Synthesis of chiral monoaza-15-crown-5 ethers from L-valinol and the enantiomeric recognition of chiral amines and their perchlorates salts

Article abstract of DOI:10.1016/j.tetasy.2003.09.037

A practical synthesis of chiral monoaza-15-crown-5 ethers 1 and 2 has been achieved from L-valinol. The molecular recognition by these chiral crown ethers for (RS)-α-phenylethylamine, (RS)-α-(1-naphthyl)ethylamine and their perchlorate salts has been characterized by UV-vis.

Full text of DOI:10.1016/j.tetasy.2003.09.037

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 14 (2003) 3815–3818
Synthesis of chiral monoaza-15-crown-5 ethers from -valinol
L
and the enantiomeric recognition of chiral amines and their
perchlorates salts
Y. Turgut and H. Hos¸go¨ren*
University of Dicle, Faculty of Science, Department of Chemistry, 21280 Diyarbakır, Turkey
Received 8 August 2003; accepted 18 September 2003
Abstract—A practical synthesis of chiral monoaza-15-crown-5 ethers 1 and 2 has been achieved from L-valinol. The molecular
recognition by these chiral crown ethers for (RS)-a-phenylethylamine, (RS)-a-(1-naphthyl)ethylamine and their perchlorate salts
has been characterized by UV–vis.
© 2003 Elsevier Ltd. All rights reserved.
1. Introduction
sium and sodium salts and ammonium perchlorate salt4
by NMR, UV–vis, extraction and transport experi-
ments.5–7 Here, we report a practical synthesis of chiral
amino alcohol precursors, two chiral monoaza crown
ethers, their enantiomeric recognition, the binding con-
stants (Ka) and free-energy chances (−DG°) for the
enantiomers of (RS)-phenylethylamine, (RS)-a-(1-
naphthyl)ethylamine and their perchlorate salts deter-
mined by UV–vis titration method in CHCI3.
The design, synthesis, and use of macrocycles capable
of selective recognition of other molecules is of great
interest in a variety of fields. Various types natural and
synthetic chiral compounds have been used as chiral
subunits for constructing optically active crown ethers,
and continuing development of chiral building blocks
has resulted in the production of a wide variety of
optically active crown ethers exhibiting characteristic
chiral recognition behavior.1 Cram et al. first described
in 1973 the syntheses and characterization of a number
of chiral crown ethers capable of enantiomeric recogni-
tion towards primary ammonium salts.2,3 Since then,
the study of enantiomeric recognition by crown ethers
and other molecules blossomed.
2. Results and discussion
2.1. Synthesis
The synthesis of
from -valine according to procedures described in the
literature.8 The conversion of
-valinol to N-benzyl
amino alcohol derivatives was carried out by our previ-
L-valinol was accomplished in one step
L
There has been continuing interest in the molecular
recognition of amino acids esters, amino acids potas-
L
Scheme 1. Reagents and conditions: (i) NaBH4–I2, THF; (ii) PhCH2CI, Na2CO3, 110°C, (iii) ethylene oxide, MeOH, −20°C.
* Corresponding author. E-mail: hosgoren@dicle.edu.tr
0957-4166/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2003.09.037

3816
Y. Turgut, H. Hos¸go¨ren / Tetrahedron: Asymmetry 14 (2003) 3815–3818
Scheme 2. Reagents and conditions: NaH, THF, reflux, 50 h.
ous method.9 The conversion of 3 to 4 was carried out
at −20°C, as shown in Scheme 1. Chiral macrocycles 1
and 2 were prepared in the 47, 33% yields, respectively,
as shown in Scheme 2. Tosylates 5 and 6 were prepared
according to the reported procedure.9,10 Crown ether 1
was obtained as white solid (mp 81–82°C) and crown 2
was isolated as a yellow oil. The structures proposed
for these new chiral macrocycles and amino alcohols
1
are consistent with data obtained from H, 13C NMR,
IR spectra and elemental analyses.
2.2. UV–vis
Figure 1. UV–vis spectra of 1 (1.4×10−4 mol dm−3) in the
presence of (R)-NapEtHCIO4 (5.0×10−5–1.1×10−3 mol dm−3).
