Efficient stereospecific synthesis of (S,S)-3-methoxy-4-methylaminopyrrolidine

Article abstract of DOI:10.1016/S0957-4166(01)00302-0

Efficient stereospecific synthesis of (S,S)-3-methoxy-4-methylaminopyrrolidine, an important intermediate for a novel quinolone antitumor agent AG-7352 is presented. Starting from either D- or L-tartaric acid, a stereospecific synthesis of the chiral pyrrolidine was achieved via two S_N2 displacement reactions. From the results of this synthetic study, the absolute structure of AG-7352 was chemically determined.

Full text of DOI:10.1016/S0957-4166(01)00302-0

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 12 (2001) 1793–1799
Efficient stereospecific synthesis of
(S,S)-3-methoxy-4-methylaminopyrrolidine
Yasunori Tsuzuki,* Katsumi Chiba and Katsuhiko Hino
Discovery Research Laboratories, Dainippon Pharmaceutical Co. Ltd., Enoki 33-94, Suita, Osaka 564-0053, Japan
Received 12 June 2001; accepted 27 June 2001
Abstract—Efficient stereospecific synthesis of (S,S)-3-methoxy-4-methylaminopyrrolidine, an important intermediate for a novel
quinolone antitumor agent AG-7352 is presented. Starting from either D- or L-tartaric acid, a stereospecific synthesis of the chiral
pyrrolidine was achieved via two SN2 displacement reactions. From the results of this synthetic study, the absolute structure of
AG-7352 was chemically determined. © 2001 Elsevier Science Ltd. All rights reserved.
1. Introduction
We needed to prepare the (+)-enantiomer of 3-
methoxy-4-methylaminopyrrolidine 2 for a synthesis of
(+)-1. While a synthesis of ( )-2 is known,4 a synthesis
of optically active 2 has not been reported to date. Our
original synthesis of optically active 2 was carried out
from 3-pyrroline through an optically active intermedi-
ate obtained by optical resolution,2b and the absolute
configuration of (+)-2 could not be confirmed by this
method. Therefore, we developed a new stereospecific
synthesis of the chiral pyrrolidine to determine its abso-
lute configuration without optical resolution of the
racemate. Herein, we describe that an efficient
stereospecific synthesis of (+)-enantiomer 2 could be
Chiral, non-racemic pyrrolidines are common structural
subunits found in many natural and unnatural products
with interesting and important biological activity.1 One
such compound is AG-7352 (+)-1, which is a novel
anti-tumor agent created at our laboratories and is now
under development. It shows anti-tumor activities equal
or superior to those of cisplatin and etoposide against
human breast, ovarian and colon cancers implanted in
mice.2 It has recently been reported that some
quinolone-related compounds show anti-tumor activity
with inhibition of eukaryotic topoisomerase II.3 While
those reported compounds have in common
a
achieved from commercially available
acid via two SN2 displacement reactions. Furthermore,
starting from -(R,R)-tartaric acid, another stereospe-
D-(S,S)-tartaric
quinolone structure as basic frame, the basic structure
of (+)-1 is 4-oxo-1,8-naphthyridine-3-carboxylic acid.
Thus, (+)-1 is structurally a new type of antitumor
agent.
L
cific synthesis of the same chiral pyrrolidine could be
also achieved. The result allowed us to determine the
absolute structure of (+)-2 as (3S,4S) and the absolute
structure of (+)-1 was deduced as (3%S,4%S).
In addition to the naphthyridine ring, (+)-1 has a
3-methoxy-4-methylaminopyrrolidinyl group at C(7)
(see Fig. 1).
2. Results and discussion
O
Me
NH
CO2H
The synthesis of (+)-2 requires the stereospecific con-
struction of two stereogenic centers on the pyrrolidine
ring. The retrosynthetic analysis outlined in Scheme 1
suggests the use of tartaric acid, an extremely useful
and versatile chiral building block, as the starting mate-
rial. The efficient differentiation of the two adjacent
hydroxyl groups could be attained by this synthetic
route with tartaric acid. Starting from tartaric acid, the
route includes a key intermediate ((R,R)-3 or (S,S)-3)
which has a hydroxyl function protected by a bulky
MeO
Me
HN
N
N
N
N
H
N
S
MeO
2
AG-7352 ((+)-1)
Figure 1.
