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

Review
Cite This: ACS Chem. Neurosci. XXXX, XXX, XXX−XXX pubs.acs.org/chemneuro
The DARK Side of Total Synthesis: Strategies and Tactics in

Psychoactive Drug Production
Schuyler A. Chambers,† Jenna M. DeSousa,† Eric D. Huseman,† and Steven D. Townsend*,†,‡
†
Department of Chemistry, Vanderbilt University, 7330 Stevenson Center, Nashville, Tennessee 37235, United States
‡
Institute of Chemical Biology, Vanderbilt University, 896 Preston Research Building, Nashville, Tennessee 37232, United States
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.
KEYWORDS: Opiate, opioid, psychoactive, stimulant, benzodiazepines, hallucinogens
1. INTRODUCTION Table 1. Psychoactive Drug Addiction in Americaa

Psychoactive drugs affect cognition by influencing the synaptic estimated number of Americans with substance use
operation of neurotransmitters in the central nervous system substance disorder (SUD)
(CNS).1−4 This action occurs through one of three general tobacco 52 million
mechanisms:5 (1) as agonists that mimic the operation of a alcohol 17 million
neurotransmitter; (2) as antagonists that block the action of a marijuana 8.3 million
neurotransmitter; or (3) by blocking the reuptake of neuro- pain killersb 3.8 million
transmitters at the synapse. In this regard, psychoactive drugs cocaine 1.9 million
mimic or enhance naturally occurring states of consciousness; hallucinogenc 1.2 million
for example, sleeping pills promote drowsiness while methamphetamine 900 K
benzodiazepines create a state of relaxation. Long-term use, heroin 330 K
whether medicinally or recreationally, often leads to tolerance, a
Values taken from ref 6. bOpiates, opioids, and benzodiazepines.
requiring the user to increase a drug’s dosage in order to c
LSD, PCP, MDMA, mescaline, DMT, and ketamine.
achieve the baseline effect. As drug use increases, the user may
also develop dependence in one of two forms. The first is
psychological dependence, in which the user feels the urge to neglectful to not briefly discuss the “DARK” and highly
use the drug but abstinence poses no risk. The second form is politicized nature of the topic. Virtually all known civilizations
physical dependence where serious physical and mental effects have used psychoactive drugs in an effort to self-medicate,
develop when a drug is withdrawn. In the United States anesthetize from emotional or physical trauma, or for
millions of people use psychoactive drugs everyday (Table 1).6 recreational and religious purposes. In the United States,
While misuse is prominent, approximately one in three aggressive marketing of painkillers has led to a generation of
Americans are prescribed an opiate/opioid for pain manage- individuals with opioid use disorders and a death toll closing in
ment every year,7 a testament to the importance of licit drug on 200 people per day. In both the second world war and
use for maintaining human health and wellness. Vietnam war, the Department of Defense employed “speed” or
amphetamine to empower soldiers on the frontlines and
sedatives and neuroleptics to prevent mental breakdowns from
2. SCOPE OF THIS REVIEW
2.1. The United States Overdose Epidemic. While the Special Issue: DARK Classics in Chemical Neuroscience
goal of this survey is to review synthetic strategies used to
produce the carbon frameworks of psychoactive drugs, it is Received: December 28, 2017
undeniable that the scholarly exercises completed by organic Accepted: January 17, 2018
chemists have guided illicit drug production. Thus, we would be Published: January 17, 2018
© XXXX American Chemical Society A DOI: 10.1021/acschemneuro.7b00528

