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A convenient method for functionalization of the 2-position of cyclodextrins
Te.tmhedrcm Lemm. Vol31. No.30.pp 42754278.1990 Printedin GreatBritain
00404039EJo 53.00+ .Oo Pqmon Presspk
A CONVENIENT METHOD FOR FUNC’IlONALIZA’iION
OF
THE 2-POSITION OF CYCLODEXTRINS Ding Rong and Valerian T. D’Sotua* Deparbnent of Chemistry,Universi(yof Missouri-St.Louis, St. Louis, MO 43121
Abstruct: A new convenient strategy for functionalktion of the 2-position of cyclodextrins involving deprotonation of cyclodexti by sodium hydride followed by a nucleophilic attack of the &taut cyclodextrin oxyauion on the desired ektrophile gives a high yield of the cyclodexuiu derivative. Cyclodextrins are cyclic oligosacchatides consisting of 6 (in a-), 7 (in j%)or 8 (ii y) glucose units linked togetherby u-1,4 linkages to form torus like saucture s. All the secondary hydmxyl gmups at the 2, and 3-positions oftheglucoseunitsareononesi&ofthe#rrusand~theprimaryhy~xylgroupsatthe6~tio~ofthtglucose units an on the other side of the ring.’ Cyclodextrins have gained prominence in recent years because their cavity, which is hydrophobic in natme, is capable of binding ammatic and other small organic molecules and &z&m provide ideal binding sites to which catalytic functional groups can be attached to form enyme environments at the primary aud the w
sides ofcyclodexlrin.9 afe difkent
mimk2
The
and hence tknctionakakn
with
catalytic groups at each of these sites can yield enzyme mimics with diffkrent selectivities. functionalization of the primary and the sccondq
Several strategies have been developed to selectively functional& the seco&ry
groups? but the complexity of the problem is kreased
(mono-, di-, etc.) is deshed
Selective
hydroxyl groups is complicated by statistical and steric problems. either all the prirxuq hydmxyl gmups3 or all if control on the degtee of functionakakm
Methods available to achieve such control often are cum&
or provi& low yield
of the product.6 Among these methods, selective monotosylation at the 6positions is nlatively easy and pmvide masonable a yield of the 6tosyl cyclodexti?
Thus catalytic groups attached to the 6positions of cyclodextks
have played a major role in enzyme mimic chemistry.8 imporknt
However,thesecondarysideisshowntobethemme
side of cyclodextrin in binding studies? Although functionalkadon
of the secondaty side are molt
difiicult, they are more important in the design and synthesis of enzyme mimics. The conventional method to modify cyclodexlrins
at the secondary side’o involves tosylation by group transfer followed by au iutiamolecular
nucleophilic substitution by the oxygen atom at tht 3-position to give manno-2,3-epoxide.”
Riug opening of the
epoxide by a nucleophile of the desired catalytic moiety yields g slightly distorted cyclodextrin with one glm converted to &rose.
We now report a simple mthod
for the monofunction&adon
unit
of cyclodextrins at the 2-
position. We have also extended this method to functionalize selectively all the hydroxyl groups at the 2-positions. The strategy involves deprotonation of the hydmxyl group at the 2-position witb sodium hydride to afford 4275
4276
the cyckldextrin oxyanion (2) aud then reacdon of the oxyanion (2) with an elec@ophilic nagellt to yield exclusively the Zsubstituted cyclodextria.
The degree functionalization can be achieved by controlling the amount of sodium
hydride used in the naction.
1
CHGH
C&OH
U&OH
2 RXlSANRU3CTROPHlL3CRRAGRNT; R IS
XISAUMYINOGRGU?AND
TRB DESIRRD FUNCTIONALGRGUP.
