Enantiospecific synthesis of pyridinylmethyl pyrrolidinemethanols and catalytic asymmetric borane reduction of prochiral ketones

Article abstract of DOI:10.1016/j.tetasy.2003.10.037

Three chiral pyridinylmethyl pyrrolidinemethanol derivatives have been synthesized from N-alkylation of (S)-α,α-diphenyl-2- pyrrolidinemethanol and N-carbonylation of L-proline methyl ester. The catalytic asymmetric borane reduction of prochiral ketones was examined in the presence of chiral oxazaborolidine catalysts prepared in situ from chiral pyridinylmethyl pyrrolidinemethanol derivatives. The corresponding chiral secondary alcohols were obtained with good to excellent enantiomeric excesses (up to 98% ee) using (S)-2-(diphenylmethanol)-l-(2-pyridylmethyl)pyrrolidine 1 in THF at reflux and moderate to good enantiomeric excesses using C ₂-symmetric compound 2 (up to 86% ee) in THF.

Full text of DOI:10.1016/j.tetasy.2003.10.037

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 15 (2004) 177–182
Enantiospecific synthesis of pyridinylmethyl pyrrolidinemethanols
and catalytic asymmetric borane reduction of prochiral ketones
*
€
Yong-Xin Zhang, Da-Ming Du, Xiao Chen, Shao-Feng Lu and Wen-Ting Hua
Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education, College of Chemistry and
Molecular Engineering, Peking University, Beijing 100871, PR China
Received 23 July2003; revised 29 October 2003; accepted 31 October 2003
Abstract—Three chiral pyridinylmethyl pyrrolidinemethanol derivatives have been synthesized from N-alkylation of (S)-a,a-
diphenyl-2-pyrrolidinemethanol and N-carbonylation of L-proline methyl ester. The catalytic asymmetric borane reduction of
prochiral ketones was examined in the presence of chiral oxazaborolidine catalysts prepared in situ from chiral pyridinylmethyl
pyrrolidinemethanol derivatives. The corresponding chiral secondary alcohols were obtained with good to excellent enantiomeric
excesses (up to 98% ee) using (S)-2-(diphenylmethanol)-l-(2-pyridylmethyl)pyrrolidine 1 in THF at reflux and moderate to good
enantiomeric excesses using C2-symmetric compound 2 (up to 86% ee) in THF.
ꢀ 2003 Elsevier Ltd. All rights reserved.
1. Introduction
cyanosilylation of ketones have been reported.10b To the
best of our knowledge, the use of pyridinylmethyl
pyrrolidinemethanol derivatives in the reduction of
ketones has not been reported to date. It should be of
interest to investigate the catalytic ability of pyridinyl-
methyl pyrrolidinemethanol derivatives. We have an
ongoing project on the synthesis and application of
chiral pyridine derivative in chiral molecular recogni-
tion11 and asymmetric synthesis and we want to evaluate
the effect resulting from the introduction of a pyridinyl
moietyonto the catalysts. We expect that the coopera-
tion of pyridine unit and chiral prolinol unit in the new
ligands mayresult in unique properties for suitable
catalytic reactions. Herein, the synthesis and structure of
enantiomerically pure pyridinylmethyl pyrrolidine-
methanol and their applications as ligands in the cata-
lytic enantioselective reduction of ketones by borane.
