Design of Experiments: A Rational Approach Toward Non-­Covalent Asymmetric Organocatalysis

Abstract

This account describes, from a personal point of view, the possible strategies to tackle and optimize non-covalent organocatalyzed reactions. When chemical intermediates are covalently bound, predictive mechanistic scenarios can be depicted. In contrast, there are several organocatalyzed transformations (e.g., those employing cinchona alkaloids) for which optimization is essentially based on a trial-and-error approach. The experience of the authors is that these reactions can be tackled with a rational approach employing Design of Experiments (DoE). This tool is widely exploited in industrial process chemistry, but is little known within academia. The purpose of this account is to show the effectiveness and utility of DoE in asymmetric non-covalently organocatalyzed reactions, discussing selected examples.

1 Introduction: Covalently and Non-Covalently Asymmetric Organocatalyzed Reactions

2 The Challenge: Optimizing (in a Rational Way) Non-Covalently Organocatalyzed Reactions without Deep Knowledge of the Mechanism. Case Study 1

3 The Solution: DoE Might be the Best Possible Tool to Approach these Issues

4 The Application of DoE to Kinetic Resolution. Case Study 2

5 Conclusions and Outlook

Key words

organocatalysis - Design of Experiments - non-covalent organocatalysis - asymmetric synthesis - synthetic methodologies

• References

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