Synthesis of 1,4-imino-L-lyxitols modified at C-5 and their evaluation as inhibitors of GH38 α-mannosidases

• Maroš Bella,
• Sergej Šesták,
• Ján Moncoľ,
• Miroslav Koóš and
• Monika Poláková

Beilstein J. Org. Chem. 2018, 14, 2156–2162, doi:10.3762/bjoc.14.189

• be more potent and selective inhibitors of the target enzyme. Moreover, proposed N-benzyl substituent at the pyrrolidine core was also confirmed to be essential for selectivity [30]. In this study, we explored structure–activity relationships (SAR) of pyrrolidine derivatives 1 with different

• modifications at position 5. The benzyl moiety was chosen to be (4-halo)benzyl as the pyrrolidines 1 bearing these structural fragments were the most effective and selective against GMIIb [30]. The synthesis of modified pyrrolidine derivatives 2–5 (Figure 1) and GH38 α-mannosidases inhibition studies are

• inhibitors for GMIIb. The inhibitory activity of the tested pyrrolidines against GMIIb was affected by modification at C-5 of the imino-L-lyxitol core. Elongation of the C-5 position in pyrrolidine 1a by a methyl group led to a pair of diastereoisomers 4a and 5a which differ in the configuration at the new C

An efficient and facile access to highly functionalized pyrrole derivatives

• Meng Gao,
• Wenting Zhao,
• Hongyi Zhao,
• Ziyun Lin,
• Dongfeng Zhang and
• Haihong Huang

Beilstein J. Org. Chem. 2018, 14, 884–890, doi:10.3762/bjoc.14.75

• considerable efforts have been expended to build stereogenic centers of pyrrolidine derivatives using chiral catalysts [7]. As our aim was to construct a small library of polysubstituted pyrroles for antibacterial screening, it prompted us to develop a concise and efficient synthesis of pyrrolo[3,4-c]pyrrole

• racemic pyrrolidine 11a using N-methylmaleimide (10a) as the simple dipolarophile without any chiral catalysts/ligands. To our delight, in the presence of 10 mol % of AgOAc, the reaction reached almost completion in CH2Cl2 within 1 h at room temperature and afforded the desired cycloadduct in moderate

• decomposition pathways, we increased the amount of 9a up to 1.5 equivalents, which delivered the bicyclic pyrrolidine 11a in excellent yield (82%, Table 2, entry 5). Prolonging the reaction time from 3 h to 6 h had no influence on the yield (Table 2, entry 6), which demonstrated that appropriate increase on the

Methyl isocyanide as a convertible functional group for the synthesis of spirocyclic oxindole γ-lactams via post-Ugi-4CR/transamidation/cyclization in a one-pot, three-step sequence

• Amarendar Reddy Maddirala and
• Peter R. Andreana

Beilstein J. Org. Chem. 2018, 14, 875–883, doi:10.3762/bjoc.14.74

• spiro[indoline-3,2'-pyrrolidine]-2,5'-diones, via a post-Ugi-domino transamidation/cyclization sequential process, has been achieved in three sequential steps utilizing a one-pot reaction protocol. The variation in carboxylic acid substrates allows for the generation of new chiral racemic quaternary

• synthetic method for these molecules that allows for structural diversity is also important but not necessarily trivial. For these and other reasons, we became interested in synthesizing spiro[indoline-3,2'-pyrrole]-2,5'(1'H)-dione and spiro[indoline-3,2'-pyrrolidine]-2,5'-dione scaffolds (a class of

• '-pyrrolidine]-2,5'-diones. Zhu et al. [38] reported 3-substituted-2-indolinones via a microwave-assisted post-Ugi-4CR/Buchwald–Hartwig reaction and another similar approach was illustrated by Van der Eycken et al. [39] for spiro[indoline-3,2'-pyrrole]-2,5'(1'H)-diones. In previous efforts to study 3

Functionalization of N-arylglycine esters: electrocatalytic access to C–C bonds mediated by n-Bu₄NI

