Discovery of ianthelliformisamines D–G from the sponge Suberea ianthelliformis and the total synthesis of ianthelliformisamine D

• Sasha Hayes,
• Yaoying Lu,
• Bernd H. A. Rehm and
• Rohan A. Davis

Beilstein J. Org. Chem. 2024, 20, 3205–3214, doi:10.3762/bjoc.20.266

• from the amide proton linked the propyl-2-pyrrolidine moiety to the brominated acrylamide fragment and thus the full chemical structure of 4 was elucidated and assigned to ianthelliformisamine D. A refined literature search using Scifinder Scholar [16] revealed that compound 4 contains a novel scaffold

Hypervalent iodine-mediated intramolecular alkene halocyclisation

• Charu Bansal,
• Oliver Ruggles,
• Albert C. Rowett and
• Alastair J. J. Lennox

Beilstein J. Org. Chem. 2024, 20, 3113–3133, doi:10.3762/bjoc.20.258

• pyrrolidine intermediates A can undergo further transformations (Scheme 10), depending on their structure and the iodane reagent being used. For example, higher yields of 3-fluoropiperidine products 6 were observed when using cyclic iodane reagents 21 and 22 (Scheme 10), which was suggested to be because a

Computational design for enantioselective CO₂ capture: asymmetric frustrated Lewis pairs in epoxide transformations

• Maxime Ferrer,
• Iñigo Iribarren,
• Tim Renningholtz,
• Ibon Alkorta and
• Cristina Trujillo

Beilstein J. Org. Chem. 2024, 20, 2668–2681, doi:10.3762/bjoc.20.224

• this FLP is situated within a five-membered ring. Using this structural insight, an asymmetric catalyst was subsequently designed by strategically modifying the pyrrolidine substituent (C5 in Figure 4) based on the most efficient FLP. The coupling reaction proposed in Scheme 3 was studied. In order to

• plot analysis reveals that the best candidate is F3_NB_C5_CF3, which is the catalyst based on the 2-borylbenzenamine scaffold, with a pyrrolidine substituent on the nitrogen atom and CF3 substituents on the boron. Through strategic modification of the Lewis base substituents, a stereoselective catalyst

A review of recent advances in electrochemical and photoelectrochemical late-stage functionalization classified by anodic oxidation, cathodic reduction, and paired electrolysis

• Nian Li,
• Ruzal Sitdikov,
• Ajit Prabhakar Kale,
• Joost Steverlynck,
• Bo Li and
• Magnus Rueping

Beilstein J. Org. Chem. 2024, 20, 2500–2566, doi:10.3762/bjoc.20.214

• . Additionally, pyrrolidine, anazepane, and morpholine scaffolds successfully underwent the reaction. Another notable feature of this method is its high diastereoselectivity. All products were ultimately obtained as p-toluenesulfonic acid salts (Scheme 27). In 2021, Zhang et al. developed an electrochemical

Hypervalent iodine-mediated cyclization of bishomoallylamides to prolinols

• Smaher E. Butt,
• Konrad Kepski,
• Jean-Marc Sotiropoulos and
• Wesley J. Moran

Beilstein J. Org. Chem. 2024, 20, 2455–2460, doi:10.3762/bjoc.20.209

• the alkene and the amide increased from two to three atoms. In the latter case, cyclization at the amide nitrogen to form the pyrrolidine ring was favored over cyclization at the amide oxygen. A DFT study was undertaken to rationalize the change in mechanism of this cyclization process. In addition

• , reaction conditions were developed, and the scope of this cyclization studied. Keywords: cyclization; DFT; hypervalent iodine; mechanism; proline; Introduction Proline is one of the 20 DNA-encoded proteinogenic amino acids that are essential to life [1][2]. In addition, the pyrrolidine core is present in