* Corresponding author. Tel.: +6-6337-5900; fax: +6-6338-7656;
e-mail: yasunori-tuduki@dainippon.co.jp
0957-4166/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(01)00302-0

1794
Y. Tsuzuki et al. / Tetrahedron: Asymmetry 12 (2001) 1793–1799
R-O
OH
HO
OH
Me
NH
HO2C CO2H
D-Tartaric Acid
N
MeO
Boc
(R,R)-3
two SN2
reactions
N
H
R-O
HO
OH
OH
(S,S)-2
HO2C CO2H
L-Tartaric Acid
N
Boc
(S,S)-3
R: protecting group
Scheme 1.
tert-butyldimethylsilyl residue. By this simple protec-
tion, the two functional groups on the pyrrolidine ring
could be clearly distinguished. The intermediate ((R,R)-
reprotected with di-tert-butyl dicarbonate (Boc2O) to
give compound (R,R)-3a in good yield. The alcohol
(R,R)-3a was converted into the corresponding mesyl-
ate, and SN2 displacement of the mesylate by azide
anion (NaN3) in DMF introduced the nitrogen func-
tion, thus the cis-azide 6 was obtained in 71% yield
with complete inversion of configuration. The stereo-
chemistry of azide-bearing carbon in 6 was confirmed
3) from -tartaric acid would be converted into (S,S)-2
D
via two SN2 displacement reactions with inversion of
configuration. (S,S)-2 could also be synthesized via two
SN2 displacement reactions through the pyrrolidine
derivative (S,S)-3 from L-tartaric acid. Another enan-
1
tiomer (R,R)-2 could be synthesized by the same strat-
by NOESY experiments in H NMR. After catalytic
egy with opposite starting materials.
hydrogenation of the azide group over Pd–C, followed
by treatment with Boc2O, the silyl group was removed
by treatment with tetrabutylammonium fluoride
(TBAF) to give the cis-alcohol 7 in 71% yield. The
alcohol 7 was converted into mesylate, followed by
treatment with AcOK and successive basic treatment
with K2CO3, giving the trans-alcohol 8 in 76% yield
with another complete inversion of configuration. Thus,
compound 8, possessing the required stereochemistry,
was obtained by one inversion of each hydroxyl group
on the pyrrolidine ring of (S,S)-4. Compound 8 was
smoothly methylated with NaH and MeI in DMF to
give the N,O-dimethyl analog in quantitative yield.
Removal of both Boc groups from the N,O-dimethyl
compound with p-toluenesulfonic acid (TsOH) in i-
PrOH completed the synthesis of one enantiomer (S,S)-
2·2TsOH in 81% yield. Spectroscopic data and the
Our synthesis started with the monoprotection of the
known tartarimide (S,S)-45 which was readily prepared
from commercially available D-tartaric acid (Scheme 2).
Any attempt to monoprotect the tartarimide (S,S)-4
with methyl, acetyl or benzyl group resulted in failure.
On the other hand, the protection of (S,S)-4 with a
bulky silyl group successfully afforded a monoprotected
compound. Thus, (S,S)-4 was treated with 1.0 equiv. of
tert-butyldimethylsilyl chloride (TBSCl) and 2.1 equiv.
of imidazole in DMF at 0°C to give the monosilyl ether
in quantitative yield. The imide moiety of the monosilyl
ether was reduced by borane-tetrahydrofuran complex
(BH3·THF) to give the pyrrolidine derivative (R,R)-5 in
68% yield. After removal of benzyl group of compound
(R,R)-5, the resulting secondary amine was immediately
D-Tartaric Acid
(93%)
TBSO
OH
HO
O
OH
O
TBSO
N3
TBSO
OH
1) H2, Pd-C
2) Boc2O
1) MsCl
2) NaN3
1) TBSCl, Imidazole
2) BH3•THF
(68%)
N
N
N
N
Boc
Boc
CH2Ph
CH2Ph
(R,R)-5
(96%)
(71%)
6
(R,R)-3a
(S,S)-4
H
NBoc
Me
NH
H
NBoc
HO
MeO
HO
1) MsCl
2) AcOK
1) H2, Pd-C
2) Boc2O
1) NaH, MeI
2) TsOH
N
N
H
N
2TsOH
3) TBAF
3) K2CO3
Boc
Boc
(71%)
(76%)
(81%)
(S,S)-2
8
7
Scheme 2.

Y. Tsuzuki et al. / Tetrahedron: Asymmetry 12 (2001) 1793–1799
1795
specific rotation of this enantiomer (S,S)-2·2TsOH
{[h]2D9=+10.4 (c 1.00, MeOH)} were in good agreement
with the values of our originally synthesized (+)-enan-
tiomer 2·2TsOH {[h]2D9=+10.5 (c 1.00, MeOH)}. Since
easily converted to the monomethyl ether 11 in good
yield by methylation and successive removal of silyl
group. The alcohol 11 was converted to the desired
cis-acetate 12 in 53% yield by mesylation and SN2
displacement of the mesylate. The stereochemistry of
acetoxy group in 12 was also confirmed by NOE in the
the desired (S,S)-2 was obtained from
D-(S,S)-tartaric
acid of known configuration in 19% overall yield by the
stereospecific and efficient way, the absolute configura-
tion of AG-7352 was deduced as (3%S,4%S). Also, utiliz-
ing this methodology, the opposite enantiomer (R,R)-2)
1
nuclear of H NMR spectra. Compound 12 was treated
with K2CO3, and the given alcohol was converted to
the trans-azide 13 in 74% yield by mesylation and
displacement with NaN3. Thus, compound 13, possess-
ing the required stereochemistry, was successfully
obtained by two inversions of either hydroxyl group on
pyrrolidine ring of (R,R)-4. After catalytic hydrogena-
tion of the azide group over Pd–C, the resulting amine
was protected with Boc2O to give the compound 14 in
97% yield. Compound 14 was methylated with NaH
and MeI in DMF, followed by removal of both Boc
groups with TsOH to give the desired (S,S)-2·2TsOH in
82% yield. The chiral pyrrolidine (S,S)-2 was obtained
could be obtained conveniently from
L-tartaric acid.
