Total Synthesis of (+)-Irciniastatin A (a.k.a. Psymberin) and (−)-Irciniastatin B

A unified synthetic strategy to access (+)-irciniastatin A (a.k.a. psymberin) and (−)-irciniastatin B, two cytotoxic secondary metabolites, has been achieved. Highlights of the convergent strategy comprise a boron-mediated aldol union to set the C(15)–C(17) <i>syn–syn</i> triad, reagent control to set the four stereocenters of the tetrahydropyran core, and a late-stage Curtius rearrangement to install the acid-sensitive stereogenic <i>N</i>,<i>O</i>-aminal. Having achieved the total synthesis of (+)-irciniastatin A, we devised an improved synthetic route to the tetrahydropyran core (13 steps) compared to the first-generation synthesis (22 steps). Construction of the structurally similar (−)-irciniastatin B was then achieved via modification of a late-stage (−)-irciniastatin A intermediate to implement a chemoselective deprotection/oxidation sequence to access the requisite oxidation state at C(11) of the tetrahydropyran core. Of particular significance, the unified strategy will permit late-stage diversification for analogue development, designed to explore the biological role of substitution at the C(11) position of these highly potent tumor cell growth inhibitory molecules