Sweet anion receptors: Recognition of chiral carboxylate anions by d-glucuronic-acid-decorated diindolylmethane

Article abstract of DOI:10.1021/ol402074u

Anion receptors containing glucuronic acid were synthesized, and their anion binding ability studied. Chirality of anionic guests derived from mandelic acid and amino acids can be distinguished not only in terms of stability constants but also by signific

Full text of DOI:10.1021/ol402074u

ORGANIC
LETTERS
2013
Vol. 15, No. 18
4730–4733
Sweet Anion Receptors: Recognition
of Chiral Carboxylate Anions
by D‑Glucuronic-Acid-Decorated
Diindolylmethane
Jaroszaw M. Granda and Janusz Jurczak*
Institute of Organic Chemistry, Polish Academy of Sciences, Kasprzaka 44/52,
01-224 Warsaw, Masovian, Poland
janusz.jurczak@icho.edu.pl
Received July 23, 2013
ABSTRACT
Anion receptors containing glucuronic acid were synthesized, and their anion binding ability studied. Chirality of anionic guests derived from mandelic
acid and amino acids can be distinguished not only in terms of stability constants but also by significant differences in chemical shift changes for sugar
moiety protons.
Molecular recognition, especially its chiral variants,
plays an important role in many natural systems, for
instance, the 2-deoxyribose-driven structure of the DNA
double helix and the R-amino-acid-driven secondary struc-
ture of proteins.1 Recently, much attention has been paid
to chiral recognition and sensing by artificial systems con-
taining stereogenic elements.2 So far, two general approaches
to these problems have been taken. The first one uses
noncovalent host/guest interactions, which leads to chirality
transfer to a host molecule having a signaling unit.3 The
other one applies to a covalent attachment of chiral moiety
to a host backbone. The latter receptor type can recognize
chiral guests by the difference in stability constants between
the two diastereomeric complexes (R)-host/(R)-guest and
(R)-host/(S)-guest.4 In particular, hosts that can differentiate
chiral anions have received increasing attention owing to the
importance of anions in nature,5 enantiomer separation
processes,6 applications in organocatalysis,7 etc.
The field of anion recognition is relatively recent (when
compared with early studied cations), having been explored
seriously in the last 20 years, and has led to development of
many neutral receptor motifs.8 A common strategy involves
the use of H-bond donors such as pyrroles,9 indoles,9
amides,10 ureas,11 etc., to coordinate a potential anionic
(5) Sessler, J. L.; Gale, P.; Cho, W.-S.; Rowan, S. J.; Aida, T.; Rowan,
A. E. Anion Receptor Chemistry; The Royal Society of Chemistry: London,
2006.
(1) Lawrence, D. S.; Jiang, T.; Levett, M. Chem. Rev. 1995, 95, 2229–
2260.
(2) Hembury, G. A.; Borovkov, V. V.; Inoue, Y. Chem. Rev. 2008,
108, 1–73.
(6) Stibor, I.; Zlatuskova, P. Chiral recognition of anions. In Anion
Sensing; Stibor, I., Ed.; Springer: Berlin, Germany, 2005; Vol. 255, pp
31ꢀ63.
(7) Zhang, Z.; Schreiner, P. R. Chem. Soc. Rev. 2009, 38, 1187–1198.
(8) (a) Gale, P. A. Chem. Soc. Rev. 2010, 39, 3746–3771. (b) Gale,
P. A. Chem. Commun. 2011, 47, 82–86. (c) Wenzel, M.; Hiscock, J. R.;
Gale, P. A. Chem. Soc. Rev. 2012, 41, 480–520.
(3) (a) Pu, L. Chem. Rev. 2004, 104, 1687–1716. (b) Leung, D.; Kang,
S. O.; Anslyn, E. V. Chem. Soc. Rev. 2012, 41, 448–479. (c) Wolf, C.;
Bentley, K. W. Chem. Soc. Rev. 2013, 42, 5408–5424. (d) Shinoda, S.
Chem. Soc. Rev. 2013, 42, 1825–1835.
(4) (a) Miyaji, H.; Hong, S.-J.; Jeong, S.-D.; Yoon, D.-W.; Na, H.-K.;
Hong, J.; Ham, S.; Sessler, J. L.; Lee, C.-H. Angew. Chem., Int. Ed.
2007, 46, 2508–2511. (b) Bencini, A.; Coluccini, C.; Garau, A.; Giorgi,
C.; Lippolis, V.; Messori, L.; Pasini, D.; Puccioni, S. Chem. Commun.