Furthermore, starting from -tartaric acid, a stereospe-
L
cific synthesis of (S,S)-2 was also achieved via two SN2
displacement reactions (Scheme 3). By the similar
method for the synthesis of (R,R)-3a, benzyl group of
the monoprotected intermediate (S,S)-5 obtained from
(R,R)-4 was removed by catalytic hydrogenation, fol-
lowed by treatment with Boc2O to give the correspond-
ing alcohol (S,S)-3a. The alcohol (S,S)-3a was
converted into mesylate, followed by treatment with
AcOLi to afford the cis-acetate 9. The stereochemistry
of 9 was confirmed by NOEs in the 1H NMR spectrum.
Compound 9, however, gave racemate ( )-cis-10 when
it was treated with alkaline such as K2CO3 and NH3.6
The deacetylated compound given under basic condi-
tions was presumably racemized since an oxygen ion
attacked the neighboring silicon. The formation of 10
inspired us to design a replacement of O-silyl group of
9 by O-methyl group. Thus, compound (S,S)-3a was
from
stereoselective way, while this method included addi-
tional one step to the above method from -tartaric
L-tartaric acid in 17% overall yield by the
D
acid. Spectroscopic data and the specific rotation of
(S,S)-2·2TsOH {[h]2D6=+10.3 (c 1.01, MeOH)} were in
good agreement with the values of our originally syn-
thesized (+)-enantiomer 2·2TsOH. As a result, the
stereospecific synthesis of the chiral pyrrolidine (S,S)-2
was achieved from both enantiomers of tartaric acid.
L-Tartaric Acid
(91%)
TBSO
OH
TBSO
OAc
HO
O
OH
O
TBSO
OH
1) H2, Pd-C
2) Boc2O
(98%)
1) TBSCl, Imidazole
2) BH3•THF
(66%)
1) MsCl
2) AcOLi
(38%)
N
N
N
N
Boc
Boc
(S,S)-3a
CH2Ph
CH2Ph
(S,S)-5
9
(R,R)-4
TBSO
K2CO3 or NH3
OH
N
Boc
( )-cis-10
±
MeO
N3
HO
MeO
OMe
1) MsCl
OAc
1) K2CO3
2) MsCl
1) NaH, MeI
(S,S)-3a
N
N
N
2) TBAF
2) AcOLi
3) NaN3
Boc
Boc
Boc
(53%)
(74%)
(94%)
11
13
12
H
NBoc
Me
NH
MeO
MeO
1) NaH, MeI
1) H2, Pd-C
N
N
H
(S,S)-2
2) TsOH
2TsOH
2) Boc2O
Boc
(82%)
(97%)
14
Scheme 3.

1796
Y. Tsuzuki et al. / Tetrahedron: Asymmetry 12 (2001) 1793–1799
3. Conclusion
Hz), 2.72 (dd, 1H, J=9.9, 1.8 Hz), 3.20 (dd, 1H,
J=9.9, 6.4 Hz), 3.61 (d, 1H, J=13.0 Hz), 3.66 (d, 1H,
J=13.0 Hz), 3.92–3.98 (m, 1H), 4.10–4.15 (m, 1H),
7.24–7.35 (m, 5H); MS m/z 308 (M++1); IR (KBr):
3350 cm−1. Anal. calcd for C17H29NO2Si: C, 66.40; H,
9.51; N, 4.55. Found: C, 66.20; H, 9.46; N, 4.48%.
In summary, a concise synthesis of (S,S)-2 was
achieved through a simple and efficient reaction
sequence with a stereospecific manner, starting from
D-
or -tartaric acid. Based on the result, the absolute
L
configuration of (+)-2 was determined as (3S,4S) and
AG-7352 was found to have (3%S,4%S) absolute configu-
ration. In addition, this approach could be readily
applicable to the general synthesis of optically active
3,4-disubstituted pyrrolidine derivatives. A large scale
synthetic method for (S,S)-2 will be reported in a
future.
4.3. (3R,4R)-1-tert-Butoxycarbonyl-3-(tert-butyl-
dimethylsilyl)oxy-4-hydroxypyrrolidine (R,R)-3a
A solution of (R,R)-5 (13.9 g, 45.3 mmol) in EtOH (85
mL) was hydrogenated over 5% Pd–C (1.39 g) at 40°C
for 2 h. The mixture was filtered and EtOH (120 mL)
was added to the filtrate. Then Boc2O (10.4 g, 47.5
mmol) was added to the mixture under ice cooling. The
reaction mixture was stirred at rt for 3 h, and then
concentrated in vacuo. The residue was chro-
matographed on silica gel with CHCl3–MeOH (100:1)
to give (R,R)-3a as a colorless oil (13.8 g, 96%): [h]2D6=
4. Experimental
4.1. General
1
All melting points were determined on a Yanagimoto
micromelting point apparatus and are uncorrected.
