Synthesis of carbamate-containing cyclodextrin analogues

Article abstract of DOI:10.1021/ol005648v

The one-pot cyclooligomerization of a saccharide-derived p-nitrophenyl carbamate monomer was developed to generate a series of novel carbamate-containing cyclodextrin analogues. The "transcarbamoylation" occurs by initial base-induced activation to the is

Full text of DOI:10.1021/ol005648v

ORGANIC
LETTERS
2000
Vol. 2, No. 8
1093-1096
Synthesis of Carbamate-Containing
Cyclodextrin Analogues
Pek Y. Chong and Peter A. Petillo*
Department of Chemistry, UniVersity of Illinois at Urbana-Champaign,
600 S. Mathews AVenue, Urbana, Illinois 61801
alchmist@alchmist.scs.uiuc.edu
Received February 10, 2000
ABSTRACT
The one-pot cyclooligomerization of a saccharide-derived p-nitrophenyl carbamate monomer was developed to generate a series of novel
carbamate-containing cyclodextrin analogues. The “transcarbamoylation” occurs by initial base-induced activation to the isocyanate, followed
by polycondensation/cyclization of the isocyanato alcohol. In the presence of NaH, only cyclized oligomers were observed, suggesting the
importance of Na+ in promoting the efficiency of the cyclization process. The facile deprotection of the oligomers was achieved.
Since their discovery in 1891, cyclodextrins (CDs) have
attracted considerable interest, particularly in the field of
supramolecular chemistry, as a result of their ability to form
inclusion complexes with a wide range of substrates.1
Because of these remarkable inclusion properties, CDs have
found numerous applications.1d For example, immobilized
CDs have been employed for the separation of compounds
based on their selective retention of guest molecules, and
mobile CDs have been used as delivery systems.1e However,
most of the applications of CDs make use of their ability to
modify the chemical and physical properties of guest
molecules. Thus, CDs have been used to both increase and
decrease the availability of drugs by changing their solubili-
ties upon complexation. Additionally, CDs have been used
to stabilize active substances from degradation and to bind
and catalyze reactions.1f
applications, for example, as enzyme mimics, and to alter
their binding characteristics to tailor them for specific guest
molecules.1g The complexation characteristics of CDs are
dictated by the internal cavity size and shape, which in native
CD is somewhat fixed by the R(1 f 4) linked glucopyranosyl
units within the backbone. As derivatizations at the C2, C3,
and C6 hydroxyl groups of native CD have a limited effect
on the cavity shape, analogues of CDs that have configura-
tionally and/or constitutionally modified backbones are of
particular interest in the development of organic hosts with
different complexation properties.2-8 Despite the synthetic
challenge that these targets pose, a variety of cycloglycans
have been prepared by a total synthetic approach (stepwise
(2) Mori, M.; Ito, Y.; Ogawa, T. Carbohydr. Res. 1989, 192, 131-146.
(3) Kuyama, H.; Nukada, T.; Nakahara, Y.; Ogawa, T. Tetrahedron Lett.
1993, 34, 2171-2174.
(4) Collins, P. M.; Ali, M. H. Tetrahedron Lett. 1990, 31, 4517-4520.
(5) (a) Gattuso, G.; Nepogodiev, S. A.; Stoddart, J. F. Chem. ReV. 1998,
98, 1919-1958. (b) Ashton, P. R.; Brown, C. L.; Menzer, S.; Nepogodiev,
S. A.; Stoddart, J. F.; Williams, D. J. Chem. Eur. J. 1996, 2, 580-591.
(6) (a) Bukownik, R. R.; Wilcox, C. S. J. Org. Chem. 1988, 53, 463-
471. (b) Penade´s, S.; Cotero´n, J. M. J. Chem. Soc., Chem. Commun. 1992,
683-684.
(7) (a) Dumont, B. D.; Joly, J.-P,; Chapleur, Y. Bioorg. Med. Chem.
Lett. 1994, 4, 1123-1126. (b) Haslegrave, J. A.; Stoddart, J. F.; Thompson,
D. J. Tetrahedron Lett. 1979, 24, 2279-2282. (c) Pietraszkiewicz, M.;
Jurczak, J. J. Chem. Soc., Chem. Commun. 1983, 132-133. (d) Kanakamma,
P. P.; Mani, N. S.; Nair, V. Synth. Commun. 1995, 25, 3777-3787. (e)
Ellinghaus, R.; Schroder, G. Liebigs Ann. Chem. 1985, 418-420.
A large number of chemical modifications have been made
to native CDs in order to fine-tune them for specific
(1) Representative reviews: (a) Wenz, G. Angew. Chem., Int Ed. Engl.
1994, 33, 803-822. (b) Connors, K. A. Chem. ReV. 1997, 97, 1325-1357.
Within Chem. ReV. 1998, 98, 8, issue 5: (c) Szejtli, J. Chem. ReV. 1998,
98, 1743-1753. (d) Rekharsky, M. V.; Inoue, Y. Chem. ReV. 1998, 98,
1875-1917. (e) Uekama, K.; Hirayama, F.; Irie, T. Chem. ReV. 1889, 98,
2045-2076. (f) Breslow, R.; Dong, S. D. Chem. ReV. 1998, 98, 1997-
2011. (g) Khan, A. R.; Forgo, P.; Stine, K. J.; D’Souza, V. T. Chem. ReV.
1998, 98, 1977-1996.
10.1021/ol005648v CCC: $19.00 © 2000 American Chemical Society
Published on Web 03/24/2000

