Organocatalytically enantioselective approach to polysubstituted tetrahydropyridines and piperidines

Article abstract of DOI:10.1002/cjoc.201180327

A convenient and highly enantioselective method for assembly of functionalized 1,2,3,4,5-pentasubstituted tetrahydropyridines and piperidines was developed. This method relies on preparing the required enantiopure cyclic semi-acetals via an organocatalyzed Michael addition/cyclization cascade reaction of aldehydes and α-keto-α,β-unsaturated esters, and subsequent reductive amination/condensation with primary amines. Copyright

Full text of DOI:10.1002/cjoc.201180327

FULL PAPER
Organocatalytically Enantioselective Approach to Polysubsti-
tuted Tetrahydropyridines and Piperidines
Yu, Fanga(于芳)
Zhang, Xiaojing*,a(张晓菁)
Jiang, Yongwen*,b(蒋咏文)
a Shenyang Pharmaceutical University, 103 Wenhua Lu, Shenyang, Liaoning 110016, China
b State Key Laboratory of Bioorganic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry,
Chinese Academy of Sciences, Shanghai 200032, China
A convenient and highly enantioselective method for assembly of functionalized 1,2,3,4,5-pentasubstituted
tetrahydropyridines and piperidines was developed. This method relies on preparing the required enantiopure cyclic
semi-acetals via an organocatalyzed Michael addition/cyclization cascade reaction of aldehydes and α-keto-α,β-
unsaturated esters, and subsequent reductive amination/condensation with primary amines.
Keywords organocatalysis, Michael addition, reductive amination, substituted piperidine, tetrahydropyridine
Introduction
dihydropyrones 4 could be prepared from semi-actals 3
that was produced via a O-TMS protected diphenyl-
prolinol catalyzed domino Michael addition/cyclization
process (Scheme 1, Eq. 1).8b Obviously, condensation of
3 with primary amines followed by reductive amination
would give polysubstituted tetrahydropyridines 6, which
could be converted into polysubstituted piperidine 7 by
further reduction (Scheme 1, Eq. 2).
Polysubstituted piperidines are common subunits in
natural products and biologically relevant molecules.1
The classical approaches for constructing these com-
pounds include aza-Prins cyclizations,2 hetero-Diels-
Alder reactions,3 intramolecular Michael reactions,4 and
[3＋3] annulations of aziridines with allenoates.5 Re-
cently, some novel methods for enantioselective synthe-
sis of polysubstituted piperidines and related com-
pounds have been disclosed. For example, Davies and
coworkers discovered that tetrasubstituted piperidin-2-
ones could be synthesized via a homochiral lithium am-
ide-controlled process;6 while Chen group reported that
pentasubstituted piperidin-2-ones could be elaborated
through highly diasteroselective nitro-Mannich reac-
tion.7
Results and discussion
With this idea in hand, we started our attempt to
construct polysubstituted tetrahydropyridines. Under
our optimized reaction conditions,8b the reaction of
1-tert-butyl 4-ethyl 2-acetylmaleate (1a) and n-butanal
worked well to afford cyclic semi-acetal 3a. As ex-
pected, reductive amination of 3a with benzylamine
under the action of NaBH(OAc)3 proceeded smoothly,
affording the desired tetrahydropyridine 6a in 47%
During the investigations on the enamine-based Mi-
chael addition reactions,8 we found that polysubstituted
Scheme 1
O
OH
RCH2CHO 2
Cat./AcOH
O
R
R
Oxidation
O
O
R
R
R
R'
R
H2O/ 0 oC—r.t.
R'
R'
CO2R''
(1)
CO2R''
CO2R''
Cat.:
Ph
1
3
4
N
Ph
OTMS
H
OH
O
R'
R'
R
R''O2C
R
BnNH2 (5a)
R''O2C
R
Further reduction
R
R
(2)
Reductive amination/
condensation
R'
N
N
CO2R''
Bn
7
Bn
3
6
*
E-mail: xiaojinzhang62@163.com & jiangyw@sioc.ac.cn
Received March 8, 2011; revised and accepted May 17, 2011.
Project supported by the National Natural Science Foundation of China (No. 20921091).
Chin. J. Chem. 2011, 29, 1873— 1879
© 2011 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
1873

Yu, Zhang & Jiang
FULL PAPER
yield, together with piperidine 7a in 20% yield and
1,4-dihydropyridine 8a in 12% yield (Scheme 2). Simi-
lar results were observed when two other semi-acetals
were used.
H
H3C
H
a
H
2
6
The direct formation of piperidines 7 in the above
process prompted us to study the reaction conditions for
reductive amination in order to improve the yields of 7.
After some experimentations, we found that we could
reach this goal by adding HOAc to adjust pH to 6—7,
and increasing the amount of amine and NaBH(OAc)3.
Under these conditions, 1,2,3,4,5-pentasubstituted
piperidine 7d was isolated in 81% yield and 97% ee
(Table 1, Entry 1). Further studies indicated that chang-
ing amines and semi-acetals was possible, thereby giv-
ing 1,2,3,4,5-pentasubstituted piperidines with good
diversity. For examples, PMB and cyclopropanyl groups
could be introduced at the 1-position using suitable
amines; some functional groups could be added at the 4-
and 5-positions. Noteworthy is that reduction of 7g—7j
with LAH was necessary because the resultant alcohol
could be used for enantiopurity determination.
