Chiral synthesis of (+)-febrifugine and (-)-isofebrifugine by means of samarium diiodide-promoted carbon-nitrogen bond cleavage reaction

Article abstract of DOI:10.3987/COM-05-S(T)12

(+)-Febrifugine, a potential anti-malarial piperidine alkaloid, was synthesized from (4S)-hydroxyproline methyl ester, stereoselectively, where a samarium diiodide-promoted carbon-nitrogen bond cleavage reaction was involved as a key reaction. A stereocon

Full text of DOI:10.3987/COM-05-S(T)12

HETEROCYCLES, Vol. 67, No. 1, 2006
189
HETEROCYCLES, Vol. 67, No. 1, 2006, pp. 189 - 204. © The Japan Institute of Heterocyclic Chemistry
Received, 3rd June, 2005, Accepted, 4th July, 2005, Published online, 5th July, 2005. COM-05-S(T)12
CHIRAL SYNTHESIS
OF (+)-FEBRIFUGINE
AND
(-)-ISOFEBRIFUGINE BY MEANS OF SAMARIUM
DIIODIDE-PROMOTED
CLEAVAGE REACTION†
CARBON-NITROGEN
BOND
Miho Katoh, Ryuichiro Matsune, and Toshio Honda*
Faculty of Pharmaceutical Sciences, Hoshi University, Ebara 2-4-41,
Shinagawa-ku, Tokyo 142-8501, Japan
Abstract – (+)-Febrifugine, a potential anti-malarial piperidine alkaloid, was
synthesized from (4S)-hydroxyproline methyl ester, stereoselectively, where a
samarium diiodide-promoted carbon-nitrogen bond cleavage reaction was
involved as a key reaction. A stereocontrolled formal synthesis of
(-)-isofebrifugine was also described.
Febrifugine (1) and isofebrifugine (2) were isolated from the roots of Dichroa febrifuga Lour.
(Chinese Name: Cháng Shan) in 1947, 1 and are recognized as active principles against malaria.2
Structures including the absolute stereochemistries of those alkaloids were unambiguously
established by their syntheses in 1999.3
HO
O
N
N
O
HO
O
N
N
N
N
H
O
H
1. Febrifugine
2. Isofebrifugine
Figure 1. The structures of (+)-febrifugine and (+)-isofebrifugine.
Since these alkaloids exhibit the attractive biological activity, a number of their racemic and chiral
syntheses have been established.4
Recently, we have developed a novel carbon-nitrogen bond cleavage reaction of α-amino carbonyl
compounds by using samarium diiodide as a one electron reducing agent,5 and have applied the
methodology to the synthesis of biologically active natural products.6 As part of our continuing
exploration of the samarium diiodide-promoted carbon-nitrogen bond cleavage reaction, we are interested
in the synthesis of potential anti-malarial piperidine alkaloids, febrifugine and isofebrifugine.
Our synthesis of (+)-febrifugine starts from the stereoselective preparation of 4-hydroxy-5-alkyl-L-
prolinate, as follows.
Oxidation of methyl N-Boc-(4S)-tert-butyldimethylsilyloxy-L-prolinate (3) with ruthenium tetroxide

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HETEROCYCLES, Vol. 67, No. 1, 2006
according to the literature gave the lactam (4).7 In order to synthesize (+)-febrifugine, a stereoselective
introduction of an alkyl side chain at the 5-position of 4 with the 2,5-trans-stereochemistry would be
required. Although a number of strategies have been developed for stereoselective introduction of an alkyl
side chain at the 5-position of pyroglutamic acid ester,8 some of them were found to have a limitation, in
terms of nucleophilic species, conversion yield, reaction conditions, and stereoselectivity. Among the
various reaction conditions attempted, we could find that a tandem Horner-Emmons-Michael reaction9
gave the best results for introducing the desired alkyl side chain, in terms of yield and stereoselectivity.
Thus, the lactam (4) was reduced with lithium triethylborohydride to give the aminal (5), which without
purification, was treated with triethylphosphonoacetate in the presence of sodium hydride to afford the
diester (6) in 62% from 4. Although the diester (6) was obtained as a mixture of the amide rotamers, the
stereochemistry at the 5-position was assumed to be R-configuration based on the analysis of the NMR
spectral data. To determine the stereoselectivity of this reaction, the N-Boc group of 6 was removed by
treatment with trifluoroacetic acid to give the amine (7) as the sole product. The spectroscopic data of 7
clearly indicated that a tandem Horner-Emmons-Michael reaction proceeded, stereoselectively, and the
stereochemistry at the 5-position of 6 would be controlled during the intramolecular Michael addition of
the nitrogen to the α,β-unsaturated ester, generated by the Horner-Emmons reaction, where the addition of
the nitrogen might occur from the sterically less hindered side of the substrate.9b As the difficulties were
mentioned for the selective reduction of the ethyl ester to manipulate the side chain prior to the reduction
of the methyl ester, we attempted to prepare a more versatile precursor for further modification of the side
chain.
TBSO
TBSO
TBSO
a
b
CO2Me
CO2Me
HO
CO2Me
O
N
N
N
Boc
Boc
Boc
3
4
5
TBSO
TBSO
c
R1
CO2Me
CO2Me
N
R2
O
Z
HN
Boc
1
2
6 R = CO Et, R = Boc
2
d
d
1
2
7 R = CO Et, R = H
2
Z = OEt or N(OMe)Me
1
2
8 R = CON(OMe)Me, R = Boc
1
2
9 R = CON(OMe)Me, R = H
Scheme 1. Reagents and conditions: (a) RuO (cat), NaIO , AcOEt/H O, rt (86%);
2
4
2
(b) LiBEt H, THF, -78°C; (c) (EtO) P(O)CH CO Et or (EtO) P(O)CH CON(OMe)Me, NaH,
3
2
2
2
2
2
THF, rt (6: 62% from 4, 8: 83% from 4); (d) TFA, CH Cl , 0°C ~ rt (7: 53%, 9: 56%).
2
2
Treatment of 5 with diethyl (N-methoxy-N-methylcarbamoylmethyl)phosphonate in the presence of
sodium hydride provided the amide (8) in 83% from 4. The configuration at the 5-position of 8 was
assumed to be R based on the analyses of NOE experiments, and was unambiguously determined by the
X-Ray crystallographic analysis of the corresponding NH compound (9).
Since we could achieve the introduction of the side chain at the 5-position with the desired
stereochemistry, we focused our attention on further utilization of the amide (8) in the synthesis of

HETEROCYCLES, Vol. 67, No. 1, 2006
191
(+)-febrifugine. Treatment of the amide (8) with methylmagnesium bromide gave the ketone (10), as the
sole product, in 88% yield, which was further converted into the olefin (11) by methylenation with the
Wittig reagent in 43% yield.
Figure 2. ORTEP Drawing of the compound (9).
The olefin (11) was also synthesized by treatment of 10 with Tebbe’s reagent10 in an improved yield
(81%). After selective removal of the Boc group of 11 with zinc bromide, the resulting amine (12) was
subjected to the key reductive deamination reaction by using samarium diiodide in the presence of
methanol as the proton source to give the δ-lactam (13) arising from a recyclization of the
carbon-nitrogen bond cleavage product, in 90% yield. Lithium aluminum hydride reduction of 13,
followed by treatment of the resulting hydroxy-amine (14) with CbzCl afforded the carbamate (15),
where deprotection of the silyl group was observed during the reduction of the amide function. Protection
of the secondary hydroxy group of 15 with benzyl bromide in the presence of sodium hydride gave the
benzyl ether (16), which, on ozonolysis, followed by the usual reductive work-up with methyl sulfide,
furnished the methyl ketone (17) in 83% yield from 15.
TBSO
TBSO
O
TBSO
O
a
b
CO2Me
CO2Me
N
N
Me N
OMe
CO2Me
N
R
Boc
Boc
11 R = Boc
12 R = H
10
8
c
BnO
O
TBSO
R2O
TBSO
h
e
d
CO2Me
NH2
N
Cbz
N
H
O
N
R1
13
14 R1 = R2 = H
15 R1 = Cbz, R2 = H
16 R1 = Cbz, R2 = Bn
17
f
g
Scheme 2. Reagents and conditions: (a) MeMgBr, THF, 0°C (88%); (b) Tebbe's reagent, THF,
-40°C ~ rt (81%); (c) ZnBr2, CH2Cl2, rt; (d) SmI2, THF-HMPA, MeOH, 0°C ~ rt (90% from 11); (e)
LiAlH4, THF, 65°C; (f) CbzCl, TEA, DMAP, CH2Cl2, rt (95% from 13); (g) BnBr, NaH, DMF, 0°C
(90%); (h) O3, MeOH, -78°C then Me2S (92%).

