Tropinone
| Tropinone | |
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8-Methyl-8-azabicyclo[3.2.1]octan-3-one |
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Other names
3-Tropinone |
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| Identifiers | |
| CAS number | 532-24-1  |
| PubChem | 446337 |
| ChemSpider | 393722  |
| DrugBank | DB01874 |
| ChEBI | CHEBI:16656 |
| Jmol-3D images | Image 1 |
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| Properties | |
| Molecular formula | C8H13NO |
| Molar mass | 139.195 g/mol |
| Appearance | Brown solid |
| Melting point |
42.5 °C, 316 K, 109 °F |
| Boiling point |
(decomposes) |
| Hazards | |
| NFPA 704 |
 1
2
0
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 (verify) (what is:  / ?)Except where noted otherwise, data are given for materials in their standard state (at 25 °C, 100 kPa) |
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| 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.
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[edit] 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]
The 1917 synthesis by Robinson is considered a classic in total synthesis[5] 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.[6][7]
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".
[edit] Reaction mechanism
The main features apparent from the reaction sequence below are:
- Nucleophilic addition of methylamine to succinaldehyde, followed by loss of water to create an imine
- Intramolecular addition of the imine to the second aldehyde unit and first ring closure
- Intermolecular Mannich reaction of the enolate of acetone dicarboxylate
- New enolate formation and new imine formation with loss of water for
- Second intramolecular mannich reaction and second ring closure
- Loss of 2 carboxylic groups to tropinone
Some authors have actually tried to retain one of the CO2H groups.[8]
CO2R-tropinone has 4 stereoisomers, although the corresponding ecgonidine alkyl ester there is only a pair of enantiomers.
[edit] References
- ^ Robinson, R. (1917). "LXIII.?A synthesis of tropinone". Journal of the Chemical Society, Transactions 111: 762–768. doi:10.1039/CT9171100762.
- ^ 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. doi:10.1002/(SICI)1521-3773(20000103)39:1<44::AID-ANIE44>3.0.CO;2-L. PMID 10649349.
- ^ a b Organic Synthesis. 1998. doi:10.1039/9781847551573. ISBN 978-0-85404-544-0.
- ^ 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.
- ^ 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.
- ^ Wang, S; Sakamuri, S; Enyedy, IJ; Kozikowski, AP; Deschaux, O; Bandyopadhyay, BC; Tella, SR; Zaman, WA et al (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): 351–60. doi:10.1021/jm990516x. PMID 10669562.
- ^ 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.
- ^ Findlay, S. P. (1957). Journal of Organic Chemistry 22 (11): 1385–1394. doi:10.1021/jo01362a022.