ACS Chem. Neurosci. XXXX, XXX, XXX−XXX
ACS Chemical Neuroscience Review
Figure 1. Structures of various natural and semisynthetic opioid alkaloids. aHydrocodone is also referred to as dihydrocodeinone. bVicodin is a
combination of hydrocodone and acetaminophen. cPercocet is a combination of oxycodone and acetaminophen. dSuboxone is a combination of
naloxone and buprenorphine. Structural requirements of the so-called “morphine rule” are highlighted in pink.
combat stress.8 The crack-cocaine epidemic of the 1980s and Ultimately, the closing of pill mills combined with an inability
early 1990s wreaked havoc among low-income, urban to treat addiction initiated a dark chapter in psychoactive drug
Americans. Similarly, “backyard”-produced methamphetamine use: the resurgence of heroin and the emergence of fentanyl.
reached its pinnacle among poorer rural Americans in the This has resulted in nearly 1000 deaths per week due to drug
1990s and early 21st century. One difference between those overdose, two-thirds of which are opioid related fatalities. The
crises and the current iteration of the American drug epidemic problem is so great that the illicit drug trade is currently the
is that opioid use disorder has its genesis at the pharmacy second most lucrative industry in the world, after weapons.10
counter and crosses broad demographic groups. While the most problematic players in the drug crisis, and the
2.2. Chemistry’s Role in the Crisis. From a chemistry largest section of this review, are opium alkaloids, they are not
perspective, the current epidemic can likely be traced back to the only burdensome psychoactive drugs. In fact, deciding
the introduction of OxyContin. “Oxy” is a semisynthetic opioid which agents are defined as drugs, how drug supply and use is
that shares structural homology with morphine, vide inf ra. regulated, and how society responds to drug users are hotly
Strong analgesics of this type have historically been reserved to debated issues. The fact that the two drugs that cause the most
manage pain associated with cancer therapy or surgery. During impairment and damage in the worldtobacco and alcohol
the mid-1990s oxycodone was marketed to treat chronic pain. are both legal in most countries illustrates this point. As does
As the use of opioids increased, pill distribution spread from the fact that caffeine, the world’s most popular stimulant, is
primary-care practitioners to neighborhood dealers. Pills were legal and unregulated worldwide. What role does organic
also sold in large quantities from poorly regulated pain chemistry play in the field of psychoactive drug synthesis and
treatment centers colloquially known as “pill mills”. The use? As one reads through the annals of published efforts, it is
problem appeared so rapidly that the American Public Health clear that legendary figures in the field, ranging from Larry
Association published a report in 2009 describing the Overman11 and Phil Magnus,12 to Kathy Parker13 and James
prescription drug crisis titled “The promotion and marketing White,14 have trained scores of students using these molecules
of OxyContin: Commercial triumph, public health tragedy”.9 as training tools. While the approaches are scholarly in nature,
B DOI: 10.1021/acschemneuro.7b00528
Scheme 1. Three Total Syntheses of (−)-Morphine by the Gates, Gaunt, and Fukuyama Labs
one cannot help but recognize the dichotomy: academic lessons tactics whereas industry has viewed their efforts as exercises in
assist in fueling both licit and clandestine drug use. scale and efficiency. Meanwhile, the underworld of synthesis
Given the level of intrigue that accompanies this class of relies upon operational simplicity and material availability to
molecules, several comprehensive accounts have been written make their syntheses practical. As a result, the de novo total
to describe both the synthesis and the reactivity of these syntheses of the academic world are commonly translated into
substrates.15−18 The gap that this review fills is to compare and large-scale semisyntheses in industrial settings that are further
contrast syntheses in academic, industrial, and clandestine simplified for illicit manufacturing in makeshift clandestine
settings. Historically, academic pursuits have focused on laboratories. With this in mind, we chose to take a similar
demonstrating novel bond forming strategies and assembly approach in the construction of this review and have
C DOI: 10.1021/acschemneuro.7b00528
highlighted various academic and industrial syntheses of the be remiss to attempt a full recapitulation of morphine’s rich
chosen psychoactive compounds before delving into their illicit synthetic history; instead, we aim to paint a broad picture and
synthesis as appropriate. It is our hope that this review will would direct the reader to the literature for a more detailed
provide the reader with a foundation for delving deeper into the exhibition.
psychoactive drug literature and give context to how scholarly The review begins with the Gates’ total synthesis of
exercises are translated to clandestine drug synthesis. morphine (Scheme 1a).24,29−32 Starting from dienophile 14,
cycloaddition with butadiene provided racemic Diels−Alder
3. THE OPIATES adduct (±)-15 in moderate yield, best represented as its enol
3.1. Historical Perspective. Opium extracts have been tautomer (±)-16.29 Cu2Cr2O5 mediated reductive hydro-
used for millennia. The earliest reference to opium production, genation was accompanied by cyclization to give (±)-17,
in which the inhabitants of southern Mesopotamia cultivated closing what would ultimately emerge as the piperidine D ring.
Papaver somniferum, the opium poppy, predates 4000 B.C.19 Six further transformations, including a chiral resolution with L-
Known as Hul Gil, or the joy plant, the art of poppy culling was (+)-dibenzoyl tartaric acid, gave enantiopure tetracycle (−)-18.
passed from the Sumerians to the Assyrians, Babylonians, and At this junction, two major obstacles remained: (1) inversion of
the ancient Egyptians. Eventually, its cultivation spread along the C-14 stereocenter and (2) closure of the dihydrofuran-like
the Silk Road from the Mediterranean to the Far East where the E ring. Thus, treatment of (−)-18 with two equivalents of Br2
British sale of opium in China was the catalyst for the Opium followed by the addition of 2,4-dinitrophenyl hydrazine
Wars of the mid-1800s.20 By way of definition, opiates are (NH2NHAr) produced an α,β-unsaturated hydrazone which
defined as any compounds, natural or semisynthetic, that share underwent epimerization at C-14 to give the thermodynami-
structural homology with opium alkaloids. We use the term cally favored β-hydrogen substituted product. Hydrolysis of the
opioid to refer to substances that elicit similar CNS effects but hydrazone and chemoselective catalytic hydrogenation gave
do not share structural homology with naturally occurring (−)-19 which was exposed to excess Br2 followed by 2,4-
poppy alkaloids.21 Regardless of their structural classification, dinitrophenyl hydrazine to simultaneously close the E ring and
opiates and opioids are large components of the illicit drug install the requisite C7−C8 unsaturation. Hydrolysis of the
market, generating revenue in excess of $55 billion per year.7 hydrazone gave enone (−)-20 which was converted to
While the pharmacology of these molecules will be covered in (−)-codeine (2) after reduction of the enone (in a 1,2 fashion)
detail in other parts of the DARK special issue, we briefly and aryl bromide. Finally, exposure to BBr3 under modified
mention here that opiates and opioids act on the CNS to Rapoport conditions gave (−)-morphine (1).
produce effects ranging from analgesia to sedation. In 2014, the Gaunt lab completed a formal synthesis of
3.2. Structure. The opiates (Figure 1) mimic the activity of (−)-morphine (Scheme 1b).33 The effort began with a seven
the endorphins, the body’s natural pain relievers. Structurally, step sequence highlighted by a Noyori transfer hydrogenation
the opiates feature a pentacyclic scaffold containing a phenolic to give chiral aldehyde (−)-22 from isovanillin (21). A
A ring, a bridging bicyclic piperidine D ring, and a dihydrofuran PhI(OAc)2 mediated, intramolecular oxidative coupling was
like E ring (Figure 1C). While masked, most receptor active followed by Michael addition to give enone (+)-24. Next, the
opiates and opioids share structural homology. These enone was elaborated to Boc-protected amine (−)-25. Luche
similarities are known as the “morphine rule” in which reduction gave the corresponding allylic alcohol, which was
compounds generally incorporate into their carbon framework heated under microwave irradiation with HCl to fragment the
(1) a tertiary nitrogen with a small alkyl substituent; (2) a cyclic enol ether and deprotect the amine. Dehydrative ring
quaternary carbon; (3) a phenyl ring or its equivalent attached closure, reductive amination, and carbamate protection gave
to the quaternary carbon; and (4) an ethyl linker between the (−)-28, completing the formal synthesis of (−)-morphine (1).
quaternary carbon and the tertiary nitrogen. This complex A third, noteworthy synthesis of morphine was reported by
architecture has served as the motivation for synthetic efforts the Fukuyama lab in 2017 (Scheme 1c).34 The synthesis began
spanning Gates’ synthesis of morphine in 1952 to the work of with the transformation of 7-methoxy-2-tetralone into chiral
Fukuyama in 2017, vide inf ra. bicycle (+)-29 using the d’Angelo approach.35 Elimination of
3.3. Natural Opiates. By weight the opium poppy P. the tertiary alcohol accompanied acid mediated ring closure.
somniferum contains ca. 8−19% morphine (1), 1−5% codeine Next, hydroselenation of the resulting olefin and oxidative
(2), and 1−5% thebaine (4). Morphine and codeine are elimination of the selenoxide gave vinyl tertiary alcohol (+)-30.
pharmaceutical agents, with morphine serving as an analgesic A retro-aldol/aldol sequence provided tetracycle 31 which was
and codeine as a cough suppressant. Contrarily, oripavine (3) transformed into diene (−)-32 in five further steps. At this
and thebaine are starting materials for semisynthetic opiates. point Diels−Alder cycloaddition with singlet oxygen gave
3.3.1. Morphine. First isolated by Sertürner in the early endoperoxide 33 which then underwent selective fragmentation
1800s,22 morphine (1) was widely prescribed because it to enone (+)-34. Elimination of the tertiary alcohol was
provides greater pain relief capacity than processed opium. followed by amine liberation and subsequent 1,6-conjugate
Morphine is one of the most effective analgesics and is the addition to give a 1:1.4 ratio of neopinone to codeinone which
standard against which new pain relievers are measured. converged to pure codeinone after acid treatment. Reduction of
Though the molecule’s structure, first proposed by Robinson23 the enone gave (−)-codeine (2) and finally (−)-morphine (1)
and later confirmed by Gates (total synthesis)24 and Hodgkin after treatment with BBr3.
(X-ray crystallography),25 has inspired several syntheses, there 3.3.2. Codeine. Codeine (2) is prescribed for the relief of
is currently no practical source of morphine, either by chemical moderate pain and cough suppression. It has less analgesic
synthesis or through fermentation, that can compete with ability than morphine and is usually taken orally. The
isolation. Nevertheless, synthetic efforts toward morphine have recommended dose is 15−60 mg every 4−6 h, not exceeding
pushed the field of organic synthesis forward and have been 360 mg/day. Given its availability, codeine is commonly
appropriately recounted.26−28 Consequently, this review would abused. When cough syrup is mixed with soft drinks, the brews
D DOI: 10.1021/acschemneuro.7b00528
Scheme 2. Synthesis of Codeine by the Trost and Stork Labs
are referred to as “lean” and “sizzurp”, among other names. followed by oxidation and LiAlH 4 reduction to give
Originating in Houston, Texas, lean gained popularity within (±)-codeine (2).
southern hip-hop culture and has been associated with a 3.4. Licit Semisynthetic Opiates. While codeine and
number of deaths. Users risk overdose once consumption morphine are important analgesics, a number of semisynthetic
approaches 500 mg/day. Synthetically, codeine serves as a key opiates are also important therapeutics.
intermediate in most morphine syntheses. 3.4.1. Hydromorphone. (−)-Hydromorphone (5, Dilaudid)
Our summary begins with Trost’s 2002 synthesis of is a potent semisynthetic opiate. Structurally, it is identical to
(−)-codeine (Scheme 2a).36 Corey−Fuchs olefination of chiral morphine with additional oxygenation at the C6 position. As a
cyanoaldehyde (−)-3537 and regioselective dehalogenation result, it is more water-soluble than morphine and displays
gave (Z)-alkene (−)-36. Next, an intramolecular Heck reaction increased efficacy (Table 2).39
was used to close the B ring. SeO2 oxidation of the resulting
tetracycle (+)-37 occurred preferentially at C6 to give a mixture Table 2. Opioid Conversion Charta
of alcohol and ketone (−)-38 oxidation products that
drug parenteral (mg) oral (mg)
converged after a Dess−Martin periodinane oxidation. Next,
morphine (1) 10 30
the cyanoketone was reduced to the corresponding hydroimine.
codeine (2) 100−130 200
Subsequent amine formation occurred in the presence of
hydromorphone (5) 1.5−2 7.5−8
methyl amine and reduction then gave (−)-39. Irradiation of
oxymorphone (6) 1 10
precursor (−)-39 and LDA in THF afforded (−)-codeine (2)
hydrocodone (7) NAb 30−45
by way of an intramolecular hydroamination. Irradiation was
oxycodone (8) NAb 20−30
critical as treatment with LDA alone did not result in a
cyclization. Values from ref 21. bNA = not available.
The Stork lab published a synthesis of (±)-codeine using a
Diels−Alder cycloaddition to establish the B and C rings in a Recently, the Hudlicky group published a second generation,
single move (Scheme 2b).38 The synthesis began by exposing chemoenzymatic formal synthesis of ent-hydromorphone
(E)-1-methoxybut-1-en-3-yne to Schwartz’s reagent followed (Scheme 3).40 Beginning with (2-bromoethyl)benzene (46),
by the addition of aldehyde 41 to give (±)-42. Heating this enzymatic dihydroxylation provided chiral diene (+)-47 which
compound in a sealed tube in the presence of Et3N produced could be elaborated to phenol (+)-48 in seven additional steps.
the Diels−Alder adduct (±)-43 as a 4:1 mixture of In a series of key transformations, oxidative phenol
diastereomers. After 10 steps, amine (±)-44 underwent 6- dearomatization was followed by Diels−Alder cycloaddition
exo-tet closure to give (±)-45. Protection of the amine was to establish the B and E rings in a single step. While Hudlicky’s
E DOI: 10.1021/acschemneuro.7b00528
Scheme 3. Hudlicky’s Second Generation Chemoenzymatic Synthesis of ent-Hydromorphone
Scheme 4. Total Synthesis of Hydrocodone from the Rice and Mulzer Labs
first generation synthesis used a Pb(OAc)4 oxidation and and the C6 carbon to their proper oxidation states and (2)
subsequent heating to give the desired Diels−Alder adduct in closure of the piperidine D ring. Rearomatization followed by
50% yield,41 the second generation approach replaced Pb- addition of TFA provided a phenolic amine that was tosylated
(OAc)4 with an iodine(III) oxidant. In the event, treatment of to give bis-tosylate (−)-51. At this stage, the first and second-
(+)-48 with PhI(OAc)2 gave ortho-quinone like intermediate generation syntheses intercepted, thus completing the formal
49. After workup and heating in toluene 49 underwent synthesis of ent-hydromorphone (ent-5).
intramolecular Diels−Alder cycloaddition to give (+)-50. 3.4.2. Hydrocodone. Hydrocodone (7) is commonly found
Two challenges remained: (1) adjustment of the A ring phenol in combination with acetaminophen in the brand named
F DOI: 10.1021/acschemneuro.7b00528
analgesic Vicodin. Synthetically, it serves as an intermediate in hydrogenation with Wilkinson’s catalyst provided enone 70.
the synthesis of codeine and morphine.42,43 At this stage, acylation of the C14 alcohol with methyl malonyl
The survey begins with Rice’s racemic effort which is chloride followed by exposure to Cs2CO3 resulted in
regarded as the approach most amenable to industrial scale up intramolecular Michael addition to form the benzylic
(Scheme 4A).44 The synthesis began with condensation of quaternary carbon. Subsequent Krapcho decarboxylation and
carboxylic acid 52 and amine 53. The amide, thus obtained, was deprotection generated phenol 71. After five additional steps
treated with POCl3 to initiate a Friedel−Crafts like acylation amide 72 was treated with PhI(OAc)2 to induce an oxidative
event completed by the reduction of the intermediate imine.45 Hofmann rearrangement. The amine, resulting from aqueous
Selective Birch reduction of the less electron rich C ring was hydrolysis of the intermediate isocyanate, ring opened the
followed by N-formylation to give formamide (±)-55. Methyl neighboring lactone to reveal the C14 alcohol and establish the
enol ether hydrolysis and concomitant ketalization set the stage piperidine D ring. A final two step sequence converted 73 to
for C1 electrophilic aromatic bromination. Acidic hydrolysis of (−)-oxycodone (8).
the acetal gave cyclization precursor (±)-56. Exposure of 3.4.4. Buprenorphine and Naloxone. Buprenorphine (10,
(±)-56 to NH4F·HF in TfOH provided cyclization product Subutex) and naloxone (9, Narcan) are semisynthetic opiates
(±)-57. The C1 bromide in the preceding step is critical to used to treat drug dependence or overdose, respectively.
obtaining the desired cyclization product as previous studies Buprenorphine is a partial μ-receptor agonist often prescribed
indicate a high propensity for para cyclization at the expense of as an alternative to methadone to treat opioid dependence. It
the desired ortho closure.46,47 Next, hydrolysis of (±)-57 has less abuse potential than methadone, a full μ-receptor
revealed the free secondary amine. α-bromination was followed agonist,53 and is also sold as a combination therapy with
by a 5-exo-tet ring closure to establish the E ring. Finally, naloxone under the brand name Suboxone to further deter
reductive amination was accompanied by aryl bromide removal abuse. Naloxone is a μ-receptor antagonist that is United States
to give (±)-hydrocodone (7). Food and Drug Administration (FDA) approved for emergency
Mulzer and Trauner published a synthesis of (−)-hydro- treatement of known or suspected opioid and opiate over-
codone (Scheme 4b).48,49 Their effort began with aldol dose.54 It is interesting to note that while naloxone is a receptor
condensation of (±)-58 and methyl formate. After Robinson antagonist the majority of opiates are receptor agonists.
annulation with MVK, treatment with KOH cleaved the Synthetically, buprenorphine is made through semisynthesis
formate via a retro-Claisen reaction. Next, the racemic enone from known opiate precursors. Starting from (−)-oripavine (3),
(±)-59 was resolved using chiral chromatography to give amine alkylation and subsequent thiol mediated N-demethyla-
(−)-59. 1,4-addition of a Grignard-copper(I) species was tion gave diene (−)-74 (Scheme 7).55 An endo selective Diels−
followed by trapping with TMSCl to give a transient silyl Alder cycloaddition with MVK followed by Grignard addition
enol ether. This species was reacted with NBS to give α-bromo and hydrogenation provide (−)-buprenorphine (10). The
ketone (−)-60. Heating of (−)-60 at 140 °C led to closure of observed diastereoselectivity of the Grignard addition can be
the E ring. Following ketalization, a hydroboration, quenched rationalized by invoking model (75) in which the oxygens of
with basic H2O2 installed a distal primary alcohol. Subsequent the carbonyl and proximal methyl ether coordinate to
dechlorination with Raney nickel gave intermediate (−)-61. magnesium, locking the carbonyl in place for top-side attack.
After amine installation via Mitsunobu reaction with protected Similarly, the Hudlicky group recently disclosed a semisyn-
methylamine, a point of unsaturation was introduced via radical thesis of (−)-naloxone (9) from (−)-oxymorphone (6)
benzylic bromination and elimination. Dissolving metal (Scheme 8).56 The synthesis commenced with acetate
reduction liberated the amine and set in motion reductive protection of the phenolic alcohol followed by amine oxidation.
closure of the D ring. Ketal hydrolysis gave (−)-hydrocodone Next, dehydration with the Burgess reagent gave imine 77.
(7). While disfavored, 5-endo-trig ring closure at this stage would
3.4.3. Oxycodone. Oxycodone (8) is structurally identical to provide oxazolidine 79. One could argue that an alternative
hydrocodone (7) sans C14 oxygenation. Industrially, (8) is mechanism featuring a favored 5-exo-tet cyclization (78) is
accessed through semisynthesis from (−)-thebaine (4) through more likely. In either case, oxazolidine 79 is next protected as
a redox sequence (Scheme 5).50,51 its dimethyl acetal to allow for clean oxazolidine opening with a
vinyl Grignard reagent. Hydrolysis of the acetal protecting
Scheme 5. Conversion of (−)-Thebaine to (−)-Oxycodone group reveals (−)-naloxone (9).
3.5. Illicit Semisynthetic Opiates. While most opiate
abuse is enabled through prescriptions, some are illicitly
synthesized for recreational use.
3.5.1. Heroin. First synthesized from morphine in 1874, the
Bayer Company of Germany introduced heroin for medical use
in 1898. Physicians remained unaware of its addictive potential
for years, and, in 1903, heroin abuse had risen to alarming levels
in the United States. Heroin was made federally illegal in 1924.
The Fukuyama lab reported the first total synthesis of Later, the Counter-Narcotics Police of Afghanistan (CNPA)
oxycodone that circumvents thebaine as an intermediate offered German authorities the opportunity to observe and
(Scheme 6).52 Starting from aryl bromide 65, a Fagnou document the illicit synthesis of heroin (Scheme 9).57 The
palladium catalyzed direct acylation closed the B-ring to give synthesis began with the isolation of morphine base from raw
tricycle 66. A further three step sequence provided phenol 67. opium (82). Treatment of raw opium with lime (calcium
In a key-step, oxidative dearomatization in the presence of oxide) and hot water resulted in a biphasic mixture in which the
PhI(OAc)2 proceeded through oxonium intermediate 68 to morphine base (1) resided in the lower aqueous layer.
give C14 hydroxylated product 69. Next, chemoselective Siphoning of the aqueous layer into a fresh barrel followed
G DOI: 10.1021/acschemneuro.7b00528
Scheme 6. Fukuyama’s 2014 Total Synthesis of (−)-Oxycodone
Scheme 7. Synthesis of Buprenorphine 3.5.2. Krokodil. (−)-Desomorphine (12) or krokodil (from

