Stereoselective synthesis of 3-deoxy-piperidine iminosugars from l-lysine

Article abstract of DOI:10.1016/j.tetasy.2009.11.028

A new method using electrochemical oxidation and/or OsO₄ oxidation has been used for the stereoselective synthesis of 2,3,6-trihydroxylated (5S)-piperidine derivatives. The electrochemical method was successively used for the conversion of N-pr

Full text of DOI:10.1016/j.tetasy.2009.11.028

Tetrahedron: Asymmetry 20 (2009) 2677–2687
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Stereoselective synthesis of 3-deoxy-piperidine iminosugars from L-lysine
*
Noriaki Moriyama, Yoshihiro Matsumura, Masami Kuriyama, Osamu Onomura
Graduate School of Biomedical Sciences, Nagasaki University, 1-14 Bunkyo-machi, Nagasaki 852-8521, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
A new method using electrochemical oxidation and/or OsO4 oxidation has been used for the stereoselective
synthesis of 2,3,6-trihydroxylated (5S)-piperidine derivatives. The electrochemical method was succes-
sively used for the conversion of N-protected piperidines to N-protected 1-methoxypiperidines and for
the conversion of 2,3-didehydro-1-methoxypiperidine derivatives to 2,3-trans-1,2,3-triacetoxypiperidine
derivatives. These triacetates were easily transformed into (2S,3S)-6-triacetoxy-(5S)-methylpiperidine
and (2R,3R)-6-triacetoxy-(5S)-methylpiperidine. In addition, the 2,3-cis-dihydroxylation of 2,3-didehy-
dro-1-methoxypiperidine derivatives with OsO4 afforded (2R,3S)-6-triacetoxy-(5S)-methylpiperidine
and (2S,3R)-6-triacetoxy-(5S)-methylpiperidine.
Received 15 September 2009
Accepted 25 November 2009
Available online 5 January 2010
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
(OH)n
3
4
5
2
1
Polyhydroxylated (5S)-methylpiperidines 1, a class of piperi-
dine iminosugars, have attracted great interest due to their biolog-
ical properties.1,2 Some of them are potential inhibitors of
glycosidases and glycoprotein-processing enzymes. They are
widely investigated as candidates for drugs to treat a variety of
carbohydrate-mediated diseases, such as diabetes, and viral infec-
tions including HIV, and cancer metastasis (see Fig. 1). Their inhib-
itory activities depend on the configuration and the number of
hydroxyl groups. Amongst 1, 2,3,6-trihydroxy-(5S)-methylpiperi-
dines 2 are noteworthy since it has recently been reported that
(2R,3S)-6-trihydroxy-(5S)-methylpiperidine 2a, one of the possible
stereoisomers 2a–d (Fig. 2), has high inhibitory activities toward
glycosidases. However, there have not been any convenient syn-
thetic methods reported for 2a–d.3,4 We have exploited a facile
method for the stereoselective synthesis of 2a–d, and reported
the synthesis of 2b and c using electrochemical 2,3-trans-diacet-
oxylation.5 Herein, we report the synthesis for 2b,c as well as those
for 2a,d using 2,3-cis-dihydroxylation with OsO4.
OH
N
R
6
1
R = H or alkyl
Figure 1.
2. Results and discussion
2.1. Electrochemical 2,3-trans-diacetoxylation
Our strategy is based on the preparation of triacetate 6, a pre-
cursor of 2, from the (5S)-acetoxymethylpiperidine derivative 3
by electrochemical oxidation; electrochemical 1-methoxylation
of 3 and electrochemical triacetoxylation of (5S)-acetoxymethyl-
2,3-didehydro-1-methoxypiperidine derivative 4 (Eq. 1).
OH
OH
3
OH
OH
OH
HO
HO
HO
HO
HO
2
5
OH
OH
OH
OH
OH
N
H
N
H
N
H
N
H
N
H
6
2
2a
2b
2c
2d
(2R,3S)
(2S,3S)
(2R,3R)
(2S,3R)
Figure 2. Stereoisomers 2a–d of 2,3,6-trihydroxy-5S-methylpiperidines 2.
* Corresponding author. Tel.: +81 95 819 2429; fax: +81 95 819 2476.
0957-4166/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2009.11.028

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N. Moriyama et al. / Tetrahedron: Asymmetry 20 (2009) 2677–2687
OAc
OAc
AcO
AcO
AcO
−2e
−2e
reduction
OAc
OAc
OAc
OAc
ð1Þ
N
MeO
N
N
N
CO2Me
CO2Me
CO2Me
CO2Me
3
4
5
6
The first key electrochemical reaction in the scheme has already
been used in the transformation of N-methoxycarbonylpiperidine
7a to 2,3-didehydro-1-methoxypiperidine 10a. The transformation
consisted of the electrochemical oxidation of 7a to afford 1-meth-
oxypiperidine 8a,6 the elimination of MeOH from 8a to give
1,2-didehydropiperidine 9a,7 which then underwent bromine
oxidation8 followed by base-induced dehydrobromination to form
2,3-didehydro-1-methoxypiperidine 10a (Eq. 2).9 The other 2,3-
didehydro -1-methoxypiperidines 10b–d were similarly prepared
from 7b–d.
Fortunately, the main product (2S,3S,5S)-6 crystallized, and the
absolute stereochemistry was determined to be (2S,3S,5S) by its
X-ray analysis (Fig. 3).14
On the other hand, the electrochemical oxidation of bicyclic car-
bamate 19, which was prepared from the
L-pipecolic acid deriva-
tive 16 or from
L
-lysine derivative 22 via 1713 and 18,15 followed
by reduction of the oxidation product 20 (70% yield) with Et3SiH
gave a single stereoisomer 21 (Scheme 2), of which the absolute
stereochemistry was also determined by X-ray analysis (Fig. 4).14
−2e
Br2, NaOMe
1)
2)
N
MeO
N
N
MeO
N
MeOH
Et4NOTs
DBU
DMF
NH4Cl
O
R
O
R
O
R
O
R
−MeOH
Pt electrodes
ð2Þ
7a-d
10a-d
9a-d
8a-d
a:
b:
R = OMe
R = OCH2Ph
86%
91%
97%
90%
92%
83%
58%
70%
68%
c: R = H
d:
R = Ph
90%
84%
60%
With 10a–d in hand, we examined the second key electrochem-
ical triacetoxylation of 10a–d, which was carried out in acetic acid
containing potassium acetate (Eq. 3).10 As expected, the oxidation
gave triacetoxylated products 11a–d, although their stereochemis-
try was not determined at this stage. Next, we achieved the reduc-
tive elimination of the 1-acetoxyl groups of 11a–d by Et3SiH to
afford 2,3-diacetoxypiperidines 12a–d. The yields of 11a–d and
12a–d are shown together with the trans/cis ratio in Table 1.
The reaction mechanism for the electrochemical triacetoxyla-
tion is tentatively proposed as follows (Scheme 3). Since it was
found that 10a was immediately converted to 3-acetoxy-1,2-dide-
hydropiperidine 239i under the reaction conditions, oxidation of 23
may be responsible for the formation of 11a by EC mechanism
through dication A or by ECEC mechanism through cation radical
B, radical C, and cation D.10 Similarly, the electrochemical tri-
acetoxylation of 4 and 19 may proceed via 3-acetoxypiperidine
OAc
AcO
OAc
Et3SiH
(1.2 equiv)
AcO
−2e
10a-d
AcO
N
ð3Þ
N
AcOH
AcOK
MeSO3H
(1.5 equiv)
/ CH2Cl2
O
R
O
R
11a-d
12a-d
The stereochemistry (trans/cis) of 12a–d was slightly dependent
on R (70/30–54/46).11 We attempted the preparation of 4 from the
Table 1
readily available
L
-lysine derivative 1312 instead of the expensive
Electrochemical oxidation of 10a–d followed by reduction of 11a–d with Et3SiH
L
-pipecolic acid derivative 3 through 14 and 1513 to obtain 4 in a
Entry
10a–d
R
Yield (%)
trans:cis
12a–d
similar way to the transformation of 7 to 10. The result is shown
in Scheme 1. The electrochemical oxidation of 4 under conditions
similar to the oxidation of 10 to 11 afforded tetraacetoxylated
piperidine 5, which when reduced with Et3SiH gave 2,3,6-triacet-
oxy-5S-methylpiperidine 6 as a mixture of stereoisomers. The ratio
of the diastereoisomers was determined to be 91/3/3/3.
