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...

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Bibliographic Details
Published in:Journal of the American Chemical Society 2006-02, Vol.128 (6), p.2105-2114
Main Authors: Aggarwal, Varinder K, Charmant, Jonathan P. H, Fuentes, Daniel, Harvey, Jeremy N, Hynd, George, Ohara, Diasuke, Picoul, Willy, Robiette, Raphaël, Smith, Catherine, Vasse, Jean-Luc, Winn, Caroline L
Format: Article
Language:English
Subjects:
Amides - chemical synthesis
Camphor - analogs & derivatives
Camphor - chemistry
Chemistry
Crystallography, X-Ray
Dicarboxylic Acids - chemical synthesis
Epoxy Compounds - chemistry
Exact sciences and technology
Leukotriene Antagonists - chemical synthesis
Molecular Conformation
Organic chemistry
Propionates - chemistry
Stereoisomerism
Sulfides - chemical synthesis
Sulfonium Compounds - chemistry
Thermodynamics
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Summary: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.
ISSN:0002-7863
1520-5126
DOI:10.1021/ja0568345