Carbamate triserine lactone receptors for anion recognition

Article abstract of DOI:10.1016/j.tetlet.2008.08.081

We have taken advantage of the ability of the cyclic triester of l-serine to organize ligand units appended to the three α-amine functionalities, as in enterobactin, a siderophore produced by enteric bacteria that binds ferric ion exceptionally well (K_f = 10⁴⁹). As an extension of the preorganization concept, this work describes the preparation and characterization of carbamate triserine lactone receptors 1-6 and their ability to act as molecular receptors for anions. These receptors bind halides (F^- ? Cl^- > Br^- > I^-) with binding constants K in the range 21-7350 L mol^-1.

Full text of DOI:10.1016/j.tetlet.2008.08.081

Tetrahedron Letters 49 (2008) 6410–6412
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Carbamate triserine lactone receptors for anion recognition
*
Yizhe Wang, Edward Duran, David Nacionales, Amber Valencia, Christopher Wostenberg, Eric R. Marinez
Department of Chemistry and Biochemistry, California State University, Long Beach, 1250 Bellflower Boulevard, Long Beach, CA 90840, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
We have taken advantage of the ability of the cyclic triester of
L
-serine to organize ligand units appended
Received 1 August 2008
Revised 22 August 2008
Accepted 22 August 2008
Available online 28 August 2008
to the three a-amine functionalities, as in enterobactin, a siderophore produced by enteric bacteria that
binds ferric ion exceptionally well (Kf = 1049). As an extension of the preorganization concept, this work
describes the preparation and characterization of carbamate triserine lactone receptors 1–6 and their
ability to act as molecular receptors for anions. These receptors bind halides (FÀ ꢀ ClÀ > BrÀ > IÀ) with
binding constants K in the range 21–7350 L molÀ1
.
Ó 2008 Elsevier Ltd. All rights reserved.
The important roles that anions play in medicine, biology, cata-
lysis, and the environment have resulted in considerable interest in
studying anion recognition phenomena.1–3 Early study of anion
recognition by positively charged receptors relied heavily on elec-
trostatic interactions.3 A recent focus has been the development of
electroneutral receptors that bind via weaker hydrogen bonds.1,2
To strengthen anion binding and selectivity, receptors have been
designed to utilize rigid tripodal backbones that preorganize acidic
hydrogen bond donors in well-defined binding pockets, including
the hexasubstituted arene rings reported by Ansyln4 and by
Steed,5 the cholapods by Davis,6 tris(aminoethyl)amine analogs
by Reinhoudt7 and by Schneider,8 and the cis-1,3,5-tris(amino-
methyl)cyclohexane derivatives reported by Morán.9,10
constant15 (Kf = 1049) and exclusively in a -cis configuration.16
D
Although many synthetic analogs have been prepared, none
exhibits a greater ferric ion complex stability than enterobactin
including those that use the tris(aminoethyl)amine17 (TRENCAM
Kf = 1043.6), 2,4,6-triethylmesityl18 (Et3MECAM Kf = 1047), and
cis-1,3,5-tris(aminomethyl)-cyclohexane19 (sat-MECAM Kf = 1043
)
backbones. It has been recently shown that enterobactin’s ability
to sequester iron so effectively is due in good measure to the con-
formation of the trilactone that predisposes the catecholate groups
for metal ion binding.20
Our ability to produce the triserine lactone platform of enterob-
actin21,22 in gram scale has propelled us to investigate other appli-
cations of the preorganization concept. We describe here the
preparation of carbamate triserine lactone receptors 1–6, their
conformational analysis by 1H NMR, and their ability to bind
halides.
Because of their biochemical need for iron and its environmen-
tal insolubility, microorganisms produce iron chelators (sidero-
phores) that solubilize ferric ion and make it bioavailable.11
Enterobactin (Scheme 1), a cyclic triester of N-(2,3-dihydroxyben-
Preparation of receptors 1–6 (Scheme 2) began with the trimer-
zoyl)-
L
-serine that is produced by Escherichia coli and other enteric
ization of N-trityl-L-serine methyl ester 7 to tris-N-trityl trilactone
8, followed by removing the trityl groups with anhydrous HCl to
bacteria,12–14 binds ferric ion with an enormous formation
O
O
O
O
O
O
O
O
O
O
Fe3+
O
O
HN
O
NH
HN
O
O
NH
NH
O
N
O
O
H
O
HO
HO
OH
OH
O
O
O
HO
HO
Fe3+
O
O
1
Fe-1
Scheme 1. Enterobactin and Fe-enterobactin.
* Corresponding author. Tel.: +1 562 985 7773; fax: +1 562 985 8557.
E-mail address: emarinez@csulb.edu (E. R. Marinez).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.08.081

