DARK Classics in Chemical Neuroscience: Cocaine

Abstract

In this Review, we consider the story of cocaine from its humble origins in South America to its status as one of the most abused substances in 21st century society. The synthesis and biosynthesis of cocaine are discussed, as well as its pharmacokinetics, metabolism, pharmacology, and importance in modern neuroscience and molecular imaging.

Keywords: Alkaloids; Cocaine; Crack cocaine; Molecular imaging; Pablo Escobar; Stimulant.

Figure 1

Erthroxylon coca (left, reprinted with permission from reference. Copyright 2015, Elsevier) and cocaine (right, personal photograph by the authors).

Figure 2

Crack cocaine (left, cropped from an image that is a work of a Drug Enforcement Administration employee, taken or made as part of that person’s official duties. As a work of the U.S. federal government, the image is in the public domain in the United States), and a laboratory crack pipe (right, reprinted with permission from reference. Copyright 1989, American Society of Pharmaceutics and Experimental Therapeutics).

Figure 3

Mariani Wine (Image reprinted from reference and courtesy of the Smithsonian Libraries. No copyright in the United States).

Figure 4

Cocaine Toothache Drops (Reprinted from the U.S. National Library of Medicine. Image is in the public domain).

Figure 5

FDA-approved Cocaine hydrochloride marketed by Genus Lifesciences, Inc. (Reprinted from the U.S. National Library of Medicine. Image is in the public domain).

Figure 6

Juan Pablo Escobar (mugshot taken by the regional Colombia control agency in Medellin in 1977. Image is in the public domain).

Figure 7

Stereoisomers of Cocaine

Figure 8

Metabolites of Cocaine: benzoylecgonine (59); benzoylnorecgonine (60); ecgonine (6); ecgonidine (61); ecgonidine methyl ester (62); ecgonine methyl ester (5); norecgonidine methyl ester (63); norecgonine methyl ester (64); m-hydroxycocaine (65); p-hydroxycocaine (66); norcocaine (67); m-hydroxybenzoylecgonine (68); cinnamoylcocaine (69); cinnamoylecgonine (70). Ethanol induced metabolites: cocaethylene (71); norcocaethylene (72).

Figure 9

Cocaine and related local anesthetics

Figure 10

An average of 17 brain PET images with [¹¹C]cocaine ([¹¹C]1)at 4 different time frames after injection (5, 10, 20 and 30 minutes). Images have been normalized to the highest activity in a given time frame. The top row illustrated the Tailarach-Tournoux section. Arrows indicate the nucleus accumbens. (Reprinted with permission from reference. Copyright 2001, Elsevier).

Figure 11

Regional brain activity as measured by fMRI following administration of cocaine (1) and saline control. (Reprinted with Permission from reference. Copyright 1997, Elsevier).

Scheme 1

Wilstatter’s Total Synthesis of Cocaine. Conditions: (i) a. Na/EtOH, CO₂; (ii) MeOH, H₃O⁺; (iii) a. Na/Hg; (iv) Bz₂O, D-tartaric acid chiral resolution.

Scheme 2

De Jong’s Conversion of Ecgonine (6) to Cocaine (1). Conditions: (i) MeOH, Benzene; (ii) BzCl, MeOH, Na₂CO₃.

Scheme 3

Noyori’s General Synthesis of Tropane Alkaloids via the Polybromo Ketone-Iron Carbonyl Reaction. Conditions: i) a) Fe₂(CO)₉, benzene, 50°C, 72 h; ii) H₂ 10% Pd/C, ethanol; iii) DIBAH, THF, −78°C, 10 h.

Scheme 4

[4+2] Nitroso Cyloaddition route to Tropane Alkaloids. Conditions: (i) EtOH: CCl₄, −20°C, 5 h, then −20°C, 14 d; (ii) H₂ Pd/C, MeOH, 7h; (iii) Na₂CO₃, Benzyl chloroformate; (iv) Thionyl chloride, Pyridine, CDCl₃, 0°C, 1h; (v) K^tBuO; (vi) a) H₂, Pd/C, MeOH, b) 90% aq. Formic acid, 37% aq. formaldehyde, reflux, 5 h; c) conc. HCl, recrystallized from ethanol:water.

