Asymmetric synthesis of 2-substituted piperidin-3-ols

Article abstract of DOI:10.1016/S0957-4166(02)00133-7

Starting from a protected glycol aldehyde hydrazone a flexible asymmetric synthesis of 2-substituted piperidin-3-ols was achieved. An α-alkylation/1,2-addition sequence furnished the intermediate hydrazines which were subjected to reductive cleavage of th

Full text of DOI:10.1016/S0957-4166(02)00133-7

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 13 (2002) 587–593
Asymmetric synthesis of 2-substituted piperidin-3-ols
Dieter Enders,* Bert Nolte and Jan Runsink
Institut fu¨r Organische Chemie, Rheinisch-Westfa¨lische Technische Hochschule, Professor-Pirlet-Straße 1,
52074 Aachen, Germany
Received 6 March 2002; accepted 12 March 2002
Abstract—Starting from a protected glycol aldehyde hydrazone a flexible asymmetric synthesis of 2-substituted piperidin-3-ols was
achieved. An a-alkylation/1,2-addition sequence furnished the intermediate hydrazines which were subjected to reductive cleavage
of the chiral auxiliary. After acidic workup and simultaneous deprotection the title compounds were obtained in moderate overall
yields and excellent diastereomeric and enantiomeric excesses (de, ee >96%) by ring closure under reductive amination conditions.
© 2002 Elsevier Science Ltd. All rights reserved.
1. Introduction
(+)-Febrifugine 3 was first isolated from the Chinese
medicinal plant Dichroa febrifuga (Chinese name:
Chang Shan) and exhibits strong antimalarial proper-
ties comparable to that of the clinically used drug
chloroquinine.3,4 As the rare amino acid building block
hydroxypipecolic acid 4 is present in certain bioactive
natural products such as tetrazomine, a promising can-
didate with antitumor and antimicrobial activity.5 Most
of the reported syntheses of 2-substituted piperidin-3-
ols were directed to specific molecules, such as (+)-
febrifugine 34b,6 and hydroxy pipecolic acid 4,7 or
focused on special substitution patterns which are nec-
essary for further transformations into more complex
structures, e.g. indolizidine alkaloids.8 Only a few publi-
cations describe a more general and flexible method for
the preparation of 2-substituted piperidin-3-ols, which
allows the introduction of different substituents in the
2-position of the ring.9
Piperidine alkaloids are an important class of natural
products and due to their broad range of bioactivities
are of great pharmacological interest. 2,3-Disubstituted
derivatives, especially the 2-substituted piperidin-3-ol
skeleton, play an important role as natural and syn-
thetic bioactive compounds (Fig. 1). The pyrrolidinyl
substituted derivative 1 for example was tested for its
activity as k-opioid receptor agonist.1 The hydroxy
piperidinyl substituted propanoic acid 2 is a new potent
analogue of baclofen, which shows significant in vitro
activity as a GABA receptor binder.2
2. Results and discussion
In a previous article we described an efficient methodol-
ogy for the synthesis of 2-(a-hydroxyalkyl)-piperdines,
which was also applied to accomplish the first asym-
metric synthesis of (−)-a-conhydrine.10 Herein, we wish
to report on the extension of our versatile procedure to
another class of hydroxylated piperidines, the 2-substi-
tuted piperidin-3-ols.
Figure 1. Examples of natural and synthetic pharmacologi-
cally active 2-substituted piperidin-3-ols.
2.1. Retrosynthetic analysis
A retrosynthetic analysis of the target molecule 5 leads
to the amino aldehyde precusor 6. The construction of
* Corresponding author. Tel.: +49 (241)8094676; fax: +49
(241)8092127; e-mail: enders@rwth-aachen.de
0957-4166/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(02)00133-7

588
D. Enders et al. / Tetrahedron: Asymmetry 13 (2002) 587–593
the piperidine skeleton can be achieved by ring closure
performed under reductive amination conditions
(Scheme 1). The key intermediate 6 is based on a
disubstituted 1,2-amino alcohol subunit. The desired
substitution pattern can be obtained by a diastereose-
lective nucleophilic 1,2-addition of various organo-
metallic compounds to the chiral, a-substituted glycol
aldehyde hydrazone 7.11 The required carbonyl func-
tionality can be introduced by a-alkylation of the pro-
tected glycol aldehyde SAMP hydrazone 9 with the
acetal-containing electrophile 8. The use of this class of
hydrazones as versatile chiral synthons for the synthesis
of miscellaneous substituted 1,2-amino alcohol units
applying the SAMP/RAMP hydrazone method12 has
already been reported by our group.13
According to the proposed mechanisms for the a-alkyl-
ation and subsequent 1,2-addition supported by this
auxiliary, the formation of the (2R,3S)-trans products
are expected.10,13
2.2. Asymmetric synthesis of 2-substituted piperidin-3-ols
As depicted in Scheme 2, treatment of hydrazone 10
with LDA at low temperature gave the intermediate
lithium azaenolat, which was trapped at the same tem-
perature with the acetal protected b-iodo propanal 11
to form the a-substituted hydrazine 12 in moderate
yield and good diastereomeric excess. The functional-
ized electrophile 11 is easily available from acroleine by
the one-pot procedure described by Larson and
Klesse.14 Treatment of the key intermediate 12 with
various alkyllithium reagents afforded the light- and
air-sensitive hydrazines 13a–e (Table 1). Commercially
The enantiopure TBS-protected glycol aldehyde SAMP
hydrazone 10 is readily available in high yield by a
three-step sequence on a multigram scale from commer-
cially available (Z)-butenediol, which is first protected
prior to ozonolytic cleavage under reductive workup
conditions and final condensation with the hydrazine
SAMP to yield 10.13c
Scheme 2. Asymmetric synthesis of 2-substituted piperidin-3-
ols 5a–e. Reagents and conditions: (i) LDA, THF, −78°C, then
11, −78°C; (ii) RLi, THF, −78°C, then NaHCO3 (aq.); (iii)
BH3·THF, THF, D, then 3 M HCl (aq.), CH2Cl2, rt; (iv)
NaBH4, EtOH, rt.
