Synthesis of a new family of aminocyclitols from D-(-)-quinic acid

Article abstract of DOI:10.1080/00397910802281429

In continuation of our interest in the synthesis of glycosidase inhibitors, we report herein an efficient synthesis of three new polyhydroxylated amino cyclohexane derivatives (aminocyclitols) that may potentially possess important biological activities. The key step involved the highly stereoselective dihydroxylation of protected azido cyclohexene derivatives 5, 9, and 15, which were easily red from D-(-)-quinic acid. The subsequent hydrogenation step was conducted under acidic conditions to provide the target molecules in an efficient manner with high overall yields. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910802281429

This article was downloaded by: [University of York]
On: 19 August 2014, At: 14:34
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954
Registered office: Mortimer House, 37-41 Mortimer Street, London W1T 3JH,
UK
Synthetic Communications: An
International Journal for Rapid
Communication of Synthetic
Organic Chemistry
Publication details, including instructions for
authors and subscription information:
http://www.tandfonline.com/loi/lsyc20
Synthesis of a New Family
of Aminocyclitols from D-(-)-
Quinic Acid
Tzenge-Lien Shih a , Heng-Yi Li a , Ming-Shin Ke a &
Wei-Shen Kuo a
a Department of Chemistry, Tamkang University,
Tamsui, Taipei County , Taiwan, China
Published online: 31 Oct 2008.
To cite this article: Tzenge-Lien Shih , Heng-Yi Li , Ming-Shin Ke & Wei-Shen Kuo
(2008) Synthesis of a New Family of Aminocyclitols from D-(-)-Quinic Acid, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic
Organic Chemistry, 38:23, 4139-4149, DOI: 10.1080/00397910802281429
To link to this article: http://dx.doi.org/10.1080/00397910802281429
PLEASE SCROLL DOWN FOR ARTICLE
Taylor & Francis makes every effort to ensure the accuracy of all the
information (the “Content”) contained in the publications on our platform.
However, Taylor & Francis, our agents, and our licensors make no
representations or warranties whatsoever as to the accuracy, completeness,
or suitability for any purpose of the Content. Any opinions and views
expressed in this publication are the opinions and views of the authors, and
are not the views of or endorsed by Taylor & Francis. The accuracy of the
Content should not be relied upon and should be independently verified with
primary sources of information. Taylor and Francis shall not be liable for any

losses, actions, claims, proceedings, demands, costs, expenses, damages,
and other liabilities whatsoever or howsoever caused arising directly or
indirectly in connection with, in relation to or arising out of the use of the
Content.
This article may be used for research, teaching, and private study purposes.
Any substantial or systematic reproduction, redistribution, reselling, loan,
sub-licensing, systematic supply, or distribution in any form to anyone is
expressly forbidden. Terms & Conditions of access and use can be found at
http://www.tandfonline.com/page/terms-and-conditions

Synthetic Communications1, 38: 4139–4149, 2008
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910802281429
Synthesis of a New Family of Aminocyclitols
from D-(-)-Quinic Acid
Tzenge-Lien Shih, Heng-Yi Li, Ming-Shin Ke, and Wei-Shen Kuo
Department of Chemistry, Tamkang University, Tamsui, Taipei County,
Taiwan, China
Abstract: In continuation of our interest in the synthesis of glycosidase inhibitors,
we report herein an efficient synthesis of three new polyhydroxylated amino
cyclohexane derivatives (aminocyclitols) that may potentially possess important
biological activities. The key step involved the highly stereoselective dihydroxyla-
tion of protected azido cyclohexene derivatives 5, 9, and 15, which were easily red
from D-(-)-quinic acid. The subsequent hydrogenation step was conducted under
acidic conditions to provide the target molecules in an efficient manner with high
overall yields.
Keywords: Aminocyclitol, dihydroxylation, quinic acid
INTRODUCTION
The cyclic polyhydroxylated amines, also known as aminocyclitols,
possess a wide variety of biological activities.[1] These sugar-mimetic com-
pounds have collected much interest because they were not only consid-
ered as glycosidase inhibitors but also constituted a key segment of
aminoglycoside antibiotics.[2] There were few cases reported in the synth-
esis of these quercitol-like aminocyclitols. Their synthetic tactics were
mainly based on either the chiral pool or enantioselestive approaches.[3]
During the past few years, we had experience in the synthesis of
quercitols.[4] Quercitols have been reported in possession of biological
Received February 26, 2008.
Address correspondence to Tzenge-Lien Shih, Department of Chemistry,
Tamkang University, Tamsui, Taipei County, Taiwan 25137, China. E-mail:
tlshih@mail.tku.edu.tw
4139

