Multiple sclerosis (MS) is an autoimmune disorder of the central nervous system characterized by inflammatory demyelination and currently has no cure. Caspase-1, also known as interleukin-1� converting enzyme (ICE), is recognized to play an important role in regulation of the inflammatory processes leading to demyelination. Studies over the years, using ICE deficient mice, have indicated prominent role of ICE in inflammatory processes. Inhibitors of ICE, therefore, have the potential to culminate in a possible treatment option for MS.Stierle and coworkers isolated Berkeleyamide A (BerkA) from the fungus Penicillum rubrum in 2008, which exhibited low micromolar ICE inhibitory activity. BerkA has a pyrrolidone scaffold containing three stereogenic centers with ambiguous absolute configuration. The total synthesis was achieved by constructing the target molecule from commercially available amino acids. Key reactions, such as asymmetric aldol reaction, Horner-Wadsworth-Emmons reaction, azide transfer reaction and palladium catalyst mediated cyclization will be discussed. This study will aid in identification of bioactive isomer of the natural product, which then will be subjected to further structure activity relationship studies.

Total synthesis of Berkeleyamide-A: A potent caspase-1 inhibitor

239th National Meeting (2010)

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