The enantioselective reduction of prochiral ketones with
borane in the presence of a chiral ligand leading to
enantiomericallypure secondaryalcohols has received
considerable attention in recent years.1 Enantiomerically
pure secondaryalcohols are important intermediates for
the synthesis of various other organic compounds such
as halides, esters, ethers, ketones, and amines and many
biologicallyactive compounds. 2 The pioneering work of
4
Itsuno et al.3 and Coreyet al. inspired the research
interests of chemists and the asymmetric reduction of
prochiral ketones to opticallyactive alcohols using chi-
ral oxazaborolidine catalysts has become one of the
most active research fields. A great number of studies
have been reported and manynew ligands have been
prepared in order to find more effective catalysts.5 The
studyof chiral amino alcohols based on prolinol is still
an active research area and new derivatives such as
sulfonyl prolinol,6 polymer-supported sulfonamide,7
chiral phosphinamides,8 and chiral squaric prolinols9
were reported recentlyand high iyelds and good
enantioselectivities were obtained. The applications
of pyridinylmethyl pyrrolidinemethanol N-oxides in
asymmetric reduction of ketone10a and corresponding
chiral N-oxide-titanium(IV) complexes in asymmetric
2. Results and discussion
(S)-2-(Diphenylmethanol)-l-(2-pyridylmethyl)pyrrol-
idine 1 was first synthesized by Chelucciꢀs group from
N-alkylation of L-proline methyl ester with 2-chloro-
methylpyridine followed by a Grignard addition reac-
tion.12 We use an alternative convenient procedure, by
treating (S)-a,a-diphenyl-2-pyrrolidinemethanol with
2-bromomethylpyridine in a mixture of K2CO3 and
KI in ethanol at room temperature afforded the corre-
sponding pyrrolidinemethanol 1 in 76% yield. The new
* Corresponding author. Tel.: +86-10-6275-6568; fax: +86-10-6275-
1708; e-mail: dudm@pku.edu.cn
0957-4166/$ - see front matter ꢀ 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2003.10.037

178
Y.-X. Zhang et al. / Tetrahedron: Asymmetry 15 (2004) 177–182
chiral C2-symmetric pyridinylmethyl pyrrolidinemetha-
nol derivatives 2 and 4 were synthesized from N-alkyl-
ation of (S)-a,a-diphenyl-2-pyrrolidinemethanol and
activities, which maybe ascribed to the difficultyin
forming the catalytic complex in low temperature. On
the other hand, solvent also has an effect on the
enantioselectivityof the reaction, THF is better than
toluene. These results demonstrated that mono-pyridyl
prolinol ligand in refluxing THF was beneficial for the
improvement of the enantioselectivity. This above result
is the same as the previous reports that the higher
enantioselectivitywas obtained at a higher reaction
temperature.13 Then the reduction of 2-acetylnaphthal-
ene with chiral catalyst 1 was carried out under similar
experimental conditions, the corresponding (R)-a-2-
naphthylethanol was obtained in 98% ee (93% yield) and
45% ee (94% yield) in THF and toluene solution at
reflux, respectively. This result further confirmed that
THF at reflux maintained good enantioselectivities and
this condition was applied to the reduction of other
prochiral ketones. We applied catalyst 1 to the reduction
of various aromatic ketones, and the results are also
shown in Table 1. For the examined ketones, the cata-
lyst 1 gave moderate to high enantioselectivities and
chemical yields. The results show that the reduction of
bromoacetophenone could give a higher enantioselec-
tivity(93% ee) than other ketones such as 1-methly,
1-ethyl, 20-methoxy, and 30-methoxysubstituted aceto-
phenone (entries 6–10). The steric hindrance also had a
significant effect on the reduction reaction, 1-acetyl-
naphthalene, and 1-naphthyl phenyl ketone give lower
enantioselectivityand chemical yield (entries 11 and 12),
this maybe due to the steric repulsion of the substitution
on C1 position of naphthalene.
N-carbonylation of L-proline methyl ester. Treatment of
(S)-a,a-diphenyl-2-pyrrolidinemethanol with 2,6-dibro-
momethylpyridine using K2CO3 as base in ethanol
afforded the corresponding chiral prolinol derivative 2
as a solid in 80% yield. The ligand 4 was easilysynthe-
sized (70% yield) through the lithium aluminum
hydride reduction of compound 3, which was obtained
in 86% yield from with reaction of 2,6-pyridinedi-
carboxylic dichloride with
L-proline methyl ester
hydrochloride in the presence of triethylamine
(Scheme 1).
In order to evaluate the efficiencyof these ligands in the
catalytic asymmetric reduction, we carried out the
enantioselective reduction of ketones with borane. We
first examined the reduction of acetophenone in the
presence of 10 mol % chiral catalyst 1 under various
experimental conditions to find the optimum reaction
conditions (Table 1). When the reaction was carried out
at room temperature in THF, the reduction of ace-
tophenone bythe complex prepared in situ from com-
pound 1 with BH3ÆSMe2 afforded the corresponding
(R)-1-phenylethanol in 62% ee (91% yield). When the
reaction was carried out at reflux, the corresponding
(R)-1-phenylethanol was obtained in 97% ee and 84%
yield (entry 1). When the reaction was carried out in
toluene, the ee value decreased from 97% to 48% (entries
2 and 3), though the yield increased. The results suggest
that the temperature had a significant effect on the
reaction. The best result (97% ee) was obtained at reflux
catalyzed by 1, lower temperatures reduced the catalytic
Also as shown in Table 1, we found that the nature of
catalyst has a dramatic influence on the catalytic activ-
N
K2CO3
C2H5OH
+
Ph
N
HO
Ph
N
H
N
CH2Br
Ph
HO
Ph
1
N
K2CO3
N
N
+
Ph
Ph
BrCH2
N
H
CH2Br
N
C2H5OH
Ph
Ph
HO
Ph
Ph
OH
HO
2
O
O
N
CH2Cl2
Et3N
+
N
N
CO2CH3
COCl
ClOC
N
N
H
CH3O2C
CO2CH3
3
N
LiAlH4
THF
N
N
HOH2C
CH2OH
4
Scheme 1. Synthesis of pyridine prolinol derivatives 1–4.

