The development of a method to achieve a convergent synthesis combining smaller polypeptide fragments is critical in terms of both minimizing the cost of production of peptide therapeutics (such as the attention-catching anti-retroviral drug fuzeon) and realizing chemical synthesis of large peptides that have been problematic or nearly impossible. In contrast with conventional fragment coupling, chemoselective ligations�such as native chemical ligation, sugar-assisted ligation, and advanced proline ligation�have provided advantageous methods to achieve an efficient convergent synthesis.In this study, a hydroxyproline-based chemoselective ligation method is studied, utilizing Salicyladheyde ester-induced chemoselective peptide ligation at the hydroxyproline site. It uses an O (S)-salicyladehyde ester at the C-terminus, reacting with N-terminal hydroxyproline to promote peptide ligations. The utilitiy of the S-salicylaldehyde ester enables the rapid coupling reaction and the production of an N,O(S)-benzylidene acetal intermediate, which is readily converted into native peptidic linkages at the ligation site.Further, the aplicability of the novel Salicylaldehyde ester-induced chemoselective ligation at hydroxyproline ligation site is demonstrated as a ring-closing/contraction strategy in synthesis of cyclic tetrapeptides.

Advanced hydroxyproline chemoselective ligation methodology for coupling of peptide fragments

247th National Meeting (2014)

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