• , the iodane moiety in 12 is eliminated by an intramolecular attack by the amide nitrogen to form the aziridinium 13. Finally, ring-opening by SN2 attack of trifluoroacetate leads to the final product 14 [20]. In this case, the kinetic pyrrolidine product is obtained due to the electron-withdrawing

Asymmetric organocatalytic synthesis of chiral homoallylic amines

• Nikolay S. Kondratyev and
• Andrei V. Malkov

Beilstein J. Org. Chem. 2024, 20, 2349–2377, doi:10.3762/bjoc.20.201

• –Sakurai reaction of allyltrimethylsilane with N-Fmoc aldimines. The pyrrolidine unit gem-methyl group conformational control in the squaramide-based catalyst [34]. The energetic difference between the transition states of the two proposed modes of the reaction (SN1 and SN2 mechanisms). The concerted SN2

Electrochemical radical cation aza-Wacker cyclizations

• Sota Adachi and
• Yohei Okada

Beilstein J. Org. Chem. 2024, 20, 1900–1905, doi:10.3762/bjoc.20.165

• ), with platinum (Pt) as a cathode. To our delight, a constant-current condition at 1 mA was productive, and the desired five-membered pyrrolidine 2 was obtained in high yield (Table 1, entry 2). During the screening of conditions, the addition of acetonitrile (CH3CN) was found to be effective, probably

• was in good accordance with the observation reported by Yoon (Table 1, entry 4). The use of acetic acid (AcOH) instead of TFA gave a slightly lower yield of the five-membered pyrrolidine 2 (Table 1, entry 5). Although a constant-potential condition at 1.8 V was also productive, the constant-current

• cyclization (Table 1, entry 7) and the six-membered piperidine 3, instead of the five-membered pyrrolidine 2, was obtained in excellent yield without electricity (Table 1, entry 8). Thus, it is proposed that the electrochemical aza-Wacker cyclization under acidic conditions proceeded via radical cations to

Harnessing unprotected deactivated amines and arylglyoxals in the Ugi reaction for the synthesis of fused complex nitrogen heterocycles

• Javier Gómez-Ayuso,
• Pablo Pertejo,
• Tomás Hermosilla,
• Israel Carreira-Barral,
• Roberto Quesada and
• María García-Valverde

Beilstein J. Org. Chem. 2024, 20, 1758–1766, doi:10.3762/bjoc.20.154

• benzodiazepine with different bases (caesium carbonate, sodium hydroxide). However, the complete cyclisation to the pyrrolobenzodiazepinone was not achieved, so the described three-step strategy starting from 2-nitrobenzoic acid (Ugi reaction/cyclization to pyrrolidine/reduction sequence) remains as a better

Syntheses and medicinal chemistry of spiro heterocyclic steroids

• Laura L. Romero-Hernández,
• Ana Isabel Ahuja-Casarín,
• Penélope Merino-Montiel,
• Sara Montiel-Smith,
• José Luis Vega-Báez and
• Jesús Sandoval-Ramírez

Beilstein J. Org. Chem. 2024, 20, 1713–1745, doi:10.3762/bjoc.20.152

• . The oxetane compound 6 was further derivatized to incorporate a pyrrolidine moiety in presence of ammonia. Upon debenzylation at C-3, the target compound 7 was obtained in an 18% overall yield from 3. The pyrrolidino-oxetane derivative exhibited potent inhibition of Hedgehog signaling, comparable to

• /mL. Since the cytotoxicity of the parent 16-arylidene steroids was LC50 > 100 µg/mL, it was concluded that the presence of the pyrrolidine moiety was essential for the activity [28]. Additional derivatives have been reported on different steroidal positions [29] or with variations in the methodology

Regio- and stereochemical stability induced by anomeric and gauche effects in difluorinated pyrrolidines

