Participation of host 'spacer' atoms in carboxylic acid binding: Implications for amino acid recognition

Article abstract of DOI:10.1016/j.tet.2005.06.096

Chiral 4,4′-diamido-2,2′-biimidazoles were synthesized and found to bind N-Boc protected amino acids in CDCl₃. The biimidazole that features (R)-tetrahydrofurfuryl units discriminates between N-Boc-l-Ser (K_assoc=120 M^-1) and its non-natural d-enantiomer (270 M^-1). X-ray diffraction and computational analyses show that members of this receptor class adopt a cleft-like conformation, presenting a donor-spacer-donor-acceptor H-bonding array. Complexes of such biimidazoles with the -COOH unit of amino acids are stabilized by direct involvement of what is nominally a 'spacer' atom, unlike other D-Sp-D-A hosts.

Full text of DOI:10.1016/j.tet.2005.06.096

Tetrahedron 61 (2005) 8366–8371
Participation of host ‘spacer’ atoms in carboxylic acid binding:
implications for amino acid recognition
*
Daniel K. Barnhill, Andrew L. Sargent and William E. Allen
Department of Chemistry, East Carolina University, Greenville, NC 27858-4353, USA
Received 22 April 2005; revised 15 June 2005; accepted 27 June 2005
Available online 18 July 2005
Abstract—Chiral 4,40-diamido-2,20-biimidazoles were synthesized and found to bind N-Boc protected amino acids in CDCl3. The
biimidazole that features (R)-tetrahydrofurfuryl units discriminates between N-Boc-L-Ser (KassocZ120 MK1) and its non-natural
D-enantiomer (270 MK1). X-ray diffraction and computational analyses show that members of this receptor class adopt a cleft-like
conformation, presenting a donor-spacer-donor-acceptor H-bonding array. Complexes of such biimidazoles with the –COOH unit of amino
acids are stabilized by direct involvement of what is nominally a ‘spacer’ atom, unlike other D-Sp-D-A hosts.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
Comparing a new set of 2,20-biimidazoles to other cleft-
shaped hosts, we find that the spacer group can play an
active role in the recognition process. This result calls into
question the assumption that mode A is always operative,
and may have practical consequences for the design of
enantioselective sensors and chiral stationary phases.10
Biological recognition of amino acids is accomplished by
macromolecules with binding sites that are complementary
to their designated substrates. Each of the aminoacyl-tRNA
synthetases, for example, presents a unique array of
functional groups and hydrophobic surfaces to detect
differences in the structures of amino acid side chains.1
Selectivity arises from a combination of noncovalent
interactions like hydrogen bonding and van der Waals
contacts. Individually, such interactions are generally weak;
cumulatively, several such interactions can be relatively
strong. Complexes of synthetic hosts and amino acid guests2
can therefore be quite robust if stabilized by multiple
H-bonds, particularly in nonpolar solvents.3–5
In the design of artificial receptors for carboxylic acids, the
donor-spacer-donor-acceptor arrays present in 16 and 27
offer several advantages. Binding occurs according to mode
A, which places the most acidic proton of the guest close to
the H-bond Acceptor, while the lone pair electrons of the
carbonyl O are ‘saturated’ with hydrogen bonds from the
D-H units.8 Nitrogen or oxygen spacer atoms (Sp) help
maintain receptor rigidity via intramolecular D-H/Sp
interactions, but are not expected to directly bind to a
carboxylic acid guest. As part of a program to evaluate the
supramolecular chemistry of biheterocycles,9 the present
paper examines the factors that drive recognition between
the –COOH unit of amino acids and D-Sp-D-A receptors.
Keywords: Biimidazole; Amino acid recognition; Hydrogen bonding; DFT.
*
Corresponding author. Tel.: C1 2523289779; fax: C1 2523286210;
e-mail: allenwi@mail.ecu.edu
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.06.096

D. K. Barnhill et al. / Tetrahedron 61 (2005) 8366–8371
8367
Scheme 1.