5
Ar
4
H
b
1
N
H
3
H
CH3
PMB
COOEt
7f
δ 1.74 (t, J = 10.8 Hz, 1H)
H
H
a
δ 3.0 (dd, J = 4.0,
11.2 Hz, 1H)
δ 2.50 (dd, J = 4.8,
11.6 Hz, 1H)
H3C
H
2
6
5
4
Ar
H
b
1
N
H
3
H
δ 2.74 (t, J = 4.8 Hz, 1H)
CH3
PMB
COOEt
7f
Ar
Based on our previous studies, the configuration at
the 4 and 5 position in 7 should be R,R. To determine
the relative stereochemistry in the two newly generated
stereocenters, we carried out NOESY study to
piperidine 7f and found that substituents at 2, 3 and 4
positions were cis to each other (Figure 1). Strong NOE
between 2-H/6-Ha, 2-H/4-H, 4-H/6-Ha and 4-H/2-H
shows that 2-H, 4-H and 6-Ha are on the same face in
the molecule. The coupling constants of 4-H and 6-Ha
(11.6, 10.8 Hz) indicate that 4-H, 5-H and 6-Ha should
occupy the axial (ax) positions, hence the other sub-
stituents at position 4, 5, 6 must be equatorial (eq) and
2-H must be axial (ax). The significant NOE between
4-H and 3-H shows that they are cis to each other and
3-H should be equatorial (eq). The coupling constant of
3-H (4.8 Hz) confirms its equatorial position. The cou-
pling constants of 6-Hb (4.0, 11.2 Hz) also confirm its
equatorial position. It is reasonable because during the
second reductive amination, the borohydride anion
might attack the iminium 10 from Si face to get favored
conformation B, thereby giving the present product.
EtO2C
Ar
PMB
Si face attack
N
CO2Et
N
PMB
10
A
Ar
EtO2C
H
Ar
N
N
PMB
CO2Et
PMB
7
chair transition state
favor
B
Figure 1 Determination of relative stereochemistry of 7.
tive compounds.
Experimental
General information
For thin-layer chromatography (TLC), silica gel
plates GF254 were used and compounds were visual-
ized by irradiation with UV light, I2, or by treatment
with a solution of phosphomolybdic acid in ethanol fol-
lowed by heating. Optical rotations were measured by
using a Perkin-Elmer 241MC polarimeter in the solvent
Conclusion
In conclusion, we have developed a convenient and
highly enantioselective method for the assembly of
functionalized pentasubstituted piperidines. This
method may find special usages in synthesis of bioac-
indicated. H and 13C NMR spectra were recorded on
1
MERCURY300, Bruker DRX-400, and Bruker AV-500
Scheme 2 Synthesis of tetrahydropyridines
CO2Et
OH
CO2Et
CO2Et
t-BuO2C
R
R
t-BuO2C
R
t-BuO2C
R
O
BnNH2 (5a)/NaBH(OAc)3
R
R
+
+
THF/0 oC—r.t.
N
EtOOC
N
N
Bn
CO2Bu-t
Bn
Bn
3a: R = n-Pr
3b: R = i-Pr
3c: R = CH2=CH(CH2)7
6a (47%, >99% ee)
6b (52%, >99% ee)
6c (48%, >99% ee)
7a (20%)
7b (28%)
7c (33%)
8a (12%)
8b (15%)
8c (10%)
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Chin. J. Chem. 2011, 29, 1873— 1879

Enantioselective Approach to Polysubstituted Tetrahydropyridines and Piperidines
Table 1 Synthesis of polysubstituted piperidine 7a
R'
N
R'
O
o
HOH2C
R
R''O2C
R
LAH
(1) RCH2CHO (2), Cat., HOAc, H2O/0 C—r.t.
R'
(2) R'''NH2 (5)/NaBH(OAc)3/HOAc
THF/0 oC—r.t.
CO2R''
N
R'''
R' = Ar, alkyl
R'''
1b−1g
9g−9j
7d−7j
Yieldb/%
(1st/2nd step)
Yieldb/%
Entry
Product
eec/% Entry
Product
eec/%
(1st/2nd step)
OMe
EtO2C
OBn
EtO2C
1
70/81
79/60
80/69
78/87
97
5
6
7
80/70
80/69
77/87
97d
N
6
Bn
N
Bn
7h
7d
Ph
EtO2C
OBn
EtO2C
6
97d
N
2
3
4
98
N
PMB
7e
7i
NO2
OBn
t-BuO2C
EtO2C
97
97d
N
Bn
N
PMB
7j
7f
C4H9-n
t-BuOOC
OBn
97d
N
Bn
7g
a Reaction conditions for first step: 1 (0.25 mmol), cat. (0.025 mmol), aldehyde 2 (0.5 mmol), HOAc (0.125 mmol), water (0.25 mL), 0
℃ for 1 h, then r.t. for the indicated time. For second step: amine (4.5 equiv., based on semi-acetal 3), NaBH(OAc)3 (7.0 equiv., based on
semi-acetal 3), r.t., 16 h. b Isolated yield. c Determined by chiral-phase HPLC analysis. d The ee value of 9 was determined.
spectrometers with TMS as the internal standard.
mL) was added aldehyde 2 (1.0 mmol) at 0 ℃. The
HRMS were recorded by using either FTMS-7 or Ion-
Spec 4.7 spectrometers. HPLC was carried out using a
Water 515 pump, a Waters 2487 UV detector, a Millen-
nium workstation, and a Daicel Chiralpak HPLC col-
umn. Yields refer to pure compounds, unless otherwise
indicated.
reaction mixture was stirred for 1 h at the same tem-
perature and then allowed to warm to r.t. The stirring
was continued until 1 was consumed (monitored by
TLC). Ethyl acetate and saturated NaCl were added.
