Tropinone

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Tropinone
Tropinone.png
Tropinone-3D-sticks.png
Names
IUPAC name
8-Methyl-8-azabicyclo[3.2.1]octan-3-one
Other names
3-Tropinone
Identifiers
532-24-1 N
ChEBI CHEBI:16656 YesY
ChemSpider 393722 YesY
DrugBank DB01874 YesY
Jmol-3D images Image
PubChem 446337
Properties
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
Flammability code 1: Must be pre-heated before ignition can occur. Flash point over 93 °C (200 °F). E.g., canola oil Health code 2: Intense or continued but not chronic exposure could cause temporary incapacitation or possible residual injury. E.g., chloroform Reactivity code 0: Normally stable, even under fire exposure conditions, and is not reactive with water. E.g., liquid nitrogen Special hazards (white): no codeNFPA 704 four-colored diamond
Except where noted otherwise, data is given for materials in their standard state (at 25 °C (77 °F), 100 kPa)
 N verify (what isYesY/N?)
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[edit]

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]

Willstatter tropinone synthesis.png[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]

Robinson tropinone synthesis.png

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[edit]

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
Tropinone synthesis

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

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

See also[edit]

References[edit]

  1. ^ Robinson, R. (1917). "LXIII. A Synthesis of Tropinone". Journal of the Chemical Society, Transactions 111: 762–768. doi:10.1039/CT9171100762.  edit
  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.  edit
  3. ^ a b "Organic Synthesis". 1998. doi:10.1039/9781847551573. ISBN 978-0-85404-544-0.  edit
  4. ^ Humphrey, A. J.; O'Hagan, D. (2001). "Tropane alkaloid biosynthesis. A century old problem unresolved". Natural Product Reports (Royal Society of Chemistry) 18 (5): 494–502. doi:10.1039/b001713m. PMID 11699882.  edit
  5. ^ Green Chemistry and Engineering. Oxford [u.a.]: Elsevier inc. 2007. p. 34. ISBN 978-0-12-372532-5.  |first1= missing |last1= in Authors list (help)
  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.  edit
  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.  edit
  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.  edit
  9. ^ Findlay, S. P. (1957). "Concerning 2-Carbomethoxytropinone". Journal of Organic Chemistry 22 (11): 1385–1394. doi:10.1021/jo01362a022.  edit

External links[edit]