A Hexavalent Basket for Bottom-Up Construction of Functional Soft Materials and Polyvalent Drugs through a “Click” Reaction

Article abstract of DOI:10.1002/chem.201805246

Inspired by polyvalency and its prevalence in nature, we developed an efficient synthetic route for accessing a large variety of multivalent and dual-cavity baskets from inexpensive and abundant starting materials. First, the cycloaddition of vinyl acetate to anthracene was optimized to, upon hydrolysis, give dibenzobarrelene derivative 6, which after five functional group transformations and then cyclotrimerization gave heptiptycene dodecaester 4 in an overall 17 % yield. Following that, compound 4 was converted into D_3h symmetric 1, composed of two fused cavitands each holding three terminal alkynes at the rim for conjugation to functional molecules using the highly efficient CuAAC reaction. To survey the reactivity of hexavalent 1, we “clicked” 2-acetamido-2-deoxy-β-d-glucopyranosyl azide 3,4,6-triacetate (carbohydrate), methoxypolyethylene glycol azide (PEG, M_n=2000; polymer) and benzyl azide (aromatic) to obtain hexavalent conjugates 12–14 in 50–79 % yields. In summary, dual-cavity 1 is an accessible, structurally-unique and hexavalent host that can be “clicked” to a variety of functional molecules for (a) combinatorial lead identification of drugs, (b) preparation of hierarchical soft materials and (c) design of selective chemosensors, scavengers, or supramolecular catalysts.

Full text of DOI:10.1002/chem.201805246

A Journal of
Accepted Article
Title: A Hexavalent Basket for Bottom-Up Construction of Functional
Soft Materials and Polyvalent Drugs via “Click” Reaction
Authors: Jovica D Badjic, Taylor Neal, Weikun Wang, Lei Zhiquan,
Ruojing Peng, Priti Soni, and han xie
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Chem. Eur. J. 10.1002/chem.201805246
Link to VoR: http://dx.doi.org/10.1002/chem.201805246
Supported by

Chemistry - A European Journal
10.1002/chem.201805246
FULL PAPER
A Hexavalent Basket for Bottom-Up Construction of Functional
Soft Materials and Polyvalent Drugs via “Click” Reaction
[
a]
[a]
[a]
[a]
[a]
[a]
Taylor Neal, Weikun Wang, Lei Zhiquan, Ruojing Peng, Priti Soni, Han Xie and Jovica D.
[
a]
Badjić*
Abstract: Inspired by polyvalency and its prevalence in nature, we
developed an efficient synthetic route for accessing a large variety of
multivalent and dual-cavity baskets from inexpensive and abundant
starting materials. First, the cycloaddition of vinyl acetate to
Terminal
alkynes
anthracene
was
optimized
to,
upon
hydrolysis,
give
dibenzobarrelene derivative 6, which after five functional group
transformations and then cyclotrimerization gave heptiptycene
dodecaester 4 in an overall 17% yield. Following, compound 4 was
converted into D3h symmetric 1, composed of two fused cavitands
each holding three terminal alkynes at the rim for conjugation to
functional molecules using the highly efficient CuAAC reaction. To
survey the reactivity of hexavalent 1, we “clicked” 2-acetamido-2-
deoxy-β-D-glucopyranosyl azide 3,4,6-triacetate (carbohydrate),
Cu(I)
click”
“
6
methoxypolyethylene glycol azide (PEG, M
benzyl azide (aromatic) to obtain hexavalent conjugates 12-14 in 50-
9% yields. In summary, dual-cavity 1 is an accessible, structurally-
n
= 2000; polymer) and
7
unique and hexavalent host that can be “clicked” to a variety of
functional molecules for (a) combinatorial lead identification of drugs,
1
Terminal
alkynes
(
b) preparation of hierarchical soft materials and (c) design of
selective chemosensors, scavengers or supramolecular catalysts.
Figure 1. Energy-minimized conformer (MMFF, Spartan) of dual-cavity 1
carrying six alkynes (red) at its southern and northern ends. We hypothesized
that “clicking’ various substrates (β-D-glucopyranosyl azide is shown) to hexa-
alkyne 1, using Cu(I) catalyzed alkyne-azide cycloaddition (CuAAC), should
give structurally-unique, hexavalent and allosteric hosts (see ref. 30).