11a–d
12a–d
1
2
3
4
OMe
OCH2Ph
H
81
54
78
80
84
82
65
45
70:30
58:42
66:34
54:46
Ph

N. Moriyama et al. / Tetrahedron: Asymmetry 20 (2009) 2677–2687
2679
−2e
1) Br2, MeOH-Et3N
OAc
MeOH
OAc
OAc
N
OAc
MeO
N
N
MeO
AcO
N
NH4Cl
2) DBU in DMF
56%
CO2Me
CO2Me
CO2Me
CO2Me
3
14
15
4
80% from 3
66% from 13
−2e
AcOH / AcOK
−2e
1) MeOH-AcOH
2) H+
OAc
OAc
AcO
AcO
Et3SiH (1.2 equiv)
OAc
OAc
OAc
MeSO3H (1.5 equiv)
HN
CO2Me
HN
MeO2C
N
N
º
0 C
CO2Me
CO2Me
53% from 4
13
5
6
91 : 3 : 3 : 3
trans/cis = 94/6
Scheme 1. Preparation of (2S,3S,5S)-6starting from 3 or 13.
Figure 4. Ortep drawing of (2R,3R,5S)-21.
Figure 3. Ortep drawing of (2S,3S,5S)-6.
the endo-side might be more crowded than the exo-side, to exclu-
sively afford a trans-isomer 25 without a cis-isomer 250.15b
The oxidation potentials of some 1,2-didehydro- and 2,3-dide-
hydro-piperidine derivatives shown in Table 2 support this pro-
posed mechanism.
derivatives 24 and 25, respectively (Fig. 5). Since the cis-isomer 24
was thermodynamically more stable than its trans-isomer 240, 24
should be formed stereospecifically. On the other hand, treatment
of 19 with acetic acid could generate a cationic species E, in which
1) Br2, NaOMe
MeOH
−2e
1)
NaBH4
N
CO2Me
MeO
N
N
N
CO2Me DME/MeOH
MeOH
2) DBU
DMF
68%
2) H+
62%
CO2Me
O
CO2Me
O
80%
O
O
16
19
17
18
−2e
−2e
1)
MeOH
2) H+
51%
AcOH / AcOK
OAc
OAc
AcO
AcO
AcO
Et3SiH (1.2 equiv)
HN
CO2Me
CO2Me
HN
MeO2C
N
MeSO3H (1.5 equiv)
N
º
0 C
57% from 19
O
O
O
O
22
20
21
Scheme 2. Preparation of (2R,3R,5S)-21starting from 16 or 22.

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N. Moriyama et al. / Tetrahedron: Asymmetry 20 (2009) 2677–2687
The predominant formation of (2S,3S,5S)-5 and (2R,3R,5S)-20
First, we investigated the OsO4 oxidation of 10a. Compound 10a
was oxidized with catalytic OsO4 and 1.5 equiv of NMO followed
by acetylation with acetic anhydride and pyridine to produce
2,3,4-triacetoxypiperidine 11a in 71% yield. Compound 11a was
easily reduced with Et3SiH to give cis-2,3-diacetoxypiperidine
12a (Eq. 4).
may be explained by an ECEC mechanism shown in Scheme 4. As
for the 3-acetoxy-1,2-didehydropiperidine intermediate 24, it is
possible that the plausible intermediary species could be the
electrochemically generated cation radical F.10b,16 Therefore, the
observed high diastereoselectivity in the electrochemical oxidation
OAc
OAc
4% aq. OsO4
(0.006 equiv)
AcO
AcO
AcO
Ac2O
Et3SiH (1.2 equiv)
ð4Þ
MeO
N
pyridine
N
MeSO3H (1.5 equiv)
CH2Cl2, 15 min
N
NMO (1.5 equiv)
H2O/acetone
CO2Me
CO2Me
CO2Me
10a
12 h
12a, 70%
11a, 71%
of (3S,5S)-24 can be explained as follows: the acetate ion attack on
the cationic intermediate F is easier from the axial direction than
from the the equatorial direction to produce (2S,3S,5S)-5 through
the radical intermediate G. The stereoselectivity is explained in
terms of the participating effect of the 3-acetoxyl group or thermo-
dynamic control of the product. On the other hand, in the case of
electrochemical oxidation of (3R,5S)-25, the acetate ion attack onto
the cation radical H is easier from the equatorial direction than
from the the axial direction to produce (2R,3R,5S)-20 through the
radical intermediate I.
Encouraged by this result, we attempted to apply the same
conditions to (5S)-acetoxymethylpiperidine derivatives
4
(Scheme 6). As expected, the OsO4 oxidation and subsequent
acetylation proceeded smoothly, but the reaction product was a
mixture of 2,3-diacetoxy-(5S)-acetoxymethyl-1-methoxy-N-meth-
oxycarbonylpiperidine 29a and 1,2,3-triacetoxy-(5S)-acetoxy-
methyl-N-methoxycarbonylpiperidine 29b. Without purification
of the mixture, reduction with Et3SiH was carried out to provide
only one product, 2,3-diacetoxy-(5S)-acetoxymethyl-N-meth-
oxycarbonylpiperidine 27. Since 27 did not crystallize, we tried
to prepare its tosylated derivatives to determine the absolute ste-
reochemistry of the two hydroxyl groups at the 2,3-position by
X-ray analysis.
The less stereoselective triacetoxylation of 10a–d may be due to
the conformational flexibility of the piperidine ring, which has no
substituent at the 5-position.
The OsO4 oxidation of 4 and successive reduction with Et3SiH
gave 2,3-dihydroxylated derivative 30 as a single diastereomer
(Scheme 7). Compound 30 was then treated with tosyl chloride
to afford crystal 2,3-ditosyloxylated derivative 31. The X-ray anal-
ysis of compound 31 determined its absolute stereoconfiguration,
(2S,3R,5S) (see Fig. 6).14
2.2. cis-Selective 2,3-dihydroxylation with OsO4
To prepare 2,3-cis-dihydroxylated compounds 2a and 2d, the
oxidation of
4
or 19 with OsO4 seems to be convenient
(Scheme 5).2e
OAc
OAc
OAc
AcO
AcO
AcOH
+
−2e
2AcOH
+
N
MeO
N
N
−2H+
N
CO2Me
CO2Me
CO2Me
CO2Me
−e
10a
A
11a
23
−e
OAc
OAc
AcOH
-H+
AcO
+
AcOH
−H+
N
N
CO2Me
CO2Me
C
B
Scheme 3. Plausible mechanism for electrochemical triacetoxylation of 10a.
OAc
OAc
OAc
OAc
endo side
O
O
+
OAc
OAc
N
N
N
N
N
exo side
CO2Me
CO2Me
O
O
O
O
−OAc
24
25
24'
25'
E
Figure 5. Plausible intermediary species for electrochemical oxidation of 4 and 19 in AcOH.

N. Moriyama et al. / Tetrahedron: Asymmetry 20 (2009) 2677–2687
2681
Next, the OsO4 oxidation of bicyclic carbamate 19 and successive
acetylation with Ac2O–pyridine were examined to give 1-methoxy-
2,3-diacetoxylated compound 32. In this case, the 1-methoxy group
remained unchanged under these reaction conditions. Finally, com-
pound 32 was reduced by Et3SiH to afford 2,3-diacetoxylated bicy-
clic carbamate 28 as a single diastereomer (Eq. 5). The absolute
stereoconfiguration of 28 was determined by X-ray analysis to be
(2R,3S,5S) (Fig. 7).14
8100A. Mass spectra were obtained on a JEOL JMS-DX 303 instru-
ment. HPLC analyses were achieved by using a LC-10AT VP and a
SPD-10A VP of Shimadzu Seisakusho, Inc. Specific rotations were
measured with JASCO DIP-1000. Melting points are uncorrected.
Elemental analyses were carried out at the Center for Instrumental
Analysis, Nagasaki University. All reagents and solvents were used
as supplied without further purification.
