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.
Aggarwal
Varinder K
VK
School of Chemistry and Structural Chemistry Laboratory, School of Chemistry, University of Bristol, Cantock's Close, Bristol BS8 1TS, U.K. v.aggarwal@bristol.ac.uk
Charmant
Jonathan P H
JP
Fuentes
Daniel
D
Harvey
Jeremy N
JN
Hynd
George
G
Ohara
Diasuke
D
Picoul
Willy
W
Robiette
Raphaël
R
Smith
Catherine
C
Vasse
Jean-Luc
JL
Winn
Caroline L
CL
D000577:Amides / Q000138:chemical synthesis*; D002164:Camphor / Q000031:analogs & derivatives* / Q000737:chemistry; D018360:Crystallography, X-Ray; D003998:Dicarboxylic Acids / Q000138:chemical synthesis; D004852:Epoxy Compounds / Q000737:chemistry*; D020024:Leukotriene Antagonists / Q000138:chemical synthesis; D008968:Molecular Conformation; D011422:Propionates / Q000737:chemistry*; D013237:Stereoisomerism; D013440:Sulfides / Q000138:chemical synthesis; D013452:Sulfonium Compounds / Q000737:chemistry*; D013816:Thermodynamics
D000577:Amides; D003998:Dicarboxylic Acids; D004852:Epoxy Compounds; D020024:Leukotriene Antagonists; D011422:Propionates; D013440:Sulfides; D013452:Sulfonium Compounds; C007869:glycidic acid; D002164:Camphor; C052393:pobilukast