Scheme 1. Retrosynthetic analysis of 2-substituted piperidin-
3-ols 5.
Table 1. Results of the asymmetric synthesis of 2-substituted piperidin-3-ols 5a–e
R
Product
Yield (%)b
de (%)c
Prod.
Yield (%)d
de (%)e
ee (%)f
Mea
n-Bu
t-Bu
13a
13b
13c
13d
13e
53
75
77
45
91
\96
\96
\96
\96
\96
5a
5b
5c
5d
5e
59
62
51
67
76
\96
\96
\96
\96
\96
\96
\96
\96
\96
\96
n-Hexa
(CH2)2Phg
a Due to the less reactive organolithium reagents the addition reaction was carried out at −30°C.
b Isolated by flash column chromatography.
c Determined by 13C NMR spectroscopy after purification.
d Isolated by flash column chromatography. Yield after two steps.
e Determined by 13C NMR spectroscopy.
f In correlation to the de value of the corresponding hydrazines 13a–e assuming the following steps take place without any detectable
racemization.16,17
g Prepared from the corresponding iodide and t-butyllithium according to a procedure of Negishi and Bailey.15

D. Enders et al. / Tetrahedron: Asymmetry 13 (2002) 587–593
589
available organolithium compounds as well as 2-
phenylethyllithium, prepared by halogen–metal
3-ols 5a–e starting from protected glycol aldehyde
SAMP hydrazone 10.
exchange reaction15 from the corresponding iodide,
reacted well in moderate to excellent yields in the highly
diastereoselective 1,2-addition (de >96%) to the car-
bonꢀnitrogen double bond of hydrazone 12.13 Due to
their lower reactivity, reactions of methyl- and n-hexyl-
lithium were carried out at higher temperature (−30°C).
The lower chemical yields of 13a,d were due to side
reactions, which occured at that temperature.
3. Conclusion
In summary, we have successfully extended our method
for the synthesis of hydroxylated piperidines. Applying
our SAMP/RAMP hydrazone methodology for the a-
alkylation/1,2-addition of chiral glycol aldehyde hydra-
zones, the 2-substituted piperidin-3-ols were obtained in
moderate to good overall yields and excellent diastereo-
and enantiomeric excesses. Investigations towards the
employment of functionalized nucleophiles in the 1,2-
addition, which would allow the application of the
2-substituted piperidine-3-ols as building blocks in the
synthesis of bioactive compounds (Fig. 1), are currently
in progress.
Because of the incomplete asymmetric induction in the
alkylation of 10 to form 12, the minor diastereomers of
13a–e were expected, but NMR spectroscopic investiga-
tions showed no significant signals. We assume that the
undesired isomers were separated during the purifica-
tion procedure.
The chiral auxiliary was removed from the hydrazines
13a–e after isolation by flash chromatography. Nitro-
genꢀnitrogen bond cleavage was achieved with a
BH3THF complex in refluxing THF.16 After comple-
tion, the reaction mixtures were treated with hydrochlo-
ric acid to destroy excess borane. In addition,
acid-catalyzed silyl ether cleavage and acetal hydrolysis
occured and the resulting amino aldehydes underwent
spontaneous cyclization to the corresponding imines.
The solvents were evaporated and the remaining
residue was dissolved in EtOH without further purifica-
tion. Finally, NaBH4 reduction completed the reductive
amination to afford the 2-substituted piperidin-3-ols
5a–e in moderate to good yields over two steps (Table
1). Due to the longer and less polar side chains the
isolation of 5b, 5d and 5e by flash chromatography
were achieved in higher yields in comparison to the
more polar compounds 5a and 5c. Starting from glycol
aldehyde hydrazone 10 the title compounds 5a–e were
obtained in overall yields of 13–29% with both
diastereomeric and enantiomeric excesses greater than
4. Experimental
4.1. General
Methyllithium (1.6 M in diethyl ether), n-butyllithium
(1.6 M in hexane) and t-butyllithium (1.6 M in hexane)
were purchased from Merck, Darmstadt. n-Hexyl-
lithium (2.5 M in hexane) was purchased from Aldrich.
2-Phenylethyllithium was freshly prepared from the cor-
responding iodide.15 Melting points were determined on
a Tottoli melting point apparatus and are uncorrected.
