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Removal of acid-labile protecting or anchoring groups in the presence of polyfluorinated alcohol: Application to solid-phase peptide synthesis

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Abstract

We describe herein a new method for cleaving from resin and removing acid-labile protecting groups in solid-phase peptide synthesis in the presence of a polyfluorinated alcohol (either trifluoroethanol, TFE, or hexafluoroisopropanol, HFIP). It was shown that 0.1 M HCl in hexafluoroisopropanol or trifluoroethanol removes the acid-labile protecting groups commonly used in Fmoc SPPS for the protection of amino acid side-chains, such as t-butyl ester and ether, Boc, trityl, and Pbf groups including the most acid-resistant p-hydroxymethylphenoxyacetyl group (HMPA), p-benzyloxy benzyl ester (Wang resin), Rink amide, and peptide amide linker (PAL). The addition of 5–10% of a hydrogen-bonding solvent was shown to considerably retard or even fully inhibit the reaction. However, nonhydrogen-bonding solvents, such as dichloromethane, do not slow down the reaction.

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Abbreviations

Boc:

tert-butyloxycarbonyl

Bpoc:

p-biphenylisopropyloxycarbonyl

DMS:

dimethylsulfide

ESI HRMS:

electrospray ionization high resolution mass spectrometry

Fmoc:

9-fluorenylmethoxycarbonyl

HATU:

hexafluorophosphate 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide

HFIP:

1,1,1,3,3,3-hexafluoroisopropanol

HMPA:

p-hydroxymethylphenoxy acetyl

MALDI-TOF:

Matrix Assisted Laser Desorption/Ionization time-of-flight

MBHA:

p-methylbenzhydrylaminopolystyrene

MSA:

methanesulfonic acid

NMP:

N-methyl-2-pyrrolidone

RP-HPLC:

reverse-phase high performance liquid chromatography

PAL:

peptide amide linker

Pam:

phenylacetamide linker

Pbf:

2,2,4,6,7-pentamethyldihydrobenzofuran-5-sulfonyl

PEG:

polyethylene glycol

Pmc:

2,2,5,7,8-pentamethylchroman-6-sulfonyl

PS:

polystyrene

TA:

thioanisole

TFE:

2,2,2-trifluoroethanol

TFMSA:

trifluoromethanesulfonic acid

TMSOTf:

trimethylsilyltriflate

TFA:

trifluoroacetic acid

TIS:

triisopropylsilane

Trt:

triphenylmethyl (trityl)

TSA:

p-toluenesulfonic acid

Z:

benzyloxycarbonyl

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Authors and Affiliations

  1. Institute of Chemical Biology and Fundamental Medicine, Siberian Branch, Russian Academy of Sciences, pr. Lavrent’eva 8, Novosibirsk, 630090, Russia

    D. A. Stetsenko, V. S. Apukhtina & B. P. Chelobanov

  2. Novosibirsk State University, ul. Pirogova 2, Novosibirsk, 630090, Russia

    D. A. Stetsenko, V. S. Apukhtina & B. P. Chelobanov

  3. Université degli Studi di Catania, Dipartimento di Scienze Chimiche, Viale Andrea Doria 6, Catania, 95125, Italia

    P. Palladino

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  1. D. A. Stetsenko
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  2. V. S. Apukhtina
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  3. B. P. Chelobanov
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  4. P. Palladino
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Correspondence to D. A. Stetsenko.

Additional information

Results were presented at the VII Russian All-Russian Symposium “Proteins and Peptides;” July 12–17, 2015, Novosibirsk, Russia.

Original Russian Text © D.A. Stetsenko, V.S. Apukhtina, B.P. Chelobanov, P. Palladino, 2016, published in Bioorganicheskaya Khimiya, 2016, Vol. 42, No. 2, pp. 160–170.

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Stetsenko, D.A., Apukhtina, V.S., Chelobanov, B.P. et al. Removal of acid-labile protecting or anchoring groups in the presence of polyfluorinated alcohol: Application to solid-phase peptide synthesis. Russ J Bioorg Chem 42, 143–152 (2016). https://doi.org/10.1134/S106816201602014X

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