The organic phase was separated and the aqueous phase
was extracted with ethyl acetate. The combined organic
layers were dried over Na2SO4 and concentrated to give
the crude product. Purification of the residue by flash
column chromatography (silica gel) eluting with 10∶1
petroleum ether/ethyl acetate afforded the cyclic he-
miacetal 3.
General procedure for synthesis of cyclic semi-acetal
3 via the Michael addition/aldol addition process
To a suspension of (S)-α,α-diphenylprolinol O-TMS
ether (10 mol%) and acetic acid (50 mol%) and
α-keto-α,β-unsaturated ester 1 (0.5 mmol) in H2O (0.2
Chin. J. Chem. 2011, 29, 1873— 1879
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1875

Yu, Zhang & Jiang
FULL PAPER
General procedure for sythesis of 6a— 6c, 7a— 7c,
and 8a— 8c
(CDCl3, 100 MHz) δ: 174.14, 168.03, 149.49, 138.27,
128.97 (2C), 127.68, 127.37, 125.94 (2C), 114.18, 96.65,
79.44, 60.54, 53.72, 45.63, 34.73, 28.50 (3C), 20.1＋5,
The cyclic hemiacetal 3a—3c (0.2 mmol) was dis-
solved in dry THF (1 mL). NaBH(OAc)3 (0.4 mmol, 4
equiv.) and BnNH2 (0.24 mmol) were added to the solu-
tion at 0 ℃. After 10 min, the solution was allowed to
warm up to r.t. After 16 h , ethyl acetate and 2 mL satu-
rated NaHCO3 were added. The organic phase was
separated and the aqueous phase was extracted with
ethyl acetate. The combined organic layers were washed
with saturated NaCl and dried over Na2SO4, then con-
centrated in vacuo. Purification of the residue by flash
column chromatography eluting with 10∶1 petroleum
ether/ethyl acetate afforded the corresponding
piperidine derivatives 6, 7 and 8. The enantiomeric ex-
cess (ee) value of 6a—6c was determined by analysis of
the piperidine derivative using HPLC on a chiral phase.
(4R,5R)-3-tert-Butyl-4-ethyl-1-benzyl-2-methyl-5-
propyl-1,4,5,6-tetrahydropyridine-3,4-dicarboxylate
(6a) 80% yield for Michael addition/aldol addition,
47% yield for reductive amination; [α]2D5 ＋78.67 (c 0.7,
CHCl3); 1H NMR (CDCl3, 400 MHz) δ: 7.18—7.36 (m,
5H), 4.52 (d, J＝17.2 Hz, 1H), 4.44 (d, J＝17.2 Hz, 1H),
4.12 (q, J＝6.8 Hz, 2H), 3.31—3.35 (m, 2H), 2.82 (dt,
J＝2.0, 13.2 Hz, 1H), 2.49 (s, 3H), 1.88—1.92 (m, 1H),
1.42 (s, 9H), 1.17—1.37 (m, 7H), 0.85 (t, J＝7.2 Hz,
3H); 13C NMR (CDCl3, 100 MHz) δ: 176.52, 168.75,
154.52, 137.98, 128.81 (2C), 127.35, 126.57 (2C), 92.66,
78.44, 60.43, 54.73, 49.47, 45.86, 34.39, 33.48, 28.60
(3C), ＋20.38, 16.48, 14.46, 14.09; ESI-MS m/z: 402.3 (M
＋H) ; ESI-HRMS calcd for C24H35NO4 (M＋H)＋
402.2652, found 402.2639; HPLC (Chiralpak OD-H,
hexane/i-PrOH＝98∶2, flow rate 0.5 mL/min, λ＝214
nm), tR＝19.08 (major), 20.28 (minor) min; ee＞99%.
(2R,3R,4R,5R)-3-tert-Butyl-4-ethyl-1-benzyl-2-
15.47, 14.51, 13.88; ESI-MS m/z: 400.3 (M＋H) ;
＋
ESI-HRMS calcd for C24H33N1NaO4 (M ＋ Na)
422.2319, found 422.2301.
(4R,5R)-3-tert-Butyl-4-ethyl-1-benzyl-5-isopropyl-
2-methyl-1,4,5,6-tetrahydropyridine-3,4-dicarboxy-
late (6b) 65% yield for Michael addition/aldol addi-
tion, 52% yield for reductive amination; [α]2D5 ＋58.03 (c
1.0, CHCl3);1H NMR (CDCl3, 400 MHz) δ: 7.18—7.35
(m, 5H), 4.57 (d, J＝16.4 Hz, 1H), 4.38 (d, J＝16.4 Hz,
1H), 4.12 (q, J＝6.8 Hz, 2H), 3.63 (s, 1H), 3.27 (dd, J＝
3.2, 13.2 Hz, 1H), 2.98 (dt, J＝2.4, 13.2 Hz, 1H), 2.48
(s, 3H), 1.55—1.61 (m, 2H), 1.44 (s, 9H), 1.25 (t, J＝
7.2 Hz, 3H), 0.96 (d, J＝6.4 Hz, 3H), 0.79 (d, J＝6.4 Hz,
3H); 13C NMR (CDCl3, 100 MHz) δ: 176.65, 168.70,
154.90, 137.99, 128.86 (2C), 127.37, 126.60 (2C), 93.06,
78.40, 60.42, 54.81, 47.81, 43.49, 40.61, 28.64 (3C),
27.50, 2＋1.17, 20.32, 16.49, 14.48; ESI-MS m/z: 402.＋1
(M＋H) ; ESI-HRMS calcd for C24H35NO4 (M＋H)
402.2643, found 402.2639; HPLC (Chiralpak OD-H,
hexane/i-PrOH＝98∶2, flow rate 0.5 mL/min, λ＝214
nm), tR＝14.37 (major), 15.90 (minor) min; ee＞99%.