UV–vis spectroscopy is a convenient and widely used
method for the study of binding phenomena. When the
receptor (or substrate) absorbs light at different wave-
lengths in free and complexed states, the differences in
ultraviolet spectrophotometry may suffice for estima-
tion of molecular recognition. In the UV spectroscopic
titration experiments, addition of varying concentra-
tions of guests molecules resulted in gradual increase or
decrease of characteristic absorptions of the host
molecules. The typical UV spectral changes upon the
addition of (R)-NapEtHCIO4 to 1 are shown in Figure
1.
It should be equally true that the variation of guest
structure will also affect the extent of enantiomeric
recognition displayed by a given ligand and stability of
the complex formed between the guest and the given
ligand.
The association constant of supramolecular system
formed were calculated according to the modified Ben-
esi–Hildebrand equation, Eq. (1),11 where [H]o and [G]o
refer to the total concentration of crown ether and free
chiral amine or their perchlorate salt, respectively, Dm is
the change in molar extinction coefficient between the
free and complexed crown ether and DA denotes the
absorption changes of crown ether on addition of free
amine or perchlorate salts (Scheme 3).
Figure 2. Typical plot of [H]o[G]o/DA versus [G]o for the
host–guest complexation of 1 and (R)-PhEtHCIO4 in CHCI3.
[H]o[G]o/DA=1/KaDm+[G]o/Dm
(1)
The data in Table 1 show that important differences
were not observed in the Ka values for 1 in the enan-
tiomeric recognition of (R)-PhEt and (S)-PhEt. On the
other hand, the Ka values for its perchlorate salt were
found to be significantly different. It can be concluded
that 1 has a greater recognition ability against (R)-
PhEtHCIO4, also in the case of (R)- and (S)-
The binding constants (Ka) and free-energy changes
(−DG°) of these hosts with guest molecules obtained
from usual curve fitting analyses (R>0.9651) of
observed Ka values and −DG° changes are summarized
in Table 1. Typical plots are shown for the complexa-
tion of 1 with (R)-PhEtHCIO4 in Figure 2.

Y. Turgut, H. Hos¸go¨ren / Tetrahedron: Asymmetry 14 (2003) 3815–3818
3817
Scheme 3. Chiral amine and their perchlorate salts.
Table 1. Binding constants (Ka) and free energy of com-
plexation (−DGo) for 1:1 complexes between 1, 2 and chi-
ral amines and their perchlorate salts
cified.
L
-Valine was purchased from Fluka chemical
company. Silica gel 60 (Merck, 0.040–0.063 mm) and
silica gel/TLC- cards (F254) were used for flash column
chromatography and TLC. Melting points were deter-
mined with a Gallenkamp Model apparatus with open
Host
Guest
Ka (dm3 mol−1
)
−DG° (kJ mol−1
)
capillaries. Infrared Spectra were recorded on
a
1
(R)-PhEt
(S)-PhEt
(R)-PhEtHCIO4
(S)-PhEtHCIO4
(R)-NapEt
(6.5 0.022)×103
(7.0 0.042)×103
(1.2 0.050)×104
(6.6 0.043)×103
(1.0 0.038)×103
(5.0 0.065)×103
5.29×103
5.33×103
5.65×103
5.30×103
4.16×103
5.13×103
6.21×103
6.27×103
Mattson 1000 FTIR model spectrometer. Elemental
analyses were performed with a Carlo-Erba 1108 model
apparatus. Optical rotations were taken on a Perkin–
1
Elmer 341 model polarimeter. H (400 MHz) and 13C
(S)-NapEt
(100 MHz) NMR spectra were recorded on a Bruker
DPX-400 High Performance Digital FT-NMR
Spectrometer.
(R)-NapEtHCIO4 (3.0 0.054)×103
(S)-NapEtHCIO4 (3.3 0.054)×104
2
(R)-PhEt
(S)-PhEt
(R)-PhEtHCIO4
(S)-PhEtHCIO4
(R)-NapEt
(2.7 0.052)×103
(3.0 0.010)×103
(4.5 0.070)×103
(1.4 0.033)×103
(1.1 0.07)×103
(1.0 0.054)×103
4.77×103
4.82×103
5.06×103
4.36×103
4.25×103
4.16×103
3.06×103
5.13×103
3.2. UV spectral measurements
The abilities of crown ethers to coordinate to free
amines and their perchlorate salts were investigated
using UV spectroscopic titration.12 The UV–vis spectra
were measured at 30 0.1°C with thermostated cell com-
partment by Shimadzu 160 UV spectrometer. The same
concentration of guest solution were added to the sam-
ple cell and reference cell. The maximum wavelengths
are 241.5 and 277.4 nm for 1, 242.8 nm for 2. CHCI3
was used as the solvent. The concentration of the hosts
are 5.0×10−5–1.1×10−3 mol dm−3 with the increasing
concentration of the added guest.
