Editing Cocaine (section)

==== Biosynthesis ====
{{Main|Biosynthesis of cocaine}}
[[File:Biosynthesis of cocaine.png|class=skin-invert-image|thumb|400px|Biosynthesis of cocaine]]

The first synthesis and elucidation of the cocaine molecule was by [[Richard Willstätter]] in 1898.<ref name="Humphrey2001">{{Cite journal | vauthors = Humphrey AJ, O'Hagan D | title = Tropane alkaloid biosynthesis. A century-old problem unresolved | journal = Natural Product Reports | volume = 18 | issue = 5 | pages = 494–502 | date = October 2001 | pmid = 11699882 | doi = 10.1039/b001713m }}</ref> Willstätter's synthesis derived cocaine from [[tropinone]]. Since then, [[Robert Robinson (organic chemist)|Robert Robinson]] and Edward Leete have made significant contributions to the mechanism of the synthesis. (-NO<sub>3</sub>)

The additional carbon atoms required for the synthesis of cocaine are derived from [[acetyl-CoA]], by addition of two acetyl-CoA units to the ''N''-methyl-Δ<sup>1</sup>-pyrrolinium cation.<ref>{{Cite book | vauthors = Dewick PM |title=Medicinal Natural Products |publisher=Wiley-Blackwell |location=Chichester|year=2009 |isbn=978-0-470-74276-1}}</ref> The first addition is a [[Mannich reaction|Mannich]]-like reaction with the [[enolate]] anion from acetyl-CoA acting as a [[nucleophile]] toward the pyrrolinium cation. The second addition occurs through a [[Claisen condensation]]. This produces a racemic mixture of the 2-substituted pyrrolidine, with the retention of the thioester from the Claisen condensation. In formation of [[tropinone]] from [[racemic]] ethyl [2,3-13C<sub>2</sub>]<sub>4</sub>(Nmethyl-2-pyrrolidinyl)-3-oxobutanoate there is no preference for either stereoisomer.<ref>{{Cite journal|doi = 10.1021/ja964461p|title = The Biosynthesis of Tropane Alkaloids in Datura stramonium: The Identity of the Intermediates between ''N''-Methylpyrrolinium Salt and Tropinone|year = 1997 | vauthors = Robins RJ, Abraham TE, Parr AJ, Eagles J, Walton NJ |journal = J. Am. Chem. Soc.|volume = 119|pages = 10929–10934|issue = 45| bibcode=1997JAChS.11910929R }}</ref>

[[File:Tropane alkaloids biochemistry.png|class=skin-invert-image|right|thumb|Biological source of cocaine molecule in the context of the tropane class of molecules. The biological source of each tropane alkaloid is indicated by species, and below that a phylogenetic map is provided.]]

In cocaine biosynthesis, only the (S)-enantiomer can cyclize to form the tropane ring system of cocaine. The [[stereoselectivity]] of this reaction was further investigated through study of prochiral methylene hydrogen discrimination.<ref>{{Cite journal | vauthors = Hoye TR, Bjorklund JA, Koltun DO, Renner MK | title = N-methylputrescine oxidation during cocaine biosynthesis: study of prochiral methylene hydrogen discrimination using the remote isotope method | journal = Organic Letters | volume = 2 | issue = 1 | pages = 3–5 | date = January 2000 | pmid = 10814231 | doi = 10.1021/ol990940s }}</ref> This is due to the extra chiral center at C-2.<ref>{{Cite journal|doi = 10.1021/ja00024a039|title = Late intermediates in the biosynthesis of cocaine: 4-(1-methyl-2-pyrrolidinyl)-3-oxobutanoate and methyl ecgonine|year = 1991| vauthors = Leete E, Bjorklund JA, Couladis MM, Kim SH |journal = J. Am. Chem. Soc.|volume = 113|pages = 9286–9292|issue = 24| bibcode=1991JAChS.113.9286L }}</ref> This process occurs through an oxidation, which regenerates the pyrrolinium cation and formation of an enolate anion, and an intramolecular Mannich reaction. The tropane ring system undergoes [[hydrolysis]], SAM-dependent methylation, and reduction via [[NADPH]] for the formation of [[methylecgonine]]. The [[benzoyl]] moiety required for the formation of the cocaine diester is synthesized from [[phenylalanine]] via [[cinnamic acid]].<ref>{{Cite journal|doi = 10.1016/0031-9422(88)87026-2|title = The biosynthesis of the benzoyl moiety of cocaine|year = 1988 | vauthors = Leete E, Bjorklund JA, Kim SH |journal = Phytochemistry|volume = 27|pages = 2553–2556|issue = 8| bibcode=1988PChem..27.2553L }}</ref> [[Benzoyl-CoA]] then combines the two units to form cocaine.

