A convenient synthesis of piperidine-based β-amino alcohols from L-Phe and highly enantioselective addition of diethyl zinc to aldehydes

Article abstract of DOI:10.1016/S0957-4166(03)00122-8

β-Amino alcohols 4a-e were easily prepared from L-phenylalanine in three simple straightforward steps. The key intermediate compound (S)-3 was achieved in high yield (up to 92%) with glutaraldehyde and NaBH₄/H₂SO₄ in THF at room temperature. These five ligands were applied to catalyze enantioselective addition of diethyl zinc to aldehydes, high asymmetric induction was observed with 4c and 4e, and the ee value was up to 98%. The effect of the substitutes on the nitrogen atom was also observed via comparing piperidine-based amino alcohols with pyrrolidine-based similar ligands.

Full text of DOI:10.1016/S0957-4166(03)00122-8

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 14 (2003) 659–665
A convenient synthesis of piperidine-based b-amino alcohols from
L
-Phe and highly enantioselective addition of diethyl zinc to
aldehydes
Chao-shan Da, Zhi-jian Han, Ming Ni, Fan Yang, Da-xue Liu, Yi-feng Zhou and Rui Wang*
Department of Biochemistry & Molecular Biology, School of Life Sciences, Lanzhou University, Lanzhou 730000, China
Received 16 October 2002; revised 1 December 2002; accepted 2 December 2002
Abstract—b-Amino alcohols 4a–e were easily prepared from
L-phenylalanine in three simple straightforward steps. The key
intermediate compound (S)-3 was achieved in high yield (up to 92%) with glutaraldehyde and NaBH4/H2SO4 in THF at room
temperature. These five ligands were applied to catalyze enantioselective addition of diethyl zinc to aldehydes, high asymmetric
induction was observed with 4c and 4e, and the ee value was up to 98%. The effect of the substitutes on the nitrogen atom was
also observed via comparing piperidine-based amino alcohols with pyrrolidine-based similar ligands. © 2003 Elsevier Science Ltd.
All rights reserved.
1. Introduction
azacyclo products are always low. Furthermore, the
diiodoalkanes are expensive and unstable.
Among the numerous methods available for CꢀC bond
formation, the enantioselective addition of organozinc
to aldehydes appears to be one of the most useful
methods and remains the focus of much research activ-
ity as evidenced by hundreds of research papers and
several review articles.1,2 Our group have continuously
centered our interest on developing efficient chiral cata-
lysts with cheap starting materials as well as easy and
straightforward synthetic methods via short steps.3 Nat-
ural amino acids form one of the best and the cheapest
available chiral pools and many chiral ligands have
been developed from them.4 Herein we report our
preparation of piperidine-based b-amino alcohols con-
In searching for a good substituent synthetic method,
we observed that Vyskocˇil et al.7 had reported an
efficient way for the synthesis of C2-chiral N-alkylated
NOBIN, which used reductive alkylation with a series
of ketones and NaBH4/H2SO4 in THF at room temper-
ature within only 15–30 min. But we could not find
examples of this protocol employed to the alkylamine
for azacircle synthesis. Although some results had been
disclosed using similar reductive alkylation method to
prepare the pyrrolidine or piperidine ring with sodium
cynoborohydride under acidic circumstances, that
reported process covered longer reaction time and did
not achieve so high yield as this novel method.8 In spite
of this, we decided to make an effort to our designed
amino alcohols with this process. If successful, this
protocol would open a straightforward entry into many
piperidine-based amino alcohols derived from amino
acids. After several trials, this method proved to be
very successful and efficient (Scheme 1). After the typi-
veniently as well as efficiently from L-phenylalanine and
its application to highly enantioselective addition of
diethyl zinc to aldehydes.
2. Results and discussion
The azacyclo b-amino alcohols are among the most
efficient chiral ligands reported in this catalytic asym-
metric reaction,5 and many of them were derived from
amino acids.3a,4a The aza ring is usually synthesized
with diiodoalkanes and potassium carbonate in
MeCN.6 By this method, however, the yields of the
cal methyl esteration of -phenylalanine, (S)-2 in THF
L
and solid NaBH4 were simultaneously introduced into
the reaction bottle containing 20% H2SO4 and glutaric
dialdehyde at ambient temperature. This reductive
alkylation afforded the desired piperiding-containing
compound (S)-3 in 92% yield within 30 min.9 The
successively reaction of the Grignard reagents
with (S)-3 achieved amino alcohols 4a–d10 in 60–92%
yields.
* Corresponding author. Tel.: +86-931-891-2567; fax: +86-931-891-
2561; e-mail: dachaoshan@lzu.edu.cn
0957-4166/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0957-4166(03)00122-8

660
C. Da et al. / Tetrahedron: Asymmetry 14 (2003) 659–665
solvent, hexane was the best (entry 5). Toluene obvi-
ously made the reaction sluggish and afforded lower
enantioselectivity (entry 9). Under room temperature
condition, the enantioselectivity did not change signifi-
cantly (entry 10).
