Biosynthesis of cocaine

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Chemical structure 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]

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.

racemic
ethyl [2,3-13C2]4(Nmethyl- 2-pyrrolidinyl)-3-oxobutanoate there is no preference for either stereoisomer.
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

Robert Robinson and Edward Leete also made significant contributions.[10]

References

  1. ^
    PMID 2236285
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  2. S2CID 4264282
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  3. S2CID 45912704
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  4. ISBN 978-0-470-74276-1
    .
  5. doi:10.1021/ja964461p
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  6. PMID 10814231
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  7. doi:10.1021/ja00024a039
    .
  8. doi:10.1016/0031-9422(88)87026-2
    .
  9. PMID 11699882
    .
  10. ISBN 978-3-540-66573-1
    .
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