Chiral recognition of α-phenylethylamine by sucrose-based macrocyclic receptors

Article abstract of DOI:10.1039/b816476b

Simple chiral aza-crown ethers based on sucrose display high enantioselectivity in complexation of phenylethylammonium chlorides. The Royal Society of Chemistry 2008.

Full text of DOI:10.1039/b816476b

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Chiral recognition of a-phenylethylamine by sucrose-based macrocyclic
receptorsw
Bartosz Lewandowski and Slawomir Jarosz*
Received (in Cambridge, UK) 19th September 2008, Accepted 7th October 2008
First published as an Advance Article on the web 4th November 2008
DOI: 10.1039/b816476b
Simple chiral aza-crown ethers based on sucrose display high
enantioselectivity in complexation of phenylethylammonium
chlorides.
analogs (at either terminal position: C10,C6,C60). Another
derivative: 10,2,3,30,4,40-hexa-O-benzylsucrose (2) was applied
to the preparation of the crown ether analogs by the coupling
of their C6 and C60 (Fig. 1).
The azacoronands 3 and 4 prepared in a few steps from 2
have shown interesting complexing properties. The stability
constants of these receptors towards the ammonium cation
(NMR titration of NH4SCN) were—as expected13—much
higher than the oxygen analogs; for example, the correspond-
ing data for 3 was assigned as 560 Mꢀ1, while for the crown 3a
Molecular recognition plays a crucial role in biological sys-
tems: receptors, antibodies or enzymes, all recognize their
specific reaction partners.1 Synthetic analogs of such receptors
are of great interest, since they may be used as enzyme models,
ligands for enantioselective reactions or applied for construc-
tion of synthetic biochemical sensors.
it was only 17 Mꢀ1 14
The receptor containing three nitrogen
.
Chiral crown ethers and their analogs are particularly
useful; they can be applied in enantioselective reactions2 (also
as stable complexes with mono- and poly-valent cations) and,
moreover, they are capable of differentiation of chiral guests.3
An especially interesting case represents enantioselective re-
cognition of chiral ammonium cations derived from amines or
amino acids. The pioneer works on this topic have been
carried out in the 1970s by Cram. He studied the chiral
recognition ability for binaphtol based chiral macrocycles
using the picrate salts extraction method.4 Stoddart deter-
mined the stability of complexes of D-mannitol based crowns
with ammonium cations using NMR spectroscopy.5 Since
then it has become one of the most popular methods of
studying host–guest interactions for numerous types of recep-
tors (apart from UV-Vis spectroscopy, photophysical and
electrochemical methods).6,7,8 It also led to the application
of several examples of crowns as chiral derivatizing agents for
NMR spectroscopy (by Wenzel, Joly and others).9,10 The main
area of application of chiral macrocycles, however, was as
chiral modification for HPLC columns, capillary electro-
phoresis and MS study of molecular recognition in the gaseous
phase. The study of enantiomeric recognition of protonated
amine derivatives is of high significance due to the presence of
such moieties in many biologically active molecules. From all
of the chiral scaffolds applied, sugars prove to be the most
promising, due to their availability and biocompatibility. Up
to date, only monosugars have found a widespread application
in the synthesis of crown ether analogs.11 The disaccharide
scaffold is much less pronounced.
atoms in the ring (3) has shown the highest Ka value, while the
Ka value for the receptor 4 (containing two nitrogen atoms)
was much lower than for 3 (see Table 1).
This may result either from a too large cavity of this
macrocycle or the presence of only two nitrogen atoms in
the ring. To find out the reasonable explanation we decided to
prepare the macrocycle with the same cavity as 4, but contain-
ing four nitrogen atoms in the ring. The synthesis of such
derivatives (compounds 7 and 8) is outlined in Scheme 1.
The partially protected sucrose 2 was converted into
the 6,60-diamine derivative 5 as described previously.14 Reac-
tion of this compound either with a proper ditosylate or
N,N0-dibenzyl-ethylenediamine, under the standard condi-
tions, afforded the corresponding macrocycles 7 and 8, respec-
tively (see ESI for experimental details).w
In the past several years we have been involved in the
transformation of sucrose into fine chemicals.12 We succeeded
in efficient preparation of 2,3,30,4,40-penta-O-benzylsucrose
(1) which was applied in the targeted synthesis of the sucrose
Institute of Organic Chemistry Polish Academy of Sciences,
Kasprzaka 44/52, 01-926 Warsaw, Poland. E-mail: sljar@icho.edu.pl;
Fax: +48 22 632 66 81; Tel: +48 22 343 23 22
w Electronic supplementary information (ESI) available: Experimental
details, titration curves and Job plot. See DOI: 10.1039/b816476b
Fig. 1 Synthesis of aza-crowns based on sucrose.
