Synthesis of an optically pure synthetic intermediate of aloperine from a yeast-reductive product

Article abstract of DOI:10.1271/bbb.69.1589

Optically pure (S)- and (R)-vinylpiperidine 2 and (S)-and (A)-(hydroxyethyl)piperidine 3, which were key intermediates for the synthesis of aloperine, were synthesized from yeast-reductive products.

Full text of DOI:10.1271/bbb.69.1589

Biosci. Biotechnol. Biochem., 69 (8), 1589–1594, 2005
Synthesis of an Optically Pure Synthetic Intermediate of Aloperine
from a Yeast-Reductive Product
y
Satoshi YAMAUCHI and Yasushi OMI
Faculty of Agriculture, Ehime University, Tarumi 3-5-7, Matsuyama, Ehime 790-8566, Japan
Received April 8, 2005; Accepted May 16, 2005
Optically pure (S)- and (R)-vinylpiperidine 2 and (S)-
and (R)-(hydroxyethyl)piperidine 3, which were key
intermediates for the synthesis of aloperine, were
synthesized from yeast-reductive products.
synthetic processes. The preparation of 2 or 3 with a
higher ee value will lead to the synthesis of aloperine
with a correspondingly higher ee value.
The application of yeast-reductive products 4 and 5 to
preparing 2 and 3 is described in this report. Compounds
4 and 5 had already been converted to (R)-7 and (S)-7
via (R)-6 and (S)-6, respectively8) (Scheme 1). These
Key words: piperidine; aloperine; yeast-reductive prod-
uct
Piperidine derivatives are important synthetic inter-
mediates for the synthesis of alkaloids, and some
reviews on the synthesis of piperidine are known.1,2)
Aloperine (1) has been isolated from plants which were
used as the traditional Chinese medicine for the treat-
ment of inflammation.3) The structure of aloperine (1)
containing its absolute configuration has been deter-
mined,4) and two synthetic studies are known (Fig. 1). L.
E. Overman and co-workers have synthesized aloperine
(1) with 97% ee from (R)-vinylpiperidine 2 of 97%
ee.5) D. Passarella and coworkers have prepared (R)-
(hydroxyethyl)piperidine 3 with 90% ee,6) and then
converted to aloperine with 90% ee.7) These reports
demonstrate that the ee values of key intermediates 2
and 3 determined the ee value of aloperine in these
Fig. 1. Previous Synthetic Study of (þ)-Aloperine (1).
Scheme 1. Conversion of Yeast-Reductive Products 4 and 5 to (R)-7 and (S)-7.8)
y
To whom correspondence should be addressed. Fax: +81-89-977-4364; E-mail: syamauch@agr.ehime-u.ac.jp

1590
S. YAMAUCHI and Y. OMI
Scheme 2. Retrosynthetic Analysis of (S)-2.
Scheme 3. Synthesis of (S)-2.
(a) (1) MsCl, Et3N, CH2Cl2, r.t., 12 h; (2) NaN3, DMF, 100 ꢁC, 1 h (99%, 2 steps); (b) HCO2Hꢁ, ether, 0 ꢁC, 1 h (91%); (c) PCC, NaOAc, MS
.
4A, CH2Cl2, r.t., 15 h (74%); (d) 2-methyl-2-butene, NaH2PO4 2H2O, NaClO2, aq. tert-BuOH, 0 C, 1 h (97%); (e) (1) H2, Pd(OH)2, EtOH, r.t.,
4 h; (2) toluene, reflux, 1 h (90%, 2 steps); (f) DIBAL-H, CH2Cl2, 0 ꢁC, 1 h (48%); (g) (Boc)2O, K2CO3, aq. THF, 0 ꢁC, 2 h (97%); (h) (n-
Bu)4NF, THF, 0 ꢁC, 8 h (76%); (i) (2-NO2C6H4)SeCN, (n-Bu)3P, THF, r.t., 12 h (92%); (j) MCPBA, phosphate buffer at pH 8, CH2Cl2, 0 ꢁC,
30 min (81%).
(R)- and (S)-7 were selected as intermediates for the
syntheses of (S)-2 and (S)-3, and (R)-2 and (R)-3.
Scheme 2 shows the retrosynthetic analysis. (S)-Vinyl-
piperidine 2 would have been obtained from (S)-
(hydroxyethyl)piperidine 3 by dehydration, and the
reduction of (S)-amide 8 would have then give a (S)-
piperidine 3. (R)-Alcohol 7 could be converted to (S)-
amide 8 by SN2 introduction of an amino group,
deprotection followed by oxidation to carboxylic acid.
