trans-Benzoxanthene receptors for enantioselective recognition of amino acid derivatives

Article abstract of DOI:10.1016/S0040-4039(01)01100-5

Neutral cleft-type hydrogen-bonding receptors based on a trans-benzoxanthene skeleton have shown good stereoselective association towards carbamate derivatives of amino acids. Among these, the best results corresponded to the commercially available benzyloxycarbamate (Cbz) while the t-butyloxycarbamate (Boc) protecting group afforded disappointing results. Preparative TLC impregnated in ethoxycarbonyl proline provided a rapid way to resolve the receptor racemic mixture. X-Ray analysis and Overhauser effects allow us to suggest a structure for these complexes and the reasons for the observed chiral discrimination.

Full text of DOI:10.1016/S0040-4039(01)01100-5

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 5853–5856
trans-Benzoxanthene receptors for enantioselective recognition of
amino acid derivatives
Emilio M. Pe´rez, Ana I. Oliva, Jose´ V. Herna´ndez, Luis Simo´n, Joaqu´ın R. Mora´na,* and
Francisca Sanzb
aDepartamento de Qu´ımica Orga´nica, Plaza de los Caidos 1-5, Universidad de Salamanca, E-37008 Salamanca, Spain
bServicio de Difraccio´n de Rayos X, Universidad de Salamanca, E-37008 Salamanca, Spain
Received 22 May 2001; revised 20 June 2001; accepted 21 June 2001
Abstract—Neutral cleft-type hydrogen-bonding receptors based on a trans-benzoxanthene skeleton have shown good stereoselec-
tive association towards carbamate derivatives of amino acids. Among these, the best results corresponded to the commercially
available benzyloxycarbamate (Cbz) while the t-butyloxycarbamate (Boc) protecting group afforded disappointing results.
Preparative TLC impregnated in ethoxycarbonyl proline provided a rapid way to resolve the receptor racemic mixture. X-Ray
analysis and Overhauser effects allow us to suggest a structure for these complexes and the reasons for the observed chiral
discrimination. © 2001 Elsevier Science Ltd. All rights reserved.
Stereoselective receptors1 for a-amino acids or peptides
could have many possible applications due to the tech-
nical and biological importance of these molecules.2
tion constants were obtained by standard NMR
titrations6 in CDCl3 using the racemic mixture of recep-
tor 1 and two different guests: naphthalene-1-carboxylic
acid (Kass=6×103 M−1) and ethoxycarbonylglycine
(Kass=5.4×104 M−1). The presence of the t-butyl groups
in the receptor provide an easy way to follow these
titrations even under high dilution conditions.
Chromenone-benzoxazole receptors are very suitable
for carboxylic acid association.3 However, the
chromenone skeleton lacks chiral centers and hence has
little attraction for the design of enantioselective recep-
tors. This problem can be solved by the use of a new
base molecule, trans-benzoxanthene, which already
includes chirality. The trans-benzoxanthene skeleton is
easily obtained and functionalized as shown in Scheme
1.
These high association constants permitted the crystal-
lization of the complex between receptor 1 and several
carboxylic acids. Slow evaporation of a solution of
receptor 1 and propionic acid in THF yielded crystals
suitable for X-ray analysis. The crystalline structure of
the complex is shown in Fig. 1.
Oxidative cyclization5 affords a mixture of the trans-
and cis-benzoxanthenes; however, only the more rigid
trans compound crystallizes. As one of our major pur-
poses was to prove that the hydroxyl group in C-6
could settle a second H-bond with the carbonyl oxygen
of the carboxylic acid, we decided to carry on with the
trans isomer only.
X-Ray analysis shows that receptor 1 is capable of
establishing three hydrogen bonds with carboxylic
acids. The secondary alcohol in C-6 and the NH group
in C-4 bind the carbonyl oxygen of the carboxylic acid,
while the basic nitrogen in the benzoxazole forms a
strong hydrogen bond with the hydroxyl group of
propionic acid. It should be noted that receptor 1 is
already a chiral receptor, as the ethoxycarbonyl located
on C-5a makes both faces of the trans-benzoxanthene
different. Receptor 1 already shows a chiral cleft; how-
ever, it associates amino acid derivatives with low enan-
Receptor 1 does not associate amino acids as zwitteri-
ons, probably due to their lack of solubility in apolar
solvents, but it readily associates carboxylic acids and
amino acid derivatives in chloroform solution. Associa-
tioselectivities
or
in
most
cases
with
no
enantioselectivity at all. To increase discrimination, we
attempted to establish a further interaction with the
substituents on the amino acid a-carbon in order to
prevent its free rotation. Molecular models show that
Keywords: trans-benxoxanthene; hydrogen-bonding receptors; chiral
recognition; amino acid derivatives.
* Corresponding author.
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01100-5