Under such optimized reaction conditions, ligand 4c
was subsequently employed to induce the enantioselec-
tive addition of diethyl zinc to a representative family
of aromatic aldehydes. The results are shown in Table
2. Except for two examples, most aldehydes afforded
Table 2. Asymmetric addition of diethylzinc to aldehydes
promoted by ligand 4c
Scheme 1. Preparation of b-amino alcohols from L-Phe.
Entry Aldehydes
Yield (%)a Ee (%)a Config.b
Ligands (S)-4a–d were initially tested in the asymmetric
addition of diethyl zinc to benzaldehyde (Table 1). The
results showed that ligands 4a and 4d possessing rigid
substituents at the carbon of the hydroxyl group
afforded low enantioselectivity (entries 1 and 4) than
ligands 4b and 4c (entries 2 and 3). Ligand 4d has the
most rigid substitute and gave the lowest ee, but ligand
4c possesses the most flexible substituent and gave the
highest ee value. Another interesting phenomenon that
could be observed was that the bulkier the substituents
at the carbon of the hydroxyl groups, the more efficient
the chemical catalytic activity obtained. The velocity of
the reactions promoted by ligands 4a and 4c was much
faster than ligands 4b and 4d (entries 1–4). The relative
configurations of the resultant alcohols catalyzed by
4a–d, all were R.
1
Benzaldehyde
98
99
99
99
96
96
95
94
96
98
98
96
32
30
37
96
97
93
97
94
95
96
92
90
83
94
88
83
54
74
R
R
R
R
R
R
R
R
R
R
R
R
2
4-Fluorobenzaldehyde
2-Chlorobenzaldehyde
4-Chlorobenzaldehyde
3-Bromobenzaldehyde
3-Tolualdehyde
3c
4
5d
6
7
8
9
10
11
12
13e
14e
15e
4-Tolualdehyde
a-Naphthaldehyde
b-Naphthaldehyde
2-Anisaldehyde
3-Anisaldehyde
4-Anisdaldehyde
Isobutyraldehyde
Lauraldehyde
Crotonaldehyde
a The yield and ee value are determined by chiral HPLC with Chiracel
OD column.
b Assigned by the retention time of the major peak of the isomers11
and the direction of optical rotation with the literature.7a
c 12% ligand 4c was used.
It could be obviously seen that ligand 4c was the most
efficient asymmetric catalyst among these four ligands.
When 4% 4c equivalent to benzaldehyde was used, the
enantioselectivity was up to 96% (entry 5). Increasing
the amount of the catalyst could not cause higher
asymmetric induction (entries 5–7). For the promising
d 10% 4c was used.
e 15% 4c was used and the ee was measured by analyzing the benzoate
of the alcohol by HPLC with Daicel chiracel OD column.3b The
yield was isolated yield of the benzoate of the alcohol.
Table 1. Enantioselective addition of diethylzinc to benzaldehyde catalyzed by ligands 4a–d
Entry
Liganda
Solvent
Time (h)
Yield (%)b
Ee (%)b
Config.c
1
2
3
4
5
6
7
8
4a (2%)
4b (2%)
4c (2%)
4d (2%)
4c (4%)
4c (7%)
4c (10%)
4c (4%)
4c (4%)
4c (4%)
Hexane
Hexane
Hexane
Hexane
Hexane
Hexane
Hexane
Benzene
Toluene
Hexane
4
20
6
20
5
5
5
10
36
4
99
95
99
86
98
96
98
93
95
96
62
64
89
46
96
95
95
93
89
93
R
R
R
R
R
R
R
R
R
R
9
10d
a The number in the bracket was the employed amount of the ligands.
b Determined by chiral HPLC with Chiracel OD column.
c Determined by the retention time of the major peak of the isomers11 and the direction of optical rotation with the literature.7a
d The reaction was performed under room temperature.

C. Da et al. / Tetrahedron: Asymmetry 14 (2003) 659–665
661
high enantioselectivity and the ee value was up to 97%.
When alkyl aldehydes were used as substrates, the ee
value was also afforded as high as 84%. The a-branched
alkyl aldehydes gave the highest ee among the three
aldehydes. a,b-Unsaturated alkyl aldehydes afforded
good enantioselectivity, but the linear alkyl aldehyde
gave the poorest ee value (entries 13–15).
The efficient enantioselectivity of 4c made us to like to
prepare more bulky subsituents on the carbon of the
hydroxy group and to discover their effects in this
asymmetric reaction. 4e which possessing two propyl
substituents was readily synthesized as the same
efficient course (Scheme 1) with 91% yield. But the
more bulkier ligand with two isopropyl substituents
could not be succeeded due to the isopropyl group too
large to achieve the desired 1,2-amino alcohol but get
the intermediate ketone product, and optical rotation
value of the recovery (S)-3 showed heavily racemization
when it was exposed in this bulky strong base long
time.
