Asymmetric Diels-Alder Reaction: Toward an Ideal Catalyst

Enantioselective homogeneous catalysis represents a broad interdisciplinary research field spanning from biomolecular, organic, inorganic, physical to computational chemistry. The area of transition metal catalysis constitutes an especially appealing way of producing enantiomerically pure compounds, which are very often bioactive and of pharmacological relevance. Despite considerable progress in this field in recent years, there remains much to be achieved and further development and optimization is therefore imperative. In our research proposal, we introduce, based on experimental observations and data (EPR spectroscopy), modern, advanced state of the art theoretical methodology to provide detailed and systematic insight into the intrinsic characteristics of transition metal catalysts. We propose a computational project, which will be focused on the investigations of specific alterations of the ligand sphere around Cu(II) centers in the course of enantioselective Diels-Alder reactions. The goal is to obtain a substantially enhanced knowledge about fundamental aspects of Diels-Alder reactions catalyzed by C2 -symmetric Cu(II) complexes and constructing theoretical procedures used for evaluating and designing catalysts of high selectivity, activity and efficiency. Based on recently obtained spectroscopic data and by systematic analysis of the influence of metal centers, ligands, solvent molecules and counterions within the course of catalytic reactions, we want to contribute to the development of optimally performing catalysts by becoming able to predict efficient systems. Main tasks to be addressed in the project: 1. Influence of the counterions on the structure and reactivity of various bis(oxazoline) and bis(sulfoximine) systems. 2. Influence of the solvent on various bis(oxazoline) and related complexes and its impact on the acidity at the Cu(II) center. 3. Influence of various substituents of bis(oxazoline) ring on the activity of the Cu(II) center The computations will be performed in cooperation with the groups of Prof. Martin Kaupp (Technische Universität, Berlin), Prof. Frank Neese (University of Bonn), and Prof. Sason Shaik (Hebrew University of Jerusalem, Israel).

Homogeneous catalysis forms one of the most important methods for obtaining new chemicals. It is crucial for the development and the optimization of such processes to understand their molecular background. Such mechanistic considerations are mostly based on the knowledge of solid-state structures of the reacting molecules. However in reality, these reactions are conducted in solution, i.e., the catalytic systems consist of metal salts, molecules, that primarily react with these salts and form the catalysts, and the substrates. Consequently, the interactions between the reactants, the solvent molecules and the ions of the metal salts (counterions) are crucial for a matching description of the catalytic reaction. The aim of our research was to find out in how far the "real" chemical environment, consisting of all the above components directs the coarse of catalytic reactions. We have chosen the "(hetero) Diels-Alder reaction" catalyzed by copper salts and nitrogen-containing molecules forming the catalytically active complex as the paradigm for our investigations. This method has been utilized for many years as a very efficient synthetic procedure for the synthesis of technically and pharmacologically relevant molecules. Nevertheless optimizations have been predominately based on a trial-and-error strategy. The foundations of our work were observations and data from reaction mixtures providing indirect insights onto the molecular topologies likely to be formed during the catalytic procedures. Using theoretical calculations, we targeted our investigations toward achieving a consistent and predictive model for the course of the Diels-alder reactions. Indeed, we could show that that we can systematically follow the effects of each single component in the reaction mixture. In first instance, we have performed calculations using static methods (several stages of the reaction were computationally optimized). In the advanced stage of the project, we have switched to molecular-dynamics simulations, a novel approach in this field, which is rapidly emerging. The result of our research indicates that we are able to model the influence of basically all components present in the reaction solution. We could show that the hitherto (in terms of modeling) mostly omitted solvent molecules and counterions have a substantial influence on the geometry of the species formed during all reaction stages, substantially deviating from solid-state structures. Our results show that computations including a complex molecular environment allow reasonable predictions for preferable reaction conditions.