OAc
OAc
1) OsO4 (0.006 equiv)
AcO
AcO
Et3SiH (5.0 equiv)
MeSO3H (5.0 eqquiv)
NMO (1.5 equiv)
H2O/Acetone
MeO
N
ð5Þ
N
MeO
N
CH2Cl2
2) Ac2O-Pyridine
O
O
O
O
O
O
81%
19
32, 85%
(2R,3S,5S)-28
The observed high diastereoselectivity by the OsO4 oxidation in
this case can be explained by the anomeric effect of the 1-methoxyl
group. Since the methoxyl group is mainly located at the axial po-
sition, it is difficult for OsO4 to get close to 19 from the lower side
(approach B), while OsO4 can easily get close to 19 from the upper
side (approach A) (Scheme 8). Accordingly, the OsO4 oxidation of
19 and successive reduction exclusively afforded dihydroxylated
compound J as a precursor for (2R,3S,5S)-28.
4.2. Measurement of oxidation potentials
BAS CV-50W was used as a voltametric analyzer. A solution of
substrate (0.1 mmol) in MeCN (10 mL) containing 0.1 M Et4NBF4
was measured. The reference electrode was Ag/AgNO3 in saturated
aqueous KCl; the working electrode was a glassy carbon, and the
counter electrode was a platinum wire. Scan rate was 100 mV/s.
Next, bicyclic carbamate 33, which has no 1-methoxyl group, was
examined. OsO4 oxidation of 33 followed by acetylation afforded a
mixture of (2R,3S)-isomer (2R,3S,5S)-28 and (2S,3R)-isomer
(2S,3R,5S)-28, whose ratio was 24:76 (Eq. 6). This contrasting result
for33and19supportsourproposedstereochemicalcourseasshown
in Scheme 8. The result represents the importance of the steric effect
of 1-methoxyl group on the observed high diastereoselectivity.
4.3. Preparation of 2,3-didehydro-1-methoxy-N-acylpiperidines
10a–d
Transformations of 1-acylpiperidines 7a–d to 2,3-didehydro-1-
methoxy-N-acylpiperidines 10a–d were carried out according to
our reported method.9 Compounds 8a,6a 8b,6c 8c,6b 8d,9c 9a,7b
9b,7d 9c,7a 9d,7c 10a,9b and 10d9d are known.
OAc
N
OAc
N
AcO
AcO
NaBH4 (10 equiv)
OsO4 (0.006 equiv)
Ac2O
+
MeO
N
N
ð6Þ
AcOH
NMO (1.5 equiv)
H2O/acetone
pyridine
O
O
O
O
O
O
O
O
24 : 76
(2R,3S,5S)-28
70%
80%
19
33
(2S,3R,5S)-28
3. Conclusion
The characterization data for unknown compounds 10b and 10c
are described below.
In conclusion, the stereoselective formal syntheses of 2,3,6-
trihydroxylated (5S)-methylpiperidines 2a–d from -lysine and
-pipecolic acid has been accomplished by using tandem electro-
L
4.3.1. N-Benzyloxycarbonyl-2,3-didehydro-1-methoxypiperidine
10b
L
1H NMR (CDCl3) d 1.92–2.05 (m, 1H), 2.10–2.30 (m, 1H), 3.05–
3.25 (m, 1H), 3.29 and 3.39 (2s, 3H), 4.02–4.25 (m, 1H), 5.12–
5.26 (m, 2H), 5.40–5.55 (m, 1H), 5.70–5.84 (m, 1H), 5.95–6.06
(m, 1H), 7.36 (s, 5H); IR (neat) 3038, 2936, 1713, 1655, 1428,
1200, 1082, 982, 698 cmꢀ1; HRMS (EI) m/z Calcd for C14H17NO3
(M+): 247.1208. Found: 247.1181.
chemical oxidation or OsO4 oxidation.
4. Experimental section
4.1. General
Electrochemical reactions were carried out using DC Power Sup-
ply (GP 050ꢀ2) of Takasago Seisakusho, Inc. 1H NMR spectra were
measured on a Varian Gemini 300 spectrometer with TMS as an
internal standard. IR spectra were obtained on a Shimadzu FTIR-
4.3.2. 2,3-Didehydro-N-formyl-1-methoxypiperidine 10c
1H NMR (CDCl3) d 2.02–2.35 (m, 2H), 2.98 (td, J = 13.1 and
6.0 Hz, 2/3H), 3.30 and 3.39 (2s, 2H and 1H), 3.45–3.52

2682
N. Moriyama et al. / Tetrahedron: Asymmetry 20 (2009) 2677–2687
Table 2
4.4. Preparation of optically active 2,3-didehydro-1-methoxy-
N-methoxycarbonylpiperidine 4
Oxidation potential of didehydropiperidine derivatives
Entry
Compound
Oxidation potentiala (V)
1.44
Compound 4 was prepared from either L-lysine derivative 13 or
L
-pipecolic acid derivative 3 by our reported method.12b Compound
1
9a
14 was transformed into compound 15 without purification. The char-
acterization data for compounds 3, 4, 13, and 15 are described below.
N
CO2Me
4.4.1. (5S)-Acetoxymethyl-N-methoxycarbonylpiperidine 3
a 2D8
ꢁ
¼ ꢀ45:6 (c 1.1, CHCl3); 1H NMR (CDCl3) d 1.34–1.55 (m,
2
3
26
1.96
1.66
½
N
2H), 1.58–1.74 (m, 4H), 2.04 (s, 3H), 2.88 (t, J = 12.9 Hz, 1H), 3.69
(s, 3H), 4.00–4.10 (m, 1H), 4.15 (dd, J = 11.4 and 6.6 Hz, 1H), 4.24
(dd, J = 11.4 and 8.7 Hz, 1H), 4.51 (br s, 1H); IR (neat) 2944, 1748,
1655, 1449, 1262, 1049, 841, 770 cmꢀ1; HRMS (EI) m/z Calcd for
C10H17NO4 (M+): 215.1157. Found: 215.1146.
CO2Me
10a
MeO
N
CO2Me
OAc
4.4.2. (5S)-Acetoxymethyl-2,3-didehydro-1-methoxy-N-methoxy
carbonylpiperidine 4
4
5
6
23
4
1.65
1.72
1.71
½
a 2D8
ꢁ
¼ þ71:6 (c 1.0, CHCl3); 1H NMR (CDCl3) d 2.06 (s, 3H),
N
2.08–2.17 (m, 1H), 2.28–2.46 (m, 1H), 3.37 and 3.42 (2br s, 3H),
3.77 (s, 3H), 4.09–4.26 (m, 2H), 4.57–4.85 (m, 1H), 5.34–5.61 (m,
1H), 5.72–5.94 (m, 2H); IR (neat) 2957, 1744, 1709, 1445, 1368,
CO2Me
1231, 1123, 1082, 980, 770 cmꢀ1
; HRMS (EI) m/z Calcd for
OAc
MeO
N
C11H17NO5 (M+): 243.1107. Found: 243.1090.
CO2Me
OAc
4.4.3. (5S)-Acetoxymethyl-1,2-didehydro-N-methoxy
carbonylpiperidine 15
a 2D7
ꢁ
¼ ꢀ72:2 (c 1.2, methanol); 1H NMR (CDCl3) d 1.69–2.07 (m,
24
½
OAc
N
4H), 2.06 (s, 3H), 3.77 (s, 3H), 4.01 (dd, J = 10.8 and 7.2 Hz, 1H),
4.06–4.22 (m, 1H), 4.45–4.70 (m, 1H), 4.82–5.02 (m, 1H), 6.71
and 6.85 (2d, J = 8.7 and 9.0 Hz, 1H); IR (neat) 2965, 1742, 1712,
1660, 1448, 1362, 1240 cmꢀ1. Anal. Calcd for C10H15NO4: C,
56.33; H, 7.09; N, 6.57. Found: C, 56.07; H, 7.17; N, 6.40.
CO2Me
7
8
MeO
N
O
19
25
1.73
1.71
O
4.4.4. (2S)-6-Bis(methoxycarbonylamino)hexyl acetate 13
OAc
N
½
a 2D8
ꢁ
¼ þ17:1 (c 1.0, methanol); mp 97–98 °C; 1H NMR (CDCl3) d
1.35–1.60 (m, 6H), 2.07 (s, 3H), 3.10–3.26 (m, 2H), 3.66 (s, 3H), 3.67
(s, 3H), 3.82–3.93 (m, 1H), 4.04–4.12 (m, 2H), 4.64–4.84 (m, 2H); IR
(KBr) 3335, 2980, 1755, 1700, 1555, 1230, 1068 cmꢀ1. Anal. Calcd
for C12H22N2O6: C, 49.65; H, 7.64; N, 9.65. Found: C, 49.38; H,
7.79; N, 9.90.
