Synthesis of cyclodextrin-based carbohydrate clusters by photoaddition reactions

Article abstract of DOI:10.1021/jo010705z

The syntheses of homogeneous cyclodextrin-based carbohydrate clusters, persubstituted with β-D-thioglucosyl or D-thiolactosyl residues on either (a) the primary face, (b) the secondary face, or (c) both the primary and the secondary faces of their cyclodextrin tori, are described. The key step in the synthetic methodology, namely the attachment of the carbohydrate residues to the cyclodextrin torus, proceeds in moderate-good yields (42-70%) by the photoaddition of thiol groups, positioned at the anomeric centers of the carbohydrate residues, to allyl ether functions on the cyclodextrins. Facile removal of protecting groups then affords the free cluster compounds. Extensive 1-D and 2-D NMR spectroscopic investigations were performed on these compounds to determine their structures and establish their homogeneities, and a brief computer molecular modeling study allowed estimates of the dimensions of the clusters to be determined.

Full text of DOI:10.1021/jo010705z

J . Org. Chem. 2001, 66, 8309-8319
8309
Syn th esis of Cyclod extr in -Ba sed Ca r boh yd r a te Clu ster s by
P h otoa d d ition Rea ction s
David A. Fulton and J . Fraser Stoddart*
Department of Chemistry and Biochemistry, University of California, Los Angeles, 405 Hilgard Avenue,
Los Angeles, California 90095-1569
stoddart@chem.ucla.edu
Received J uly 13, 2001
The syntheses of homogeneous cyclodextrin-based carbohydrate clusters, persubstituted with â-D-
thioglucosyl or D-thiolactosyl residues on either (a) the primary face, (b) the secondary face, or (c)
both the primary and the secondary faces of their cyclodextrin tori, are described. The key step in
the synthetic methodology, namely the attachment of the carbohydrate residues to the cyclodextrin
torus, proceeds in moderate-good yields (42-70%) by the photoaddition of thiol groups, positioned
at the anomeric centers of the carbohydrate residues, to allyl ether functions on the cyclodextrins.
Facile removal of protecting groups then affords the free cluster compounds. Extensive 1-D and
2-D NMR spectroscopic investigations were performed on these compounds to determine their
structures and establish their homogeneities, and a brief computer molecular modeling study allowed
estimates of the dimensions of the clusters to be determined.
In tr od u ction
of calix[4]resorcarene-based carbohydrate cluster com-
pounds and have outlined how these hosts can be used
to deliver guest molecules to surfaces5a and to lectins.5d
More recently, the J apanese group has shown5f how
saccharide units can be used to “mask” the hydrophobic-
ity of the macrocyclic core of calix[4]resorcarene- and
porphyrin-based carbohydrate clusters, thus preventing
nonspecific hydrophobic interactions between the cluster
compounds and the cells. By utilizing fluorescence mi-
croscopy, they have also shown that galactoside clusters
exhibit a remarkable selectivity for hepatocytes versus
the analogous glucoside clusters and that this interaction
is solely a consequence of carbohydrate-receptor interac-
tions.
The cyclodextrins6 (CDs) are naturally occurring cyclic
oligosaccharides that display a promiscuous appetite for
guest inclusion which has already been exploited7 in drug
formulations. It is possible that CD-based glycoclusters
could prove more useful for receptor-mediated drug
delivery than those based on calixarenes or resorcarenes
Contemporary carbohydrate research has been driven
largely by the realization that cell surface protein-
carbohydrate interactions play crucial roles in many
biological processes, as well as by the understanding that
nature compensates for the low intrinsic affinities of
carbohydrates for proteins through the cooperative bind-
ing of multiple copies of ligands and receptors, the so-
called “multivalent” and “glycoside-cluster effect”.1 Of the
many molecular scaffolds that have been used to display
carbohydrate ligands in multivalent arrays, those that
also possess the intrinsic potential to act as hosts for the
complexation of guest molecules may prove to be the most
useful in the development of “intelligent” drug delivery
systems.2 At a basic level, the synthetic strategy used
for the construction of such cluster compounds is straight-
forward. It involves attachment of carbohydrate residues
onto an appropriately functionalized macrocycle that is
known to complex with certain guest molecules. For
example, research groups headed by Dondoni3 and Roy4
have reported the attachment of carbohydrate residues
onto calixarene scaffolds. Aoyama and co-workers5 have
reported their findings on the synthesis and properties
(3) (a) Marra, A.; Scherrmann, M.-C.; Dondoni, A.; Casnati, A.;
Minari, P.; Ungaro, R. Angew. Chem., Int. Ed. Engl. 1994, 33, 2479-
2481. (b) Marra, A.; Dondoni, A.; Sansone, F. J . Org. Chem. 1996, 61,
5155-5158. (c) Dondoni, A.; Marra, A.; Schermann, M.-C.; Casnati,
A.; Sansome, F.; Ungaro, R. Chem.-Eur. J . 1997, 3, 1774-1782. (d)
Dondoni, A.; Kleban, M.; Marra, A. Tetrahedron Lett. 1997, 38, 7801-
7804.
(4) (a) Meunier, S. J .; Roy, R. Tetrahedron Lett. 1996, 37, 5469-
5472. (b) Roy, R.; Kim, J . M. Angew. Chem., Int. Ed. 1999, 38, 369-
372.
(5) (a) Fujimoto, T.; Shimizu, C.; Hayashida, O.; Aoyama, Y. J . Am.
Chem. Soc. 1997, 119, 6676-6677. (b) Hayashida, O.; Shimizu, C.;
Fujimoto, T.; Aoyama, Y. Chem. Lett. 1998, 13-14. (c) Ariga, K.;
Isoyama, K.; Hayashida, O.; Aoyama, Y.; Okahata, Y. Chem. Lett. 1998,
1007-1008. (d) Fujimoto, T.; Shimizu, C.; Hayashida, O.; Aoyama, Y.
J . Am. Chem. Soc. 1998, 120, 601-602. (e) Hayashida, O.; Kato, M.;
Akagi, K.; Aoyama, Y. J . Am. Chem. Soc. 1999, 121, 11597-11598. (f)
Fujimoto, K.; Miyata, T.; Aoyama, Y. J . Am. Chem. Soc. 2000, 122,
3558-3559.
(6) (a) Wenz, G. Angew. Chem., Int. Ed. Engl. 1994, 33, 803-822.
(b) Szejtli, J . Chem. Rev. 1998, 98, 1743-1755. (c) Khan, A. R.; Forgo,
P.; Stine, K. J .; D’Souza, V. T. Chem. Rev. 1998, 98, 1977-1996.
(7) Uekama, K.; Hirayama, F.; Irie, T. Chem. Rev. 1998, 98, 2045-
2076.
* To whom correspondence should be addressed. Tel: 310-206-7078.
Fax: 310-206-1843.
(1) (a) Lee, Y. C.; Lee, R. T.; Rice, K.; Ichikawa, Y.; Wong, T.-C. Pure
Appl. Chem. 1991, 63, 499-506. (b) Lee, Y. C.; Lee, R. T. Acc. Chem.
Res. 1995, 28, 321-327. (c) Sigal, G. B.; Mammen, M.; Dahmann, G.;
Whitesides, G. M. J . Am. Chem. Soc. 1996, 118, 3789-3800. (d) Mann,
D. A.; Kanai, M.; Maly, D. J .; Kiessling, L. L. J . Am. Chem. Soc. 1998,
120, 10575-10582. (e) Dimick, S. M.; Powell, S. C.; McMahon, S. A.;
Moothoo, D. N.; Naismith, J . H.; Toone, E. J . J . Am. Chem. Soc. 1999,
121, 10286-10296. (f) Davis, B. G. J . Chem. Soc., Perkin Trans. 1 1999,
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(2) (a) Parrot-Lopez, H.; Galons, H.; Coleman, A. W.; Mahuteau, J .;
Miocque, M. Tetrahedron Lett. 1992, 33, 209-212. (b) Parrot-Lopez,
H.; Leray, E.; Coleman, A. W. Supramol. Chem. 1993, 3, 37-42. (c)
Attioui, F.; Al-Omar, A.; Leary, E.; Parrot-Lopez, H.; Finance, C.;
Bonaly, R. Biol. Cell 1994, 82, 161-167. (d) Leray, E.; Parrot-Lopez,
H.; Auge, C.; Coleman, A. W.; Finance, C.; Bonaly, R. J . Chem. Soc.,
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10.1021/jo010705z CCC: $20.00 © 2001 American Chemical Society
Published on Web 11/08/2001

8310 J . Org. Chem., Vol. 66, No. 25, 2001
Fulton and Stoddart
from a perspective of biocompatability and H2O solubility.
Since Driguez and co-workers8 reported the synthesis of
perthioglucosylated derivatives of â-CD in 1994, several
other groups9 have recently described alternative syn-
thetic strategies for the perfunctionalization of CDs, but
on their primary faces only, with carbohydrate append-
ages. In at least one instance,9c the ability of compounds
of this type to interact with plant lectins has been
demonstrated.
In the course of our ongoing research10 on glycoden-
drimers, we became interested in developing efficient
methods for derivatizing CDs with saccharide residues
on (1) the secondary, as well as the primary faces of CDs
and then extending this strategy to the perfunctional-
ization of (2) both the primary and the secondary faces of
CDs, simultaneously. Perfunctionalization of the second-
ary face of CDs with carbohydrate residues could result
in cluster compounds that have several advantages over
their primary face-substituted counterparts. It is gener-
ally accepted that the principal mode of CD-guest binding
is via the secondary face of the CD.
We reported recently11 the results of our preliminary
investigations concerning the synthesis of CD-based
carbohydrate cluster compounds. Here, we describe in
detail the efficient synthesis of some â-CD-based carbo-
hydrate cluster compounds and their complete charac-
terization.
F igu r e 1. Graphical representation of the key synthetic step
(involving the simultaneous reaction of seven carbohydrate
units with the CD core) in the synthesis of CD-based carbo-
hydrate cluster compounds.
core is the most crucial step in the synthesis of CD-based
cluster molecules. With this thought in mind, it is worth
noting some important considerations that arise in the
quest for a successful synthetic strategy. First, the
functionalities X and Y (Figure 1) should be easy to
introduce onto the carbohydrate appendages and the CD
cores, respectively, to ensure the rapid synthesis of the
building blocks. Second, the reaction chosen for the
attachment of the carbohydrate units onto the CD core
has to be inherently a very high yielding one since it must
be performed six or more times on the same molecule.13
Third, the attachment of carbohydrate residues onto the
CD core should be performed as late as possible in the
synthetic scheme. This consideration arises because any
further synthetic manipulations on large CD-based mol-
ecules results inevitably in the loss of precious compound,
in addition to being almost certainly nontrivial to imple-
ment.
Previous synthetic methods for the attachment of
carbohydrate units onto CDs include nucleophilic dis-
placements with thiolate anions,9c-e as well as amide2a-d,9h
and thiourea2e,9b bond formations. Although all these
synthetic methods do lead to the attachment of carbo-
hydrate residues to CD cores, they suffer from a lack of
synthetic flexibility, viz., it is not straightforward to
extend these methods for the attachment of carbohydrate
residues to either the secondary or both faces of CDs.
