Chiral recognition of secondary amines by using chiral crown ether and podand

Article abstract of DOI:10.1016/S0040-4039(02)02030-0

Chiral crown ether (S,S)-3 having a pseudo-24-crown-8 ring and chiral podand (R,R)-4 were prepared and both exhibited good chiral recognition ability toward secondary amines, N-α-dimethylbenzylamine (15) and propranolol (16).

Full text of DOI:10.1016/S0040-4039(02)02030-0

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 8539–8542
Chiral recognition of secondary amines by using chiral crown
ether and podand†
Keiji Hirose,* Akihito Fujiwara, Kazuhisa Matsunaga, Nobuaki Aoki and Yoshito Tobe
Department of Chemistry, Faculty of Engineering Science, Osaka University, and CREST, Japan Science and Technology
Corporation (JST), Toyonaka, Osaka 560-8531, Japan
Received 27 August 2002; revised 17 September 2002; accepted 19 September 2002
Abstract—Chiral crown ether (S,S)-3 having a pseudo-24-crown-8 ring and chiral podand (R,R)-4 were prepared and both
exhibited good chiral recognition ability toward secondary amines, N-a-dimethylbenzylamine (15) and propranolol (16). © 2002
Published by Elsevier Science Ltd.
A number of chiral amines are known to possess potent
biological activities and many of them are employed as
important pharmaceuticals and their intermediates.
Since each enantiomer of these amines has, in principle,
different activities, it is an important issue to develop
convenient methods for optical resolution and determi-
nation of optical purity. Despite the abundance of
reports on chiral recognition of primary amines,1 to the
best of our knowledge, there are only two reports on
chiral recognition of secondary amines.2 Namely, Fuji
et al. reported that binaphthyl derivatives bound valine
derivatives with high enantiomer selectivity.3 Recently,
Steffeck et al. achieved enantiomeric separation of
racemic secondary amines with a liquid chromatogra-
phy stationary phase based on a chiral 18-crown-6.4 On
the other hand, we reported that the optically active
pseudo-18-crown-6 ethers like (S,S)-1 exhibited high
enantiomer selectivity toward primary amines.5 Accord-
ingly, we planned to prepare artificial receptors having
the same structural features as those of (S,S)-1 for the
enantiomer discrimination of secondary amines. The
salient features of (S,S)-1 involve (i) a phenolic hydroxy
group which binds neutral amines to form a salt com-
plex, (ii) a strong electron-withdrawing group attached
to the para position of the OH group, facilitating
binding with amines and (iii) phenyl groups introduced
to the right position of the macrocyclic framework as
chiral barriers. Since we anticipated that the ring size of
(S,S)-1 would be too small for binding a secondary
amine, we designed larger macrocycle (S,S)-3 and
Figure 1. The structures of hosts (S,S)-1–3 and (R,R)-4.
Keywords: chiral recognition; secondary amine; crown ether; podand.
* Corresponding author. Tel.: +81-6-6850-6228; fax: +81-6-6850-6229; e-mail: hirose@chem.es.osaka-u.ac.jp
† This paper is dedicated to Emeritus Professor Soichi Misumi on the occasion of his 77th birthday.
0040-4039/02/$ - see front matter © 2002 Published by Elsevier Science Ltd.
PII: S0040-4039(02)02030-0

