Asymmetric [2+2] cycloaddition of ketenes: Toward the total synthesis of (+)-lactacystin and (-)-salinosporamide A.

The ability of proteasome inhibitors to inhibit cell proliferation and selectively induce apoptosis in proliferating cells makes them attractive candidates as anti-cancer drugs. Proteasome inhibition has been efficient in anti-tumoral treatment and lead to the approval by the FDA of Bortezomib in 2003. Other proteasome inhibitors are currently under study such as lactacystin and salinosporamide A. Isolated in 2003, salinosporamide A inhibits all three catalytic activities of the proteasome (IC50∼1 nM) and is currently in phase I clin. trial for the treatment of multiple myeloma and refractory lymphoma. The enantioselective total syntheses of lactacystin and salinosporamide A published to date illustrate the structural complexity of this target despite its small size. The strategy of our team is to develop an original and efficient synthesis of salinosporamides via an asym. [2+2] cycloaddn. between a ketene and chiral enol ethers. Cycloaddn. limited to the use of dichloroketene hitherto was extended to a wide range of ketenes (alkyl, aryl, furyl), leading to various highly functionalized cyclobutanones. These chiral cyclobutanones were engaged in the total synthesis of natural products: lactacystin and salinosporamide A. The unified strategy involved a Beckmann type ring expansion and late side chains functionalization thanks to the use of an original siloxane ketene.


Asymmetric [2+2] cycloaddition of ketenes: Toward the total synthesis of (+)-lactacystin and (-)-salinosporamide A.
Type de publication
Conference Paper
Année de publication
Conference Name
Abstracts of Papers, 250th ACS National Meeting {&} Exposition, Boston, MA, United States, August 16-20, 2015
American Chemical Society
Soumis le 17 mai 2018