Beyond symmetric self-assembly and effective molarity: unlocking functional enzyme mimics with robust organic cages

• Keith G. Andrews

Beilstein J. Org. Chem. 2025, 21, 421–443, doi:10.3762/bjoc.21.30

• active site (binding a substrate in an orientation that directs internally catalyzed reactivity) [347][348]. The examples of cavities with functionality discussed above, from Cram’s “full serine protease model” [87], to MOCs with flexible peripheral groups [349], to frameworks with internal proline

Three-component reactions of conjugated dienes, CH acids and formaldehyde under diffusion mixing conditions

• Dmitry E. Shybanov,
• Maxim E. Kukushkin,
• Eugene V. Babaev,
• Nikolai V. Zyk and
• Elena K. Beloglazkina

Beilstein J. Org. Chem. 2025, 21, 262–269, doi:10.3762/bjoc.21.18

• characteristic triplets at 5.76 and 2.77 ppm (J = 7.0 Hz). Compound 3 was also formed in almost quantitative yield in acetonitrile within one day in the presence of ʟ-proline (Table 1, entry 10), which is an effective catalyst for crotonic condensation [22]. Since the reaction of diketone 1 in the presence and

• absence of ʟ-proline was carried out under otherwise identical conditions in the same apparatus (Table 1, entries 9 and 10), the significant difference in the conversion of compound 1 could not be explained only by the evaporation and absorption processes of CH2O. Apparently, the reaction rate also played

• an important role; the presence of the condensation catalyst ʟ-proline accelerated the absorption of formaldehyde vapors by the reaction mixture. Carrying out the same reaction in the absence of a catalyst in CDCl3 and subsequent 1H NMR spectroscopy analysis showed that the mixture contained 42% of

Giese-type alkylation of dehydroalanine derivatives via silane-mediated alkyl bromide activation

• Perry van der Heide,
• Michele Retini,
• Fabiola Fanini,
• Giovanni Piersanti,
• Francesco Secci,
• Daniele Mazzarella,
• Timothy Noël and
• Alberto Luridiana

Beilstein J. Org. Chem. 2024, 20, 3274–3280, doi:10.3762/bjoc.20.271

• -protected Michael acceptor, derived from proline, allowed for preparation of compound 27 with a 35% yield in 4 hours without control of diastereoselectivity (dr = 1:1). Finally, to prove that the optimized reaction also works at a larger scale, the model reaction was carried out on a 2.2 mmol scale (Figure

The scent gland composition of the Mangshan pit viper, Protobothrops mangshanensis

• Jonas Holste,
• Paul Weldon,
• Donald Boyer and
• Stefan Schulz

Beilstein J. Org. Chem. 2024, 20, 2644–2654, doi:10.3762/bjoc.20.222

• , proline-containing diketopiperazines were identified for the first time in snake scent glands, although an artificial formation from amino acids likely present in the secretion cannot be excluded. Keywords: carboxylic acids; identification; mass spectrometry; pheromones; snakes; Introduction Located in

• diketopiperazines (DKPs) in the SGS, all containing proline. Fragments m/z 70 [C4H8N]+ and m/z 154 [C7H10O2N2]+, which are characteristic of diketopiperazines of proline, showed intense peaks. The mass spectrum of cyclo(valyl-proline) is shown in Figure 5. In summary, six DKPs were identified by their

• characteristic mass spectra [33], cyclo(valyl-proline), cyclo(leucyl-proline), cyclo(isoleucyl-proline), cyclo(prolyl-proline), cyclo(phenylalanyl-proline), and cyclo(methionyl-proline) (Table 1). Most of the DKPs occurred as a mixture of diastereomers with two peaks in the chromatogram. Although naturally

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

• , 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

• important area of study as this ring system is prevalent in many useful molecules. Typical literature procedures include multistep derivations of proline itself, e.g., the destruction of the stereocenter and then its reinstallation by an enantioselective conjugate addition [9]. Other methods include the

