Chemistry Reference
In-Depth Information
L-cysteine-HCl
(2 equiv.)
NaHCO
3
(2 equiv.)
FeSO
4
(0.1equiv.)
HO
H
H
3
H
H
O
O
HO
O
O
AcO
AcO
O
O
+
+
5
O
O
O
O
MeCN/H
2
O
11
r.t. 4 h
12
10%
26%
OMe
OMe
44%
OMe
OMe
Artemether
Organic phase
3′
3
H
1′
14
1′
3′
HOOC
S
H
HOOC
S
2′
HO
2′
H
2
N
O
AcO
NH
2
+
+
15
O
O
3.2%
1.4%
O
OMe
12
13
Aqueous phase
168
169
OH
Scheme 5-29
confirmed by the separation of an adduct 167 of cysteine and a derivative of
qinghaosu from their Fe catalyzed reaction mixture (Scheme 5-28).
186
Recently the
degradation reaction with artemether and a catalytic amount of Fe(II/III) in the pre-
sence of cysteine was also performed, which gives not only the adduct (168)ofthe
primary radical, but also the adduct (169) of the secondary radical for the first time
(Scheme 5-29).
282
In the 1990s, several laboratories engaged in the study on the reaction of
ferrous ion and qinghaosu compounds and proposed that it was a free radical reac-
tion.
283-287
Posner et al. have proposed that a high-valent iron-oxo was also inter-
mediated during this reaction, but this viewpoint has not been generally
accepted.
283
At the same time, Robert et al. also identified the adduct of radical
162 and tetraphenylporphyrin or heme and hence confirmed the intermediacy of
the carbon-centered free radical.
287
In line with these data, it can be concluded
that the reaction of qinghaosu and its derivatives with ferrous ion is definitely a
free radical reaction through a short-lived O-radical-anion and subsequent primary
and secondary C-centered radical.
5.6.4 Antimalarial Activity and the Free Radical Reaction
of Qinghaosu and Its Derivatives
With the clarification of the C-centered free radical's participated mechanism of the
reaction of 1 and ferrous ion, it is then interesting to note whether this free radical
mechanism is related to its antimalarial activity. Recently, for the study of the mode
of action, several stable and UV-detectable C-12 aromatic substituted derivatives of
1 were synthesized. Using the usual Lewis acid as the catalyst, the Friedel-Crafts
alkylation gave the desired product 170 or 172 and 11-methyl epimer 171 or 173 as
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