2. Results and discussion
NMR titrations in CDCl3,15 for 3a and 3b with both
enantiomers of two different N-Boc amino acids. Downfield
chemical shifts in the amide NH protons of the receptors
occurred with increasing amino acid concentration, consist-
ent with H-bond donation to the guests. Control experiments
using an esterified amino acid (N-Boc-L-Phe-OMe) estab-
lished that guest binding takes place largely at the –COOH
group; although N-Boc-L-Phe is bound relatively strongly
by 3a (KassocZ100 MK1), N-Boc-L-Phe-OMe induced
Biimidazoles 3 were prepared by adapting previously
described procedures,9b as shown in Scheme 1. Molecular
diversity was provided by treating acid chloride 4 separately
with (S)-a-methylbenzylamine and (R)-tetrahydrofurfuryl-
amine; these arms were chosen for their potential to
participate in p interactions11 or H-bonds with aromatic
or polar amino acids, respectively. Products 3a and 3b were
judged to be enantiomerically pure by chiral HPLC
(CH3CN–H2O gradient, monitoring 295 nm) and by 1H
NMR (CDCl3, 500 MHz).
1
negligible shifts in the H resonances of the same receptor
(Kassocz0 MK1).
Table 1. Binding constants Kassoc (MK1 a
amino acid derivatives in CDCl3 at 23 8C
)
for chiral biimidazoles with
A solid-state structure was obtained for an achiral
diastereomer of 3a (Fig. 1).12 As observed in other
biimidazole diamides,9b meso-3a adopts an anti confor-
mation in which the imidazole rings are nearly coplanar.
Assuming that a planar orientation is retained in solution,
two essentially identical chiral clefts (with NH/
Complex
Kassoc
3a$N-Boc-L-Phe, -D-Phe
3a$N-Boc-L-Ser, -D-Ser
3b$N-Boc-L-Phe, -D-Phe
3b$N-Boc-L-Ser, -D-Ser
100, 65
!60, 65
65, 65
120, 270
˚
a Values represent averages of at least two replicate titrations, rounded to
HNz4.2 A) are available to bind carboxylic acid guests.
the nearest G5 MK1. Errors in individual fits were %15%.
Participation of the imidazole NH groups in guest binding
could not be established from the experiments described
above, because the heterocycle NH signals disappeared
upon addition of the amino acids in Table 1. However,
complexes of ‘half biimidazoles’ 5a and 5b were
significantly less robust than those formed from the
corresponding full receptors; Kassoc for 5a$N-Boc-L-Phe
and 3a$N-Boc-L-Phe in CDCl3 were 15 and 100 MK1
,
respectively, while 5b$N-Boc-D-Ser and 3b$N-Boc-D-Ser
had values of 80 and 270 MK1. That the imidazole NH
groups make a significant contribution, two possible amino
acid binding modes were examined with DFT compu-
tational methods.13,14 Using receptor 3b for illustration,
Figure 2a shows an interaction analogous to mode A
described above. Alternatively, the carboxylic acid proton
can interact with the imidazole nitrogen (Fig. 2b), an atom
which is several orders of magnitude more basic than the
ethereal oxygen. To highlight the direct involvement of so-
called spacer atoms in such complexes, we describe them as
occurring by mode S.
Figure 1. Structure of meso-3a$(CH3OH)2 in the crystal.
Computational modeling13,14 of several biimidazole con-
formations and tautomers reveals that the anti structure
observed in the crystal minimizes steric congestion while
maximizing intramolecular N–H/N hydrogen bonding.
Both the amide NH groups and the imidazole N and NH are
involved in this stabilizing intramolecular interaction. The
syn conformer, in its various tautomeric forms, disrupts the
network of intramolecular hydrogen bonding and replaces
these stabilizing interactions with steric clashes between
adjacent NH atoms, increasing the energy anywhere from
5.6 to 21.3 kcal/mol (see the Supplementary data).
Although all of the complexes listed in Table 1 are weak,
modest enantioselectivity was observed between 3b and the
N-Boc-serines. This result is difficult to rationalize within
the context of mode A, which places the stereogenic a
carbon of the amino acid far from the chiral arm of the
receptor. Both the relatively high Kassoc values and degree of
1
Table 1 shows the association constants, derived from H

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D. K. Barnhill et al. / Tetrahedron 61 (2005) 8366–8371
Figure 3. Comparison of acetic acid complexes derived from (a) 1, (b)
model receptor 1-pent, and (c) their ‘free floating’ donor–acceptor
fragments. As the DH/HD distance increases (from (a) to (c)), the O–
C]O unit of the guest becomes more nearly coplanar with the D-‘Sp’-D
atoms.
˚
tiny cleft in receptor 2 (calcd NH/HN !3 A) precludes
approach of acid guests in mode S.