Scheme 2. Synthesis of pyrrlidine-based 1,2-amino alcohols.
Ligand 4e was successively applied to catalyze the
enantioselective addition of diethyl zinc to aldehydes
(Table 3). The results showed that ligand 4e also had
high asymmetric catalytic activity. The reaction time
with it was similar to ligand 4c, and so the reaction also
behaved fast reactive velocity (Table 3, entry 1). For
some aldehydes compared to ligand 4c, higher enan-
tioselectivity had been succeeded, and the ee up to 98%
was achieved (entry 5).
and 63% yield. Then the two compounds were allowed
to react with 1,4-dibromobutane and K2CO3 in dry
MeCN. This process afforded two pyrrolidine-based
b-amino alcohols 6a and 6b. But to our surprised, the
diethyl product had too lower yield compared to the
biphenyl ligand. Although we repeated the diethyl lig-
and’s preparation, no obvious increase of it was
achieved. This might be the flexible diethyl group
blocking formation of the pyrrolidinyl ring. Of cause
the dibromo substituted alkane might be the one main
cause of the low yield.
For checking the effects of the substituents of the
nitrogen atom on the asymmetric induction, we pre-
pared two pyrrolidine-based 1,2-amino alcohols.
Although these two ligands may be succeeded accord-
ing to this novel efficient method, we synthesized them
using the traditional course with dihaloalkane6 (Scheme
2) due to 1,4-butanedialdehyde was not commercial
available. Salt of (S)-2 with hydrogen chloride was
introduced with freshly prepared PhMgBr or EtMgBr
to afford the Grignard products 5a and 5b with 70%
Ligands 6a and 6b were applied to induct this asymmet-
ric reaction. Out of our good expectation on them,
these two ligands showed both of poor chemical and
enantioselective catalytic activity (Table 4). Compared
with 4c and 4a, the reaction changed much more slug-
gish, and the enantioselectivity was drastically low.
Low reaction temperature could only increase the ee
value slightly. Another interesting results could be
observed that ligand 6b which possessed diethyl sub-
stituents did not had much higher superiority in asym-
metric induction to 6a having biphenyl groups,
although 6b afforded higher ee than 6a similarly.
Table 3. Enantioselective addition of diethyl zinc to alde-
hydes promoted by ligand 4ea
Entry Aldehydes
Ee (%)b Yield (%)b Config.c
1d
2e
3
Benzaldehyde
97
95
90
97
98
96
47
98
99
99
98
95
99
96
R
R
R
R
R
R
R
2-Chlorobenzaldehyde
a-Naphthaldehyde
b-Naphthaldehyde
3-Bromobenzaldehyde
m-Tolualdehyde
3. Conclusion
4f
5
We have conveniently synthesized five piperidine-based
chiral amino alcohols from natural phenylalanine in
three steps. Compared with reported methods, the
preparative protocol of the compound (S)-3 made the
synthesis of piperidine ring quite efficient. Ligand 4c
and 4e proved to be efficient chiral catalysts in the
highly enantioselective addition of diethyl zinc to alde-
hydes. And the piperidine-based 1,2-amino alcohols
showed much superior in both of chemical catalytic
activity and asymmetric induction to the pyrrolidinyl-
based ligands derived from the same chiral resource.
6
7
p-Anisaldehyde
a 4% ligand 4e used.
b The yield and ee value are determined by chiral HPLC with
Chiracel OD column.
c Assigned by the retention time of the major peak of the isomers and
the direction of optical rotation with the literature.
d The reaction lasted for 5 h.
e 12% ligand 5e was used.
f 8% ligand 6e was used.

662
C. Da et al. / Tetrahedron: Asymmetry 14 (2003) 659–665
Table 4. Catalytic addition of diethyl zinc to benzaldehyde catalyzed by ligands 6a and 6b
Entry
Ligand (4%)
Time (h)
Ee (%)c
Yield (%)c
Config.d
1
2
3
4
6aa
6ab
6ba
6bb
24
21
24
22
31
42
50
49
96
95
96
98
R
R
R
R
a The reaction was performed under ambient temperature after stirring for 0.5 h at 0°C.
b The reaction was performed at 0°C.
c Determined by chiral HPLC with Chiracel OD column.
d Assigned by the retention time of the major peak of the isomers and the direction of optical rotation with the literature.
4. Experimental
4.1. General methods
4.3. General procedure for preparation of (S)-3-phenyl-
2-piperidinopropionic acid methyl ester, (S)-(−)-3
A solution of 1.0 g (5.58 mmol) (S)-(+)-2 in 56 ml THF
and solid NaBH4 1.477 g (39.05 mmol) were slowly
added (simultaneously) to a solution of 50% glutaralde-
hyde 11.9 ml (66.95 mmol) and 20% H2SO4 5.6 ml in 28
ml THF over a period of 15 min at room temperature.
