Asymmetric organocatalyzed synthesis of coumarin derivatives

• Natália M. Moreira,
• Lorena S. R. Martelli and
• Arlene G. Corrêa

Beilstein J. Org. Chem. 2021, 17, 1952–1980, doi:10.3762/bjoc.17.128

• stereogenic centers. Review A plethora of highly effective small‐molecule organocatalysts have enriched the field of organic synthesis [27], including chiral proline derivatives, N‐heterocyclic carbenes, chiral thioureas and Brønsted acids as well as phase‐transfer catalysts (PTC), such as the quaternary

• starting material in the asymmetric organocatalyzed reaction, the Enders group described the use of (S)-proline as catalyst in an intramolecular aldol reaction, enabling a new strategy to obtain coumarin natural products [34]. As for example, the total synthesis of (+)-smyrindiol (17), a linear

• dihydrofuranocoumarin isolated from the roots of Smyrniopsis aucheri, was developed [35]. The 5-enolexo aldol key step of this synthesis was performed using 40 mol % of (S)-proline and the desired product 14 was obtained in good yield (71%), and high diastereo- and enantioselectivities (Scheme 4). Moreover, the natural

On the application of 3d metals for C–H activation toward bioactive compounds: The key step for the synthesis of silver bullets

• Renato L. Carvalho,
• Amanda S. de Miranda,
• Mateus P. Nunes,
• Roberto S. Gomes,
• Guilherme A. M. Jardim and
• Eufrânio N. da Silva Júnior

Beilstein J. Org. Chem. 2021, 17, 1849–1938, doi:10.3762/bjoc.17.126

• amino acids and peptide scaffolds compatible with the transformation. The late-stage oxidation of proline 76 to 5-hydroxyproline furnished interesting intermediates, giving access to relevant motifs in peptide chemistry (Scheme 27C). Sesquiterpenes are known to present complex polycyclic structures with

Cationic oligonucleotide derivatives and conjugates: A favorable approach for enhanced DNA and RNA targeting oligonucleotides

• Mathias B. Danielsen and
• Jesper Wengel

Beilstein J. Org. Chem. 2021, 17, 1828–1848, doi:10.3762/bjoc.17.125

• relative to the downregulation of the reference ASO (Oblimersen) [91]. In an entirely different approach, the 2’-amino group of amino-LNA-thymine (amino-LNA-T) has been explored as an attachment point for various cationic groups. As one example, amino acids such as glycine, lysine, and proline in different

• out for the synthesis of stereochemically pure PS-ONs and one of these methods employs the proline-derived bicyclic oxazaphospholidine monomer [122] which was later used in the scalable synthetic process of therapeutic stereopure PS-ASOs [123]. When the modified ONs were hybridized with their

Natural products in the predatory defence of the filamentous fungal pathogen Aspergillus fumigatus

• Jana M. Boysen,
• Nauman Saeed and
• Falk Hillmann

Beilstein J. Org. Chem. 2021, 17, 1814–1827, doi:10.3762/bjoc.17.124

• . They occur most often in Aspergillus and Penicillium species [160]. Fumitremorgin A (20), B (21) and C (22) can all be found in A. fumigatus (Figure 7). They are based on the precursers ʟ-tryptophan and ʟ-proline and are further derived from breviamide F, proposedly via tryprostatin B which is

Sustainable manganese catalysis for late-stage C–H functionalization of bioactive structural motifs

• Jongwoo Son

Beilstein J. Org. Chem. 2021, 17, 1733–1751, doi:10.3762/bjoc.17.122

• late-stage methylation of complex drug derivatives, such as of indoprofen (anti-inflammatory), tedizolid (antibiotic), and celecoxib (anti-inflammatory), successfully delivered methylated drug candidates 22f–h, respectively. In addition, methylation of proline-containing multipeptides was achieved via

A recent overview on the synthesis of 1,4,5-trisubstituted 1,2,3-triazoles

• Pezhman Shiri,
• Ali Mohammad Amani and
• Thomas Mayer-Gall

Beilstein J. Org. Chem. 2021, 17, 1600–1628, doi:10.3762/bjoc.17.114

• -modified MCM-41 (ClCH2-MCM-41). In the next step, ʟ-proline-modified MCM-41 (ʟ-proline-MCM-41) was produced by the treatment of ClCH2-MCM-41 with N-Boc-trans-4-hydroxy-ʟ-proline in THF in the presence of NaH as base, which was then deprotected using TFA in CH2Cl2. In the last step, the immobilized copper