(2R,3R,4R,5R)-3-tert-butyl-4-ethyl-1-benzyl-5-iso-
propyl-2-methylpiperidine-3,4-dicarboxylate
(7b)
65% yield for Michael addition/aldol addition, 28%
1
yield for reductive amination; H NMR (CDCl3, 300
MHz) δ: 7.21—7.36 (m, 5H), 4.06—4.18 (m, 2H), 3.85
(d, J＝13.5 Hz, 1H), 3.29 (d, J＝13.8 Hz, 1H), 2.62—
2.84 (m, 4H), 2.32—2.42 (m, 1H), 1.86—1.93 (m, 2H),
1.48 (s, 9H), 1.25 (t, J＝7.2 Hz, 3H), 1.21 (t, J＝5.4 Hz,
3H), 0.84 (d, J＝6.6 Hz, 3H), 0.70 (d, J＝6.6 Hz, 3H);
13C NMR (CDCl3, 100 MHz) δ: 173.45, 170.74, 140.11,
128.60 (2C), 128.22 (2C), 126.74, 80.44, 60.46, 57.88,
57.37, 50.18, 49.05, 46.28, 38.53, 28.29 (3C), 27.4＋2,
21.10, 17.50, 15.55, 14.36; ESI-MS m/z: 404＋.1 (M＋H) ;
ESI-HRMS calcd for C24H38NO4 (M＋H) 404.2785,
found 404.2795.
methyl-5-propylpiperidine-3,4-dicarboxylate
(7a)
80% yield for Michael addition/aldol addition, 20%
1
yield for reductive amination; H NMR (CDCl3, 300
MHz) δ: 7.21—7.35 (m, 5H), 4.06—4.19 (m, 2H), 3.93
(d, J＝14.1 Hz, 1H), 3.22 (d, J＝14.1 Hz, 1H), 2.93 (dd,
J＝3.9, 15.6 Hz, 1H), 2.83—2.86 (m, 1H), 2.61—2.69
(m, 1H), 2.42—2.53 (m, 1H), 2.28—2.33 (m, 1H), 1.63
—1.72 (m, 1H), 1.47 (s, 9H), 1.22—1.27 (m, 10H), 0.79
(t, J＝7.2 Hz, 3H); 13C NMR (CDCl3, 100 MHz) δ:
173.04, 170.45, 140.04, 128.35 (2C), 128.08 (2C),
126.56, 80.38, 60.27, 57.84, 57.34, 56.24, 49.62, 49.17,
34.80, 32.69, 28.13 (3C), 25.35, 19.89, 16.68, 14.21;
ESI-MS m/z: 404.3 (M＋H)＋; ESI-HRMS calcd for
C24H38NO4 (M＋H)＋ 404.2807, found 404.2794.
(R)-3-tert-Butyl-4-ethyl-1-benzyl-5-isopropyl-2-
methyl-1,4-dihydropyridine-3,4-dicarboxylate (8b)
65% yield for Michael addition/aldol addition, 15%
1
yield for reductive amination; H NMR (CDCl3, 400
MHz) δ: 7.22—7.36 (m, 5H), 5.80 (s, 1H), 4.71 (d, J＝
17.2 Hz, 1H), 4.52 (d, J＝17.2 Hz, 1H), 4.27 (s, 1H),
4.09—4.19 (m, 2H), 2.30—2.42 (m, 1H), 2.33 (s, 3H),
1.45 (s, 9H), 1.25 (t, J＝7.2 Hz , 3H), 1.06 (d, J＝6.8
Hz, 3H), 1.01 (d, J＝6.8 Hz, 3H); 13C NMR (CDCl3,
100 MHz) δ: 174.52, 168.02, 149.44, 138.30, 128.94
(2C), 127.34, 126.45, 125.95 (2C), 120.42, 96.74, 79.42,
60.51, 53.97, 44.27, 30.31, 28.54 (3C), ＋21.96, 20.76,
15.54, 14.46; ESI-MS m/z: 400.1 (M＋＋H) ; ESI-HRMS
calcd for C24H33N1NaO4 (M＋Na) 422.2311, found
422.2302.
