Stereoselective synthesis of azasugars by electrochemical oxidation

Article abstract of DOI:10.1016/j.tetlet.2004.09.036

A new method using electrochemical oxidation has been exploited for the stereoselective synthesis of 2,3,6-trihydroxylated 5S-piperidine derivatives. The electrochemical method was successively used for the conversion of N-protected piperidines to N-prote

Full text of DOI:10.1016/j.tetlet.2004.09.036

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 8177–8181
Stereoselective synthesis of azasugars by electrochemical oxidation
Shigeru Furukubo, Noriaki Moriyama, Osamu Onomura and Yoshihiro Matsumura*
Graduate School of Biomedical Sciences, Nagasaki University, 1-14 Bunkyo-machi, Nagasaki 852-8521, Japan
Received 17 August 2004; revised 2 September 2004; accepted 3 September 2004
Available online 21 September 2004
Abstract—A new method using electrochemical oxidation has been exploited for the stereoselective synthesis of 2,3,6-trihydroxyl-
ated 5S-piperidine derivatives. The electrochemical method was successively used for the conversion of N-protected piperidines to
N-protected 1-methoxypiperidines and for the conversion of 1-methoxy-2,3-didehydropiperidine derivatives to 1,2,3-triacetoxypi-
peridine derivatives. The method provided a new synthetic route to 2S,3S,6-triacetoxy-5S-methylpiperidine and 2R,3R,6-triacet-
oxy-5S-methylpiperidine.
ꢀ 2004 Elsevier Ltd. All rights reserved.
Polyhydroxylated 5S-methylpiperidines 1, a class of aza-
sugars, have attracted great interest due to their biolog-
ical properties.1 Some of them are potential inhibitors of
glycosidases and glycoprotein-processing enzymes. Now
they have being widely investigated as candidates of
drugs to treat a variety of carbohydrate-mediated dis-
eases such as diabetes, viral infection including HIV,
and cancer metastasis. The inhibitory activities depend
on the configuration and the number of hydroxyl groups
(Fig. 1). Among 1, 2,3,6-trihydroxy-5S-methylpiperi-
dines 2 are worth of note since recently it has been re-
ported that 2R,3S,6-trihydroxy-5S-methylpiperidine
(2a), one of the possible stereoisomers 2a–d (Fig. 2),
has high inhibitory activities towards glycosidases.2
However, there has not been any synthetic method for
2b–d.2,3 This paper describes a new method for a stereo-
selective synthesis of precursors of 2b,c.
Our strategy to this end is based on a preparation of tri-
acetate 6, a precursor of 2, from 5S-acetoxymethylpi-
peridine derivative 3 by electrochemical oxidation;
electrochemical 1-methoxylation of 3 and electrochemi-
cal triacetoxylation of 1-methoxy-2,3-didehydro-5S-
acetoxymethylpiperidine derivative 4 (Eq. 1).
OH
(OH)n
HO
The first key electrochemical reaction in the strategy has
already been used in the transformation of N-meth-
oxycarbonylpiperidine 7a to 1-methoxy-2,3-didehydropi-
peridine 10a. The transformation consisted of
electrochemical oxidation of 7a in MeOH to afford 1-
methoxypiperidine 8a, elimination of MeOH from 8a
to 1,2-didehydropiperidine 9a, bromine oxidation of 9a
3
2
5
OH
5
N
R
OH
N
H
6
1
2
R=H or alkyl
Figure 1.
OAc
OAc
AcO
AcO
AcO
-2e
reduction
-2e
OAc
OAc
OAc
OAc
ð1Þ
N
CO2Me
N
N
N
CO2Me
MeO
CO2Me
CO2Me
4
5
6
3
Keywords: Azasugar; Electrochemical oxidation; Stereoselective; Acetoxylation.