After a preliminary survey of possible reactions, we
focused our attention on the well-known14 anti-Mark-
ovnikov photoaddition of thiols to allyl ethers to yield
thioethers as the key step in the attachment of carbohy-
drate appendages to CD cores. This reaction has a proven
record in both carbohydrate15 and CD16 chemistry, with
an example described by Lindhorst et al.15b being a
particularly encouraging one since it involves the suc-
cessful occurrence of five photoadditions per molecule.
Additionally, these photoadditions are performed under
mild conditions and are tolerant of a range of function-
alities. Moreover, the ease of introduction of (1) allyl ether
Resu lts a n d Discu ssion
Syn th etic Str a tegy. The precise and clean perfunc-
tionalization of CDs is notoriously difficult to accom-
plish.12 We sought a synthetic strategy which would allow
us to perfunctionalize either or both the primary and the
secondary faces of cyclodextrins with carbohydrate ap-
pendages. Our chosen strategy had to recognize the fact
that the attachment of carbohydrate units onto the CD
(8) de Robertis, L.; Lancelon-Pin, C.; Driguez, H.; Attioui, F.; Bonaly,
R.; Masura, A. Bioorg. Med. Chem. Lett. 1994, 4, 1127-1130.
(9) (a) Laine´, V.; Coste-Sarguet, A.; Gadelle, A.; Defaye, J .; Perly,
B.; Djeda¨ıni-Pilard, F. J . Chem. Soc., Perkin Trans. 2 1995, 1479-
1487. (b) Mellet, C. O.; Benito, J . M.; Garc´ıa Ferna´ndez, J . M.; Law,
H.; Chmurski, K.; Defaye, J .; O’Sullivan, M. L.; Caro, H. N. Chem.-
Eur. J . 1998, 4, 2523-2531. (c) Garc´ıa-Lo´pez, J . J .; Herna´ndez-Mateo,
F.; Isac-Garc´ıa, J .; Kim, J . M.; Roy, R.; Santoyo-Gonza´lez, F.; Vargas-
Berenguel, A. J . Org. Chem. 1999, 64, 522-531. (d) Garc´ıa-Lo´pez, J .
J .; Santoyo-Gonza´lez, F.; Vargas-Berenguel, A.; Gime´nez-Mart´ınez, J .
J . Chem.-Eur. J . 1999, 5, 1775-1784. (e) Furuike, T.; Aiba, S. Chem.
Lett. 1999, 69-70. (f) Ichikawa, M.; Woods, A. S.; Mo, H.; Goldstein, I.
J .; Ichikawa, Y. Tetrahedron: Assymetry 2000, 11, 389-392. (g) Roy,
R.; Hernandez-Mateo, F; Santoyo-Gonza´lez, F. 2000, 65, 8743-8746.
(h) Fulton, D. A.; Pease, A. R.; Stoddart J . F. Isr. J . Chem. 2001, 40,
325-333.
(10) (a) Ashton, P. R.; Boyd, S. E.; Brown, C. L.; J ayaraman, N.;
Nepogodiev, S. A.; Stoddart, J . F. Chem.-Eur. J . 1996, 2, 1115-1128.
(b) Ashton, P. R.; Boyd, S. E.; Brown, C. L.; J ayaraman, N.; Stoddart,
J . F. Angew. Chem., Int. Ed. Engl. 1997, 36, 732-735. (c) Ashton, P.
R.; Boyd, S. E.; Brown, C. L.; Nepogodiev, S. A.; Meijer, E. W.;
Peerlings, H. W. I.; Stoddart, J . F. Chem.-Eur. J . 1997, 3, 974-984.
(d) J ayaraman, N.; Nepogodiev, S. A.; Stoddart, J . F. Chem.-Eur. J .
1997, 3, 1193-6770. (e) J ayaraman, N.; Stoddart, J . F. Tetrahedron
Lett. 1997, 38, 6767-6770. (f) Ashton, P. R.; Hounsell, E. F.; J ayara-
man, N.; Nielsen, T. M.; Spencer, N.; Stoddart, J . F.; Young, M. J .
Org. Chem. 1998, 63, 3429-2437. (g) Turnbull, W. B.; Pease, A. R.;
Stoddart, J . F. ChemBioChem. 2000, 1, 70-74.
(13) The consequences of a reaction’s yield when performed several
times simultaneously on a molecule such as â-CD are important. For
example, a reaction with a yield of 80% would afford a derivative in
(0.8)7 ) 21% yield when performed seven times on â-CD.
(14) Griesbaum, K. Angew. Chem., Int. Ed. Engl. 1970, 9, 273-287.
(15) For examples, see: (a) Lee, R. T.; Lee, Y. C. Carbohydr. Res.
1974, 37, 193-196. (b) Kieburg, C.; Dubber, M.; Lindhorst, T. K. Synlett
1997, 1447-1449.
(16) (a) Hanessian, S.; Benalil, A.; Laferrie`re, C. J . Org. Chem. 1995,
60, 4786-4797. (b) Leydet, A.; Moullet, C.; Roque, J . P.; Witvrouw,
M.; Pannecouque, C.; Andrei, G.; Snoeck, R.; Neyts, J .; Schols, D.; De
Clerq, E. J . Med. Chem. 1998, 41, 4927-4932.
(11) Fulton, D. A.; Stoddart J . F. Org. Lett. 2000, 2, 1113-1116.
(12) Perfunctionalization of R-, â-, or γ-CD is an inherently divergent
process that may demand up to 18, 21, or 24 reactions to be performed
on each molecule. Chemical reactions that are performed on CDs must
therefore be highly efficient to avoid the formation of undersubstituted
products that usually prove to be chromatographically similar to the
target compounds and also lack the high axial symmetry of fully
substituted CDs that is necessary to allow easy and definitive
characterization by NMR spectroscopy.

Cyclodextrin-Based Carbohydrate Clusters
J . Org. Chem., Vol. 66, No. 25, 2001 8311
Sch em e 1. Syn th esis of Th ioglycosid es 1 a n d 2a
Sch em e 2. Syn th esis of Allyl Eth er â-CD Cor esa
a
Reagents and conditions: (a) thiourea, acetone, reflux; (b)
K2S2O5, H2O, CHCl3, reflux, 1, 40%, 2, 77%.
functions onto the CD torus and (2) thiol groups onto the
anomeric centers of saccharides makes this photoaddition
an appealing choice of reaction to use in the key step.
Syn th esis of Bu ild in g Block s. We chose as the thiol
components, â-D-thioglucose (1) and â-D-thiolactose (2),
both of which are easily prepared (Scheme 1) from their
corresponding glycosyl bromides. Stereospecific nucleo-
philic displacement of peracetyl-R-D-bromoglucose and
R-D-bromolactose with thiourea, followed by treatment
of the isothiouronium intermediates with aqueous potas-
sium bisulfite in a biphasic reaction, afforded17 the thiols
1 and 2 in 40% and 77% yields, respectively.18
a
Reagents and conditions: (a) allyl bromide, NaH (60%), DMF,
32%; (b) allyl bromide, NaH (95%), DMF, 26%; (c) allyl bromide,
We chose to prepare three different allyl ether-
substituted â-CD cores, one of which was perfunctional-
ized with allyl ethers on (1) the primary face of â-CD,
another on (2) the secondary face of â-CD, and yet
another on (3) both faces of â-CD. Thus, reaction (Scheme
2) of 319 with sodium hydride and allylbromide in DMF
afforded (32%) 4, a compound which is persubstituted on
the primary face of the CD torus with seven allyl ether
functions. The synthesis of a â-CD derivative persubsti-
tuted on its secondary face with allyl ether functions was
accomplished using a known procedure20 by reaction of
521 with sodium hydride and allylbromide in DMF to
afford 6 in 26% yield. Finally, reaction22 of â-CD with
allylbromide in the presence of BaO and Ba(OH)2‚8H2O
in a mixture of DMF and DMSO gave, in only 17% yield,
a â-CD derivative 7, persubstituted with seven allyl ether
functions on each face of its CD torus.
BaO, Ba(OH)2‚8H2O, DMF/DMSO (1:1), 17%.
Sch em e 3. Syn th esis of th e Glu cose a n d La ctose
Ser ies of Clu ster Com p ou n d s Su bstitu ted on Th eir
P r im a r y F a cesa
Syn th esis of P r im a r y F a ce-Su bstitu ted Clu ster s.
The primary face modification of â-CD with seven
carbohydrate appendages was achieved efficiently (Scheme
3) when a methanolic solution of a mixture of 1 (21 equiv)
and 4 was irradiated with UV light from an Hg lamp.
After 5 h, TLC indicated an almost quantitative conver-
sion to 8 when the concentration of 2 in the reaction
mixture was ca. 5 mM. At lower concentrations, under-
substitution of 2 occurs; if the concentration of the
reactants is too high, then the major product of the
(17) Stanek, J .; Sindlerova, M.; Cerny, M. Collect. Czech. Chem.
Commun. 1965, 30, 297-302.
(18) By carefully following the procedure described in ref 17, it was
observed that substantial amounts of hemiacetal were formed in the
nucleophilic displacement with thiourea, lowering the yield of thiol 1.
Thus, for the synthesis of thiol 2, all reagents were dried overnight
over P2O5 in a drying pistol under high vacuum, and acetone was
distilled from anhydrous calcium sulfate. By taking these precautions,
the procedure resulted in a substantially higher yield of 2.
(19) Takeo, K.; Mitoh, H.; Uemura, K. Carbohydr. Res. 1989, 187,
203-221.
(20) Ko¨nig, W. A.; Icheln, D.; Runge, T.; Pfaffenberger, B.; Ludwig,
P.; Hu¨hnerfuss, H. J . High Resolut. Chromatogr. 1991, 14, 530-536.
(21) Takeo, K.; Mitoh, H.; Uemura, K. J . Carbohydr. Chem. 1988,
7, 293-308.
(22) Bergeron, R. J .; Meeley, M. P.; Machidia, Y. Bioorg. Chem. 1976,
5, 121-126.
a
Reagents and conditions: (a) hν, MeOH, 5 h, 8, 67%, 9, 58%;
(b) NaOMe, MeOH, 5 h, 10, 99%, 11, 96%.
reaction is the disulfide formed by dimerization of two
molecules of 1. Purification of the crude product from the
photochemical reaction by silica gel column chromatog-
raphy afforded a pure compound in 67% yield.23 Matrix-
assisted laser desorption ionization-time-of-flight (MALDI-
TOF) mass spectrometry of this compound revealed a
(23) The reported yields have not been optimized.

8312 J . Org. Chem., Vol. 66, No. 25, 2001
Fulton and Stoddart
Sch em e 4. Syn th esis of th e Glu cose a n d La ctose
Ser ies of Clu ster Com p ou n d s Su bstitu ted on Th eir
Secon d a r y F a cesa
Sch em e 5. Syn th esis of Glu cose a n d La ctose
Ser ies of Clu ster Com p ou n d s Su bstitu ted w ith
Ca r boh yd r a te Un its on Both Th eir P r im a r y a n d
Secon d a r y F a cesa
aReagents and conditions: (a) hν, MeOH, C6H6, 5 h, 12, 42%,
13, 84%; (b) BF3‚OEt2, CH2Cl2, 4 h, 14, 74%, 15, 75%; (c) NaOMe,
MeOH, 1-2 d, 16, 99%, 17, 90%.
peak at m/z 4185 [M + Na]+ corresponding to â-CD
derivative 8, fully adorned with seven â-D-thioglucose
residues. The identity of 8 was established unequivocally
from close inspection of its 1H and 13C NMR spectra.