(S)-NapEt
(R)-NapEtHCIO4 (1.6 0.034)×102
(S)-NapEtHCIO4 (5.0 0.014)×103
NapEtHCIO4 salts, the (S) forms are recognized more
than the (R) forms. Enantiomeric recognition for the
homochiral forms of (R)-PhEtHCIO4 and (S)-
NapEtHCIO4 free energy values are greater than other
measured forms values. Thus, as predicted, phenyl sub-
stituent provides sufficient steric hindrance that one of
the enantiomeric guest is recognized over the other
form.
3.3. (S)-N-Benzyl-2-amino-3-methyl-1-butanol 3
S-Valinol (33 g, 0.32 mol), benzyl chloride (10.13 g,
0.08 mol) and anhydrous Na2CO3 (8.48 g, 0.08 mol)
were placed in a 250 mL two-necked round bottomed
flask equipped. The mixture was stirred at 110°C for 12
h under dry N2. Then the mixture was cooled and
CHCI3 (150 mL) was added to the mixture and refluxed
for 2 h. The CHCI3 layer was separated from the solid
phase. The solid phase was re-extracted with CHCI3
(3×150 mL). The combined organic phase were dried
over anhydrous MgSO4, filtered and evaporated, The
product was then distilled under reduced pressure to
give 12 g (78%); bp 110–112°C/0.8 mmHg, [h]2D0 −10.5
(c 1, MeOH), IR: w 3397, 3095, 3070, 3024, 2960, 2877,
1612, 1503, 1464, 1406, 1375, 1162, 1060, 918, 874, 739
cm−1; 1H NMR (CDCI3) l 0.87–1.02 (m, 6H), 1.86–1.91
(m, 1H), 2.44–2.48 (m, 1H), 3.39–3.44 and 3.62–3.65
(dd, 2H), 3.74–3.81(dd, 2H), 7.23–7.36 (m, 5H); 13C
NMR (CDCI3) l 18.86, 19.84, 29.09, 52.04, 60.98,
64.29, 127.42, 128.84, 140.97. Anal. calcd for
C12H19NO: C,70,61; H, 9.84; N, 7.25. found: C, 70.50;
H, 9.80; N, 7.00.
By comparison with the binding constant for 2, it can
be seen that recognition against (R)-PhEtHCIO4 is
much better than (S)-form of its salts. However, the
binding constant for (R)-NapEtHCIO4 is quite small
relative to (S)-NapEtHCIO4.
In conclusion, by comparison of 1 and 2 in the ring of
1, the p–p interaction overlap between the naphthyl and
phenyl group of (S)-NapEtHCIO4 and (R)-PhEtHClO4
respectively, and benzo unit of 1 is evidently not abso-
lutely necessary to cause good chiral recognition, but
p–p interactions may contribute to enantiomeric recog-
nition when present.
3. Experimental
3.1. General information
All chemicals were reagent grade unless otherwise spe-

3818
Y. Turgut, H. Hos¸go¨ren / Tetrahedron: Asymmetry 14 (2003) 3815–3818
3.4. (S)-N-Benzyl-4-hydroxymethyl-3-aza-5-methyl-hex-
1439, 1343, 1297, 1246, 1119, 1027, 932, 732, 701 cm−1;
1H NMR (CDCI3) l 0.84–1.02 (m, 8H), 1.28–2.09 (m,
4H), 3.58–3.90 (m, 16H), 7.20–7.37 (m, 5H); 13C NMR
(CDCI3) l 20.93; 21.54; 29.11, 51.39; 56.36; 66.99;
70.69; 70.79; 70.89; 71.03; 71.13; 71.62; 126.88; 128.41;
128.93; 141.84. Anal. calcd for C20H33NO4: C, 68.37; H,
9.47; N, 3.99, found: C, 68.30; H, 9.50; N, 3.38.
