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.

The reaction of an amide-stabilized sulfonium ylide bearing chiral groups on sulfur has been investigated. We have discovered that the camphor-derived amide-stabilized ylide reacts with aldehydes at -50 degrees C in ethanol to give glycidic amides in one step with up to 99% ee and complete diastereoselectivity. From analyzing reactions of different ratios of diastereomers at sulfur it was found that the major diastereomer gave very high enantioselectivity, while the minor one gave much lower selectivity (54% ee). Further mechanistic studies have revealed that enantioselectivity is controlled not in the betaine-forming step (C-C bond formation is reversible) but in the different barriers to bond rotation around the newly formed C-C of the two diastereomeric betaines. Further transformations of epoxyamides were investigated. It was found that epoxyamides could be converted into epoxyketones by reaction with organolithium reagents and that they could be ring-opened by nucleophiles with complete regioselectivity using Yb(OTf)3. The practicality of the process has been exemplified in the synthesis of SK&F 104353, a leukotriene D4 antagonist in the potential treatment of bronchial asthma.

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