Alpha,beta-unsaturated beta-silyl imide substrates for catalytic, enantioselective conjugate additions: a total synthesis of (+)-lactacystin and the discovery of a new proteasome inhibitor.
Chiral (salen)Al mu-oxo dimer 1 catalyzes the highly enantioselective conjugate addition of carbon-centered nucleophiles to alpha,beta-unsaturated silyl imides. Allyldimethylsilane-substituted imide 4 was identified as an optimal substrate, undergoing addition reactions with a variety of nitrile nucleophiles in high yield and enantiomeric excess. The silicon-containing products are synthetically useful chiral building blocks, as demonstrated by their application to an enantioselective total synthesis of the potent proteasome inhibitor (+)-lactacystin (2). Elaboration of lactam 5a to the natural product was effected in 12 steps and in 11% overall yield and proceeded through an unusual spiro beta-lactone intermediate (11). This compound was found to inhibit the chymotrypsin-like site of the 26S proteasome at similar levels to known inhibitor clasto-lactacystin beta-lactone (omuralide).
Balskus
Emily P
EP
Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA 02138, USA.
Jacobsen
Eric N
EN
D000111:Acetylcysteine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry; D000818:Animals; D002384:Catalysis; D004353:Drug Evaluation, Preclinical / Q000379:methods; D007094:Imides / Q000737:chemistry; D007769:Lactams / Q000737:chemistry; D007783:Lactones / Q000737:chemistry / Q000494:pharmacology; D015394:Molecular Structure; D011480:Protease Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D061988:Proteasome Inhibitors; D011817:Rabbits; D013237:Stereoisomerism
D007094:Imides; D007769:Lactams; D007783:Lactones; D011480:Protease Inhibitors; D061988:Proteasome Inhibitors; C117645:omuralide; C067713:lactacystin; D000111:Acetylcysteine