the Russian word meaning crocodile) became popular in Russia
around 2003 and is a opioid synthesized from codeine and
other readily obtained materials.58 Over the past 15 years
krokodil has slowly spread across Europe. It has also been
sensationalized in a number of media reports as a drug that
“turns the user into a zombie”. Indeed, krokodil can leave
abusers disfigured via skin discoloration that results from
cutaneous infection, gangrene, and necrosis.1 The synthesis of
krokodil begins with extraction of codeine containing tablets
using alkaline pipe cleaner, gasoline, and HCl (Scheme 10).59
The resulting hydrochloride salt (2·HCl) is then reduced with
I2 and red phosphorus through a Nagai Type reaction.
4. THE OPIOIDS
4.1. Historical Perspective. The term opioids was
originally coined in the 1960s by George H. Acheson to
“refer to any chemical with morphine-like properties.” These
compounds were originally synthesized to develop both less
addictive and more powerful analgesics. From this research,
compounds like fentanyl (84) emerged. While all of the opioids
are addictive, some are larger targets for abuse such as Demerol
(83) and methadone (85), while others are less abused due to
their high potency and increased likelihood for overdose.
4.2. Structure. Based on the morphine rule, opioids have
similar (or stronger) effects as the opiates due to their masked
structural homology, vida supra. Thus, each molecule features a
tertiary amine linked to an aryl ring (Figure 2).
4.3. Demerol. Demerol (83, also known as meperidine or
by treatment with solid ammonium chloride resulted in the pethidine) was first synthesized in 1939 and advertised as a
precipitation of morphine base. Next, the solid was treated with “less addictive form of morphine” throughout the mid-1900s.
approximately 5 equiv of Ac2O to convert morphine freebase to However, a high level of dependence develops after initial use.
heroin. Addition of Na2CO3 neutralized the AcOH formed Celebrities ranging from Elvis Presley to Michael Jackson have
during the quench, precipitating brown heroin base in the infamously suffered from Demerol addiction. In 1939, the
process. Purification over activated carbon and precipitation Eisleb lab patented a synthesis of piperidine compounds, where
with aq. NH3 gave white heroin which was treated with HCl di(β-halogenalkyl)-amine 87 is treated with benzyl cyanide.
and acetone to give heroin hydrochloride (11·HCl). Cyclization is accompanied by nitrile hydrolysis to produce
H DOI: 10.1021/acschemneuro.7b00528
Scheme 8. Hudlicky’s 2013 Synthesis of (−)-Naloxone
Scheme 9. Illicit Synthesis of Heroin from Raw Opium
Demerol 83 (Scheme 11).60 Many of the current industrial that either α-phenyl or α-hydroxyl migration can occur
syntheses use this method. (transition states 90 and 92, respectively). Although not
While lacking the practicality of Eisleb, Hite’s 1959 synthesis, directly applicable, comparison of the A-values for the phenyl
featuring a quasi-Favorskii rearrangement, provides an interest- (3.0 kcal mol−1) and hydroxyl (≤1.0 kcal mol−1) substituents
ing alternative (Scheme 12).61 Starting with monochloroketone prove instructive in evaluating the relative amount of diaxial-like
89, available in six steps from isonicotinic acid, treatment with strain felt by each group when positioned antiperiplanar to the
NaOH induced the desired rearrangement, albeit in modest exiting chloride. Returning to the synthesis, Fischer ester-
yield as the reaction’s minor product. Further inspection reveals ification of 91 gives Demerol (83).
I DOI: 10.1021/acschemneuro.7b00528
Scheme 10. Illicit Synthesis of Krokodil amination, acylation, and amine deprotection/alkylation
(Scheme 13).64 Though first brought to the market as an
Scheme 13. Janssen Company’s 1965 Synthesis of Fentanyl
intravenous analgesic, fentanyl soon became a common