4140
T.-L. Shih et al.
properties against certain enzymes.[5] Because of the structural similarity
between quercitols and aminocyclitols, compounds 4, 7, and 13 were used
as intermediates in our synthesis of the title molecules (vide infra). The
subsequent steps were highly stereoselective dihydroxylation and depro-
tection to successfully synthesize three new aminocylitols (1, 2, and 3)
in a very efficient manner.
RESULTS AND DISCUSSION
We envisioned the synthesis of aminocyclitols 1, 2, and 3 in Schemes 1
and 2. Our strategy began with the azido 5, which was prepared from 4
based on the literature procedure.[6] Compound 5 was subject to dihy-
droxylation under KMnO4=MgSO4 reaction condition,[7] to provide a
highly diastereoselective adduct 6 as the only isolated product in 60%
yield. The resulting stereochemistry of 6 was then determined by coupling
constants, correlation spectroscopy (COSY) and nuclear Overhauser
effect spectroscopy (NOESY) experiments (Fig. 1a). This result was
Scheme 1. Synthesis of aminocyclitols 1 and 2 from D-(-)-quinic acid. Reagents
and conditions: (a) KMnO4 (2 equiv.)=MgSO4 (2 equiv.), EtOH=H2O¼6=1
(v=v); (b) H2, Pd=C, MeOH=2N HCl; (c) CCl3CN, DBU, CH2Cl2; (d) xylene,
reflux; (e) LiOH (3 equiv.), MeOH=H2O; (f) K2CO3, MeOH; (g) 6 N HCl.

Aminocyclitol Synthesis
4141
Figure 1. Coupling constants account for the determination of stereochemistry of
dihydroxylation of 5, 9, and 15.
consistent with our previous observation in dihydroxylation of 4 in which
the resulting stereochemistry of diol was trans relationship to the C5
hydroxyl group.[4] Compound 6 was further hydrogenated over Pd=C
under acidic conditions to afford the desired aminocyclitol 1 in 85% yield.
Compound 7 was treated with trichloroacetonitrile and 1,8-diazabi-
cyclo[5.4.0]undec-7-ene (DBU) to afford 8 in 86% yield after simple pur-
ification of this mixture. Compound 8 subsequently underwent Overman
rearrangement[8] under refluxing conditions in xylene to afford 9 in 90%
yield. Then compound 9 was subject to the same dihydroxylation condi-
tion to isolate the sole stereoisomer 10 in 65% yield (the resulting stereo-
chemistry as indicated in Fig. 1b). No minor diasteromer was isolated
from column chromatography or detected by NMR at this stage. The tri-
chloroacyl and cyclohexyl groups of 10 were then removed by sequential
treatment of base and acid, respectively. In an attempt to deprotect tri-
chloroacetamide by using K2CO3 at ambient temperature,[9] the stable
oxazolidinone 11 was formed as the major product. However, lithium
hydroxide (3 equiv.) was used under refluxing condition for 4 h and fol-
lowed by acidification with 6 N HCl, sequentially, to give 2 in 70% yield.
Compound 13 was treated with methanesulfonyl chloride and
triethyl amine to give 14 (Scheme 2). When compound 14 was heated with
sodium azide along with a catalytic amount of 15-crown-5, the unex-
pected compound 15 was received instead of the expected compound
16. The mechanism was followed a SN20 pathway and rationalized as indi-
cation in Fig. 2. Dihydroxylation of 15 gave a highly diastereoselective
and inseparable mixture based on the analysis of NMR spectrum.
Separation of these two isomers from this mixture was tried in their
acetylation. Fortunately, the major isomer 18 was isolated from this mix-
ture in 70% yield. Its stereochemistry was clearly determined by NMR
studies (Fig. 1c). This result indicated that the dihydroxylation of 15

4142
T.-L. Shih et al.
Scheme 2. Synthesis of aminocyclitol 3 from D-(-)-quinic acid. Reagents and con-
ditions: (a) MsCl, CH2Cl2, Et3N; (b) NaN3, DMF, 15-crown-5 (cat); (c)
KMnO4=MgSO4 then Ac2O, pyr., and (d) H2=Pd=C, 6 N HCl=MeOH.
was conducted in an anti relationship relative to the azido group to give
mainly 17. The acetylated minor isomer did not show from column
chromatography because of the very tiny amount. Although the stereose-
lectivity was not exclusive, this result was still consistent with our pre-
vious case[4] in dihydroxylation of 13, which gave moderate selectivity
depending on the different protecting groups used (Fig. 3). Compound
18 was then subjected to hydrogenation under acidic conditions (6N
HCl) to afford the resulting aminocyclitols 3 in 85% yield. With com-
pounds 1, 2, and 3 in hand, we tried to utilize of 17 to synthesize a piper-
idine derivative 19 based on our previous strategy[6] (Scheme 3).
Unfortunately, no aminocyclization product 20 was received, and only
the reducing product 21 was obtained.
Figure 2. The plausible mechanism of synthesis of 15.