IR spectra were recorded on a Perkin Elmer 1750
1
FT-IR spectrometer. H and 13C NMR spectra were
recorded at 300 or 500 MHz and 75 or 125 MHz,
respectively, on Varian VXR 300, Varian Gemini 300
3
or Varian Unity spectrometers. JH,H coupling con-
stants were expressed in Hz. All measurements were
performed in CDCl3 and chemical shifts are expressed
in ppm (l) with tetramethylsilane as an internal stan-
dard. Mass spectra (MS) were obtained on a Varian
MAT 212 or Finnigan SSQ 7000. Optical rotations
were measured on a Perkin Elmer P 241 polarimeter.
Microanalyses were performed on Elementar Vario EL.
In case of sensitive compounds high resolution mass
spectra (HR-MS) were obtained on a Finnigan MAT
95.
1
96%, as determined by H and 13C NMR.
Finally, the proposed (2R,3S)-configuration for the
products 5a–e was confirmed by NOESY experiments
on 5b (Fig. 2). Due to the trans configured product a
less strong interaction between the relevant hydrogen
atoms was expected. In fact, irradiation of the C(2)
proton of 5b gave no significant enhancement of the
C(3) proton resonance due to the greater distance
between these nuclei. Other interactions confirming the
trans stereochemistry of 5b could not be observed. The
determined relationship was in accord with that
reported in previous publications for the a-alkylation/
1,2-addition sequence10,13 and confirmed the (2R,3S)-
absolute configuration of the 2-substituted piperidin-
4.1.1. General procedures
4.1.1.1. 1,2-Addition of organolithium reagents to
hydrazone 12. A solution of the corresponding organo-
lithium compound was slowly added to a solution of 12
in dry THF (5 mL/mmol) at −100°C. In the case of a
freshly prepared lithium reagent, the hydrazone solu-
tion was added. After stirring the mixture for 15 h at
this temperature the reaction mixture was allowed to
warm to room temperature. The reaction was quenched
with a saturated aqueous NaHCO3 solution (10 mL/
mmol) and the aqueous portion was extracted with
Et2O (3×10 mL/mmol). The combined organic layers
were washed with brine, dried over anhydrous Na2SO4
and concentrated in vacuo. Flash column chromatogra-
phy of the residue on silica gel eluting with pentane–
Et2O gave the hydrazines 13a–e as pale yellow liquids.
Figure 2. Determination of the relative configuration of 5b by
NOESY experiments.

590
D. Enders et al. / Tetrahedron: Asymmetry 13 (2002) 587–593
+
’
(NꢁCH). MS (CI): m/z (%) 389 (6, M +3), 388 (23,
+ + +
4.1.1.2. NꢀN bond cleavage of hydrazines 13a–e and
’
’
’
ring closure by reductive amination to 2-substituted pipe-
ridin-3-ols 5a–e. A solution of BH3·THF (1 M, 10.0
equiv.) in THF was slowly added to a solution of 13 in
dry THF (2 mL/mmol) at room temperature. After
heating the mixture under reflux for 4 h, the mixture
was allowed to cool to room temperature and carefully
quenched with 3 M aqueous HCl (10 mL/mmol).
CH2Cl2 (8 mL/mmol) was added and the mixture was
stirred for 1 h at this temperature. The solvents were
removed in vacuo and the residue was dissolved in
EtOH (10 mL/mmol). NaBH4 (6.0 equiv.) was added
slowly to the solution at room temperature and the
mixture was then stirred at this temperature for 2 h.
The reaction was quenched with 3 M HCl (1 mL/mmol)
and conc. NH3 was added until a basic pH value was
measured. H2O (10 mL/mmol) and CH2Cl2 (15 mL/
mmol) were added and after separation of the organic
layer the aqueous portion was extracted further with
CH2Cl2 (4×10 mL/mmol). The combined organic layers
were dried over anhydrous Na2SO4 and concentrated in
vacuo. The isomer ratio was determined and flash
column chromatography of the residue on silica gel
eluting with CH2Cl2–MeOH gave 5a–e as colourless
solids.
M +2), 387 (96, M +1), 386 (18, M ), 341 (6), 329
(6), 256 (14), 255 (100), 133 (25). IR (film): w 3077,
2955, 2929, 2887, 2857, 2857 (CH), 2709, 1589 (CꢁN),
1472, 1463, 1409, 1389, 1360, 1341, 1301, 1283, 1253,
1198, 1124, 1097, 1075, 1039, 1006, 991, 941, 837, 815,
777, 678. Anal. calcd for C19H38O4N2Si: C, 59.03; H,
9.91; N, 7.25. Found: C, 58.71, H, 10.15; N, 7.47%.
4.2.2. (1R,2S,2S)-(−)-N-[2-(tert-Butyldimethylsilyloxy)-
4-([1,3]dioxolan-2-yl)-1-methyl-butyl]-N-(2-methoxy-
methylpyrrolidin-1-yl)-amine 13a. Hydrazone 12 (780
mg, 2.0 mmol) was allowed to react with 3.0 equiv. of
methyllithium according to the procedure described in
Section 4.1.1.1 at −30°C. Flash column chromatogra-
phy (silica, pentane–Et2O, 2:1) gave 13a (426 mg, 53%).
Rf (silica, pentane–Et2O, 2:1): 0.2. de >96% (13C NMR).