The reaction mixture was stirred for additional 15 min
and then was introduced with diluted aqueous KOH to
pH 9.0. The resulting suspension was extracted with
ethyl acetate three times, and the combined organic
layer was washed with brine and dried with anhydrous
Na2SO4. The crude product was purified by chromatog-
raphy on silica gel to give the piperidine-based a-amino
ester (S)-3 as a yellow oil 1.27 g, 92%; [h]1D9=−30.2 (c
4.11, CH3COOC2H5); 1H NMR (400 MHz): l 7.18–
7.27 (m, 5H, Ph-H), 3.58 (s, 3H, CH3), 3.39–3.43 (dd,
1H, CHCO, J=5.2 Hz, J=9.8 Hz), 3.04–3.10 (dd, 1H,
PhCH, J=13.2 Hz), 2.93–2.97 (dd, 1H, PhCH), 2.62–
2.67 (m, 2H, NCH2), 2.50–2.55 (m, 2H, NCH2), 1.55–
1.61 (m, 4H, CH2), 1.43–1.46 (m, 2H, CH2); IR (KBr):
3062, 3027, 2933, 2852, 2808, 1733, 1652, 1603, 1495,
1451, 1348, 1195, 1155, 1113, 1054, 1033, 1005, 748, 699
cm−1; HR-MS calcd for (M+H)+: 248.1645, found:
248.1641.
All reactions were carried out under an argon atmo-
sphere condition and solvents were dried according to
established procedures. Reactions were monitored by
thin layer chromatography (TLC), Column chro-
matography purifications were carried out using silica
gel. All aldehydes and
L-phenylalanine were pur-
chased from Acros or Fluka. Diethyl zinc was pre-
pared from EtI with Zn and then was diluted with
hexane to 1.0 M. Melting points was uncorrected and
recorded on X-4 melting point apparatus. 1H NMR
spectra were measured on Bruker Am 400 MHz and
DRX-200 MHz spectrometers (NMR in CDCl3 with
TMS as an internal standard). IR spectra were
obtained on a Nicolet AVATAR 360 FT-IR. Optical
rotations were recorded on a Perkin–Elmer 341 polar-
imeter. HR-MS were measured with an APEX II 47e
mass spectrometer and the ESI-MS was recorded on
a Mariner® biospectrometer. The ee value determina-
tion was carried out using chiral HPLC with a Daicel
Chiracel® OD column on Waters® with a 996 UV-
detector.
4.2. Preparation of (S)-phenylalanine methylester, (S)-
(+)-2
4.4. General procedure for preparation of (S)-4 via the
reaction of (S)-(−)-3 with Grignard reagents
To a mixture of 9.7 g (58.8 mmol)
L-phe in 300 ml
A solution of 497 mg (2 mmol) (S)-3 in 3 ml ether was
added dropwise under argon atmosphere at 0°C to a
solution of RMgBr (10 mmol)† in diethyl ether, which
was freshly prepared in the usual way. The reaction was
then stirred at room temperature over 4 h. When the
reaction was complete checked by TLC, cold saturated
aqueous NH4Cl was dropped into the mixture under
vigorous stirring. Then the mixture was extracted with
ether three times. The combined solvent was washed
with brine and dried with anhydrous Na2SO4, concen-
trated in vacuum and the crude amino alcohol was
purified by column Chromatography with petroleum
ether and ethyl acetate as mobile phase.
methanol was given dropwise at −30°C SOCl2 21.53
ml (294.95 mmol). After warming up to room tem-
perature the reaction mixture was refluxed for 2 h.
The organic solvent was concentrated in vacuum, and
then the residue was introduced with NH3·H2O into
pH 9.0 or so. The mixture was extracted three times
with Et2O. The combined organic layers were washed
with little brine, dried over anhydrous Na2SO4 and
concentrated in vacuum, then obtained 10.0 g (S)-2,
95%; [h]2D3=+25.0 (c 4.04, C2H5OH); 1H NMR (200
MHz): l 7.11–7.30 (m, 5H, Ph-H), 3.65–3.71 (m, 4H,
CHN, CH3, J=5.2 Hz, J=8.0 Hz), 2.99–3.08 (dd,
1H, PhCH, J=13.4 Hz), 2.74–2.85 (dd, 1H, PhCH),
1.44 (s, 2H, NH2); IR (KBr): 3380, 3314, 3061, 3028,
2950, 2852, 1738, 1602, 1495, 1438, 1276, 1198, 1174,
1112, 1076, 1010, 839, 747, 701 cm−1; ESI-MS for
(M+H)+: 180.
† The Grignard reagents used for (S)-4b and (S)-4d were CH3MgI
and BrMg(CH2)4MgBr, respectively.