2012, 48, 10428–10430. (c) Wu, X.; Starnes, S. D. Org. Lett. 2012, 14,
3652–3655.
(9) (a) Dydio, P.; Lichosyt, D.; Jurczak, J. Chem. Soc. Rev. 2011, 40,
2971–2985. (b) Gale, P. A. Chem. Commun. 2008, 4525–4540. (c) Makuc,
D.; Lenarcic, M.; Bates, G. W.; Gale, P. A.; Plavec, J. Org. Biomol.
Chem. 2009, 7, 3505–3511. (d) Caltagirone, C.; Gale, P. A.; Hiscock,
J. R.; Brooks, S. J.; Hursthouse, M. B.; Light, M. E. Chem. Commun.
2008, 3007–3009. (e) Bates, G. W.; Triyanti; Light, M. E.; Albrecht, M.;
Gale, P. A. J. Org. Chem. 2007, 72, 8921–8927.
r
10.1021/ol402074u
Published on Web 08/29/2013
2013 American Chemical Society

guest. Among various anion binding pockets, derivatives
of 2,20-diindolylmethane of type 1 (Figure 1) draw a special
attention for researchers seeking to construct an effective
receptor for anions.12 Such receptors have proven efficient
even in very competitive solvents such as DMSO mixtures
with water or methanol.13 The diindolylmethane system
has been also used as a selectivity controlling unit in
transition-metal-catalyzed hydrogenation and hydrofor-
mylation reactions.14
Apart from amino acids, hydroxy acids, and terpenes,
saccharides are an important part of the chiral pool.15
They play a crucial role in many processes such as asym-
metric synthesis and catalysis,16 chiral recognition,17 and
chromatographic separation of enantiomers.18 As such,
simple monosacharides look to be the most potent source
of chirality for planned receptors, useful in chiral recogni-
tion studies.
In this study we decided to pursue the idea of chiral
recognition of anions by neutral receptors by synthesizing
a hybrid, sugar-decorated receptor containing a diindolyl-
methane unit. As compound 1 can be easily functionalized
by the formation of amide, readily available peracetylated
D-glucuronic acid (2)19 (Figure 1) was chosen to provide
a source of chirality. Anion receptor 3 was prepared
by treating 7,70-diamino-2,20-dindolylmethane (1) with
acid chloride of 2 in 68% yield. The reference receptor 4
was synthesized in a similar manner from 7-aminoindole
(Figure 1).
Figure 2. Fragment of 600 MHz 1H NMR spectrum of receptor
3 in DMSO-d6.
The structure of receptors 3 and 4 was confirmed by 1H
and 13C NMR spectra. In the case of receptor 3, two sets of
signals were observed in the 1H NMR spectrum for amide
and indole NH’s, δ = 9.87 and 9.97 ppm (for indole NH)
and δ = 10.04 and 10.07 ppm (for amide NH), respectively
(Figure 2). Protons H1 and H5 in the glucopyranose ring
appeared as two well separated doublets, similarly as for
acetyl and methyl groups of diindolylmethane. This has
enabled complete assignment of 1H and 13C NMR spectra
using COSY, HSQC, and HMBC experiments (for details
see Supporting Information).
The binding properties of compounds 3 and 4 were
studied under 1H NMR controlled titrations at a constant
concentration of receptor (∼1 ꢁ 10ꢀ2 M). In all cases,
binding affinities were measured by anion complexation-
induced resonance shift change upon addition of anionic
guests in the form of tetrabutylammonium salts.20 Substan-
tial changes in the NMR spectra could be observed not only
for indole and amide NH’s, but also for protons belonging
to the glucopyranose ring as well as to acetyl groups.
Atthe beginningofthe bindinginvestigations, receptor3
was studied in order to compare the effect of chiral barrier
on binding affinities. For this experiment, achiral anions of
typical geometries, chloride, dihydrogenphosphate, acet-
ate, and benzoate, were used, and the results are collected
in Table 1.
Figure 1. Structures of 7,70-diamino-2,20-dindolylmethane (1),
peracetylated D-glucuronic acid 2, and chiral anion receptors 3
and 4 investigated in this study.
(10) (a) Kavallieratos, K.; Bertao, C. M.; Crabtree, R. H. J. Org.
Chem. 1999, 64, 1675–1683. (b) Coles, S. J.; Frey, J. G.; Gale, P. A.;
Hursthouse, M. B.; Light, M. E.; Navakhun, K.; Thomas, G. L. Chem.