===== ''N''-methyl-pyrrolinium cation =====

The [[biosynthesis]] begins with L-[[Glutamine]], which is derived to L-[[ornithine]] in plants. The major contribution of L-ornithine and L-[[arginine]] as a precursor to the tropane ring was confirmed by Edward Leete.<ref>{{Cite journal | vauthors = Leete E, Marion L, Spenser ID | title = Biogenesis of hyoscyamine | journal = Nature | volume = 174 | issue = 4431 | pages = 650–1 | date = October 1954 | pmid = 13203600 | doi = 10.1038/174650a0 | bibcode = 1954Natur.174..650L | s2cid = 4264282 }}</ref> Ornithine then undergoes a [[pyridoxal phosphate]] (PLP)-dependent [[decarboxylation]] to form [[putrescine]]. In some animals, the [[urea cycle]] derives putrescine from ornithine. L-ornithine is converted to L-arginine,<ref>{{Cite journal | vauthors = Robins RJ, Waltons NJ, Hamill JD, Parr AJ, Rhodes MJ | title = Strategies for the genetic manipulation of alkaloid-producing pathways in plants | journal = Planta Medica | volume = 57 | issue = 7 Suppl | pages = S27-35 | date = October 1991 | pmid = 17226220 | doi = 10.1055/s-2006-960226 | bibcode = 1991PlMed..57S..27R | s2cid = 45912704 }}</ref> which is then decarboxylated via PLP to form agmatine. Hydrolysis of the [[imine]] derives ''N''-carbamoylputrescine followed with hydrolysis of the urea to form putrescine. The separate pathways of converting ornithine to putrescine in plants and animals have converged. A [[S-Adenosyl methionine|SAM]]-dependent ''N''-methylation of putrescine gives the ''N''-methylputrescine product, which then undergoes [[oxidative deamination]] by the action of [[diamine oxidase]] to yield the [[Aminoaldehydes and aminoketones|aminoaldehyde]]. [[Schiff base]] formation confirms the biosynthesis of the ''N''-methyl-Δ<sup>1</sup>-pyrrolinium cation.

[[File:Biosynthesis of N-methyl-pyrrolinium cation.png|class=skin-invert-image|center|thumb|500px|Biosynthesis of ''N''-methyl-pyrrolinium cation]]

===== Robert Robinson's acetonedicarboxylate =====
The biosynthesis of the [[tropane alkaloid]] is still not understood. Hemscheidt proposes that [[Robert Robinson (chemist)|Robinson]]'s acetonedicarboxylate emerges as a potential intermediate for this reaction.<ref>{{Cite journal|doi = 10.1007/3-540-48146-X|title = Tropane and Related Alkaloids|year = 2000| vauthors = Hemscheidt T, Vederas JC | journal = Top. Curr. Chem.|volume = 209|page = 175|series = Topics in Current Chemistry | veditors = Leeper FJ, Vederas JC | url=https://link.springer.com/chapter/10.1007/3-540-48146-X_4|url-access=subscription| isbn = 978-3-540-66573-1}}</ref> Condensation of ''N''-methylpyrrolinium and acetonedicarboxylate would generate the [[Ketobutyric acid|oxobutyrate]].{{which|date=May 2025}} Decarboxylation leads to [[tropane]] alkaloid formation.

[[File:Robinson biosynthesis of tropane.png|class=skin-invert-image|center|thumb|500px|Robinson biosynthesis of tropane]]

===== Reduction of tropinone =====
The reduction of tropinone is mediated by [[NADPH]]-dependent reductase enzymes, which have been characterized in multiple plant species.<ref>{{Cite journal|doi = 10.1016/0031-9422(92)80247-C|title = Two tropinone reducing enzymes from Datura stramonium transformed root cultures|year = 1992 | vauthors =  Portsteffen A, Draeger B, Nahrstedt A |journal = Phytochemistry|volume = 31|pages = 1135–1138|issue = 4| bibcode=1992PChem..31.1135P }}</ref> These plant species all contain two types of the reductase enzymes, tropinone reductase I and tropinone reductase II. TRI produces [[tropine]] and TRII produces [[pseudotropine]]. Due to differing kinetic and pH/activity characteristics of the enzymes and by the 25-fold higher activity of TRI over TRII, the majority of the tropinone reduction is from TRI to form tropine.<ref>{{Cite journal | vauthors = Boswell HD, Dräger B, McLauchlan WR, Portsteffen A, Robins DJ, Robins RJ, Walton NJ | title = Specificities of the enzymes of N-alkyltropane biosynthesis in Brugmansia and Datura | journal = Phytochemistry | volume = 52 | issue = 5 | pages = 871–8 | date = November 1999 | pmid = 10626376 | doi = 10.1016/S0031-9422(99)00293-9 | bibcode = 1999PChem..52..871B }}</ref>