(R)-Vinylpiperidine 2 and (R)-(hydroxyethyl)piperidine
3 could be obtained from (S)-alcohol 7. It can be
assumed that direct conversion of 6 to amide 8 by
Beckmann rearrangement under acidic condition would
be difficult because of selection of the protective group.
Since reported yeast-reductive products 4 and 5 each
have a high ee value, syntheses of vinylpiperidine 2 and
(hydroxyethyl)piperidine 3 with higher ee value could
be expected. The purpose of this project is to synthesize
(S)-2 and (S)-3 with a high ee value, as well as (R)-2 and
(R)-3. The success of this project will make it possible to
synthesize (ꢀ)- and (þ)-aloperine with high ee value
and contribute to biological research. Kibayashi has
succeeded in the preparation of enantiopure (R)-(2-
hydroxyethyl)piperidine by using a chiral auxiliary.9)
Our challenge is to synthesize enantiopure (R)- and (S)-2
and (R)- and (S)-3 by using yeast-reductive products
obtained from one racemic compound.
Results and Discussion
Scheme 3 shows the synthesis of (S)-3 and (S)-2. (R)-
Alcohol 7, which was prepared from yeast-reductive
product 4,8) was converted to a corresponding mesylate
by using mesyl chloride and triethylamine, and the crude
mesylate was then converted to azide 9 by employing
NaN3 in 99% yield through 2 steps. After cleavage of
the trityl ether using formic acid in ether in 91% yield,
resulting alcohol 10 was oxidized to carboxylic acid 12
by pyridinium chlorochromate and subsequent NaClO2
oxidation in 72% yield through 2 steps. Conversion of
azido-carboxylic acid 12 to amide 13 was achieved by
treatment with H2 and Pd(OH)2/C followed by heating
in toluene in 90% yield. DIBAL-H reduction of amide
13 gave (S)-piperidine 14 in 48% yield, amide 13 being
recovered in 51%. The enantiomeric excess of (S)-
piperidine 14 was determined as >99% after the
reaction with (ꢀ)-menthyl chloroformate.
After introduction of tert-butoxycarbonyl (Boc) group
by using (Boc)2O and K2CO3 in 97% yield, cleavage of
the silyl ether by employing (n-Bu)4NF was performed
to give (S)-(hydroxyethyl)piperidine 3 in 76% yield. The
NMR spectrum agreed with that in the literature.6)
Dehydration of (S)-3 to (S)-vinylpiperidine 2 by the
Chugaev reaction failed to give any useful products.
However, dehydration via selenide 16 gave 2. After

Synthetic Intermediate of Aloperine
1591
Table 1. Conversion of (S)-Selenide 16 to (S)-Vinylpiperidine 2
Reaction condition
Yield
ee
a) 30% H2O2/THF (0.3/5), 0 ꢁC to r.t., 12 h
92%
85%
85%
81%
54%
92%
b) 30% H2O2/CH2Cl2 (1/1), 0 ꢁC to r.t., 2 h
c) 2 eq. NaIO4, THF/H2O (1/1.2), 0 ꢁC to r.t., 12 h
d) 2.3 eq. MCPBA, CH2Cl2/phosphate buffer at pH 8 (1/1), 0 ꢁC, 30 min
93%
>99%
conversion of (S)-alcohol 3 to selenide 16 by employing
2-nitrophenyl selenocyanate and (n-Bu)3P10) in 92%
yield, the reaction conditions for oxidation and elimi-
nation were examined to give optically pure (S)-2
(Table 1). When selenide 16 was treated with m-
chloroperbenzoic acid in CH2Cl2 and a phosphate buffer
(pH 8), optically pure (S)-vinylpiperidine 2 (>99% ee)
was obtained. Employing H2O2 or NaIO4 did not give
optically pure (S)-2. There is the possibility for a radical
or anion to be formed at the C-2 allylic position in the
presence of some oxidants. It was assumed that this was
the reason for racemization, so the buffer was employed
to avoid the production of a radical or anion. The NMR
spectrum agreed with that in the literature.5) The optical
purity was determined by a modification of the describ-
ed method.5) After removal of the Boc group and
reaction with (ꢀ)-menthyl chloroformate, the resulting
product was applied to a chiral column. (R)-Vinyl-
piperidine 2 and (R)-(hydroxyethyl)piperidine 3 were
also obtained from (S)-7, which had been prepared from
yeast-reductive product 5, by the same synthetic process
as that for (S)-2 and (S)-3. The optical purity of (R)-2
and (R)-3 was also determined as >99% ee.
