Molecular complexity as a driving force for the advancement of organic synthesis

Abstract

The generation of molecular complexity is a primary goal in the field of synthetic chemistry. In the context of retrosynthetic analysis, the concept of molecular complexity is central to identifying productive disconnections and the development of efficient total syntheses. However, this field-defining concept is frequently invoked on an intuitive basis without precise definition or appreciation of its subtleties. Methods for quantifying molecular complexity could prove useful for characterizing the state of synthesis in a more rigorous, reliable and reproducible fashion. As a first step to evaluating the importance of these methods to the state of the field, here we present our perspective on the development of molecular complexity quantification and its implications for chemical synthesis. The extension and application of these methods beyond computer-aided synthesis planning and medicinal chemistry to the traditional practice of ‘complex molecule’ synthesis could have the potential to unearth new opportunities and more efficient approaches for synthesis. Quantifying molecular complexity has the potential to enhance retrosynthetic analysis and, thus, aid the development of efficient total syntheses. This Perspective discusses methods for rigorous, reproducible complexity measurement, highlighting their potential to revolutionize traditional complex molecule synthesis and uncover new synthetic opportunities.