A convenient procedure for the synthesis of 6-O-mono-phosphate β-cyclodextrins

Article abstract of DOI:10.1080/10426507.2013.797419

The synthesis of β-cyclodextrin derivatives bearing one phosphate group on the primary rim is reported. These compounds were prepared in good to excellent yields, by reacting β-cyclodextrin with dialkyl chlorophosphates in the presence of 4-dimethyl amino

Full text of DOI:10.1080/10426507.2013.797419

This article was downloaded by: [University Library Utrecht]
On: 04 October 2013, At: 05:37
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
Phosphorus, Sulfur, and Silicon and the
Related Elements
Publication details, including instructions for authors and
subscription information:
http://www.tandfonline.com/loi/gpss20
A Convenient Procedure for the
Synthesis of 6-O-Mono-Phosphate β-
Cyclodextrins
Siphamandla Simelane a , Brillance Bhekie Mamba a & Xavier
Yangkou Mbianda a
a Department of Applied Chemistry , Faculty of Sciences, University
of Johannesburg, Doornfontein Campus , Johannesburg , South
Africa
Accepted author version posted online: 26 Jul 2013.Published
online: 03 Oct 2013.
To cite this article: Siphamandla Simelane , Brillance Bhekie Mamba & Xavier Yangkou Mbianda (2013)
A Convenient Procedure for the Synthesis of 6-O-Mono-Phosphate β-Cyclodextrins, Phosphorus, Sulfur,
and Silicon and the Related Elements, 188:12, 1675-1679, DOI: 10.1080/10426507.2013.797419
To link to this article: http://dx.doi.org/10.1080/10426507.2013.797419
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

Phosphorus, Sulfur, and Silicon, 188:1675–1679, 2013
Copyright ꢀC Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426507.2013.797419
A CONVENIENT PROCEDURE FOR THE SYNTHESIS
OF 6-O-MONO-PHOSPHATE β-CYCLODEXTRINS
Siphamandla Simelane, Brillance Bhekie Mamba,
and Xavier Yangkou Mbianda
Department of Applied Chemistry, Faculty of Sciences, University of Johannesburg,
Doornfontein Campus, Johannesburg, South Africa
GRAPHICAL ABSTRACT
Abstract The synthesis of β-cyclodextrin derivatives bearing one phosphate group on the
primary rim is reported. These compounds were prepared in good to excellent yields, by reacting
β-cyclodextrin with dialkyl chlorophosphates in the presence of 4-dimethyl amino pyridine
(DMAP) catalyst and dimethylformamide (DMF) as solvent. The methodology described is
highly selective and the purification of the title compounds is simple, because difficulties due
to phosphate regioisomers mixture are avoided.
Keywords β-Cyclodextrin; 6-O-monophosphate β-cyclodextrin; 4-Dimethyl amino pyridine;
Cyclodextrin phosphate
Received 26 February 2013; accepted 16 April 2013.
The authors thank the National Research Foundation (NRF) of South Africa, for financial support.
Address correspondence to Xavier Yangkou Mbianda, Department of Applied Chemistry, Faculty of
Sciences, University of Johannesburg, Doornfontein Campus, Johannesburg 2028, South Africa. E-mail:
mbianday@uj.ac.za
1675