C. Da et al. / Tetrahedron: Asymmetry 14 (2003) 659–665
663
4.4.1. (S)-1,1,3-Tripheny-2-piperidinopropan-1-ol, (S)-(+)-
4a. A pale yellow oil, 610 mg, 82%; [h]2D0=+39.0 (c 1.0,
cm−1; HR-MS cacld. For (M+H)+: 304.2635, found:
304.2635.
1
CH3COOC2H5); H NMR (400 MHz): l 7.57 (d, 2H,
Ph-H, J=7.6 Hz), 7.51 (d, 2H, Ph-H, J=7.4 Hz),
7.21–7.37 (m, 11H, Ph-H), 6.42 (br., 1H, OH), 3.69–
3.92 (dd, 1H, CHN, J=1.9 Hz, J=12.1 Hz), 3.14–3.17
(dd, 1H, PhCH, J=14.7 Hz), 2.70–2.77 (dd, 1H,
PhCH), 2.39 (br., 2H, NCH2), 1.99–2.05 (m, 2H,
NCH2), 1.33–1.41 (m, 4H, CH2), 1.23–1.28 (m, 2H,
CH2); IR (KBr): 3268 (br.), 3058, 3026, 2931, 2849,
2822, 1600, 1493, 1445, 1276, 1159, 1109, 1050, 1029,
758, 727, 699, 662, 635 cm−1; HR-MS calcd for (M+H)+
: 372.2322, found: 372.2323.
4.5. General procedure for preparation of pyrrolidine-
containing ligands 6a and 6b
4.5.1. Preparation of (S)-1,1,3-tripheny-2-aminopropan-
1-ol, (S)-(−)-5a. The hydrogen chloride salt of (S)-2
(the work-up of preparation of (S)-2 was not intro-
duced with diluted base but directly concentrated and
then afforded the salt) 1.0775 g (5 mmol) was intro-
duced with freshly prepared Grignard reagent PhMgBr
(50 mmol) in the usual way under 0°C and argon
atmosphere in diethyl ether. Then the mixture was
stirred at ambient temperature overnight, and cold
saturated NH4Cl was dropped into it under vigorous
stirring. The mixture was extracted with ethyl acetate
three times. The combined organic layer was washed
with brine and dried with anhydrous Na2SO4, concen-
trated in vacuum. This residue was recrystallized with
ethyl acetate and petroleum ether and gave 5a as a
colorless crystal, 70% yield (1.06 g); mp 134–136°C;
[h]2D1=−86.0 (c 1.53, CH2Cl2); 1H NMR (400 M): l 7.66
(d, 2H, Ph-H, J=7.4 Hz), 7.62 (d, 2H, Ph-H, J=7.9
Hz), 4.52 (br, 1H, OH), 4.18–4.21 (q, 1H, CHN, J=2.5
Hz, J=10.9 Hz), 2.64–2.68 (dd, 1H, PhCH, J=13.9
Hz), 2.43–2.49 (dd, 1H, PhCH), 1.21 (s, 2H, NH2); IR
(KBr): 3396 (br.), 3243, 3082, 3057, 3023, 2919, 2850,
1594, 1491, 1445, 1364, 1321, 1273, 1168, 1105, 1056,
1028, 958, 900, 857, 749, 700 cm−1; HR-MS calcd For
(M+H)+: 304.1696, found: 304.1696.
4.4.2. (S)-2-Methyl-4-phenyl-3-piperidinobutan-2-ol, (S)-
(−)-4b. 479 mg, 97%. Needles, mp 58–59°C; [h]2D0=
1
−49.0 (c 1.0, CH3COOC2H5); H NMR (400 MHz): l
7.21–7.30 (m, 5H, Ph-H), 5.14 (s, 1H, OH), 2.89–2.95
(dd, 1H, PhCH, J=9.6 Hz, J=13.8 Hz), 2.72–2.83 (dq,
2H, CHN, PhCH, J=−3.8 Hz), 2.48–2.57 (m, 4H,
NCH2), 1.40–1.56 (m, 4H, CH2), 1.31 (br., 2H, CH2),
1.20 (s, 3H, CH3), 1.19 (s, 3H, CH3); IR (KBr): 3418
(br.), 3061, 3026, 2968, 2929, 2851, 2815, 1602, 1494,
1453, 1383, 1363, 1159, 1103, 1034, 1012, 966, 756, 731,
698 cm−1; HR-MS calcd for (M+H)+: 248.2009, found:
248.2005.