anesthetic for cardiac and vascular surgeries. Later develop-
ments allowed for administration via transdermal patches,
buccal lozenges (lollipops), and intranasal sprays.63 Fentanyl is
a synthetic analgesic that is 50−100 times more potent than
morphine. Given its powerful pain-relieving effects, and its ease
of synthesis, fentanyl is often mixed with heroin and other
Figure 2. Structures of various opioids. drugs. In many parts of the United States and Canada, fentanyl
has all but replaced heroin, unbeknownst to the user.65
Scheme 11. Eisleb’s 1939 Synthesis of Demerol 4.5. Methadone. In 1938, Bockmühl and Erhart synthe-
sized compound VA 10820 that exhibited stronger analgesic
effects than Demerol. Later named methadone (85), this
compound is prescribed to treat opiate addiction. As
methadone itself is highly addictive, many users cycle through
the use of both opiates and opioids in an attempt to break
dependence. The original synthesis of methadone (85) starts
with racemic 1-dimethylamino-2-propanol (97) (Scheme 14).
Reaction with sodium diphenyl acetonitrile produces amino-
nitrile (±)-99 via intermediate (±)-98. A Grignard addition
Scheme 12. Hite’s Synthesis of Demerol concludes the synthesis to produce (±)-methadone (85).
Scheme 14. Synthesis of (±)-Methadone
5. THE BENZODIAZEPINES
5.1. Historical Perspective. Research to expand the ring of
quinazoline-3-oxides in the late 1950s led to the development
of the benzodiazepines. Leo Sternbach investigated the
heterocycles of benzheptoxdiazines, known in the German
literature in the late 1800s as acylindazoles, in order to replace
4.4. Fentanyl. In 1953, Paul Janssen set out to develop a the use of the highly addictive barbiturates.66 During his
new analgesic that would improve upon morphine and research, Sternbach made a library of compounds that were not
Demerol.62 Hypothesizing that increased lipophilicity would assayed until a colleague rediscovered them ca. 2 years later.
increase CNS penetration and potency, Janssen and co-workers The molecules showed remarkable activity as sedatives and
began modifying Demerol.63 These efforts led to the synthesis sparked a major development campaign into this new class of
of fentanyl (84) through a five step process involving reductive compounds.67 A series of substituted benzodiazepines were
J DOI: 10.1021/acschemneuro.7b00528
synthesized and marketed as the antianxiety medications readily Scheme 15. Sternbach’s Synthesis of Valium
prescribed today. Others, like flunitrazepam (104), affect
cognitive function and promote anterograde amnesia, leading
to abuse as the “date rape” drug commonly known as a
“Roofie”. After some time, it would be demonstrated that the
benzodiazepines were as addictive as the barbiturates they
hoped to replace. Nonetheless, the benzodiazepines offered a
new chemical scaffold that medicinal chemists continue to
manipulate today.
5.2. Structure. Benzodiazepines are named according to
their fusion of the benzene and diazepine ring systems (Figure
3). Benzodiazepine drugs are most commonly 1,4-substituted
and can be differentiated based on modifications at the C2′, C4′,
and C7 positions.
Scheme 16. Synthesis of Valium
Scheme 17. Gates’s Synthesis of Valium
Figure 3. Structures of various benzodiazepines.
5.3. Valium. After the discovery of the first benzodiazepine

