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

• maleimides. The general scope is not very wide but enantioselections obtained are quite good. Very interesting pyrrolidines with a trans-arrangement were obtained after hydrogenation of the pyrroline precursor. Chiral gold(I) complexes employed in 1,3-DC involving azomethine ylides. Positive non-linear

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

• 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

The rapid generation of isothiocyanates in flow

• Marcus Baumann and
• Ian R. Baxendale

Beilstein J. Org. Chem. 2013, 9, 1613–1619, doi:10.3762/bjoc.9.184

• pyrrolidines, isoxazolines and their derivatives [49][50][51][52]. We therefore considered that it should be possible to develop a mild and practical flow-based process to form isothiocyanates from the corresponding reactive nitrile oxide intermediates. Our strategy makes use of two immobilised reagents (a

An organocatalytic route to 2-heteroarylmethylene decorated N-arylpyrroles

• Alexandre Jean,
• Jérôme Blanchet,
• Jacques Rouden,
• Jacques Maddaluno and
• Michaël De Paolis

Beilstein J. Org. Chem. 2013, 9, 1480–1486, doi:10.3762/bjoc.9.168

• Ullmann-type condensation [8][9][10], the regioselective functionalization of pyrroles is less trivial when asymmetric substrates are targeted. An indirect solution, based on the construction of substituted pyrrolidines that oxidize into elaborated pyrroles, can be employed fruitfully [11][12]. We

• recently described a one-pot organo-catalyzed synthesis of N-heteroarylmethylene pyrrolidines 4 [13] from readily available aldehydes 1 and imine 2 by a sequence of Mannich coupling [14][15][16][17][18][19][20][21][22][23][24], Wittig olefination with phosphonium 3, and proton-mediated hydroamination

• silica gel before isomerization is more rewarding: following this route, the global yield for the whole process reaches 59% yield. Applying this procedure, various 2-heteroarylmethylenepyrrolidines 4b–h prepared from aldehydes 1b–h and imine 2a were exposed to DBU (1.1 equiv). Pleasingly, pyrrolidines 4b

One-pot tandem cyclization of enantiopure asymmetric cis-2,5-disubstituted pyrrolidines: Facile access to chiral 10-heteroazatriquinanes

• Ping-An Wang,
• Sheng-Yong Zhang and
• Henri B. Kagan

Beilstein J. Org. Chem. 2013, 9, 265–269, doi:10.3762/bjoc.9.32

• Moléculaire, Université Paris-Sud, 15 rue Georges Clemenceau, 91405 Orsay Cedex, France 10.3762/bjoc.9.32 Abstract A series of chiral 10-heteroazatriquinanes were synthesized from enantiopure asymmetric cis-2,5-disubstituted pyrrolidines through a one-pot tandem cyclization procedure. The structures and

• complexes and calixiform scaffolds (Figure 1). Previously, we established a facile access to enantiopure asymmetric cis-2,5-disustituted pyrrolidines 4 from commercially available starting materials diethyl meso-2,5-dibromoadipate and (S)-(−)-1-phenylethylamine (Figure 2) [9]. The preparations of compounds

• ][13][14] from compounds 4 through three steps, including reduction, debenzylation and cyclization (Scheme 1), but this failed. However, we have found a novel one-pot tandem cyclization of these enantiopure asymmetric cis-2,5-disubstituted pyrrolidines to produce chiral trisubstituted 10

A quantitative approach to nucleophilic organocatalysis

• Herbert Mayr,
• Sami Lakhdar,
• Biplab Maji and
• Armin R. Ofial

Beilstein J. Org. Chem. 2012, 8, 1458–1478, doi:10.3762/bjoc.8.166

• range –10 < E < –5 were determined for iminium ions derived from cinnamaldehyde and common organocatalysts, such as pyrrolidines and imidazolidinones, by studying the rates of their reactions with reference nucleophiles. Iminium activated reactions of α,β-unsaturated aldehydes can, therefore, be