Infrared (IR) spectra were recorded on a Perkin–Elmer
+16.1 (c 1.06, MeOH); H NMR (CDCl3): l 0.08 (s,
6H), 0.87 (s, 9H), 1.46 (s, 9H), 1.84 (br s, 1H), 3.18–
3.38 (m, 2H), 3.51–3.66 (m, 2H), 4.03–4.11 (m, 2H); MS
m/z 318 (M++1); IR (NaCl): 3410, 1675 cm−1. Anal.
calcd for C15H31NO4Si·0.25H2O: C, 55.95; H, 9.86; N,
4.35. Found: C, 56.11; H, 9.82; N, 4.33%.
1
1600 Series FT-IR spectrophotometer. H NMR spec-
tra were taken at 300 MHz on a JOEL JNM-LA 300
spectrometer. Chemical shifts are expressed in ppm (l)
with tetramethylsilane as an internal standard. Mass
spectra (MS) were obtained on a Hitachi M-80B or
Hitachi M-1000 spectrometer. Optical rotations were
measured on a Jasco P-1020 digital polarimeter.
4.4. (3S,4R)-3-Azido-1-tert-butoxycarbonyl-4-(tert-
butyldimethylsilyl)oxypyrrolidine 6
A solution of methanesulfonyl chloride (5.90 g, 51.5
mmol) in CH2Cl2 (60 mL) was added to a mixture of
(R,R)-3a (13.6 g, 42.9 mmol) and triethylamine (6.07 g,
60.1 mmol) in CH2Cl2 (400 mL) over a period of 10
min under ice cooling. The reaction mixture was stirred
at rt for 1.5 h, taken up with water, and extracted with
CH2Cl2. The extract was washed with saturated NaCl,
dried over Na2SO4, and then concentrated in vacuo. A
mixture of the residual mesylate and sodium azide (5.58
g, 85.8 mmol) in DMF (100 mL) was heated at 120°C
for 8 h. The reaction mixture was poured into water
and the mixture was extracted with toluene. The extract
was washed with saturated NaCl, dried over Na2SO4,
and then concentrated in vacuo. The residue was chro-
matographed on silica gel with hexane–AcOEt (25:1) to
give 6 as a colorless oil (10.4 g, 71%): [h]2D6=−85.3 (c
4.2. (3R,4R)-1-Benzyl-3-(tert-butyldimethylsilyl)oxy-4-
hydroxypyrrolidine (R,R)-5
A solution of tert-butyldimethylsilyl chloride (20.7 g,
0.137 mol) in dry DMF (150 mL) was added to a
mixture of (3S,4S)-1-benzyl-2,5-pyrrolidinedione (S,S)-
45 (30.0 g, 0.136 mol) and imidazole (19.4 g, 0.285 mol)
in dry DMF (400 mL) over a period of 30 min at 0°C.
The reaction mixture was stirred at rt for 24 h, concen-
trated in vacuo, and AcOEt was added. The precipitate
that formed was filtered off and the filtrate was succes-
sively washed with saturated NH4Cl and saturated
NaCl, dried over Na2SO4, and then concentrated in
vacuo. The residue was triturated with i-Pr2O, and the
resultant precipitates were collected by filtration. The
given monosilyl compound was dissolved in dry THF
(400 mL), and then the solution was added into
borane–tetrahydrofuran complex (1 M solution in
THF, 500 mL, 0.50 mol) over a period of 1 h under ice
cooling. The mixture was stirred at rt for 2 h, and then
heated at 70°C for 2 h. The solvent was distilled off
under reduced pressure and EtOH (900 mL) was added
to the resulting residue. The mixture was heated under
reflux for 15 h and concentrated in vacuo to leave a
residue. The residue was dissolved in water, and the
mixture was extracted with CHCl3. The extract was
washed with saturated NaCl, dried over Na2SO4 and
concentrated in vacuo. The resulting residue was chro-
matographed on silica gel with CHCl3–MeOH (50:1) to
give (R,R)-5 as white crystals (28.1 g, 68%): mp 55–
1
1.02, MeOH); H NMR (CDCl3): l 0.10 (s, 3H), 0.12
(s, 3H), 0.88 (s, 9H), 1.46 (s, 9H), 3.21–3.52 (m, 3H),
3.55 (dd, 1H, J=11.0, 5.8 Hz), 3.74–3.79 (m, 1H), 4.38
(ddd, 1H, J=10.2, 6.0, 4.2 Hz); MS m/z 343 (M++1);
IR (NaCl): 2105, 1695 cm−1. Anal. calcd for
C15H30N4O3Si: C, 52.60; H, 8.83; N, 16.36. Found: C,
52.57; H, 8.89; N, 16.45%. The NOE observed from
C(3)H to C(4)H enabled structural assignment of 6.