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

• commercially available derivative of ʟ-proline, (S)-(−)-α,α-bis(3,5-dimethylphenyl)-2-pyrrolidinemethanol (62) (Scheme 12). This catalyst is capable of asymmetric activation of N-(2-hydroxyphenyl)imines through the reversible chelation to the N-(2-hydroxyphenyl) group, forming a rigid intermediate, while the

Factors influencing the performance of organocatalysts immobilised on solid supports: A review

• Zsuzsanna Fehér,
• Dóra Richter,
• Gyula Dargó and
• József Kupai

Beilstein J. Org. Chem. 2024, 20, 2129–2142, doi:10.3762/bjoc.20.183

• , giving easily recyclable asymmetric catalysts. The asymmetric sites can be different types, commonly they are binaphthyl-, biphenyl- [91][92][93] and proline-based [94][95]. COFs are a type of crystalline porous material, consisting of covalently linked organic ligands [96][97]. Since the framework only

Allostreptopyrroles A–E, β-alkylpyrrole derivatives from an actinomycete Allostreptomyces sp. RD068384

• Marwa Elsbaey,
• Naoya Oku,
• Mohamed S. A. Abdel-Mottaleb and
• Yasuhiro Igarashi

Beilstein J. Org. Chem. 2024, 20, 1981–1987, doi:10.3762/bjoc.20.174

• S55 in Supporting Information File 1). Biosynthetically, pyrrole-2-carboxylic acid is known to be derived from ʟ-proline [2]. Similarly, pyrrole-2-carbaldehydes have been isolated from various natural sources including plants, marine invertebrates, and fungi [7], while 1–5 are the first to have formyl

Methyltransferases from RiPP pathways: shaping the landscape of natural product chemistry

• Maria-Paula Schröder,
• Isabel P.-M. Pfeiffer and
• Silja Mordhorst

Beilstein J. Org. Chem. 2024, 20, 1652–1670, doi:10.3762/bjoc.20.147

• , and proline is methylated by BmbJ/BotRMT3 (Figure 4) [81]. Three derivatives of bottromycin were obtained through fermentation of the natural producer. The proline residue methylation pattern varies, with bottromycin A2 being monomethylated, bottromycin B2 being unmethylated, and bottromycin C2 being

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

• 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

• conformational stability of proline-rich proteins such as collagen [2]. Therefore, pyrrolidine derivatives are particularly susceptible to conformational control induced by a fluorine substituent. The 5-membered pyrrolidine ring is a cyclic alkylamine that adopts a conformation that resembles the familiar

Three-component N-alkenylation of azoles with alkynes and iodine(III) electrophile: synthesis of multisubstituted N-vinylazoles

• Jun Kikuchi,
• Roi Nakajima and
• Naohiko Yoshikai

Beilstein J. Org. Chem. 2024, 20, 891–897, doi:10.3762/bjoc.20.79

• between 4ba and 4-methoxybenzenethiol furnished the N,S-substituted olefin 7 in 59% yield. The treatment of 4aa with stoichiometric CuI and ʟ-proline effected the iodine(III)-to-iodine(I) conversion to give the vinyl iodide 8 in 76% yield. Compound 8 was used for the Ullmann coupling with imidazole

• , DMF/H2O, 60 °C, 18 h. (b) Pd(OAc)2, PPh3, CuI, phenylacetylene, Et3N, 50 °C, 5 h. (c) CuI, neocuproine, 4-MeOC6H4SH, NaOt-Bu, toluene, 110 °C, 13 h. (d) CuI, ʟ-proline, DMF, 80 °C, 14 h. (e) CuI, imidazole, Cs2CO3, DMF, 120 °C, 15 h. (f) 3-Methoxy-2-(trimethylsilyl)phenyl triflate, CsF, MeCN, rt, 18 h