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HETEROCYCLES, Vol. 67, No. 1, 2006
Bromination of 17 was achieved by treatment with trimethylsilyl triflate and subsequently with
N-bromosuccinimide to give the bromo ketone (18), which, without purification, was further coupled with
4-hydroxyquinazoline in the presence of potassium hydride in DMF to provide the protected febrifugine
(19).
BnO
O
BnO
O
BnO
O
N
O
a
b
c
(+)-febrifugine
1
Br
N
N
Cbz
N
Cbz
N
Cbz
19
17
18
Scheme 3. Reagents and conditions: (a) i. TMSOTf, DIPEA, CH Cl , rt; ii. NBS, rt; (b) 4-hydroxyquinazoline,
2
2
KH, DMF, 70°C (57% from 17); (c) 6N HCl, reflux (92%).
Finally, deprotection of 19 with 6N hydrochloric acid furnished (+)-febrifugine (1) in 92% yield. The
spectroscopic data of the synthesized compound including the specific optical rotation were identical with
those reported in the literatures, mp 139-140 °C; [α]D +16.0° (c 0.4, MeOH) {lit.,1b mp 139-140 °C; lit.,4b
mp 138-139 °C; lit.,1c [α]D +13.0° (c 0.65, MeOH)}. Thus, we could develop a novel synthetic pathway
to (+)-febrifugine by employing samarium diiodide-promoted reductive deamination, as a key reaction.
Since this strategy seems to be applicable to the construction of functionalized piperidine rings in
optically active forms, we next attempt the stereoselective synthesis of (-)-isofebrifugine, an antipodal
form of the natural product, due to the accessibility of a starting material.
TBSO
TBSO
O
TBSO
HO
a
b
c
CO2Me
CO2Me
CO2Me
N
N
N
Boc
Boc
Boc
20
21
22
TBSO
TBSO
TBSO
R1
R1
+
d
CO2Me
CO2Me
CO2Me
O
HN
Boc
N
R2
N
R2
Z
1
2
1
2
24 R = CO Et, R = Boc
23 R = CO Et, R = Boc
2
2
1
2
Z = OEt or N(OMe)Me
d
1
2
26 R = CO Et, R = H
25 R = CO Et, R = H
2
2
1
2
1
2
30 R = CON(OMe)Me, R = Boc
29 R = CON(OMe)Me, R = Boc
Scheme 4. Reagents and conditions: (a) RuO (cat), NaIO , AcOEt/H O, rt (83%); (b) LiBEt H, THF, -78°C;
2
4
2
3
(c) (EtO) P(O)CH CO Et or (EtO) P(O)CH CON(OMe)Me, NaH, THF, rt (29: 5.5% from 21, 30: 60% from 21);
2
2
2
2
2
(d) TFA, CH Cl , 0°C ~ rt (25: 26% from 21, 26: 51% from 21).
2
2
For the synthesis of (-)-isofebrifugine, an introduction of an alkyl side chain at the 5-position of
4-hydroxypyroglutamate would be required with the relative stereochemistry of 2,5-trans- and
4,5-cis-relationships.

HETEROCYCLES, Vol. 67, No. 1, 2006
193
Thus, a commercially available (4R)-hydroxy-L-proline was converted into the known N-Boc methyl
ester (20),7 which on oxidation with ruthenium tetroxide, gave the lactam (21) in 83% yield. Reduction of
the lactam (21) with lithium triethylborohydride as described above, afforded the aminal (22). A tandem
Horner-Emmons-Michael reaction of 22 with triethyl phosphonoacetate and sodium hydride in DMF gave
an inseparable mixture of diastereomers (23 and 24), which, on deprotection of the N-Boc group with
trifluoroacetic acid gave separable two compounds (25 and 26) in 77% yield, in a ratio of ca. 1 : 2. The
structures of these compounds (25 and 26) were determined by treatment with tetrabutylammonium
fluoride to furnish the alcohol (27) and the lactone (28), respectively.
TBSO
EtO2C
HO
TBAF, THF, 0°C, 89%
TBAF, THF, 0°C, 68%
EtO2C
CO2Me
CO2Me
CO2Me
N
H
N
H
23
27
TBSO
EtO2C
O
O
CO2Me
N
H
N
H
24
28
Scheme 5. Structure determination of the compounds (23 and 24).
When a tandem Horner-Emmons-Michael reaction of 22 was carried out by using diethyl
(N-methoxy-N-methylcarbamoylmethyl)phosphonate as the Wittig reagent, the ratio of the products (29
and 30) was improved to ca. 1 : 11, where the desired compound (30) was found to be the major product.
After separation by silica gel column chromatography, those amides (29 and 30) were converted into the
secondary amines, respectively, as follows. Diisobutylaluminum hydride reduction of the amides (29 and
30), followed by methylenation of the resulting aldehydes (31 and 32) with methyltriphenylphosphonium
bromide and n-butyllithium, provided the olefins (33 and 34).
TBSO
R
TBSO
b
CO2Me
CO2Me
N
N
R
Boc
33 R = Boc
35 R = H
29 R = CON(OMe)Me
31 R = CHO
c
a
TBSO
R
TBSO
TBSO
N
O
b
HO
O
d
N
CO2Me
N
CO2Me
N
R
N
H
O
N
H
Boc
37
30 R = CON(OMe)Me
32 R = CHO
34 R = Boc
36 R = H
(-)-isofebrifugine
a
c
+
-
Scheme 6. Reagents and conditions: (a) DIBAL, THF, -78°C; (b) Ph P MeBr , n-BuLi, THF, -78°C ~ rt (33: 25%
3
from 29, 34: 60% from 30); (c) ZnBr , CH Cl ; (d) SmI2, THF-HMPA, MeOH, 0°C ~ rt (71% from 34).
2
2
2

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HETEROCYCLES, Vol. 67, No. 1, 2006
Selective removal of the N-Boc groups of 33 and 34 was achieved by treatment with zinc bromide as
described above to give the amines (35 and 36), respectively. The stereochemistries of 35 and 36 were
determined based on the NMR spectral analysis, and the observed NOEs were depicted in Figure 3.11
11.4%
2.3%
H
H
TBSO
H
TBSO
H
CO2Me
CO2Me
N
H
N
H
35
36
Figure 3. NOE Assignments of the compounds (35 and 36).
With the desired compound (36) in hands, we attempted its conversion into the corresponding δ-lactam
by means of samarium diiodide-promoted reductive deamination reaction. Treatment of 36 with
samarium diiodide in the presence of methanol as the proton source in THF-HMPA afforded the desired
δ-lactam (37) in 71% yield. Again, spectroscopic data of 37 were identical with those reported in the
literature4m except for the sign of optical rotation, {[α]D +4.6° (c 0.2, CHCl3); lit.,4m [α]D -4.5° (c 1.05,
CHCl3)}. Since ent-37 was already transformed into (+)-isofebrifugine,4h this synthesis constitutes the
formal synthesis of (-)-isofebrifugine.
In summary, we have established novel chiral syntheses of (+)-febrifugine and (-)-isofebrifugine.
Although the synthesis of isofebrifugine gave the antipodal form of the natural product, we believe that
the strategy developed here should provide a useful tool for finding new anti-malarial drugs.
EXPERIMENTAL
Melting points were measured with a Yanagimoto MP apparatus and are uncorrected. IR spectra were
obtained using a JASCO FT/IR-200 spectrophotometer. 1H- and 13C-NMR spectra were obtained on JEOL
LAMBDA-270 (1H-NMR: 270 MHz, 13C-NMR: 67.8 MHz), or JEOL LA-500 (1H-NMR: 500 MHz,
13C-NMR: 125 MHz) instrument for solutions in CDCl3 unless otherwise noted, and chemical shifts are
reported on the δ scale from internal TMS. MS spectra were measured with a JEOL JMS-D 300
spectrometer. Elemental analyses were performed on a Yanaco-MT5.
(3S,5S)-1-tert-Butoxycarbonyl-3-tert-butyldimethylsilyloxy-5-methoxycarbonylpyrrolidin-2-one (4):
To a stirred suspension of RuO4 [prepared from RuO2 hydrate (0.74 g, 5.57 mmol) and NaIO4 (14.9 g,
69.6 mmol) in H2O (245 mL)] was added a solution of the prolinate (3) (10.0 g, 27.9 mmol) in AcOEt
(123 mL), and the resulting mixture was stirred at ambient temperature for overnight. After removal of
insoluble materials by filtration through Celite pad, the filtrate was extracted with AcOEt. The organic
layer was washed with brine and dried over Na2SO4. Evaporation of the solvent gave a residue, which
was subjected to column chromatography on silica gel. Elution with AcOEt:hexane (1:4) afforded the