Y. Wang et al. / Tetrahedron Letters 49 (2008) 6410–6412
6411
NH +Cl-
3
NHTrt
O
O
O
SnBu2
O
O
anhydrous HCl
O
O
OO
O
O
O
m-xylene
85%
99%
HO
OCH3
NHTrt
O
O
-Cl+H3N
NH3+Cl-
TrtHN
NHTrt
O
7
8
9
Hβ1
O
O
Cl
O
O
Hβ1
Hα
O
R1
Hα
O
R2
R3
O
O
O
H
O
1 R1=R2=R3=H
O
Hβ2
O
H
2 R1=R2=H, R3=t-Bu
3 R1=R2=H, R3=Cl
4 R1=R3=H, R2=Cl
5 R1=Cl, R2=R3=H
6 R1=R2=H, R3=Br
R1
O
O
NH
NH
HN
N
O
R1
R2
R1
R1
R1
R2
R2
O
O
R2
R3
R2
R3
O
O
R2
R3
R2
R3
Et3N
R1
R1
R1
R1
R2
R2
Scheme 2. Synthesis for carbamate triserine lactone receptors 1–6.
produce tris-ammonium salt 9.21,22 A series of chloroformates,
either commercially available or synthesized23,24 by treating the
phenol with a dilute solution of phosgene, were then reacted with
backbone 9 producing carbamate ligands 1–6 in excellent yield
(90–95%).
Table 1
Association constantsa of receptors 1–6 with Bu4N+FÀ b
,
Et4N+ClÀ
,
Et4N+BrÀ and
Bu4N+IÀb in CDCl3 by 1H NMR titration method at 298 K
Receptor
Ka (L molÀ1
)
Ka (L molÀ1
)
Ka (L molÀ1
)
Ka (L molÀ1
)
with Bu4N+FÀ
with Et4N+ClÀ
with Et4N+BrÀ
with Bu4N+IÀ
3827d
1189d
4200d
140d
190d
213d
1114d
212c
191d
75d
21c
At room temperature, 1H and 13C NMR spectra for 1–6 reveal
that they all exhibit pseudo C3 symmetry in CDCl3. The receptors
display well-resolved 1H NMR spectra and allow for conforma-
tional analysis using the spin–spin coupling of alpha-methine
1
2
3
4
5
6
161d
146d
329c
175d
106d
23c
75c
7350d
109c
115c
81c
e
3550d
(H ) and beta-methylene protons (Hb1 and Hb2) on each seryl unit
a
(Scheme 2). The data are consistent with a pseudoaxial conforma-
tion for receptors 1–6: Hb1 and Hb2 have a large geminal coupling
constant (ꢁ11 Hz), but the coupling values of both Hb1 and Hb2
a
Errors estimated as 610% for Ka.
b
Bu4N+FÀ and Bu4N+IÀ were used due to limited solubility of Et4N+FÀ and Et4N+IÀ
in CDCl3, respectively.
c
Changes of NH chemical shift were used to calculate Ka.
NH peaks were broadened so changes of seryl methylene proton chemical shifts
to H are small (ꢁ3.2 Hz) since both methylene protons are gauche
a
d
to it. Consequently, results of conformational analysis in CDCl3
reveal receptors 1–6 to be preorganized.
were used to calculate Ka.
e
Not determined due to peak broadening of NH and seryl protons.
The energy minimized conformation of receptor 1 has been
computed using SpartanPro at the DFT-B3LYP-6-31G* level and
also confirms the pseudoaxial conformation with the carbamate
N–H bonds pointing toward the interior of the receptor, while
the carbonyl of the carbamate points outwards. The three NH
bonds form a hydrogen bonding core defined by the trilactone ring.
Proton NMR titration experiments were used to investigate the
anion binding properties of receptors 1–6.25 The addition of halides
as either tetraethyl or tetrabutyl ammonium salts to the receptors
in CDCl3 caused changes in chemical shift in the receptor’s 1H NMR.
The largest change in chemical shift was observed for the carba-
mate NH protons and is indicative of their role in the anion recog-
nition event via hydrogen bonding. Anion binding constants were
calculated from the titration data using a nonlinear least-squares
curve-fitting program, and all titration curves fitted a 1:1 recep-
tor/anion binding model. Compared to Davis’ cholapods,6 receptors
of increasing basicity, IÀ < BrÀ < ClÀ < FÀ. However, the observed
selectivity for fluoride ion (1.36 Å) also seems to parallel the cavity
size that is generated by appending the carbamate residues onto
the triserine lactone core. The larger halides ClÀ (1.81 Å), BrÀ
(1.95 Å), and IÀ (2.16 Å) bind weakly (see Table 1).3 For receptors
1–6, the average distance between the hydrogen atoms on each
carbamate NH is approximately 3.3 Å. Therefore, the binding core
is very small and limits the binding of large anions.
Interestingly, dichlorophenyl carbamate receptors
substituted) and 5 (ortho substituted) reveal large differences in
their ability to bind chloride ion. Receptor 4 (Ka = 1114 L molÀ1
4 (meta
)
binds chloride five times stronger than receptor 5 (Ka = 212
L molÀ1): ortho substitution may decrease the binding event
perhaps due to steric effects.
In conclusion, receptors 1–6 show selective binding affinity
toward fluoride over other halides. Since this is the first report of
anion recognition utilizing the enterobactin triserine lactone plat-
form, we are currently examining aryl amide triserine lactone
receptors for anion recognition as well as for exploring the ability
of receptors 1–6 to bind other anions including nitrate and
phosphate.
1
–6 show moderate affinity and selectivity for fluoride ion with
association constants Ka in the range of 1190–7350 L molÀ1 (Table
1). Placement of electron-withdrawing substituents onto the aryl
groups of receptors 3 and 4 show the largest binding constants
for fluoride ion (Ka = 4200 L molÀ1 and Ka = 7350 L molÀ1, respec-
tively), and is consistent with enhanced acidity of the carbamate
N–H leading to augmentation of its hydrogen bond donor ability.
Our attempts to further increase the N–H acidity by preparing
the tris-(2,4,6-trichlorophenyl) carbamate receptor has failed.
Since stronger bases form stronger hydrogen bonds to acidic
protons, basicity plays an important role in anion binding.6,8,26
The observed order of binding to our receptors parallels the order
Acknowledgments
We thank the National Institutes of Health (RISE and SCORE) for
generous support of this work. ERM also thanks the Department of

6412
Y. Wang et al. / Tetrahedron Letters 49 (2008) 6410–6412
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Supplementary data
General procedure and spectral data (1H and 13C NMR) for all
new compounds prepared are provided. Tables and graphs for 1H
NMR titrations are also provided for reference. Supplementary data
associated with this article can be found, in the online version, at
doi:10.1016/j.tetlet.2008.08.081.
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