*
Corresponding author. Tel.: +81 95 819 2429; fax: +81 95 819 2476; e-mail: matumura@net.nagasaki-u.ac.jp
0040-4039/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.09.036

8178
S. Furukubo et al. / Tetrahedron Letters 45 (2004) 8177–8181
OH
OH
OH
OH
HO
HO
HO
HO
OH
OH
OH
OH
N
H
N
H
N
H
N
H
2a
2b
2c
2d
2R,3R
2S,3S
2S,3R
2R,3S
Figure 2. Stereoisomers 2a–d of 2,3,6-trihydroxy-5S-methylpiperidines 2.
followed by base-induced dehydrobromination to
1-methoxy-2,3-didehydropiperidine 10a (Eq. 2).4 Accord-
ing to this method, the other 1-methoxy-2,3-didehyd-
ropiperidines 10b–d were similarly prepared from 7b–d.
result is shown in Eq. 4. The desired 4 was also obtained
from x-amino-2-amino alcohol derivative 15, easily
available from L-lysine.9 Electrochemical oxidation of
4 afforded tetraacetoxylated piperidine 5,10 of which
-2e
Br2, NaOMe
1)
2)
N
N
N
MeO
MeOH
Et4NOTs
N
MeO
DBU
DMF
NH4Cl
O
R
O
R
-MeOH
O
R
O
R
(+) Pt - Pt (-)
ð2Þ
7a-d
9a-d
10a-d
8a-d
a: R=OMe
b:
c: R=H
d: R=Ph
86%
91%
97%
90%
90%
92%
83%
84%
58%
70%
68%
60%
R=OCH2Ph
With 10a–d in hand, we examined the second key electro-
chemical triacetoxylation of 10a–d, which was carried
out in acetic acid containing potassium acetate (Eq.
3).5 As expected, the oxidation gave triacetoxylated
products 11a–d, though their stereochemistry was not
determined at this stage. Then we achieved the reductive
elimination of 1-acetoxyl group of 11a–d by Et3SiH to
afford 2,3-diacetoxypiperidines 12a–d.6 The yields of
11a–d and 12a–d are shown together with the trans/cis
ratio in Table 1.
reduction with Et3SiH gave 2,3,6-triacetoxy-5S-methyl-
piperidine 6 in 53% from 4 (Eq. 4). Although 6 was ob-
tained as a mixture of stereoisomers (91/3/3/3),11 the
main isomer 62S,3S (Fig. 3) fortunately crystallized.12
The absolute stereochemistry was determined to be
(2S,3S) by its X-ray analysis.13
In contrast to the electrochemical oxidation of 4, that of
bicyclic carbamate 19, which was prepared from L-pipe-
colinic acid derivative 169a or from L-lysine derivative 22
through 17 and 18,14 followed by reduction of the oxida-
tion product 20 (70% yield) with Et3SiH gave a single
stereoisomer 21 as a crystal (Eq. 5).15 The absolute
stereochemistry was also determined to be (2R,3R) by
its X-ray analysis.13
The stereochemistry (trans/cis) of 12a–d was somewhat
dependent on R (70/30 ꢀ 54/46).7 Then, we tried the
preparation of 4 from 38 through 13 and 149b to obtain
4 in a similar way to a transformation of 7 to 10. The
The reaction mechanism for electrochemical triacetoxyl-
ation is tentatively proposed as follows (Eq. 6). Since
it was found that 10a was immediately converted to 3-
acetoxy-1,2-didehydropiperidine 23 under the reaction
conditions, oxidation of 23 may be responsible for the
formation of 11a. We already reported electrochemical
1,2-diacetoxylation of 1,2-didehydropiperidines.5
OAc
OAc
Et3SiH
AcO
AcO
AcO
(1.2 equiv)
-2e
10a-d
N
R
N
R
AcOH
AcOK
MeSO3H
(1.5 equiv)
/CH2Cl2
O
O
11a-d
12a-d
ð3Þ
As for 3-acetoxy-1,2-didehydropiperidine intermediates
involved in electrochemical triacetoxylation of 4 and
Table 1. Electrochemical oxidation of 10a–d followed by reduction
11a–d with Et3SiH
OAc
AcO
Entry
10a–d R
Yields
trans:cis (12a–d)
OAc
N
11a–d
12a–d
1
2
3
4
OMe
OCH2Ph
H
81%
54%
78%
50%
84%
82%
65%
45%
70:30
58:42
66:34
54:46
CO2Me
62S,3S
Ph
Figure 3.