Aminocyclitol Synthesis
4143
Figure 3. Steric effect accounts for the highly diastereoselective dihydroxylation
of 15.
CONCLUSION
In conclusion, we have demonstrated a general route and successfully
synthesized three new aminocyclitols (1, 2, and 3 )from D-(-)-quinic acid
in a facile manner. Dihydroxylation of 5 and 9 is highly diastereoselective
in accordance with our previous observations. These compounds will be
used for biological studies and may be readily served as intermediates for
synthesis of antibiotics.
EXPERIMENTAL
Optical rotations were measured on a Horiba Sepa-300. Melting
points were determined by Fargo MP-2D and are uncorrected.
1H and 13C NMR spectra were recorded on either Bruker 300- or
600-MHz instruments. Chemical shifts were reported in parts per mil-
lion(ppm) relative to the residual of solvents used [CDCl3: 7.26 ppm
(1H); 77.0 ppm (13C); CD3OD: 4.78 ppm (1H): 49.0 ppm (13C); D2O:
4.69 ppm (1H)].
Scheme 3. Attempt at the synthesis of a piperidine derivative 20. Reagents and
conditions: (a) H2, Pd=C, MeOH then CbzCl, NaHCO3, 1,4-dioxane; (b) NaIO4,
MeOH; (c) NaBH3 CN, AcOH, MeOH; and (d) H2, Pd=C, 6 N HCl.

4144
T.-L. Shih et al.
(1R,2R,3R,4R,5S)-5-Azido-1,2-O-cyclohexylidene-cyclohexane-1,2,3,4-
tetrol (6)
Compound 5 (0.280 g, 1.2 mmol) in EtOH (6 mL) was added dropwise to
KMnO4 (0.370 g, 2.4 mmol) and MgSO4 (0.289 g, 2.4mmol) in H2O
(1 mL) solution at 0 ꢀC. The mixture was allowed to warm up to ambient
temperature and stirred for 8 h, at the end of which time the mixture was fil-
tered through Celite1 and washed with EtOAc. The organic solvent was
removed, diluted with H2O, and extracted with EtOAc. The organic layer
was dried over MgSO4 and purified by flash column chromatography
(230–400 mesh SiO2, EtOAc=hexane ¼ 1=4–1=1) to afford 6 (0.194 g, 60%)
24
1
as a pale yellow syrup. ½aꢁD þ 92.4 (c 0.6, MeOH). H NMR (600MHz,
CD3OD) d 4.33 (dd, J¼ 11.7, 5.5 Hz, 1H), 4.13 (dd, J ¼ 5.5, 3.8 Hz, 1H),
3.96 (dd, J ¼ 3.8, 2.8 Hz, 1H), 3.74 (dd, J ¼ 8.0, 2.8 Hz, 1H), 3.65 (ddd,
J¼ 13.5, 8.0, 5.6 Hz, 1H), 2.25 (dt, J ¼ 14.5, 5.6Hz, 1H), 1.77 (dt,
J¼ 14.5, 6.9 Hz, 1H), 1.70–1.62 (m, 4H), 1.60–1.54 (m, 4H), 1.43–1.37 (m,
2H). 13C NMR (150 MHz, CD3OD) d 110.7, 79.0, 73.0, 72.9, 71.8, 60.2,
39.2, 35.9, 32.2, 26.3, 25.2, 24.9. ESI-HRMS calcd. for C12H19N3NaO4
[M þ Na]þ 292.1273. Found: 292.1268.
(1R,2S,5R)-5-[(2,2,2-Trichloroethanimidoyl)oxy]-1,2-O-
cyclohexylidene-3-cyclohexene-1,2,5-triol (8)
DBU (3.60 mL, 23.0 mmol) and trichloroacetonitrile (2.40 mL, 23.0 mmol)
were added to a solution of 7 (2.50 g, 11.85 mmol) in CH2Cl2 (50 mL)
at 0 ꢀC and stirred at ambient temperature for 9 h, at the end of which time
the mixture was diluted with NaHCO3 (saturated) and extracted with
CH2Cl2. The organic layer was dried over MgSO4 and purified by flash col-
umn chromatography (230–400 mesh SiO2, CH2Cl2=hexane ¼ 1=5 to 1=3) to
25
afford 8 (3.60 g, 86%) as a white solid. Mp ¼ 79.5–80 ꢀC. ½aꢁD þ83.1 (c 0.42,
1
MeOH). H NMR (300 MHz, CDCl3) d 8.37 (br s, 1H), 6.02 (dd, J ¼ 10.2,
2.2 Hz, 1H), 5.90 (ddt, J¼ 11.3, 4.2, 1.4 Hz, 1H), 5.63–5.52 (br m, 1H), 4.55–
4.45 (m, 2H), 2.58 (dt, J ¼ 13.6, 4.8 Hz, 1H), 1.97 (ddd, J ¼ 13.6, 8.5, 2.5 Hz,
1H), 1.60 (br s, 8H), 1.37 (br s, 2H). 13C NMR (75MHz, CDCl3) d 161.9,
129.4, 128.5, 109.6, 91.4, 71.7, 71.4, 70.7, 37.5, 35.7, 30.8, 25.0, 24.0, 23.8.
HRMS (FAB) calcd. for C14 H18Cl3NO3 [M]þ 353.0352. Found: 353.0339.
(1R,2S,3R)-3-[(2,2,2-Trichloroacetyl)amino]-1,2-O-cyclohexylidene-4-
cyclohexene-1,2-diol (9)
A solution of 8 (0.192 g, 0.543 mmol) in xylene (10 mL) was heated to reflux
at 150 ꢀC for 48 h, at the end of which time the organic solvent was removed

