title: An efficient, stereocontrolled synthesis of a potent omuralide-salinosporin hybrid for selective proteasome inhibition.
abstract: A short and highly stereocontrolled synthesis of the potent proteasome inhibitor 3 from the (S)-threonine-derived oxazoline 4 has been developed. The synthetic sequence is summarized in Scheme 1. Aldol coupling of the zinc enolate of 4 with isobutyraldehyde and subsequent silylation provided the TBS ether 5 diastereoselectively (10:1). Reductive cleavage of the oxazoline ring of 5 followed by Swern oxidation of the resulting amino alcohol afforded amino ketone 6, converted further by N-acylation to the acrylamide 7, whose structure was confirmed by X-ray crystallographic analysis. Acrylamide 7 was cyclized to 8 by a novel application of the Kulinkovich Ti(II)-cyclopentene complex. Silylation of 8 to 9 and radical cyclization at low temperature produced the bicyclic lactam 10 with complete control of all stereocenters. Hydroxy desilylation and N-deprotection of 10 gave the dihydroxy ester 11, which was converted to 3 by a novel three-step sequence: (1) demethylation with [Me2AlTeMe]2, (2) combined beta-lactonization and chlorination, and (3) desilylation to effect cleavage of the TBS ether.
authors.affiliation: Department of Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts 02138, USA.
authors.forename: Leleti Rajender
authors.initials: LR
authors.lastname: Reddy
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Fournier
authors.forename: B V
authors.initials: BV
authors.lastname: Subba Reddy
authors.forename: E J
authors.initials: EJ
authors.lastname: Corey
mesh_terms: D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D007783:Lactones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D008968:Molecular Conformation; D061988:Proteasome Inhibitors; D011758:Pyrroles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013237:Stereoisomerism
chemical_list: D004791:Enzyme Inhibitors; D007783:Lactones; D061988:Proteasome Inhibitors; D011758:Pyrroles; C117645:omuralide; C475865:marizomib