(R)-3-tert-Butyl-4-ethyl-1-benzyl-2-methyl-5-pro-
pyl-1,4-dihydropyridine-3,4-dicarboxylat (8a) 80%
yield for Michael addition/aldol addition, 12% yield for
1
reductive amination; H NMR (CDCl3, 400 MHz) δ:
7.21—7.36 (m, 5H), 5.77 (s, 1H), 4.66 (d, J＝16.4 Hz,
1H), 4.51 (d, J＝16.4 Hz, 1H), 4.09—4.22 (m, 2H),
4.16 (s, 1H), 2.35 (s, 3H), 2.05—2.13 (m, 1H), 1.89—
1.93 (m, 1H), 1.54—1.56 (m, 2H), 1.44 (s, 9H), 1.26 (t,
J＝7.2 Hz, 3H), 0.89 (t, J＝7.2 Hz, 3H); 13C NMR
(4R,5R)-3-tert-Butyl-4-ethyl-1-benzyl-2-methyl-5-
(non-8-enyl)-1,4,5,6-tetrahydropyridine-3,4-dicarb-
oxylate (6c) 75% yield for Michael addition/aldol
addition, 48% yield for reductive amination; [α] D25
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Chin. J. Chem. 2011, 29, 1873— 1879

Enantioselective Approach to Polysubstituted Tetrahydropyridines and Piperidines
1
＋128.27 (c 1.10, CHCl3); H NMR (CDCl3, 400 MHz)
δ: 7.18—7.36 (m, 5H), 5.76—5.86 (m, 1H), 4.92—5.01
(m, 2H), 4.50 (d, J＝16.4 Hz, 1H), 4.45 (d, J＝16.4 Hz,
1H), 4.12 (q, J＝6.8 Hz, 2H), 3.30—3.34 (m, 2H), 2.83
(dt, J＝2.4, 12.8 Hz, 1H), 2.49 (s, 3H), 2.03 (q, J＝7.2
Hz, 2H), 1.86—1.88 (m, 1H), 1.44 (s, 9H), 1.31—1.39
(m, 2H), 1.16—1.27 (m, 13H); 13C NMR (CDCl3, 100
MHz) δ: 176.55, 168.87, 154.55, 139.32, 138.02, 128.85
(2C), 127.40, 126.63 (2C), 114.29, 92.61,78.48, 60.46,
54.74, 49.42, 46.00, 33.92, 33.81, 32.24, 29.64, 29.50,
29.19, 29.02, 28.62＋(3C), 27.31, 16.53, 14.50; ESI-MS
m/z: 484.3 (M＋H) ; ESI-HRMS calcd for C30H45NO4
(M＋H)＋ 484.3432, found 484.3421; HPLC (Chiralpak
AD-H, hexane/i-PrOH＝98∶2, flow rate 0.5 mL/min,
λ＝214 nm), tR＝18.62 (major), 22.43 (minor) min; ee
＞99%.
saturated NaHCO3 were added. The organic phase was
separated and the aqueous phase was extracted with
ethyl acetate. The combined organic layers were washed
with saturated NaCl and dried over Na2SO4, then con-
centrated in vacuo. Purification of the residue by col-
umn chromatography eluting with 150∶1—80∶1
DCM/MeOH afforded the corresponding piperidine de-
rivative 7d—7f.
(2R,3R,4R,5R)-Ethyl-1-benzyl-4-(4-methoxyphen-
yl)-2-methyl-5-(non-8-enyl)piperidine-3-carboxylate
(7d) 70% yield for Michael addition/aldol addition,
81% yield for reductive amination; [α]2D5 ＋25.00 (c 2.5,
CHCl3); 1H NMR (CDCl3, 400 MHz) δ: 7.25—7.42 (m,
5H), 7.06 (d, J＝8.4 Hz, 2H), 6.79 (d, J＝8.6 Hz, 2H),
5.72—5.82 (m, 1H), 4.89—4.98 (m, 2H), 4.06 (d, J＝
14.0 Hz, 1H), 3.86—3.92 (m, 2H), 3.77 (s, 3H), 3.30 (d,
J＝14.0 Hz, 1H), 3.14 (dd, J＝4.4, 11.2 Hz, 1H), 2.64—
2.77 (m, 3H), 2.42 (dd, J＝4.4, 11.6 Hz, 1H), 1.97 (q,
J＝7.2 Hz, 2H), 1.74 (t, J＝10.8 Hz, 1H), 1.21—1.31
(m, 3H), 1.01—1.21 (m, 15H); 13C NMR (CDCl3, 100
MHz) δ: 171.84, 158.21, 139.98, 139.39, 133.90, 129.46
(2C), 128.68 (2C), 128.26 (2C), 126.66, 114.19, 113.73
(2C), 59.54, 59.33, 58.61, 57.27, 55.90, 55.31, 50.62,
33.89, 33.69, 31.67, 29.75, 29.40, 29.12,＋28.99, 26.53,
18.86, 14.33; ESI-MS m/z: 492.4 (M＋H) ; ESI-HRMS
calcd for C32H45NO3 (M ＋ H) ＋ 492.3464, found
492.3472; HPLC (Chiralpak AD-H, hexane/i-PrOH＝
95∶5, flow rate 0.7 mL/min, λ＝214 nm), tR＝5.97
(minor), 8.22 (major) min; ee＝97%.
(2R,3R,4R,5R)-3-tert-Butyl-4-ethyl-1-benzyl-2-
methyl-5-(non-8-en-1-yl)piperidine-3,4-dicarboxylate
(7c) 75% yield for Michael addition/aldol addition,
1
33% yield for reductive amination; H NMR (CDCl3,
400 MHz) δ: 7.20—7.35 (m, 5H), 5.74—5.84 (m, 1H),
4.90—4.99 (m, 2H), 4.06—4.20 (m, 2H), 3.91 (d, J＝
14.0 Hz, 1H), 3.23 (d, J＝14.0 Hz, 1H), 2.92 (dd, J＝
4.0, 11.6 Hz, 1H), 2.85 (t, J＝4.0 Hz, 1H), 2.63—2.68
(m, 1H), 2.42—2.50 (m, 1H), 2.29—2.32 (m, 1H), 2.01
(q, J＝7.2 Hz, 2H), 1.66—1.72 (m, 1H), 1.47 (s, 9H),
1.04—1.41 (m, 18H); 13C NMR (CDCl3, 100 MHz) δ:
173.23, 170.64, 140.21, 139.40, 128.50 (2C), 128.23
(2C), 126.72, 114.22, 80.52, 60.45, 57.92, 57.49, 49.67,
49.24, 33.93, 33.02, 32.64, 29.86 (2C), 29.47, 29.21,
29.03, 28.27 (3C), 26.84, 16.72, 14.38; ESI-MS m/z:
486.3 (M＋H)＋; ESI-HRMS calcd for C30H48NO4 (M＋
H)＋ 486.3599, found 486.3577.
