Practical synthesis of (3S,4S)-3-methoxy-4-methylaminopyrrolidine

Article abstract of DOI:10.1016/S0957-4166(01)00530-4

Three synthetic methods for the preparation of (3S,4S)-3-methoxy-4-methylaminopyrrolidine, an important intermediate in the synthesis of the novel quinolone antitumur agent, AG-7352, have been developed. By one route, an efficient and large-scale preparation of the chiral pyrrolidine could be achieved through resolution of (±)-1-Boc-3-benzylamino-4-hydroxypyrrolidine, which is prepared from either 3-pyrroline or 1,4-dichloro-2-butene.

Full text of DOI:10.1016/S0957-4166(01)00530-4

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 12 (2001) 2989–2997
Practical synthesis of
(3S,4S)-3-methoxy-4-methylaminopyrrolidine
Yasunori Tsuzuki,* Katsumi Chiba, Kazuhiro Mizuno, Kyoji Tomita and Kenji Suzuki
Chemistry Research Laboratories, Dainippon Pharmaceutical Co., Ltd., Enoki 33-94, Suita, Osaka 564-0053, Japan
Received 24 October 2001; accepted 8 November 2001
Abstract—Three synthetic methods for the preparation of (3S,4S)-3-methoxy-4-methylaminopyrrolidine, an important intermedi-
ate in the synthesis of the novel quinolone antitumor agent, AG-7352, have been developed. By one route, an efficient and
large-scale preparation of the chiral pyrrolidine could be achieved through resolution of ( )-1-Boc-3-benzylamino-4-hydroxypyrroli-
dine, which is prepared from either 3-pyrroline or 1,4-dichloro-2-butene. © 2002 Published by Elsevier Science Ltd.
1. Introduction
the naphthyridine ring. Thus, it is very important to
establish a practical synthetic method for homochiral 2
because 1 is synthesized by the reaction of 2 with the
7-chloro-1,8-naphthyridine derivative. While a synthesis
of ( )-2 is known,4 no asymmetric synthesis of 2 has
been reported to date. We have previously reported the
stereospecific synthesis of 2 via two SN2 displacement
reactions, and the result allowed us to deduce the
absolute structure of diastereomerically pure 2 as
(3S,4S).5 Herein, we describe three methods for the
synthesis of the pyrrolidine (S,S)-2, including our origi-
nal synthesis. Using one route, (S,S)-2 was derived
successfully from 3-pyrroline or 1,4-dichloro-2-butene
through resolution of racemic 1-Boc-3-benzylamino-4-
hydroxypyrrolidine on a large scale. Furthermore, the
absolute configuration of this chiral pyrrolidine was
unambiguously confirmed as (3S,4S) by X-ray crystal-
lographic analysis.
Chiral, non-racemic pyrrolidines are common structural
subunits found in many natural and unnatural products
with interesting and important biological activities.1
One such compound is AG-7352 1, which is a novel
antitumor agent created at our laboratories and is now
under development. AG-7352 1 shows antitumor activi-
ties equal or superior to those of cisplatin and
etoposide against human breast, ovarian and colon
cancers implanted in nude mice.2 It has recently been
reported that some quinolone-related compounds show
antitumor activity with inhibition of eukaryotic
topoisomerase II.3 While those reported compounds
have in common a quinolone structure as their basic
framework, the basic structure of 1 is 4-oxo-1,8-naph-
thyridine-3-carboxylic acid. Thus, in terms of the chem-
ical structure, 1 is a new type of antitumor agent.
As shown in Fig. 1, AG-7352 1 has an optically active
3-methoxy-4-methylaminopyrrolidinyl group at C(7) of
2. Results and discussion
The key challenge of the synthesis is the effective gener-
ation of two stereogenic centers at positions 3 and 4 of
the pyrrolidine ring. Based on retrosynthetic analysis,
we designed three routes to (S,S)-2 (Routes A–C,
Scheme 1). Each route includes a key intermediate
( )-3, ( )-4 or ( )-5 which give (S,S)-2 via classical
resolution or separation of diastereoisomers. To pre-
pare these intermediates, 3-pyrroline 6 or 1,4-dichloro-
2-butene 7 are regarded as a common starting material,
of these, 7 is preferable since it is more easily available.
The synthesis of (S,S)-2 could be readily achieved in
Figure 1.
* Corresponding author. Tel.: +81-6-6337-5900; fax: +81-6-6338-7656;
e-mail: yasunori-tuduki@dainippon-pharm.co.jp
0957-4166/01/$ - see front matter © 2002 Published by Elsevier Science Ltd.
PII: S0957-4166(01)00530-4

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Y. Tsuzuki et al. / Tetrahedron: Asymmetry 12 (2002) 2989–2997
Scheme 1.
several steps from the resolved compounds (S,S)-3,
(S,S)-4 or (S,S)-5.
2.2. Route B
We examined more practical routes to (S,S)-2 than the
above method. ( )-trans-3-Hydroxy-4-methylaminopy-
rrolidine ( )-4 was obtained in three steps from 3-
pyrroline 6. Attempts to resolve compound ( )-4 with
various resolving agents were unsuccessful. We there-
fore tried to obtain (S,S)-4 by diastereomeric separa-
tion via N-acylation with an amino acid (Scheme 3).6
2.1. Route A
The first synthesis of (S,S)-2 was achieved by Route A
(Scheme 2). ( )-trans-3-Amino-1-Boc-4-methoxy pyrro-
lidine ( )-9 was readily prepared in five steps from
3-pyrroline 6 via azide compound ( )-8, but attempted
resolution of ( )-9 with various resolving agents was
not successful. On the other hand, after removal of the
Boc group from ( )-9, the resulting secondary amine
selectively reacted with benzyl chloride to give com-
pound ( )-3, and resolution of ( )-3 with (+)-tartaric
acid in MeOH–H2O afforded (S,S)-3 in 32% yield.
Compound (S,S)-3 was treated with Boc2O to give
compound 10 in 97% yield. Compound 10 was con-
verted to compound 11 in 90% yield by reduction of the
Boc group with LiAlH4 and successive treatment with
Boc2O. Debenzylation of 11 was effected by hydrogena-
tion in the presence of Pd–C then afforded the desired
(S,S)-2a in 95% yield. However, this route has several
drawbacks: it requires 13 steps and the use of NaN3
and LiAlH4, unsuitable materials for large-scale
synthesis.
