Letter to the Editor: The Controversial Cannabidiol Cyclization: Its Conceptual Origin

Dear Editor,

The acid catalyzed cyclization of cannabidiol (through its isopropenyl group) to both delta-9-tetrahydrocannabinol and its more thermodynamically stable olefin isomer delta-8-tetrahydrocannabinol has been known for 80 years. This reaction has also prompted recent controversy with the suggestion and detailed rebuttal¹ that this same chemistry might occur during human oral ingestion of cannabidiol. Although its synthetic utility is diminished because of its nature as a product mixture, this cyclization is still unique and fascinating in that nonintoxicating cannabidiol is directly converted to several intoxicating cannabinoids. Only rarely in medicinal chemistry does a single step bond-forming reaction accomplish such a dramatic pharmacological transformation. It is widely acknowledged² that the first experimental report of the cannabidiol cyclization can be attributed to natural products chemist Roger Adams at the University of Illinois in 1940 during a prolific program of Cannabis chemistry exploration.³ Remarkably, Adams also described this transformation with only an incomplete structural understanding of the substances involved.

The brief account mentioned provides some needed historical perspective for the cannabidiol cyclization, aspects of which are scattered in the literature. However, the purpose of this note is to reveal a key fact that appears (by a SciFinder^® database search) to have been overlooked in the many thousands of articles involving cannabidiol, namely, the earliest conceptual origin of this profound reaction. Given his many important technical contributions to cannabinoid chemistry, it may be natural to assume that Roger Adams not only experimentally discovered but was also the first to even imagine the cannabidiol cyclization. However, a closer examination of earlier literature has revealed a different and perhaps surprising conclusion. British chemist Robert S. Cahn (1899–1981) had a long and storied career, best known for his contributions to chemical nomenclature and stereochemistry, especially the Cahn-Ingold-Prelog Rules.⁴ What is likely less known about him is that starting in 1930, Cahn also published a series of four Cannabis chemistry articles in the Journal of the Chemical Society as he traveled from the Egyptian University, Cairo, to the University College of North Wales. In his fourth and final article,⁵ Cahn ventured a flawed yet impressive guess at the structure of cannabinol. His proposed terpene-derived ring portion of the cannabinol structure was correct, but the resorcinol substituents were incorrectly positioned. However, despite this faulty structural model, Cahn still made a novel and prescient chemistry proposal a few pages deeper into his article.

As shown on page 1402 (Fig. 1; reproduced by permission of The Royal Society of Chemistry) of that article at the end of the second full paragraph was drawn the partial structure of a cannabinoid terpene-derived (A) ring and resorcinol (B) ring. Clearly seen in this structure and described in the accompanying text was Cahn's remarkably accurate prediction that Cannabis would likely contain an unknown cannabinoid decorated with an isopropenyl moiety (like cannabidiol), synthetically capable of undergoing an “intramolecular ring closure” to a dibenzopyran ring system. This hunch was of course the exact reaction that Adams experimentally discovered for cannabidiol a decade later at the chemistry bench. A Cannabis literature search has produced no other description or image of an isopropenyl group associated with a cannabinoid before this publication. Cahn also correctly stopped short of suggesting that this transformation was a Cannabis biosynthetic pathway. This was Cahn's last article in the Cannabis area before moving on to other topics of interest to him. It provides compelling evidence that Robert S. Cahn was not only the first to propose the existence of a cannabidiol-like substance in Cannabis but also its facile cyclization.

FIG. 1.

Page 1402 of J. Chem. Soc. 1933;1400–1405 (reproduced by permission of The Royal Society of Chemistry). The homepage for the Journal of the Chemical Society is at: https://pubs.rsc.org/en/journals/journalissues/js#!issueid=js1877_32_0&type=archive&issnprint=0368-1769

Author Disclosure Statement

No competing financial interests exist.

Cite this article as: Filer CN (2021) Letter to the editor: The controversial cannabidiol cyclization: Its conceptual origin, Cannabis and Cannabinoid Research 6:4, 358–359, DOI: 10.1089/can.2020.0099.