Stereoselective construction of cyclic quaternary stereocenters by Prins cyclization with ketones

Abstract

We report a general Prins-type cyclization that enables the efficient construction of tetrahydropyrans bearing quaternary carbon centers from ketone substrates. The transformation accommodates a broad range of cyclic, acyclic, and heterocyclic ketones, providing access to highly substituted and spirocyclic frameworks with high efficiency. Notably, the method resolves a long-standing stereochemical challenge associated with unsymmetrical ketones, delivering predictable and high levels of diastereocontrol (up to 95 : 5 dr) through steric differentiation of the ketone substituents. Increasing steric demand at the carbonyl substituent directly translates into enhanced selectivity at the newly formed quaternary center. The reaction operates under both iodide- and bromide-mediated conditions, representing the first example of a bromide-enabled Prins cyclization of ketones. Furthermore, the resulting halogenated tetrahydropyrans function as versatile intermediates for downstream functionalization. Together, this work establishes a broadly applicable and stereocontrolled ketone-based Prins cyclization and substantially broadens the synthetic scope of this classical transformation.