Enantioselective Three-Component Amination of Enecarbamates Enables the Synthesis of Structurally Complex Small Molecules

The control of asymmetric synthesis
tools represents a major challenge,
especially when it comes to the synthesis of bioactive molecules.
In this context, the asymmetric synthesis of 1,2-diamines through
amination of enecarbamates has been proposed as a highly efficient
and tunable approach. Indeed, reactivity of the latter species could
be exploited to realize a double functionalization via an electrophilic
amination followed by nucleophilic trapping. Herein, we describe a
chiral phosphoric acid catalyzed electrophilic amination of enecarbamates
with dibenzyl azodicarboxylate and oxygenated or thiol-containing
nucleophiles affording stable precursors of α-hydrazinoimines
in high yields and with almost complete enantioselectivities (up to
>99%). These precursors were successfully functionalized with various
silylated nucleophiles without epimerization of the stereogenic center,
giving access to a wide range of 1,2-disubstituted 1,2-diamines. We
also show that the thiolated precursors were successfully engaged
in a Friedel–Crafts reaction against a variety of aromatic
and heteroaromatic nucleophiles, leading to various 1-(hetero)­aryl-1,2-diamines
without loss of enantioselectivity and with complete diastereoselectivity.
Reductive N–N bond cleavage provided the N,N-diprotected 1,2-diamines with no loss in diastereo-
or enantioselectivity. The protocol was successfully scaled up to
a multigram scale and the catalyst was successfully recovered, demonstrating
the potential applications of this new methodology.