1676
S. SIMELANE ET AL.
INTRODUCTION
Cyclodextrins (CD) are cyclic oligosaccharides typically containing six (α-CD),
seven (β-CD), and eight (γ -CD) glucopyranose units forming a toroidal shape. This orien-
tation enables cyclodextrins to form inclusion complexes when a guest molecule is partially
or fully contained in the interior of the cavity.1 Due to this characteristic feature, cyclodex-
trins and cyclodextrin-based polymers have been studied for a number of applications
including chromatography, environmental, and pharmaceutical science.1,2
Over the past five decades, modified cyclodextrins have received increasing interest
due to their applications in various fields, ranging from supramolecular chemistry to drug
delivery, biosensors, and water purification.3 The selective modification of cyclodextrins is
a challenge because of the presence of three different types of hydroxyl groups in their struc-
ture as well as due to the hydrophobic nature of their cavity. The various hydroxyl groups
compete for the modifying reagent making the extent of the functionalization (mono, di,
tri, etc.) difficult to control. Alternatively, the hydrophobic cavity is capable of complexing
the reagent and directing substitution to the formation of unexpected products.4–6 The size
of the cyclodextrin cavity and the solvent used are the other factors that can also affect the
reaction product. Few methods are known for the preparation of monosubstituted cyclodex-
trins bearing organophosphate groups.7,8 However, these methods have drawbacks, such as
the use of pyridine which is a toxic solvent, tedious work-up procedures, and poor yield. For
example, Breslow’s research group7 reports the preparation of 6-O-monophosphorylated
β-cyclodextrins using a method containing a series of protection–deprotection and recrys-
tallization steps leading to poor yields. Pyridine was selected as solvent in these methods,
because of its ability to orient the substitution reactions to the primary hydroxyl groups
of the cyclodextrin moiety. However, it also forms a pyridinium complex, with the cavity
of CDs, which complicates the work-up procedure6 and leads to poor yield. Our current
interest in the application of modified cyclodextrins polymers for water purification9–11 led
our quest for convenient ways of obtaining these compounds with high yield and purity.
In this letter, we wish to report a convenient and better yielding method for the
monophosphorylation of β-cyclodextrin 1 using dialkyl or diaryl chlorophosphates in
the presence of 4-dimethylamino pyridine (DMAP) as a catalyst and dimethylformamide
(DMF) as a solvent (Scheme 1) to produce the corresponding 6-O-monophosphate β-
cyclodextrin compound 2 in good to excellent yields.
RESULTS AND DISCUSSION
In this study, DMF as solvent with DMAP as catalyst is proposed as an attractive
alternative to pyridine (non–user-friendly solvent) used in most of the approaches reported
for the monosubstitution of cyclodextrins in the literature. DMAP is known to catalyze
a wide variety of reactions like acylation, carbamylation, silylation, sulphonylation, and
phosphorylation of amino and hydroxyl groups.12 According to Loannou and colleagues13,
DMAP also activates acylation toward primary hydroxyl groups over secondary hydroxyl.
In addition, it functions as an acid (HCl) scavenger to prevent the hydrolysis of the phosphate
esters. Another advantage of using DMAP is that it is a non-hygroscopic solid, easy to handle
when compared with liquid tertiary amines that are commonly used. In this procedure,
the cyclodextrin and the phosphorylating agent were reacted at room temperature (25◦C) and
in diluted solution to avoid highly substituted derivatives. In addition, the phosphorylating
agent was added slowly to ensure that the cyclodextrin remained in excess in the reaction

A CONVENIENT PROCEDURE FOR THE SYNTHESIS OF 6-O-MONO-PHOSPHATE 1677
Scheme 1 Preparation of compound 2.
flask.14 This reaction was highly regioselective, because only a single signal was observed
in the 31P NMR spectra of the crude products (Table 1). At higher temperatures or with
more concentrated solution of phosphorochloridate, the reaction selectivity was lost and
multiple signals were observed in the 31P NMR spectra of the crude products.
The proposed mechanism for phosphorylation by DMAP-catalyzed reaction is illus-
trated in Scheme 2.
It begins with a nucleophilic attack of DMAP on the phosphoryl halide to generate a
phosphorylpyridinium-anion-pair intermediate, which reacts selectively with the primary
hydroxyl groups of the cyclodextrin to yield the phosphate ester product while regenerating
the DMAP.
The work-up procedure for obtaining the final products involved: precipitation with
diethyl ether, and washing several times with isopropanol to remove DMAP and its hy-
drochloride salt.15 This protocol afforded the production of the title compounds in yields
ranging from 60% to 85% as shown in Table 1. To the best of our knowledge, the synthesis
Table 1 Percentage yields and spectroscopic data for cyclodextrin phosphorylated derivatives
Compound R
% Yield
69%
31P NMR δ(PPM)
FT-IR (ν, cm−1
)
(2a)
CH3-
(2b)
CH3CH2-
(2c)
(CH3)2CH-
(2d)
1.1
−0.9
1.0
1 251 cm−1 (P O)
1 025 cm−1 (P-OCH3)
1 252.2 cm−1 (P O)
85%
1 026 cm−1 (P-OCH2CH3)
1 241 cm−1 (P O)
70%
1 027 cm−1 (P-OCH(CH3)2)
1 247 cm−1 (P O)
60%a
−11.5
C6H5-
1 194 cm−1 (P-OC6H5)
aYield = 32% and 49% in ref.7 and ref.8 respectively.