5854
E. M. Pe´rez et al. / Tetrahedron Letters 42 (2001) 5853–5856
COOEt
COOEt
O
O
6
O
5
O
4
7
O
3
ONa
COOEt
b
8
5a
11a
Cl
9
a
Cl
2
Cl
12
Cl
11
10
1
benzoxanthene
3:2
cis:trans
c, d, e, f, g
t-Bu
O
H
R
t-Bu
t-Bu
H
O
O
N
N
COOEt
O
H
COOEt
O
O
NH
t-Bu
h, i
O
N
O
Cl
Cl
H
H
receptor 1
Scheme 1. Preparation of the benzoxanthene base molecule, receptor 14, and its complex with a carboxylic acid. Numbering of
the benzoxanthene has been included for clarity. (a) Diglyme, T=80°C, yield 70%; (b) Mn(OAc)3·4H2O, AcOH/Ac2O, T=90°C,
yield 75%; (c) HNO3/H2SO4, Ac2O, T=−10°C, yield 83%; (d) SnCl2, rt, yield 69%; (e) thiophosgene, Na2CO3, CH2Cl2/H2O, rt,
yield 90%; (f) 2-amino-4,6-di-tert-butylphenol, toluene, T=50°C, yield 80%; (g) MeI, 2,4,6-trimethylpyridine, EtOH/THF, rt, yield
85%; (h) NaBH4, MeOH, rt, yield 96%; (i) carboxylic acid.
The most interesting aspects in Table 1 are the impor-
tant effects of the N-protecting group and the amino
acid side chain. In both cases, steric hindrance can be
invoked to explain why recognition is poor if these
groups are bulky. t-Butyloxy carbonyl protecting
groups probably collide with the triflate fluorine atoms,
while the isopropyl group in valine cannot be placed
close to the receptor in the conformation in which the
fourth H-bond is set.
The best results are obtained with proline derivatives;
apparently, the rigidity of the five member ring pro-
vides the best preorganization for a good fit in the
strong complex.
The good results with the previous guest suggested that
it might be possible to make use of its supramolecular
Figure 1. X-Ray structure4 of receptor 1 complex with propi-
onic acid.
properties to resolve the host 2 racemic mixture. Usu-
ally, these kind of strong complexes appear to be more
apolar species than weak ones, as a result of their lack
of suitable sites for interaction with SiO2. In strong
complexes, the hydrogen bonds are closed between the
host and the guest and they cannot interact strongly
with the SiO2 of the stationary phase. Therefore these
aggregates show low polarity and are easily eluted. If
the complex is weak, SiO2 competes by breaking the
associate and fixing the receptor to its surface through
many H-bonds. Therefore, large Rf differences are
expected in chromatography for both enantiomeric
receptors if an optically suitable host is present. Prepar-
ative SiO2 TLCs impregnated in a 3% chloroform solu-
this kind of interaction could occur in the complex
between receptor 2 and amino acid ethoxycarbonyl
derivatives. In these associates we expect a further
H-bond to be set up from the receptor NH triflate to
the carbonyl of the protecting group of the amino acid.
Preparation of receptor 2 from receptor 1 is straightfor-
ward (Scheme 2). Aminolysis of the ethoxycarbonyl
group can be achieved with m-phenylenediamine
lithium salt, and the new compound is triflated with
trifluoromethanesulfonic anhydride in the absence of an
added base since the benzoxazole group of the receptor
is already suitable for this purpose.
tion of L-ethoxycarbonyl-proline provided an easy way
to achieve the separation of enantiomeric receptors,
since upon elution with chloroform they show two
spots corresponding to diastereomeric complexes of
different stability. Each host is recovered from the SiO2
as the corresponding proline complex. Washing an
ethylacetate solution of the complex with aqueous
sodium carbonate provides the pure receptors.8
By means of competitive experiments7 in CDCl3 it was
clear that receptor 2 showed promising results, discrim-
inating between amino acid enantiomers (Table 1).