Y.-X. Zhang et al. / Tetrahedron: Asymmetry 15 (2004) 177–182
179
Table 1. Asymmetric borane reduction of prochiral ketones catalyzed by pyridinyl prolinol ligand 1, 2, and 4
0
EntryLigand
R
R
Solvent
Temp.
Yield (%)a
Ee (%)b
Config.c
1
1
1
1
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
4
4
4
Ph
Ph
Me
Me
Me
Me
Me
Et
THF
THF
Toluene
THF
Toluene
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
rt
91
84
95
93
94
93
95
95
93
93
40
90
92
71
93
90
92
90
90
90
98
98
62
97
48
98
45
86
87
93
84
84
83
39
10
81
54
84
86
53
0
R
R
R
R
R
R
R
S
2
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
3
Ph
4
2-Naphthyl
2-Naphthyl
Ph
5
6
7
Ph
Ph
n-Pr
CH2Br
Me
Me
Ph
8
9
2-MeOPh
3-MeOPh
1-Naphthyl
1-Naphthyl
Et
R
R
R
R
R
R
R
S
10
11
12
13
14
15
16
17
18
19
20
21
22
Me
Me
Me
n-Pr
CH2Br
Me
Ph
Ph
Ph
Ph
2-Naphthyl
2-Naphthyl
Et
R
R
––
––
R
R
Me
Me
Me
Me
Et
Ph
0
7
19
2-Naphthyl
a Isolated yield by chromatographic purification.
b Ee values were determined byHPLC (Daicel Chiracel OB Column, elution with hexane/isopropanol 95:5, 0.5–1.0 mL/min) and Chiral GC (beta
DEX Column).
c
4;14
The absolute configuration of the product was determined bycomparison of the sign of the specific rotation to the literature data.
ity. For example, use of the above optimum reaction
condition in the presence of 10 mol % C2-symmetric
catalysts 2 and 4 gave good chemical yields but with
lower enantioselectivities (entries 14–22). From above
results we can see that: (1) catalyst 1 containing a mono-
prolinol gave the best enantioselectivities; (2) mono-
prolinol catalyst 1 is more effective than C2-symmetric
ligands 2 and 4; (3) the catalyst 2, which has two phenyl
groups on substituent, is move effective than catalyst 4;
(4) the results also indicated that the larger substitution
and no C2-symmetry of ligand is important for
improving the enantioselectivity; (5) the enantioselec-
tivities for the reduction of aromatic ketones are better
than dialkyl ketone (entries 13, 19, and 20). (6) The
stereochemical course of the reductions were the same,
the (R)-isomer of corresponding secondaryalcohol was
formed preferentiallyfor all ketones tested except
a-bromoacetophenone (entries 8 and 16).
In order to obtain direct information of the pyridinyl-
methyl pyrrolidinemethanol ligand, the stereostructure
of ligands 1 was determined byX-raycrystallographic
diffraction analysis.15 Compound 1 was obtained as air-
stable, colorless single crystals upon slow evaporation of
a solution of 1 in ethyl acetate–petroleum ether (v/v 1:1).
A perspective view of compound 1 is shown in Figure 1,
there are two independent molecules in each unit cell of
this molecule. The pyridine ring and pyrrolidine ring has
Figure 1. Perspective view of compound 1, showing 30% probability
ellipsoids for the nonhydrogen atoms and the numbering scheme of the
atoms in the molecule.

