Chemospecific monofunctionalization of α-cyclodextrin in the solid state

Article abstract of DOI:10.1021/ol9912635

(matrix presented) The properties of the self-assembling aziadamantane inclusion complex with two α-cyclodextrin molecules have been exploited to perform a chemospecific monofunctionalization of α-cyclodextrin. The insertion of the photochemically generated carbenes takes place chemospecifically into the cyclodextrin's C-3-OH and C-2-OH bonds in 39 and 18% yield, respectively. This model reaction surpasses conventional methods in terms of yield as well as selectivity.

Full text of DOI:10.1021/ol9912635

ORGANIC
LETTERS
2000
Vol. 2, No. 3
315-318
Chemospecific Monofunctionalization of
r-Cyclodextrin in the Solid State†
Daniel Krois, Michael M. Bobek, Andreas Werner,‡ Hanspeter Ka1hlig, and
,§
Udo H. Brinker*
Institut fu¨r Organische Chemie der UniVersita¨t Wien, Wa¨hringer Strasse 38,
A-1090 Wien, Austria
udo.brinker@uniVie.ac.at
Received November 19, 1999
ABSTRACT
The properties of the self-assembling aziadamantane inclusion complex with two r-cyclodextrin molecules have been exploited to perform a
chemospecific monofunctionalization of r-cyclodextrin. The insertion of the photochemically generated carbenes takes place chemospecifically
into the cyclodextrin’s C-3-OH and C-2-OH bonds in 39 and 18% yield, respectively. This model reaction surpasses conventional methods in
terms of yield as well as selectivity.
The preparation of monofunctionalized cyclodextrins (Cy’s)
continues to attract much interest.1 These toroidal-shaped
cyclic oligosaccharides have been used in numerous instances
as catalysts and enzyme mimics.2 For such endeavors, the
secondary hydroxyl groups, or their corresponding O-
derivatives, on C-2 and C-3 (on the wider aperture) perform
a more important role than their primary counterparts on C-6,
which lie on the opposite face.3
selectively modify the hydroxyl groups on C-2, C-3, or
both.5-7 Multistep procedures are required, and direct func-
tionalizations of the C-3 hydroxyl group suffer from very
low product yields of less than 20%.8 Often, in addition to
monofunctionalized Cy’s, formation of several di- and
oligosubstituted compounds occurs,9 which accounts for the
low recovery no greater than 40%.7-9 In light of these
difficulties, a supramolecular approach should be much more
fruitful (see Scheme 1).
While several methods have been developed to transform
the C-6 positions,4 it remains a synthetic challenge to
Scheme 1
† Carbene Rearrangements. 52. For part 51, see: Brinker, U. H.; Miebach,
T. J. Org. Chem. 1999, 64, 8000-8003.
‡ Deceased.
§ Phone: (43)-1-4277-52121. Fax: (43)-1-4277-52140.
(1) Wenz, G. Angew. Chem., Int. Ed. Engl. 1994, 33, 803-822.
(2) (a) Murakami, Y.; Kikuchi, J.-I.; Hisaeda, Y.; Hayashida, O. Chem.
ReV. 1996, 96, 721-758. (b) Breslow, R.; Dong, S. D. Chem. ReV. 1998,
98, 1997-2011.
(3) D’Souza, V. T.; Bender, M. L. Acc. Chem. Res. 1987, 20, 146-152.
(4) (a) Sallas, F.; Leroy, P.; Marsura, A.; Nicolas, A. Tetrahedron Lett.
1994, 35, 6079-6082. (b) Matsui, Y.; Okimoto, A. Bull. Chem. Soc. Jpn.
1978, 51, 3030-3034. (c) Fu¨gedi, P.; Nanasi, P.; Szejtli, J. Carbohydr.
Res. 1988, 175, 173-81. (d) Petter, R. C.; Salek, J. S.; Sikorski, C. T.;
Kumaravel, G.; Lin, F.-T. J. Am. Chem. Soc. 1990, 112, 3860-3868.
10.1021/ol9912635 CCC: $19.00 © 2000 American Chemical Society
Published on Web 01/20/2000