Introduction
Multivalent noncovalent interactions play
a pivotal role in
[
1]
directing chemical processes in living systems. Viral and
bacterial infections, protein-carbohydrate and protein-protein
interactions, as well as cell surface adhesions, present an
archetype of polyvalency in which multiple noncovalent contacts
[
5]
(
ΔGºpoly<iΔGºmono). Perhaps, the omnipresence of polyvalency
in nature is not surprising; it is easier to multiply existing
[
6]
interactions than evolve a single monovalent contact. At
present, there exists a great potential for employing multivalency
[
2]
mediate complex biological events. In essence, a molecule
with two or more identical groups (i.e. epitopes) binds to a
multivalent receptor (or causes a clustering of receptors) with
[
7]
[8]
in developing more effective antibiotics, viral drugs, drug-
[
9]
[10]
delivery modules, tissue replacement materials and imaging
[
11]
[12]
[
3]
agents. Moreover, multivalency has also been utilized in the
enhanced affinity (i.e. avidity)
to permit high fidelity in
[
3, 5b]
[
4]
area of supramolecular chemistry,
playing an important role
completing signal transduction or other chemical processes.
[
13]
in the bottom-up construction of nanostructured materials,
The standard free energy (ΔGºmulti) corresponding to the binding
of two multivalent entities, both having i recognition sites, is in
this way more favourable than the sum of free energies
[
14]
nano-patterning of surfaces and development of molecular
machines. For putting multivalency to work, selecting a proper
[
15]
[
16]
[17]
natural
difficulties.
kinetics and thermodynamics of complex recognition events,
or non-natural
scaffold has been met with
(
ΔGºmono) from i equivalent monovalent contacts
[
18]
That is to say, the paucity of information about
[
3, 19]
which one is trying to mimic or develop, is often a source of
ambiguity pertaining to the valency, spacing and dynamics of
[
a]
T. Neal, W. Wang, Dr. L. Zhiquan, R. Peng, P. Soni, H. Xie & Prof.
J. D. Badjić
Department of Chemistry & Biochemistry
[
20]
required multivalent structures.
Indeed, diversity-oriented
[13b, 21]
[13f, 22]
approaches
or other creative solutions
have been
The Ohio State University
th
explored for developing more effective binders, yet the scope of
synthetically accessible, biocompatible and topologically
1
00 West 18 Avenue, 43210 Columbus, Ohio USA.
E-mail: badjic.1@osu.edu
[
20, 23]
different structures remains limited.
In this vein, we hereby
Supporting information for this article is given via a link at the end of
the document.
describe an effective synthetic method for obtaining structurally
unique host 1 (Figure 1) containing six terminal alkynes at the
This article is protected by copyright. All rights reserved.

Chemistry - A European Journal
10.1002/chem.201805246
FULL PAPER
(
A)
Br
LG
H
3
CO
2
C
C
CO
2
CH
3
3
H
H
CO
CO
C
C
CO
CO
CH
CH
bromination
elimination
3
2
2
3
carbonylation
Br
Br
Br
bromination
Diels-Alder
LG
H
3
CO
2
CO
2
CH
Br elimination
3
2
2
3
Br
3
(
B)
CO
2
3
CH
3
2 3
CO CH
CH
3
H
3
CO
2
C
CO
H
CO
2
C
2
2 3
CO CH
O
O
O
O
9 steps
0%
Br
Pd(OAc)
n-Bu
2
/ Ph
NBr
O
3
P /
Pd(0)
H
3
CO
2
C
C
CO
2
CH
3
3
1
4
O
4
2 3
K CO / 4A MS /
H
3
CO
2
CO
2
CH
5
.0g-to-1.2g
Br
N
2
/ Dioxane
O
2
3
50 %
H
3
CO
2
C
CO2CH3
H
3
CO
2
C
2 3
CO CH
CO CH
2 3
$
120 per 100 g
2 3
CO CH
6
steps
33%
(
C)
1. Br
2 4
/ CCl / Δ
2. DBU/ DMF / 80 ºC
5
.0g-to-5.5g
9
0 %
Br
Br
OCOCH
3
OH
Br
Br
Br
Br
H
H
3
CO
2
C
CO
2
CH
3
3
Br
Br
Br
Br
1
.