We now describe iu some detail the experimental procedun? used to prepare 2-0-(4-methylamino-3nitro)benzyl-~yclodexhin 40 ml DMF (tied
(3). To a solution of lg (0.88 mmoles) of ~cyclodextxin (dried overnight at 117°C) iu
over CaH) was added 35 mg (60% in oil, 0.88 mmoles) of NaH and the mixture was stined
overnight until the solution became clear. This solution was added drop wise to a solution of 0.173g (0.88 mmoles) of N-methyM-chloro~thyl-2-nitmaniEne 30 min. ~Cyclodextrin
in 5ml DMF with stirring and allowed to stand at room temperatuxe for
and its derivatives were precipitated out by addition of 500 ml of acetone. The pn&pitate
was filtemd and washed with 100 ml of acetone to nzmove all the unreacted reagent and to give almost quantitative recovery of cyclodextrin products. TLC on silica gel using n-butanol, ethanol, water (5:4:3 by volume) showed two spots one at Rf = 0.35 for cyclodextrin and another at Rf = 0.54 for the product (3). The mixture was separated by Sephadex chromatography to furnish 0.40 g (35% yield) of the pure yellow product. Proton NMR (Me#O-&) the product gave peaks at 6 2.96 (3H, d, J=4.9Hx, N-CHS), 7.01 (U-l, d, .M.lHz,
5-H), 7.60 (U-I, d, J=8.8Hz, 6-H).
8.07 (lH, s, 2-H), 8.21 (lH, m, N-H) for the substituent and all the normal peaks for cyclodextrin. product showed peaks at 29.8 (N-CIQ,
of
13C NMR of the
114.8, 124.5, 126.1, 130.5, 137.4, 145.9 for the aromatic carbons and the
six normal peaks for cyclodextrin and the peaks for the substituted glucose unit as shown in Fig. 1. As elegantly explained by Breslow,” a large downfield chemical shift of C-2 and a small upfield chemical shift of C-3 aad no change in the shit of C-6 of the substituted glucose unit with respect to unsubstituted glucose units clearly indicate that the substituent is at the Zposition of cyclodexhin.
4211
6
.
.
rII.~IIIr~l'
II
Figure 1.
11’1
II
11
I
60
100
I
111
60
The 13C NMR spectnun of 2-0-(4-methyl~~3-~~)~~l-itro>benzyl-gcyclode in DMSO_ds in the carbohydrate region.
Signals for the substituent are not shown.
‘I&e numbers indicate the peak
assignments.
Reaction of 2.878 (2.53 mmoles) of ~-cyclodextrin with 0.48Og (2.53 mmoles) of tosyl chloride as described above and work up as prescribed by Bres10w’~ gave 1SOg of the crude pmd~.~~ amounts of cyclodextrin, pndominance
(ca. 70% by ‘H NMR) of the 2-tosylate (4)
ditosylates as the major side product (ca. 30% by ‘H NMR). authentic 2-tosyl-@cyclodextriu qczted
TLC anslysis showed negligible
1Hand13CNMRspectrawezeidemicaltothe
in refemnce 10. Attempts to optimize tbe react&~ yield by averse add&ion
and by varying the amounts of NaH and tosyl chloride used did not increase the yield of 2tosyLJ3-cyclodext& To functional&
all the hydroxyl groups at the 2-position of cyclodextrh~ l.Og (0.88 mmoles) of j3-
cyclodextrin was reacted with 7 eq. of NaH (0.246g, 60% in oil, 6.16 mmoles) and 7 eq. of methyl iodide (0.88g, 6.16 mmoles) in DMSO following a @me heptakis(2-0~methyl)-~-cyclodexuin.
similar to that described above to affotd 0.9Og (83% yield) of
TLC using the same solvent system as above showed one spot at Q = 0.43
aud the 13C NMR spectrum showed 7 peaks at 59.5 (C!H+),
59.8 (C-a), 71.5 (C-5). 72.8 (C-3), 81.9 (C-2). 82.1
(C-4). 99.7 (C-l) indicating that the substitutions have taken place at the 2-position. Of the three types of cyclodextrin hydroxyl groups (at 2-, 3- snd 6- positions) those at the 3-position ate the least reactive and resist functions&a&n.