The condensation of ( )-4 with N-Boc-
of 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide
L-Phe by means
hydrochloride (EDC) in CH2Cl2 gave a 1:1 mixture of
diastereomers (TLC: high Rf=0.37 and low Rf=0.21,
CHCl3:MeOH=50:1), which were easily separated by
column chromatography to obtain pure 12 with 99%
d.e. as the higher Rf component in 34% yield. Cleavage
of the amide of 12 with 20% NaOH in EtOH at 50°C
smoothly afforded (S,S)-4 in 93% yield and protection
of (S,S)-4 with Boc2O afforded 13 in 98% yield. Com-
pound 13 was methylated with NaH and MeI in DMF,
followed by removal of both Boc groups with p-toluene-
sulfonic acid (TsOH) in i-PrOH to give the desired
(S,S)-3-methoxy-4-methylaminopyrrolidine di-p-toluene-
sulfonate salt (S,S)-2b in 83% yield.7
Scheme 2.

Y. Tsuzuki et al. / Tetrahedron: Asymmetry 12 (2002) 2989–2997
2991
Scheme 3.
This method is better than the Route A because it
consists of less steps and does not require the use of
dangerous materials. Also, this approach could be read-
ily applicable to the general synthesis of optically active
3,4-disubstituted pyrrolidine derivatives. However, this
method does involve separation of the diastereoisomers
by column chromatography, and thus, it is unsuitable
for the large-scale preparation of (S,S)-2b.
in DMF to afford the N,O-dimethylated product.8
Removal of both Boc groups from the intermediate by
treatment with TsOH completed the synthesis of (S,S)-
2b (99.8% purity and 100% e.e.9) in 97% yield. Thus,
the desired (S,S)-2b was obtained from 6 via crystalline
compound ( )-5, (S,S)-5 and 14 without the need for
column chromatography.
In order to manufacture (S,S)-2, we needed to develop
an efficient process for the important intermediate 5,
avoiding the use of expensive 3-pyrroline 610 and haz-
ardous m-chloroperbenzoic acid (m-CPBA). We took
advantage of cis-1,4-dichloro-2-butene 7 as a commer-
cially available and inexpensive starting material. Com-
2.3. Route C
We examined another route to (S,S)-2 that did not
require chromatographic purifications. Replacement of
the N-methyl group of ( )-4 with an N-benzyl group
was first completed because the N-benzyl derivative
( )-5 was expected to give crystals of its salts in a
racemate resolution process. In fact, resolution of ( )-
pound
7 was treated with NaH and tert-butyl
carbamate,11 which was prepared from Boc2O and NH3
in 98% yield, in DMF at 50°C to generate 1-Boc-3-
pyrroline 15 in 60% yield. Reaction of 15 with N-bro-
mosuccinimide (NBS) in DMSO–H2O yielded
bromohydrin ( )-16. Under basic conditions, the bro-
mohydrin ( )-16 was converted to the epoxide, fol-
lowed by treatment with benzylamine to give the
desired intermediate ( )-5 in 59% yield. These two steps
could be carried out more conveniently in a one-pot
operation without isolation of the epoxide. Thus, the
trans-3-benzylamino-4-hydroxylpyrrolidine
( )-5
derived from 3-pyrroline 6 successfully afforded (S,S)-5
with high enantiomeric purity (100% e.e.) in 39% yield
on reaction with (+)-mandelic acid in CH3CN–H2O
(Scheme 4). Debenzylation of (S,S)-5 with Pd–C was
followed by treatment with Boc2O to give crystalline
compound 14 in 98% yield. Compound 14 was then
methylated with NaH (2.5 equiv.) and MeI (3.0 equiv.)
Scheme 4.

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Y. Tsuzuki et al. / Tetrahedron: Asymmetry 12 (2001) 2989–2997
Figure 2. ORTEP drawing of 2b.
intermediate ( )-5 was prepared from 1,4-dichloro-2-
butene 7 via 1-Boc-3-pyrroline 15 in four steps without
using the expensive starting material 6 and hazardous
peracid. The synthetic method for (S,S)-2 from 7 via
(S,S)-5 is much improved over the two former methods
and is highly suited to large-scale preparation.
tra were recorded at 200 MHz on a Varian Gemini-200
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 Jasco DIP-370 or P-1020 digital polarime-
ter. HPLC analyses were performed with Shimadzu
LC-6AD or LC-10AS.
The absolute configuration of (S,S)-2 was unambigu-
ously confirmed by X-ray crystallographic analysis. Fig.
2 shows the crystal structure of (S,S)-2b. As can be
seen from Fig. 2, the absolute configuration of this
chiral pyrrolidine is (3S,4S) and thus AG-7352 is found
to have (3%S,4%S) absolute configuration from this data.
4.2. Route A
4.2.1.( )-trans-3-Azido-1-tert-butoxycarbonyl-4-methoxy-
pyrrolidine (( )-8). Di-tert-butyl dicarbonate (314 g,
1.44 mol) was added dropwise to a solution of 3-pyrro-
line 6 (100 g, 0.940 mol, purity of 65%) in MeOH (400
mL) over a period of 30 min at 0°C. The reaction
mixture was then stirred at room temperature for 15 h.
After evaporation of the solvent, the residue was dis-
solved in CH2Cl2 (1.3 L). The mixture was cooled to
0°C and m-CPBA (278 g, 1.12 mol, purity of 70%) was
added over a period of 6 h. After stirring the mixture at
room temperature for 2 days, the precipitate was
filtered off and the filtrate was successively washed with
saturated NaHSO3, 5% aqueous K2CO3 and saturated
NaCl, dried over Na2SO4 and then concentrated in
vacuo. The resulting residue was chromatographed on
silica gel with hexane–AcOEt (10:1) to give the epoxide
(134 g). The epoxide was dissolved in 1,4-dioxane (1.25
L) and water (250 mL). Sodium azide (141 g, 2.17 mol)
was added at room temperature. After the reaction
mixture was stirred at 100°C for 15 h, water was added
at 0°C and the mixture was extracted with AcOEt. The
organic layer was washed with water, dried over
Na2SO4 and concentrated in vacuo. A solution of the
residue in dry THF (1 L) was added to a suspension of
NaH (60% dispersion in oil, 31.8 g, 0.796 mol, washed
with dry hexane before use) in dry THF (2 L). After
stirring at room temperature for 1 h, the mixture
3. Conclusions
In summary, three different synthetic methods for the
preparation of (S,S)-2 were achieved in excellent purity
through resolution or separation of diastereoisomers.
