Synthesis of structurally defined scaffolds for bivalent ligand display based on glucuronic acid anilides. The degree of tertiary amide isomerism and folding depends on the configuration of a glycosyl azide

Article abstract of DOI:10.1021/jo050200z

Syntheses and structural analyses of bivalent carbohydrates based on anilides of glucuronic acid are described. Secondary anilides predominantly adopted the Z-anti structure; there is also evidence for population of the Z-syn isomer. Bivalent tertiary anilides displayed two signal sets in their NMR spectra, consistent with the presence of (i) a major isomer where both amides have E configurations (EE) and (ii) a minor isomer where one amide is E and the other Z (EZ). Qualitative NOE/ROE spectroscopic studies in solution support the proposal that the anti conformation is preferred for E amides. The crystal structure of one bivalent tertiary anilide showed E-anti and E-syn structural isomers; intramolecular carbohydrate-carbohydrate stacking was observed and mediated by carbonyl-pyranose, azide-azide, and pyranose-aromatic interactions. The EE to EZ isomer ratio, or the degree of folding, for tertiary amides, was greatest for a bivalent compound containing two α-glycosyl azide groups; this was enhanced in water, suggesting that hydrophobic interactions are partially but not wholly responsible. Computational methods predicted azide-aromatic (N...H-C interaction) and azide-azide interactions for folded isomers. The close contact of the azide and aromatic protons (N...H-C interaction) was observed upon examination of the close packing in the crystal structure of a related monomer. It is proposed that the α-azide group is more optimally aligned, compared to the β-azide, to facilitate interaction and minimize the surface area of the hydrophobic groups exposed to water, and this leads to the increased folding. The alkylation of bivalent secondary anilides induces a switch from Z to E amide that alters the scaffold orientation. The synthesis of a bivalent mannoside, based on a secondary anilide scaffold, for investigation of mannose-binding receptor cross-linking and lattice formation is described.

Full text of DOI:10.1021/jo050200z

Synthesis of Structurally Defined Scaffolds for Bivalent Ligand
Display Based on Glucuronic Acid Anilides. The Degree of
Tertiary Amide Isomerism and Folding Depends on the
Configuration of a Glycosyl Azide
Manuela Tosin and Paul V. Murphy*
Centre for Synthesis and Chemical Biology, Department of Chemistry, Conway Institute of Biomolecular
and Biomedical Research, University College Dublin, Belfield, Dublin 4, Ireland
Paul.V.Murphy@ucd.ie
Received January 31, 2005
Syntheses and structural analyses of bivalent carbohydrates based on anilides of glucuronic acid
are described. Secondary anilides predominantly adopted the Z-anti structure; there is also evidence
for population of the Z-syn isomer. Bivalent tertiary anilides displayed two signal sets in their
NMR spectra, consistent with the presence of (i) a major isomer where both amides have E
configurations (EE) and (ii) a minor isomer where one amide is E and the other Z (EZ). Qualitative
NOE/ROE spectroscopic studies in solution support the proposal that the anti conformation is
preferred for E amides. The crystal structure of one bivalent tertiary anilide showed E-anti and
E-syn structural isomers; intramolecular carbohydrate-carbohydrate stacking was observed and
mediated by carbonyl-pyranose, azide-azide, and pyranose-aromatic interactions. The EE to EZ
isomer ratio, or the degree of folding, for tertiary amides, was greatest for a bivalent compound
containing two R-glycosyl azide groups; this was enhanced in water, suggesting that hydrophobic
interactions are partially but not wholly responsible. Computational methods predicted azide-
aromatic (N‚‚‚H-C interaction) and azide-azide interactions for folded isomers. The close contact
of the azide and aromatic protons (N‚‚‚H-C interaction) was observed upon examination of the
close packing in the crystal structure of a related monomer. It is proposed that the R-azide group
is more optimally aligned, compared to the â-azide, to facilitate interaction and minimize the surface
area of the hydrophobic groups exposed to water, and this leads to the increased folding. The
alkylation of bivalent secondary anilides induces a switch from Z to E amide that alters the scaffold
orientation. The synthesis of a bivalent mannoside, based on a secondary anilide scaffold, for
investigation of mannose-binding receptor cross-linking and lattice formation is described.
1. Introduction
binding subsites. Herein, we describe an extension of this
work that involves the placement of multiple recognition
groups on pyranose-derived multivalent scaffolds gener-
ating novel multivalent ligands.5,6 Multivalent carbohy-
drates are of interest as they form part of a high-density
coding system involved in a variety of biological processes6b
and are relevant for the development of new therapeu-
tics7 or synthetic vaccines.8 There has been little pub-
The use of pyranose scaffolds as peptidomimetics was
first explored by Hirschmann, Nicolaou, Smith, and co-
workers1 and extended into other areas of bioorganic
chemistry by these and other researchers.2-4 This re-
search involves the placement or grafting of pharma-
cophoric groups onto the saccharide scaffold; the scaffold
orients the attached groups in the direction of their
10.1021/jo050200z CCC: $30.25 © 2005 American Chemical Society
Published on Web 04/19/2005
J. Org. Chem. 2005, 70, 4107-4117
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Tosin and Murphy
lished work concerning the detailed 3D structures of
bivalent or higher-order multivalent carbohydrate ligands.
Recent indications show that multivalent carbohydrate
ligands with increased rigidity9 or defined architecture10
can have enhanced affinity and selectivities. These
observations suggest that detailed 3D structure-activity
relationships will be interesting. The mechanisms of
action of multivalent ligands are complex11 and include
cross-linking of glycan-binding proteins that can result
in the formation of soluble lattices that can alter receptor
function at the cell surface.6e,12 For glycoclusters, it may
be difficult to define bioactive conformations, assuming
these exist, if flexible scaffolding is used for the display
of the recognition components. The presentations of
ligands preorganized on structurally defined scaffolds will
be of interest. We have previously described the synthesis
and structural analysis of bivalent N-glycosylbenzamides
(1,2) in this context.13 The synthesis and structural
analysis of secondary and tertiary anilides derived from
glucuronic acid (3,4) is reported in the previous article.14
Herein, these studies are extended to the synthesis and
structural analysis of 5. The synthesis of a structurally
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(15) One of the referees suggested that we explain why glycosyl
azides were used. They were chosen for the ease and reliability with
which they can be synthesized from readily available donors. Also,
glycosyl azides are generally very stable under a wide range of reaction
conditions, including acid and base. In addition, they are bioorthogonal
and suitable for further functionalization should this be of interest in
future.
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International Carbohydrate Symposium, Glasgow, U.K., July 2004,
C44.
(18) The full experimental details are provided in the Supporting
Information.
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4108 J. Org. Chem., Vol. 70, No. 10, 2005

Glucuronic Acid Anilides
CHART 1. Structural Preferences Displayed by Bivalent Glycosylamides 1 and 2 and Glucuronic Acid
Anilides 3 and 4, and the Structure of Scaffolding 5 and Bivalent Mannoside 6 Synthesized in This Study
defined bivalent mannoside ligand 6, with the potential
to cross-link mannose-binding receptors, is described.
produced 15, whereas alkylation of 14 using sodium
hydride and iodomethane in DMF produced 16, which
was converted to 17 by deacetylation.
2. Results and Discussion
SCHEME 2
2.1. Synthetic Studies. 2.1.1. Synthesis of Novel
Scaffolds. The synthesis of 8-11 (Scheme 1) was carried
out from acid 7.14 This acid was first converted to the
SCHEME 1
bivalent secondary amide 8 via reaction of its acid
chloride with 1,4-phenylenediamine in the presence of
pyridine in dichloromethane. Removal of the acetate
protecting groups from 8 using catalytic sodium meth-
oxide in methanol produced 9, whereas methylation of 8
produced 10 and the subsequent deacetylation 11.