180
Y.-X. Zhang et al. / Tetrahedron: Asymmetry 15 (2004) 177–182
dihedral angles 39.5ꢁ (mean planes C19–C20–C21–C22–
C23–N2 and C14–C15–C16–C17–N1) and 57.9ꢁ (mean
planes C42–C43–C44–C45–C46–N4 and C37–C38–
C39–C40–N3), respectively. The two phenyl ringꢀs
dihedral angles are 112.1ꢁ (mean planes C2–C3–C4–C5–
C6–C7 and C8–C9–C10–C11–C12–C13) and 67.7ꢁ
(mean planes C25–C26–C27–C28–C29–C30 and C31–
C32–C33–C34–C35–C36), respectively. The torsion
angles between the pyridine and prollidine rings are
)87.5ꢁ (N1–C18–C19–N2) and )89.9ꢁ (N3–C41–C42–
N4), respectively. From the crystal structure we can see
that the coordination of either of the two nitrogen atoms
to the boron atom mayprovide a chiral environment for
the asymmetric reduction.
prolinol catalysts 2 and 4. These results should provide
useful information for the design of new types of cata-
lysts. The results presented also show that these pyrid-
inyl prolinol compounds may have potential as new
catalysts for other asymmetric reactions. Further mod-
ifications and studies are in progress in our laboratoryin
order to expand the applications of these chiral ligand to
other asymmetric reactions.
3. Experimental section
Melting points were measured on an XT-4 melting point
apparatus and were uncorrected. 1H NMR spectra were
recorded on a Mercury200 MHz or Bruker ARX
400 MHz spectrometer with tetramethylsilane (TMS)
serving as internal standard. Infrared spectra were
obtained on a Bruker Vector 22 spectrometer. Mass
spectra were obtained on a VG-ZAB-HS mass spec-
trometer. Optical rotations were measured on a Perkin–
Elmer 241 MC spectrometer. Elemental analyses were
carried out on an Elementar Vario EL instrument. The
enantiomeric excesses were determined byHPLC anal-
ysis using a chiral column (Daicel Chiralcel OB; eluent,
hexane–isopropyl alcohol 95:5; flow rate, 0.5 mL/min;
UV detector, 254 nm). The absolute configuration of the
major enantiomer was assigned according to the sign of
the specific rotation. Solvents used were purified and
Although the introduction of N-alkyl substituents pre-
vents the formation of N–B covalent bond, an amine–
borane complex could be formed instead of an oxaza-
borolidine. The strong coordination of the pyridinyl
group to borane mayprovide an alternative catalytic
pathway. The following catalytic model may be pro-
posed based on the above explanation (Scheme 2).
Model I is coordination of pyridinyl to borane form an
eight-membered ring, the second borane coordination is
to a pyrrolidine nitrogen atom. Model II is formation of
oxazaborolidine-like five-membered ring, and pyridinyl
nitrogen coordination to the second borane. Both
pathways facilitate the formation of the si-face attack
product. It maybe difficult for the C2-symmetric ligands
2 and 3 to form the above-mentioned complex, consis-
tent with lower selectivities being obtained compared
with 1. As shown in Table 1 the reactivityand the
enantioselectivityare decreased compared to the case of
the corresponding oxazaborolidine catalyzed borane
reduction of ketone, this maybe ascribed to the lower
stabilityof amine–borane complexes compared to
oxazaborolidines.
dried bystandard procedures.
pyrrolidinemethanol was synthesized according to the
( S)-a,a-Diphenyl-2-
literature procedure.16
3.1. (S)-2-(Diphenylmethanol)-l-(2-pyridylmethyl)pyrrol-
idine 1
A solution of (S)-a,a-diphenyl-2-pyrrolidinemethanol
(0.25 g, 1 mmol), 2-bromomethylpyridine hydrobromide
(0.25 g, 1 mmol), potassium carbonate (0.27 g, 2 mmol),
and KI (10 mg) in ethanol (15 mL) was stirred at room
temperature for 10 h. The solution was filtered, the sol-
vent was removed in vacuo and water (50 mL) was
added to the residue. The aqueous solution was
extracted with ethyl acetate (20 mL · 3). The organic
phase was washed with brine and dried with anhydrous
sodium sulfate. The solvent was concentrated and the
crude product was purified bycolumn chromatography
(eluent: petroleum ether–ethyl acetate 1:1) to afford
H
BH2
N
N
H
BH2
BH2
O
Si
R
R
N
Si
BH2
O
O
N
CH3
CH3
O
Ph Ph
Ph
Ph
II
I
Scheme 2.