8540
K. Hirose et al. / Tetrahedron Letters 43 (2002) 8539–8542
In order to examine the binding ability of (S,S)-2,
(S,S)-3 and (R,R)-4 with secondary amines, N-methyl-
benzylamine (14) was selected as a guest. The enan-
tiomer selective complexation of (S,S)-3 and (R,R)-4
was studied with R and S enantiomers of N,a-dimethyl-
benzylamine (15) which has a methyl group at a-posi-
tion of 14 and propranolol (16) having a chiral center
at b-position of an amino group. The binding constants
for complexes of (S,S)-2 and (S,S)-3 with the amines
were determined by the non-linear least-squares curve
acyclic host (R,R)-4. In the case of a podand type host,
however, introduction of a 2,4-dinitrophenylazo group
at the para position of the OH group resulted in the
product which existed as both azophenol and its tau-
tomeric hydrazone forms.6 Therefore, a nitro group is
used instead since its electron-withdrawing property is
same as that of a 2,4-dinitrophenylazo group.7 Pseudo-
18-crown-6 (S,S)-2 possessing the same ring size as that
of (S,S)-1 was prepared for comparison. The ring size
of pseudo-24-crown-8 (S,S)-3 is assumed to be almost
the same as that of dibenzo-24-crown-8 which is
reported to form a stable complex with a dibenzylam-
monium ion.8 Podand (R,R)-4 should have a larger
binding site than that of (S,S)-3 (Fig. 1).
1
fitting method on the basis of the H NMR titration in
CDCl3 at 15°C. Because of the limited solubility of
(R,R)-4 in CDCl3, the binding constants for complexes
of (R,R)-4 with the amines were determined by the
Rose–Drago method on the basis of the UV–vis titra-
tion in CHCl3 at 15°C.14 The binding constants of the
hosts with 14, 15 and 16 and enantiomer selectivities of
the hosts toward 15 and 16 which are the ratio of
binding constants (KS/KR), are summarized in Table 1.
As shown in Table 1, the binding constant of pseudo-
24-crown-8 (S,S)-3 with 14 is three times as large as
that of pseudo-18-crown-6 (S,S)-2. Similarly, the bind-
ing constant of podand (R,R)-4 is eight times larger
than that of (S,S)-2. These results clearly exhibit that
the cavity of pseudo-18-crown-6 (S,S)-2 is too small for
a secondary amine, while pseudo-24-crown-8 (S,S)-3
and podand (R,R)-4 possess large binding sites enough
to include a secondary amine.15 Next, we investigated
chiral recognition abilities of the hosts toward amine
15. Since (S,S)-2 did not bind S and R enantiomers of
15 (K<1 M−1), we could not estimate the selectivity.
Thus introduction of a methyl group in the guest amine
The preparation of (S,S)-2, (S,S)-3 and (R,R)-4 was
carried out using diol 5 as a common intermediate as
shown in Scheme 1. Ring closure of (S,S)-59 with
diethylene glycol ditosylate under high dilution condi-
tion gave (S,S)-6. Reductive removal of the bromo
group of (S,S)-6 gave (S,S)-7, and its demethylation
afforded (S,S)-8. Nitration at the para position of the
OH group of (S,S)-8 gave (S,S)-2,11 pseudo-24-crown-8
(S,S)-312 (through (S,S)-9, (S,S)-10 and (S,S)-11) and
podand (R,R)-413 were prepared by essentially the same
procedure as that for the preparation of (S,S)-2, except
that R,R isomer of 5 was used as the starting material
for (R,R)-4 and the two OH groups of (R,R)-5 was first
protected by MOM groups to give (R,R)-12. Reduction
and deprotection gave (R,R)-13, which was subjected to
demethylation and nitration to furnish (R,R)-4.
Scheme 1. Reagents and conditions: (i) diethylene glycol ditosylate, NaH, 53% (n=1), tetraethylene glycol ditosylate, NaH, 36%
(n=3); (ii) 1. n-BuLi, then H2O, 62% (n=1), 62% (n=3); (iii) EtSNa, 91% (n=1), 86% (n=3); (iv) HNO3, NaNO2, 58% (n=1),
34% (n=3); (v) (CH3O)2CH2, LiBr, TsOH, 45%; (vi) 1. n-BuLi, then H2O, 2. 6N HCl, 53%; (vii) 1. EtSNa, 2. HNO3, NaNO2,
19%.