O
O
a
V vs Ag/AgNO3, 0.1 M Et4NClO4/MeCN, 100 mV/s.
4.5. Preparation of optically active bicyclic compound 19
(m, 2/3H), 4.35 (dd, J = 13.5 and 6.4 Hz, 2/3H), 4.75 and 5.63 (2d,
J = 3.0 and 3.0 Hz, 2/3H and 1/3H), 5.78–5.88 (m, 1H), 5.92–6.10
(m, 1H), 8.26 and 8.29 (2s, 1/3H and 2/3H); IR (neat) 3567, 2938,
1692, 1655, 1433, 1084, 957, 669 cmꢀ1; HRMS (EI) m/z Calcd for
C7H11NO2 (M+): 141.0790. Found: 141.0770.
Compound 19 was prepared from
-pipecolic acid derivative 16 by procedures similar to the prepara-
tion of 4.
The characterization data for compounds 16, 17, 18,15 19,15 and
22 are described below.
L
-lysine derivative 2212a or
L
AcO
N
AcO
N
axial
AcO
AcO
AcO
OAc
−e
2
−e
attack
1
OAc
OAc
AcOH
OAc
AcOH
AcOH
MeO2C
MeO2C
N
5
MeO2C
N
MeO2C
3
OAc
OAc
F
G
(3S,5S)-24
(2S,3S,5S)-5
O
O
AcO
O
equatorial
attack
O
N
2
OAc
OAc
O
3
1
−e
AcOH
−e
AcOH
O
O
O
OAc
OAc
OAc
AcOH
N
OAc
N
N
5
I
(2R,3R,5S)-20
H
(3R,5S)-25
Scheme 4. Plausible mechanism for electrochemical 2,3-trans-acetoxylation of 24 and 25.

N. Moriyama et al. / Tetrahedron: Asymmetry 20 (2009) 2677–2687
2683
OAc
AcO
3
2
OsO4
NMO
Ac2O
reduction
reduction
5
2a
OAc
OAc
1
MeO
N
N
CO2Me
CO2Me
4
(2S,3R,5S)-27
3
OAc
AcO
2
OsO4
NMO
Ac2O
5
2d
1
MeO
N
N
O
O
O
O
19
(2R,3S,5S)-28
Scheme 5. Strategy for the preparation of 2a and 2d.
OAc
OAc
OsO4 (0.006 equiv)
NMO (1.5 equiv)
AcO
AcO
AcO
Ac2O
OAc
OAc
OAc
OAc
+
40 : 60
Pyridine
MeO
N
MeO
N
N
H2O/Acetone
CO2Me
CO2Me
CO2Me
77% (for two steps)
4
29a
29b
OAc
AcO
Et3SiH (1.2 equiv)
MeSO3H (1.5 equiv)
CH2Cl2
N
CO2Me
27, 70%
Scheme 6. Preparation of 27.
OH
N
Et3SiH (1.5 equiv)
HO
OsO4 (0.006 equiv)
OAc
MeSO3H (2.0 equiv)
CH2Cl2
OAc
MeO
N
NMO (1.5 equiv)
H2O/acetone
CO2Me
CO2Me
4
78% (for two steps)
TsO
30
OTs
TsCl (5.0 equiv)
Et3N (1.2 equiv)
OAc
N
DMAP (5.0 equiv)
CO2Me
CH2Cl2
(2S,3R,5S)-31, 46%
Scheme 7. Preparation of (2S,3R,5S)-31.
4.5.1. (5S)-N-Bis(methoxycarbonyl)piperidine 16
J = 9.0 and 8.7 Hz, 2/3H and 1/3H); IR (neat) 2950, 1755, 1720,
1445, 1360 cmꢀ1. Anal. Calcd for C9H13NO4: C, 54.26; H, 6.58; N,
7.03. Found: C, 54.17; H, 6.73; N, 6.74.
½
a 2D5
ꢁ
¼ ꢀ60:9 (c 1.5, methanol); 1H NMR (CDCl3) d 1.16–1.52 (m,
2H), 1.58–1.75 (m, 3H), 2.16–2.30 (m, 1H), 2.88–3.11 (m, 1H), 3.73
(s, 3H), 3.74 (s, 3H), 3.92–4.19 (m, 1H), 4.75–4.99 (m, 1H); IR (neat)
2950, 1750, 1710, 1450, 1265, 1210, 1170, 1095 cmꢀ1. Anal. Calcd
for C9H15NO4: C, 53.72; H, 7.51; N, 6.96. Found: C, 53.70; H, 7.74; N,
6.67.
4.5.3. (6S)-1-Aza-2,3-didehydro-8-oxabicyclo[4.3.0]nonan-9-
one 18
½
a 2D8
ꢁ
¼ þ164:9 (c 1.0, CHCl3); mp 45–46 °C; 1H NMR (CDCl3) d
4.5.2. 1,2-Didehydro-(5S)-N-bis(methoxycarbonyl)piperidine 17
1.50–1.80 (m, 1H), 2.05–2.32 (m, 3H), 3.95–4.15 (m, 2H), 4.50–
4.70 (m, 1H), 5.03–5.15 (m, 1H), 6.60 (d, J = 10.0 Hz, 1H); IR (KBr)
1752, 1720, 1445, 1360 cmꢀ1. Anal. Calcd for C7H9NO2: C, 60.43;
H, 6.51; N, 10.07. Found: C, 60.16; H, 6.56; N, 9.90.
½
a 2D7
ꢁ
¼ ꢀ46:9 (c 1.0, CHCl3); 1H NMR (CDCl3) d 1.83–2.05 (m,
3H), 2.30–2.42 (m, 1H), 3.74 (s, 3H), 3.75 and 3.80 (2s, 2H and
1H), 4.81–4.91 (m, 1H), 4.93–5.02 (m, 1H), 6.81 and 6.94 (2d,

2684
N. Moriyama et al. / Tetrahedron: Asymmetry 20 (2009) 2677–2687
4.5.5. Methyl (2S)-6-Bis(methoxycarbonylamino)hexanoate 22
½
a 2D8
ꢁ
¼ þ16:5 (c 1.0, CHCl3); mp 50–51 °C (uncorrected); 1H
NMR (CDCl3) d 1.27–1.44 (m, 2H), 1.46–1.59 (m, 2H), 1.62–1.76
(m, 1H), 1.78–1.90 (m, 1H), 3.15–3.20 (m, 2H), 3.66 (s, 3H), 3.69
(s, 3H), 3.74 (s, 3H), 4.31–4.39 (m, 1H), 4.77 (br s, 1H), 5.31 (br s,
1H); IR (KBr) 3290, 2950, 1730, 1695, 1550, 1275 cmꢀ1. Anal. Calcd
for C11H20N2O6: C, 47.82; H, 7.30; N, 10.14. Found: C, 48.05; H,
7.40; N, 10.27.
4.6. Preparation of racemic 3-acetoxy-1,2-didehydro-N-metho-
xycarbonylpiperidine 23, and optically active 3-acetoxy-1,2-
didehydro-N-acylpiperidines 24 and 25
Compounds 10a, 4, and 19 were easily transformed into 3-acet-
oxylated derivatives 23, 24, and 25 by stirring in acetic acid for a
few minutes with quantitative yield.
4.6.1. 3-Acetoxy-1,2-didehydro-N-methoxycarbonylpiperidine 23
1H NMR (CDCl3) d 1.83–2.03 (m, 2H), 2.05 (s, 3H), 3.30–3.45 (m,
1H), 3.79 (s, 3H), 3.87–4.10 (m, 1H), 4.97–5.15 (m, 1H), 5.17–5.25
(m, 1H), 6.97 and 7.11 (2br d, J = 9.2 Hz, 1H); IR (neat) 2957, 1717,
1648, 1447, 1364, 1235, 1007, 768 cmꢀ1; HRMS (M+) m/z Calcd for
C9H13NO4 (M+): 199.0845. Found: 199.0822.
4.6.2. (3S)-Acetoxy-(5S)-acetoxymethyl-1,2-didehydro-N-metho-
xycarbonylpiperidine 24
Figure 6. Ortep drawing of (2S,3R,5S)-31.
