Axially Chiral Cannabinoids: Design, Synthesis, and Cannabinoid Receptor Affinity.

The resorcinol-terpene phytocannabinoid template is a privileged scaffold for the development of diverse therapeutics targeting the endocannabinoid system. Axially chiral cannabinols (axCBNs) are unnatural cannabinols (CBNs) that bear an additional C10 substituent, which twists the cannabinol biaryl framework out of planarity creating an axis of chirality. This unique structural modification is hypothesized to enhance both the physical and biological properties of cannabinoid ligands, thus ushering in the next generation of endocannabinoid system chemical probes and cannabinoid-inspired leads for drug development. In this full report, we describe the philosophy guiding the design of axCBNs as well as several synthetic strategies for their construction. We also introduce a second class of axially chiral cannabinoids inspired by cannabidiol (CBD), termed axially chiral cannabidiols (axCBDs). Finally, we provide an analysis of axially chiral cannabinoid (axCannabinoid) atropisomerism, which spans two classes (class 1 and 3 atropisomers), and provide first evidence that axCannabinoids retain─and in some cases, strengthen─affinity and functional activity at cannabinoid receptors. Together, these findings present a promising new direction for the design of novel cannabinoid ligands for drug discovery and exploration of the complex endocannabinoid system.

Axially Chiral Cannabinols: A New Platform for Cannabinoid-Inspired Drug Discovery.

Phytocannabinoids (and synthetic analogs thereof) are gaining significant attention as promising leads in modern medicine. Considering this, new directions for the design of phytocannabinoid-inspired molecules is 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 two main factors directing our interest to these scaffolds: (a) ax-CBNs would have ground-state three-dimensionality; ligand-receptor interactions can be more significant with complimentary 3D-topology, and (b) ax-CBNs at their core structure are biaryl molecules, generally attractive platforms for pharmaceutical development due to their ease of functionalization and stability. Herein we report a synthesis of ax-CBNs, examine physical properties experimentally and computationally, and perform a comparative analysis of ax-CBN and THC in mice behavioral studies.

Tetrahydrobenzochromene Synthesis Enabled by a Deconjugative Alkylation/Tsuji-Saegusa-Ito Oxidation on Knoevenagel Adducts.

A modular and practical route to versatile cyano-1,3-dienes by a sequence involving deconjugative alkylation and "Tsuji-Saegusa-Ito oxidation" is reported. In this letter, the versatility of the products is also explored, including a route to benzochromene scaffolds common to many natural products.

Deconjugative alkylation/Heck reaction as a simple platform for dihydronaphthalene synthesis.

A simple platform for carbocycle synthesis by Knoevenagel adduct deconjugative alkylation/Heck reaction is described. Deconjugative alkylation of Knoevenagels adducts is two-fold synthetically enabling because C-C bond formation is (1) operationally simple due to the ease of Knoevenagel adduct carbanion generation and (2) results in alkene migration, which poises the substrate for cyclization. Furthermore, the gem-dinitrile moiety serves as a functional group for synthetic manipulation.

Knoevenagel Adducts as Trimethylenemethane Dipole Surrogates.

Knoevenagel adducts derived from readily available acetoxyacetone and malonic acid derivatives served as trimethylenemethane surrogates for formal 1,3-difunctionalization through a sequence of selective γ-deprotonation/α-alkylation and palladium(0)-catalyzed allylic alkylation. Herein, we report the discovery and development of a three-component 1,3-difunctionalization of Knoevenagel adducts as well as a unique palladium(0)-catalyzed branch-selective allylic alkylation.