The synthesis of 14 and 16-18, in which the glycosyl
azide groups15 have R-configurations, was carried out
from 12 (Scheme 2). The bivalent amide 13 was first
obtained via the coupling reaction of the acid chloride
prepared from 12 and 1,4-phenylenediamine. The reac-
2.1.2. Synthesis of a Bivalent Mannoside. The bis-
silylated compound 18 was first synthesized18 as a
potential intermediate to be used for the preparation of
6. It can be converted to the bis-alkylated derivative 19
by a reaction with sodium hydride and iodomethane in
DMF (Scheme 3). However the removal of the silyl groups
from either 18 or 19 to produce the required acceptors
for glycosidation was unsuccessful and resulted in mix-
tures.
An alternative route was developed as shown in
Scheme 4. The 6,3-lactone 2114 reacts readily with allyl
alcohol to produce 22. The Schmidt glycosidation of 22
with 2319 gave 24. The allyl ester was removed by
palladium catalysis to yield acid 25.20 The coupling of 26
with p-phenylenediamine promoted by HBTU/HOBt
produced, after a prolonged reaction time, the protected
divalent compound 26. Removal of the acetate protecting
groups by commonly used methods (NaOMe/MeOH,
LiOH, and hydrazine) was unexpectedly problematic and
resulted in a mixture containing unidentified products.
16
tion of 13 with azidotrimethylsilane and SnCl4 in
dichloromethane produced, after chromatography, a frac-
tion containing a 77:23 mixture of 14, a compound in
which both anomeric azide groups have the R-configu-
ration, and 8. The stereoselectivity observed in this
reaction was unexpected: the 1,2-cis-glycoside was pref-
erentially obtained in the presence of the 2-acyl partici-
pating group. The mechanism involves anomerization of
the initially formed â-azide.17 The deprotection of 14
J. Org. Chem, Vol. 70, No. 10, 2005 4109

Tosin and Murphy
SCHEME 3
the scaffolds reported herein. The research described in
the previous paper14 shows that secondary amides, such
as 3, prefer the Z configuration. The crystal structure
(e.g., for 32) and solid-state IR spectroscopic studies
generally show that these amides can be involved in
(intra- and intermolecular) hydrogen bonding in the solid
state; IR spectroscopy indicates that this hydrogen bond-
1
ing does not occur, in most cases, in solution. The H
NMR spectra of secondary amides recorded in solution
show one signal set, assigned to the Z amide. This
contrasted with tertiary anilide 4 which showed two
signal sets. They were assigned to slowly interconverting
E- and Z-amide isomers; the E-configured amide is more
populated in solution (>85%). Qualitative NOE studies
and molecular mechanics calculations supported the
proposal that the E-anti structure is preferred for the
monomers.
However, the use of dibutyltin oxide in methanol proved
to be satisfactory for the removal of the acetates and gave
6.21
SCHEME 4
CHART 2. Amide Structure and Nomenclature
2.2.1. X-ray Crystal Structure of Dimer 10. The
X-ray crystal structure of 10 was discussed in a recent
communication.23 One of the amides of 10 was found to
be E-anti, whereas the other amide was E-syn. The
structure can be considered folded as the carbohydrates
stacked and adopted a cis or U-shaped conformation.24
The stacking was mediated by noncovalent interactions.
Interatomic distances that support intramolecular van
der Waals interactions have been provided previously.23
There were clear interactions (Figure 1) between (i) the
oxygen atom of both pyranoses and the aromatic carbon
and hydrogen atoms, (ii) the E-syn 2-acetate carbonyl
oxygen atom and the E-anti pyranose ring protons, and
(iii) the two azide groups.
2.2.2. NMR and IR Spectroscopic Analysis of
Dimeric Compounds. One set of signals was observed
for secondary amides (Table 1) by 1H NMR (and 13C
NMR) spectroscopy, consistent with the presence of only
the Z-configured amide. The chemical shifts for the NH
groups (δNH ) 7.95-8.30) of the protected compounds,
recorded in CDCl3, are consistent with those observed for
monomeric compound 3 (δNH ) 7.94-8.21). The IR data
(Table 2) for 8, 13, and 14 were also consistent with the
data obtained for 3; there is evidence for hydrogen
bonding in the solid state (NH stretch <3350 cm-1) but
2.2. Structural Studies. A number of amide struc-
tural types (Chart 2)22 are relevant to the structure of
(21) The attempts to alkylate the amide of 26, using sodium hydride
and iodomethane as described for 8, 14, and 18, were not successful
in this case; they resulted in a complex mixture of products.
(22) The E and Z nomenclature refers to the amide configuration.
For the Z isomer, the two groups of highest priority, according to Cahn
Ingold Prelog rules (i.e., the aromatic group and oxygen atom), are on
the same side of the bond with double bond character (amide bond);
for the E isomer, these same two groups are on opposite sides of the
amide bond. The syn and anti nomenclature refers to the torsion angle
defined by H5-C5-C6-O. For the anti isomer, this angle is 180 ( 90°;
for the syn isomer, this angle is 0 ( 90°. Z hydrogen-bonded refers to
the hydrogen-bonded structure observed in the crystal structure of 32.
1
not in solution (NH stretch >3410 cm-1). The H NMR
(23) Tosin, M.; Mu¨ller-Bunz, H.; Murphy, P. V. Chem. Commun.
2004, 494.
(24) The U-shaped conformation has the carbohydrate groups on
the same side of the plane defined by the aromatic ring; the S-shaped
conformation has the carbohydrates on opposite sides of the ring.
4110 J. Org. Chem., Vol. 70, No. 10, 2005

Glucuronic Acid Anilides
estimated temperature coefficient, ∆δ/∆T, was -7.0
ppb/K and is significantly larger than that found for
protected glucuronic acid anilides (-1.6 ppb/K) suggest-
ing the engagement of the amide proton in an intermo-
lecular hydrogen bond,25 presumably with the solvent.
The NOE spectroscopic studies of the secondary amides
also showed results similar to those of 3; strong NOE
enhancements (Figure 3) of similar intensity were ob-
served between the NH proton and both H-5 and H-4,
and this suggests an equilibrium between the Z-anti and
Z-syn isomers in solution. It is not possible to conclude
that Z-syn is significantly populated on the basis of the
NOE studies because the distance between NH and H-4
in this isomer would be 1.99 Å and the distance between
NH and H-5 in the Z-anti structure is 2.33 Å.14 No NOE
cross-peaks were observed between aromatic protons and
H-2, H-4, or H-5 protons for secondary amides, ruling out
the presence of E-anti and E-syn structures in solution.
On the basis of the analogy with 3, we propose that Z-anti
is preferred in solution for all secondary amides and that
Z-syn is populated to a lesser degree. The bivalent
secondary anilide structure can be represented by 27a
and 27b (Chart 3).
The observation of both E-syn and E-anti isomers in
the crystal structure of tertiary amide 10 would indicate
that two signal sets of equal intensity should be observed
if this structure is stable in solution; however, this is not
the case. There are multiple signal sets in the NMR
spectrum of 10, and these are assigned to two slowly
interconverting configurational isomers. The first of
these, the major isomer, is C2 symmetric, whereas the
second isomer is asymmetric. The NMR data for the C2
symmetric isomer can be explained if (i) both amides of
10 adopt the E-anti structure (similar to U-shaped 30a
or S-shaped 30b), (ii) both amides adopt the E-syn
structure, or (iii) the E-anti to E-syn interconversion is
dynamic but too rapid to be detected by NMR. Qualitative
NOE data obtained for 10 in CDCl3 indicate that E-anti
amides are preferred: a strong NOE cross-peak is
observed between H-5 of the sugar reside and the
aromatic protons but not between the methyl group and
H-4 or H-5. H-5 of the E-anti pyranose and H-4 of the
E-syn pyranose were 3.16 and 2.51 Å, respectively, from
the nearest aromatic protons in the crystal structure of
10; a significantly stronger NOE enhancement between
H-4 and the aromatic protons than that between H-5 and
the aromatic protons may, thus, have been expected if
the E-syn isomer was populated, even to a minor extent.
