Proceedings book download - 5Z.com

Proceedings of the 31 st European Peptide SymposiumMichal Lebl, Morten Meldal, Knud J. Jensen, Thomas Hoeg-Jensen (Editors)European Peptide Society, 2010Cyclic Amino Acid-Containing α-helical Peptide-CatalyzedEnantioselective Epoxidation ReactionMasakazu Tanaka 1 , Masanobu Nagano 2 , Mitsunobu Doi 3 ,Masaaki Kurihara 4 , and Hiroshi Suemune 21 Graduate School of Biomedical Sciences, Nagasaki University, 1-14 Bunkyo-machi,Nagasaki, 852-8521, Japan; 2 Graduate School of Pharmaceutical Sciences, KyushuUniversity, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan; 3 Division of OrganicChemistry, National Institute of Health Sciences, Tokyo, 158-8501, Japan; 4 OsakaUniversity of Pharmaceutical Sciences, Osaka, 569-1094, JapanIntroductionPoly L-α-amino acid-catalyzed asymmetric epoxidation of chalcone was reported by Juliá,Colonna and co-workers [1]. They studied the generality of substrates, reaction conditions,effect of the length of oligomers, and reaction mechanisms. In the reaction, poly L-α-aminoacids might form α-helical structures, and their α-helical N-termini are important forasymmetric induction. To stabilize the α-helical structure of catalyst, polyethyleneglycoland resin-attached L-Leu oligomers have been developed, and thus, the high molecularweight and insolubility of catalysts were in part overcome [2].Also, α,α-disubstituted amino acids (dAAs) were used to induce a helical structure,but dAA-containing oligomers formed not α-helices but 3 10 -helices, which did not giveepoxide of high enantiomeric excess [3]. Recently, we have disclosed that cyclic aminoacid-containing L-Leu-based peptides preferentially formed right-handed (P) α-helices [4].Thus, we reasoned that cyclic amino acid-containing L-Leu-based peptides would catalyzethe asymmetric epoxidation of (E)-chalcone. Here we demonstrate the enantioselectiveepoxidation of (E)-chalcone, and the relationship between the secondary structure ofcatalysts and the enantiomeric excesses of epoxides [5].Results and DiscussionWe prepared chiral cyclic dAA-containing oligomers R-{L-Leu-L-Leu-dAA} n -OMe {R =Boc, or H; n = 2, 3, 4; dAA = Aib, (R,R)-Ac 5 c dOM , (S,S)-Ac 5 c dOM , (1R,3S)-Ac 5 c OM , and(1S,3S)-Ac 5 c OM } using solution phase-methods.First, asymmetric epoxidation of (E)-chalcone using 25 mol % of Boc-{L-Leu-L-LeudAA}n -OMe was examined under conditions of urea-H 2 O 2 (1.1 equiv) and DBU (5.6equiv) in THF at 0 °C to room temperature for 24 h. Although the reactions catalyzed byhexamers afforded epoxide of low enantiomeric excesses (7–11% ee) in 77–91%conversion yield (not shown), elongation of the peptide chain improved enantiomericexcesses, except for Aib-containing peptides. It should be noted that side-chain chiralcenters affected enantiomeric excesses, and those by (1S,3S)-Ac 5 c OM -containing nonamerand dodecamer were 82–83% ee, which are in contrast to other cases. X-raycrystallographic analysis revealed that the (1S,3S)-Ac 5 c OM hexamer assumed a mixture of(P) 3 10 -/α-helix, where intramolecular hydrogen bonds of i←i+3 type are formed on theN-terminal side (i = 0, 1) and those of i←i+4 type are formed on the C-terminal side (i = 1,2). Three crystallographic independentconformers, which aresimilar in the peptide backbone,exist in asymmetric units.Contrary to the 3 10 -/α-helix ofhexamer, the (1S,3S)-nonamerformed fully developed righthandedα-helices, wherei←i+4-type hydrogen bondswere observed.MeMeH 2 N CO 2 HAib31H 2 N CO 2 H H 2 N CO 2 H H 2 N CO 2 H(S,S)-Ac 5 c dOM (1S,3S)-Ac 5 c OM (1R,3S)-Ac 5 c OMIn Boc-protected 3 10 -helical peptides, intramolecular hydrogen bonds of i←i+3 typeare formed, and the two N-terminal NH protons are not involved in intramolecularhydrogen bonding. On the other hand, in α-helical peptides, intramolecular hydrogen bondsof i←i+4 type are formed, and the first three N-terminal NH protons are free ofintramolecular hydrogen bonding. According to Roberts’ model [2], the three N-terminalMeOOMeFig. 1. Structure of dAAs.OMeMeO622