Aminocyclitol Synthesis
4145
under the reduced pressure, and the resulting mixture was purified by flash
column chromatography (230–400 mesh SiO2, CH2Cl2=hexane ¼ 1=5 to
1=3) to afford 9 (0.172g, 90%) as a white solid. Mp¼ 113.0–113.5 ꢀC.
26
1
½aꢁD ꢂ 97.7 (c 0.65, MeOH). H NMR (300 MHz, C6D6) d 6.40–6.25 (br s,
1H), 5.45–5.35 (m, 2H), 4.37–4.27 (m, 1H), 4.03–3.95 (m, 1H), 3.76
(t, J¼ 6.3 Hz, 1H), 2.15–2.06 (m, 2H), 1.80–1.68 (m, 2H), 1.68–1.42
(m, 6H), 1.31–1.11 (m, 2H). 13C NMR (75 MHz, C6D6) d 162.3, 128.2,
127.5, 110.0, 93.9, 77.3, 72.0, 53.0, 38.4, 35.6, 29.0, 26.1, 25.0, 24.7. HRMS
(FAB) calcd. for C14H18Cl3NO3 [M]þ 353.0352. Found: 353.0338.
(1R,2S,3R,4S,5R)-3-[(2,2,2-Trichloroacetyl)amino]-5,6-O-
cyclohexylidene-cyclohexane-1,2,4,5-tetrol (10)
Flash column chromatography (230–400 mesh SiO2, EtOAc=hexane ¼ 1=4
to 1=2) afforded 10 as a white solid in 65% yield. Mp¼ 165.0–165.5 ꢀC.
23
1
½aꢁD ꢂ 148.3 (c 1.2, MeOH). H NMR (600 MHz, CD3OD) d 4.32 (ddd,
J¼ 8.8, 4.9, 2.9 Hz, 1H), 4.19 (dd, J ¼ 8.6, 4.9 Hz, 1H), 3.96 (dd, J ¼ 8.6,
2.3 Hz, 1H), 3.92 (ddd, J ¼ 10.2, 5.9, 2.0Hz, 1H), 3.82 (t, J¼ 2.1 Hz, 1H),
2.14–2.04 (br m, 2H), 1.70–1.63 (m, 2H), 1.62–1.56 (m, 2H), 1.56–1.50 (m,
4H), 1.40–1.32 (br m, 2H). 13C NMR (150 MHz, CD3OD) d 164.2, 110.7,
94.1, 76.2, 74.5, 73.4, 68.3, 57.2, 39.3, 36.6, 30.3, 26.3, 25.2, 24.9. ESI-HRMS
calcd. for C14H20Cl3NNaO5 [Mþ Na]þ 410.0283. Found 410.0299.
(1R,2S,3S,4S,5R)-3-Amino-3-N,2-O-carbonyl-4,5-O-cyclohexylidene-
cyclohexane-1,2,4,5-tetrol (11)
Flash column chromatography (230–400 mesh SiO2, EtOAc=hexane ¼ 1=1)
afforded 11 in 57% yield as a white solid. Mp ¼ 200 ꢀC (decomposed)
26
1
½aꢁD þ 13.8 (c 0.15, MeOH). H NMR (300MHz, CDCl3) d 6.08 (br s,
1H), 4.85 (dd, J¼ 8.8, 3.7 Hz, 1H), 4.53–4.47 (m, 1H), 4.27–4.14 (m, 2H),
2.60–2.41 (br s, 1H), 2.08 (ddd, J ¼ 14.4, 10.4, 5.4 Hz, 1H), 1.79 (dt,
J¼ 14.4, 2.5 Hz, 1H), 1.75–1.50 (m, 8H), 1.39 (br s, 2H). 13C NMR
(75 MHz, CDCl3) d 158.8, 109.5, 73.8, 71.6, 63.8, 53.9, 36.7, 33.6, 30.1,
29.9, 25.2, 24.1, 23.7. ESI-HRMS calcd. for C13H20NO5 [M þ H]þ
270.1341. Found: 270.1341.
(1R,2R,5R)-5-Chloro-1,2-[(2S,3S)-2,3-dimethoxybutane-2,3-
diyldioxy]-3-cyclohexene-1,2-diol (14)
Et3N (0.58 mL, 5.73 mmol) and methanesulfonic chloride (0.24 mL,
3.15 mmol) were added sequentially to a solution of 13 (0.345 g,

