Enantioselective total synthesis of (+)-Lactacystin: Development of α,β-unsaturated β-silyl imide substrates for asymmetric catalytic conjugate additions

ORGN 300

Emily P. Balskus, ebalskus@fas.harvard.edu and Eric N. Jacobsen, jacobsen@chemistry.harvard.edu. Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA 02138
Chiral (salen)Al complex 1 catalyzes the highly enantioselective conjugate addition of carbon-based nucleophiles to α,β-unsaturated β-silyl imides. Allyldimethylsilane-substituted imide 2 is an optimal substrate, providing adducts in high yield and enantiomeric excess. A variety of activated nitrile nucleophiles can be used in this transformation. The chiral silicon-containing products are useful building blocks for total synthesis, as demonstrated by their application to an enantioselective total synthesis of the potent proteasome inhibitor (+)-lactacystin. Elaboration of lactam 3 to the natural product proceeds in 12 steps and in good overall yield.

 

Asymmetric Reactions and Syntheses
1:00 PM-5:00 PM, Monday, 11 September 2006 Moscone Center -- Room 131, Oral

Division of Organic Chemistry

The 232nd ACS National Meeting, San Francisco, CA, September 10-14, 2006