1678
S. SIMELANE ET AL.
Scheme 2 Proposed mechanism of catalysis of phosphorylation by DMAP.
of these compounds have never been reported in the literature, except for the mono(6-
O-diphenoxyphosphoryl)-β-cyclodextrin (2d) that have been synthesized by Breslow and
colleagues7 and Liu and colleagues8 with 32% and 49% yield respectively.
CONCLUSION
We have developed a convenient and efficient method for the synthesis of 6-O-
monophosphorylated β-cyclodextrin derivatives in good yields. The monophosphorylation
of cyclodextrins is selectively obtained in DMF by controlled addition of the phosphorylat-
ing agent, with DMAP being a catalyst and base. The work-up and purification procedures
of the title compounds are simple, because the production of phosphate regioisomer mix-
tures that leads to purification difficulties, as described in other procedures in the literature,
is avoided.
REFERENCES
1. Romo, A.; Penas, F. J.; Isasi, J. R.; Garcıa-Zubiri, I. X.; Gonzalez-Gaitano, G. React. Funct.
Polym. 2008, 68, 406-413.
2. Girek, T.; Shin, D-H.; Lim, S-T. Carbohyd. Polym. 2000, 42, 59-63.
3. Zhen, C.; Bradshaw, J. S.; Shen, Y.; Habata, Y.; Lee, M. L. J. Org. Chem. 1997, 62, 8529-8543.
4. Wang, W.; Pearce, A. J.; Zhang, Y.; Sinay, P. Tetrahedron: Asymmetry 2001, 12, 517-523.
´
5. Lo´pez, O.; Bols M. Tetrahedron 2008, 64, 7587-7593.
6. Khan, A. R.; Forgo, P.; Stine, K. J.; D’Souza, V. T. Chem. Rev. 1998, 98, 1977-1996.
7. Siegel, B.; Pinter, A.; Breslow, R. J. Am. Chem. Soc. 1977, 99(7), 2309-2312.
8. Liu, Y.; Li, B.; Han B-H., Li, Y-M.; Chen, R-T. J. Chem. Soc. Perkin Trans. 1997, 2, 1275-1278.
9. Mamba, B. B.; Krause, R. W.; Malefetse, T. J.; Nxumalo, E. N. Environ. Chem. Lett. 2007, 5,
79-84.
10. Mamba, G.; Mbianda, X. Y.; Govender, P. P.; Mamba, B. B.; Krause, R. J. Applied Sci. 2010, 10,
940-949.
11. Simelane, S.; Master thesis, University of Johannesburg, 2011; UJDigispace http://hdl.handle.
net/10210/5051