4146
T.-L. Shih et al.
1.43 mmol) in CH2Cl2 (10 mL) and stirred at ambient temperature for 6 h.
At the end of which time, the mixture was diluted with CH2Cl2 (ꢃ 2) and
washed with saturated NaHCO3 (ꢃ 2). The organic layer was dried over
MgSO4, concentrated, and purified by flash column chromatography
(230–400 mesh SiO2, CH2Cl2=hexane ¼ 1=4 to 1=1) to afford 14
26
(0.368 g, 94%) as a white solid. Mp ¼ 81–84 ꢀC. ½aꢁD þ 292.0 (c 1.3,
1
MeOH). H NMR (300 MHz, CDCl3) d 5.75 (d, J ¼ 10.9 Hz, 1H), 5.71
(d, J ¼ 10.9 Hz, 1H), 4.72 (m, 1H), 4.21 (d, J ¼ 9.0 Hz, 1H), 4.12 (ddd,
J ¼ 12.4, 9.2, 3.7 Hz, 1H), 3.30 (s, 3H), 3.26 (s, 3H), 2.27–2.19 (m, 1H),
2.13 (ddd, J ¼ 14.1, 11.7, 5.0 Hz, 1H), 1.34 (s, 3H), 1.31 (s, 3H). 13C
NMR (75 MHz, CDCl3) d 129.7, 128.3, 100.5, 100.1, 69.4, 64.6, 54.4,
47.9 (ꢃ 2), 35.5, 17.8 (ꢃ 2).
(1R,2R,3S)-3-Azido-1,2-[(2S,3S)-2,3-dimethoxybutane-2,3-diyldioxy]-4-
cyclohexene-1,2-diol (15)
NaN3 (0.250 g, 3.81 mmol) and a catalytic amount of 15-crown-5 were
added to a solution of 14 (0.10 g, 0.380 mmol) in DMF (3.0 mL).
The resulting mixture was heated at 50–60 ꢀC for 12 h, at the end of
which time the mixture was diluted with Et2O and washed with H2O.
The organic solvent was dried over MgSO4 and removed under the
reduced pressure. The resulting mixture was purified by flash column
chromatography (230–400 mesh SiO2, CH2Cl2=hexane ¼ 1=4 to 1=1) to
26
afford 15 (92 mg, 90%) as a white solid. Mp ¼ 53–55 ꢀC. ½aꢁD þ 239.3
(c 3.56, MeOH). 1H NMR (300 MHz, CDCl3) d 5.77–5.67 (m, 1H),
5.46–5.38 (m, 1H), 4.15–4.07 (m, 1H), 3.84 (dt, J ¼ 10.1, 5.9 Hz, 1H),
3.77 (dd, J ¼ 10.1, 8.3 Hz, 1H), 3.34 (s, 3H), 3.27 (s, 3H), 2.38–2.26
(m, 1H), 2.26–2.12 (m, 1H), 1.35 (s, 3H), 1.30 (s, 3H). 13C NMR
(75 MHz, CDCl3) d 127.4, 124.8, 99.5, 99.2, 73.1, 66.0, 61.0, 48.0, 30.0,
17.7. ESI-HRMS calcd for C12H20N3O4 [M þ H]þ 270.1454. Found:
270.1448.
(1R, 2S, 3R, 4R, 5R)-1,2-O-Diacetyl-3-azido-4,5-[(2S,3S)-2,3-
dimethoxybutane-2,3-diyldioxy]-cyclohexane-1,2,4,5-tetrol (18)
Flash column chromatography (230–400 mesh SiO2, EtOAc=
hexane ¼ 1=8) afforded 18 as a white solid in 77% yield. Mp ¼ 82–84 ꢀC.
26
½aꢁD þ 99.1 (c 1.8, MeOH). 1H NMR (600 MHz, CDCl3) d 5.44 (t,
J ¼ 3.0 Hz, H-1), 4.69 (dd, J ¼ 10.4, 3.2 Hz, H-2), 3.98 (ddd, J ¼ 14.5,
10.0, 4.6 Hz, H-5), 3.88 (t, J ¼ 10.4 Hz, H-3), 3.55 (t, J ¼ 10.4 Hz, H-4),
3.23 (s, –OCH3), 3.29 (s, –OCH3), 2.13 (s, –OCOCH3), 2.10