1H NMR (CDCl3) d 1.93–2.23 (m, 1H), 2.02 (s, 3H), 2.05 (s, 3H),
2.18–2.30 (m, 1H), 3.80 (s, 3H), 4.15–4.31 (m, 2H), 4.53–4.78 (m,
1H), 5.02–5.24 (m, 2H), 6.95 and 7.09 (2d, J = 7.0 and 6.4 Hz, 1H);
IR (neat) 2959, 1752, 1648, 1447, 1334, 1073, 768 cmꢀ1; HRMS
(EI) m/z Calcd for C12H17NO6 (M+): 271.1056. Found: 271.1066.
4.6.3. (4R,6S)-1-Aza-4-acetoxy-2,3-didehydro-8-oxabicyclo[4.3.0]
nonan-9-one 25
Mp 77–79 °C; 1H NMR (CDCl3) d 1.72 (td, J = 12.8 and 3.8 Hz,
1H), 2.06 (s, 3H), 2.24 (d, J = 12.8 Hz, 1H), 4.01 (t, J = 9.0 Hz, 1H),
4.07–4.21 (m, 1H), 4.67 (t, J = 8.1 Hz, 1H), 5.25–5.33 (m, 2H), 6.87
(d, J = 6.6 Hz, 1H); IR (KBr) 2905, 1784, 1644, 1426, 1269, 1055,
992, 756 cmꢀ1; HRMS m/z Calcd for C9H11NO4 (M+): 197.0689.
Found: 197.0668.
4.7. Electrochemical acetoxylation of 2,3-didehydro- and 1,2-
didehydropiperidine derivatives 10a–d, 4, 19, and 23
A typical procedure is illustrated by the anodic oxidation of 4.
Into a glass beaker (15 mL) equipped with two Pt plate electrodes
(10 mm ꢂ 20 mm) was added a solution of 4 (0.243 g, 1 mmol) and
AcOK (1.00 g, 10 mmol) in acetic acid (10 mL). After 15 F/mol of
electricity was passed at a constant current of 0.1A (4 h, terminal
voltage: ca 15 V) through the solution cooled with water, saturated
aqueous NaHCO3 (20 mL) was added into the reaction mixture. The
organic portion was extracted with AcOEt (20 mL ꢂ 3) and the
combined organic layer was washed with saturated aqueous NaH-
CO3 (20 mL). After the extract was dried over MgSO4 and the sol-
vent was removed in vacuo, the residue was chromatographed
on silica gel (AcOEt/n-hexane = 1:3) to afford 1,2,3-triacetoxy-
(5S)-acetoxymethyl-N-methoxycarbonylpiperidine 5 in 85% yield.
1H NMR (CDCl3) d 1.91–2.24 (m, 14H), 3.69–3.82 (m, 3H), 4.03–
4.39 (m, 2H), 4.45–4.60 (m, 1H), 4.88–5.07 (m, 1H), 5.15–5.38
(m, 1H), 6.64–6.90 (m, 1H); IR (neat) 2952, 1755, 1597, 1447,
1372, 1240, 1044, 776 cmꢀ1; HRMS (EI) m/z Calcd for C14H19NO8
(M+ꢀAcOH): 329.1111. Found: 329.1111.
Figure 7. Ortep drawing of (2R,3S,5S)-28.
4.5.4. (6S)-1-Aza-3,4-didehydro-2-methoxy-8-oxabicyclo[4.3.0]
nonan-9-one 19
½
a 2D8
ꢁ
¼ ꢀ226:6 (c 1.0, CHCl3); mp 34–36 °C; 1H NMR (CDCl3) d
2.09–2.35 (m, 2H), 3.45 (s, 3H), 3.92–4.04 (m, 1H), 4.09 (dd,
J = 8.7 and 3.6 Hz, 1H), 4.56 (t, J = 8.4 Hz, 1H), 5.14 (d, J = 1.2 Hz,
1H), 5.81–5.91 (m, 1H), 5.94–6.02 (m, 1H); IR (KBr) 2982, 1767,
1414, 982, 763 cmꢀ1; HRMS (EI) m/z Calcd for C8H11NO3 (M+):
169.0739. Found: 169.0731.
4.7.1. 1,2,3-Triacetoxy-N-methoxycarbonylpiperidine 11a
1H NMR (CDCl3) d 1.77–2.25 (m, 11H), 3.08–3.17 (m, 1H), 3.74
and 3.76 (2s, 3H), 3.95–4.14 (m, 1H), 4.82–5.02 and 5.14–5.28

N. Moriyama et al. / Tetrahedron: Asymmetry 20 (2009) 2677–2687
2685
O
OH
O
approach A
Os
O
O
O
O
N
OH
OH
O
O
N
OMe
I
O
MeO
O
N
OMe
19
O
O
Os
O
O
O
O
N
approach B
OMe
OH
J
Scheme 8. Effect of a methoxyl group at the 1-position of 19.
(2 m, 2H), 6.56–6.78 and 6.93–7.08 (2 m, 1H); IR (neat) 2980, 1786,
1420, 1375, 1256, 1051, 764 cmꢀ1. Anal. Calcd for C13H19NO8: C,
49.21; H, 6.04; N, 4.41. Found: C, 49.14; H, 6.22; N, 4.35.
6: ½a 2D6
ꢁ
¼ þ40:0 (c 0.5, CHCl3); mp 102–104 °C; 1H NMR (CDCl3) d
1.77–1.87 (m, 1H), 2.04 (s, 3H), 2.06 (s, 3H), 2.10 (s, 3H), 2.10–
2.23 (m, 1H), 3.34 (d, J = 15.0 Hz, 1H), 3.71 (s, 3H), 4.13 (dd,
J = 11.3 and 5.9 Hz, 1H), 4.23 (d, J = 15.0 Hz, 1H), 4.40 (t,
J = 9.7 Hz, 1H), 4.54–4.70 (m, 1H), 4.76–4.87 (m, 1H), 4.91–4.99
(m, 1H); IR (KBr) 2959, 1750, 1701, 1441, 1374, 1223,1069,
772 cmꢀ1. Anal. Calcd for C14H21NO8: C, 50.75; H, 6.39; N, 4.23.
Found: C, 50.88; H, 6.68; N, 4.26. Major isomer of 6 was detected
by HPLC method; YMC-Pack SIL (0.46 cm ꢂ 15 cm), n-hexane/eth-
anol = 10:1, wavelength: 210 nm, flow rate: 0.5 mL/min, retention
time: 11.4 min.
4.7.2. 1,2,3-Triacetoxy-N-benzyloxycarbonylpiperidine 11b
1H NMR (CDCl3) d 1.75–2.24 (m, 11H), 3.09–3.27 (m, 1H), 3.97–
4.26 (m, 1H), 4.95–5.31 (m, 4H), 6.80 and 7.10 (2d, J = 1.0 and
4.0 Hz, 1H), 7.35 (s, 5H); IR (neat) 2953, 1748, 1717, 1370, 1215,
;
1053, 698 cmꢀ1 HRMS (EI) m/z Calcd for C19H23NO8 (M+):
393.1424. Found: 393.1464.
4.7.3. 1,2,3-Triacetoxy-N-formylpiperidine 11c
1H NMR (CDCl3) d 1.80–2.29 (m, 11H), 2.81–3.17 (m, 1H), 4.15–
4.46 (m, 1H), 4.91–5.08 (m, 1H), 5.22–5.37 (m, 1H), 5.95, 6.04, 6.35
and 6.43 (4d, J = 0.8, 1.0, 3.0 and 4.0 Hz, 1H), 8.25 and 8.28 (2s, 1H);
IR (neat) 3567, 2942, 1759, 1698, 1433, 1374, 1256, 1053,
704 cmꢀ1; HRMS (EI) m/z Calcd for C12H17NO7 (M+): 287.1005.
Found: 287.0981.
4.8.1. 2,3-Diacetoxy-N-methoxycarbonylpiperidine 12a
1H NMR (CDCl3) d 1.86–2.19 (m, 8H), 3.20–3.50 (m, 2H), 3.70 (s,
3H), 3.77–3.98 (m, 1H), 4.71–4.87 (m, 1H), 4.88–4.98 (m, 1H),
4.99–5.13 (m, 1H); IR (neat) 2959, 1755, 1471, 1374, 1057,
770 cmꢀ1; HRMS m/z Calcd for C11H17NO6 (M+): 259.1055. Found:
259.1042. Diastereomeric ratio of 12a was determined by HPLC
method; YMC-Pack SIL (0.46 cmø ꢂ 15 cm), n-hexane/etha-
nol = 10:1, wavelength: 210 nm, flow rate: 0.5 mL/min, retention
time: 8.2 min for trans-isomer, 9.1 min for cis-isomer.
