Photoredox catalyzed cycloadditions of carbonyl ylides and synthesis of neocannabinoids
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Abstract
Herein is a comprehensive synthetic platform for producing classical lignan natural products and their unnatural analogs, emphasizing methodologies that enhance structureactivity relationship studies for potential therapeutic applications. This work leverages a convergent synthetic route involving photoredox catalyzed [3+2] dipolar cycloadditions of carbonyl ylides from epoxides, and dipolarophiles, resulting in structurally complex cyclic ethers. These ethers, integral to classical lignans, are converted into densely functionalized dihydronaphthalenes and arylnaphthalenes, enabling the total synthesis of bioactive products and diverse derivatives. The research further explores selectivity challenges in the photoredox cycloaddition of carbonyl ylides, aiming to achieve regioselective synthesis. By employing 𝛼-cyano epoxides to control regioselectivity, the methodology was advanced to incorporate unsymmetrical reaction partners. This advancement led to the regioselective synthesis of classical lignan natural products which were inaccessible in the prior work.In tandem with the classical lignan project, an exploration into cannabinoids was undertaken. Over recent years, synthetic cannabinoid isomers and novel cannabinoid receptors, beyond the classical CB1 and CB2 receptors, have expanded the scope of cannabinoid-based drug discovery. In this work, controlled Friedel-Crafts reactions were employed to synthesize a variety of neocannabinoid isomers, including ortho- and parasubstituted analogs. This approach facilitates the generation of both normal and abnormal cannabidiol analogs, providing insights into kinetic and thermodynamic parameters critical for optimizing neocannabinoid synthesis. Additionally, the research includes the enumeration of a virtual library of neocannabinoids to accelerate the identification of bioactive compounds, presenting a streamlined pathway for drug discovery within the cannabinoid field.
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2025