A CONVENIENT PROCEDURE FOR THE SYNTHESIS OF 6-O-MONO-PHOSPHATE 1679
12. Singh, S.; Das, G.; Singh, O. V.; Han, H. Tetrahedron Lett. 2007, 48, 1983-1986.
13. Loannou, P. V.; Tsivgoulis, G. M. Chem. Phys. Lipids 2010, 63, 51-55.
14. Synthesis of 6-O-mono-phosphate β-Cyclodextrin Materials: DMF was dried by distilling over
calcium hydride under reduced pressure. β-cyclodextrin was dried by heating at 65◦C for 24 h
under vacuum. Other reagents were obtained from Sigma Aldrich and they were used without
further purification. All the reactions were carried out under argon. General procedure: To a
solution of β-cyclodextrin (5 g, 4.41 mmol) and DMAP (0.298 g, 2.44 mmol) in DMF (100 mL),
dialkyl (or diaryl) chlorophosphate (0.761 g, 4.41 mmol) in DMF (50 mL) was added drop-wise
under argon. The reaction was stirred at room temperature for 4 d under argon. The solvent was
removed from the reaction mixture under reduced pressure, and the residue was triturated with
diethyl ether (100 mL) and stirred for 2 d. The obtained suspension was filtrated and washed
5 times with isopropanol (80 mL). The product was dried at room temperature under vacuum to
give the title compound. Instruments: 1H, 13C, and 31P NMR spectra were recorded at 300 MHz on
a Varian Gemini-300 Spectrometer or at 400 MHz on a Bruker Avance Spectromer in dimethyl
sulfoxide (DMSO-d6) or dimethyl formamide (DMF-d7). FT-IR spectra were obtained on a
Perkin Elmer Spectrum 100 spectrometer. (2a) (2.34 g, 69%). FT-IR ν (cm−1) 3291, 2896, 1651,
1565, 1409, 1327, 1294, 1251, 1223, 1153, 1102, 1079, 1025, 999, 938, 854, 755, 7036. 1H NMR
(DMSO-d6) δ 5.70 broad (m, 14H, OH-2, OH-3), 4.81 (s, 7H, H-1), 4.20–3.42 (m, 41H, OCH3,
H-6, H-5, H-3, H2O), 3.36–2.71 (m, 23H, H-4, H-2, OH-6).13C NMR (DMF-d7) δ 103.2 (C-1),
82.8 (C-4), 74.1 (C-3), 73.7 (C-5), 73.1 (C-2), 63.2 (OCH3), 61.2 (C-6).31P NMR (DMSO-d6) δ
1.1. Found: C, 39.92; H, 6.27. Calc. For C44H75O38P.5H2O: C, 39.63; H, 6.38%. (2b) (4.90 g,
85%). FT-IR: ν (cm−1) 3286, 2924, 1703, 1658, 1404, 1364, 1328, 1294, 1253, 1223, 1153, 1079,
1026, 1000, 938, 846, 795, 753, 703. 1H NMR (DMSO-d6) δ 5.76–5.71 (m, 14H, OH-2, OH-3,),
4.81 (s, 7H, H-1), 4.47 (m, 4H, OCH2-), 3.64–3.53 (m, 34H, H-6, H-5, H-3, H2O), 3.35–3.28
(m, 21H, H-4, H-2, OH-6), 1.18–1.10 (m, 6H, CH3). 13C NMR (DMF-d7): δ 103.2 (C-1), 82.9
(C-4), 74.2 (C-3), 73.80 (C-5), 73.2 (C-2), 61.3–61.0 (OCH2,C-6, C-6’), 16.8–16.7 (CH3).31P
NMR (DMSO-d6) δ -0.9. Found: C, 40.49; H, 6.47. Calc. For C46H79O38P.5H2O: C, 40.58; H,
6.54%. (2c) (4.10 g, 70%). FT-IR ν (cm−1) 3301, 2926, 1659, 1411, 1362, 1328, 1296, 1241,
1154, 1080, 1027, 1000, 937, 890, 846, 795, 754, 706. 1H NMR (DMSO-d6) δ 5.18 broad (m,
20H, OH-2, OH-3, OH-6), 4.81–4.08 (m, 7H, H-1), 3.79–3.04 (m, 52H, OCH(CH3)2, H-6, H-5,
H-3, H-4, H-2, H2O), 1.18–1.11 (m, 12H OCH(CH3)2).13C NMR (DMF-d7) δ 103.2 (C-1), 82.8
(C-4), 74.2 (C-3), 73.7 (C-5), 73.2 (C-2), 61.3 (C-6), 24.3–24.2 (CH3). 31P NMR (DMSO-d6) δ
1.0.. Found: C, 40.77; H, 6.25. Calc. For C52H83O38P.10H2O: C, 40.89; H, 6.01%. (2d)(8) (2.42 g,
60%). FT-IR ν (cm−1) 3284, 2914, 1649, 1592, 1490, 1413, 1368, 1330, 1300, 1247, 1195, 1154,
1098, 1079, 1024, 1000, 937, 862, 753, 702, 686; 1H NMR (DMSO-d6) δ 7.26 – 6.94 (m, 10H,
Ar), 5.69 broad (m, 20H, OH-2, OH-3, OH-6), 4.80 (s, 7H, H-1), 3.65–3.16 (m, 62H, H-6, H-5,
H-3, H-4, H-2, H2O); 13C NMR (DMF-d7) δ 129.7, 123.3, 120.7–120.6 (phenyl), 103.2 (C-1),
82.8 (C-4), 74.1 (C-3), 73.7 (C-5), 73.1 (C-2), 61.2 (C-6); 31P NMR (DMSO-d6) δ -11.5 .Found:
C, 41.75; H, 6.60. Calc. For C54H79O38P.10H2O: C, 41.91; H, 6.40%.
15. Vervoort, L.; Van den Mooter, G.; Augustijns, P.; Busson, R.; Toppet, S.; Kinget, R. Pharm. Res.
1997, 14, 1730-1737.