, 230 ºC
Br2
t-BuOK / THF
3
CO
2
C
CO
2
CH
2
. CH
3
OH / NaOH
9
a
5
6
65 %
7
95 %
8
9
5 %
$8 per 100 g
2 6 6
1. Br / C H / hν
7
0 %
OCOCH
3
OH
2. DBU/ DMF / 80 ºC
Br
Br
Br
Br
(
BINAP)PdCl
2
/ Et
3
N
H
H
3
CO
2
2
C
C
CO
2
CH
3
CO (50 psi) / CH
3
OH
5
a
6a
8
9 %
3
CO
CO
2
CH
3
(
D)
(i)
(iii)
9
Br
Br
OH
2
Br
Br
Br
Br
(ii)
Br
Br
(iv)
Br
Br
Br
Br
(v)
Br
Br
Br
Br
Br
6
a
Br
Br
Following, palladium-catalyzed cyclotrimerization of
3
[30]
was
The
[
24]
Figure 2. (A) Retrosynthetic scheme pertaining to the preparation of the key
intermediate 3. (B) Earlier reported methodology for the conversion of
dianhydride 2 into dual-cavity 4. (C) More effective and optimized synthesis of
compound 3 using anthracene and vinyl acetate as inexpensive starting
materials. (D) Hypothesized intermediates occurring in the conversion of 6 into
optimized
to give dual-cavity 4 in circa 50% yield.
procedure is labour-intensive with 5 grams of compound 2 giving
.4 grams of dual-cavity 4 (Figure 2B). It takes about ten weeks
0
for an experienced chemist to complete the synthesis, with the
process necessitating costly reagents, copious amounts of
organic solvents and tedious purification steps commonly
resulting in the loss of product.
7
.
[
24]
periphery of its two fused cavitands. To demonstrate the utility
In a quest for a more effective method for obtaining
[
31]
of dual-cavity 1 as a building block in modular synthesis, we
dibenzobarrelene 3, we came up with a retrosynthetic strategy
for rapidly accessing this key intermediate (Figure 2A). First, we
reasoned that a catalytic polycarbonylation of 2,3,6,7-tetrabromo
[
25]
used the highly efficient CuAAC
“ click ”
reaction for
conjugating six carbohydrates, PEG polymers and aromatics
carrying azide functional groups (Figure 1). Since such
polyvalent baskets could be designed to assemble into
[
32]
dibenzobarrelene might, on the basis of a literature precedent,
be possible to promote with Co (CO) catalyst. To obtain the
tetrabromo compound, we hypothesized that regioselective
brominations of dibenzobarrelene derivative could give
2
8
[
26]
[18b]
vesicles,
six recognition groups
could be branching from
[
27]
their curved surface with a potential use in the preparation of
a
[
13a, 18a, 28]
[33]
functional soft materials.
Hexavalent 1 could also serve
satisfactory results (Figure 2A). Finally, [4+2] cycloaddition of
an alkene carrying a proper leaving group to anthracene could,
as a building block in combinatorial lead identification and
[
29]
[34]
optimization studies,
with the benefit of using a small
perhaps, be optimized to yield the desired dibenzobarrelene.
[
30]
molecule(s) to occupy juxtaposed cavities and act as effectors
for tuning the function (Figure 1).
The planned synthetic protocol is inexpensive, requiring a short
period of time for completion. Moreover, several principles of
[
35]
green chemistry are also incorporated: (a) atom economy with
maximization of the overall yield and minimization of waste (b)
scalability with minimal loss in efficiency and (c) facile
purifications using time-efficient precipitation or crystallization
procedures.
Results and Discussion
[
24]
Some time ago,
we developed a synthetic method for
obtaining dodecaester derivative of heptiptycene 4 (Figure 2B) in
In line with the strategy, we began by optimizing the
[
36]
<
5% overall yield. In brief, commercially available dianhydride 2
cycloaddition of vinyl acetate to anthracene (Figure 2C).
Because all of the atoms from the diene and dienophile are
[
24]
was converted into dibromoalkene 3 in nine linear steps.
This article is protected by copyright. All rights reserved.

Chemistry - A European Journal
10.1002/chem.201805246
FULL PAPER
0
0
.01
.02
N-H
0
0
.05
.10
H
B
Imidazole / Urea / DMF
50 ºC
1
4
11
0.25
H
A
0
.5
1
1
.0
.5
Br
/ DMF
0 %
2 3
Cs CO
2
2
.0
.2
5
N-H
H
B
H
A
11.2
10.8
10.4
10.0
9.6
9.2
8.8
8.4
8.0
7.6
7.2
6.8
H
D
δ (ppm)
H
C
H
B
H
A
*
H
C
H
A
H
B
H
D
H
A
1
8
.0
7.0
6.0
5.0
4.0
3.0
2.0
δ (ppm)
the EAS reaction as the side product. In this regard,
Figure 3. The preparation of hexa-imide 11 and hexa-alkyne 1 from 4. (Top)
dibenzobicyclo[2.2.2]octadienes of type 5a/6/6a are, in aliphatic
1
Variable concentration H NMR spectra (600 MHz, 298 K) of 11 in (CD
3
)
2
SO.