HETEROCYCLES, Vol. 67, No. 1, 2006
195
1
lactam (4) (8.93 g, 86%) as a colorless oil; [α]D -30.7° (c 1.00, CHCl3) H NMR (270 MHz, CDCl3): δ
4.45 (t, J = 7.4 Hz, 1H), 4.26 (t, J = 7.4 Hz, 1H), 3.75 (s, 3H), 2.55 (dt, J = 7.4, 13.0 Hz, 1H), 1.97 (dt, J =
7.4, 13.0 Hz, 1H), 1.48 (s, 9H), 0.87 (s, 9H), 0.15 (s, 3H), 0.11 (s, 3H); IR (thin film): 2960, 2930, 2860,
1800, 1760, 1720, 1320, 1150, 970, 840, 780 cm-1; CIMS (m/z): 374 (M++1); HRMS calcd for
C17H32NO6Si (M++1): 374.1999, found 374.1971.
Methyl (4S,5R)-4-tert-butyldimethylsilyloxy-5-ethoxycarbonylmethyl-L-prolinate (7): To a stirred
solution of 4 (200 mg, 0.54 mmol) in THF (4 mL) was added LiBEt3H (1.0 M in THF, 0.65 mL, 0.65
mmol) at -78 °C, and the resulting mixture was stirred for further 30 min at the same temperature. To this
mixture were added saturated NaHCO3 solution and 30% H2O2 solution (3 drops) at 0 °C. After stirring
for 20 min, the mixture was extracted with Et2O, and the ethereal layer was dried over Na2SO4.
Evaporation of the solvent gave the aminal (5), which, without purification, was dissolved in THF (2.1
mL). This solution was added to a solution of the Wittig reagent [prepared from NaH (65-75% in oil, 26
mg, 0.65 mmol) and triethyl phosphonoacetate (0.13 mL, 0.65 mmol) in THF (1.4 mL)], and the whole
was stirred at rt for overnight. After treatment with saturated NH4Cl solution, the mixture was extracted
with AcOEt, and the extract was washed with brine and dried over Na2SO4. Evaporation of the solvent
gave a residue, which was purified by silica gel column chromatography using AcOEt:hexane (1:4) as an
eluent to furnish the ester (6) (145 mg, 62%) as a colorless oil. To a stirred solution of 6 (50 mg, 0.11
mmol) in CH2Cl2 (1.1 mL) was added TFA (87 µL, 1.11 mmol) at 0 °C, and the mixture was gradually
warmed up to rt and stirred for further 18 h. The organic layer was washed with saturated NaHCO3
solution, and dried over Na2SO4. Evaporation of the solvent gave the amine (7) (20.5 mg, 53%), as a
colorless oil; 1H NMR (500 MHz, CDCl3, assigned by 1H-1H correlation experiments): δ 4.15 (q, J = 7.1
Hz, 2H, OCH2CH3), 3.92 (dt, J = 4.6, 5.5 Hz, 1H, 4-H), 3.79 (dd, J = 4.6, 8.9 Hz, 1H, 2-H), 3.72 (s, 3H,
OCH3), 3.45 (dt, J = 4.6, 8.5 Hz, 1H, 5-H), 2.46 (dt, J = 5.2, 15.6 Hz, 1H, COCH2), 2.33 (ddd, J = 5.5, 8.9,
13.4 Hz, 1H, 3-H), 2.29 (dd, J = 8.5, 15.6 Hz, 1H, COCH2), 1.98 (dt, J = 4.6, 13.1 Hz, 1H, 3-H), 1.27 (t, J
13
= 7.1 Hz, 3H, OCH2CH3), 0.85 (s, 9H, t-Bu), 0.05 (s, 3H, SiCH3), 0.03 (s, 3H, SiCH3); C NMR (125
MHz, CDCl3): δ -4.8, -4.7, 14.2, 17.8, 25.6, 37.6, 39.5, 52.1, 57.6, 60.5, 62.0, 75.5, 171.9, 175.4; IR (thin
film): 3360, 2950, 2930, 2860, 1780, 1250, 1180, 835, 780 cm-1; EIMS (m/z): 345 (M+); HRMS calcd for
C16H31NO5Si 345.1971, found 345.1992.
Methyl
(4S,5R)-1-tert-butoxycarbonyl-4-tert-butyldimethylsilyloxy-5-[(N-methoxy-N-methyl-
carbonyl)methyl]-L-prolinate (8): To a stirred solution of 4 (0.23 g, 0.61 mmol) in THF (4.8 mL) was
added LiBEt3H (1.0 M in THF, 0.73 mL, 0.73 mmol) at -78 °C, and the resulting mixture was stirred for
further 30 min at the same temperature. To this mixture were added saturated NaHCO3 solution and 30%
H2O2 solution (3 drops) at 0 °C. After stirring for 20 min, the mixture was extracted with Et2O, and the
ethereal layer was dried over Na2SO4. Evaporation of the solvent gave the aminal (5), which, without
purification, was dissolved in THF (2.3 mL). This solution was added to a solution of the Wittig reagent
[prepared from NaH (65-75% in oil, 29 mg, 0.73 mmol) and diethyl (N-methoxy-N-methylcarbamoyl-
methyl)phosphonate (0.15 mL, 0.73 mmol) in THF (1.6 mL)], and the whole was stirred at rt for
overnight. After treatment with saturated NH4Cl solution, the mixture was extracted with AcOEt, and the
extract was washed with brine and dried over Na2SO4. Evaporation of the solvent gave a residue, which
was purified by silica gel column chromatography using AcOEt:hexane (1:4) as an eluent to furnish the

