Desymmetrisation of biphenyl-based carbohydrate receptors: A nonbonding pillar in one corner of the cage

Article abstract of DOI:10.1055/s-2008-1078020

We report a new addition to the family of biphenyl-based carbohydrate receptors, derived by replacing one out of four isophthalamide (diamide) linkages with the corresponding diester. The alteration results in lower binding constants, perhaps reflecting the entropic penalty for lowering receptor symmetry. However, the synthesis allows access to many related host molecules, with potential for restoring and raising affinities and tuning selectivities. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2008-1078020

LETTER
2137
Desymmetrisation of Biphenyl-Based Carbohydrate Receptors:
A Nonbonding Pillar in One Corner of the Cage
A
D
esymmetris
e
edCarbohy
e
drate Receptor Challinor, Emmanuel Klein, Anthony P. Davis*
School of Chemistry, University of Bristol, Bristol BS8 1TS, UK
Fax +44(117)9298611; E-mail: Anthony.Davis@bristol.ac.uk
Received 1 July 2008
This paper is dedicated to Prof. Jack E. Baldwin on the occasion of his 70th birthday.
sence of a pyridine nitrogen.6 In the present work we
aimed to lower symmetry still further, by changing one
corner of the cage. We were also interested to test the ef-
fect of removing H-bonding functionality from a pillar.
Abstract: We report a new addition to the family of biphenyl-based
carbohydrate receptors, derived by replacing one out of four iso-
phthalamide (diamide) linkages with the corresponding diester. The
alteration results in lower binding constants, perhaps reflecting the
entropic penalty for lowering receptor symmetry. However, the Molecular modelling4a suggested that, in the ground state
synthesis allows access to many related host molecules, with poten-
tial for restoring and raising affinities and tuning selectivities.
conformation of complex 1 + 2 (R = OH), one of the
isophthalamide units of 1 makes no hydrogen bonds with
the carbohydrate. If so, the amides in this pillar might not
be needed for strong binding. We were therefore drawn to
receptor 3 (Figure 1, b), an analogue of 1b in which one
isophthalamide is replaced by a diester (isophthalate) unit.
Key words: carbohydrates, supramolecular chemistry, bioorganic
chemistry, esters, biaryls
Carbohydrate recognition continues to attract the interest Esters cannot act as H-bond donors, and are also relatively
of supramolecular chemists.1,2 On the one hand, saccha- poor H-bond acceptors. We now report the successful
rides are challenging substrates because of their complex- synthesis of 3, and a study of its carbohydrate-binding
ity and the subtle differences between their structures. On properties.
the other they hold great importance for biology, not only
The synthetic route to 3 is summarised in Schemes 1
and 2. The key novel component was biphenyl 9
(Scheme 1), with a free hydroxy group and two types of
as fuels and structural materials but also as labels for cells
and proteins.3 We have developed a family of oligo-
phenyl-based receptors which have successfully targeted
masked amino functionality. This required a xylyl compo-
‘all-equatorial’ carbohydrates (glucose, b-glucosides, cel-
nent with differentially functionalised benzylic positions.
lobiose, etc.).4 The design strategy is illustrated in
The necessary asymmetry was established in the first step
Figure 1 (a) for the monosaccharide receptors 1.4a–c Two
by treating dibromide 44b with one equivalent of potassi-
biphenyl units serve as roof and floor of a tricyclic cage,
um acetate, giving monobromide 5.7 Treatment with sodi-
um azide gave 6, and was followed by Suzuki–Miyaura
providing apolar surfaces which complement the axial CH
groups of a b-glucosyl substrate 2. The aromatic surfaces
can contribute to binding through CH-p interactions in
nonpolar solvents, and through hydrophobic interactions
in water. The biphenyls are separated by isophthalamide
pillars that can hydrogen bond to the equatorially directed
polar groups of the substrate. Solubility is controlled by
externally directed groups X (lipophilic for organic-solu-
ble 1a and 1b,4a,b charged for water-soluble 1c4c). The re-
ceptors show useful binding properties in a full range of
solvents,5 with good-to-excellent selectivities for their in-
tended targets.
