Tropinone
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| Template:Longitem | C8H13NO |
| Molar mass | 139.195 g/mol |
| Appearance | Brown solid |
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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]
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]
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]
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:
- 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.[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
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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]
See also
- Benztropine
- Daturaolone
- 2-Carbomethoxytropinone (2-CMT) an intermediate in the creation of ecgonine cocaine analogues
- Ecgonidine
References
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- ↑ a b Script error: No such module "citation/CS1".
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- ↑ Chemical Entities of Biological Interest Identification code: ChEBI:57851 "tropiniumone"
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- ↑ U.S. patent 8609690
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