Concise asymmetric synthesis of (+)-febrifugine utilizing trans-selective intramolecular conjugate addition

Article abstract of DOI:10.1055/s-2008-1067271

Intramolecular conjugate addition of γ-substituted (E)- α,β-unsaturated ketones with a Lewis acid (BF₃· OEt₂) selectively afforded trans-2,3-disubstituted piperidine derivatives. Chiral substrates were synthesized by Sharpless asymmetric dihydroxylation of the enamine; the antimalarial compound febrifugine was synthesized from the major product of the conjugate addition reaction. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2008-1067271

PAPER
3081
Concise Asymmetric Synthesis of (+)-Febrifugine Utilizing trans-Selective
Intramolecular Conjugate Addition
Synthesis of (+
a
)
-Febrifugi
t
ne oshi Sukemoto,a Miyo Oshige,a Masahiro Sato,a Ken-ichiro Mimura,a Hiromi Nishioka,a Hitoshi Abe,b
Takashi Harayama,c Yasuo Takeuchi*a
a
Faculty of Pharmaceutical Sciences, Okayama University, Tsushima-naka 1-1-1, Okayama 700-8530, Japan
Fax +81(86)2517964; E-mail: take@pharm.okayama-u.ac.jp
Faculty of Engineering, Toyama University, Gofuku 3190, Toyama 930-8555, Japan
Faculty of Pharmaceutical Sciences at Kagawa Campus, Tokushima Bunri University, Shido, Sanuki 769-2193, Japan
b
c
Received 13 May 2008; revised 6 June 2008
substituted a,b-unsaturated ketones 2 and the asymmetric
synthesis of (+)-febrifugine7 by stereoselective conjugate
addition (Scheme 1). Although febrifugine is an antima-
larial compound, it is precluded from use as a clinical drug
Abstract: Intramolecular conjugate addition of g-substituted (E)-
a,b-unsaturated ketones with a Lewis acid (BF3·OEt2) selectively
afforded trans-2,3-disubstituted piperidine derivatives. Chiral sub-
strates were synthesized by Sharpless asymmetric dihydroxylation
of the enamine; the antimalarial compound febrifugine was synthe- due to its liver toxicity.8 Therefore, derivatives of febri-
sized from the major product of the conjugate addition reaction.
fugine that may become valuable leads for novel drugs
have been synthesized and, as a result, many methods for
its synthesis have been developed.
Key words: Lewis acid, intramolecular conjugate addition, febri-
fugine, asymmetric synthesis
RO
HO
N
O
The piperidine ring is a basic structural element of many
natural products. Examples of natural products that con-
tain a 2,3-disubstituted piperidine ring are (+)-febrifugine
(1), which has antimalarial activity,1,2 (–)-swainsonine,
which has anticancer activity,3 and (–)-7-epi-deoxyn-
upharidine, which has insecticidal activity (Figure 1).4
N
HN
N
H
R
O
O
(+)-febrifugine (1)
2
RO
HO
O
N
HO
OH
HO
N
R
N
R
H
HO
N
N
H
N
Scheme 1
O
(+)-febrifugine (1)
(–)-swainsonine
Racemic g-substituted a,b-unsaturated ketones 2a and 2b
were prepared from 2-hydroxypiperidines 3a9 and 3b7i by
Wittig reactions, and 2c was synthesized by protecting 2a
(Scheme 2).
H
N
The results of the intramolecular conjugate addition of the
g-substituted a,b-unsaturated ketones 2 with a base
(K2CO3) or an acid (BF3·OEt2) are shown in Table 1. The
O
(–)-7-epi-deoxynupharidine
RO
Figure 1 2,3-Disubstituted piperidine derivatives
RO
MeCOCH=PPh3
HN
Cbz
toluene, reflux
It is well known that 2,3-disubstituted piperidine rings can
be formed by intramolecular conjugate addition in the
presence of a base, and many studies have focused on this
reaction.5 However, only a few studies have been con-
ducted on acid-catalyzed conjugate addition. In our previ-
ous study, we successfully carried out conjugate addition
with a Lewis acid.6 Here we report the stereoselectivity of
the acid-catalyzed intramolecular conjugate addition of g-
HO
N
O
Cbz
2a R = H (75%)
2b R = Bn (36%)
3a R = H
3b R = Bn
CbzO
CbzCl, DMAP, Et3N
CH2Cl2
HN
55%
Cbz
O
SYNTHESIS 2008, No. 19, pp 3081–3087
Advanced online publication: 05.09.2008
x
x.
x
x
.
2
0
0
8
2c
DOI: 10.1055/s-2008-1067271; Art ID: F10608SS
© Georg Thieme Verlag Stuttgart · New York
Scheme 2

