A concise and straightforward total synthesis of (+/-)-salinosporamide A, based on a biosynthesis model.
A 14-step total synthesis of (+/-)-salinosporamide A (1), a potent inhibitor of the 20S proteasome isolated from the marine bacterium Salinospora tropica, is described. The synthesis is based on a diastereoselective intramolecular aldolisation of a substituted beta-keto amide intermediate, i.e. 13, derived from a beta-keto acid, viz. 21, and an alpha-amino malonate, leading to the pyrrolidinone ring 24 in the natural product. This synthetic approach closely mimics the origin of the pyrrolidinone ring in salinosporamide A in vivo. Another key feature of the total synthesis is a regioselective reduction of the malonate derivative 31 to the key aldehyde intermediate 32, using Super-hydride.
Mulholland
Nicholas P
NP
School of Chemistry, University of Nottingham, Nottingham, UK.
Pattenden
Gerald
G
Walters
Iain A S
IA
D000447:Aldehydes / Q000737:chemistry; D007783:Lactones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008314:Malonates / Q000737:chemistry; D008954:Models, Biological; D015394:Molecular Structure; D046988:Proteasome Endopeptidase Complex / Q000187:drug effects; D061988:Proteasome Inhibitors; D011758:Pyrroles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011760:Pyrrolidinones / Q000737:chemistry; D013237:Stereoisomerism
D000447:Aldehydes; D007783:Lactones; D008314:Malonates; D061988:Proteasome Inhibitors; D011758:Pyrroles; D011760:Pyrrolidinones; C475865:marizomib; C030290:malonic acid; D046988:Proteasome Endopeptidase Complex