UC Berkeley

The prevalence of saturated azacycles within pharmaceuticals, natural products, and agrochemicals has prompted the development of many methods that modify their periphery. In contrast, technologies that interconvert distinct saturated azacyclic frameworks, which would uniquely facilitate access to underexplored chemical space, are highly limited. Existing approaches for modifying the core of azacycles usually require either the installation of reactive functionality, which must later be removed in subsequent steps, or the use of tailored substrates, limiting applicability to drug discovery. Herein, we report a borane-catalyzed contraction of saturated N-hydroxy azacycles. This transformation is uniquely enabling, allowing reorganization of the connectivity of the substrate without altering the molecular formula and generating products without vestigial functionality derived from auxiliary groups. The outcome of the reductive Stieglitz-type contraction can be attributed to a key stereoelectronic interaction enforced by geometric constraints, the mechanism of which we investigate using density functional theory. The method developed here enables the rapid late-stage reorganization of bioactive molecules featuring cyclic and linear amines. Overall, a general platform for saturated amine constitutional isomerization has been achieved.