3082
S. Sukemoto et al.
PAPER
Table 1 Conjugate Addition Reactions
RO
O
RO
O
O
RO
acid or base
+
+
HN
Cbz
HN
N
N
Cbz
O
Cbz
Cbz
2
cis-4
trans-4
5
Entry
Substrates 2
R
Acid or base (mol%) Conditions
Yield (%)
cis-4
trans-4
5
–
–
–
7
–
–
1
2
3
4
5
6
2a
2b
2c
2a
2b
2c
H
K2CO3 (250)
K2CO3 (250)
K2CO3 (250)
BF3·OEt2 (50)
BF3·OEt2 (50)
BF3·OEt2 (50)
DMF, r.t., 16 h
cis-4a, 5
trans-4a, 76
trans-4b, 7
trans-4c, 5
trans-4a, 77
trans-4b, 74
trans-4c, 82
Bn
Cbz
H
DMF, 80 °C, 24 h
DMF, r.t., 16 h
cis-4b, 74
cis-4c, 76
–
MeCN, 0 °C, 15 min
MeCN, 0 °C, 15 min
MeCN, 0 °C, 15 min
Bn
Cbz
cis-4b, 7
cis-4c, 16
reactions of 2, which are Baldwin-favored 6-exo-trig cy- ducts.5 According to Hirama et al.,5a A1 and A2, in which
clizations, afforded cis or trans adducts in good yields. the allylic alkoxy group (electron-withdrawing group) is
The reaction of 2a, in which the hydroxy group was not antiperiplanar to the nitrogen nucleophile, are the transi-
protected, with the base (entry 1), preferentially gave the tion states in the reactions of 2b and 2c with the base
trans adduct (trans-4a) over the cis adduct (cis-4a10). In (Figure 2). However, steric repulsions between methyl
contrast, the reactions of 2b and 2c, in which the hydroxy ketone and the N-protecting group indicate that A1, which
group was protected, with the base, afforded the cis ad- produces cis-4b and cis-4c, is more likely to be the transi-
ducts (cis-4b and cis-4c) with high selectivity (entries 2 tion state in these reactions than A2. With regard to 2a, we
and 3). It is noteworthy that the conjugate additions of 2a– postulate that B1 and B2, in which the allylic oxygen an-
c with the Lewis acid, selectivity afforded the trans ad- ions (electron-donating groups) are not antiperiplanar to
ducts (trans-4a–c) (entries 4–6).11 The reaction of 2a with the nitrogen anion nucleophile,12 are the transition states
the Lewis acid did not afford cis-4a but instead gave 5 as in its reaction. However, B2 is assumed to be the preferred
a minor product (entry 4). It is known that cis-4a can be transition state, which produces trans-4a. Since electrons
transformed into 5.10
in the p-orbital of the nitrogen atom attack the double
bond under acidic conditions, the conformation of the Cbz
group under these conditions differs from that adopted un-
der basic conditions. In such a case, the plane of the car-
bamate group is parallel to that of the enone group, and
these planes do not repel each other strongly. Thus, we as-
In order to explain the selectivities of the above reactions,
we considered the following transition states. Generally,
the intramolecular conjugate addition of a g-substituted
(E)-a,b-unsaturated compound with a base, yields cis ad-
Me
O
H
H
H
RO
H
H
RO
O
H
H
trans-4b,c
cis-4b,c
N
N
H
H
H
H
H
O
BnO
A1
O
BnO
Me
R = Cbz, Bn
A2
O
BnO
O–
O
BnO
O–
O
Me
H
H
H
N
H
H
N
H
H
cis-4a
trans-4a
H
H
H
H
H
Me
O
B1
B2
–
+
Me
H
BF3
O
H
H
H
RO
H
RO
H
cis-4a–c
trans-4a-c
H
H
F3B–
H
+
O
N
H
N
H
O
O
H
H
H
Me
BnO
BnO
R = Cbz, Bn, H
C1
C2
Figure 2
Synthesis 2008, No. 19, 3081–3087 © Thieme Stuttgart · New York

PAPER
Synthesis of (+)-Febrifugine
3083
CbzCl, DMAP,
CH2Cl2, r.t.,
recrystallization
HO
HO
HO
CbzO
O
HO
BF3⋅OEt2,
MeCOCH=PPh3
toluene, reflux
O
MeCN, r.t.
HN
Cbz
N
79%
58%, >99% ee
75%
N
N
Cbz
Cbz
Cbz
O
(+)-3
(+)-trans-2a
(–)-trans-4a
(–)-trans-4c
1) TMSOTf, DIPEA,
CH2Cl2, r.t.
2) NBS, r.t.
CbzO
HO
N
N
N
6 M HCl aq
reflux
O
O
N
82%
3) 4-hydroxyquinazolinone,
K2CO3, DMF, r.t.
N
N
H
⋅2HCl
O
Cbz
O
3 steps 64%
febrifugine⋅2HCl (1⋅2HCl)
(–)-11
Scheme 3
sume that C1 and C2, in which steric repulsions between trans product, (–)-trans-4a, was obtained by the Wittig re-
methyl ketone and the N-protecting group are negligible, action of (+)-3a, followed by trans-selective conjugate
constitute the transition states formed under acidic condi- addition with BF3·OEt2. Enhanced optical activity (99%
tions. Although transition states C1 and C2 are similar, ee) was achieved by recrystallizing (–)-trans-4c, which
Felkin–Anh modeling studies13 predict that the C2 confor- was synthesized after protecting the hydroxy group of
mation is preferred.
(–)-trans-4a with CbzCl. Protected febrifugine (–)-11 was
successfully obtained by the silylation of (–)-trans-4c,
bromination, and a coupling reaction with 4-hydroxy-
quinazolinone. Deprotection of (–)-11 with 6 N hydro-
chloric acid afforded febrifugine dihydrochloride
(1·2HCl; Scheme 3).
