Minor Cannabinoid Synthesis by Flow Chemistry

It is commonly accepted that the simple yet profound preparation of urea by Friedrich Wohler in 1828 was the first documented natural product synthesis. ¹ Since then, equally successful and impressive syntheses of thousands of other far more complex natural products have been achieved. However, nearly two hundred years after the Wohler synthesis and even with increasingly advanced organic chemistry methodology, most natural product syntheses continue to be accomplished (like urea) by a single batch (per reaction step) method. For each reaction step of a batch process, a highly trained organic chemist 1) assembles the unique (often complex) reaction apparatus, 2) performs the reaction, 3) conducts a preliminary reaction work-up and 4) purifies the desired reaction product in a highly manual way. This 4-part batch process is then repeated for each synthetic step. Often, such syntheses also require the exacting precautions of oxygen or moisture exclusion.

Interestingly, over the past 25 years another emerging chemistry concept has been developed to streamline the efficient construction of organic substances and is referred to as “flow chemistry.” To be clear, flow chemistry often utilizes precisely the same chemistry as the widely practiced traditional synthesis / batch method just described. However, instead of the labor and time-intensive batch process synthesis, flow chemistry is significantly automated, usually conducted in a dedicated space equipped with the appropriate reaction vessels, necessary liquid handling and real time reaction monitoring by analytical systems. ² Even complicated multi-reaction step syntheses can often be accommodated by flow chemistry as one reaction step “module” is connected or “telescoped” into the next. Many current or newly discovered reactions can likely be performed by flow chemistry in a more controlled, robust and safer way. Flow chemistry is often described as “continuous” and in theory capable of working for prolonged periods of time. Proof of this paradigm shift is the accelerated growth of thousands of diverse flow chemistry publications especially during the last decade (SciFinder® chemistry database).

Remarkably, even though there have been notable thought leaders like Steven Ley (University of Cambridge) who have strongly advocated using flow chemistry in natural product synthesis, ³ a literature search reveals that natural product applications of flow chemistry have been relatively underrepresented. One specific synthetic area which would appear to greatly benefit from flow chemistry would be the Cannabis natural product collection. To date, characterization of the cannabinoid family has been extremely disproportionate and largely focused on its ensemble of four major chemical constituents: delta-9-tetrahydrocannabinol (THC), cannabidiol (CBD), cannabigerol (CBG) and cannabichromene (CBC) mostly because of their higher Cannabis concentrations and / or ease of isolation. Aside from these four main compounds, the remaining cannabinoids (in often lesser amounts with more challenging purifications) have been simply designated as “minor.” However, in the past few years, there has been renewed interest in the minor cannabinoids catalyzed by their potential therapeutic value. Unfortunately, progress in the minor cannabinoid area has been delayed by their meager amounts and resulting lack of thorough evaluation.^4–6

So far, there have only been a mere handful of cannabinoid synthesis articles^7–9 among the thousands of peer-reviewed flow chemistry publications. Although most of these few papers dealt with CBD or THC, they were all impactful and demonstrated that cannabinoid synthesis can in principle be accomplished by flow chemistry. In fact, one of these articles ⁹ even described the use of flow chemistry for the efficient assembly of the minor cannabinoids cannabidibutol (CBDB) and cannabidivarin (CBDV). A Reviewer asked for comment about the possible reasons for the slow adoption of flow chemistry in the cannabinoid area. One likely factor is simply the lack of familiarity with this unique technology. Ideally, this discussion will heighten awareness of how flow chemistry can be more fully employed as a powerful synthetic tool to thoroughly explore the minor cannabinoid family as possible therapeutic agents.