Figure 2. Model complexes of 3b$N-Boc-L-Ser, optimized at the BOP/
DNP level of theory. (a) Mode A; (b) Mode S. Binding energies are given in
Table 2.
3. Conclusions
For receptors with D-Sp-D-A topology, binding of
carboxylic acids may occur at ‘spacer’ atoms with good
accessibility/basicity. If close contact between the stereo-
genic centers of a chiral receptor and chiral analyte is
desired (e.g., as a means to enantioselective recognition),
the binding pocket of the host should be carefully
engineered to control the preference for mode A or mode S.
stereodifferentiation are better explained if complexation
occurs predominantly by mode S,16 which allows a
tetrahydrofuranyl ring in 3b to accept a hydrogen bond
from the –CH2OH side chain. Computational studies of
serine complexes predict small enhancements (K2 to
K3 kcal/mol) in binding energies for 3b relative to 3a,
consistent with weak O–HSer/O3b interactions (Table 2).
4. Experimental
Unlike biimidazole 3b, the groups Sp and A in molecule 1
are electronically similar (i.e., both are nitrogen atoms from
substituted pyridines). As such, this host allows for more
direct assessment of the geometric factors that influence
guest binding, divorced from effects arising from differ-
ences in the basicities of the groups Sp and A. Gas phase
calculations indicate that N-Boc-L/D-Phe and N-Boc-L/D-Ser
prefer to associate with 1 via traditional mode A, with the
intrinsic helicity of the host giving rise to small energy
differences between complexes of enantiomers (Table 2).
However, calculations using acetic acid as a model guest
show that mode S can be competitive with mode A as the
binding cleft of the host becomes less concave. Parent 1
favors mode A over mode S by K5.9 kcal/mol, largely
because its ‘pinched’ binding pocket prevents host–guest
coplanarity in mode S (Fig. 3a). Removal of a bridging
methylene group yields the hypothetical 1-pent, which
features a greater NH/HN separation and a mode A bias of
just K2.7 kcal/mol (Fig. 3b). This analysis was extended to
determine the optimal placement of donor pyrroles and
spacer/acceptor pyridine, in the absence of a receptor
scaffold. In Figure 3c, the heterocycles were allowed to
move independently of each other, with the single constraint
that the three host nitrogen atoms and the carboxyl carbon of
the acid guest remain planar. Under these conditions, mode
S is favored by 0.7 kcal/mol. At the opposite extreme, the
4.1. (S)-5-Propyl-1H-imidazole-4-carboxylic acid
(1-phenylethyl)amide (5a)
Under N2, a stirring mixture of freshly prepared acid
chloride 49b (0.92 g, 5.3 mmol) and neat (S)-a-methyl-
benzylamine (4.2 mL, 33 mmol) was warmed with a heat
gun for 15 min. Upon cooling, the green-gold syrup was
dissolved in 100 mL of EtOAc, and the precipitated
hydrochloride salt was filtered off. The filtrate was
evaporated and purified by flash column chromatography
on silica gel using EtOAc as the eluent to afford 1.25 g
(92%) of the product as a viscous brown oil. TLC (EtOAc):
RfZ0.32; 1H NMR (CDCl3) d 0.95 (t, JZ7.2 Hz, 3H), 1.57
(d, JZ6.9 Hz, 3H), 1.64 (m, 2H), 3.01 (m, 2H), 5.25 (m, JZ
7.2 Hz, 1H), 7.20–7.38 (m, 6H), 7.45 (d, JZ7.2 Hz, 1H),
10.21 (br s, 1H); 13C NMR (CDCl3) d 13.7, 22.6, 26.9, 48.4,
126.0, 127.2, 128.6, 129.7, 132.5, 136.2, 143.8, 163.1; Anal.
Calcd for C15H19N3O$0.5(H2O): C 67.64, H 7.57, N 15.78.
Found: C 67.99, H 7.51, N 15.46.