We synthesized (+)-febrifugine by trans-selective conju-
gate addition as shown in Scheme 3. Chiral 2-hydroxypi-
peridine was produced by asymmetric dihydroxylation14
in good yield (62–96%) and moderate enantioselectivity
(40–77% ee) (Table 2). High enantioselectivity was not
obtained irrespective of the ligand [(DHQ)2PYR, entry 2; In summary, we have found that the major product of the
(DHQ)2PHAL, entry 3], the solvent (t-BuOH–H2O, entry intramolecular conjugate addition of g-substituted (E)-
2; acetone–H2O, entry 3; MeCN–H2O, entry 4), the pres- a,b-unsaturated ketones with a Lewis acid (BF3·OEt2) dif-
ence of MeSO2NH2 (entries 4 and 5), or the protecting fered from that obtained using a base. This will be useful
group used (Cbz, entry 5; PhOCO, entry 6; t-Boc, entry 7). in the synthesis of other compounds. Thus, we have dem-
The best result was 94% yield and 74% ee (entry 5). The
Table 2 Asymmetric Dihydroxylation
HO
K2OsO4⋅2H2O, K3Fe(CN)6
ligand, K2CO3, MeSO2NH2, 0 °C
HO
N
R
N
R
6–8
(+)-3a, 9, 10
Entry Substrate R
Liganda
Solvent
MeSO2NH2 Time
Product
Yield
(%)
ee
cis/transb
(mol%)
100
100
100
100
–
(h)
(%)b
1
2
3
4
5
6
7
6
6
6
6
6
7
8
Cbz
(DHQ)2PYR
t-BuOH–H2O
t-BuOH–H2O
acetone–H2O
MeCN–H2O
MeCN–H2O
MeCN–H2O
MeCN–H2O
2.0
(+)-3a
(+)-3a
(+)-3a
(+)-3a
(+)-3a
(+)-9c
(+)-10c
80
96
70
83
94
80
62
59
56
60
77
74
72
40d
95:5
99:1
Cbz
(DHQ)2PHAL
(DHQ)2PHAL
(DHQ)2PHAL
(DHQ)2PHAL
(DHQ)2PHAL
(DHQ)2PHAL
4.0
2.0
Cbz
100:0
100:0
100:0
85:5
Cbz
48.0
48.0
72.0
48.0
Cbz
PhOCO
Boc
–
–
100:0e
a DHQ: dihydroquinine; PYR: diphenylpyrimidine; PHAL: phthalazine.
b Determined by chiral HPLC analysis.
c The absolute configuration was not determined.
d Determined by chiral HPLC analysis as tert-butyl N-[(E)-4-hydroxy-7-oxo-5-octenyl]carbamate via reaction with MeCOCH=PPh3.
e Determined by 1H NMR analysis.
Synthesis 2008, No. 19, 3081–3087 © Thieme Stuttgart · New York

3084
S. Sukemoto et al.
PAPER
jected to column chromatography (SiO2; EtOAc–hexane, 1:1) to
give 2b.
onstrated the asymmetric synthesis of febrifugine in good
yield in the smallest number of reaction steps.
Yield: 1.37 g (36%); colorless oil.
IR (neat): 3340, 1720, 1680 cm–1.
1H NMR (300 MHz, acetone-d6): d = 1.51–1.74 (m, 4 H), 2.24 (s,
3 H), 3.16 (q, J = 6.0 Hz, 2 H), 4.05–4.16 (m, 1 H), 4.45 and 4.58
(AB q, J = 12.0 Hz, 2 H), 5.05 (s, 2 H), 6.22 (d, J = 16.2 Hz, 1 H),
6.34 (br s, 1 H), 6.75 (dd, J = 16.2, 6.6 Hz, 1 H), 7.24–7.40 (m,
10 H).
13C NMR (75 MHz, acetone-d6): d = 26.5, 27.1, 32.8, 41.3, 66.4,
71.5, 78.9, 128.3, 128.6, 129.1, 131.9, 138.5, 139.7, 147.7, 157.2,
198.1.
Melting points were determined on a Yanagimoto micro melting
point apparatus and are uncorrected. IR spectra were recorded on a
JASCO FT/IR 350 spectrometer. Mass spectra (MS) were recorded
on an AutoSpec spectrometer. 1H NMR and 13C NMR spectra were
run on a Varian Mercury 300, a Varian VXR500 or a Varian Unity
INOVA AS600 spectrometer. Optical rotations were measured on a
JASCO DIP-1000 spectrometer. Merck silica gel 60 (230–400
mesh) and Wako activated alumina (300 mesh) were employed for
column chromatography.
N-Benzyloxycarbonyl-1,2,3,4-tetrahydropyridine (6)
Prepared according to the literature.7i
HRMS-FAB: m/z [M + H]+ calcd for C23H28NO4: 382.2018; found:
382.2007.
N-Phenoxycarbonyl-1,2,3,4-tetrahydropyridine (7)15
Prepared by extending a method described in the literature7i as fol-
lows: To a solution of oxalyl chloride (1.00 mL, 11.1 mmol) in
CH2Cl2 (16 mL) was added DMSO (1.57 mL, 22.1 mmol) at –78 °C
and the mixture was stirred for 2 min. A solution of 5-amino-N-
phenoxycarbonylpentanol16 (1.90 g, 8.5 mmol) in CH2Cl2 (16 mL)
was added dropwise below –60 °C, and the reaction mixture was
stirred at –78 °C for 1 h. The reaction was quenched with Et3N (6.28
mL, 45.1 mmol) at the same temperature and the mixture was
warmed to 0 °C for 1 h. Aqueous HCl (3 M, 25 mL) was added and
the suspension was warmed to r.t. and stirred vigorously for 14 h at
the same temperature. The mixture was extracted with CH2Cl2
(2 × 30 mL) and the combined organic layers were washed with
H2O (30 mL), sat. aq NaHCO3 (30 mL), and brine (30 mL), dried
over anhydrous MgSO4, filtered and concentrated. The residue was
subjected to column chromatography (SiO2; EtOAc–hexane, 1:6) to
give 7 as colorless solid (1.22 g, 71%). The structure was confirmed
by comparison of its spectral data with those of an authentic sam-
ple.15
Benzyl (E)-4-Benzyloxycarbonyloxy-7-oxooct-5-enylcarbam-
ate (2c)
To a solution of 2a (582 mg, 2.0 mmol) in CH2Cl2 (10 mL) was add-
ed DMAP (489 mg, 4.0 mmol) and CbzCl (571 mL, 4.0 mmol). The
mixture was stirred at r.t. for 2 h, then the mixture was poured into
H2O (30 mL) and extracted with EtOAc (2 × 30 mL). The combined
organic layers were washed with brine (30 mL), dried over anhy-
drous MgSO4, filtered, and concentrated. The residue was subjected
to column chromatography (SiO2; EtOAc–hexane, 1:3) to give 2c.
