A Concise, Enantioselective Approach to the Synthesis of (-)-Rhodomollanol-A

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PROJECT SUMMARY The number of people suffering with type II diabetes has nearly quadrupled in the past four decades. While many treatments exist, new biological targets for small molecule therapeutic development are needed. In this regard, a promising target is protein tyrosine phosphatase 1B, which is overexpressed in obese/diabetic individuals, weakening the effects of insulin for these people. Inhibition of this enzyme would be an attractive option for a diabetes drug, however selective inhibition without off-target activity is a difficult problem. Recently, a new diterpenoid possessing a previously unknown carbon skeleton was isolated and characterized, and was found to exhibit notable protein tyrosine phosphatase 1B inhibition. This new diterpenoid, rhodomollanol A, shares many structural features with the well-known grayanane diterpenoid class, though the right hand portion of the molecule is significantly rearranged, changing its shape substantially. Despite these structural differences, grayanane diterpenoids have also been reported to exhibit protein tyrosine phosphatase 1B inhibitory activity on par with that reported for rhodomollanol A. The discovery of rhodomollanol A provides a new structural class upon which to base the search for a safe, selective protein tyrosine phosphatase 1B inhibitor, and given the reported inhibitory activity for the structurally distinct grayanane diterpenoids, represents a unique opportunity to better understand the structural criteria required for inhibition of this important target. Only six milligrams of pure rhodomollanol A was isolated from twenty-five kilograms of plant material, making obtaining the requisite material for studies a significant barrier to fully evaluating the potential of this structural class. Herein, we propose a total synthesis of rhodomollanol A. A linear sequence of twenty- one steps is proposed starting from 2,2-dimethylcyclopent-4-ene-1,3-dione, featuring a proposed intramolecular Pauson-Khand reaction and an oxyallyl cation [3+2] as the key steps to rapidly assemble the rhodomollane skeleton. The proposed route allows for ample modification to the core structure, providing opportunities to synthesize derivatives of rhodomollanol-A with potentially more potent protein tyrosine phosphatase 1B inhibition. The inhibitory activity of these derivatives will be studied in collaboration with the research group of Professor Eli Chapman, whose lab has developed several types of assays to examine protein tyrosine phosphatase inhibition, and has demonstrated expertise in this area through their recent publication (Biochemistry, 2019, 58, 3225).