The second route is good to obtain gram quantities of
(S,S)-2 because of short steps and a convenient syn-
thetic method. The third route is the most attractive in
terms of practical, economical and large-scale process.
The process is free of chromatography and affords high
purity (99.8%, 100% e.e.). We have demonstrated the
efficient process to provide the key intermediate for a
novel quinolone antitumor agent, AG-7352.
4. Experimental
4.1. General
All melting points were determined on a Yanagimoto
micromelting point apparatus and are uncorrected.
Infrared (IR) spectra were recorded on a Perkin–Elmer
1
1600 Series FT-IR spectrophotometer. H NMR spec-

Y. Tsuzuki et al. / Tetrahedron: Asymmetry 12 (2001) 2989–2997
2993
was allowed to gradually warm to 50°C over 3 h. MeI
(118 g, 0.833 mol) was added to the mixture at 0°C
which was then stirred at room temperature for 15 h.
After evaporation of the solvent, AcOEt and water
were added to the residue. The organic layer was
washed with saturated NaCl, dried over Na2SO4 and
then concentrated in vacuo. The resulting residue was
chromatographed on silica gel with hexane–AcOEt
3·1.5(+)-tartaric acid as white crystals: mp 206–208°C
1
(dec.); [h]2D9 +33.0 (c 1.00, H2O); H NMR (DMSO-d6)
l 2.39 (dd, 1H, J=9.9, 3.5 Hz), 2.48–2.58 (m, 1H), 2.75
(dd, 1H, J=10.1, 6.6 Hz), 2.96 (dd, 1H, J=9.9, 6.4
Hz), 3.25 (s, 3H), 3.44–3.53 (m, 1H), 3.57 (d, 1H,
J=13.1 Hz), 3.67 (d, 1H, J=13.1 Hz), 3.76–3.84 (m,
1H), 4.00 (s, 3H), 7.24–7.35 (m, 5H), 8.20 (br s, 8H);
MS m/z 207 (M++1); IR (KBr) 3370, 2925, 1735, 1600
cm−1. Anal. calcd for C12H18N2O·1.5C4H6O6: C, 50.11;
H, 6.31; N, 6.49. Found: C, 49.85; H, 6.26; N, 6.27%.
1
(10:1) to give ( )-8 as a colorless oil (124 g, 55%): H
NMR (CDCl3) l 1.47 (s, 9H), 3.33–3.63 (m, 4H), 3.39
(s, 3H), 3.74–3.79 (m, 1H), 3.95–4.00 (m, 1H); MS m/z
243 (M++1); IR (neat) 2105, 1695 cm−1. Anal. calcd for
C10H18N4O3·0.25H2O: C, 48.67; H, 7.56; N, 22.70.
Found: C, 48.98; H, 7.47; N, 22.44%.
The crystals were treated with 3% K2CO3 and the
liberated amine was extracted three times with AcOEt.
The combined organic layer was washed with saturated
NaCl and dried over Na2SO4. Evaporation of the sol-
vent under reduced pressure gave 7.94 g (32%) of
(S,S)-3 as a colorless oil: [h]2D7 +32.2 (c 1.05, MeOH);
1H NMR (CDCl3) l 1.55 (br s, 2H), 2.33 (dd, 1H,
J=9.6, 4.5 Hz), 2.47 (dd, 1H, J=10.0, 4.0 Hz), 2.85
(dd, 1H, J=9.6, 6.3 Hz), 2.95 (dd, 1H, J=10.0, 6.3
Hz), 3.31 (s, 3H), 3.34 (ddd, 1H, J=6.3, 4.6, 2.4 Hz),
3.56 (ddd, 1H, J=6.3, 4.0, 2.4 Hz), 3.56 (d, 1H, J=12.8
Hz), 3.65 (d, 1H, J=12.8 Hz), 7.20–7.33 (m, 5H); MS
m/z 207 (M++1); IR (neat) 2935, 1605 cm−1. Anal. calcd
for C12H18N2O: C, 69.87; H, 8.80; N, 13.58. Found: C,
69.90; H, 8.81; N, 13.68%; e.e. 99% (S,S); HPLC
analysis using CHIRALCEL OJ-H 4.6×250 mm (hex-
ane:i-PrOH, 85:15), 0.4 mL/min; (S,S)-3 tr=17.97 min;
(R,R)-3 tr=18.98 min.
4.2.2. ( )-trans-3-Amino-1-tert-butoxycarbonyl-4-meth-
oxypyrrolidine ( )-9. A solution of ( )-8 (76.0 g, 0.317
mol) in EtOH (370 mL) was hydrogenated over 5%
Pd–C (7.0 g) at room temperature for 10 h. The mixture
was filtered and then concentrated in vacuo to give
1
( )-9 as a colorless oil (67.0 g, 98%): H NMR (CDCl3)
l 1.45 (s, 9H), 1.58 (br s, 2H), 3.05–3.48 (m, 3H), 3.35
(s, 3H), 3.50–3.69 (m, 3H); MS m/z 203 (M++1); IR
(neat) 2950, 1690 cm−1. Anal. calcd for C10H20N2O3: C,
55.53; H, 9.32; N, 12.95. Found: C, 55.58; H, 9.33; N,
13.02%.
4.2.3. ( )-trans-3-Amino-1-benzyl-4-methoxypyrrolidine
( )-3. A solution of 35% HCl–EtOH (80.2 mL) was
added to a solution of ( )-9 (50.0 g, 0.231 mol) in
EtOH (180 mL) over a period of 1 h at 0°C and the
reaction mixture was stirred at room temperature for 8
h. The mixture was cooled to 0°C and the resultant
precipitates were collected by filtration, washed with
EtOH and dried to give 39.6 g of white crystals. Benzyl
chloride (25.2 g, 0.199 mol) was added into a mixture of
the intermediate, Et3N (93.9 g, 0.993 mol), CH3CN (1.5
L) and water (15 mL) over a period of 1 h at 0°C. The
mixture was allowed to warm gradually to room tem-
perature for 15 h. After neutralization with 2% K2CO3
at 0°C, AcOEt was added. The organic layer was
washed with saturated NaCl, dried over Na2SO4 and
then concentrated in vacuo. The resulting residue was
chromatographed on silica gel with hexane–AcOEt
4.2.5.
