Highly Enantioselective, Hydrogen-Bond-Donor Catalyzed Additions to Oxetanes

A precisely designed
chiral squaramide derivative is shown to promote
the highly enantioselective addition of trimethylsilyl bromide (TMSBr)
to a broad variety of 3-substituted and 3,3-disubstituted oxetanes.
The reaction provides direct and general access to synthetically valuable
1,3-bromohydrin building blocks from easily accessed achiral precursors.
The products are readily elaborated both by nucleophilic substitution
and through transition-metal-catalyzed cross-coupling reactions. The
enantioselective catalytic oxetane ring opening was employed as part
of a three-step, gram-scale synthesis of pretomanid, a recently approved
medication for the treatment of multidrug-resistant tuberculosis.
Heavy-atom kinetic isotope effect (KIE) studies are consistent with
enantiodetermining delivery of bromide from the H-bond-donor (HBD)
catalyst to the activated oxetane. While the nucleophilicity of the
bromide ion is expected to be attenuated by association to the HBD,
overall rate acceleration is achieved by enhancement of Lewis acidity
of the TMSBr reagent through anion abstraction.