preparation of a linear precursor followed by cyclization)
and by a one-pot polycondensation/cyclization approach
(using a “monomer” to generate a variety of macrocycles).2-5
The incorporation of nonsaccharide components within the
backbone has also been employed to access a variety of
constitutional CD analogues with profound changes in the
cavity shape. These include the “glycophanes”6 that incor-
porate aromatic components and others that utilize crown
ether units7 and butadiyne units.8
Herein, we report the synthesis of a series of novel
carbamate-containing CD analogues 3 from isocyanato
alcohol monomer 2, which is generated in situ from the
activated carbamate monomer 1 (Scheme 1).
with p-methoxybenzaldehyde dimethyl acetal. Reacetylation
of 7 at the C2 and C3 positions gave 8. Regioselective
reduction of the benzylidene at the C6 position was achieved
using the conditions of Johansson and Samuelsson to afford
alcohol 9.10 Finally, azide reduction and carbamoylation with
p-nitrophenyl chloroformate gave the desired saccharide-
bound p-nitrophenyl carbamate 1. The heterogeneous condi-
tions of Choy and co-workers were used for the carbamoy-
lation,11 as the activated carbamate could be isolated and
purified in good yield with minimal base-induced decom-
position.12
Although the reaction of p-nitrophenyl carbamates with
amines to form ureas is, in most cases, facile and well-
documented, their reaction with stoichiometric amounts of
alcohols proceeds with lower yields while requiring harsher
conditions that involve prior activation to the isocyanate.13
Lewis acids such as chlorosilanes may be used in the
presence of base to quantitatively cleave the activated
carbamate to its isocyanate; however, the presence of Et3N
alone will often readily generate the isocyanate to varying
extents of conversion.14
Scheme 1. Synthesis of the Carbamate-Containing CD
Analogues 3
Our oligomerization conditions for monomer 1 were
developed from optimization of the parallel reaction between
model compounds 9 and 10 (Scheme 3). It is worth noting
Scheme 3. Model Reaction between 9 and 10
In monomer 1, the p-nitrophenyl carbamate acts as a stable
isocyanate precursor. Access to this carbamate was obtained
by glycosylation of the fully acetylated glucopyranosyl
trichloroacetimidate 4 with 2-chloroethanol to give the
2-chloroethyl glycoside as the â-anomer 5 in 82% yield
(Scheme 2). Subsequent displacement of chloride with NaN3
afforded the 2-azidoethyl glycoside 6 in 95% yield.9 The
2-azidoethyl glycoside 6 was deacetylated and benzylidenated
that protection of the C4 hydroxyl group as the PMB ether
in both monomers 1 and 9 was necessary, as it prevented
Scheme 2. Synthesis of Monomer 1
(8) (a) Burli, R.; Vasella, A. HelV. Chim. Acta 1999, 82, 485-493. (b)
Burli, R.; Vasella, A. Angew. Chem., Int. Ed. Engl. 1997, 36, 1852-1853.
(c) Burli, R.; Vasella, A. HelV. Chim. Acta 1997, 80, 1027-1052. (d) Burli,
R.; Vasella, A. HelV. Chim. Acta 1997, 80, 2215-2237.
(9) This two-step route avoids the use of the explosive 2-azidoethanol
as the glycosyl acceptor. Glycosylations using 2-hydoxyethyl carbamic acid
esters as glycosyl acceptors led to the predominant formation of the
undesired R anomer.
(10) Johansson, R.; Samuelsson, B. J. Chem. Soc., Perkin Trans. 1 1984,
2371.
(11) Choy, N.; Moon, K. Y.; Park, C.; Son, Y. C.; Jung, W. H.; Choi,
H.; Lee, C. S.; Kin, C. R.; Kim, S. C.; Yoon, H. Org. Prep. Proced. Int.
1996, 28, 173-177.
(12) When soluble base conditions were used, the product underwent
base-induced decomposition during purification, resulting in lowered yields.
(13) (a) Hutchins, S. M.; Chapman, K. T. Tetrahedron Lett. 1994, 35,
4055-4058. (b) Hutchins, S. M.; Chapman, K. T. Tetrahedron Lett. 1995,
36, 2583-2586. (c) Koh, H. J.; Kim, O. S.; Lee, H. W.; Lee, I. J. Phys.
Org. Chem. 1997, 10, 725-730. (d) Umezawa, S.; Takagi, Y.; Tsuchiya,
T. Bull. Chem. Soc. Jpn. 1971, 44, 1411-1415. (e) Fukuda, Y.; Kitasato,
H.; Sakai, H.; Suami, T. Bull. Chem. Soc. Jpn. 1982, 55, 880-886.
(14) (a) Greber, G.; Kricheldorf, H. R. Angew. Chem., Int. Ed. Engl.
1968, 7, 941. (b) Pirkle, W. H.; Hauske, J. R. J. Org. Chem. 1977, 42,
2781. (c) Chong, P. Y.; Janicki, S. J.; Petillo, P. A. J. Org. Chem. 1998,
63, 8515-8521 and references therein.
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Org. Lett., Vol. 2, No. 8, 2000