First, a stoichiometric complex is formed with a reagent
bearing an appropriate trigger. A subsequent activation step
initiates a reaction between the guest and Cy molecules, most
likely in a selective way. Inclusion of precursor reagents into
the Cy cavity prior to activation has been claimed in several
cases in solution.10 Here, however, ligand exchange can
inhibit selectivity. Until now, only one functionalization by
a solid-state reaction has been reported.11 This attempt,
however, suffered from very low isolated yields (4-12%)
and only modest chemoselectivity.
Recently, we described the formation of a well-character-
ized 1:2 complex of aziadamantane (1) with R-cyclodextrin
(6-Cy).12 It was shown by UV-vis spectroscopy and circular
dichroism (CD) that the sparingly soluble 1@2(6-Cy)
complex experienced strong noncovalent interactions be-
tween guest and host, even in dilute solution.12 This should
also be the case for the solid complex itself. Diazirines13 are
convenient and popular precursors of carbenes. Upon photo-
chemical or thermal activation, they react readily with
hydroxyl groups to form ethers.14 Some years ago, we began
to investigate the reaction behavior of these carbene precur-
sors entrapped within the cavities of 7-Cy’s and found
markedly different carbene selectivities.15 With this back-
ground, the 1@2(6-Cy) system seemed very promising to
test the supramolecular approach to monofunctionalization
as outlined above.
Table 1. Product Distributions (mol percent) Obtained After
Photolysis in the Solid State and in Aqueous Solution by
Quantitative GC and RP-HPLC
photolysis of 1@2(6-Cy)
solid state
aqueous solutiona
2
3
4
5
39
18
31
9
15
9
13
2
6
1
1
55
1
2-ethoxyadamantane
a Clear solution of 1 (7.0 × 10-4 M) and 6-Cy (5.7 × 10-3 M) in water
and 0.7% v/v ethanol; under this condition >90% of 1 is present as 1@2(6-
Cy) as verified by UV-vis and CD spectroscopy.
and 11% yield (based on 1), respectively. The total recovery
of cyclodextrins amounted to ca. 90%.16
The structure of the 2-adamantyl-substituted cyclodextrins
was established by homo- and heteronuclear 2D NMR
spectroscopy in water-d2. The linkage positions were deter-
mined from pulsed field gradient enhanced HMBC spectra.
The major isomer shows cross-peaks over three bonds
between the H-3′ of one glucose unit and the C-2 of the
adamantane moiety and between the corresponding glucose
C-3′ and adamantane H-2 signals, respectively. In addition,
Photolysis of 1@2(6-Cy) in the solid state was performed
at 20-30 °C under reduced pressure of argon for 6 h
(Scheme 2).16 Subsequent liquid-liquid extraction gave the
product distribution shown in Table 1.
(10) (a) McAlpine, S. R.; Garcia-Garibay, M. A. J. Am. Chem. Soc. 1996,
118, 2750-2751. (b) Onozuka, S.; Kojima, M.; Hattori, K.; Toda, F. Bull.
Chem. Soc. Jpn. 1980, 53, 3221-3224. (c) Takahashi, K.; Hattori, K.; Toda,
F. Tetrahedron Lett. 1984, 25, 3331-3334. (d) Komiyama, M.; Hirai, H.
J. Am. Chem. Soc. 1983, 105, 2018-2021.
(11) (a) Smith, S. H.; Forrest, S. M.; Williams, D. C.; Cabell, Jr. M. F.;
Acquavella, M. F.; Abelt, C. J. Carbohydr. Res. 1992, 230, 289-297. (b)
Abelt, C. J.; Lokey, J. S.; Smith, S. H. Carbohydr. Res. 1989, 192, 119-
130. (c) Abelt, C. J.; Pleier, J. M. J. Org. Chem. 1988, 53, 2159-2162.