4.7.4. 1,2,3-Triacetoxy-N-benzoylpiperidine 11d
1H NMR (CDCl3) d 1.84–2.38 (m, 11H), 3.10–3.49 (m, 1H), 4.18–
4.59 (m, 1H), 4.92–5.13 (m, 1H), 5.21–5.41 (m, 1H), 6.15–6.44 and
6.61–6.88 (2 m, 1H), 7.24–7.51 (m, 5H); IR (neat) 3063, 2940, 1755,
1659, 1374, 1252, 1057, 702 cmꢀ1. Anal. Calcd for C18H21NO7: C,
59.50; H, 5.83; N, 3.85. Found: C, 59.23; H, 6.23; N, 3.65.
4.8.2. 2,3-Diacetoxy-N-benzyloxycarbonylpiperidine 12b
1H NMR (CDCl3) d 1.90–2.12 (m, 8H), 3.30–4.05 (m, 4H), 4.18–
5.12 (m, 4H), 7.35 (s, 5H); IR (neat) 3033, 2942, 1752, 1433,
1254, 1055, 766, 700 cmꢀ1; HRMS m/z Calcd for C17H21NO6 (M+):
335.1369. Found: 335.1349. Diastereomer ratio of 12b was
determined by HPLC method; YMC-Pack SIL (0.46 cmø ꢂ 15 cm),
n-hexane/ethanol = 15:1, wavelength: 210 nm, flow rate: 0.5 mL/
min, retention time: 9.3 min for trans-isomer, 10.4 min for cis-
isomer.
4.7.5. (3R,4R,6S)-2,3,4-Triacetoxy-1-aza-8-oxabicyclo[4.3.0]
nonan-9-one 20
1H NMR (CDCl3) d 1.94 (td, J = 12.0 and 1.8 Hz, 1H), 2.05–2.18
(m, 10H), 4.02 (dd, J = 8.6 and 6.6 Hz, 1H), 4.20–4.30 (m, 1H),
4.52–4.58 (m, 1H), 5.06–5.10 (m, 2H), 6.31 and 6.59 (2d, J = 1.0
and 1.8 Hz, 3/4H and 1/4H); IR (neat) 2940, 1782, 1420, 1374,
1285, 1048, 764 cmꢀ1
; HRMS (EI) m/z Calcd for C11H13NO6
(M+ꢀAcOH): 255.0743. Found: 255.0726.
4.8.3. 2,3-Diacetoxy-N-formylpiperidine 12c
1H NMR (CDCl3) d 1.80–2.08 (m, 8H), 3.15–3.75 and 3.95–4.35
(2m, 4H), 4.75–4.88 and 4.95–5.45 (2m, 2H), 7.95, 7.97, 8.08, and
8.10 (4s, 1H); IR (neat) 3650, 2940, 1759, 1690, 1439, 1372,
1260, 1046 cmꢀ1; HRMS m/z Calcd for C10H15NO5 (M+): 229.0950.
Found: 229.0975. Diastereomer ratio of 12c was determined by
HPLC method; YMC-Pack SIL (0.46 cmø ꢂ 15 cm), n-hexane/etha-
nol = 10:1, wavelength: 210 nm, flow rate: 0.5 mL/min, retention
time: 9.0 min for trans-isomer, 9.7 min for cis-isomer.
4.8. Reduction of 1,2,3-triacetoxy-N-acylpiperidine derivatives
5, 11a–d, and 20
A typical procedure is illustrated by the reduction of 5. Into a
solution of 5 (0.389 g, 1 mmol) and Et3SiH (0.140 g, 1.2 mmol) in
CH2Cl2 (3 mL) was added methanesulfonic acid (0.144 g, 1.5 mmol)
at 0 °C. After stirring for 10 min, into a mixture of AcOEt (20 mL)
and saturated aqueous NaHCO3 (20 mL) was poured the reaction
mixture. The organic portion was extracted with AcOEt
(20 mL ꢂ 3) and the combined organic layer was washed with sat-
urated aqueous NaHCO3 (20 mL). After the extract was dried over
MgSO4 and the solvent was removed in vacuo, the residue was
chromatographed on silica gel (AcOEt/n-hexane = 1:2) to afford
4.8.4. 2,3-Diacetoxy-N-benzoylpiperidine 12d
1H NMR (CDCl3) d 1.70–2.20 (m, 8H), 3.20–4.40 (m, 4H), 4.68–
5.22 (m, 2H), 7.41 (s, 5H); IR (neat) 2940, 1744, 1640, 1431,
1372, 1248, 706 cmꢀ1; HRMS m/z Calcd for C16H19NO5 (M+):
305.1263. Found: 305.1273. Diastereomer ratio of 12d was deter-
mined by HPLC method; YMC-Pack SIL (0.46 cmø ꢂ 15 cm), n-hex-
ane/ethanol = 10:1, wavelength: 210 nm, flow rate: 0.5 mL/min,
retention time: 25.9 min for trans-isomer, 29.5 min for cis-isomer.
2,3-diacetoxy-5S-acetoxymethyl-N-methoxycarbonylpiperidine
6
in 62% yield as a mixture of stereoisomers. Recrystallization of 6
from AcOEt and n-hexane afforded (2S,3S,5S)-isomer. (2S,3S,5S)-

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N. Moriyama et al. / Tetrahedron: Asymmetry 20 (2009) 2677–2687
4.8.5. (3R,4R,6S)-3,4-Diacetoxy-1-aza-8-oxabicyclo[4.3.0]nonan-
9-one 21
3.37 (2s, 1.2H), 3.75 and 3.77 (2s, 3H), 4.07–4.20 (m, 1H), 4.22–
4.41 (m, 1H), 4.54–4.79 (m, 1H), 5.18–5.52 (m, 2H), 5.72–5.84
(m, 0.4H), 6.70–6.90 (m, 0.6H); IR (neat) 2959, 1744, 1445, 1370,
½
a 2D6
ꢁ
¼ ꢀ75:2 (c 0.6, CHCl3); mp 127–129 °C (from AcOEt and n-
hexane), (uncorrected); 1H NMR (CDCl3) d 1.90–2.05 (m, 2H), 2.09
(s, 3H), 2.13 (s, 3H), 3.33 (dd, J = 15.0 and 2.1 Hz, 1H), 3.92–4.05 (m,
3H), 4.38–4.48 (m, 1H), 4.80–4.85 (m, 1H), 5.08–5.12 (m, 1H); IR
(neat) 2932, 1744, 1422, 1372, 1221, 1061, 914, 768 cmꢀ1. Anal.
Calcd for C11H15NO6: C, 51.36; H, 5.88; N, 5.45. Found: C, 51.49;
H, 6.08; N, 5.44. Major isomer of 21 was detected by HPLC method;
YMC-Pack SIL (0.46 cmø ꢂ 15 cm), n-hexane/ethanol = 5:1, wave-
length: 210 nm, flow rate: 0.5 mL/min, retention time: 18.9 min.
1225, 1090, 774 cmꢀ1
.
4.10.1. (3R,4S,6S)-3,4-Diacetoxy-2-methoxy-1-aza-8-
oxabicyclo[4.3.0]nonan-9-one 32
(85% yield from 19): 1H NMR (CDCl3) d 1.84–2.02 (m, 2H), 2.04
(s, 3H), 2.11 (s, 3H), 3.38 (s, 3H), 3.98–4.10 (m, 2H), 4.48–4.56 (m,
1H), 5.01 (d, J = 2.4 Hz, 1H), 5.19–5.29 (m, 2H); IR (neat) 2940,
1771, 1414, 1374, 1238, 1102, 970, 764 cmꢀ1; HRMS (EI) m/z Calcd
for C12H17NO7 (M+): 287.1005. Found: 287.1014.
4.9. Preparation of 2,3-didehydropiperidine derivative 33
Using similar oxidation procedure, 33 was successively oxidized
and acetoxylated to afford a mixture of (3S,4R,6S)-3,4-diacetoxy-1-
aza-8-oxabicyclo[4.3.0]nonan-9-one (2S,3R,5S)-28 and (3R,4S,6S)-
isomer (2R,3S,5S)-28 [(2S,3R,5S)-28: (2R,3S,5S)-28 = 76:24] in 80%
yield.
