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Synthese von [2,7‐Cystin]‐Gramicidin S, einem künstlichen homodet‐heterodet‐bicyclischen Decapeptid
Author(s) -
Ludescher Urs,
Schwyzer Robert
Publication year - 1972
Publication title -
helvetica chimica acta
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.74
H-Index - 82
eISSN - 1522-2675
pISSN - 0018-019X
DOI - 10.1002/hlca.19720550624
Subject(s) - chemistry , stereochemistry , bicyclic molecule , cysteine , peptide , carbodiimide , gramicidin s , gramicidin , triethylamine , organic chemistry , biochemistry , membrane , enzyme
The first synthesis of a homodetic‐heterodetic‐bicyclic polypeptide, [2,7‐cystine]‐gramicidin S, is described. For the protection of the C‐terminal carboxyl and the cysteine sulfhydryl functions, the 2‐(toluene‐ p ‐sulfonyl)‐ethyl‐ (Tsa) and the acetamidomethyl‐ (Acm) groups, respectively, were used. Stepwise synthesis from the C‐terminus, using N α Boc‐amino acids, and selective removal of protecting groups yielded the two pentapeptide derivatives: Boc · Val‐Cys‐(Acm)‐Lem)‐Leu‐phe‐Pro · OH and H · Val‐Cys(Acm)‐Leu‐phe‐Pro · OTsa. They were condensed with dicyclohexyl‐carbodiimide and 1‐hydroxybenzotriazole to give the crystalline decapeptide Boc · [Val‐Cys(Acm)‐Leu‐phe‐Pro] 2 · OTsa. Removal of the Tsa group by β‐elimination at pH 11.5 yielded the crystalline free acid, which was further converted (by treatment with di‐ p ‐nitrophenyl sulfite followed by TFA) to TFA, H · [Val‐Cys(Acm)‐Leu‐phe‐Pro] 2 · ONp. Cyclization of the active ester in warm pyridine gave a mixture of (2,7‐bis‐S‐acetamidomethyl‐cysteine]‐gramicidin S (27% yield) and (2,7‐cysteine)‐gramicidin S (4%). The former compound was readily converted to the latter by treatment with I 2 in MeOH. In the bicyclic peptide, the decapeptide ring is contained in a β‐type secondary structure, identical with that in gramicidin S; the disulfide bridge shows P‐helical chirality and gives rise to a negative Cotton effect at 271 nm [3].