room temperature for 12 h. After addition of H2O, the
organic solution was separated, washed with brine, and
dried (Na2SO4). Concentration gave a crude mesylate. A
reaction solution of the crude mesylate and NaN3
(6.47 g, 99.5 mmol) in DMF (300 ml) was stirred at
100 ꢁC for 1 h before additions of H2O and EtOAc. The
organic solution was separated, washed with brine, and
dried (Na2SO4). Concentration followed by silica gel
column chromatography (EtOAc=hexane ¼ 1=9) gave
(S)-azide 9 (32.4 g, 49.5 mmol, 99%) as a colorless oil,
20
½ꢀꢂ
¼ þ1:8 (c 1.4, CHCl3). 1H-NMR (CDCl3) ꢁ 1.05
D
(9H, s, tert-Bu), 1.38–1.56 (5H, m), 1.57–1.68 (2H, m),
1.73 (1H, m), 3.07 (2H, t, J ¼ 6:6 Hz, 7-H2), 3.53 (1H,
m, 3-H), 3.72 (1H, ddd, J ¼ 10:7, 10.7, 5.4 Hz, 1-HH),
3.80 (1H, ddd, J ¼ 10:7, 8.3, 5.4 Hz, 1-HH), 7.20–7.30
(9H, m, ArH), 7.34–7.45 (12H, m, ArH), 7.64–7.67 (4H,
m, ArH). 13C-NMR (CDCl3) ꢁ 19.2, 22.9, 26.8, 29.8,
34.5, 37.0, 59.7, 60.5, 63.2, 86.4, 126.8, 127.69, 127.71,
128.7, 129.7, 133.5, 133.7, 135.49, 135.53, 144.4.
IRꢂmax (CHCl3): 3073, 2934, 2103, 1113, 1088, 909
cmꢀ1. Anal. Calcd. for C42H47O2N3Si: C, 77.14; H,
7.24; N, 6.43. Found: C, 77.37; H, 7.35; N, 6.36.
20
(R)-9, ½ꢀꢂ
¼ ꢀ1:8 (c 1.7, CHCl3).
D
The syntheses of optically pure (S)-vinylpiperidine 2
and (S)-(hydroxyethyl)piperidine 3, which are key
intermediates for the synthesis of (ꢀ)-aloperine, were
achieved from yeast-reductive products. Optically pure
(R)-2 and (R)-3 were also obtained. The optical purity of
these synthetic compounds was higher than that of
compounds reported in the literature.5–7) This is a new
synthetic route to a piperidine derivative, which is an
intermediate for the synthesis of aloperine5,7) and other
alkaloids,6,9) from yeast-reductive products.
(S)-5-Azido-7-(tert-butyldiphenylsilyloxy)-1-heptanol
(10). To a solution of (S)-trityl ether 9 (5.50 g,
8.41 mmol) in ether (55 ml) was added HCO2H (55 ml)
at 0 ꢁC. The reaction solution was stirred at 0 ꢁC for 1 h
before additions of EtOAc and H2O. The organic
solution was separated, successively washed with a sat.
aq. NaHCO3 solution and brine, and dried (Na2SO4).
Concentration followed by silica gel column chroma-
tography (EtOAc=hexane ¼ 1=9) gave (S)-alcohol 10
20
(3.15 g, 7.65 mmol, 91%) as a colorless oil, ½ꢀꢂ
¼
D
1
Experimental
þ3:3 (c 4.0, CHCl3). H-NMR (CDCl3) ꢁ 1.06 (9H, s,
tert-Bu), 1.40–1.62 (6H, m), 1.66 (1H, m), 1.76 (1H, m),
3.58 (1H, m, 5-H), 3.66 (2H, t, J ¼ 6:3 Hz, 1-H2), 3.74
(1H, ddd, J ¼ 10:5, 10.5, 5.6 Hz, 7-HH), 3.80 (1H, ddd,
J ¼ 10:5, 8.1, 5.4 Hz, 7-HH), 7.37–7.43 (6H, m, ArH),
7.65–7.67 (4H, m, ArH). 13C-NMR (CDCl3) ꢁ 19.2,
22.4, 26.8, 32.4, 34.4, 37.0, 50.7, 60.5, 62.7, 127.7,
129.7, 133.5, 133.6, 135.50, 135.54. IRꢂmax (CHCl3):
3500, 2934, 2103, 1429, 1113, 1092, 909, 824. Anal.