• Mi-Hai Luo,
• Yang-Ye Jiang,
• Kun Xu,
• Yong-Guo Liu,
• Bao-Guo Sun and
• Cheng-Chu Zeng

Beilstein J. Org. Chem. 2018, 14, 499–505, doi:10.3762/bjoc.14.35

• ]. Later on, arylation, vinylation and alkynylation of glycine derivatives were also accomplished by the same group (Scheme 1) [13]. Using the Cu(OAc)2/pyrrolidine dual catalysts system, Huang developed the oxidative cross coupling of glycine derivatives with acetone in the presence of TBHP or DDQ as

5-Aminopyrazole as precursor in design and synthesis of fused pyrazoloazines

• Ranjana Aggarwal and
• Suresh Kumar

Beilstein J. Org. Chem. 2018, 14, 203–242, doi:10.3762/bjoc.14.15

• antitumor activities against various human cancer cell lines. The compound 198 with a pyrrolidine moiety was identified as most potent and promising member as it showed superior antitumor activities over other derivatives. Bakavoli et al. [115] reported the synthesis of pyrazolo[3,4-d]pyrimidine derivatives

CF₃SO₂X (X = Na, Cl) as reagents for trifluoromethylation, trifluoromethylsulfenyl-, -sulfinyl- and -sulfonylation. Part 1: Use of CF₃SO₂Na

• Hélène Guyon,
• Hélène Chachignon and
• Dominique Cahard

Beilstein J. Org. Chem. 2017, 13, 2764–2799, doi:10.3762/bjoc.13.272

• aminotrifluoromethylation of alkenes in an intramolecular version was reported by Zhang and co-workers in 2017 (Scheme 14) [33]. Langlois’ conditions with tert-butyl hydroperoxide and a catalytic amount of copper(II) triflate were used to prepare a series of CF3-containing indoline, pyrrolidine, lactam and lactone

Development of a fluorogenic small substrate for dipeptidyl peptidase-4

• Futa Ogawa,
• Masanori Takeda,
• Kanae Miyanaga,
• Keita Tani,
• Ryuji Yamazawa,
• Kiyoshi Ito,
• Atsushi Tarui,
• Kazuyuki Sato and
• Masaaki Omote

Beilstein J. Org. Chem. 2017, 13, 2690–2697, doi:10.3762/bjoc.13.267

• + calcd for C16H16N2O5, 316.3086; found, 316.1051. (S)-N-(2,4-Bis((E)-3,3,3-trifluoroprop-1-en-1-yl)phenyl)-1-(2-(1,3-dioxo-2H-isoindolin-2-yl)acetyl)pyrrolidine-2-carboxamide (7): 5 (2 mmol) and lithium hydroxide (12 mmol) were placed in a flask. To the flask was added THF (4.8 mL), methanol (1.5 mL

• residue was purified by column chromatography to give (S)-N-(2,4-bis((E)-3,3,3-trifluoroprop-1-en-1-yl)phenyl)-1-(2-(1,3-dioxo-2H-isoindolin-2-yl)acetyl)pyrrolidine-2-carboxamide (7) in 31% yield (71.9 mg, 0.12 mmol). A white solid: mp 181–182 °C; 1H NMR (CDCl3) δ 1.87–1.97 (m, 1H), 2.14–2.28 (m, 2H

• = 2.2, 6.4 Hz, 3F); MS m/z: M+ 565, 468, 285, 257, 188, 160; HRMS m/z: M+ calcd for C27H21F6N3O4, 565.1436; found, 595.1437. N-(S)-1-(2-Aminoacetyl)-N-(2,4-bis((E)-3,3,3-trifluoroprop-1-en-1-yl)phenyl)pyrrolidine-2-carboxamide (H-Gly-Pro-1): To solution of 7 (0.05 mmol) in ethanol was added hydrazine

Recent progress in the racemic and enantioselective synthesis of monofluoroalkene-based dipeptide isosteres

