Synthesis
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.
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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. |
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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.
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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.
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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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