Regioselectivity in the ring opening of epoxides for the synthesis of aminocyclitols from D-(-)-quinic acid

Article abstract of DOI:10.3390/molecules17044498

Efficient syntheses of four aminocyclitols are reported. Each synthesis is accomplished in eight steps starting from D-(-)-quinic acid. The key step involves a highly regioselective ring opening of epoxides by sodium azide.

Full text of DOI:10.3390/molecules17044498

Molecules 2012, 17, 4498-4507; doi:10.3390/molecules17044498
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molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Article
Regioselectivity in the Ring Opening of Epoxides for the
Synthesis of Aminocyclitols from D-()-Quinic Acid
Tzenge-Lien Shih * and Shu-Yu Yang
Department of Chemistry, Tamkang University, No151 Yingzhuan Rd, 25137 Tamsui Dist.,
New Taipei City, Taiwan; E-Mail: 699180088@s99.tku.edu.tw
* Author to whom correspondence should be addressed; E-Mail: tlshih@mail.tku.edu.tw;
Tel./Fax: +886-2-8631-5024.
Received: 26 March 2012; in revised form: 9 April 2012 / Accepted: 10 April 2012 /
Published: 16 April 2012
Abstract: Efficient syntheses of four aminocyclitols are reported. Each synthesis is
accomplished in eight steps starting from D-()-quinic acid. The key step involves a highly
regioselective ring opening of epoxides by sodium azide.
Keywords: aminocyclitols; epoxides; glycosidase inhibitors; D-()-quinic acid;
regioselective ring opening
1. Introduction
Aminocyclitols, also known as aminocarbasugars [1], contain at least one amino or substituted
amino moiety in the cyclitols (polyhydroxylated cycloalkanes) [2]. Many natural and synthetic
products containing aminocyclitol scaffolds have shown a variety of biological activities [3,4], such as,
valienamine [5], pancratistatin [6], oseltamivir [7], and voglibose [4] (Figure 1). The synthesis of
biological active aminocyclitols and assessment of their structure and activity relationship have
generated considerable interest in recent years [4,8–17].
Previously, we have synthesized three aminocyclitols from D-()-quinic acid in nine to ten steps via
stereoselective dihydroxylation as a key step [18] (Figure 2). These quercitol-like structures of
aminocyclitols are also called as deoxyinosamines [4]. We described herein an alternative synthesis of
two known aminocyclitols 5 and 6 along with two new aminocyclitols 10 and 11. The synthesis was
accomplished in eight steps via a regioselective ring opening reaction of epoxides.

Molecules 2012, 17
Figure 1. Representative natural or synthetic products containing aminocyclitol moiety.
4499
Figure 2. The previously synthesized aminocyclitols.
OH
NH2
OH
OH
HO
CO2H
OH
OH
OH
OH
9 to 10 steps
OH
HO
NH2
HO
HO
HO
NH2
OH
OH
OH
-()-quinic acid
D
2. Results and Discussion
Unlike the strategy we previously used in the synthesis of aminocyclitols (Figure 2), we started
from the epoxides 1, 2 and 7, which were prepared from D-()-quinic acid in six steps, respectively [19].
When compounds 1 and 2 were treated with sodium azide in DMF under reflux conditions, they
underwent a highly regioselective opening at the C4 position to afford 3 and 4, respectively (Scheme 1).
Scheme 1. Synthesis of aminocyclitols 5, 6, 10 and 11.
Reagents and conditions: (i) NaN3, DMF, 15-crown-5 (cat), reflux; (ii) (a) H2/Pd/C (b) 80% TFA.