In conclusion, we have synthesized a series of pyri-
dinylmethyl pyrrolidinemethanol catalysts from (S)-a,a-
diphenyl-2-pyrrolidinemethanol and
colorless solid 0.26 g (76% yield); mp 111–113 ꢁC (lit.12
20
mp 119 ꢁC); ½aŠ ¼ 69.0 (c ¼ 0:98, CHCl3); IR (KBr): m
D
3415, 3068, 2951, 2864, 2829, 1639, 1591, 1482, 1442,
L
-proline methyl
1
ester hydrochloride, respectively. The catalytic activity
for the asymmetric borane reduction of prochiral
ketones was investigated. Moderate to high enantio-
meric excesses and excellent yields were obtained in the
asymmetric borane reduction of prochiral aromatic
ketones catalyzed by 1 or 2, up to 98% ee was afforded
by pyridinyl mono-prolinol catalyst 1. In general, the
pyridinyl mono-prolinol catalyst 1 demonstrated better
enantioselectivitythan the new C2-symmetric pyridinyl
1375, 1309, 1188 cmÀ1; H NMR (CDCl3): d 8.43–8.40
(m, 1H, ArH), 7.71–7.54 (m, 5H, ArH), 7.33–7.04 (m,
8H, ArH), 4.98 (s, 1H, OH), 4.11–4.04 (q, J ¼ 4:6 Hz,
1H, CH), 3.35 (s, 2H, CH2), 3.00–2.95 (m, 1H, CH),
2.58–2.49 (m, 1H, CH2), 1.96–1.61 (m, 4H, CH2); 13C
NMR (50 MHz, CDCl3): 159.58, 148.52, 147.68, 146.34,
136.21, 128.02, 127.92, 126.30, 126.16, 125.55, 122.37,
121.71, 77.93, 70.85, 62.08, 55.63, 29.53, 24.28; MS
(FAB): m=z 345 (M+1)þ; Anal. Calcd for C23H24N2O: C,

Y.-X. Zhang et al. / Tetrahedron: Asymmetry 15 (2004) 177–182
181
80.20; H, 7.02; N, 8.13. Found: C, 80.34; H, 7.13; N,
8.19.
3.4. (S,S)-1,10-(2,6-Pyridinyldimethyl)-bis[2-(hydroxy-
methyl)pyrrolidine] 4
Compound 3 (0.55 g, 1.4 mmol) was dissolved in THF
(30 mL), the mixture heated to reflux, and the suspen-
sion of LiAlH4 (0.45 g, 12 mmol) in THF (25 mL) then
added dropwise. The reaction mixture was further re-
fluxed for 7 h. The reaction mixture was filtered through
Celite, the filter cake was further refluxed with ethanol
for 1 h, and filtered again. The filtrate were combined,
the ethanol was evaporated, the residue was dissolved in
dichloromethane (30 mL) and washed with 2 N HCl
(30 mL). The aqueous phase was adjust to pH ¼ 8 with
saturated NaHCO3 solution. The aqueous phase was
then extracted with dichloromethane (30 mL · 3), dried
over anhydrous Na2SO4. The solvent was concentrated
and the crude product was purified bycolumn chro-
3.2. (S,S)-1,10-(2,6-Pyridinyldimethyl)-bis[2-(diphenyl-
methanol)pyrrolidine] 2
A solution of (S)-a,a-diphenyl-2-pyrrolidinemethanol
0.54 g (2.05 mmol), 2,6-dibromomethylpyridine hydro-
bromide 0.265 g (1 mmol), potassium carbonate (0.4 g,
3 mmol), and KI (10 mg) in ethanol (15 mL) was stirred
at room temperature for 8 h. The solution was filtered,
the solvent was removed in vacuo, and dichloromethane
(30 mL) was added to the residue. The solution was
washed with water and brine (25 mL) for once. The
aqueous solution was extracted with dichloromethane
(30 mL). The combined organic phases was dried with
anhydrous sodium sulfate. The solvent was concentrated
and the crude product was purified bycolumn chro-
matography(eluent: petroleum ether–ethly acetate–
matography(eluent: dichloromethane–methanol 9:1) to
20
D
afford yellow liquid 0.30 g (70% yield); ½aŠ ¼ )29.2
(c ¼ 1:0, CH2Cl2): IR (KBr): m 3380, 2960, 2875, 1655,
1
dichloromethane 1:1:1) to afford colorless solid 0.49 g
1594, 1577, 1459, 1086, 1044 cmÀ1; HNMR (CDCl3): d
20
D
(80% yield); mp 210–212 ꢁC (dec); ½aŠ ¼ +45.0 (c ¼ 0:1,
7.62 (t, J ¼ 7:6 Hz, 1H, ArH), 7.15 (d, 2H, J ¼ 11:4 Hz,
ArH), 4.18 (br s, 2H, OH), 4.11 (d, J ¼ 14 Hz, 2H,
CH2), 3.68 (d, J ¼ 14 Hz, 2H, CH2), 3.64 (dd, J ¼ 2:5,
11.5 Hz, 2H, CH), 3.47 (dd, J ¼ 4:8, 11.5 Hz, 2H, CH),
3.10–3.03 (m, 2H, CH2) 2.85–2.80 (m, 2H, CH2), 2.50–
2.43 (m, 2H, CH2), 1.95–1.87 (m, 2H, CH2), 1.75–1.72
(m, 6H, CH2); 13C NMR (CDCl3): d 158.84, 137.50,
121.38, 65.87, 63.37, 60.09, 55.31, 27.32, 23.44; MS
(FAB): m=z 306 (M+1)þ.
