Alkylation of g‐Azaproline Creates Conformationally Adaptable Proline Derivatives for pH‐Responsive Collagen Triple Helices

Cgamma-substituted proline derivatives are valuable tools for developing functionalized collagen peptides for biological and materials investigations, yet the stereochemistry at Cgamma can produce undesired steric or stereoelectronic constraints. Alkylated gamma-azaproline (gamma-azPro) derivatives are proline mimetics that lack a stereogenic center at the gamma-position of the ring and can thus utilize the invertibility of nitrogen to adapt their conformation. NMR spectroscopic analyses and DFT calculations highlight how alkylated g-azPro derivatives are conformationally dynamic and adopt conformational preferences through ring pucker flip along with nitrogen inversion. Lastly, incorporation of alkylated g-azPro into collagen peptides produced functionalized pH-responsive triple helices with similar thermal stabilities, regardless of their placement in the Xaa or Yaa position within the characteristic Xaa-Yaa-Gly repeating unitof collagen peptides.