Highly enantioselective darzens reaction of a camphor-derived sulfonium amide to give glycidic amides and their applications in synthesis.
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.
School of Chemistry, Bristol University, Cantock's Close, UK.
Varinder K
VK
Aggarwal
George
G
Hynd
Willy
W
Picoul
Jean-Luc
JL
Vasse
D000577:Amides / Q000138:chemical synthesis / Q000737:chemistry*; D002164:Camphor / Q000031:analogs & derivatives* / Q000737:chemistry; D003998:Dicarboxylic Acids / Q000138:chemical synthesis; D004852:Epoxy Compounds / Q000138:chemical synthesis / Q000737:chemistry*; D020024:Leukotriene Antagonists / Q000138:chemical synthesis; D011422:Propionates / Q000138:chemical synthesis / Q000737:chemistry*; D013237:Stereoisomerism; D013452:Sulfonium Compounds / Q000737:chemistry*
D000577:Amides; D003998:Dicarboxylic Acids; D004852:Epoxy Compounds; D020024:Leukotriene Antagonists; D011422:Propionates; D013452:Sulfonium Compounds; C007869:glycidic acid; D002164:Camphor; C052393:pobilukast