Commun. 2003, 568–569. (c) Chmielewski, M. J.; Jurczak, J. Chem.ꢀ
Eur. J. 2005, 11, 6080–6094. (d) Dabrowa, K.; Pawlak, M.; Duszewski,
P.; Jurczak, J. Org. Lett. 2012, 14, 6298–6301.
(11) (a) Gomez, D. E.; Fabbrizzi, L.; Licchelli, M.; Monzani, E. Org.
Biomol. Chem. 2005, 3, 1495–500. (b) Hay, B. P.; Firman, T. K.; Moyer,
B. A. J. Am. Chem. Soc. 2005, 127, 1810–1819. (c) Amendola, V.;
Fabbrizzi, L.; Mosca, L. Chem. Soc. Rev. 2010, 39, 3889–3915.
(12) Dydio, P.; Zielinski, T.; Jurczak, J. Chem. Commun. 2009, 4560–
4562.
Table 1. Association Constants and NH Shift Changes of
Protons Involved in Hydrogen Bonding of Receptor 3 With
Achiral Guests in DMSO-d6 þ 0.5% H2O
Δδmax/ppmdΔδmax/ppmdΔδmax/ppmdΔδmax/ppmd
anionc K/Mꢀ1a NH indole NH indole NH amide NH amide
Clꢀ
95.1
1.55
2.72
2.75
2.71
1.39
2.41
2.38
2.56
0.33
1.94
0.71
0.81
ꢀ0.12
1.89
0.55
0.68
H2PO4 1500b
PhCOOꢀ 2421
ꢀ
(13) (a) Dydio, P.; Zielinski, T.; Jurczak, J. Org. Lett. 2010, 12, 1076–
1078. (b) Dydio, P.; Lichosyt, D.; Zielinski, T.; Jurczak, J. Chem.ꢀEur.
J. 2012, 18, 13686–13701.
AcOꢀ
>104
(14) (a) Dydio, P.; Dzik, W. I.; Lutz, M.; de Bruin, B.; Reek, J. N. H.
Angew. Chem., Int. Ed. 2011, 50, 396–400. (b) Dydio, P.; Rubay, C.;
Gadzikwa, T.; Lutz, M.; Reek, J. N. H. J. Am. Chem. Soc. 2011, 133,
17176–17179. (c) Dydio, P.; Reek, J. N. H. Angew. Chem., Int. Ed. 2013,
52, 3878–3882.
a Estimated error less than 10% b Slow binding equilibrium. c Used as
tetrabutylammonium salts. d Asymptotic change in chemical shift ob-
tained by nonlinear curve fitting.
(15) Koskinen, A. M. P. Asymmetric Synthesis of Natural Products;
John Wiley & Sons, Ltd.: Chichester, U.K., 2012.
(16) Boysen, M. M. K. Carbohydrate Auxiliaries, in Carbohydratesꢀ
Tools for Stereoselective Synthesis; Wiley-VCH Verlag GmbH & Co.
KGaA: Weinheim, Germany, 2013.
(17) Berthod, A.; Chen, X. H.; Kullman, J. P.; Armstrong, D. W.;
Gasparrini, F.; D’Acquarica, I.; Villani, C.; Carotti, A. Anal. Chem.
2000, 72, 1767–1780.
Org. Lett., Vol. 15, No. 18, 2013
4731

The addition of tetrabutylammonium chloride to recep-
tor 3 causes a downfield shift for one of the amide NH
protons and an upfield shift for the other (Table 1, entry 1).
It appears that the receptor cavity is to small to accom-
modate the spherical chloride anion, which moreover sug-
gests that receptor 3 lacks symmetry. Titration of receptor
3 with dihydrogenphosphate revealed slow complexation
equilibrium on the NMR time scale (entry 2). In the case of
two carboxylates, sterically demanding benzoate showed
a binding constant of 2476 Mꢀ1 (entry 3), while acetate, the
least spatially demanding, was found to bind anion recep-
tor 3 more strongly with binding constant greater than
10000 Mꢀ1 (entry 4).
hand, for (R)-MA, the indole protons swapped places: the
one proton that was the most upfielded in the free ligand
(δ =9.87ppm) had thelargest chemicalshift afteraddition
of (R)-MA (12.76 ppm), 0.8 ppm more than the second
indole proton (11.94 ppm) (Figure 3).
The enantioselective recognition characteristics of hosts
3 and 4 were probed in the presence of model chiral anionic
guests S(þ)-mandelate ((S)-MA) or R(ꢀ)-mandelate ((R)-
MA) in various solvents. In an effort to determine the
binding constants for 3 with (S)-MA and (R)-MA, titra-
tions were performed under standard conditions (DMSO-
d6 þ 0.5% H2O at 298 K), and the results are collected in
Table 2.
