Abstract
The development of the structurally complex MDM2/p53 inhibitor AM-8553 was impeded by the low yield of the initial synthesis. A second generation synthesis is described that features a Noyori dynamic kinetic resolution, a highly diastereoselective allylation, and a novel oxazoline-assisted piperidinone forming reaction to provide AM-8553 in 35.6% yield and 11 steps.
MeSH terms
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Acetates / chemical synthesis*
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Acetates / chemistry
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Amino Alcohols / chemical synthesis
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Amino Alcohols / chemistry
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Antineoplastic Agents / chemical synthesis*
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Antineoplastic Agents / chemistry
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Cyclization
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Humans
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Lactones / chemical synthesis
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Lactones / chemistry
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Models, Molecular
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Oxazoles / chemical synthesis
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Oxazoles / chemistry
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Piperidones / chemical synthesis*
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Piperidones / chemistry
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Proto-Oncogene Proteins c-mdm2 / antagonists & inhibitors*
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Stereoisomerism
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Tumor Suppressor Protein p53 / antagonists & inhibitors*
Substances
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2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(2-hydroxypentan-3-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid
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Acetates
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Amino Alcohols
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Antineoplastic Agents
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Lactones
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Oxazoles
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Piperidones
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Tumor Suppressor Protein p53
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MDM2 protein, human
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Proto-Oncogene Proteins c-mdm2