1
[h]2D7 −52.7 (c 1.01, CHCl3). H NMR (300 MHz): l
0.06 (s, 3H, SiCH3), 0.07 (s, 3H, SiCH3), 0.87 (s, 9H,
C(CH3)3), 0.94 (d, J=7.2, 3H, CHCH3), 1.50–2.22 (m,
8H, NCH2CH2CH2, (CH2O)2CHCH2CH2), 2.56 (m,
1H, NCHCH2OCH3), 2.92 (m, 1H, NCHCH3), 3.27
(d/d, J=9.0/3.0, 1H, CHHOCH3), 3.36 (s, 3H, OCH3),
3.46 (m, 2H, NCH2CH2), 3.54 (m, 1H, CHHOCH3),
3.77 (m, 1H, CHOSi), 3.85 (m, 2H, OCH2CH2O), 3.96
(m, 2H, OCH2CH2O), 4.87 (m, 1H, (CH2O)2CHCH2).
13C NMR (75 MHz): l −4.52 (SiCH3), −4.37 (SiCH3),
14.21 (NCHCH3), 18.05 (C(CH3)3), 21.10 (NCH2CH2),
4.2. Synthesis of 2-substituted piperidin-3-ols
4.2.1. (2S,2S)-(−)-(E)-N-[2-(tert-Butyldimethylsilyloxy)-
4-([1,3]dioxolan-2-yl)-but-1-ylidene]- N-(2-methoxy-
methylpyrrolidin-1-yl)-amine 12. A solution of 10 (2.87
g, 10 mmol) in dry THF (5 mL) was slowly added to a
solution of 2.0 equiv. LDA (freshly prepared from a
solution of n-butyllithium (1.6 M) in hexane (12.5 mL,
20 mmol) and diisopropylamine (2.9 mL, 20.5 mmol) in
dry THF (20 mL) at −78°C. The mixture was stirred at
this temperature for 15 h. Iodide 11 (6.84 g, 30 mmol)
was added at −100°C. The solution was stirred for 1 h
and then allowed to warm to room temperature within
20 h. The reaction mixture was quenched with a satu-
rated NH4Cl solution (15 mL). The aqueous portion
was extracted with Et2O (3×10 mL), and the combined
organic layers were washed with brine, dried over anhy-
drous Na2SO4 and concentrated in vacuo. After the
isomer ratio was determined, flash column chromatog-
raphy of the residue on silica gel eluting with pentane–
Et2O (1:1, 1 vol.% of Et3N) gave 12 (940 mg, 42%, 85%
conversion). Rf (silica, pentane–Et2O, 1:1): 0.6. de 90%
25.17
(NCHCH2),
25.92
(C(CH3)3),
26.58
((CH2O)2CHCH2CH2), 30.66 ((CH2O)2CHCH2), 57.53
(NCH2), 58.11 (NCHCH3), 59.08 (CH2OCH3), 64.81
((CH2O)2CH), 65.84 (NCHCH2), 73.51 (CHOSi), 75.39
(CH2OCH3), 104.97 ((CH2O)2CH). MS (EI): m/z (%)
402 (16, M+·), 158 (9), 157 (100), 129 (11), 114 (5), 113
(5), 85 (7), 73 (10), 70 (8). IR (film): w 2957, 2857 (CH),
2709, 1729, 1472, 1463, 1448, 1408, 1390, 1377, 1361,
1255, 1198, 1123, 1096, 1061, 1041, 987, 939, 917, 835,
814, 775, 665. HR-MS calcd for C20H42N2O4Si :
402.2914. Found: 402.2912.
+
’
4.2.3. (1R,2S,2S)-(−)-N-{1-[1-(tert-Butyldimethylsilyl-
oxy)-3-[1,3]dioxolan-2-yl-propyl]-pentyl}-N-(2-methoxy-
methylpyrrolidin-1-yl)-amine 13b. Hydrazone 12 (740
mg, 1.9 mmol) was allowed to react with 2.0 equiv. of
n-butyllithium according to the procedure described in
Section 4.1.1.1. Flash column chromatography (silica,
pentane–Et2O, 3:1) gave 13b (635 mg, 75%). Rf (silica,
pentane–Et2O, 2:1): 0.3. de >96% (13C NMR). [h]D28
1
1
(1H, 13C NMR). [h]D24 −50.1 (c 1.04, CHCl3). H NMR
−75.9 (c 1.48, CHCl3). H NMR (300 MHz): l 0.08 (s,
(400 MHz): l 0.03 (s, 3H, SiCH3), 0.08 (s, 3H, SiCH3),
