An issue met during reaction optimization is the lack of a rational strategy usage. Generally, trial-and-error approaches and chemical intuition are employed. When the catalyst forms a covalent bond with the substrate the resulting adduct can be characterized by spectroscopic techniques and its geometry studied/calculated by computational chemistry. Predictive models can therefore be built. On the contrary, the construction of a reliable model employing non-covalent catalysis is much more difficult, considering that enantioselectivity arises from a minimal energy difference between two diastereomorphic transition states (just 2 kcal/mol for 90% ee). If the reactions were to be studied by computational chemistry, the error introduced could be comparable or larger than the absolute value arising from the calculations. Several variables are to be taken into consideration, such as solvent interaction, the catalyst’s molecular weight and a transition state involving weak interactions between the catalyst and the substrate(s). In order to tackle this issue a rational approach is highly desirable. Currently, the preferred strategy is the One-Variable-at-a-Time (OVAT) approach. However for a non-covalent asymmetric reaction, variables (concentration, choice of the solvent, temperature, catalyst loading) are likely to strongly interact with one another. Therefore, the rational exploration of chemical space requires the investigation of a multidimensional surface, where chemical intuition can be of limited help. The exploration of chemical space by means of Design of Experiment (DoE) methodologies allows to have an overall picture of the transformation leading to optimization in a rational way. The purpose of this talk is to illustrate how Design of Experiment (DoE) is a valid strategy to explore the chemical space in a rational way for non-covalent catalyzed asymmetric reactions. Following this strategy, we optimized two organocatalyzed transformations. The first reaction we studied was a challenging aza-Michael addition of imides to enones. The second reaction was the kinetic resolution of 4-substituted oxazinones. It should be stressed that this approach also allows a significant saving on time and resources, because only a small number of target experiments are actually run, and the maximum information is extracted from them. The main advantage is the possibility to fully optimize a reaction in a rational way, in contrast to trial-and-error approaches.

Design of experiments (DoE): A rational approach towards non-covalent asymmetric organocatalysis

254th National Meeting (2017)

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