Synthesis and Complete Stereochemical Assignment of Psymberin/Irciniastatin A

We describe a concise and flexible synthetic avenue for the preparation of compounds with structures relevant to those proposed for the novel marine-derived differential cytotoxins psymberin and irciniastatin A. Our efforts led to their complete stereochemical assignment and the notion that psymberin and irciniastatin A are identical compounds. Our total synthesis features an interesting termini-differentiating lactolization of a dialdehyde obtained from a C2-symmetrical bis-olefin precursor, a mild platinum-catalyzed hydrolysis of an epimerizable nitrile, a novel protocol to prepare sensitive methyl imidates, and a one-pot conversion of these imidates to N-acyl aminals. Starting from fragments 5−7 (prepared in 7−8 steps each, 30−49% overall yield) the synthesis of psymberin/irciniastatin A was completed in an additional 9 steps and 30% yield (17 steps longest linear sequence, 8.9% overall).