(12) Krois, D.; Brinker, U. H. J. Am. Chem. Soc. 1998, 120, 11627-
11632.
Scheme 2
(13) (a) Chemistry of Diazirines, Volumes I and II; Liu, M. T. H., Ed.;
CRC: Boca Raton, 1987. (b) Kupfer, R.; Rosenberg, M. G.; Brinker, U.
H. Tetrahedron Lett. 1996, 37, 6647-6648.
(14) For reactions of carbenes with alcohols, see: Kirmse, W. In
AdVances in Carbene Chemistry, Volume I; Brinker, U. H., Ed.; JAI:
Greenwich, 1994; pp 1-57.
(15) (a) Brinker, U. H.; Buchkremer, R.; Kolodziejczyk, M.; Kupfer,
R.; Rosenberg, M.; Poliks, M. D.; Orlando, M.; Gross, M. L. Angew. Chem.,
Int. Ed. Engl. 1993, 32, 1344-1345. (b) Brinker, U. H.; Rosenberg, M. G.
In AdVances in Carbene Chemistry, Volume II; Brinker, U. H., Ed.; JAI:
Stamford, 1998; pp 29-44.
(16) 1@2(6-Cy)12 (1.08 g, content 96%, 0.49 mmol) was photolyzed
for 6 h at 20 °C under reduced pressure of argon using a medium-pressure
mercury lamp (Heraeus TQ718-Z4, 700 W, doped with FeI2). The solid
was dissolved in 300 mL of water and continuously extracted with
dichloromethane to remove all products of 1 which were not covalently
bound to 6-Cy. Their identification and quantification was accomplished
by GC (FID) by comparison with standard samples (see Table 1). After
the water was evaporated in vacuo, the residue (1.08 g) was dissolved in
the minimum amount of water-methanol (7/3) (ca. 35 mL). A small aliquot
(corresponding to ca. 5 mg) was diluted to give a water-methanol (6/4)
mixture and was analyzed by analytical RP-HPLC [HP-1090 instrument
equipped with the RI-detector HP1047 and the interface 35900E (Hewlett-
Packard) using a Nucleosil 100-5C18 5 µm column (4 × 290 mm, FZ
Seibersdorf)]; isocratic elution with 0.5 mL/min gave, by comparison with
standards, the quantified distribution of water-soluble products (Table 1).
Preparative RP-HPLC purification was accomplished [Pump AP-250-150
(Armen Instruments) equipped with a preparative differential refractometer
type 98100 (Knauer) using a Lichrospher RP18 7 µm column (50 × 220
mm, Merck)]; isocratic elution with water-methanol (7/3) (30 mL/min flow
at 37 bar) yielded 204 mg of 2 (34%) and 69 mg of 3 (11%). In addition,
704 mg of unsubstituted R-Cy’s (0.65 mmol) (eluted as first fraction) were
recovered which consisted of pure 6-Cy and 10-15% of oxidized 6-Cy as
shown by UV-vis; total recovery of 6-Cy was thus 89%.
Preparative reversed phase (RP) HPLC afforded three well-
separated fractions. After elution of unsubstituted R-cyclo-
dextrins, two monosubstituted isomers were collected in 34
(5) Khan, A. R.; Forgo, P.; Stine, K. J.; D’Souza, V. T. Chem. ReV.
1998, 98, 1977-1996.
(6) Fukudome, M.; Okabe, Y.; Yuan, D.-Q.; Fujita, K. Chem. Commun.
1999, 1045-1046.
(7) (a) Yuan, D.-Q.; Ohta, K.; Fujita, K. Chem. Commun. 1996, 821-
822. (b) van Dienst, E.; Snellink, B. H. M.; Piekartz, I. v.; Grote Gansey,
M. H. B.; Venema, F.; Feiters, M. C.; Nolte, R. J. M.; Engbersen, J. F. J.;
Reinhoudt, D. N. J. Org. Chem. 1995, 60, 6537-6545.
(8) (a) Tian, S.; Forgo, P.; D’Souza, V. T. Tetrahedron Lett. 1996, 37,
8309-8312. (b) Iwakura, Y.; Uno, K.; Toda, F.; Onozuka, S.; Hattori, K.;
Bender, M. L. J. Am. Chem. Soc. 1975, 97, 4432-4434.
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Koga, T. J. Am. Chem. Soc. 1986, 108, 2030-2034.
316
Org. Lett., Vol. 2, No. 3, 2000