Figure 3. Comparison of binding isotherms of receptor 3 and
R(ꢀ)-mandelate (left) and S(þ)-mandelate (right) tetrabuty-
lammonium salts in DMSO-d6 þ 0.5% H2O. Chemical shift
changes for indole (rectangle) and amide (triangle).
Under the above conditions, receptor 3 showed a sub-
stantial decrease in binding affinity, roughly 10 times lower
for enantiomeric mandelates, as compared with benzoate,
and the binding constants were different for both enantio-
mers (cf. Table 1, entry 3 and Table 2, entries 1 and 2). (R)-
MA was found to be bound with a larger binding constant,
(S)-MA with smaller.
In addition, smaller but fairly observable chemical shift
changes of protons in the glucopyranose ring, after anion
addition, suggest different conformational changes of
the receptor for each complex. For example, protons H5
(neighboring to the carbonyl group of glucuronic acid),
after addition of (S)-MA, were both down shielded by
about 0.1 ppm. After addition of (R)-MA only one proton
was down shielded. The protons H5 were not differentiated
by association of host 3 with achiral acetate anion (Figure 4).
Further, the structure of receptor 3 complexes with
mandelates was investigated by 2D ROESY technique.
ROESY spectrum of the receptor 3 and (R)-MA system
shows correlations between aromatic protons of guest and
sugar protons (H3 and H5). For weaker bounded (S)-MA
additional cross peaks can be also found indicating deeper
penetration of an anion into receptor 3 cavity. This is
also reflected by different cross peak signals arising from
mandelates R-proton and sugar moiety protons. The main
correlation for (R)-MA was from proton H5 located in a
proximity to anion binding pocket. On the other hand,
the main cross peak for (S)-MA R-proton was from
hydrogen H1 in anomeric position (for details see Support-
ing Information). Such results clearly suggest two distinct
modes of anion binding. It may be concluded that receptor
3 geometry forces (S)-MA to interact with both sugar
moieties while (R)-MA interacts only with one pyranose
ring. This may also explain chemical shift changes of
protons H5 during titrations with mandelates shown in
Figure 4.
Table 2. Chiral Recognition of Mandelic Acid Anions
b
entry aniona ligand K/Mꢀ1
solvent
KR/KS
1
2
(S)-MA
(R)-MA
(S)-MA
(R)-MA
(S)-MA
(R)-MA
(S)-MA
(R)-MA
(S)-MA
(R)-MA
3
3
3
3
3
3
4
4
4
4
119
DMSO-d6 þ 0.5% H2O 1.95
DMSO-d6 þ 0.5% H2O
233
3
58.6
118
DMSO-d6 þ 5% H2O
DMSO-d6 þ 5% H2O
MeCN-d3
2.01
4
c
5
6147
>104
22.0
20.7
693
ꢀ
6
MeCN-d3
7
DMSO-d6 þ 0.5% H2O 0.94
DMSO-d6 þ 0.5% H2O
8
9
MeCN-d3
MeCN-d3
1.07
10
740
a Anions used as tetrabutylammonium salts. b Estimated errors less
than 10%. c Binding constants too large to be accurately compared.
When chemical shift changes were tracked for indole
protons, after the addition of mandelates, the titration
curves showed a very interesting pattern: for the weaker
bounded (S)-MA both indole protons behaved in the same
way and exhibited similar shift changes (δmax) of 11.81 and
12.15 ppm, respectively, after anion addition. On the other
To investigate the influenceof the solvent, titrations of 3,
carried out in DMSO-d6 þ 5% H2O and in MeCN-d3, were
compared. Increasing water content to 5% caused an
expected decrease in binding constant for (S)-MA and
(R)-MA (Table 2, entries 3 and 4), but it did not diminish
the chiral recognition ability of receptor 3. On the other
hand, the use of a less polar solvent such as acetonitrile
resulted in binding constants too large to be quantified
(18) (a) Okamoto, Y.; Yashima, E. Angew. Chem., Int. Ed. 1998, 37,
1020–1043. (b) Berthod, A. Chiral Recognition in Separation Methods;
Springer: Berlin, Germany, 2010.
(19) Tosin, M.; Murphy, P. V. Org. Lett. 2002, 4, 3675–3678.
(20) Binding constants were obtained using nonlinear regression of
experimental data using the program HypNMR. All data fit well into a
1:1 binding model, and binding stoichiometry has additionally been
confirmed by Job plots (for details see Supporting Information).