. A
[38]
substitutions, prone to Wagner-Meerwein rearrangements
as
1
(
Bottom) H NMR spectrum of compound 1 (700 MHz, 298 K) in CD
2
Cl
2
mediated by phenylium and secondary carbocationic
structural representation of 100 conformers of 1 (from 0 to 0.1 kcal/mol of
[
43]
[38, 42, 44]
relative steric energy) obtained from the Monte-Carlo conformational search
intermediates (Figure 2D). In light of such reports,
we
(
OPLS3, Schrodinger) in implicit water solvent.
hypothesize that the principal formation of 7 could be resulting
from the electron withdrawing bromides within 6a (or other
polybrominated intermediates, Figure 2D) reducing the extent of
[
38]
being incorporated into the product, this transformation
π-to-σ* homohyperconjugation to retard the departure rate of
the leaving group and concurrently lower the stability of
carbocationic intermediates. In this way, the reaction pathway (i)
in Figure 2D dominates over (ii-v) to give 7 as the kinetic product.
[
37]
embodies the highest degree of atom economy.
Alder and
[
36]
Rickert carried out the same cycloaddition in 1939, prescribing
its completion in xylene at 220 ºC (autoclave) so that the yield of
dibenzobicyclo[2.2.2]octadiene cycloadduct 5a was in the range
In another scenario, a greater thermodynamic stability of [2.2.2]
[
34, 38]
[42, 44]
of 40 to 50%.
Interestingly, we realized that this same
over [3.2.1] bicyclic frameworks
could lead to the formation
transformation became practically quantitative when two molar
equivalents of neat vinyl acetate were used as both reactant and
solvent (Figure 2C). In fact, the reaction can be run safely on a
of 7 as the thermodynamic product if all of the reactions are
reversible on the time scale of the experiment. A facile and
effective elimination of HBr from 7 was promoted with t-BuOK,
5
g scale in a 10 mL vessel placed in a sand bath at 230 ºC.
with the work-up necessitating
a few extractions to give
[
45]
While compound 5a could be isolated by precipitation, we
sufficiently pure 8 in 95% yield. To complete the carbonylation
decided to, without any purification, treat it with NaOH to form
of 2,3,6,7-tetrabromo dibenzobarrelene 8, we considered two
[
39]
racemic 6 in an overall 95% yield.
regioselective bromination of 5a and 6.
aromatic substitution (EAS) of 5a, using bromine with catalytic
Next, we examined
procedures: (a) palladium-catalyzed carbonylations optimized for
[
33]
[46]
The electrophilic
heterocyclic and electron-rich aromatics
catalytic and cobalt-based
polycarbonylations. Both methods gave satisfactory results,
albeit relatively inexpensive (BINAP)PdCl was found to, under
and (b) photo-
methodology
for
[
40]
[32]
quantities of iron,
disappointing <10% yield. On the contrary, a slow addition of
led to the formation of 7 in rather
2
[
41] [42]
[
46]
neat bromine
to 6 gave pentabromo-bicyclic 7 in 65% yield
mild reaction conditions, facilitate the conversion of 8 into 9 in
excellent 89% yield (Figure 2C). As in this transformation the
reactant must undergo four consecutive reactions, the yield of
each step is 97% on average! The conversion is scalable,
with purification requiring a quick filtration of the reaction’s
product. Allegedly, the substitution of hydroxyl group in 5 with
nucleophilic bromide anion was initiated with HBr, generated in
This article is protected by copyright. All rights reserved.

