Biomimetic Approaches to Synthesis of Cannabidiol

Found in cannabis, cannabidiol (CBD) holds promise as a nonpsychoactive cannabinoid in treating a number of conditions, including anxiety, schizophrenia, and some forms of epilepsy. However, large scale studies on the therapeutic use of CBD are lacking, and more research is needed to precisely establish its safety and efficacy. Extraction of CBD from cannabis is challenging, and past methods of synthesizing CBD have suffered from at least one of the following: poor selectivity, low yields, complex and laborious reaction sequences, or unavailable starting materials. We report here a concise approach to CBD synthesis from readily available nerol. This route uses directed orthometallation to regioselectively allylate olivetol dimethyl ether, followed by a biomimetic oxidative cyclization with Mn(III) to cleanly generate dimethyl CBD in low yield. We also demonstrate that using cationic polyene cyclization as the key ring-forming step produces a similar yield of dimethyl CBD in a complex mixture of isomers.