Pd(II)-Catalyzed Enantioselective Iodination

The direct CH bond functionalization is a highly attractive and one of the most investigated but also most challenging topics in modern organic synthesis. The general aim of CH activation reactions is to introduce groups with a higher complexity to hydrocarbon structures. One of the most challenging quests is the development of enantioselective CH activation reactions. Although many direct functionalizations have been reported in recent years, there are only few examples of performing such a transformation in an enantioselective fashion. Yu and coworkers reported in this context an exceedingly practical palladium-catalyzed method for the direct alkylation of C(sp 2 )H and C(sp 3 )H bonds using monoprotected amino acids as effective chiral ligands. The goal of this project is now the "palladium-catalyzed enantioselective iodination of CH bonds using amino acids as chiral ligands". The direct substitution of hydrogen with iodine is a process of great significance and, overall, might result in new and distinctive synthetic features. Iodine labeled compounds can be used as radiopharamaceutical, for labeling proteins or clinical studies. Furthermore, iodine is an excellent leaving group and can therefore be converted to a vast number of functional groups. The enantioselective introduction of such a leaving group would be a superior starting point for the synthesis of more complex chiral compounds. In the course of the project an effective catalyst/ligand/oxidant/additive/solvent system has to be established for these transformations whereby preliminary results from the Yu group on related problems can be used as starting point. Furthermore, different starting materials with different directing groups (= DG) have to be synthesized. Subsequently, reactions shall be optimized with respect to yield, ligand, substrate scope, temperature and time. In the optimization process mechanistic studies will be included to get more detailed information on the reaction pathway. Tuning of the ligand will address special needs of the reaction regarding the enantioselectivity. Intelligent changing of the electronic and steric properties of the amino acid is expected to lead to an improved reaction outcome.

The direct CH bond functionalization is a highly attractive and one of the most investigated but also most challenging topics in modern organic synthesis. The selective, direct C?H bond functionalization of organic substrates by transition metal catalysts is a very attractive method for structural elaboration. The general aim of CH bond activation reactions is to introduce groups with a higher complexity to hydrocarbon structures, subsequently allowing the synthesis of complex biologically active compounds. The goal of this project was the diversification of naturally occurring chiral natural products, aiming to expand the synthetic utility of these readily available molecules as chiral synthons in asymmetric synthesis. A number of naturally occurring chiral carboxylic acids are readily available, however, there are only a few reports concerning the use of free carboxylic acids to direct CH functionalization events in literature and the majority of these established protocols are based on the derivatization of simple benzoic acid derivatives which do not contain chiral centers. Recently, the Jin-Quan Yu group made strides on this front with the discovery that naturally occurring mono-N-protected amino acid ligands could accelerate the palladium catalyzed C-H bond functionalization. These ligand accelerated reactions set the stage for us to further investigate whether CH activation methods can be modified to directly functionalize enantiomerically pure ?-substituted phenyl acetic acid substrates such as mandelic acid and ? -phenylglycine. Notably, these scaffolds can already be found in many pharmaceutical drugs (e.g. Homatropine, Cyclandelate, Cefalexin, Clopidogrel) and the ability to directly derivatize them may lead to further medicinal investigation of these classes of compounds. Within this project, a variety of ortho-CH functionalizations based on different catalytic cycles were investigated. The results should help to synthesize new complex molecules in a feasible way, investigate new drugs and improve existing drugs.