Environmental Control of Regio‐/Stereoselectivity Across Mechanistically Similar Transformations

The control of regio‐ and stereoselectivity in organic transformations remains a foundational challenge in synthetic chemistry. While chemoselectivity can often be influenced by careful selection of reagents or protective groups, controlling regio‐ and stereoselectivity is far more nuanced, often requiring highly specific reaction conditions. In this work, a unified approach for controlling both regio‐ and stereoselectivity across mechanistically related transformations is explored, specifically focusing on epoxide openings and carbonyl additions. It is demonstrated that the same environmental factors, here the nature of the Lewis acid (LA), can be leveraged to influence divergent outcomes in these two reaction types by amplifying inherent differences between reaction sites/faces, leading to highly selective transformations. The systematic evaluation of over 30 Lewis acids revealed a dichotomy between “labile” and “strong” activation modes, where strong LAs, such as AlCl 3 and SnCl 4 , drive the highest levels of regio‐ and diastereoselectivity for both transformations. Further, there exists nuanced differences between the degree of influence of some LA within these mechanistically related transformations. These findings suggest that environmental factors can be broadly applied across different mechanistic classes to achieve selectivity, offering a versatile strategy for reaction optimization.