Yield: 522 mg (66%); colorless oil.
IR (neat): 3340, 1745, 1720, 1700, 1680 cm–1.
1H NMR (300 MHz, acetone-d6): d = 1.51–1.66 (m, 2 H), 1.72–1.87
(m, 2 H), 2.23 (s, 3 H), 3.18 (q, J = 6.6 Hz, 2 H), 5.05 (s, 2 H), 5.19
(s, 2 H), 5.35 (q, J = 5.7 Hz, 1 H), 6.17 (d, J = 16.2 Hz, 1 H), 6.38
(br s, 1 H), 6.79 (dd, J = 16.2, 5.7 Hz, 1 H), 7.25–7.45 (m, 10 H).
13C NMR (75 MHz, CDCl3): d = 25.6, 27.8, 31.1, 40.5, 66.8, 70.1,
76.3, 128.2, 128.5, 128.6, 128.8, 128.8, 130.7, 135.0, 136.6, 142.7,
154.4, 156.5, 197.8.
N-(tert-Butoxycarbonyl)-1,2,3,4-tetrahydropyridine (8)17
Prepared according to the method described for compound 7, start-
ing from 5-amino-N-tert-butoxycarbonylpentanol18 in 81% yield as
a colorless oil. The structure was confirmed by comparison of its
spectral data with those of an authentic sample.17
Anal. Calcd for C24H27NO6: C, 67.75; H, 6.40; N, 3.29. Found: C,
67.68; H, 6.21; N, 3.34.
Synthesis of 4 and 5
Base-Mediated Conjugate Addition; General Procedure
To a solution of 2 (0.20 mmol) in DMF (4 mL) was added K2CO3
(69 mg, 0.50 mmol). The mixture was stirred at r.t. (or 80 °C) for
16–24 h then poured into H2O (20 mL) and extracted with EtOAc
(2 × 10 mL). The combined organic layers were washed with brine
(10 mL), dried over anhydrous MgSO4, filtered, and concentrated.
The residue was subjected to column chromatography (SiO2;
EtOAc–hexane) to give the desired compounds.
Benzyl (E)-4-Hydroxy-7-oxooct-5-enylcarbamate (2a)
A solution of 3a (7.6 g, 30 mmol) and acetyl methylenetriphe-
nylphosphorane (14.3 g, 45 mmol) in toluene (120 mL), was stirred
at reflux for 2 h. After removal of the solvent, the residue was sub-
jected to column chromatography (SiO2; EtOAc–hexane, 1:1 then
i-PrOH–hexane, 1:7) to give 2a.
Yield: 6.6 g (75%); colorless oil.
IR (neat): 3340, 1695, 1680 cm–1.
1H NMR (600 MHz, acetone-d6): d = 1.50–1.70 (m, 4 H), 2.21 (s,
3 H), 3.18 (q, J = 6.0 Hz, 2 H), 4.24 (d, J = 4.8 Hz, 1 H), 4.31–4.36
(m, 1 H), 5.05 (s, 2 H), 6.21 (dd, J = 16.2, 1.2 Hz, 1 H), 6.36 (br s,
1 H), 6.84 (dd, J = 16.2, 4.8 Hz, 1 H), 7.28–7.38 (m, 5 H).
Lewis Acid Mediated Conjugate Addition; General Procedure
To a solution of 2 (0.20 mmol) in MeCN (2 mL) was added
BF3·OEt2 (12 mL, 0.10 mmol) at 0 °C. The mixture was stirred at the
same temperature for 10 min then poured into sat. aq KHCO3 (10
mL) and extracted with EtOAc (2 × 10 mL). The combined organic
layers were washed with brine (10 mL), dried over anhydrous
MgSO4, filtered, and concentrated. The residue was subjected to
column chromatography (SiO2; EtOAc–hexane) to give the desired
compounds.
13C NMR (150 MHz, acetone-d6): d = 26.6, 27.1, 34.5, 41.4, 66.4,
70.7, 128.5, 128.6, 129.1, 129.5, 138.4, 150.9, 157.3, 198.5.
Anal. Calcd for C16H22NO4: C, 65.96; H, 7.27; N, 4.81. Found: C,
65.83; H, 7.08; N, 4.85.
(2R*,3R*)-1-Benzyloxycarbonyl-3-hydroxy-2-(2-oxopropyl)pi-
peridine (cis-4a)10
(+)-2a
Colorless oil; [a]D19 +12.3 (c 1.00, EtOH).
Colorless oil.
IR (neat): 3420, 1700, 1680 cm–1.
1H NMR (300 MHz, DMSO-d6): d = 1.22–1.48 (m, 2 H), 1.53–1.68
(m, 2 H), 2.03 and 2.09 (2 × br s, total 3 H), 2.75 (dd, J = 14.7, 3.9
Benzyl (E)-4-Benzyloxy-7-oxooct-5-enylcarbamate (2b)
A solution of 3b (3.41 g, 10 mmol) and acetyl methylenetriphe-
nylphosphorane (6.36 g, 20 mmol) in toluene (30 mL), was stirred
at reflux for 20 h. After removal of the solvent, the residue was sub-
Synthesis 2008, No. 19, 3081–3087 © Thieme Stuttgart · New York

PAPER
Synthesis of (+)-Febrifugine
3085
Hz, 2 H), 3.48–3.60 (m, 1 H), 3.72–3.84 (m, 1 H), 4.70 (br s, 1 H),
4.95–5.11 (m, 3 H), 7.22–7.43 (m, 5 H).