0.88 (s, 9H, SiC(CH3)3), 1.63–2.00 (m, 8H,
NCH2CH2CH2CH, (CH2O)2CHCH2CH2), 2.79 (m, 1H,
NCHHCH2), 3.24–3.74 (m, 3H, NCHHCH2, NCH-
CHHOCH3), 3.36 (s, 3H, OCH3), 3.54 (d/d, J=3.3/8.7,
1H, NCHCHHOCH3), 3.85 (m, 2H, OCH2CH2O), 3.96
(m, 2H, OCH2CH2O), 4.20 (m, 1H, CHOSi), 4.88 (m,
1H, (CH2O)2CH), 6.38 (d, J=6.6, 1H, HCꢁN). 13C
NMR (100 MHz): l −4.73 (SiCH3), −4.10 (SiCH3),
18.15 (C(CH3)3), 22.08 (NCH2CH2), 25.88 (C(CH3)3),
26.62 (NCHCH2), 29.76 ((CH2O)2CHCH2), 31.28
((CH2O)2CHCH2CH2), 49.44 (NCH2), 59.10 (OCH3),
62.81 (NCH), 64.74 ((CH2O)2CH), 73.28 (CHOSi),
74.60 (CH2OCH3), 104.40 ((CH2O)2CH), 138.11
3H, SiCH3), 0.09 (s, 3H, SiCH3), 0.90 (s, 9H, C(CH3)3),
1.16–1.37 (m, 9H, CH(CH2)3CH3), 1.40–2.05 (m, 8H,
NCH2CH2CH2, (CH2O)2CHCH2CH2), 2.50 (m, 1H,
NCHCH2OCH3), 2.82 (m, 1H, NCH(CH2)3CH3), 3.27–
3.50 (m, 3H, NCH2CH2, CHHOCH3), 3.37 (s, 3H,
OCH3), 3.55 (d/d, J=9.0/4.0, 1H, CHHOCH3), 3.74–
4.01 (m, 5H, CHOSi, OCH2CH2O), 4.80 (t, J=4.5, 1H,
(CH2O)2CH). 13C NMR (75 MHz): l −4.61 (SiCH3),
−4.05 (SiCH3), 14.22 (CH2CH3), 18.07 (C(CH3)3),
20.93 (NCH2CH2), 23.28 (CH2CH3), 24.77 (NCHCH2),
25.98 (C(CH3)3), 26.06 ((CH2O)2CHCH2CH2), 28.53
(CH2CH2CH3),
30.64
((CH2O)2CHCH2),
31.03
(CH2(CH2)2CH3), 56.60 (NCH2), 59.00 (CH2OCH3),
62.97 (NCH(CH2)3CH3), 64.85 ((CH2O)2CH), 65.84

D. Enders et al. / Tetrahedron: Asymmetry 13 (2002) 587–593
591
(NCHCH2), 72.84 (CHOSi), 74.75 (CH2OCH3), 104.90
((CH2O)2CH). MS (EI): m/z (%) 444 (6, M+·), 200 (13),
199 (100), 129 (8), 114 (7), 113 (5), 85 (6), 73 (10), 70
(9). IR (film): w 2955, 2858 (CH), 1729, 1471, 1408,
1380, 1361, 1256, 1198, 1131, 1097, 1062, 1005, 941,
919, 897, 836, 813, 775, 738, 663. HR-MS calcd for
C23H48N2O4Si+·: 444.3383. Found: 444.3384.
(CH2(CH2)4CH3), 56.73 (NCH2), 59.09 (CH2OCH3),
62.98 (NCH(CH2)4CH3), 64.83 ((CH2O)2CH), 65.11
(NCHCH2), 72.90 (CHOSi), 75.74 (CH2OCH3), 105.06
+
’
((CH2O)2CH). MS (EI): m/z (%) 472 (11, M ), 228
(15), 227 (100), 129 (10), 114 (7), 113 (6), 73 (8), 70 (9).
IR (film): w 2955, 2928, 2856 (CH), 1471, 1407, 1390,
1361, 1255, 1197, 1128, 1095, 1060, 1041, 1006, 940,
916, 836, 814, 775, 665. HR-MS calcd. for
+
’
C25H52N2O4Si : 472.3696. Found: 472.3699.
4.2.4.
(1R,2S,2S)-(−)-N-[1-tert-Butyl-2-(tert-butyldi-
methylsilyloxy)-4-[1,3]dioxolan-2-yl-butyl]-N-(2-meth-
oxymethylpyrrolidin-1-yl)-amine 13c. Hydrazone 12 (880
mg, 2.3 mmol) was allowed to react with 2.0 equiv. of
t-butyllithium according to the procedure described in
Section 4.1.1.1. Flash column chromatography (silica,
pentane–Et2O, 3:1) gave 13c (780 mg, 77%). Rf (silica,
pentane–Et2O, 2:1): 0.6. de >96% (13C NMR). [h]D30
4.2.6. (1R,2S,2S)-(−)-N-{1-[2-(tert-Butyldimethylsilyl-
oxy)-4-[1,3]dioxolan-2-yl-1-phenylethylbutyl]}-N-(2-
methoxymethylpyrrolidin-1-yl)-amine 13e. Hydrazone 12
(610 mg, 1.58 mmol) was allowed to react with 3.0
equiv. of 2-phenylethyllithium according to the proce-
