Due to opioid overdose, over 130 people die each day. With about 25% of prescribed patients abusing opioids, an alternative to an incredibly addictive drug is necessary to eradicate the ‘opioid crisis.’ Considering natural products’ rich history in drug development, the class of molecules provides an excellent starting point for drug discovery. In 2015, rhodojaponin III, a grayanane-type natural product, was determined to be a more potent inhibitor of acute and inflammatory derived pain compared to morphine and 100-fold more potent in diabetic neuropathic pain compared to gabapentin. Interestingly, rhodojaponin III does not affect the endogenous opioid peptidergic system, which provides an alternative mode of action compared to that of morphine. Therefore, the goal of this project is to complete the first total synthesis of rhodojaponin III and investigate the mode of action of this natural product to aid in research for a new non-opioid analgesic.
Our strategy utilizes a convergent approach, in which two major fragments will be synthesized separately and then coupled together to provide the core of rhodojaponins. Currently, our research has established a synthetic route for the first of two coupling partners, a practical approach for coupling the two major fragments together, utilizing a Nozaki–Hiyama–Kishi coupling, and an efficient method for establishing the 5/6 fused ring system via a Conia-ene cyclization. Upon completion of the total synthesis, mode of action studies will be conducted, analogs will be developed and structure activity relationships (SARs) will be elucidated to guide future development of non-opioid analgesics.