13C NMR (150 MHz, CDCl3): d (rotamers) = 19.1, 23.5, 29.6, 38.6,
38.9, 43.2, 50.6, 67.1, 69.5, 73.0, 127.4, 127.5, 127.8, 128.2, 128.3,
128.4, 128.4, 134.9, 136.4, 154.2, 155.3, 155.6, 204.7, 205.5.
(2R*,3S*)-1-Benzyloxycarbonyl-3-hydroxy-2-(2-oxopropyl)pi-
peridine (trans-4a)
Colorless needles; mp 74–75 °C.
Anal. Calcd for C24H27NO6: C, 67.75; H, 6.40; N, 3.29. Found: C,
67.87; H, 6.40; N, 3.41.
IR (neat): 3440, 1695 cm–1.
Benzyl 3-(5-Methylfuran-2-yl)propylcarbamate (5)10
Colorless oil.
IR (neat): 3334, 1696 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.84 (tt, J = 7.2, 7.2 Hz, 2 H), 2.23
(s, 3 H), 2.62 (t, J = 7.5 Hz, 2 H), 3.25 (q, J = 6.3 Hz, 2 H), 4.80 (br
s, 1 H), 5.10 (s, 2 H), 5.81–5.89 (m, 2 H), 7.26–7.40 (m, 5 H).
1H NMR (300 MHz, CDCl3): d = 1.40 and 1.45 (2 × br s, total 1 H),
1.58–1.98 (m, 3 H), 2.14 (br s, 3 H), 2.65 (d, J = 7.5 Hz, 2 H), 2.87
(t, J = 12.3 Hz, 1 H), 3.82 (br s, 1 H), 4.07 (d, J = 11.7 Hz, 1 H),
4.67–4.80 (br s, 1 H), 5.13 (s, 2 H), 7.27–7.37 (m, 5 H).
13C NMR (75 MHz, CDCl3): d = 19.0, 25.9, 30.0, 39.5, 43.7, 54.0,
66.8, 67.3, 127.7, 127.8, 128.3, 136.4, 156.0, 205.8.
Asymmetric Dihydroxylation; General Procedure
Anal. Calcd for C16H21NO4: C, 65.96; H, 7.27; N, 4.81. Found: C,
65.67; H, 7.06; N, 4.90.
To a solution of AD-mix-a (1.4 g per 1 mmol of olefin) [or
K2OsO4·2H2O (10 mol%), K3Fe(CN)6 (300 mol%), (DHQ)2PYR
(25 mol%), and K2CO3 (300 mol%)] and MeSO2NH2 in t-BuOH–
H2O (1:1) at 0 °C was added enamine 6–8. The mixture was stirred
for 1.5–72 h then quenched with sodium sulfite (600 mol%). The
mixture was poured into H2O (8 mL/mmol of enamine) and extract-
ed with EtOAc (2 × 8 mL/mmol of enamine). The combined organic
layers were washed with brine (1 × 8 mL/mmol of enamine), dried
over anhydrous MgSO4, filtered, and concentrated. The residue was
subjected to column chromatography (SiO2; EtOAc–hexane) to
give the desired compounds.
(2R*,3R*)-3-Benzyloxy-1-benzyloxycarbonyl-2-(2-oxopro-
pyl)piperidine (cis-4b)
Colorless oil.
IR (neat): 1700 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.37–1.79 (m, 3 H), 1.86–1.97 (m,
1 H), 2.06 and 2.17 (2 × br s, total 3 H), 2.42–2.58 (m, 1 H), 2.69–
2.97 (m, 2 H), 3.53 (br s, 1 H), 3.98 (br s, 1 H), 4.44–4.74 (m, 2 H),
5.03–5.28 (m, 3 H), 7.24–7.41 (m, 10 H).
13C NMR (150 MHz, CDCl3): d (rotamers) = 23.8, 24.2, 25.6, 29.9,
30.5, 38.7, 39.8, 50.4, 67.4, 70.9, 75.3, 127.7, 127.8, 127.9, 128.1,
128.5, 128.6, 136.7, 138.2, 155.2, 155.4, 206.3, 207.1.
HRMS-FAB: m/z [M + H]+ calcd for C23H28NO4: 382.2018; found:
382.2060.
(2S,3S)-N-Benzyloxycarbonyl-2,3-dihydroxypiperidine
[(+)-3a]7i
Colorless oil; 74% ee [HPLC (CHIRALCEL OD, i-PrOH–hexane,
1:6, flow rate: 1.0 mL/min, UV = 254 nm); tR = 10.4 (minor), 13.7
min (major)]; [a]D20 +22.1 (c 1.00, EtOH).
IR (neat): 3400, 1680 cm–1.
(2R*,3S*)-3-Benzyloxy-1-benzyloxycarbonyl-2-(2-oxopro-
pyl)piperidine (trans-4b)7k,m
Colorless oil.
IR (neat): 1700 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.32–1.46 (m, 1 H), 1.55–1.69 (m,
1 H), 1.78–2.01 (m, 2 H), 2.12 (br s, 3 H), 2.56–2.73 (m, 2 H),
2.75–2.94 (m, 1 H), 3.44 (br s, 1 H), 4.11 (br s, 1 H), 4.42–4.80 (m,
2 H), 4.90–5.18 (m, 3 H), 7.24–7.39 (m, 10 H).
1H NMR (300 MHz, CDCl3): d = 1.40–1.87 (m, 4 H), 2.41 (br s,
1 H), 3.04 (td, J = 12.6, 3.0 Hz, 1 H), 3.52–3.66 (m, 1 H), 3.84 (d,
J = 12.0 Hz, 1 H), 5.14 (s, 2 H), 5.74 (t, J = 3.6 Hz, 1 H), 7.28–7.38
(m, 5 H).