Irradiation of H-5 led to a strong positive enhancement
of signals for H-1 and H-3 and to medium enhancements
for H-4 and the aromatic protons. There were no en-
hancements of the H-5 or H-4 proton signal upon irradia-
tion of the N-methyl signals as would have been expected
if Z-anti or Z-syn were preferred isomers. The NMR data
for the minor structural isomer are explained by an
isomer with the general features of the unsymmetric
L-shaped 30c, i.e., there is one E-anti amide and one
Z-configured amide. All other tertiary amides (11, 16, 17,
and 19) had NMR spectra (Table 1) similar to that of 10.
FIGURE 1. van der Waals surfaces were calculated using
Macromodel 8.1 for the crystal structure of 10. Shown are the
(a) azide-azide and carbonyl-pyranose proton interactions
and (b) pyranose oxygen-aromatic interactions.
FIGURE 2. Temperature dependence of the NH shift of 9 in
10% D2O/H2O.
FIGURE 3. Summary of results from the NOE experiments
for secondary amides 8, 13, 14, and 18.
spectrum recorded for 9 in D2O/H2O (10:90) showed a
shift of the NH signal to a lower field (δNH ) 10.01) which
suggests an increase in hydrogen bonding for the unpro-
tected compounds. An upfield shift of this signal was
observed with increasing temperature (Figure 2); the
(25) (a) Vasella, A.; Witzig, C. Helv. Chim. Acta 1995, 78, 1971. (b)
Fowler, P.; Bernet, B.; Vasella, A. Helv. Chim. Acta 1996, 79, 269. (c)
Stevens, E. S.; Sugawara, N.; Bonora, G. M.; Toniolo, C. J. Am. Chem.
Soc. 1980, 102, 7048.
J. Org. Chem, Vol. 70, No. 10, 2005 4111

Tosin and Murphy
TABLE 1. Selected NMR Dataa for Anilides and Z/E Ratios for Tertiary Amides
δ (1H-NMRa)
compd
H-1 (J1,2) Z
H-1 (J1,2) E
H-5 (J4,5) Z
H-5 (J4,5) E
NH
Z/E
EZ/EE
6
4.98 (9.0)
-
4.24 (9.5)
-
nd
Z
-
8
4.87 (8.9)
4.92 (8.8)
4.73 (8.5)
4.89 (8.9)
5.84 (7.5)
5.76 (4.2)
5.56 (4.1)
5.80 (br s)
5.68 (br s)
4.65 (9.0)
4.54 (8.9)
4.73 (8.8)
-
4.15 (9.5)
4.16 (9.5)
4.56 (9.5)
-
8.30
Z
-
9
-
-
10.01b
-
Z
-
10
11
13
14
15
16
17
18
19
26
29
30
4.22 (8.3)
4.53 (8.3)
4.11 (9.2)
4.04 (9.7)
1:4.6
1:11
Z
1:1.8
1:5
-
nd
4.23 (9.4)
4.47 (10.2)
4.30 (9.6)
4.95 (9.7)
7.95
8.09
nd
-
-
-
-
Z
Z
-
-
1:4
1:14
-
1:6.7
-
5.63 (4.5)
5.55 (4.4)
-
4.45 (10.0)
4.27 (9.5)
-
1:9
1:29
Z
nd
4.00 (9.6)
7.99
4.09 (8.9), 3.99(8.9)
4.04 (9.6)
4.32 (9.7)
-
4.43 (9.3)
4.40 (9.9)
4.02 (9.9), 3.88 (9.4)
8.01
-
-
Z
-
4.86 (3.3)
4.97 (3.9)
-
-
E
4.94 (br s), 5.04 (4.2)
4.17 (9.3), 5.08 (10.0)
1:12.3
a NMR data recorded for protected compounds in CDCl3 and for unprotected compounds in D2O at 5 °C. b 1H NMR spectrum recorded
in 10:90 D2O/H2O.
TABLE 2. Infrared Spectroscopic Data
IR (cm-1
)
compd
NH
-N3 asymm.
CdO (amide)
8
solid state
CDCl3
solid state
CDCl3
solid state
solid state
CDCl3
CCl4
solid state
CDCl3
solid state
solid state
CDCl3
3337.9
3411.1
-
2124.5
2122.5
2121.5
2120.6
2121.0
1692.6
1694.0
1676.2
1674.2
1667.9
1682.3
1695.4
1702.5
1673.4
1672.3
1667.9
1673.4
1675.5
10
-
11
13
14
3346.9
3410.8
2122.2
2119.9
2123.6
2121.0
2121.9
2120.0
2120.6
3418.4
16
-
-
-
-
-
17
19
FIGURE 4. Summary of results from the NOE experiments
for tertiary amides 10, 15, and 17.
30,28 and also by variable-temperature experiments. For
example, the 1H NMR spectrum of 17 displayed a signal
at δ 3.51 (s), assigned to one N-methyl group of the EZ
isomer, and a signal at δ 3.38 (s), assigned to the
N-methyl group of the EE isomer; the 2D-NOESY and
2D-ROESY spectra showed a cross-peak with the same
sign as the diagonal peaks between these two signals,
CHART 3
1
and coalescence of these signals was observed in the H
NMR spectra recorded at 70 °C in D2O. These experi-
ments confirm that there is an exchange process occur-
ring between the E and Z isomers. Similar phenomena
were observed for the other signals (Table 1) of the
bivalent tertiary amides. The chemical shifts of protons
(H-5 and H-1) of the E isomer, in closest proximity to
the aromatic ring, appear at a higher field than those of
the Z isomer, a pattern that is consistent with that
displayed by 4.14,27 A structural study of the constrained
macrocycles 29 and 30 (Chart 4) has been carried out28
in parallel with the work described herein, and they show
similar NMR spectroscopic behavior. Macrocycle 29 is
sufficiently constrained so that only the E-anti amides29
can be accessed, and therefore only one signal set was
NOE enhancements similar to those described for 10
were observed for 11, 16, and 17 (Figure 4). However for
19, the 2D-NOE spectra are more complex, and enhance-
ments were observed which indicate that the E-syn
isomer may have a higher population in this case.
Evidence for dynamic interconversion of the EE and EZ
structures was generally obtained by 1D- and 2D-
NOESY/ROESY experiments,26 as described for 314 and
(27) The NOE experiments for tertiary amides were generally
carried out at 5 °C as broadening of signals often occurred at room
temperature.
(28) (a) Velasco-Torrijos, T.; Murphy, P. V. Tetrahedron: Asymmetry
2005, 16, 261. (b) The crystal structure of 30c has been determined
and shows the L-shaped structure with both E-anti and Z-anti amides.
Murphy, P. V.; Mu¨ller-Bunz, H.; Velasco-Torrijos, T. Carbohydr. Res.
2005, 340, 1437.
(26) Both the NOESY and ROESY experiments had similar results
for the cases where both techniques were investigated (e.g., 17). The
results were also consistent over a range of mixing times (τm ) 0.4-
1.0 s).
4112 J. Org. Chem., Vol. 70, No. 10, 2005

Glucuronic Acid Anilides
CHART 4. Structures of Bivalent Amides 28-30
observed in its 1H NMR spectrum. Macrocycle 30 is more
flexible and can access structures in which (i) both amides
can be E-anti (30a and/or 30b) or (ii) one is Z-anti and
the other E-anti (30c);28b in this case the 1H NMR
spectrum contains two signal sets, and they are assigned
to the C2 symmetric EE structural isomer and the
EZ isomer (Table 1). The phase-sensitive NOESY and
ROESY spectra for 29 and 30 showed cross-peaks similar
to those described herein, and VT experiments confirmed
the E to Z amide exchange process for 30 also.28 It can
be concluded, in general, that the E-anti isomer is
preferred for the bivalent glucuronides described herein.
