Probing Competitive and Co-operative Hydroxyl and Ammonium Hydrogen-Bonding Directed Epoxidations

The
diastereoselectivities and rates of epoxidation (upon treatment
with Cl3CCO2H then m-CPBA)
of a range of cis- and trans-4-aminocycloalk-2-en-1-ol
derivatives (containing five-, six-, and seven-membered rings) have
been investigated. In all cases where the two potential directing
groups can promote epoxidation on opposite faces of the ring scaffold,
evidence of competitive epoxidation pathways, promoted by hydrogen-bonding
to either the in situ formed ammonium moiety or the hydroxyl group,
was observed. In contrast to the relative directing group abilities
already established for the six-membered ring system (NHBn ≫
OH > NBn2), an N,N-dibenzylammonium
moiety appeared more proficient than a hydroxyl group at directing
the stereochemical course of the epoxidation reaction in a five- or
seven-membered system. In the former case, this was rationalized by
the drive to minimize torsional strain in the transition state being
coupled with assistance from hydrogen-bonding to the ammonium moiety.
In the latter case, this was ascribed to the steric bulk of the ammonium
moiety disfavoring conformations in which hydrogen-bonding to the
hydroxyl group results in direction of the epoxidation to the syn face. In cases where the two potential directing groups
can promote epoxidation on the same face of the ring scaffold, an
enhancement of epoxidation diastereoselectivity was not observed,
while introduction of a second, allylic heteroatom to the substrate
results in diminishment of the rate of epoxidation in all cases. Presumably,
reduction of the nucleophilicity of the olefin by the second, inductively
electron-withdrawing heteroatom is the dominant factor, and any assistance
to the epoxidation reaction by the potential to form hydrogen-bonds
to two directing groups rather than one is clearly unable to overwhelm
it.