Tropinone

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Tropinone
IUPAC name

8-Methyl-8-azabicyclo[3.2.1]octan-3-one

Other names

3-Tropinone

Identifiers
CAS number 532-24-1 N
PubChem 446337
ChemSpider 393722 YesY
DrugBank DB01874
ChEBI CHEBI:16656 YesY
Jmol-3D images {{#if:CN1[C@@H]2CC[C@H]1CC(=O)C2|Image 1
Properties
Molecular formula C8H13NO
Molar mass 139.195 g/mol
Appearance Brown solid
Melting point 42.5 °C; 108.5 °F; 315.6 K
Boiling point (decomposes)
Hazards
NFPA 704
1
2
0
 N (verify) (what is: YesY/N?)
Except where noted otherwise, data are given for materials in their standard state (at 25 °C (77 °F), 100 kPa)
Infobox references

Tropinone is an alkaloid, famously synthesised in 1917 by Robert Robinson as a synthetic precursor to atropine, a scarce commodity during World War I.[1][2] Tropinone and the alkaloids cocaine and atropine all share the same tropane core structure.

Synthesis

The first synthesis of tropinone was by Richard Willstätter in 1901. It started from the seemingly related cycloheptanone, but required many steps to introduce the nitrogen bridge; the overall yield for the synthesis path is only 0.75%.[3] Willstätter had previously synthesized cocaine from tropinone, in what was the first synthesis and elucidation of the structure of cocaine.[4]

[5]

The 1917 synthesis by Robinson is considered a classic in total synthesis[6] due to its simplicity and biomimetic approach. Tropinone is a bicyclic molecule, but the reactants used in its preparation are fairly simple: succinaldehyde, methylamine and acetonedicarboxylic acid (or even acetone). The synthesis is a good example of a biomimetic reaction or biogenetic-type synthesis because biosynthesis makes use of the same building blocks. It also demonstrates a tandem reaction in a one-pot synthesis. Furthermore the yield of the synthesis was 17% and with subsequent improvements exceeded 90%.[3]

This reaction is described as an intramolecular "double Mannich reaction" for obvious reasons. It is not unique in this regard, as others have also attempted it in piperidine synthesis.[7][8]

In place of acetone, acetonedicarboxylic acid is known as the "synthetic equivalent" the 1,3-dicarboxylic acid groups are so-called "activating groups" to facilitate the ring forming reactions. The calcium salt is there as a "buffer" as it is claimed that higher yields are possible if the reaction is conducted at "physiological pH".

Reaction mechanism

The main features apparent from the reaction sequence below are:

  1. Nucleophilic addition of methylamine to succinaldehyde, followed by loss of water to create an imine
  2. Intramolecular addition of the imine to the second aldehyde unit and first ring closure
  3. Intermolecular Mannich reaction of the enolate of acetone dicarboxylate
  4. New enolate formation and new imine formation with loss of water for
  5. Second intramolecular mannich reaction and second ring closure
  6. Loss of 2 carboxylic groups to tropinone



Some authors have actually tried to retain one of the CO2H groups.[9]

CO2R-tropinone has 4 stereoisomers, although the corresponding ecgonidine alkyl ester there is only a pair of enantiomers.

References

  1. ↑ Robinson, R. (1917). "LXIII. A Synthesis of Tropinone". Journal of the Chemical Society, Transactions 111: 762–768. doi:10.1039/CT9171100762. 
  2. ↑ Nicolaou, K. C.; Vourloumis, D.; Winssinger, N.; Baran, P. S. (2000). "The Art and Science of Total Synthesis at the Dawn of the Twenty-First Century". Angewandte Chemie International Edition 39 (1): 44–122. doi:10.1002/(SICI)1521-3773(20000103)39:1<44::AID-ANIE44>3.0.CO;2-L. PMID 10649349. 
  3. ↑ 3.0 3.1 Organic Synthesis. 1998. doi:10.1039/9781847551573. ISBN 978-0-85404-544-0. 
  4. ↑ Humphrey, A. J.; O'Hagan, D. (2001). "Tropane alkaloid biosynthesis. A century old problem unresolved". Natural Product Reports 18 (5): 494–502. doi:10.1039/b001713m. PMID 11699882. 
  5. ↑ Green Chemistry and Engineering. Oxford [u.a.]: Elsevier inc. 2007. p. 34. ISBN 978-0-12-372532-5. 
  6. ↑ Birch, A. J. (1993). "Investigating a Scientific Legend: The Tropinone Synthesis of Sir Robert Robinson, F.R.S". Notes and Records of the Royal Society of London (1938-1996) 47 (2): 277–226. doi:10.1098/rsnr.1993.0034. JSTOR 531792. 
  7. ↑ Wang, S.; Sakamuri, S.; Enyedy, I. J.; Kozikowski, A. P.; Deschaux, O.; Bandyopadhyay, B. C.; Tella, S. R.; Zaman, W. A.; Johnson, K. M. (2000). "Discovery of a novel dopamine transporter inhibitor, 4-hydroxy-1-methyl-4-(4-methylphenyl)-3-piperidyl 4-methylphenyl ketone, as a potential cocaine antagonist through 3D-database pharmacophore searching. Molecular modeling, structure-activity relationships, and behavioral pharmacological studies". Journal of Medicinal Chemistry 43 (3): 351–360. doi:10.1021/jm990516x. PMID 10669562. 
  8. ↑ Wang, S.; Sakamuri; Enyedy; Kozikowski; Zaman; Johnson (2001). "Molecular modeling, structure--activity relationships and functional antagonism studies of 4-hydroxy-1-methyl-4-(4-methylphenyl)-3-piperidyl 4-methylphenyl ketones as a novel class of dopamine transporter inhibitors". Bioorganic & Medicinal Chemistry 9 (7): 1753–1764. doi:10.1016/S0968-0896(01)00090-6. PMID 11425577. 
  9. ↑ Findlay, S. P. (1957). "Concerning 2-Carbomethoxytropinone". Journal of Organic Chemistry 22 (11): 1385–1394. doi:10.1021/jo01362a022. 

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