Chemical ligation of large peptide fragaments opens up opportunity to study peptides that is inaccessible using biological isolation or recombinant DNA expression. In critical aspect, chemical ligation shows advantages with high purity and freedom to manipulate amino acid fragments. The utility of coupling peptide fragments to study biologically relevant topics is seen for example in the coupling of the constituent peptide fragments of the HIV protease, which can not be chemically synthesized using conventional solid phase method. Furthermore, peptides and peptoids are a promising candidate in drug design.Despite the biological relevance and potential, the chemist's arsenal for coupling amino acid/peptide fragments is incomplete. Ligation at the proline site is especially difficult and as such there is a dearth of successful methodologies due to high steric hindrance. To address this problem, we explored a novel advanced hydroxyproline ligation strategy. An auxiliary salicylaldehyde is first installed on the C-terminus of one peptide. This provides an electrophilic aldehyde for the N-terminus to attack forming a iminium intermediate. Once the second peptide is captured, a first rearrangement is undertaken in which the hydroxyl group at the 4 positions attacks the schiff's base, forming an aminal. The nitrogen is then free to undergo the second rearrangement where the nitrogen attacks the carbonyl of the C-terminus and establishing the native peptide links in light acidic condition.We used this method to couple various models using two amino acid fragments, and with our sucessful results, we are using this method to access difficult proline containing peptides that are inaccessible by other contemporary methodlogy.

Advanced hydroxyproline chemoselective ligation methodology as a potential tool to achieve difficult large peptide fragment coupling

248th National Meeting (2014)

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