• complex (ʟ-proline-MCM-41-CuCl) was obtained by the reaction of ʟ-proline-MCM-41 with CuCl in acetone at mild temperature (Scheme 21) [51]. A possible mechanism for this reaction is shown in Scheme 22. Initially, copper(I)-substituted acetylide intermediate 70 is produced via the reaction of copper

Methodologies for the synthesis of quaternary carbon centers via hydroalkylation of unactivated olefins: twenty years of advances

• Thiago S. Silva and
• Fernando Coelho

Beilstein J. Org. Chem. 2021, 17, 1565–1590, doi:10.3762/bjoc.17.112

• ). Natural products like α and β-pinene that contain an olefinic moiety were also used as substrates, and these afforded ring-opened products like 89e, thereby corroborating a radical mechanism hypothesis [111]. Enantiopure substrates, like limonene oxide (88f) and the proline derivative 88h, afforded the

A comprehensive review of flow chemistry techniques tailored to the flavours and fragrances industries

• Guido Gambacorta,
• James S. Sharley and
• Ian R. Baxendale

Beilstein J. Org. Chem. 2021, 17, 1181–1312, doi:10.3762/bjoc.17.90

• as proline. However, a major drawbacks of these process are the long reaction times and high catalyst loading that often need to be used [101][102]. In 2009, Seeberger et al. described a version of an enantioselective aldol reaction in flow using a microreactor (Scheme 6) [103]. The approach allowed

• media was optimised by Gröger et al. using a modified proline catalyst. In this example, the authors employed tubular coiled reactors and, to enhance the mixing effect, high flow rates and long tube lengths were applied (Scheme 7). As biocatalysis is becoming more and more important, one of the major

• same year, the same group developed a polystyrene resin-supported proline, which was confirmed to be highly suitable for continuous-flow setup whose efficiency and selectivity was highly stable over 30 hours of continuous runtime, allowing to isolate roughly 5 grams of pure aldol 68 (Scheme 9) [107

N-tert-Butanesulfinyl imines in the asymmetric synthesis of nitrogen-containing heterocycles

• Joseane A. Mendes,
• Paulo R. R. Costa,
• Miguel Yus,
• Francisco Foubelo and
• Camilla D. Buarque

Beilstein J. Org. Chem. 2021, 17, 1096–1140, doi:10.3762/bjoc.17.86

• described the diastereoselective synthesis of aziridines 42 in one-step using the Cu(I)/ʟ-proline complex as a catalyst and N-tert-butasulfinylamide in an aminotrifluoromethylation reaction of alkenes. All the aziridines 42 were obtained with high diastereoselectivity (dr > 25:1) and good yields (56–98

• hand, natural amino acids proline and hydroxyproline are functionalized pyrrolidines that have found great application in organic synthesis as chiral organocatalysts in stereoselective processes [93][94]. Cyclizations involving a position in the starting chiral imine Arylation of chiral sulfinyl imines

• corresponding methyl ester, to give compounds 101. Subsequent, reductive ammination with 3-phenyl-2-propynal led to reaction intermediates 102, which under typical Pauson–Khand reaction conditions gave cyclopenta[c]proline derivatives 103 in moderate yields, with high diastereoselectivities (Scheme 30

Effective microwave-assisted approach to 1,2,3-triazolobenzodiazepinones via tandem Ugi reaction/catalyst-free intramolecular azide–alkyne cycloaddition

• Maryna O. Mazur,
• Oleksii S. Zhelavskyi,
• Eugene M. Zviagin,
• Svitlana V. Shishkina,
• Vladimir I. Musatov,
• Maksim A. Kolosov,
• Elena H. Shvets,
• Anna Yu. Andryushchenko and
• Valentyn A. Chebanov

