Mild regioselective phosphorylation of β-cyclodextrin with trivalent phosphorus acid amides

Article abstract of DOI:10.1134/S1070363206100045

Phosphorylation of β-cyclodextrin with trivalent phosphorus acid diamides in pyridine is found to proceed selectively at primary hydroxy groups under mild conditions (20°C) due to the supramolecular effect of the cyclodextrin cavity. The compounds obtained are of practical interest for further synthesis on their basis of amphiphilic glycophospholipids immobilized on the cyclodextrin matrix. Nauka/Interperiodica 2006.

Full text of DOI:10.1134/S1070363206100045

ISSN 1070-3632, Russian Journal of General Chemistry, 2006, Vol. 76, No. 10, pp. 1533 1536.
Pleiades Publishing, Inc., 2006.
Original Russian Text M.K. Grachev, I.A. Senyushkina, G.I. Kurochkina, L.K. Vasyanina, E.E. Nifant’ev, 2006, published in Zhurnal Obshchei Khimii,
2006, Vol. 76, No. 10, pp. 1599 1602.
Mild Regioselective Phosphorylation of -Cyclodextrin
with Trivalent Phosphorus Acid Amides
M. K. Grachev, I. A. Senyushkina, G. I. Kurochkina,
L. K. Vasyanina, and E. E. Nifant’ev
Moscow State Pedagogical University, Nesvizhskii per. 3, Moscow, 119021 Russia
e-mail: chemdept@mtu-net.ru
Received August 10, 2006
Abstract Phosphorylation of -cyclodextrin with trivalent phosphorus acid diamides in pyridine is found
to proceed selectively at primary hydroxy groups under mild conditions (20 C) due to the supramolecular
effect of the cyclodextrin cavity. The compounds obtained are of practical interest for further synthesis on
their basis of amphiphilic glycophospholipids immobilized on the cyclodextrin matrix.
DOI: 10.1134/S1070363206100045
Dialkylamides of trivalent phosphorus acids are
known to be capable of phosphorylating hydroxyl-
containing compounds only at elevated temperatures
(above 70 80 C) with distilling off the liberated di-
alkylamine [1]. Unfortunately, phosphorylation by this
method of complex oligohydroxyl-containing com-
pounds proceeds with a low selectivity at hydroxy
groups of different nature, e.g., primaryand secondary.
In such cases, more reactive P(III) acid azolides which
phosphorylate already at room temperature and pre-
ferably at primary hydroxy groups, even when the
latter are present together with secondary hydroxyls
[2], are commonly used. However, P(III) acid azolides
are often hardly available and easily hydrolyzed,
which restricts their practical application. Still more
challenging problems arise on attempted phosphoryla-
tion with P(III) acid dialkylamides under ordinary
conditions, i.e. on heating, of such a complex oligo-
hydroxy compound as -cyclodextrin (I) containing 7
primary and 14 secondary hydroxy groups. It is
known that regioselective functionalization of -cyclo-
dextrin is generally quite an intricate problem which
could only be successfully solved in selected cases [3].
-Cyclodextrin is most frequently phosporylated with
nonselective P(III) acid chlorides to obtain, as a rule,
perphosphorylated -cyclodextrin derivatives [4]. For
regioselective phosphorylation selectively protected
-cyclodextrins are commonly used, but this method
is complicated by the necessity of introducing and
subsequently removing protective groups. As to func-
tionalization of -cyclodextrin, it was noted that the
nature of the solvent [5] and even temperature, as, for
example, in silylation [6], can strongly affect the
regioselectivity of substitution of cyclodextrin hydroxy
groups. With -cyclodextrin, an additional problem
arises due to its re- stricted solubility in most solvents
used for this reaction, except for pyridine and DMF.
On the other hand, we previously showed that phos-
phorylation of free -cyclodextrin by the simplest
phosphorous triamide unexpectedly proceeds under
mild conditions (20 C) selectively by primary
hydroxy groups [7].
Accounting for the importance of selective phos-
phorylation of free (unprotected) -cyclodextrin, we
set ourselves the task to find conditions for mild
regioselective phosphorylation with more complex
phosphorylating agents, phosphorous diamidoesters:
1,2-O-isopropylideneglycerol tetraethylphosphorodi-
amidite (II) and benzyl tetraethylphosphorodiamidite
(III). The choice of these phosporylating agents was
motivated by the possibility of their further use as
starting materials in the synthesis of complex natural
compounds, e.g., glycophospholipids, using known
experimental approaches [8]. Such glycophospholipids
immobilized on a cyclodextrin matrix are ampiphilic
compounds and present considerable practical interest,
combining in one molecule specific properties of the
cyclodextrin cavity as a host and transport functions
of phospholipids in biological membranes [9]. In view
of the above-mentioned data [7], phosphorylation was
performed in pyridine, and the reaction progress was
monitored by 31P NMR spectroscopy. We found that
the reaction of -cyclodextrin I with 3 mol of phos-
phorylating agents II or III proceeds under mild con-
ditions (20 C) and leads to P(III)-containing products
IV or V, respectively, which have the structure of
1533