coupling with 74b to give 8. Notably, both the azide and
the acetate in 6 survived this step. Hydrolysis of the ace-
tate group yielded 9,8 which was reacted with the bispen-
tafluorophenyl ester 104b (Scheme 2). The resulting
diester 11 was treated with trimethylphosphine to reduce
the azides to amino groups. Cyclisation with 10 under
high dilution gave macrocycle 12. Finally, removal of the
N-Boc protecting groups and a [2+2] cyclisation with two
equivalents of 10 gave macrotricycle 3.9
Diester 3 was tested as a carbohydrate receptor in CDCl3–
CD3OD (92:8), the solvent system used previously for 1a
and 1b. In organic media such as this, it is necessary to use
lipophilic carbohydrate derivatives as substrates. In the
present case, the experiments employed the octyl glyco-
sides 13–15 (Figure 2). Complex formation could be de-
Given the asymmetry of the carbohydrate substrates, it
seems unlikely that the highly symmetrical structure 1 is
optimal for binding; a receptor which is perfectly comple-
mentary for 2 should reflect the asymmetry of 2. More-
over, less-symmetrical cages might show altered and
complementary selectivities. We have previously de-
scribed the preparation of receptors in which the ends of
the cage are differentiated, through the presence or ab-
1
tected by H NMR. On addition of the glycosides to a
solution of 3, the signals from the aromatic protons of the
receptor broadened and moved significantly. An example
is shown in Figure 3. The broadening precluded analysis
for many of the resonances, but for each substrate at least
two signals could be followed throughout a titration. The
data were analysed by nonlinear least-squares curve-fit-
SYNLETT 2008, No. 14, pp 2137–2141
2
2
.0
8
.2
0
0
8
Advanced online publication: 31.07.2008
DOI: 10.1055/s-2008-1078020; Art ID: D24508ST
© Georg Thieme Verlag Stuttgart · New York

2138
L. Challinor et al.
LETTER
X = OC5H11
1a
a)
H
N
N
H
N
H
X
H
X
O
O
N
H
H
H
H
OH
OBn
OBn
OBn
O
O
H
O
O
NH
O
X =
1b
HO
HO
OR
H
OH
O
O
O
O
H
NH
O
HN
O
2
O
O–
X
X
N
N
O
H
H
O
NH
X =
1c
O–
O
O
O–
O
b)
H
N
N
H
H
X
O
X
O
N
O
O
O
O
O
O
O
O
O
OBn
NH
O
HN
O
NH
X =
OBn
OBn
X
X
N
O
H
3
Figure 1 a) High-symmetry biphenyl-based monosaccharide receptors 1, and b-glucosyl substrates 2. Apolar units are shown in blue, polar
groups in red, and solubilising groups in green. b) The lower-symmetry design described in this paper. The ester groups in the isophthalate pillar
are highlighted in yellow.
I
I
I
a
b
97%
41%
Br
Br
Br
OAc
N3
OAc
4
5
6
NHBoc
NHBoc
NHBoc
NHBoc
O
O
B
d
c
96%
51%
NHBoc
NHBoc
N3
OAc
N3
OH
9
8
7
Scheme 1 Reagents and conditions: a) KOAc, Bu4NBr, DMF; b) NaN3, DMF; c) PdCl2(dppf), Na2CO2 aq, DMF; d) Cs2CO3, THF–MeOH.
ting to a 1:1 binding model.10 An example of experimental ever, compared to the high-symmetry, all-amide receptors
and calculated curves is given in Figure 4.
1, the affinities measured for 3 are quite low. For example,
the binding constants of 1a and 1b for b-glucoside 13
were 980 and 720 M–1, respectively. It therefore seems
that all eight amide groups in 1 are important for binding.