(100, Librium), diazepam (101, Valium) was synthesized and
demonstrated to be more potent. Valium would ultimately
become the top selling drug in the United States from 1968 to
1982 but eventually received backlash as negative effects on
cognition started to surface.68 Beginning with ortho-amino-
benzophenone (108), quinazoline-3-oxide (105) was generated
in three steps.69,70 After treatment with NaOH, 105 underwent
ring expansion to give the cyclic 7-membered lactam 107 which
could be elaborated to Valium (101) in two steps (Scheme 15).
Subsequent optimization reduced the synthesis from six steps
to two (Scheme 16).66,68 This route began with condensation
of ortho-aminobenzophenone (108) with glycine ethyl ester to reaction with (EtO)3CCH3 to give 113. Treatment with O3
establish the benzodiazepine ring system. Amide methylation followed by oxidative workup with aq. NaI and AcOH gave
completes the synthesis. ketone 114 in good yield. Mechanistically (Scheme 18b), one
The Gates lab achieved the first academic synthesis of Valium can envision that collapse of secondary ozonide (±)-115 could
in 1980 (Scheme 17).71 Isatoic anhydride 109 was converted to occur after iodide attack to yield aldehyde 116 and an
1,4-benzodiazepine-2,5-dione 110 via nucleophilic attack of the equivalent of hydroiodite (IO−). Reduction of this +1 iodine
amine and subsequent decarboxylation and cyclization. species could occur in situ under the influence of iodide and
Acetylation and Grignard addition resulted in aminobenzophe- acid to give molecular iodine (I2) which could in turn serve to
none derivative 111 which yielded Valium (101) upon oxidize 116. After deprotonation of 117, resonance stabilized
deacetylation and treatment with NaHSO4. acylium cation 118 is generated. Cation quenching with water
5.4. Xanax. The Upjohn Company patented the first would give carboxylic acid 120 which, following heterocycle
synthesis of alprazolam (103, Xanax) in 1971 (Scheme protonation ((±)-121), can undergo decarboxylation to yield
18a).72,73 Starting with quinoline derivative 112, treatment final product 114. Returning to the synthesis, hydroxymethy-
with hydrazine gave the corresponding 2-hydrazinyl quinoline lation of 114 with paraformaldehyde, formation of the chloride,
(not pictured) via an SNAr (nucleophilic aromatic substitution) and subsequent displacement with NH3 provided an amine that
mechanism. Installation of the 1,2,4-triazole was realized after cyclizes after condensation to give Xanax (103).
K DOI: 10.1021/acschemneuro.7b00528
Scheme 18. Upjohn Company’s 1971 Synthesis of Xanax
6. THE STIMULANTS
6.1. Historical Perspective. Stimulants promote wakeful-
ness and decrease fatigue. Compounds in this category range
from caffeine to cocaine, amphetamine, ephedrine, and MDMA
(ecstasy).
6.2. Structure. Cocaine (122) is a bicyclic tropinone
alkaloid, which represents one of the more complex stimulant
structures (Figure 4). Amphetamine, ephedrine, methamphet-
amine, and methylphenidate are classified as phenethylamines.
MDMA is a phenethylamine derivative containing a 3,4-
methylenedioxy bridge.
6.3. Cocaine. The euphoric effects that result from chewing
the leaves of the Erythroxylum coca plant have been known to
humankind for millenia.74 However, it was not until the mid-
19th century that the coca-alkaloid cocaine (122) was isolated
from this natural source.75,76 Soon after, cocaine gained
popularity in the United States as a local anesthetic, a cure
for opiate use disorder, and an additive to cigarettes and soda.
At the turn of the century, cocaine’s addictive nature emerged,
and the United States responded with the 1914 Harrison Act to Figure 4. Structures of various stimulants. aBronkaid is combination of
restrict the drug’s sale and distribution. This largely ended the (−)-ephedrine and guaifenesin. bThe active ingredient in Ritalin and
country’s first cocaine epidemic. Concerta is (±)-methylphenidate.
From a synthetic perspective, cocaine’s compact bicyclic
structure and biological activity has long attracted attention. tropinone core and set a new precedent for the complexity that
The Willstätter lab completed the first synthesis of (−)-cocaine chemical synthesis could reach. The synthesis began with the
(122) in 1903 (Scheme 20).77,78 This was a landmark moment transformation of cycloheptanone into cycloheptatriene (130).
in organic synthesis, as it involved the formation of the Treatment of 130 with Br2 and (CH3)2NH followed by
L DOI: 10.1021/acschemneuro.7b00528
chemoselective reduction provided unsaturated amine 131. accompanied by decarboxylation of the resulting vinylic acid
After dibromination of the remaining olefin, intramolecular carboxylic acid affording a chiral amino acid which, upon
bromide displacement provided bicyclic bromide salt (±)-133, reprotection of the liberated carboxylic acid and amine
presumably through a transition state similar to 132. Bromide functionalities, was transformed into (+)-142. KHMDS
elimination and amine monodemethylation gave olefin (±)-134 mediated Dieckmann cyclization gave bicyclic β-keto ester
which was subjected to bromination, hydrolysis, and oxidation (+)-143. Nucleophilic decarboxylation followed by Bamford-
to complete the synthesis of tropinone (135). Treatment of Stevens reduction gave tropene intermediate (+)-144 which
tropinone with Na in EtOH in the presence of CO2 gave the α- underwent an exo selective [3 + 2] dipolar cycloaddition to give
carboxylic acid which was converted to methyl ester (±)-136 4,5-dihydroisoxazole (−)-145. Ester hydrolysis followed by
under acidic conditions. Reduction with Na(Hg) and thermal decarboxylation and concomitant cleavage of the N−O
subsequent benzoylation afforded (±)-cocaine (122). A chiral bond gave β-hydroxyl cyanide (+)-146 which was elaborated in
resolution with D-tartaric acid allowed for the isolation of six further steps to (−)-cocaine (122).
naturally occurring (−)-cocaine (122). In regard to its illicit use, cocaine reemerged as a highly
While trying to elucidate the biosynthetic pathways abused drug in the United States in the latter half of the 20th
responsible for the synthesis of the tropinone scaffold, Sir century. It is primarily consumed in one of two forms: powder
Robert Robinson demonstrated a simplified synthesis of cocaine and crack cocaine (Scheme 22). Powder cocaine, better
tropinone (135) in 1917 (Scheme 19).79,80 In a one-pot chemically defined as the HCl salt of (−)-cocaine (122·HCl), is
used via injection or insufflation. While this is the form in which
Scheme 19. Robinson’s 1917 Synthesis of Tropinone cocaine is most commonly isolated, the free amine commonly
known as crack cocaine is far more addictive. Crack cocaine
reaches the brain quicker than the hydrochloride salt and
produces a more intense high. The name “crack” is derived
from the sound this form of cocaine makes when burned. This
form of cocaine is illicitly made from the cocaine salt (Scheme
22). In this process, powder cocaine (122·HCl) is treated with
aq. NaHCO3. After heating, the free base (122) separates from
procedure, aqueous methylamine was added to a solution of the water into an oil that can be solidified.
succinaldehyde (137) and calcium acetonedicarboxylate (138). 6.4. Phenethylamines. The phenethylamines represent
Following condensation of methylamine with aldehyde 137, one of the most widely abused and illicitly produced classes of
consecutive Mannich reactions gave tropinone (135). This drugs today. The structural backbone of the class is seen in
reaction laid the groundwork for Robinson’s proposal for the amphetamine (123), which features a single stereocenter and a
biosynthetic pathway of cocaine and similar alkaloids, an area of key primary amine (Figure 4). Their structural similarity makes
research that eventually earned him the Nobel Prize in them easy to interconvert and alter. In this section, we describe
Chemistry in 1947. general synthetic techniques used to produce these compounds
Unsurprisingly, cocaine’s intricate bicyclic structure has and detail their illicit production.
continued to attract the interest of synthetic chemists long 6.4.1. Amphetamine. Amphetamine (123) is a stimulant
after the seminal efforts of Willstätter and Robinson. Rappaport that increases wakefulness and focus while decreasing fatigue
and co-workers reported an enantioselective synthesis of and appetite. Physicians often prescribe amphetamine as a
(−)-cocaine (122) in 1998 (Scheme 21).81 Using the chiral 1:1:1:1 mixture, by weight, of four salts (Figure 5) to treat
pool as its source of asymmetry, the synthesis began with the attention deficit hyperactivity disorder (ADHD). This mixture,
Eschenmoser sulfide contraction of racemic dibenzyl malate sold under the brand name Adderall, and other stimulants
(139) and D-glutamic acid derived chiral thiolactam (−)-140. prescribed to treat ADHD, such as (+)-lisdexamfetamine
Treatment of (±)-139 with Tf2O afforded the corresponding (Vyvanse, 124) and (+)-methylphenidate (Focalin, Ritalin,
α-triflate which was displaced after addition of the thiolactam. Concerta, 128), are often abused by college students as “study
Addition of PPh3 as a sulfur scavenger followed by the drugs”.
introduction of a tertiary amine base completed the one pot Synthetically, Edeleanu first prepared amphetamine (123) in
reaction sequence to give vinyl amine (+)-141 as an 1887 and subsequently adapted the synthesis to access both
inconsequential mixture of E and Z isomers. Catalytic ephedrine (125) and methamphetamine (127).82 However,
hydrogenation of (+)-141 resulted in debenzylation and was interest in developing these compounds for use as drugs did not
Scheme 20. Willstätter’s Synthesis of (−)-Cocaine from 1903
M DOI: 10.1021/acschemneuro.7b00528
Scheme 21. Rapoport’s 1998 Synthesis of (−)-Cocaine
Scheme 22. Conversion of Powder Cocaine to Crack Scheme 23. Belovsky’s Synthesis of (±)-Amphetamine
Cocaine
synthesis in two simple transformations. A variety of other

