Approaches to Pyranuronic β‐Sugar Amino Acid Building Blocks of Peptidosaccharide Foldamers

Gőz, Viktória Goldschmidt; Pintér, István; Harmat, V.; Perczel, András

doi:10.1002/ejoc.201701612

Cited by 8 publications

(8 citation statements)

References 32 publications

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“…b-Sugar amino acids were synthetized in our laboratory based on our previous works. 24,25 NMR measurements 1 H NMR experiments were performed at 298-300 K on Bruker Avance DRX 250 MHz spectrometer equipped with 5 mm SB dual probe with z-gradient, operating at 250.13 MHz for 1 H and/ or on a Bruker Avance III 700 spectrometer operating at 700.05 MHz using a Prodigy TCI H&F-C/N-D, z-gradient probe head. Spectra were recorded in DMF-d 7 using the solvent residual peaks as the 1 H internal reference: 2.75, 2.93 and 8.03 ppm.…”

Section: Reagents and Instrumentationsmentioning

confidence: 99%

“…Furthermore, an inert atmosphere is sometimes used during residue coupling, thus these traces of water molecules deeply perturbing the reaction, as besides the peptide bond formation of interest, the hydrolysis of the water sensitive active esters proceeds as a side reaction. Recently, we have tested some commonly used coupling reagents for selected Fmoc-protected b-sugar amino acids, Fmoc-b-SAA-OH, 24,25 indeed hard to activate and couple. 26 Considering the time needed for the active ester to be formed without hydrolysis for SAA derivatives the PyBOP/DIEA system turned out to be the best choice with respect to coupling efficacy, in parallel to minimize or totally avoid racemization.…”

Section: Introductionmentioning

confidence: 99%

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Unwanted hydrolysis or α/β-peptide bond formation: how long should the rate-limiting coupling step take?

Gőz¹,

Nagy

Farkas³

et al. 2019

RSC Adv.

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Nowadays, in Solid Phase Peptide Synthesis (SPPS), being either manual, automated, continuous flow or microwave-assisted, the reaction with various coupling reagents takes place via in situ active ester formation. In this study, the formation and stability of these key active esters were investigated with time-resolved 1 H NMR by using the common PyBOP/DIEA and HOBt/DIC coupling reagents for both aand b-amino acids. Parallel to the amide bond formation, the hydrolysis of the a/b-active esters, a side reaction that is a considerable efficacy limiting factor, was studied. Based on the chemical nature/ constitution of the active esters, three amino acid categories were determined: (i) the rapidly hydrolyzing ones (t < 6 h) with smaller (Ala) or even longer side chains (Arg) holding a large protecting group; (ii) branched amino acids (Ile, Thr) with slowly hydrolyzing (6 < t < 24 h) propensities, and (iii) nonhydrolyzing ones, such as the hard-to-couple b-amino acids or b-sugar amino acid derivatives, stable for longer times (t > 24 h) in solution. The current insight into the kinetics of this key hydrolysis side reaction serves as a guide to optimize the coupling conditions of aand b-amino acids, thereby saving time and minimizing the amounts of reagents and amino acids to be usedall key factors of more environmentally friendly chemistry. a 10 min: typical time of active ester formation; 1 and 3 hours: typical reaction time used for coupling. b Active ester was decomposed. c Active ester is formed >99% conversion aer 3 hours. 30724 | RSC Adv., 2019, 9, 30720-30728 This journal is a Hydrolysis already started before the rst measured point since [AC] 0,calc > [AC] 0,meas . b [H 2 O] 0 was xed at 0.25 mM during parameter estimation. c The value not signicant, condence intervals are to large. d [H 2 O] used as initial water concentration. e With [AC] 0 ¼ 0.1 and [H 2 O] ¼ 0.25 mM. f Not applicable; the estimated water concentration was inferior to that of half of the active ester concentration.This journal is Fig. 3 Classification of the proteinogenic aand selected b-amino acids based on their molecular topology. Fast hydrolyzing ones are highlighted green, slow hydrolyzing ones with blue and no-hydrolyzing ones with red.30726 | RSC Adv., 2019,9,[30720][30721][30722][30723][30724][30725][30726][30727][30728] This journal is

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Section: Reagents and Instrumentationsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Unwanted hydrolysis or α/β-peptide bond formation: how long should the rate-limiting coupling step take?

Gőz¹,

Nagy

Farkas³

et al. 2019

RSC Adv.

