Exploring the Chemistry of Bicyclic Isoxazolidines for the Multicomponent Synthesis of Glycomimetic Building Blocks

Starting
from a chiral furanone, the nitrone–olefin [3 +
2] cycloaddition can be used to obtain bicyclic isoxazolidines for
which we report a set of reactions to selectively modify each functional
position. These synthetically versatile bicyclic isoxazolidines allowed
us to obtain complex glycomimetic building blocks, like iminosugars,
via multicomponent chemistry. For example, a library of 20 pipecolic
acid derivatives, a recurring motif in various prescription drugs,
could be obtained via a one-pot Staudinger/aza-Wittig/Ugi three-component
reaction of a bicyclic isoxazolidine-derived azido-hemiacetal. Notably,
specific pipecolic acids in this library were obtained via hydrolysis
of an unique tricyclic imidate side product of the Ugi reaction. The
azido-hemiacetal was also converted into an aza-C-glycoside iminosugar via an unprecendented one-pot Staudinger/aza-Wittig/Mannich
reaction.