CH2Cl2); IR (KBr): m 3344, 3087, 3030, 2942, 2871,
2831, 2797, 1589, 1575, 1491, 1458, 1449, 1376, 1300,
1170, 1112 cmÀ1 1H NMR (CDCl3): d 7.68–6.84 (m,
;
23H, ArH), 5.20 (s, 2H, OH), 4.12–4.05 (q, J ¼ 4:4 Hz,
2H, CH), 3.30 (s, 4H, CH2), 2.97–2.90 (q, J ¼ 4:6 Hz,
2H, CH2), 2.54–2.41 (q, 2H, J ¼ 8:2 Hz, CH2), 2.01–1.62
(m, 8H); 13C NMR (50 MHz, CDCl3): 159.57, 156.21,
155.31, 147.58, 146.25, 138.02, 137.21, 128.01, 127.91,
126.75, 126.30, 126.17, 126.17, 125.74, 125.54, 122.00,
121.58, 120.75, 77.97, 70.80, 61.69, 55.64, 46.63, 46.31,
29.53, 24.33; MS (FAB): m=z 610 (M+1)þ; Anal. Calcd
for C41H43N3O2: C, 80.75; H, 7.11; N, 6.89. Found: C,
80.91; H, 7.18; N, 6.79.
3.5. Typical procedure for the reduction of prochiral
ketones
BH3ÆSMe2 (0.6 mL, 2 M) was added bysryinge to a
solution of chiral ligand (0.1 mmol) in dryTHF (4 mL)
under nitrogen at 0 ꢁC. The mixture was stirred for
10 min at 0 ꢁC and then was refluxed for 3 h. A solution
of acetophenone (1 mmol) in dryTHF (5 mL) was added
dropwise over a period of 1 h at refluxing temperature.
After refluxing for another 1 h, the cooled reaction
mixture was then quenched bydropwise addition of 10%
NH4Cl (5 mL). The alcohol product was isolated by
extraction with ethyl acetate (10 mL · 3). The organic
phase was washed with brine, dried over anhydrous
sodium sulfate. After concentration byrotatoryevapo-
ration, the product was purified bycolumn chroma-
tographyon silica gel (petroleum ether/ethyl acetate 5:1)
to afford the corresponding alcohol. The enantiomeric
excess were determined byHPLC with a chiral column
(Daicel Chiralcel OB; eluent, hexane–isopropyl alcohol
95:5; flow rate, 0.5 mL/min; UV detector, 254 nm).
3.3. (S,S)-1,10-(2,6-Pyridinyldimethyl)-bis[2-(methoxy-
carboxyl)pyrrolidine] 3
To an ice-cold solution of
L-proline methyl ester
hydrochloride (5.0 g, 30 mmol) in CH2Cl2 (60 mL), Et3N
(8.28 mL, 60 mmol) was added followed bydropwise
addition of 2,6-pyridinedicarbonyl dichloride (2.95 g,
14.5 mmol) in CH2Cl2 (10 mL). The reaction mixture
was stirred for 1 h at 0 ꢁC, and then allowed to warm to
room temperature and stirred for 8 h. The reaction
mixture was washed with saturated citric acid solution
to dissolve the precipitate. The organic layer was sepa-
rated and was washed with water (40 mL), saturated
NaHCO3 solution (40 mL), and water (40 mL). The
organic layer was then dried over anhydrous Na2SO4,
and filtered. The filtrate was concentrated in vacuo to
afford the crude yellow oil, which was recrystallized
from petroleum ether (bp 60–90 ꢁC) to give colorless
solid 4.86 g (86% yield); mp 128–130 ꢁC; IR (KBr): m
3455, 3075, 2980, 2956, 2866, 1738, 1626, 1581, 1569,
3.6. X-ray crystallographic analysis
1
1440, 1399, 1339, 1266, 1173 cmÀ1; HNMR (CDCl3): d
A colorless crystal was selected and mounted on a fine-
focus sealed tube and used for data collection. Cell
constants and an orientation matrix for data collection
were obtained byleast-squares refinement of the dif-
fraction data from 25 reflections in the 2h range from
2.31ꢁ to 27.48ꢁ in a Rigaku AFC6S diffractometer
8.01–7.79 (m, 3H, ArH), 4.88–4.84 (m, 1H, CH), 4.73–
4.61 (m, 1H, CH), 3.94–3.48 (m, 10H, CH3+CH2), 2.35–
2.02 (m, 8H, CH2); MS (FAB): m=z 390 (M+1)þ; Anal.