New variochelins from soil-isolated Variovorax sp. H002

• Jabal Rahmat Haedar,
• Aya Yoshimura and
• Toshiyuki Wakimoto

Beilstein J. Org. Chem. 2024, 20, 692–700, doi:10.3762/bjoc.20.63

• showed a molecular weight of m/z 535.7912 for the [M − 2H]2− ion, inferring a chemical formula of C47H83O17N11 (calcd 535.7911 for the double-negative ion). A combination of 1H NMR and COSY analyses revealed a peptidic structure comprising two Nδ-acetyl-Nδ-hydroxyornithine residues, a proline (Pro), a

• , Ser: serine, Pro: proline, Orn: ornithine). (b) Validation of var biosynthetic gene cluster. The plasmid constructed for the generation of the varG null-mutant strain (varG::cmR) using the cmR gene cassette (left), and HPLC-profile comparison of the Variovorax sp. H002 wild type strain and the varG

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

• depends on the relative configuration of the ligand used; cis-configuration of ligand affords the nitroaldols with major enantiomer S- (up to 97% ee), whereas the application of ligands with trans-configuration led to nitroaldols with major R-enantiomer (up to 96% ee). The “proline-type” ligand IV was

• -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

• catalytic features of the proline derivate IV in detail. Although various proline derivatives have been described for the use in asymmetric aldol reactions [25], the optimal reaction conditions for achieving maximal enantioselectivity and conversions vary and must be tailored to the specific catalyst used

Green and sustainable approaches for the Friedel–Crafts reaction between aldehydes and indoles

• Periklis X. Kolagkis,
• Eirini M. Galathri and
• Christoforos G. Kokotos

Beilstein J. Org. Chem. 2024, 20, 379–426, doi:10.3762/bjoc.20.36

• -proline-modified magnetic nanoparticles (LPMNPs) that combine organocatalytic protocols with nanocatalysis, which enhances the surface-to-volume ratio of the catalyst opening up new possibilities [107]. The ʟ-proline molecules were anchored on a Fe3O4@SiO2 nanoparticle, which was already known for its

• also evaluated, where it was observed that even after 8 cycles without any treatment the morphology of the nanotubes remained the same, without leaching of considerable amounts of ʟ-proline into the reaction mixture. The mechanism of action involves the activation of the aldehyde by the grafted ʟ

• -proline on the surface of the magnetic nanoparticle via iminium formation as seen in Scheme 18, allowing the indole to attack the formed double bond and initiate the Michael-type mechanism [107]. In an effort to replace the widespread use of nano-iron oxides, which present issues, such as aggregation, and

Mechanisms for radical reactions initiating from N-hydroxyphthalimide esters

• Carlos R. Azpilcueta-Nicolas and
• Jean-Philip Lumb

Beilstein J. Org. Chem. 2024, 20, 346–378, doi:10.3762/bjoc.20.35

• of N-Boc-proline-derived TCNHPI ester 104 with q-OAc in MeCN resulted in the formation of a yellow solution, which upon blue light irradiation provided the aminodecarboxylation product 105 in 69% yield. It was hypothesized that the reaction involved the formation of EDA complex 106 that led to the

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

• group on the α-carbon atom are semi-stabilized (Scheme 1) [16]. The B1-type AMYs can be generated from the decarboxylative condensation of aldehydes with α- and N-dialkylglycines or from cyclic amino acids (such as proline) [31][32][33], while AMYs of type B2 are accessible through the decarboxylative

• stereoselectivity which limits the synthetic utility of non-stabilized AMYs of type C. There are over 300 papers on the amino acid-based decarboxylative [3 + 2] cycloadditions of N–R-type AMYs B1 (such as that derived from proline) and B2 [31][32][33][34][35][36][37][38][39][40][41][42][43][44][45][46][47][48][49

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

• scaffolds is the introduction of a benzylidene moiety on C5 via a Knoevenagel reaction. Here, a facile synthesis of 5-arylidenerhodanines via a Knoevenagel reaction in an ʟ-proline-based deep eutectic solvent (DES) is reported. This method is fast (1 h at 60 °C), easy, catalyst-free and sustainable as no

