The DARK Side of Total Synthesis: Strategies and Tactics in Psychoactive Drug Production

Abstract

Humankind has used and abused psychoactive drugs for millennia. Formally, a psychoactive drug is any agent that alters cognition and mood. The term “psychotropic drug” is neutral and describes the entire class of substrates, licit and illicit, of interest to governmental drug policy. While these drugs are prescribed for issues ranging from pain management to anxiety, they are also used recreationally. In fact, the current opioid epidemic is the deadliest drug crisis in American history. While the topic is highly politicized with racial, gender, and socioeconomic elements, there is no denying the toll drug mis- and overuse is taking on this country. Overdose, fueled by opioids, is the leading cause of death for Americans under 50 years of age, killing ca. 64,000 people in 2016. From a chemistry standpoint, the question is in what ways, if any, did organic chemists contribute to this problem? In this targeted review, we provide brief historical accounts of the main classes of psychoactive drugs and discuss several foundational total syntheses that ultimately provide the groundwork for producing these molecules in academic, industrial, and clandestine settings.

Identification and associated hazards of clandestine drug laboratories

“…Of these classes, the 1,4‐benzodiazepines are the most common, with over 3,000 analogues reported in 2013 (Chambers, DeSousa, Huseman, & Townsend, 2018; Golovenko & Larionov, 2014).…”

“…Originally, BZO synthesis was believed to only occur in Malaysia (International Narcotics Control Board, 2013a), however, recently there has been an increase in BZO production in western and central Europe (International Narcotics Control Board, 2019b), and BZO pill pressing operations have been on the rise (“BBC News,” 2018; Moosmann, Bisel, & Auwärter, 2014). Many of the BZOs encountered were first synthesized and evaluated by pharmaceutical companies, and the pharmacological data and reaction mechanisms and pathways are published in the literature or can be found in patents (Batlle, Lizano, Viñas, & Pujol, 2019; Chambers et al, 2018; EMCDDA, n.d.‐a; Z. Li et al, 2007; Majid, Khanday, & Tomar, 2012; Moosmann et al, 2013; Moosmann, King, & Auwärter, 2015; Sternbach, Fryer, Metlesics, Reeder, et al, 1962; Sternbach, Fryer, Metlesics, Sach, & Stempel, 1962). In addition to the synthetic pathways being readily obtainable, many of the BZO syntheses are rather straightforward and do not require significant knowledge of chemistry (Cooper, 1988).…”

Fully Validated, Multi-Kilogram cGMP Synthesis of MDMA

“…Clandestine chemists preparing MDMA for the black market have additionally developed a number of synthetic routes from readily available starting materials like catechol ( 7 ), 19 eugenol ( 8 ), 19 isosafrole ( 9 ), 20 and piperine ( 10 ), 21 though most still approach MDMA through a safrole 22 or (less frequently) piperonal 21 intermediate. These synthetic methods often rely on chemicals readily available to ordinary consumers, in an effort to circumvent controlled substance precursor regulations.…”

“…16 A novel approach from piperonal, via Curtius rearrangement, was reported by Schulze, in 2010, 17 and a handful of asymmetric syntheses of (S)-MDMA, some relying on alternate starting materials, have also appeared in the literature (Scheme 1). 18 Clandestine chemists preparing MDMA for the black market have additionally developed a number of synthetic routes from readily available starting materials like catechol (7), 19 eugenol (8), 19 isosafrole (9), 20 and piperine (10), 21 though most still approach MDMA through a safrole 22 or (less frequently) piperonal 21 intermediate. These synthetic methods often rely on chemicals readily available to ordinary consumers, in an effort to circumvent controlled substance precursor regulations.…”

Deconstructive Asymmetric Total Synthesis of Morphine‐Family Alkaloid (−)‐Thebainone A

“…Consequently,m orphine alkaloids have continuously attracted significant attentions from the synthetic community for more than 70 years.Since the first synthesis of morphine by Gates in 1952, [3] over 40 synthesis routes of morphine alkaloids have been reported and more than 30 prominent synthetic research groups have been involved. [4][5][6] Beyond just at arget of synthesis,t he morphine scaffold has more or less become atouchstone for examining efficiency of new synthetic strategies or robustness of new synthetic methods.…”