A reliable synthesis of 2- and 6-amino-β-cyclodextrin and permethylated-β-cyclodextrin

Article abstract of DOI:10.1016/j.tetlet.2005.09.099

A new, reliable method for the introduction of an amine group at positions 2 or 6 of β-cyclodextrin and permethyl-β-cyclodextrin is described. It involves selective tosylation followed by azide substitution and almost quantitative reduction with triphenylphosphine followed by hydrolysis of the phosphinimine intermediate.

Full text of DOI:10.1016/j.tetlet.2005.09.099

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 7905–7907
A reliable synthesis of 2- and 6-amino-b-cyclodextrin and
permethylated-b-cyclodextrin
I. Wayan Muderawan,a Teng Teng Ong,b Teck Chia Lee,a David J. Young,c,*
Chi Bun Chinga and Siu Choon Nga,*
aDivision of Chemical and Biomolecular Engineering, Nanyang Technological University, Singapore 639798, Singapore
bInstitute of Chemical and Engineering Sciences Ltd, 1 Pesek Road, Jurong Island, Singapore 627833, Singapore
cSchool of Science, Griffith University, Nathan 4111, Australia
Received 12 July 2005; revised 8 September 2005; accepted 16 September 2005
Available online 4 October 2005
Abstract—A new, reliable method for the introduction of an amine group at positions 2 or 6 of b-cyclodextrin and permethyl-b-
cyclodextrin is described. It involves selective tosylation followed by azide substitution and almost quantitative reduction with tri-
phenylphosphine followed by hydrolysis of the phosphinimine intermediate.
ꢀ 2005 Elsevier Ltd. All rights reserved.
Cyclodextrins and their derivatives are of interest pri-
marily because of their ability to form inclusion com-
plexes with hydrophobic guest molecules such as Class
II drugs.1–3 The relatively low solubility of native cyclo-
dextrins in water as well as in organic solvents, however,
is the principal limitation to inclusion complexation pro-
cesses and reactions. Moreover, this poor solubility in
organic solvents, in particular, makes them difficult to
modify chemically and purify.4 A synthetic challenge is
the selective modification of the three different types of
hydroxyl group on the hydrophilic surface of the toroi-
dal structure. The more reactive primary hydroxyl (posi-
tion 6) presents at the smaller opening of the toroid
while the less reactive secondary hydroxyls (positions 2
and 3) appear at the larger opening. A number of groups
have made the more water soluble mono-6-amino-6-
deoxy-b-cyclodextrin hydrochloride by tosylation of
the primary (6-) hydroxyl and displacement with ammo-
nia under pressure (106 N mꢀ2, 18 h)5 or by displace-
ment of tosylate by azide followed by catalytic
hydrogenation.6,7 These reports of both procedures indi-
cate low yields, incomplete reactions and/or impure
products. There has been no reported synthesis of the
organic soluble permethylated derivative or of amina-
tion at the less reactive 2- or 3-positions. We now report
a much-improved synthesis of mono-6-amino-6-deoxy-
b-cyclodextrin and the first syntheses of the correspond-
ing 2-amino constitutional isomer and of 2- and 6-
amino-6-deoxypermethyl-b-cyclodextrin.
Our modified synthetic approach for mono-6-amino-6-
deoxy-b-cyclodextrin 4a consists of three steps from b-
cyclodextrin, all of which proceed in much better yield
than previously reported (Scheme 1). Mono-6-(p-tolu-
enesulfonyl)-b-cyclodextrin 2, prepared from b-CD 1
by a selective tosylation as previously reported by
Brady,8 was converted to the mono-6-azido-6-deoxy-b-
cyclodextrin 3a by excess sodium azide in water. Reduc-
tion of 3a was achieved with triphenylphosphine in
DMF followed by hydrolysis of the phosphinimine
intermediate to provide 4a in almost quantitative yield.9
Titration of 4a with dilute hydrochloric acid gave the
highly water soluble mono-6-ammonium-b-CD chloride
5a. The corresponding 2-amino isomer 8a and hydro-
chloride 9a were made by the same sequence of reactions
but starting from the secondary tosylate prepared as
described by Murakami and co-workers and in approx-
imately the same yield.10–13
The monoazido-b-cyclodextrins 3a and 7a were per-
methylated to provide 3b14 and 7b15 and reduced with
triphenylphosphine and water to provide amines 4b16
and 8b.17 Titration with hydrochloric acid yielded
Keywords: Modified cyclodextrin; Amino b-cyclodextrin; Amino per-
methyl-b-cyclodextrin.