• compounds are the more active ones. Keywords: antioxidant; deep eutectic solvent; Knoevenagel; ʟ-proline DES; rhodanine; Introduction Rhodanines and related five-membered heterocycles with multiple heteroatoms (i.e., thiazolidinediones, thiazolidinones, hydantoins, thiohydantoins) are very interesting

• melting point of 17 °C which is more acidic and less viscous than ChCl/urea [18][19] (Table 1). In addition, proline-based natural deep eutectic solvents (NaDES) were also studied and it was shown that they presented higher viscosity values than the ChCl-based NaDES, suggesting that the HBA used for the

Functions of enzyme domains in 2-methylisoborneol biosynthesis and enzymatic synthesis of non-natural analogs

• Binbin Gu,
• Lin-Fu Liang and
• Jeroen S. Dickschat

Beilstein J. Org. Chem. 2023, 19, 1452–1459, doi:10.3762/bjoc.19.104

• studied. Several 2-methylisoborneol synthases have a proline-rich N-terminal domain of unknown function. The results presented here demonstrate that this domain leads to a reduced enzyme activity, in addition to its ability to increase long-term solubility of the protein. Furthermore, the substrate scope

• versions of 2MIBSs exhibit a proline-rich N-terminal domain of unknown function that appears disordered in the crystal structure [28]. As a first aspect of this study, we have investigated the possible function of this N-terminal domain. 2MIBS is known to form several methylated monoterpenes as side

• changed alkylation pattern. Results and Discussion Function of the proline-rich N-terminal domain of 2MIBS S. coelicolor 2MIBS was selected to investigate the function of the proline-rich N-terminal domain (hereafter termed A domain, the C-terminal domain is named as domain B). Based on a sequence

One-pot nucleophilic substitution–double click reactions of biazides leading to functionalized bis(1,2,3-triazole) derivatives

• Hans-Ulrich Reissig and
• Fei Yu

Beilstein J. Org. Chem. 2023, 19, 1399–1407, doi:10.3762/bjoc.19.101

• presence of sodium ascorbate as reducing agent and sodium carbonate as base as well as ʟ-proline as ligand in a DMF/water mixture at 60 °C provided this promising result. These conditions applied are similar to those described by Fokin et al. [24], which had also been employed by other groups [37][38]. The

• allowed to lower the reaction temperature from 60 °C to 40 °C, but it also induced full consumption of the intermediate biazide derived from dihalide 11 (Scheme 4, reaction 3); 0.2 equiv of copper(II) sulfate pentahydrate, 0.4 equiv of sodium ascorbate and 0.4 equiv of ʟ-proline in very little of

A new oxidatively stable ligand for the chiral functionalization of amino acids in Ni(II)–Schiff base complexes

• Alena V. Dmitrieva,
• Oleg A. Levitskiy,
• Yuri K. Grishin and
• Tatiana V. Magdesieva

Beilstein J. Org. Chem. 2023, 19, 566–574, doi:10.3762/bjoc.19.41

• give rise to additional dispersion interactions with the phenyl ring in the proline auxiliary, making the Schiff base complexes more conformationally rigid, thus increasing the stereochemical outcome of the functionalized amino acids as compared to the parent ligand L1. In the present paper, the new

• . Results and Discussion Synthesis The synthetic approach to the chiral ligand L7 as well as to its Ni–Schiff base derivatives containing glycine, serine, dehydroalanine, and cysteine is given in Scheme 2. Commercially available (S)-proline was used as the starting material. To obtain the starting t-Bu

• benzyl fragment was observed. This indicated that H-2 is located on the same side of the nickel coordination plane as the benzyl substituent at the proline nitrogen atom, leading to the ʟ-configuration of the α-amino acid stereocenter. Notably, the major stereoisomer of all thiolated compounds (RCysNi)L7

