A new concise stereoselective method for the preparation of a β- hydroxyfurfurylamine derivative and synthesis of 1-deoxyazasugar isomers

Article abstract of DOI:10.1016/S0957-4166(99)00382-1

A new method to prepare a chiral building block, a β- hydroxyfurfurylamine derivative, is achieved and 1-deoxyazasugar isomers are synthesized.

Full text of DOI:10.1016/S0957-4166(99)00382-1

Pergamon
Tetrahedron: Asymmetry 10 (1999) 3649–3657
A new concise stereoselective method for the preparation of a
β-hydroxyfurfurylamine derivative and synthesis of
1-deoxyazasugar isomers
Li-Xin Liao,a Zhi-Min Wang,a Hong-Xing Zhang b and Wei-Shan Zhou a,∗
aShanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Lu, Shanghai 200032, China
bDepartment of Organic Chemistry, Pharmacy School, Shanghai Medical University, Shanghai 200032, China
Received 23 August 1999; accepted 31 August 1999
Abstract
A new method to prepare a chiral building block, a β-hydroxyfurfurylamine derivative, is achieved and
1-deoxyazasugar isomers are synthesized. © 1999 Elsevier Science Ltd. All rights reserved.
1. Introduction
Polyhydroxylated piperidine alkaloids, such as (+)-1-deoxynojirimycin 11 and (−)-1-deoxy-
mannojirimycin 22 (Fig. 1) can be regarded as 1-deoxyazasugars. Owing to the variety of their biological
activities, many efforts have been devoted in recent years to develop appropriate synthetic methods.3
Figure 1.
In connection with our previous work on the kinetic resolution of racemic α-furfurylamine by using
a modified Sharpless epoxidation reagent,4 recently, Zhou et al. applied the chiral dihydropyridone
4 (R=Me) obtained from the kinetic resolution of the racemic β-hydroxyfurfurylamine derivative 3a
to synthesize (−)- and (+)-1-deoxymannojirimycin as well as (−)- and (+)-deoxyaltronojirimycin.5 In
the meanwhile, Altenbach and Wischnat6 synthesized a protected mannojirimycin derivative through
∗
Corresponding author. Tel: 86-21-64163300; fax: 86-21-64166128; e-mail: zhws@pub.sioc.ac.cn
0957-4166/99/$ - see front matter © 1999 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(99)00382-1

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the racemic dihydropyridone 4 (R=Ac) obtained from the racemic β-hydroxyfurfurylamine derivative
3b which was prepared from furfuryl glycine (Scheme 1). In addition, very recently, Zhou et al.7a
and O’Doherty et al.7b employed independently the Sharpless asymmetric aminohydroxylation7 c of
vinylfuran for the preparation of a useful chiral building block, β-hydroxyfurfurylamine derivative.
Scheme 1.
2. Results and discussion
A new concise method to prepare chiral β-hydroxyfurfurylamine derivative 3c by using Sharpless
asymmetric dihydroxylation (AD)8 as the key step with high chemical yield and high enantioselectivity
is described. This new method has advantages over the above mentioned kinetic resolution, not only
because of its convenient manipulation, but also its suitability for large scale preparation. As depicted in
Scheme 2, furfuryl glycol 69 was obtained by Sharpless AD8 from vinyl furan 510 with (DHQD)2–PHAL
as a ligand, in 92% yield. Then the dihydroxyl group was protected with dimethyl carbonate by heating
in the presence of a catalytic amount of NaOH to give 7 in 94% yield and 92% e.e.11 Compound 7
was treated with NaN3 in the presence of 1 equiv. H2O in DMF to give 8 in 91% yield and 91% e.e.11
The azido-compound 8 was produced stereospecifically with inversion.12 The β-hydroxyfurfurylamine
derivative 3c (R=Bn) was then obtained by protection of the primary hydroxyl group of 8 with a benzyl
group, then reduction with LiAlH4 in THF and final protection of the primary amino group with p-
toluenesulfonyl chloride in pyridine in 74% yield from 8 and 94% e.e.11 (after recrystallization with
petroleum ether–ethyl acetate). The overall yield is 59% in five steps (Scheme 2).