K. Hirose et al. / Tetrahedron Letters 43 (2002) 8539–8542
8541
Table 1. Binding constants and enantioselectivities in com-
binding ability than pseudo-18-crown-6 (S,S)-2 toward
an achiral secondary amine and good enantiomer selec-
tivity toward chiral secondary amines which have a
chiral center at a or b position. The enantiomer selec-
tivity of (S,S)-3 and (R,R)-4 toward other chiral sec-
ondary amines and further modification of the host
structure are currently under investigation.
plexations of (S,S)-2, (S,S)-3 and (R,R)-4 with 14, 15 and
16
(S,S)-2a
(S,S)-3a
(R,R)-4b
14
(1.490.2)×10
(4.690.1)×10
(1.090.1)×102
15 KS
15 KR
15 KS/KR
B1
B1
–
(1.890.1)×10
8.890.7
2.0
(1.090.1)×102
(7.290.7)×10
1.4
Acknowledgements
16 KS
16 KR
16 KS/KR
–
–
–
(5.390.1)×10
(3.190.2)×10
1.7
(2.390.1)×102
(3.790.5)×102
0.6
This work was partially supported by SUNBOR foun-
dation from Suntory Institute for Bioorganic Research
and a Grant-in-Aid for Scientific Research from the
Ministry of Education, Science, Sports and Culture of
Japan.
a Measured by 1H NMR spectroscopy (270 MHz) in CDCl3 at 15°C.
b Measured by UV–vis spectroscopy in CHCl3 at 15°C.
reduce the binding ability of (S,S)-2 dramatically, sug-
gesting a severe steric repulsion between the a-methyl
group of 15 and the host. With (S,S)-3, however, the
binding constants with S and R enantiomers of 15 were
18 and 8.8 M−1, respectively. As we expected, consider-
able enantiomer selectivity was observed (KS/KR=2.0).
The binding constants of (S,S)-3 with S and R enan-
tiomers of 15 decreased considerably compared with
that with 14. In the case of (R,R)-4, binding constants
with S and R enantiomers of 15 were 100 and 72 M−1,
respectively. The enantiomer selectivity (1.4) is smaller
than that of (S,S)-3, indicating the role of macrocyclic
ring in molecular recognition. In contrast to the case of
(S,S)-2 and (S,S)-3, the binding constants of (R,R)-4
with 15 scarcely decreased from that with achiral amine
14, a result consistent with the relatively low enan-
tiomer selectivity of (R,R)-4. Chiral recognition abilities
toward 16 were investigated by using (S,S)-3 and
(R,R)-4 which showed high binding abilities toward
chiral secondary amine 15. Amine 16 is one of the
bioactive aminoalcohols possessing a hydroxy group on
a chiral center at b-position of an amino group. In the
case of (S,S)-3, the binding constants with S and R
enantiomers of 16 were 53 and 31 M−1, respectively.
The binding constants with both enantiomers of 16
considerably increased compared with those of 15 and
good enantiomer selectivity (1.7) was observed. Simi-
larly, the binding constants of (R,R)-4 with both enan-
tiomers of 16 were 2 to 5 times larger than those in the
case of 15. The binding constants with S and R enan-
tiomers of 16 were 230 and 370 M−1, respectively. In
this case, considerable enantiomer selectivity (0.6) was
also observed (Fig. 2).
References
1. Zhang, X. X.; Bradshaw, J. S.; Izatt, R. M. Chem. Rev.
1997, 97, 3313–3361.
2. Kinetic chiral recognition in the chiral crown ether –sec-
ondary ammonium complex has been reported:
Tachibana, Y.; Kihara, N.; Ohga, Y.; Takata, T. Chem.
Lett. 2000, 806–807.
3. Kawabata, T.; Kuroda, A.; Nakata, E.; Takasu, K.; Fuji,
K. Tetrahedron Lett. 1996, 37, 4153–4156.
4. Steffeck, R. J.; Zelechonok, Y.; Gahm, K. H. J. Chro-
matogr. A 2002, 947, 301–305.
5. (a) Naemura, K.; Fuji, J.; Ogasahara, K.; Hirose, K.;
Tobe, Y. Chem. Commun. 1996, 2749–2750; (b) Hirose,
K.; Ogasahara, K.; Nishioka, K.; Tobe, Y.; Naemura, K.
J. Chem. Soc., Perkin Trans. 2 2000, 1984–1993.
6. For example, the azophenol podand (i) exists in equi-
librium with its hydrazone form (ii) in a ratio of 5:1 in
CDCl3 at 30°C.
In conclusion, we prepared chiral pseudo-24-crown-8
(S,S)-3 and podand (R,R)-4 which exhibited stronger
7. Naemura, K.; Nishikawa, Y.; Fuji, J.; Hirose, K.; Tobe,
Y. Tetrahedron: Asymmetry. 1998, 9, 563–574.
8. (a) Glink, P. T.; Schiavo, C.; Stoddart, J. F.; Williams, D.
J. Chem. Commun. 1996, 1483–1490; (b) Ashton, P. R.;
Chrystal, E. J. T.; Glink, P. T.; Menzer, S.; Schiavo, C.;
Spencer, N.; Stoddart, J. F.; Tasker, P. A.; White, A. J.
P.; Williams, D. J. Chem. Eur. J. 1996, 2, 709–728.
9. Diol (S,S)-5 was prepared by the same procedure as that
of -1,3-bis[(4S)-4-hydroxy-4-phenyl-2-oxabutyl]-2,5-di-
methoxybenzene10 from 5-bromo-1,3-bis(bromomethyl)-
2-methoxybenzene.
Figure 2. The structures of the amines 14, 15 and 16.