1534
GRACHEV et al.
phosphorous amidodiesters and show a typical 31P
chemical shift of 148 ppm. Therewith, under these
prosphorylation conditions, only 2 mol of phosphory-
lating agent II or III entered reaction and no possible
cyclophosphorylated compounds with expected 31P
chemical shifts of 152 ppm [7] were detected.
X
O
O
(HO )5
(OH
(Et2N)2PO
; S
O P O
NEt2
O
O
2
II
OH)7
(
OH)7
IV, VI
X
(OH
OH)7
(Et2N)2POCH2C6H5; S
(HO )5
(OH
O P OCH2C6H5
NEt2
I
2
III
OH)7
V, VII
IV, V: X = lone electron pair, VI, VII: X = S.
-Cyclodextrin phosphorus amidodiester derivatives
IV and V were treated with sulfur in situ to obtain the
corresponding thiophosphoric derivatives VI and VII
which were isolated as individual compounds and
signals of methyl protons in the region of 1.01
1.08 ppm and amido methylene protons in the region
of 2.89 2.96 ppm. The presence of the amido group,
too, implies the absence of phosphocyclization under
the experimental conditions. From a comparison of
the integral intensities of the aromatic benzyl and
cyclodextrin frame proton signals we concluded that
here, too, the degree of substitution of -cyclodextrin
hydroxyls is equal to two. It can be assumed that the
mild and specific influence of pyridine as a solvent
on the phosphorylation course and regioselectivity is
defined by the supramolecular effect of the cyclo-
dextrin cavity, like we observed previously in certain
cases [10]. To provide evidence for this assumption,
we investigated the possibility and features of the
synthesis of diamidoesters II and III in pyridine. Note
that the synthesis of these compounds was described
long ago, but the reaction of phosphorous hexaethyl-
triamide (VIII) with 1,2-O-isopropylideneglycerol
(IX) or benzyl alcohol (X), was performed, as a rule,
without solvent with distilling off the liberated di-
ethylamine [11].
1
analyzed by H, 13C and 31P NMR spectroscopy and
1
TLC. In the H NMR spectrum of derivative VI,
1,2-O-isopropylideneglycerol methyl protons give
signals in the region of 1.27 1.33 ppm with the in-
tegral intensity equal to that of amido methyl protons
(
1.01 1.08 ppm), indicating the absence of phos-
P
phocyclization due to the possible reaction of the
second amide function at P(III) with one of the re-
sidual primary hydroxy groups in the course of phos-
phorylation. The number of introduced phosphorus
substituents was judged about from a comparison of
the integral intensities of the 1,2-O-isopropylidene-
glycerol methyl and cyclodextrin frame proton signals.
The average degree of substitution in this case was
equal to two. In the 13C NMR spectrum of derivative
VI, the cyclodextrin C5 and C6 signals were shifted,
implying substitution by primary hydroxy groups.
1
The H NMR spectrum of derivative VII contained
O
HO
O
IX
HNEt2
O
O
II + Et2NP
O
2
P(NEt2)3
VIII
XI
HOCH2C6H5
X
III + Et2NP(OCH2C6H5)2
HNEt2
XII
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 76 No. 10 2006