traditional syntheses of racemic amphetamine exist and use key
transformations such as the Ritter reaction, Friedel−Crafts
acylation, Knoevenagal condensation, Curtius rearrangement
and Wolff rearrangement.84
While effective as a racemate, studies with enantiopure
amphetamine have revealed that (+)-amphetamine demon-
strates higher potency in the CNS while (−)-amphetamine has
a larger effect on cardiovascular activity. As such, many have put
forth efforts to access amphetamine in enantiopure form either
through chiral resolution or enantioselective synthesis. These
synthetic efforts engender chirality through the use of chiral
starting materials, asymmetric hydrogenations, or enzymatic
transformations.84 Perhaps most prominent of these methods is
Yamaguchi’s use of chiral aziridines (Scheme 24).85 Beginning
Scheme 24. Yamaguchi’s Synthesis of (+)-Amphetamine
Figure 5. Structures of the four amphetamine salts that constitute

Adderall.
emerge until the early 1960s, at which point several syntheses

made racemic amphetamine widely available. For example, in with chiral building block L-alinol (153), phosphonate
1968, Belovsky and co-workers demonstrated a simple protection followed by mesylation provided 154. Next, this
synthesis of (±)-amphetamine (123) from phenylacetone intermediate underwent base promoted intramolecular dis-
(151) and formamide (Scheme 23).83 The synthesis began placement to give chiral aziridine (155). Treatment of the
with the condensation of phenylacetone (151) and formamide aziridine with a mixture of PhMgBr and catalytic CuCl resulted
under Leuckhart conditions to give (±)-152. Subsequent in nucleophilic attack at the less substituted carbon. Finally,
hydrolysis yielded (±)-amphetamine (123), completing the acid mediated removal of the N-phosphonate revealed
N DOI: 10.1021/acschemneuro.7b00528
enantiopure (+)-amphetamine (123). A number of variations common starting materials as various routes exist for the
on this method have been reported.86 reduction of (pseuo)ephedrine to methamphetamine (127).
6.4.2. (Pseudo)ephedrine. Indiscriminate hydroxylation of The most common strategy employes HI (Nagai route) or
the benzylic position of amphetamine yields two enantiomeric Birch reduction.
sets of diastereomers (Figure 6). The erythro diastereomers In recent years, a modification of the Birch reduction referred
to as “shake and bake” has become the method of choice for
illicit methamphetamine synthesis (Scheme 25). This method
usually starts with (−)-pseudoephedrine containing decongest-
ants. The pills are crushed and subsequently added to a plastic
bottle. NH4NO3, Li0, solid NaOH, and xylenes, chemicals
available to the layperson from the household goods high-
lighted in red, are added. Next, iterative cycles of shaking and
venting are used. After gas evolution ceases, the reaction is
filtered and acidified with gaseous HCl to give methamphet-
amine (127) as its hydrochloride salt.
6.5. MDMA. Commonly referred to as “ecstasy” or “Molly”,
MDMA (129) is a strong stimulant that prevents synaptic
reuptake of serotonin, dopamine, and norepinephrine. It is so
Figure 6. Comparison of ephedrine and pseudoephedrine stereo-
effective that, when used repeatedly, it can deplete the number
chemistry. The medicinally used enantiomer of each compound is
depicted. of neurotransmitters available in the brain, producing a mental
and physical crash that results in long-term depression. MDMA
also affects the temperature-regulating mechanisms of the brain
constitute the ephedrines (125) while the threo diastereomers with users commonly dying from hyperthermia and hypona-
comprise the pseudoephedrines (126). Medicinally, the erythro tremia (depletion of sodium content). Merck patented the first
and threo diastereomers demonstrate different activities. commercial MDMA (129) synthesis in 1912 (Scheme 26).88
Ephedrine stimulates the central nervous system, promoting
wakefulness and decreased appetite, while pseudoephedrine Scheme 26. Merck’s 1912 Synthesis of (±)-MDMA
acts on the peripheral nervous system and is used as a nasal
decongestant sold under the brand name Sudafed.
6.4.3. Methamphetamine. Mono-N-methylation of amphet-
amine (123) yields methamphetamine (127), a commonly
abused drug with street names such as “meth” and “crank”. Due
to the relative ease with which it can be synthesized, many
clandestine laboratories manufacture this highly addictive drug.
However, such synthetic work is not without danger as Beginning with safrole (156), Markovnikov hydrobromination
methamphetamine production frequently leads to “lab” of the terminal olefin gives the corresponding secondary
explosions and house fires. The impact of such accidents as bromide. Finkelstein reaction provides a secondary iodide that
well as the socioeconomic ramification of methamphetamine is displaced with methylamine to give (±)-MDMA (129).
addiction make plain the motivation behind the controlled The Shulze lab recently published an MDMA synthesis that
nature of pseudoephedrine (126) containing medications, features a Curtius rearrangement (Scheme 27).89 Treatment of
methylating reagents, and reducing agents. helional (157) with sodium propionate and propionic
Synthetically, methylation of amphetamine (123) with anhydride resulted in a Perkin reaction to give unsaturated
dimethyl sulfate can generate methamphetamine (127); carboxylic acid 158. Olefin hydrogenation followed by acyl
however, the high propensity for these conditions to yield chloride synthesis gave (±)-159. At this point, generation of
dimethylamphetamine makes this method less appealing.87 The the acyl azide and subsequent Curtius rearrangement provided
mono-N-methylated ephedrine (125) and pseudoephedrine an isocyanate. Exposure of this intermediate to t-BuOK gave
(126) (jointly referred to as (pseudo)ephedrine) are more the corresponding Boc carbamate. N-Methylation followed by
Scheme 25. Illicit Synthesis of Methamphetamine via the “Shake and Bake” Method
O DOI: 10.1021/acschemneuro.7b00528
Scheme 27. Schulze’s 2010 Synthesis of (±)-MDMA
Figure 7. Structures of dopamine and serotonin, two neuro-

transmitters.
Americans campaigned for the decriminalization of (+)-lysergic

acid diethylamide (164, LSD).
7.2. Structure. As noted above, many hallucinogenic
compounds share structural homology with either dopamine
(162) or serotonin (163) (Figures 7 and 8). This is most
acid mediated Boc deprotection provided (±)-MDMA (129)

which was isolated as its oxalate salt.
In the hands of the clandestine chemist, illicit MDMA
synthesis often begins with distillation of safrole (156) from the
more readily available sassafras oil (Scheme 28). Subsequent
Scheme 28. Illicit Synthesis of MDMA
Figure 8. Structures of various hallucinogens. aResemblance to

serotonin is highlighted in red.
readily seen in the structures of mescaline (167) and N,N-