Scheme 2. Reagents and conditions: (a) (DHQD)2–PHAL, K2OsO2(OH)4, K3Fe(CN)6, K2CO3, 0°C, 10 h, 92%; (b) (MeO)2CO,
KOH, 60° -→ 90°C, 94%, 92% e.e.; (c) NaN3, DMF, H2O, 120°C, 10 h, 91%, 91% e.e.; (d) NaH, BnBr, 80.7%; (e) (i) LiAlH4,
THF, reflux; (ii) TsCl, Py, 0°C, 93% (two steps), 94%, e.e. (after recrystallization)
Synthesis of the target molecules starting from 3c was carried out as shown in Scheme 3. The
procedure for preparation of these target molecules was similar to that prepared previously by Zhou et al.5
Compound 10 was obtained by oxidation of β-hydroxyfurfurylamine derivative 3c with m-CPBA leading
to the cis-stereochemistry13 of 2H and 6H in 10 which was confirmed by X-ray14 diffraction (Fig. 2). The
hydroxyl group of 10 was then protected with triethylorthoformate in the presence of BF3·Et2O15 to give
11 which was reduced with NaBH4 in the presence of CeCl3 to give solely the C3-β-hydroxyl compound
12. The configuration of this hydroxyl group was assigned by 2D-NOESY spectroscopic analysis.5b

L.-X. Liao et al. / Tetrahedron: Asymmetry 10 (1999) 3649–3657
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Scheme 3. Reagents and conditions: (a) m-CPBA, CH2Cl2, rt, 82.4%; (b) HC(OEt)3, BF3·Et2O, 4 Å sieves, THF, 0°C, 4 h, 90%;
(c) NaBH4, CeCl3·7H2O, MeOH, −30°C, 2 h, 97%; (d) Ac2O, Et3N, DMAP, CH2Cl2, 0°C, 2 h, 86%; (e) NaBH4, HCOOH,
0°C, 85.9%; (f) (DHQD)2–PHAL, K2OsO2(OH)4, K3Fe(CN)6, K2CO3, tBuOH:H2O (1:1), 0°C, 94%; (g) Ac2O, Et3N, DMAP,
CH2Cl2, 0°C, 2 h, 86% in the ratio of 4:1; (h) Pd/C, H2, EtOAc, rt, 4 h, 82.0% for 17, 84.0% for 19; (i) Na/NH3(l), −78°C, 4 h,
52% for 20, 55% for 21
Compound 12 was protected by Ac2O in the presence of Et3N and catalytic amount of DMAP. The ethoxy
group in 13 was removed by using NaBH4 in formic acid to give 14. However, removal of ethoxy group
of 12 without protection of C3-OH group under the same conditions as for 13 gave a complex mixture.
Compound 14 was subjected to the Sharpless asymmetric dihydroxylation with (DHQD)2–PHAL as a
ligand to give the mixture of 15, which was separated through flash column chromatography on silica gel
to afford 16 and 18 after acetylation in the ratio of 4:1. The major isomer is the α-hydroxy compound.
Debenzylation of 16 and 18 with Pd–C gave 17 and 19, respectively. The configurations of 16 and 18 were
distinguished by 2D–1H NOESY spectrum as shown in Fig. 3. Deprotection of 17 and 19 with sodium
and liquid ammonia16 gave 1-deoxyazasugar isomer 20 along with minor isomer 21, respectively.
In summary, a new method to prepare the chiral building block, β-hydroxyfurfurylamine derivative
3c, the e.e. value of which is 94%, was achieved in five steps in an overall yield of 58%. The chiral
β-hydroxyfurfurylamine derivative 3c is a useful building block, since it could be easily transformed into
chiral dihydropyridone derivatives which are used for synthesis of the polyhydroxylated alkaloids,5,17
such as azasugars, by conversion of α,β-unsaturated ketone into the desired functional groups with
various methods. 1-Deoxyazasugar isomers 20 and 21 were prepared in overall yields of 16% and 3.5%,
respectively.
