Despite the prevalence of the RyR in cardiac function, only a few therapies have been developed for the prevention and treatment of cardiac disease that target the ryanodine receptor (RyR). To determine whether or not such therapies might be developed from the isoryanodane framework, we propose to complete a total synthesis of the natural isoryanodanes perseanol and 18-hydroxyperseanol. Access to the isoryanodanes will position us to assess the ability of these diterpenes to bind to the RyR, specifically, through the preparation of unnatural isoryanodanes bearing the critical pyrrole-2-carboxylate ester. Two highly convergent strategies aimed at efficiently establishing the polycyclic framework of these natural products are detailed. In the first strategy, a Heck cyclization/Stille cross-coupling cascade is proposed. The resulting allyl group serves as a handle to forge the 7- membered D-ring lactone in a two-step sequence involving a highly chemoselective Stahl aerobic oxidation. In the second strategy, a late-stage SmI2-mediated ketyl radical cyclization is envisioned to forge, at once, the C8?C9 bond and a critical all-carbon quaternary center. The development of an efficient and general approach will allow a comprehensive evaluation of these small molecules for the preparation of RyR isoform-selective molecular probes. The result of such a systematic approach will be the ability to rationally design small molecules for the treatment of cardiac disease. In doing so, we believe novel and potentially more effective cardiac treatments will be produced.
The AHA has predicted that costs dedicated to the treatment of heart failure will continue to rise, attributed in part to the lack of growth in new strategies to prevent and treat heart failure. Our work on the total synthesis of the isoryanodanes offers a unique and new entry to a potentially vast area of research targeted at better understanding the RyR. Specifically, we seek to expand the library of compounds?beyond those accessible by isolation chemistry and degradation alone?for the evaluation and development of new drugs, which may prove useful in reducing the incidence of heart failure.
| Xu, Chen; Han, Arthur; Reisman, Sarah E (2018) An Oxidative Dearomatization Approach To Prepare the Pentacyclic Core of Ryanodol. Org Lett 20:3793-3796 |
