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

J Am Chem Soc. 2006 May 31;128(21):6810-2. doi: 10.1021/ja061970a.

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).

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Acetylcysteine / analogs & derivatives*
  • Acetylcysteine / chemical synthesis
  • Acetylcysteine / chemistry
  • Animals
  • Catalysis
  • Drug Evaluation, Preclinical / methods
  • Imides / chemistry
  • Lactams / chemistry
  • Lactones / chemistry
  • Lactones / pharmacology
  • Molecular Structure
  • Protease Inhibitors / chemistry*
  • Protease Inhibitors / pharmacology*
  • Proteasome Inhibitors*
  • Rabbits
  • Stereoisomerism

Substances

  • Imides
  • Lactams
  • Lactones
  • Protease Inhibitors
  • Proteasome Inhibitors
  • omuralide
  • lactacystin
  • Acetylcysteine