3. Experimental
3.1. General
Melting points were determined with a Büchi 535 melting point apparatus and were uncorrected.
All additions were made by syringes. Reactions were monitored by using thin layer chromatography
(TLC). The silica gel used in flash chromatography was silica gel H (10–40 µ) which was produced by
the Qingdao Chemical Plant, China. IR spectra were measured on a Schimadzu IR 400 spectrometer.
1H NMR spectra were recorded on a Bruker AM-300 (300 MHz) with CDCl3 as solvent and values
were reported in ppm using TMS or residual CHCl3 as internal standard. MS spectra were conducted
20
on a Finnigan 4021 GC–MS instrument and JMS-01U spectrometer. The optical rotations, [α]D
,
were measured on a Perkin–Elmer 241 MC automatic polarimeter in a 1 dm cell and recorded in
units of 10−1deg cm2 g−1. Element analysis were performed by the Analytical Department of this

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Figure 2. The molecule structure of 10
Figure 3.
institute. Dichloromethane was distilled from calcium hydride. Tetrahydrofuran was freshly distilled
from Na–benzophenone.
3.2. (S)-1-(α-Furyl)-1,2-ethanediol 6
A 2 l round bottom flask was charged with tert-butyl alcohol (0.8 l), water (0.8 l), K3Fe(CN)6 (157.5
g, 0.48 mol), K2CO3 (66.1 g, 0.48 mol) and (DHQD)2–PHAL (248 mg, 2% equiv.). After the resulting
mixture was cooled to 0°C, compound 5 (15.0 g, 0.16 mol) and K2OsO2(OH)4 (117 mg, 2% equiv.)
were added to the resulting heterogeneous slurry which was then vigorously stirred at 0°C for 4 h.
The reaction was quenched by addition of Na2SO3 (60.6 g, 0.48 mol) to the mixture and stirred for 1
h. The salt added caused the organic layer separation. The aqueous layer was separated and extracted
with ethyl acetate (3×250 ml). The combined organic layer was dried over Na2SO4 and concentrated
under reduced pressure to give an oil which was purified by flash column chromatography on silica gel
[petroleum ether:ethyl acetate (20:10)] to afford an oil 6 (19.2 g, 94%). [α]D20=−32.8 (c=2.8, CHCl3)

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1
[lit.9: [α]D20=−34.2, (c=0.4, CHCl3)]; H NMR δ: 3.84 (d, 2H, J=5.9 Hz, CH2OH), 4.78 (t, 1H, J=5.5
Hz, CHOH), 6.30 (d, 1H, J=3.2 Hz, furyl 3-H), 6.34 (dd, 1H, J=1.9, 3.2 Hz, furyl 4-H), 7.37 (d, 1H, J=1.3
Hz, furyl 5-H); IR: 3400 cm−1; MS m/z: 128 (M+), 111 (M++1−H2O).
3.3. (S)-4-(α-Furyl)-1,3-dioxolane-2-one 7
A 250 ml round bottom flask was charged with compound 6 (19.2 g, 0.15 mol), dimethyl carbonate
(100 ml) and solid KOH (8.4 g). After the mixture was heated at 60°C for 2 h, the resulting methanol
and unreacted dimethyl carbonate were distilled out at 95°C and 110°C, respectively. After the residue
was cooled to rt, ethyl acetate (100 ml) and water (50 ml) were added. The aqueous layer was separated
and extracted with ethyl acetate (3×100 ml). The combined organic layer was dried over Na2SO4 and
concentrated under reduced pressure to give an oil which was purified by flash column chromatography
on silica gel [petroleum ether:ethyl acetate (40:10)] to afford an oil 7 (19.6 g, 84%). [α]D20=+63.4 (c=1.1,
EtOH); 1H NMR δ: 4.70 (dd, 2H, J=2.1, 8.2 Hz, CH2O), 5.70 (t, 1H, J=8.0 Hz), 6.44 (dd, 1H, J=1.8, 3.2
Hz, furyl 4-H), 6.60 (d, 1H, J=3.2 Hz, furyl 3-H), 7.53 (d, 1H, J=1.8 Hz, furyl 5-H); IR: 1736 cm−1; MS
m/z: 154 (M+), 110 (M+−CO2); HRMS (M+) for C7H6O4: calcd: 154.0268; found: 154.0270.