2.2.3. Conformational Analysis Using Molecular
Modeling. Molecular modeling (Macromodel 8.5)31 was
used to generate 3D models of the structural isomers
accessible to the multivalent scaffolds. The crystal struc-
ture of 10, which contained both the E-syn and E-anti
amides, was optimized by DFT at the BLYP level of
theory with the 6-31+G** basis set in Jaguar 5.0;32 there
was no change to the geometry which indicates that it is
a local minimum structure. This structure was used as
the starting point for a Monte Carlo conformational
search using the SUMM method in Macromodel;33 the
amide torsions were constrained so that only conforma-
tional isomers with E amides would be obtained. All
isomers that were generated within 10 kJ/mol of the
minimum-energy isomer had only the E-anti structure.
Both U-shaped and S-shaped conformations (similar to
30a and 30b) of similar energies were generated. Low-
energy structures for 11 and 17 were also generated by
a similar conformational search. Selected conformers of
17 that had E-anti amides were further optimized by
DFT at the BLYP level of theory with the 6-31+G** basis
set in Jaguar 5.0, and these are shown in Figure 5.
Parallel azide-aromatic-azide stacking is a feature of
the S-shaped conformation, shown in Figure 5a. The
azide group nitrogen atoms of this conformer are 5.0-
5.3 Å from the aromatic group; this distance is too remote
to propose that stabilization by van der Waals interac-
tions occurs. Azide-aromatic stacking also occurs for a
low-energy U-shaped conformer (Figure 5c) in which the
azide and aromatic groups are in closer proximity (3.7-
4.5 Å), indicating that closer packing of these groups
might be possible. The carbohydrate-carbohydrate stack-
1
Integration of the signal sets in the H NMR spectra
thus gives E/Z or EE/EZ isomer ratios (Table 1) for the
dimeric tertiary amides. There are some trends worth
noting. The EE/EZ ratio is the highest for 17 at 14:1 (in
D2O at 5 °C), whereas for 11 it is 5:1. This provides
evidence for enhanced isomerization to the EE-amide
structure in 17. A similar trend is observed when
comparing 10 and 16 where EE/EZ ratios in CDCl3 are
1.8:1 and 4:1, respectively.30 These observations also
show that the population of the E amide (or EE
amide) is enhanced if the azide group is axial rather
than equatorial and is further enhanced in water (com-
pared to chloroform) when no protecting groups are
present.
The azide stretching frequencies for divalent com-
pounds (Table 2) are consistent with those observed for
3 and 4. Although 10 shows an azide-azide interaction
in the solid state, there was no major alteration to the
asymmetric azide stretching frequency. In general, the
carbonyl stretch for secondary amides appeared at a
higher frequency than that for tertiary amides.
(31) 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.
(32) Jaguar 5.0; Schrodinger, LLC: Portland, OR, 1991-2003.
(33) Minimization was carried out using the Merck Molecular Force
Field which gave the most accurate geometries for the azide groups.
(29) The U-shaped conformer is also expected to be strongly
preferred because it was calculated to be 70 kJ/mol lower in energy
than the S-shaped conformer.
(30) A similar trend was noted for monomeric analogues. See ref
10.
J. Org. Chem, Vol. 70, No. 10, 2005 4113

Tosin and Murphy
FIGURE 6. Structure of 32 and the van der Waals surfaces
calculated using Macromodel for intermolecular azide-
aromatic hydrogen interactions observed in the close-packed
structure of 32. Distances between the terminal azide nitrogen
atom and the closest aromatic hydrogen atoms were 2.84 and
3.07 Å.
FIGURE 7. CD spectra for 9, 11, 15, 17, 29, and 30. See
Table 3.
generated. Conformers with features, such as those in
panels a-c of Figure 5, that minimize the surface area
of water exposed to the hydrophobic surfaces more than
other isomers may, thus, provide a basis for a hydropho-
bic effect which would enhance the folding of the divalent
structures, and consequently, the EE/EZ ratio would be
higher. The effect is not totally hydrophobic, as the NMR
data would indicate, and some interaction of the azide
groups with the aromatic ring, such as N‚‚‚H-C aromatic
interactions, may be involved in enhancing the stabiliza-
tion of the EE amide.
2.3. Circular Dichroism Studies. The circular dich-
roic (CD) spectra34 of unprotected divalent compounds
were recorded in water; these were compared with those
of macrocycles 29 and 30,28 and the results are sum-
marized in Table 3 and Figure 7. The pyranose groups
of macrocycle 29 are constrained into a U-shape arrange-
ment, and the spectrum of 29 shows positive maxima at
191.5 (1B) and 214.5 nm (1La) as well as a negative
maximum of a significantly higher magnitude at 243.5
nm (1Lb). In contrast, the spectrum of 30 has two negative
maxima at 189.5 and 209.5 nm and a significant positive
maximum at 240 nm for differential dichroic absorptions
corresponding to same three π f p* transitions. Macro-
cycle 30 is more flexible; it is potentially capable of
FIGURE 5. Low-energy conformers of 17. (a) S-shaped
conformer with azide-aromatic-azide stacking. (b) S-shaped
conformer that has the terminal nitrogen atom of azide in
contact with aromatic protons. Selected interatomic distances
(Å): N-N ) 3.25 and N-H ) 3.01 and 3.43. (c) U-shaped
conformer that shows azide-aromatic and azide-azide stack-
ing.
ing observed is mediated by the azides since there are
saccharide protons within 3.8 Å of the nitrogen atoms of
the azide group. The alternative low-energy S-shaped
conformer (shown in Figure 5b) shows that each terminal
azide nitrogen atom is within 3.01 and 3.43 Å of the
aromatic protons, suggestive of azide N‚‚‚H-C aromatic
interactions, and within 3.25 Å of the other terminal
azide nitrogen atom. Examination of the close packing
in the crystal structure of 3214 revealed that intermo-
lecular N‚‚‚H-C aromatic interactions, similar to those
calculated as described herein, are possible. The distances
between the terminal azide nitrogen atom and the two
closest aromatic hydrogen atoms were 2.84 and 3.07 Å
in the X-ray structure (Figure 6).
There is a possibility of azide-carbohydrate and
azide-aromatic interactions for 11, but because of the
directional properties of the azide, it would seem that a
greater reorganization of the â-azide group than of the
R-azide group would have to occur for these to be
(34) McReynolds, K. D.; Gervay-Hague, J. Tetrahedron: Asymmetry
2000, 11, 337.