(2R,3R,4R,5R)-Ethyl-1-(4-methoxybenzyl)-2-meth-
yl-5-(non-8-enyl)-4-phenylpiperidine-3-carboxylate
(7e) 79% yield for Michael addition/aldol addition,
60% yield for reductive amination; [α]2D5 ＋37.2 (c 0.65,
CHCl3); 1H NMR (CDCl3, 400 MHz) δ: 7.14—7.33 (m,
7H), 6.87 (d, J＝8.4 Hz, 2H), 5.73—5.83 (m, 1H), 4.90
—4.99 (m, 2H), 4.01 (d, J＝13.6 Hz, 1H), 3.86—3.94
(m, 2H), 3.82 (s, 3H), 3.31 (d, J＝12.8 Hz, 1H), 3.16 (d,
J＝8.4 Hz, 1H), 2.72—2.82 (m, 2H), 2.64 (m, 1H), 2.48
(m, 1H), 1.98 (q, J＝6.8 Hz, 2H), 1.69—1.75 (m, 1H),
1.05—1.33 (m, 15H), 0.98 (t, J＝6.8 Hz, 3H); 13C NMR
(CDCl3, 100 MHz) δ: 171.72, 158.51, 141.77, 139.38,
131.53, 129.89 (2C), 128.57 (2C), 128.35 (2C), 126.51,
114.19 (2C), 113.65, 59.51, 58.98, 58.34, 56.53, 55.72,
55.38, 51.49, 33.89, 33.41, 31.70, 29.75, 29.39, 29.1＋2,
28.99, 26.54, 18.79, 14.23; ESI-MS m/z: 492.5 (M＋H) ;
ESI-HRMS calcd for C32H45NO3(M＋H)＋ 492.3469,
found 492.3472; HPLC (Chiralpak AD-H, hexane/
i-PrOH＝95∶5, flow rate 0.7 mL/min, λ＝214 nm),
tR＝6.51 (minor), 8.88 (major) min; ee＝98%.
(R)-3-tert-Butyl-4-ethyl-1-benzyl-2-methyl-5-(non-
8-en-1-yl)-1,4-dihydropyridine-3,4-dicarboxylate (8c)
75% yield for Michael addition/aldol addition, 10%
1
yield for reductive amination; H NMR (CDCl3, 400
MHz) δ: 7.20—7.38 (m, 5H), 5.76—5.85 (m, 1H), 5.76
(s, 1H), 4.90—5.0 (m, 2H), 4.65 (d, J＝17.6 Hz, 1H),
4.51 (d, J＝17.2 Hz, 1H), 4.09—4.21 (m, 2H), 4.18 (s,
1H), 2.34 (s, 3H), 1.91—2.11 (m, 2H), 1.56 (m, 2H),
1.44 (s, 9H), 1.25—1.37 (m, 13H); 13C NMR (CDCl3,
100 MHz) δ: 174.15, 168.04, 149.47, 139.35, 138.27,
128.97 (2C), 127.55, 127.38, 125.93 (2C), 114.41,
114.29, 96.63, 79.44, 60.54, 53.73, 45.67, 33.95, 32.60,
29.43, 29.35, 29.25, 29.06, 28.51 ＋(3C), 26.97, 15.47,
14.52; ESI-MS m/z: 482.3 (M＋H) ; ESI-HRMS calcd
for C24H35N1NaO4 (M＋Na)＋ 504.3105, found 504.3084.