3.4. (R)-2-(α-Furyl)-2-triazo-1-ethanol 8
A 250 ml round bottom flask was charged with DMF (50 ml), NaN3 (3.25 g, 0.15 mol), distilled
water (0.9 ml, 0.05 mol) and compound 7 (7.70 g, 0.05 mol). After reaction for 12 h at 120°C, ethyl
acetate (100 ml) and water (50 ml) were added. The organic layer was separated, washed with water,
dried over Na2SO4 and concentrated under reduced pressure to give an oil which was purified by flash
column chromatography on silica gel [petroleum ether:ethyl acetate (40:10)] to afford an oil 8 (6.96 g,
91%). [α]D20=+95.3 (c=1.3, EtOH); 1H NMR δ: 3.92 (d, 2H, J=6.3 Hz, CH2OH), 4.65 (t, 1H, J=6.2 Hz,
CHN3), 6.39 (m, 2H), 7.44 (d, 1H, J=1.4 Hz, furyl 5-H); IR: 2176, 3400 cm−1; MS m/z: 153 (M+), 111
(M+−N3) 122 (M+−CH2OH); HRMS (M+) for C6H7N3O2: calcd: 153.0518; found: 153.0498.
3.5. (R)-2-((1-Triazo-2-phenylmethoxy)ethyl)furan 9
To sodium hydride (1.33 g, 0.055 mol) in 100 ml of DMF at 0°C was added 8 (7.65 g, 0.05 mol) for 0.5
h, then benzyl bromide (5.8 ml, 0.055 mol) was added slowly for another 0.5 h. After being stirred for 2
h, 20 ml of aqueous NH4Cl and 20 ml of water were added sequentially. The mixture was extracted with
ethyl acetate and the combined organic layer was washed with water, dried over Na2SO4 and evaporated
under reduced pressure to afford a crude oil which was purified by flash column chromatography on
silica gel [petroleum ether:ethyl acetate (90:10)] to afford an oil 9 (9.8 g, 80.7%). [α]D20=+26.3 (c=1.5,
EtOH); 1H NMR δ: 3.84 (m, 2H), 4.62 (d, 2H J=4.0 Hz, PhCH2), 4.70 (m, 1H), 6.36 (m, 2H), 7.41 (m,
6H); IR: 2100 cm−1; MS m/z: 243 (M+), 152 (M+−Bn). Anal. calcd for C13H13N3O2: C, 64.19; H, 5.39;
N, 17.12. Found: C, 64.25; H, 5.41; N, 17.56.
3.6. (R)-1-(α-Furyl)-2-phenylmethoxy-N-tosylethylamine 3c
To LiAlH4 (0.62 g, 0.016 mol) in THF (10 ml) at 0°C was added a solution of 9 (2.38 g, 0.010 mol) in
THF (2 ml) for 0.5 h. After being stirred for 0.5 h, the mixture was warmed up to rt and stirred at rt for 1
h, and then reluxed for 4 h. The reaction was quenched by addition of water. The mixture was filtered and
the filtrate was dried over Na2SO4 and evaporated under reduced pressure to afford a crude oil. To the

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solution of the crude oil in pyridine (15 ml) was added p-toluenesulfonyl chloride (1.95 g, 10.8 mmol)
at 0°C. After being stirred for 0.5 h, 20 ml of water was added. Working up as usual afforded a solid
which was purified by flash column chromatography on silica gel [petroleum ether:ethyl acetate (90:10)]
to afford 3c (3.2 g, 93%) as a solid. M.p. 72–74°C, [α]D20=+7.5 (c=0.6, EtOH); 1H NMR δ: 2.39 (s, 3H,
Ts-CH3), 3.62 (m, 1H), 3.74 (m, 1H), 4.47 (s, 2H, PhCH2), 4.63 (m, 1H), 5.21 (d, 1H, J=7.4 Hz, N-H),
6.13 (d, 1H, J=3.2 Hz, furyl 3-H), 6.21 (dd, 1H, J=1.8, 3.1 Hz, furyl 4-H), 7.18–7.39 (m, 8H), 7.65 (d,
2H, J=8.1 Hz, Ph); IR: 3256 cm−1; MS m/z: 371 (M+), 250 (M+−BnOCH2), 216 (M+−Ts). Anal. calcd
for C20H21NO4S: C, 64.67; H, 5.70; N, 3.77. Found: C, 64.35; H, 5.63; N, 3.47.
