From very early on, chemists identified cyclic peptides as important targets for the development of synthetic protocols because peptide macrocycles have found applications that range from drug discovery to nanomaterials. New and improved strategies lead to more efficient synthesis of complex peptide targets, opening the way to both new drug candidates and a deeper understanding of the intimate relation between sequence, conformation and properties. Despite recent progress and the arsenal of reagents available, synthesis of medium ring-sized cyclo-peptide remains challenging: complex targets and regulatory authority constraints in terms of purity for drugs are continuously stimulating chemists to improve and rethink synthetic approaches. Reducing the number of steps is usually a synonym of better yields and ease of purification, which explains the success of convergent peptide synthesis. We now report the development of synthetic methods and approaches targeting medium-sized cyclic peptides including: dimerization-macrocyclization, conformationally assisted marco-cyclization, intramolecular Staudinger ligation. Our novel methodologies in combination with convergent synthesis schemes should provide the key elements for the total chemical synthesis of natural or fully unnatural linear and medium-sized cyclic peptides with yet to be discovered properties.

Development of macrolactamization methods for synthesis of medium sized cyclic peptides � an underexploited class

247th National Meeting (2014)

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