• Ana Flávia Candida Silva,
• Francisco A. Martins and
• Matheus P. Freitas

Beilstein J. Org. Chem. 2024, 20, 1572–1579, doi:10.3762/bjoc.20.140

• of the pyrrolidine ring in proline motifs has been found to induce significant conformational changes that impact the structure and biological roles of modified peptides and proteins. Vicinal difluorination of fluoroproline, for example, in (3S,4R)-3,4-difluoroproline, serves to mitigate the inherent

• conformational bias of the pyrrolidine ring by inducing stereoelectronic effects that attenuate this conformational bias. In this investigation, we present a quantumchemical analysis of the conformational equilibrium and effects that are induced in difluorinated pyrrolidines, with a particular focus on exploring

• Lewis interactions from a natural bond orbital perspective. Keywords: anomeric effect; fluoropyrrolidine; gauche effect; stereochemistry; Introduction The pyrrolidine ring structure is prevalent in numerous natural alkaloids and is an important feature of the proline and hydroxyproline residues that

Rapid construction of tricyclic tetrahydrocyclopenta[4,5]pyrrolo[2,3-b]pyridine via isocyanide-based multicomponent reaction

• Xiu-Yu Chen,
• Ying Han,
• Jing Sun and
• Chao-Guo Yan

Beilstein J. Org. Chem. 2024, 20, 1436–1443, doi:10.3762/bjoc.20.126

• dihydropyridine ring connects with the pyrrolidine ring in cis-position. The 4-aryl group exists on the trans-position to the 2,3-pyrrolidine ring. The methoxycarbonyl group in the ring of the cyclopentadiene stretches to the cis-position of the 4-aryl group in the dihydropyridine ring. Thus, it can be assigned

• can be performed with a wide variety of substrates. The molecular structure of the compound 6g was determined by single crystal X-ray diffraction method (Figure 2). The o-methoxyphenyl group exists on the trans-position of the fused pyrrolidine unit. The methoxycarbonyl group also exists on the cis

Enantioselective synthesis of β-aryl-γ-lactam derivatives via Heck–Matsuda desymmetrization of N-protected 2,5-dihydro-1H-pyrroles

• Arnaldo G. de Oliveira Jr.,
• Martí F. Wang,
• Rafaela C. Carmona,
• Danilo M. Lustosa,
• Sergei A. Gorbatov and
• Carlos R. D. Correia

Beilstein J. Org. Chem. 2024, 20, 940–949, doi:10.3762/bjoc.20.84

• ). The total yields were determined to be 49% for (R)-baclofen hydrochloride (6) and 61% (R)-rolipram (5b) from starting pyrrolidine 1d. Determination of the absolute stereochemistry of the Heck adducts/lactams and rationalization of the enantioselectivity The absolute stereochemistry of the products was

• palladium(II)–N,N-ligand complex (II), to which the pyrrolidine substrate coordinates (III). Next, migratory insertion takes place generating the alkylpalladium species (IV), which upon a sequence of β-elimination (V) and hydride insertion leads to alkylpalladium intermediate (VI). Finally, upon

Synthesis and characterization of water-soluble C₆₀–peptide conjugates

• Yue Ma,
• Lorenzo Persi and
• Yoko Yamakoshi

Beilstein J. Org. Chem. 2024, 20, 777–786, doi:10.3762/bjoc.20.71

• , and HMBC spectra (Figures S3–S9, Supporting Information File 1), all peaks corresponding to the pyrrolidine part, linker part, and oligo-Lys part were assigned as shown in the chemical structure. In the sp2 region of 5a (Figure 6a, top), 17 signals (1C × 3 + 2C × 13) were observed similarly to the

Evaluation of the enantioselectivity of new chiral ligands based on imidazolidin-4-one derivatives

• Jan Bartáček,
• Karel Chlumský,
• Jan Mrkvička,
• Lucie Paloušová,
• Miloš Sedlák and
• Pavel Drabina

