An expeditious synthesis of the MDM2-p53 inhibitor AM-8553.
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.
Department of Medicinal Chemistry, Amgen, Inc., S. San Francisco, California 94080, United States. blucas@amgen.com
Brian S
BS
Lucas
Benjamin
B
Fisher
Lawrence R
LR
McGee
Steven H
SH
Olson
Julio C
JC
Medina
Eugene
E
Cheung
D000085:Acetates / Q000138:chemical synthesis* / Q000737:chemistry; D000605:Amino Alcohols / Q000138:chemical synthesis / Q000737:chemistry; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry; D003500:Cyclization; D006801:Humans; D007783:Lactones / Q000138:chemical synthesis / Q000737:chemistry; D008958:Models, Molecular; D010080:Oxazoles / Q000138:chemical synthesis / Q000737:chemistry; D010881:Piperidones / Q000138:chemical synthesis* / Q000737:chemistry; D051736:Proto-Oncogene Proteins c-mdm2 / Q000037:antagonists & inhibitors*; D013237:Stereoisomerism; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors*
C575269:2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(2-hydroxypentan-3-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid; D000085:Acetates; D000605:Amino Alcohols; D000970:Antineoplastic Agents; D007783:Lactones; D010080:Oxazoles; D010881:Piperidones; D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2