• Myriam Drouin and
• Jean-François Paquin

Beilstein J. Org. Chem. 2017, 13, 2637–2658, doi:10.3762/bjoc.13.262

• the chiral sulfinylimine, reduction into the corresponding sulfinylamine using DIBAL, deprotection of the terminal alcohol and Mitsunobu ring closure into the corresponding pyrrolidine derivative. Then, simultaneous deprotection of the amine and the alcohol in acidic conditions followed by coupling

One-pot three-component route for the synthesis of S-trifluoromethyl dithiocarbamates using Togni’s reagent

• Azim Ziyaei Halimehjani,
• Martin Dračínský and
• Petr Beier

Beilstein J. Org. Chem. 2017, 13, 2502–2508, doi:10.3762/bjoc.13.247

• afforded the corresponding isothiocyanate in high yield. A variable temperature NMR study revealed a rotational barrier of 14.6, 18.8, and 15.9 kcal/mol for the C–N bond in the dithiocarbamate moiety of piperidine, pyrrolidine, and diethylamine adducts, respectively. In addition, the calculated barriers of

• experimentally and computationally higher than in the other two compounds (4a and 4c). This can be explained by the conformational strain in the five-membered ring in the transition state. In the ground state, the conformation of the pyrrolidine ring is 4T3 with limited steric interactions between adjacent CH2

• hydrogen atoms (Figure 3). On the other hand, a 1E conformation is found in the transition state structure. Hydrogen atoms are close to unfavorable syn-periplanar arrangement in this conformation, which leads to an increased energy demand for the pyrrolidine rotation. Conclusion In conclusion, we have

Hydrolysis, polarity, and conformational impact of C-terminal partially fluorinated ethyl esters in peptide models

• Vladimir Kubyshkin and
• Nediljko Budisa

Beilstein J. Org. Chem. 2017, 13, 2442–2457, doi:10.3762/bjoc.13.241

• ]. Side chain conformation The side-chain conformations of proline are restricted by the pyrrolidine ring structure. The two main envelope conformations are exo- and endo- (alternatively designated as up-/down-, respectively), in which by the C4-ring atom is oriented toward or away from the carboxyl group

Dialkyl dicyanofumarates and dicyanomaleates as versatile building blocks for synthetic organic chemistry and mechanistic studies

• Grzegorz Mlostoń and
• Heinz Heimgartner

Beilstein J. Org. Chem. 2017, 13, 2235–2251, doi:10.3762/bjoc.13.221

• - and Z-1b, and depending on the substitution pattern of the aziridine ring, the formation of the pyrrolidine derivative 34 occurred either with complete stereoselectivity or mixtures of isomeric products were obtained. The [3 + 2]-cycloaddition of the azomethine ylide E,Z-32a, formed via conrotatory

A mechanochemical approach to access the proline–proline diketopiperazine framework

• Nicolas Pétry,
• Hafid Benakki,
• Eric Clot,
• Pascal Retailleau,
• Farhate Guenoun,
• Fatima Asserar,
• Chakib Sekkat,
• Thomas-Xavier Métro,
• Jean Martinez and
• Frédéric Lamaty

Beilstein J. Org. Chem. 2017, 13, 2169–2178, doi:10.3762/bjoc.13.217

• explained by DFT calculations. Using this method, an enantiopure disubstituted Pro–Pro diketopiperazine was synthesized in 4 steps, making 5 new bonds using a ball mill. Keywords: ball mill; DFT calculations; diketopiperazine; mechanochemistry; pyrrolidine; Introduction 2,5-Diketopiperazines (DKPs) are

• preparation of substituted Pro–Pro DKPs. For this purpose, we considered using dimethyl (2R,5S)-pyrrolidine-2,5-dicarboxylate (cis-11) as a building block in the synthesis of dipeptides and diketopiperazines. This building block was used in a very limited number of cases for the formation of DKP in

• ). Pyrrolidine cis-11 is an N-protected amino ester, which can be used in the synthesis of diketopiperazines by deprotecting either the amino group or the ester function. Hydrogenolysis of the benzyl group of cis-11 provided the nitrogen-free pyrrolidine derivative 12 in excellent yield and purity after

Pd(OAc)₂/Ph₃P-catalyzed dimerization of isoprene and synthesis of monoterpenic heterocycles