(3S,4S)-1-Benzyl-3-(N-tert-butoxycarbonyl)-
amino-4-methoxypyrrolidine 10. Di-tert-butyl dicarbon-
ate (7.15 g, 32.8 mmol) was added dropwise to a
solution of (S,S)-3 (6.42 g, 31.2 mmol) in MeOH (80
mL) at 0°C. The reaction mixture was stirred at room
temperature for 4 h and then concentrated in vacuo to
leave a residue. The resulting residue was chro-
matographed on silica gel with CHCl3–MeOH (100:1)
to give 10 as white crystals (9.26 g, 97%): mp 44–45°C;
1
[h]2D9 +9.5 (c 1.04, MeOH); H NMR (CDCl3) l 1.44 (s,
9H), 1.75 (br s, 1H), 2.24 (dd, 1H, J=10.5, 4.1 Hz),
2.55 (dd, 1H, J=10.0, 4.8 Hz), 2.70 (dd, 1H, J=9.9, 5.8
Hz), 3.15 (dd, 1H, J=10.5, 6.6 Hz), 3.39 (s, 3H), 3.60
(s, 2H), 3.90–4.04 (m, 1H), 4.85–5.00 (m, 1H), 7.20–7.32
(m, 5H); MS m/z 307 (M++1); IR (KBr) 2975, 1710,
1530 cm−1. Anal. calcd for C17H26N2O3: C, 66.64; H,
8.55; N, 9.14. Found: C, 66.49; H, 8.51; N, 9.28%.
1
(50:1) to give ( )-3 as a colorless oil (27.0 g, 57%): H
NMR (CDCl3) l 1.63 (br s, 2H), 2.34 (dd, 1H, J=9.7,
4.6 Hz), 2.48 (dd, 1H, J=10.4, 4.0 Hz), 2.85 (dd, 1H,
J=9.7, 6.3 Hz), 2.95 (dd, 1H, J=10.4, 6.3 Hz), 3.32 (s,
3H), 3.34 (ddd, 1H, J=6.3, 4.6, 2.4 Hz), 3.53 (ddd, 1H,
J=6.3, 4.0, 2.4 Hz), 3.56 (d, 1H, J=12.8 Hz), 3.65 (d,
1H, J=12.8 Hz), 7.21–7.34 (m, 5H); MS m/z 207
(M++1); IR (neat) 2950, 1600 cm−1. Anal. calcd for
C12H18N2O·0.2H2O: C, 68.67; H, 8.87; N, 13.35.
Found: C, 68.82; H, 8.78; N, 13.48%.
4.2.6.
(3S,4S)-1-Benzyl-3-(N-tert-butoxycarbonyl)-
methylamino-4-methoxypyrrolidine 11. A solution of 10
(8.20 g, 27.5 mmol) in dry THF (60 mL) was added to
a suspension of LiAlH4 (3.13 g, 82.5 mmol) in dry THF
(120 mL) at room temperature. After stirring the mix-
ture at room temperature for 1 h, the mixture was
heated under reflux for 5 h. After cooling to 0°C, water
was added and the mixture was filtered. The filtrate was
extracted with AcOEt and the organic layer was washed
with saturated NaCl, dried over Na2SO4 and then
concentrated in vacuo. Di-tert-butyl dicarbonate (6.00
g, 27.5 mmol) was added to a solution of the residue in
CH2Cl2 (100 mL) at 0°C. The reaction mixture was
stirred at room temperature for 2 h and then concen-
trated in vacuo. The resulting residue was chro-
4.2.4. (3S,4S)-3-Amino-1-benzyl-4-methoxypyrrolidine
(S,S)-3. A mixture of ( )-3 (25.0 g, 121 mmol) and
(+)-tartaric acid (25.4 g, 169 mmol) in MeOH (395 mL)
and H2O (5 mL) was heated at 65°C and cooled to
room temperature. The resultant crystalline precipitates
were collected by filtration, washed with MeOH and
recrystallized from MeOH–H2O, giving 18.8 g of (S,S)-

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Y. Tsuzuki et al. / Tetrahedron: Asymmetry 12 (2001) 2989–2997
matographed on silica gel with CHCl3–MeOH (150:1)
to give 11 as a colorless oil (7.93 g, 90%): [h]2D9 +9.9 (c
concentrated in vacuo to leave a residue. The resulting
residue was chromatographed on silica gel with CHCl3
to give a higher Rf diastereomer 12 as a colorless oil
1
1.00, MeOH); H NMR (CDCl3) l 1.45 (s, 9H), 2.44
1
(dd, 1H, J=10.0, 5.2 Hz), 2.54 (dd, 1H, J=10.0, 4.8
Hz), 2.70–2.79 (m, 1H), 2.87 (s, 3H), 2.91–3.02 (m, 1H),
3.34 (s, 3H), 3.50 (d, 1H, J=12.8 Hz), 3.65 (d, 1H,
J=12.8 Hz), 3.84–3.92 (m, 1H), 4.40–4.53 (m, 1H),
7.19–7.32 (m, 5H); MS m/z 321 (M++1); IR (neat) 2975,
1695, 1540 cm−1. Anal. calcd for C18H28N2O3: C, 67.47;
H, 8.81; N, 8.74. Found: C, 67.09; H, 8.78; N, 8.76%.
(5.11 g, 34%): [h]2D5 +52.0 (c 0.15, MeOH); H NMR
(CDCl3) l 1.41 (s, 9H), 1.46 (s, 9H), 1.85 (br s, 2H),
2.57(s, 1H), 2.73 (s, 3H), 2.91–3.10 (m, 3H), 3.43–3.77
(m, 2H), 4.02–4.45 (m, 2H), 4.78–4.92 (m, 1H), 5.28–
5.42 (m, 1H), 7.15–7.31 (m, 5H); MS m/z 464 (M++1);
IR (neat) 3335, 1690, 1635, 1600 cm−1. Anal. calcd for
C24H37N3O6: C, 62.18; H, 8.04; N, 9.06. Found: C,
61.89; H, 7.94; N, 9.03%; d.e. 99.0%; HPLC analysis
using CAPCELL PAK SG120 4.6×250 mm
(CH3CN:0.05% aq. TFA, 43:57), 1.0 mL/min; 12 tr=
19.36 min; isomer of 12 tr=20.34 min.