Into a round-bottomed flask (25 mL) equipped with a magnetic
stirrer and containing 19 (0.423 g, 2.5 mmol) in acetic acid (10 mL)
was added NaBH4 (0.946 g, 10 mmol). The reaction vessel was
cooled with water. After stirring for 10 min, water (10 mL) was
added slowly to the reaction solution at 0 °C. The mixture was ex-
tracted with AcOEt (20 mL ꢂ 3). The combined extracts were
washed with saturated aqueous NaHCO3 (20 mL). After the ex-
tracts were dried over anhydrous MgSO4, filtered, and concen-
trated in vacuo, the residue was chromatographed on silica gel
(AcOEt/n-hexane = 1:2) to afford 33 in 70% yield.
4.10.2. (3S,4R,6S)-3,4-Diacetoxy-1-aza-8-oxabicyclo[4.3.0]nonan-
9-one (2S,3R,5S)-28
½
a 2D8
ꢁ
¼ ꢀ53:3 (c 1.5, CHCl3), [containing 4% of (3R,4S,6S)-isomer
(2S,3R,5S)-28]; 1H NMR (CDCl3) d 1.70–1.83 (m, 1H), 2.03 (s, 3H),
2.07–2.13 (m, 1H), 2.14 (s, 3H), 3.22 (t, J = 12.0 Hz, 1H), 3.89–4.09
(m, 3H), 4.46 (t, J = 9.3 Hz, 1H), 4.80–4.90 (m, 1H), 5.50 (br s,
1H); IR (neat) 2940, 1781, 1485, 1375, 1266, 1177, 1071, 974,
762 cmꢀ1; HRMS (EI) m/z Calcd for C11H15NO6 (M+): 257.0899.
Found: 257.0892.
4.9.1. 6S-1-Aza-3,4-didehydro-8-oxabicyclo[4.3.0]nonan-9-one
33
½
a 3D0
ꢁ
¼ ꢀ166:9 (c 1.0, CHCl3); 1H NMR (CDCl3) d 2.11–2.37 (m,
2H), 3.64–3.75 (m, 1H), 3.76–3.89 (m, 1H), 4.03 (dd, J = 8.7 Hz
and 5.7 Hz, 1H), 4.08–4.14 and 4.16–4.21 (2 m, 1H), 4.52 (t,
J = 8.3 Hz, 1H), 5.70–5.89 (m, 2H); IR (neat) 2977, 1777, 1457,
1242, 1208, 1078, 961, 764 cmꢀ1; HRMS (EI) m/z Calcd for
C7H9NO2 (M+): 139.0633, Found: 139.0609.
4.11. Reduction of the a-alkoxyl group of 11a, 29a, 29b, and 32
A typical procedure is illustrated by the reduction of 11a. To
1 mmol of 11a was added Et3SiH (0.174 g, 1.5 mmol) in CH2Cl2
(3 mL), after which methanesulfonic acid (0. 192 g, 2.0 mmol)
was added at 0 °C. After stirring for 10 min, the reaction mixture
was added into a mixture of AcOEt (20 mL) and saturated aqueous
NaHCO3 (20 mL). The organic portion was extracted with AcOEt
(20 mL ꢂ 3) and the combined organic layers were washed with
saturated aqueous NaHCO3 (20 mL). After the extracts were dried
over anhydrous MgSO4, filtered, and concentrated in vacuo, the
residue was chromatographed on silica gel (AcOEt/n-hexane = 1:5)
to afford 2,3-diacetoxy-N-methoxycarbonylpiperidine 12a in 70%
yield. cis–2,3–Diacetoxy-N-methoxycarbonylpiperidine cis-12a: 1H
NMR (CDCl3) d 1.72–1.83 (m, 1H), 1.87–2.02 (m, 1H), 2.07 and
2.08 (2s, 6H), 3.20–3.48 (m, 2H), 3.70 (s, 3H), 3.87 and 3.91 (2d,
J = 6.0 and 6.0 Hz, 2H), 4.98–5.13 (m, 2H); IR (neat) 2959, 1755,
1474, 1372, 1278, 1057, 770 cmꢀ1; HRMS (EI) m/z Calcd for
C11H17NO6 (M+): 259.1056. Found: 259.1049.
4.10. Osmium oxidation of 2,3-didehydropiperidine derivatives
4, 19, 10a, and 33 and successive acetoxylations
A typical procedure is illustrated by the osmium oxidation of
10a. Into a round-bottomed flask (25 mL) equipped with a mag-
netic stirrer was added a solution of 5 (0.171 g, 1 mmol) and
NMO (50% in water, 0.351 g, 1.5 mmol) in acetone (0.5 mL) and
H2O (2.5 mL). To a stirred solution at room temperature was added
osmium tetraoxide (4 wt % solution in water, two drops,
0.01 mmol). After the mixture was stirred overnight at room tem-
perature, 10% aqueous Na2S2O3 (5 mL) was added into the reaction
mixture. The resulting mixture was concentrated under reduced
pressure. Pyridine (2 mL) and acetic anhydride (2 mL) were then
added to the residue and the mixture was stirred at room temper-
ature for 2 h. The mixture was concentrated under reduced pres-
sure. To the residue was added water (10 mL) and the organic
portion was extracted with AcOEt (20 mL ꢂ 3). The combined ex-
tracts were dried over anhydrous MgSO4, filtered, and concen-
trated in vacuo. The residue was chromatographed on silica gel
4.11.1. (2S,3R)-Diacetoxy-(5S)-acetoxymethyl-N-methoxycarbon-
ylpiperidine (2S,3R,5S)-27 (70% yield from a mixture of 29a and
29b)
½
a 3D0
ꢁ
¼ þ37:0 (c 1.0, CHCl3); 1H NMR (CDCl3) d 1.75 and 1.78 (2d,
J=4.4 Hz, 1H), 2.02 and 2.07 and 2.08 (3s, 9H), 2.09–2.11 (m, 1H),
3.19 (d, J = 15.0 Hz, 1H), 3.72 (s, 3H), 4.10 and 4.15 (2d, J = 5.7 Hz,
1H), 4.23–4.38 (m, 2H), 4.69–4.82 (br s, 1H), 5.03–5.13 (m, 1H),
5.19 (br s, 1H); IR (neat) 2959, 1755, 1709, 1451, 1374, 1256,
1055, 770 cmꢀ1; HRMS m/z Calcd for C14H21NO8 (M+): 331.1267.
Found: 331.1258. Major isomer of 27 was detected by HPLC meth-
od; YMC-Pack SIL (0.46 cmø ꢂ 15 cm), n-hexane/ethanol = 10:1,
wavelength: 210 nm, flow rate: 0.5 mL/min, retention time:
12.2 min.
(AcOEt/n-hexane = 1:5)
to
afford
1,2,3-triacetoxy-N-meth-
oxycarbonylpiperidine 11a in 71% yield. Compound 11a: 1H NMR
(CDCl3) d 1.78–1.88 (m, 1H), 1.92–2.05 (m, 1H), 2.01, 2.10 and
2.11 (3s, 9H), 3.09–3.23 (m, 1H), 3.76 (s, 3H), 4.06–4.29 (m, 1H),
5.18–5.28 (m, 2H), 6.71 (br s, 1H); IR (neat) 2959, 1748, 1449,
1372, 1223, 1057, 772 cmꢀ1; HRMS (EI) m/z Calcd for C13H19NO8
(M+): 317.1111. Found: 317.1116.
