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<p>Phytocannabinoids, molecules isolated from cannabis, are gaining attention as promising leads in modern
medicine, including pain management. Considering the urgent need for combating the opioid crisis, new
directions for the design of cannabinoid-inspired analgesics are of immediate interest. In this regard, we have
hypothesized that axially-chiral-cannabinols (ax-CBNs), unnatural (and unknown) isomers of cannabinol (CBN)
may be valuable scaffolds for cannabinoid-inspired drug discovery. There are multiple reasons for thinking this:
(a) ax-CBNs would have ground-state three-dimensionality akin to THC, a key bioactive component of cannabis,
(b) ax-CBNs at their core structure are biaryl molecules, generally attractive platforms for pharmaceutical
development due to their ease of functionalization and stability, and (c) atropisomerism with respect to
phytocannabinoids is unexplored “chemical space.” Herein we report a scalable total synthesis of ax-CBNs,
examine physical properties experimentally and computationally, and provide preliminary behavioral and
analgesic analysis of the novel scaffolds.
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