dimethyltryptamine (168, herein referred to as DMT),
respectively. However, careful examination of the structure of
LSD (164) also reveals a resemblance to serotonin. On the
other hand, ketamine (165) and phencyclidine (166, herein
referred to as PCP) do not resemble either of the
aforementioned neurotransmitters yet still elicit hallucinogenic
effects.
7.3. LSD. In the midst of a synthetic effort directed at
Wacker−Tsuji oxidation using PdCl2 (available as a photograph accessing various amide analogues of lysergic acid, Albert
developing agent) yields the ketone MDP2P (161). Sub- Hofmann unwittingly constructed a derivative that would
sequent reductive amination with methylamine utilizing any quickly permeate the world as a hallucinogen: LSD (164).
one of a variety of reducing agents (e.g., aluminum amalgam, However, it was not until 5 years later that Hofmann would
available from the treatment of aluminum foil with a accidentally ingest a small amount of LSD and discover the
mercury(I) salt) provides (±)-MDMA (129). An interesting psychedelic properties of this semisynthetic ergot alkaloid.90
variation on this reaction bypasses the need for the highly While initially used by the medical community, LSD soon
regulated methylamine, instead using the more readily available became a prominent illegal recreational drug.91 Structurally,
nitromethane to generate methylamine in situ upon addition to LSD shares a tetracyclic skeleton with clinically relevant ergot
the reaction’s reducing environment. alkaloids such as ergometrine (170) and ergotamine (171)
(Figure 9).92
7. THE HALLUCINOGENS Industrial access to clinically relevant ergot alkaloids relies on
7.1. Historical Perspective. Naturally occurring halluci- direct isolation from fermentation or field cultivation.93,94
nogens have been used for thousands of years as recreational Similarly, one can imagine LSD resulting from the amination of
drugs. Consumed for their spiritual and cognitive effects, many lysergic acid (169) or arising from the hydrolysis of drugs such
of these compounds structurally mimic neurotransmitters such as ergometrine (170) or ergotamine (171). Consequently, the
as dopamine (162) and serotonin (163) (Figure 7) and have syntheses covered in the following section revolve around the
significant impacts on the CNS with users often claiming to synthesis of lysergic acid as a formal synthesis of LSD.
have “spiritual awakenings” under their influence. Woodward and co-workers published the first total synthesis
In response, a number of countries, have challenged their of (±)-lysergic acid (169) in 1954 (Scheme 29).95,96 Beginning
legality over the last century. In particular, during the mid- from known dihydroindole derivative (±)-172, acyl chlorina-
1960s counterculture movements in the United States, many tion followed by AlCl3 mediated Friedal−Crafts acylation
P DOI: 10.1021/acschemneuro.7b00528
closed the C ring to furnish (±)-173, a 2,2-α-dihydro derivative

of Uhle’s ketone. Ketone (±)-173 was treated with pyridinium
tribromide to afford the corresponding α-bromide which could
be displaced with methylamino ketal 174. Subsequent acid
hydrolysis of the ketal and benzamide protecting groups
revealed diketone (±)-175 which, upon treatment with
NaOMe, underwent aldol condensation to close the D ring
and give (±)-176. Six subsequent transformations completed
the first total synthesis of (±)-lysergic acid 169.
Fukuyama’s 2013 asymmetric synthesis of (+)-lysergic acid
was equally instructive (Scheme 30).97 Chiral β-hydroxyl
hydrazide (−)-177, the product of Evans aldol condensation
and subsequent auxiliary cleavage with hydrazine, was treated
with t-BuONO to generate acyl azide 178. In situ Curtius
rearrangement afforded isocyanate 179 which underwent
intramolecular trapping to produce oxazolidinone (−)-180.
Figure 9. Structures of various ergot alkaloids.
After three transformations, ring closing metathesis installed the
A ring, giving (−)-182. Next, a Heck cyclization closed the B
Scheme 29. Woodward’s Approach to (±)-Lysergic Acid
ring to give (−)-184 after β-hydride elimination. Functional
group interconversions over the course of 11 steps transformed
this compound into the final product, (+)-lysergic acid (169). It
is worth noting the authors’ judicious control of the β-hydrogen
stereochemistry in intermediate 183; the syn positioning of this
hydrogen and the palladium species enabled β-hydride
elimination, demonstrating a firm command of mechanistic
understanding.
In a similar vein, Fujii and Ohno published a 2011 formal
synthesis of (+)-lysergic acid (169) featuring an amino-
palladation cascade that established the C and D rings in a
single step (Scheme 31).98 Starting with enyne 186, available in
four steps from 4-bromoindole (185), Shi epoxidation utilizing
catalyst 187 afforded epoxide 188 which was taken forward as a
mixture of diastereomers. Silyl protection of the primary
alcohol followed by Zn(OTf)2 mediated reductive oxirane
opening yielded ynol 189. At this stage, the authors established
the allene needed for the amino-palladation cascade via a
Movassaghi modified Myers allenation;99 stereoselective
formation of 192 occurred, presumably, through the concerted
Alder-Ene reaction of intermediate 191. With the allene in
hand, TBAF deprotection of the primary alcohol and
subsequent treatment with Pd(Ph3)4 and K2CO3, cyclization
conditions previously established by the authors,100 yielded
Scheme 30. Fukuyama’s Synthesis of (±)-Lysergic Acid
Q DOI: 10.1021/acschemneuro.7b00528
Scheme 31. Fujii and Ohno’s Synthesis of (±)-Lysergic Acid
tetracycle 194. The amino-palladation precursor and the Scheme 33. Zhang’s Synthesis of (±)-Ketamine
resulting product (194) intersected with a previously disclosed
synthesis of (+)-lysergic acid by the authors.100
7.4. Ketamine. A molecule of many uses, ketamine (165)
has long served as an anesthetic, analgesic, and recreational
drug known on the street by the name “Special K.”101 Parke-
Davis and Company disclosed the seminal synthesis of
(±)-ketamine in a 1956 patent (Scheme 32).102 The synthesis
Scheme 32. Parke-Davis and Company’s 1956 Synthesis of While both of these syntheses provide facile access to
(±)-Ketamine (±)-ketamine, research has demonstrated that (−)-ketamine
exhibits greater potency than the corresponding (+)-ketamine
antipode in regards to anesthesia and analgesia.104 As such,
methods for accessing (−)-ketamine are gaining importance.
Kiyooka recently published the first105 and second106
asymmetric syntheses of (−)-ketamine (165).
Kiyooka’s second synthesis begins with an enantioselective
Mukaiyama aldol condensation mediated by chiral oxazobor-
olidinone 201 with α,β-unsaturated aldehyde (P/M)-200
(Scheme 34). The resulting enantioenriched (86% ee) β-
hydroxyl ester (P/M)-202 was subjected to LiAlH4 reduction
and selective benzylation of the resulting primary alcohol.
Acylation of the secondary alcohol with trichloroacetyl
isocyanate and subsequent hydrolysis gave carbamate (P/M)-
203. After dehydration, the carbamate was converted to
isocyanate (−)-205. Mechanistically, this reaction occurs via
began with o-chlorobenzonitrile (195) which yielded ketone dehydration of the carbamate to form intermediate allyl cyanate
196 after treatment with a cyclopentyl Grignard reagent. (P/M)-204 which undergoes a stereoselective [3,3]-sigma-
Subsequent α-bromination followed by imine formation and tropic rearrangement giving the isocyanate product with 1,3-
bromide hydrolysis gave α-hydroxyl imine 197, the precursor chirality transfer. Finally, reduction of the isocyanate (205) to
for the synthesis’ key pinacol-like rearrangement. In the event, give the corresponding methylamine was followed by reductive
heating 197 in decalin resulted in [1,2] migration to give ozonolysis to give enantioenriched (−)-ketamine (165) in 87%
(±)-ketamine (165). ee.
More recently, Zhang and co-workers reported a racemic 7.5. PCP. While Kötz and Merkel reported the first synthesis
ketamine synthesis that started from ketone (±)-198 (Scheme of PCP (166) in 1926,107 the compound was not fully
33).103 Direct α-nitration mediated by ceric ammonium nitrate investigated for is biological properties until the late 1950s
(CAN) and Cu(OAc)2 provided α-nitro ketone (±)-199. Nitro when it was made available as an anesthetic (Sernyl).108
reduction and subsequent reductive amination with aqueous Research demonstrated that the compound elicited the desired
formaldehyde yielded (±)-ketamine (165). anesthetic effects but was also a strong hallucinogen. This
R DOI: 10.1021/acschemneuro.7b00528
Scheme 34. Kiyooka’s Second Generation Synthesis of Clandestine syntheses of PCP often proceed according to
(−)-Ketamine routes similar to that depicted in Scheme 34 and can be
performed on large scales. One such manifestation is termed
the “The Bucket Method” (Scheme 37).109 Following
instructions seized from a clandestine PCP laboratory by the
United States Drug Enforcement Administration (DEA), the
starting materials are first divided into two buckets, Bucket A
and Bucket B; to Bucket A are added cyclohexanone (206) and
Na2S2O5 (209, which can generate NaHSO4 in situ when
exposed to water), while piperidine (210) and an alkali cyanide
salt are added to Bucket B. Addition of the contents of Bucket
A to those of Bucket B (or vice versa) yields masked iminium
species PCC (207). In a third bucket, Bucket C, bromobenzene
(211) is added to magnesium turnings to generate PhMgBr.
This Grignard reagent is then added to a solution of PCC in
naphtha to give PCP (166). Because such processes can readily
produce large batches of PCP, the DEA stringently monitors
several related compounds, such as piperidine and potassium
cyanide.
7.6. Mescaline. Native Americans in Central and North
America have used mescaline (167), the active component in
the peyote cactus, for thousands of years in spiritual
ceremonies. The “buttons” of the cactus are often dried and
eaten or soaked in water to drink. Mescaline (167) is believed
to mimic the neurotransmitter dopamine (162) (vide supra)
promptly led to its discontinued use in 1965. The and causes intense hallucinations and altered states of
hallucinogenic effects, however, fueled abuse of PCP. consciousness. Mescaline was first synthesized by Späth and
Traditional syntheses of PCP are based on common co-workers in 1919 (Scheme 38).112 Beginning with eudesmic
cyclohexanone precursors, making them optimal for conversion acid (212), treatment with SOCl2 gave the corresponding acyl
into clandestine syntheses. 109,110 One commonly used chloride. Reduction under Rosenmund’s conditions gave
procedure is exemplified by Parke-Davis and Company’s 1965 aldehyde 213 which could be elaborated to nitrostyrene 214
synthesis of PCP (Scheme 35). Beginning from cyclohexanone through a Henry reaction with nitromethane. With the
molecule’s carbon skeleton established, successive reductions
Scheme 35. Parke-Davis and Company’s 1965 Synthesis of with Zn in AcOH and then with Na(Hg) provided mescaline
PCP (167). In 1950, Morin and co-workers reported a similar
synthesis using LiAlH4 to convert the nitrostyrene intermediate
214 directly into the primary amine in higher yields.113
Tsao published a complementary mescaline synthesis in 1951
(Scheme 39).114 Beginning with eudesmic acid (212), a three
step sequence of esterification, reduction, and chlorination
yielded benzyl chloride 215. Addition of the remaining
aminomethylene unit was accomplished through Kolbe nitrile
synthesis and LiAlH4 reduction.
7.7. DMT. An entheogen is any psychoactive substance that
(206), reaction with aq. NaHSO4 provided an addition product induces a spiritual experience. Ayahuasca is a spiritual medicinal
that was treated with aqueous piperidine and KCN to give PCC brew traditionally used in ceremonies by peoples of the
(207). PhMgBr addition to the imine intermediate, presumably
Amazon river basin. DMT (168) is the active component in
formed in situ from 207, provides PCP (166).
ayahuasca.115 Its biosynthesis occurs within plants via the
An alternative synthesis from Pons began with conversion of
shikimate pathway.116 This pathway is also responsible for the
tertiary alcohol 208 to the corresponding tertiary azide
biosynthesis of the amino acid tryptophan as well as various
(Scheme 36).111 Presumably, this substitution proceeds
indole alkaloid precursors. The direct precursor of DMT is
through an SN1 manifold via a benzylic carbocation. Reduction
tryptamine (216), which was first chemically synthesized by
of the azide provided a tertiary amine, which was elaborated to
Shapiro and co-workers in 1956 (Scheme 40).117 The synthesis
PCP (166) in good yield after dialkylation with 1,5-
begins with an intermolecular Michael addition between diethyl
dibromopentane.
malonate (217) and acrylonitrile (218) to give a product that
cyclizes after Raney nickel reduction to yield (±)-219. A Japp−
Scheme 36. Pons’s Synthesis of PCP Klingemann reaction with benzenediazonium chloride gives
hydrazine 220 which undergoes cyclization when exposed to
polyphosphoric acid to give (±)-221. Amide hydrolysis and
subsequent decarboxylation yielded tryptamine (216).
Conversion of tryptamine (216) to DMT (168) occurs
under standard methylating conditions or through reductive
amination (Scheme 41).118
S DOI: 10.1021/acschemneuro.7b00528
Scheme 37. Illicit Synthesis of PCP by the “Bucket” Method
Scheme 38. Späth’s 1919 Synthesis of Mescaline Scheme 40. Shapiro’s Synthesis of Tryptamine
Scheme 39. Tsao’s Synthesis of Mescaline
Scheme 41. Conversion of Tryptamine to DMT
with countless players distributed worldwide. Academic

