Biosynthesis of cocaine

For broader coverage of this topic, see Cocaine.

Chemical structure of cocaine

The biosynthesis of cocaine is the natural metabolic process by which the coca plant (Erythroxylum species) produces cocaine, a tropane alkaloid, through a multi-step enzymatically catalyzed pathway beginning with ornithine or arginine and culminating in the formation of the cocaine metabolite benzoylecgonine.

The biosynthesis of cocaine has long attracted the attention of biochemists and organic chemists. This interest is partly motivated by the strong physiological effects of cocaine, but a further incentive was the unusual bicyclic structure of the molecule. The biosynthesis can be viewed as occurring in two phases, one phase leading to the N-methylpyrrolinium ring, which is preserved in the final product. The second phase incorporates a C4 unit with formation of the bicyclic tropane core. ^[1]

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. ^[2] 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, ^[3] 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 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 aminoaldehyde. Schiff base formation confirms the biosynthesis of the N-methyl-Δ¹-pyrrolinium cation.

Biosynthesis of N-methyl-pyrrolinium cation. MeSR₂ refers to the methylating agent S-adenosyl methionine.

Beyond its role in cocaine, the N-methyl-pyrrolinium cation is a precursor to nicotine, hygrine, cuscohygrine, and other natural products. ^[1]

Reduction of tropinone

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-Δ¹-pyrrolinium cation. ^[4] The first addition is a Mannich-like reaction with the enolate anion from acetyl-CoA acting as a nucleophile towards 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 [2,3-13C2]4(Nmethyl- 2-pyrrolidinyl)-3-oxobutanoate there is no preference for either stereoisomer. ^[5]

In the biosynthesis of cocaine, however, 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. ^[6] This is due to the extra chiral center at C-2. ^[7] 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 reduction of tropinone is mediated by NADPH-dependent reductase enzymes, which have been characterized in multiple plant species. ^[8] 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. ^[9] The benzoyl moiety required for the formation of the cocaine diester is synthesized from phenylalanine via cinnamic acid. ^[10] Benzoyl-CoA then combines the two units to form cocaine.

Reduction of tropinone

Cocaine biosynthesis from the pyrrolium cation intermediate. MeSR₂ refers to the methylating agent S-adenosyl methionine.

Robert Robinson's acetonedicarboxylate

The biosynthesis of the tropane alkaloid is still not understood. Hemscheidt proposes that Robinson's acetonedicarboxylate emerges as a potential intermediate for this reaction. ^[11] Condensation of N-methylpyrrolinium and acetonedicarboxylate would generate the oxobutyrate.^{[ which? ]} Decarboxylation leads to tropane alkaloid formation.

Robinson biosynthesis of tropane

Structure elucidation and total synthesis

In 1898, using classical methods of chemical degradation and derivatization, Richard Willstätter successfully elucidated the chemical structure of cocaine and subsequently achieved its total synthesis. ^[12] His synthetic route involved the construction of the cocaine molecule from simpler precursors, including tropinone. Significant subsequent contributions to the understanding and synthesis of cocaine were made by Robert Robinson and Edward Leete. ^[13]

References

1. Leete E (Aug 1990). "Recent Developments in the Biosynthesis of the Tropane Alkaloids1". Planta Medica. 56 (4): 339–352. Bibcode:1990PlMed..56..339L. doi: 10.1055/s-2006-960979 . PMID   2236285.
2. Leete E, Marion L, Spenser ID (October 1954). "Biogenesis of hyoscyamine". Nature. 174 (4431): 650–1. Bibcode:1954Natur.174..650L. doi:10.1038/174650a0. PMID   13203600. S2CID   4264282.
3. Robins RJ, Waltons NJ, Hamill JD, Parr AJ, Rhodes MJ (October 1991). "Strategies for the genetic manipulation of alkaloid-producing pathways in plants". Planta Medica. 57 (7 Suppl): S27-35. Bibcode:1991PlMed..57S..27R. doi:10.1055/s-2006-960226. PMID   17226220. S2CID   45912704.
4. Dewick PM (2009). Medicinal Natural Products. Chicester: Wiley-Blackwell. ISBN   978-0-470-74276-1.
5. Robins RJ, Abraham TW, Parr AJ, Eagles J, Walton NJ (1997). "The Biosynthesis of Tropane Alkaloids in Datura stramonium: The Identity of the Intermediates between N-Methylpyrrolinium Salt and Tropinone". J. Am. Chem. Soc. 119 (45): 10929–10934. Bibcode:1997JAChS.11910929R. doi:10.1021/ja964461p.
6. Hoye TR, Bjorklund JA, Koltun DO, Renner MK (January 2000). "N-methylputrescine oxidation during cocaine biosynthesis: study of prochiral methylene hydrogen discrimination using the remote isotope method". Organic Letters. 2 (1): 3–5. doi:10.1021/ol990940s. PMID   10814231.
7. Leete E, Bjorklund JA, Couladis MM, Kim SH (1991). "Late intermediates in the biosynthesis of cocaine: 4-(1-methyl-2-pyrrolidinyl)-3-oxobutanoate and methyl ecgonine". J. Am. Chem. Soc. 113 (24): 9286–9292. Bibcode:1991JAChS.113.9286L. doi:10.1021/ja00024a039.
8. Portsteffen A, Draeger B, Nahrstedt A (1992). "Two tropinone reducing enzymes from Datura stramonium transformed root cultures". Phytochemistry. 31 (4): 1135–1138. Bibcode:1992PChem..31.1135P. doi:10.1016/0031-9422(92)80247-C.
9. Boswell HD, Dräger B, McLauchlan WR, Portsteffen A, Robins DJ, Robins RJ, et al. (November 1999). "Specificities of the enzymes of N-alkyltropane biosynthesis in Brugmansia and Datura". Phytochemistry. 52 (5): 871–8. Bibcode:1999PChem..52..871B. doi:10.1016/S0031-9422(99)00293-9. PMID   10626376.
10. Leete E, Bjorklund JA, Sung HK (1988). "The biosynthesis of the benzoyl moiety of cocaine". Phytochemistry. 27 (8): 2553–2556. Bibcode:1988PChem..27.2553L. doi:10.1016/0031-9422(88)87026-2.
11. Hemscheidt T, Vederas JC (2000). Leeper FJ, Vederas JC (eds.). "Tropane and Related Alkaloids" . Top. Curr. Chem. Topics in Current Chemistry. 209: 175. doi:10.1007/3-540-48146-X. ISBN   978-3-540-66573-1.
12. Humphrey AJ, O'Hagan D (October 2001). "Tropane alkaloid biosynthesis. A century old problem unresolved". Natural Product Reports. 18 (5): 494–502. doi:10.1039/b001713m. PMID   11699882.
13. Vederas JC, Hemscheidt T (2000). Leeper FJ, Vederas JC (eds.). "Tropane and Related Alkaloids". Top. Curr. Chem. Topics in Current Chemistry. 209: 175. doi:10.1007/3-540-48146-X. ISBN   978-3-540-66573-1.