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

A review of asymmetric synthetic organic electrochemistry and electrocatalysis: concepts, applications, recent developments and future directions

• Munmun Ghosh,
• Valmik S. Shinde and
• Magnus Rueping

Beilstein J. Org. Chem. 2019, 15, 2710–2746, doi:10.3762/bjoc.15.264

• oxidation 201 were prepared from the corresponding cinnamic acids via condensation with ʟ-proline tert-butyl ester followed by ester hydrolysis. Upon oxidative dimerization under Ronlan’s electrochemical conditions, substrates 201 were converted to bislactones 202 with good enantioselectivity. The authors

Current understanding and biotechnological application of the bacterial diterpene synthase CotB2

• Ronja Driller,
• Daniel Garbe,
• Norbert Mehlmer,
• Monika Fuchs,
• Keren Raz,
• Dan Thomas Major,
• Thomas Brück and
• Bernhard Loll

Beilstein J. Org. Chem. 2019, 15, 2355–2368, doi:10.3762/bjoc.15.228

• class I TPSs. Interestingly, in CotB2, α-helix D is rather short as a proline residue, adjacent to the third aspartate of the aspartate-rich motif, introduces a kink. In the closed conformation D110 is directly involved in the coordination of Mg2+A and Mg2+C, whereas D111 forms a salt bridge with R294

Recent advances in transition-metal-catalyzed incorporation of fluorine-containing groups

• Xiaowei Li,
• Xiaolin Shi,
• Xiangqian Li and
• Dayong Shi

Beilstein J. Org. Chem. 2019, 15, 2213–2270, doi:10.3762/bjoc.15.218

• amide (Scheme 19). With this method, both mono- and difluorinated benzoic acid derivatives can be selectively obtained in high yields. In 2014, Pu and co-workers [58] devised the regioselective Pd(PPh3)4-catalyzed electrophilic ortho-fluorination of 2-arylbenzothiazoles with NFSI and ʟ-proline as the

Recent advances on the transition-metal-catalyzed synthesis of imidazopyridines: an updated coverage

• Gagandeep Kour Reen,
• Ashok Kumar and
• Pratibha Sharma

Beilstein J. Org. Chem. 2019, 15, 1612–1704, doi:10.3762/bjoc.15.165

Synthesis and conformational preferences of short analogues of antifreeze glycopeptides (AFGP)

• Małgorzata Urbańczyk,
• Michał Jewgiński,
• Joanna Krzciuk-Gula,
• Jerzy Góra,
• Rafał Latajka and
• Norbert Sewald

Beilstein J. Org. Chem. 2019, 15, 1581–1591, doi:10.3762/bjoc.15.162

• [18]. The synthesis of the retro-inverso analogue had been envisaged to prove that changing the amino acid configuration from ʟ to ᴅ and reversing of the peptide sequence should place the side chains in a similar manner as for the parent compound. Interestingly, replacing alanine by proline in AFGP

• analogues, which occasionally occurs in smaller natural AFGP (and furthermore proline is a precursor of the PP II helix) significantly decreased the inhibitory effect on the ice recrystallization of the compounds [19]. Here we present the synthesis of a series of model peptides comprising structural motifs

Genomics-inspired discovery of massiliachelin, an agrochelin epimer from Massilia sp. NR 4-1

• Jan Diettrich,
• Hirokazu Kage and
• Markus Nett

Beilstein J. Org. Chem. 2019, 15, 1298–1303, doi:10.3762/bjoc.15.128

• ) domain in the MicG homolog from Massilia sp. NR 4-1 revealed an aspartic acid residue at position 95 and a proline residue at position 144, which are both indicative for the formation of B-type alcohol stereochemistry [29]. The two motifs are also conserved in MicG and HMWP1 from micacocidin and

Ugi reaction-derived prolyl peptide catalysts grafted on the renewable polymer polyfurfuryl alcohol for applications in heterogeneous enamine catalysis

• Alexander F. de la Torre,
• Gabriel S. Scatena,
• Oscar Valdés,
• Daniel G. Rivera and
• Márcio W. Paixão

Beilstein J. Org. Chem. 2019, 15, 1210–1216, doi:10.3762/bjoc.15.118

• incorporate proline [15] and the furan functionality into pseudo-peptide catalysts. As shown in Scheme 2, Boc-L-proline and acetone were employed as acid and oxo components, respectively, in combination either with furfurylamine and cyclohexyl isocyanide or with (S)-α-methylbenzylamine and furfuryl isocyanide

• -peptide 1. Furfurylamine (177 µL, 2 mmol), acetone (116 mg, 2 mmol), Boc-L-Pro-OH (431 mg, 2 mmol) and cyclohexyl isocyanide (249 µL, 2 mmol) were reacted in MeOH (5 mL) according to the general procedure A. Flash column chromatography purification (EtOAc/hexane 1:1, v/v) afforded the Boc-proline-based

• ) were reacted in MeOH (5 mL) according to the general procedure A. Flash column chromatography purification (EtOAc/hexane 1:1, v/v) afforded the proline-based peptide 2 as colorless oil. Yield: 78%; Rf 0.30 (EtOAc/hexane 1:1, v/v); [α]D23 −6.26 (c 0.0047 g·cm−3, MeOH); 1H NMR (400 MHz, CDCl3) δ 1.40 (s