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HETEROCYCLES, Vol. 67, No. 1, 2006
amide (8) (232 mg, 83%) as colorless powder; mp 73-75 °C, [α]D -38.3° (c 0.40, CHCl3); 1H NMR (270
MHz, CDCl3): δ 4.02-4.52 (m, 3H), 3.72 (s, 3H), 3.68 (s, 3H), 3.22 (s, 3H), 2.91-3.28 (m, 1H), 2.02-2.42
(m, 3H), 1.42 (and rotamer at 1.49) (s, 9H), 0.83 (and rotamer at 0.84) (s, 9H), 0.07 (and rotamer at 0.09)
(s, 3H), 0.03 (and rotamer at 0.04) (s, 3H); IR (KBr): 2930, 2860, 1750, 1680, 1675, 1400, 1085 cm-1;
CIMS (m/z): 461 (M++1); HRMS calcd for C21H41N2O7Si (M++1) 461.2683, found 461.2693.
Methyl (4S,5R)-4-tert-butyldimethylsilyloxy-5-[(N-methoxy-N-methylcarbonyl)methyl]-L-prolinate
(9): To a stirred solution of 8 (50 mg, 0.11 mmol) in CH2Cl2 (1.1 mL) was added TFA (84 µL, 1.07
mmol) at 0 °C, and the mixture was gradually warmed up to rt and stirred for further 18 h. The organic
layer was washed with saturated NaHCO3 solution, and dried over Na2SO4. Evaporation of the solvent
gave the amine (9) (21.9 mg, 56%), as a colorless solid. A part of the amine (9) was crystallized from
1
hexane to give colorless needles; mp 89-91 °C; [α]D +22.9° (c 0.21, CHCl3); H NMR (270 MHz,
CDCl3): δ 3.97 (dt, J = 4.6, 4.6 Hz, 1H), 3.82 (d, J = 4.6, 8.9 Hz, 1H), 3.71 (s, 3H), 3.66 (s, 3H), 3.47 (dt,
J = 4.6, 8.7 Hz, 1H), 3.16 (s, 3H), 2.53 (dd, J = 4.6, 15.8 Hz, 1H), 2.44 (dd, J = 8.7, 15.8 Hz, 1H), 2.33
(ddd, J = 4.6, 8.9, 14.1 Hz, 1H), 1.97 (dt, J = 4.6, 14.1 Hz, 1H), 0.86 (s, 9H), 0.05 (s, 6H); 13C NMR (67.5
MHz, CDCl3): δ -5.3, -5.2, 17.4, 25.2, 36.3, 37.1, 51.7, 57.2, 60.7, 61.6, 75.1, 172.1, 174.7; IR (KBr):
3460, 2960, 2920, 2860, 1730, 1345, 1215, 1105, 1070, 775 cm-1; CIMS (m/z): 361 (M++1); HRMS calcd
for C16H33N2O5Si (M++1) 361.2158, found 361.2149.
Crystal data for 9: C16H32N2O5Si, M=360.52, monoclinic, space group P21, a=6.7052(5), b=7.6518(7),
c=20.608(2) Å, β=91.043(7)°, V=1057.2(2) Å3, Z=2, Dcalcd=1.129 g/cm3. The data were collected at a
temperature of 25±1°C using the ω scan technique to a maximum 2θ values of 136.6°. Of the 5762
reflections that were collected, 2073 were unique (Rint=0.036); equivalent reflections were merged. The
intensities of three representative reflections were measured after every 150 reflections. No decay
correction was applied. The structure was solved using SIR92. R=0.045, Rw=0.039.
Methyl
(4S,5R)-1-tert-butoxycarbonyl-4-tert-butyldimethylsilyloxy-5-(2-oxopropyl)-L-prolinate
(10): To a stirred solution of the amide (8) (5.1 g, 11.1 mmol) in THF (110 mL) was added MeMgBr
(0.93 M in THF, 23.8 mL, 22.2 mmol) at 0 °C, and the resulting solution was stirred for further 30 min at
the same temperature. After treatment with saturated NH4Cl solution, the whole mixture was extracted
with AcOEt. The extract was washed with brine, and dried over Na2SO4. Evaporation of the solvent gave
a residue, which was subjected to column chromatography on silica gel. Elution with AcOEt:hexane (1:4)
1
gave the ketone (10) (4.0 g, 88%) as colorless powders; mp 65-58 °C; [α]D -30.7° (c 1.00, CHCl3); H
NMR (270 MHz, CDCl3): δ 4.33 (and rotamer at 4.43), (dd, J = 1.3, 9.0 Hz, 1H), 3.96-4.14 (m, 2H), 3.68
(and rotamer at 3.67) (s, 3H), 3.15 (and rotamer at 2.97) (dd, J = 4.5, 16.5 Hz, 1H), 2.18-2.33 (m, 2H),
2.16 (s, 3H), 2.01-2.18 (m, 1H), 1.41(and rotamer at 1.48) (s, 9H), 0.83 (and rotamer at 0.84) (s, 9H), 0.02
(and rotamer at 0.08) (s, 6H); IR (KBr): 2950, 2930, 2860, 1760, 1735, 1700, 1295, 1090, 735 cm-1;
CIMS (m/z): 416 (M++1); HRMS calcd for C20H38NO6Si (M++1) 416.2468, found 416.2463.
Methyl
(4S,5R)-1-tert-butoxycarbonyl-4-tert-butyldimethylsilyloxy-5-(2-methylprop-2-en-1-yl)-L-
prolinate (11): To a stirred solution of the ketone (10) (1.66 g, 4.01 mmol) in THF (36 mL) was added
Tebbe’s reagent (0.5 M in THF, 8.0 mL, 1.01 mmol) at -40 °C, and the whole was stirred at the same
temperature for further 30 min, and then for 2 h at rt. After cooling to -78 °C, 1 M NaOH solution (6.3
mL) was added to this solution, and the resulting mixture was filtered through Celite pad to remove

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197
insoluble materials. The filtrate was washed with brine and dried over Na2SO4. Evaporation of the solvent
gave a residue, which was subjected to column chromatography on silica gel. Elution with AcOEt:hexane
(1:4) afforded the olefin (11) (1.33 g, 81%) as a colorless solid; mp 35-38 °C; [α]D -23.5° (c 1.00,
CHCl3); 1H NMR (500 MHz, CDCl3): δ 4.81 (and rotamer at 4.82) (br s, 1H), 4.69 (and rotamer at 4.70)
(br s, 1H), 4.41 (and rotamer at 4.46) (br d, J = 4.9 Hz, 1H), 4.08 (and rotamer at 4.10) (br d, J = 2.1 Hz,
1H), 3.91 (and rotamer at 3.75) (br dd, J = 1.3, 6.1 Hz, 1H), 3.67 (and rotamer at 3.66) (s, 3H), 2.68 (and
rotamer at 2.52) (br d, J = 7.3 Hz, 1H), 2.31 (and rotamer at 2.26) (ddd, J = 2.1, 4.9, 7.0 Hz, 1H), 2.08 (br
d, J = 7.0 Hz, 1H), 1.81 (and rotamer at 1.78) (s, 3H), 1.70-1.77 (m, 1H), 1.41 (and rotamer at 1.50) (s,
9H), 0.81 (and rotamer at 0.82) (s, 9H), -0.01 (br s, 3H), -0.03 (br s, 3H); 13C NMR (125 MHz, CDCl3):
major rotamer; δ -5.0, -4.9, 17.7, 22.3, 25.5, 28.3, 37.5, 40.5, 51.7, 58.9, 65.2, 73.7, 79.6, 113.1, 143.0,
153.5, 172.8 ; minor rotamer; δ -4.9, -4.8, 17.8, 22.1, 25.5, 28.5, 36.3, 41.8, 51.8, 58.7, 65.0, 74.7, 79.9,
113.6, 142.6, 154.2, 171.8; IR (KBr): 2950, 2930, 2860, 1765, 1700, 1390, 1080, 840, 775 cm-1; CIMS
(m/z): 414 (M++1); Anal. Calcd for C21H39N2O5Si: C, 60.98; H, 9.50; N, 3.39. Found: C, 60.83; H, 9.33;
N, 3.47.
(5S,6R)-5-tert-Butyldimethylsilyloxy-6-(2-methylprop-2-en-1-yl)piperidin-2-one (13): To a stirred
suspension of ZnBr2 (1.33 g, 5.93 mmol) in CH2Cl2 (10 mL) was added a solution of the olefin (11) (1.22
mg, 2.96 mmol) in CH2Cl2 (20 mL), and the resulting mixture was stirred for overnight at rt. After
removal of insoluble materials by filtration through Celite pad, the filtrate was treated with saturated
NaHCO3 solution, and extracted with CH2Cl2. The extract was washed with brine, and dried over Na2SO4.
1
Evaporation of the solvent gave the amine (12) as a colorless oil; H NMR (500 MHz, CDCl3, assigned
1
by H-1H correlation experiments): δ 4.79 (br s, 1H, =CH2), 4.75 (br s, 1H, =CH2), 3.87 (dt, J = 4.3, 5.8
Hz, 1H, 4-H), 3.78 (dd, J = 4.3, 9.1 Hz, 1H, 2-H), 3.71(s, 3H, OCH3), 3.20 (ddd, J = 4.3, 5.8, 8.9 Hz, 1H,
5-H), 2.35 (ddd, J = 5.8, 9.1, 13.5 Hz, 1H, 3-H), 2.15 (dd, J = 5.8, 13.5 Hz, 1H, =C-CH2), 1.91-1.99 (m,
2H, H-3, =C-CH2), 1.74 (s, 3H, =C-CH3), 0.84 (s, 9H, t-Bu), 0.03 (s, 3H, SiCH3), 0.02 (s, 3H, SiCH3);
1
13C NMR (125 MHz, CDCl3, assigned by H-13C correlation experiments): δ -4.9 (SiCH3), -4.7 (SiCH3),
17.8 (SiCMe3), 22.4 (=C-CH3), 25.6 (3C, t-Bu), 37.9 (C-3), 43.1 (=C-CH2), 52.0 (OCH3), 57.5 (C-2),
63.2 (C-5), 75.8 (C-4), 112.0 (=CH2), 143.3 (=C), 175.7 (C=O); IR (thin film): 3360, 2950, 2930, 2900,
2860, 1740, 1650, 840, 775 cm-1; EIMS (m/z): 313 (M+); HRMS calcd for C16H31NO3Si 313.2073, found
313.2076. The amine obtained was used without further purification in the next step.
To a stirred solution of the amine (12) in THF (10 mL) was added a solution of SmI2 (0.2 M in THF, 38.3
mL, 7.67 mmol) containing HMPA (1.3 mL, 7.67 mmol) and MeOH (155 µL, 3.84 mmol) at 0 °C. The
solution was gradually warmed up to rt, and stirred for further 2 h at the same temperature. To this
solution were added excess of saturated NaHCO3 and Et2O, and the whole was stirred for 30 min. After
removal of insoluble materials by filtration through Celite pad, the filtrate was extracted with AcOEt , and
the extract was washed with brine, and dried over Na2SO4. Evaporation of the solvent gave a residue,
which was subjected to column chromatography on silica gel. Elution with AcOEt:hexane (5:1) gave the
δ-lactam (13) (678 mg, 90%) as a colorless oil; [α]D +12.0° (c 1.00, CHCl3); 1H NMR (500 MHz, CDCl3,
1
assigned by H-1H correlation experiments): δ 5.62 (br s, 1H, NH), 4.93 (s, 1H, =CH2), 4.80 (s, 1H,
=CH2), 3.59 (ddd, J = 3.6, 6.9, 10.0 Hz, 1H, 5-H), 3.26 (ddd, J = 3.0, 6.9, 10.4 Hz, 1H, 6-H), 2.47-2.55
(m, 2H, 3-H and =C-CH2), 2.34 (ddd, J = 6.4, 10.0, 18.0 Hz, 1H, 3-H), 1.77-1.86 (m, 1H, 4-H), 1.90 (dd,