4114 J. Org. Chem., Vol. 70, No. 10, 2005

Glucuronic Acid Anilides
TABLE 3. UV and CD Spectroscopic Data
ferent saccharide hydroxyl group to locate the binding
groups.35 The synthesis of 6 was carried out to illustrate
an application of the scaffold to the synthesis of diman-
nosides for studies of their biological properties; the
mannose groups are grafted to the 3-OH groups of the
scaffold. Further synthesis and biological evaluation of
bivalent ligands are underway, and the results of their
biological evaluation will be reported in due course. The
structural studies are relevant for the development of
novel â-cyclodextrin36 mimics; macrocycle 30 has shown
the ability to bind to and reverse the quenching of
fluorescence of a hydrophobic dye. The bivalent com-
pounds based on glycosyl azides described herein do not
display these phenomena. Macrocycle 29 has been pro-
posed as a scaffold for development of R-helical peptido-
mimetics,37 and azides 11 and 17 can access similar
conformations. The anomeric substituent and its config-
uration alter the degree of isomerism of the amide and
folding38 of the divalent scaffold. Systems which are
“molecular torsion balances”39 are useful for the study of
noncovalent interactions.40 These studies are also rel-
evant for the synthesis and structure of carbopeptoids
and foldamers.41
UV
CD
λmax (nm),
absorbance
ellipticity
compd
conc (µΜ)
λ (nm)
(mdeg)
9
49
198.0, 1.94
262.0, 1.02
184.5
191.0
200.5
208.0
220.0
245.5
187.5
194.5
201.0
214.0
220.5
240.5
183.5
188.5
201.0
218.0
229.0
241.0
186.5
202.5
224.0
236.0
201.0
221.5
236.5
191.5
214.5
243.5
189.5
209.5
240.0
+14.01
-4.00
+8.67
-4.63
+2.78
-6.46
-27.02
+17.12
+32.30
+18.16
+18.62
+23.63
+4.52
+5.65
+13.11
+4.84
-8.18
-5.77
+4.56
+75.03
+50.95
+66.13
+47.86
+26.95
+32.70
+32.1
+30.6
-87.0
-55.1
-7.8
11
15
17
46
49
93
194.0, 2.09
231.0, 0.79
202.0, 1.60
264.0, 1.08
198.9, 2.78
230.0, 1.25
46
25
25
194.0, 1.73
204.0, 1.50
232.0, 0.67
240.0, 0.822
3. Experimental Section
29
30
Preparation of 8. Oxalyl chloride (0.11 mL, 1.261 mmol)
and DMF (0.15 mL) were added to 7 (408 mg, 1.182 mmol) in
dichloromethane (18 mL) and at 0 °C under an atmosphere of
N2, and the mixture was stirred for 30 min while it was cooling
on ice; the mixture was then stirred for a further 1 h at room
temperature. p-Phenylenediamine (66 mg, 0.610 mmol) and
pyridine (0.20 mL, 2.473 mmol) were stirred in dichlo-
romethane (5 mL) in the presence of 4 Å molecular sieves until
the amine had completely dissolved. The mixture containing
the acid chloride was then cooled to 0 °C, and the solution
containing the diamine was slowly added to it; the mixture
was stirred for 30 min at 0 °C and for 2.5 h at room
temperature. The mixture was washed with aq NaHCO3 (20
mL); the organic layer was washed with 0.1 M HCl (20 mL),
dried (Na2SO4), and filtered, and the solvent was removed to
produce a yellow oil (250 mg). Chromatography (dichlo-
romethane/EtOAc gradient elution) yielded 8 as a white solid
(134 mg, 30%): [R]D -51° (c 0.5, CH2Cl2); 1H NMR (300 MHz,
CDCl3) δ 8.30 (s, 2H, NH), 7.44 (s, 4H, aromatic H), 5.33 (t,
2H, J2,3 ) 9.0, J3,4 ) 9.0, H-3), 5.24 (t, 2H, H-4), 4.97 (t, 2H,
J1,2 ) 8.9, H-2), 4.87 (d, 2H, H-1), 4.15 (d, 2H, J4,5 ) 9.5, H-5),
2.11, 2.08, 2.03 (each s, each 6H, each COCH3); 13C NMR (500
MHz, CDCl3) δ 169.8, 169.6, 169.2 (each s, each COCH3), 163.7
(s, CONHAr), 133.4 (s, aromatic C), 121.4 (d, aromatic CH),
88.2 (d, C-1), 74.7, 71.8, 70.6, 69.1 (each d, C-2-C-5), 20.7,
20.6, 20.5 (each q, each COCH3); FTIR (KBr) 3427, 2972, 2927,
2124, 175, 1691, 1517, 1375, 1237, 1069, 1039 cm-1; FAB-
HRMS found 785.1997, required 785.1990 [M + Na]+.
239.0, 1.08
+91.3
adopting both U-shape and S-shape conformations where
both amides are E-anti as well as a structure where one
amide is E-anti and the other Z-anti. The CD spectrum
of 30, compared to that of 29, could be interpreted as
being a result of the S-shape arrangement being pre-
ferred. Both 11 and 30 have negative maxima at 187.5
and 189 nm, whereas 17 showed a small positive absorp-
tion at 186.5 nm. Apart from this difference, both 11 and
17 otherwise displayed similar profiles and showed
positive maxima (at 240.5 and 241 nm) of lower intensity
than 30, indicating that they may have similar confor-
mational preferences and that 11 and 17 preferentially
adopt S-shaped structures. Significantly more experi-
mental work would be required to confirm these propos-
als. The secondary amide derivatives 9 and 16 show CD
spectra substantially different from those observed for
the tertiary amides, in agreement with the proposal that
the secondary and tertiary anilides have divergent
secondary structures.
2.4. Summary and Conclusions. The synthesis and
structure of novel multivalent scaffolds based on glucu-
ronic acid anilides have been investigated. As for mono-
mers, the structural preferences of the bivalent secondary
anilides, which prefer Z amides, are different than those
of the tertiary anilides, which prefer E amides. Alkylation
of the amides leads, again, to configurational switching.
Under such circumstances, the structural space or ori-
entation of the carbohydrate residues of the secondary
amides will diverge significantly from those of the
tertiary amides. In addition to the configurational changes
affected by the alkylation of amides, it should be possible
to increase structural diversity further by using a dif-
(35) Tosin, M.; Gouin, S. G.; Murphy, P. V. Org. Lett. 2005, 7, 211.
(36) Cyclodextrins have found wide application in pharmaceutics:
Davis, M. E.; Brewster, M. E. Nat. Rev. Drug Discovery 2004, 3, 1024.
(37) Velasco-Torrijos, T.; Murphy, P. V. Org. Lett. 2004, 5, 3961.
(38) Hill, D. J.; Mio, M. J.; Prince, R. B.; Hughes, T. S.; Moore, J. S.
Chem. Rev. 2001, 101, 3893.
(39) (a) Paliwal, S.; Geib, S.; Wilcox, C. S. J. Am. Chem. Soc. 1994,
116, 4497. (b) Kim, E.-I.; Paliwal, S.; Wilcox, C. S. J. Am. Chem. Soc.
1998, 120, 11192.
(40) Hof, F.; Scofield, D. M.; Schweizer, W. B.; Diederich, F. Angew.
Chem., Int. Ed. 2004, 43, 5056.
(41) (a) Nicolaou, K. C.; Florke, H.; Egan, M. G.; Barth, T.; Estevez,
V. A. Tetrahedron Lett. 1995, 36, 1775. (b) Smith, M. D.; Long, D. D.;
Claridge, T. D. W.; Fleet, G. W. J.; Marquess, D. G. Chem. Commun.
1998, 2039. (c) Appella, D. H.; Christianson, L. A.; Klein, D. A.; Powell,
D. R.; Huang, X.; Barchi, J. J., Jr.; Gellman, S. H. Nature 1997, 387,
381.
J. Org. Chem, Vol. 70, No. 10, 2005 4115

Tosin and Murphy
Preparation of 10. Sodium hydride (14 mg, 0.365 mmol,
60% dispersion in mineral oil) and methyl iodide (0.02 mL,
0.321 mmol) were added to an ice-cold solution of 8 (65 mg,
0.085 mmol) in DMF (2.7 mL) under an atmosphere of N2, and
the mixture was stirred for 30 min. Then, water and EtOAc
were added, and the layers were separated; the organic layer
was dried (Na2SO4), and the solvent was removed. Chroma-
tography (dichloromethane/EtOAc gradient elution) yielded 10
as a white solid (43 mg, 64%): 1H NMR (EE isomer, 300 MHz,
CDCl3) δ 7.42 (s, 4H, aromatic H), 5.50 (t, 2H, J3,4 ) 9.4, H-4),
5.15 (t, 2H, J2,3 ) 9.2, H-3), 5.24 (t, 2H, H-4), 4.87 (t, 2H, H-2),
4.22 (d, 2H, J1,2 ) 8.3, H-1), 4.11 (d, 2H, J4,5 ) 9.2, H-5), 3.35
(s, 6H, NCH3), 2.02 (2s, 12H, overlapping COCH3), 2.00 (s, 6H,
COCH3); 13C NMR (300 MHz, CDCl3) δ 170.6, 169.3, 169.1
(each s, each COCH3), 164.3 (s, CONMeAr), 142.6 (s, aromatic
C), 129.0 (d, aromatic CH), 88.6 (d, C-1), 72.7, 72.4, 70.3, 69.7
(each d, C-2-C-5), 38.5 (q, NCH3), 20.9, 20.8, 20.7 (each q, each
COCH3); selected 1H NMR data (EZ isomer, 500 MHz, CDCl3
at 0 °C) δ 4.73 (d, 1H, J1,2 ) 8.5, H-1), 4.56 (d, 1H, J4,5 ) 9.5,
H-5), 3.57 (s, 6H, NCH3); FTIR (KBr) 2936, 2120, 1756, 1670,
1511, 1435, 1369, 1237, 1074, 1039 cm-1; FAB-HRMS found
813.2304, required 813.2303 [M + Na]+.
