Racemization studies of Fmoc-Ser(tBu)-OH during stepwise continuous-flow solid-phase peptide synthesis

Fenza, Armida Di; Tancredi, Mariella; Galoppini, C.; Rovero, Paolo

doi:10.1016/s0040-4039(98)01891-7

Cited by 40 publications

(39 citation statements)

References 13 publications

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“…30 The tripeptide models H-Gly-Ser-Phe-NH 2 7 and H-Gly-Cys-Phe-NH 2 8 were manually assembled by stepwise solid-phase synthesis using 5 min preactivation and Ser(tBu) and Cys(Trt) as protecting group for 7 and 8, respectively. 22,31,32 Again, THF and ACN achieved greater suppression of racemization than DMF in both cases. In order to demonstrate the efficiency of THF and ACN in 15 peptide synthesis, Aib-enkephaline pentapeptide 9 was used as a model for solid-phase peptide synthesis.…”

Section: Resultsmentioning

confidence: 92%

“…An aliquot (10 µL) of the solution was then picked up and diluted to 1 mL with a mixture of CH 3 CN/H 2 O (1:2), and 5µL was injected into a reverse-phase HPLC apparatus. Study of serine racemization during assembly of H-Gly-Ser-Phe-NH 2 on solid phase 29,31 Experiments consisted of the study of the stepwise coupling of 55 Ser and Gly residues onto previously formed H-Phe-RinkAmide-AM-ChemMatrix-resin (0.52 mmolg -1 , 100 mg), with the use of the Fmoc/tBu and Ser( t Bu) protection strategy. Glycine was introduced in order to achieve better separation of LL and DL isomers than des-Gly dipeptides.…”

Section: General Methods For the Racemization Experiments 33 36mentioning

confidence: 99%

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Peptide synthesis beyond DMF: THF and ACN as excellent and friendlier alternatives

et al. 2015

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To date, DMF has been considered as the only solvent suitable for peptide synthesis. Here we demonstrate the capacity of THF and ACN, which are friendlier solvents than DMF, to yield the product in higher purity than DMF. Using various peptide models, both THF and ACN reduced racemization in solution-phase and solid-phase synthesis when compared with DMF. Moreover, the use of ACN and THF in the solid-phase peptide synthesis of hindered peptides, such as Aib-enkephalin pentapeptide and Aib-ACP decapeptide, in combination with a complete polyethylene glycol resin (ChemMatrix), gave a better coupling efficiency than DMF.

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Section: Resultsmentioning

confidence: 92%

Section: General Methods For the Racemization Experiments 33 36mentioning

confidence: 99%

Peptide synthesis beyond DMF: THF and ACN as excellent and friendlier alternatives

et al. 2015

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“…No racemization was found in most of the cases investigated. Serine, however, is known to easily racemize during peptide coupling,11 and the serine-derived coupling system did show slight racemization. Using Boc protected L -serine (in place of Cbz protection used for the other amino acids), the high enantiopurity thiol ester reactant L -Boc-Ser- S - p -tolyl can be obtained in high enantiopurity after recrystallization from CH 2 Cl 2 /hexanes (ee > 99%).…”

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confidence: 99%

Synthesis of High Enantiopurity N-Protected α-Amino Ketones by Thiol Ester−Organostannane Cross-Coupling Using pH-Neutral Conditions

Yang

Liebeskind

2008

Org. Lett.

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An efficient synthesis of high enantiopurity N-protected α-amino ketones is described. Complementing other studies using boronic acids and thiol esters, this Cu(I) diphenylphosphinate (CuDPP)-mediated, palladium-catalyzed coupling of α-amino thiol esters with aryl, heteroaryl, allyl and alkenyl organostannanes gives N-protected α-amino ketones in high yields with high enantiopurity (in almost all cases) under mild and pH-neutral reaction conditions. The viability of π-deficient heteroarylstannanes is an advantage of this reaction compared to the related boronic acid system. Peptidic ketones and their derived α-ketoheterocycles represent significant functionalities for the development of molecular therapeutics. 1 Potent enzyme inhibitors based on the peptidic α-ketoheterocycle motif have been found for a large number of enzymes. 1b Many different approaches for the synthesis of α-amino ketones and aldehydes are known, with recent studies focusing on the construction of enantiopure α-amino ketones starting from naturally occurring amino acids. 2 Among these newer protocols, the use of organozinc reagents by Fukuyama/Tokuyama 2c and Rovis 2p provides improved functional group compatibility relative to organolithium and organomagnesium reagents, but none of the known reactions takes place under non-basic (non-epimerizing) conditions, nor are they adequately functional group selective to be broadly general.In contrast to the use of RLi, RMgX and RZnX-based protocols, the metal-catalyzed reaction of COOH-equivalent functionalities with boronic acids offers the potential for a fully general and functional group compatible approach to peptidic ketone synthesis. However, known ‡ Dedicated to our new Emory colleague, Professor Huw M. L. Davies. chemLL1@emory.edu ¥ Current address: Abbott Laboratories, GPRD, Process R&D, R450-NCR13-323A, 1401 Sheridan Road, North Chicago, IL, 60064Supporting Information Available Experimental procedures, synthesis and characterization of all new compounds (27 pages) and scanned spectra (89 pages). This material is available free of charge via the internet at http://pubs.acs.org NIH Public Access To address this issue a pH-neutral, room temperature, desulfitative synthesis of peptidyl ketones from thiol esters and boronic acids using palladium catalysts and stoichiometric Cu I carboxylate cofactors was recently described. 6 The reaction occurs at or near ambient temperature and has proven valuable for the synthesis of racemization sensitive peptidyl ketones. 7 As a follow-up to that first study, we describe herein a highly effective and general variant of that chemistry in which organostannanes rather than boronic acids are the reaction partners. Although organostannanes have not previously been used as reaction partners for thiol esters, vinylstannanes have been coupled with acid chlorides derived from N-protected α-amino acids. 8 Compared to the related boronic acid system, the new organostannanepeptidic thiol ester coupling provides an efficient reaction using only 1.1 equiv of t...

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“…However, the correct choice of coupling reagent and the base employed (collidine) reduces racemization to an acceptable extent [199]. It is removed with TFA (1-2 h at room temperature), with HCl/TFA, and with concentrated HCl at 0 C under an inert gas atmosphere within 10 min.…”

Section: Hydroxy Protectionmentioning

confidence: 99%

Peptide Synthesis

Sewald

Jakubke

2009

Peptides: Chemistry and Biology

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Racemization studies of Fmoc-Ser(tBu)-OH during stepwise continuous-flow solid-phase peptide synthesis

Cited by 40 publications

References 13 publications

Peptide synthesis beyond DMF: THF and ACN as excellent and friendlier alternatives

Peptide synthesis beyond DMF: THF and ACN as excellent and friendlier alternatives

Synthesis of High Enantiopurity N-Protected α-Amino Ketones by Thiol Ester−Organostannane Cross-Coupling Using pH-Neutral Conditions

Peptide Synthesis

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