S. Furukubo et al. / Tetrahedron Letters 45 (2004) 8177–8181
8179
-2e
1) Br2, MeOH
-Et3N
OAc
OAc
OAc
OAc
N
N
MeO
NH4Cl
2) DBU in DMF
56%
N
N
MeOH
MeO
CO2Me
CO2Me
CO2Me
CO2Me
13
14
4
3
80% from 3
-2e
66% from 15
AcOH / AcOK
-2e
MeOH-
AcOH
ð4Þ
OAc
OAc
AcO
AcO
(1.2 equiv)
Et3SiH
OAc
OAc
N
OAc
MeSO3H (1.5 equiv)
0o
HN
CO2Me
HN
MeO2C
N
AcO
C
CO2Me
CO2Me
53% from 4
6
15
5
91 : 3 : 3 : 3
Br2, NaOMe
MeOH
1)
2)
1) -2e
MeOH
2) H+
62%
NaBH4
N
CO2Me
N
O
N
N
CO2Me DME/MeOH
DBU
DMF
68%
MeO
CO2Me
CO2Me
O
80%
O
O
16
17
18
19
-2e
-2e
1)
ð5Þ
AcOH / AcOK
MeOH
2) H+
51%
CO2Me
OAc
N
OAc
N
AcO
AcO
AcO
Et3SiH (1.2 equiv)
HN
HN
MeO2C
MeSO3H (1.5 equiv)
0o
C
CO2Me
O
O
O
57% from 19
O
22
20
21
19, the stereochemistry must be taken into an account.
The plausible intermediates may be 243S,5S and 253R,5S
but not 243R,5S and 253S,5S, respectively, because of eas-
ier attack of acetic acid on the C-3 of allylic cations A
and B from the equatorial direction than from the axial
direction (Scheme 1).16
The observed high stereoselectivity in electrochemical
oxidation of 243S,5S and 253R,5S may be also explainable
in terms of equatorial attack of acetic acid on the C-2 of
plausible cationic intermediates17 C and D to produce
51,2R,3S,5S and 201,2S,3R,5S, respectively (Scheme 2).16
The less stereoselective triacetoxylation of 10a–d may
be due to a conformational flexibility of the piperidine
ring, which has no substituent at the 5-position.
OAc
OAc
AcO
AcO
-2e
AcOH
AcOH
N
ð6Þ
MeO
N
N
CO2Me
CO2Me
CO2Me
11a
10a
23
3S
5S
AcO
equatorial
attack
OAc
MeO2C
N
243S,5S
5S
AcO
AcO
AcOH
+
OAc
MeO2C
MeO2C
N
5S
N
AcO
axial
attack
3R
MeO
A
MeO2C
N
4
243R,5S
5S
N
OAc
equatorial
attack
O
O
3R
O
N
5S
N
O
253R,5S
AcOH
MeO
O
+
O
5S
N
O
3S
axial
attack
B
OAc
19
O
253S,5S
Scheme 1. Plausible mechanism for stereoselective formation of 243S,5S and 253R,5S
.

8180
S. Furukubo et al. / Tetrahedron Letters 45 (2004) 8177–8181
3S
5S
AcO
OAc
OAc
MeO2C
N
1
2R
AcOH
AcOH
AcO
5S
3S
51,2R,3S,5S
AcO
-2e
AcO
OAc
OAc
MeO2C
MeO2C
N
AcO
AcOH
3S
N
5S
+
AcO
OAc
MeO2C
C
N
AcO
243S,5S
2S
1
OAc
51,2S,3S,5S
5S
N
AcO
2S
OAc
1
AcOH
3R
OAc
O
O
5S
N
N
-2e
OAc
AcO
201,2S,3R,5S
OAc
O
3R
+
AcOH
O
O
OAc
O
5S
N
253R,5S
AcO
O
AcOH
OAc
1
D
2R
3R
O
201,2R,3R,5S
Scheme 2. Plausible mechanism for stereoselective formation of 51,2R,3S,5S and 201,2S,3R,5S
.
azawa, T.; Aoki, T. J. Am. Chem. Soc. 1982, 104, 6697–
6703; (c) Shono, T.; Matsumura, Y.; Tsubata, T. Org.