dure described in Section 4.1.1.1. Flash column chro-
matography (silica, pentane–Et2O, 3:1) gave 13e (710
mg, 91%). Rf (silica, pentane–Et2O, 1:1): 0.7. de >96%
(13C NMR). [h]D24 −79.95 (c 1.10, CHCl3). 1H NMR
(300 MHz): l 0.08 (s, 3H, SiCH3), 0.10 (s, 3H, SiCH3),
0.91 (s, 9H, C(CH3)3), 1.15–2.08 (m, 10H, CH2CH2Ph,
NCH2CH2CH2, (CH2O)2CHCH2CH2), 2.55 (m, 1H,
NCHCH2OCH3), 2.68 (m, 1H, CH2CH2Ph), 3.27–3.52
(m, 5H, NCH2CH2, NCHCH2CH2Ph, CH2OCH3), 3.32
(s, 3H, OCH3), 3.62 (m, 1H, CHOSi), 3.76–4.05 (m,
4H, (CH2O)2CH), 4.88 (m, 1H, CH2O)2CH), 7.16–7.28
(m, 5H, Ar–H). 13C NMR (75 MHz): l −4.68 (SiCH3),
−4.17 (SiCH3), 18.07 (C(CH3)3), 20.98 (NCH2CH2),
1
−91.4 (c 1.15, CHCl3). H NMR (300 MHz): l 0.08 (s,
3H, SiCH3), 0.09 (s, 3H, SiCH3), 0.91 (s, 9H,
SiC(CH3)3), 1.01 (s, 9H, NCHC(CH3)3), 1.45–1.99 (m,
8H, NCH2CH2CH2, (CH2O)2CHCH2CH2), 2.50 (m,
1H, NCHCH2OCH3), 2.71 (m, 1H, NCHC(CH3)3),
3.31–3.52 (m, 3H, NCH2CH2, CHHOCH3), 3.35 (s, 3H,
OCH3), 3.74 (m, 1H, CHHOCH3), 3.71–4.01 (m, 5H,
CHOSi, OCH2CH2O), 4.80 (m, 1H, (CH2O)2CH). 13C
NMR (75 MHz): l −4.64 (SiCH3), −3.70 (SiCH3),
18.08 (SiC(CH3)3), 20.69 (NCH2CH2), 26.05 (SiC-
(CH3)3), 26.64 (NCHCH2), 27.05 ((CH2O)2CH-
CH2CH2), 28.86 (SiC(CH3)3), 31.35 ((CH2O)2CHCH2),
34.26 (NHC(CH3)3), 56.22 (NCH2), 58.96 (CH2OCH3),
64.81 ((CH2O)2CH), 66.33 (NCHC(CH3)3), 70.23
24.92
(NCHCH2),
25.95
(C(CH3)3),
26.26
(CH2CH2Ph), 30.89, 32.25, 32.85 ((CH2O)2CHCH2-
CH2, CH2CH2Ph), 56.44 (NCH2), 58.96 (CH2OCH3),
62.03 (NCHCH2CH2Ph), 64.78, 64.79 ((CH2O)2CH),
65.79 (NCHCH2), 73.16 (CHOSi), 75.01 (CH2OCH3),
104.75 ((CH2O)2CH), 125.59 (Ar–Cpara), 128.19, 128.39
(NCHCH2), 72.86 (CHOSi), 75.36 (CH2OCH3), 104.74
((CH2O)2CH). MS (EI): m/z (%) 444 (5, M ), 200 (13),
199 (100), 129 (5), 114 (6), 99 (6), 73 (9), 70 (9), 57 (6).
+
’
IR (film): w=2955, 2858 (CH), 1472, 1392, 1361, 1256,
(Ar–Cortho,meta), 142.63 (Ar–Cipso). MS (EI): m/z (%)
492 (8, M ), 341 (16), 261 (9), 248 (17), 247 (100), 245
(8), 201 (11), 131 (6), 129 (12), 117 (17), 115 (14), 114
(11), 113 (25), 99 (13), 91 (33), 85 (8), 75 (25), 73 (65),
70 (13). IR (film): w 3014, 2953, 2930, 2884, 2857, 1469,
+
’
1216, 1200, 1128, 1075, 1037, 1006, 982, 941, 835, 813,
+
’
774, 759, 666. HR-MS calcd. for C23H48N2O4Si :
444.3383. Found: 444.3383.
1254, 1217, 1127, 1090, 1047, 1006, 835, 716, 700.
HR-MS calcd. for C27H48N2O4Si : 492.3383. Found:
492.3384.
+
’
4.2.5. (1R,2S,2S)-(−)-N-{1-[1-(tert-Butyldimethylsilyl-
oxy)-3-[1,3]dioxolan-2-yl-propyl]-heptyl}-N-(2-methoxy-
methylpyrrolidin-1-yl)-amine 13d. Hydrazone 12 (615
mg, 1.59 mmol) was allowed to react with 3.0 equiv. of
n-hexyllithium according to the procedure described in
Section 4.1.1.1 at −30°C. Flash column chromatogra-
phy (silica, pentane–Et2O, 3:1) gave 13d (342 mg, 45%).
Rf (silica, pentane–Et2O, 2:1): 0.7. de >96% (13C NMR).
