title: Total synthesis of (+)-irciniastatin A (a.k.a. psymberin) and (-)-irciniastatin B.
abstract: 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) syn-syn triad, reagent control to set the four stereocenters of the tetrahydropyran core, and a late-stage Curtius rearrangement to install the acid-sensitive stereogenic N,O-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.
authors.affiliation: Department of Chemistry, Laboratory for Research on the Structure of Matter and Monell Chemical Senses Center, University of Pennsylvania, Philadelphia, Pennsylvania 19104, United States.
authors.forename: Chihui
authors.initials: C
authors.lastname: An
authors.forename: Jon A
authors.initials: JA
authors.lastname: Jurica
authors.forename: Shawn P
authors.initials: SP
authors.lastname: Walsh
authors.forename: Adam T
authors.initials: AT
authors.lastname: Hoye
authors.forename: Amos B
authors.initials: AB
authors.lastname: Smith
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D060326:Chemistry Techniques, Synthetic; D003374:Coumarins / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D055808:Drug Discovery; D015394:Molecular Structure; D013237:Stereoisomerism
chemical_list: D000970:Antineoplastic Agents; D003374:Coumarins; C483487:irciniastatin B; C498383:psymberin