Ibogaine: The Occurrence, Bioactivity, Biosynthesis, And Synthesis Of Ibogaine

Ibogaine: The Occurrence, Bioactivity, Biosynthesis, and Synthesis of Ibogaine Christopher Barberi, Fall 2009

Figure 1: Ibogaine, an indole alkaloid extracted from the root bark of the Tabernanthe iboga shrub in Central Africa. Ibogaine is mainly used for its anti-addictive properties[3]

Introduction Ibogaine, classified under the Iboga terpenoids, is a psychoactive terpene indole alkaloid commonly found in root bark extracts throughout the Congo and other regions of Central Africa. Though it can be toxic at high doses, Ibogaine is mainly useful for its treatment for opiate, alcohol, and cocaine addiction. However, as a result of hallucinations, paralysis, and cardiac arrest at high doses, Ibogaine has been banned in many countries today. Like the vast majority of indole alkaloids, Ibogaine is derived from the aromatic amino acid tryptophan which is then assembled with a naturally abundant molecule called Secologanin which forms the skeletal backbone of Ibogaine. Though the biosynthetic pathway of Ibogaine has yet to be fully determined, the synthetic N route is up to date and relatively H3CO convergent. Thus the following paper will encompass the natural occurrence N H and biological activity of Ibogaine as well as synthetic and biosynthetic approaches.

I.

Occurrence

Despite the fact that it’s relatively hard to isolate from the other Iboga alkaloids present in the root bark extract, Ibogaine can be found and readily extracted from a shrub called Tabernanthe iboga. This shrub is said to contain 6 % indole alkaloids by composition. Being that Ibogaine is considered to be the most common of the Iboga alkaloids, it’s fair to say that the Tabernanthe iboga shrub serves as the richest source of the alkaloid itself.[6] Despite the fact the Tabernanthe iboga shrub is scarcely dispersed throughout regions of South Africa, the plant requires a climate that is specific to the geographical location of the central regions. Prior to its use for anti-addiction, Ibogaine was primarily used in spiritual rituals for they were said to have “healing” powers. See figure 2 for a photo of the African Tabernanthe shrub.[20][9]

Figure 2: The Tabernanthe Iboga shrub from Congo

that a lack of serotonin can lead to susceptibility towards addiction and dependence.[2][3] Moreover, 12 Hydroxy Ibogamine is also said to be a moderate opioid agonist. As a result, the chemical replaces opiates and opiate derivatives at the receptor site in a similar manner to that of methadone. Moreover, the bridged nitrogen on the compound is relatively consistent with that of cocaine. Being that Ibogaine doesn’t have the same effects as cocaine, it’s an effective candidate for helping with cocaine addiction.[2][11] Thus this drug acts on three different receptors all in harmony in efforts to decrease withdraw symptoms in some of the most widely abused drugs today.

III. II.

Biological Activity

After Ibogaine is ingested by an organism, it gets metabolized by an enzyme called O-methyltransferase to a different chemical called 12-Hydroxy Ibogamine. [6][15] It is this metabolite that is responsible for the medicinal characteristics of Ibogaine. During phase 1 metabolism, the methyl group located on the oxygen on carbon number 12 gets cleaved off by the demethylating enzyme. As a result, a hydroxyl groups resides on carbon number 12 in lieu of the methoxy group. Now with the resulting 5HT analogue, it’s no surprise that this metabolite can serve as a selective serotonin reuptake inhibitor. Nonetheless it’s been proven

Biosynthesis.

Ibogaine is a Tryptamine derivative, as seen by looking at the structure above. Tryptamine is formed by the decarboxylation of the aromatic amino acid Tryptophan, which is derived from the Shikimate biosynthetic pathway. Due to the complexity and elite obscure stereocenters engulfed in this molecule, the biosynthetic pathway is a bit abstract in some areas.[12][20] There is still some question as to the sources of certain reducing and oxidizing agents.[1] [2] Nonetheless, the complete step by step biosynthesis of Ibogaine is summarized in Figure 3. Once Tryptophan is decarboxylated into Tryptamine it becomes oxidized with a hydroxyl group on carbon number 12. This hydroxyl group is then methylated by SAM (S-Adenosylmethionine). The

next step is a Mannich reaction with a molecule called Secologanin. Once the Secologanin analogue is installed, glucose is cleaved off of the Secologanin portion of the molecule in efforts to open the ring via hydrolysis. [8] After the Secologanin ring has been opened, the resulting aldehyde is nucleophilically attacked by the NH2 group on the Tryptamine analogue, ultimately forming the stable imminium ion. [13][5] The molecule is then able to tautaumerize from an enamine to an immine. Next an acid is added in efforts to move the double bond into a position where it can be conjugated. [19] Following this step, a series of ring rearrangements create triple bridged nitrogen joining an unhindered diene and dienophile. Thus the Diels-Alder reaction forms the principle backbone of the Iboga alkaloid. The end of the biosynthesis involves a hydrolysis followed by the decarboxylation of the resulting COOH group.[4][9] The final step is a reduction of the last double bond to give the final biosynthetic product. Figure 3: Biosynthesis of Ibogaine 2

3 H NH 2 H 3CO

O

+ OHC N H

H CO2Me

H 3CO

5

H

NH

N H

OGlc

H MeO2C

H

NH

H3CO

7

N H

OH

H MeO 2C

8

NH

H 3CO

N H

OHC

H

Imminium Formation (Immine-Enamine Tautaumerism)

OH

H H

NH2

O

9

N H N H

N H

NH2

NH2

H 3CO

SAM

N H

OH

H H MeO2C

1 N H

10

H

H

N

H 3CO

HO

H2O

O

H

MeO2C

CO2

6 Glucose

O

H

CO2H

NH2

4 OGlc

N

H 3CO

N H

Diels-Alder

H3 CO

N

CO2 Me

N H

OH

H H MeO2C

2. CO2 1. H2O N H3CO

3. NADPH N H

CO2 Me

11 N

H 3CO H

CH 2 OH

N MeO2 C

15-16 17 N H 3 CO

N H

12

N

H

H 3CO H

N MeO2C

CH2 OH

IV.

