TOTAL SYNTHESIS OF THE SERINE-THREONINE PHOSPHATASE INHIBITOR MICROCYSTIN-LA

Reversible protein phosphorylation, which is mediated by kinases and p hosphatases, is a major control element of the cell. There is a divers e group of toxic natural products that inhibit certain phosphatases, t hereby disrupting normal biochemical pathways. These toxins can be use ful for dissecting the individual biochemical pathways associated with each of these enzymes. This Article describes the first total synthes is of one such toxin, the cyclic heptapeptide microcystin-LA. The synt hesis features a convergent route that is amenable to analog preparati on in the search for selective phosphatase inhibitors. A new route to the unusual amino acid Adda is described, which incorporates an effici ent diastereoselective aspartate alkylation and diene synthesis via a Suzuki coupling reaction. This work also features an efficient prepara tion of an N-methylalanine containing peptide via a Homer-Emmons conde nsation and several difficult amino acid coupling reactions that relie d heavily on Carpino's remarkable HATU reagent.