COREY SYNTHESIS | Other routes


  Due to the rarity of the compound, synthesis of epibatidine was a widely researched area, with over 50 reported syntheses by 2001. Although a racemate of epibatidine is potent as an analgesic, research is often concerned with one enantiomer, so stereospecific synthesis is also important. As synthesis of compounds derived from epibatidine is also important in the the search for effective analgesics, a route that is easily modified to produce analogues is useful.

The Corey Synthesis

This was published in the Journal of Organic Chemistry in July 1993, just 1 year after Daly had released the structure of epibatidine. The route consists of a 9 step synthesis, progressing via intermediates 2 to 10. The yields for individual steps are very high, and so overall the yield is just over 40%.

The levo and dextro forms of epibatidine can be easily separated by liquid chromatography, and the reaction is stereospecific, so that the endo- form is not produced, unlike most other syntheses at the time.

The first two steps create 2 ring systems.

  Step 1 converts the starting material, 6-chloropyridine-3-carboxaldehyde, 2, into the (Z)-stereoisomer of the α,β-unsaturated ester, 3. Why is this (Z)-stereospecific?

  Step 2 is a Diels-Alder addition of 1,3-butadiene onto 3. (Keep mouse over link for mechanism).

The adduct, cis-ester, 4, is formed.


Step 3, the saponification of the ester, 4,to carboxylic acid, 5, is followed by Step 4, part 1, the formation of an acyl azide, the azide group transferred from the phenylphosphonic azide. The acyl azide undergoes the Curtius rearrangement to form 6, the cis-carbamate.

Step 5, the TMS protecting group is removed with t-butylammonium fluoride, then acylated with tetrafluoroacetic anhyride to form 7.





The amide 7, was stereospecifically halogenated in the presence of bromine, and a source of bromide ion. (Step 6). This is due to the kinetic favorability of the bromonium ion cis to the NHCOCF3 group.

The excess source of bromide ion (10 equiv.) is essential to selectivity, as this stabilises the cis-bromonium ion.

The bicyclic ring is formed in Step 7, under basic condtions and nucleophilic attack.

Debromination and deacetylation with tri-n-butyltinhydride and methanolic methoxide respectively formed a racemic mixture of Epibatidine.



Separation of isomers was performed on intermediate 10, which, when run through a HPLC (high performance liquid chromatography column), will be separated into levo and dextro enantiomers due to their different eluting times. The fractions can be tested for optical rotatory power, with the (-)-epibatidine rotating light -5° and the (+)-epibatidine rotating light +5° at 23°C

Other syntheses...

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