Synth. 1984, 63, 206–213, 1990, Coll. Vol. VII, 307–312;
(d) Shono, T.; Matsumura, Y.; Onomura, O.; Ogaki, M.;
Kanazawa, T. J. Org. Chem. 1987, 52, 536–541; (e) Shono,
T.; Matsumura, Y.; Onomura, O.; Yamada, Y. Tetrahe-
dron Lett. 1987, 28, 4073–4074; (f) Matsumura, Y.;
Onomura, O.; Suzuki, H.; Furukubo, S.; Maki, T.; Li,
C.-J. Tetrahedron Lett. 2003, 44, 5519–5522.
In summary, a stereoselective formal synthesis of two
stereoisomers 2b,c of 2,3,6-trihydroxyl-5S-methylpiperi-
dines 2 from L-lysine and L-pipecolinic acid has been
accomplished by using electrochemical oxidation.
Exploitation of the synthetic method for the other
stereoisomer 2d is now under investigation.
Acknowledgements
5. (a) Shono, T.; Matsumura, Y.; Onomura, O.; Kanazawa,
T.; Habuka, M. Chem. Lett. 1984, 1101–1104; (b) Shono,
T.; Matsumura, Y.; Onomura, O.; Sato, M. J. Org. Chem.
1988, 53, 4118–4121.
6. DeNinno, M. P.; Etienne, J. B.; Duplantier, K. C.
Tetrahedron Lett. 1995, 36, 669–672.
This study was supported by a Grant-in-Aid for Scien-
tific Research on Priority Areas (No. 412: Exploitation
of Multi-Element Cyclic Molecules) from the Ministry
of Education, Culture, Sports, Science and Technology,
Japan, and by a Grant-in-Aid for Scientific Research (C)
(No. 15550094) from Japan Society for the Promotion
of Sciences.
7. The ratio of 12cis and 12trans was determined on the basis
of the NMR spectrum of 12btrans; Williams, S. J.; Hoos,
R.Withers, S. G. J. Am. Chem. Soc. 2000, 122, 2223–2235.
8. Compound 3 was prepared by hydrogenation of 14. 3;
28
1
½aꢁD ꢂ45.6 (c 1.1, CHCl3); H NMR (CDCl3) d 1.34–1.55
(m, 2H), 1.58–1.74 (m, 4H), 2.04 (s, 3H), 2.88 (t,
J = 12.9Hz, 1H), 3.69 (s, 3H), 4.00–4.10 (m, 1H), 4.15
(dd, J = 11.4 and 6.6Hz, 1H), 4.24 (dd, J = 11.4 and
8.7Hz, 1H), 4.51 (br s, 1H).
References and notes
1. (a) Heightman, T. D.; Vasella, A. T. Angew. Chem., Int.
Ed. 1999, 38, 750–770; (b) Asano, K.; Hakogi, T.; Iwama,
S.; Katsumura, S. Chem. Commun. 1999, 41–42; (c)
Butters, T. D.; Dwek, R. A.; Platt, F. M. Chem. Rev.
2000, 100, 4683–4696; (d) Sawada, D.; Takahashi, H.;
Ikegami, S. Tetrahedron Lett. 2003, 44, 3085–3088; (e)
Takahata, T.; Banba, Y.; Ouchi, H.; Nemoto, H. Org.
Lett. 2003, 5, 2527–2529; (f) Moriyama, H.; Tsukida, T.;
Inoue, Y; Yokota, K.; Yoshino, K.; Kondo, H.; Miura,
N.; Nishimura, S. J. Med. Chem. 2004, 47, 1930–1938; (g)
Felpin, F.-X.; Bouberkeur, K.; Lebrenton, J. J. Org.
Chem. 2004, 69, 1497–1503, and references cited therein.
9. (a) Shono, T.; Matsumura, Y.; Inoue, K. J. Chem. Soc.,
Chem. Commun. 1983, 1169–1171; (b) Matsumura, Y.;
Nakamura, Y.; Maki, T.; Onomura, O. Tetrahedron Lett.
2000, 41, 7685–7689.
