Tropinone

Tropinone is an alkaloid, famously synthesised in 1917 by Robert Robinson as a synthetic precursor to atropine, a scarce commodity during World War I.[2][3] 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.[4]

Tropinone
Names
IUPAC name
8-Methyl-8-azabicyclo[3.2.1]octan-3-one
Other names
3-Tropinone
Identifiers
3D model (JSmol)
ChEBI
ChemSpider
DrugBank
ECHA InfoCard 100.007.756
UNII
  • InChI=1S/C8H13NO/c1-9-6-2-3-7(9)5-8(10)4-6/h6-7H,2-5H2,1H3/t6-,7+ checkY
    Key: QQXLDOJGLXJCSE-KNVOCYPGSA-N checkY
  • InChI=1S/C8H13NO/c1-9-6-2-3-7(9)5-8(10)4-6/h6-7H,2-5H2,1H3/t6-,7+
    Key: QQXLDOJGLXJCSE-KNVOCYPGBG
  • Key: QQXLDOJGLXJCSE-KNVOCYPGSA-N
  • CN1[C@@H]2CC[C@H]1CC(=O)C2
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
GHS labelling:
GHS05: CorrosiveGHS07: Exclamation mark[1]
Danger
H302, H314[1]
NFPA 704 (fire diamond)
NFPA 704 four-colored diamond
2
1
0
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
☒N verify (what is checkY☒N ?)
Infobox references

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%.[5] Willstätter had previously synthesized cocaine from tropinone, in what was the first synthesis and elucidation of the structure of cocaine.[6]

Willstatter tropinone synthesis [7]

Robinson's "double Mannich" reaction

The 1917 synthesis by Robinson is considered a classic in total synthesis[8] 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%.[5]

Robinson tropinone synthesis

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.[9][10]

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
Tropinone synthesis

Some authors have actually tried to retain one of the CO2H groups.[11]

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

From cycloheptanone

IBX dehydrogenation (oxidation) of cycloheptanone (suberone) to 2,6-cycloheptadienone [1192-93-4] followed by reaction with an amine is versatile a way of forming tropinones.[12][13] The mechanism evoked is clearly delineated to be a double Michael reaction (i.e. conjugate addition).

Biochemistry method

[14]

Reduction of tropinone

The reduction of tropinone is mediated by NADPH-dependent reductase enzymes, which have been characterized in multiple plant species.[15] These plant species all contain two types of the reductase enzymes, tropinone reductase I and tropinone reductase II. TRI produces tropine and TRII produces pseudotropine. Due to differing kinetic and pH/activity characteristics of the enzymes and by the 25-fold higher activity of TRI over TRII, the majority of the tropinone reduction is from TRI to form tropine.[16]

Reduction of tropinone

See also

References
  1. "Tropinone". Substance Information. ECHA.
  2. Robinson, R. (1917). "LXIII. A Synthesis of Tropinone". Journal of the Chemical Society, Transactions. 111: 762–768. doi:10.1039/CT9171100762.
  3. 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.
  4. Chemical Entities of Biological Interest Identification code: ChEBI:57851 "tropiniumone"
  5. Smit, Wim A.; Smit, William A.; Bochkov, Alekseĭ Feodosʹevich; Caple, Ron (1998). Organic Synthesis. doi:10.1039/9781847551573. ISBN 978-0-85404-544-0.
  6. 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.
  7. Doble, Mukesh; Kruthiventi, Anil Kumar (2007). Green Chemistry and Engineering. Oxford: Elsevier. p. 34. ISBN 978-0-12-372532-5.
  8. 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. 47 (2): 277–296. doi:10.1098/rsnr.1993.0034. JSTOR 531792. S2CID 143267467.
  9. 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.
  10. 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.
  11. Findlay, S. P. (1957). "Concerning 2-Carbomethoxytropinone". Journal of Organic Chemistry. 22 (11): 1385–1394. doi:10.1021/jo01362a022.
  12. U.S. Patent 8,609,690
  13. Nicolaou, K. C.; Montagnon, T.; Baran, P. S.; Zhong, Y. L. (2002). "Iodine(V) reagents in organic synthesis. Part 4. O-Iodoxybenzoic acid as a chemospecific tool for single electron transfer-based oxidation processes". Journal of the American Chemical Society. 124 (10): 2245–58. doi:10.1021/ja012127+. PMID 11878978.
  14. Bedewitz, Matthew A.; Jones, A. Daniel; D’Auria, John C.; Barry, Cornelius S. (2018). "Tropinone synthesis via an atypical polyketide synthase and P450-mediated cyclization". Nature Communications. 9 (1): 5281. Bibcode:2018NatCo...9.5281B. doi:10.1038/s41467-018-07671-3. ISSN 2041-1723. PMC 6290073. PMID 30538251.
  15. A. Portsteffen; B. Draeger & A. Nahrstedt (1992). "Two tropinone reducing enzymes from Datura stramonium transformed root cultures". Phytochemistry. 31 (4): 1135. doi:10.1016/0031-9422(92)80247-C.
  16. Boswell HD, Dräger B, McLauchlan WR, et al. (November 1999). "Specificities of the enzymes of N-alkyltropane biosynthesis in Brugmansia and Datura". Phytochemistry. 52 (5): 871–8. doi:10.1016/S0031-9422(99)00293-9. PMID 10626376.
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