• data in Figure 18 and Figure 19 now explains why the Jørgensen-Hayashi diphenylprolinol trimethylsilyl ether [81], the precursor of 32b, and structurally related pyrrolidines have previously been employed for catalyzing the reactions of aldehydes and ketones with weak electrophiles, such as β

Low-generation dendrimers with a calixarene core and based on a chiral C₂-symmetric pyrrolidine as iminosugar mimics

• Marco Marradi,
• Stefano Cicchi,
• Francesco Sansone,
• Alessandro Casnati and
• Andrea Goti

Beilstein J. Org. Chem. 2012, 8, 951–957, doi:10.3762/bjoc.8.107

• with more complex and/or biologically relevant iminosugars. Keywords: calixarenes; cation-responsive system; dendrimers; iminosugars; multivalency; Introduction Polyhydroxylated pyrrolidines are one of the main classes of naturally occurring sugar mimics [1][2] and belong to the so-called iminosugars

• open the way for the construction of more complex systems, decorated with biologically active polyhydroxylated pyrrolidines or piperidines. The synthesis of first- and second-generation iminosugar-based calixarene-dendrimers 2 and 3 (Figure 1) was addressed in order to prove the viability of such a

• both as a dendrimeric building block and iminosugar model; its substitution at the hydroxy groups with more complex and biologically active iminosugars, such as polyhydroxylated pyrrolidines, would also allow the investigation of the corresponding calixarene dendrimers in interactions with enzymatic

Carbohydrate-auxiliary assisted preparation of enantiopure 1,2-oxazine derivatives and aminopolyols

• Marcin Jasiński,
• Dieter Lentz and
• Hans-Ulrich Reissig

Beilstein J. Org. Chem. 2012, 8, 662–674, doi:10.3762/bjoc.8.74

• samarium diiodide leading to enantiopure acyclic aminopolyols. We also report on our attempts to convert these compounds into enantiopure hydroxylated pyrrolidine derivatives. Keywords: aminopolyols; carbohydrates; chiral auxiliaries; lithiated alkoxyallenes; 1,2-oxazines; pyrroles; pyrrolidines; samarium

Synthesis and biological evaluation of nojirimycin- and pyrrolidine-based trehalase inhibitors

• Davide Bini,
• Francesca Cardona,
• Matilde Forcella,
• Camilla Parmeggiani,
• Paolo Parenti,
• Francesco Nicotra and
• Laura Cipolla

Beilstein J. Org. Chem. 2012, 8, 514–521, doi:10.3762/bjoc.8.58

• scarcely characterised. Keywords: glycosidases inhibitors; iminosugars; nojirimycins; pyrrolidines; trehalases; Introduction Trehalase (EC3.2.1.28) is a glycosidase that catalyses trehalose (α-D-glucopyranosyl-α-D-glucopyranoside 1, Figure 1) [1][2][3] hydrolysis. It was found initially at the end of the

• alkyl chain (Figure 3). These two compounds can help answer whether a medium-sized lipophylic chain can be accommodated into the catalytic site, and whether any difference could be due to the positioning of the chain itself. Only the “α-D-arabino-configured” pyrrolidines 20, 21 were considered here

• , since preliminary data showed that “β-D-ribo-configured” pyrrolidines were not active at all (for details, see Enzyme assays). Chemical synthesis Based on the structure of lead compound 8 (Figure 2), which showed some selectivity towards insect trehalase from C.riparius [18], we envisaged the

Continuous-flow enantioselective α-aminoxylation of aldehydes catalyzed by a polystyrene-immobilized hydroxyproline

• Xacobe C. Cambeiro,
• Rafael Martín-Rapún,
• Pedro O. Miranda,
• Sonia Sayalero,
• Esther Alza,
• Patricia Llanes and
• Miquel A. Pericàs

Beilstein J. Org. Chem. 2011, 7, 1486–1493, doi:10.3762/bjoc.7.172

• subsequently applied to the synthesis of several biologically active compounds [18][19][20]. Proline is the most frequently used catalyst in α-aminoxylation reactions, but other catalytic species have also been developed and used. Chiral secondary amines, such as substituted pyrrolidines other than proline [21