4.2.7. (3S,4S)-3-(N-tert-Butoxycarbonyl)methylamino-4-
methoxypyrrolidine ((S,S)-2a)12. A solution of 11 (7.15
g, 22.3 mmol) in EtOH (70 mL) was hydrogenated over
5% Pd–C (700 mg) at 50°C. The mixture was filtered
and then concentrated in vacuo to give of (S,S)-2a as a
colorless oil (4.87 g, 95%): [h]2D9 +12.5 (c 1.05, MeOH);
1H NMR (CDCl3) l 1.45 (s, 9H), 1.86 (br s, 1H),
2.74–2.84 (m, 1H), 2.84 (s, 3H), 2.96 (dd, 1H, J=12.0,
3.1 Hz), 3.07 (dd, 1H, J=11.9, 5.2 Hz), 3.28 (dd, 1H,
J=12.0, 8.6 Hz), 3.34 (s, 3H), 3.81–3.85 (m, 1H),
4.19–4.31 (m, 1H); MS m/z 231 (M++1); IR (neat) 2975,
1695 cm−1. Anal. calcd for C11H22N2O3: C, 57.37; H,
9.63; N, 12.16. Found: C, 57.09; H, 9.60; N, 12.05%. It
was confirmed that AG-7352·HCl {[h]2D8 +50.1 (c 1.00,
1N NaOH)} derived from (S,S)-2a had >99% e.e. based
on HPLC analysis.
4.3.3. (3S,4S)-1-tert-Butoxycarbonyl-3-hydroxy-4-meth-
ylaminopyrrolidine (S,S)-4. A mixture of 12 (4.70 g,
10.2 mmol) and 20% NaOH (50 mL) in EtOH (75 mL)
was heated at 50°C for 7 h and 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 concen-
trated in vacuo. The residue was triturated with i-Pr2O
to give (S,S)-4 as white crystals (2.05 g, 93%): mp
105–107°C; [h]D26 −8.7 (c 1.00, MeOH); 1H NMR
(CDCl3) l 1.47 (s, 9H), 1.90 (br s, 2H), 2.47 (s, 3H),
2.99–3.35 (m, 3H), 3.57–3.75 (m, 2H), 4.07–4.17 (m,
1H); MS m/z 217 (M++1); IR (KBr) 3290, 2970, 1695
cm−1. Anal. calcd for C10H20N2O3: C, 55.53; H, 9.32; N,
12.95. Found: C, 55.39; H, 9.39; N, 12.96%.
4.3. Route B
4.3.1.
( )-trans-1-tert-Butoxycarbonyl-3-hydroxy-4-
methylaminopyrrolidine ( )-4. Di-tert-butyl dicarbonate
(314 g, 1.44 mmol) was added dropwise to a solution of
3-pyrroline 6 (100 g, 0.940 mol, purity of 65%) in
MeOH (1 L) over a period of 30 min at 0°C and the
reaction mixture was stirred at room temperature for 15
h. After evaporation of the solvent, the residue was
dissolved in CH2Cl2 (1.8 L). The mixture was cooled to
0°C and then m-CPBA (240 g, 1.12 mol, purity of 80%)
was added over a period of 6 h. After stirring at room
temperature for 2 days, the precipitated solid was
filtered off and the filtrate was successively washed with
saturated NaHSO3, 5% K2CO3 and saturated NaCl,
dried over Na2SO4 and then concentrated in vacuo. A
solution of 40% methylamine–water (1 L) was added
into the residue and the reaction mixture was stirred at
room temperature for 15 h. After evaporation of the
solvent, the residue was triturated with i-Pr2O to give
4.3.4. (3S,4S)-1-tert-Butoxycarbonyl-3-(N-tert-butoxy-
carbonyl)methylamino-4-hydroxypyrrolidine 13. Di-tert-
butyl dicarbonate (2.12 g, 9.72 mmol) was added
dropwise to a solution of (S,S)-4 (2.00 g, 9.26 mmol) in
MeOH (40 mL) at 0°C. The reaction mixture was
stirred at room temperature for 4 h and then concen-
trated in vacuo to leave a residue. The resulting residue
was chromatographed on silica gel with CHCl3–MeOH
(50:1) to give 2.87 g (98%) of 13 as a colorless oil: [h]D25
1
+21.7 (c 0.60, MeOH); H NMR (CDCl3) l 1.45 (s,
9H), 1.47 (s, 9H), 2.81 (s, 3H), 3.15–3.39 (m, 2H),
3.58–3.77 (m, 2H), 4.23–4.43 (m, 3H); MS m/z 317
(M++1); IR (neat) 3335, 1695 cm−1. Anal. calcd for
C15H28N2O5: C, 56.94; H, 8.92; N, 8.85. Found: C,
56.75; H, 8.93; N, 8.55%.
4.3.5. (3S,4S)-3-Methoxy-4-methylaminopyrrolidine di-
p-toluenesulfonic acid (S,S)-2b5. A solution of 13 (2.80
g, 8.86 mmol) in dry DMF (25 mL) was added to a
suspension of NaH (60% dispersion in oil, 444 mg, 11.1
mmol, washed with dry hexane before use) in dry DMF
(25 mL) and MeI (1.89 g, 13.3 mmol) over a period of
10 min at 0°C. After stirring at 0°C for 1 h, the mixture
was stirred at room temperature for 5 h. After neutral-
ization with 2% AcOH under ice-cooling, toluene was
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 (42 mL) and then
p-toluenesulfonic acid (3.44 g, 18.1 mmol) was added.
The reaction mixture was stirred at 65°C for 3 h and
1
( )-4 as white crystals (133 g, 66%): mp 98–100°C; H
NMR (CDCl3) l 1.46 (s, 9H), 2.29 (br s, 2H), 2.47 (s,
3H), 3.01–3.36 (m, 3H), 3.57–3.76 (m, 2H), 4.08–4.17
(m, 1H); MS m/z 217 (M++1); IR (KBr) 3295, 2970,
1695 cm−1. Anal. calcd for C10H20N2O3: C, 55.53; H,
9.32; N, 12.95. Found: C, 55.66; H, 9.31; N, 13.05%.