Chemistry - A European Journal
10.1002/chem.201805246
FULL PAPER
AcO
AcO
OAc
Hi
AcO
O
OAc
AcHN
HF
H
K/L
Ac
AcO
*
*
N
HG
O
AcO
AcO
O
N
N
N
OAc
N
HJ
Ac
H
H
H
D
N
N
N
N
HE
NHAc
HC
O O
HC
HJ/K/L
N
N O O
N
N
HD
O
O
Hi
HB
HF
HB
HA
HA
1
2
HG
HE
H
H
O
O
O
N
O
N O
8.0
7.0
6.0
5.0
4.0
3.0
2.0
1.0
O
N
N
N
AcHN
δ (ppm)
N
OAc
OAc
OAc
AcO
N
N
N
O
N
NHAc
N
O
N
NHAc
AcO
AcO
O
OAc
OAc
O
AcO AcO
O
AcO
AcO
N
N
OO
N
N3
O
O
O
NHAc
CuI, DIPEA
THF, 60 ºC
5
0%
CuI, DIPEA
THF, 60 ºC
7
9%
O
1
CuI, DIPEA
THF, 60 ºC
6
7%
O
n
N
3
O
O
O
N
N
O
N
N3
O
O
n
n
n
O
O
O
O
O
O
HE
N
N
N
N
N
N
N
N
HD
N
HC
N
N
N
N
N
O
N
N
N
N
O
N
OO
N
O
N
O
O
N
O
N
OO
170
160
150
140
130
120
O
N
H
B
O
δ (ppm)
HA
1
3
1
4
O
O
HB
HD
HE
O
N
O
N
HC
N
HA
O
O
N
N
O
O
O
N
O
N
N
O
N
N
N
N
N
N
N
O
N
N
N
O
O
O
n
N
N
N
N
8
.4
7.6
6.8
6.0
5.2
4.4
3.6
n
N
N
δ (ppm)
O
O
O
1
3
1
CD
3
COCD
3
. (Bottom) Partial C and H NMR spectra (700 MHz, 298 K) of
OD and CD CN, respectively.
PEG conjugate 13 in CD
3
3
Figure 4. Conjugation of 2-acetamido-2-deoxy-β-D-glucopyranosyl azide
,4,6-triacetate, methoxypolyethylene glycol azide (PEG, M = 2000) and
benzyl azide to 1 was catalyzed with Cu(I) to give 12, 13 and 14. (Top)
NMR spectrum (600 MHz, 298 K) of β-D-glucopyranosyl conjugate 12 in
3
n
1
H
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Chemistry - A European Journal
10.1002/chem.201805246
FULL PAPER
can be run safely on a multi-gram scale (50 psi pressure of CO)
Figure 4) and are not magnetically shielded to indicate that
carbohydrates reside outside the host’s cavities; note that
glucopyranosyl units akin to those in 12 are often conjugated to
active components of drug molecules, but not necessarily act as
drugs themselves. In case of dendritic polymer 13 (Mw = 13248,
with facile and quick purification of crude 9. To transform 9 into 3
[
24]
(
Figure 2C), we used published
bromination/dehydrobromination
homocoupling of 3 was catalyzed with Pd(OAc)
yet somewhat modified
procedures. Finally, the
to give dual-
2
1
13
cavity 4 in 50% yield. To sum up, using the newly optimized
procedure, one should be able to convert 5 grams of anthracene
into 2.0 grams of multivalent 4 in circa ten days (Figure 2C). This
Figure S36), however, we noted a single set of H and C NMR
signals (Figure 4, bottom). The result is in line with the
heptiptycene cage being fully functionalized with six PEG chains
[
24]
1
is in a stark contrast with the original protocol, which on this
scale (a) provides 440 milligrams of the multivalent host, (b) is
more costly and (c) requires a considerably longer time for
completion.
(Mn = 2000): (1) H NMR integration ratio of H
B
(from the
1
3
host):H
E
(from polymeric residues) = 1.00:1.05, (2) seven
C
NMR singlets from the aromatic part of the molecule and (3) no
1
H signals at 2.1 ppm from terminal alkynes (Figure S34); note
With a quicker access to larger quantities of 4, we began
examining the incorporation of six terminal alkynes into this
molecule (Figure 3). Notably, D3h symmetric 4 possesses twelve
esters to require a series of highly efficient reactions for its
functionalization. Inspired by our earlier work with
that a significant population of partly functionalized molecules
1
3
would make NMR spectrum more complex and, presumably,
reveal the presence of terminal alkynes. The bolaamphiphilic
and dendritic polymers of type 13 are expected to, in water,
[
28]
assemble into unique polymersomes
characteristics. At last, the conjugation of benzyl azide to 1 gave
with stimuli-responsive
[
47]
[48]
phthalimides and their biocompatibility, we decided to probe
the preparation of hexa-imide 11 from 4 (Figure 3). Thermally
unstable urea is known to, in the presence of imidazole, serve
as a source of ammonia for the effective conversion of phthalic
1
13
product 14 in 67% yield (Figure 4) with H/ C NMR spectra
corresponding to, on average, a D3h symmetric molecule (Figure
S37-39). The effective formation of these types of molecules
opens a way for rapidly accessing a variety of hosts capable of
[
49]
acids into phthalimides.
