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N
OMe
AcO
OAc
N
Ph
3
P
+
C
2
H
5
Br
-
OMe
O
H
n-BuLi
Pd (OAc)
2
/Ph
3
P/TMG
O
OMe
O
COOMe
2a
N
N
OMe
OMe
PhSH
20% NaOH
AIBN
COOMe
COOMe
(E/Z=9/1)
(E/Z=1/ 9)
N
N
1. (PhO)
2
P(O)N
3
/Et
3
N
1.TMSI/ CHCl
3
, reflu
x
OMe
OMe
(±)-HA
2. MeOH
2.MeOH, reflux
3.TfOH, dioxane
COOH
NHCOOMe
Scheme 4-4. Pd-catalyzed route to (
)-HA.
Xia and Kozikowski developed a palladium-catalyzed bicycloannulation route
(Scheme 4-4) to racemic HA from 2a in 40% overall yield.
98
The three-carbon
bridge was more efficiently introduced by Pd-catalyzed alkylation of 2a with
2-methylenepropane-1,3-diyl diacetate on both sides of the ketone carbonyl.
Compared with (
)-HA (IC
50
for AChE inhibition 0.047 mM), the racemate exhib-
ited an IC
50
of 0.073 mM, which is, within error, as expected if the unnatural enan-
tiomer is inactive.
Camps et al. developed a route to (
)-HA from a keto capamate 7, which was
obtained in 22% overall yield from 1,4-cyclohexanedione monoethylene ketal
(3) (Scheme 4-5).
99-101
This new approach to racemic HA features the elaboration
of the pyridone moiety of HA in a late stage. In this way, we can access the different
heterocyclic analogs instead of the pyridone moiety in HA. However, the total yield
of HA was not markedly improved, compared with that of other approaches, and the
purification of the isomers proved to be a tedious and difficult task.
4.6.2
Synthesis of Optically Pure (
)-HA
For the AChE inhibition effect of natural (
)-HA being 38-fold more than its enan-
tiomer (
þ
)-HA, to synthesize natural (
)-HA attracted widespread attention.
Yamada et al. first reported the route to optically pure (
)-HA in 1991.
102
On
the basis of the route established to (
)-HA, Yamada et al. chose to introduce
absolute stereochemistry at the stage of the Michael-aldol reaction, which creates
the bridging ring of HA. As shown in Scheme 4-6, 2a was transesterified with
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