4.4.3. (S)-3-Ethyl-1-phenyl-2-piperidinopentan-3-ol, (S)-
(−)-4c. Pale yellow oil, 506 mg, 92%; [h]2D0=−26.0 (c 1.0,
1
CH3COOC2H5); H NMR (400 MHz): l 7.18–7.30 (m,
5H, Ph-H), 3.00–3.05 (dd, 1H, CHN, J=3.2 Hz, J=
10.7 Hz), 2.87–2.93 (q, 1H, PhCH, J=14.4 Hz), 2.73–
2.77 (d, 1H, PhCH), 2.53 (br., 4H, NCH2), 1.44–1.50
(m, 6H, CH2), 1.26–1.30 (m, 4H, CH2Me), 0.959 (t, 3H,
CH3, J=7.3 Hz), 0.952 (t, 3H, CH3, J=7.1 Hz); IR
(KBr): 3585, 3389 (br), 3066, 3026, 2931, 2852, 1715,
1656, 1494, 1455, 1397, 1374, 1157, 1105, 1033, 957,
727, 698 cm−1; HR-MS calcd for (M+H)+: 276.2322,
found: 276.2327.
4.5.2. Preparation of (S)-3-ethyl-1-phenyl-2-aminopen-
tan-3-ol, (S)-(−)-5b. Compound 5b was prepared using
the same procedure as 5a. After the usual work-up, the
residue was introduced with acetic acid 90% equivalent
to the starting salt of (S)-2, recrystallized the ammo-
nium salt with little THF and afforded a colorless
crystal with mp: 92–94°C, [h]1D9=−39.0 (c 0.94, CHCl3).
After that, the crystals was treated with dilute NaOH
and extracted with ethyl acetate, which was then dried
and concentrated to afford (S)-5b as a pale yellow oil
with 63% yield (652 mg); [h]2D1=−41 (c 1.83, CH2Cl2);
1H NMR (400 MHz): l 7.19–7.35 (m, 5H, Ph-H),
2.97–3.00 (q, 1H, CHN, J=3.5 Hz, J=9.0 Hz), 2.29–
2.35 (q, 2H, PhCH2, J=12.0 Hz), 1.44–1.57 (m, 4H,
CH2), 1.11 (s, 2H, NH2), 0.97 (t, 3H, CH3, J=7.3 Hz),
0.96 (t, 3H, CH3); IR (KBr): 3391 (br.), 3059, 3026,
2964, 2926, 2851, 1595, 1494, 1457, 1397, 1376, 1316,
1260, 1153, 1076, 1028, 952, 750, 697 cm−1; HR-MS
calcd for (M+H)+: 208.1696, found: 208.1701.
4.4.4. (S)-(−)-1-(2%-Phenyl-1%-piperidinoethyl)cyclopenta-
nol, (S)-(−)-4d. Yield 60%, a pale yellow oil; [h]2D0=
1
−26.0 (c 1.0, CH3COOC2H5); H NMR (400 MHz): l
7.20–7.31 (m, 5H, Ph-H), 3.04–3.07 (dd, 1H, CHN,
J=3.6 Hz, J=9.6 Hz), 2.90–2.96 (dd, 1H, PhCH, J=
14.4 Hz), 2.62–2.66 (dd, 1H, PhCH), 2.44–2.51 (m, 4H,
NCH2), 1.63–1.70 (m, 6H, CH2), 1.41–1.56 (m, 6H,
CH2), 1.31–1.34 (m, 2H, CH2); IR (KBr): 3592, 3335
(br.), 3025, 2931, 2852, 1730, 1652, 1602, 1493, 1447,
1383, 1157, 1104, 1031, 998, 730, 698 cm−1; HR-MS
calcd for (M+H)+: 274.2165, found: 274.2171.