syntheses, however, are primarily instructional. Even in an era
8. CONCLUSION where synthetic approaches are arguably the shortest they have
A number of key lessons were learned during the assembly of ever been, the use of total synthesis in matching the efficiency
this document. First, the field of psychoactive drug synthesis is of direct isolation or semisynthesis is futile (at least in the case
rich with foundational strategies and tactics to prepare both of the complex opium or coca alkaloids). Perhaps in time an
polycyclic and linear alkaloids. While the seminal Gates “ideal” four to six-step synthesis will emerge that challenges
synthesis was completed 65 years ago, the field remains vibrant plant isolation.
T DOI: 10.1021/acschemneuro.7b00528
Second, it is clear that the early exercises of our synthetic Na(Hg), sodium amalgam; PPh3, triphenyl phosphine;
education are showcased throughout psychoactive drug KHMDS, potassium bis(trimethylsilyl)amide; NaHCO3, so-
production. Whether it is the ability to produce a 5- or 6- dium bicarbonate; SOCl2, thionyl chloride; AlCl3, aluminum
membered ring (the latter via Diels−Alder technology) or trichloride; NaOMe, sodium methoxide; Zn(OTf)2, zinc(II)-
introduce tertiary amines through reductive amination, basic triflate; TBAF, tetrabutylammonium fluoride; K2CO3, potas-
organic chemistry maneuvers are critical to the production of sium carbonate; KCN, potassium cyanide
■
psychoactive drugs, be it in the lab or in the garage.
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X DOI: 10.1021/acschemneuro.7b00528

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Cite This: ACS Chem. Neurosci. XXXX, XXX, XXX−XXX pubs.acs.org/chemneuro

The DARK Side of Total Synthesis: Strategies and Tactics in

1. INTRODUCTION Table 1. Psychoactive Drug Addiction in Americaa

© XXXX American Chemical Society A DOI: 10.1021/acschemneuro.7b00528

Scheme 2. Synthesis of Codeine by the Trost and Stork Labs

Scheme 3. Hudlicky’s Second Generation Chemoenzymatic Synthesis of ent-Hydromorphone

Scheme 6. Fukuyama’s 2014 Total Synthesis of (−)-Oxycodone

Scheme 7. Synthesis of Buprenorphine 3.5.2. Krokodil. (−)-Desomorphine (12) or krokodil (from

Scheme 8. Hudlicky’s 2013 Synthesis of (−)-Naloxone

Scheme 9. Illicit Synthesis of Heroin from Raw Opium

Scheme 13. Janssen Company’s 1965 Synthesis of Fentanyl

intravenous analgesic, fentanyl soon became a common

Scheme 14. Synthesis of (±)-Methadone

Scheme 16. Synthesis of Valium

Scheme 17. Gates’s Synthesis of Valium

Figure 3. Structures of various benzodiazepines.

5.3. Valium. After the discovery of the ﬁrst benzodiazepine

Scheme 18. Upjohn Company’s 1971 Synthesis of Xanax

Scheme 20. Willstätter’s Synthesis of (−)-Cocaine from 1903

Scheme 21. Rapoport’s 1998 Synthesis of (−)-Cocaine

synthesis in two simple transformations. A variety of other

Scheme 24. Yamaguchi’s Synthesis of (+)-Amphetamine

Figure 5. Structures of the four amphetamine salts that constitute

emerge until the early 1960s, at which point several syntheses

Scheme 27. Schulze’s 2010 Synthesis of (±)-MDMA

Figure 7. Structures of dopamine and serotonin, two neuro-

Americans campaigned for the decriminalization of (+)-lysergic

acid mediated Boc deprotection provided (±)-MDMA (129)

Scheme 28. Illicit Synthesis of MDMA

Figure 8. Structures of various hallucinogens. aResemblance to

readily seen in the structures of mescaline (167) and N,N-

closed the C ring to furnish (±)-173, a 2,2-α-dihydro derivative

Scheme 30. Fukuyama’s Synthesis of (±)-Lysergic Acid

Scheme 31. Fujii and Ohno’s Synthesis of (±)-Lysergic Acid

Scheme 37. Illicit Synthesis of PCP by the “Bucket” Method

Scheme 39. Tsao’s Synthesis of Mescaline

Scheme 41. Conversion of Tryptamine to DMT

with countless players distributed worldwide. Academic

(118) Brandt, S. D., Moore, S. A., Freeman, S., and Kanu, A. B.

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