• Dominik Kellner,
• Maximilian Weger,
• Andrea Gini and
• Olga García Mancheño

Beilstein J. Org. Chem. 2017, 13, 1807–1815, doi:10.3762/bjoc.13.175

• simple screw cap vials or schlenks, leading to the desired dimer in good yields. Finally, the synthetic potential of this method for the synthesis of valuable heterocyclic terpenic derivatives was demonstrated with the preparation of several pyran, tetrahydroisobenzofurane and pyrrolidine derivatives by

Sustainable synthesis of 3-substituted phthalides via a catalytic one-pot cascade strategy from 2-formylbenzoic acid with β-keto acids in glycerol

• Lina Jia and
• Fuzhong Han

Beilstein J. Org. Chem. 2017, 13, 1425–1429, doi:10.3762/bjoc.13.139

• presence of pyrrolidine (Table 1, entry 6). Gratifyingly, the desired product was obtained in the presence of primary amines in good yields (Table 1, entries 7–9). In addition, the use of several inorganic bases delivered no catalytic activation (Table 1, entries 10 and 11). Notably, a higher reaction

Nitration of 5,11-dihydroindolo[3,2-b]carbazoles and synthetic applications of their nitro-substituted derivatives

• Roman A. Irgashev,
• Nikita A. Kazin,
• Gennady L. Rusinov and
• Valery N. Charushin

Beilstein J. Org. Chem. 2017, 13, 1396–1406, doi:10.3762/bjoc.13.136

• , such as n-butylamine or pyrrolidine. In addition, substitution of the nitro group in 17b with an alkylthio residue can be performed easily by the usage of potassium thiolates. It shows that consecutive displacement of both nitro groups in 6,12-dinitro-ICZs can be realized through combination of N- and

A concise and practical stereoselective synthesis of ipragliflozin L-proline

• Shuai Ma,
• Zhenren Liu,
• Jing Pan,
• Shunli Zhang and
• Weicheng Zhou

Beilstein J. Org. Chem. 2017, 13, 1064–1070, doi:10.3762/bjoc.13.105

• , (ipragliflozin L-proline 1, (1S)-1,5-anhydro-1-C-{3-[(1-benzothiophen-2-yl)methyl]-4-fluorophenyl}-D-glucitol (2S)-pyrrolidine-2-carboxylic acid (1:1), Figure 1), was launched into the Japanese market in January 2014 [7][8]. Due to its efficacy and safety, 1 can be used as monotherapy or in combination with

Ultrasound-promoted organocatalytic enamine–azide [3 + 2] cycloaddition reactions for the synthesis of ((arylselanyl)phenyl-1H-1,2,3-triazol-4-yl)ketones

• Gabriel P. Costa,
• Natália Seus,
• Juliano A. Roehrs,
• Raquel G. Jacob,
• Ricardo F. Schumacher,
• Thiago Barcellos,
• Rafael Luque and
• Diego Alves

Beilstein J. Org. Chem. 2017, 13, 694–702, doi:10.3762/bjoc.13.68

• , entries 9 and 10). Reactions performed with other catalysts (L-proline and pyrrolidine) gave lower yields of 3a than those using 1 mol % of Et2NH (Table 1, entry 7 vs entries 11 and 12). From Table 1, optimum reaction conditions to obtain 1-(5-methyl-1-(2-(phenylselanyl)phenyl)-1H-1,2,3-triazol-4-yl)ethan

Synthesis of new pyrrolidine-based organocatalysts and study of their use in the asymmetric Michael addition of aldehydes to nitroolefins

• Alejandro Castán,
• Ramón Badorrey,
• José A. Gálvez and
• María D. Díaz-de-Villegas

Beilstein J. Org. Chem. 2017, 13, 612–619, doi:10.3762/bjoc.13.59

• Alejandro Castan Ramon Badorrey Jose A. Galvez Maria D. Diaz-de-Villegas Instituto de Síntesis Química y Catálisis Homogénea (ISQCH), CSIC - Universidad de Zaragoza, Departamento de Química Orgánica, Pedro Cerbuna 12, E-50009 Zaragoza, Spain 10.3762/bjoc.13.59 Abstract New pyrrolidine-based