10. Electrochemical oxidation of 4; into a glass beaker (15mL)
equipped with two Pt plate electrodes (10mm · 20mm)
without a diaphragm was added a solution of 4 (0.243g,
1mmol) and AcOK (1.00g, 10mmol) in acetic acid
(10mL). After 15F/mol of electricity was passed at a
constant current of 0.1A (4h) through the solution, a
saturated aqueous NaHCO3 solution (20mL) was added
into the reaction mixture. The organic portion was
extracted with AcOEt (20mL · 3) and the combined
organic layer was washed with a saturated aqueous
NaHCO3 solution (20mL). After the extract was dried
over MgSO4 and the solvent was removed in vacuo, the
residue was subjected on chromatography (silica gel)
(AcOEt:n-hexane = 1:3) to afford 1,2,3-triacetoxy-5S-acet-
2. Andersen, S. M.; Ekhart, C.; Lundt, I.; Stutz, A. E.
¨
Carbohydr. Res. 2000, 326, 22–33.
3. Lemaire, M.; Veny, N.; Gefflaut, T.; Gallienne, E.;
ˆ
Chenevert, R.; Bolte, J. Synlett 2002, 1359–1361.
4. (a) Shono, T.; Hamaguchi, H.; Matsumura, Y. J. Am.
Chem. Soc. 1975, 97, 4264–4268; (b) Shono, T.; Matsu-
mura, Y.; Tsubata, T.; Sugihara, Y.; Yamane, S.-I.; Kan-

S. Furukubo et al. / Tetrahedron Letters 45 (2004) 8177–8181
8181
oxymethyl-N-methoxycarbonyl piperidine (5) in 85%
yield.
sweep was performed using w oscillations between ꢂ19.0ꢁ
and 23.0ꢁ at v = 90.0ꢁ. The crystal-to-detector distance
was 40.7mm, and the detector swing angle was ꢂ5.0ꢁ. The
data were corrected for Lorentz and polarization effects.
The structures were solved by direct methods (SIR92) and
refined by full matrix least squares methods. All calcula-
tions were performed using TEXSAN.
CCDC 246337 & 246338 contains 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 e-mailing 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.
11. Determined by HPLC method; YMC-Pack SIL
(0.46cmB · 15cm), n-hexane/ethanol = 10/1, wavelength:
210nm, flow rate: 0.5mL/min, retention time of major
isomer: 11.4min.
26
12. 62S,3S; mp 102–104ꢁC (from AcOEt–n-hexane), ½aꢁD +40.0
(c 0.5 CHCl3).
13. Crystallographic
data
for
62S,3S
:
C14H21NO8,
FW = 331.32, orthorhombic, P212121(#19) space group,
˚
a = 6.7419(7), b = 10.5386(3), c = 23.9189(7)A, V =
1699.4(2)A , Z = 4, Dcalc = 1.295gcmꢂ3
, l(Mo,Ka) =
Crystal size
3
˚
1.07cmꢂ1
,
F000 = 704,
T = 296K,
(mm) = 0.55 · 0.40 · 0.30. Crystallographic data for 21:
C11H15NO6, FW = 257.24, orthorhombic, P212121(#19)
14. (a) Matsumura, Y.; Tomita, T. Tetrahedron Lett. 1994, 35,
3737–3740; (b) Matsumura, Y.; Yoshimoto, Y.; Hori-
kawa, C.; Maki, T.; Watanabe, M. Tetrahedron Lett. 1996,
37, 5715–5718.
space
20.4793(6)A, V = 1192.9(1)A , Z = 4, Dcalc = 1.432
gcmꢂ3 l(Mo,Ka) = 1.17cmꢂ1
F000 = 544, T = 297K,
group,
˚
a = 6.6474(7),
b = 8.7625(2),
c =
3
˚
,
,
26
crystal size (mm) = 0.55 · 0.25 · 0.20. Compounds 62S,3S
and 21 were mounted on a glass fiber. All measurements
were made on a Quantum CCD area detector coupled
with a Rigaku AFC7 diffractometer using graphite-mon-
15. 21: mp 127–129ꢁC (from AcOEt–n-hexane), ½aꢁD ꢂ75.2 (c
0.6 CHCl3).
16. The stereoselectivity can be also explainable in terms of a
participating effect of 3-acetoxyl group or thermodynamic
control of the products.
˚
ochromated Mo Ka radiation (k = 0.71069A) at
296–297K. Data were collected in 0.50ꢁ oscillations with
30.0s exposures. A sweep of data was done using /
oscillations from 0.0ꢁ to 190.0ꢁ at v = 0ꢁ and a second
17. A mechanism involving an initial attack of acetic acid on
C-2 of a cation (C-2) radical (C-1) intermediate cannot be
denied.