[h]2D6 −99.8 (c 1.03, CHCl3). 1H NMR (300 MHz):
l=0.04 (s, 3H, SiCH3), 0.05 (s, 3H, SiCH3), 0.88 (s,
9H, C(CH3)3), 1.20 (t, J=8.3, 3H, CH(CH2)5CH3), 1.26
(m, 10H, CH(CH2)5CH3), 1.46–2.09 (m, 8H,
NCH2CH2CH2, (CH2O)2CHCH2CH2), 2.52 (m, 1H,
NCHCH2OCH3), 2.70 (m, 1H, NCH(CH2)5CH3), 3.22
(d/d, J=18.0/8.8, 1H, CHHOCH3), 3.35 (s, 3H,
OCH3), 3.54 (d/d, J=9.2/4.0, 1H, CHHOCH3), 3.83
(m, 2H, OCH2CH2O), 3.97 (m, 2H, OCH2CH2O), 4.87
(m, 1H, CH(OCH2)2) ppm. 13C NMR (75 MHz): l
−4.48 (SiCH3), −4.42 (SiCH3), 14.09 (CH2CH3), 18.05
(C(CH3)3), 21.03 (NCH2CH2), 22.65 (CH2CH3), 24.92
(NCHCH2), 25.94 (C(CH3)3), 25.98 (CH2CH2CH3),
26.81 ((CH2O)2CHCH2CH2), 27.11 (CH2(CH2)2CH3),
29.63 (CH2(CH2)3CH3), 31.68 ((CH2O)2CHCH2), 31.75
4.2.7. (2R,3S)-(+)-2-Methyl-piperidin-3-ol 5a. According
to the procedure described in Section 4.1.1.2. Hydrazine
13a (400 mg, 0.99 mmol) was employed in the cleavage
of the auxiliary and the subsequent ring closure. Flash
column chromatography (silica, CH2Cl2–MeOH, 1:1)
gave 5a (59 mg, 59%). Rf (silica, MeOH): 0.1. de, ee
>96% (1H, 13C NMR). [h]D26 16.2 (c 0.92, CHCl3). Mp
130°C. 1H NMR (400 MHz): l 0.93 (t, J=7.4, 3H,
NCHCH3), 1.35–1.62 (m, 2H, CHHCHO, NCH2-
CHH), 1.77 (m, 1H, NCH2CHH), 1.97 (m, 1H, CHH-
CHO), 2.41 (m, 1H, NCH), 2.49 (br s, 2H, NH, OH),
2.54 (m, 1H, NCHH), 2.81 (m, 1H, NCHH), 3.25 (m,
1H, CHO). 13C NMR (100 MHz): l 15.32 (NCHCH3),
22.89 (NCH2CH2), 33.76 (CH2CHO), 45.71 (NCH2),
62.64 (NCH), 71.65 (OCH). Mass (CI): m/z (%) 117 (6,
+
+
+
’
’
’
M +2), 116 (100, M +1), 84 (7, M −OH, –CH3), 70
(8). IR (CHCl3): w 3399 (br s, NH, OH), 2943, 2757,
2685, 2490, 1626, 1460, 1397, 1120, 1068, 1039. Anal.
calcd for C6H13NO: C, 62.57; H, 11.34; N, 12.16.
Found: C, 62.43, H, 11.21; N, 12.25%.

592
D. Enders et al. / Tetrahedron: Asymmetry 13 (2002) 587–593
4.2.8. (2R,3S)-(+)-2-n-Butyl-piperidin-3-ol 5b. Accord-
ing to the procedure described in Section 4.1.1.2 hydra-
zine 13b (800 mg, 1.79 mmol) was employed in the
cleavage of the auxiliary and the subsequent ring clo-
sure. Flash column chromatography (silica, CH2Cl2–
MeOH, 1:1) gave 5b (170 mg, 62%). Rf (silica,
CH2Cl2–MeOH): 0.2. de, ee >96% (1H, 13C NMR). [h]D26
(CH2CH3), 24.97 (NCH2CH2), 25.75, 29.40, 31.76
(CH2(CH2)3CH3), 31.92 (NCHCH2), 33.61 (CH2CHO),
45.49 (NCH2), 62.69 (NCH), 71.52 (OCH). Mass (EI):
+
+
’
’
m/z (%) 185 (8, M ), 128 (13, M −nBu), 126 (5), 101
+
’
(6), 100 (100, M −nhex), 84 (19), 71 (5), 70 (5). IR
(KBr): w 3421 (OH), 3291 (NH), 3154 (OH), 2933, 2854,
2823 (CH), 1470, 1341, 1176, 1122, 1103, 1061, 1045,
1022, 980, 929, 911, 888, 846, 724, 592. Anal. calcd for
C11H23NO: C, 71.30; H, 12.51; N, 7.56. Found: C,
71.05, H, 12.62; N, 7.67%.
1
28.6 (c 1.90, CHCl3). Mp 117°C. H NMR (400 MHz):
l 0.91 (t, J=7.1, 3H, CH2CH3), 1.23–1.57 (m, 7H,
CH2CH2CH3, CHHCHO, NCH2CHH, NCHCHH),
1.72 (m, 1H, NCH2CHH), 1.86 (m, 1H, NCHCHH),
2.03 (m, 1H, CHHCHO), 2.33 (t/d, J=8.2/3.1, 1H,
CHN), 2.42 (s, 2H, OH, NH), 2.55 (t/d, J=11.6/3.0,
1H, NCHH), 2.96 (m, 1H, NCHH), 3.32 (d/d/d, J=
6.1/8.5/10.2, 1H, CHO). 13C NMR (100 MHz): l 14.05
(CH2CH3), 22.93 (CH2CH3), 25.27 (NCH2CH2), 27.96
(CH2CH2CH3), 31.75 (NCHCH2), 33.83 (CH2CHO),
4.2.11. (2R,3S)-(+)-2-(2-Phenylethyl)-piperidin-3-ol 5e.