4.5. (3S,4R)-1-tert-Butoxycarbonyl-3-tert-butoxycarbon-
ylamino-4-hydroxypyrrolidine 7
A solution of 6 (9.05 g, 26.4 mmol) in EtOH (90 mL)
was hydrogenated over 5% Pd–C (450 mg) at 20°C for
2 h. The mixture was filtered and EtOH (70 mL) was
added to the filtrate. Then Boc2O (6.05 g, 27.7 mmol)
was added to the mixture under ice cooling. The reac-
tion mixture was stirred at rt for 15 h, and then
1
56°C; [h]2D6=−33.8 (c 1.00, MeOH); H NMR (CDCl3):
l 0.05 (s, 3H), 0.07 (s, 3H), 0.88 (s, 9H), 1.80 (br s, 1H),
2.17 (dd, 1H, J=9.9, 4.6 Hz), 2.66 (dd, 1H, J=10.0, 4.8

Y. Tsuzuki et al. / Tetrahedron: Asymmetry 12 (2001) 1793–1799
1797
concentrated in vacuo. The residue was chro-
matographed on silica gel with CHCl3–MeOH (200:1).
The given tert-butylcarbonylamino compound was dis-
solved in THF (90 mL), and then the solution was
added into tetrabutylammonium fluoride (1 M solution
in THF, 36.1 mL, 36.1 mmol) under ice cooling. The
mixture was stirred at rt for 1 h, and then concentrated
in vacuo. The residue was poured into water and the
mixture was extracted with AcOEt. The extract was
washed with saturated NaCl, dried over Na2SO4, and
then concentrated in vacuo. The residue was chro-
matographed on silica gel with CHCl3–MeOH (200:1)
to give 7 as white crystals (5.66 g, 71%): mp 107–108°C;
added. The organic layer was separated, and the
aqueous layer was extracted with toluene. The com-
bined organic layer was washed with saturated NaCl,
dried over Na2SO4, and then concentrated in vacuo.
The residue was dissolved in i-PrOH (60 mL), and
p-toluenesulfonic acid (5.21 g, 27.4 mmol) was added.
The reaction mixture was heated at 65°C for 2 h, and
then cooled to 0°C. The resultant precipitates were
collected by filtration, washed with i-PrOH, and dried
to give (S,S)-2·2TsOH as white crystals (4.79 g, 81%):
1
mp 163–164°C; [h]2D9=+10.4 (c 1.00, MeOH); H NMR
(DMSO-d6): l 2.30 (s, 6H), 2.69 (s, 3H), 3.24–3.49 (m,
3H), 3.33 (s, 3H), 3.66 (dd, 1H, J=13.2, 7.5 Hz),
3.80–3.89 (m, 1H), 4.19–4.25 (m, 1H), 7.13 (d, 4H,
J=8.0 Hz), 7.49 (d, 4H, J=8.0 Hz), 9.02 (br s, 4H);
MS m/z 131 (M++1); IR (KBr): 3060, 1615, 1570 cm−1.
Anal. calcd for C6H14N2O·2C7H8O3S: C, 50.62; H, 6.37;
N, 5.90; S, 13.51. Found: C, 50.48; H, 6.44; N, 5.90; S,
13.51%.
1
[h]2D6=+3.5 (c 1.01, MeOH); H NMR (CDCl3): l 1.45
(s, 18H), 3.08–3.19 (m, 1H), 3.35–3.57 (m, 2H), 3.73
(dd, 1H, J=10.3, 7.7 Hz), 4.08–4.20 (m, 1H), 4.27–4.34
(m, 1H), 5.02 (br s, 2H); MS m/z 303 (M++1); IR
(KBr): 3450, 3350, 1685 cm−1. Anal. calcd for
C14H26N2O5·0.25H2O: C, 54.8; H, 8.70; N, 9.13. Found:
C, 55.04; H, 8.51; N, 9.00%.
4.8. (3S,4S)-1-Benzyl-3-(tert-butyldimethylsilyl)oxy-4-
hydroxypyrrolidine (S,S)-5
4.6. (3S,4S)-1-tert-Butoxycarbonyl-3-tert-butoxycarbon-
ylamino-4-hydroxypyrrolidine 8
Following the procedure described for (R,R)-5, com-
pound (R,R)-4 was converted to (S,S)-5 (95.0 g, 68%)
as white crystals: mp 55–56°C; [h]2D6=+33.9 (c 1.02,
MeOH). Anal. calcd for C17H29NO2Si: C, 66.40; H,
9.51; N, 4.55. Found: C, 66.11; H, 9.41; N, 4.54%.
A solution of methanesulfonyl chloride (2.46 g, 21.5
mmol) in CH2Cl2 (20 mL) was added into a mixture of
7 (5.40 g, 17.9 mmol) and triethylamine (2.54 g, 25.1
mmol) in CH2Cl2 (90 mL) over a period of 10 min
under ice cooling. The reaction mixture was stirred at rt
for 2 h, taken up with water, and extracted with
CH2Cl2. The extract was washed with saturated NaCl,
dried over Na2SO4, and then concentrated in vacuo. A
mixture of the residual mesylate and potassium acetate
(4.73 g, 48.2 mmol) in DMF (120 mL) was heated at
110°C for 2 h. The reaction mixture was poured into
water and extracted with toluene. The extract was
washed with saturated NaCl, dried over Na2SO4, and
then concentrated in vacuo. The residue was chro-
matographed on silica gel with CHCl3–MeOH (200:1).