4.3.2. (3S,4S)-1-tert-Butoxycarbonyl-3-(N-tert-butoxy-
carbonyl-L-phenylalanyl)methylamino-4-hydroxy pyrro-
lidine 12. L-Boc-Phe (10.3 g, 38.9 mmol) and EDC
(8.07 g, 42.1 mmol) were added successively to a solu-
tion of ( )-4 (7.00 g, 32.4 mmol) in CH2Cl2 (200 mL) at
0°C. After stirring for 20 h at room temperature, water
and CHCl3 were added. The organic phase was washed
with saturated NaCl, dried over Na2SO4 and then

Y. Tsuzuki et al. / Tetrahedron: Asymmetry 12 (2001) 2989–2997
2995
then cooled to 0°C. The resultant precipitates were
collected by filtration, washed with i-PrOH and dried
to give (S,S)-2b as white crystals (3.44 g, 83%): mp
163–164°C (lit. 163–164°C); [h]2D9 +10.3 (c 1.00, MeOH)
The combined organic layer was washed with saturated
NaCl and dried over Na2SO4. Evaporation of the sol-
vent under reduced pressure left a residual oil, which
was crystallized from i-Pr2O. The resultant crystals
were collected by filtration, washed with i-Pr2O and
dried to give (S,S)-5 as white crystals (275 g, 39%); mp
69–70°C; [h]2D9 +18.0 (c 0.50, MeOH); 1H NMR
(CDCl3) l 1.46 (s, 9H), 2.03 (br s, 2H), 3.08–3.33 (m,
3H), 3.57–3.75 (m, 2H), 3.82 (d, 2H, J=5.0 Hz), 4.06–
4.15 (m, 1H), 7.22–7.39 (m, 5H); MS m/z 293 (M++1);
IR (KBr) 3250, 1670, 1605 cm−1. Anal. calcd for
C16H24N2O3; C, 65.73; H, 8.27; N, 9.58. Found: C,
65.54; H, 8.41; N, 9.59%; e.e. 100% (S,S); HPLC
analysis using CHIRALCEL OJ 4.6×250 mm (hex-
ane:EtOH, 95:5), 0.8 mL/min; (S,S)-5 tr=14.39 min;
(R,R)-5 tr=19.00 min.
1
(lit. [h]2D9 +10.4 (c 1.00, MeOH)); H NMR (DMSO-d6)
l 2.31 (s, 6H), 2.70 (s, 3H), 3.22–3.40 (m, 3H), 3.32 (s,
3H), 3.60–3.72 (m, 1H), 3.80–3.90 (m, 1H), 4.19–4.26
(m, 1H), 7.14 (d, 4H, J=9.9 Hz), 7.50 (d, 4H, J=9.9
Hz), 9.02 (br s, 4H); MS m/z 131 (M++1); IR (KBr)
3050, 1615, 1570 cm−1. Anal. calcd for C6H14N2O·
2C7H8O3S: C, 50.62; H, 6.37; N, 5.90; S, 13.51. Found:
C, 50.59; H, 6.38; N, 5.99; S, 13.40%. It was confirmed
that AG-7352·HCl {[h]2D7 +50.4 (c 1.01, 1N NaOH)}
derived from (S,S)-2b had more than 99% e.e. based on
HPLC analysis.
4.4. Route C
4.4.3. (3S,4S)-1-tert-Butoxycarbonyl-3-tert-butoxycar-
bonylamino-4-hydroxypyrrolidine 14.5 A solution of
(S,S)-5 (274 g, 0.938 mol) in BuOH (1.2 L) was hydro-
genated over 5% Pd–C (13.7 g) at 40°C for 5 h. The
mixture was filtered and EtOH (0.8 L) was added to the
filtrate. Di-tert-butyl dicarbonate (215 g, 0.985 mol)
was added to the mixture over a period of 10 min at
0°C. The reaction mixture was stirred at room tempera-
ture for 15 h and then concentrated in vacuo. The
residue was triturated with i-Pr2O to give 278 g (98%)
of 14 as white crystals: mp 148–149°C (lit. 147–148°C);
[h]2D9 +1.80 (c 1.00, MeOH) (lit. [h]2D4 +1.50 (c 1.00,
MeOH)); 1H NMR (CDCl3) l 1.45 (s, 9H), 1.46 (s,
9H), 3.10–3.38 (m, 2H), 3.61–4.01 (m, 3H), 4.16–4.29
(m, 1H), 4.70 (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, 55.80; H, 8.74; N,
9.27%.
4.4.1. ( )-1-tert-Butoxycarbonyl-trans-3-benzylamino-4-
hydroxypyrrolidine ( )-5. Di-tert-butyl dicarbonate
(1.51 kg, 6.93 mol) was added dropwise to a solution of
3-pyrroline 6 (486 g, 6.60 mol, purity of 93.9%) in
CHCl3 (5.8 L) over a period of 1.5 h at 0°C and the
reaction mixture was stirred at room temperature for 17
h. The whole was cooled to 0°C and then m-CPBA
(1.67 kg, 7.26 mol, purity of 75%) was added over a
period of 6 h. After stirring at room temperature for 2
days, the precipitate that formed was filtered off and
the filtrate was successively washed with saturated
NaHSO3 (5 L), 5% K2CO3 (5 L) and saturated NaCl (3
L), dried over Na2SO4 and then concentrated in vacuo.
