The proposed program aims at the development of a new synthetic platform for controlled selective functionalizations of aliphatic molecules possessing unreactive C(sp3)?H bonds. The existing synthetic methods toward complex molecules and pharmaceuticals mostly rely on employment of pre-functionalized substrates. Employment of non-functionilized saturated hydrocarbon groups is much more appealing as these moieties are much more abundant and cheap. Moreover, the aliphatic C(sp3)?H bonds are often present in complex biologically important molecules and pharmaceuticals, and thus their selective functionalization offers a powerful tool for late stage modifications. The few existing methods for desaturation/functionalization of saturated groups are not general, as the functionalization site is usually substrate-dependent. Also, these methods operate under acidic conditions and/or employ external oxidants, which limits the substrate scope. Thus, mild regio- and stereo-controlled desaturation/functionalization of saturated groups remains a holy grail in modern synthetic chemistry. We propose the development of a novel catalytic methodology for regiocontrolled, mild and external oxidant-free functionalizations of saturated groups. The site of functionalization will be controlled by a designed tool-kit of temporary auxiliaries, which are easily installed onto substrate and removed from the product. Based on a substantial amount of preliminary results obtained in our lab, a successful development of this project is feasible. The proposed project consists of three major Sections: 1. Development of efficient catalytic systems for desaturation of aliphatic groups. 2. Development of a tool-kit for general efficient and controlled proximal and remote desaturations of various organic molecules. 3. Exploration of novel cascade reactions including C(sp3)?H functionalizations.
The proposed work aims at developing new methods for selective and efficient conversion of unreactive aliphatic compounds into functionalized molecules, which are of potential importance for synthetic and medicinal chemistry. The proposed approaches include employment of hybrid transition metal- catalyzed/radical desaturation, atom transfer, cross-coupling, and and cascade functionalization methods. If fully developed, these methods would dramatically broaden the arsenal of synthetic tools available for medicinal chemists and biologists, and will most certainly impact drug discovery research and related health- oriented sciences.
