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      Total synthesis of (+)-irciniastatin A (a.k.a. psymberin) and (-)-irciniastatin B.

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          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.

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          Author and article information

          Journal
          J. Org. Chem.
          The Journal of organic chemistry
          American Chemical Society (ACS)
          1520-6904
          0022-3263
          May 03 2013
          : 78
          : 9
          Affiliations
          [1 ] Department of Chemistry, Laboratory for Research on the Structure of Matter and Monell Chemical Senses Center, University of Pennsylvania, Philadelphia, Pennsylvania 19104, United States.
          Article
          NIHMS462505
          10.1021/jo400260m
          3651581
          23510264
          2c80395b-c63e-4a90-ac83-e1c8af47089d
          History

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