4.2. (R)-5-Propyl-1H-imidazole-4-carboxylic acid (tetra-
hydrofuran-2-ylmethyl)amide (5b)
Under N2, a biphasic stirring mixture of acid chloride 49b
(1.55 g, 9.8 mmol), (R)-tetrahydrofurfurylamine (1.00 g,
Table 2. Calculated binding energies (kcal/mol) for complexes of amino acid derivatives
Complex
Mode A
Mode S
1$N-Boc-L-Phe, -D-Phe
1$N-Boc-L-Ser, -D-Ser
3a$N-Boc-L-Phe, -D-Phe
3a$N-Boc-L-Ser, -D-Ser
3b$N-Boc-L-Phe, -D-Phe
3b$N-Boc-L-Ser, -D-Ser
K8.2, K7.3
K9.1, K11.7
ND,a NDa
C0.1, K2.3
K5.3, K6.1
K7.1, K5.7
K7.8, K7.6
K7.3, K7.1
K9.5, K10.4
ND,a NDa
K4.5, ND
K4.6, ND
a The a-methylbenzyl groups of receptor 3a lack classical H-bond acceptor atoms like O or N. See Ref. 11. ND, not determined.

D. K. Barnhill et al. / Tetrahedron 61 (2005) 8366–8371
8369
9.9 mmol), and N,N-diisopropylethylamine (6.8 mL) was
4.6. meso-5,50-Dipropyl-1H,10H-[2,20]biimidazolyl-4,40-
dicarboxylic acid bis[(1-phenylethyl)amide] (meso-3a)
warmed with a heat gun for 10 min. Upon cooling, the top
layer was decanted away, and the bottom layer was treated
with 100 mL of EtOAc. The precipitated hydrochloride salt
was removed by filtration, and the filtrate was evaporated.
Flash column chromatography on silica gel using EtOAc–
MeOH (9:1, v:v) as the eluent provided 1.89 g (81%) of the
product as a yellow oil which solidified upon standing. Mp
The reactions described above (Scheme 1, 4/3) were
repeated using racemic a-methylbenzylamine instead of
(S)-a-methylbenzylamine. Product meso-3a was isolated as
a tan solid after flash column chromatography on silica gel
using CH2Cl2–EtOAc (2:1, v:v) as the eluent. TLC
(CH2Cl2–EtOAc, 2:1) RfZ0.43; 1H NMR (CD3OD) d
0.94 (t, JZ7.5 Hz, 6H), 1.55 (d, JZ7.0 Hz, 6H), 1.68 (m,
4H), 2.98 (m, 4H), 5.17 (m, JZ7.0 Hz, 2H), 7.23–7.40 (m,
12H); 13C NMR (CD3OD) d 14.0, 22.7, 24.0, 27.8, 127.1,
128.2, 129.6, 139.4, 145.2; Anal. Calcd for C30H36N6O2: C
70.29, H 7.08, N 16.39. Found: C 70.15, H 7.11, N 16.48.
1
98–100 8C; TLC (EtOAc–MeOH, 9:1) RfZ0.31; H NMR
(CDCl3) d 0.88 (t, JZ7.2 Hz, 3H), 1.64 (m, 3H), 1.85–2.05
(m, 3H), 2.98 (t, JZ7.2 Hz, 2H), 3.37 (m, 1H), 3.60 (m,
1H), 3.75 (q, JZ6.9 Hz, 1H), 3.88 (q, JZ6.3 Hz, 1H), 4.06
(m, 1H), 7.44 (s, 1H), 7.53 (t, 1H), 11.76 (br s, 1H); 13C
NMR (CDCl3) d 13.6, 22.6, 25.7, 26.9, 28.6, 42.5, 68.0,
77.8, 129.5, 133.0, 136.2, 164.2; Anal. Calcd for
C12H19N3O2: C 60.74, H 8.07, N 17.71. Found: C 60.58,
H 8.06, N 17.34.