Preparation of 9. Deacetylation of 8 produced 9: 1H NMR
(300 MHz, D2O) δ 7.55 (s, 2H, Ar H), 4.92 (d, 1H, J1,2 ) 8.8,
H-1), 4.16 (d, 1H, J4,5 ) 9.5, H-5), 3.73 (t, 1H, J3,4 ) 9.3, H-4),
3.65 (t, 1H, J2,3 ) 9.0, H-3), 3.40 (t, 1H, H-2); 13C NMR (500
MHz, D2O) δ 171.3 (s, CONHAr), 136.4 (s, Ar C ipso), 125.9
(d, Ar CH), 93.1 (d, C-1), 80.0, 78.1, 75.2, 73.9 (each d, C-2-
C-5); ES-HRMS found 533.1349, required 533.1357 [M +
Na]+.
Preparation of 11. Deacetylation of 10 followed by puri-
fication via reverse-phase HPLC using a YMC-Pack C-4 (S 10
µm, 250 × 20 mm) reverse-phase column (isocratic elution
H2O/CH3CN 70:30, flow rate 10 mL/min) produced 11: 1H
NMR (EE isomer, 300 MHz, D2O) δ 7.55 (s, 2H, Ar H), 4.53
(d, 1H, J1,2 ) 8.3, H-1), 4.04 (d, 1H, J4,5 ) 9.7, H-5), 3.81 (t,
1H, J3,4 ) 9.3, H-4), 3.38 (s, 3H, NCH3), 3.37 (t, 1H, H-2,
overlapping with NMe), 3.28 (t, 1H, J2,3 ) 9.0, H-3); 13C NMR
(500 MHz, D2O) δ 171.2 (s, CONHAr), 144.7 (s, aromatic C),
131.7 (d, aromatic CH), 93.2 (d, C-1), 77.7, 76.3, 75.1, 73.6 (each
d, C-2-C-5), 40.7 (q, NCH3); selected 1H NMR data (EZ-isomer,
300 MHz, D2O) δ 4.89 (d, 1H, J1,2 ) 8.9, H-1), 3.57 (s, 3H,
NCH3); ES-HRMS found 561.1664, required 561.1670 [M +
Na]+.
2129, 1746, 1619, 1429, 1376, 1232, 1046, 901, 794, 601 cm-1
,
FAB-HRMS found 819.2079, required 819.2072 [M + Na]+.
Preparation of 14. Azidotrimethylsilane (0.085 mL, 0.646
mmol) and tin(IV) tetrachloride (0.015 mL, 0.128 mmol) were
added to a solution of 13 (100 mg, 0.126 mmol) in dry
dichloromethane (5 mL), and the mixture was stirred for 3 h
under an atmosphere of N2. Aqueous NaHCO3 (5 mL) was then
added, and the biphasic mixture was stirred for 1 h. The layers
were separated; the organic portion was dried (Na2SO4), and
the solvent was removed. Chromatography of the residue
(dichloromethane/EtOAc gradient elution) produced a white
solid (58 mg, 60%), and NMR analysis showed that this was a
77:23 mixture of 14 and 8: FAB-HRMS found 785.1989,
required 785.1990 [M + Na]+. Analytical data for 14: 1H NMR
(300 MHz, CDCl3) δ 8.09 (s, 2H, NH), 7.46 (s, 4H, Ar H), 5.76
(d, 2H, J1,2 ) 4.2, H-1), 5.48 (t, 2H, J2,3 ) 9.8, J3,4 ) 9.8, H-3),
5.18 (t, 2H, H-4), 4.94 (dd, 2H, H-2), 4.47 (d, 2H, J4,5 ) 10.2,
H-5), 2.12, 2.09, 2.04 (each s, each 6H, each COCH3); 13C NMR
(CDCl3) δ 170.3, 170.0, 169.9 (each s, each COCH3), 164.7 (s,
CONHAr), 133.7 (s, aromatic C), 121.5 (d, aromatic CH), 86.3
(d, C-1), 70.3, 70.2, 69.4, 68.9 (each d, C-2-C-5), 20.9, 20.8,
20.7 (each q, each COCH3); FTIR (KBr) 3410, 2962, 2124, 1756,
1696, 1660, 1519, 1370, 1224, 1047 cm-1
.
Preparation of 16. Sodium hydride (88 mg, 60% dispersion
in mineral oil, 2.296 mmol) and methyl iodide (0.14 mL, 2.249
mmol) were added to an ice-cold solution of the 77:23 mixture
of 14 and 8 (407 mg, 0.534 mmol) in DMF (17 mL) under an
atmosphere of nitrogen. The reaction was judged to be
complete after 30 min, and water and EtOAc were added; the
layers were separated. The organic layer was dried (Na2SO4),
and the solvent was removed; the residue was subjected to
silica gel chromatography (dichloromethane/EtOAc gradient
elution) to yield a 77:23 mixture of 16 and 10 (111 mg, 26%):
FAB-HRMS found 813.2311, required 813.2303 [M + Na]+.
1
Analytical data for 16: H NMR (300 MHz, CDCl3) δ 7.43 (s,
4H, Ar H), 5.63 (d, 2H, J1,2 ) 4.5, H-1), 5.52 (t, 2H, J3,4 ) 9.7,
H-4), 5.24 (t, 2H, J2,3 ) 10.0, H-3), 4.90 (dd, 2H, H-2), 4.42 (d,
2H, J4,5 ) 10.0, H-5), 3.37 (s, 6H, NCH3), 2.04, 2.02, 1.98 (each
s, each 6H, each COCH3); 13C NMR (300 MHz, CDCl3) δ 170.4,
170.1, 168.9 (each s, each COCH3), 165.4 (s, CONMeAr), 142.8
(s, aromatic C), 129.5 (d, aromatic CH), 87.8 (d, C-1), 69.8, 69.7,
69.6, 67.2 (each d, C-2-C-5), 38.0 (q, NCH3), 20.9, 20.8, 20.6
(each q, each COCH3); FTIR (KBr) 2933, 2854, 2124, 1759,
1674, 1511, 1435, 1368, 1236, 1073, 1044 cm-1
.