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“…This can be amended by introducing sugar amino acids (SAAs) (Risseeuw et al 2009 , 2013 ) which are more hydrophilic by nature. It has been shown particularly, both for five- and six-membered cyclic SAAs (H-SAA-OHs) to behave as appropriate building blocks (Nagy et al 2017 ; Csordás et al 2016 ; Goldschmidt Gőz et al 2018 ; Suhara et al 2006 ; Chandrasekhar et al 2004 ; Gruner et al 2002a , b ; Pandey et al 2011 ). Furanoid β-SAAs, e.g., 3-amino-3-deoxy- d -furanuronic acids (AFUs), primarily, d - xylo ( 1 , 2 ) and d - ribo ( 3 , 4 ) epimeric pairs (Nagy et al 2017 ) are hydrophilic analogs of cis - and trans -ACPC (Fig.…”

Section: Introductionmentioning

confidence: 99%

Synthesis of chimera oligopeptide including furanoid β-sugar amino acid derivatives with free OHs: mild but successful removal of the 1,2-O-isopropylidene from the building block

2021

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Complementary to hydrophobic five membered ring β-amino acids (e.g. ACPC), β-sugar amino acids (β-SAAs) have found increasing application as hydrophilic building blocks of foldamers and α/β chimeric peptides. Fmoc-protected β-SAAs [e.g. Fmoc-RibAFU(ip)-OH] are indeed useful Lego elements, ready to use for SPPS. The removal of 1,2-OH isopropylidene protecting group increasing the hydrophilicity of such SAA is presented here. We first used N3-RibAFU(ip)-OH model compound to optimize mild deprotection conditions. The formation of the 1,2-OH free product N3-RibAFU-OH and its methyl glycoside methyl ester, N3-RibAFU(Me)-OMe were monitored by RP-HPLC and found that either 50% TFA or 8 eqv. Amberlite IR-120 H+ resin in MeOH are optimal reagents for the effective deprotection. These conditions were then successfully applied for the synthesis of chimeric oligopeptide: -GG-X-GG- [X=RibAFU(ip)]. We found the established conditions to be effective and—at the same time—sufficiently mild to remove 1,2-O-isopropylidene protection and thus, it is proposed to be used in the synthesis of oligo- and polypeptides of complex sequence combination.

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“…A commonly used sugar amino acid type is β‐Sugar Amino Acid, βSAA, in which the carboxyl and amino functions are in β‐position with respect to each other [1,4–6,18–20] . Among them, both five‐membered ring derivatives, like d ‐ribo‐ [4] and d ‐xylofuranuronic acids [5,19,21] ‐RibAFU(ip)‐ and ‐XylAFU(ip)‐ and six‐membered ring derivatives, e. g ., D‐glucosamine carboxylic acid are widely used as monomeric building blocks [3,6,18,22] .…”

Section: Introductionmentioning

confidence: 99%

“…Here we present the comprehensive analysis of manual and flow‐based SPPS of small but biologically relevant oligopeptides and their chimera analogues containing either the furanoid [19] ( 1 ) or pyranoid [20] ( 2 ) βSAAs. These building blocks have tunable hydrophilicity as 1,2‐ O ‐isopropylidene and 2,3‐di‐ O ‐benzyl protecting groups are now selectively removable.…”

Section: Introductionmentioning

confidence: 99%

Application of Sugar Amino Acids: Flow Chemistry Used for α/β‐Chimera Synthesis

et al. 2021

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Two ring size β-Sugar Amino Acids, βSAAs, Fmoc-RibAFU(ip)-OH and Fmoc-GlcAPU(Me,Bn)-OH, as Lego-elements are introduced to make α/β-chimera peptides by flow-based solid phase peptide synthesis (SPPS). Their synthesis alongside selected αamino acids, αAA, is fine-tuned. The recently published 50 % TFA cleavage protocol of tBu protected shorter (Ser, Asp) and larger aromatic (Tyr, Trp), with bulky side chain protected Arg (Pbf) and Gln(Trt) residues was probed. We found that this milder condition is sufficient to successfully remove both the 1,2-O-isopropylidene from RibAFU(ip) and tBu, Pbf and Trt from the other αAA residues, but to preserve the 2,3-di-O-benzyl protection of GlcAPU(Me,Bn). Note that O-benzyl groups can be subsequently cleaved by HF or catalytic hydrogenation. Tuned protocols allow the efficient synthesis of 16-mer penetratin analogues via continuous flow conditions incorporating either RibAFU(ip) or GlcAPU(Me,Bn) βSAAs. Both acid concentration (50 %/95 %) and type (TFA/HF) allow a versatile protecting group removal and thus, to fine-tune the hydrophilicity and aromaticity of the above building blocks in chimera constructs.

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Approaches to Pyranuronic β‐Sugar Amino Acid Building Blocks of Peptidosaccharide Foldamers

Cited by 8 publications

References 32 publications

Unwanted hydrolysis or α/β-peptide bond formation: how long should the rate-limiting coupling step take?

Unwanted hydrolysis or α/β-peptide bond formation: how long should the rate-limiting coupling step take?

Synthesis of chimera oligopeptide including furanoid β-sugar amino acid derivatives with free OHs: mild but successful removal of the 1,2-O-isopropylidene from the building block

Application of Sugar Amino Acids: Flow Chemistry Used for α/β‐Chimera Synthesis

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