4.7. (R,R)-5,50-Dipropyl-1H,10H-[2,20]biimidazolyl-4,40-
dicarboxylic acid bis[(tetrahydrofuran-2-ylmethyl)
amide] (3b)
4.3. (S)-2-Iodo-5-propyl-1H-imidazole-4-carboxylic acid
(1-phenylethyl)amide (6a)
Homocoupling of 6b (1.60 g, 4.4 mmol) using tetrakis-
(triphenylphosphine)palladium(0) (0.20 g, 0.17 mmol)
under conditions previously described9b afforded 0.47 g
(45%) of biimidazole 3b as a white crystalline solid after
flash column chromatography on silica gel using EtOAc–
MeOH (9:1, v:v) as the eluent. Mp O260 8C; TLC (EtOAc–
Reaction of 5a (1.02 g, 4.0 mmol) with N-iodosuccinimide
(95%; 1.10 g, 4.6 mmol) under conditions previously
described9b afforded 1.07 g (70%) of iodide 6a as a light
yellow oil after flash column chromatography on silica gel
1
1
MeOH, 9:1) RfZ0.54; H NMR (CDCl3) d 0.99 (t, JZ
using EtOAc as the eluent. TLC (EtOAc): RfZ0.61; H
7.5 Hz, 6H), 1.62 (m, 2H), 1.72 (m, JZ7.5 Hz, 4H), 1.92
(m, 4H), 2.01 (m, 2H), 3.07 (t, JZ7.5 Hz, 4H), 3.26 (m,
2H), 3.73 (m, 2H), 3.79 (q, JZ6.0 Hz, 2H), 3.88 (q, JZ
7.0 Hz, 2H), 4.08 (m, 2H), 7.40 (t, JZ7.0 Hz, 2H), 10.28 (br
s, 2H); 13C NMR (CDCl3) d 13.8, 22.6, 25.8, 27.0, 28.8,
42.6, 78.2, 130.9, 135.8, 137.3, 163.4; UV/vis (CH2Cl2):
lmax (3 MK1 cmK1)Z290 (29,000), 298 (31,000), 313
(18,000); Anal. Calcd for C24H36N6O4: C 61.00, H 7.68, N
17.78. Found: C 60.89, H 7.82, N 18.05.
NMR (CDCl3) d 0.79 (t, JZ7.5 Hz, 3H), 1.51 (m, 2H), 1.54
(d, JZ6.9 Hz, 3H), 2.85 (m, 2H), 5.21 (m, JZ7.2 Hz, 1H),
7.15–7.35 (m, 5H), 7.45 (d, JZ8.1 Hz, 1H), 11.62 (br s,
1H); 13C NMR (CDCl3) d 13.7, 22.4, 26.9, 48.5, 81.4, 126.0,
127.2, 128.5, 133.5, 141.4, 143.3, 162.0.
4.4. (R)-2-Iodo-5-propyl-1H-imidazole-4-carboxylic acid
(tetrahydrofuran-2-ylmethyl)amide (6b)
1
4.8. H NMR binding studies
Reaction of 5b (1.08 g, 4.6 mmol) with N-iodosuccinimide
(95%; 1.19 g, 5.0 mmol) under conditions previously
described9b afforded 1.60 g (97%) of iodide 6b as a faintly
yellow syrup. TLC (EtOAc): RfZ0.49; 1H NMR (CDCl3) d
0.92 (t, JZ7.5 Hz, 3H), 1.63 (m, 3H), 1.85–2.05 (m, 3H),
2.97 (t, JZ7.5 Hz, 2H), 3.35 (m, 1H), 3.59 (m, 1H), 3.79 (m,
1H), 3.91 (m, 1H), 4.12 (m, 1H), 7.37 (s, 1H), 8.68 (br s,
1H); 13C NMR (CDCl3) d 13.7, 22.6, 25.7, 26.9, 28.8, 42.7,
68.0, 77.9, 81.3, 133.6, 140.9, 162.7.
A sample of 3a or 3b was dissolved in 1.0 mL of CDCl3
such that its concentration was near 0.01 M, then the
solution was transferred to an NMR tube. Solid amino acid
was added to a concentration of approximately 0.005 M, the
tube was vigorously shaken, and a proton NMR spectrum
was acquired. Successive additions of amino acid were
made, and spectra recorded, until [amino acid] was at least
five times [biimidazole]. During several titrations with 3a,
aryl proton peaks obscured the amide NH resonances,
preventing their use in derivations of Kassoc. In these cases,
chemical shifts of the benzylic CH were followed instead.