Amines as key building blocks in Pd-assisted multicomponent processes

• Didier Bouyssi,
• Nuno Monteiro and
• Geneviève Balme

Beilstein J. Org. Chem. 2011, 7, 1387–1406, doi:10.3762/bjoc.7.163

• ]. For instance, Balme and coworkers reported a Pd-catalyzed three-component assembly of highly functionalized 4-benzyl- and allyl-pyrrolidines 46 based on a combination of allylamines (in situ transformed to their sodium salts by treatment with NaH), gem-diactivated alkenes 45 as Michael acceptors, and

Combination of gold catalysis and Selectfluor for the synthesis of fluorinated nitrogen heterocycles

• Antoine Simonneau,
• Pierre Garcia,
• Jean-Philippe Goddard,
• Virginie Mouriès-Mansuy,
• Max Malacria and
• Louis Fensterbank

Beilstein J. Org. Chem. 2011, 7, 1379–1386, doi:10.3762/bjoc.7.162

• the elucidation of the mechanism and Selectfluor was suggested to play the double role of promoting the oxidation of gold(I) to a gold(III) active species and also the electrophilic fluorination of the enamine intermediates. Keywords: cycloisomerization reactions; fluorinated pyrrolidines; gold

• summarized in Table 1. The reaction of 1a in the presence of commercially available Ph3PAuCl (5 mol %) and Selectfluor (1.1 equiv) in acetonitrile at rt afforded an inseparable mixture of pyrrolidines 3a in 75% yield and 4a in 17% yield (Table 1, entry 1). Difluoro derivative 4a was isolated as a single

• fluorinated pyrrolidines 3a, 4a and 2-pyrroline 5a are unknown and could be interesting building blocks for organic synthesis. Following the previous catalyst screening, we stuck with the use of PPh3AuCl as the catalyst and next investigated the effect of the concentration of 1a and the stoichiometry of

Synthesis of novel 5-alkyl/aryl/heteroaryl substituted diethyl 3,4-dihydro-2H-pyrrole-4,4-dicarboxylates by aziridine ring expansion of 2-[(aziridin-1-yl)-1-alkyl/aryl/heteroaryl-methylene]malonic acid diethyl esters

• Satish S. More,
• T. Krishna Mohan,
• Y. Sateesh Kumar,
• U. K. Syam Kumar and
• Navin B. Patel

Beilstein J. Org. Chem. 2011, 7, 831–838, doi:10.3762/bjoc.7.95

• substituted novel pyrroline derivatives have been synthesized by this methodology and the products can be used as key intermediates in the synthesis of substituted pyrrolines, pyrroles and pyrrolidines. Keywords: 5-alkyl/aryl/heteroaryl substituted 3,4-dihydro-2H-pyrrole-4,4-dicarboxylates; aziridine; N

• materials in the preparation of substituted pyrroles, pyrrolines and pyrrolidines. The pyrrolines as well as pyrrolidines with substitution at the 2-position are important structural units in many natural products. A few of the natural products that contain 2-substituted pyrroline and 2-substituted

• at 100–110 °C for a period of 12 h, the mono ester 24 was isolated as the major product in 65% yield along with 10% of unreacted starting material and 10% of pyrroline derivative 23 (Scheme 3). The imine bond reduction in pyrrolines to pyrrolidines can be carried out by established procedures in

Synthetic applications of gold-catalyzed ring expansions

• David Garayalde and
• Cristina Nevado

Beilstein J. Org. Chem. 2011, 7, 767–780, doi:10.3762/bjoc.7.87

• starting from allenyl cyclobutanols [23]. 1.2 Cyclopropylmethanols Cyclopropyl methanols can be used, alternatively, as pre-electrophiles in gold-catalyzed reactions. In 2008 Chan and co-workers developed an efficient synthetic route to pyrrolidines via a tandem amination/ring expansion of these substrates

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

• ; iminocyclitols; natural products; olefin metathesis; Ru-alkylidene catalysts; Review Introduction Synthetic and natural polyhydroxylated N-heterocyclic compounds (pyrrolidines, piperidines, piperazines, indolizines, etc., and higher homologues), commonly referred to as azasugars, iminosugars or iminocyclitols