Corresponding authors. E-mail addresses: d.young@griffith.edu.au;
*
ngsc@ntu.edu.sg
0040-4039/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.09.099

7906
I. W. Muderawan et al. / Tetrahedron Letters 46 (2005) 7905–7907
(OH)14
(OR)14
(OR)14
(OR)14
HCl(aq)
1. PPh3
2. H2O
TsIm/H2O
(41%)
NaN3
H2O
OTs
(93%)
NH3+Cl-
)
)
6
(HO
(HO
)
(HO
N3
)
(RO
6
NH2
6
6
(OH)14
2
3a
3b
1. NaH/DMF
2. R-I
(97%)
5a R = H (99%)
4a R = H (97%)
5b R = CH3 (99%)
4b R = CH3 (87%)
NH3+Cl-
(OH)13
OTs
(OR)13
N3
(
(OR)13
NH2
(OR)13
OH)7
1
(Bu)2SnO
HCl(aq)
1. PPh3
2. H2O
NaN3
TsCl
(29%)
H2O
(72%)
(
(
OH)7
OR)7
7a
(
OR)7
(
OR)7
6
1. NaH/DMF
2. R-I
(80%)
8a R = H (95%)
9a R = H (100%)
8b R = CH3 (79%)
9b R = CH3 (98 %)
7b
Scheme 1.
NMR (75 MHz, DMSO-d6) d: 41.7 (C-60), 59.9 (C-6),
72.0 (C2), 72.4 (C-3), 73.0 (C-5), 81.5, 81.6, 82.8 (C-4),
101.9 (C-1).
ammonium hydrochlorides 5b and 9b, which are soluble
in water as well as in polar organic solvents.
10. Murakami, T.; Harata, K.; Marimoto, S. Tetrahedron
Lett. 1987, 28, 321–324.
Acknowledgements
11. Mono-2-azido-2-deoxy-b-cyclodextrin 7a: A mixture of 6
(5.0 g, 4.0 mmol) and sodium azide (3.90 g, 60 mmol) in
water (20 mL) was stirred at 80 ꢁC for 3 days. The
resulting solution was then concentrated to half its volume
and acetone (10 mL) added to precipitate a white solid
which was redissolved in water (10 mL) and reprecipitated
with acetone (10 mL). This process was repeated a further
time to provide 3.25 g of product (yield 72%); mp 220 ꢁC
(dec.). MS ESI (m/z): calcd 1159 [M]+, found 1158.6 [M]+;
calcd 1182 [M+Na]+, found 1182.6 [M+Na]+. Anal. for
C42H69O34N3Æ4H2O; found C = 40.21%; H = 6.86%;
N = 3.28%, calcd C = 40.19%; H = 6.25%; N = 3.41%.
IR (KBr) m: 3229 (OH), 2928 (C-H); 2117 (N3 str); 1659,
1417, 1339 (C-H), 1155, 1079, 1022 (C–Ostr). 1H NMR
(500 MHz, DMSO-d6) d: 3.60–3.67 (m, 14H, H-6), 3.81–
3.95 (m, 28H, H-3,5, H-2,4), 4.5 (s, 7H, OH-6); 4.8 (m, 7H,
H-1); 5.6–5.8 (br s, 13H, OH-2,3). 13C NMR (125 MHz,
DMSO-d6) d: 59.9 (C-6); 61.4 (C-30); 70.2 (C-50); 72.0 (C-
5); 72.2 (C-2); 73.0 (C-3); 80.2 (C-20); 81.2 (C-40); 81.7 (C-
4); 102.8 (C-1); 103.2 (C-10).
We acknowledge the Institute of Chemical and Engi-
neering Sciences Ltd (ICES) Singapore, for research
funding.
References and notes
1. Szejtli, J. Chem. Rev. 1998, 98, 1743–1753.
2. Connors, K. A. Chem. Rev. 1997, 97, 1325–1357.
3. Schneider, H.-J.; Hacket, F.; Rudiger, V. Chem. Rev. 1998,
¨
98, 1755–1785.
4. Khan, A. R.; Forgo, P.; Stine, K. J.; DꢀSouza, V. T. Chem.
Rev. 1998, 98, 1977–1996.