ane-1-ol 4
A solution of 3 (20 g, 0.01 mol) in 250 mL methanol
was cooled to −20°C in a 100 mL flask. Ethylene oxide
(3.8 mL, 0.1 mol) in 10 mL of methanol was added to
the solution drop wise at −20°C. The mixture was kept
at −20°C during addition in deepfreeze. After addition
the mixture was stirred for 24 h at −20°C and 24 h at
+4°C. The mixture was kept for one day at rt in a
closed flask. Methanol was evaporated in rotary evapo-
rator. The product was purified by distillation under
reduced pressure to give 21 g (89%); bp 160–162°C/0.8
mmHg; [h]2D0 −14.9 (c 1, MeOH), IR: w 3352, 3070,
3024, 2973, 1956, 1599, 1490, 1464, 1375, 1157, 1053,
References
1. (a) Stoddart, J. F. In Progress in Macrocyclic Chemistry;
Izatt, R. M.; Christensen, J. J., Eds.; Synthetic Chiral
Receptor Molecules From Natural Product; Wiley-Inter-
science: New York, 1981; Vol. 2, pp. 173–250; (b) Gokel,
G. W.; Korzeniowski, S. H. Macrocyclic Polyether Syn-
theses; Springer-Verlag: New York, 1982; (c) Potvin, P.
G.; Lehn, J. M. In Synthesis of Macrocycles: The Design
of Selective Complexing Agents; Izatt, R. M.; Chris-
tensen, J. J., Eds.; Design of Cation and Anion Recep-
tors, Catalysts and Carriers; Wiley-Interscience: New
York, 1987; pp. 167–237; (d) Stoddart, J. F. In Topics in
Stereochemistry; Eliel, E. L.; Wilen, S. H., Eds.; Chiral
Crown Ethers; Wiley-Interscience: New York, 1988; Vol.
17, pp. 207–288; (e) Misumi, S. Top. Curr. Chem. 1993,
165, 163.
2. Kyba, E. P.; Koga, K.; Siegel, M. G.; Sousa, L. R.;
Cram, D. J. J. Am. Chem. Soc. 1973, 95, 2692.
3. Stoddart, J. F. In Topics in Stereochemistry; Eliel, E. L.;
Wilen, S. H., Eds.; Chiral Crown Ethers; Wiley-Inter-
science: New York, 1988; Vol. 17, p. 207.
4. (a) Samu, E.; Huszthy, P.; Horvath, G.; Szo¨llosy, A.;
Neszmelyi, A. Tetrahedron: Asymmetry 1999, 10, 3615–
3626; (b) Izatt, R. M.; Wang, T.; Hathaway, J. K.;
Zhang, X. X.; Curtis, J. C.; Bradshaw, J. S.; Zhu, C. Y.
J. Inc. Phenomena Molecular Recognition Chem. 1994, 17,
157–175.
1
913, 746, 701 cm−1; H NMR (CDCI3) l 0.86–1.07 (m,
6H), 1.85–1.91 (m, 1H), 2.50–2.56 (m, 1H), 2.80–2.92
(m, 2H), 3.55–3.44 and 3.63–3.69 (m, 4H), 3.37–3.91
(dd, 2H) 7.20–7.36 (m, 5H); 13C NMR (CDCI3) l
22.45, 29.18, 55.90, 60.89, 61.14, 68.89, 77.38, 77.70,
127.44, 128.83, 129.23, 141.14. Anal. calcd for
C14H23NO2: C, 70.89; H, 9.70; N, 5.91, found: C, 70.95;
H, 9.70; N, 5.95.
3.5. (S)-2-Isopropyl-N-benzyl-4,7,10,13-tetraoxa-8,9-
benzo-1-azacyclopentadec-8-ene 1
To a suspension of NaH (2.52 g, 0.084 mol, % 80 in
mineral oil) in 100 mL dry THF at 0°C was added a
solution of diol 4 (5 g, 0.021 mol) in 250 mL of THF.