3.7. (2R,6S)-1,6-Dihydro-1-tosyl-6-hydroxy-2-phenylmethoxymethyl-3(2H)-pyridinone 10
The procedure was the same as that of our previous paper.18
3.8. (2R,6S)-1,6-Dihydro-1-tosyl-6-ethoxy-2-phenylmethoxymethyl-3(2H)-pyridinone 11
The procedure was the same as that of our previous paper.18
3.9. (2R,3R,6S)-1-Tosyl-6-ethoxy-2-phenylmethoxymethyl-1,2,3,6-tetrahydropyridin-3-ol 12
To a solution of compound 11 (0.971 g, 2.34 mmol) in MeOH (10 ml) was added CeCl3 (0.288 g,
1.17 mmol). NaBH4 (0.267 g, 7.02 mmol) was added in portions at −30°C to the mixture which was then
stirred at the same temperature for 2 h. Water (5 ml) was added at −10°C to the mixture which was filtered.
MeOH was evaporated from the filtrate under reduced pressure and the aqueous residue was extracted
with ethyl acetate. The combined organic layer was washed with brine, dried over Na2SO4 and evaporated
under reduced pressure to afford a crude oil which was purified by flash column chromatography on silica
gel [petroleum ether:ethyl acetate (40:10)] to afford an oil 9 (0.95 g, 97.4%). [α]D20=−34.3 (c=0.53,
EtOH); 1H NMR δ: 1.16–1.26 (m, 3H), 2.41 (s, 3H, CH3 of Ts), 3.64–3.70 (m, 4H), 4.22 (m, 2H), 4.48
(s, 2H, PhCH2), 5.40 (m, 1H), 5.74 (m, 2H), 7.24–7.32 (m, 7H), 7.69 (d, 2H, J=8.3 Hz); IR: 3400 cm−1;
MS m/z: 372 (M+−EtO), 262 (M+−Ts), 155 (Ts), 91 (Bn). Anal. calcd for C22H27NO5S: C, 63.29; H,
6.51; N, 3.35. Found: C, 63.47; H, 6.03; N, 3.07.
3.10. (2R,3R,6S)-1-Tosyl-6-ethoxy-2-phenylmethoxymethyl-1,2,3,6-tetrahydro-3-pyridyl acetate 13
To a solution of compound 12 (0.720 g, 1.73 mmol) in CH2Cl2 (15 ml) were added triethylamine
(0.48 ml, 3.46 mmol) and DMAP (42 mg, 0.346 mmol) at 0°C. After being stirred for 0.5 h, acetic
anhydride (0.33 ml, 3.46 mmol) was added at the same temperature. The mixture was then stirred at
0°C for another 2 h. Water (5 ml) was added and the aqueous layer was extracted with ethyl acetate.
The combined organic layer was washed with brine, dried over Na2SO4 and evaporated under reduced
pressure to afford a crude oil which was purified by flash column chromatography on silica gel [petroleum
ether:ethyl acetate (40:10)] to afford an oil 13 (0.674 g, 86%). [α]D20=−96.1 (c=1.33, EtOH); 1H NMR
δ: 1.16 (t, 3H, J=7.0 Hz, CH3CH2O), 1.84 (s, 3H, AcO), 2.41 (s, 3H, CH3 of Ts), 3.47–3.87 (m, 4H),
4.38–4.57 (m, 4H), 4.75 (d, 1H, J=1.9 Hz), 5.47–5.85 (m, 2H), 7.25–7.30 (m, 7H), 7.76 (d, 2H, J=8.3 Hz,
Ph); MS m/z: 458 (M+−1), 414 (M+−EtO), 155 (Ts), 91 (Bn). Anal. calcd for C24H29NO6S: C, 62.73; H,
6.36; N, 3.04. Found: C, 62.83; H, 6.48; N, 2.64.

