Stereocontrolled spirocyclization of exo-glycals with arylamines for the synthesis of (1S)-spiro-tetrahydroquinoline glycosides

Abstract

Herein, we present a ZnCl₂-promoted coupling of exo-glycals and arylamines for the stereospecific synthesis of (1S)-spiro-tetrahydroquinoline glycosides in a one-pot fashion. The reactions are proposed to proceed via a tandem dehydrative amination/hydration/spirocyclization sequence to construct the C–C and C–N bonds and afford the anomeric spiro glycosides in 60–90% yields with excellent stereoselectivity. An excellent diastereomeric ratio is observed in reactions involving either exo-glucal or exo-galactal substrates, and only the S-isomers were obtained. This methodology can be applied to alkyl-, F-, Br-, Cl-, NO₂- and ester-substituted anilines, as well as sterically congested 1-aminoanthraquinone and 4-benzylaniline, for the synthesis of spiro-4-tetrahydroquinoline glycosides as SGLT2 inhibitor tofogliflozin mimics.