• development [1][2][3][4] and it is now considered to be the third pillar of enantioselective catalyses together with metal complex-mediated catalysis and biocatalysis. Among the different structures usually found in organocatalysis, the five-membered secondary amine structure of pyrrolidine has proven to be a

• evaluated as chiral organocatalysts in the enantioselective α-chlorination of β-ketoesters, with excellent results obtained after optimisation of the organocatalyst structure [12]. In an effort to identify new, easily accessible and tuneable organocatalysts with the privileged pyrrolidine motif from the

Effect of the ortho-hydroxy group of salicylaldehyde in the A³ coupling reaction: A metal-catalyst-free synthesis of propargylamine

• Sujit Ghosh,
• Kinkar Biswas,
• Suchandra Bhattacharya,
• Pranab Ghosh and
• Basudeb Basu

Beilstein J. Org. Chem. 2017, 13, 552–557, doi:10.3762/bjoc.13.53

• component (Figure 1). Changing the phenylacetylene to other substituted arylacetylenes like p-tolylacetylene, o-bromophenylacetylene, p-bromophenylacetylene or switching from morpholine to other amines like piperidine, 4-benzylpiperidine and pyrrolidine also react smoothly to afford the corresponding

Posttranslational isoprenylation of tryptophan in bacteria

• Masahiro Okada,
• Tomotoshi Sugita and
• Ikuro Abe

Beilstein J. Org. Chem. 2017, 13, 338–346, doi:10.3762/bjoc.13.37

• tricyclic skeleton that bears a newly formed pyrrolidine, similar to proline. The post-translational dimethylallylation of two tryptophan residues of a cyclic peptide, kawaguchipeptin A, from cyanobacteria has also been reported. Interestingly, the modified tryptophan residues of kawaguchipeptin A have the

• either a geranyl or farnesyl group at the gamma position to form tricyclic skeleton that bears a newly formed pyrrolidine, which is similar to proline (Figure 3A) [26][27][28]. The posttranslational modification of ComX pheromones with an isoprenoid plays an essential role for specific quorum sensing

• position of its indole ring. Conclusion The posttranslational isoprenylation of tryptophan involving pyrrolidine ring formation was first discovered in a B. subtilis peptide pheromone, as a crucial modification for the pheromonal function. In addition, the discovery of the ComXnatto pheromone revealed that

Iodination of carbohydrate-derived 1,2-oxazines to enantiopure 5-iodo-3,6-dihydro-2H-1,2-oxazines and subsequent palladium-catalyzed cross-coupling reactions

• Michal Medvecký,
• Igor Linder,
• Luise Schefzig,
• Hans-Ulrich Reissig and
• Reinhold Zimmer

Beilstein J. Org. Chem. 2016, 12, 2898–2905, doi:10.3762/bjoc.12.289

• proceeded well and afforded the expected 5-(1,2,3-triazolyl)-substituted 1,2-oxazine syn-26 in moderate yield (54%). Hydrogenolysis belongs to the well-established transformations of 1,2-oxazines, often successfully leading to valuable compounds including 1,4-amino alcohols or pyrrolidine derivatives. We

• alcohol derivative 27 in 51% yield as 96:4 mixture of two diastereomers (Scheme 9). Subsequent ring closure of γ-amino alcohol 27 by treatment with mesyl chloride in the presence of triethylamine [53] furnished the N-mesylated pyrrolidine derivative 28 in 65% yield with excellent diastereoselectivity (dr

• alcohols 27a,b and subsequent ring closure to pyrrolidine derivatives 28a,b. Hydrogenation of 1,2-oxazine anti-24 to products anti-29 and anti-30. Supporting Information Supporting Information File 399: General information, all experimental procedures and analytical data. Supporting Information File 400

Multicomponent synthesis of spiropyrrolidine analogues derived from vinylindole/indazole by a 1,3-dipolar cycloaddition reaction

