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Article

Regioselectivity in the Ring Opening of Epoxides for the Synthesis of Aminocyclitols from D-(-)-Quinic Acid

by
Tzenge-Lien Shih
* and
Shu-Yu Yang
Department of Chemistry, Tamkang University, No151 Yingzhuan Rd, 25137 Tamsui Dist., New Taipei City, Taiwan
*
Author to whom correspondence should be addressed.
Molecules 2012, 17(4), 4498-4507; https://doi.org/10.3390/molecules17044498
Submission received: 26 March 2012 / Revised: 9 April 2012 / Accepted: 10 April 2012 / Published: 16 April 2012
(This article belongs to the Section Organic Chemistry)
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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.

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 [4,8,9,10,11,12,13,14,15,16,17].
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 17 04498 g001 550
Figure 1. Representative natural or synthetic products containing aminocyclitol moiety.
Figure 1. Representative natural or synthetic products containing aminocyclitol moiety.
Molecules 17 04498 g001
Molecules 17 04498 g002 550
Figure 2. The previously synthesized aminocyclitols.
Figure 2. The previously synthesized aminocyclitols.
Molecules 17 04498 g002

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).
Molecules 17 04498 g003 550
Scheme 1. Synthesis of aminocyclitols 5, 6, 10 and 11.
Scheme 1. Synthesis of aminocyclitols 5, 6, 10 and 11.
Molecules 17 04498 g003
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).
Molecules 17 04498 g004 550
Figure 3. Plausible mechanism for the formation of 9.
Figure 3. Plausible mechanism for the formation of 9.
Molecules 17 04498 g004
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).
Molecules 17 04498 g005 550
Figure 4. Three-dimensional representations of structures 7 and 12a.
Figure 4. Three-dimensional representations of structures 7 and 12a.
Molecules 17 04498 g005
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, 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.
Molecules 17 04498 g006 550
Figure 5. Three-dimensional representations of structures 1 and 13.
Figure 5. Three-dimensional representations of structures 1 and 13.
Molecules 17 04498 g006
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 Table 1 and Table 2.
Table
Table 1. Selected 1H (600 MHz) and 13C (150 MHz) NMR data for 3, 4, 8, and 9 in CD3OD. Molecules 17 04498 i001
Table 1. Selected 1H (600 MHz) and 13C (150 MHz) NMR data for 3, 4, 8, and 9 in CD3OD. Molecules 17 04498 i001
CompoundH1 ( J)/C1H2 ( J)/C2H3 ( J)/C3H4 ( J)/C4H5 ( J)/C5H6 ( J)/C6
34.33–4.30 (m) 74.73.92 (dd, 7.0, 5.3) 81.44.04–4.01 (m) 69.33.21 (dd, 10.0, 2.7) 86.84.07–4.04 (m) 71.92.25 (dt, 15.7, 3.6) 1.93 (ddd, 15.7, 7.1, 3.7) 32.1
44.30 (dt, 6.5, 2.3) 74.13.89 (dd, 7.6, 5.2) 81.03.38 (dd, 10.4, 7.6) 76.13.04 (t, 10.2) 71.53.62 (td, 11.2, 4.9) 68.62.34 (ddd, 14.9, 4.9, 2.2) 1.75 (ddd, 14.9, 11.5, 4.1) 34.1
83.88 (ddd, 11.6, 10.1, 4.7) 65.33.95 (dd, 10.0, 3.4) 71.13.85 (t, 3.5) 64.53.79 (t, 3.0) 72.53.74 (ddd, 11.6, 5.2, 3.0) 67.61.79–1.74 (m) 1.71 (t, 11.6) 32.8
93.51–3.40 (m) 66.13.78 (tm, 9.5, 0.8) 75.03.32 (td, 9.4, 0.8) 72.33.13 (td, 9.5, 1.7) 73.03.45–3.42 (m) 69.72.01 (dt, 12.1, 4.6) 1.51 (ddd, 13.3, 12.3, 1.4) 36.3
Table
Table 2. Selected 1H (600 MHz) and 13C (150 MHz) NMR data for 5, 6, 10, and 11 in D2O. Molecules 17 04498 i002
Table 2. Selected 1H (600 MHz) and 13C (150 MHz) NMR data for 5, 6, 10, and 11 in D2O. Molecules 17 04498 i002
CompoundH1 ( J)/C1H2 ( J)/C2H3 ( J)/C3H4 ( J)/C4H5 ( J)/C5H6 ( J)/C6
54.03 (dd, 6.3, 3.1) 70.03.45 (dd, 9.4, 2.8) 73.83.90 (t, 9.8) 67.23.12 (d, 10.3, 3.2) 56.74.09 (dd, 6.5, 3.2) 66.92.08 (dt, 15.6, 3.5) 1.70 (dt, 15.6, 2.9) 32.6
63.96–3.94 (m) 68.33.41–3.34 (m)a 73.93.41–3.34 (m)a 71.72.53 (t, 9.8) 59.43.59 (ddd, 14.5, 10.0, 4.6) 67.61.98 (dt, 14.0, 4.2) 1.47 (td, 14.0, 2.5) 36.3
103.91 (dt, 9.1, 3.5) 67.03.75–3.65 (m)a 68.33.75–3.65 (m)a 67.23.12 (t, 4.0) 52.63.75–3.65 (m)a 72.11.85 (td, 13.1, 4.1) 1.75–1.62 (m) 32.9
113.39 (ddd, 11.9, 9.4, 4.6) 68.63.15 (t, 9.3) 77.02.99 (t, 9.6) 74.02.49 (d, 9.8) 58.83.30 (td, 11.4, 4.4) 68.72.06 (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