The given acetoxy compound was dissolved in MeOH
(90 mL), and then K2CO3 (4.01 g, 29.0 mmol) was
added under ice cooling. The mixture was stirred at rt
for 4 h, poured into water and extracted with AcOEt.
The extract was washed with saturated NaCl, dried
over Na2SO4, and then concentrated in vacuo to give 8
as white crystals (4.10 g, 76%): mp 147–148°C; [h]2D4=
4.9. (3S,4S)-1-tert-Butoxycarbonyl-3-(tert-butyl-
dimethylsilyl)oxy-4-hydroxypyrrolidine (S,S)-3a
Following the procedure described for (R,R)-3a, com-
pound (S,S)-5 was converted to (S,S)-3a (95.0 g, 68%)
as a colorless oil: [h]D26=−16.2 (c 1.04, MeOH). Anal.
calcd for C15H31NO4Si·0.25H2O: C, 55.95; H, 9.86; N,
4.35. Found: C, 56.19; H, 9.78; N, 4.37%.
4.10. (3R,4S)-3-Acetoxy-1-tert-butoxycarbonyl-4-(tert-
butyldimethylsilyl)oxypyrrolidine 9
A solution of methanesulfonyl chloride (2.18 g, 19.0
mmol) in CH2Cl2 (40 mL) was added to a mixture of
(S,S)-3a (5.00 g, 15.8 mmol) and triethylamine (2.23 g,
22.1 mmol) in CH2Cl2 (75 mL) over a period of 10 min
under ice cooling. The reaction mixture was stirred at rt
for 1.5 h, taken up with water, and extracted with
CH2Cl2. The extract was washed with saturated NaCl,
dried over Na2SO4, and then concentrated in vacuo. A
mixture of the residual mesylate and lithium acetate
(3.13 g, 47.4 mmol) in DMF (80 mL) was heated at
150°C for 15 h. The reaction mixture was poured into
water and the mixture was extracted with toluene. The
extract was washed with saturated NaCl, dried over
Na2SO4, and then concentrated in vacuo. The residue
was chromatographed on silica gel with hexane–AcOEt
(15:1) to give 9 as a colorless oil (2.15 g, 38%): [h]2D6=
+18.2 (c 1.02, MeOH); 1H NMR (CDCl3): l 0.05 (s, 3H),
0.06 (s, 3H), 0.87 (s, 9H), 1.45 (s, 9H), 2.08 (s, 3H),
3.15–3.27 (m, 1H), 3.32–3.63 (m, 3H), 4.26–4.35 (m,
1H), 5.11–5.19 (m, 1H); MS m/z 360 (M++1); IR
(NaCl): 1747, 1700 cm−1. Anal. calcd for C17H33NO5Si:
C, 56.79; H, 9.25; N, 3.90. Found: C, 56.89; H, 9.20; N,
1
+1.50 (c 1.00, MeOH); H NMR (CDCl3): l 1.45 (s,
9H), 1.46 (s, 9H), 3.11–3.38 (m, 2H), 3.61–3.81 (m, 2H),
3.82–3.99 (m, 1H), 4.16–4.26 (m, 1H), 4.72 (br s, 2H);
MS m/z 303 (M++1); IR (KBr): 3470, 3300, 1670 cm−1.
Anal. calcd for C14H26N2O5: C, 55.61; H, 8.67; N, 9.26.
Found: C, 55.69; H, 8.62; N, 9.24%.
4.7. (3S,4S)-3-Methoxy-4-methylaminopyrrolidine di-p-
toluenesulfonic acid (S,S)-2·2TsOH
A solution of 8 (3.79 g, 12.5 mmol) in dry DMF (30
mL) was added to a suspension of NaH (1.25 g of 60%
oil suspension, 31.3 mmol, washed with dry hexane
before use) in a mixture of dry DMF (40 mL) and MeI
(7.10 g, 50.0 mmol) over a period of 10 min at 0°C. The
reaction mixture was stirred at rt for 2 h. After neutral-
ization with 2% AcOH under ice cooling, toluene was

1798
Y. Tsuzuki et al. / Tetrahedron: Asymmetry 12 (2001) 1793–1799
3.93%. The NOE observed from C(4)H to C(3)H
enabled structural assignment of 9.
calcd for C12H21NO5: C, 55.58; H, 8.16; N, 5.40.
Found: C, 55.22; H, 7.94; N, 5.31%. The NOE
observed from C(3)H to C(4)H enabled structural
assignment of 12.