acetyl migrations originating from C2 and C3, thereby
allowing us to maintain the position of the free alcohol at
C6. Reaction between 9 and 10 with the use of both NaH
and Et3N in CH2Cl2, afforded carbamate 11 in 92% yield,
the reaction reaching completion within 1 h. In addition to
increasing the nucleophilicity of the alcohol, the NaH plays
an important role in driving the reaction to completion by
precipitating the byproduct p-nitrophenol out of solution as
the phenolate salt.
Polycondensation of monomer 2 produced a series of low
molecular weight cyclized oligomers 3, linear growth being
terminated by intramolecular cyclization. The formation of
these oligomers is apparent from the MALDI mass spectrum
(Figure 1) in which the MW of each successive oligomer
Figure 2. 1H NMR specta (in CDCl3) of (a) cyclic 2-mer at 20
°C, (b) cyclic 3-mer at 20 °C, and (c) cyclic 3-mer at 50 °C.
(Figure 2). Increasing the ring size of the cyclic oligomer is
expected to increase the degree of conformational flexibility;
therefore, this observation is not surprising.16
Although less entropically favored, cyclization of the larger
oligomers was observed. We believe that this tendency
toward cyclization may be due to coordination (perhaps of
the O atoms within the backbone) with Na+ ions, which
structurally preorganizes the oligomer for cyclization. In
support of this, the same reaction in the absence of NaH led
to the formation of the linear oligomers, although the more
entropically favored cyclization of the smaller oligomers was
also observed (Figure 3).17
Figure 1. MALDI mass spectrum of cyclized oligomers 3 obtained
by cyclooligomerization of monomer 1. All masses correspond to
(M + Na)+, for example, the peak at 929.56 corresponds to the
cyclic 2-mer (MW ) 906.3).
increases by 453 mass units (corresponding to a monomer
unit).
These CD analogues are structurally interesting with
potential utility in host-guest chemistry. The cyclic 2-mer,
3-mer, and 4-mer are isolable from the reaction mixture and
have been purified (by silica gel flash chromatography) and
fully characterized. The high degree of symmetry of these
protected cyclized oligomers was apparent from their NMR
spectra. Each oligomer gave rise to one set of pyranoside
signals, corresponding to the repeating monomer unit.
Connectivities were established by COSY NMR spectra, and
molecular compositions were confirmed by HRMS-FAB.
1
The 2-mer showed no broadened signals in the H NMR
spectrum, and the appearance of the NH signal as a dd
indicates a fairly conformationally restricted structure. On
the other hand, both the 3-mer and 4-mer showed some signal
broadening, as well as some asymmetry at 20 °C.15 When
the temperature was elevated to 50 °C, these signals
coalesced and/or sharpened to some degree, suggesting that
line broadening is the result of slow-equilibrating conformers
Figure 3. MALDI mass spectrum of the result of the reaction in
the absence of NaH. Although cyclized oligomers 3 are observed
at low MW, the uncyclized counterparts appear to dominate at and
beyond the 4-mer. All masses correspond to (M + Na)+.17
(15) The NMR spectra of the 3-mer and 4-mer at 50 °C are very similar
with similar chemical shifts and almost identical coupling constants for
H1, H2, and H3.
Our deprotection sequence was performed on the isolated
cyclic 2-mer 3b to evaluate its efficiency for these systems.
Org. Lett., Vol. 2, No. 8, 2000
1095