Aminocyclitol Synthesis
4147
(s, –OCOCH3), 2.00 (dt, J ¼ 14.2, 4.0 Hz, H-6), 1.69 (ddd, J ¼ 14.2, 12.6,
2.5 Hz, H-6), 1.38 (s, CH3), 1.31 (s, CH3). 13C NMR (150 MHz, CDCl3) d
169.9, 169.7, 99.9, 99.8, 72.6 (C-4), 72.5 (C-2), 67.7 (C-1), 64.7 (C-5), 60.1
(C-3), 48.1 (–OCH3), 48.0 (–OCH3), 30.5 (C-6), 20.9 (CH3CO–), 20.7
(CH3CO–), 17.6 (CH3), 17.5 (CH3). ESI-HRMS calcd. for C16H25N3O8
[M þ Na]þ 410.1539. Found: 410.1544.
(1R,2R,3R,4R,5S)-5-Aminocyclohexane-1,2,3,4-tetrol (1)
A solution of 6 (0.299 g, 1.02 mmol) in MeOH (1.0 mL) and 2 N HCl
(1.0 mL) was hydrogenated over 10% Pd=C (12 mg, 0.01 mmol) for
48 h. At the end of which time, the mixture was filtrated through
Celite1 and washed with MeOH. The filtrate was concentrated and
washed with Et2O and H2O. The aqueous layer was concentrated and
purified by flash column chromatography (230–400 mesh SiO2,
MeOH=CH2Cl2=10% NH4OH ¼ 2=10=0.5 to 2=3.5=0.5) to afford 1
25
(0.143 g, 85%) as a pale yellow syrup. [a]D ꢂ 44.4 (c 0.05, MeOH).
1H NMR (600 MHz, D2O) d 3.95 (ddd, J ¼ 11.6, 4.3, 3.2 Hz, 1H),
3.92 (t, J ¼ 4.0 Hz, 1H), 3.92–3.87 (br m, 1H), 3.61 (dd, J ¼ 10.0,
2.6 Hz, 1H), 3.06 (ddd, J ¼ 14.2, 11.5, 4.2 Hz, 1H), 1.89 (dt, J ¼ 11.7,
4.3 Hz, 1H), 1.62 (td, J ¼ 11.7, 11.7 Hz, 1H). 13C NMR (150 MHz,
D2O) d 72.0, 71.8, 70.8, 66.0, 48.2, 31.4. ESI-HRMS calcd. for
C6H14NO4 [M þ H]þ 164.0923. Found: 164.0917.
(1R, 2S, 4S, 5R)-3-Aminocyclohexane-1,2,4,5-tetrol (2)
A solution of 10 (0.060 g, 0.154 mmol) in MeOH=H2O [9.0 mL,
(v=v) ¼ 1=8] was treated with LiOH (0.011 g, 0.462 mmol) and heated to
110—120ꢀC for 4 h. The organic solvent was removed under reduced
pressure. The resulting solid was diluted with CH2Cl2 and H2O. The aqu-
eous layer was concentrated to afford 12 (85%) as a white solid. To this
solid was added 6 N HCl and stirred for 12 h. The solution was concen-
trated, and the resulting mixture was purified by flash column chromato-
graphy (230–400 mesh SiO2, MeOH=CH2Cl2=10% NH4OH ¼ 2=10=0.5
to 2=3.5=0.5) to afford 2 as a pale yellow syrup in 70% yield.
[a]D ꢂ 58.1 (c 0.53, MeOH). 1H NMR (600 MHz, D2O) d 4.01 (dt,
24
J ¼ 6.2, 3.0 Hz, 1H), 3.94 (dd, J ¼ 8.1, 2.8 Hz, 1H), 3.92 (dd, J ¼ 4.7,
2.8 Hz, 1H), 3.55 (d, J ¼ 10.5 Hz, 1H), 2.97–2.93 (m, 1H), 1.87–1.82 (m,
1H), 1.80 (ddd, J ¼ 14.5, 12.1, 2.8 Hz, 1H). 13C NMR (150 MHz, D2O)
d 71.8, 70.5, 68.2, 66.0, 51.3, 32.3. ESI-HRMS calcd. for C6H14NO4
[M þ H]þ 164.0923. Found: 164.0871.