Stereoselective synthesis of four possible isomers of streptopyrrolidine

• Debendra K. Mohapatra,
• Barla Thirupathi,
• Pragna P. Das and
• Jhillu S. Yadav

Beilstein J. Org. Chem. 2011, 7, 34–39, doi:10.3762/bjoc.7.6

• Streptomyces sp. found in deep sea sediments [12]. The system is present in many biologically active compounds [13][14][15][16][17][18][19][20][21] and it could act as a versatile intermediate for the synthesis of a wide range of γ-amino acids as well as pyrrolidines [22][23]. The interesting chemical

Prins fluorination cyclisations: Preparation of 4-fluoro-pyran and -piperidine heterocycles

• Guillaume G. Launay,
• Alexandra M. Z. Slawin and
• David O'Hagan

Beilstein J. Org. Chem. 2010, 6, No. 41, doi:10.3762/bjoc.6.41

• methodology was extended to the aza-Prins reaction using N-tosyl-homoallylic amines to generate the corresponding 4-fluoropyrrolidines. In general, these reactions leading to both the 4-fluorotetrahydropyrans and 4-fluoro-pyrrolidines occur with good to high conversions, however the diastereoselectivities are

Diastereoselective functionalisation of benzo-annulated bicyclic sultams: Application for the synthesis of cis-2,4-diarylpyrrolidines

• Susan Kelleher,
• Pierre-Yves Quesne and
• Paul Evans

Beilstein J. Org. Chem. 2009, 5, No. 69, doi:10.3762/bjoc.5.69

• place to afford cis-2,4-diaryl-substituted pyrrolidines 35–37. Keywords: cyclic sulfonamides; diastereoselective alkene functionalisation; double reduction; Pd-mediated cross coupling; Introduction Substituted pyrrolidine ring systems represent a common structural motif in a range of biologically

• active compounds, including pharmaceutical agents and natural products. In relation to these general targets, we have recently developed a method that enables the construction of aryl-substituted pyrrolidines, featuring the double reduction of cyclic aromatic sulfonamides [1][2][3][4]. As illustrated in

• preparation of 2,4-diaryl-substituted pyrrolidines from more readily available, albeit racemic, substrates. Results and Discussion Bicyclic aromatic cyclic sulfonamides 5a and 5b were formed according to the 3-step sequence previously described [1][2][3][10]. Originally, inclusion of triphenylphosphine was

Radical cascades using enantioenriched 7-azabenzonorbornenes and their applications in synthesis

• David M. Hodgson and
• Leonard H. Winning

Beilstein J. Org. Chem. 2008, 4, No. 38, doi:10.3762/bjoc.4.38

• -azabenzonorbornadienes. Oxidation (using RuO4) and Birch reduction of the 2-aza-5,6-benzonorbornenes provide access to substituted pyrrolidines and tetrahydroindenes, respectively. Keywords: asymmetric synthesis; deoxygenation; radicals; rearrangements; tandem reactions; Introduction Carbon-centred radicals have been

• –oxidation with (−)-Ipc2BH to be determined by chemical correlation. Pyrrolidine 35 was independently prepared from (1R)-(−)-2-azabicyclo[2.2.1]hept-5-en-3-one (Vince’s lactam [36], 37) via reduction with LiAlH4, Boc-protection and oxidative cleavage [37] (Scheme 9). The pyrrolidines prepared from rearranged

• the intermediate radical undergoes rearrangement prior to electrophile trapping, thereby providing a new route to substituted 2-aza-5,6-benzonorbornenes. These adducts have been shown to lead on to pharmaceutically significant [40] (aminomethyl)indenes, and to substituted pyrrolidines and

C₂-symmetric bisamidines: Chiral Brønsted bases catalysing the Diels- Alder reaction of anthrones

