Total Synthesis of Motuporin (Nodularin-V)

Abstract

The serine/threonine phosphatase (protein phosphatase 1 and 2A) inhibitors constitute a biologically and structurally interesting class of natural products. Among this class of inhibitors are cyclic pentapeptides (nodularins) and cyclic heptapeptides (microcystins), both of which inhibit at the nanomolar level and are the only peptide inhibitors of these enzymes. Described herein is the total synthesis of motuporin, which utilizes an Ugi four-component condensation (4CC) reaction to synthesize the 2-( N )-methylaminobutenyl residue, Matteson's dihalomethyllithium insertion methodology for the construction of a key fragment, and an overall synthetic strategy amenable to the synthesis of analogues.