Beilstein J. Org. Chem. 2024, 20, 684–691, doi:10.3762/bjoc.20.62

• -position of the imidazolidine ring on the enantioselectivity of the reaction. Hence, we developed a ligand incorporating an unsubstituted pyrrolidine ring instead of the imidazolidine unit (Figure 1 – ligand IV). This structure characterises a 'proline-type' derivative, enabling its use not only in a

• IV structure arose from the ligand IIIb structure – the imidazolidin-4-one ring present at ligand IIIb was formally replaced by a pyrrolidine one. Here, we presume the comparable coordinating ability of both species of heterocycles. However, the pyrrolidine cycle of ligand IV does not contain alkyl

• significantly less enantioselective (37–55% ee) than the complex of ligand IIIb. Thus, the alkyl substitution at position 5 of the imidazolidin-4-one or pyrrolidine ring of ligands I–IV can be considered as a fundamental part of the ligand’s structure, which enables them to possess high enantioselectivity. All

Regioselective quinazoline C2 modifications through the azide–tetrazole tautomeric equilibrium

• Dāgs Dāvis Līpiņš,
• Andris Jeminejs,
• Una Ušacka,
• Anatoly Mishnev,
• Māris Turks and
• Irina Novosjolova

Beilstein J. Org. Chem. 2024, 20, 675–683, doi:10.3762/bjoc.20.61

• further optimized since the products were only needed for analytical purposes. Two different pyrrolidine-substituted derivatives were additionally synthesized to prove the regioselectivity of the sulfonyl group dance products (Scheme 8). Compound 16 was obtained in the C4-selective SNAr reaction between

• diazidoquinazoline 13 and pyrrolidine in 93% yield. A cross peak for the H–C5 position of quinazoline and CH2 groups of pyrrolidine at the second position was observed in the NOESY spectrum and unequivocally proved the structure 16. Selective C2 substitution was achieved between sulfonylquinazoline 12 and

• pyrrolidine in CHCl3 yielding product 17a. No NOESY signals were seen between the quinazoline core and the pyrrolidine moiety. Interestingly, the C4 substitution was achieved when DMF was used as a solvent in the transformation 12 → 18, resulting in product 18. In addition, the reaction 12a + pyrrolidine in

Palladium-catalyzed three-component radical-polar crossover carboamination of 1,3-dienes or allenes with diazo esters and amines

• Geng-Xin Liu,
• Xiao-Ting Jie,
• Ge-Jun Niu,
• Li-Sheng Yang,
• Xing-Lin Li,
• Jian Luo and
• Wen-Hao Hu

Beilstein J. Org. Chem. 2024, 20, 661–671, doi:10.3762/bjoc.20.59

• reactive under the photocatalytic conditions, providing the corresponding 1,2-adducts 6a, 6b, and 6c smoothly in 73%, 93% and 34% yields, respectively. Commercially available amines with a broad range of heterocyclic rings (e.g., morpholine, piperazine, pyrrolidine, homopiperazine) also readily

Entry to new spiroheterocycles via tandem Rh(II)-catalyzed O–H insertion/base-promoted cyclization involving diazoarylidene succinimides

• Alexander Yanovich,
• Anastasia Vepreva,
• Ksenia Malkova,
• Grigory Kantin and
• Dmitry Dar’in

Beilstein J. Org. Chem. 2024, 20, 561–569, doi:10.3762/bjoc.20.48

• synthesis of spiro-annulated pyrrolidine-2,5-diones by catalyzed spirocyclizations involving aldehydes [11], tetrahydrofuran [12][13], and in the O–H insertion/Claisen rearrangement/intramolecular oxa-Michael addition cascade [14] (Scheme 1). Herein, we report our findings obtained, while investigating the

• properties are exhibited by compounds based on a THF and THP core spiro-conjugated with the pyrrolidine ring. These frameworks are present in a number of synthetic biologically active compounds (such as NaV1.7 blocker XEN907 for the treatment of pain [31], σ1 receptor ligand 6 [32], histamine-3 receptor