1H (600 MHz) and 13C-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, 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 a white solid. Yield = 67%. MP = 122−128 °C. [α]D25 +36.2 (c 0.31, MeOH). 1H-NMR (CD3OD)δ 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, J = 15.7, 7.1, 3.7 Hz, 1H), 1.72−1.54 (m, 8H), 1.48−1.42 (m, 2H). 13C-NMR (CDCl3) δ 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 a white solid. Yield = 69%. Mp = 125−130 °C. [α]D25−146.6 (c 0.45, MeOH). 1H-NMR (CD3OD) δ 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), 1.39−1.30 (m, 1H).13C-NMR (CD3OD) δ 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) afforded a white solid. Yield = 71%. MP = 178−182 °C. [α]D25 +157.4 (c 0.19, MeOH). 1H-NMR (CD3OD) δ 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) δ 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) afforded a white solid. Mp = 179−185 °C. Yield = 14%. [α]D25 +164.3 (c 0.28, MeOH). 1H-NMR (CD3OD) δ 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, J = 13.3, 12.3, 1.4 Hz, 1H), 1.27 (s, 3H), 1.24 (s, 3H). 13C-NMR (CD3OD) δ 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 = 1/10−1/1) afforded a pale yellow syrup. Yield = 70%. [α]D25−76.7 (c 0.21, H2O). 1H-NMR (D2O) δ 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, 1H). 13C-NMR (D2O) δ 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 = 1/10−1/1) afforded a pale yellow syrup. Yield = 71%. [α]D25−19.4 (c 0.33, H2O). 1H-NMR (D2O) δ 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), 1.98 (dt, J = 14.0, 4.2 Hz, 1H), 1.47 (td, J = 14.0, 2.5 Hz, 1H). 13C-NMR (D2O) δ 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 = 1/10−1/1) afforded a pale yellow syrup. Yield = 73%. [α]D25−48.2 (c 0.19, H2O). 1H-NMR (D2O) δ 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, 1H), 1.75−1.62 (m, 1H). 13C-NMR (D2O) δ 72.1, 68.3, 67.2, 67.0, 52.6, 32.9. HRMS (ESI) calcd for C6H14NO4 [M+H]+ 164.0923. Found: 164.0920.

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 = 1/10−1/1) afforded a pale yellow syrup. Yield = 68%. [α]D25−69.4 (c 0.18, H2O). 1H-NMR (D2O) δ 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, 1H). 13C-NMR (D2O) δ 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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  • Sample Availability: Samples of the compounds 1−11 are available from the authors.

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Shih, T.-L.; Yang, S.-Y. Regioselectivity in the Ring Opening of Epoxides for the Synthesis of Aminocyclitols from D-(-)-Quinic Acid. Molecules 2012, 17, 4498-4507. https://doi.org/10.3390/molecules17044498

AMA Style

Shih T-L, Yang S-Y. Regioselectivity in the Ring Opening of Epoxides for the Synthesis of Aminocyclitols from D-(-)-Quinic Acid. Molecules. 2012; 17(4):4498-4507. https://doi.org/10.3390/molecules17044498

Chicago/Turabian Style

Shih, Tzenge-Lien, and Shu-Yu Yang. 2012. "Regioselectivity in the Ring Opening of Epoxides for the Synthesis of Aminocyclitols from D-(-)-Quinic Acid" Molecules 17, no. 4: 4498-4507. https://doi.org/10.3390/molecules17044498

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