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HETEROCYCLES, Vol. 67, No. 1, 2006
J = 10.4, 13.7 Hz, 1H, =C-CH2), 1.93-1.99 (m, 1H, 4-H), 1.72 (s, 3H, =C-CH3), 0.89 (s, 9H, t-Bu), 0.08 (s,
1
6H, 2×SiCH3); 13C NMR (125 MHz, CDCl3, assigned by H-13C correlation experiments): δ -4.8
(SiCH3), -4.2 (SiCH3), 17.9 (SiCMe3), 21.7 (=C-CH3), 25.6 (3C, t-Bu), 28.7 (C-3), 28.8 (C-4), 42.7
(=C-CH2), 55.9 (C-6), 69.9 (C-5), 114.9 (=CH2), 140.8 (=C), 170.9 (C=O); IR (thin film): 3220, 2960,
2930, 2860, 1670, 1090, 840, 770 cm-1; EIMS (m/z): 283 (M+); Anal. Calcd for C15H29NO2Si: C, 63.55; H,
10.31; N, 4.94. Found: C, 63.51; H, 10.32; N, 4.97.
(2R,3S)-3-Benzyloxy-1-benzyloxycarbonyl-2-(2-methylprop-2-en-1-yl)piperidine (16): To a stirred
solution of the lactam (13) (200 mg, 0.71 mmol) in THF (8.4 mL) was added LiAlH4 (161 mg, 4.24
mmol) at rt, and the resulting mixture was heated at 65 °C for 3 h. The mixture was diluted with THF, and
1 M NaOH solution were carefully added to this mixture at 0 °C. After removal of insoluble materials by
filtration through Celite pad, the filtrate was dried over Na2SO4. Evaporation of the solvent gave the
1
1
amine (14); H NMR (500 MHz, CDCl3, assigned by H-1H correlation experiments): δ 4.86 (br s, 1H,
=CH2), 4.82 (br s, 1H, =CH2), 3.26 (ddd, J = 4.5, 8.6, 10.7 Hz, 1H, 3-H), 2.98 (br d, J = 11.6 Hz, 1H,
6-H), 2.64 (dd, J = 3.4, 13.5 Hz, 1H, =C-CH2), 2.53 (dt, J = 2.8, 11.6 Hz, 1H, 6-H), 2.43 (ddd, J = 3.4, 8.6,
10.1 Hz, 1H, 2-H), 2.03-2.08 (m, 1H, 4-H), 2.00 (dd, J = 10.1, 13.5 Hz, 1H, =C-CH2), 1.76 (s, 3H,
=C-CH3), 1.68-1.74 (m, 3H, H-5, NH, OH), 1.49-1.61 (m, 1H, 5-H), 1.33 (ddt, J = 4.5, 10.4, 12.3 Hz, 1H,
4-H); CIMS (m/z): 156 (M++1); HRMS calcd for C9H18NO (M++1) 156.1388, found 156.1366, which,
without further purification, was used in the next step.
To a stirred solution of the amine (14) in CH2Cl2 (3.5 mL) were added CbzCl (0.12 mL, 0.85 mmol), TEA
(0.12 mL, 0.85 mmol) and DMAP (8.6 mg, 0.07 mmol) at 0 °C, and the whole was stirred for overnight at
ambient temperature. After treatment with saturated NH4Cl solution, the mixture was extracted with
CH2Cl2. The extract was washed with brine, and dried over Na2SO4. Evaporation of the solvent gave a
residue, which was subjected to column chromatography on silica gel. Elution with AcOEt:hexane (2:1)
afforded the carbamate (15) (195 mg, 95%), as a colorless oil. To a stirred solution of the carbamate (15)
(78.0 mg, 0.27 mmol) in DMF (1 mL) were added NaH (65-75% in oil, 16.0 mg, 0.40 mmol) and BnBr
(0.05 mL, 0.40 mmol) at 0 °C, and the mixture was stirred for further 4 h. After treatment with saturated
NH4Cl solution, the mixture was extracted with AcOEt, and the extract was washed with brine, and dried
over Na2SO4. Evaporation of the solvent gave a residue, which was subjected to column chromatography
on silica gel. Elution with AcOEt:hexane (1:9) afforded the benzyl ether (16) (92 mg, 90%), as a colorless
1
oil; [α]D -41.9° (c 1.00, CHCl3); H NMR (270 MHz, CDCl3): δ 7.15-7.40 (m, 10H), 4.35-5.21 (m, 7H),
3.95-4.21 (m, 1H), 3.38-3.51 (m, 1H), 2.80-3.00 (m, 1H), 1.08-2.41 (m, 9H); IR (thin film): 1950, 2860,
1695, 1500, 1425, 1260, 700 cm-1; CIMS (m/z) 380 (M++1); Anal. Calcd for C24H29NO3: C, 75.96; H,
7.70; N, 3.69. Found: C, 76.16; H, 7.91; N, 3.69.
(2R,3S)-3-Benzyloxy-1-benzyloxycarbonyl-2-(2-oxopropyl)piperidine (17): The stream of ozone was
bubbled through a stirred solution of the olefin (16) (225 mg, 0.59 mmol) in MeOH (20 mL) at -78 °C
until disappearance of the starting material on TLC. The reaction mixture was flushed with argon and
treated with Me2S (0.45 mL, 5.95 mmol). The resulting mixture was allowed to warm to rt and stirred for
further 18 h at the same temperature. After removal of the solvent, the residue was subjected to column
chromatography on silica gel. Elution with AcOEt:hexane (1:9) afforded the methyl ketone (17) (209 mg,
92%) as a colorless oil; [α]D -32.8° (c 1.00, CHCl3); 1H NMR (270 MHz, CDCl3): δ 7.25-7.32 (m, 10H),

