Biosynthesis of cocaine

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]

Chemical structure of cocaine

Biosynthesis of N-methyl-pyrrolinium cation

The biosynthesis begins with L-glutamine, which is derived from L-ornithine in plants. The roles of L-ornithine and L-arginine was confirmed by Edward Leete.[2] Ornithine then undergoes a PLP-dependent decarboxylation to form putrescine. In animals, however, 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, which then undergoes oxidative deamination by the action of diamine oxidase to yield the aminoaldehyde, which spontaneously cyclizes to 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]

Conversion of N-methyl-pyrrolinium cation to the tropane

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 benzoyl moiety required for the formation of the cocaine diester is synthesized from phenylalanine via cinnamic acid.[8] Benzoyl-CoA then combines the two units to form cocaine.

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

Chemical synthesis

The synthesis and structure elucidation of cocaine was reported by Richard Willstätter in 1898.[9] Willstätter's synthesis derived cocaine from tropinone. Robert Robinson and Edward Leete also made significant contributions.[10]

gollark: I think the problem is that everyone thinks "Oh wow, CC is so unlike Windows! And I have never seen any desktop OS but Windows! I must make it more like Windows so it is more familiar. Clearly nobody else has done this, or it would already be the default, because this is obviously better"
gollark: > Instead write an actual program. Something fun, something useful, something completely useless and over-complicated. Whatever. As long as you learn a ton and have fun I don't care - that is what ComputerCraft is about :). But please don't just make an operating system.
gollark: Importantly:> Don't. Find something else interesting to write. Most operating systems end up being glorified startup screens. The ones which don't generally opt for features which are "cool" or exist in real life operating systems rather than those which make life easier for the user.
gollark: Oops, sent it twice!
gollark: https://gist.github.com/SquidDev/6fa444798bbe01f4068bf82a76ac273f

References
  1. Leete, Edward (1990). "Recent Developments in the Biosynthesis of the Tropane Alkaloids1". Planta Medica. 56 (4): 339–352. doi:10.1055/s-2006-960979. PMID 2236285.
  2. Leete E, Marion L, Sspenser ID (October 1954). "Biogenesis of Hyoscyamine". Nature. 174 (4431): 650–1. Bibcode:1954Natur.174..650L. doi:10.1038/174650a0. PMID 13203600.
  3. Robins, Richard; Waltons, Nicholas; Hamill, John; Parr, Adrian; Rhodes, Michael (1991). "Strategies for the Genetic Manipulation of Alkaloid-Producing Pathways in Plants". Planta Medica. 57 (7 Suppl): S27–S35. doi:10.1055/s-2006-960226. PMID 17226220.
  4. Dewick, P. M. (2009). Medicinal Natural Products. Chicester: Wiley-Blackwell. ISBN 978-0-470-74276-1.
  5. R. J. Robins; T. W. Abraham; A. J. Parr; J. Eagles; N. J. Walton (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. 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". Org. Lett. 2 (1): 3–5. doi:10.1021/ol990940s. PMID 10814231.
  7. E. Leete; J. A. Bjorklund; M. M. Couladis & S. H. Kim (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. doi:10.1021/ja00024a039.
  8. E. Leete; J. A. Bjorklund & S. H. Kim (1988). "The biosynthesis of the benzoyl moiety of cocaine". Phytochemistry. 27 (8): 2553. doi:10.1016/0031-9422(88)87026-2.
  9. Humphrey AJ, O'Hagan D (October 2001). "Tropane alkaloid biosynthesis. A century old problem unresolved". Nat Prod Rep. 18 (5): 494–502. doi:10.1039/b001713m. PMID 11699882.
  10. T. Hemscheidt; Vederas, John C. (2000). Leeper, Finian J.; Vederas, John C. (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.
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