13

N

CH3OH H 3CO H

Rearrangment N MeO C 2 H

14

CH 2 OH

Synthesis

The synthetic route for this chemical begins with the assembly of Tryptamine with a six member ring to give the standard skeletal backbone of the Iboga alkaloid. First, the cyclohexene with an acetal ester fused onto it. After this ring gets a two carbon fragment installed onto it, it then reacts with MCPBA to form an epoxide on the double bond.[2] [3] Once this happens, the resulting carbonyl can be nucleophilically attacked by the NH2 group on Tryptamine. This reaction is followed by a hydroxylation and methylation via SN2 on carbon number 12.[16] Now that the basic framework has been assembled, the resulting hydroxyl group on the

steric portion of the molecule is replaced with Tosyl chloride.[3][12] Finally the resulting carbonyl is reduced with LiAlH4 to give the final product. [17][18] SYNTHESIS O

CO 2CH3 1) EtMgI, THF, N2, 30C, CuI, Me2S

O

MCPBA

2) MeCOCl, MeOH 3) NaOMe, MeOH, N2, Heat 4) MeCOCl, MeOH

H Et

CO2CH3

N H3CO

HO

1) Tryptamine, EtOH, Heat, H2O2, AlCl3, CH3Br 2) N2, 160C 4 Hrs H3) N2, 90C 1 Hr O

O TSCl, THF

N H

Et O

H3C O

STO

N

H3CO

N O

N H

AlCl3, Toluene 100C

N H

N LiAlH4

H3 CO

N H

potential live saver in regards to three of the most dangerous controlled substances in the world. VI.

References

1. Yong, J.; Du, J. A New Indole Alkaloid from Ervatamia. Fitoterapia. 2010, 81, 63-65. 2. Hanajri, K.; Rull, M.; Takuro, M. Chemical and DNA Analyses for the Products of Voacanga. Yakugaku Zaishi. 2009, 129, 975-982. 3. Borne, R.; Levi, M.; Khan, M. Solution Phase Parallel Synthesis of Indole Alkaloids. Letters in Drug Design and Discovery. 2009, 6i, 78-81. 4. Lim, K,; Kam, T. Analysis of Toxic Alkaloids in Body Samples. Tetrahedron Letters. 2009, 50, 3756-3759. 5. Levi, M.; Randall, C.; Norman, T. Isoquinuclidines: Chemical and Pharmacological Properties. J. Nat. Prod. 2009, 34, 753-787. 6. McCallum, S.; Glick, S. 18Methoxycoronaridine Blocks Acquisition of Cocaine. Neuroscience Letters. 2009, 458, 57-59.

V.

Conclusions

In conclusion, it’s evident that Ibogaine is a relatively difficult compound to synthesis because of its hindered nitrogen bridge as well as the chiral carbons located on the non-aromatic portion of the molecule. Furthermore, it’s the efficacy of this drug that makes it so useful. Nonetheless it can be a

7. Dewick, P. Medicinal Natural Products: A Biosynthetic Approach, 2nd ed., Wiley&Sons: West Sussex, England, 2001, p347. 8. Houlihan, W. Indole Part Two: The Chemistry of Heterocyclic Compounds., Wiley&Sons: West Sussex, England, 1974, p183.

9. Ali, S. Cellular and Molecular Mechanisms of Drugs of Abuse., New York Academy of Sciences: Brooklyn, N.Y, 2001, p197. 10. Ali, S. Neurobiological mechanisms of Drugs of Abuse., New York Academy of Sciences: Brooklyn, N.Y, 2000, p136. 11. Beal, D.; De Rienzo, P. Report on the Staten Island Project: The Ibogaine Story. Autonomedia: Brooklyn, N.Y, 1997, p15-p30. 12. Rahman, A. Biosynthesis of Indole Alkaloids., Clarendon Press: Brooklyn, N.Y, 1983, p165. 13. Sundberg, R. The Chemistry of Indoles., Academic Press: Brooklyn, N.Y, 1970, p171. 14. Robinson, B. The Fisher Indole Synthesis., Wiley&Sons: West Sussex, England, 1982, p154. 15. Buchi, G.; Coffen, D.; Kocsis, K. The Total Synthesis of Iboga Alkaloids. Bioorg. Med. Chem. 2003, 11, 30994007. 16. Manfred, H. Indole Alkaloids., Weinheim: Brooklyn, N.Y, 1974, p76. 17. Stafford, P. Psychedelics Encyclopedia., Ronin Pub: Berkeley, CA, 1992, p117. 18. Taylor, W. Indole Alkaloids: An introduction to the Enamine Chemistry of Natural Products. Pergamon Press: Oxford, N.Y, 1966, p176. 19. Saxton, J. The Indoles: The Monoterpenoid Indole Alkaloids.

Wiley&Sons: West Sussex, England, 1983, p11-p23. 20. Blaschko, H. 5-Hydroxytryptamine and Related Indolealkylamines. Springer-Verlab: Brooklyn, N.Y, 1966, p123.