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Proceedings of the 31 st European Peptide SymposiumMichal Lebl, Morten Meldal, Knud J. Jensen, Thomas Hoeg-Jensen (Editors)European Peptide Society, 2010Racemization-Free Synthesis of Cyclic Peptides by Use of theO-Acyl Isopeptide MethodHiroyuki Kawashima, Taku Yoshiya, Yuka Hasegawa, KazuhiroOkamoto, Tooru Kimura, Youhei Sohma, and Yoshiaki KisoDepartment of Medicinal Chemistry, Center for Frontier Research in Medicinal Science,Kyoto Pharmaceutical University, Kyoto, 607-8412, JapanIntroductionCyclic peptides generally possess higher biological activity and metabolic stability thantheir corresponding linear peptides due to conformational constraints. Despite the promisesof the cyclic peptides in drug development, a head-to-tail cyclization reaction of thecorresponding linear peptide is often accompanied by incomplete coupling and/orepimerization [1]. The epimerization occurs because peptides, in contrast to urethaneprotectedamino acids, easily form chirally labile oxazolones upon C-terminal carboxylactivation.We previously reported a novel convergent method of peptide synthesis: racemizationfreesegment condensation methodology based on the O-acyl isopeptide method [2-5]. Theidea was that an N-segment with a C-terminal O-acyl isopeptide structure at a Ser or Thrresidue could be coupled to an amino group of the C-segment without epimerization,because the amino group of the C-terminal isopeptide is protected by a urethane-typeprotective group. Thus, formation of the racemization-inducible oxazolone was suppressedon the carboxyl group activation. Finally, the target peptide was generated from the O-acylisopeptide via an O-to-N intramolecular acyl migration reaction.If the racemization-free segment condensation strategy is applied to an intramolecularsystem, a linear peptide with a C-terminal O-acyl isopeptide could undergo epimerizationfreecyclization due to the urethane-type protective group at the Ser or Thr residue, andfollowing the O-to-N acyl migration of the cyclic O-acyl isopeptide, would give the targetcyclic peptide [6,7].Results and DiscussionThe cyclization of protected linear O-acyl hexapeptide 1 Boc-Ser(H-Arg(Pmc)-Ala-Gly-Asn(Trt)-Ala)-OH was performed under three conditions (Table 1): HATU–collidinemethod in DMF (Entry 1), HATU–collidine method in CH 2 Cl 2 (1% DMF contained, EntryTFA· HRAGNHNBocHNOOOHO(protected)ONHNH OOOOHN( i ) Pmc( ii )HHN NNHOONHONHBocHNHN Trt1·TFA 2TFA· H 2 NHNNHOONHONHNHHNOHNONH 2 ·TFAOOONH 2O-acyl isopeptide 3·TFA (53% after two steps from 1) 4·TFA (99%)( iii )TFA· H 2 NHNNHOONHNHONHHNOHNHNOHOOONH 2Scheme 1. Reagents and conditions: i) HATU (2 eq), 2,4,6-collidine (4 eq), CH 2 Cl 2(containing 6% DMF), final peptide conc: 1 mM, 3 h, rt; ii) TFA (92.5%)-m-cresol(2.5%)-thioanisole (2.5%)-H 2 O (2.5%), 60 min, rt; iii) 3-(trimethylammonium)propylfunctionalizedsilica gel carbonate (2 eq), CH 3 CN/H 2 O (1:1), 3 h, rt, then treated with0.1% aqueous TFA.120