4.4.5. (S)-3-Propyl-1-phenyl-2-piperidinohexan-3-ol, (S)-
(−)-4e. 91% (551 mg), a pale yellow oil; [h]2D2=−29.0 (c
1.7, CH3COOC2H5); 1H NMR (200 M): l 7.20–7.30 (m,
5H, Ph-H), 4.47 (br., 1H, OH), 2.96–3.03 (dd, 1H,
CHN, J=10.4 Hz, J=2.8 Hz), 2.84–2.89 (d, 1H,
PhCH,, J=12.6 Hz), 2.72–2.78 (dd, 1H, PhCH,), 2.49–
2.54 (m, 4H, NCH2), 1.41–1.51 (m, 8H, CH2), 1.26–1.36
(m, 6H, CH2), 0.93 (t, 3H, CH3), 0.91 (t, 3H, CH3,
J=7.0 Hz); IR (KBr): 3443 (br.), 3062, 3026, 2956,
2928, 2853, 1602, 1494, 1457, 1398, 1375, 1344, 1311,
1159, 1107, 1076, 1034, 1005, 912, 859, 763, 729, 698
4.5.3. (S)-1,1,3-Tripheny-2-pyrrolidinopropan-1-ol, (S)-
(+)-6a. Typical procedure for the preparation of (S)-6:
To a solution of 909 mg (3 mmol) (S)-5a in acetonitrile,
1,4-dibromobutane 0.36 ml (3 mmol), and anhydrous
potassium carbonate 828 mg (6 mmol) were added, and
the mixture was reflued for 24 h. After filtration of the
reaction mixture and evaporation, the residue was dis-
solved in diethyl ether, washed with little water and
dried over anhydrous Na2SO4. Then the residue was
concentrated and purification via column chromatogra-
phy to give (S)-6a as pale yellow oil with 48% yield

664
C. Da et al. / Tetrahedron: Asymmetry 14 (2003) 659–665
1
(514 mg); [h]D19=+14 (c 1.07, CH3COOC2H5); H NMR
(400 MHz): l 7.61 (d, 2H, Ph-H, J=7.5 Hz), 7.56 (d,
2H, Ph-H, J=7.5 Hz), 7.18–7.37 (m, 11H, Ph-H), 4.25–
4.27 (d, 1H, CHN, J=11.2 Hz), 3.07–3.11 (d, 1H,
PhCH, J=14.7 Hz), 2.84–2.90 (dd, 1H, PHCH), 2.59–
2.63 (m, 2H, NCH2), 2.22–2.23 (m, 2H, NCH2), 1.42–
1.54 (m, 4H, CH2); IR (KBr): 3377 (br.), 2924, 1595,
1486, 1445, 1375, 1312, 1164, 1124, 1027, 748, 702
cm−1; HR-MS calcd For (M+H)+: 358.2165, found:
358.2161.
(c) Noyori, R.; Kitamura, M. Angew. Chem., Int. Ed.
Engl. 1991, 30, 49.
2. For some excellent results on enantioselective addition of
organozinc to aldehydes, see: (a) Nugent, W. A. Org.
Lett. 2002, 4, 2133; (b) Fontserat, M.; Verdaguer, X.;
Sola`, L.; Vidal-Ferran, A.; Reddy, K. S.; Riera, A.;
Perica`s, M. A. Org. Lett. 2002, 4, 2381; (c) Priego, J.;
Mancheno, O. G.; Cabrera, S.; Carretero, J. C. J. Org.
Chem. 2002, 67, 1346; (d) Chen, Y. K.; Costa, A. M.;
Walsh, P. J. J. Am. Chem. Soc. 2001, 123, 5378; (e) Wipf,
P.; Wang, X. Org. Lett. 2002, 4, 1197–1200; (f) Huang,
W. S.; Hu, Q. S.; Pu, L. J. Org. Chem. 1998, 63, 1364.
3. (a) Yang, X. W.; Shen, J. H.; Da, C. S.; Wang, R.; Choi,
M. C. K.; Yang, L. W.; Wong, K. Y. Tetrahedron:
Asymmetry 1999, 10, 133; (b) Yang, X. W.; Shen, J. H.;
Da, C. S.; Wang, H. S.; Su, W.; Wang, R.; Chan, A. S.
C. J. Org. Chem. 2000, 65, 295; (c) Yang, X. W.; Su, W.;
Liu, D. X.; Wang, H. S.; Shen, J. H.; Da, C. S.; Wang,
R.; Chan, A. S. C. Tetrahedron 2000, 56, 3511; (d) Yang,
X. W.; Shen, J. H.; Da, C. S.; Wang, H. S.; Su, W.; Liu,
D. X.; Wang, R.; Choi, M. C. K.; Chan, A. S. C.
Tetrahedron Lett. 2001, 42, 6573; (e) Liu, D. X.; Zhang,
L. C.; Wang, Q.; Da, C. S.; Xin, Z. Q.; Wang, R.; Choi,
M. C. K.; Chan, A. S. C. Org. Lett. 2001, 3, 2733.
4. For selected examples from natural amino acids, see: (a)
Soai, K.; Ookawa, A.; Kaba, T.; Ogawa, K. J. Am.
Chem. Soc. 1987, 109, 7111; (b) Okaniwa, M.; Yanada,
R.; Ibuka, T. Tetrahedron Lett. 2000, 8, 1047; (c) Delair,
P.; Einhorn, C.; Einhorn, J.; Luche, J. L. J. Org. Chem.
1994, 59, 4680–4682; (d) Kossenjans, M.; Martens, J.
Tetrahedron: Asymmetry 1998, 9, 1409; (e) Dai, W. M.;
Zhu, H.; Hao, X. J. Tetrahedron: Asymmetry 2000, 11,
2315; (f) Beliczey, J.; Giffels, G.; Kragl, U.; Wandrey, C.
Tetrahedron: Asymmetry 1997, 8, 1529; (g) Wolf, C.;
Francis, C. J.; Hawes, P. A.; Shah, M. Tetrahedron:
Asymmetry 2002, 13, 1733.