This has been attributed to the hydrogen bonds formed between the protons
of the hydroxyl groups at the 3-position and the oxygen at&m of the hydmxyl groups at the 2-positkn~~~ The hydroxyl groups at the 6-position a~ most nactive towards electrophilic nagents because they m primary hydmxyl groups and their pK, can be compared with other primary hydroxyl groups (PK, = 15-16). Thus, cmmtional
4218
methods of tosylation using tosyl chloride in pyridine yields pqonderance
of dtosyl derivatives.
The hydmxyl
gmups at the 2position BTCthe most acidic of the three hydroxyl groups with apK, of 12.1. This can be attributed to the hydrogen bond between the hydroxyl groups at 2 and 3-positions described above which can stabilize the oxyanion.
This can also be attributed in part to the proximity of this hydroxyl group to the electron withdrawing
acetal functionality. at Qosition
‘Ihe most acidic hydroxyl group in an unsubstituted methyl glucoside is known to he the one
with a pK,, of 12.35. l4 The carbohydrate oxyanions are known to be attacked by electrophilic magents
at the 2-position for this =ason.15
Thus, it is not surprising that the oxyanions of cyclodextrin are attackd by
electmphiles in a similar manner providing a convenient method to funtionalize them at the 2-position. It is possible that the active base in this reaction is the hydroxide ion formed due to insufficient drying of cyclodextrin in this mthod aud the low pK, of the hydtoxyl gmup involved
However, use of potassium hydroxide as a base in this
method affolded only the starting ma&riaL16 Earlier attempts to synthesize 2-tosyl+cyclodextrin
using aqueous
hydroxide ion had resulted in 6tosyl-P_cyclode~trin.~~ ‘Ike mthod desuibcd here avoids steteochemical conversions as in the conventional method and presumably does not alter the srruchue of cyclodextrin. We are in the process of utilizing this technique to synthesize ardfkkl redoxenzyms. AC~OW~GEiUEhV’Sz
Support of this work by the University of Missouri-St. Louis, Mallinckrodt, Inc. the
Missouri Research Assistance Act and the Petroleum Research Fund is gratefully acknowledged REFERENCES 1.
Bender, M. L.; Komiyama, M. CycZo&aTri!~Chemistry; Springer-Verlag: New York, 1978.
2.
D’Souza, V. T.; Bender, M. L. Act. Chem. Res. 1987,20, 146.
3.
Fujita, IL; Yamamura, &; Matsunaga, A.; Imoto, T. Mihashi, K. Fujioka, T. J. Am. Chem. Sec. l986.108, 4509.
4.
Takeo, K.; Uemura, IL; Mitoh, M. J. Carbohydrate Chem. 1988,7,293.
5.
Murakami, T.; Harata, K.; Morimoto, S. Tetrahedron L&t. I!M7,28,321.
6.
Takaha&i, t; Hattori, K., Toda, F. Tetrahedron Left. 1984,25,3331.
7.
Melton, L. D.; Slesser, K. N. Carbohydrate. Res. 1971, 19, 29.
8.
Breslow, R Cold Spring Harbor Symp. Quant.Biol., 1987,52,75.
9.
Van l&en, R. C.; Sebastian, J. F.; Clowes, G. A.; Bender, M. L. J. Am. Chem. Sot. 1%7,69,3242.
10.
Ueno, A.; Breslow, R. TetrahedronL&t. 1982,23,3451.
11.
Breslow, R. and Czamik, A. W. J. Am. Chem. Sot. 1983,105, 1390.
12.
Mkmanalysis
13.
Menger, F. M.; Dulany, M. A. Tetrahedron L&t. 1985,26,267
14.
Rendleman, J. A. Carbohyhtes in Solution;Gould, R. F. Ed.; Advances in Chemistry Series 117, Americaa Chemical Society: Washington DC, 1973, ~54.
15.
Rowland, S. P. Carbohyd. Res. 1971,16.243.
16.
Authors acknowledge the referee’s comments leading to this observation.
of the crude product indicate the presence of 6.36% inorganic residue.
