Re-revision of the stereo structure of piperidine lactone, an intermediate in the synthesis of febrifugine.

Article abstract of DOI:10.1248/cpb.50.1011

The stereo structure of piperidine lactone (3), an intermediate of the antimalarial agent febrifugine ((+)-1) prepared by a synthetic method, was re-revised to the cis-form from the trans-form.

Full text of DOI:10.1248/cpb.50.1011

July 2002
Communications to the Editor
Chem. Pharm. Bull. 50(7) 1011—1012 (2002)
1011
(Table 1). The dihedral angle between H3a–C3a–C7a–H7a in-
volving the bridge-head protons of cis-3b was smaller than in
cis-3a. These results showed that even if the configuration of
3 was cis, the coupling constant between H3a–H7a would rea-
sonably be 8.5 Hz. Since this result strongly supports our hy-
pothesis, we discuss the exact structure of 3 synthesized by
Baker et al. and corrected by Barringer et al.
Re-revision of the Stereo Structure of
Piperidine Lactone, an Intermediate in
the Synthesis of Febrifugine
Yasuo TAKEUCHI,* Kumiko AZUMA, Hitoshi ABE,
Kenji SASAKI, and Takashi HARAYAMA*
cis-Piperidine lactone (cis-3), an intermediate of (Ϯ)-
isofebrifugine (Ϯ-2), was prepared from cis-2-allyl-3-hy-
droxypiperidine derivatives (4) using our previously reported
method18,19) (Chart 1). Ozonolysis of 4, followed by PCC oxi-
dation afforded cis-piperidine lactone (cis-5) with a cbz
group. Hydrogenolysis and benzoylation of cis-5 gave cis-3,
Faculty of Pharmaceutical Sciences, Okayama University; 1–1–1
Tsushima-naka, Okayama 700–8530, Japan.
Received April 10, 2002; accepted May 26, 2002
The stereo structure of piperidine lactone (3), an intermediate
of the antimalarial agent febrifugine ((؉)-1) prepared by a syn-
thetic method, was re-revised to the cis-form from the trans-
form.
1
which has the same H-NMR spectrum as reported by Bar-
ringer et al.11) Each proton on the bridge-head of cis-3 in the
1H-NMR (60 MHz) spectrum was observed at d 4.69 and
5.15 ppm, with a coupling constant of 7.7 Hz (Table 2).
The configuration of piperidine lactone (3) synthesized by
Key words febrifugine; piperidine lactone; structure determination
Febrifugine ((ϩ)-1) and isofebrifugine ((ϩ)-2) are anti-
malarial agents that were isolated from Dichroa febrifuga
and Hydrangea umbellate, respectively (Fig. 1).1—4) The
plane structure5) of (ϩ)-1 and (ϩ)-2 was first proposed in
1950. Subsequently, their relative6) and absolute7) structures
were proposed, based on Baker’s synthetic work.8—10) The
relative configuration11) of (ϩ)-1 was corrected in 1973 and
then the absolute structures12,13) of (ϩ)-1 and (ϩ)-2 were cor-
rected in 1999. Currently, dramatic medical14—17) and syn-
thetic18—25) studies of (ϩ)-1 are in progress.
Fig. 1. The Final Corrected Structures of (ϩ)-1 and (ϩ)-2
Historically, Barringer et al.11) corrected the configuration
of febrifugine to the trans-form from the cis-form in 1973,
1
based on the H-NMR data of an intermediate, piperidine
lactone (3), which Baker et al. synthesized.9) Each proton on
the bridge-head of 3 was observed at d 4.69 and 5.15 ppm
with a coupling constant of 8.5 Hz (Table 2). Recently,
Kobayashi et al. synthesized dimethyl derivatives of trans-3
in which each proton on the bridge-head was observed at d
3.09 and 4.09 ppm with a coupling constant of 10.4 Hz.26,27)
From these directly opposing results, we thought that the
structure of 3 could not be determined from the coupling
constant.
Reagents and conditions: a, i) O3, MeOH, Ϫ78 °C, 2 h; ii) Me2S,
room temperature (rt), 1 h; b, PCC, AcONa, CH2Cl2, rt, 3 h, 55%;
c, H2, Pd(OH)2/C, acetone, rt, 24 h; d, PhCOCl, Et3N, CHCl3, rt,
1 h, 32%.
Chart 1
Table 2
In a molecular calculation, cis-3 afforded two optimized
conformers with similar heats of formation, but differing
chair (cis-3a) and boat (cis-3b) forms of the piperidine ring
Table 1
1H-NMR
Compound mp (°C)
H3a
H7a
3
99—101 5.15
(q, Jϭ8.5 Hz)a)
85—86 5.15
(q, Jϭ7.7 Hz)a)
5.09
4.69
(m, Jϭ8.5, 8.5, 5.0 Hz)a)
4.69
(dt, Jϭ7.7, 4.9 Hz)a)
4.68
cis-3d)
Heat of formation
(kcal/mol)
Dihedral angle
(H3a–C3a–C7a–H7a)
(q, Jϭ7.8 Hz)b,c) (dd, Jϭ12.5, 7.5 Hz)b,c)
Calculation
method
trans-3e) 133—134 3.24—3.65 (m)a) 3.97—4.08 (m)a)
3.30—3.39 (m)b) 4.06
3a
3b
3a
3b
(ddd, Jϭ11.0, 10.0, 4.0 Hz)b)
PM3
AM1
MNDO
Ϫ98.19
Ϫ86.63
Ϫ88.43
Ϫ97.73
Ϫ86.39
Ϫ89.06
Ϫ22.9
Ϫ22.5
Ϫ15.2
Ϫ4.2
Ϫ10.6
8.3
a) 60 MHz. b) 500 MHz. c) 80 °C. d) NOE between H3a and H7a in NOESY
spectrum was observed. e) NOE between H3a and H7a in NOESY spectrum was not
observed.
To whom correspondence should be addressed. e-mail: take@pharm.okayama-u.ac.jp
© 2002 Pharmaceutical Society of Japan

1012
Vol. 50, No. 7
process of determining at which stage in Baker’s synthesis of
febrifugine the isomerization occurs.
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The melting point and 1H-NMR data of 3 reported by Bar-
ringer et al., cis-3, and trans-3 are summarized in Table 2. It
is clear that 3 is cis-3, since the difference in the melting
points of 3 and trans-3 was larger than that between 3 and
cis-3. Moreover, Burgess et al., who reported another method
of synthesizing febrifugine in 1996, used Barringer’s result to
determine the syn or anti configuration of a derivative of 4
prepared by the reaction of piperidine oxide with allyl
silane.28) This result should also be corrected.
Now, we know that the configuration of substituents on the
piperidine ring in febrifugine is trans, without a doubt.
Therefore, our result suggests that the isomerization of the
cis-form to the trans-form occurs in the synthetic stage after
3 in Baker’s synthesis of febrifugine. We are now in the