Beilstein J. Org. Chem. 2021, 17, 678–687, doi:10.3762/bjoc.17.57

• , reflux, 24 h; (b) (1) 4 Å MS, EtOH, rt, 20 h, (2) Base, rt, 30 min, (3) EtOH, reflux, 3 h; (c) (1) MeOH, 24–48 h, rt, (2) PhH, reflux, 4–18 h; (d) (1) MeOH, rt, 8 h; (2) NaN3, CuI, ʟ-proline, DMSO, 120 °C, 24 h; (e) (1) MeOH, rt, 24 h, (2) NaN3, CuI, DMSO, 100 °C, 3 h. Azide precursor synthesis

Biochemistry of fluoroprolines: the prospect of making fluorine a bioelement

• Vladimir Kubyshkin,
• Rebecca Davis and
• Nediljko Budisa

Beilstein J. Org. Chem. 2021, 17, 439–460, doi:10.3762/bjoc.17.40

• structure and distinct conformational profile, proline is unique in the repertoire of the 20 amino acids coded into proteins. Here, we summarize the biochemical work on the replacement of proline with (4R)- and (4S)-fluoroproline as well as 4,4-difluoroproline in proteins done mainly in the last two decades

• . We first recapitulate the complex position and biochemical fate of proline in the biochemistry of a cell, discuss the physicochemical properties of fluoroprolines, and overview the attempts to use these amino acids as proline replacements in studies of protein production and folding. Fluorinated

• proline replacements are able to elevate the protein expression speed and yields and improve the thermodynamic and kinetic folding profiles of individual proteins. In this context, fluoroprolines can be viewed as useful tools in the biotechnological toolbox. As a prospect, we envision that proteome-wide

Synthesis of legonmycins A and B, C(7a)-hydroxylated bacterial pyrrolizidines

• Wilfred J. M. Lewis,
• David M. Shaw and
• Jeremy Robertson

Beilstein J. Org. Chem. 2021, 17, 334–342, doi:10.3762/bjoc.17.31

• ]. Proteins coded by three of these genes (LgnA, LgnB, and LgnD) were shown to assemble legonindolizidines A (1) and B (2) – from proline, threonine, and a fatty acid component – which are then converted by LgnC, a flavin-dependent monooxygenase, into the corresponding legonmycins (3 and 4) via a sequence of

• electrophilic activation and hydrolysis of the resulting electron-rich pyrroles in an overall N-acylation/C(7a) hydroxylation. This transformation is central to a synthesis of legonmycins A and B that requires just three laboratory operations from commercially available proline derivative 15. It is noteworthy

• atmosphere, was added dropwise propionitrile (7.33 mL, 103 mmol). The mixture was stirred vigorously at −78 °C for 40 min, after which time a solution of proline derivative 15 (11.2 g, 48.8 mmol) in THF (60 mL) was added dropwise via syringe. The mixture was warmed to rt and stirred for 42 h. The mixture was

¹⁹F NMR as a tool in chemical biology

• Diana Gimenez,
• Aoife Phelan,
• Cormac D. Murphy and
• Steven L. Cobb

Beilstein J. Org. Chem. 2021, 17, 293–318, doi:10.3762/bjoc.17.28

• tyrosine [16] (pFtBTyr, 9) and proline [17] (4R and 4S-pFtBHyp, 10 and 11, Figure 1) have also been utilised as 19F NMR probes, both showing promise as valuable tools for biomolecular studies. Particularly impressive is that by incorporating pFtBTyr (9) into a model peptide, Tressler and Zondlo were able

• thermodynamic equilibrium binding constants (K) and kinetic rates of association (kon) and dissociation (koff) in protein–ligand binding events [37]. In order to achieve this, they analysed the binding of four different proline-rich peptides to a 5-FTrp-labelled Src homology 3 (SH3) recognition protein domain

Molecular basis for protein–protein interactions

• Brandon Charles Seychell and
• Tobias Beck

Beilstein J. Org. Chem. 2021, 17, 1–10, doi:10.3762/bjoc.17.1

• interactions but have a high propensity to form interprotein interactions. In contrast, serine, threonine, asparagine (polar uncharged), alanine, valine, isoleucine (hydrophobic), cysteine, proline, and glycine are less likely to form interprotein interactions and bifurcated interactions. The binding mode in