Facile removal of the PMB groups was achieved using
Kahne’s conditions (10% TFA/CH2Cl2) to afford 12b in 92%
yield.18 Following this, Zemple´n deacetylation provided the
fully deprotected 2-mer 13b in 98% yield (Scheme 4).
Scheme 4. Deprotection of the Cyclic 2-Mer 3b
The same deprotection sequence was then performed on
the oligomeric mixture 3 (Scheme 5). PMB ether deprotec-
Scheme 5. Deprotection of the CD Analogues 3
Figure 4. (a) MALDI mass spectrum of the C4-deprotected CD
analogues 12. (b) MALDI mass spectrum of the fully deprotected
CD analogues 13. All masses correspond to (M + Na)+.
carbamate to the isocyanato alcohol. Facile deprotection of
the oligomers was also achieved.
tion proceeded cleanly to produce oligomers 12 with the
MALDI mass spectrum shown in Figure 4a, each successive
oligomer being separated by 333 units (corresponding to the
mass of a C4-deprotected monomer unit). Final deacetylation
afforded the fully deprotected oligomers 13 (Figure 4b).
In conclusion, we have developed a facile one-pot poly-
condensation/cyclization approach to access novel carbamate-
containing cyclodextrin analogues. This cyclooligmerization
involves the activation of a saccharide-derived p-nitrophenyl
Acknowledgment. We gratefully acknowledge the NIH,
PRF, American Heart Association, UIUC Research Board,
and Critical Research Initiatives Program for financial
support. We also extend special thanks to Professor Jeffrey
Moore for useful suggestions. All mass spectra were obtained
by the UIUC Mass Spectrometry Lab.
(16) Our observed line broadening and temperature dependence of the
spectra is similar to that observed in Vasella’s cyclic hybrids of 2,2′-
bipyridine and acetylenosaccharides (ref 8a).
(17) The uncyclized oligomers have molecular weights 26 units lower
than their cyclic counterparts because the p-nitrophenyl carbamate is
hydrolyzed on workup to the amines.
Supporting Information Available: Detailed experi-
mental procedures and compound characterization data. This
material is free of charge via the Internet at http://pubs.acs.org.
(18) Yan, L.; Kahne, D. Synlett 1995, 523-524.
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