4148
T.-L. Shih et al.
(1R,2S,3S,4S,5R)-3-Aminocyclohexane-1,2,4,5-tetrol (3)
Flash-column chromatography (230–400 mesh SiO2, MeOH=
CH2Cl2=10% NH4OH ¼ 2=10=0.5 to 2=3.5=0.5) afforded 3 as a white
24
solid in 85% yield. Mp ¼ 170–180 ꢀC (decomposed). [a]D ꢂ 34.5 (c
1
0.44, MeOH). H NMR (600 MHz, D2O) d 4.02 (dd, J ¼ 6.0, 3.0 Hz,
1H), 3.73 (ddd, J ¼ 13.9, 9.2, 4.8 Hz, 1H), 3.59 (dd, J ¼ 10.5, 3.0 Hz,
1H), 3.29 (dd, J ¼ 9.7, 9.6 Hz, 1H), 3.10 (t, J ¼ 10.5 Hz, 1H), 2.07 (ddd,
J ¼ 14.2, 4.8, 3.9 Hz, 1H), 1.49 (ddd, J ¼ 14.2, 12.0, 2.5 Hz, 1H).
13C NMR (150 MHz, D2O) d 74.4, 71.1, 68.3, 68.1, 54.4, 34.7.
ESI-HRMS calcd. for C6H14NO4 [M þ H]þ 164.0923. Found: 164.0871.
ACKNOWLEDGMENT
We gratefully acknowledge the National Science Council (NSC95-2113-
M-032-004-MY3) and Tamkang University for financial support of
this work. We also thank the National Center for High-Performing
Computing for assistance.
REFERENCES
1. (a) Stutz, A. (Ed.) Iminosugars as Glycosidase Inhibitors; Wiley-VHC:
¨
Weinheim, 1999; (b) Berecibar, A.; Crandjean, C.; Siriwardena, A. Synthesis
and biological activity of natural aminocyclopentitol glycosidase inhibitors:
mannostatins, trehazolin, allosamidins, and their analogues. Chem. Rev.
1999, 99, 779–844.
2. (a) Flatt, P. M.; Mahmud, T. Biosynthesis of aminocyclitol-aminoglycoside
antibiotics and related compounds. Nat. Prod. Rep. 2007, 24, 358–392; (b)
Mahmud, T.; Flatt, P. M.; Wu, X. Biosynthesis of unusual aminocyclitol-
containing natural products. J. Nat. Prod. 2007, 70, 1384–1391.
3. (a) Chakraborty, C.; Vyavahare, V. P.; Dhavale, D. D. Intra-molecular
nitrone-olefin cyclization of D-glucose derived allylic alcohol: Synthesis of
new aminocyclohexitols. Tetrahedron 2007, 63, 11984–11990; (b) Serrano, P.;
ꢀ
Casas, J.; Zucco, M.; Emeric, G.; Egido-Gabas, M.; Llebaria, A.; Delgado,
A. Combinatorial approach to N-substituted aminocyclitol libraries by solu-
tion-phase parallel synthesis and preliminary evaluation as glucocerebrosidase
inhibitors. J. Comb. Chem. 2007, 9, 43–52; (c) Alegret, C.; Benet-Buchholz, J.;
Riera, A. Stereodivergent syntheses of conduramines and aminocyclitols.
Org. Lett. 2006, 8, 3069–3072; (d) Serrano, P.; Llebaria, A.; Delgado, A.
Regio- and stereoselective synthesis of aminoinositols and 1,2-diaminoinosi-
tols from conduritol B epoxide. J. Org. Chem. 2005, 70, 7829–7840; (e) Ogawa,
S.; Asada, M.; Ooki, Y.; Mori, M.; Itoh, M.; Korenaga, T. Design and synth-
esis of glycosidase inhibitor 5-amino-1,2,3,4-cyclohexanetetrol derivatives

