting pyrrolidine functionalised

• suggest that this difference alone is too small to explain the position of these features. We note also that 2 and 5 are mixtures of two regioisomers of the pyrrolidine functionalised C70 [19], in a ratio of 6:4 as determined by 1H NMR spectroscopy (see Experimental section). It is possible that these

• range (26–29 G) as that observed for other triplet biradicals of pyrrolidine-functionalised C60 derivatives in C60–bridge–C60 triads [15][28] and gives an average distance of 10 Å between the unpaired electrons [16], a distance well within the range predicted by models of 4 (Figure S4b, Supporting

Organocatalytic asymmetric fluorination of α-chloroaldehydes involving kinetic resolution

• Kazutaka Shibatomi,
• Takuya Okimi,
• Yoshiyuki Abe,
• Akira Narayama,
• Nami Nakamura and
• Seiji Iwasa

Beilstein J. Org. Chem. 2014, 10, 323–331, doi:10.3762/bjoc.10.30

• to form iminium intermediate I, which undergoes deprotonation from the side opposite to the bulky substituent X (X = CAr2OTMS) of the pyrrolidine ring to afford enamine intermediate (Z)-11 (path A). Then, NFSI attacks (Z)-11 from the side opposite to X to yield (R)-3a. Although deprotonation may also

• steric repulsion between the methylene group on the pyrrolidine ring and the benzyl substituent on 2a. Alternatively, (S)-2a reacts with (S)-1 to form iminium intermediate II, which also undergoes deprotonation to form (E)- or (Z)-11. In these cases, deprotonation from the side opposite to X (path C) is

Total synthesis and cytotoxicity of the marine natural product malevamide D and a photoreactive analog

• Werner Telle,
• Gerhard Kelter,
• Heinz-Herbert Fiebig,
• Peter G. Jones and
• Thomas Lindel

Beilstein J. Org. Chem. 2014, 10, 316–322, doi:10.3762/bjoc.10.29

• separated in the 13C NMR spectrum are, for instance, the ester carbonyl signals of the conformers (174.0 and 173.3 ppm), the carbonyl signals of the pyrrolidine amide (170.5 and 170.6 ppm), and all phenyl carbon signals. Of the eastern section, only three of the four pyrrolidine carbon signals are broad

• belonging to different signal sets are located at δH 3.84 (one of the diastereotopic OCH2 signals) and 5.21 ppm (acylated carbinol). The two sets of signals are probably caused by the presence of both conformers of the acyl pyrrolidine. An assignment of the data sets to either of the two conformers was not

• afforded building block 26. Coupling with Boc-protected dolaproine (27, DCC/DMAP/CSA) yielded ester 28 as a mixture of two diastereomers. After deprotection of the pyrrolidine, coupling with tripeptide 12 afforded O-silylated diazirinyl-substituted malevamide D (29, 68%). Desilylation (TBAF, THF/H2O 19:1

The regioselective synthesis of spirooxindolo pyrrolidines and pyrrolizidines via three-component reactions of acrylamides and aroylacrylic acids with isatins and α-amino acids

• Tatyana L. Pavlovskaya,
• Fedor G. Yaremenko,
• Victoria V. Lipson,
• Svetlana V. Shishkina,
• Oleg V. Shishkin,
• Vladimir I. Musatov and
• Alexander S. Karpenko

Beilstein J. Org. Chem. 2014, 10, 117–126, doi:10.3762/bjoc.10.8

• their inherent rigid chiral structure. The spirooxindolo pyrrolidine and pyrrolizidine frameworks form core units of many naturally occurring molecules possess significant pharmacological activities. Among them are alkaloids such as horsfiline from Horsfieldia superbа [1][2][3], elacomine from Elaeagnus

• inhibitors there are compounds containing a pyrrolidine-2-one as a part of the spirocyclic system [34]. In the present work we report the synthesis of spirooxindolo pyrrolidines and pyrrolizidines by utilizing a 1,3-dipolar cycloaddition of hitherto uninvestigated acrylamides and aroylacrylic acids with