Melting point (mp) data are uncorrected. NMR data
were measured by a JNM-EX400 spectrometer, IR
spectra were determined with a Shimadzu FTIR-8100
spectrophotometer and optical rotation values were
evaluated with a Horiba SEPA-200 instrument. The
silica gel used was Wakogel C-300 (Wako, 200–300
mesh). HPLC analyses were performed with Shimadzu
LC-6AD and SPD-6AV instruments.
Calcd. for C23H33O2N3Si: C, 67.11; H, 8.08; N, 10.21.
20
Found: C, 67.23; H, 8.16; N, 10.09. (R)-10, ½ꢀꢂ
ꢀ3:3 (c 3.4, CHCl3).
¼
D
(S)-3-Azido-1-(tert-butyldiphenylsilyloxy)-7-trityloxy-
heptane (9). To a solution of (R)-trityl ether 7 (31.5 g,
50.1 mmol) and Et3N (7.67 ml, 55.0 mmol) in CH2Cl2
(50 ml) was added MsCl (4.26 ml, 55.0 mmol) at 0 ꢁC,
and then the resulting reaction solution was stirred at
(S)-5-Azido-7-(tert-butyldiphenylsilyloxy)heptanal (11).
A reaction mixture of (S)-alcohol 10 (17.6 g, 42.8
mmol), PCC (10.1 g, 46.9 mmol), NaOAc (3.86 g,

1592
S. YAMAUCHI and Y. OMI
47.1 mmol) and MS 4A (0.3 g) in CH2Cl2 (300 ml) was
stirred at room temperature for 15 h before filtration. The
resulting filtrate was concentrated, and the residue was
applied to silica gel column chromatography (EtOAc=
(2H, m), 2.27 (1H, ddd, J ¼ 17:8, 10.9, 5.9 Hz, 3-HH),
2.39 (1H, m, 3-HH), 3.60 (1H, m, 6-H), 3.72–3.80 (2H,
m, CH2OTBDPS), 6.31 (1H, br. s, NH), 7.38–7.46 (6H,
m, ArH), 7.65–7.66 (4H, m, ArH). 13C-NMR (CDCl3) ꢁ
19.1, 19.9, 26.8, 29.0, 31.2, 39.0, 52.0, 61.8, 127.78,
127.80, 129.8, 129.9, 133.1, 133.2, 135.5, 171.8. IRꢂmax
(CHCl3): 3376, 2934, 1649, 1472, 1113, 1092, 909.
Anal. Calcd. for C23H31O2NSi: C, 72.39; H, 8.19; N,
hexane ¼ 1=9) to give (S)-aldehyde 11 (13.0 g, 31.7
20
mmol, 74%) as a colorless oil, ½ꢀꢂ
¼ þ3:1 (c 1.3,
D
CHCl3). 1H-NMR (CDCl3) ꢁ 1.06 (9H, s, tert-Bu), 1.46–
1.62 (2H, m), 1.62–1.85 (4H, m), 2.47 (2H, td, J ¼ 7:1,
1.5 Hz, 2-H2), 3.59 (1H, m, 5-H), 3.74 (1H, ddd, J ¼
10:7, 10.7, 5.4 Hz, 7-HH), 3.80 (1H, ddd, J ¼ 10:7, 7.8,
4.9 Hz, 7-HH), 7.37–7.45 (6H, m, ArH), 7.64–7.67 (4H,
m, ArH), 9.77 (1H, d, J ¼ 1:5 Hz, CHO). 13C-NMR
(CDCl3) ꢁ 18.7, 19.2, 26.8, 33.9, 36.9, 43.4, 59.4, 60.3,
127.7, 129.7, 133.5, 133.6, 135.50, 135.54, 201.8.
IRꢂmax (CHCl3): 3073, 2932, 2103, 1725, 1113, 909,
824. Anal. Calcd. for C23H31O2N3Si: C, 67.44; H, 7.63;
3.67. Found: C, 72.35; H, 8.14; N, 3.73. (R)-13,
20
½ꢀꢂ
¼ ꢀ3:8 (c 1.3, CHCl3).