Chem. Commun., 2008, 6399–6401 | 6399
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Table 1 Stability constants for complexes of aza-crowns with
ammonium cation
Receptor
Ka (NH4SCN, acetone-d6)/Mꢀ1
3
4
7
8
560 ꢃ 36 (ref. 14)
230 ꢃ 18 (ref. 14)
112 ꢃ 18 (this work)
129 ꢃ 10 (this work)
Fig. 2 Enantioselective receptors for phenyethylammonium cations.
There are numerous examples of chiral receptors which
exhibit chiral recognition towards the cations derived from
phenylethylamine. Among them the mono-aza-benzo-15-
crown-5 derivative 9 investigated by Turgut15 displays the
highest enantioselectivity (the stability constants with the
enantiomers of phenylethylamine perchlorates are: KR
=
9.53 ꢂ 103, KS = 4.77 ꢂ 103, KR/KS = 2.00). Special attention
should also be paid to the tris-oxazoline receptor 10 studied by
Kim16 and the biphenantryl-18-crown-6 11 derivative synthe-
sised by Yamamoto17 (Fig. 2). Both of these compounds
displayed considerably stronger interaction with one enantio-
mer of phenylethylamine hydrochloride as it was demon-
strated by the liquid/liquid extraction experiments (the
respective ee values are 42% (R) and 45% (S)). To date there
is no precedent of higher enantioselectivity displayed towards
derivatives of phenylethylamine.
Scheme 1 Synthesis of aza-crowns 7 and 8. Conditions: a. 5,
TsOCH2CH2N(Ts)CH2CH2N(Ts)CH2CH2OTs, Na2CO3, MeCN; b.
6, BnN(H)CH2CH2N(H)Bn, Na2CO3, MeCN.
These newly prepared aza-crowns were tested for their
complexing ability towards simple ammonium cations and
the results are collected in Table 1. The association constant
for receptor 7 was significantly low, even lower than for
macrocycle 4 (with only two N-atoms), which might be
associated with the presence of two electron withdrawing
(tosyl) groups placed on both ring-nitrogen atoms. Receptor
8, where all of the nitrogen atoms are protected with benzyl
groups, exhibited slightly stronger interaction with the ammo-
nium cation than 7 but again much weaker than the previously
tested macrocycles. This is presumably connected with the
bigger size of the cavity of these receptors which makes the
larger macrocycle less rigid, and consequently formation of
the complex requires a much higher loss of free energy. The
stability constants of the complexes of crowns 4, 7 and 8 with
the ammonium cation are, therefore, significantly lower than
analogous data found for 3. Thus, the presence of additional
nitrogen atoms in the macrocyclic ring does not play a
significant role in the binding.
The results of the complexation study performed by us on
sucrose-based aza-crowns 3, 4, 7, and 8 are presented in
Table 2. Macrocycle 7 did not show any affinity either to
(S)- or (R)-a-phenyl-ethylamine.
As proven by our NMR titration experiments, the remain-
ing three receptors all showed the preferential complexation of
the (S)-amine. The highest value (Ka = 1244 Mꢀ1) was noted
for the complex of compound 3 (the association constant was
determined by NMR titration methodology18 in deuterated
chloroform). The stability constant of the complex of 3 with
the (R)-amine was significantly lower (Ka = 837 Mꢀ1), which
assigned the value KS/KR at 1.84.
Both remaining receptors: 4 and 8 have remarkably inter-
esting complexing abilities. Although the stability constants
with the (S)-amine were significantly lower than for 3 (Ka4
=
945 Mꢀ1, Ka8 = 264 Mꢀ1) these macrocycles did not complex
the (R)-enantiomer of a-phenylethylamine (see Table 2). We
did not observe any shift of the signals of sucrose backbone
during titration of the guest into the solution.
Chiral receptors are especially designed for the enantio-
selective recognition of chiral guests. Having known that the
sucrose based macrocycles do complex the ammonium cation
we turned our attention to the problem of discrimination of
chiral amines. Both enantiomers of a-phenylethylamine (as
hydrochloride salts) were selected for this study.
The reason for the decreased value of the association
constant for compound 8 in comparison to 4 is probably the
presence of two additional benzyl groups on the nitrogen
atoms which results in a larger steric hindrance preventing
the interaction with the guest cation. Compound 7 showed
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Table 2 Stability constants for complexes of aza-crowns with phenyl-
ethylammonium cation
This work was financed by the Grant No PBZ-KBN-126/
T09/07 from the Ministry of Science and Higher Education.
Receptor
Ka (S(ꢀ), CDCl3)/Mꢀ1
1244 ꢃ 192
Ka (R(+), CDCl3)/Mꢀ1
References
3
4
7
8
837 ꢃ 104
a
1 Receptors antibodies etc.: L. Kovbasyuk and R. Kramer, Chem.
¨
Rev., 2004, 104, 3161–3187; R. Jelinek and S. Kolusheva, Chem.
Rev., 2004, 104, 5987–6015.
945 ꢃ 221
a
a
a
264 ꢃ 36
No signal shift observed in the NMR during titration.