By similar procedures as mentioned above, 4 was converted
into a mixture of 2,3-diacetoxy-(5S)-acetoxymethyl-1-methoxy-
N-methoxycarbonylpiperidine 29a and 1,2,3-triacetoxy-(5S)-acet-
oxymethyl-N-methoxycarbonylpiperidine 29b was obtained in
77% yield (29a/29b = 0.4:0.6). 1H NMR (CDCl3) d 1.85–1.95 (m,
2H), 2.02, 2.03, 2.06, 2.07, 2.096, 2.100, 2.12 (7s, 10.8H), 3.34 and
4.11.2. (3R,4S,6S)-3,4-Diacetoxy-1-aza-8-oxabicyclo[4.3.0]nonan-
9-one (2R,3S,5S)-28 (81% yield from 32)
½
a 2D9
ꢁ
¼ ꢀ48:0 (c 0.5, CHCl3); mp 122–123 °C (from AcOEt and n-
hexane), (uncorrected); 1H NMR (CDCl3) d 1.89–1.99 (m, 2H), 2.05

N. Moriyama et al. / Tetrahedron: Asymmetry 20 (2009) 2677–2687
2687
(s, 3H), 2.11 (s, 3H), 3.13 (dd, J = 12.8 and 1.8 Hz, 1H), 3.84–3.95 (m,
1H), 4.04 (dd, J = 8.4 and 3.3 Hz, 1H), 4.10 (d, J = 12.5 Hz, 1H), 4.44
(t, J = 7.8 Hz, 1H), 4.92–5.03 (m, 1H), 5.19 (br s, 1H); IR (KBr) 2936,
1763, 1431, 1374, 1258, 1073, 986, 764 cmꢀ1. Anal. Calcd for
C11H15NO6: C, 51.36; H, 5.88; N, 5.45. Found: C, 51.43; H, 5.93;
N, 5.40. Major isomer of 11 was detected by HPLC method; YMC-
Pack SIL (0.46 cmø ꢂ 15 cm), n-hexane/ethanol = 5:1, wavelength:
210 nm, flow rate: 0.5 mL/min, retention time: 21.6 min.
1124, 918, 770 cmꢀ1. Anal. Calcd for C24H29NO10S2: C, 51.88; H,
5.26; N, 2.52. Found: C, 51.92; H, 5.39; N, 2.52.
References
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4.12. Synthesis of (5S)-acetoxymethyl-(2S,3R)-dihydroxy-N-
methoxycarbonylpiperidine (2S,3R,5S)-30 and successive
tosylation
Into a round-bottomed flask (25 mL) equipped with a magnetic
stirrer and containing a solution of 4 (0.243 g, 1 mmol) in acetone
(0.5 mL) and H2O (2.5 mL) was added NMO (50% in water, 0.351 g,
1.5 mmol). To a stirred solution at room temperature was added
osmium tetraoxide (4 wt % solution in water, two drops,
0.01 mmol). After the mixture was stirred overnight at room tem-
perature, 10% aqueous Na2S2O3 (5 mL) was added into the reaction
mixture. The resulting mixture was concentrated under reduced
pressure and to the residue was added water (1 mL). The organic
portion was extracted with AcOEt (15 mL ꢂ 8). The combined
extracts were dried over anhydrous MgSO4, filtered, and concen-
trated in vacuo to afford a crude mixture of (5S)-acetoxymethyl-
1,2,3-trihydroxy-N-methoxycarbonylpiperidine and (5S)-acetoxy-
methyl-2,3-dihydroxy-1-methoxy-N-methoxycarbonylpiperidine
(0.5:0.5): 1H NMR (CDCl3) d 1.70–1.85 (m, 1H), 1.89–2.04 (m, 1H),
2.06 (s, 3H), 3.33 (s, 1.5H), 3.74 and 3.76 (2s, 3H), 3.91–4.08 (m,
1H), 4.10–4.20 (m, 1H), 4.21–4.42 (m, 2H), 4.47–4.75 (m, 1H),
5.35–5.44 and 5.51–5.62 and 5.79–5.84 (3m, 1H); IR (neat) 3413,
2959, 1742, 1449, 1356, 1240, 1086, 774 cmꢀ1
.
To the mixture was added Et3SiH (0.174 g, 1.5 mmol) in CH2Cl2
(3 mL) and added methanesulfonic acid (0.192 g, 2.0 mmol) at 0 °C.
After stirring for 10 min, the reaction mixture was added to a mix-
ture of AcOEt (20 mL) and saturated aqueous NaHCO3 (20 mL). The
organic portion was extracted with AcOEt (20 mL ꢂ 3) and the com-
bined organic layers were washed with saturated aqueous NaHCO3
(20 mL). After the extracts were dried over anhydrous MgSO4, fil-
tered, and concentrated in vacuo, the residue was chromatographed
on silica gel (AcOEt/n-hexane = 3:1) to afford 5S-acetoxymethyl-
2S,3R-dihydroxy-N-methoxycarbonylpiperidine (302S,3R,5S) in 78%
yield from 4. (2S,3R,5S)-30: ½a D30
ꢁ
¼ ꢀ6:0 (c 1.0, CHCl3); 1H NMR
(CDCl3) d 1.73 and 1.77 (2d, J = 4.2 Hz, 1H), 1.91–2.02 (m, 1H), 2.05
(s, 3H), 2.24 (d, J = 6.5 Hz, 1H), 2.31–2.48 (br s, 1H), 3.10 (d,
J = 15.0 Hz, 1H), 3.72 (s, 3H), 3.80–3.96 (m, 2H), 4.06–4.38 (m, 3H),
4.57–4.73 (br s, 1H); IR (neat) 3447, 2959, 1744, 1698, 1456, 1370,
1258, 1140, 1080, 770 cmꢀ1; HRMS m/z Calcd for C10H17NO6 (M+):
247.1056. Found: 247.1058.
To (2S,3R,5S)-30 (0.1 g, 0.4 mmol) was added p-toluenesulfonyl
chloride (0.381 g, 2 mmol), Et3N (0.049 g, 0.48 mmol), and DMAP
(0.244 g, 2 mmol) in CH2Cl2 (2 mL). After the mixture was stirred for
three days at room temperature, into a mixture of AcOEt (20 mL)
and saturatedaqueousNaHCO3 (10 mL)was pouredthe reactionmix-
ture. The organic portion was extracted with AcOEt (20 mL ꢂ 3). After
the extracts were dried over anhydrous MgSO4, filtered, and concen-
trated in vacuo, the residue was chromatographed on silica gel
(AcOEt/n-hexane = 1:6) to afford 5S-acetoxymethyl-2S,3R-bis(p-tol-
uenesulfonyloxy)-N-methoxycarbonylpiperidine (2S,3R,5S)-31 in
13. Methoxylated compound 14 purified with silica gel column chromatography
was transformed into a certain amount of unsaturated compound 15 as a by-
product. Accordingly the yield of 15 by two steps without purification of 14
was better than that with purification of 14. The yield of 17 was improved
without purification of the corresponding methoxylated compound.
14. Crystallographicdata for (2S,3S,5S)-6, (2R,3R,5S)-21, (2S,3R,5S)-31, and (2R,3S,5S)-
28: CCDC 246337, 246338, 746282, and 746283, contain the supplementary
crystallographic data for this paper. The data can be obtained free of charge via
www.ccdc.cam.ac.uk/data_request/cif, by emailing data_request@ccdc.cam.ac.
uk, or by contacting The Cambridge Crystallographic Data Centre, 12, Union Road,
Cambridge CB2 1EZ, UK; fax: +44(0)-1223-336033.
15. (a) Matsumura, Y.; Tomita, T. Tetrahedron Lett. 1994, 35, 3737–3740; (b)
Matsumura, Y.; Yoshimoto, Y.; Horikawa, C.; Maki, T.; Watanabe, M.
Tetrahedron Lett. 1996, 37, 5715–5718; (c) Matsumura, Y.; Asano, T.;
Nakagiri, T.; Onomura, O. J. Chin. Chem. Soc. 1998, 45, 297–302.
16. The allylic 1,3-strain in F may compel the acetoxymethyl group at the 5-
position to be quasiaxial: (a) Hoffmann, R. W. Chem. Rev. 1989, 89, 1841–1860;
(b) Momose, T.; Toyooka, N. J. Org. Chem. 1994, 59, 943–945; (c) Matsumura, Y.;
Inoue, M.; Nakamura, Y.; Talib, I. L.; Maki, T.; Onomura, O. Tetrahedron Lett.
2000, 41, 4619–4622.
46% yield. ½a 3D0
¼ þ32:4 (c 1.0, CHCl3); mp 136–139 °C (from AcOEt
ꢁ
and n-hexane); 1H NMR (CDCl3) d 1.64 and 1.71 (2d, J = 3.6 Hz, 1H),
2.01 (s, 3H), 2.10–2.26 (m, 1H), 2.46 (s, 6H), 3.09 (d, J = 15.3 Hz, 1H),
3.69 (s, 3H), 3.97–4.16 (m, 2H), 4.45 (d, J = 15.3 Hz, 1H), 4.55–4.72
(m, 3H), 7.30–7.39 (m, 4H), 7.64 (d, J = 8.1 Hz, 2H), 7.79 (d,
J = 8.4 Hz, 2H); IR (KBr) 2957, 1748, 1701, 1449, 1364, 1246, 1140,