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Total Synthesis of Axially-Chiral Cannabinols: A New Platform for Cannabinoid-Based Drug Discovery

preprint
submitted on 05.11.2019 and posted on 13.11.2019 by Primali Navaratne, Jenny Wilkerson, Kavindri Ranasinghe, Evgeniya Semenova, Lance McMahon, Adrian Roitberg, Ion Ghivirga, Alex Grenning

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.

Funding

We thank the University of Florida for start-up funds

History

Email Address of Submitting Author

grenning@ufl.edu

Institution

University of Florida

Country

United States

ORCID For Submitting Author

0000-0002-8182-9464

Declaration of Conflict of Interest

No Conflict of Interest

Version Notes

First version of submission

Exports