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Conformationally stable peptide macrocycles assembled using the Petasis borono-Mannich reaction
Akitake Yamaguchi1, Sherif J Kaldas, Solomon D Appavoo
1Davenport Research Laboratories, Department of Chemistry, University of Toronto, 80 St. George Street, Toronto, Ontario M5S 3H6, Canada. andrei.yudin@utoronto.ca.
Chemical Communications (Cambridge, England)
|August 17, 2019
Summary
The Petasis borono-Mannich reaction creates diverse macrocycles from linear peptides. An intramolecular hydrogen bond involving the endocyclic amine controls macrocycle conformation, yielding homogenous structures.
Area of Science:
- Organic Chemistry
- Medicinal Chemistry
- Chemical Biology
Background:
- Peptide macrocycles are important in drug discovery.
- Controlling the conformation of peptide macrocycles is challenging.
- The Petasis borono-Mannich reaction offers a route to peptide macrocycles.
Purpose of the Study:
- To explore the macrocyclization of linear peptides using the Petasis borono-Mannich reaction.
- To investigate the conformational properties of the resulting peptide macrocycles.
- To identify key structural features governing macrocycle conformation.
Main Methods:
- Synthesis of linear peptide precursors.
- Application of the Petasis borono-Mannich reaction for macrocyclization.
- Structural analysis of peptide macrocycles using techniques like NMR spectroscopy and X-ray crystallography.
Main Results:
- Successful macrocyclization of diverse linear peptide precursors.
- Formation of macrocycles containing an endocyclic amine.
- Identification of a critical hydrogen bond between the endocyclic amine and an adjacent amide NH.
- Demonstration that this hydrogen bond dictates conformationally homogenous structures.
Conclusions:
- The Petasis borono-Mannich reaction is a versatile method for synthesizing peptide macrocycles.
- The endocyclic amine-amide NH hydrogen bond is a key determinant of conformational homogeneity.
- This finding provides a powerful strategy for designing conformationally constrained peptide macrocycles.
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