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

• Published in: Journal of organic chemistry 2013-05, Vol.78 (9), p.4278-4296
• Main Authors: An, Chihui, Jurica, Jon A, Walsh, Shawn P, Hoye, Adam T, Smith, Amos B
• Format: Article
• Language: English
• Subjects: Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Chemistry Techniques, Synthetic; Coumarins - chemical synthesis; Coumarins - chemistry; Coumarins - pharmacology; Drug Discovery; Molecular Structure; Stereoisomerism
• ISSN: 0022-3263; 1520-6904
• DOI: 10.1021/jo400260m

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.