Preparation of 15. The 77:23 mixture of 14 and 8 (0.069
g, 0.090 mmol) was deacetylated to produce 15 and 9 (0.043
g, 94%): ES-HRMS found 511.1550, required 511.1537 [M +
H]+. Analytical data for 16: 1H NMR (300 MHz, D2O) δ 7.42
Preparation of 13. Acid 12 (474 mg, 1.31 mmol) was
dissolved in dichloromethane (10 mL), and the mixture was
cooled to 0 °C under N2. Oxalyl chloride (0.11 mL, 1.31 mmol)
and dry DMF (0.10 mL) were added, and the mixture was
stirred for 30 min while it was cooling on ice; the mixture was
then stirred for a further 1 h at room temperature and for a
further 30 min at room temperature. p-Phenylenediamine (70
mg, 0.65 mmol) was stirred in dichloromethane (5 mL) in the
presence of pyridine (0.22 mL, 2.72 mmol) and 4 Å molecular
sieves until it had completely dissolved. The solution contain-
ing the diamine was added dropwise to the solution of the acid
chloride at 0 °C, and the mixture continued to be stirred at
this temperature for 30 min and for a further 2 h at room
temperature. The reaction mixture was washed with saturated
aq NaHCO3 (15 mL) and dilute 0.1 M HCl (15 mL). The organic
layer was dried (Na2SO4), and the solvent was removed. A solid
residue was obtained which upon trituration in hot petroleum
ether produced 13 (307 mg, 59%) as a white solid: [R]D +5° (c
(s, 4H, Ar H), 5.56 (d, 2H, J1, 2 ) 4.1, H-1), 4.30 (m, 2H, J4, 5
)
9.6, H-5), 3.67 (dd, 2H, J2,3 ) 9.8, H-2), 3.57 (m, 4H, H-3 and
H-4 overlapping); 13C NMR (D2O) δ 171.9 (s, CONHAr), 136.4
(s, Ar C), 125.8 (d, Ar CH), 92.2 (d, C-1), 76.2, 75.0, 74.0, 73.8
(each d, C-2-C-5).
Preparation of 17. The mixture containing 15 and 10 was
deacetylated and purified by reverse-phase HPLC using a
YMC-Pack C-4 reverse-phase (S 10 µm, 250 × 20 mm) column
(isocratic elution H2O/CH3CN 80:20, flow rate 10 mL/min) to
produce 17: ES-HRMS found 561.1652, required 561.1670
[M + Na]+. Analytical data for the EE isomer: 1H NMR (300
MHz, D2O) δ 7.60 (s, 2H, aromatic H), 5.55 (d, 1H, J1,2 ) 4.4,
H-1), 4.27 (d, 1H, J4,5 ) 9.7, H-5), 3.81 (t, 1H, J3,4 ) 9.5, H-4),
3.69 (dd,1H, J2,3 ) 9.5, H-2), 3.45 (t, 1H, H-3), 3.38 (s, 3H,
NCH3); 13C NMR (500 MHz, D2O) δ 171.8 (s, CONHAr), 145.1
(s, aromatic C), 131.9 (d, aromatic CH), 93.1 (d, C-1), 74.8, 73.5,
72.9, 72.2 (each d, C-2-C-5), 40.4 (q, NCH3). Analytical data
1
0.4, acetone); H NMR (300 MHz, CDCl3) δ 7.95 (s, 2H, NH),
7.43 (s, 4H, aromatic H), 5.84 (d, 2H, J1,2 ) 7.5, H-1), 5.35 (m,
4H, H-3 and H-4, overlapping), 5.15 (m, 2H, J2,3 ) 8.6, H-2),
4.23 (m, 2H, J4,5 ) 9.4, H-5), 2.14, 2.09, 2.07, 2.03 (each s, each
6H, each COCH3); 13C NMR (CDCl3) δ 170.0, 169.8, 169.5,
169.1 (each s, each COCH3), 164.3 (s, CONHAr), 133.7 (s,
aromatic C), 121.3 (d, aromatic CH), 91.9 (d, C-1), 73.6, 72.1,
70.8, 68.9 (each d, C-2-C-5), 21.0, 20.9 (each q, each COCH3),
20.8 (two q, each COCH3, overlapping); FTIR (KBr) 3498, 2955,
1
for the EZ isomer: selected H NMR data (300 MHz, D2O) δ
7.50 (s, 2H, Ar H), 5.68 (br s, 1H, H-1), 3.59 (s, 3H, NCH3).
Preparation of Uronate 22. Lactone 2114 (0.401 g, 1.406
mmol) was dissolved in freshly distilled THF (5 mL) in the
presence of 4 Å molecular sieves, and allyl alcohol (0.19 mL,
2.794 mmol) was added. The solution was refluxed at 65 °C
under N2 overnight, then cooled to room temperature, and
4116 J. Org. Chem., Vol. 70, No. 10, 2005

Glucuronic Acid Anilides
filtered through Celite. Evaporation of the solvent under
reduced pressure produced a crude brown-red material (0.6
g). Solid impurities were precipitated from dichloromethane
and petroleum ether, and the evaporation of the mother liquor
in vacuo produced 22 as a yellow oil (0.327 g, 68%): 1H NMR
(300 MHz, CDCl3) δ 5.91 (m, 1H, CHdCH2), 5.34 (m, 2H, CHd
CH2), 5.15 (t, 1H, J3,4 ) 9.3, H-4), 4.87 (t, 1H, J2,3 ) 9.1, H-2),
4.65 (m, 3H, J1,2 ) 8.8, OCH2CHdCH2 and H-1), 4.07 (d, 1H,
J4,5 ) 10.0, H-5), 3.80 (t, 1H, H-3), 2.90 (b s, 1H, OH), 2.16,
2.09 (each s, each 3H, each COCH3); 13C NMR (CDCl3) δ 170.5
(two s overlapping, each COCH3), 166.4 (s, COOAll), 131.3 (d,
CHdCH2), 119.8 (t, CHdCH2), 88.3 (d, C-1), 74.6, 73.3, 73.1,
71.7 (each d, C-2-C-5), 67.0 (t, OCH2CHdCH2), 21.0, 20.9
(each q, each COCH3); FTIR (CH2Cl2 solution) 3431, 2957,
2120, 1753, 1432, 1375, 1230, 1082, 1039 cm-1; FAB-HRMS
found 361.1361, required 361.1359 [M + NH4]+.
20.7, 20.7, 20.6 (two signals overlapping) (each q, each COCH3);
FTIR (CH2Cl2 sol.) 3494, 3075, 2980, 2923, 2855, 2123, 1750,
1641, 1433, 1374, 1227, 1140, 1093, 1043 cm-1; FAB-HRMS
found 678.1373, required 678.1371 [M + 2Na - H]+.