Three-component reactions of aromatic amines, 1,3-dicarbonyl compounds, and α-bromoacetaldehyde acetal to access N-(hetero)aryl-4,5-unsubstituted pyrroles

• Wenbo Huang,
• Kaimei Wang,
• Ping Liu,
• Minghao Li,
• Shaoyong Ke and
• Yanlong Gu

Beilstein J. Org. Chem. 2020, 16, 2920–2928, doi:10.3762/bjoc.16.241

• , the transformations can generally be realized through the following three approaches (Scheme 1): (i) [1 + 1 + 3] annulation, in which (hetero)arylamines are reacted with a C3 donor and a C1 donor to construct pyrrole scaffolds. Kumar et al. [26] developed a proline-catalyzed Mannich reaction

Natural dolomitic limestone-catalyzed synthesis of benzimidazoles, dihydropyrimidinones, and highly substituted pyridines under ultrasound irradiation

• Kumar Godugu,
• Venkata Divya Sri Yadala,
• Mohammad Khaja Mohinuddin Pinjari,
• Trivikram Reddy Gundala,
• Lakshmi Reddy Sanapareddy and
• Chinna Gangi Reddy Nallagondu

Beilstein J. Org. Chem. 2020, 16, 1881–1900, doi:10.3762/bjoc.16.156

• –proline, trimethylsilyl chloride (TMSCl), Amberlite® IR-120, indion 190, trifluoroethanol, YCl3, HClO4–SiO2, MMZY zeolite, Er(OTf)3, etc. [22][23][24][25][26][27][28][29][30]. Developments in already established multicomponent reactions (MCRs) are interesting topics in organic synthesis. For instance, the

• catalysts for the above reaction [48][49][50][51][52][53][54][55][56][57][58]. Only few basic catalysts, such as t-BuOK, Ph3P, and ʟ-proline are reported for the Biginelli reaction [59][60][61]. 2-Amino-4-aryl-3,5-dicarbonitrile-6-sulfanylpyridines have gained considerable attention due to their wide

Polarity effects in 4-fluoro- and 4-(trifluoromethyl)prolines

• Vladimir Kubyshkin

Beilstein J. Org. Chem. 2020, 16, 1837–1852, doi:10.3762/bjoc.16.151

• Vladimir Kubyshkin University of Manitoba, Dysart Rd. 144, Winnipeg, R3T 2N2, Canada 10.3762/bjoc.16.151 Abstract Fluorine-containing analogues of proline are valuable tools in engineering and NMR spectroscopic studies of peptides and proteins. Their use relies on the fundamental understanding of

• isomerism were examined for diastereomeric 4-fluoroprolines, 4-(trifluoromethyl)prolines, and 1,1-difluoro-5-azaspiro[2.4]heptane-6-carboxylates. The preferred conformation on the proline ring originated from a preferential axial positioning for a single fluorine atom, and an equatorial positioning for a

• C4-exo conformation of the pyrrolidine ring. Keywords: amino acids; cis–trans isomerism; fluorine; polarity; proline; Introduction Polarity is among the key features essential for understanding the behavior of organic molecules of biological origin. In particular, there is a set of polarity-related

Et₃N/DMSO-supported one-pot synthesis of highly fluorescent β-carboline-linked benzothiophenones via sulfur insertion and estimation of the photophysical properties

• Dharmender Singh,
• Vipin Kumar and
• Virender Singh

Beilstein J. Org. Chem. 2020, 16, 1740–1753, doi:10.3762/bjoc.16.146

• combination of DABCO and DMSO also afforded the desired product via a clean reaction within 20 min, although only 60% yield of the product was obtained (Table 1, entry 10). This promising result using DABCO encouraged us to explore other amines like DBU, ʟ-proline, pyridine, DMAP, and pyrrolidine as an

An overview on disulfide-catalyzed and -cocatalyzed photoreactions

• Yeersen Patehebieke

Beilstein J. Org. Chem. 2020, 16, 1418–1435, doi:10.3762/bjoc.16.118

• engage with the peptide backbone via an H-bonding interaction, and in order to achieve a high enantioselectivity, the amide functionalization of the peptide at the 4-proline position is essential. Amide-substituted vinylcyclopropanes have a relatively good H-bond-donating ability, so they are more