Control experiments confirmed that using data for either the
amide NH or benzylic CH gave the same Kassoc values
within G5 MK1. Binding curves (i.e., plots of dNH/CH vs
[amino acid]) were fit using the program WinEQNMR.15
4.5. (S,S)-5,50-Dipropyl-1H,10H-[2,20]biimidazolyl-4,40-
dicarboxylic acid bis[(1-phenylethyl)amide] (3a)
Homocoupling of 6a (1.00 g, 2.6 mmol) using tetrakis-
(triphenylphosphine)palladium(0) (0.12 g, 0.10 mmol)
under conditions previously described9b afforded 0.36 g
(54%) of biimidazole 3a as a tan solid after flash column
chromatography on silica gel using CH2Cl2–EtOAc (2:1,
v:v) as the eluent. Mp 165 8C dec.; TLC (CH2Cl2–EtOAc,
2:1) RfZ0.36; 1H NMR (CDCl3) d 0.96 (t, JZ7.0 Hz, 6H),
1.58 (d, JZ6.5 Hz, 6H), 1.68 (m, JZ7.5 Hz, 4H), 3.04 (m,
4H), 5.27 (m, JZ7.5 Hz, 2H), 7.23–7.37 (m, 12H), 9.96 (br
s, 2H); 13C NMR (CDCl3) d 13.6, 22.1, 22.2, 26.9, 48.4,
125.9, 127.1, 128.5, 130.7, 135.7, 137.6, 143.2, 162.6; UV/
vis (CH2Cl2): lmax (3 MK1 cmK1)Z291 (32,000), 299
(33,000), 314 (19,000); Anal. Calcd for C30H36N6O2: C
70.29, H 7.08, N 16.39. Found: C 70.39, H 7.30, N 16.20.
1
During H NMR titration with N-Boc-L-Phe, the benzylic
CH nuclei of biimidazole 3a experienced a small upfield
shift (DdZK0.015 ppm) which was not observed with
any other amino acids in Table 1. This phenomenon
was examined using computational methods (see the
Supplementary data).
1H NMR titrations were also performed for 3a and 3b with
N-Boc-L/D-Pro, but a reliable association constant could

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D. K. Barnhill et al. / Tetrahedron 61 (2005) 8366–8371
Vaidehi, N.; Floriano, W. B.; Goddard, W. A., III J. Phys.
Chem. B 2003, 107, 11549–11557.
only be derived in one case (3a$N-Boc-D-Pro, Kassoc
Z
30 MK1). Binding curves for 3a$L-Pro and 3b$L/D-Pro were
not strictly hyperbolic, but instead featured an initial region
in which dNH moved upfield. Exclusion of these ‘inverted’
regions from the curve fits allowed for calculation of Kassoc
values, but with errors of O20%. The anomalous binding
curves may reflect the presence of competing equilibria
involving weakly self-associated biimidazole oligomers.9
2. Amino acid ‘binding’ via covalent bonds or metal ion
coordination: (a) Rusin, O.; St. Luce, N. N.; Agbaria, R. A.;
Escobedo, J. O.; Jiang, S.; Warner, I. M.; Dawan, F. B.; Lian,
K.; Strongin, R. M. J. Am. Chem. Soc. 2004, 126, 438–439.
(b) Feuster, E. K.; Glass, T. E. J. Am. Chem. Soc. 2003, 125,
¨
16174–16175. (c) Aıt-Haddou, H.; Wiskur, S. L.; Lynch, V.
1
A H NMR dilution experiment17 using 3b in CDCl3, in
M.; Anslyn, E. V. J. Am. Chem. Soc. 2001, 123, 11296–11297.
3. Binding of amino acids as N-protected carboxylates: (a) Kyne,
G. M.; Light, M. E.; Hursthouse, M. B.; de Mendoza, J.;
Kilburn, J. D. J. Chem. Soc., Perkin Trans. 1 2001, 1258–1263.
(b) Konishi, K.; Yahara, K.; Toshishige, H.; Aida, T.; Inoue, S.
J. Am. Chem. Soc. 1994, 116, 1337–1344.
which the chemical shift of the imidazole NH was
monitored as a function of [3b], gave KdimerZ25 MK1
.
4.9. Computational methods
Preliminary geometry optimizations were performed using
Gaussian 0318 with a restricted Hartree–Fock (RHF) wave
function and a 3-21G basis set.19 These structures were
subsequently refined using the density functional theory20
package DMol313 with the Becke–Tsuneda–Hirao gradient-
corrected exchange-correlation functional14 (BOP) and a
double numerical plus polarization (DNP) basis set.
4. Binding of amino acids as O-protected ammoniums: (a) Wong,
W.-L.; Huang, K.-H.; Teng, P.-F.; Lee, C.-S.; Kwong, H.-L.
Chem. Commun. 2004, 384–385. (b) Chen, X.; Du, D.-M.;
Hua, W.-T. Tetrahedron: Asymmetry 2003, 14, 999–1007.