MILD REGIOSELECTIVE PHOSPHORYLATION OF -CYCLODEXTRIN
1535
We found that in our case alcohols IX and X do
not enter phosphorylation in pyridine at 20 C at all.
The reaction starts at 70 C and is complete in 3 h.
The 31P NMR spectrum of the reaction mixture con-
tained, along with expected compounds II and III
with 5 ml of diethyl ether. Compound VI was filtered
off and washed with ether (2 5 ml). The solvents
were removed in a vacuum, and the powder-like
yellowish product was kept for 4 h at 70 C in a
vacuum (1.5 mm Hg). Yield 1.74 g (78 %), decomp.
point 208 210 C, Rf 0.75. 1H NMR spectrum (DMSO-
(
136 ppm), up to 15 20 mol% of phosphorous
P
amidodiesters XI and XII (
148 ppm). It is
3
important to note that on introduPction to this reaction
mixture of the corresponding quantity of -cyclodex-
trin diamidoesters II and III react with it even at 20 C
to form phosphorous amidodiesters IV and V, respect-
ively, as noted above for the reaction of individual
diamidoesters II and III with -cyclodextrin. Note-
worthy, amidodiesters XI and XII formed by side
reactions do not react with -cyclodextrin under these
conditions, due, probably, to steric hindrances from
their bulky substituents. This observation gives further
evidence for our assumption that it is the cyclodextrin
cavity that is responsible for the mild phosphorylation
conditions of -cyclodextrin with P(III) acid diamides.
d6), , ppm: 1.12 t [12 H, N(CH2CH3)2; JHCCH
7.2 Hz], 1.27 s (12H), 1.33 s (12H) [C(CH3)2], 2.91 q
3
[8H, N(CH2CH3)2; JHCCH 7.5 Hz], 3.1 4.3 m (42H;
C2H C5H, C6H2), 4.50 br.s (5H, C6OH), 4.84 d (7H,
C1H), 5.75 br.s (14H; C2OH, C3OH). 13C NMR spec-
trum (DMSO-d6), C, ppm: 11.1 14.1 [(CH3CH2)2N],
25.3, 26.6 [C(CH3)2], 41.3 [(CH3CH2)2N], 59.6
(C6OH), 63.1 (POCH2CHCH2O), 65.4 (C6OP), 66.5
(POCH2CHCH2O), 70.0 (C5C6OP), 72.5 73.6 (C2, C3,
C5, POCH2CHCH2O), 81.5 (C4), 101.9 (C1), 108.8
[C(CH3)2]. 31P NMR spectrum (pyridine):
76 ppm.
Found, %: C 44.26; H 6.59; P 3.74. C62HP110O41N2
P2S2. Calculated, %: C 44.71; H 6.66; P 3.72.
Thus, our present research opens up new possibi-
lities for mild regioselective synthesis of such prac-
tically important compounds as phosphorylated
-cyclodextrins.
6I,6II-Bis-O-[(benzyloxy)(diethylamino)phos-
phinothioyl]- -cyclodextrin (VII). To a solution of
1.8 g of -cyclodextrin in 10 ml of pyridine, 1.33 g of
benzyl tetraethylphosphorodiamidite was added drop-
wise with stirring at 20 C. The reaction mixture was
stirred for 12 h at 20 C. 31P NMR spectrum of the
EXPERIMENTAL
1
The H and 13C NMR spectra were registered on a
reaction mixture (compound V):
148 ppm. Finely
ground sulfur, 0.15 g, was then adPded to the reaction
mixture, and stirring was continued for 2 h at 20 C.
The residual sulfur was filtered off, the solvent was
distilled off in a vacuum, and the oily residue was
triturated with 5ml of diethyl ether. Compound VII
was filtered off and washed with ether (2 5 ml). The
solvents were removed in a vacuum, and the powder-
like light brown product was dried at 70 C in a
vacuum (1.5 mm Hg) for 4 h. Yield 1.61 g (78 %),
decomp. point 210 212 C, Rf 0.71. 1H NMR spectrum
Bruker AC-200 instrument at 200 and 50.32 MHz,
respectively. The chemical shifts are given relatively
to internal TMS.
The 31P NMR spectra were registered on a Bruker
WP-80 instrument at 32.4 MHz, external reference
85% H3PO4.
All syntheses with trivalent phosphorus compounds
were performed under dry argon in an anhydrous
solvent purified by a conventional procedure.
Thin-layer chromatography was performed on Si-
lufol UV-254 plates in the system acetonitrile water
25% ammonia, 6:3:2.
6I,6II-Bis-O-[(diethylamino)(2,2-dimethyl-1,3-
dioxolan-4-yloxy)phosphinothioyl]- -cyclodextrin
(VI). To a solution of 1.8 g of -cyclodextrin in 10 ml
of pyridine, 1.44 g of 1,2-O-isopropylideneglycerol
tetraethylphosphorodiamidite was added dropwise
with stirring at 20 C. The reaction mixture was stirred
for 12 h at 20 C. 31P NMR spectrum of the reaction
(DMSO-d6), , ppm: 3.20 4.30 m (42H; C2H C5H,
C6H2), 4.50 br.s (5H, C6OH), 4.84 br.s (7H, C1H),
5.75 br.s (14H; C2OH, C3OH), 7.37 s (10H, C6H5).
31P NMR spectrum (pyridine ): P 76 ppm. Found, %:
C 44.04; H 6.30; P 3.85. C64H102O37N2P2S2. Calcu-
lated, %: C 47.52; H 6.36; P 3.83.
ACKNOWLEDGMENTS
This work was financially supported by the Rus-
sian Foundation for Basic Research (project no. 05-03-
33083a) and by the Grant of the President of the Russian
Federation for Support of Leading Scientific Schools
of the Russian Federation (no. NSh-5515.2006.3).
mixture (compound IV):
148 ppm. Finely ground
P
sulfur, 0.15 g, was then added to the reaction mixture,
and stirring was continued for 2 h at 20 C. The re-
sidual sulfur was filtered off, the solvent was distilled
off in a vacuum, and the oily residue was triturated
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GRACHEV et al.
7. Grachev, M.K., Senyushkina, I.A., Kurochkina, G.I.,
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