E. M. Pe´rez et al. / Tetrahedron Letters 42 (2001) 5853–5856
5855
OEt
CF3
O
S
H
H
O
N
H
N
CH3
O
H
O
H
H
t-Bu
t-Bu
H
N
O
a, b
c
N
HN
Receptor 1
O
O
4% nOe
O
O
Cl
H
receptor 2
Scheme 2. Preparation of receptor 2 and its complex with ethoxycarbonyl alanine. (a) Benzene-1,3-diamine, BuLi, THF,
T=−30°C, yield 74%; (b) trifluoromethanesulfonic anhydride, toluene, T=−78°C, yield 63%; (c) N-ethoxycarbonylalanine.
Table 1. Enantioselective discrimination of receptor 2
Guest Krel
2.7
ROESY experiments support the geometry shown in
Scheme 2 for the strong complex between receptor 2
and ethoxycarbonylalanine. The Overhauser effect
found between the amino acid a hydrogen and the
m-phenylene diamine H-2 fixed the geometry of the
complex. This proximity also explains the discrimina-
tion between the enantiomers, since exchanging the
amino acid a hydrogen for the methyl group results in
steric hindrance and therefore a weakening of the
complex.
a
Boc-
Ethoxycarbonyl-
Cbz- -leucine
L-leucine
L
-leucine
7.4
7.7
L
Ethoxycarbonyl-
Ethoxycarbonyl-
L
L
-proline
-alanine
14.0
8.5
Cbz-
Ethoxycarbonyl-
L
-phenylalanine
-valine
4.5
1.0
L
a Krel refers to relative association constants between the guest and
the two enantiomers of receptor 2.
Acknowledgements
Once the optically pure receptors had been purified it
was possible to measure the absolute association con-
stants with conventional titration. Our first experiments
suggested that the complexes were very stable in chloro-
form solution and that errors would be very large for
the higher association constants. We therefore mea-
sured the smallest association constants and deduced
the larger ones from competitive experiments. The
results can be seen in Table 2.
We thank Anna Lithgow for the 400 MHz NMR
spectra, Ce´sar Raposo for the mass spectra and the
‘Direccio´n General de Investigacio´n Cient´ıfica y Te´c-
nica’ (DGICYT Grant PB 98-0275) for the financial
support of this work. A.I.O. and L.M.S. acknowledge
their predoctoral fellowships from the Spanish MEC.
References
The results in Table 2 again show the importance of
steric hindrance in complex stability, both in the amino
acid side chain and in the N-substituent. Alanine show
the strongest associates.
1. (a) Hartley, J. H.; James, T. D.; Ward, C. J. J. Chem. Soc.,
Perkin Trans.
1 2000, 3155–3184; (b) Dowden, J.;
Edwards, P. D.; Flack, S. S.; Kilburn, J. D. Chem. Eur. J.
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2. Dugas, H.; Penney, C. Bioorganic Chemistry; Springer:
New York, 1981; pp. 13–19.
Table 2. Association constants for receptor 2 and several
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Mora´n, J. R. J. Am. Chem. Soc. 1998, 120, 3516–3517.
4. Selected physical data for receptor 1: FABMS: 57 (M+),
a
amino acid derivatives measured in CDCl3
Guest
Kass (+)receptor 2 Kass (−)receptor 2
(M−1 (M−1
1
100%; 603, 50%; 605, 20%; 385, 15%; 483, 10%; H NMR
)
)
(400 MHz, CDCl3): l 8.22 (d, J=2 Hz, 1H), 7.65 (d, J=8
Hz, 1H), 7.41 (s, 1H), 7.29–7.21 (m, 2H), 7.14–7.11 (m,
2H), 6.70 (d, J=2 Hz, 1H), 5.09 (s, 1H), 4.07 (dd, J=8
Hz, 2H), 3.20–2.95 (m, 2H), 2.86 (d, J=8 Hz), 2.70–2.52
(m, 2H), 1.49 (s, 9H), 1.38 (s, 9H), 1.00 (t, J=8 Hz, 3H);
mp 136–138°C.
Ethoxycarbonyl-
Ethoxycarbonyl-
Ethoxycarbonyl-
L
L
L
-leucine 1.0×105
-proline 1.1×105
-alanine 2.3×105
2.4×105
7.4×105
1.5×106
1.9×106
1.8×106
1.9×105
Cbz-L
-Leucine
Boc-L
-Leucine
7.2×104
Crystal data for receptor 1: C38H45ClN2O7, M=677.21,
orthorhombic, space group Pbca (no. 61), a=11.987(2),
a These constants were calculated with an uncertainty of 20%.