2 Selected examples: K. Hori, et al., Tetrahedron Lett., 2006, 47,
3115–3118; S. Kobayashi and S. Nagayama, J. Am. Chem. Soc.,
2000, 122, 11531–11532; D. J. Cram and G. D. Y. Sogar, J. Chem.
Soc., Chem. Commun., 1981, 626–628; N. G. Lukyanenko,
A. V. Lobach and O. N. Leus, Russ. J. Org. Chem., 2003, 39,
1042–1047; B. L. Allwood, H. Shahriari-Zavareh, J. F. Stoddart
and D. J. Williams, J. Chem. Soc., Chem. Commun., 1984,
1461–1464; J. Brussee, et al., Tetrahedron: Asymmetry, 1995, 6,
1123–1132; L. Toke, et al., Tetrahedron: Asymmetry, 1999, 10,
4539–4551; S. Kobayashi, et al., J. Am. Chem. Soc., 2003, 125,
2989–2996.
a
3 Review: X. X. Zhang, J. S. Bradshaw and R. M. Izatt, Chem. Rev.,
1997, 97, 3313–3361; selected examples: D. J. Cram, et al., J. Am.
Chem. Soc., 1978, 100, 4555–4568; A. E. Lovely and T. J. Wenzel,
Org. Lett., 2006, 8, 2823–2836; A. V. Lobach, O. N. Leus,
N. Y. Titova and N. G. Lukyanenko, Russ. J. Org. Chem., 2003,
39, 1037–1041; Y. Turgut, N. Demirel and H. Hosgoren, J. Incl.
Phenom. Macrocycl. Chem., 2006, 54, 29–33; Y. Turgut, E. Sahin,
M. Togrul and H. Hosgoren, Tetrahedron: Asymmetry, 2004, 15,
1583–1588; J. S. Bradshaw, et al., J. Org. Chem., 1999, 55,
3129–3137; Y. Li and L. Echegoyen, J. Org. Chem., 1994, 59,
6539–6542.
Fig. 3 Titration curve for macrocycle 4 and S(ꢀ)-phenylethylammonium
chloride. The shift of the signal of the anomeric proton of sucrose was
followed during the experiment, (for other titration curves see ESI).w
4 D. J. Cram, et al., J. Am. Chem. Soc., 1978, 100, 4555–4678.
5 W. D. Curtis, D. A. Laidler and J. F. Stoddart, J. Chem. Soc.,
Perkin Trans. 1, 1977, 1756–1769.
6 W. Bussmann, J. M. Lehn, U. Oesch, P. Plumere and W. Simon,
Helv. Chim. Acta, 1981, 64, 657–661.
7 W. A. Nugent and R. L. J. Harlow, J. Am. Chem. Soc., 1980, 102,
1760–1762.
8 J. Huskens, M. A. Deij and D. N. Reinhoudt, Angew. Chem., Int.
Ed., 2002, 4467–4471.
9 T. J. Wenzel and J. E. Thurston, J. Org. Chem., 2000, 65,
1243–1248.
10 T. J. Wenzel, J. E. Thurston, D. C. Sek and J.-P. Joly, Tetrahedron:
Asymmetry, 2001, 12, 1125–1130.
11 Review on the synthesis and complexing properties of such crown
ethers: S. Jarosz and A. Listkowski, Curr. Org. Chem., 2006, 10,
643–662.
12 S. Jarosz and M. Mach, Eur. J. Org. Chem., 2002, 769–780;
Y. Queneau, S. Jarosz, B. Lewandowski and J. Fitremann, Adv.
Carbohydr. Chem. Biochem., 2007, 61, 217–300.
13 J. M. Lehn and P. Vierling, Tetrahedron Lett., 1980, 21, 1323.
14 S. Jarosz and B. Lewandowski, Carbohydr. Res., 2008, 343,
965–969.
very weak interaction with both enantiomers of the chiral salt,
again presumably due to the electron withdrawing influence of
the tosylate groups attached to the nitrogen atoms.
The association constants could be determined using the
method described by Fielding only with the assumption that
the receptors and the chiral salts form 1 : 1 host–guest
complexes. To confirm this stoichiometry a Job plot was
recorded for the interaction between host 4 and S(ꢀ)-phenyl-
ethylammonium chloride (see ESI for details).w It confirmed
the assumed 1 : 1 interaction although the different shapes of
the curve’s slopes suggest that there are two separate binding
modes responsible for the interaction.
A convenient route to the sucrose-based azacoronads was
proposed. The stability constants of the complexes of these
receptors with a-phenylethylamine were rather moderate
(highest value Ka = 1244 Mꢀ1), however, we have noted that
these macrocycles show remarkably high affinity towards the
(S)-a-phenylethylamine, Fig. 3.
15 Y. Turgut, et al., Tetrahedron: Asymmetry, 2004, 14, 1583–1588.
16 S. Kim, et al., J. Am. Chem. Soc., 2002, 124, 591–596.
17 K. Yamamoto, et al., J. Chem. Soc., Chem. Commun., 1984,
1111–1113.
18 L. Fielding, Tetrahedron, 2000, 56, 6151–6170.
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