Deprotection (NaOMe/MeOH) of 8 yielded (99%) 10,
a
Reagents and conditions: (a) hν, MeOH, C6H6, 5 h, 18, 70%,
19, 66%; (b) NaOMe, MeOH, 1-2 d, then NaOH, 20, 99%, 21, 99%.
(NaOMe/MeOH), furnished the fully deprotected glucose
and lactose cluster compounds 16 and 17, respectively.
Syn th esis of Clu ster s Su bstitu ted on Both F a ces.
The next obvious question was could this photochemical
approach be used to modify entirely both the primary and
the secondary faces of a â-CD derivative by means of a
reaction that would involve the formation of no less than
14 thioether bonds per molecule? Reaction (Scheme 5) of
per-2,6-diallyl-â-CD (7) with 1 or 2 in MeOH/C6H6 gave
the desired protected glucose and lactose cluster com-
pounds, namely 18 and 19 in 70% and 66% yields,
respectively. Deprotection of 18 and 19 afforded the free
cluster compounds 20 and 21, respectively, which were
fully characterized by both 1H and 13C NMR spec-
troscopies. It is worth noting that compounds 20 and 21
contain a total of 21 and 35 pyranoside residues, respec-
tively, demonstrating that large, well-defined carbohy-
drate clusters can be prepared in very few synthetic steps
using this particular synthetic methodology.
Str u ctu r a l Ch a r a cter iza tion . The purified products
obtained from the photochemical additions were thor-
oughly analyzed by spectroscopic techniques to establish
(1) that the product was homogeneous and contained no
under-“substituted” products and (2) that the product was
of a satisfactory purity.
1H NMR Sp ectr oscop y. A common feature of the H
NMR spectra of the acetylated compounds 8, 9, 12-15,
18, and 19 is that they display broadened signals27
arising from their CD protons, while the signals for the
1
which was also fully characterized by H and 13C NMR
spectroscopies. The lactose analogue of 10 was prepared
in an almost identical manner. Reaction of 2 with 4
afforded a crude reaction mixture which was more
conveniently purified by gel filtration chromatography24
to give the acetylated lactose cluster compound 9. Deacet-
ylation (NaOMe/MeOH) of 9 afforded the free lactose
cluster compound 11 in almost quantitative yield. Again,
both the acetylated cluster compound 9 and the free
1
cluster compound 11 were fully characterized by H and
13C NMR spectroscopies and MALDI-TOF mass spec-
trometry.
Syn th esis of Secon d a r y F a ce-Su bstitu ted Clu s-
t er s. The same synthetic strategy was followed to
prepare â-CD derivatives perfunctionalized on their
secondary faces with seven carbohydrate appendages.
Reaction (Scheme 4) of the thiols 1 or 2 with 6, under
essentially the same conditions as those described above
for the synthesis of 10 and 11, gave the fully substituted
glucose and lactose cluster compounds, namely 12 and
13 in 42% and 84% yields, respectively. O-Desilylation25
of 12 and 13 with BF3‚OEt2 afforded the glucose (14) and
lactose (15) intermediates,26 which, after deprotection
1
(24) The glucose series of compounds was purified by column
chromatography (SiO2, EtOAc/hexanes). However, this technique often
resulted in “band-broadening”, probably as
a consequence of the
relatively large molecular mass of the compounds in question and,
consequently, low yields of pure compounds. Therefore, the lactose
series of compounds was purified by gel filtration chromatography (LH-
20), a technique which was found to be far superior for the purification
of these compounds.
(25) Kelly, D. R.; Roberts, S. M.; Newton, R. F. Synth. Commun.
1979, 9, 295-299.
(26) Deprotection with tetrabutylammonium fluoride (TBAF) in THF
consistently failed to deprotect compound 12 efficiently. We hypothesize
that TBAF is basic enough to cause partial deacetylation of the
carbohydrate appendages.

Cyclodextrin-Based Carbohydrate Clusters
J . Org. Chem., Vol. 66, No. 25, 2001 8313
protons on the carbohydrate appendages are sharp. This
phenomenon is revealed also in the 13C NMR spectra,
where the signals corresponding to the CD carbons are
much weaker and broader than those arising from the
carbons in the glucose appendages. The reason for this
signal broadening is most likely the expression of a
dynamic phenomenon; the glucose appendages cause the
CD glucose residues to move on a time scale approaching
that of the NMR time scale, hence inducing the line
widths of the CD signals to increase. This signal broad-
ening could be alleviated to some extent by heating the
sample, and so in some cases, NMR spectra were recorded
in (CD3)2NCDO, which allowed the samples to be warmed
to 360-370 K.
1
The H NMR spectra of the purified compounds, that
is, 8, 9, 12, 13, 18, and 19, obtained from the photoad-
ditions, did not reveal any signals corresponding to the
allyl ether protons of the CD starting materials. Instead,
signals corresponding to -(CH2)3- units were present,
displaying the expected chemical shifts and integrations
and thus supporting the hypothesis that all the allyl
ether functions on the CD torus had reacted with a thiol
group. Further useful structural information was gained
1
from the H NMR signal for the H-2 proton of the CD
torus.28 In nearly all cases, this signal was evident as
the expected doublet of doublets; in others, signal broad-
ening decreased its resolution to that of a partially
1
resolved doublet of doublets. The H NMR spectra of the
protected glucose cluster compounds 8, 12, and 18 are
shown in Figure 2. Broadening of the H-2 signal is most
severe in the spectrum (Figure 2c) of 18, while 8 and 12
give spectra (Figure 2a,b) with better resolution of this
H-2 signal. Other signals corresponding to the protons
on the CD torus of 18 are also significantly broadened.29
The fact that 18 is adorned on both faces of the CD torus
F igu r e 2. The “carbohydrate region” of the 1H NMR (500
MHz, CDCl3) spectra of the O-acetylated glucose series (a) 8,
(b) 12, and (c) 18. Note that the presence of an appended
carbohydrate residue at C-2 results in a small upfield shift
for H-1.
1
with glucose units can also be inferred from its H NMR
spectrum. Since the glucose units on the primary face of
the CD torus occupy a different constitutional environ-
ment to the corresponding glucose units on the secondary
faces, the resonances associated with each appended
glucose unit appear at slightly different chemical shifts.
For example, the anomeric protons corresponding to the
appended glucose residues appear as two partially over-
lapping doublets centered at δ 4.54 and 4.57. However,
some signals corresponding to the glucose appendages
resonate at essentially the same chemical shifts. This fact
is well demonstrated (Figure 2c) for the H-2′ and H-3′
protons of the glucose appendages, which overlap so well
with their H-2′′ and H-3′′ counterparts that each ef-
fectively appears as a single “triplet”. It was not possible
to assign unambiguously the protons of the glucose
appendages as being associated with either the glucose
units on the primary face or those on the secondary face.
High-quality and informative 2-D spectra, however, could
(27) Broadening of the 1H NMR signals was most severe for the
series which are persubstituted on both faces of the CD torus with
carbohydrate appendages. This signal broadening was least severe for
the series which are persubstituted on only their primary faces with
carbohydrate appendages.
F igu r e 3. The partial HMQC (500 MHz, (CD3)2NCDO, 370
K) spectrum of the O-acetylated lactose cluster 9.
(28) Although the 1H NMR signal corresponding to the H-1 proton
of the CD torus is generally the most useful and diagnostic probe signal
for the CD torus, for many of these compounds, this signal was “hidden”
beneath signals arising from protons in the carbohydrate appendages.
Fortunately, the signal for H-2 could always be observed, and thus it
was often the most diagnostic for the CD torus.
be obtained for all the acetylated compounds, as il-
lustrated by the fully assigned heteronuclear multiple-
quantum coherence (HMQC) spectrum (Figure 3) of 9,
despite signal broadening problems. By using a combina-
tion of 2-D-COSY and HMQC experiments, it was pos-
sible to assign fully the 1H NMR spectra for all the
acetylated glucose and lactose cluster compounds.
(29) Presumably, having two glucose units appended to each CD
residue leads to more pronounced signal-broadening than when only
one glucose unit is attached to each CD residue.

8314 J . Org. Chem., Vol. 66, No. 25, 2001
Fulton and Stoddart
F igu r e 4. The 1H NMR (500 MHz, D2O) spectrum of the
lactose cluster 11. The water signal has been presaturated for
clarity.
F igu r e 5. The 13C DEPT NMR (125 MHz, CDCl3) spectrum
of O-acetylated glucose cluster 18 showing the carbohydrate
region.
Ta ble 1. Ap p r oxim a te Molecu la r Dim en sion s of
Dep r otected Ca r boh yd r a te Clu ster Com p ou n d s a s
Estim a ted fr om Com p u ter Molecu la r Mod elin g
The 1H NMR spectra of the final deacetylated com-
pounds 10, 11, 16, 17, 20, and 21, reveal that, apart from
the anomeric protons, all other carbohydrate protons
resonate in the region δ ≈ 3.0-4.0, and so not many
peaks in these spectra can be assigned. For most of these
deacetylated compounds, the resonances associated with
the anomeric protons in the CD torus reveal themselves
to be broadened singlets, whereas the resonances associ-
ated with the anomeric proton(s) of the carbohydrate
appendages appear as their expected doublets. Impor-
tantly, the integrations of the signals corresponding to
the anomeric protons of the CD torus and the signals
corresponding to the anomeric proton(s) of the appendage
carbohydrate units have essentially the same value.
These features can be observed in the 1H NMR spectrum
(Figure 4) of 11.
molecular width
(Å)a
molecular height
(Å)b
carbohydrate cluster
10
11
16
17
20
21
23
34
31
36
31
43
17
18
13
21
31
43
a
Approximate molecular width is defined as the diameter of
b
the molecule when viewed along the CD toroidal axis. Approxi-
mate molecular height is defined as the height of the molecule
when viewed perpendicular to the CD toroidal axis.
MALDI-TOF Mass Spectr om etr y. MALDI-TOF mass
spectrometry proved to be a useful technique for char-
acterizing the acetylated cluster compounds. The ex-
pected mass ions, which did not give rise to any frag-
mentation, were observed for all of these acetylated
compounds. However, their deacetylated analogues gave
very weak mass ions. As no fragmentation was observed
for the acetylated cluster compounds, MALDI-TOF mass
spectrometry also served as a useful check of the homo-
geneities of compounds. Any under-substituted com-
pounds present as impurities should also reveal peaks
corresponding to one or more carbohydrate appendages
less than the expected mass ion. However, no peaks
corresponding to under-substituted compounds were
observed in any of the MALDI-TOF mass spectra of the
acetylated cluster compounds.
Molecu la r Mod elin g. In an attempt to gain some
insight into the nature of the three-dimensional structure
of the carbohydrate cluster compounds, we performed a
molecular dynamics study using the Macromodel30 pro-
gram. This modeling allowed us to visualize several
feasible low-energy conformations of the clusters, predict
any significant intramolecular noncovalent interactions
which could affect the compounds’ potential performance
as delivery vehicles, and estimate the molecular dimen-
sions of each cluster (Table 1). Even though these models
do not give an accurate representation of the “time-
averaged” conformations of the highly flexible cluster
molecules, they do nevertheless provide a useful “snap-
shot” of their structures.