13C NMR (75 MHz, CDCl3): d = 23.6, 26.5, 38.1, 67.6, 69.2, 76.6,
128.0, 128.2, 128.6, 136.3, 156.0.
HRMS-FAB: m/z [M + H – H2O]+ calcd for C13H16NO3: 234.1130;
found: 234.1141.
(2R*,3R*)-1-Benzyloxycarbonyl-3-benzyloxycarbonyloxy-2-(2-
oxopropyl)piperidine (cis-4c)
Colorless needles; mp 76–78 °C.
(–)-trans-3a
Colorless oil; [a]D20 –19.3 (c 1.00, EtOH).
IR (neat): 1750, 1700 cm–1.
N-Phenoxycarbonyl-2,3-dihydroxypiperidine [(+)-9]
Colorless needles; ratio cis/trans = 84:16; 72% ee [HPLC
(CHIRALPAK AD, i-PrOH–hexane, 1:6, flow rate: 1.0 mL/min,
UV = 254 nm); tR = 8.9 (trans, major), 9.5 (trans, minor), 11.4 (cis,
major), 12.9 min (cis, minor)]; mp 98–100 °C; [a]D23 +25.1 (c 1.00,
EtOH).
1H NMR (500 MHz, CDCl3): d = 1.46–2.02 (m, 4 H), 2.07 and 2.17
(2 × br s, total 3 H), 2.59 (br s, 1 H), 2.78 (dd, J = 15.0, 5.5 Hz, 2 H),
4.05 (br s, 1 H), 4.72–4.79 (m, 1 H), 5.07–5.19 (m, 5 H), 7.29–7.41
(m, 10 H).
13C NMR (75 MHz, CDCl3): d = 23.6, 24.6, 29.9, 38.4, 39.9, 49.5,
67.4, 69.8, 73.5, 127.9, 128.0, 128.3, 128.4, 128.5, 128.6, 135.0,
136.4, 153.8, 155.1, 205.3.
IR (neat): 3420, 1720, 1700 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.46–2.03 (m, 4 H), 2.44–2.54 (m,
1 H), 2.98–3.39 (m, 1 H), 3.48–3.79 (m, 1 H), 3.85–4.06 (m, 1 H),
5.62 (br s, 0.14 H), 5.79 (br s, 0.86 H), 7.05–7.46 (m, 5 H).
Anal. Calcd for C24H27NO6: C, 67.75; H, 6.40; N, 3.29. Found: C,
67.89; H, 6.49; N, 3.35.
13C NMR (150 MHz, CDCl3): d = 23.2, 23.5, 24.6, 26.2, 38.0, 38.6,
66.8, 68.9, 76.5, 78.1, 121.6, 121.7, 125.5, 129.2, 129.2, 150.9,
153.7, 154.6.
(2R*,3S*)-1-Benzyloxycarbonyl-3-benzyloxycarbonyloxy-2-(2-
oxopropyl)piperidine (trans-4c)
Colorless needles; mp 74–76 °C.
IR (neat): 1745, 1695 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.41–1.98 (m, 4 H), 2.11 and 2.24
(2 × br s, total 3 H), 2.58–2.75 (m, 2 H), 2.88 (br s, 1 H), 4.14 (br s,
1 H), 4.68 (br s, 1 H), 4.95–5.20 (m, 5 H), 7.23–7.44 (m, 10 H).
Anal. Calcd for C12H15NO4: C, 60.75; H, 6.37; N, 5.90. Found: C,
60.73; H, 6.36; N, 5.88.
cis-N-tert-Butoxycarbonyl-2,3-dihydroxypiperidine [(+)-10]
23
Colorless needles; 40% ee; mp 98–100 °C; [a]D +14.6 (c 1.00,
EtOH).
Synthesis 2008, No. 19, 3081–3087 © Thieme Stuttgart · New York

3086
S. Sukemoto et al.
PAPER
IR (nujol): 3410, 3210, 1690 cm–1.
Yield: 61 mg (82%); colorless powder; mp 217–219 °C (dec.)
[Lit.19 223–225 °C (dec.)]; [a]D28 +13.3 (c 1.00, H2O) [Lit.19 +12.8
(c 0.85, H2O)].
1H NMR (300 MHz, CDCl3): d = 1.34–1.89 (m, 4 H), 1.47 (s, 9 H),
2.29 (br s, 1 H), 2.96 (td, J = 12.6, 2.7 Hz, 1 H), 3.51–3.66 (m, 1 H),
3.74 (d, J = 11.7 Hz, 1 H), 5.67 (br s, 1 H).
13C NMR (150 MHz, CDCl3): d = 23.5, 26.7, 28.3, 38.2, 69.1, 76.0,
80.5, 155.3.
Febrifugine (1)
Mp 138–140 °C (Lit.2a 139–140 °C); [a]D21 +15.9 (c 0.65, MeOH)
[Lit.20 +13.0 (c 0.65, MeOH)].
Anal. Calcd for C10H19NO4: C, 55.28; H, 8.81; N, 6.45. Found: C,
55.38; H, 8.66; N, 6.50.
Anal. Calcd for C16H19N3O3: C, 63.77; H, 6.36; N, 13.94. Found: C,
63.58; H, 6.28; N, 13.84.