Disposable cartridge concept for the on-demand synthesis of turbo Grignards, Knochel–Hauser amides, and magnesium alkoxides

• Mateo Berton,
• Kevin Sheehan,
• Andrea Adamo and
• D. Tyler McQuade

Beilstein J. Org. Chem. 2020, 16, 1343–1356, doi:10.3762/bjoc.16.115

• combined with a solution-phase reagent, including: (1) copper(I) oxide to produce N-heterocyclic carbene–Cu(I) complexes for use as catalysts [13]; (2) proline to perform proline-based catalytic reactions [14]; (3) zinc powder to produce organozinc halides in tandem with Negishi couplings [15]; (4) zinc

A cyclopeptide and three oligomycin-class polyketides produced by an underexplored actinomycete of the genus Pseudosporangium

• Shun Saito,
• Kota Atsumi,
• Tao Zhou,
• Keisuke Fukaya,
• Daisuke Urabe,
• Naoya Oku,
• Md. Rokon Ul Karim,
• Hisayuki Komaki and
• Yasuhiro Igarashi

Beilstein J. Org. Chem. 2020, 16, 1100–1110, doi:10.3762/bjoc.16.97

• elucidated the presence of three amino acid residues, N-acetyltyrosine (AcTyr), proline (Pro), and tryptophane (Trp) (Figure 2). HMBC correlations from H-2' and H-3' to C-4' and from H-4' and H-5' to C-3' joined two COSY-defined fragments, H-2'/H-3' and H-4'/H-5'. Further HMBC correlations from H-2' to C-5

• 0.1 M NaHCO3 solution (100 μL) was added to the dried hydrolysate of 1, as well as to the standard of ʟ- and ᴅ-proline (Pro). A solution of ʟ-FDLA in acetone (0.05 mg in 50 μL) was added to each reaction vial. Each vial was sealed and incubated at 50 °C for 3 h. To quench reactions, 2 M HCl (50 μL

Fabclavine diversity in Xenorhabdus bacteria

• Sebastian L. Wenski,
• Harun Cimen,
• Natalie Berghaus,
• Sebastian W. Fuchs,
• Selcuk Hazir and
• Helge B. Bode

Beilstein J. Org. Chem. 2020, 16, 956–965, doi:10.3762/bjoc.16.84

• (Ala) and the sixth position (R2/R3) between proline (Pro), valine (Val) and threonine (Thr). The polyamine can differ in the length from three to five amine units (m) and is connected via one to three partially reduced polyketide C2 units (n) with the NRPS part. In this work, 22 yet unknown

Recent applications of porphyrins as photocatalysts in organic synthesis: batch and continuous flow approaches

• Rodrigo Costa e Silva,
• Luely Oliveira da Silva,
• Aloisio de Andrade Bartolomeu,
• Timothy John Brocksom and
• Kleber Thiago de Oliveira

Beilstein J. Org. Chem. 2020, 16, 917–955, doi:10.3762/bjoc.16.83

• -aryltetrahydroisoquinoline, ketones, and ʟ-proline using a low PdTPFPP loading (Scheme 62) [97]. Zhang and co-workers demonstrated that the MOF-catalyst (UNLPF-12) can also be used for the Mannich reactions. The authors reported that the coupling between N-aryltetrahydroisoquinolines and acetone using visible light and

A systematic review on silica-, carbon-, and magnetic materials-supported copper species as efficient heterogeneous nanocatalysts in “click” reactions

• Pezhman Shiri and
• Jasem Aboonajmi

Beilstein J. Org. Chem. 2020, 16, 551–586, doi:10.3762/bjoc.16.52

Why do thioureas and squaramides slow down the Ireland–Claisen rearrangement?

• Dominika Krištofíková,
• Juraj Filo,
• Mária Mečiarová and
• Radovan Šebesta

Beilstein J. Org. Chem. 2019, 15, 2948–2957, doi:10.3762/bjoc.15.290

• organocatalysts, including chiral squaramides, thioureas, alkaloids and their derivatives, taddols, binol, chiral phosphoric acid, (S)-proline and its derivatives, amide of tryptophan (Figure 1). These catalysts feature varying steric properties from sterically encumbered, such as C1, C5, C8, or C10, to less