Origami with small molecules: exploiting the C–F bond as a conformational tool

• Patrick Ryan,
• Ramsha Iftikhar and
• Luke Hunter

Beilstein J. Org. Chem. 2025, 21, 680–716, doi:10.3762/bjoc.21.54

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

• 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

• -fluoroalkylamines and the respective cations [6]. Intramolecular hydrogen bonds involving either the carboxy or hydroxy group of 4R- and 4S-hydroxyproline have been identified as key factors in stabilizing the favored conformations in the gas phase. Therein, the contribution of a gauche effect due to electron

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

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

• 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

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

• fluoroprolines from the medium can occur without additional manipulations. For some analogues, an osmotic shock triggers the uptake and accumulation of proline substitutes into the cells. Gruskin and co-workers successfully demonstrated the incorporation of hydroxyproline into recombinant proteins in proline

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

Synthesis of nonracemic hydroxyglutamic acids

• Dorota G. Piotrowska,
• Iwona E. Głowacka,
• Andrzej E. Wróblewski and
• Liwia Lubowiecka

Beilstein J. Org. Chem. 2019, 15, 236–255, doi:10.3762/bjoc.15.22

• pyroglutamic acids, proline and 4-hydroxyproline). Since various hydroxyglutamic acids were identified as components of complex natural products, syntheses of orthogonally protected derivatives of hydroxyglutamic acids are also covered. Keywords: amino acids; asymmetric synthesis; chiral catalysis; chiral

• [(2S,4S)-3] was found in several plants, e.g., Phlox decussata [29] and other Phlox species [30], as well as in Linaria vulgaris [31]. It has also been discovered in mammalian cells as an intermediate in the degradation of hydroxyproline [32][33]. Its various amides have been identified in numerous

• dipeptide containing O-protected (2S,4R)-4-hydroxyglutamic acid 3 (Scheme 19). The cycloadduct 75 can be transformed in a similar manner into non-proteinogenic D-amino acids. From 4-hydroxyproline 4-Hydroxyproline could be used as a starting material in the chemical synthesis of 4-hydroxyglutamic acids when

Recent applications of chiral calixarenes in asymmetric catalysis

• Mustafa Durmaz,
• Erkan Halay and
• Selahattin Bozkurt

Beilstein J. Org. Chem. 2018, 14, 1389–1412, doi:10.3762/bjoc.14.117

• . reported the synthesis of a series of prolinamide and hydroxyprolinamide organocatalysts based on the calix[4]arene scaffold (Figure 8) [59]. Treatment of Boc-protected-L-proline or hydroxyproline with various aminocalix[4]arenes under one of the appropriate coupling conditions and subsequent deprotection

Nanoreactors for green catalysis

• M. Teresa De Martino,
• Loai K. E. A. Abdelmohsen,
• Floris P. J. T. Rutjes and
• Jan C. M. van Hest

Beilstein J. Org. Chem. 2018, 14, 716–733, doi:10.3762/bjoc.14.61

• cyclohexanone and p-nitrobenzaldehyde was chosen to verify the performance of this nanoreactor. PQS-proline and the analogous mixed diester derivative of 4-hydroxyproline were prepared and tested in this process. The aldol product was achievable only by using the proline compound 4b, therefore different

Intramolecular glycosylation

• Xiao G. Jia and
• Alexei V. Demchenko

Beilstein J. Org. Chem. 2017, 13, 2028–2048, doi:10.3762/bjoc.13.201

• a solid supported peptide sequence that was connected to the 6-hydroxy groups of the sugar units using carbonate linkages (Scheme 10) [79]. The hydroxyproline (Hyp, (2S,4R)-4-hydroxypyrrolidine-2-carboxylic acid) linked glycosyl donor and acceptor system failed to provide the product of the

Enduracididine, a rare amino acid component of peptide antibiotics: Natural products and synthesis

• Darcy J. Atkinson,
• Briar J. Naysmith,
• Daniel P. Furkert and
• Margaret A. Brimble

Beilstein J. Org. Chem. 2016, 12, 2325–2342, doi:10.3762/bjoc.12.226

• -enduracididine by Yuan et al.: In 2015, Yuan et al. reported their synthesis of protected L-allo-enduracididine 63 from L-4-hydroxyproline 64 (Scheme 12) [66]. The C-4 stereocentre was installed through inversion of the hydroxy group of proline derivative 64 via mesylation and azide displacement to afford 65

Natural products from microbes associated with insects

• Christine Beemelmanns,
• Huijuan Guo,
• Maja Rischer and
• Michael Poulsen

Beilstein J. Org. Chem. 2016, 12, 314–327, doi:10.3762/bjoc.12.34

• cultures of M. anisopliae, a commercial biocontrol product called Green Muscle [129]. Serinocyclin A contains several non-proteinogenic amino acids. Among them are the uncommon 1-aminocyclopropane-1-carboxylic acid, (2R,4S)-4-hydroxylysine, and the more frequently encountered hydroxyproline, β-alanine, and

