Pushing the limits of catalytic C–H amination in polyoxygenated cyclobutanes

A synthetic route to a new class of conformationally constrained iminosugars based on a 5-azaspiro[3.4] octane skeleton has been developed by way of Rh(II)-catalyzed C(sp(3))-H amination. The pivotal stereo-controlled formation of the quaternary C-N bond by insertion into the C-H bonds of the cyclobutane ring was explored with a series of polyoxygenated substrates. In addition to anticipated regioselective issues induced by the high density of activated alpha-ethereal C-H bonds, this systematic study showed that cyclobutane C-H bonds were, in general, poorly reactive towards catalytic C-H amination. This was demonstrated inter alia by the unexpected formation of a oxathiazonane derivative, which constitutes a very rare example of the formation of a 9-membered ring by way of catalyzed C(sp(3))-H amination. A complete stereocontrol could be however achieved by activating the key insertion position as an allylic C-H bond in combination with reducing the electron density at the undesired C-H insertion sites by using electron-withdrawing protecting groups. Preliminary biological evaluations of the synthesized spiro-iminosugars were performed, which led to the identification of a new class of correctors of the defective F508del-CFTR gating involved in cystic fibrosis.