13C NMR Sp ectr oscop y. Analysis of the 13C NMR
spectra of the acetylated compounds 8, 9, 12, 13, 18, and
19 revealed no signals corresponding to those carbons
associated with the allyl ether functions of compounds
4, 6, and 7. Instead, signals corresponding to the -(CH2)3-
linker between the CD and the appended carbohydrate
unit were evident in the spectrum. By using the 13C 135-
DEPT pulse sequence, it was possible to assign easily all
the carbon atoms in the -(CH2)3- linker, as well as all
C-6 carbon atoms on account of the negative phasing of
these signals. By utilizing HMQC and DEPT experi-
ments, it was possible to assign unambiguously the
carbon resonances in the spectra of all the acetylated
compounds.
Further proof that compounds 18 and 19 are com-
pletely substituted on both the primary and the second-
ary faces of their CD tori comes from the analyses of their
13C DEPT NMR spectra. Analysis of the carbohydrate
region of the 13C DEPT NMR spectrum (Figure 5) of 18
reveals signals corresponding to all the carbon atoms in
the glucose appendages on the primary and secondary
faces of the cyclodextrin torus. The signals corresponding
to the carbon atoms on both the primary and the
secondary face glucose appendages appear at more or less
1
identical chemical shifts. As in the case of the H NMR
spectra of these compounds, however, it was not possible
to assign unambiguously carbon signals to the carbohy-
drate units on a particular face of the CD torus.
Although the decetylated cluster compounds also af-
1
forded good quality 13C NMR spectra, like their H NMR
(30) Mohamadi, F.; Richards, N. G. J .; Guida, W. C.; Liskamp, R.;
Lipton, M.; Caufield, C.; Chang, G.; Hendrickson, T.; Still, W. C. J .
Comput. Chem. 1990, 11, 440.
counterparts, these spectra defied unambiguous assign-
ment of signals to carbon atoms.

Cyclodextrin-Based Carbohydrate Clusters
J . Org. Chem., Vol. 66, No. 25, 2001 8315
models indicated that the spacer arms attached to both
the primary and the secondary faces were unlikely to
even partially include themselves in the hydrophobic
cavity of the CD, principally because the spacer arms are
too short to form a complementary fit with the CD cavity.
Additionally, analysis of CPK models indicate that the
spacer arms on the primary face are further discouraged
from being included through the primary face on account
of the narrower diameter of this face.32 However, it is
not unreasonable to assume that longer alkyl spacer arms
could become included within the CD cavity, especially
spacer arms present on the secondary face.
The computer-generated models also indicate that,
although each carbohydrate appendage has a significant
degree of conformational freedom, they are situated close
enough to each other that a certain amount of interre-
sidual H-bonding is almost certain to occur.
Con clu sion s
We have described a novel synthetic strategy for the
permodification of either or both faces of â-CD with
carbohydrate residues in good yields. This strategy relies
on the photoaddition of thiols to allyl ethers, a reaction
that has proven to be a surprisingly good candidate for
the key synthetic step, namely, the attachment of car-
bohydrate residues to CD cores, in the synthesis of
carbohydrate cluster compounds. As it is relatively easy
to prepare saccharides with thiol functions at their
anomeric centers, this strategy could probably be ex-
tended easily to the attachment of more complicated
oligosaccharides onto CD cores. In fact, given the high
efficiency of this photoaddition reaction, it may be of
considerable general utility in the preparation of a vast
range of multivalent conjugates.
F igu r e 6. View of the three-dimensional structure of the
glucose-7-mer 10 as determined by computer molecular model-
ing, looking through the CD torus from the secondary face of
the CD. The CD torus is depicted in light gray, and the glucose
appendages are depicted in dark gray.
Exp er im en ta l Section
Gen er a l Meth od s. Chemicals were purchased from com-
mercial suppliers and used as received. All solvents were used
as purchased with the exception of CH2Cl2 (distilled from
CaH2) and MeOH (distilled from Mg turnings). All photoad-
ditions were performed in borosilicate glass vials. Thin-layer
chromatography (TLC) was carried out on aluminum sheets
precoated with silica gel 60 F. The plates were developed by
charring with 5% H2SO4 in EtOH. Column chromatography
was carried out using silica gel 60 F (230-400 mesh). Gel
filtration chromatography was performed using either (1) a
column packed with Sephadex LH-20 (3 cm × 90 cm) eluting
with MeOH at 1 mL min-1 or (2) a column packed with Biogel
P-6 (3 cm × 93 cm) eluting with H2O at 1 mL min-1. In both
cases, the eluant was monitored with a refractive index
detector. Fast atom bombardment mass spectra (FAB-MS)
were obtained from a mass spectrometer, using m-nitrobenzyl
alcohol as matrix. Matrix-assisted laser desorption ionization-
time-of-flight mass spectra (MALDI-TOF-MS) were recorded
on an instrument using a trans-indole acrylic acid matrix and
an average of 50 laser shots per sample. 1H NMR spectra were
recorded on either a 400 or 500 MHz spectrometer with either
the residual solvent or the external TMS as calibrants. 13C
F igu r e 7. A side-on view of the three-dimensional structure
of the lactose-14-mer 21 as determined by computer molecular
modeling. The CD core is depicted in light gray, and the
glucose appendages are depicted in dark gray.
Modeling indicated that, in the case of all compounds,
the glucosyl residues in their CD tori would adopt their
preferred 4C1 chair conformations. There were no unusual
interglycosidic torsion angles, which indicated that in all
cases, there was not a significant deviation from C7
symmetry. Compounds 16 and 17 are slightly wider than
their primary face-substituted counterparts 10 (Figure
6) and 11. Compounds 20 and 21 (Figure 7) adopt a more
globular appearance, with their height and widths being
of similar lengths.
(31) For examples, see: (a) Impellizzeri, G.; Pappelardo, G.;
D’Alessandro, F.; Rizzarelli, E.; Saviano, M.; Iacovino, R.; Benedetti,
E.; Pedone, C. Eur. J . Org. Chem. 2000, 1065-1076. (b) Tanabe, T.;
Usui, S.; Nakamura, A.; Ueno, A. J . Inclusion Phenom. Macrocyclic
Chem. 2000, 36, 79-93. (c) Nelissen, H. F. M.; Venema, F.; Uitten-
bogaard, R. M.; Feiters, M. C.; Nolte, R. J . M. J . Chem. Soc., Perkin
Trans. 2 1997, 2045-2053. (d) Berthault, P.; Duchesne, D. D.; Desvaux,
H.; Gilquin, B. Carbohydr. Res. 1995, 276, 267-87.
There are several reported examples31 of hydrophobic
alkyl chains, which are covalently attached to a CD,
including themselves within the CD cavity. For all cluster
compounds, that is, 10, 11, 16, 17, 20, and 21, our
modeling indicated no inclusion, or indeed even partial
inclusion, of either the hydrophobic -(CH2)3- spacer
arms or their carbohydrate appendages. Inspection of
space-filling Covey-Pauling-Koultun (CPK) molecular
(32) Parrot-Lopez and co-workers reported2a a â-CD derivative with
a C7 alkyl spacer arm terminated with an N-glyucosyl residue. On the
basis of NMR evidence, they concluded that the C7 alkyl spacer arm
did not self-include within the CD cavity.

8316 J . Org. Chem., Vol. 66, No. 25, 2001
Fulton and Stoddart
NMR spectra were recorded at either 100 or 125 MHz.
Chemical shifts are expressed in ppm, and the coupling con-
stants in the case of 1H NMR spectra are quoted in Hertz (Hz)
and are within an error range of ca. (0.5 Hz. The following
abbreviations are used to explain the multiplicities: s, singlet;
bs, broad singlet; d, doublet; t, triplet; m, multiplet; dd, double
doublet.
in CH2Cl2 (10 mL) and washed with H2O (10 mL) and aqueous
saturated NaCl solution (10 mL). The organic layer was dried
(MgSO4), filtered, and evaporated to dryness to yield a pale
yellow oil (408 mg). This oil was purified by column chroma-
tography (SiO2, 1% MeOH/CHCl3) to afford pure 4 as a white
1
foam (114 mg, 32%). H NMR (300 MHz, CDCl3): δ 3.17 (7H,
dd, 3J 1,2 ) 3.5 Hz, 3J 2,3 ) 9.5 Hz, H-2), 3.46-3.52 (7H, m, H-3),
3.49 (21H, s, MeO), 3.59-3.66 (14H, m, H-4, H-5), 3.64 (21H,
s, MeO), 3.77-3.87 (14H, m, H6a, H6b), 3.94-4.07 (14H, m,
OCH2CHdCH2), 5.12-5.16 (7H, m, H-1, CHdCHH cis), 5.24
2,3,4,6-Tetr a-O-acetyl-â-D-1-th ioglu copyr an osyl (1). Thio-
urea (1.91 g, 25.1 mmol) was added to a solution of 2,3,4,6-
tetra-O-acetyl-R-D-glucopyranosyl bromide (10.3 g, 25.1 mmol)
in Me2CO (11.0 mL), and the suspension was heated under
reflux until all the thiourea dissolved. Following the formation
of a white precipitate (∼10 min), further Me2CO was added,
and the resulting slurry was heated under reflux for a further
20 min, after which time TLC indicated the disappearance of
the bromide. Solvents were removed in vacuo, and H2O (10
mL) and CH2Cl2 (10 mL) were added to the reaction mixture.