Chemoselective O-acylation of hydroxyamino acids and amino alcohols under acidic reaction conditions: History, scope and applications

• Tor E. Kristensen

Beilstein J. Org. Chem. 2015, 11, 446–468, doi:10.3762/bjoc.11.51

• derivatives of many amino acids often become annoyingly strenuous due to the necessity of employing protecting groups, on one or more of the amino acid functionalities, during the synthetic sequence. However, in the case of hydroxyamino acids such as hydroxyproline, serine, threonine, tyrosine and 3,4

• more elaborate procedures for chemoselective O-acylation reactions, spur its further development, and finally to chronicle the informative, but poorly documented history of its development. Keywords: amino alcohols; chemoselectivity; DOPA; hydroxyamino acids; hydroxyproline; O-acylation

• method in biochemical circles, as a result of investigations into protein chemistry in organic solvents (also evidenced in the venue for publication), may have obscured its visibility somewhat to the community of organic chemists. The absence of hydroxyproline is also noticeable. Instructively, Previero

A simple copper-catalyzed two-step one-pot synthesis of indolo[1,2-a]quinazoline

• Chunpu Li,
• Lei Zhang,
• Shuangjie Shu and
• Hong Liu

Beilstein J. Org. Chem. 2014, 10, 2441–2447, doi:10.3762/bjoc.10.254

• detected with 1,4-dioxane and DMF led to low yield (18%) (Table 1, entries 10–12). Among the ligands screened, L-proline was more beneficial to the catalysis than L-hydroxyproline and picolinic acid (Table 1, entries 6, 13 and 14). When the reaction temperature was changed to 70 °C only traces of product

Chiral phosphines in nucleophilic organocatalysis

• Yumei Xiao,
• Zhanhu Sun,
• Hongchao Guo and
• Ohyun Kwon

Beilstein J. Org. Chem. 2014, 10, 2089–2121, doi:10.3762/bjoc.10.218

• -catalyzed asymmetric [3 + 2] annulation. In the key transformation, using 10 mol % of the P-chiral [2.2.1]bicyclic phosphine A3 derived from trans-L-4-hydroxyproline, asymmetric [3 + 2] annulation of 4-ethyl-2,3-butadienoate with an N-tosylaldimine (prepared in 90% yield through condensation of p

A new charge-tagged proline-based organocatalyst for mechanistic studies using electrospray mass spectrometry

• J. Alexander Willms,
• Rita Beel,
• Martin L. Schmidt,
• Christian Mundt and
• Marianne Engeser

Beilstein J. Org. Chem. 2014, 10, 2027–2037, doi:10.3762/bjoc.10.211

• now [43][53]. They consist of an imidazolium salt attached to hydroxyproline via an ester group at the end of a flexible alkyl spacer. Interestingly, such charge tags can cause an enhancement of the catalytic performance through electrosteric activation [53], but backfolding can also alter and disturb

• -tagged catalyst 1 starting from doubly-protected hydroxyproline 6 [57] is depicted in Scheme 3. To introduce a suitable leaving group for the following step of the synthesis, compound 6 was mesylated to give the derivative 7 [58] for which crystals suitable for X-ray analysis have been obtained (Figure 2

Isocyanide-based multicomponent reactions towards cyclic constrained peptidomimetics

• Gijs Koopmanschap,
• Eelco Ruijter and
• Romano V.A. Orru

Beilstein J. Org. Chem. 2014, 10, 544–598, doi:10.3762/bjoc.10.50

• hydroxylated pyrrolidines was published by the group of Chapman (Scheme 15) [58]. Hydroxyproline derivatives have been reported as proline peptidase inhibitors [47]. The authors performed a Joullié–Ugi reaction with either the erythritol or the threitol imine 47a,b and afforded both isomers 48a and 49b

Stereoselectively fluorinated N-heterocycles: a brief survey

• Xiang-Guo Hu and
• Luke Hunter

Beilstein J. Org. Chem. 2013, 9, 2696–2708, doi:10.3762/bjoc.9.306

• -exo ring pucker of 12 was demonstrated in spectacular fashion: Raines and co-workers showed that the thermal stability of collagen was increased when 12 was incorporated in place of collagen’s naturally-present (4R)-hydroxyproline residues [25]. This hyperconjugation effect has also been exploited in

C–C Bond formation catalyzed by natural gelatin and collagen proteins

• Dennis Kühbeck,
• Basab Bijayi Dhar,
• Eva-Maria Schön,
• Carlos Cativiela,
• Vicente Gotor-Fernández and
• David Díaz Díaz

Beilstein J. Org. Chem. 2013, 9, 1111–1118, doi:10.3762/bjoc.9.123

• composition of gelatin in terms of its amino acids content has been reported in several publications (arginine, glutamic acid, alanine, glycine, proline and hydroxyproline are the most abundant amino acids (ca. 10–25%)) [1], which makes the protein itself suitable for catalytic studies. The Henry (nitroaldol

