<div> <div> <div> <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. </p> </div> </div> </div>

<p>Cascade reactions (also known as domino- or tandem reactions) are an efficient strategy for generating molecular complexity. We report that synergizing the thermal reactivity of 3,3-dicyano-1,5-dienes and <i>tert</i>-butyl carbonates result in stereospecific 2,3,4-trisubstituted tetrahydrofuran synthesis. While substituted tetrahydrofurans can be challenging to synthesize, this discovery converts readily available 1,5-dienes derived from aldehydes, malononitrile, and <i>cis</i>-buten-1,4-diol into complex tetrahydrofurans <i>via </i>a process involving <i>thermal </i>Cope rearrangement, Boc-deprotection, and <i>oxy</i>-Michael addition. Described herein includes background related to the discovery, optimization and scope, and representative functional group interconversion chemistry for the scaffolds. </p>

<div> <div> <div> <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. </p> </div> </div> </div>