Author Topic: Epimerization of tropine to pseudotropine  (Read 4519 times)

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  • Guest
Epimerization of tropine to pseudotropine
« on: February 09, 2002, 01:21:00 AM »
Can tropine be epimerized to pseudotropine? There is just this little beta-oriented cyclohexanol that really really would like to become alpha-oriented. I believe that pseudotropine is the energetically most stable product, but how is the reaction performed? A simple reflux with a base?

Would the energetically favored isomer change if there was an axial carboxylic function at C2 (i. e. next to the alcohol)?

Sorry, but I'm really off when it comes to stereochemistry.


  • Guest
Re: Epimerization of tropine to pseudotropine
« Reply #1 on: February 09, 2002, 03:15:00 AM »
Hey Rhodium
I think you'll like this  :)

Stereochemistry of reduction of tropinone.    
Beckett, A. H.; Harper, N. J.; Balon, A. D. J.; Watts, T. H. E.    
Tetrahedron  (1959),  6  319-30.

Equilibration of tropines

(i) Sodium/n-pentanol. The following general procedure was adopted. A solution of the alcohol (2 g) in n-pentanol(20 cc) was added to sodium n-pentoxide prepared from sodium (4 g) and n-pentanol (20 cc) and the mixture refluxed. After cooling and decomposing with water, dilute hydrochloric
acid was added and the aqueous layer separated. This was made alkaline with dilute sodium hydroxide solution and extracted with chloroform, which on evaporation gave the equilibrium alcohol mixture(34-36).

35) Reflux (Tropine"a") 12 hours,
    Result  pseudotropine 91%, tropine 8%, tropinone 1%
36) Reflux (PseudoTropine) 12 hours,
    Result  pseudotropine 88%, tropine 11%, tropinone 1%

(ii) Aluminium isopropoxide. The following general procedure was adopted, The alcohol (1.5 g) was added to a solution of aluminium isopropoxide (2.16 g) in iso-propanol (50 cc), acetone (0.5 cc) added, and the mixture refluxed. On completion of the reaction, acetic acid was added, the mixture made alkaline with concentrated ammonium hydroxide solution and extracted with chloroform,which on evaporation gave the equilibrium alcohol mixture (29-33).

29) Reflux (Tropine"a") 20 hours,
    Result  pseudotropine 36%, tropine 60%, tropinone 4%
30) Reflux (Tropine"a") 40 hours, Inverse Addition
    Result  pseudotropine 54%, tropine 43%, tropinone 3%
31) Reflux (Tropine"a") 288 hours,
    Result  pseudotropine 83.5%, tropine 16%, tropinone 0.5%
32) Reflux (PseudoTropine) 40 hours,
    Result  pseudotropine 93%, tropine 6%, tropinone 1%
33) Reflux (PseudoTropine) 288 hours,
    Result  pseudotropine 88%, tropine 11%, tropinone 1%

(iii) Sodium isobutoxide. A solution of tropine (1 g) in a mixture of isobutanol (l.5 cc) and toluene
(10 cc was added, yith stirring, to an ice-cooled suspension of sodium (0.33 g) in toluene (10 cc) over 1 hr. The solution was stirred overnight and water (5 cc) added, and the aqueous layer separated and extracted with chloroform. The combined organic layers were evaporated to give 0.91 g equilibrium alcohol mixture (37).

37) Reflux (Tropine) 18 hours,
    Result  pseudotropine 14%, tropine 81%, tropinone 5%