4732
Org. Lett., Vol. 15, No. 18, 2013

(K > 10000 Mꢀ1, entries 5 and 6). The reference com-
pound 4 was not able to differentiate between enatiomeric
mandelates, with binding constants identical within the
experimental error (entries 7ꢀ10).
Table 3. Chiral Recognition of Amino Acids by Receptor 3
b
entry
aniona
K/Mꢀ1
KR/KS
1
2
3
4
5
6
Boc-N-D-Trp-COOꢀ
Boc-N-L-Trp-COOꢀ
Boc-N-D-Val-COOꢀ
Boc-N-L-Val-COOꢀ
Boc-N-D-Phe-COOꢀ
Boc-N-L-Phe-COOꢀ
227
88.0
305
126
224
93.3
2.57
2.42
2.40
a Anions used as tetrabutylammonium salts. b Stability constants in
DMSO-d6 þ 0.5% H2O obtained from 1H NMR titrations. Estimated
errors less than 10%.
˚
(dN10ꢀO14 = 2.706 A). A similar observation was reported
earlier for secondary anilides of glucuronic acid.21 In the
syn conformation (Figure 5B) amide NH, as in former
case, is involved in intramolecular hydrogen bonding
Figure 4. Stacked plots from 1H NMR titrations of host 3 with
acetate (left) S-mandelate (middle) and R-mandelate (right). H5
protons in glucopyranuronic ring, Hb bridging proton in diin-
dolylmethane in DMSO-d6 þ 0.5% H2O.
˚
(dN49ꢀO53 = 2.612 A) with the anomeric oxygen atom.
The glucopyranose ring is almost perpendicular to the
indole moiety and thus shields one face of compound 4.
These two motifs are connected by a hydrogen bond of
indole NH fragment A and the acetyl group of fragment B,
forming 1-D hydrogen bond network. These intramolecu-
lar hydrogen bonds look to play a crucial role in preorga-
nizing the host molecule.
To broaden the field of our investigation, we decided to
use several N-protected amino acid anions as guests. Three
N-Boc-protected amino acids were used, tryptophane, va-
line, and phenylalanine, and the results are shown in Table 3.
The anion receptor 3 prefers D-enantiomers in all cases
studied. Stability constants for these enantiomers were in
every case (Table 3, entries 1ꢀ6) at least twice as big as for
L-amino acids. For titrations of receptor 3 with amino
acids, similar characteristics were observed to those ob-
tained for the recognition of enantiomeric mandelates.
To summarize, receptor 3, being a sugar derivative of
diindolylmethane was synthesized and characterized for the
first time. We demonstrated the chiral recognition ability of
receptor 3 and its preference for carboxylates having R con-
figuration on the R carbon atom. Additionally, we found that
enantiomeric anions can be differentiated not only by the dif-
ference in stability constants but also by chemical shift changes
after the addition of enantiomeric guests to receptor 3.
Figure 5. Fragments A and B in crystal structure of receptor 4 in
anti and syn conformation. The atomic displacement param-
eters are at 50% probability level. Hydrogen atoms have been
omitted for clarity.
In order to gain insight into the structural factors
responsible for chiral recognition, we tried to grow crystals
of 3 suitable for X-ray analysis, yet despite many attempts
we were unable to obtain a single crystal. We therefore
turned our attention to compound 4, which gave a single
crystal appropriate for X-ray analysis. There are two
distinct motifs, shown in Figure 5A and B, present in the
same crystal structure and differing in conformation of the
pyranose ring with respect to an indole fragment (syn vs
anti).
Consideration of the anti conformation of the com-
pound 4 (Figure 5A) revealed that amide NH as well
as indole NH were involved in intramolecular hydro-
gen bonding interactions. The indole NH participates in
a hydrogen bond with the carbonyl group of glucuronic
Acknowledgment. This research was financed by the
European Union within the European Regional Develop-
ment Fund, Project POIG.01.01.02.-14-102/09.
Supporting Information Available. Complete experi-
1
mental procedures, Job plots, description of H NMR
titrations, crystallographic data for 4 (CCDC 943660).
This material is available free of charge via the Internet at
http://pubs.acs.org.
˚
acid (dN1ꢀO12 = 2.743 A), while amide NH is involved
in a hydrogen bond with the anomeric oxygen atom
(21) Tosin, M.; O’Brien, C.; Fitzpatrick, G. M.; Muller-Bunz, H.;
Glass, W. K.; Murphy, P. V. J. Org. Chem. 2005, 70, 4096–4106.
The authors declare no competing financial interest.
Org. Lett., Vol. 15, No. 18, 2013
4733