Scheme 5

Tufariello’s Stereospecific Synthesis of (-)-Cocaine. Conditions: (i) toluene, reflux; (ii) mCPBA, CH₂Cl₂; (iii) methyl acrylate, benzene, reflux; (iv) a) MsCl, pyridine; b) 1,5 diaza-bicylco[4.3.0]non-5-ene, benzene; (v) xylene, reflux; (vi) a) MeI, CH₂Cl₂; b) Zn, AcOH; c) benzoyl chloride, MeOH, Na₂CO₃.

Scheme 6

Cheng’s Total Synthesis of (-)-Cocaine. Conditions: (i) a) HC≡CMgCl added dropwise at −40 °C, THF, then 0 °C for 1 h; b) 5% Lindler catalyst, H₂, THF, ~10 min; c) H₂C=CHCH₂MgBr, Et₂O, −40 °C, 1 h; d) aq NaOH, MeOH, THF 60 °C, 1 h; e) Boc₂O, K₂CO₃, CH₂Cl₂, rt,1 h; (ii) Grubbs II (0.025 eq) CH₂Cl₂, reflux, 12h; (iii) dibromoformaldoxime, Na₂CO₃, EtOAc, 10°C, 40 h; (iv) NaOMe, MeOH, reflux, 8 h; (v) Raney-Ni, H₂, H₃BO₃, aq MeOH, rt, 3 h; (vi) BzCl, DMAP, Et₃N, CH₂Cl₂, rt, 12 h; (vii) a) TFA, CH₂Cl₂, rt, 1 h b) 37% aq CH₂O, NaBH₃CN, rt, 1 h.

Scheme 7

Shing & So Synthesis of (-)-Cocaine from D-(-)-Ribose. Conditions: (i) a) aq In, allyl bromide, H₂O: EtOH; b) acetone, aq. AcOH, BzCl; c) methyl acrylate, Grubbs II, CH₂Cl₂, reflux; d) 80% AcOH reflux; e) NaIO4, silica gel, CH₂Cl₂, rt; f) MeNHOH, tol, reflux; (ii) Tf₂O, 2,4,6-collidine, CH₂Cl₂, −78°C; b) K₂CO₃, MeOH, rt; (iii) H₂, Raney Ni, AcOH, MeOH, rt to 60 °C; (iv) BzCl, Et₃N, DMAP, CH₂Cl₂, 0 °C, then MsCl, rt; (v) H₂, Raney Ni, MeOH, 50 °C; (vi) MsCl Et₃N, CH₂Cl₂, rt to 70 °C, (vii) H₂, Raney Ni, MeOH, rt, 14 h.

Scheme 8

Concise Catalytic, Asymmetric Total Synthesis of Tropane Alkaloids. Conditions: (i) a) CHCl₃, 4 °C, 17 h; b) cat PdCl₂ (10 mol%), Et₃N, Et₃SiH, CH₂Cl₂, reflux 6 h; c) 3M HCl:THF, rt, 2h; (ii) a) Al(O^tBu)₃ (50 mol%) toluene, rt, 4 h, + 64 h at 150°C; b) MsOMe, CH₂Cl₂, reflux, 24 h. (iii) cat Pd/C, H₂, MeOH, rt, 48 h; (iv) PhCOCl, Et₃N, cat DMAP, CH₂Cl₂, rt, 17 h.

Scheme 9

Robinson’s One-pot synthesis of Tropinone (2). Conditions: (i) H₂NMe (53), H₂O.

Scheme 10

Biosynthesis of (-)-Cocaine. Conditions: (i) N-methyltransferase, (ii) oxidation, enzyme unknown, (iii) spontaneous cyclization, (iv) two acetyl groups are incorporated, enzyme unknown (v) Tropinone reductase, (vi) methylecgonone reductase, (vii) cocaine synthase, a BAHD acetyltransferase.

Scheme 11

Radiosynthesis of [N-Methyl-C]Cocaine ([¹¹C]1). Condition: (i) [¹¹C]CH₃I, 50 °C, 5 min.