Preparation of Diamide 26. Disaccharide 25 (0.081 g,
0.128 mmol), HOBt (0.040 g, 0.296 mmol), p-phenylenediamine
(0.006 g, 0.055 mmol), and DIPEA (0.02 mL, 0.114 mmol) were
dissolved in anhydrous dimethylformamide (0.8 mL) at 0 °C
under a N2 atmosphere. HBTU (0.060 g, 0.158 mmol) was
added, and the reaction mixture was stirred for 1 h at 0 °C
and then overnight at room temperature. The crude solution
was then worked up with deionized water (10 mL) and EtOAc
(10 mL): the organic layer was separated, dried (Na2SO4),
filtered, and concentrated to produce a yellow oily residue. This
was subjected to slow column chromatography (1:4 EtOAc/
dichloromethane) to yield 26 as a white powder (0.030 g,
42%): Rf 0.61 (9:1 EtOAc/dichloromethane); 1H NMR (300
MHz, CDCl3) δ 8.01 (s, 2H, NH), 7.45 (s, 4H, Ar H), 5.32 (t,
2H, J3′, ) 10.0, J4′, ) 10.0, H-4′), 5.26 (t, 2H, J3, ) 9.0,
Preparation of 24. Trimethylsilyl triflate (1.5 mL of a 0.04
M solution in dry dichloromethane, 0.060 mmol) was added
dropwise to an ice-cold solution of ester 22 (0.210 g, 0.612
mmol) and imidate 23 (0.301 g, 0.631 mmol) in freshly dried
dichloromethane (15 mL) in the presence of 4 Å molecular
sieves under a N2 atmosphere. Within 30 min the reaction was
complete; NaHCO3 (∼0.2 g) was added, and stirring was
continued for 5 min. The mixture was then filtered and
concentrated to produce a yellow foam (0.480 g); its purification
by slow column chromatography (9:1 dichloromethane/EtOAc)
produced disaccharide 24 as a white solid (0.165 g, 40%): Rf
0.47 (1:4 EtOAc/dichloromethane); mp 85-87 °C; [R]D +12° (c
0.4, (CH3)2CO); 1H NMR (300 MHz, CDCl3) δ 5.92 (m, 1H, CHd
CH2), 5.32 (m, 4H, CHdCH2, H-4′ and H-4), 5.13 (m, 2 H, J2′,3′
) 3.4, H-2′ and H-3′), 5.01 (t, 1H, J2,3 ) 9.0, H-2), 4.96 (d, 1H,
J1′,2′ ) 1.8, H-1′), 4.64 (m, 2H, OCH2CHdCH2), 4.56 (d, 1H,
J1,2 ) 8.5, H-1), 4.21 (dd, 1H, J5′,6′a ) 4.0, J6′a,6′b ) 12.5, H-6′a),
4.12 (m, 1H, H-6′b), 4.04 (d, 1H, J4,5 ) 9.8, H-5), 3.97 (d t, 1H,
J4′,5′ ) 10.0, J5′,6b ) 2.5, H-5′), 3.90 (t, 1H, J3,4 ) 9.0, H-3), 2.15,
4′
5′
4
H-4), 5.14 (dd, 2 H, J2′,3′ ) 3.1, H-3′), 5.08 (m, 2H, H-2′), 5.01
(apt s, 2H, H-1′, overlapping with H-2), 5.01 (t, 2H, J2,3 ) 9.0,
H-2), 4.73 (d, 2H, J1,2 ) 8.8, H-1), 4.22 (dd, 2H, J5′,6′a ) 3.8,
J6′a,6′b ) 12.6, H-6′a), 4.10 (m, 2H, H-6′b), 4.04 (d, 2H, J4,5
)
9.6, H-5), 3.97 (t, 2H, H-3), 3.97 (m, 2H, H-5′, completely
overlapped by H-3), 2.18, 2.16, 2.15, 2.12, 2.02, 1.95 (each s,
each 6H, each COCH3); 13C NMR (CDCl3) δ 170.8, 170.1, 170.0,
169.8, 169.7, 169.3 (each s, each COCH3), 164.0 (s, CONH),
133.6 (s, Ar C), 121.9 (d, Ar CH), 99.4 (d, C-1′), 88.4 (d, C-1),
79.6, 75.2, 71.6, 70.4, 70.0, 69.7, 68.8, 65.7 (each d, C-2-C-5
and C-2′-C-5′), 62.2 (t, C-6′), 21.1, 21.0, 21.0, 20.9, 20.9, 20.8
(each q, each COCH3); ES-HRMS found 1361.3748, required
1361.3681 [M + Na]+.
Preparation of Diamide 6. Protected dimer 27 (7 mg, 5.23
µmol) and dibutyltin oxide (20 mg, 0.080 mmol) were sus-
pended in dry methanol (1.5 mL) and refluxed at 60 °C for 36
h. The solvent was evaporated, and a white residue remained.
This was partially redissolved in methanol (5 mL) and filtered.
The filtrate was concentrated to a white powder (3.7 mg, 85%)
which was further purified by reverse-phase HPLC using an
YMC-Pack ODS-AQ reverse-phase (S 5 µm, 250 × 20 mm)
column and isocratic elution with H2O and CH3CN (85:15)
(flow rate 10 mL/min): 1H NMR (500 MHz, D2O) δ 7.60 (s,
2.14, 2.12, 2.12, 2.03, 1.96 (each s, each 3H, each COCH3); 13
C
NMR (CDCl3) δ 170.8, 170.3, 169.9, 169.8, 169.7, 169.4 (each
s, each COCH3), 166.2 (s, COOAll), 131.3 (d, CHdCH2), 119.9
(t, CHdCH2), 99.7 (d, C-1′), 88.2 (d, C-1), 80.6, 74.6, 71.5, 70.0
(two signals overlapping), 69.6, 68.9, 65.4 (each d, C-2-C-5
and C-2′-C-5′), 67.0 (t, OCH2CHdCH2), 62.0 (t, C-6′), 21.1,
21.0, 20.9, 20.8 (signals overlapping), (each q, each COCH3);
FTIR (KBr) 2969, 2124, 1754, 1432, 1378, 1225, 1091, 1041
cm-1; FAB-HRMS found 696.1859, required 696.1854 [M +
Na]+.
4H, Ar H), 5.35 (d, 2H, J1′,2′ ) 1.4, H-1′), 4.98 (d, 2H, J1,2
)
9.0, H-1), 4.24 (d, 2H, J4,5 ) 9.5, H-5), 4.14 (m, 2H, H-2′), 4.06
(m, 2H, H-6′b), 3.96-3.86 (m, 10H, H-6′a, H-4′, H-5′, H-3′, H-3),
3.81 (t, 2H, J3,4 ) 10.0, H-4), 3.54 (t, 2H, J2,3 ) 9.0, H-2); 13C
NMR (D2O): δ 171.2 (s, CONH), 136.4 (s, Ar C), 125.9 (d, Ar
CH), 103.8 (d, C-1′), 93.1 (d, C-1), 84.1, 79.9, 75.7, 74.4, 74.0,
73.2, 73.1, 69.3 (each d, C-2-C-5 and C-2′-C-5′), 63.5 (t, C-6′);
ES-HRMS found 835.2626, required 835.2594 [M + H]+.
(2,3,4,6-Tetra-O-acetyl-r-D-mannopyranosyl)-(1f3)-2,4-
di-O-acetyl-â-D-glucopyranuronosyl Azide 25. Pd(Ph3)4
(0.029 g, 0.025 mmol) and pyrrolidine (0.02 mL, 0.240 mmol)
were added to an ice-cold solution of 24 (0.165 g, 0.245 mmol)
in dry acetonitrile (1.5 mL). The reaction was judged complete
within 25 min by TLC (1:4 EtOAc/dichloromethane); the
mixture was filtered through Celite, and the solvent was
removed to produce a yellow foam that was taken into EtOAc
and washed with water. The two layers were separated, and
the aqueous layer was acidified to pH 2 using Amberlite IR-
120. The beads were filtered off, and the aqueous layer was
extracted into EtOAc, then dried (Na2SO4), filtered, and
evaporated in vacuo to produce 25 as a colorless syrup (0.125
g, 81%): 1H NMR (300 MHz, CDCl3) δ 5.33 (m, 2H, H-4′ and
H-4), 5.14 (m, 2 H, H-3′ and H-2′), 4.99 (m, 2H, H-1′and H-2),
4.74 (d, 1H, J1,2 ) 7.8, H-1), 4.17 (m, 3H, H-6′a, H-6′b and
H-5), 4.04 (m, 1H, H-5′), 3.96 (t, 1H, J2,3 ) 8.0, J3,4 ) 8.0, H-3),
2.49 (br s, 1H, OH), 2.22, 2.20, 2.18, 2.11, 2.11, 2.05 (each s,
each 3H, each COCH3); 13C NMR (CDCl3) δ 171.0, 170.3, 170.1,
169.9, 169.8, 169.3, 168.8 (each s, COCH3 and COOH), 99.4
(d, C-1′), 87.7 (d, C-1), 80.0, 73.7, 71.3, 69.7, 69.7, 69.4, 68.8,
65.2 (each d, C-2-C-5 and C-2′-C-5′), 61.9 (t, C-6′), 21.0, 20.9,
Acknowledgment. The authors thank Geraldine
Fitzpatrick (UCD) for NMR spectra, Dr. W. Kenneth
Glass for assistance with IR spectra, Dr. Dilip Rai
(UCD) for mass spectrometry measurements, and Joe
Leonard and Thorri Gunnlaugsson at Trinity College
Dublin for access to the CD spectrometer. Funding was
provided by Enterprise Ireland (SC/00/182) and IRCSET
(Ph.D. Scholarship to M.T.).
Supporting Information Available: NMR spectra, ad-
ditional experimental procedures, molecular modeling coordi-
nates, and crystallographic information file. This material is
available free of charge via the Internet at http://pubs.acs.org.
JO050200Z
J. Org. Chem, Vol. 70, No. 10, 2005 4117