The spectral data were in agreement with those of the natural com-
pound.20
(2R,3S)-N-Benzyloxycarbonyl-3-benzyloxycarbonyloxy-2-(2-
oxopropyl)piperidine [(–)-trans-4c]
To a solution of (–)-trans-4a (291 mg, 1.0 mmol) in CH2Cl2 (4 mL)
was added DMAP (146 mg, 1.2 mmol) and CbzCl (171 mL, 1.2
mmol). The mixture was stirred at r.t. for 1.5 h then DMAP (146
mg, 1.2 mmol) and CbzCl (171 L, 1.2 mmol) were added. The mix-
ture was stirred at r.t. for 1.5 h then poured into H2O (10 mL) and
extracted with EtOAc (2 × 10 mL). The combined organic layers
were washed with brine (10 mL), dried over anhydrous MgSO4, fil-
tered, and concentrated. The residue was subjected to column chro-
matography (SiO2; EtOAc–hexane, 1:3) and recrystallized (EtOAc–
hexane, 1:2) to give (–)-trans-4c.
tert-Butyl N-[(E)-4-Hydroxy-7-oxo-5-octenyl]carbamate
Prepared according to the method described for compound 2b start-
ing from (+)-10.
Yield: 82%; colorless oil; 40% ee [HPLC (CHIRALCEL OD,
i-PrOH–hexane, 1:12, flow rate: 1.0 mL/min, UV = 254 nm);
tR = 15.6 (major), 17.5 min (minor)]; [a]D23 +9.3 (c 1.00, EtOH).
IR (neat): 3360, 1684 cm–1.
1H NMR (300 MHz, acetone-d6): d = 1.39 (s, 9 H), 1.49–1.70 (m,
4 H), 2.21 (s, 3 H), 3.02–3.15 (m, 2 H), 4.23 (d, J = 5.1 Hz, 1 H),
4.29–4.38 (m, 2 H), 5.96 (br s, 1 H), 6.21 (dd, J = 16.2, 1.8 Hz,
1 H), 6.84 (dd, J = 16.2, 4.8 Hz, 1 H).
Yield: 245 mg (58%); colorless needles; 99% ee [HPLC (CHIRAL-
PAK AD, i-PrOH–hexane, 1:4, flow rate: 1.0 mL/min,
UV = 254 nm); tR = 13.4 (minor), 14.9 min (major)]; mp 80–82 °C;
[a]D24 –39.0 (c 1.0, EtOH).
13C NMR (150 MHz, acetone-d6): d = 26.7, 27.1, 28.7, 34.5, 40.8,
70.7, 78.5, 129.5, 151.0, 156.8, 198.5.
HRMS-FAB: m/z [M + H]+ calcd for C13H24NO4: 258.1705; found:
258.1705.
(2R,3S)-1-Benzyloxycarbonyl-3-benzyloxycarbonyloxy-2-{2-
oxo-3-[4-oxoquinazolin-3(4H)-yl]propyl}piperidine [(–)-11]
To a solution of (–)-trans-4c (213 mg, 0.50 mmol) in CH2Cl2 (3 mL)
was added DIPEA (139 mL, 0.80 mmol) and TMSOTf (136 mL, 0.80
mmol). The mixture was stirred at r.t. for 0.5 h then NBS (124 mg, Acknowledgment
0.70 mmol) was added. The mixture was stirred at r.t. for 0.5 h then
We are grateful to the SC-NMR Laboratory of Okayama University
for the use of the facilities.
poured into aq Na2S2O3 (10%, 10 mL) and extracted with EtOAc
(2 × 15 mL). The combined organic layers were washed with sat. aq
KHCO3 (15 mL) and brine (15 mL), dried over anhydrous MgSO4,
filtered, and concentrated. A solution of the residue, 4-hydroxy-
quinazolinone (110 mg, 0.75 mmol), and K2CO3 (110 mg, 0.80
mmol) was stirred for 7 h, then the mixture was poured into H2O
(30 mL) and extracted with EtOAc (2 × 30 mL). The combined or-
ganic layers were washed with H2O (30 mL) and brine (30 mL),
dried over anhydrous MgSO4, filtered, and concentrated. The resi-
due was subjected to column chromatography (Al2O3; EtOAc–hex-
ane, 1:1) to give (–)-11.
References
(1) Koepfli, J. B.; Mead, J. F.; Brockmann, J. A. Jr. J. Am.
Chem. Soc. 1947, 69, 1837.
(2) Koepfli, J. B.; Mead, J. F.; Brockmann, J. A. Jr. J. Am.
Chem. Soc. 1949, 71, 1048.
(3) El Nemr, A. Tetrahedron 2000, 56, 8579.
(4) Miyazawa, M.; Yoshio, K.; Ishikawa, Y.; Kameoka, H.
J. Agric. Food Chem. 1998, 46, 1059.
Yield: 183 mg (64%); colorless oil; [a]D19 –28.3 (c 1.00, EtOH).
IR (neat): 1740, 1700, 1685, 1675 cm–1.
(5) (a) Hirama, M.; Iwakuma, T.; Itô, S. J. Chem. Soc., Chem.
Commun. 1987, 1523. (b) Akiyama, E.; Hirama, M. Synlett
1996, 100. (c) Hirama, M.; Itô, S. Heterocycles 1989, 28,
1229. (d) Oishi, T.; Iwakuma, T.; Hirama, M.; Itô, S. Synlett
1995, 404.
(6) Takeuchi, Y.; Tokuda, S.; Takagi, T.; Koike, M.; Abe, H.;
Harayama, T.; Shibata, Y.; Kim, H.-S.; Wataya, Y.
Heterocycles 1999, 51, 1869.
(7) For recent syntheses of febrifugine, see: (a) Burgess, L. E.;
Gross, E. K. M.; Jurka, J. Tetrahedron Lett. 1996, 37, 3255.
(b) Kobayashi, S.; Ueno, M.; Suzuki, R.; Ishitani, H.; Kim,
H.-S.; Wataya, Y. J. Org. Chem. 1999, 64, 6833.
(c) Takeuchi, Y.; Abe, H.; Harayama, T. Chem. Pharm. Bull.