(Received in USA 9 April 1990, accepted 6 June 1990)
00404039EJo 53.00+ .Oo Pqmon Presspk
A CONVENIENT METHOD FOR FUNC’IlONALIZA’iION
OF
THE 2-POSITION OF CYCLODEXTRINS Ding Rong and Valerian T. D’Sotua* Deparbnent of Chemistry,Universi(yof Missouri-St.Louis, St. Louis, MO 43121
Abstruct: A new convenient strategy for functionalktion of the 2-position of cyclodextrins involving deprotonation of cyclodexti by sodium hydride followed by a nucleophilic attack of the &taut cyclodextrin oxyauion on the desired ektrophile gives a high yield of the cyclodexuiu derivative. Cyclodextrins are cyclic oligosacchatides consisting of 6 (in a-), 7 (in j%)or 8 (ii y) glucose units linked togetherby u-1,4 linkages to form torus like saucture s. All the secondary hydmxyl gmups at the 2, and 3-positions oftheglucoseunitsareononesi&ofthe#rrusand~theprimaryhy~xylgroupsatthe6~tio~ofthtglucose units an on the other side of the ring.’ Cyclodextrins have gained prominence in recent years because their cavity, which is hydrophobic in natme, is capable of binding ammatic and other small organic molecules and &z&m provide ideal binding sites to which catalytic functional groups can be attached to form enyme environments at the primary aud the w
sides ofcyclodexlrin.9 afe difkent
mimk2
The
and hence tknctionakakn
with
catalytic groups at each of these sites can yield enzyme mimics with diffkrent selectivities. functionalization of the primary and the sccondq
Several strategies have been developed to selectively functional& the seco&ry
groups? but the complexity of the problem is kreased
(mono-, di-, etc.) is deshed
Selective
hydroxyl groups is complicated by statistical and steric problems. either all the prirxuq hydmxyl gmups3 or all if control on the degtee of functionakakm
Methods available to achieve such control often are cum&
or provi& low yield
of the product.6 Among these methods, selective monotosylation at the 6positions is nlatively easy and pmvide masonable a yield of the 6tosyl cyclodexti?
Thus catalytic groups attached to the 6positions of cyclodextks
have played a major role in enzyme mimic chemistry.8 imporknt
However,thesecondarysideisshowntobethemme
side of cyclodextrin in binding studies? Although functionalkadon
of the secondaty side are molt
difiicult, they are more important in the design and synthesis of enzyme mimics. The conventional method to modify cyclodexlrins
at the secondary side’o involves tosylation by group transfer followed by au iutiamolecular
nucleophilic substitution by the oxygen atom at tht 3-position to give manno-2,3-epoxide.”
Riug opening of the
epoxide by a nucleophile of the desired catalytic moiety yields g slightly distorted cyclodextrin with one glm converted to &rose.
We now report a simple mthod
for the monofunction&adon
unit
of cyclodextrins at the 2-
position. We have also extended this method to functionalize selectively all the hydroxyl groups at the 2-positions. The strategy involves deprotonation of the hydmxyl group at the 2-position witb sodium hydride to afford 4275
4276
the cyckldextrin oxyanion (2) aud then reacdon of the oxyanion (2) with an elec@ophilic nagellt to yield exclusively the Zsubstituted cyclodextria.
The degree functionalization can be achieved by controlling the amount of sodium
hydride used in the naction.
1
CHGH
C&OH
U&OH
2 RXlSANRU3CTROPHlL3CRRAGRNT; R IS
XISAUMYINOGRGU?AND
TRB DESIRRD FUNCTIONALGRGUP.