• Manjunatha Narayanarao,
• Lokesh Koodlur,
• Vijayakumar G. Revanasiddappa,
• Subramanya Gopal and
• Susmita Kamila

Beilstein J. Org. Chem. 2016, 12, 2893–2897, doi:10.3762/bjoc.12.288

• the compounds are provided in Supporting Information File 1. The 1H NMR spectrum of compound 7a (X–R = CH, Y–R = N–CH3) proved the formation of the desired product which showed a characteristic doublet of doublets for the H1 proton at δ 3.99 ppm. The CH2 group adjacent to the pyrrolidine nitrogen

• appeared as a triplet of doublets (δ 3.42 ppm) and multiplet (δ 3.59 ppm), and the N–CH3 of the pyrrolidine ring as a singlet at δ 2.36 ppm. Further, the structures of 7a and 7f were confirmed by single crystal X-ray diffraction studies and the corresponding ORTEP representations are given in Figure 2

Synthesis of spiro[isoindole-1,5’-isoxazolidin]-3(2H)-ones as potential inhibitors of the MDM2-p53 interaction

• Salvatore V. Giofrè,
• Santa Cirmi,
• Raffaella Mancuso,
• Francesco Nicolò,
• Giuseppe Lanza,
• Laura Legnani,
• Agata Campisi,
• Maria A. Chiacchio,
• Michele Navarra,
• Bartolo Gabriele and
• Roberto Romeo

Beilstein J. Org. Chem. 2016, 12, 2793–2807, doi:10.3762/bjoc.12.278

• , 129.2, 129.0, 128.9, 128.5, 128.4, 128.2, 127.8, 127.6, 127.3, 126.8, 125.0, 124.4, 123.0, 100.0, 66.1, 65.5, 62.9, 59.7, 53.5, 44. 7, 43.4, 41.9; HRMS–ESI (m/z): [M + H]+ calcd for C29H30N3O4, 484.2236; found, 484.2271. (1RS,4'RS)-2'-Benzyl-2-butyl-4'-(pyrrolidine-1-carbonyl)spiro[isoindoline-1,5

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

• piperidine or a pyrrolidine-based precursor, with few reports of alternative approaches. The approach adopted by our research group to the synthesis of these and related bicyclic alkaloids takes advantage of enaminone chemistry [10][11][12][13][14][15][16][17][18][19]. Our interest in the enaminone manifold

• approach most commonly comprise a nitrogen atom in a pyrrolidine or piperidine ring conjugated at C-2 through an exocyclic vinyl fragment to an ester (vinylogous urethane) or another electron-withdrawing substituent (usually ketone, nitrile, nitro or sulfone). When suitable carbon chains bearing terminal

Biomimetic synthesis and HPLC–ECD analysis of the isomers of dracocephins A and B

• Viktor Ilkei,
• András Spaits,
• Anita Prechl,
• Áron Szigetvári,
• Zoltán Béni,
• Miklós Dékány,
• Csaba Szántay Jr,
• Judit Müller,
• Árpád Könczöl,
• Ádám Szappanos,
• Attila Mándi,
• Sándor Antus,
• Ana Martins,
• Attila Hunyadi,
• György Tibor Balogh,
• György Kalaus (†),
• Hedvig Bölcskei,
• László Hazai and
• Tibor Kurtán

Beilstein J. Org. Chem. 2016, 12, 2523–2534, doi:10.3762/bjoc.12.247

• conjugates of racemic naringenin ((±)-1) with pyrrolidine-2-one with C-6–C-5” and C-8–C-5” linkage, respectively. Due to the two chirality centers, four possible stereoisomers exist for each regioisomer, and accordingly, the isolated substances were verified to be 1:1 mixtures of two diastereoisomeric

• showed 2D NOESY cross peaks between multiplets of the pyrrolidine ring and H-2’, corresponding to dracocephins B. Aliquots of sample (±)-2a–d and sample (±)-3a–d were dissolved in DMSO-d6 in order to allow comparison with literature data. The 1H chemical shifts of the herein synthesized dracocephins A