4.11. ( )-cis-tert-Butoxycarbonyl-3-(tert-butyl-
dimethylsilyl)oxy-4-hydroxypyrrolidine ( )-cis-10
4.14. (3S,4S)-3-Azido-1-tert-butoxycarbonyl-4-
methoxypyrrolidine 13
A solution of compound 9 (1.60 g, 4.32 mmol) in
MeOH (30 mL), was treated with K2CO3 (678 mg, 4.91
mmol) with ice cooling. The mixture was stirred at rt
for 30 min, poured into water and extracted with
AcOEt. The extract was washed with saturated NaCl,
dried over Na2SO4, and then concentrated in vacuo.
The residue was chromatographed on silica gel with
hexane–AcOEt (5:1) to give ( )-cis-10 as a colorless oil
(1.37 g, 97%): [h]2D5=0 (c 0.52, MeOH); 1H NMR
(CDCl3): l 0.19 (s, 6H), 0.91 (s, 9H), 1.45 (s, 9H), 2.61
(br s, 1H), 3.15–3.24 (m, 1H), 3.29–3.54 (m, 2H),
3.56–3.64 (m, 1H), 4.04–4.11 (m, 1H), 4.18–4.25 (m,
1H); MS m/z 318 (M++1); IR (NaCl): 3445, 1700 cm−1.
( )-cis-10 was converted to ( )-2 (43% yield for seven
steps) as the racemate {[h]2D5=0 (c 0.20, MeOH)}.
Compound 12 (1.75 g, 6.76 mmol) was dissolved in
MeOH (35 mL), and then K2CO3 (1.03 g, 7.44 mmol)
was added under ice cooling. The mixture was stirred at
rt for 30 min, poured into water and extracted with
AcOEt. The extract was washed with saturated NaCl,
dried over Na2SO4, and then concentrated in vacuo.
The resulting residue and triethylamine (875 mg, 8.65
mmol) were dissolved in CH2Cl2 (30 mL), and then a
solution of methanesulfonyl chloride (850 mg, 7.42
mmol) in CH2Cl2 (15 mL) was added into the mixture
over a period of 10 min under ice cooling. The reaction
mixture was stirred at rt for 1.5 h, taken up with water,
and extracted with CHCl3. The extract was washed
with saturated NaCl, dried over Na2SO4, and then
concentrated in vacuo. A mixture of the residual mesyl-
ate and sodium azide (806 mg, 12.4 mmol) in DMF (25
mL) was heated at 110°C for 2 h. The reaction mixture
was poured into water and the mixture was extracted
with AcOEt. The extract was washed with saturated
NaCl, dried over Na2SO4, and then concentrated in
vacuo. The residue was chromatographed on silica gel
with hexane–AcOEt (10:1) to give 13 as a colorless oil
4.12. (3S,4S)-1-tert-Butoxycarbonyl-3-methoxy-4-
hydroxypyrrolidine 11
A solution of (S,S)-3a (3.00 g, 9.46 mmol) in dry THF
(25 mL) was added to a suspension of NaH (456 mg of
60% suspension in oil, 11.4 mmol, washed with dry
hexane before use) in a mixture of dry THF (25 mL)
and MeI (2.02 g, 14.2 mmol) over a period of 5 min
under ice cooling. The reaction mixture was stirred at rt
for 5 h. After neutralization with saturated NH4Cl
under ice cooling, toluene was added. The organic layer
was separated, and the aqueous layer was extracted
with toluene. The combined organic extract was washed
with saturated NaCl, dried over Na2SO4, and then
concentrated in vacuo. The given methoxy compound
was dissolved in THF (25 mL), and then the solution
was added into tetrabutylammonium fluoride (1 M
THF solution, 11.4 mL, 11.4 mmol) under ice cooling.
The mixture was stirred at rt for 2 h, and then concen-
trated in vacuo. The residue was poured into water and
the mixture was extracted with AcOEt. The extract was
washed with saturated NaCl, dried over Na2SO4, and
then concentrated in vacuo. The residue was chro-
matographed on silica gel with CHCl3–MeOH (100:1)
to give 11 as white crystals (1.93 g, 94%): mp 82–84°C;
1
(1.21 g, 74%): [h]2D5=+14.5 (c 1.01, MeOH); H NMR
(CDCl3): l 1.47 (s, 9H), 3.33–3.64 (m, 4H), 3.39 (s, 3H),
3.73–3.78 (m, 1H), 3.95–4.00 (m, 1H); MS m/z 243
(M++1); IR (NaCl): 2105, 1695 cm−1. Anal. calcd for
C10H18N4O3: C, 49.58; H, 7.49; N, 23.13. Found: C,
49.66; H, 7.54; N, 22.84%.
