Concise synthesis of dl-febrifugine

Article abstract of DOI:10.1248/cpb.53.868

Racemic compound (1) of the antimalarial agents febrifugine (d-1) was synthesized using an stereoselective Michael reaction of an ω-amidoenone (5) which was prepared by the Wittig reaction of piperidinediol (7).

Full text of DOI:10.1248/cpb.53.868

868
Communications to the Editor
Chem. Pharm. Bull. 53(7) 868—869 (2005)
Vol. 53, No. 7
without using the very expensive, toxic, or dangerous
reagents used in other reports.25—30) We are now progress the
asymmetric synthesis using this method.
Concise Synthesis of dl-Febrifugine
Yasuo TAKEUCHI,* Miyo OSHIGE, Kumiko AZUMA,
Hitoshi ABE, and Takashi HARAYAMA*
Acknowledgments We are grateful to the SC-NMR Laboratory of
Okayama University for the use of the facilities.
Faculty of Pharmaceutical Sciences, Okayama University; 1–1–1
Tsushima-naka, Okayama 700–8530, Japan.
Received April 1, 2005; accepted May 17, 2005; published online
May 18, 2005
Racemic compound (1) of the antimalarial agents febrifugine
(d-1) was synthesized using an stereoselective Michael reaction
of an w-amidoenone (5) which was prepared by the Wittig reac-
tion of piperidinediol (7).
Key words total synthesis; stereoselective Michael reaction; Wittig re-
action; febrifugine; antimalarial activity
Chart 1
Febrifugine (d-1) is an antimalarial agent that has been
isolated from Dichroa febrifuga and Hydrangea umbellate
along with isofebrifugine (d-2).1—4) It is well known that d-1
and d-2 are related to each other’s isomerization via w-
aminoenone5,6) (3) (Chart 1).
Among reported methods7—20) of d-1, we had believed that
our method10,13) was widely applicable to the synthesis of the
derivatives needed to study the structure–activity relationship
of d-1. However, we could not successfully prepare some
derivatives because our method involved uncontrollable
trans–cis isomerization in the final step. In recent our study,
we found that cis form of N-protected febrifugine derivatives
(cis-4) also afforded a mixture of trans-4 and cis-4 form
under the presence of acid by the isomerization (Chart 2).21)
From those findings, we planed a synthetic strategy via an
w-amidoenone (5) as a key intermediate, which would afford
trans piperidine derivative (trans-6) by the intramolecular
Michael reaction with the stereoselectivity (Chart 3). In this
paper, we describe a novel synthesis of dl-febrifugine (dl-1).
The synthesis of the key intermediate, w-amidoenone (5),
was achieved to utilize the Wittig reaction of 2-hydroxy-
piperidine derivative which we have developed in our syn-
thetic study of deoxyfebrifugine.22) The Wittig reaction of
2,3-piperidinediol (7), which was easily prepared in 84%
yield from tetrahydropyridine (8) by Oxone®-acetone oxida-
tion,23) afforded (E)-w-amidoenone (E-5) in which the dou-
ble bond had E configuration based on the coupling constant
Chart 2
Chart 3
1
(Jꢀ16 Hz) of olefinic protons in H-NMR. The Michael re-
action of trans-5 (E-5) with BF3·OEt2 afforded the Michael
adduct (trans-6). N-Cbz febrifugine (10) was afforded by
successive reactions, silylation of the hydroxy and ketone
group, bromination, and coupling with 4(3H)-quinazolinone.
Hydrogenolysis of 10 gave dl-1 which was identical with the
reported one by mp or 1H-NMR data (Chart 4).
In the Michael reaction of E-5 with BF3·OEt2, we could
obtain the furan derivative (9) and 1,4-diketone derivative
(11) along with trans-6. It is known that 9 and 11 can be
transformed from cis-6 by acid.24) Decreasing yield of trans-
6 with the prolongation of the reaction time or heat of reac-
tion mixture suggests that there is an equilibrium relationship
via E-5 between trans-6 and cis-6 in the presence of Lewis
acid (Table 1).
Herein, we could develop the the synthetic method for dl-
febrifugine derivatives in high total yield and short steps
Chart 4
∗ To whom correspondence should be addressed. e-mail: take@pharm.okayama-u.ac.jp
© 2005 Pharmaceutical Society of Japan

July 2005
869
Table 1. Reaction of E-5 with BF3OEt2
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Yield (%)
Temp.
(°C)
Reaction
time
Entry
trans-6
9
11
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1
2
3
4
5
6
7
8
9
r.t.
r.t.
r.t.
70
70
10 min
30 min
1 h
10 min
1 h
75
72
73
50
23
14
33
28
12
11
18
14
35
32
21
32
38
32
—
—
3
12
27
30
21
17
9
70
2 h
100
100
100
10 min
30 min
1 h
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