Tropine"a"= 94% Tropine and 6% Pseudotropine

Mechanism of isomerization of tropine into y-tropine.
Kovach, E.; Shneider, I.; Uresh, F.   
Ser. Khim.  (1964),   (2),  320-6. 
Isomerization of tropine into y-tropine (i.e. 3a-tropanol into 3b-tropanol) was shown to be an equil. reaction that passed through a carbonyl-carbinol, oxidn.-redn. system.  The observations on this reaction in N, in the presence of Ph2CO, Ph2NH, fluorenone, and tropanone, coupled with existing literature data, showed that under the action of atm. O a small amt. of tropanone formed from either isomer.  In the presence of EtONa the point of equil. was shifted toward the more stable 3b-isomer through tropanone.  In the presence of ketonic additives shown above, even under N, an equil. was established with 1:9 ratio of a- to b-forms.  Ph2NH did not accelerate or affect the isomerization.  The more stable 3b-form probably had an equatorial OH group and a chair form, as shown by conformational analysis.  The estn. of isomers was done chromatographically on paper in BuOH-2N HCl and 0.5N KCl, as well as spectrometrically and electrophoretically, using a modified Dragendorff reagent (5 g. Bi carbonate in 50 ml. H2O, with 10 ml. 37% HCl, 25 g. KI, and dild. to 100 ml., with diln. prior to use in 1:25 proportion with 0.1N HCl).  Refluxing atropine in 10% HCl 5 hrs. gave after concn., extn. with Et2O, evapn. of the aq. layer, and treatment with aq. NaHCO3, 79.2% 3a-tropanol, m. 63°.  Tropanone reduced with (iso-PrO)3Al in iso-PrOH gave in 20 hrs. refluxing 12% tropine 3a-isomer and 78% 3b-isomer, m. 107.8° (from C6H6-petr. ether), b25 142-4°.

The synthesis and separation of [3-2H]tropine and [3-2H]pseudotropine (y-tropine).    
Bartholomew, Barbara A.; Smith, Michael J.; Darcy, Paul J.; Trudgill, Peter W.; Hopper, David J.    
J. Labelled Compd. Radiopharm.  (1994),  34(1), 85-91.
Tropinone was reduced using sodium borodeuteride to give a mixt. of the epimers [3-2H]tropine (I) and [3-2H]pseudotropine with the latter compd. predominanting and constituting about 70% of the mixt.  Crystn. of the product from di-Et ether gave crystals of pure [3-2H]pseudotropine and a supernatant soln. contg. a mixt. of the epimers.  Acetylation of this mixt. using acetyl chloride preferentially acetylated the pseudotropine and the acetylated products were sepd. from the tropine by flash chromatog. to leave a sample of pure [3-2H]tropine.

Thin-layer chromatography of tropine, pseudotropine, and tropinone.    
Neumann, D.; Schroeter, H. B.    Akad. Inst. Biochem. Pflanzen,  Halle,  Germany.   
J. Chromatog.  (1964),  16(2),  414. 
Journal  written in German.  
Tropine (I), pseudotropine (II), and tropinone (III) were sepd. by thin-layer chromatography on a silicagel G plate with 8:2 EtOH:25% ammonia.  The plate was prepd. by mixing 5 g. silicagel G with 12 ml. water and the paste spread on a 20 cm. ´ 20 cm. plate and the plate dried 2 hrs. at 110° in an oven before use.  A mixt. contg. 20-50 g of the alkaloid bases dissolved in CHCl3 or EtOH was applied.  The alkaloid spots were detected as violet spots by use of the Dragendorff reagent as modified by Munier.  The Rf values were 0.26, 0.44, and 0.70 for I, II, and III, resp.

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  • Guest
Re: Epimerization of tropine to pseudotropine
« Reply #2 on: February 09, 2002, 03:23:00 AM »
Wow, thanks!


  • Guest
Esters from psuedotropine???
« Reply #3 on: May 23, 2002, 05:01:00 AM »
Does anyone know of the properties of the ester derivatives of these compounds pharmacological or otherwise?
I read that the benzoyloxy ester of psuedotropine has both sympathiomimetic, and local anesthetic actions.

sounds interesting, how about applying an adaptation, using the potency increase analogy where 2-hydroxy cocaine is ten times more potent in binding to the DAT because it lends dopamine`s 3,4 dihydroxy characteristics to the benzoyl ester (in binding to the receptor)
maybe that could be cross applied here too?
Just a thought.
A mind is a terrible thing to educate by yourself.


  • Guest
Definitely not - I have educated the whole ...
« Reply #4 on: May 23, 2002, 05:48:00 PM »
Definitely not - I have educated the whole scientific part of my brain by myself - and it has worked wonders!


  • Guest
Tropine synthesis
« Reply #5 on: May 23, 2002, 05:50:00 PM »
Please check out this link. I think it might be interesting  because of the references.

There are also some reaction schemes on tropinone synthesis.

Life without chemistry would be a mistake.


  • Guest
just being sarcastic, rhodium
« Reply #6 on: May 23, 2002, 09:45:00 PM »
I was joking about the self education thing, but I like your retort to that.