Potassium persulfite (4.23 g) was added, and the biphasic
solution was brought to reflux. After 12 h, the reaction was
allowed to cool, and H2O (50 mL) and CH2Cl2 (50 mL) were
added. The organic layer was dried (MgSO4), filtered, and
evaporated to dryness. The product was purified by column
chromatography (SiO2:EtOAc/hexanes 2:5) to afford 1 as a
2
3
(7H, dd, J gem ) 1.5 Hz, J vic ) 17.0 Hz, CHdCHH trans),
5.82-5.95 (7H, m, CHdCH2), proton assignments were con-
firmed by COSY experiments. 13C NMR (75 MHz, CDCl3): δ
58.4, 61.4 (2-OMe, 3-OMe), 68.9 (C-6), 70.8 (C-5), 72.1 (OCH2-
CHdCH2), 80.2, 81.7, 98.7 (C-2, C-3, C-4), 98.7 (C-1), 116.6
(OCH2CHdCH2), 134.8 (OCH2CHdCH2). MALDI-TOF-MS
m/z: 1633 [M + Na]+. Anal. Calcd for C77H126O35: C, 57.39; H,
7.83. Found: C, 57.50; H, 8.00.
P er -6-ter t-b u t yld im et h ylsilyl-p er -2-a llyl-â-cyclod ex-
tr in (6). A solution of per-6-tert-butyldimethylsilyl-â-cyclo-
dextrin (5) (5.09 g, 2.63 mmol) in DMF (240 mL) under an
atmosphere of Ar was cooled to 0 °C, and NaH powder (95%,
0.50 g, 20.83 mmol) was added portionwise. The reaction was
allowed to stir at 0 °C for 1.5 h and then overnight at room
temperature. The reaction vessel was cooled to 0 °C, and allyl
bromide (1.64 mL, 18.95 mmol) was added dropwise. The
reaction was then allowed to stir at 0 °C for 1 h and finally
overnight at room temperature. The reaction was evaporated
to dryness, and the residue was dissolved in CH2Cl2 (250 mL)
and washed with brine (200 mL). The organic layer was dried
(MgSO4), filtered, and evaporated to dryness to afford a white
foam. Purification by column chromatography (SiO2, 15%
EtOAc/hexane to 20% EtOAc/hexanes) afforded pure 6 as a
1
white solid (3.63 g, 40%). H NMR (CDCl3, 400 MHz): δ 2.00,
2.02, 2.08, 2.09 (12H, 4s, 4 × Ac), 2.31 (1H, d, J ) 10.0 Hz,
3
SH), 3.70-3.74 (1H, m, H-5), 4.12 (1H, dd, J 5,6a ) 2.2 Hz,
3
2
2J 6a,6b ) 12.4 Hz, H-6a), 4.24 (1H, dd, J 5,6b ) 4.6 Hz, J 6a,6b
)
12.4 Hz, H-6b), 4.54 (1H, t, 3J 1,2 ≈ J 1,SH ) 10.0 Hz, H-1), 4.97
3
3
3
3
3
(1H, t, J 1,2 ≈ J 2,3 ) 10.0 Hz, H-2), 5.10 (1H, t, J 3,4 ≈ J 4,5
)
3
9.4 Hz, H-4), 5.21 (1H, t ) J 2,3
≈
3J 3,4 ) 9.4 Hz, H-3). 13C
NMR (CDCl3, 100 MHz): δ 20.68, 20.71, 20.85, 20.88, 62.1,
68.2, 73.64, 73.67, 76.4, 78.8, 169.5, 169.7, 170.2, 170.8. FAB-
ms m/z: 323 [M + H]+. Anal. Calcd for C14H20O9S: C, 46.15;
H, 5.53. Found: C, 46.23; H, 5.35.
1
white foam (1.48 g, 26%). H NMR (CDCl3, 500 MHz): δ 0.03
2,3,6-Tr i-O-a cetyl-4-O-(2,3,4,6-tetr a -O-a cetyl-â-D-ga la c-
top yr a n osyl)-â-D-1-th ioglu cop yr a n osyl (2). Thiourea (338
mg, 4.45 mmol) was added to a solution of 2,3,6-tri-O-acetyl-
4-O-(2,3,4,6-tetra-O-acetyl-â-D-galactopyranosyl)-R-D-glucopy-
ranosyl bromide (3.09 g, 4.43 mmol) in Me2CO (5.0 mL), and
the suspension was heated under reflux for 1 h, during which
time all the thiourea dissolved. Solvents were removed in
vacuo, and the residue was dissolved in H2O (5 mL) and CCl4
(10 mL). Potassium persulfite (1.67 g) was added, and the
biphasic solution was brought to reflux. After 75 min, the
reaction was allowed to cool, and H2O (50 mL) and CH2Cl2
(50 mL) were added. The organic layer was dried (MgSO4),
filtered, and evaporated to dryness. The product was purified
by column chromatography (SiO2:EtOAc/hexanes 1:1) to afford
(21H, s, SiCH3), 0.04 (21H, s, SiCH3), 0.88 (63H, s, C(CH3)),
3
3
3.31 (7H, dd, J 1,2 ) 3.5 Hz, J 2,3 ) 9.6 Hz, H-2), 3.50 (7H, t,
3J 3,4 ≈ J 4,5 ) H-4), 3.57 (7H, d, J ) 9.4 Hz, H-5), 3.66 (7H, d,
3
2J 6a,6b ) 10.4 Hz, H-6a), 3.92 (7H, dd, J 5,6a ) 2.9 Hz, J 6a,6b
)
3
2
3
3
10.4 Hz, H-6b), 3.96 (7H, t, J 2,3 ≈ J 3,4 ) 9.3 Hz, H-3), 4.23
(7H, dd, J ) 6.8 Hz, J ) 12.5 Hz, OCHa), 4.48 (7H, dd, J ) 5.3
Hz, J ) 12.5 Hz, OCHb), 4.90 (7H, d, 2J 1,2 ) 3.5 Hz, H-1), 5.21
2
(7H, d, J ) 10.3 Hz, CHdCH2 cis), 5.31 (7H, dd, J gem ) 1.4
Hz, J vic ) 17.2 Hz, CHdCH2 trans), 5.92-5.99 (7H, m, CHd
3
CH2), proton assignments were confirmed by COSY experi-
ments. 13C NMR (CDCl3, 100 MHz): δ -5.2 (SiCH3), -5.1
(SiCH3), 18.3 (C(CH3)3), 25.9 (C(CH3)3), 61.7 (C-6), 71.6, 79.5,
82.0 (C-2, C-3, C-4, C-5), 73.2 (OCH2), 101.1 (C-1), 118.2 (CH2d
CH), 134.3 (CH2dCH). MALDI-TOF m/z: 2238 [M + Na]+.
Anal. Calcd for C105H196O35Si: C, 56.93; H, 8.92. Found: C,
57.06; H, 9.04.
1
2 as a white solid (1.84 g, 77%). H NMR (CDCl3, 400 MHz):
δ 1.96, 2.041, 2.044, 2.06, 2.07, 2.13, 2.15 (21H, 7s, 7 × Ac),
2.27 (1H, d, J ) 7.9 Hz, SH), 3.61-3.65 (1H, m), 3.80 (1H, t,
J ) 9.5 Hz), 3.87 (1H, t, J ) 7.0 Hz), 4.05-4.17 (3H, m), 4.45
(1H, dd, J ) 1.9, 12.1 Hz), 4.47 (1H, d, J ) 7.9 Hz), 4.52 (1H,
t, J ) 9.7 Hz), 4.88 (1H, t, J ) 9.6 Hz), 4.94 (1H, dd, J ) 3.4,
10.4 Hz), 5.09 (1H, dd, J ) 7.9 Hz, 10.4 Hz), 5.18 (1H, t, J )
9.2 Hz), 5.34 (1H, d, J ) 3.3 Hz). 13C NMR (CDCl3, 100 MHz):
δ 20.46, 20.59, 20.61, 20.71, 20.74, 20.84, 60.8, 62.2, 66.5, 69.0,
70.7, 70.9, 73.4, 73.8, 76.0, 77.1, 78.4, 101.1. FAB-ms m/z: 653
[M + H]+. Anal. Calcd for C26H36O17S: C, 47.85; H, 5.52.
Found: C, 47.97; H, 5.72.
P er -6-O-a llyl-p er -2,3-d im eth yl-â-cyclod extr in (4). NaH
(60 wt % in oil, 197 mg, 4.92 mmol) was weighed into a reaction
vessel. Hexane (5 mL) was added and stirred for 1 min. The
suspension was allowed to settle, and the hexane was decanted
off. This hexane washing procedure was repeated two more
times to obtain oil-free NaH. DMF was added, and the
suspension was stirred under a N2 atmosphere at 0 °C. A
solution of per-2,3-dimethyl-â-cyclodextrin (3) (299 mg, 0.225
mmol) in DMF (5 mL) was added dropwise, and the reaction
was then allowed to stir at 0 °C for 1 h. Allyl bromide (0.7
mL, 8.1 mmol) was added dropwise, and the reaction mixture
was stirred at 0 °C for a further 2 h, then subsequently it was
stirred at room temperature for 42 h. MeOH (5 mL) was then
added to the reaction mixture and, after stirring for 5 min,
the solvents were removed in vacuo. The residue was dissolved
P er -2,6-d ia llyl-â-cyclod extr in (7). â-Cyclodextrin (3.0 g,
2.6 mmol) was added portionwise to a stirred suspension of
BaO (15.0 g, 97.8 mmol), Ba(OH)2‚8H2O (15.0 g, 47.5 mmol),
and allyl bromide (21.2 g, 175.2 mmol) in DMF/DMSO (1:1,
150 mL). The reaction vessel was covered with foil to protect
it from light and set aside to stir under an Ar atmosphere for
20 h. NH4OH solution (28%) was added, and the reaction
mixture was stirred for 30 min before being poured into CHCl3
(500 mL). Hexane (500 mL) was added to help precipitate
inorganic material. The mixture was filtered through a sin-
tered funnel, and the filtrate was washed with H2O (3 × 400
mL) and then dried (MgSO4). The organic layer was then
filtered and evaporated to dryness to give an off-white foam.
Purification by column chromatography (SiO2, 20% EtOAc/
CHCl3) afforded 7 as a white foam (722 mg, 17%). 1H NMR
(CDCl3, 500 MHz): δ 3.42-3.48 (14H, m), 3.65 (14H, m), 3.75
(7H, dd, J ) 3.3, 9.8 Hz), 3.94 (7H, t, J ) 9.2 Hz), 3.98 (7H,
dd, J ) 6.0, 12.8 Hz), 4.07 (7H, dd, J ) 5.3, 12.8 Hz), 4.22
(7H, dd, J ) 7.0, 12.5 Hz), 4.46 (7H, dd, J ) 5.3, 12.5 Hz),
4.90 (7H, d, J ) 3.7 Hz), 5.16 (7H, dd, J ) 1.3, 10.4 Hz), 5.21
(7H, d, J ) 10.3 Hz), 5.26 (71H, dd, J ) 1.3, 17.0 Hz), 5.29
(7H, dd, J ) 1.3, 18.4 Hz), 5.88-5.95 (14H, m). 13C NMR (125
MHz, CDCl3): δ 68.8, 70.5, 72.5, 73.6, 79.3, 83.8, 102.1, 117.2,
118.9, 134.4, 135.1. FAB-ms m/z: 1827 [M + Cs]+. Anal. Calcd
for C84H18O35: C, 59.43; H, 7.43. Found: C, 59.49; H, 7.40.

Cyclodextrin-Based Carbohydrate Clusters
J . Org. Chem., Vol. 66, No. 25, 2001 8317
1°-Glu cose-7-m er Clu ster (8). The thiol 1 (489 mg, 1.34
mmol, 21 equiv) and the CD 4 (103 mg, 64 µmol) were dissolved
in distilled MeOH (concentration of 4 ) 5 mM). A stream of
Ar was bubbled through the solution for 20 min to thoroughly
degas it. The solution, kept under an atmosphere of Ar, was
placed in front of an Hg lamp and stirred for 5 h. Following
removal of solvent, the residue was purified by column
chromatography (SiO2, EtOAc/hexanes) to afford the product
the reaction was neutralized with Amberlite IR-120 (H+ form)
ion-exchange resin and filtered. The solvents were removed
in vacuo. The resultant glass was dissolved in H2O and freeze-
dried to afford 11 as a white fluff (92 mg, 96%). Selected NMR
1
data. H NMR (D2O, 500 MHz): δ 1.86-1.96 (14H, m, CH2),
2.70-2.85 (14H, m, SCH2), 3.29 (7H, t, J ) 7.0 Hz), 3.30 (21H,
s, OCH3), 3.52 (21H, s, OCH3), 4.37 (7H, d, J ) 7.7 Hz, H-1′′),
4.48 (7H, d, J ) 9.9 Hz, H-1′), 5.15 (7H, bs, H-1). 13C NMR
(D2O, 125 MHz): δ 27.3, 30.1, 58.6, 61.0, 61.2, 61.4, 69.1, 70.3,
71.5, 72.9, 73.3, 75.8, 76.5, 81.0, 81.4, 81.9, 85.9, 100.1, 103.5.