• alcohol followed by base-promoted cyclization. The procedures developed allow to obtain derivatives of such sought-after scaffolds in the field of medicinal chemistry as Δα,β-butenolides, tetrahydrofurans, and pyrans spiro-conjugated with a pyrrolidine ring. The tandem approach proposed is characterized

Substitution reactions in the acenaphthene analog of quino[7,8-h]quinoline and an unusual synthesis of the corresponding acenaphthylenes by tele-elimination

• Ekaterina V. Kolupaeva,
• Narek A. Dzhangiryan,
• Alexander F. Pozharskii,
• Oleg P. Demidov and
• Valery A. Ozeryanskii

Beilstein J. Org. Chem. 2024, 20, 243–253, doi:10.3762/bjoc.20.24

• dibromide 15 closer in chemical properties to the parent compound 5, which also cannot be converted into the corresponding acenaphthylene by direct dehydrogenation (see above). On the other hand, heating dibromide 15 with an excess of pyrrolidine for the purpose of nucleophilic substitution of the bromo

• basic than the naphthalene "proton sponge". A convenient and high yielding method was proposed to brominate dipyridoacenaphthene at positions 5 and 8 using a H2SO4/NBS system. The resulting dibromide turned out to be inert to dehydrogenation with chloranil, however, when heated with neutral (pyrrolidine

• assumed admixture 11. Mononitration of compound 5. Dehydrogenation of compounds 10 and 11. Nucleophilic methoxylation of compounds 10(12). Electrophilic bromination of compound 5. tele-Elimination upon interaction of dibromide 15 with pyrrolidine. Interaction of dibromide 15 with anionic bases. Comparison

Photochromic derivatives of indigo: historical overview of development, challenges and applications

• Gökhan Kaplan,
• Zeynel Seferoğlu and
• Daria V. Berdnikova

Beilstein J. Org. Chem. 2024, 20, 228–242, doi:10.3762/bjoc.20.23

• and C=O bonds of the indoxyl groups are somewhat longer than typical double bonds of these types (Figure 3). On the contrary, the C–N bonds in indigo are much shorter than the single C–N bond in pyrrolidine, while the lengths of the C–C bonds in the fused benzene rings are approximately the same as in

Perspectives on push–pull chromophores derived from click-type [2 + 2] cycloaddition–retroelectrocyclization reactions of electron-rich alkynes and electron-deficient alkenes

• Michio Yamada

Beilstein J. Org. Chem. 2024, 20, 125–154, doi:10.3762/bjoc.20.13

• pyrrolidine at 0 °C, the pentafulvene derivative 36 was obtained with 63% yield via an additional ring-opening process. Similar skeletal transformation reactions were observed for azulene derivatives bearing similar substructures. The reaction of 1 with TCNE in an aqueous medium containing a surfactant

• ) [142]. In these conjugates, the push–pull chromophores and the C60 unit were effectively spatially isolated from each other – a feat achieved through the strategic incorporation of a pyrrolidine ring as the connecting bridge. Thorough examinations via steady-state fluorescence spectroscopy in toluene

Decarboxylative 1,3-dipolar cycloaddition of amino acids for the synthesis of heterocyclic compounds

• Xiaofeng Zhang,
• Xiaoming Ma and
• Wei Zhang

Beilstein J. Org. Chem. 2023, 19, 1677–1693, doi:10.3762/bjoc.19.123

• -stabilized azomethine ylide; Introduction The 1,3-dipolar cycloaddition of azomethine ylides (AMYs) [1][2][3][4][5][6] is a powerful method for the synthesis of bioactive pyrrolidine-containing compounds and natural product analogs [7][8][9][10][11][12][13][14][15]. AMYs generated from the reaction of

