Enantioselective Organocatalytic Amine-Isocyanate Capture-Cyclization: Regioselective Alkene Iodoamination for the Synthesis of Chiral Cyclic Ureas

Ureas of chiral diamines
are prominent features of therapeutics,
chiral auxiliaries, and intermediates in complex molecule synthesis.
Although many methods for diamine synthesis are available, metal-free
enantioselective alkene functionalizations to make protected 1,2-
and 1,3-diamines from simple achiral starting materials are rare,
and a single reagent that accesses a cross-section of each congener
with high enantiomeric excess is not available. We describe a method
to synthesize enantioenriched cyclic 5- and 6-membered ureas from
allylic amines and an isocyanate using a C2-symmetric bis­(amidine) (BAM) catalyst that delivers N-selectivity from an ambident sulfonyl imide intermediate, overcoming
electronic and steric deactivation at nitrogen. The geometry of 1,2-disubstituted
alkenes is correlated to 5-exo and 6-endo cyclizations without altering alkene face selectivity, which is
unexpectedly opposite that observed with O-nucleophiles.
Straightforward product manipulations to diamine and imidazolidinone
derivatives are underscored by the synthesis of an NK1 antagonist.