• case, the most common motifs in the amino acid sequence, which could be also associated with catalytic sites, are glycine-proline-X and glycine-X-hydroxyproline, where X is any other amino acid (see Supporting Information File 1). However, despite gelatin and collagen forming triple helices as a chiral

Mechanochemistry assisted asymmetric organocatalysis: A sustainable approach

• Pankaj Chauhan and
• Swapandeep Singh Chimni

Beilstein J. Org. Chem. 2012, 8, 2132–2141, doi:10.3762/bjoc.8.240

• ball-milling conditions. O-Lauroyl-trans-4-hydroxyproline (VII) was identified as the best catalyst in aqueous media, whilst α,α-diphenylprolinol trimethylsilyl ether (VIII) turned out to be the best catalyst under ball-milling conditions. Michael reaction of aliphatic aldehydes 6 with nitroalkenes 7

Organocatalytic C–H activation reactions

• Subhas Chandra Pan

Beilstein J. Org. Chem. 2012, 8, 1374–1384, doi:10.3762/bjoc.8.159

• disclosed examples of Brønsted acid catalysed decarboxylative redox-amination reactions. 2-Carboxyindoline and trans-4-hydroxyproline were used as the substrates, respectively [22][23]. Benzoic acid as catalyst and 1,4-dioxane as solvent was identified by the Pan group as the best system for the reaction

Tertiary alcohol preferred: Hydroxylation of trans-3-methyl-L-proline with proline hydroxylases

• Christian Klein and
• Wolfgang Hüttel

Beilstein J. Org. Chem. 2011, 7, 1643–1647, doi:10.3762/bjoc.7.193

• demonstrates a remarkable potential of non-heme iron(II) oxygenases to oxidize substrates selectively at sterically hindered positions. Keywords: asymmetric catalysis; enzyme catalysis; hydroxyproline; α-ketoglutarate dependent iron(II) oxygenases; regioselectivity; stereoselectivity; Findings

• -proline hydroxylases (cis-P4H) from Sinorhizobium meliloti and Mesorhizobium loti [28]. Since hydroxyprolines are important chiral building blocks for chemical synthesis [29][30], a procedure for the large-scale production of cis-3- and trans-4-hydroxyproline was established in which a recombinant E. coli

• -hydroxyproline, respectively (Scheme 2). For reference, L-proline was converted in parallel with an identical amount of the enzyme preparation. The samples were then analyzed by HPLC by using a fluorescence assay [34]. Since the fluorescence activity of the Fmoc-derivatized proline and derivatives that we have

Continuous-flow enantioselective α-aminoxylation of aldehydes catalyzed by a polystyrene-immobilized hydroxyproline

• Xacobe C. Cambeiro,
• Rafael Martín-Rapún,
• Pedro O. Miranda,
• Sonia Sayalero,
• Esther Alza,
• Patricia Llanes and
• Miquel A. Pericàs

Beilstein J. Org. Chem. 2011, 7, 1486–1493, doi:10.3762/bjoc.7.172

• prominent position is occupied by catalysts covalently immobilized onto insoluble, cross-linked polymers [37][38][39][40]. An interesting development arising from this strategy is the polystyrene-immobilized 4-hydroxyproline 1a (Figure 1), reported by our group as an extremely efficient and reusable

• Merrifield resin, and propargyloxyproline derivative 2, which was readily obtained in two steps from commercially available (2S,4R)-N-Boc-4-hydroxyproline (Scheme 2). Based on previous experience, we considered that variations in the degree of cross-linking of the support resins could have an important

• polystyrene-immobilized 4-hydroxyproline, for the direct enantioselective α-aminoxylation of simple aldehydes. The system allowed for the first time the medium-scale preparation of a series of α-oxy-substituted aldehydes through a simple flow process involving short residence times. A lack of stability of the

The C–F bond as a conformational tool in organic and biological chemistry

• Luke Hunter

Beilstein J. Org. Chem. 2010, 6, No. 38, doi:10.3762/bjoc.6.38

• is often proline (39) and Yaa is often 4(R)-hydroxyproline (63). The triple helix is partly held together by backbone hydrogen bonds and for many years it was thought that the hydroxyl groups of the 4(R)-hydroxyproline residues (63) contributed to the stability of collagen by providing extra hydrogen

• bonding. However, this theory was thrown into doubt when a collagen mimic was synthesised in which the 4(R)-hydroxyproline residues (63) were replaced with 4(R)-fluoroproline (41) [44]. Despite being unable to participate in interstrand hydrogen bonding, the 4(R)-fluoroproline residues were found to

• crystal molecules. Arrows indicate the orientation of the molecular dipole moments, which are quantified in the negative dielectric anisotropy values, Δε. Di-, tri- and tetra-fluoro liquid crystal molecules 60–62. Collagen mimics of general formula (Pro-Yaa-Gly)10 where Yaa is either 4(R)-hydroxyproline