Current pain management, relying heavily on NSAIDs and opioids, lacks efficacy or is accompanied by very serious side effects, such as addiction, dependence and tolerance. Rhodojaponin III, a grayanane-type natural product, exhibits potent antinociceptive activity against neuropathic, chemically induced and inflammatory-derived pain. More importantly, rhodojaponin III does not affect the endogenous opioid peptidergic system, potentially providing a novel class of non-opioid analgesics.<br/>Motivated by rhodojaponin III’s unique analgesic activity and potential as a chemical probe for pain research, we embarked on the synthesis of this natural product. Our strategy utilizes a convergent approach, in which a cyclopentane ring fragment can be coupled with a bicyclo[3.2.1]octane moiety to provide the rhodojaponin core. Herein, we describe our efforts towards the stereoselective synthesis of the bicyclo[3.2.1]octane moiety accomplished via an intramolecular Mn(III)-mediated radical cyclization of alkynyl ketones, which will be applicable in the total synthesis of rhodojaponin III and other grayanane-type natural products for future biological studies.

Synthesis of the bicyclo[3.2.1]octane fragment of rhodojaponin III via an intramolecular Mn(III)-mediated radical cyclization

ACS Fall 2021

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