Traceless Electrophilic Amination for the Synthesis of Unprotected Cyclic β‑Amino Acids

Electrophilic aminations involve
an umpolung of a nitrogen atom,
providing an alternate, distinctive synthetic strategy. The recent
advent of various designed O-substituted hydroxylamines
has significantly advanced this research field. An underappreciated
issue is atom economy of the transformations: The necessary activating
group on the oxygen atom is left in coproduced waste. Herein, we describe
Rh-catalyzed electrophilic amination of substituted isoxazolidin-5-ones
for the synthesis of unprotected, cyclic β-amino acids featuring
either benzo-fused or spirocyclic scaffolds. Using the cyclic hydroxylamines
allows for retaining both nitrogen and oxygen functionalities in the
product. The traceless, redox neutral process proceeds on a gram scale
with as little as 0.1 mol % catalyst loading. In contrast to related
electrophilic aminations in the literature, a series of mechanistic
experiments suggests a unique pathway involving spirocyclization,
followed by the skeletal rearrangement. The insights provided herein
shed light on a nuanced reactivity of the active species, Rh-nitrenoid
generated from the activated hydroxylamine, and extend the knowledge
on electrophilic aromatic substitutions.