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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

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

Emily P Balskus, Eric N Jacobsen

J Am Chem Soc. 2006 May 31;128(21):6810-2.

PMID: 16719460

Abstract:

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).

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP1113128	Diallyldimethylsilane		1113-12-8	Price

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