An efficient, stereocontrolled synthesis of a potent omuralide-salinosporin hybrid for selective proteasome inhibition.
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.
Reddy
Leleti Rajender
LR
Department of Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts 02138, USA.
Fournier
Jean-François
JF
Subba Reddy
B V
BV
Corey
E J
EJ
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
D004791:Enzyme Inhibitors; D007783:Lactones; D061988:Proteasome Inhibitors; D011758:Pyrroles; C117645:omuralide; C475865:marizomib