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.
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.
The resorcinol-terpene phytocannabinoid template is a privileged scaffold for the development of diverse therapeutics target-ing the endocannabinoid system. Axially chiral cannabinols (axCBNs) are unnatural cannabinols (CBNs) that bear an addi-tional C10 substituent, which twists the cannabinol biaryl framework out of planarity creating an axis of chirality. This “es-cape from flatland” is hypothesized to enhance both the physical and biological properties of cannabinoid ligands, thus ush-ering in the next generation of endocannabinoid system chemical probes and cannabinoid-inspired leads for drug develop-ment. 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) atro-pisomerism, 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 en-docannabinoid system.
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.
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.
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.
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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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Knoevenagel Adducts as Trimethylenemethane Dipole Surrogates. -A novel strategy is disclosed for the difunctionalization of Knoevenagel adducts (I) and (VIII). The process involves Pd(0)-catalyzed allylation with allyl-tert-butyl carbonates and a second Pd-catalyzed coupling with O-or C-nucleophiles. -(VERTESALJAI, P.; NAVARATNE, P. V.; GRENNING*, A. J.; Angew. Chem., Int. Ed. 55 (2016) 1, 317-320, http://dx.
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