• pyrrolidine/pyrrolizidine ring give singlets at 10.25 and 12.67 ppm, respectively. Therefore, the correct stereochemistry can be drawn as shown in Figure 3. The 13C NMR spectrum of compound 6c shows a characteristic peak at 73 ppm due to the spiro carbon nucleus. A single crystal X-ray study of compound 6a

Studies on the interaction of isocyanides with imines: reaction scope and mechanistic variations

• Ouldouz Ghashghaei,
• Consiglia Annamaria Manna,
• Esther Vicente-García,
• Marc Revés and
• Rodolfo Lavilla

Beilstein J. Org. Chem. 2014, 10, 12–17, doi:10.3762/bjoc.10.3

• ]. In a different experiment, the addition of a 9-fold excess of isocyanide 2a to the imine 1a under the usual conditions led to detection of tris(imino)pyrrolidine 5 (9%) as the minor product, and azetidine 3a as the major component (24%, Scheme 2). Structural elucidation Although we could confirm the

• insertion of the isocyanide moiety has been observed, the adduct being the tris(imino)pyrrolidine 5 (Scheme 4, route v). Conclusion As a summary, we have described structural and mechanistic features for the bis(imino)azetidines arising from the imine–isocyanide interaction, finding that the process

Four-component reaction of cyclic amines, 2-aminobenzothiazole, aromatic aldehydes and acetylenedicarboxylate

• Hong Gao,
• Jing Sun and
• Chao-Guo Yan

Beilstein J. Org. Chem. 2013, 9, 2934–2939, doi:10.3762/bjoc.9.330

• Hong Gao Jing Sun Chao-Guo Yan College of Chemistry & Chemical Engineering, Yangzhou University, Yangzhou 225002, China 10.3762/bjoc.9.330 Abstract The four-component reaction of 2-aminobenzothiazole, aromatic aldehydes, acetylenedicarboxylate and piperidine or pyrrolidine in ethanol afforded the

• spiro compounds by using the in situ generated Huisgen 1,4-dipoles [17][18][19][20][21][22][23][24]. During these research works, we noticed that even through the cyclic secondary amines such as pyrrolidine, piperidine and morpholine also reacted with electron-deficient alkynes to give the Huisgen 1,4

• reaction, we explored the scope of this promising reaction by varying the structure of the secondary cyclic amines. When excess pyrrolidine was used in the reaction by using the above reaction procedure, it was surprising to find that only very low yields of 3-(pyrrolidin-1-yl)-2-pyrrolidinones were

Modulating NHC catalysis with fluorine

• Yannick P. Rey and
• Ryan Gilmour

Beilstein J. Org. Chem. 2013, 9, 2812–2820, doi:10.3762/bjoc.9.316

• triazolium salts 5 and 6 [18][22]. The route to target 7 began by treating N-Boc-trans-4-hydroxy-L-proline methyl ester (11) with diethylaminosulfur trifluoride (DAST) in CH2Cl2 to install the first fluoro substituent (12) with clean configurational inversion (88%, Scheme 1). Oxidation of the pyrrolidine to

• were prepared by an analogous reaction sequence (Scheme 3). Commercially available (S)-(+)-(trifluoromethyl)pyrrolidine 20 was protected (21, quantitative), oxidised to the corresponding lactam (22, 38% over 2 steps) and processed to the target triazolium salt 9 (46%, 3 steps). The non-fluorinated

• triazolium salts 5, 6 and 7 were then compared to examine the conformation of the β-fluoroamine motifs that were the major motivation for this study (Figure 3) [42]. In previous analyses of (S)-2-(fluorodiphenylmethyl)pyrrolidine derivatives, the synclinal-endo conformation was almost exclusively observed in

Stereoselectively fluorinated N-heterocycles: a brief survey

• Xiang-Guo Hu and
• Luke Hunter

Beilstein J. Org. Chem. 2013, 9, 2696–2708, doi:10.3762/bjoc.9.306

• [21]. For example, O’Hagan and co-workers investigated the pyrrolidine-containing molecules 9 and 10 (Figure 3) as ligands of G-quadruplex DNA [22]. The non-fluorinated ligand 9 had some conformational disorder because the pyrrolidine rings were able to interconvert between exo and endo puckers. In