The residue was dissolved in water (1.8 L) and then
benzylamine (1.8 L, 16.5 mol) was added at room
temperature. After stirring at room temperature for 2 h,
the reaction mixture was stirred at 65°C for 3 h, water
(2 L) was added and the mixture was extracted with
AcOEt. The organic layer was washed with water and
then concentrated in vacuo. The residue was triturated
with i-Pr2O to give ( )-5 as white crystals (1.29 kg,
4.4.4. (3S,4S)-3-Methoxy-4-methylaminopyrrolidine di-
p-toluenesulfonic acid (S,S)-2b.13 A solution of 14 (177
g, 0.586 mol) in dry DMF (0.7 L) was added into the
suspension of NaH (58.8 g of 60% oil suspension, 1.47
mol, washed with dry hexane before use) in dry DMF
(1.4 L) and MeI (250 g, 1.76 mol) over a period of 1 h
at 0°C. After stirring at 0°C for 1 h, the reaction
mixture was stirred at room temperature for 15 h. After
neutralization with 2% AcOH (2.5 L) under ice-cooling,
toluene (2.5 L) 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 concen-
trated in vacuo. The residue was dissolved in THF–
MeOH (3: 1, 2.9 L) and then p-toluenesulfonic acid
(257 g, 1.35 mol) was added. After stirring at room
temperature for 30 min, the reaction mixture was
stirred at 60°C for 3 h and then cooled to 0°C. The
resultant precipitates were collected by filtration,
washed with THF and dried to give (S,S)-2b as white
crystals (270 g, 97%): mp 163–164°C; [h]2D9 +10.5 (c
1.00, MeOH). Anal. calcd for C6H14N2O·2C7H8O3S: C,
50.62; H, 6.37; N, 5.90; S, 13.51. Found: C, 50.60; H,
6.41; N, 5.98; S, 13.37%. It was confirmed that AG-
7352·HCl {[h]2D7 +51.0 (c 1.00, 1N NaOH)} derived
from (S,S)-2b had more than 99.8% e.e. based on
HPLC analysis.
1
67%): mp 140–141°C; H NMR (CDCl3) l 1.46 (s, 9H),
1.65 (br s, 2H), 3.10–3.35 (m, 3H), 3.57–3.75 (m, 2H),
3.82 (d, 2H, J=5.0 Hz), 4.06–4.15 (m, 1H), 7.21–7.38
(m, 5H); MS m/z 293 (M++1); IR (KBr) 3250, 1670,
1605 cm−1. Anal. calcd for C16H24N2O3: C, 65.73; H,
8.27; N, 9.58. Found: C, 65.76; H, 8.31; N, 9.65%.
4.4.2. (3S,4S)-3-Benzylamino-1-tert-butoxycarbonyl-4-
hydroxypyrrolidine (S,S)-5. A mixture of ( )-5 (714 g,
2.45 mol) and (+)-mandelic acid (411 g, 2.70 mol) in
CH3CN (7.5 L) and water (62 mL) was heated at 70°C
for 30 min and cooled to room temperature during 4 h.
The resultant crystalline precipitates were collected by
filtration, washed with CH3CN and recrystallized from
CH3CN–H2O (20: 1), giving 439 g of (S,S)-5·(+)-man-
delic acid: mp 189–191°C; [h]2D6 +59.8 (c 0.51, MeOH);
1H NMR (DMSO-d6) l 1.39 (s, 9H), 2.95–3.18 (m, 3H),
3.28–3.50 (m, 4H), 3.73 (s, 2H), 3.95–4.02 (m, 1H), 4.97
(s, 1H), 5.05 (br s, 2H), 7.19–7.44 (m, 10H); MS m/z
293 (M++1); IR (KBr) 3415, 3215, 1685, 1670, 1575
cm−1. Anal. calcd for C16H24N2O3·C8H8O3: C, 64.85; H,
7.26; N, 6.30. Found: C, 64.79; H, 7.45; N, 6.29%.
The crystals were treated with 3% K2CO3 (3 L) and the
liberated amine was extracted three times with AcOEt.

2996
Y. Tsuzuki et al. / Tetrahedron: Asymmetry 12 (2001) 2989–2997
4.4.5. tert-Butyl carbamate.11 A solution of di-tert-butyl
dicarbonate (400 g, 1.83 mol) in EtOH (500 mL) was
added to a solution of saturated ammonia–EtOH (500
mL) in EtOH (500 mL) over a period of 1 h at 0°C. The
reaction mixture was stirred at room temperature for 15
h and then concentrated in vacuo. Hexane (1.6 L) was
added to the resulting solid, the mixture was stirred at
65°C for 30 min and cooled to 0°C. The resultant
precipitates were collected by filtration, washed with
hexane and dried to give the title compound as white
crystals (210 g, 98%): mp 106–107°C (lit. 107–109°C);
1H NMR (CDCl3) l 1.45 (s, 9H), 4.42 (br s, 2H); MS
m/z 118 (M++1); IR (KBr) 2985, 1685 cm−1. Anal. calcd
for C5H11NO2: C, 51.26; H, 9.46; N, 11.96. Found: C,
51.20; H, 9.44; N, 11.90%.
ture. All measurements were made on a Rigaku
AFC5R diffractometer with graphite monochromated
CuKa radiation. The structure was solved by direct
methods and refined by full-matrix least-squares meth-
ods with anisotropic temperature factors for non-H
atoms. All H atoms found from difference Fourier
maps were included in the calculation of the structure
factors. The crystal data are as follows: C20H30O7N2S2,
Mr=474.59, orthorhombic, P212121, a=11.620(2), b=
3
,
,
26.562(2), c=7.421(1) A, V=2290.5(5) A , Z=4,
D
calcd=1.376 g/cm3, F(000)=1008.00, v(CuKa)=24.34
cm−1, T=293 K, R=0.038, S=1.07. Flack’s  parame-
ter (−0.02 (3)) indicated that the absolute structure of
2b was (S,S). Crystallographic details have been
deposited at the Cambridge Crystallographic Data Cen-
tre (deposition number 167835).
4.4.6. 1-tert-Butoxycarbonyl-3-pyrroline 15. cis-1,4-
Dichloro-2-butene (36.0 g, 0.288 mol) was added to a
suspension of NaH (60% dispersion in oil, 19.2 g, 0.48
mol, washed with dry hexane before use) in dry DMF
(200 mL). A solution of tert-butyl carbamate (22.5 g,
0.192 mol) in dry DMF (200 mL) was added to the
mixture. After being stirred at room temperature for 40
min, the reaction mixture was stirred at 50°C for 5 h.
After neutralization with saturated NH4Cl at 0°C,
AcOEt was added. The organic layer was separated and
the aqueous layer was extracted with AcOEt. The com-
bined organic layer was washed with saturated NaCl,
dried over Na2SO4 and then concentrated in vacuo to
give 15 as a colorless oil (19.4 g, 60%): 1H NMR
(CDCl3) l 1.47 (s, 9H), 4.03–4.18 (m, 4H), 5.70–5.82
(m, 2H).
Acknowledgements
We are grateful to Dr. K. Hino for his encouragement
throughout this work. Thanks are also due to members
of the Department of Physico Chemical Analysis of
these laboratories for elemental analyses and spectral
measurements.