Molecules 2012, 17
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The yields were mediocre but no other regioisomers were detected by TLC or isolated from column
purification [20]. Interestingly, the TMB-protected compound 7 was treated with NaN3 to afford 8 in
71% yield and its epimer 9 in 14% yield. The azide directly attacked the least hindered side of 7 at the
C4 position to give 8. However, a plausible mechanism for the formation of the minor component 9
results from the C5 hydroxide group of 7 being attacked at the C4 position to give intermediate 12a
(Figure 3).
Figure 3. Plausible mechanism for the formation of 9.
-
N3
H
O
OH
O
O
H3O+
N3
N3
HN3
NaN3
H
O
O-
O
O
O-
MeO
O
OH
MeO
O
O
MeO
O
MeO
O
O
OMe
OMe
OMe
OMe
9
12a
12b
7
Instead of attack at the least hindered side at the C5 position of 12a by azide, known as the Payne
rearrangement [21], the hydroxide group at C3 of 12a internally removed the proton of HN3
(intermediate 12b). That allowed the resulting azide to attack the vicinal C4 position of 12b to give 9.
This resulted in the retention of configuration of epoxide 7. This observation was very unusual and in
contrast to the results that occurred in the 2,3-epoxy rearrangement [22]. Based on the Chem3D
simulation, the cyclohexane core of 7 was in a boat-like conformation (Figure 4). The trans-diaxial
attack at C4 in 7 by azide leading to 8 as the major compound was energetically favorable. However,
we could not rule out the possibility in formation of 12a which was derived from the trans-axial attack
of the epoxide by C5-OH in 7. The lower yield of 9 was probably due to the half-chair like structure
12a that was less favorable than 7 for allowing by azide attack (Figure 4).
Figure 4. Three-dimensional representations of structures 7 and 12a.
7
12a
The Payne rearrangement of epoxide 7 intrigued us as an interesting issue when no rearrangement
product 13 was found when compound 1 was treated with NaN3 (Figure 5). According to the Chem3D
simulation, the conformation of cyclohexane core of 1 is a slightly twisted boat form. However,

Molecules 2012, 17
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compound 13 was in a boat conformation if the Payne rearrangement occurred. The reason was
probably due to the steric congestion in the formation of 13 because the distance between epoxide and
the C2 acetal oxygen atom of 13 is around 3.054 Å. On the contrary, the distance between the C5-OH
and C2 oxygen atom of 1 is about 3.328 Å. Therefore, the trans-diaxial attack at C4 of 1 by azide
might be kinetically or sterically controlled to lead to the major component 3.
Figure 5. Three-dimensional representations of structures 1 and 13.
-
N3
H
O
O
O
O
OH
O
H N3
O
O
13
1
1
13
In order to obtain better yields of final products 5, 6, 10, and 11, we determined that azido
compounds 3, 4, 8, and 9 should be hydrogenated first over Pd/C, followed by deprotection under
acidic conditions. The one pot reaction conditions (H2/Pd/C/HCl) afforded low yields of target
compounds accompanied by a more complicated mixture. It is worth noting that our strategy was much
shorter than the reported method in the syntheses of molecules 5 and 6 which involved sixteen steps
starting from D-mannitol [23]. The structure determinations were based on a series of NMR
experiments (COSY, 2D-NOESY, HMBC, HMQC, and HRMS) and the selected NMR data were listed
on Tables 1 and 2.
Table 1. Selected 1H (600 MHz) and 13C (150 MHz) NMR data for 3, 4, 8, and 9 in CD3OD.

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Table 1. Cont.
Compound
3
H1 (J)/C1
H2 (J)/C2
H3 (J)/C3
H4 (J)/C4
H5 (J)/C5
H6 (J)/C6
4.33–4.30 (m) 3.92 (dd, 7.0,
4.04–4.01 (m) 3.21 (dd, 10.0, 4.07–4.04 (m)
2.25 (dt, 15.7,
3.6) 1.93 (ddd,
15.7, 7.1, 3.7)
32.1
74.7
5.3) 81.4
69.3
2.7) 86.8
71.9
4
4.30 (dt, 6.5,
2.3) 74.1
3.89 (dd, 7.6, 3.38 (dd, 10.4,
3.04 (t, 10.2)
71.5
3.62 (td, 11.2,
4.9) 68.6
2.34 (ddd, 14.9,
4.9, 2.2) 1.75
(ddd, 14.9, 11.5,
4.1) 34.1
5.2) 81.0
7.6) 76.1
8
9
3.88 (ddd,
11.6, 10.1,
4.7) 65.3
3.95 (dd, 10.0,
3.4) 71.1
3.85 (t, 3.5)
64.5
3.79 (t, 3.0)
72.5
3.74 (ddd,
1.79–1.74 (m)
11.6, 5.2, 3.0) 1.71 (t, 11.6) 32.8
67.6
3.51–3.40 (m) 3.78 (tm, 9.5,
66.1 0.8) 75.0
3.32 (td, 9.4,
0.8) 72.3
3.13 (td, 9.5,
1.7) 73.0
3.45–3.42 (m)
69.7
2.01 (dt, 12.1,
4.6) 1.51 (ddd,
13.3, 12.3, 1.4)
36.3
Table 2. Selected 1H (600 MHz) and 13C (150 MHz) NMR data for 5, 6, 10, and 11 in D2O.
Compound
5
H1 (J)/C1
4.03 (dd, 6.3,
3.1) 70.0
H2 (J)/C2
3.45 (dd, 9.4,
2.8) 73.8
H3 (J)/C3
3.90 (t, 9.8)
67.2
H4 (J)/C4
3.12 (d, 10.3,
3.2) 56.7
H5 (J)/C5
4.09 (dd, 6.5,
3.2) 66.9
H6 (J)/C6
2.08 (dt, 15.6,
3.5) 1.70 (dt,
15.6, 2.9) 32.6
1.98 (dt, 14.0,
4.2) 1.47 (td,
14.0, 2.5) 36.3
1.85 (td, 13.1,
4.1) 1.75–1.62
(m) 32.9
6
3.96–3.94 (m) 3.41–3.34 (m)a 3.41–3.34 (m)a
68.3 73.9 71.7
2.53 (t, 9.8)
59.4
3.59 (ddd,
14.5, 10.0,
4.6) 67.6
10
11
3.91 (dt, 9.1, 3.75–3.65 (m)a 3.75–3.65 (m)a
3.12 (t, 4.0)
52.6
3.75–3.65 (m)a
3.5) 67.0
68.3
67.2
72.1
3.39 (ddd,
11.9, 9.4, 4.6)
68.6
3.15 (t, 9.3)
77.0
2.99 (t, 9.6)
74.0
2.49 (d, 9.8)
58.8
3.30 (td, 11.4,
4.4) 68.7
2.06 (dt, 12.2,
4.5) 1.35 (dd,
11.9, 11.9) 68.6
a Assignments were not well resolved due to signal overlaps.
3. Experimental
3.1. General Methods
13
1H (600 MHz) and C-NMR (150 MHz) spectra were recorded on a Bruker 600 MHz instrument.
The chemical shifts were reported in ppm and relative to the residual of d-solvents: CD3OD (1H,