D
(S)-2-[2-(tert-Butyldiphenylsilyloxy)ethyl]piperidine
(14). To a solution of (S)-amide 13 (3.26 g, 8.54 mmol)
in CH2Cl2 (50 ml) was added DIBAL-H (18.8 ml, 1 M in
toluene, 18.8 mmol) at 0 ꢁC. After the reaction solution
was stirred at 0 ꢁC for 1 h, a sat. aq. NH4Cl solution was
added. The organic solution was separated, washed with
brine, and dried (Na2SO4). Concentration followed by
silica gel column chromatography (CHCl3=MeOH=
Et3N ¼ 19=1=1) gave (S)-piperidine 14 (1.50 g, 4.08
mmol, 48% yield, 51% of amide was recovered) as a
N, 10.26. Found: C, 67.47; H, 7.67; N, 10.09. (R)-11,
20
½ꢀꢂ
¼ ꢀ3:1 (c 1.6, CHCl3).
D
(S)-5-Azido-7-(tert-butyldiphenylsilyloxy)heptanoic
acid (12). To an ice-cooled solution of (S)-aldehyde 11
(11.6 g, 28.3 mmol), 2-methyl-2-butene (13.2 ml, 125
20
1
colorless oil, ½ꢀꢂ
¼ ꢀ3:2 (c 2.2, CHCl3). H-NMR
D
.
mmol) and NaH2PO4 2H2O (4.42 g, 28.3 mmol) in tert-
(CDCl3) ꢁ 1.04–1.15 (1H, m), 1.05 (9H, s, tert-Bu),
1.25–1.46 (2H, m), 1.54–1.68 (4H, m), 1.75 (1H, m),
2.02 (1H, br. s, NH), 2.60 (1H, ddd, J ¼ 11:7, 11.7,
2.5 Hz, 6-HH), 2.66 (1H, m, 6-HH), 3.00 (1H, m, 2-H),
3.74 (2H, t, J ¼ 6:3 Hz, CH2OTBDPS), 7.26–7.44 (6H,
m, ArH), 7.65–7.67 (4H, m, ArH). 13C-NMR (CDCl3) ꢁ
19.2, 24.9, 26.3, 26.8, 33.0, 39.6, 47.1, 54.8, 61.8, 127.6,
129.6, 133.7, 133.8, 135.5. IRꢂmax (CHCl3): 2934, 2859,
1732, 1429, 1111. Anal. Calcd. for C23H33ONSi: C,
BuOH (70 ml) and H2O (20 ml) was added NaClO2
(8.70 g, 96.2 mmol), and then the resulting reaction
solution was stirred in an ice-cooled bath for 1 h. After
addition of CHCl3, the mixture was acidified with a 1 M
aq. HCl solution. The organic solution was separated,
washed with H2O and brine, and dried (Na2SO4).
Concentration followed by silica gel column chroma-
tography (EtOAc=hexane ¼ 1=6) gave (S)-acid 12
20
(11.7 g, 27.5 mmol, 97%) as a colorless oil, ½ꢀꢂ
¼
75.15; H, 9.05; N, 3.81. Found: C, 74.85; H, 8.90; N,
20
D
1
þ2:8 (c 5.3, CHCl3). H-NMR (CDCl3) ꢁ 1.05 (9H, s,
tert-Bu), 1.50–1.60 (2H, m), 1.60–1.85 (4H, m), 2.39
(2H, t, J ¼ 7:3 Hz, 2-H2), 3.60 (1H, m, 5-H), 3.74 (1H,
ddd, J ¼ 10:7, 10.7, 5.4 Hz, 7-HH), 3.80 (1H, ddd,
J ¼ 10:7, 7.8, 4.9 Hz, 7-HH), 7.37–7.45 (6H, m, ArH),
7.65–7.67 (4H, m, ArH). 13C-NMR (CDCl3) ꢁ 19.2,
21.2, 26.8, 33.6, 33.8, 36.9, 59.4, 60.3, 127.7, 129.7,
133.4, 133.6, 135.49, 135.53, 179.1. IRꢂmax (CHCl3):
2932, 2105, 1713, 1113, 1092, 909. Anal. Calcd. for
3.77. (R)-14, ½ꢀꢂ
¼ þ3:2 (c 2.2, CHCl3).