Accordingly, we reacted imidazole
[
50]
[26]
and urea with 4 in DMF and obtained 11. Hexa-imide 11 is
soluble in (CD ) SO and its H NMR spectrum (Figure 3) showed
3 2
assembling into nanostructured soft materials.
1
three sharp singlets corresponding to a D3h symmetric molecule.
Interestingly, a two hundred-fold dilution of 11 had no effect on
Conclusion
1
its H NMR spectrum (Figure 3), which indicates an absence of
[
51]
hydrogen-bonded aggregates.
The alkylation of six
In conclusion, we have developed and optimized
a
phthalimides with propargyl bromide (i.e. the Gabriel synthesis)
streamlined synthetic methodology for obtaining gram quantities
of multivalent and dual-cavity basket 1. In nine synthetic steps,
requiring circa two weeks for completion, one can convert
inexpensive and abundant anthracene and vinyl acetate
reactants into a functional and allosteric 1 holding six terminal
alkynes at the periphery of its two fused cavitands. Importantly,
gave desired 1 in 50% yield (Figure 3), with the product showing
1
four distinct H NMR resonances. The IR spectrum of 1 (Figure
-
1
S30) revealed
a broadened stretch at about 3278 cm ,
sp
corresponding to alkyne C -H vibrations. The broadening could
result from different conformers of 1 in which terminal alkynes
are pointing to or away from the cavity. Indeed, the results of a
molecular mechanics calculation (Monte-Carlo conformational
search with OPLS-3 field; Figure 3) suggested a negligible
energy difference for terminal alkynes assuming in/out
orientations about the rim of 1.
1
could be “clicked” to a variety of functional molecules (i.e.
carbohydrates, polymers or aromatics) for creating dendritic and
polymeric hosts. These structurally unique products could be
[
54]
easily diversified and screened for biological activity or probed
[
26]
for assembling into soft materials.
At present, we are
The Huisgen 1,3-dipolar cycloaddition of terminal alkynes
examining the assembly, biological activity and recognition
characteristics of these intriguing compounds and will report on
results in future.
[
25a]
to azides, catalyzed with Cu(I),
is quintessential click
[
52]
chemistry that has been of great service to bioconjugation and
supramolecular chemistry, materials science and drug
[
25b, 29, 53]
discovery.
clicking”of three different classes of molecules (Figure 4): β-D-
glucopyranosyl azide, PEG-azide polymer (M = 2000) and
In the case of hexa-alkyne 1, we probed the
“
Acknowledgements
n
benzyl azide. In each instance, CuI promoted the consecutive
formation of six 1,4-disubstituted triazoles in tetrahydrofuran
This work was financially supported with funds obtained from
Army Research Office (W911NF-17-1-0140). We thank graduate
student Vageesha L. G. Gunawardana (OSU) for helping with
the synthesis of dual-cavity 1.
1
solvent to give 12-14 in 50-79% yield. In particular, the H NMR
spectrum of the carbohydrate conjugate 12 showed a set of
signals corresponding to, on average,
a D3h symmetric
compound (Figure 4, top). For assigning the resonances, we
1
1
1
13
used H- H COSY (Figure S32) and H- C HSQC (Figure S33)
Keywords: Click Reaction • Multivalency • Supramolecular
1
correlations. We posit that the H NMR signals are broadened
Chemistry • Molecular Recognition • Drug Design
due to a reduced rate of the rotation of proximal carbohydrate
moieties about the central concave scaffold. In addition, singlets
from acyl groups possess similar chemical shifts (c.a. 2.0 ppm,
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Chemistry - A European Journal
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Chemistry - A European Journal
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FULL PAPER
Entry for the Table of Contents
FULL PAPER
[
a]
[a]
A structurally unique host with
six terminal alkynes, at the
periphery of its fused cavitands,
can be clicked to carbohydrates,
polymers and aromatics for
obtaining a variety of multivalent
drugs and nanostructured soft
materials.
Taylor Neal, Weikun Wang, Lei
soft
materials
[a]
[a]
Zhiquan, Ruojing Peng, Priti
[
a]
[a]
Soni, Han Xie and Jovica D.
[
a]
6 “clicks”
Cu(I)
Badjić*
Page No. – Page No.
multivalent
drugs
A Hexavalent Basket for
Bottom-Up Construction of
Functional Soft Materials and
Polyvalent Drugs via “Click”
Reaction
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