HETEROCYCLES, Vol. 67, No. 1, 2006
199
4.90-5.20 (m, 3H), 4.41-4.77 (m, 2H), 4.11 (br s, 1H), 3.44 (br s, 1H), 2.75-2.95 (m, 1H), 2.52-2.74 (m,
2H), 2.14 (br s, 3H), 1.76-2.00 (m, 2H), 1.66-1.74 (m, 1H), 1.32-1.48 (m, 1H); IR (thin film): 2945, 2860,
1720, 1695, 1425, 1260, 700 cm-1; EIMS (m/z): 381 (M+); Anal. Calcd for C23H27NO4: C, 72.42; H, 7.13;
N, 3.67. Found: C, 72.18; H, 7.24; N, 3.78.
(2R,3S)-3-Benzyloxy-1-benzyloxycarbonyl-2-[2-oxo-3-(4-oxoquinazolin-3(4H)-yl)propyl]piperidine
(19): To a stirred solution of the methyl ketone (17) (100 mg, 0.26 mmol) in CH2Cl2 (0.9 mL) were added
DIPEA (55 µL, 0.31 mmol) and TMSOTf (61 µL, 0.34 mmol) at ambient temperature, and the resulting
mixture was stirred for 20 min at the same temperature. To this solution was added NBS (57 mg, 0.31
mmol) at room temperature, and the solution was stirred for further 1 h at the same temperature. After
treatment with 10% Na2S2O3 solution, the mixture was extracted with AcOEt. The extract was washed
with saturated NaHCO3 solution, and dried over Na2SO4. Evaporation of the solvent gave the bromo
ketone (18), which, without further purification, was used in the next step.
A solution of the bromo ketone (18) in DMF (1.0 mL) was added a solution of 4-hydroxyquinazoline (96
mg, 0.66 mmol) in DMF (1.5 mL) in the presence of KH (21 mg, 0.53 mmol) at 0 °C, and the mixture
was stirred for 30 min at the same temperature and then for 10 h at 70 °C. The mixture was treated with
saturated NH4Cl solution, and extracted with Et2O. The ethereal layer was washed with brine, and dried
over Na2SO4. Evaporation of the solvent gave a residue, which was subjected to column chromatography
on silica gel. Elution with AcOEt:hexane (4:1) afforded the protected febrifugine (19) (78 mg, 57%),
whose spectroscopic data were identical with those reported; [α]D -36.0° (c 0.51, CHCl3); {lit.,4g [α]D
1
-22.0° (c 1.00, CHCl3)}; H NMR (270 MHz, CDCl3): δ 8.26 (br d, J = 7.7 Hz, 1H), 7.69-7.92 (m, 3H),
7.51 (ddd, J = 1.6, 6.6, 8.1 Hz, 1H), 7.17-7.40 (m, 10H), 5.17 (d, J = 12.4 Hz, 1H), 5.09 (d, J = 12.4 Hz,
1H), 4.99 (br t, J = 6.7 Hz, 1H), 4.85 (br s, 1H), 4.64 (d, J = 12.0 Hz, 1H), 4.52 (d, J = 12.0 Hz, 1H), 4.04
(br s, 1H), 3.51 (br s, 1H), 2.97 (br s, 1H), 2.86 (dd, J = 8.6, 14.7 Hz, 1H), 2.77 (dd, J = 6.3, 14.8 Hz, 1H),
1.90 (br d, J = 11.2 Hz, 2H), 1.53-1.79 (m, 2H), 1.38-1.51 (m, 1H); 13C NMR (67.5 MHz, CDCl3): δ 19.2,
24.1, 39.4, 40.7, 53.7, 67.2, 70.2, 73.5, 77.2, 121.6, 126.5, 127.1, 127.4, 127.5, 127.6, 127.8, 128.2, 128.3,
134.3, 136.4, 138.2, 146.3, 148.1, 156.1, 160.7, 199.9; IR (thin film): 2940, 2860, 1730, 1680, 1615, 1475,
1425, 1360, 1260, 1090, 700 cm-1; EIMS (m/z): 525 (M+); HRMS calcd for C31H31N3O5 525.2263, found
525.2280.
(+)-Febrifugine (1): A solution of 19 (119 mg, 0.23 mmol) in 6N HCl (17.1 mL) was heated at reflux for
26 h. The solution was basified with K2CO3 to pH 9, and extracted with CHCl3. The organic layer was
washed with brine and dried over K2CO3. Evaporation of the solvent gave a residue, which was subjected
to column chromatography on silica gel. Elution with ammonia saturated CHCl3:MeOH (9:1) afforded
febrifugine (1) (63 mg, 92%), whose spectroscopic data were identical with those reported; mp
139-140 °C (lit.,1b mp 139-140 °C); [α]D +16.0° (c 0.40, MeOH) {lit.,1c [α]D +13.0° (c 0.65, MeOH)}; 1H
NMR (270 MHz, CDCl3): δ 8.28 (br s, J = 7.2 Hz, 1H), 7.89 (s, 1H), 7.68-7.82 (m, 2H), 7.51 (dt, J = 1.6,
8.1 Hz, 1H), 4.89 (d, J = 17.3 Hz, 1H), 4.82 (d, J = 17.3 Hz, 1H), 3.30 (dt, J = 4.6, 9.0 Hz, 1H), 3.12 (dd,
J = 4.6, 15.8 Hz, 1H), 2.97 (br d, J = 11.9 Hz, 1H), 2.87 (ddd, J = 4.6, 7.4, 15.8 Hz, 1H), 2.65 (dd, J = 7.4,
15.8 Hz, 1H), 2.58 (dt, J = 3.0, 12.2 Hz, 1H), 1.98-2.15 (m, 1H), 1.29-1.81 (m, 3H); IR (thin film): 3360,
2930, 2850, 1725, 1670, 1615, 1475, 1370, 1325, 775 cm-1; EIMS (m/z): 301 (M+); HRMS calcd for
C16H19N3O3 301.1426, found 301.1398.