Calcd for C19H23N3O6: C, 58.60; H, 5.95; N, 10.79.
Found: C, 58.16; H, 5.76; N, 10.73.

182
Y.-X. Zhang et al. / Tetrahedron: Asymmetry 15 (2004) 177–182
3. Itsuno, S.; Ito, K.; Hirao, A.; Nakahama, S. J. Chem.
Soc., Chem. Commun. 1983, 469–470.
4. Corey, E. J.; Bakshi, R. K.; Shibata, S. J. Am. Chem. Soc.
1987, 109, 5551–5553.
equipped with a graphite crystal incident beam mono-
chromator. Data were collected at 293(2) K using MoKa
radiation (k ¼ 0:71073 A) and the x–2h variable-scan
ꢀ
mode. The intensitydata obtained were corrected for
Lorentz and polarization effects. An empirical absorp-
tion correction based on w-scan data was applied. The
crystal structure was resolved by the direct method using
SHELXS97,17 and full-matrix least-squares refinement
on F 2 was performed with SHELXL97 program.18 All
the nonhydrogen atoms were deduced from an E-map
and refined anisotropically. The positions of hydrogen
atoms were generated geometricallyand included in
structure factor calculations with assigned isotropic
thermal parameters. All computations were performed
on a FOUNDER FPþ 5-166 586 personal computer.
5. (a) Molvinger, K.; Lopez, M.; Court, J. Tetrahedron:
Asymmetry 2000, 11, 2263–2266; (b) Ma, M. F. P.; Li, K.
Y.; Zhou, Z. H.; Tang, C. C.; Chan, A. S. C. Tetrahedron:
Asymmetry 1999, 10, 3259–3261; (c) Sato, S.; Watanabe,
H.; Asami, M. Tetrahedron: Asymmetry 2000, 11, 4329–
4340; (d) Santhi, V.; Rao, J. M. Tetrahedron: Asymmetry
2000, 11, 3553–3560; (e) Brunin, T.; Cabou, J.; Bastin, S.;
ꢁ
Brocard, J.; Pelinski, L. Tetrahedron: Asymmetry 2002, 13,
1241–1243.
6. Yang, G. S.; Hu, J. B.; Zhao, G.; Ding, Y.; Tnag, M. H.
Tetrahedron: Asymmetry 1999, 10, 4307–4311.
7. (a) Hu, J. B.; Zhao, G.; Yang, G. S.; Ding, Z. D. J. Org.
Chem. 2001, 66, 303–304; (b) Hu, J. B.; Zhao, G.; Ding, Z.
D. Angew. Chem., Int. Ed. 2001, 40, 1109–1111.
8. (a) Li, K. Y.; Zhou, Z. H.; Wang, L. X.; Chen, Q. F.;
Zhao, G. F.; Zhou, Q. L.; Tang, C. C. Tetrahedron:
Asymmetry 2003, 14, 95–100; (b) Gamble, M. P.; Smith, A.
R.; Wills, M. J. Org. Chem. 1998, 63, 6068–6071.
1: C23H24N2O, FW ¼ 344:44, monoclinic, space group
ꢀ
P(2)1, a ¼ 10:855ð2Þ, b ¼ 7:9683ð16Þ, c ¼ 22:637ð5Þ A;
3
ꢀ
a ¼ 90ꢁ, b ¼ 102:78ð3Þꢁ, c ¼ 90ꢁ, V ¼ 1909:5(7) A , Z ¼
4, F ð000Þ ¼ 736, Dc ¼ 1:198 g/cm3, l ¼ 0:074 mmÀ1
.