1999, 47, 905. (d) Takeuchi, Y.; Hattori, M.; Abe, H.;
Harayama, T. Synthesis 1999, 1814. (e) Takeuchi, Y.;
Azuma, K.; Abe, H.; Harayama, T. Chem. Commun. 2000,
1643. (f) Taniguchi, T.; Ogasahara, K. Org. Lett. 2000, 2,
3193. (g) Takeuchi, Y.; Azuma, K.; Takakura, K.; Abe, H.;
Kim, H.-S.; Wataya, Y.; Harayama, T. Tetrahedron 2001,
57, 1213. (h) Ooi, H.; Urusibara, A.; Esumi, T.; Iwabuchi,
Y.; Hatakeyama, S. Org. Lett. 2001, 3, 953. (i) Okitsu, O.;
1H NMR (300 MHz, CDCl3): d = 1.42–2.03 (m, 4 H), 2.72–2.93 (m,
2 H), 3.01 (br s, 1 H), 4.07 (br s, 1 H), 4.51–4.84 (m, 2 H), 4.88–
5.27 (m, 6 H), 7.21–7.43 (m, 10 H), 7.50 (t, J = 6.9 Hz, 1 H), 7.69–
7.82 (m, 2 H), 7.99 (s, 1 H), 8.27 (d, J = 7.2 Hz, 1 H).
13C NMR (150 MHz, CDCl3): d (rotamers) = 19.1, 23.6, 38.9, 40.4,
50.4, 51.3, 53.6, 67.5, 69.9, 73.1, 121.7, 126.6, 127.1, 127.5, 127.7,
128.0, 128.4, 128.4, 128.5, 134.3, 134.8, 136.1, 146.1, 146.7, 148.2,
154.4, 156.3, 160.9, 199.4.
HRMS-FAB: m/z [M + H]+ calcd for C32H32N3O7: 570.2240; found:
570.2351.
Febrifugine Dihydrochloride (1·2HCl)
A solution of (–)-11 (114 mg, 0.20 mmol) in HCl (6 M, 6 mL), was
stirred at reflux for 2 h. The solvent was removed through azeotro-
pic treatment and recrystallization of the residue from EtOH to give
the dihydrochloride of 1.
Synthesis 2008, No. 19, 3081–3087 © Thieme Stuttgart · New York

PAPER
Suzuki, R.; Kobayashi, S. J. Org. Chem. 2001, 66, 809.
Synthesis of (+)-Febrifugine
3087
(13) (a) Heathcock, C. H.; Kiyooka, S.; Blumenkopf, T. A.
(j) Huang, P.-Q.; Wei, B.-G.; Ruan, Y.-P. Synlett 2003,
1663. (k) Katoh, M.; Matsune, R.; Nagase, H.; Honda, T.
Tetrahedron Lett. 2004, 6221. (l) Ashoorzadeh, A.; Caprio,
V. Synlett 2005, 346. (m) Katoh, M.; Matsune, R.; Honda,
T. Heterocycles 2006, 67, 189. (n) Sieng, B.; Ventura, O.
L.; Bellosta, V.; Cossy, J. Synlett 2008, 1216.
J. Org. Chem. 1984, 49, 4214. (b) Yamamoto, Y.;
Chouman, Y.; Nishii, S.; Ibuka, T.; Kitahara, H. J. Am.
Chem. Soc. 1992, 114, 7652.
(14) (a) Crispino, G. A.; Jeong, K.-S.; Kolb, H. C.; Wang, Z.-M.;
Xu, D.; Sharpless, K. B. J. Org. Chem. 1993, 58, 3785.
(b) Sharpless, K. B.; Amberg, W.; Bennani, Y. L.; Crispino,
G. A.; Hartung, J.; Jeong, K.-S.; Kwong, H.-L.; Morikawa,
K.; Wang, Z.-M.; Xu, D.; Zhang, X.-L. J. Org. Chem. 1992,
57, 2768.
(o) Takeuchi, Y.; Oshige, M.; Azuma, K.; Abe, H.;
Harayama, T. Chem. Pharm. Bull. 2005, 53, 868.
(8) De Smet, P. A. Drugs 1997, 71, 1048.
(9) Takeuchi, Y.; Azuma, K.; Oshige, M.; Abe, H.; Nishioka,
H.; Sasaki, K.; Takeuchi, Y. Tetrahedron 2003, 59, 1639.
(10) Takeuchi, Y.; Azuma, K.; Abe, H.; Harayama, T.
Heterocycles 2000, 53, 2247.
(11) Conjugate addition with TMSOTf (Lewis acid) also
selectively afforded the trans adducts.
(15) Foti, C. J.; Comins, D. L. J. Org. Chem. 1995, 60, 2656.
(16) Neffgen, S.; Kuan, J.; Fey, T.; Keul, H.; Höcker, H.
Macromol. Chem. Phys. 2000, 201, 2108.
(17) Dieter, R. K.; Sharma, R. R. J. Org. Chem. 1996, 61, 4180.
(18) Mattingly, P. G. Synthesis 1990, 366.
(19) Ablondi, F.; Gordon, S.; Morton, I. J. II; Williams, J. H.
(12) Houk, K. N.; Paddon-Row, M. N.; Rondan, N. G.; Wu,
Y.-D.; Brown, F. K.; Spellmeyer, D. C.; Metz, J. T.; Li, Y.;
Loncharich, R. J. Science 1986, 231, 1108.
J. Org. Chem. 1952, 17, 14.
(20) Murata, K.; Takano, F.; Fushiya, S.; Oshima, Y. J. Nat.
Prod. 1998, 61, 729.
Synthesis 2008, No. 19, 3081–3087 © Thieme Stuttgart · New York