8542
K. Hirose et al. / Tetrahedron Letters 43 (2002) 8539–8542
10. Ogasahara, K.; Hirose, K.; Tobe, Y.; Naemura, K. J.
Chem. Soc., Perkin Trans. 1 1997, 3227–3236.
13. Spectral data for (R,R)-4: mp 52–53°C; [h]2D6 −29.3 (c
1.01, CHCl3); IR (KBr) 3306, 2868, 1597, 1520, 1454,
11. Spectral data for (S,S)-2: mp 52–54°C; [h]2D5 +97.2 (c
0.61, CHCl3); IR (KBr) 3319, 2871, 1600, 1520, 1452,
1338, 1274, 1198, 1099, 909, 750, 701 cm−1 1H NMR
;
(270 MHz, CDCl3, ppm) l 2.74 (s, 2H, OH), 3.65 (dd,
J=8.6, 10.1, 2H, -O-CH(Ph)-CH2), 3.78 (dd, J=3.2,
10.1, 2H, -O-CH(Ph)-CH2), 4.77 (s, 4H, benzyl CH2),
5.00 (dd, J=3.2, 8.6, 2H, -O-CH(Ph)-CH2), 7.25–7.40
(m, 10H, C6H5), 8.09 (s, 2H, phenol moiety CH), 8.93 (s,
1H, phenol OH); MS (FAB) m/z 440 (M+H)+, 462
(M+Na)+. The high-resolution mass spectrum could not
be recorded because of the weak molecular ion peak.
14. (a) Rose, N. J.; Drago, R. S. J. Am. Chem. Soc. 1959, 81,
6138–6141; (b) Hirose, K. J. Incl. Phenom. Macrocyclic
Chem. 2001, 39, 193–209.
15. Regarding the binding ability toward a primary amine,
we also measured and compared the binding constants of
(S,S)-2, (S,S)-3 and (R,R)-4 with ethanolamine. The
binding constants of (S,S)-2, (S,S)-3 and (R,R)-4 with
ethanolamine were 8800, 360 and 35 M−1, respectively.
The binding constant of pseudo-18-crown-6 (S,S)-2 is 25
and 250 times as large as those of pseudo-24-crown-8
(S,S)-3 and podand (R,R)-4, respectively, indicating that
(S,S)-2 is a better binder for a primary amine than
(S,S)-3 and (R,R)-4.
1
1339, 1091, 749, 703 cm−1; H NMR (270 MHz, CDCl3,
ppm) l 3.54–3.78 (m, 12H, -OCH2-), 4.66 (dd, J=3.7, 7.2
Hz, 2H, CH), 4.83 (s, 4H, benzyl CH2), 7.30–7.38 (m,
10H, C6H5), 8.10 (s, 2H, phenol moiety CH), 9.20 (s, 1H,
OH); 13C NMR (67.8 MHz, CDCl3, ppm) l 69.0, 70.0,
70.6, 75.2, 76.5, 125.1, 125.2, 126.8, 128.1, 128.5, 138.0,
139.9, 161.2; MS (FAB) m/z 510 (M+H)+, 532 (M+Na)+;
HRMS (FAB) calcd for C28H32NO8 (M+H)+: 510.2128,
Found: 510.2102.
12. Spectral data for (S,S)-3: [h]2D5 +53.3 (c 1.06, CHCl3); IR
(neat) 3277, 2867, 1596, 1521, 1452, 1339, 1097, 751, 702
1
cm−1; H NMR (270 MHz, CDCl3, ppm) l 3.45–3.87 (m,
20H, -OCH2-), 4.70 (dd, J=5.8, 5.8 Hz, 2H, CH), 4.81,
4.85 (AB, J=12.9 Dw=17.9 Hz, 4H, benzyl CH2), 7.26–
7.40 (m, 10H, C6H5), 8.08 (s, 2H, phenol moiety CH),
9.13 (1H, s, OH); 13C NMR (67.8 MHz, CDCl3, ppm) l
68.8, 69.9, 69.9, 70.7, 70.9, 75.5, 81.7, 123.6, 125.3, 126.8,
128.1, 128.5, 138.2, 140.2, 159.6; MS (FAB) m/z 598
(M+H)+, 620 (M+Na)+; HRMS (FAB) calcd for
C32H40NO10 (M+H)+: 598.2652, Found: 598.2671.