D
Determination of the enantiomeric excess of (S)-14
and (R)-14. To an ice-cooled solution of (S)-piperidine
14 (20 mg, 54.4 mmol) in pyridine (0.5 ml) was added
(ꢀ)-menthyl chloroformate (17.5 ml, 81.6 mmol). The
reaction mixture was stirred at room temperature for 2 h,
and then CHCl3 and H2O were added. The organic
solution was separated, successively washed with a 1 M
aq. HCl solution, sat. aq. NaHCO3 solution, and brine,
and then dried (Na2SO4). After concentration, the
residue was applied to HPLC (Cica-Merk Lichrospher
Si60, 2% EtOAc in hexane, 2.0 ml/min, detected at
270 nm, tR ¼ 20 min) to determine >99% de. Product
from (R)-14, tR ¼ 16 min, >99% de.
C23H31O3N3Si: C, 64.91; H, 7.34; N, 9.87. Found: C,
20
65.11; H, 7.39; N, 9.76. (R)-12, ½ꢀꢂ
¼ ꢀ2:8 (c 1.8,
D
CHCl3).
(S)-6-[2-(tert-Butyldiphenylsilyloxy)ethyl]-2-piperidin-
one (13). A reaction mixture of (S)-azide 12 (5.30 g,
12.5 mmol) and 20% Pd(OH)2/C (0.20 g) in EtOH
(40 ml) was stirred under H2 gas at ambient temperature
for 4 h before filtration. The filtrate was concentrated,
and the resulting residue was dissolved in toluene
(80 ml), this reaction solution then beeing heated under
reflux for 1 h. After concentration, the residue was
applied to silica gel column chromatography (EtOAc=
tert-Butyl (S)-2-[2-(tert-butyldiphenylsilyloxy)]ethyl]-
piperidine-1-carboxylate (15). A reaction mixture of
(S)-piperidine 14 (1.10 g, 2.99 mmol) and (Boc)2O
(0.72 g, 3.30 mmol) in THF (10 ml) and a 2 M aq.
K2CO3 solution (10 ml) was stirred at 0 ꢁC for 2 h before
additions of EtOAc and H2O. The organic solution was
separated, washed with brine, and dried (Na2SO4).
Concentration followed by silica gel column chroma-
tography (EtOAc=hexane ¼ 1=9) gave (S)-Boc-piperi-
dine 15 (1.36 g, 2.91 mmol, 97%) as a colorless oil,
hexane ¼ 1=1) to give (S)-amide 13 (4.29 g, 11.2 mmol,
20
90%) as colorless crystals, mp 94–95 ꢁC, ½ꢀꢂ
¼ þ3:8
D
1
(c 4.8, CHCl3). H-NMR (CDCl3) ꢁ 1.07 (9H, s, tert-
Bu), 1.32–1.41 (1H, m), 1.60–1.75 (3H, m), 1.80–1.91

Synthetic Intermediate of Aloperine
1593
20
20
1
½ꢀꢂ
¼ ꢀ16 (c 0.5, CHCl3). H-NMR (CDCl3) ꢁ 1.05
colorless oil, ½ꢀꢂ
¼ ꢀ37 (c 0.5, CHCl3). (R)-2,
D
D
20
20
(9H, s, tert-Bu), 1.35 (9H, s, tert-Bu), 1.40–1.58 (6H,
m), 1.69 (1H, m), 1.97 (1H, m), 2.63 (1H, ddd, J ¼ 14:7,
14.7, 3.6 Hz, 6-HH), 3.60 (1H, ddd, J ¼ 10:3, 8.3,
5.9 Hz, CHHOTBDPS), 3.70 (1H, ddd, J ¼ 10:3, 8.3,
6.3 Hz, CHHOTBDPS), 3.90 (1H, m, 6-HH), 4.27 (1H,
m, 2-H), 7.34–7.43 (6H, m, ArH), 7.65–7.67 (4H, m,
ArH). 13C-NMR (CDCl3) ꢁ 19.05, 19.14, 25.6, 26.9,
28.4, 28.7, 32.8, 38.9, 47.4, 61.9, 79.0, 127.6, 129.52,
129.54, 133.9, 135.5, 154.9. IRꢂmax (CHCl3): 2934,
1676, 1428, 1279, 1244, 1169, 1146, 1111, 1090. Anal.