• contrast, the pyrrolidine rings of fluorinated ligand 10 were more rigid, with the fluorine atoms preferring to occupy an axial position consistent with a favourable C–F…N+ interaction (worth approximately 5.0 kcal/mol). This led to a number of changes to the DNA binding mode of 10, including a rotation of

• the entire pyrrolidine ring by 180° relative to that of 9, and several different H-bonding contacts with the DNA as a result. In contrast with the strong charge–dipole effect evident in pyrrolidine 10 (Figure 3), another more subtle interaction is observed in neutral fluorinated pyrrolidines. For

Synthetic scope and DFT analysis of the chiral binap–gold(I) complex-catalyzed 1,3-dipolar cycloaddition of azlactones with alkenes

• María Martín-Rodríguez,
• Luis M. Castelló,
• Carmen Nájera,
• José M. Sansano,
• Olatz Larrañaga,
• Abel de Cózar and
• Fernando P. Cossío

Beilstein J. Org. Chem. 2013, 9, 2422–2433, doi:10.3762/bjoc.9.280

• submitted to different transformations. For example, it could be reduced to the corresponding pyrrolidines employing sodium cyanoborohydride in acidic media. In this reaction, a 1:1 mixture of 2,5-cis-pyrrolidine 13 and its 5-epimer 14 (2,5-trans) was isolated in good chemical yield (71%) (Scheme 7

Towards stereochemical control: A short formal enantioselective total synthesis of pumiliotoxins 251D and 237A

• Jie Zhang,
• Hong-Kui Zhang and
• Pei-Qiang Huang

Beilstein J. Org. Chem. 2013, 9, 2358–2366, doi:10.3762/bjoc.9.271

• product. On the basis of the abovementioned analysis, a retrosynthetic analysis of (8S,8aS)-5 is displayed in Scheme 5, which features the formation of the fused pyrrolidine ring from the but-3-ene-1-yl group, the expected trans-diastereoselective methylation as the key step, and protected (R)-3

Cyclopamine analogs bearing exocyclic methylenes are highly potent and acid-stable inhibitors of hedgehog signaling

• Johann Moschner,
• Anna Chentsova,
• Nicole Eilert,
• Irene Rovardi,
• Philipp Heretsch and
• Athanassios Giannis

Beilstein J. Org. Chem. 2013, 9, 2328–2335, doi:10.3762/bjoc.9.267

• steps) gave sulfonylamide 21. Reduction of the ester in 21 to the primary alcohol (DIBAl-H, THF, −78 °C to −40 °C, 97%) and cyclization by employing Mitsunobu conditions (n-Bu3P, DEAD, toluene, 0 °C→25 °C, 81%) yielded pyrrolidine 22. Previously devised conditions for the deprotection (1. DDQ, DCE/pH 7

• and 9 it becomes evident that the F-ring is necessary for bioactivity. The piperidine moiety provides a rather rigidly placed nitrogen atom. Nevertheless, a pyrrolidine as in compound 23 still provides the correct orientation of the nitrogen atom. Despite compounds 8 and 9 being inactive in the assay

An overview of the synthetic routes to the best selling drugs containing 6-membered heterocycles

• Marcus Baumann and
• Ian R. Baxendale

Beilstein J. Org. Chem. 2013, 9, 2265–2319, doi:10.3762/bjoc.9.265

• specifically cleaves at proline residues, it is unsurprising that the members of this drug class exhibit an embedded pyrrolidine ring (or mimic) and additional decoration (a nitrile or fluorinated alkyl substituent is present in order to reach into a local lipophilic pocket). One specific structural liability

Synthesis of axially chiral gold complexes and their applications in asymmetric catalyses

