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]
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.
Beyond its role in cocaine, the N-methyl-pyrrolinium cation is a precursor to nicotine, hygrine, cuscohygrine, and other natural products. [1]
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.
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]
Cocaine, also known as coke, is a strong stimulant most frequently used as a recreational drug. It is commonly snorted, inhaled as smoke, or dissolved and injected into a vein. Mental effects may include loss of contact with reality, an intense feeling of happiness, or agitation. Physical symptoms may include a fast heart rate, sweating, and large pupils. High doses can result in very high blood pressure or body temperature. Effects begin within seconds to minutes of use and last between five and ninety minutes. Cocaine has a small number of accepted medical uses such as numbing and decreasing bleeding during nasal surgery.
Hyoscine, also known as scopolamine, is a medication used to treat motion sickness and postoperative nausea and vomiting. It is also sometimes used before surgery to decrease saliva. When used by injection, effects begin after about 20 minutes and last for up to 8 hours. It may also be used by mouth and as a skin patch.
Ornithine is a non-proteinogenic amino acid that plays a role in the urea cycle. Ornithine is abnormally accumulated in the body in ornithine transcarbamylase deficiency. The radical is ornithyl.
Hyoscyamine is a naturally occurring tropane alkaloid and plant toxin. It is a secondary metabolite found in certain plants of the family Solanaceae, including henbane, mandrake, angel's trumpets, jimsonweed, tomato, the sorcerers' tree, and deadly nightshade. It is the levorotary isomer of atropine and thus sometimes known as levo-atropine.
Tropinone is an alkaloid, famously synthesised in 1917 by Robert Robinson as a synthetic precursor to atropine, a scarce commodity during World War I. Tropinone and the alkaloids cocaine and atropine all share the same tropane core structure. Its corresponding conjugate acid at pH 7.3 major species is known as tropiniumone.
Spermine is a polyamine involved in cellular metabolism found in all eukaryotic cells. The precursor for synthesis of spermine is the amino acid ornithine. It is found in a wide variety of organisms and tissues and is an essential growth factor in some bacteria. It is found as a polycation at physiological pH. Spermine is associated with nucleic acids and is thought to stabilize helical structure, particularly in viruses.
Spermidine synthase is an enzyme that catalyzes the transfer of the propylamine group from S-adenosylmethioninamine to putrescine in the biosynthesis of spermidine. The systematic name is S-adenosyl 3-(methylthio)propylamine:putrescine 3-aminopropyltransferase and it belongs to the group of aminopropyl transferases. It does not need any cofactors. Most spermidine synthases exist in solution as dimers.
Methylecgonidine is a chemical intermediate derived from ecgonine or cocaine.
In enzymology, a tropinone reductase I (EC 1.1.1.206) is an enzyme that catalyzes the chemical reaction
In enzymology, a tropinone reductase II (EC 1.1.1.236) is an enzyme that catalyzes the chemical reaction
In enzymology, a putrescine N-methyltransferase is an enzyme that catalyzes the chemical reaction
In enzymology, a 2-isopropylmalate synthase (EC 2.3.3.13) is an enzyme that catalyzes the chemical reaction
In enzymology, a [3-methyl-2-oxobutanoate dehydrogenase (acetyl-transferring)] is an enzyme that catalyzes the chemical reaction
Tropane alkaloids are a class of bicyclic [3.2.1] alkaloids and secondary metabolites that contain a tropane ring in their chemical structure. Tropane alkaloids occur naturally in many members of the plant family Solanaceae. Some tropane alkaloids have pharmacological properties and can act as anticholinergics or stimulants.
(–)-2β-Carbomethoxy-3β-(4-bromophenyl)tropane is a semi-synthetic alkaloid in the phenyltropane group of psychostimulant compounds. First publicized in the 1990s, it has not been used enough to have gained a fully established profile. RTI-51 can be expected to have properties lying somewhere in between RTI-31 and RTI-55. Importantly it has a ratio of monoamine reuptake inhibition of D > S > N which is an unusual balance of effects not produced by other commonly used compounds. It has been used in its 76Br radiolabelled form to map the distribution of dopamine transporters in the brain.
Methylecgonone reductase (EC 1.1.1.334, MecgoR (gene name)) is an enzyme with systematic name ecgonine methyl ester:NADP+ oxidoreductase. This enzyme catalyses the following chemical reaction
Pseudotropine acyltransferase is an enzyme with systematic name acyl-CoA:pseudotropine O-acyltransferase. This enzyme catalyses the following chemical reaction
2-Carbomethoxytropinone (2-CMT) is a commonly used organic intermediate in the synthesis of cocaine and its analogues. As of at least 1999 no reaction pathway has been discovered that synthesizes cocaine-like compounds without utilizing the reduction of 2-CMT. The structure of cocaine was discovered by Richard Willstätter in 1898 after he synthesized it from 2-carbomethoxytropinone. Although it was originally believed that 2-CMT in nature was ultimately derived from ornithine and acetic acid, subsequent research has indicated other pathways exist for the biosynthesis of 2-CMT. A β-keto ester, 2-CMT exists in equilibrium with its keto–enol tautomer.
An O-acylpseudotropine is any derivative of pseudotropine in which the alcohol group is substituted with an acyl group.