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(3R,5S)-1-tert-Butoxycarbonyl-3-tert-butyldimethylsilyloxy-5-methoxycarbonylpyrrolidin-2-one
(21): The lactam (21) (8.64 g, 83%) was synthesized from the silyl ether (20) (10.0 g, 27.9 mmol) by the
same procedure as described for the preparation of 4. The spectroscopic data of 21 were identical with
those reported in the literature.7 1H NMR (270 MHz, CDCl3): δ 4.57 (dd, J = 1.6, 9.7 Hz, 1H), 4.41 (dd, J
= 8.2, 10.0 Hz, 1H), 3.78 (s, 3H), 2.36 (ddd, J = 1.6, 8.2, 13.3 Hz, 1H), 2.19 (dt, J = 10.0, 13.3 Hz, 1H),
1.49 (s, 9H), 0.88 (s, 9H), 0.16 (s, 3H), 0.09 (s, 3H).
Methyl (4R,5S)-4-tert-butyldimethylsilyloxy-5-ethoxycarbonylmethyl-L-prolinate (25) and methyl
(4R,5R)-4-tert-butyldimethylsilyloxy-5-ethoxycarbonylmethyl-L-prolinate (26): The reduction of the
amide (21) (200 mg, 0.54 mmol) in THF (4.3 mL) with LiBEt3H (1.0 M in THF, 0.64 mL, 0.64 mmol)
was carried out by the same procedure as described for the preparation of 5 to give the aminal (22), which,
without purification, was dissolved in DMF (2.1 mL). This solution was added to a solution of the Wittig
reagent [prepared from NaH (65-75% in oil, 26 mg, 0.65 mmol) and triethyl phosphonoacetate (0.13 mL,
0.64 mmol) in DMF (1.4 mL)], and the whole was stirred at rt for overnight. After treatment with
saturated NH4Cl solution, the mixture was extracted with AcOEt, and the extract was washed with brine
and dried over Na2SO4. Evaporation of the solvent gave a mixture of the crude diesters (23 and 24),
which were dissolved into CH2Cl2 (14.4 mL). To this solution was added TFA (1.11 mL, 14.4 mmol) at
0 °C, and the resulting mixture was stirred for further 3.5 h at rt. The mixture was washed with saturated
NaHCO3 solution, and dried over Na2SO4. Evaporation of the solvent gave a residue, which was purified
by silica gel column chromatography using AcOEt:hexane (1:2) as an eluent to furnish the amine (25)
1
(128 mg, 26%) as a colorless oil; H NMR (270 MHz, CDCl3): δ 4.09 (q, J = 7.1 Hz, 2H), 3.95 (dd, J =
7.1, 8.7 Hz, 1H), 3.86 (dt, J = 4.8, 7.1 Hz, 1H), 3.67 (s, 3H), 3.23 (dt, J = 4.8, 8.7 Hz, 1H), 2.54 (dd, J =
4.8, 16.1 Hz, 1H), 2.35 (dd, J = 8.7, 16.1 Hz, 1H), 2.08 (dt, J = 7.1, 13.0 Hz, 1H), 1.92 (ddd, J = 4.8, 8.7,
13.0 Hz, 1H), 1.21 (t, J = 7.1 Hz, 3H), 0.82 (s, 9H), 0.01 (s, 6H). Further elution with the same solvent
system afforded the amine (26) (257 mg, 51%) as a colorless oil; 1H NMR (270 MHz, CDCl3): δ 4.27 (dt,
J = 2.3, 4.3 Hz, 1H), 4.07 (q, J = 7.2 Hz, 2H), 3.95 (t, J = 7.9 Hz, 1H), 3.66 (s, 3H), 3.51 (dt, J = 4.3, 7.1
Hz, 1H), 2.48 (d, J = 7.1 Hz, 1H), 2.03 (ddd, J = 2.3, 7.9, 11.0 Hz, 1H), 1.96 (ddd, J = 4.3, 7.9, 11.0 Hz,
1H), 1.19 (t, J = 7.2 Hz, 3H), 0.82 (s, 9H), 0.01 (s, 6H).
Methyl (4R,5S)-5-ethoxycarbonylmethyl-4-hydroxy-L-prolinate (27): To a stirred solution of 25 (300
mg, 0.67 mmol) in THF (9.9 mL) was added TBAF (1.0 M in THF, 0.67 mL, 0.67 mmol) at 0 °C, and the
mixture was stirred for 1.5 h at rt. After dilution with AcOEt and H2O, the mixture was extracted with
AcOEt. The extract was washed with brine, and dried over Na2SO4. Evaporation of the solvent gave a
residue, which was purified by column chromatography on silica gel. Elution with AcOEt:hexane (1:1)
afforded the alcohol (27) (199 mg, 89%) as a colorless solid; 1H NMR (270 MHz, CDCl3): δ 4.17 (q, J =
7.2 Hz, 2H), 3.94−4.08 (m, 2H), 3.73 (s, 3H), 3.25-3.34 (m 1H), 2.09-2.31 (m, 2H), 1.28 (t, J = 7.1 Hz,
1H); IR (thin film): 3500, 2960, 2360, 2340, 1730, 1190, 1020 cm-1; EIMS (m/z): 231 (M+); HRMS calcd
for C10H17NO5 231.1106, found 231.1123.
Methyl (3aR,5S,6aR)-2-oxohexahydrofuro[3,2-b]pyrrole-5-carboxylate (28): Treatment of the amine
(26) (50 mg, 0.14 mmol) in THF (2.1 mL) with TBAF (1.0 M in THF, 0.14 mL, 0.14 mmol), followed by
purification by column chromatography on silica gel using AcOEt:hexane (9:1), by the same procedure as
1
described above provided the lactone (28) (16.6 mg, 68%) as a colorless solid; H NMR (270 MHz,

HETEROCYCLES, Vol. 67, No. 1, 2006
201
CDCl3): δ 4.90-5.04 (m, 1H), 4.00-4.16 (m, 1H), 3.84-3.96 (m, 1H), 3.68 (s, 3H), 2.70 (dd, J = 6.9, 18.1
Hz, 1H), 2.36-2.57 (m, 2H), 1.91-2.12 (m, 1H); IR (thin film): 2930, 2360, 2340, 1770, 1735, 1635, 1180,
670 cm-1; EIMS (m/z): 185 (M+); HRMS calcd for C8H11NO4 185.0688, found 185.0670.
Methyl
(4R,5S)-1-tert-butoxycarbonyl-4-tert-butyldimethylsilyloxy-5-[(N-methoxy-N-methyl-
(29) and methyl (4R,5R)-1-tert-butoxycarbonyl-4-tert-
carbonyl)methyl]-L-prolinate
butyldimethylsilyloxy-5-[(N-methoxy-N-methylcarbonyl)methyl]-L-prolinate (30): The reduction of
the amide (21) (200 mg, 0.54 mmol) in THF (4.3 mL) with LiBEt3H (1.0 M in THF, 0.64 mL, 0.64 mmol)
was carried out by the same procedure as described for the preparation of 5 to give the aminal (22), which,
without purification, was dissolved in THF (2.1 mL). This solution was added to a solution of the Wittig
reagent [prepared from NaH (65-75% in oil, 31 mg, 0.64 mmol) and diethyl (N-methoxy-N-
methylcarbamoylmethyl)phosphonate (0.13 mL, 0.64 mmol)] in THF (1.4 mL). After the similar work-up
and purification as described for the preparation of 8, the amide (29) (13.4 mg, 5.5%) was obtained as the
first eluent; [α]D -20.1° (c 0.5, CHCl3); 1H NMR (270 MHz, CDCl3): δ 4.21-4.49 (m, 2H), 4.04-4.20 (m,
1H), 3.71 (and rotamer at 3.68) (s, 3H), 3.70 (and rotamer at 3.73) (s, 3H), 3.17 (s, 3H), 2.85-3.12 (m,
1H), 2.85-3.00 (m, 1H), 1.80-2.20 (m, 2H), 1.36 (and rotamer at 1.39) (s, 9H), 0.84 (s, 9H), 0.05 (s, 3H),
0.01 (s, 3H); IR (thin film): 2960, 2930, 2860, 1760, 1700, 1670, 1390, 1260, 1090, 940, 840, 780 cm-1;
CIMS (m/z): 461 (M++1); HRMS calcd for C21H41N2O7Si (M++1) 461.2683, found 461.2696. Further
elution with the same solvent system afforded the amide (30) (146 mg, 60%); [α]D -32.2° (c 1.05,
CHCl3); 1H NMR (270 MHz, CDCl3): δ 4.44-4.57 (m, 2H), 4.18-4.25 (m, 1H), 3.66 (and rotamer at 3.67)
(s, 3H), 3.62 (s, 3H), 3.07 (and rotamer at 3.09) (s, 3H), 2.41-2.86 (m, 2H), 1.90-2.21 (m, 2H), 1.32 (and
rotamer at 1.38) (s, 9H), 0.80 (and rotamer at 0.79) (s, 9H), 0.01 (s, 3H), -0.02 (s, 3H); CIMS (m/z): 461
(M++1); HRMS calcd for C21H41N2O7Si (M++1) 461.2683, found 461.2689.
Methyl (4R,5S)-5-allyl-1-tert-butoxycarbonyl-4-tert-butyldimethylsilyloxy-L-prolinate (33): To a
stirred solution of the amide (29) (200 mg, 0.43 mmol) in THF (18 mL) was added DIBAL (0.95 M in
hexane, 0.92 mL, 0.87 mmol) at -78 °C, and the mixture was stirred for 30 min at the same temperature.
After treatment with saturated NH4Cl solution, the mixture was filtered through Celite pad to remove
insoluble materials. The filtrate was extracted with AcOEt. The extract was dried over Na2SO4.
Evaporation of the solvent gave a crude aldehyde (31), which, without further purification, was used in
the next reaction. A solution of the aldehyde in THF (3.5 mL) was added to the Wittig reagent [prepared
from methyltriphenylphosphonium bromide (250 mg, 0.70 mmol) and n-BuLi (1.58 M in hexane, 0.36
mL, 0.56 mmol) in THF (7 mL)] at 0 °C, and the resulting mixture was gradually warmed up to rt and
stirred for overnight at the same temperature. The mixture was treated with saturated NH4Cl solution, and
extracted with AcOEt. The extract was dried over Na2SO4. Evaporation of the solvent gave a residue,
which was purified by column chromatography on silica gel using AcOEt:hexane (1:6) as an eluent to
1
give the allyl derivative (33) (43.6 mg, 25%) as a colorless oil; [α]D -31.8° (c 0.20, CHCl3); H NMR
(270 MHz, CDCl3): δ 5.71-5.90 (m, 1H), 4.98-5.10 (m, 2H), 4.25-4.45 (m, 1H), 4.04-4.13 (m, 1H), 3.69
(and rotamer at 3.70) (s, 3H), 3.57-3.82 (m, 1H), 2.35-2.67 (m, 1H), 1.92-2.15 (m, 3H), 1.37 (and rotamer
at 1.42) (s, 9H), 0.81 (s, 9H), 0.00 (br s, 6H); IR (thin film): 2960, 2930, 2360, 1760, 1700, 1640, 1390,
1370, 1260, 840 cm-1; CIMS (m/z): 400 (M++1); HRMS calcd for C20H38NO5Si (M++1) 400.2519, found
400.2529.