½ꢀꢂ
¼ þ37 (c 0.6, CHCl3), lit.5) ½ꢀꢂ
¼ þ35:3 (c
D
D
1.0, CHCl3). The spectra data agreed with those in the
literature.5)
Determination of the enantiomeric excess of (S)- and
(R)-vinylpiperidine 2. After a reaction mixture of (S)-
vinylpiperidine 2 (47 mg, 0.22 mmol) and CF3CO2H
(17 ml, 0.23 mmol) in CH2Cl2 (5 ml) was stirred at room
temperature for 6 h, sat. aq. NaHCO3 and CH2Cl2 were
added. The organic solution was separated, washed with
brine, and dried (Na2SO4). After concentration, the
resulting residue was dissolved in pyridine. To this
solution was added (ꢀ)-menthyl chloroformate (57 ml,
0.27 mmol) at 0 ꢁC. The reaction solution was stirred
at room temperature for 2 h before additions of CHCl3
and a 1 M aq. HCl solution. The organic solution was
separated, successively washed with a sat. aq. NaHCO3
solution and brine, and dried (Na2SO4). After concen-
tration, the residue was applied to HPLC (Chiralpak
AD-H, 2% iso-PrOH in hexane, 0.5 ml/min, detected at
210 nm, tR ¼ 18 min) to determine >99% de. Product
from (R)-2, tR ¼ 14 min, >99% de.
Calcd. for C28H41O3NSi: C, 71.90; H, 8.84; N, 2.99.
20
Found: C, 71.85; H, 8.85; N, 3.04. (R)-15, ½ꢀꢂ
¼ þ16
D
(c 1.4, CHCl3).
tert-Butyl (S)-2-(2-hydroxyethyl)piperidine-1-carboxy-
late (3). To an ice-cooled solution of (S)-Boc-piperidine
15 (0.65 g, 1.39 mmol) in THF (20 ml) was added (n-
Bu)4NF (1.53 ml, 1 M in THF, 1.53 mmol). The reaction
solution was stirred at 0 ꢁC for 8 h before concentration.
The residue was applied to silica gel column chroma-
tography (EtOAc=hexane ¼ 1=19) to give (S)-(hy-
droxyethyl)piperidine 3 (0.24 g, 1.05 mmol, 76%) as a
20
colorless oil, ½ꢀꢂ
¼ ꢀ22 (c 1.2, CHCl3), lit.:6)
D
20
20
½ꢀꢂ
¼ ꢀ18:9 (c 1, CHCl3). (R)-3, ½ꢀꢂ
¼ þ22 (c
Acknowledgments
D
D
20
1.0, CHCl3), lit.:6) ½ꢀꢂ
¼ þ19:3 (c 1, CHCl3). The
D
spectra data agreed with those in the literature.6)
We measured the 400 MHz NMR data in INCS at
Ehime University. We are grateful to Marutomo Co.
for financial support.
tert-Butyl (S)-2-[2-(2-Nitrophenylselenyl)ethyl]piperi-
dine-1-carboxylate (16). A reaction solution of (S)-
(hydroxyethyl)piperidine 3 (0.21 g, 0.92 mmol), 2-nitro-
phenyl selenocyanate (0.25 g, 1.11 mmol), and (n-Bu)3P
(0.28 g, 1.38 mmol) in THF (20 ml) was stirred at room
temperature for 12 h. After concentration, the resulting
residue was applied to silica gel column chromatography
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(1% EtOAc in hexane) to give (S)-selenide 16 (0.35 g,
20
2) Laschat, S., and Dickner, T., Stereoselective synthesis of
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¼ ꢀ25 (c 1.0,
D
1
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m, 6-HH), 2.80–2.92 (2H, m, CH2SePh), 4.02 (1H, m, 6-
HH), 4.42 (1H, m, 2-H), 7.29–7.33 (1H, m, ArH), 7.50–
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½ꢀꢂ
¼ þ25 (c 1.0, CHCl3).
D
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reaction mixture of (S)-selenide 16 (0.29 g, 0.70 mmol)
and MCPBA (0.28 g, 1.62 mmol) in CH2Cl2 (10 ml) and
a phosphate buffer at pH 8 (10 ml) was stirred at 0 ꢁC for
30 min. After addition of a sat. aq. Na2S2O3 solution, the
organic solution was separated, washed with brine, and
dried (Na2SO4). Concentration followed by silica gel
column chromatography (ether=petroleum ether ¼ 1=9)
gave (S)-vinylpiperidine 2 (0.12 g, 0.57 mmol, 81%) as a

1594
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