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3.11. (2R,3R)-1-Tosyl-2-phenylmethoxymethyl-1,2,3,6-tetrahydro-3-pyridyl acetate 14
To a solution of 13 (200 mg, 0.436 mmol) in 88% formic acid (2 ml) at 0°C was added NaBH4 (49 mg,
1.3 mmol) in portions. After being stirred for 4 h, the mixture was evaporated under reduced pressure
and water (4 ml) was added to the residue. The resulting mixture was extracted with ethyl acetate and the
combined extracts were washed with brine, dried over Na2SO4 and evaporated under reduced pressure to
afford a crude oil which was purified by flash column chromatography on silica gel [petroleum ether:ethyl
acetate (40:10)] to afford an oil 14 (155 mg, 86%). [α]D20=−47 (c=0.67, EtOH); 1H NMR δ: 1.97 (s, 3H,
OAc), 2.38 (s, 3H, Ts-CH3), 3.38–3.57 (m, 3H), 4.07 (m, 1H), 4.33, (d, 1H, J=12.0 Hz, CHaHbPh), 4.45
(d, 1H, J=12.0 Hz, CHaHbPh), 4.76 (m, 1H), 5.30 (m, 1H), 5.54 (m, 1H), 5.71 (m, 1H), 7.20–7.35 (m,
7H), 7.75 (d, 2H, J=8.2 Hz); IR: 1750 cm−1; MS m/z: 414 (M++1), 356 (M+−OAc), 260 (M+−Ts), 294
(M+−CH2OBn). Anal. calcd for C22H25NO5S: C, 63.59; H, 6.06; N, 3.37. Found: C, 63.11; H, 6.03; N,
3.22.
3.12. (2R,3R)-1-Tosyl-4,5-dihydroxy-2-phenylmethoxymethyl-3-piperidyl acetate 15
A 25 ml round bottom flask was charged with tert-butyl alcohol (4 ml), water (4 ml), K3Fe(CN)6
(0.713 g, 2.17 mmol), K2CO3 (0.299 g, 2.17 mmol) and (DHQD)2–PHAL (28 mg, 5% equiv.). After the
resulting mixture was cooled to 0°C, compound 14 (0.300 g, 0.722 mmol) and K2OsO2(OH)4 (13 mg,
5% equiv.) were added to the resulting heterogeneous slurry which was then vigorously stirred at 0°C for
4 h. The reaction was quenched by addition of Na2SO3 (0.270 g, 2.17 mmol) to the mixture and stirred
for 1 h. The salt added caused layer separation. The aqueous layer was separated and extracted with ethyl
acetate (3×25 ml). The combined organic layer was dried over Na2SO4 and concentrated under reduced
pressure to give an oil which was purified by flash column chromatography on silica gel [petroleum
ether:ethyl acetate (20:10)] to afford a mixture of 15 (0.302 g, 93%).
3.13. (2R,3S,4S,5S)-1-Tosyl-3,4,5-triacetoxy-2-phenylmethoxymethyl piperidine 16 and (2R,3S,4R,
5R)-1-Tosyl-3,4,5-triacetoxy-2-phenylmethoxymethyl piperidine 18
To a solution of compound 15 (0.260 g, 0.579 mmol) in CH2Cl2 (10 ml) were added triethylamine
(0.097 ml, 0.70 mmol) and DMAP (7 mg, 0.058 mmol) at 0°C. After being stirred for 0.5 h, acetic
anhydride (0.13 ml, 1.4 mmol) was added at the same temperature. The mixture was then stirred at
0°C for another 2 h. Water (5 ml) was added and the aqueous layer was extracted with ethyl acetate.