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HETEROCYCLES, Vol. 67, No. 1, 2006
Methyl (4R,5S)-5-allyl-4-tert-butyldimethylsilyloxy-L-prolinate (35): To a stirred suspension of ZnBr2
(49 mg, 0.22 mmol) in CH2Cl2 (0.36 mL) was added a solution of the allyl derivative (33) (43.6 mg, 0.11
mmol) in CH2Cl2 (0.73 mL), and the resulting mixture was stirred for overnight at rt. After removal of
insoluble materials by filtration through Celite pad, the filtrate was treated with saturated NaHCO3
solution, and extracted with CH2Cl2. The extract was washed with brine, and dried over Na2SO4.
1
Evaporation of the solvent gave a crude α-amino ester (35) as a pale yellow oil; H NMR (500 MHz,
CDCl3): δ 5.79-5.87 (m, 1H), 5.05-5.17 (m, 2H), 3.96 (t, J = 8.0 Hz, 1H), 3.93 (dt, J = 4.8, 7.5 Hz, 1H),
3.73 (s, 3H), 2.98 (dt, J = 5.2, 7.5 Hz, 1H), 2.10-2.18 (m, 1H), 1.99-2.40 (m, 4H), 0.89 (s, 9H), 0.05 (s,
6H); IR (thin film): 2960, 2930, 2860, 1740, 1640, 1440, 1260, 1210, 1100, 840, 775 cm-1; CIMS (m/z):
300 (M++1); HRMS calcd for C15H30NO3Si (M++1) 300.1995, found 300.2001.
Methyl
(4R,5R)-5-allyl-1-tert-butoxycarbonyl-4-tert-butyldimethylsilyloxy-L-prolinate
(34):
Reduction of the amide (30) (1.50 g, 3.26 mmol) with DIBAL (0.95 M in hexane, 10.4 mL, 9.78 mmol)
was carried out by the same procedure as described for the preparation of 31 to give the aldehyde (32),
which, without further purification, was subjected to the Wittig reaction using methyltriphenyl-
phosphonium bromide (1.75 g, 4.89 mmol) and n-BuLi (1.6 M in hexane, 3.06 mL, 4.89 mmol) to
provide the allyl compound (34) (778 mg, 60%) as a colorless oil, after purification by column
1
chromatography on silica gel using AcOEt:hexane (1:6) as an eluent; [α]D -20.5° (c 1.01, CHCl3); H
NMR (270 MHz, CDCl3): δ 5.71-5.95 (m, 1H), 4.88-5.07 (m, 2H), 4.37-4.52 (m, 1H), 4.10-4.23 (m, 1H),
4.00-4.09 (and rotamer at 3.89-3.99) (m, 1H), 3.68 (and rotamer at 3.69) (s, 3H), 2.37-2.60 (m, 1H),
1.86-2.34 (m, 3H), 1.35 (and rotamer at 1.43) (s, 9H), 0.86 (br s, 9H), 0.03 (br s, 9H); IR (thin film): 2960,
2930, 1750, 1704, 1390, 880, 840, 780 cm-1; CIMS (m/z): 400 (M++1); HRMS calcd for C20H38NO5Si
(M++1) 400.2519, found 400.2547.
Methyl (4R,5R)-5-allyl-4-tert-butyldimethylsilyloxy-L-prolinate (36): Selective deprotection of the
N-Boc group of 34 (300 mg, 0.75 mmol) was carried out by the same procedure as for the preparation of
1
35 using ZnBr2 (338 mg, 1.50 mmol) to give a crude α-amino ester (36) as a pale yellow oil; H NMR
(500 MHz, CDCl3, assigned by 1H-1H correlation experiments): δ 5.76-5.86 (m, 1H, =CH), 5.00-5.11 (m,
2H, =CH2), 4.18-4.23 (m, 1H, 4-H), 4.00 (br t, J = 4.3 Hz, 1H, 2-H), 3.70 (s, 3H, OCH3), 3.11 (dt, J = 3.4,
7.0 Hz, 1H, 5-H), 2.01 (ddd, J = 4.3, 8.3, 13.5 Hz, 1H, 3-H), 1.94 (br s, 1H), 2.19-2.32 (m, 2H, =C-CH2),
2.11 (ddd, J = 1.9, 8.3, 13.5 Hz, 1H, 3-H), 0.88 (s, 9H, t-Bu), 0.06 (s, 3H, SiCH3), 0.05 (s, 3H, SiCH3);
13C NMR (125 MHz, CDCl3, assigned by 1H-13C correlation experiments): δ -4.8 (SiCH3), -4.4 (SiCH3),
18.0 (SiCMe3), 25.8 (3C, t-Bu), 34.1 (=C-CH2), 39.8 (C-3), 52.1 (OCH3), 57.6 (C-2), 63.4 (C-5), 73.3
(C-4), 116.4 (=CH2), 136.0 (=C), 175.8 (C=O); IR (thin film): 3350, 2955, 2930, 2860, 1740, 1255, 835,
775 cm-1; CIMS (m/z): 300 (M++1); HRMS calcd for C15H30NO3Si (M++1) 300.1995, found 300.2006.
This compound was used without further purification in the next reaction.
(5R,6R)-5-tert-Butyldimethylsilyloxy-6-(prop-2-en-1-yl)piperidin-2-one (37): Reductive deamination
of the α-amino ester (36) obtained above was carried out by the same procedure as described for the
preparation of 13 using SmI2 (0.2 M in THF, 10.8 mL, 2.15 mmol) to furnish the δ-lactam (37) (145 mg,
71%) as a colorless solid; mp 66-67 °C (lit.,4m mp 67-68 °C); [α]D +4.6° (c 0.20, CHCl3) {lit.,4m [α]D -4.5°
(c 1.05, CHCl3)}; 1H NMR (270 MHz, CDCl3): δ 5.76 (br s, 1H), 5.59-5.74 (m, 1H), 5.08-5.20 (m, 2H),
3.90-3.99 (m, 1H), 3.31 (ddd, J = 3.1, 4.1, 9.2 Hz, 1H), 2.51 (ddd, J = 6.2, 12.0, 18.3 Hz, 1H), 2.24-2.37

HETEROCYCLES, Vol. 67, No. 1, 2006
203
(m, 2H), 2.07-2.23 (m, 1H), 1.71-1.85 (m, 1H), 1.87-1.99 (m, 1H), 0.85 (s, 9H), 0.04 (s, 3H), 0.05 (s,
13
3H); C NMR (67.5 MHz, CDCl3): δ -5.1, -4.5, 17.9, 25.6, 26.2, 27.9, 36.7, 56.3, 65.7, 119.2, 133.5,
171.4; IR (thin film): 3240, 2960, 2930, 2860, 1670, 1400, 1330, 1255, 835, 775 cm-1; CIMS (m/z): 270
(M++1); HRMS calcd for C14H28NO2Si (M++1) 270.1889, found 270.1881. The spectroscopic data were
identical with those reported in the literature except for the sign of optical rotation.
ACKNOWLEDGMENT
This work was supported by a Grant-in-Aid from the Ministry of Education, Culture, Sports, Science and
Technology of Japan.
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