5. Brown, S. E.; Coates, J. H.; Coghlan, D. R.; Easton, C. J.;
van Eyk, S. J.; Janowski, W.; Lepore, A.; Lincoln, S. F.;
Luo, Y.; May, B. L.; Schiesser, D. S.; Wang, P.; Williams,
M. L. Aust. J. Chem. 1992, 46, 953–958.
6. Melton, L. D.; Slessor, K. N. Carbohydr. Res. 1971, 18,
29–37.
7. Petter, R. C.; Salek, J. S.; Sikorski, C. T.; Kumaravel, G.;
Lin, F.-T. J. Am. Chem. Soc. 1990, 112, 3860–3868.
8. Brady, B.; Lynam, N.; OꢀSullivan, T.; Ahern, C.; Darcy,
R. Org. Synth. 2000, 77, 220–224.
12. Mono-2-amino-2-deoxy-b-cyclodextrin 8a: Yield 95%; mp.
223 ꢁC (dec.). IR (KBr) m: 3246, 2928, 1645, 1417, 1368,
1156, 1001, 943, 858, 759, 709 cmꢀ1. MS ESI (m/z):1134.60
1
(M+H+), calcd 1134.30. H NMR (300 MHz, DMSO-d6)
d: 3.30–3.36 (m, 14H, H-6), 3.60 (m, 30H, H-3,5, H-2,4,
NH2), 4.57 (br s, 7H, OH-6), 4.82 (d, 7H, J = 2.84 Hz, H-
1), 5.73 (br s, 13H, OH-2,3). 13C NMR (75 MHz, DMSO-
d6) d: 59.8 (C-6), 71.5 (C-50), 71.9 (C-5), 72.1 (C-20), 72.2
(C-2), 72.7 (C-30), 72.9 (C-3), 80.0 (C-40), 81.4 (C-4), 101.8
(C-1), 103.8 (C-10). Mono-2-ammonium-2-deoxy-b-cyclo-
dextrin chloride 9a: Yield 100%; mp 216 ꢁC (dec.). IR (KBr
dish) m: 3388, 2930, 1638, 1414, 1336, 1156, 1078, 1029, 947,
758, 708, 579 cmꢀ1. MS ESI (m/z): 1134.60 (M+H+), calcd
1134.30. 1H NMR (300 MHz, DMSO-d6) d: 3.31–3.44
(m, 14H, H-6), 3.61 (m, 31H, H-3,5, H-2,4, +NH3), 4.56 (br
s, 7H, OH-6), 4.68–5.05 (m, 7H, H-1), 5.61–5.93 (m, 13H,
OH-2,3). 13C NMR (75 MHz, DMSO-d6) d: 60.2 (C-6),
72.0 (C-20), 72.3 (C-5), 72.6 (C-2), 73.3 (C-3), 81.8 (C-4),
102.2 (C-1), 103.2 (C-10).
9. Mono-6-amino-6-deoxy-b-cyclodextrin 4a: Triphenylphos-
phine (2.89 g, 11.0 mmol) was stirred with 3a (11.60 g,
10.0 mmol) in DMF (20 mL) for 2 h. Deionized water
(2.5 mL) was added and the solution refluxed for 30 min.
Addition of acetone precipitated a white solid which was
filtered, washed with acetone and dried under high
vacuum for 16 h. Yield 11.0 g (97%); mp 215 ꢁC (dec.).
IR (KBr) m: 3428, 3311, 2928, 1659, 1438, 1414, 1389,
1369, 1334, 1156, 1080, 1030, 947, 755, 707, 609, 580 cmꢀ1
.
MS ESI (m/z): 1134.50 (M+H+), calcd 1134.30. 1H NMR
(300 MHz, DMSO-d6) d: 3.34 (m, 30H, H-3,5, H-6,
NH2), 3.56–3.65 (m, 14H, H-2,4), 4.43–4.46 (m, 6H,
OH-6), 4.83 (d, 6H, J = 2.0 Hz, H-1), 4.89 (d, 1H,
J = 2.0 Hz, H-10), 5.61–5.77 (m, 14H, OH-2,3). 13C

I. W. Muderawan et al. / Tetrahedron Letters 46 (2005) 7905–7907
7907
13. Kaneda, T.; Fujimoto, T.; Goto, J.; Asano, K.; Yasufuku,
Y.; Jung, J. H.; Hosono, C.; Sakata, Y. Chem. Lett. 2002,
514–515.
d: 3.05–3.09 (m, 14H, H-3,5), 3.24 (s, 18H, 6-OCH3), 3.30–
3.46 (m, 16H, H-6 and NH2), 3.39 (s, 21H, 3-OCH3), 3.50
(s, 21H, 2-OCH3), 3.79 (m, 14H, H-2,4), 5.05 (d,
6H, J = 3.6 Hz, H-1), 5.15 (d, 1H, J = 3.6 Hz, H-10).