NaI/PPh₃-catalyzed visible-light-mediated decarboxylative radical cascade cyclization of N-arylacrylamides for the efficient synthesis of quaternary oxindoles

• Dan Liu,
• Yue Zhao and
• Frederic W. Patureau

Beilstein J. Org. Chem. 2023, 19, 57–65, doi:10.3762/bjoc.19.5

• reported a Ru(bpy)3Cl2-catalyzed synthesis of N-Boc proline oxindole derivatives under visible-light assistance [47]. Therein, N-hydroxyphthalimide (NPhth) esters were utilized as alkyl radical precursors, which can be readily prepared from highly available carboxylic acids. In 2015, Cheng and co-workers

Reductive opening of a cyclopropane ring in the Ni(II) coordination environment: a route to functionalized dehydroalanine and cysteine derivatives

• Oleg A. Levitskiy,
• Olga I. Aglamazova,
• Yuri K. Grishin and
• Tatiana V. Magdesieva

Beilstein J. Org. Chem. 2022, 18, 1166–1176, doi:10.3762/bjoc.18.121

• Figure 2). The protons of the ester group linked to the cyclopropane moiety exhibit correlation with the methylene protons of proline in the NOESY spectrum. Thus, the ester groups are at the same side of the Ni coordination plane as the proline methylene groups indicating the (S) configuration of the α

• tolyl substituent in the side chain of the amino acid moiety and H-12 and H-13 protons of the proline methylene group is observed in the NOESY spectrum (Figure 4). Hence, the amino acid side chain and the proline methylenes are at the same side of the Ni coordination plane allowing to assign the

Heterogeneous metallaphotoredox catalysis in a continuous-flow packed-bed reactor

• Wei-Hsin Hsu,
• Susanne Reischauer,
• Peter H. Seeberger,
• Bartholomäus Pieber and
• Dario Cambié

Beilstein J. Org. Chem. 2022, 18, 1123–1130, doi:10.3762/bjoc.18.115

• a narrower residence time distribution and higher yields (see Table 2). C–O coupling reaction Finally, we evaluated the use of the capillary-based reactor for the related C–O coupling of 4-iodobenzotrifluoride and N-(Boc)-proline with N-tert-butylisopropylamine (BIPA) in dimethyl sulfoxide (DMSO

• )-proline. Optimization of temperature and light intensity for the coupling of 4-iodobenzotrifluoride and sodium p-toluenesulfinate. Comparison of different reactors. Supporting Information Supporting Information File 104: Details of packed-bed assembly, experimental procedures, reaction optimization and

Synthesis of bis-spirocyclic derivatives of 3-azabicyclo[3.1.0]hexane via cyclopropene cycloadditions to the stable azomethine ylide derived from Ruhemann's purple

• Alexander S. Filatov,
• Olesya V. Khoroshilova,
• Anna G. Larina,
• Vitali M. Boitsov and
• Alexander V. Stepakov

Beilstein J. Org. Chem. 2022, 18, 769–780, doi:10.3762/bjoc.18.77

• and cannot be isolated as individual compounds. At the same time, the reaction of ninhydrin and proline results in the formation of the stable azomethine ylide. This 1,3-dipole demonstrated high reactivity towards diverse cyclopropenes, including parent cyclopropene [22]. Note that the reactions of

Inductive heating and flow chemistry – a perfect synergy of emerging enabling technologies

• Conrad Kuhwald,
• Sibel Türkhan and
• Andreas Kirschning

Beilstein J. Org. Chem. 2022, 18, 688–706, doi:10.3762/bjoc.18.70

• materials to inductively heat up glass reactors. For the Biginelli reaction solubility of the starting urea (22) as well as the products 24a and 24b were an issue being overcome by using a solvent mixture of PEG/DMF 1:1. Also the proline-catalyzed asymmetric Mannich reaction was achieved with cyclohexanone