5856
E. M. Pe´rez et al. / Tetrahedron Letters 42 (2001) 5853–5856
3
,
,
b=20.410(4), c=29.438(6) A, V=7202.6(25) A , Z=8,
Dc=1.249 Mg/m3, v(Cu Ka)=0.157, F(000)=2880; data
(3388 collected reflections and 3374 unique reflections [I>
2|(I)]) were measured on a Seifert 3003 SC rotating-anode
diffractometer with Cu Ka radiation (graphite monochro-
mator) using 2q–ꢀ scans at 268 K. Crystallographic data
for the structure reported in this paper has been deposited
at the Cambridge Crystallographic Data Center as supple-
mentary material no. CCDC 163614.
changes in the chemical shifts of the host were analyzed
using a Monte Carlo non-linear curve-fitting program.
7. Whitlock, B. J.; Whitlock, H. W. J. Am. Chem. Soc. 1990,
112, 3910–3917.
8. Selected physical data for receptor 2: FABMS: 154 (M+),
1
100%; 797, 25%; 513, 10%; 386, 5%; H NMR (400 MHz,
CDCl3): l 8.03 (s, 1H), 7.44 (d, J=5.2 Hz, 1H), 7.25 (s,
1H), 7.10–7.08 (m, 2H), 7.01–6.99 (m, 2H), 6.94 (d, J=2
Hz, 1H), 6.84 (t, J=8 Hz, 1H), 6.76 (d, J=8 Hz, 1H), 6.64
(d, J=2 Hz, 1H), 6.52 (d, J=8 Hz, 1H), 4.91 (s, 1H), 3.20
(m, 1H), 3.00 (m, 1H), 2.66 (m, 2H), 2.40 (m, 1H), 1.39 (s,
9H), 1.28 (s, 9H); mp 275–277°C; [h]2D0=−129 (c=0.10%
CHCl3); [h]2D0=+132 (c 0.12, CHCl3).
5. Snider, B. B. Chem. Rev. 1996, 96, 339–363.
6. 1H NMR (200 MHz) titrations were carried out in CDCl3
solutions at a constant 10−4 M host concentration to which
a guest was added until saturation was reached. The
.