This may imply that the modelling discussed earlier was
misleading, and that 2 binds simultaneously to amide
The results for the binding studies are summarised in
Table 1. Given the competitive nature of the solvent sys-
tem, 3 may be considered a fairly effective receptor for the
b-glucosides 13 and 15. It also shows significant selectiv-
ity for these substrates against the a-glucoside 14. How-
Synlett 2008, No. 14, 2137–2141 © Thieme Stuttgart · New York

LETTER
A Desymmetrised Carbohydrate Receptor
2139
HO
HO
O
HO
HO
O
HO
HO
OC8H17
HO
HO
OC8H17
13
14
HO
HO
O
HO
HO
O
O
HO
OC8H17
HO
HO
15
Figure 2
OBn
OBn
H
N
O
OBn
9
C6F5O2C
CO2C6F5
Figure 3 1H NMR spectra (aromatic region) from the titration of re-
ceptor 3 against glucoside 13 in CDCl3–CD3OH (92:8).
10
a
57%
OBn
OBn
OBn
H
N
O
BocHN
O
O
NHBoc
NHBoc
O
O
BocHN
N3
N3
11
b,c
O
49%
OBn
OBn
OBn
H
N
Figure 4 Experimental and calculated values for an NMR binding
study of 3 and 12 (see Figure 3; data from peak starting at d = 8.19
ppm). Calculation assumes a 1:1 binding model; Ka = 50 M–1. Limi-
ting Dd = 0.048 ppm.
O
BocHN
BocHN
O
NHBoc
NHBoc
O
O
O
O
Table 1 Association Constants Ka between Receptor 3 and Octyl
N
H
N
H
Glycosides in CDCl3–CD3OH (92:8), Measured by 1H NMR Titration
12
BnO
BnO
BnO
d,c
Glycoside
Ka (M–1) for Individual Ka (M–1)
O
N
Signalsa
(averaged)
H
37%
3
Octyl b-D-glucoside (13)
Octyl a-D-glucoside (14)
60 (8.6), 50 (8.19)
55
10
Scheme 2 Reagents and conditions: a) DIPEA, DMAP, THF;
b) Me3P, THF, H2O; c) 10, DIPEA, THF, high dilution (0.4 mM final
concentration); d) TFA, CH2Cl2.
9 (8.6), 11 (8.43), 10
(8.19)
Octyl b-D-cellobioside (15) 155 (8.25), 120 (8.10)
138
groups in all four pillars of 1. However, a second, more
subtle factor is worth noting. In moving from the high-
symmetry receptors 1 to the less symmetrical 3, a signifi-
cant entropic penalty must be paid. In the former, there are
four equivalent orientations for a fully asymmetric sub-
strate such as 2 (see Figure 5). Each strongly bound con-
formation can thus be formed in four distinct ways.
However, if one of the pillars is altered this degeneracy is
lost, so that there is only one way of assembling a given
bound conformation. Even if one of the four original pil-
lars contributed no positive binding interactions, this ef-
a Starting chemical shifts are shown in parentheses.
fect should still cause a drop in affinity. Although one
might still argue that the ideal carbohydrate receptor must
be asymmetric to be fully complementary to its substrate,
this entropic disadvantage must be borne in mind.
In conclusion, we have shown that our synthesis of carbo-
hydrate receptors 1 can be modified so that one corner of
the cage structure is different from the rest. The prepara-
Synlett 2008, No. 14, 2137–2141 © Thieme Stuttgart · New York

2140
L. Challinor et al.
LETTER
9168. (g) Cacciarini, M.; Cordiano, E.; Nativi, C.; Roelens,
S. J. Org. Chem. 2007, 72, 3933. (h) Mazik, M.; Kuschel,
M.; Sicking, W. Org. Lett. 2006, 8, 855. (i) Lu, W. B.;
Zhang, L. H.; Ye, X. S.; Su, J. C.; Yu, Z. X. Tetrahedron
2006, 62, 1806. (j) Francesconi, O.; Ienco, A.; Moneti, G.;
Nativi, C.; Roelens, S. Angew. Chem. Int. Ed. 2006, 45,
6693. (k) Bucholtz, K. M.; Gareiss, P. C.; Tajc, S. G.; Miller,
B. L. Org. Biomol. Chem. 2006, 4, 3973.
(3) (a) Gabius, H. J.; Siebert, H. C.; Andre, S.; Jiménez-Barbero,
J.; Rudiger, H. ChemBioChem 2004, 5, 740. (b) Dwek, R.
