Selective C-H functionalization of cyclobutane ß-amino acid derivatives – C_Fun_CA

In the area of foldamer science, enantiopure cis- and trans-cyclobutane ß-amino acid (cis- et trans-ACBCs) derivatives are building blocks particularly attractive as monomer units for the preparation of peptidomimetic architectures due to their resistance to proteolysis and displaying structural mimicry. Although there is an increasing demand for their synthetic access, the development of efficient, selective and step and atom economical approach to derivatize the enantiopure cis- and trans-ACBC by the construction of C-C bonds at the peripheral sites C3 and/or C4 remains a challenge.
In this context, and based on promising preliminary results, this collaborative research project C_Fun_CA, in line with societal and environmental issues, has for ambition: i) to increase the structural diversity of ACBC scaffold by opening up the hitherto unexplored chemical space to C3 and/or C4 substituted ACBC derivatives and hetero-analogues via regio- and stereoselective directed Pd-catalyzed C(sp3)-H functionalization methodologies, ii) to build a modular portfolio of reactivity, proximal C-H activation vs. distal or vice versa, and finally iii) to apply this powerful methodological tool toward the synthesis of architectural design peptidomimetics, which will participate in future innovations in the field of foldamer-based drug molecules.
All these objectives will be investigated following a methodology in five separated tasks, with increasing levels of complexity and ambition. Thanks to judicious designed directing groups, Pd-catalyzed direct C(sp3)-H functionalization strategies will be established to install regio- and stereoselectively different side chaines at the peripheral C3 and/or C4 positions of the cyclobutane core. The targeted building blocks will be subsequently used in the synthesis of peptidomimetic foldamers in order to act as potential functional and selective inhibitors of protein-protein interactions.