The combined organic layer was washed with brine, dried over Na2SO4 and evaporated under reduced
pressure to afford a crude oil which was purified by flash column chromatography on silica gel [petroleum
ether:ethyl acetate (40:10)] to afford an oil 16 (0.220 g, 71%) and 18 (0.054 g, 17%). Compound 16:
[α]D20=+5.9 (c=1.7, EtOH); 1H NMR δ: 1.97, 1.967, 2.009 (s, each 3H, OAc), 2.38 (s, 3H, CH3 of Ts),
3.067 (dd, 1H, J=14.1, 11.5Hz, H6a), 3.634 (dd, 1H, J=11.1, 9.2 Hz, He of CH2OBn), 3.812 (dd, 1H,
J=11.1, 3.1 Hz, Ha of CH2OBn), 3.830 (dd, 1H, J=14.1, 5.4 Hz, H6e), 4.431, 4.523 (ab, 2H, J=12 Hz,
CH2Ph), 4.661 (ddd, 1H, J=9.2, 6.5, 3.1 Hz, H2a), 4.687 (ddd, 1H, J=11.5, 5.4, 2.7 Hz, H5a), 4.846 (dd,
1H, J=6.5, 2.7 Hz, H3e), 5.441 (dd, 1H, J=2.7, 2.6 Hz, H4e), 7.223, 7.810 (d, each 2H, J=8.4 Hz, each Ts-
aromatic), 7.259–7.343 (m, 5H, benzyl-aromatic) (their assignments were made by COSY and NOESY
spectrum run at 600 MHz NMR); IR: 1750 cm−1; MS m/z: 378 (M+−Ts), 426 (M+−BnO), 155 (Ts), 91
(Bn). Anal. for (C26H31NO9S) calcd: C, 58.52; H, 5.85; N, 2.62; found: C, 58.43; H, 5.94; N, 2.09. 18:
[α]D20 +33.4 (c=0.3, EtOH); 1HNMR δ (ppm): 1.85 (s, 3H, AcO), 1.93 (s, 3H, AcO), 1.97 (s, 3H, AcO),
2.39 (s, 3H, CH3 of Ts), 3.65 (d, 1H, J=3.2 Hz), 3.69 (d, 1H, J=14.9 Hz), 3.93 (d, 1H, J=14.9 Hz), 4.37

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(d, 1H, J=12.2 Hz), 4.51 (d, 1H, J=12.2 Hz), 4.53 (m, 2H), 5.19 (m, 2H), 5.63 (dd, 1H, J=3.4, 10.9 Hz),
7.25–7.37 (m, 7H), 7.74 (d, 2H, J=8.3 Hz); IR: 1750 cm−1; MS m/z: 378 (M+−Ts), 426 (M+−BnO), 155
(Ts), 91 (Bn). Anal. calcd for C26H31NO9S: C, 58.52; H, 5.85; N, 2.62. Found: C, 58.34; H, 5.90; N,
2.06.
3.14. (2R,3S,4S,5S)-1-Tosyl-3,4,5-triacetoxy-2-hydroxymethyl piperidine 17
To a solution of 16 (0.110 g, 0.210 mmol) in ethyl acetate (15 ml) was added 10% Pd on carbon (0.100
g), and the mixture was placed under an atmosphere of H2 and stirred at rt. After 8 h, the reaction mixture
was filtered and the solvent was removed under reduced pressure to give a crude oil which was purified
by flash column chromatography on silica gel [petroleum ether:ethyl acetate (10:10)] to afford 17 (0.076
g, 82%) as an oil. [α]D20=−4.0 (c=2.0, EtOH); 1H NMR δ: 1.85 (s, 3H, AcO), 1.96 (s, 3H, AcO), 2.06
(s, 3H, AcO), 2.43 (s, 3H, Ts-CH3), 3.49 (m, 1H), 3.62 (dd, 1H, J=1.6, 13.8 Hz), 3.88 (m, 1H), 3.98–4.04
(m, 1H), 4.49 (m, 1H), 5.21 (m, 1H), 5.24 (dd, 1H, J=4.5, 6.4 Hz), 5.30 (dd, 1H, J=3.4, 7.6 Hz), 7.34 (d,
2H, J=8.3 Hz) 7.80 (d, 2H, J=8.3 Hz); IR: 3500, 1750 cm−1; MS m/z: 444 (M++1), 426 (M++1−H2O),
412 (M+−CH2OH). HRMS (M+−CH2OH) for C18H22NO8S: calcd: 412.1075; found: 412.1066.