[[File:Reduction of tropinone.png|class=skin-invert-image|thumb|center|500px|Reduction of tropinone]]

===== Illegal clandestine chemistry  =====
In 1991, the [[United States Department of Justice]] released a report detailing the typical process in which leaves from coca plants were ultimately converted into cocaine hydrochloride by [[Illegal drug trade in Latin America|Latin American drug cartels]]:<ref name=USDJ1992>{{Cite report |date=1991 |title=Coca Cultivation and Cocaine Processing:An Overview|publisher=U.S. Department of Justice, Drug Enforcement Administration |author=Drug Enforcement Administration Office of Intelligence Strategic Intelligence Section Latin America Unit |place=Washington, D.C. |url=https://www.ojp.gov/pdffiles1/Digitization/132907NCJRS.pdf}}</ref>
* the exact species of [[coca]] to be planted was determined by the location of its cultivation, with [[Erythroxylum coca]] being grown in tropical high altitude climates of the eastern [[Andes]] in [[Peru]] and [[Bolivia]], while [[Erythroxylum novogranatense]] was favoured in drier lowland areas of [[Colombia]]
* the average cocaine [[alkaloid]] content of a sample of coca leaf varied between 0.1 and 0.8 percent, with coca from higher altitudes containing the largest percentages of cocaine alkaloids
* the typical farmer will plant coca on a sloping hill so rainfall will not drown the plants as they reach full maturity over 12 to 24 months after being planted
* the main harvest of coca leaves takes place after the traditional [[wet season]] in March, with additional harvesting also taking place in July and November
* the leaves are then taken to a flat area and  spread out on [[tarpaulin]]s to dry in the hot sun for approximately 6 hours, and afterwards placed in {{cvt|25|lb}} sacks to be transported to market or to a cocaine processing facility depending on location
* in the early 1990s, Peru and Bolivia were the main locations for converting coca leaf to [[coca paste]] and cocaine base, while Colombia was the primary location for the final conversion for these products into cocaine hydrochloride
* the conversion of coca leaf into coca paste was typically done very close to the coca fields to minimize the need to transport the coca leaves, with  a plastic lined pit in the ground used as a "pozo"
* the leaves are added to the pozo along with fresh water from a nearby river, along with [[kerosene]] and [[sodium carbonate]], then a team of several people will repeatedly stomp on the mixture in their bare feet for several hours to help turn the leaves into paste
* the cocaine alkaloids and kerosene eventually separate from the water and coca leaves, which are then drained off / scooped out of the mixture
* the cocaine alkaloids are then extracted from the kerosene and added into a dilute [[acidic]] solution, to which more sodium carbonate is added to cause a precipitate to form
* the acid and water are afterwards drained off and the precipitate is filtered and dried to produce an off-white putty-like substance, which is coca paste ready for transportation to cocaine base processing facility
* at the processing facility, coca paste is dissolved in a mixture of [[sulfuric acid]] and water, to which [[potassium permanganate]] is then added and the solution is left to stand for 6 hours to allow the unwanted alkaloids to break down
* the solution is then filtered and the precipitate is discarded, after which [[ammonia]] water is added and another precipitate is formed
* when the solution has finished reacting the liquid is drained, then the remaining precipitate is dried under [[Infrared heater|heating lamps]], and resulting powder is cocaine base ready for transfer to a cocaine hydrochloride [[laboratory]]
* at the laboratory, [[acetone]] is added to the cocaine base and after it has dissolved the solution is filtered to remove undesired material
* [[hydrochloric acid]] diluted in [[ether]] is added to the solution, which causes the cocaine to precipitate out of the solution as cocaine hydrochloride crystals
* the cocaine hydrochloride crystals are finally dried under lamps or in [[microwave oven]]s, then pressed into {{cvt|1|kg}} blocks and wrapped in plastic ready for export