A.; Butters, T. D. Chem. Rev. 2002, 102, 283. (c) Bertozzi,
C. R.; Kiessling, L. L. Science 2001, 291, 2357.
(d) Williams, S. J.; Davies, G. J. Trends Biotechnol. 2001,
19, 356. (e) Feizi, T.; Mulloy, B. Curr. Opin. Struct. Biol.
2001, 11, 585.
Figure 5 Four equivalent orientations of a glycoside substrate in a
D2h cage receptor such as 1 (shown schematically). If one corner of
the cage is altered, these structures become inequivalent.
(4) (a) Davis, A. P.; Wareham, R. S. Angew. Chem. Int. Ed.
1998, 37, 2270. (b) Ryan, T. J.; Lecollinet, G.; Velasco, T.;
Davis, A. P. Proc. Natl. Acad. Sci. U.S.A. 2002, 99, 4863.
(c) Klein, E.; Crump, M. P.; Davis, A. P. Angew. Chem. Int.
Ed. 2005, 44, 298. (d) Ferrand, Y.; Crump, M. P.; Davis, A.
P. Science 2007, 318, 619.
(5) Klein, E.; Ferrand, Y.; Barwell, N. P.; Davis, A. P. Angew.
Chem. Int. Ed. 2008, 48, 2693.
(6) Velasco, T.; Lecollinet, G.; Ryan, T.; Davis, A. P. Org.
Biomol. Chem. 2004, 2, 645.
(7) 3-Acetyloxymethyl-5-bromomethyl-1-iodobenzene (5)
Potassium acetate (2.52 g, 25.7 mmol) was added in small
portions over 1 h to a stirred solution of 1,3-bisbromo-
methyl-5-iodobenzene 4 (10.0 g, 25.7 mmol) and TBAB
(83.0 mg, 2.57 mmol) in anhyd DMF (200 mL). The
suspension was stirred at r.t. during 25 h. Ethyl acetate (600
mL) was added to the mixture and the organic solution was
washed with H2O (3 × 200 mL), NH4Cl sat. solution (200
mL) and brine (200 mL), then filtered (MgSO4) and
concentrated under vacuum. Purification by flash
tion of diester 3 has allowed us to test the effect of remov-
ing the amide linkages from this corner. The resulting
drop in affinities is perhaps disappointing, but usefully
highlights the connection between receptor symmetry and
binding entropy. The methodology developed during this
work could be used to make a wide variety of other struc-
tures. Because the first [2+2] cyclisation (9 → 12,
Scheme 2) is performed in stepwise fashion, there is es-
sentially no limitation to the spacer groups (pillars) which
may be introduced.11 In future work we plan to exploit this
flexibility to fine-tune the cage structure and to incorpo-
rate further binding functionality into the pillars. We may
hope thereby to restore (and raise) the affinities for b-glu-
cosides, and perhaps to develop receptors with altered se-
lectivities.
chromatography (eluent: hexane–EtOAc, 90:10) afforded
acetate 5 (3.92 g, 41%). Rf = 0.50 (SiO2; hexane–EtOAc,
80:20). 1H NMR (400 MHz, CDCl3): d = 7.70 (s, 1 H, ArH),
7.63 (s, 1 H, ArH), 7.33 (s, 1 H, ArH), 5.05 (s, 2 H, CH2O),
4.39 (s, 2 H, CH2Br), 2.13 (s, 3 H, CH3). 13C NMR (100
MHz, CDCl3): d = 170.6 (CO), 140.2 (ArC), 138.8 (ArC),
137.7 (ArCH), 137.0 (ArCH), 128.0 (ArCH), 94.3 (ArCI),
64.8 (CH2OAc), 31.5 (CH2Br), 21.0 (CH3). IR: nmax = 2932,
1737, 1570, 1357, 1377, 1236, 1057, 860 cm–1. MS(CI,
NH3): m/z = 386, 388 [M + NH4]+. HRMS(EI): m/z calcd for
C10H10Br1I1O2 [M]+: 367.8903; found: 367.8907.