We now describe iu some detail the experimental procedun? used to prepare 2-0-(4-methylamino-3nitro)benzyl-~yclodexhin 40 ml DMF (tied
(3). To a solution of lg (0.88 mmoles) of ~cyclodextxin (dried overnight at 117°C) iu
over CaH) was added 35 mg (60% in oil, 0.88 mmoles) of NaH and the mixture was stined
overnight until the solution became clear. This solution was added drop wise to a solution of 0.173g (0.88 mmoles) of N-methyM-chloro~thyl-2-nitmaniEne 30 min. ~Cyclodextrin
in 5ml DMF with stirring and allowed to stand at room temperatuxe for
and its derivatives were precipitated out by addition of 500 ml of acetone. The pn&pitate
was filtemd and washed with 100 ml of acetone to nzmove all the unreacted reagent and to give almost quantitative recovery of cyclodextrin products. TLC on silica gel using n-butanol, ethanol, water (5:4:3 by volume) showed two spots one at Rf = 0.35 for cyclodextrin and another at Rf = 0.54 for the product (3). The mixture was separated by Sephadex chromatography to furnish 0.40 g (35% yield) of the pure yellow product. Proton NMR (Me#O-&) the product gave peaks at 6 2.96 (3H, d, J=4.9Hx, N-CHS), 7.01 (U-l, d, .M.lHz,
5-H), 7.60 (U-I, d, J=8.8Hz, 6-H).
8.07 (lH, s, 2-H), 8.21 (lH, m, N-H) for the substituent and all the normal peaks for cyclodextrin. product showed peaks at 29.8 (N-CIQ,
of
13C NMR of the
114.8, 124.5, 126.1, 130.5, 137.4, 145.9 for the aromatic carbons and the
six normal peaks for cyclodextrin and the peaks for the substituted glucose unit as shown in Fig. 1. As elegantly explained by Breslow,” a large downfield chemical shift of C-2 and a small upfield chemical shift of C-3 aad no change in the shit of C-6 of the substituted glucose unit with respect to unsubstituted glucose units clearly indicate that the substituent is at the Zposition of cyclodexhin.
4211
6
.
.
rII.~IIIr~l'
II
Figure 1.
11’1
II
11
I
60
100
I
111
60
The 13C NMR spectnun of 2-0-(4-methyl~~3-~~)~~l-itro>benzyl-gcyclode in DMSO_ds in the carbohydrate region.
Signals for the substituent are not shown.
‘I&e numbers indicate the peak
assignments.
Reaction of 2.878 (2.53 mmoles) of ~-cyclodextrin with 0.48Og (2.53 mmoles) of tosyl chloride as described above and work up as prescribed by Bres10w’~ gave 1SOg of the crude pmd~.~~ amounts of cyclodextrin, pndominance
(ca. 70% by ‘H NMR) of the 2-tosylate (4)
ditosylates as the major side product (ca. 30% by ‘H NMR). authentic 2-tosyl-@cyclodextriu qczted
TLC anslysis showed negligible
1Hand13CNMRspectrawezeidemicaltothe
in refemnce 10. Attempts to optimize tbe react&~ yield by averse add&ion
and by varying the amounts of NaH and tosyl chloride used did not increase the yield of 2tosyLJ3-cyclodext& To functional&
all the hydroxyl groups at the 2-position of cyclodextrh~ l.Og (0.88 mmoles) of j3-
cyclodextrin was reacted with 7 eq. of NaH (0.246g, 60% in oil, 6.16 mmoles) and 7 eq. of methyl iodide (0.88g, 6.16 mmoles) in DMSO following a @me heptakis(2-0~methyl)-~-cyclodexuin.
similar to that described above to affotd 0.9Og (83% yield) of
TLC using the same solvent system as above showed one spot at Q = 0.43
aud the 13C NMR spectrum showed 7 peaks at 59.5 (C!H+),
59.8 (C-a), 71.5 (C-5). 72.8 (C-3), 81.9 (C-2). 82.1
(C-4). 99.7 (C-l) indicating that the substitutions have taken place at the 2-position. Of the three types of cyclodextrin hydroxyl groups (at 2-, 3- snd 6- positions) those at the 3-position ate the least reactive and resist functions&a&n.