• Yin-wei Sun,
• Qin Xu and
• Min Shi

Beilstein J. Org. Chem. 2013, 9, 2224–2232, doi:10.3762/bjoc.9.261

• afforded pyrrolidine derivative 25 in 46% yield and 17% ee. While using AgSbF6 or AgNTf2 as additives, only trace amounts of 25 were formed. Further screening of silver salts revealed that AgOTs showed the best catalytic activity in this reaction, giving 25 in 72% yield and 27% ee (Table 1, entries 1–6

Synthesis and characterization of novel bioactive 1,2,4-oxadiazole natural product analogs bearing the N-phenylmaleimide and N-phenylsuccinimide moieties

• Catalin V. Maftei,
• Elena Fodor,
• Peter G. Jones,
• M. Heiko Franz,
• Gerhard Kelter,
• Heiner Fiebig and
• Ion Neda

Beilstein J. Org. Chem. 2013, 9, 2202–2215, doi:10.3762/bjoc.9.259

• natural products containing a 1,2,4-oxadiazole ring in their structure (quisqualic acid and phidianidines A and B), the natural product analogs 1-(4-(3-tert-butyl-1,2,4-oxadiazol-5-yl)phenyl)pyrrolidine-2,5-dione (4) and 1-(4-(3-tert-butyl-1,2,4-oxadiazol-5-yl)phenyl)-1H-pyrrole-2,5-dione (7) were

• compounds 4 and 5 were also confirmed by X-ray structure analysis (Figure 7, Figure 8 and Figure 9). In compound 4 the oxazoline and phenyl rings are approximately coplanar (6°), but the pyrrolidine ring is rotated by 52° with respect to the phenyl ring. The main packing interaction is an offset stacking

• ), 612 (m) cm−1. Synthesis of 1-(4-(3-tert-butyl-1,2,4-oxadiazol-5-yl)phenyl)pyrrolidine-2,5-dione (4) 0.3 g (0.94 mmol) of 4-(4-(3-tert-butyl-1,2,4-oxadiazol-5-yl)phenylamino)-4-oxobutanoic acid (3) was mixed with an equimolar amount of sodium acetate (0.077 g, 0.94 mmol) in 15 mL of acetic anhydride

The chemistry of isoindole natural products

• Klaus Speck and
• Thomas Magauer

Beilstein J. Org. Chem. 2013, 9, 2048–2078, doi:10.3762/bjoc.9.243

• -dipolar cycloaddition. Carrying out the reaction at 180 °C in tetrahydrofuran provided a separable mixture of pyrrolidine isomers 241 and 242 (1:3.6). The undesired cycloadduct 242 could be equilibrated to 241 due to the reversibility of the reaction. Conversion to the β,γ-cyclohexenone 243 was

• accomplished within 6 consecutive steps. Generation of the dienamine 244 with pyrrolidine in methanol at 60 °C triggered an intramolecular Diels–Alder reaction to provide the full carbon skeleton 245. The final transformations of the synthesis involved a Wittig olefination of the ketone and a

The chemistry of amine radical cations produced by visible light photoredox catalysis

• Jie Hu,
• Jiang Wang,
• Theresa H. Nguyen and
• Nan Zheng

Beilstein J. Org. Chem. 2013, 9, 1977–2001, doi:10.3762/bjoc.9.234

• for the outcome of the reaction and proline was more effective than pyrrolidine. Additionally, to maximize the yields, the optimal rates for the two catalytic processes need to be similar. Since formation of the iminium ions is much faster than the addition of the enamine nucleophiles, higher yields

• pyrrolidines 43 and 47 (Scheme 12). Xiao also showed that the pyrrolidine ring of 43 could be further oxidized to a fused pyrrole 44 under the same photoredox conditions or by treatment with NBS. Both Ru(bpy)3Cl2 and Ir(bpy)(ppy)2 were found to be effective catalysts. A plausible mechanism for the 1,3-dipolar

• loss of a proton. 1,3-Dipolar cycloaddition of 50 with a dipolarophile 46 furnishes fused pyrrolidine 51 that is further oxidized to pyrrole 52. The Zhu group discovered that the use of α-ketoester 53 as a pronucleophile to intercept the iminium ion of 13 triggered a new cascade reaction en route to