MALDI-TOF m/z: 4127 [M]+.
1
as a white foam (182 mg, 67%). H NMR (CDCl3, 500 MHz):
δ 1.85-1.89 (14H, m, SCH2CH2), 1.98, 2.00, 2.04, 2.06 (84H,
4s, 4 x Ac), 2.64-2.73 (7H, m, SCHa), 2.76-2.83 (7H, m, SCHb),
3
3
3.12 (7H, dd, J 1,2 ) 3.0 Hz, J 2,3 ) 9.5 Hz, H-2), 3.46-3.64
(35H, m, H-3, H-4, H-6a, H-6b, OCHa), 3.49 (21H, s, OCH3),
3.60 (21H, s, OCH3), 3.66-3.69 (7H, m, H-5), 3.71-3.81 (7H,
m, H-5′), 3.80-3.84 (7H, m, OCHb), 4.09-4.12 (7H, m, H-6a′),
2°-Glu cose-7-m er (12). To thiol 1 (239 mg, 0.66 mmol, 21
eq.) and CD 7 (68 mg, 31 µmol, concentration CD ) 5 mM)
was added distilled MeOH. C6H6 was then added dropwise
until the CD was completely dissolved. A stream of Ar was
bubbled through the solution for 20 min to thoroughly degas
it. The solution, kept under an atmosphere of Ar, was placed
in front of an Hg lamp and stirred for 5 h. Following the
removal of solvents, the residue was purified by column
chromatography (SiO2, EtOAc/hexanes, gradient elution, 60:
40 to 90:10) to afford the product as a white foam (62 mg, 42%).
1H NMR (CDCl3, 500 MHz): δ 0.029 (21H, s, SiCH3), 0.037
(21H, s, SiCH3), 0.879 (63H, s, C(CH3)), 1.92-1.94 (14H, m,
SCH2CH2), 2.02, 2.04, 2.07, 2.10 (84H, 4s, 4 x Ac), 2.77-2.91
3
2
4.24 (7H, dd, J 5′,6b′ ) 4.6 Hz, J 6a′,6b′ ) 12.4 Hz, H-6b′), 4.53
3
3
3
(7H, d, J 1′,2′ ) 10.0 Hz, H-1′), 4.98 (7H, t, J 1′,2′ ≈ J 2′,3′ ) 9.8
3
Hz, H-2′), 5.04-5.08 (14H, m, H-1, H-4′), 5.21 (7H, t, J 2′,3′
≈
3J 3′,4′ ) 9.4 Hz, H-3′). 13C NMR (CDCl3, 125 MHz): δ 20.76,
20.79, 20.92, 20.96 (4 x CH3CO), 27.3 (SCH2), 30.4 (SCH2CH2),
58.8 (CH3O), 61.5 (CH3O), 62.3 (C-6′), 68.5 (C-4′), 69.7 (OCH2),
70.0 (C-6), 70.1 (C-2′), 71.5 (C-5), 74.0 (C-3′), 75.9 (C-5′), 80.1
(C-3), 81.8 (C-4), 82.3 (C-2), 83.9 (C-1′), 99.1 (C-1), 169.5, 169.6,
170.3, 170.7 (4 x CH3CO). MALDI-TOF m/z: 4185 [M + Na]+.
3
3
Anal. Calcd for
Found: C, 50.12; H, 6.46.
C
175H266O98S7‚2H2O: C, 50.06; H, 6.48.
(14H, m, SCH2), 3.25 (7H, dd, J 1,2 ) 3.1 Hz, J 2,3 ) 9.6 Hz,
H-2), 3.48 (7H, t, 3J 3,4 ≈ J 4,5 ) 9.0 Hz, H-4), 3.54 (7H, d, 3J 5,6a
3
2
1°-La ctose-7-m er Clu ster (9). The thiol 2 (556 mg, 0.85
mmol, 21 equiv) and CD 4 (64 mg, 40 µmol) were dissolved in
distilled MeOH (concentration of 4 ) 5 mM). A stream of Ar
was bubbled through the solution for 20 min to thoroughly
degas it. The solution, kept under an atmosphere of Ar, was
placed in front of an Hg lamp and stirred for 5 h. Following
removal of solvent, the residue was purified by gel filtration
chromatography (LH-20, MeOH, 1 mL min-1) to afford the
product as a white foam (143 mg, 58%). 1H NMR ((CD3)2NCDO,
360K, 500 MHz): δ 2.06-2.14 (14H, m, SCH2CH2), 2.12, 2.23,
2.24, 2.25, 2.26, 2.31 (147H, 6s, 7 x Ac), 2.91-3.04 (14H, m,
) 9.6 Hz, H-5), 3.68 (7H, d, J 6a,6b ) 10.8 Hz, H-6a), 3.77-
3.83 (14H, m, H-5′, OCHa), 3.90-3.94 (14H, m, H-3, H-6b),
4.04-4.10 (7H, m, OCHb), 4.17 (7H, dd, 3J 5′,6a′ ) 2.3 Hz, 2J 6a′,6b′
) 12.0 Hz, H-6a′), 4.31 (7H, dd, 3J 5′,6b′ ) 4.8 Hz, 2J 6a′,6b′ ) 12.0
Hz, H-6b′), 4.64 (7H, d, 3J 1′,2′ ) 10.1 Hz, H-1′), 4.91 Hz (7H, d,
3
3J 1,2 ) 3.1 Hz, H-1), 5.05 (7H, t, 3J 1′,2′ ≈ J 2′,3′ ) 10.1 Hz, H-2′),
3
3
5.13 (7H, J 3′,4′
≈
3J 4′,5′ ) 9.8 Hz, H-4′), 5.28 (7H, t, J 2′,3′
≈
3J 3′,4′ ) 9.4 Hz, H-3′). 13C NMR (CDCl3, 125 MHz): δ -4.9,
-4.8 (Si(CH3)2), 18.5 (SiC(CH3)3), 20.8, 21.1 (CH3CO), 26.1
(SiC(CH3)3), 27.6 (SCH2CH2), 30.5 (SCH2), 61.9 (C-6), 62.4 (C-
6′), 68.6 (C-3′), 70.3 (C-2′), 71.3 (OCH2), 71.9 (C-5), 73.3 (C-3),
74.2 (C-3′), 75.9 (C-4′), 81.2 (C-2), 82.4 (C-4), 84.3 (C-1′), 101.4
(C-1), 169.6, 169.7, 170.4, 170.8 (4 x CH3CO). MALDI-TOF m/z:
4789 [M + Na]+. Anal. Calcd for C203H336O98S7Si7: C, 51.16;
H, 7.11. Found: C, 50.90; H, 7.08.
3
3
SCH2), 3.32 (7H, dd, J 1,2 ) 3.2 Hz, J 2,3 ) 9.5 Hz, H-2), 3.67
3
3
(7H, t, J 2,3 ≈ J 3,4 ) 8.7 Hz, H-3), 3.70 (21H, s, OCH3), 3.71-
3.82 (21H, m, OCH2, H-6a), 3.79 (21H, s, OCH3), 3.87 (7H, t,
3J 3,4 ≈ J 4,5 ) 9.0 Hz, H-4), 3.90-3.97 (7H, m, H-5), 4.00-4.09
3
(7H, m, H-5′), 4.10-4.14 (14H, m, H-4′, H-6b), 4.32-4.03 (21H,
m, H-6a′, H-6a′′, H-6b′′), 4.65 (7H, t, J ) 7.0 Hz, H-5′′), 5.01-
2°-La ctose-7-m er Clu ster (13). To thiol 2 (557 mg, 0.85
mmol, 21 equiv) and CD 6 (106 mg, 49 µmol, concentration
CD ) 5 mM) was added distilled MeOH. C6H6 was added
dropwise until the CD was completely dissolved. A stream of
Ar was bubbled through the solution for 20 min to thoroughly
degas it. The solution, kept under an atmosphere of Ar, was
placed in front of an Hg lamp and stirred for 5 h. Following
the removal of solvents, the residue was purified by gel
filtration chromatography (LH-20, MeOH, 1 mL min-1) to
afford the product as a white foam (536 mg, 84%). 1H NMR
((CD3)2NCDO, 370K, 500 MHz): δ 0.12 (42H, s, Si(CH3)2), 0.95
(63H, s, SiC(CH3)3), 1.93-1.97 (14H, m, SCH2CH2), 1.94, 2.00,
2.04, 2.05, 2.07, 2.12, 2.13 (147H, 7s, 7 x CH3CO), 2.73-2.89
(14H, m, SCH2), 3.32 (7H, d, J ) 9.2 Hz, H-2), 3.59 (7H, t, J
) 9.0 Hz, H-4), 3.70-3.75 (7H, m, H-5), 3.81-3.88 (21H, m,
H-6a, OCHa, H-5′), 3.94 (14H, t, J ) 9.0 Hz, H-3, H-4′), 4.03-
4.12 (14H, m, H-6b, OCHb), 4.13-4.21 (21H, m, H-6a′, H-6a′′,
H-6b′′), 4.27 (7H, t, J ) 6.4 Hz, H-5′′), 4.75 (7H, s, OH), 4.81-
4.87 (21H, m, H-1′, H-2′, H-1′′), 5.03 (7H, d, J ) 10.0 Hz, H-2′′),
5.06 (7H, s, H-1), 5.19 (7H, dd, J ) 3.1, 10.0 Hz, H-3′′), 5.22
(7H, t, J ) 8.5 Hz, H-3′), 5.38 (7H, d, J ) 3.1 Hz, H-4′′). 13C
NMR ((CD3)2NCDO, 370K, 125 MHz): δ -4.7, -4.6 (Si(CH3)2),
18.7 (SiC(CH3)3), 20.20, 20.25, 20.40, 20.50, 20.67, 20.70, 20.77
(7 x CH3CO), 26.4 (SiC(CH3)3), 27.7 (SCH2CH2), 31.0 (SCH2),
61.9 (C-6′′), 62.8 (C-6), 63.4 (C-6′), 68.4 (C-4′), 70.5 (C-2′′), 71.4
(C-5′′), 71.6 (OCH2), 71.8 (C-3′′), 71.9 (C-2′), 72.7 (C-5), 73.8
(C-3), 74.9 (C-3′), 77.1 (C-4′), 77.4 (C-5′), 82.0 (C-2), 82.8 (C-
4), 84.0 (C-1′), 101.3 (C-1′′), 101.7 (C-1), 169.6, 169.8, 169.9,
170.0, 170.4, 170.5, 170.6 (7 x CH3CO). MALDI-TOF m/z: 6350
[M + Na]+. Anal. Calcd for C249H448O154S7Si7: C, 47.00; H, 7.16.
Found: C, 46.81; H, 7.08.