General procedure for sythesis of 7d— 7f
(2R,3R,4R,5R)-Ethyl-1-(4-methoxybenzyl)-2,5-di-
methyl-4-(4-nitrophenyl)piperidine-3-carboxylate (7f)
80% yield for Michael addition/aldol addition, 69%
yield for reductive amination; [α]2D5 ＋77.88 (c 0.45,
CHCl3); 1H NMR (CDCl3, 400 MHz) δ: 8.13 (d, J＝8.8
Hz, 2H), 7.35 (d, J＝8.4 Hz, 2H), 7.30 (d, J＝8.8 Hz,
2H), 6.87 (d, J＝8.4 Hz, 2H), 4.02 (d, J＝13.6 Hz, 1H),
3.85—3.98 (m, 2H), 3.79 (s, 3H), 3.16 (d, J＝13.6 Hz,
1H), 3.0 (dd, J＝4.0, 11.2 Hz, 1H), 2.89—2.96 (m, 1H),
The cyclic hemiacetal 3d—3f (0.2 mmol) was dis-
solved in dry THF (2 mL). NaBH(OAc)3 (1.0 mmol, 5
equiv.) and amine (0.3 mmol) was added to the solution
at 0 ℃. HOAc was added to reduce the reaction pH to 6
—7. After 10 min, the solution was allowed to warm up
to r.t. (25—30 ℃). After 12 h, another potion of
NaBH(OAc)3 (0.4 mmol, 2 equiv.) and amine (0.6
mmol) was added. After 24 h, ethyl acetate and 2 mL
Chin. J. Chem. 2011, 29, 1873— 1879
© 2011 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
1877

Yu, Zhang & Jiang
FULL PAPER
2.73 (t, J＝4.8 Hz,, 1H), 2.66—2.68 (m, 1H), 2.51 (dd,
J＝4.8, 11.6 Hz, 1H), 1.74 (t, J＝10.8 Hz, 1H), 1.24 (d,
J＝6.4 Hz, 3H), 1.02 (t, J＝6.8 Hz, 3H), 0.60 (d, J＝6.4
Hz, 3H); 13C NMR (CDCl3, 100 MHz) δ: 171.06,
158.66, 149.70, 146.87, 131.47, 129.87 (2C), 129.51
(2C), 123.64 (2C), 113.76 (2C), 60.87, 59.90, 58.83,
56.38, 55.40, 55.06, 52.82, 28.89, 18.76, 17.40, 14.34;
ESI-MS m/z: 427.1 (M＋H)＋; ESI-HRMS calcd for
C24H30N2O5 (M ＋ H) ＋ 427.2227, found 427.2227;
HPLC (Chiralpak IA, hexane/i-PrOH＝90∶10, flow
rate 0.7 mL/min, λ＝214 nm), tR＝13.39 (major), 20.21
(minor) min; ee＝97%.
((2R,3R,4R,5R)-1-Benzyl-5-(2-(benzyloxy)ethyl)-2,
4-dimethylpiperidin-3-yl)methanol (9h) 80% yield
for Michael addition/aldol addition, 70% yield for re-
ductive amination/91% yield for reduction of the
1
piperidine ester; [α]2D5 －37.7 (c 1.0, CHCl3); H NMR
(CDCl3, 400 MHz) δ: 7.19—7.32 (m, 10 H), 6.06 (brs,
1H), 4.32 (s, 2H), 4.17 (d, J＝12.8 Hz, 1H), 4.07 (dd,
J＝3.2, 12.0 Hz, 1H), 3.89 (d, J＝11.2 Hz, 1H), 3.28—
3.33 (m, 2H), 2.88—2.94 (m, 2H), 2.65—2.67 (m, 1H),
1.94—1.97 (m, 1H), 1.75—1.84 (m, 1H), 1.62—1.68
(m, 1H), 1.43—1.49 (m, 4H), 1.18—1.26 (m, 2H), 1.05
(d, J＝6.8 Hz, 3H); 13C NMR (CDCl3, 100 MHz) δ:
138.57 (2C), 128.94, 128.60 (2C), 128.45 (2C), 127.74
(2C), 127.58 (2C), 127.21, 73.07, 68.76, 62.63, 59.17,
59.04, 58.10, 46.50, 40.27, 37.72, 32.39, 18.62, 17.15;
ESI-MS m/z: 368.2 (M＋H)＋; ESI-HRMS calcd for
C24H33NO2 (M ＋ H) ＋ 368.2589, found 368.2584;
HPLC (Chiralpak OD, hexane/i-PrOH＝95∶5, flow
rate 0.5 mL/min, λ＝214 nm), tR＝19.92 (major), 22.67
(minor) min; ee＝97%.
General procedure for sythesis of 9
The cyclic hemiacetal 3g—3i (0.2 mmol) was dis-
solved in dry THF (2 mL). NaBH(OAc)3 (1.0 mmol, 5
equiv.) and amine (0.3 mmol) were added to the solu-
tion at 0 ℃. HOAc was added to reduce the reaction
pH to 6—7. After 10 min, the solution was allowed to
warm up to r.t. (25—30 ℃). After 12 h, another potion
of NaBH(OAc)3 (0.4 mmol, 2 equiv.) and amine (0.6
mmol) was added. After 12 h, ethyl acetate and 2 mL
saturated NaHCO3 were added. The organic phase was
separated and the aqueous phase was extracted with
ethyl acetate. The combined organic layers were washed
with saturated NaCl and dried over Na2SO4, then con-
centrated in vacuo. Purification of the residue by col-
umn chromatography eluting with 150∶1—60∶1
DCM/MeOH afforded the corresponding piperidine de-
rivative 7g—7j.
((2R,3R,4R,5R)-5-(2-(Benzyloxy)ethyl)-1-cyclopro-
pyl-2,4-dimethylpiperidin-3-yl)methanol (9i) 80%
yield for Michael addition/aldol addition, 80% yield for
reductive amination/90% yield for reduction of the
1
piperidine ester; [α]2D5 －30.89 (c 0.8, CHCl3); H NMR
(CDCl3, 400 MHz) δ: 7.26—7.35 (m, 5H), 4.49 (dd, J＝
7.6, 16.4 Hz, 2H), 3.96 (dd, J＝4.0, 15.2 Hz, 1H), 3.80
(d, J＝15.2 Hz, 1H), 3.49 (t, J＝10.0 Hz, 2H), 3.14 (d,
J＝10.0 Hz, 1H), 2.60—2.67 (m, 1H), 1.84—2.0 (m,
3H), 1.38—1.41 (m, 6H), 1.23—1.29 (m, 2H), 1.05 (d,
J＝6.9 Hz, 3H), 0.60—0.67 (m, 2H), 0.38—0.47 (m,
To a stirred suspension of LiAlH4 (12 mg, 0.3 mmol)
in dry THF (0.5 mL) was added a solution of the
piperidine ester 7g—7j in THF (1 mL) at 0 ℃. After
being stirred overnight, water (10 µL) and 15% NaOH
(10 µL) were carefully added, filtered, and concentrated
under reduced pressure. Purification of the residue by
flash chromatography (DCM/MeOH 100∶1) gave the
corresponding alcohol 9g—9j as a colorless oil.
