Friday, July 27, 2012

Biomimetic Syntheses of Highly Complex Guaianolide Sesquiterpenoid Dimers

          Guaianolide-type sesquiterpenoid lactone dimers (e.g. 1) are characterized by complex heptacyclic ring systems, architectural features that are not easily accessed by conventional total synthesis methods. Moreover, from an organic synthetic perspective, it is difficult to envision a more daunting target than the ainsliatrimers (represented by 2), aesthetically pleasing sesquiterpene trimers characterized in 2008 by the laboratories of Hui-Zi Jin and Wei-Dong Zhang. Notably, the collective chemical synthesis of several guaianolide sesquiterpenoids related to (and including) 1 was recently reported in JACS by implementation of a concise and biomimetic strategy. The synthetic sequence, disclosed by Xiaoguang Lei and co-workers, features a brilliant one-pot cascade transformation that includes a Saegusa oxidation, intermolecular Diels-Alder cycloaddition and a radical-mediated allylic oxidation to install the tertiary hydroxyl functionality at C10.
          The advanced sesquiterpenoid lactone 3, derived synthetically from the natural product alpha-santonin (11 steps, protecting group-free), was first converted to its corresponding silyl enol ether by treatment with hexamethyldisilazane and trimethylsilyl iodide. A remarkable one-pot cascade transformation then completed the synthesis of gochnatiolide A (1).
          By exposure of 4 to Saegusa oxidation conditions in the presence of a stoichiometric excess of the dienophile (6 equivalents of 3), a Diels-Alder cycloaddition ensued (carbon connectivity shown above in brackets) that was accompanied by alkene isomerization to generate a thermodynamically favored cyclopentenone system. This olefin isomerization event then facilitates the generation of a tertiary radical at C10 (stabilized by the newly formed enone) and a subsequent reaction of the radical with molecular oxygen affords a peroxyl radical that is reduced in situ to generate 1 in a single operation. The endo transition state depicted above may or may not represent the operative pathway for this fascinating cascade transformation. Due to the concomitant alkene isomerization, it is difficult to discern the precise geometric arrangement of the cycloaddition transition state. 
          The rapid and biomimetic nature of this synthetic campaign is reminiscent of the cationic polyolefin cyclization chemistry developed by W. S. Johnson and E. J. Corey for the total synthesis of well known steroids and terpenoids. The authors report that studies directed toward the syntheses of the ainsliatrimers (e.g. 2) are underway.

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