3
5.06 (21H, m, H-1′, H-2′, H-1′′), 5.21 (7H, dd, J 1′,2′ ) 8.0 Hz,
3J 2′,3′ ) 10.0 Hz, H-2′), 5.37 (7H, dd, J 3′′,4′′ ) 3.4 Hz, J 2′′,3′′
)
3
3
10.0 Hz, H-3′′), 5.38-5.49 (14H, m, H-1, H-3′), 5.56 (7H, d, J
) 3.5 Hz, H-4′′). 13C NMR ((CD3)2NCDO, 370K, 125 MHz): δ
20.18, 20.22, 20.38, 20.49, 20.67, 20.72, 20.75 (7s, CH3CO), 27.9
(SCH2CH2), 58.5 (CH3O), 60.8 (CH3O), 61.9 (C-6′′), 63.3 (C-
6′), 68.4 (C-4′′), 70.2 (C-6, OCH2), 70.5 (C-2′), 71.4 (C-5′), 71.8
(C-3′′), 71.9 (C-2′), 72.3 (C-5), 74.9 (C-3′), 77.1 (C-4′), 77.4 (C-
5′), 79.9 (C-4), 82.9 (C-3), 83.0 (C-2), 83.9 (C-1′), 98.9 (C-1),
101.3 (C-1′′), 169.6, 169.8, 169.9, 170.0, 170.4, 170.5, 170.7
(CH3CO). MALDI-TOF m/z: 6203 [M + Na]+. Anal. Calcd for
C
259H378O154S7‚3H2O: C, 49.89; H, 6.20. Found: C, 50.03; H,
6.41.
1°-Glu cose-7-m er Clu ster (10). Methanolic NaOMe (1 M)
(0.25 mL) was added to a stirred solution of 8 (172 mg, 41
µmol) in dry MeOH (20 mL), and the reaction was allowed to
stand at room temperature. After TLC indicated completion
(5 h), the reaction was neutralized with Amberlite IR-120 (H+
form) ion-exchange resin and filtered. The solvents were
removed in vacuo. The resultant glass was dissolved in H2O
and freeze-dried to afford 10 as a white fluff (122 mg, 99%).
Selected NMR data. 1H NMR (D2O, 500 MHz): δ 1.91-2.04
(14H, m, CH2), 2.81-2.93 (14H, m, SCH2), 3.21 (7H, dd, J )
2.9 Hz, J ) 9.6 Hz, H-2), 3.54 (21H, s, OCH3), 3.64 (21H, s,
OCH3), 4.43 (7H, d, J ) 9.6 Hz, H-1′), 5.20 (7H, d, J ) 2.9 Hz,
H-1). 13C NMR (CD3OD, 125 MHz): δ 28.7, 32.1, 59.9, 62.6,
63.8, 71.6, 71.9, 72.3, 73.5, 75.2, 80.4, 81.4, 82.7, 83.9, 84.3,
88.1, 100.4. MALDI-TOF m/z: 2121 [M]+.
1°-La ctose-7-m er Clu ster (11). Methanolic NaOMe (1 M)
(1.0 mL) was added to a stirred solution of 9 (143 mg, 23 µmol)
in dry MeOH (20 mL), and the reaction was allowed to stand
at room temperature. After TLC indicated completion (5 h),
2°-Glu cose-7-m er Clu ster (14). BF3‚OEt2 (145 µL) was
added dropwise via a micropipet to a stirred solution of 12
(389 mg, 82 µmol) in CH2Cl2 (10.0 mL). The reaction was

8318 J . Org. Chem., Vol. 66, No. 25, 2001
Fulton and Stoddart
stirred at room temperature under an Ar atmosphere. After 4
h, TLC indicated that the reaction had gone to completion.
H2O (5 mL) was added, and the resulting mixture was stirred
for a further 30 min. CH2Cl2 (100 mL) and H2O (100 mL) were
added, and the organic layer was washed with brine (100 mL)
and then dried (MgSO4) and filtered. The solvents were
removed in vacuo, and the residue was purified by column
chromatography (SiO2, EtOAc/hexanes, gradient elution, 50:
50 to 70:30) to afford the product as a white foam (237 mg,
74%). 1H NMR (CDCl3, 500 MHz): δ 1.89-1.98 (14H, m,
SCH2CH2), 2.00, 2.02, 2.06, 2.08 (84H, 4s, 4 x Ac), 2.67-2.76
(14H, m, SCHa), 2.78-2.85 (14H, m, SCHb), 3.18-3.26 (7H,
during which time the precipitate dissolved. The reaction was
neutralized with Amberlite IR-120 (H+ form) ion-exchange
resin and filtered. The solvents were removed in vacuo, and
the resultant glass was dissolved in H2O and freeze-dried to
afford 17 as a white fluff (138 mg, 90%). Selected NMR data.
1H NMR (D2O, 500 MHz): δ 1.84-1.90 (14H, m, CH2), 2.68-
2.74 (7H, m, SCHa), 2.78-2.83 (7H, m, SCHb), 3.21 (7H, t, J
) 9.3 Hz), 4.35 (7H, d, J ) 7.8 Hz, H-1′′), 4.47 (7H, d, J ) 9.9
Hz, H-1′), 5.11 (7H, s, H-1). 13C NMR (D2O, 125 MHz): δ 26.3,
29.4, 60.15, 60.9, 68.4, 70.5, 70.8, 71.2, 71.9, 72.1, 72.4, 75.2,
75.6, 78.1, 78.5, 79.8, 81.1, 85.1, 99.7, 102.7. MALDI-TOF m/z:
3924 [M]+.
3
m, H-4), 3.32 (7H, d, J 2,3 ) 8.6 Hz, H-2), 3.65-3.82 (35H, m,
1°,2°-Glu cose-14-m er Clu ster (18). To thiol 1 (1.58 g, 4.31
mmol, 42 equiv) and the CD 7 (173 mg, 0.10 mmol, concentra-
tion CD ) 5 mM) was added distilled MeOH. C6H6 was added
dropwise until the CD was completely dissolved. A stream of
Ar was bubbled through the solution for 20 min to thoroughly
degas it. The solution, kept under an atmosphere of Ar, was
placed in front of an Hg lamp and stirred for 5 h. Following
the removal of solvents, the residue was purified by column
chromatography (SiO2, EtOAc/hexanes, gradient elution, 60:
40 to 100:0) to afford the product as a white foam (488 mg,
70%). 1H NMR (CDCl3, 500 MHz): δ 1.82-1.90 (28H, m,
SCH2CH2), 1.99, 2.00, 2.04, 2.06, 2.07 (168H, 5s, Ac), 2.56-
3
3
H-6a, 6-OH, H-5, OCHa, H-5′), 3.87 (7H, t, J 2,3 ≈ J 3,4 ) 8.6
Hz, H-3), 3.92-3.98 (7H, m, H-6b), 3.98-4.10 (7H, m, OCHa),
2
3
4.12 (7H, d, J 6a′,6b′ ) 12.0 Hz, H-6a′), 4.25 (7H, dd, J 5′,6b′
)
2
3
4.6 Hz, J 6a′,6b′ ) 12.4 Hz, H-6b′), 4.56 (7H, d, J 1′,2′ ) 10.0 Hz,
H-1′), 4.70 (7H, s, OH-3), 4.81 (7H, s, H-1), 5.00 (7H, t, 3J 1′,2′
≈
3J 2′,3′ ) 9.6 Hz, H-2′), 5.08 (7H, J 3′,4′ ≈ J 4′,5′ ) 9.6 Hz, H-4′),
3
3
3
5.22 (7H, t, J 2′,3′
≈
3J 3′,4′ ) 9.4 Hz, H-3′). 13C NMR (CDCl3,
125 MHz): δ 20.84, 20.99, 21.03 (CH3CO), 27.2 (SCH2CH2),
30.3 (SCH2), 61.8 (C-6), 62.5 (C-6′), 68.6 (C-4′), 70.2 (C-2′), 71.4
(OCH2), 72.1 (C-5), 73.5 (C-3), 74.1 (C-3′), 75.9 (C-5′), 80.7 (C-
2), 84.0 (C-1′), 84.3 (C-4), 101.9 (C-1), 169.6, 169.7, 170.4, 171.0
(4 x CH3CO). MALDI-TOF m/z: 3966 [M]+. Anal. Calcd for
3
2.85 (28H, m, SCH2), 3.27 (7H, d, J 2,3 ) 9.2 Hz, H-2), 3.39
C
161H238O98S7‚3H2O: C, 48.10; H, 5.96. Found: C, 47.89; H, 6.09.
2°-La ctose-7-m er Clu ster (15). BF3‚OEt2 (142 µL) was
(7H, t, J ) 9.0 Hz, H-4), 3.45-3.54 (28H, m, H-6a, H-6b,
OCH2), 3.56-3.68 (7H, m, H-5), 3.70-3.78 (21H, m, H-5′,
3
added dropwise via a micropipet to a stirred solution of 13
(368 mg, 55 µmol) in CH2Cl2 (15 mL). The reaction was stirred
at room temperature under an Ar atmosphere. After 4 h, TLC
indicated that the reaction had gone to completion. H2O (7 mL)
was added, and the resulting mixture was stirred for a further
30 min. CH2Cl2 (50 mL) and H2O (50 mL) were added, and
the organic layer was washed with brine (50 mL) and then
dried (MgSO4) and filtered. The solvents were removed in
vacuo, and the residue was purified by gel filtration chroma-
tography (LH-20, MeOH, 1 mL min-1) to afford the product
as a white foam (241 mg, 75%). 1H NMR ((CD3)2NCDO, 370K,
500 MHz): δ 1.90-1.95 (14H, m), 1.92, 2.02, 2.03, 2.042, 2.045,
2.11 (147H, 6s), 2.75-2.78 (7H, m), 2.82-2.87 (7H, m), 3.35
(7H, dd, J ) 3.3, 9.4 Hz), 3.45 (7H, t, J ) 9.3 Hz), 3.73 (7H, d,
J ) 8.1 Hz), 3.76-3.97 (42H, m), 3.98-4.01 (7H, m), 4.10-
4.20 (21H, m), 4.23 (7H, t, J ) 6.7 Hz), 4.49 (7H, d, J ) 11.8
Hz), 4.74 (7H, s), 4.80-4.85 (21H, m), 4.97-5.03 (14H, m), 5.06
(7H, s, H-1), 5.17 (7H, dd, J ) 3.4, 10.2 Hz), 5.18-5.20 (7H,
m), 5.36 (7H, d, J ) 3.4 Hz). 13C NMR (125 MHz, (CD3)2NCDO,
370 K): δ 20.2, 20.3, 20.4, 20.5, 20.70, 20.73, 20.8, 27.8, 31.8,
61.7, 62.0, 63.4, 68.5, 70.5, 71.5, 71.6, 71.9, 72.0, 73.0, 74.1,
74.9, 77.2, 77.4, 81.9, 84.0, 84.2, 101.3, 102.0, 169.7, 169.88,
169.95, 170.01, 170.49, 170.52, 170.7. MALDI-TOF m/z: 5984
[M]+. Anal. Calcd for C245H350O154S7‚3H2O: C, 48.74; H, 5.94.
Found: C, 48.57; H, 5.73.