5. Binding of uncharged amino acids: (a) Du, C.-P.; You, J.-S.;
Yu, X.-Q.; Liu, C.-L.; Lan, J.-B.; Xie, R.-G. Tetrahedron:
Asymmetry 2003, 14, 3651–3656. (b) Hayashida, O.; Sebo, L.;
Rebek, J., Jr. J. Org. Chem. 2002, 67, 8291–8298. (c) You,
J.-S.; Yu, X.-Q.; Zhang, G.-L.; Xiang, Q.-X.; Lan, J.-B.; Xie,
R.-G. Chem. Commun. 2001, 1816–1817. (d) Tye, H.; Eldred,
C.; Wills, M. J. Chem. Soc., Perkin Trans. 1 1998, 457–465.
(e) Kawabata, T.; Kuroda, A.; Nakata, E.; Takasu, K.; Fuji, K.
Tetrahedron Lett. 1996, 37, 4153–4156.
To avoid overwhelming the available computational
resources, truncated models of host–guest complexes
involving 3 were necessary and involved replacing the
chiral arm of the distal amide with a methyl group. Several
initial host–guest geometries, including those with secon-
dary H-bonding to the guest Boc group, were evaluated in
an effort to probe all relevant regions of the potential energy
surface, because algorithms for the systematic confor-
mational search of such complex systems were not
available.
6. (a) Chou, H.-C.; Hsu, C.-H.; Cheng, Y.-M.; Cheng, C.-C.; Liu,
H.-W.; Pu, S.-C.; Chou, P. T. J. Am. Chem. Soc. 2004, 126,
1650–1651. (b) Hegde, V.; Hung, C.-Y.; Madhukar, P.;
¨
Cunningham, R.; Hopfner, T.; Thummel, R. P. J. Am. Chem.
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Acknowledgements
´ ´ ´
7. (a) Perez, E. M.; Oliva, A. I.; Hernandez, J. V.; Simon, L.;
´
Moran, J. R.; Sanz, F. Tetrahedron Lett. 2001, 42, 5853–5856.
´
(b) Almaraz, M.; Raposo, C.; Martın, M.; Caballero, M. C.;
W.E.A. was a recipient of the Harriot College Research
Award for Spring 2004. The HPLC used in this work was
purchased using funds from the Research Corporation
(Grant #CC5510 to W.E.A.). X-ray crystallography was
performed by Dr. Peter S. White (UNC-Chapel Hill). The
authors thank Jesse V. Gavette and Ryan M. Phillips for
assistance with the synthesis. A.L.S. thanks the ECU Center
for Applied Computational Studies (CACS) for access to
computer resources.
´
Moran, J. R. J. Am. Chem. Soc. 1998, 120, 3516–3517.
8. Boiadjiev, S. E.; Watters, K.; Wolf, S.; Lai, B. N.; Welch, W.
H.; McDonagh, A. F.; Lightner, D. A. Biochemistry 2004, 43,
15617–15632.
9. (a) Sargent, A. L.; Hawkins, I. C.; Allen, W. E.; Liu, H.;
Sessler, J. L.; Fowler, C. J. Chem. Eur. J. 2003, 9, 3065–3072.
(b) Causey, C. P.; Allen, W. E. J. Org. Chem. 2002, 67,
5963–5968.
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Ueshige, T.; Tobe, Y. Chirality 2005, 17, 142–148. (b) Iuliano,
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Supplementary data
11. (a) Nishio, M. CrystEngComm 2004, 6, 130–158. (b) Meyer,
E. A.; Castellano, R. K.; Diederich, F. Angew. Chem. Int. Ed.
2003, 42, 1210–1250. (c) Steiner, T.; Koellner, G. J. Mol. Biol.
2001, 305, 535–557.
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tet.2005.06.
096
12. Achiral biimidazole meso-3a was derived from racemic
a-methylbenzylamine, and separated from chiral versions
thereof by flash column chromatography on silica gel, using
CH2Cl2–EtOAc (2:1, v:v) as the eluent (Rf: mesoZ0.43;
chiralZ0.36). Crystallographic data (excluding structure
factors) for the structure in this paper have been deposited
with the Cambridge Crystallographic Data Centre as sup-
plementary publication number CCDC 268683. Copies of the
data can be obtained, free of charge, on application to CCDC,
References and notes
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averaging all accessible complexes (and unbound host). Based
upon the calculated energies for 3b$N-Boc-L-Ser in modes A
and S, the contribution of the former to the observed
enantioselectivities is expected to be small.