Synthesis of 5-arylidenerhodanines in L-proline-based deep eutectic solvent

• Stéphanie Hesse

Beilstein J. Org. Chem. 2023, 19, 1537–1544, doi:10.3762/bjoc.19.110

• compounds and allow, for example, the formation of rhodanine-fused spiro[pyrrolidine-2,3′-oxindoles] D having antidiabetic activity [6]. Thiazolidinediones and thiazolidinones were found to be potent moieties of a series of furan-2-ylmethylenethiazolidinediones E that were studied as selective ATP

Complexes of resorcin[4]arene with secondary amines: synthesis, solvent influence on “in-out” structure, and theoretical calculations of non-covalent interactions

• Waldemar Iwanek

Beilstein J. Org. Chem. 2023, 19, 1525–1536, doi:10.3762/bjoc.19.109

• -polar solvents. When using N,N-dimethylamine, N,N-diethylamine, pyrrolidine, piperidine, morpholine and N-methylpiperazine as sec-amine component, the 1H NMR spectra reveal the formation of complexes with a 1:1 stoichiometry. However, for aliphatic amines with longer hydrocarbon chains, like

• stoichiometry complexes recorded in DMSO-d6 and CDCl3 solution are very different. On the other hand, complexes with a 1:2 stoichiometry are insoluble in CDCl3, hence their further analysis is limited to the solution in DMSO. Figure 1 shows the 1H NMR spectra of the 1:1 complex of R[4]A with pyrrolidine in DMSO

• -d6 and CDCl3, respectively. In DMSO, the resonances of the triplet and multiplet protons of the pyrrolidine molecule are located at 2.77 ppm and 1.62 ppm, respectively. On the other hand, in CDCl3, the protons of the pyrrolidine molecule are located at the following ppm: 3.59 (t), 3.51(t), 1.96 (m

N-Sulfenylsuccinimide/phthalimide: an alternative sulfenylating reagent in organic transformations

• Fatemeh Doraghi,
• Seyedeh Pegah Aledavoud,
• Mehdi Ghanbarlou,
• Bagher Larijani and
• Mohammad Mahdavi

Beilstein J. Org. Chem. 2023, 19, 1471–1502, doi:10.3762/bjoc.19.106

• )pyrrolidine-2,5-diones 1 using FeCl3 or BF3·OEt2 as a catalyst (Scheme 5) [46]. A wide variety of thiolated phenols 8 were produced under mild reaction conditions without using any base, ligand, or additive. For both substrates, 7 and 1 aryl rings containing electron-donating groups exhibited a higher

• ) by using an organocatalyst was reported by Wang and co-workers (Scheme 35) [67]. Several orgnocatalysts, such as piperidine, and pyrrolidine derivatives were evaluated for the coupling reaction, in which pyrrolidine trifluoromethanesulfonamide A was selected as the best catalyst for this purpose. It

• presence of TMSOTf. Catalyst-free sulfenylation by N-(sulfenyl)succinimides/phthalimides In 2015, oxysulfenylation of styrene derivatives 9 utilizing 1-(arylthio)pyrrolidine-2,5-diones 1 and alkyl/benzyl alcohols 86 toward β-alkoxy sulfides was developed by Fu et al. (Scheme 65) [95]. In this metal-free

Non-noble metal-catalyzed cross-dehydrogenation coupling (CDC) involving ether α-C(sp³)–H to construct C–C bonds

• Hui Yu and
• Feng Xu

Beilstein J. Org. Chem. 2023, 19, 1259–1288, doi:10.3762/bjoc.19.94

• . Due to the challenges associated with the activation of C(sp3)–H bonds, this kind of activation strategy has received extensive attention. Huang et al. developed a Cu-catalyzed CDC of unactivated C(sp3)–H ethers with simple ketones under the synergistic effect of CuBr2 and pyrrolidine. By this route

• extract a hydrogen from the ether C (sp3)–H bond to form radicals. Subsequently, a single electron transfer (SET) leads to the oxonium species. Then, the enamine generated in situ from methyl aryl ketone and pyrrolidine undergoes a nucleophilic reaction with the oxonium species followed by hydrolysis to