13C NMR (125 MHz, DMSO-d6) d: 41.6 (C-60), 57.9
(2-OCH3), 58.1 (6-OCH3), 60.6 (3-OCH3), 70.4 (C-5), 71.1
(C-6), 79.6 (C-4), 81.3 (C-2), 81.6 (C-3), 97.7 (C-1). Mono-
6-ammonium-6-deoxy-permethyl-b-cyclodextrin chloride
5b: Yield 99%; mp 136–138 ꢁC. IR (KBr) m: 3442
(+NH3), 2928, 1638, 1456, 1414, 1370, 1335, 1156, 1080,
14. Mono-6-azido-6-deoxy-permethyl-b-cyclodextrin 3b: Yield
97%; mp 106–108 ꢁC; [a]D = +157 (c 0.01, CHCl3). IR
(KBr) m: 2929, 2834, 2104 (N3), 1640, 1458, 1367, 1161,
1141, 1107, 1040, 970, 856, 756, 707, 558 cmꢀ1. Anal. for
C62H109N3O34Æ2H2O; found C = 50.38%, H = 7.70%,
N = 2.76%, calcd C = 50.42%, H = 7.73%, N = 2.85%.
MS ESI (m/z): 1462.60 (M+Na+, 100), calcd 1462.68.
1H NMR (300 MHz, CDCl3) d: 3.14–3.18 (m, 7H, H-5),
3.37 (s, 18H, 6-OCH3), 3.48 (s, 21H, 3-OCH3), 3.37–3.58
(m, 21H, H-3,6), 3.61 (s, 21H, 2-OCH3), 3.68–3.92 (m, 14H,
H-2,4), 5.03 (d, 1H, J = 3.6 Hz, H-10), 5.10 (d, 6H,
J = 3.6 Hz, H-1). 13C NMR (75 MHz, CDCl3) d: 52.0
(C-60), 58.4–58.6 (2-OCH3), 58.8 (6-OCH3), 61.2, 61.3, 61.4
(3-OCH3), 70.7, 70.8, 71.0 (C-5), 71.2, 71.3, 71.5 (C-6), 79.9,
80.0, 80.2, 88.3 (C-4), 81.3, 81.7 (C-2), 81.8, 82.0 (C-3), 98.3,
98.8, 99.0, 99.2 (C-1).
15. Mono-2-azido-2-deoxy-permethyl-b-cyclodextrin 7b: Yield
80%; mp 73–75 ꢁC. IR (KBr) m: 2879, 2108 (N3), 1680, 1463,
1387, 1002, 950, 909, 857, 756, 705, 660, 555 cmꢀ1. MS
ESI (m/z): 1462.60 (M+Na+), calcd 1462.70. 1H NMR
(300 MHz, CDCl3) d: 3.12–3.16 (m, 7H, H-5), 3.34 (s, 21H,
6-OCH3), 3.46 (s, 21H, 3-OCH3), 3.42–3.57 (m, 21H,
H-3,6), 3.60 (s, 18H, 2-OCH3), 3.74–3.83 (m, 14H, H-2,4),
4.97 (d, 1H, J = 3.6 Hz, H-10), 5.03–5.4 (m, 6H, H-1).
13C NMR (75 MHz, CDCl3) d: 58.4 (2-OCH3), 58.8
(6-OCH3), 61.2 (3-OCH3), 70.4, 70.8 (C-5), 71.2 (C-6),
78.5 (C-20), 80.1 (C-4), 81.6 (C-2), 81.9 (C-3), 82.6 (C-30),
98.8 (C-1), 99.8 (C-10).