Molecules 2012, 17
4503
4.78 ppm; 13C, 49.0 ppm); D2O (4.69 ppm). Optical rotations were measured with a HORIBA
SEPA-300 instrument. HRMS were measured by a Finnigan MAT 95S spectrometer.
3.2. General Procedure of Ring Opening
Compound 1 (0.838 g, 4.0 mmol), for example, was dissolved in DMF (30 mL). To this mixture
was added NaN3 (2.3 g, 36.0 mmol) and a catalytic amount of 15-crown-5 and heated under reflux for
56 h. At the end of the reaction time, the mixture was diluted with H2O (100 mL) and extracted with
Et2O (2x100 mL). The organic layer was dried (MgSO4) and purified by column chromatography.
3.3. General Procedures of Hydrogenation and Deprotection
Compound 3 (0.079 g, 0.29 mmol) for example, was dissolved in MeOH (2 mL). To this mixture
was added 10% Pd/C (10 mol%) and it was hydrogenated under one atmosphere at ambient
temperature for 2 h. The resulting mixture was filtrated through a pad of Celite and washed with
MeOH. The organic layer was concentrated and 80% TFA was added (2 mL), then stirred for 11.5 h, at
the end of which time, the solvent was evaporated and the residue purified by column chromatography.
3.4. Synthesis of the Key Intermediates and the Target Molecules
3.4.1. (1R,2R,3R,4S,5S)-4-Azido-1,2-O-cyclohexylidene-cyclohexane-1,2,3,5-tetraol (3)
Purification by flash column chromatography (230–400 mesh SiO2, EtOAc/hex = 1/81/2) afforded
25
1
a white solid. Yield = 67%. MP = 122128 °C. []D +36.2 (c 0.31, MeOH). H-NMR (CD3OD) 
4.56 (s, 2H, -OH), 4.334.30 (m, 1H), 4.074.04 (m, 1H), 4.044.01 (m, 1H), 3.92 (dd,
J = 7.0, 5.3 Hz, 1H), 3.21 (dd, J = 10.0, 2.7 Hz, 1H), 2.25 (dt, J = 15.7, 3.6 Hz, 1H), 1.93 (ddd,
13
J = 15.7, 7.1, 3.7 Hz, 1H), 1.721.54 (m, 8H), 1.481.42 (m, 2H). C-NMR (CDCl3)  110.7, 81.4,
74.7, 71.9, 69.3, 66.8, 39.4, 36.2, 32.1, 26.2, 25.1, 24.8. HRMS (ESI) calcd for C12H19N3O4 (M+)
269.1376. Found: 269.1371.
3.4.2. (1R,2R,3R,4S,5R)-4-Azido-1,2-O-cyclohexylidene-cyclohexane-1,2,3,5-tetraol (4)
Purification by flash column chromatography (230400 mesh SiO2, EtOAc/hex = 1/81/2) afforded
25
1
a white solid. Yield = 69%. Mp = 125130 °C. []D −146.6 (c 0.45, MeOH). H-NMR (CD3OD)
4.57 (s, 2H, -OH), 4.30 (dt, J = 6.5, 2.3 Hz,1H), 3.89 (dd, J = 7.6, 5.2 Hz, 1H), 3.62 (td,
J = 11.2, 4.9 Hz, 1H), 3.38 (dd, J = 10.4, 7.6 Hz, 1H), 3.04 (t, J = 10.2 Hz, 1H), 2.34 (ddd, J = 14.9,
4.9, 2.2 Hz, 1H), 1.75 (ddd, J = 14.9, 11.5, 4.1 Hz, 1H), 1.701.52 (m, 8H), 1.441.40 (m, 1H),
13
1.391.30 (m, 1H). C-NMR (CD3OD)  110.8, 81.0, 76.1, 74.1, 71.5, 68.6, 39.3, 36.2, 34.1, 26.1,
25.0, 24.8. HRMS (ESI) calcd for C12H19N3O4 (M+) 269.1376. Found: 269.1377.
3.4.3. (1R,2S,3R,4S,5S)-4-Azido-1,2-[(2S,3S)-2,3-dimethoxybutan-2,3-dioxy]-cyclohexane-1,2,3,5-
tetraol (8)
Purification by flash column chromatography (230–400 mesh SiO2, EtOAc/hex = 1/151/2)
25
1
afforded a white solid. Yield = 71%. MP = 178182 °C. []D +157.4 (c 0.19, MeOH). H-NMR

