Web Release Date: May 6,
,
-Unsaturated -Silyl Imide Substrates for Catalytic, Enantioselective
Conjugate Additions: A Total Synthesis of (+)-Lactacystin and the Discovery
of a New Proteasome Inhibitor
Department of Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts 02138
Received March 22, 2006
Abstract:
Chiral (salen)Al 
-oxo dimer 1 catalyzes the highly enantioselective conjugate addition of carbon-centered nucleophiles to ,-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 -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 -lactone (omuralide).
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