NOE cross-peaks between the glucose H-3′ and adamantane
H-2 protons in a 2D NOESY spectrum confirmed the
structure of the major compound to be 3-O-(2-adamantyl)-
R-cyclodextrin (2).17 Furthermore, many NOE signals were
observed between the 6-Cy and the pendent adamantane
(Figure 1). Weak cross-peaks between adamantyl protons
The conformational differences of 2 and 3 in aqueous
solution account for the large differences in their retention
times in RP-HPLC. Clearly, compound 2 with its adamantyl
moiety partially submerged in the cyclodextrin cavity is much
less lipophilic and, therefore, is eluted prior to compound 3,
which has its adamantyl pendant exposed to the solvent.
The exclusive formation of adamantyl ethers 2 and 3
resulting from an innermolecular18 reaction of adamanta-
nylidene with the secondary hydroxyl groups, which are all
at the wider rim of the cyclodextrin, must reflect the special
structure of complex 1@2(6-Cy). In a previous report, we
proposed four different possible arrangements12 for this
complex, based on UV-vis and CD spectra. All would
account for the apparent nonpolar environment of the
diazirine chromophore even in the extremly polar aqueous
solution. The astounding chemospecifity of the reacting
carbene intermediate with the secondary hydroxyl groups can
be best explained by structure A (Figure 2). Moreover, strong
Figure 2. Arrangement for the 2:1 complex 1@2(6-Cy) as
proposed in ref 12.
evidence for this symmetric arrangement of guest and host
molecules is presented by a 2D ROESY experiment in water-
d2 which shows only cross-peaks between the H-3 protons
of 6-Cy and all adamantyl protons. Thus, all parts of the
adamantane structure are in close proximity to the 2- and
3-hydroxyl groups of the two cyclodextrin host molecules.
This explains why no reaction of the carbene with the C-6-
OH groups took place. Furthermore, the preferred insertion
of adamantanylidene into the C-3-OH group of 6-Cy (ratio
of 2:3 ca. 2-3) is of great synthetic value since this position
had been accessible only in reasonable yields by multistep
procedures.6,7,8a
The superiority of the solid-state approach for monofunc-
tionalization of cyclodextrins becomes obvious when com-
pared with the photolysis of 1@2(6-Cy) in aqueous solution.
As expected, under these conditions, 2-adamantanol (6) is
formed as the major product (see Table 1). In contrast to
the solid-state reaction, however, the yields of the innermo-
lecular insertion products 2 and 3 are reduced by a factor of
more than two. Besides its main reaction with water
molecules, the liberated adamantanylidene shows a reaction
behavior which parallels that in the solid state. Moreover,
the results in the table suggest that 1@2(6-Cy)-even in
Figure 1. 2D NOESY spectrum of 2 showing strong interactions
between the adamantyl moity (f1 axis) and the 6-Cy (f2 axis).
away from the linkage position, i.e., H-6,7,8 and protons H-5
of unsubstituted glucose units were most instructive because
this implies a partially submerged orientation of the ada-
mantyl pendant in the cyclodextrin cavity. The minor isomer
was characterized also by a three-bond HMBC cross-peak
from a glucose H-2′ to the adamantane C-2 signal as 2-O-
(2-adamantyl)-R-cyclodextrin. The 2D NOESY spectrum
shows only a few cross-peaks between the two distinct parts,
proving a relative orientation of the adamantyl moiety outside
the cyclodextrin ring. This confirms the structure for 2-O-
(2-adamantyl)-R-cyclodextrin (3).17
(17) Selected analytical data. 2: mp ) 285-288 °C (dec), [R]20
)
D
+145°, [R]20546 ) +173° (c ) 1.02, pyridine containing 5% water). FAB-
MS: 1107 (M + 1+). Anal. Calcd for C46H74O30‚4H2O (1179.14): C, 46.86;
H, 7.01. Found: C, 44.72; H, 6.71 (corresponding to a content of 96%). 3:
no mp up to 330 °C (dec), [R]20 ) +104°, [R]20 ) +123° (c ) 0.76,
D
546
pyridine containing 5% water). FAB-MS: 1107 (M + 1+). Anal. Calcd for
C46H74O30‚5H2O (1197.16): C, 46.15; H, 7.07. Found: C, 43.85; H, 6.74
(corresponding to a content of 95%).
(18) Warmuth, R. Chem. Commun. 1998, 59-60.
Org. Lett., Vol. 2, No. 3, 2000
317

solution-exists as a complex that structurally resembles the
one in the solid state.
In conclusion, the supramolecular approach to monofunc-
tionalized cyclodextrins in the solid state described here
combines chemospecificity with high yields of products,
which by other methods are only difficult to obtain.
(project P12533-CHE) for financial support and also to
Cerestar USA, Inc., and Wacker Chemie, Germany, for
providing the cyclodextrin used in our studies. Dedicated to
Professor Karl Schlo¨gl on the occasion of his 75th birthday.
Supporting Information Available: NMR data for
compounds 2, 3, and 1@2(6-Cy). This material is available
free of charge via the Internet at http://pubs.acs.org.
Acknowledgment. We are indebted to the Fonds zur
Fo¨rderung der wissenschaftlichen Forschung in O¨ sterreich
OL9912635
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Org. Lett., Vol. 2, No. 3, 2000