Aminocyclitol Synthesis
4149
from (-)-vibo-quercitol. Bioorg. Med. Chem. 2005, 13, 4306–4314; (f) Huang,
F.; Li, Y.; Yu, J.; Spencer, J. B. Biosynthesis of aminoglycosidase antibiotics:
Cloning, expression, and characterization of an aminotransferase involved in
the pathway to
2-deoxystreptamine. Chem. Commun. 2002, 2860–2861; (g) Yu, J.; Spencer, J.
B. Convenient synthesis of 2-deoxy-scyllo-inosose and 2-deoxy-scyllo-
inosamine: Two key intermediates on the biosynthetic pathway to aminoglyco-
side antibiotics. Tetrahedron Lett. 2001, 42, 4219–4221; (h) Trost, B. M.;
Dudash, J. Jr.; Hembre, E. J. Asymmetric induction of conduritols via AAA
reactions: Synthesis of the aminocyclohexitol of hygromycin A. Chem. Eur.
J. 2001, 7, 1619–1629; (i) Marco-Contelles, J.; Pozuelo, C.; Jimeno, M. L.;
´
Martınez, L.; Martınez-Grau, A. 6-Exo free radical cyclization of acyclic car-
bohydrate intermediates: new synthetic route to enantiomerically
´
A
pure polyhydroxylated cyclohexane derivatives. J. Org. Chem. 1992, 57,
2625–2631.
4. Shih, T.-L.; Lin, Y.-L.; Kuo, W.-S. Highly stereoselective and stereospecific
syntheses of a variety of quercitols from D-(-)-quinic acid. Tetrahedron
2005, 61, 1919–1924.
5. McCasland, G. E.; Naumann, M. O.; Durham, L. J. Alicyclic carbohydrates,
XXXV: Synthesis of proto-quercitol: 220-MHz proton spectrum with the
superconducting solenoid. J. Org. Chem. 1968, 33, 4220–4227.
6. Shih, T.-L.; Kuo, W.-S.; Lin, Y.-L. A facile synthesis of a new trihydroxy
piperidine derivative and (þ)-proto-quercitol from D-(-)-quinic acid.
Tetrahedron Lett. 2004, 45, 5751–5754.
7. (a) Gultekin, M. S.; Salamci, E.; Balci, M. A novel and short synthesis of
¨
(1,4=2)-cyclohex-5-ene-triol and its conversion to (ꢄ)-proto-quercitol. Carbo-
hydr. Res. 2003, 338, 1615–1619; (b) Salamci, E.; Secen, H.; Sutbeyaz, Y.;
¨
Balci, M. A concise and convenient synthesis of DL-proto-quercitol and
DL-gala-quercitol via ene reaction of singlet oxygen combined with [2 þ 4]
cycloaddition to cyclohexadiene. J. Org. Chem. 1997, 62, 2453–2457; (c)
Hudlicky, T.; Thorpe, A. Glycoconjugate coupling strategy: Synthesis of a
L-chiro-inositol-gala-quercitol conjugate and the synthesis of (þ)-proto-
quercitol. Synlett 1994, 899–901; (d) Secen, H.; Salamci, E.; Sutbeyaz, Y.;
¨
Balci, M. An efficient and stereospecific synthesis of proto-quercitol. Synlett
1993, 609–610.
8. (a) Berger, D.; Overman, L. E.; Renhove, P. A. Enantioselective total synth-
esis of (þ)-isolaurepinnacin. J. Am. Chem. Soc. 1993, 115, 9305–9306; (b)
Overman, L. E. Mercury (II)- and palladium (II)-catalyzed [3,3]-sigmatropic
rearrangements. Angew. Chem. Int. Ed. Engl. 1984, 23, 579–586.
9. Urabe, D.; Sugino, K.; Nishikawa, T.; Isobe, M. A novel deprotection of
trichloroacetamide. Tetrahedron Lett. 2004, 45, 9405–9407.