Extension of the enantioselective, Cu-catalyzed Henry reaction to a broadly applicable synthetic tool

• Applicant: Professor Dr. Matthias Breuning
• Subject Area: Organic Molecular Chemistry - Synthesis and Characterisation
• Term: from 2018 to 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 407493296

Enantioselective Henry reactions ( = nitroaldol reaction) are praised in many publications as valuable C,C-bond forming reactions since the resulting ß-nitro alcohols can be easily converted into chiral, multifunctional synthetic building blocks. And indeed, the preconditions for that are excellent, because nowadays highly enantioselective Cu-catalysts exist (including our catalyst) and the possibilities for transforming nitro compounds are manifold. However, the latter reactions have not yet been carried out on chiral Henry products or have only been done on singular examples (exception: reductions to ß-amino alcohols). The huge potential is therefore still unexploited. And this is exactly where our project comes into play:It aims to methodologically expand the enantioselective Henry reaction and, by combination with diverse follow-up reactions of the nitro group, to advance the enantioselective Henry reaction into a powerful, broadly applicable synthetic tool.The following three subgoals are pursued: (1) Extension of the enantioselective Henry reactions to storage-stable alcohols ('oxidative' Henry reactions): This simplifies the experimental efforts and, at the same time, it is the first example of a Cu-catalyzed tandem reaction of the type oxidation–asymmetric C,C-coupling.(2) Combination of the Henry reaction with [3+2]-cycloaddition: The primarily resulting isoxazol(id)ines can be converted into versatile, highly functionalized synthetic building blocks with up to four continuous, in part freely adjustable stereocenters. (3) Combination of the Henry reaction with denitration: This permits access to enantiopure, secondary alcohols with identical inner spheres, which are otherwise difficult to prepare.Preliminary studies have been carried out that prove the fundamental feasibility of all subprojects. On this basis, it is planned to develop robust, broadly useable protocols (methodological part) and to proof their practicability and efficacy through the enantioselective synthesis of several selected natural products and drugs (application-oriented part). These applications cover simpler examples, the syntheses of which permits a direct comparison with other approaches, as well as structurally more complex systems.

• DFG Programme: Research Grants