Highly Enantioselective Synthesis of Glycidic Amides Using Camphor-Derived Sulfonium Salts. Mechanism and Applications in Synthesis

The reactions of a range of amide-stabilized sulfur ylides derived from readily available camphor-derived sulfonium salts for the synthesis of glycidic amides have been studied. Primary, secondary, and
tertiary amides were tested, and it was found that the highest enantioselectivities were observed with tertiary
amides, which provided glycidic amides in good to excellent yields, exclusive trans selectivity, and excellent
enantioselectivities. The reaction was general for aromatic aldehydes, but aliphatic aldehydes gave more
variable enantioselectivities. The epoxy amides could be converted cleanly into epoxy ketones by treatment
with organolithium reagents. We were also able to effect selective ring opening of the epoxy amides with
a variety of nucleophiles, followed by hydrolysis of the amide to yield the corresponding carboxylic acid.
This methodology was applied to the total synthesis of the target compound SK&F 104353. A combination
of crossover experiments and theoretical calculations has revealed that the rate- and selectivity-determining
step is ring closure, not betaine formation as was the case for phenyl-stabilized ylides.