Acknowledgment
Financial support from the EU (RTN contract HPRN-CT-2002-
00190) and the EPSRC (EP/D060192/1) is gratefully acknowl-
edged. Mass spectra were provided by the EPSRC National MS Ser-
vice Centre at the University of Swansea.
References and Notes
(1) Reviews: (a) Davis, A. P.; James, T. D. In Functional
Synthetic Receptors; Schrader, T.; Hamilton, A. D., Eds.;
Wiley-VCH: Weinheim, 2005, 45–109. (b) Davis, A. P.;
Wareham, R. S. Angew. Chem. Int. Ed. 1999, 38, 2978.
(c) Striegler, S. Curr. Org. Chem. 2003, 7, 81. (d) James,
T. D.; Phillips, M. D.; Shinkai, S. Boronic Acids in
Saccharide Recognition; RSC: Cambridge, 2006. (e)James,
T. D.; Shinkai, S. Topics Curr. Chem. 2002, 218, 159.
(f) James, T. D.; Sandanayake, K. R. A. S.; Shinkai, S.
Angew. Chem., Int. Ed. Engl. 1996, 35, 1910.
(8) Data for biphenyl 9: Rf = 0.30 (SiO2; hexane–EtOAc, 50:50).
1H NMR (400 MHz, CDCl3): d = 7.52 (s, 1 H, ArH), 7.39 (s,
1 H, ArH), 7.37 (s, 2 H, ArH), 7.30 (s, 1 H, ArH), 7.17 (s, 1
H, ArH), 5.00 (br s, 2 H, NH), 4.76 (s, 2 H, CH2OH), 4.39 (s,
2 H, CH2N3), 4.34 [d, 3J(H,H) = 5.0 Hz, 4 H, CH2NH], 1.46
(s, 18 H, CH3C). 13C NMR (100 MHz, CDCl3): d = 153.6
(CO), 140.0 (ArC), 138.6 (ArC), 138.4 (ArC), 137.3 (ArC),
133.4 (ArC), 123.0 (ArCH), 122.9 (ArCH), 122.8 (ArCH),
122.7 (ArCH), 122.6 (ArCH), 77.3 [C(CH3)3], 61.7
(CH2OH), 52.0 (CH2N3), 41.8 (CH2NHBoc), 25.8 (CH3). IR:
(2) Selected recent contributions: (a) Reenberg, T.; Nyberg, N.;
Duus, J. O.; van Dongen, J. L. J.; Meldal, M. Eur. J. Org.
Chem. 2007, 5003. (b) Nativi, C.; Cacciarini, M.;
n
max = 3406, 3335, 2978, 2932, 2096, 1684, 1513, 1247,
1160, 852 cm–1. MS(ES+): m/z = 516 [M + NH4]+, 521 [M +
Na]+. MS (ES–): m/z = 497 [M – H+]–. HRMS(ES+): m/z
calcd for C26H39N6O5 [M + NH4]+: 515.2976; found:
515.2971.
Francesconi, O.; Vacca, A.; Moneti, G.; Ienco, A.; Roelens,
S. J. Am. Chem. Soc. 2007, 129, 4377. (c) Terraneo, G.;
Potenza, D.; Canales, A.; Jiménez-Barbero, J.; Baldridge, K.
K.; Bernardi, A. J. Am. Chem. Soc. 2007, 129, 2890.
(d) Mazik, M.; Buthe, A. C. J. Org. Chem. 2007, 72, 8319.