4.5.4. (S)-3-Ethyl-1-phenyl-2-pyrrolidinopentan-3-ol, (S)-
(−)-6b. According to the same course of preparation of
(S)-6a, (S)-6b was also synthesized with 12% yield;
[h]2D1=−35 (c 1.01, CH3COOC2H5); 1H NMR (400
MHz): l 7.17–7.30 (m, 5H, Ph-H), 3.33–3.36 (q, 1H,
CHN, J=3.9 Hz, J=9.8 Hz), 2.86–2.92 (dd, 1H,
PhCH, J=14.4 Hz), 2.72–2.76 (dd, 1H, PhCH), 2.55–
2.56 (m, 4H, NCH2), 1.53–1.60 (m, 4H, CH2), 1.24–1.48
(m, 2H, CH2), 1.23–1.30 (m, 2H, CH2), 0.95 (t, 3H,
CH3, J=7.4 Hz), 0.92 (t, 3H. CH3, J=7.4 Hz); IR
(KBr): 3307, 3061, 3026, 2964, 2936, 2877, 1600, 1494,
1457, 1396, 1371, 1168, 1122, 1030, 955, 731, 699 cm−1;
HR-MS calcd For (M+H)+: 262.2165, found: 262.2169.
4.6. Typical procedure of asymmetric addition of
diethylzinc to aldehydes
To a solution of chiral b-amino alcohol 4c (5.5 mg, 0.02
mmol) in hexane (1.0 ml) was added dropwise a solu-
tion of diethyl zinc (1.0 ml, 1.0 M in hexane) at 0°C.
After stirring for 30 min, benzaldehyde (53 mg, 0.50
mmol) was added at 0°C, and the reaction was contin-
ued to stirred under the same condition until the reac-
tion was complete checked by TLC. The reaction
mixture was quenched by 5% cold aqueous HCl solu-
tion and extracted with ether. The combined organic
extracts were washed with little brine, dried with anhy-
drous Na2SO4, and evaporated under reduce pressure
to give an oily residue. The residue was analyzed by
HPLC to give the yield and ee value.
5. (a) Reddy, K. S.; Sola`, L.; Moyano, A.; Perica`s, M. A.;
Riera, A. J. Org. Chem. 1999, 64, 3969; (b) Sola`, L.;
Reddy, K. S.; Vidal-Ferran, A.; Moyano, A.; Perica`s, M.
A.; Riera, A.; Alvarez-Larena, A.; Piniella, J.-F. J. Org.
Chem. 1998, 63, 7078; (c) Reddy, K. S.; Sola`, L.; Moy-
ano, A.; Perica`s, M. A.; Riera, A. Synthesis 2000, 165; (d)
Matsumoto, Y.; Chno, A.; Lu, S.-j.; Hayashi, T.; Oguni,
N.; Hayashi, M. Tetrahedron: Asymmetry 1993, 4, 1763;
(e) Nugent, W. A. J. Chem. Soc., Chem. Commun. 1999,
1369.
Acknowledgements
6. (a) Kawanami, Y.; Mitsuie, T.; Miki, M.; Sakamoto, T.;
Nishitani, K. Tetrahedron 2000, 56, 175–178; (b) Sibi, M.;
Chen, J. X.; Cook, G. R. Tetrahedron Lett. 1999, 40,
3301; (c) Soai, K.; Yokoyama, S.; Hayasaka, T. J. Org.
Chem. 1991, 56, 4264.
We thank the National Natural Science Foundation of
China (No. 29972016 and QT Program), the Teaching
and Research Award Program for Outstanding Young
Teachers, and The Key Research Program of Science &
Technology; and Specialized Research Fund for The
Doctoral Program in Higher Education Institutions of
the Ministry of Education of China, and the Young
Scientists’ Fund of the Natural Science Foundation of
Gansu (YS021-A23-008) for their financial support.
&
&
7. (a) Vyskocˇil, S.; Jaracz, S.; Smrcˇina, M.; St´ıchna, M.;
Hanusˇ, V.; Pola´sˇek, M.; Kocˇovsky´, P. J. Org. Chem.
&
1998, 63, 7727; (b) Smrcˇina, M.; Vyskocˇil, S.; Pol´ıvkova´,
J.; Sejbal, J.; Hanusˇ, V.; Pola´sˇek, M.; Verrier, H.;
Kocˇovsky´, P. Tetrahedron: Asymmetry 1997, 8, 537.
8. (a) Trost, B. M.; Schroeder, G. M.; Kristensen, J. Angew.
Chem., Int. Ed. 2002, 41, 3492; (b) Sarnes, D.; Polt, R.
Synlett 1995, 552; (c) Costello, G. F.; James, R.; Shaw, J.
S.; Slater, A. M.; Stutchburg, N. C. J. J. Med. Chem.
1991, 34, 181; (d) Kawaguchi, M.; Hayashi, O.;
Kanamoto, M.; Hamada, M.; Yamamoto, Y.; Oda, J.
Agric. Biol. Chem. 1987, 51, 435.
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