Molecules 2012, 17
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(CD3OD)  3.95 (dd, J = 10.0, 3.4 Hz, 1H), 3.88 (ddd, J = 11.6, 10.1, 4.7 Hz, 1H), 3.85 (t,
J = 3.5 Hz, 1H), 3.79 (t, J = 3.0 Hz, 1H), 3.74 (ddd, J = 11.6, 5.2, 3.0 Hz, 1H), 3.24 (s, 6H), 1.791.74
(m, 1H), 1.71 (t, J = 11.6 Hz, 1H), 1.28 (s, 3H), 1.24 (s, 3H). 13C-NMR (CD3OD)  101.4, 100.6, 72.5,
71.1, 67.6, 65.3, 64.5, 48.2, 48.1, 32.8, 18.0, 17.9. HRMS (ESI) calcd for C12H21N3NaO6 [M+Na]+
326.1328. Found: 326.1308.
3.4.4. (1R,2S,3R,4R,5S)-4-Azido-1,2-[(2S,3S)-2,3-dimethoxybutan-2,3-dioxy]-cyclohexane-1,2,3,5-
tetraol (9)
Purification by flash column chromatography (230–400 mesh SiO2, EtOAc/hex = 1/151/2)
25
1
afforded a white solid. Mp = 179185 °C. Yield = 14%. []D +164.3 (c 0.28, MeOH). H-NMR
(CD3OD) 3.78 (td, J = 9.5, 0.8 Hz, 1H), 3.513.40 (m, 2H), 3.32 (td, J = 9.4, 0.8 Hz, 1H), 3.27 (s,
3H), 3.21 (s, 3H), 3.13 (td, J = 9.5, 1.7 Hz, 1H), 2.01 (dt, J = 12.1, 4.6 Hz, 1H), 1.51 (ddd,
13
J = 13.3, 12.3, 1.4 Hz, 1H), 1.27 (s, 3H), 1.24 (s, 3H). C-NMR (CD3OD)  100.7 (×2), 75.0, 73.2,
72.3, 69.7, 66.1, 48.3, 48.2, 36.3, 17.9 (x2). HRMS (ESI) calcd for C12H21N3NaO6 [M+Na]+ 326.1328.
Found: 326.1328.
3.4.5. (1R,2R,3R,4S,5S)-4-Aminocyclohexane-1,2,3,5-tetraol (5)
Purification by flash column chromatography (230–400 mesh SiO2, MeOH/CH2Cl2/5%NH4OH =
25
1
1/101/1) afforded a pale yellow syrup. Yield = 70%. []D −76.7 (c 0.21, H2O). H-NMR (D2O) 
4.09 (dd, J = 6.5, 3.2 Hz, 1H), 4.03 (dd, J = 6.3, 3.1 Hz, 1H), 3.90 (t, J = 9.8 Hz, 1H), 3.45 (dd, J = 9.4,
2.8 Hz, 1H), 3.12 (dd, J = 10.3, 3.2 Hz, 1H), 2.08 (dt, J = 15.6, 3.5 Hz, 1H), 1.70 (dt, J = 15.6, 2.9 Hz,
13
1H). C-NMR (D2O)  73.8, 70.0, 67.2, 66.9, 56.7, 32.6. HRMS (ESI) calcd for C6H14NO4 [M+H]+
164.0923. Found: 164.0919.
3.4.6. (1R,2R,3R,4S,5R)-4-Aminocyclohexane-1,2,3,5-tetraol (6)
Purification by flash column chromatography (230–400 mesh SiO2, MeOH/CH2Cl2/5%NH4OH =
25
1
1/101/1) afforded a pale yellow syrup. Yield = 71%. []D −19.4 (c 0.33, H2O). H-NMR (D2O)
3.963.94 (m, 1H), 3.59 (ddd, J = 14.5, 10.0, 4.6 Hz, 1H), 3.413.34 (m, 2H), 2.53 (t, J = 9.8 Hz, 1H),
13
1.98 (dt, J = 14.0, 4.2 Hz, 1H), 1.47 (td, J = 14.0, 2.5 Hz, 1H). C-NMR (D2O)  73.9, 71.7, 68.3,
67.6, 59.4, 36.3. HRMS (ESI) calcd for C6H13NO4 (M+) 163.0845. Found: 163.0835.
3.4.7. (1R,2S,3R,4S,5S)-4-Aminocyclohexane-1,2,3,5-tetraol (10)
Purification by flash column chromatography (230–400 mesh SiO2, MeOH/CH2Cl2/5%NH4OH =
25
1
1/101/1) afforded a pale yellow syrup. Yield = 73%. []D −48.2 (c 0.19, H2O). H-NMR (D2O) 
3.91 (dt, J = 9.1, 3.5 Hz, 1H), 3.753.65 (m, 3H), 3.12 (t, J = 4.0 Hz, 1H), 1.85 (dt, J = 13.1, 4.1 Hz,
13
1H), 1.751.62 (m, 1H). C-NMR (D2O)  72.1, 68.3, 67.2, 67.0, 52.6, 32.9. HRMS (ESI) calcd for
C6H14NO4 [M+H]+ 164.0923. Found: 164.0920.