The reaction mixture was refluxed for 2 h. The reaction
after cooling to 0°C, a solution of 5 (10.67 g, 0.021 mol)
in 250 mL of THF slowly added. The suspension was
refluxed for 50 h. The solvent was evaporated and 100
mL of water was added to the residue. The mixture was
extracted with CH2CI2 (3×150). The combined organic
layers were washed with 100 mL water again, dried on
anhydrous Na2SO4 and the solvent was evaporated.
The crude product was purified by flash column chro-
matography on silica gel (eluent: triethylamine/ethyl
acetate/petroleum ether 60–80=3/17/80) to give 4 g
(47%); mp 81–82°C, [h]2D0 −26.3 (c 1, CHCI3), IR: w
3070, 3037, 2960, 1606, 1503, 1458, 1368, 1323, 1259,
5. Pietraszkiewicz, M.; Kozbial, M.; Pietraszkiewicz, O. J.
Membrane Sci. 1998, 138, 109–113.
6. Peng, X.-bin.; Huang, J.-W.; Li, T.; Ji, L.-N. Inorg. Chim.
Acta 2000, 305, 111–117.
7. Chen, X.; Du, D.-M.; Hua, W.-T. Tetrahedron: Asymme-
try 2003, 14, 999–1007.
8. Marc, J.; McKennon, A.; Meyers, I. J. Org. Chem. 1993,
58, 3568–3571.
1
1208, 1118, 1047, 938, 790, 758, 732, 701,617 cm−1; H
8
9. Ozbey, S.; Hos¸go¨ren, H.; Turgut, Y.; Topal, G. J. Inc.
NMR (CDCI3) l 0.90–1.02 (dd, 6H), 1.97–2.38 (m,
2H), 3.01–3.07 (m, 2H), 3.70–4.17 (m, 14H), 6.89–6.92
(m, 4H), 7.23–7.35 (m, 5H); 13C NMR (CDCI3) l
20.92, 21.61, 28.66, 50.94, 56.87, 67.04, 68.85, 61.61,
69.85, 69.96, 70.80, 71.45, 113.27, 113.40, 121.37,
121.42, 126.88, 128.38, 141,84. Anal. calcd for
C24H33NO4: C, 72.89; H, 8.88; N, 3.2, found: C, 72.18;
H, 8.27; N, 3.51.
Phenomena Macrocyclic Chem. 2001, 39, 315–320.
8
10. Ozbey, S.; Kaynak, F. B.; Togrul, M.; Demirel, N.;
Hos¸go¨ren, H. J. Inc. Phenomena Macrocyclic Chem.
2003, 45, 123–128.
11. (a) Polster, J.; Lachman, H. Spectrometric Titrations;
VCH: Weinheim, 1989; (b) Connors, K. A. Binding Con-
stants. The Measurement of Molecular Complex; Wiley:
New York, 1987; (c) Benesi, H. A.; Hildebrand, J. H. J.
Am. Chem. Soc. 1949, 71, 2703.
12. Examples of the UV–vis titremetric method being used in
molecular recognition: (a) Pietraszkiewicz, M.; Kozbial,
M.; Pietraszkiewicz, O. J. Membrane Sci. 1998, 138,
109–113; (b) Peng, X.-bin; Huang, J.-W.; Li, T.; Ji, L.-N.
Inorg. Chim. Acta 2000, 305, 111–117; (c) Chen, X.; Du,
D.-M.; Hua, W.-T. Tetrahedron: Asymmetry 2003, 14,
999–1007; (d) Yuan, Y.; Gao, G.; Jiang, Z.-L.; You, J.-S.;
Zhou, Z.-Y.; Yuan, D.-Q.; Xie, R.-G. Tetrahedron 2002,
58, 8993–8999 and references cited therein.
3.6. (S)-2-Isopropyl-N-benzyl-4,7,10,13-tetraoxa-1-aza-
cyclopentadecane 2
This compound was prepared in similar manner 1.
Using NaH (2.52 g, 0.084 mol), 4 (5 g, 0.021 mol) and
6 (9.66 g, 0.021 mol). The crude product was purified
by flash column chromatography on silica gel (eluent:
triethylamine/ethyl acetate/petroleum ether 60–80=3/
17/80), yield was obtained as yellow oil 2.5 g (33%);
[h]2D0 −16.4 (c 1, CHCI3), IR: w 3089, 3070, 3024, 2954,