According to the procedure described in Section 4.1.1.2
hydrazine 13e (700 mg, 1.42 mmol) was employed in
the cleavage of the auxiliary and the subsequent ring
closure. Flash column chromatography (silica, CH2Cl2–
MeOH, 1:1) gave 5e (220 mg, 76%). Rf (silica, CH2Cl2–
MeOH, 1:1): 0.3. de, ee >96% (1H, 13C NMR). [h]D26
45.66 (NCH2), 62.74 (NCH), 71.76 (OCH). Mass (EI):
1
+
26.8 (c 1.0, CHCl3). Mp 116°C. H NMR (300 MHz): l
’
m/z (%) 157 (10, M ), 128 (11), 101 (5), 100 (100,
+
1.22–1.90 (m, 4H, NCH2CH2CHH, CHHCH2Ph),
1.95–2.10 (m, 1H, NCH2CH2CHH), 2.15–2.28 (m, 1H,
CHHCH2Ph), 2.35–2.71 (m, 5H, NH, OH, CHHPh,
NCHH, NCH), 2.73–2.84 (m, 1H, CHHPh), 2.92–3.05
(m, 1H, NCHH), 3.18–3.30 (m, 1H, CHO), 7.14–7.29
(m, 5H, Ar–H). 13C NMR (75 MHz): l 25.48
(NCH2CH2), 32.23 (CH2Ph), 34.06, 34.13 (NCHCH2,
CH2CHO), 45.74 (NCH2), 62.54 (NCH), 71.68 (OCH),
’
M −nBu), 84 (19), 71 (6), 56 (13). IR (KBr): w 3434
(OH), 3291 (NH), 2933, 2858, 2875 (CH), 1653, 1636,
1496, 1469, 1383, 1341, 1177, 1153, 1122, 1103, 1081,
1051, 1010, 985, 952, 929, 895, 871, 854, 828, 773, 740,
593, 455. Anal. calcd for C9H19NO: C, 68.74; H, 12.18;
N, 8.91. Found: C, 68.93, H, 11.89; N, 8.59%.
4.2.9.
(2R,3S)-(+)-2-tert-Butyl-piperidin-3-ol
5c.
125.78 (Ar–Cpara), 128.33, 128.38 (Ar–Cortho,meta),
According to the procedure described in Section 4.1.1.2
hydrazine 13c (780 mg, 1.75 mmol) was employed in
the cleavage of the auxiliary and the subsequent ring
closure. Flash column chromatography (silica, CH2Cl2–
MeOH, 1:1) gave 5c (140 mg, 51%). Rf (silica, CH2Cl2–
MeOH, 1:2): 0.3. de, ee >96% (1H, 13C NMR). [h]D26
+
’
142.23 (Ar–Cipso). Mass (EI): m/z (%) 205 (22, M ),
174 (16), 160 (8), 134 (18), 133 (8), 132 (22), 117 (11),
+
’
114 (23), 100 (100, M −(CH)2Ph), 90 (44), 84 (6), 70
(8), 69 (8). IR (KBr): w 3439 (OH), 3286 (NH), 3155
(OH), 3061 (Ar–H), 2944, 2894, 2859, 2825 (CH), 1601,
1494, 1463, 1336, 1177, 1107, 1075, 1052, 1025, 982,
931, 898, 878, 854, 741, 695, 585. Anal. calcd for
C13H19NO: C, 76.06; H, 9.33; N, 6.82. Found: C, 75.95,
H, 9.24; N, 7.04%.
1
35.7 (c 1.04, CHCl3). Mp. 109°C. H NMR (400 MHz):
l 0.95 (s, 9H, C(CH3)3), 1.41–1.72 (m, 2H, NCH2CH2),
1.84 (m, 1H, CHHCHO), 2.01 (m, 1H, CHHCHO),
2.11 (d, J=8.8, NCH), 2.50 (t/d, J=11.8/3.0,
NCHHCH2), 2.61 (s, 2H, NH, OH), 3.01 (m, 1H,
NCHHCH2), 3.54 (m, 1H, CHO). 13C NMR (100
MHz): l 25.94 (NCH2CH2), 26.73 (CH2CHO), 27.70
(C(CH3)3), 34.47 (C(CH3)3), 47.12 (NCH2), 65.47
(NCH), 71.43 (OCH). Mass (CI): m/z (%) 159 (4,
Acknowledgements
This work was supported by the Deutsche Forschungs-
gemeinschaft (Sonderforschungsbereich 380) and the
Fonds der Chemischen Industrie. For the donation of
chemicals we thank the companies Aventis, BASF AG,
Bayer AG, Degussa AG, and Wacker Chemie. We also
thank Pascal Buskens for his contribution to the exper-
imental part of this work.
+
+
+
’
’
’
M +2), 158 (49, M +1), 141 (10), 140 (100, M −OH),
+
’
100 (10, M −tert-butyl). IR (CHCl3): w 3364 (OH,
NH), 2951, 2868 (CH), 1476, 1396, 1364, 1261, 1120,
1073, 1000, 755. Anal. calcd for C9H19NO: C, 68.74; H,
12.18; N, 8.91. Found: C, 68.91, H, 12.03; N, 8.69%.
4.2.10. (2R,3S)-(+)-2-n-Hexyl-piperidin-3-ol 5d. Accord-
ing to the procedure described in Section 4.1.1.2 hydra-
zine 13d (270 mg, 0.57 mmol) was employed in the
cleavage of the auxiliary and the subsequent ring clo-
sure. Flash column chromatography (silica, CH2Cl2–
MeOH, 1:1) gave 5d (70 mg, 67%). Rf (silica,
CH2Cl2–MeOH, 1:1): 0.2. de, ee >96% (1H, 13C NMR).
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