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Table 1. Cyclization of linear O-acyl isopeptide 1 to give the cyclic peptide 2a peptide concentration = 1 mM; temp = rt; b Yields were estimated by the peak area inanalytical HPLC; c Authentic D-Ser derivative was synthesized independently and used todetermine the ratio of epimerization by RP-HPLC; d cyclo(RAGNA) + the [D-Ala]derivative; e N.D. = Not detected. (detection limit: 0.5%); f containing 1% DMF.2) and DPPA (diphenylphosphoryl azide)–NaHCO 3 method in DMF (Entry 3). In Entry 1,the desired 2 (94%, HPLC yield) was obtained after 12 h reaction and the D-Ser derivativederived from epimerization was not detected in the crude sample. This result indicates thatthe [D-Ser] formation (39% in the cyclization of the corresponding native peptide by theconventional method) could be suppressed in the cyclization at the Boc-protected O-acylisopeptide, suggesting that the ring-closing reaction did not involve the formation of theoxazolone. In Entry 2 with CH 2 Cl 2 (1% DMF contained), 94% of 2 was formed after 1 hreaction without epimerization. In the cyclization with DPPA (Entry 3), the des-Serbyproduct (36%) was detected in addition to the desired 2, and a few percent of a peakderived from the D-Ser derivative was detected. Finally, the isolated yield of cyclic O-acylisopeptide 3·TFA after two steps from 1 was 53% (Scheme 1).In neutral phosphate buffer (pH 7.6), the isopeptide 3·TFA was converted to the nativecyclic peptide 4 via the O-to-N intramolecular acyl migration reaction within 1 min.Instead, when the isopeptide 3·TFA was dissolved in water/CH 3 CN (1:1) in the presence oftwo molar excess of 3-(trimethylammonium)propyl-functionalized silica gel carbonate, aquantitative O-to-N acyl migration was observed after 3 h reaction without any sidereaction. The pure target peptide 4 was isolated after filtration followed by lyophilization ofthe filtrate.Secondary structures of 3 and 4 were examined by CD spectrometry. (Figure 1) TheO-acyl isopeptide 3 and cyclic peptide 4adopted different secondary structures,suggesting that a well-known secondarystructure disrupting effect by theintroduced O-acyl isopeptide observedin many linear peptides [2,3] is alsoexerted in cyclic peptides.In conclusion, the head-to-tailcyclization of the linear peptide with aC-terminal O-acyl isopeptide proceededto give the cyclic O-acyl isopeptidewithout epimerization. Interestingly, thecyclic O-acyl isopeptide possessed adifferent secondary structure whencompared to the native cyclic peptide.Finally, the isopeptide was efficientlyconverted to the desired cyclic peptidevia the O-to-N acyl migration reaction. Fig. 1. CD spectra of cyclic peptides.References1. Davies, J.S. J. Peptide Sci. 9, 471-501 (2003).2. Sohma, Y., et al. Chem. Commun. 124-125 (2004).3. Sohma, Y., et al. Biopolymers (Pept. Sci.) 88, 253-262 (2007).4. Yoshiya, T., et al. Tetrahedron Lett. 47, 7905-7909 (2006).5. Yoshiya, T., et al. Org. Biomol. Chem. 7, 2894-2904 (2009).6. Lécaillon, J., et al. Tetrahedron Lett. 49, 4674-4676 (2008).7. Yoshiya, T., Kawashima, H., et al. J. Peptide Sci. 16, 437-442 (2010).121