13
1H), 0.18—0.27 (m, 1H); C NMR (CDCl3, 100 MHz)
δ: 138.65, 128.52 (2C), 127.79 (2C), 127.67, 73.14,
68.90, 64.60, 61.48, 58.97, 45.93, 39.98, 37.87, 36.97,
32.52＋, 18.24, 17.09, 10.12, 4.51; ESI-MS m/z: 318.1 (M
＋H) ; ESI-HRMS calcd for C20H31NO2 (M＋H)＋
318.2423, found 318.2427; HPLC (Chiralpak OD, hex-
ane/i-PrOH＝100∶1, flow rate 0.7 mL/min, λ＝214
nm), tR＝15.63 (minor), 17.02 (major) min; ee＝97%.
((2R,3R,4R,5R)-5-Allyl-1-benzyl-4-(2-(benzyloxy)-
((2R,3R,4R,5R)-1-Benzyl-5-(2-(benzyloxy)ethyl)-
4-butyl-2-methylpiperidin-3-yl)methanol (9g) 78%
yield for Michael addition/aldol addition, 87% yield for
reductive amination/91% yield for reduction of the
piperidine ester; [α]2D5 －17.86 (c 0.75, CHCl3); 1H NMR
(CDCl3, 300 MHz) δ: 7.20—7.35 (m, 10H), 4.32 (s, 2H),
4.17 (d, J＝13.2 Hz, 1H), 4.07 (dd, J＝3.3, 11.7 Hz,
1H), 3.81 (d, J＝11.4 Hz, 1H), 3.26—3.32 (m, 2H),
2.86—2.91 (m, 2H), 2.59—2.62 (m, 1H), 1.94—2.0 (m,
1H), 1.76—1.90 (m, 1H), 1.60—1.68 (m, 2H), 1.38—
1.45 (m, 3H), 1.10—1.25 (m, 9H), 0.88 (t, J＝6.9 Hz,
3H); 13C NMR (CDCl3, 100 MHz) δ: 138.54 (2C),
129.05, 128.62 (2C), 128.44 (2C), 127.73 (2C), 127.60
(2C), 127.32, 73.08, 68.74, 62.80, 59.24, 58.93, 58.14,
44.99, 41.66, 36.54, 32.16, 29.27, 28.94, 23.04, 18.72,
14.25; ESI-MS m/z: 410.＋3 (M＋H)＋; ESI-HRMS calcd
for C27H39NO2 (M＋H) 410.3059, found 410.3053;
HPLC (Chiralpak OD, hexane/i-PrOH＝80∶20, flow
rate 0.7 mL/min, λ＝214 nm), tR＝9.05 (major), 11.36
(minor) min; ee＝97%.
ethyl)-2-methylpiperidin-3-yl)methanol (9j)
77%
yield for Michael addition/aldol addition, 87% yield for
reductive amination/92% yield for reduction of the
piperidine ester; [α]2D5 －58.06 (c 0.25, CHCl3); 1H NMR
(CDCl3, 400 MHz) δ: 7.22—7.36 (m, 10H), 5.53—5.64
(m, 1H), 4.86—4.91 (m, 2H), 4.49 (s, 2H), 4.16 (d, J＝
12.0 Hz, 1H), 4.07 (dd, J＝3.2, 11.6 Hz, 1H), 3.82 (d,
J＝11.6 Hz, 1H), 3.46 (t, J＝6 Hz, 2H), 2.81—2.90 (m,
2H), 2.57—2.59 (m, 1H), 2.17—2.21 (m, 1H), 2.01 (m,
1H), 1.73—1.80 (m, 2H), 1.59—1.64 (m, 2H), 1.32—
1.44 (m, 3H), 1.25 (s, 3H); 13C NMR (CDCl3, 100 MHz)
δ: 138.60 (2C), 135.18, 129.74 (2C), 128.95 (2C),
128.51 (2C), 127.78 (2C), 127.72 (2C), 117.09, 73.13,
70.47, 63.51, 62.95, 58.12, 57.86, 43.47, 41.36, 36.8＋0,
35.92, 27.12, 25.51, 17.97; ESI-MS m/z: 408＋.2 (M＋H) ;
ESI-HRMS calcd for C27H38NO2 (M＋H) 408.2888,
found 408.2897; HPLC (Chiralpak OD-H, hexane/
i-PrOH＝70∶30, flow rate 0.7 mL/min, λ＝214 nm),
1878
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© 2011 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2011, 29, 1873— 1879

Enantioselective Approach to Polysubstituted Tetrahydropyridines and Piperidines
tR＝6.14 (major), 9.12 (minor) min; ee＝97%.
Pozo, C. Org. Lett. 2007, 9, 5283.
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A. C.; Wilson, C. Org. Lett. 2008, 10, 2877.
Guo, H.; Xu, Q.; Kwon, O. J. Am. Chem. Soc. 2009, 131,
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Chin. J. Chem. 2011, 29, 1873— 1879
© 2011 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
1879