OCHa), 3.81 (7H, t, J 2,3 ) 9.0 Hz, H-3), 3.97-4.04 (7H, m,
2
OCHb), 4.11 (14H, d, J 6a′,6b′ ) 10.9 Hz, H-6a′), 4.24 (14H, dd,
2
3
3J 5′,6b′ ) 3.5 Hz, J 6a′,6b′ ) 11.5 Hz, H-6b′), 4.54 (7H, d, J 1′,2′
)
3
10.0 Hz, H-1′), 4.57 (7H, d, J 1′,2′ ) 10.0 Hz, H-1′), 4.82 (7H,
3
3
bs, H-1), 4.98 (14H, t, J 2′,3′ ) 9.2 Hz, H-2′), 5.06 (7H, t, J 3′,4′
3
) 9.7 Hz, H-4′), 5.07 (7H, t, J 3′,4′ ) 9.7 Hz, H-4′), 5.22 (7H, t,
3J 3′,4′ ) 9.3 Hz, H-3′). 13C NMR (CDCl3, 125 MHz): δ 20.4, 20.66
(CH3CO), 26.9, 27.0 (SCH2CH2), 29.5, 30.0 (SCH2), 62.2 (C-
6′), 68.4 (C-4′), 69.1 (C-6), 69.9 (OCH2), 70.0, 70.1 (C-2′), 70.6
(C-5), 71.3 (OCH2), 73.1 (C-3), 73.9, 74.0 (C-3′), 75.7, 75.8 (C-
5′), 80.7 (C-2), 83.3 (C-4), 83.7, 83.9 (C-1′), 101.9 (C-1), 169.20,
169.23, 169.29, 169.77, 169.96, 170.02, 170.37, 170.47 (8 x
CH3CO). MALDI-TOF m/z: 6820 [M + Na]+. Anal. Calcd for
C
280H406O161S14‚4H2O: C, 48.96; H, 6.07. Found: C, 48.73; H,
5.76.
1°,2°-La ctose-14-m er Clu ster (19). To thiol 2 (540 mg, 828
µmol, 28 equiv) and CD 7 (50 mg, 30 µmol, concentration CD
) 5 mM) was added distilled MeOH. C6H6 was added dropwise
until the CD was completely dissolved. A stream of Ar was
bubbled through the solution for 20 min to thoroughly degas
it. The solution, kept under an atmosphere of Ar, was placed
in front of an Hg lamp and stirred for 5 h. Following the
removal of solvents, the residue was purified by gel filtration
chromatography (LH-20, 20% CHCl3/MeOH, 1 mL min-1) to
afford the product as a white foam (212 mg, 66%). 1H NMR
((CD3)2NCDO, 380K, 500 MHz): δ 1.91-1.98 (28H, m,
SCH2CH2), 1.95, 2.05, 2.06, 2.07, 2.08, 2.09, 2.14 (294H, 7s, 7
x AcO), 2.72-2.91 (28H, m, SCH2), 3.36 (14H, d, J ) 9.0 Hz,
H-2), 3.51 (7H, t, J ) 8.7 Hz, H-4), 3.55-3.63 (21H, m, H-6a,
OCH2), 3.76-3.78 (7H, m, H-5), 3.82-3.91 (21H, m, H-5′,
OCHa), 3.93-3.97 (28H, m, H-3, H-4′), 4.01-4.06 (14H, m,
H-6b, OCHb), 4.14-4.22 (42H, m, H-6a′, H-6a′′, H-6b′′), 4.25
(14H, t, J ) 6.5 Hz, H-5′′), 4.52 (14H, d, J ) 11.0 Hz, H-6b′),
4.80-4.88 (42H, m, H-1′, H-2′, H-1′′), 5.02 (7H, bs, H-1), 5.04
(7H, t, J ) 8.1 Hz, H-2′′), 5.18-5.24 (28H, m, H-3′, H-3′′), 5.39
(14H, d, J ) 3.3 Hz, H-4′′). 13C NMR ((CD3)2NCDO, 370K, 125
MHz): δ 20.7, 20.8, 20.9, 21.04, 21.08, 21.3, (6 x CH3CO), 28.28,
28.38 (SCH2CH2), 31.56, 31.66 (SCH2), 62.5 (C-6′′), 63.9 (C-
6′), 68.9 (C-4′), 70.5 (C-6), 71.0 (OCH2), 71.1 (C-2′′), 72.0 (C-
5′′), 72.2 (OCH2), 72.4 (C-3′′,C-5), 72.5 (C-2′), 74.4 (C-3), 75.5
(C-3′), 77.6 (C-4′), 78.0 (C-5′), 80.0 (C-2), 82.4 (C-4), 84.4 (C-
1′), 84.5 (C-1′), 101.8 (C-1′′), 102.8 (C-1), 170.1, 170.3, 170.45,
170.55, 170.9, 171.9 (6 x CH3CO). MALDI-TOF m/z: 10833
[M]+. Anal. Calcd for C448H630O273S14‚6H2O: C, 49.18; H, 5.91.
Found: C, 49.23; H, 5.89.
2°-Glu cose-7-m er Clu ster (16). Methanolic NaOMe (1 M)
(0.4 mL) was added to a stirred solution of 14 (95 mg, 25 µmol)
in dry MeOH (5.0 mL), and the reaction was left at room
temperature. After TLC indicated completion (2 d), H2O (10
mL) was added to dissolve precipitates, and the reaction was
left to stir for a further 1 h, during which time the precipitate
dissolved. The reaction was neutralized with Amberlite IR-
120 (H+ form) ion-exchange resin and filtered. The solvents
were removed in vacuo, and the resultant glass was dissolved
in H2O and freeze-dried to afford 16 as a white fluff (67 mg,
99%). Selected NMR data. 1H NMR (D2O, 500 MHz): δ 1.85-
1.92 (14H, m, CH2), 2.71-2.77 (7H, m, SCHa), 2.80-2.86 (7H,
m, SCHb), 3.25 (7H, t, J ) 9.8 Hz, H-2′), 3.37 (7H, dd, J ) 2.0
Hz, J ) 5.7 Hz, H-2), 3.41 (7H, t, J ) 9.0 Hz, H-3′), 4.45 (7H,
d, J ) 9.8 Hz, H-1′), 5.12, (7H, s, H-1). 13C NMR (D2O, 125
MHz): δ 26.3, 29.4, 60.0, 60.8, 69.4, 70.4, 71.1, 72.1, 73.5, 79.7,
80.9, 85.2, 99.6. MALDI-TOF m/z: 2789 [M]+.
2°-La ctose-7-m er Clu ster (17). Methanolic NaOMe (1 M)
(1.5 mL) was added to a stirred solution of 15 (189 mg, 31
µmol) in dry MeOH (5.0 mL), and the reaction was allowed to
stand at room temperature. After TLC indicated completion
(1 d) of the reaction, H2O (10 mL) was added to dissolve
precipitates, and the reaction was left to stir for a further 1 h,
1°,2°-Glu cose-14-m er Clu ster (20). Methanolic NaOMe (1
M) (4.0 mL) was added to a stirred solution of 18 (372 mg, 55
µmol) in dry MeOH (20 mL), and the reaction was allowed to

Cyclodextrin-Based Carbohydrate Clusters
J . Org. Chem., Vol. 66, No. 25, 2001 8319
stand at room temperature. After TLC had indicated comple-
tion (1 d) of the reaction, 1 M NaOH (2 mL) was added to
dissolve precipitates, and the reaction was left to stir for a
further 1 d, during which time the precipitate dissolved. The
reaction was neutralized with Amberlite IR-120 (H+ form) ion-
exchange resin and filtered. The solvents were removed in
vacuo, and the resultant glass was dissolved in H2O and freeze-
dried to afford 20 as a white fluff (307 mg, 99%). An analytical
sample was prepared by gel filtration chromatography (Biogel
P-6, H2O, 1 mL min-1). Selected NMR data. 1H NMR (D2O,
360 K, 500 MHz): δ 2.33-2.41 (28H, m, CH2), 3.19-3.35 (28H,
m, SCH2), 4.91 (7H, d, J ) 9.9 Hz, H-1′), 4.93 (7H, d, J ) 9.9
Hz, H-1′′), 5.56 (7H, d, J ) 3.0 Hz, H-1). 13C NMR (D2O, 345
K, 125 MHz): δ 23.7, 26.9, 27.1, 29.9, 30.1, 61.59, 61.66, 69.4,
70.1, 70.3, 70.9, 71.3, 71.6, 72.89, 72.97, 77.82, 77.89, 80.30,
80.35, 81.96, 85.81, 85.88, 100.4. MALDI-TOF m/z: 4381 [M]+.
1°,2°-La ctose-14-m er Clu ster (21). Methanolic NaOMe (1
M) (0.5 mL) was added to a stirred solution of 19 (305 mg, 28
µmol) in dry MeOH (10 mL) and THF (4 mL). Within 1 min,
a suspension appeared which dissolved upon the addition of
H2O (10 mL). The reaction was left to stir at room temperature,
and 1 M methanolic NaOMe was added (0.3 mL) if the pH
dropped below 9. After the pH remained constant (pH ) 9)
for 4 h, the reaction was neutralized with Amberlite IR-120
(H+ form) ion-exchange resin and filtered. The solvents were
removed in vacuo, and the resultant glass was dissolved in
H2O and freeze-dried to afford 21 as a white fluff (189 mg,
99%). An analytical sample was prepared by gel filtration
chromatography (Biogel P-6, H2O, 1 mL min-1). Selected NMR
H-1′′), 4.44 (14H, d, J ) 9.8 Hz, H-1′), 5.02 (7H, bs, H-1). 13C
NMR (D2O, 300 K, 125 MHz): δ 26.9, 27.1, 29.9, 30.1, 61.0,
61.3, 69.0, 70.3, 70.9, 71.3, 71.4, 72.8, 73.1, 75.7, 76.3, 76.4,
79.0, 80.4, 82.2, 85.7, 100.7, 103.3. MALDI-TOF m/z: 6713
[M]+.
Molecu la r Mod elin g. Molecular modeling was carried out
using the Amber* force field as implemented in Macromodel30
(V 5.0). The assembly was built within the INPUT submode,
and the geometry optimization was carried out by first fully
minimizing the initial structure (final gradient < 0.05 kJ Å-1
)
using the Polak Ribie`re Conjugate Gradient (PRCG) algo-
rithm33 with extended nonbonded cutoffs (4 Å for hydrogen
bonding, 8 Å for van der Waals, and 20 Å for electrostatic
interactions). The assembly was then subjected to a molecular
dynamics simulation (10 ps, 1.5 fs time step, 300 K, Amber*,
extended cutoffs) to afford a system conformationally dis-
similar to the initial structure. The structure of the super-
molecule was then fully minimized again (PRCG, Amber*,
extended cutoffs, final gradient < 0.05 kJ Å-1) to afford the
conformation displayed. For all steps, solvent effects were
considered in the form of the GB/SA34 solvation model for H2O.
Ack n ow led gm en t. We thank UCLA for generous
financial support. We also thank Dr. Anthony R. Pease
for assistance with molecular modeling experiments.
J O010705Z
(33) Polak, E.; Ribie`re, G. Rev. Fr. Inf. Rech. Oper. 1969, 16, 35-
41.
(34) Still, W. C.; Tempczyk, A.; Hawley, R. C.; Hendrickson, T. J .
Am. Chem. Soc. 1990, 112, 6127-6129.
1
data. H NMR (D2O, 300 K, 500 MHz): δ 1.77-1.89 (28H, m,
CH2), 2.61-2.87 (28H, m, SCH2), 4.32 (14H, d, J ) 7.7 Hz,