3.15. (2R,3S,4R,5R)-1-Tosyl-3,4,5-triacetoxy-2-hydroxymethyl piperidine 19
To a solution of 18 (0.150 g, 0.281 mmol) in ethyl acetate (15 ml) was added 10% Pd on carbon (0.120
g), and the mixture was placed under an atmosphere of H2 and stirred at rt. After 6 h, the reaction mixture
was treated in the way as described for 17 to afford 19 (0.105 g, 84%) as an oil. [α]D20=+36.2 (c=2.5,
EtOH); 1H NMR δ: 1.99 (s, 3H, AcO), 2.04 (s, 3H, AcO), 2.09 (s, 3H, AcO), 2.45 (s, 3H, Ts-CH3), 3.27
(m, 1H), 3.76 (dd, 1H, J=2.0, 10.1 Hz), 4.12 (dd, 1H, J=7.2, 14.3 Hz), 4.32 (m, 1H), 4.52 (m, 1H), 4.58
(dd, 1H, J=2.7, 6.6 Hz), 5.36 (t, 1H, J=2.7 Hz), 7.38 (d, 2H, J=8.3 Hz, Ph), 7.84 (d, 2H, J=8.3 Hz, Ph);
IR: 3500, 1750 cm−1; MS m/z: 444 (M++1), 426 (M++1−H2O), 412 (M++1−CH2OH). Anal. calcd for
C19H25NO9S: C, 51.45; H, 5.68; N, 3.15. Found: C, 51.27; H, 5.57; N, 2.75.
3.16. (2R,3S,4S,5S)-3,4,5-Trihydroxy-2-hydroxymethyl piperidine 20
To the liquid ammonia (15 ml) at −78°C was added 17 (0.060 g, 0.135 mmol) (dissolved in 5 ml of
THF) and sodium to keep the solution a blue color. After being stirred for 3.5 h, the sat. NH4Cl was
added. Warming up to rt under N2, liquid ammonia was evaporated. The residue was purified by column
chromatography on ion exchange resin (Dowex 50) to afford a colorless solid 20 (9 mg, 41%). M.p.:
148–149.6°C; [α]D20=−16.2 (c=0.3, EtOH); 1H NMR δ (D2O): 3.07 (dd, 1H, J=4.7, 7.1 Hz), 3.33 (dd,
1H, J=4.7, 7.1 Hz), 3.64 (m, 1H), 3.98–4.15 (m, 2H), 4.33 (m, 1H), 4.42 (m, 1H), 4.60 (m, 1H); IR: 3500
cm−1; MS (ESI) m/z: 164 (M+H), 186 (M+Na).
3.17. (2R,3S,4R,5R)-3,4,5-Trihydroxy-2-hydroxymethyl piperidine 21
To the liquid ammonia (15 ml) at −78°C was added 19 (0.080 g, 0.135 mmol) (dissolved in 5 ml
of THF) and sodium to keep the solution a blue color. The reaction solution was treated in the way as
described for 20 to afford a colorless solid 21 (12 mg, 41%). M.p. 150–151°C; [α]D20=+30.4 (c=0.3,
1
EtOH); H NMR δ (ppm) (D2O): 2.79 (m, 1H), 2.95 (dd, 1H, J=4.8, 12.3 Hz), 3.10 (dd, 1H, J=8.9,
8.4Hz), 3.61–3.66 (m, 2H), 3.92–4.01 (m, 3H); IR: 3500 cm−1; MS (ESI) m/z: 164 (M+H), 186 (M+Na).

L.-X. Liao et al. / Tetrahedron: Asymmetry 10 (1999) 3649–3657
3657
Acknowledgements
Project (29732061) supported by the National Natural Science Foundation of China. We thank Prof.
Hou-Ming Wu and Prof. Xing-Xiang Xu for their valuable discussions for 1H NMR. We also thank Prof.
Li-Jun Xia and Min-Hua Tang for performing the HPLC analysis.
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