4.15. (3S,4S)-1-tert-Butoxycarbonyl-3-tert-butoxycar-
bonylamino-4-methoxypyrrolidine 14
A solution of 13 (1.04 g, 4.30 mmol) in EtOH (10 mL)
was hydrogenated over 5% Pd–C (100 mg) at 20°C for
2 h. The mixture was filtered and EtOH (20 mL) was
added to the filtrate. Then Boc2O (987 mg, 4.52 mmol)
was added to the mixture under ice cooling. The reac-
tion mixture was stirred at rt for 15 h, and then
concentrated in vacuo. The residue was chro-
matographed on silica gel with CHCl3 to give 14 as a
colorless oil (1.32 g, 97%): [h]2D5=−18.1 (c 1.08, MeOH);
1H NMR (CDCl3): l 1.45 (s, 18H), 3.20–3.55 (m, 3H),
3.41 (s, 3H), 3.59 (dd, 1H, J=11.7, 5.5 Hz), 3.71–3.80
(m, 1H), 4.05–4.13 (m, 1H), 4.56 (br s, 1H); MS m/z
317 (M++1); IR (NaCl): 3330, 1695 cm−1. Anal. calcd
for C15H28N2O5·0.35H2O: C, 55.83; H, 8.96; N, 8.68.
Found: C, 56.08; H, 8.79; N, 8.28%.
1
[h]2D5=−13.7 (c 1.05, MeOH); H NMR (CDCl3): l 1.46
(s, 9H), 2.25 (br s, 1H), 3.28–3.64 (m, 4H), 3.37 (s, 3H),
3.67–3.76 (m, 1H), 4.22–4.29 (m, 1H); MS m/z 218
(M++1); IR (KBr): 3412, 1670 cm−1. Anal. calcd for
C10H19NO4: C, 55.28; H, 8.81; N, 6.45. Found: C,
55.08; H, 8.61; N, 6.31%.
4.13. (3R,4S)-3-Acetoxy-1-tert-butoxycarbonyl-4-
methoxypyrrolidine 12
4.16. (3S,4S)-3-Methoxy-4-methylaminopyrrolidine di-
p-toluenesulfonic acid (S,S)-2·2TsOH
Following the procedure described for 9, compound 11
was converted to 12 (2.17 g, 53%) as a colorless oil:
1
[h]2D4=+8.1 (c 1.00, MeOH); H NMR (CDCl3): l 1.46
A solution of 14 (1.12 g, 3.54 mmol) in dry DMF (15
mL) was added into the suspension of NaH (177 mg of
60% suspension in oil, 4.43 mmol, washed with dry
hexane before use) in a mixture of dry DMF (20 mL)
(s, 9H), 2.13 (s, 3H), 3.25–3.70 (m, 4H), 3.39 (s, 3H),
3.91 (ddd, 1H, J=10.6, 6.6, 4.1 Hz), 5.24–5.36 (m, 1H);
MS m/z 260 (M++1); IR (NaCl): 1745, 1700 cm−1. Anal.

Y. Tsuzuki et al. / Tetrahedron: Asymmetry 12 (2001) 1793–1799
1799
and MeI (1.01 g, 7.08 mmol) over a period of 10 min at
0°C. The reaction mixture was stirred at rt for 2 h.
After neutralization with 2% AcOH under ice cooling,
toluene was added. The organic layer was separated,
and the aqueous layer was extracted with toluene. The
combined organic layer was washed with saturated
NaCl, dried over Na2SO4, and then concentrated in
vacuo. The residue was dissolved in i-PrOH (20 mL),
and p-toluenesulfonic acid (1.55 g, 8.14 mmol) was
added. The reaction mixture was heated at 65°C for 2
h, and then cooled to 0°C. The resultant precipitates
were collected by filtration, washed with i-PrOH, and
dried to give 1.37 g (82%) of (S,S)-2·2TsOH as white
crystals: mp 162–163°C; [h]2D6=+10.3 (c 1.01, MeOH).
Anal. calcd for C6H14N2O·2C7H8O3S: C, 50.62; H, 6.37;
N, 5.90; S, 13.51. Found: C, 50.49; H, 6.45; N, 5.81; S,
13.53%.
Brossi, A., Ed.; Academic Press: New York, 1986; Vol. 27,
Chapter 3; (c) Numata, A.; Ibuka, T. In The Alkaloids;
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2. (a) Tomita, K.; Tsuzuki, Y.; Shibamori, K.; Kashimoto,
S.; Chiba, K. 217th ACS National Meeting 1999, Abstract
249; (b) Chiba, K.; Tsuzuki, Y.; Tomita, K.; Mizuno, K.;
Sato, Y. 218th ACS National Meeting 1999, Abstract 127.
3. (a) Kohlbrenner, W. E.; Wideburg, N.; Weigl, D.; Saldi-
var, A.; Chu, D. T. W. Antimicrob Agents Chemother.
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Acknowledgements
We are grateful to Dr. T. Karasawa for his encourage-
ment throughout this work. Thanks are also due to
members of the Department of Physico Chemical Anal-
ysis of these laboratories for elemental analyses and
spectral measurements.
4. Peterson, U.; Schenke, T.; Krebs, A.; Grohe, K.;
Schriewer, M.; Haller, I.; Metzger, K. G.; Endermann, R.;
Zeiler, H. J. Jpn. Pat. Kokai 2-69474, 1990; Chem. Abstr.
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5. Nagel, U.; Kinzel, E.; Andrade, J.; Prescher, G. Chem.
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