References
1. (a) Attygalle, A. B.; Morgan, D. E. Chem. Soc. Rev.
1984, 13, 245; (b) Massiot, G.; Delaude, C. In The
Alkaloids; Brossi, A., Ed.; Academic Press: New York,
1986; Vol. 27, Chapter 3; (c) Numata, A.; Ibuka, T. In
The Alkaloids; Brossi, A., Ed.; Academic Press: New
York, 1987; Vol. 31, Chapter 6; (d) Elbein, A.;
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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,
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3. (a) Kohlbrenner, W. E.; Wideburg, N.; Weigl, D.; Saldi-
var, A.; Chu, D. T. W. Antimicrob Agents Chemother.
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Res. 1994, XX, 177.
4.4.7. ( )-trans-3-Bromo-1-tert-butoxycarbonyl-4-hydro-
xypyrrolidine ( )-16. To a stirred mixture of 15 (17.3 g,
0.102 mol), DMSO (120 mL) and H2O (6 mL), NBS
(21.7 g, 0.122 mol) was gradually added over 15 min at
0°C. After stirring at room temperature for 2 h, water
(140 mL) was added and the mixture was extracted
with AcOEt. The organic layer was washed with satu-
rated NaCl, dried over Na2SO4 and then concentrated
1
in vacuo to give crude ( )-16 as an oil (27.8 g): H
NMR (CDCl3) l 1.47 (s, 9H), 2.23 (br s, 1H), 3.32–3.48
(m, 1H), 3.68–3.94 (m, 2H), 3.96–4.11 (m, 1H), 4.12–
4.20 (m, 1H), 4.43–4.53 (m, 1H); MS m/z 266 (M++1),
268 (M++3); IR (neat) 3350, 1655 cm−1.
4.4.8. ( )-trans-3-Benzylamino-1-tert-Butoxycarbonyl-4-
hydroxypyrrolidine ( )-5. A mixture of crude ( )-16
(27.8 g) and aqueous NaOH (1N, 128 mL, 0.128 mol)
was stirred at room temperature for 1 h. The mixture
was treated with benzylamine (27.3 g, 0.255 mol) and
stirred at 65°C for 2 h, then cooled to 0°C. The
resultant precipitates were collected by filtration,
washed with water and i-Pr2O and dried to give ( )-5 as
white crystals (17.5 g, 59% based on 15). The spectral
data were identical to that of an authentic sample of
( )-5.
4. Peterson, U.; Schenke, T.; Krebs, A.; Grohe, K.;
Schriewer, M.; Haller, I.; Metzger, K. G.; Endermann,
R.; Zeiler, H. J. Japanese Patent Kokai 2-69474, 1990;
Chem. Abstr. 1990, 113, 97462q.
4.4.9. X-Ray crystallographic analysis. The colorless
prismatic crystals of (S,S)-2b having approximate
dimensions of 1.00×0.40×0.2 mm were obtained from
MeOH solution by slow evaporation at room tempera-
5. Tsuzuki, Y.; Chiba, K.; Hino, K. Tetrahedron: Asymme-
try 2001, 12, 1793.

Y. Tsuzuki et al. / Tetrahedron: Asymmetry 12 (2001) 2989–2997
2997
6. The separation of a racemic amine into two enantiomers
by acylation with amino acid has been reported, see:
Rittle, K. E.; Evans, B. E.; Bock, M. G.; DiPardo, R. M.;
Whitter, W. L.; Homnick, C. F.; Veber, D. F.;
Freidinger, R. M. Tetrahedron Lett. 1987, 28, 521.
7. By the study of a variety of acids, p-toluenesulfonic acid
was selected because only (S,S)-2b was non-hygroscopic.
It is not necessary to protect the methylamino group of
(S,S)-2 because it was found that the methylamino group
was less nucleophilic than the pyrrolidine for the nucle-
ophilic substitution reaction with 1,8-naphthyridone
derivative.
8. When 13 was methylated with NaH (1.2 equiv.) and MeI
(1.1 equiv.) in THF, it gave an O-methylated product
solely. This result implies that optically active 3-amino-4-
methoxypyrrolidine could be prepared by this method.
9. The purity of (S,S)-2b was determined based on HPLC
analyses of 2-(3-methoxy-4-methylamino pyrrolidinyl)-3-
nitropyridine derived from the reaction with 2-chloro-3-
nitropyridine.
2230; (b) Hudson, C. B.; Robertson, A. V. Tetrahedron
Lett. 1967, 4015; (c) Brandange, S.; Rodriguez, B. Syn-
thesis 1988, 347; (d) Warmus, J. S.; Dilley, G. J.; Meyers,
A. I. J. Org. Chem. 1993, 58, 270.
11. tert-Butyl carbamate is commercially available but expen-
sive. tert-Butyl carbamate could be obtained from the
reaction of hazardous sodium cyanate and t-BuOH with
TFA, see: Loev, B.; Kormendy, M. F.; Goodman, M. M.
Org. Synth. 1968, 48, 32.
12. Following the procedure described for (S,S)-2a, com-
pound ( )-3 was converted to (R,R)-2a by the use of
(−)-tartaric acid via (R,R)-3, (R,R)-10 and (R,R)-11;
(R,R)-3·1.5(−)-tartaric acid, [h]2D9 −33.4 (c 1.02, MeOH);
(R,R)-3, [h]2D7 −32.7 (c 1.02, MeOH); (R,R)-10, [h]2D9 −9.5
(c 1.08, MeOH), (R,R)-11, [h]2D9 −10.1 (c 1.05, MeOH);
(R,R)-2a, [h]2D9 −12.2 (c 1.00, MeOH).
13. Following the procedure described for (S,S)-2b, com-
pound ( )-5 was converted to (R,R)-2b by the use of
(−)-mandelic acid via (R,R)-5 and (R,R)-14; (R,R)-5·(−)-
mandelic acid, [h]D26 −60.0 (c 0.50, MeOH); (R,R)-5, [h]2D9
−18.5 (c 0.52, MeOH); (R,R)-14, [h]2D8 −1.4 (c 1.01,
MeOH); (R,R)-2b, [h]2D6 −10.2 (c 1.00, MeOH).
10. For synthesis of 3-pyrroline, see: (a) Bobbit, J. M.;
Amundsen, L. H.; Steiner, R. I. J. Org. Chem. 1960, 25,