• Deniz Akalay,
• Gerd Dürner,
• Jan W. Bats and
• Michael W. Göbel

Beilstein J. Org. Chem. 2008, 4, No. 28, doi:10.3762/bjoc.4.28

• exerted by chiral Brønsted bases. Moderate to excellent stereoselectivities of products 3 have been reported using pyrrolidines 4 [1][2], cyclic guanidine 5 [3], or cinchona alkaloids 6 [4] as catalysts. Recently, we could promote this type of cycloaddition by metal-free bisoxazolines 7 in up to 70% ee

Knorr- Rabe partial reduction of pyrroles: Application to the synthesis of indolizidine alkaloids

• Brendon S. Gourlay,
• John H. Ryan and
• Jason A. Smith

Beilstein J. Org. Chem. 2008, 4, No. 3, doi:10.1186/1860-5397-4-3

• confirmed by comparison of the spectral data with that reported by Huxtable who prepared 9 as an intermediate in the synthesis of lentiginosine [12]. For the partial reduction of electron rich pyrroles reported previously, over reduction to give pyrrolidines is a problematic side-reaction. For example

Desymmetrization of 7-azabicycloalkenes by tandem olefin metathesis for the preparation of natural product scaffolds

• Wolfgang Maison,
• Marina Büchert and
• Nina Deppermann

Beilstein J. Org. Chem. 2007, 3, No. 48, doi:10.1186/1860-5397-3-48

• -azabicycloalkenes by intra- and intermolecular tandem metathesis sequences with ruthenium based catalysts. Conclusion Desymmetrization of 7-azabicycloalkenes by olefin metathesis is an efficient process for the preparation of common natural product scaffolds such as pyrrolidines, indolizidines and isoindoles

• azabicycloalkane scaffolds was first described by Grubbs[23] for the synthesis of peptide mimetics and later extended by several other groups. [24][25][26][27][28][29][30][31] Key intermediates in these approaches are often alkenyl substituted pyrrolidines, which are N-acylated with an unsaturated carboxylic acid

• and submitted to a ring closing metathesis (RCM). As a part of a general synthetic concept using azabicycloalkenes as masked analogs of functionalized pyrrolidines or piperidines [32][33][34][35][36][37][38][39] we have previously applied the concept of intramolecular ring-opening/ring-closing

The enantiospecific synthesis of (+)-monomorine I using a 5-endo- trig cyclisation strategy

• Malcolm B. Berry,
• Donald Craig,
• Philip S. Jones and
• Gareth J. Rowlands

Beilstein J. Org. Chem. 2007, 3, No. 39, doi:10.1186/1860-5397-3-39

• University, Private Bag 11 222, Palmerston North, New Zealand 10.1186/1860-5397-3-39 Abstract We have developed a general strategy for the synthesis of 2,5-syn disubstituted pyrrolidines that is based on the multi-faceted reactivity of the sulfone moiety and a 5-endo-trig cyclisation. This methodology was

• , such as tetrahydrofurans and pyrrolidines, makes these motifs attractive targets for synthesis. Over the last decade we have developed a powerful general strategy for the preparation of such compounds based upon the multi-faceted reactivity of the sulfone group and the formally disfavoured 5-endo-trig

• mode of cyclisation. [1][2][3][4][5][6] The methodology allows the conversion of epoxides (X = O) or aziridines (X = N-PG) (2) into the desired trisubstituted tetrahydrofurans or pyrrolidines (5) via a series of sulfone-mediated transformations (Scheme 1). Ring-opening 2 with the sulfone-stabilised

An asymmetric synthesis of all stereoisomers of piclavines A1-4 using an iterative asymmetric dihydroxylation

• Yukako Saito,
• Naoki Okamoto and
• Hiroki Takahata

Beilstein J. Org. Chem. 2007, 3, No. 37, doi:10.1186/1860-5397-3-37

• monocyclic compounds (pyrrolidines) to bicyclic derivatives (indolizidines) provides rigid conformation and causes close proximity (a change from 1,5- to 1,3-relationship) between the two asymmetric centers. With indolizidine (5R, 8aR)-18 in hand, we examined partial-reduction of their triple bonds. First