€
9. (a) Zhou, H. B.; Lu, S. M.; Xie, R. G.; Chan, A. S. C.;
Crystal size 0.30 · 0.20 · 0.15 mm; index ranges
À14 6 h 6 14, À10 6 k 6 10, À29 6 l 6 28; reflections
collected/unique, 12,691/4640 (Rint ¼ 0:0531); data/
restraints/parameters, 4640/1/514; goodness-of-fit on F 2
0.879; absolute structure parameter: )3(2); extinction
Yang, T. K. Tetrahedron Lett. 2001, 42, 1107–1110; (b)
Zhang, J.; Zhou, H. B.; Liu, S. M.; Luo, M. M.; Xie, R.
G.; Choi, M. C. K.; Zhou, Z. Y.; Chan, A. S. C.; Yang, T.
K. Tetrahedron: Asymmetry 2001, 12, 1907–1912.
10. (a) OꢀNeil, I. A.; Turner, C. D.; Kalindjian, S. B. Synlett
1997, 777–778; (b) Shen, Y. C.; Feng, X. M.; Zhang, G. L.;
Jiang, Y. Z. Synlett 2002, 1353–1355.
coefficient: 0.021(2); final
R
R
indices [I > 2rðIÞ]:
R1 ¼ 0:0493, wR2 ¼ 0:1162;
indices (all data):
R1 ¼ 0:1075, wR2 ¼ 0:1354; largest diff. peak and hole,
11. Chen, X.; Du, D. M.; Hua, W. T. Tetrahedron: Asymmetry
2003, 14, 999–1007.
À3
ꢀ
0.147 and )0.143 e A
.
12. This compound has been synthesized using an alternative
procedure: Chelucci, G.; Falorni, M.; Glacomelli, G.
Tetrahedron: Asymmetry 1990, 1, 843–849.
13. Brunel, J. M.; Maffei, M.; Buono, G. Tetrahedron:
Asymmetry 1993, 4, 2255–2260.
Acknowledgements
14. (a) Itsuno, S.; Nakano, M.; Miyazaki, K.; Masuda, H.;
Ito, K. J. Chem. Soc., Chem. Commun. 1985, 2039–2044;
(b) Chen, C. P.; Prasad, K.; Repic, O. Tetrahedron Lett.
1991, 32, 7175–7178; (c) Mathie, D. J.; Thompson, A. S.;
Douglas, A. W.; Hoogsteen, K.; Carroll, J. D.; Corley, E.
G.; Grabowski, E. J. J. J. Org. Chem. 1993, 58, 2880–2888.
15. Crystallographic data (excluding structure factors) for the
structures in this paper have been deposited with the
Cambridge Crystallographic Data Centre as supplemen-
tarypublication number CCDC-215883. Copies of the
data can be obtained, free of charge, on application to
CCDC, 12 Union Road, Cambridge CB2 1EZ, UK [fax:
+44(0)-1223-336033 or e-mail: deposit@ccdc.cam.ac.uk].
16. Corey, E. J.; Shibata, S.; Bakshi, R. K. J. Org. Chem.
1988, 53, 2861–2863.
Project supported bythe National Natural Science
Foundation of China (grant no. 20172001 and
20372001) and Peking University.
References and Notes
1. (a) Deloux, L.; Srebnik, M. Chem. Rev. 1993, 93, 763–784;
(b) Corey, E. J.; Helal, C. J. Angew. Chem., Int. Ed. Engl.
1998, 37, 1986–2012; (c) Schunicht, C.; Biffis, A.; Wulff, G.
Tetrahedron 2000, 56, 6041.
2. (a) Togni, A.; Venanzi, L. M. Angew. Chem., Int. Ed. Engl.
1994, 33, 497–526; (b) Larsen, R. D.; Corley, E. G.; King,
A. O.; Carroll, J. D.; Davis, P.; Verhoeven, T. R.; Reider,
P. J.; Labelle, M.; Gauthier, J. Y.; Xiang, Y. B.; Zamboni,
R. J. J. Org. Chem. 1996, 61, 3398–3405; (c) Ponzo, V. L.;
Kaufman, T. S. Tetrahedron Lett. 1995, 36, 9105–9108.
17. Sheldrick, G. M. SHELXS-97. Program for the Solution of
Crystal Structures, Universityof Goettingen, German,y
1997.
18. Sheldrick, G. M. SHELXL-97. Program for the Refine-
ment of Crystal Structure, Universityof Goettingen,
Germany, 1997.