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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, 2010Structural Control of Diastereomeric Leu-Leu-Aib-Leu-Leu-AibSequencesYosuke Demizu 1 , Mitsunobu Doi 2 , Yukiko Sato 1 , Masakazu Tanaka 3 ,Haruhiro Okuda 1 , and Masaaki Kurihara 11 Division of Organic Chemistry, National Institute of Health Sciences, Tokyo, 158-8501,Japan; 2 Osaka University of Pharmaceutical Sciences, Osaka, 569-1094, Japan; 3 GraduateSchool of Biomedical Sciences, Nagasaki University, Nagasaki, 852-8521, JapanIntroductionThe de novo design of peptides that fold into well-defined secondary structures is cruciallyimportant in a wide variety of fields such as organic chemistry and biological and materialsciences. As templates for stabilizing the secondary structures of peptides, , -disubstituted -amino acids have been widely used [1]. Among them, -aminoisobutyricacid (Aib) has been found to be particularly useful as a helical promoter [2]. We haverecently reported that the placement of Aib residues in an L-leucine-based hexapeptide(L-Leu-L-Leu-Aib-L-Leu-L-Leu-Aib) stabilized its right-handed (P) 3 10 -helical structure[3]. Incidentally, the placement of L-amino acids in a helical sequence containingenantiomeric D-amino acids generally destabilizes the helical structure [4]. However, theaccurate design of hybrid peptides with an effective combination of L- and D-amino acids isuseful for constructing novel specific conformations [5]. Therefore, we speculated that newsecondary structures could be built by appropriate design of Leu-based hexapeptides with aprimary structure of Leu-Leu-Aib-Leu-Leu-Aib containing D-Leu residue in variouscombinations. Here, we designed three diastereomeric peptides using the same contents ofL-Leu, D-Leu, and Aib residues; Boc-L-Leu-L-Leu-Aib-D-Leu-D-Leu-Aib-OMe (1), Boc-L-Leu-D-Leu-Aib-L-Leu-D-Leu-Aib-OMe (2), and Boc-L-Leu-D-Leu-Aib-D-Leu-L-Leu-Aib-OMe (3), and studied their preferred conformations in the crystalline state (Figure 1).Fig. 1. The design of peptides 1, 2, and 3.Results and DiscussionPeptides 1, 2, and 3 were synthesized by conventional solution-phase methods according toa fragment condensation strategy using O-benzotriazole-N,N,N ’ ,N ’ -tetramethyluroniumhexafluorophosphate (HBTU) and 1-hydroxybenzotriazole (HOBT) as coupling reagents.The conformation of peptides 1, 2, and 3 in the crystalline state was studied by X-raycrystallographic analysis. The preferred conformation of 1 was a left-handed (M)580