This has been attributed to the hydrogen bonds formed between the protons
of the hydroxyl groups at the 3-position and the oxygen at&m of the hydmxyl groups at the 2-positkn~~~ The hydroxyl groups at the 6-position a~ most nactive towards electrophilic nagents because they m primary hydmxyl groups and their pK, can be compared with other primary hydroxyl groups (PK, = 15-16). Thus, cmmtional
4218
methods of tosylation using tosyl chloride in pyridine yields pqonderance
of dtosyl derivatives.
The hydmxyl
gmups at the 2position BTCthe most acidic of the three hydroxyl groups with apK, of 12.1. This can be attributed to the hydrogen bond between the hydroxyl groups at 2 and 3-positions described above which can stabilize the oxyanion.
This can also be attributed in part to the proximity of this hydroxyl group to the electron withdrawing
acetal functionality. at Qosition
‘Ihe most acidic hydroxyl group in an unsubstituted methyl glucoside is known to he the one
with a pK,, of 12.35. l4 The carbohydrate oxyanions are known to be attacked by electrophilic magents
at the 2-position for this =ason.15
Thus, it is not surprising that the oxyanions of cyclodextrin are attackd by
electmphiles in a similar manner providing a convenient method to funtionalize them at the 2-position. It is possible that the active base in this reaction is the hydroxide ion formed due to insufficient drying of cyclodextrin in this mthod aud the low pK, of the hydtoxyl gmup involved
However, use of potassium hydroxide as a base in this
method affolded only the starting ma&riaL16 Earlier attempts to synthesize 2-tosyl+cyclodextrin
using aqueous
hydroxide ion had resulted in 6tosyl-P_cyclode~trin.~~ ‘Ike mthod desuibcd here avoids steteochemical conversions as in the conventional method and presumably does not alter the srruchue of cyclodextrin. We are in the process of utilizing this technique to synthesize ardfkkl redoxenzyms. AC~OW~GEiUEhV’Sz
Support of this work by the University of Missouri-St. Louis, Mallinckrodt, Inc. the
Missouri Research Assistance Act and the Petroleum Research Fund is gratefully acknowledged REFERENCES 1.
Bender, M. L.; Komiyama, M. CycZo&aTri!~Chemistry; Springer-Verlag: New York, 1978.
2.
D’Souza, V. T.; Bender, M. L. Act. Chem. Res. 1987,20, 146.
3.
Fujita, IL; Yamamura, &; Matsunaga, A.; Imoto, T. Mihashi, K. Fujioka, T. J. Am. Chem. Sec. l986.108, 4509.
4.
Takeo, K.; Uemura, IL; Mitoh, M. J. Carbohydrate Chem. 1988,7,293.
5.
Murakami, T.; Harata, K.; Morimoto, S. Tetrahedron L&t. I!M7,28,321.
6.
Takaha&i, t; Hattori, K., Toda, F. Tetrahedron Left. 1984,25,3331.
7.
Melton, L. D.; Slesser, K. N. Carbohydrate. Res. 1971, 19, 29.
8.
Breslow, R Cold Spring Harbor Symp. Quant.Biol., 1987,52,75.
9.
Van l&en, R. C.; Sebastian, J. F.; Clowes, G. A.; Bender, M. L. J. Am. Chem. Sot. 1%7,69,3242.
10.
Ueno, A.; Breslow, R. TetrahedronL&t. 1982,23,3451.
11.
Breslow, R. and Czamik, A. W. J. Am. Chem. Sot. 1983,105, 1390.
12.
Mkmanalysis
13.
Menger, F. M.; Dulany, M. A. Tetrahedron L&t. 1985,26,267
14.
Rendleman, J. A. Carbohyhtes in Solution;Gould, R. F. Ed.; Advances in Chemistry Series 117, Americaa Chemical Society: Washington DC, 1973, ~54.
15.
Rowland, S. P. Carbohyd. Res. 1971,16.243.
16.
Authors acknowledge the referee’s comments leading to this observation.
of the crude product indicate the presence of 6.36% inorganic residue.
(Received in USA 9 April 1990, accepted 6 June 1990)