1029, 756, 707, 579 cmꢀ1
. MS ESI (m/z): 1414.60
(M+), calcd 1414.70. 1H NMR (300 MHz, DMSO-d6)
d: 3.04–3.08 (m, 14H, H-3,5), 3.25 (s, 18H, 6-OCH3),
3.31–3.47 (m, 17H, H-6 and +NH3), 3.40 (s, 21H, 3-
OCH3), 3.51 (s, 21H, 2-OCH3), 3.80 (m, 14H, H-2,4),
5.06 (d, 6H, J = 3.6 Hz, H-1), 5.16 (d, 1H, J = 3.6 Hz,
13
H-10). C NMR (75 MHz, DMSO-d6) d: 41.5 (C-60),
57.8 (2-OCH3), 58.2 (6-OCH3), 60.7 (3-OCH3), 70.5
(C-5), 71.2 (C-6), 79.7 (C-4), 81.4 (C- 2), 81.7 (C-3), 97.8
(C-1).
17. Mono-2-amino-2-deoxy-permethyl-b-cyclodextrin
8b:
Yield 79%; mp 93–95 ꢁC. IR (KBr) m: 3510 (NH2), 2930,
2834, 1680, 1460, 1368, 1140, 1101, 1036, 970, 857, 702,
544 cmꢀ1. MS ESI (m/z): 1414.50 (M+H+), calcd 1414.70.
1H NMR (300 MHz, CDCl3) d: 3.14–3.19 (m, 7H, H-5),
3.24 (t, 1H, J = 4.8 Hz, H-30), 3.36 (s, 21H, 6-OCH3), 3.48
(s, 21H, 3-OCH3), 3.45–3.64 (m, 22H, H-3,6, NH2), 3.62
(s, 18H, 2-OCH3), 3.74–3.93 (m, 13H, H-2,4), 4.03 (dd,
1H, J = 3.21 Hz, H-40), 4.96 (d, 1H, J = 3.6 Hz, H-10),
5.04–5.14 (m, 6H, H-1). 13C NMR (75 MHz, CDCl3) d:
58.4 (2-OCH3), 58.8 (6-OCH3), 61.3 (3-OCH3), 70.9 (C- 5),
71.3 (C-6), 80.1 (C-4), 81.0 (C-20), 81.7 (C-2), 82.4 (C-3),
98.8 (C-1), 102.5 (C-10). Mono-2-ammonium-2-deoxy-
permethyl-b-cyclodextrin chloride 9b: Yield 98%; mp
108–110 ꢁC. IR (KBr) m: 3491 (+NH3), 2930, 2834, 1641,
1461, 1369, 1193, 1140, 1089, 1038, 969, 857, 702,
544 cmꢀ1. MS ESI (m/z): 1414.60 (M+), calcd 1414.70.
1H NMR (300 MHz, CDCl3) d: 3.14–3.18 (m, 7H, H-5),
3.24 (t, 1H, J = 4.41 Hz, H-30), 3.35 (s, 21H, 6-OCH3),
3.48 (s, 21H, 3-OCH3), 3.45–3.69 (m, 23H, H-3,6, +NH3),
3.61 (s, 18H, 2-OCH3), 3.77–3.85 (m, 13H, H-2,4), 3.97
(dd, 1H, J = 3.21 Hz, H-40), 5.03 (d, 1H, J = 2.82 Hz, H-
10), 5.07–5.13 (m, 6H, H-1). 13C NMR (75 MHz, CDCl3)
d: 58.8 (2-OCH3), 59.6 (6-OCH3), 62.0 (3-OCH3), 71.6
(C-5), 72.0 (C-6), 80.9 (C-4), 82.4 (C-2), 82.7 9C-3, 83.5
(C-20), 99.6 (C-1).
16. Mono-6-amino-6-deoxy-permethyl-b-cyclodextrin 4b: A
solution of triphenylphosphine (2.89 g, 11.0 mmol) and
3b (14.41 g, 10.0 mmol) in acetone (25 mL) was stirred at
room temperature for 2 h and then water (2.5 mL) added
and the solution refluxed for 30 min. The acetone was
removed and water (50 mL) added to precipitate to
triphenylphosphine oxide which was removed by filtra-
tion. The aqueous filtrate was extracted (3 · 75 mL,
CH2Cl2), and the combined organic extracts dried
(Na2SO4) and concentrated to give a crude product which
was recrystallized from CH2Cl2/hexane (1:5) to give pale
yellow solid (12.31 g, 87%); mp 121–123 ꢁC. IR (KBr) m:
3447 (NH2), 2931, 2835, 1640, 1460, 1369, 1161, 1103,
1038, 970, 857, 755, 704, 544 cmꢀ1. MS ESI (m/z): 1414.50
1
(M+H+), calcd 1414.70. H NMR (500 MHz, DMSO-d6)