Molecules 2012, 17
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3.4.8. (1R,2S,3R,4R,5S)-4-Aminocyclohexane-1,2,3,5-tetraol (11)
Purification by flash column chromatography (230–400 mesh SiO2, MeOH/CH2Cl2/5%NH4OH =
25
1
1/101/1) afforded a pale yellow syrup. Yield = 68%. []D 69.4 (c 0.18, H2O). H-NMR (D2O)
3.39 (ddd, J = 11.9, 9.4, 4.6 Hz, 1H), 3.30 (td, J = 11.4, 4.4 Hz, 1H), 3.15 (t, J = 9.3 Hz, 1H), 2.99
(t, J = 9.6 Hz, 1H), 2.49 (t, J = 9.8 Hz, 1H), 2.06 (dt, J = 12.2, 4.5 Hz, 1H), 1.35 (dd, J = 11.9, 11.9 Hz,
13
1H). C-NMR (D2O)  77.3, 74.0, 68.7, 68.6, 58.8, 38.0. HRMS (ESI) calcd for C6H14NO4 [M+H]+
164.0923. Found: 164.0918.
4. Conclusions
In conclusion, aminocyclitols are a very important class of aminocarbasugars. We have synthesized
two known and two new aminocyclitols in an efficient manner from D-()-quinic acid. Especially, our
method provided a short alternative in syntheses of 5 and 6 than the literature. The ring opening of
epoxide in 1, 2 and 7 by sodium azide to provide moderate to good yields of 3, 4, and 8, respectively,
was highly regioselective owing to the steric effect. The studies of the biological activities of these
compounds are currently ongoing and will be reported in due course.
Acknowledgments
The National Science Council (NSC98-2119-M-032-004-MY3) and Tamkang University are
gratefully acknowledged for the financial support of this research. Authors also thank the National
Center for High-Performing Computing for assistance.
Conflicts of Interest
The authors declare no conflicts of interest.
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23. The NMR data and optical rotation values of compounds 5 and 6 were reported to be dissolved in
CDCl3 and MeOH, respectively (see reference 8). But, in general, these compounds and other
related analogues are more soluble in D2O or CD3OD than in CDCl3. The NMR data and HRMS
are satisfied for molecules 5 and 6.
Sample Availability: Samples of the compounds 111 are available from the authors.
© 2012 by the authors; licensee MDPI, Basel, Switzerland. This article is an open access article
distributed under the terms and conditions of the Creative Commons Attribution license
(http://creativecommons.org/licenses/by/3.0/).