(e) Li, C.; Wang, G. T.; Yi, H. P.; Jiang, X. K.; Li, Z. T.;
Wang, R. X. Org. Lett. 2007, 9, 1797. (f) Goto, H.;
Furusho, Y.; Yashima, E. J. Am. Chem. Soc. 2007, 129,
(9) Data for receptor 3: Rf = 0.50 (SiO2; toluene–EtOAc–EtOH,
50:50:5). 1H NMR [400 MHz, CDCl3–CD3OD (92:8)]:
d = 8.60 (s, 2 H, spacer-ArH), 8.43 (s, 2 H, spacer-ArH),
8.29 (s, 2 H, spacer-ArH), 8.27 (s, 2 H, spacer-ArH), 8.22 [t,
3J(H,H) = 4.8 Hz, 2 H, NH], 8.19 (s, 1 H, spacer-ArH), 8.11
(s, 1 H, spacer-ArH), 8.07 [t, 3J(H,H) = 4.8 Hz, 2 H, NH],
Synlett 2008, No. 14, 2137–2141 © Thieme Stuttgart · New York

LETTER
7.93 (s, 1 H, spacer-ArH), 7.91 (s, 1 H, spacer ArH), 7.83 [t,
A Desymmetrised Carbohydrate Receptor
2141
129.7, 129.6, 129.0, 128.8 (ArCH), 128.4 (BnArCH), 128.1,
128.0 (ArCH), 127.7 (BnArCH), 127.4, 126.8, 126.5, 126.4,
126.1 (ArCH), 75.5 (BnCH2), 68.8, 68.7 (CCH2OBn), 68.1
(CH2OCOAr), 60.9, 60.8, 60.7, 60.6 (CCH2OBn), 44.8
(CH2NHCOAr). IR: nmax = 3306, 3029, 2862, 1721, 1659,
1515, 1452, 1255, 1091, 1075733 cm–1. MS (MALDI+):
m/z = 2772 [M + K]+.
3J(H,H) = 4.6 Hz, 2 H, NH], 7.69 (s, 2 H, ArH), 7.67 (s, 2 H,
ArH), 7.62 (s, 2 H, ArH), 7.61 (s, 2 H, ArH), 7.52–7.05 (m,
64 H, ArH), 6.85 (s, 1 H, NHC), 6.82 (s, 1 H, NHC), 6.79 (s,
1 H, NHC), 6.77 (s, 1 H, NHC), 5.46 [A part of AB system,
2J(H,H) = 11.7 Hz, 2 H, CH2OCOAr], 5.05 [(B part of AB
system, 2J(H,H) = 11.7 Hz, 2 H, CH2OCOAr], 4.73 [A part
of AB system, 2J(H,H) = 13.7 Hz, 2 H, CH2NHCOAr],
4.50–4.45 (m, 32 H, BnCH2, CH2NHCOAr), 4.34 [B part of
AB system, 2J(H,H) = 13.7 Hz, 2 H, CH2NHCOAr], 3.90 (s,
6 H, CCH2OBn), 3.88 (s, 18 H, CCH2OBn). 13C NMR (100
MHz, CDCl3): d = 166.8, 166.7, 166.6, 166.0, 165.6, 165.3
(CO), 139.4, 139.3, 139.2, 139.0, 138.1 (ArC), 138.0
(BnArC), 136.7, 136.6, 136.5, 136.3, 136.2, 135.2, 135.1,
134.4 (ArC), 133.0, 131.7 (ArCH), 131.0 (ArC), 129.8,
(10) The analysis programme was implemented as an Excel
spreadsheet.
(11) In contrast, the single-step [2+2] cyclisation which forms the
other end of the cage, and which is used twice in the
synthesis of 1, is limited to spacers that cannot perform [1+1]
cyclisations with the diaminobiphenyl units. The rigid
isophthaloyl groups fulfil this criterion but many other
potential spacers do not.
Synlett 2008, No. 14, 2137–2141 © Thieme Stuttgart · New York

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