New chiral ammonium salt hosts derived from amino acids: very efficient
optical resolution of 2,2A-dihydroxy-1,1A-binaphthyl by complexation with these
host compounds
Fumio Toda* and Kenya Tanaka
Department of Applied Chemistry, Faculty of Engineering, Ehime University, Matsuyama, Ehime 790, Japan
Chiral ammonium salt hosts are prepared from amino acids
by transformation of their NH2 and CO2H groups into
Me3N+Br2 and CH2OH groups, respectively, via three
simple reaction steps; by complexation with these hosts,
2,2A-dihydroxy-1,1A-binaphthyl is resolved very efficiently.
For example, treatment of l-leucinol 4c, prepared by LiAlH4
reduction of l-leucine 3c in 99% yield,7 with formaldehyde and
formic acid according to the reported procedure8 gave N,N-
dimethyl-l-leucinol 5c in 98% yield. Treatment of 5c with
MeBr gave the quaternary ammonium salt host, (+)-1-hydroxy-
methyl-3-methylbutyl(trimethyl)ammonium bromide 6c in
77% yield as colourless prisms.† By the same procedure,
(2)-6a, (+)-6b and (+)-6d were prepared from l-alanine (3a),
l-valine (3b) and l-isoleucine (3d), respectively.
When a solution of (+)-6c (0.5 g, 2.08 mmol) and rac-1 (1.19
g, 4.16 mmol) in EtOH (6 ml) was kept at room temperature for
24 h, a 1:1 inclusion complex of (+)-6c and (+)-1 was obtained
as colourless prisms. The crude complex was recrystallised
from diethyl ether to give pure complex crystals‡ and then the
pure complex crystals were dissolved in a mixture of diethyl
ether and water. From the diethyl ether solution, (+)-1 (100%
ee)§ was obtained (0.42 g, 70% yield). From aqueous solution,
6c was recovered (0.43 g, 86% yield). By the same complexa-
tion experiments of rac-1 with (2)-6a, (+)-6b and (+)-6d, (2)-1
(100% ee, 68% yield), (+)-1 (100% ee, 36% yield) and (2)-1
(100% ee, 48% yield) were obtained, respectively. In all cases,
host compounds were recovered in almost quantitative yield and
could be reused.
It has been reported that Aonium salts such as ammonium1–5 and
phosphonium salts6 form inclusion complexes with alcohol and
phenol derivatives via hydrogen bond formation between the
counter anion of the Aonium salt host and the hydroxy group of
the alcohol or phenol guest. In these inclusion complexes,
molecular recognition between the host and guest occurred and
separation of isomers of the guest was accomplished. When a
chiral Aonium salt host is used, rac-guest compounds were
resolved. For example, rac-2,2A-dihydroxy-1,1A-binaphthyl 1
H
OH
OH
Cl –
HO
C
N
N
+
Bn
(–)-2
1
In comparison to the resolution of rac-1 by complexation
with 2, the present resolution with 6 of about half mole of 2 has
many advantages. Since 6 can easily be prepared in large
quantities from cheap l-amino acid via a simple three step
reaction, the present resolution method is more economical than
that via the relatively expensive 2. Furthermore, either (+)-1 or
(2)-1 can be obtained according to demand, as (2)-6a and
(+)-6d include (2)-1 and (+)-6b and (+)-6c include (+)-1.
By using the precise chiral recognition between 1 and 6 in the
inclusion complex, rac-6 can also be resolved by optically
active 1. For example, when a solution of rac-6d (0.34 g, 1.40
mmol), prepared from rac-isoleucine (rac-3d) and (2)-1 (0.2 g,
0.69 mmol) in EtOH (3.5 ml) was kept at room temperature for
24 h, a 1:1 complex of (2)-1 and (+)-6d was obtained, after
recrystallisation from EtOH, as colourless prisms (0.28 g, 76%
yield). The pure complex crystals were dissolved in a mixture of
diethyl ether and water. From aqueous solution, (+)-6d (100%
ee) was obtained (0.13 g, 76% yield). From diethyl ether
solution, (2)-1 was recovered (0.15 g, 76% yield).
was
easily
resolved
by
complexation
with
N-benzylcinchonidinium chloride 2, because 2 forms a 1:1
inclusion complex with (R)-(+)-1 selectively.4 X-Ray crystal
structure analysis of the complex showed that the complex is
mainly constructed via formation of an intermolecular hydrogen
bond between Cl2 of 2 and the OH group of 1. It was also found
that an intramolecular hydrogen bond between the OH group of
2 and Cl2 plays an important role in forming the complex.5 This
finding suggests that a chiral compound which has Me3N+X2
and OH groups would be a good host for resolution of rac-1.
According to this idea, chiral b-hydroxy trimethylammonium
bromide hosts 6a–d were prepared from the corresponding
b-amino acids 3a–d by transformation of their NH2 and CO2H
groups into Me3N+Br2 and CH2OH groups, respectively, via
the three step reaction shown in Scheme 1.
CHCO H
R
CHCH OH
R
2
2
i
We thank the Ministry of Education, Science and Culture,
Japan, for a grant-in-aid for Scientific Research on Priority
Areas, No. 0642105.
NH2
NH2
3
4
ii
Footnotes
iii
CHCH OH
NMe3Br–
CHCH OH
R
+
R
2
2
* E-mail: toda@en3.ehime-u.ac.jp
NMe2
† Selected data for (2)-6a: no clear mp; [a]D 24.6 (c 0.5, MeOH); nmax
(Nujol)/cm21 3292 (OH); Calc. for C6H16ONBr: C, 36.38; H, 8.14; N, 7.07.
Found: C, 36.35; H, 8.12; N, 7.10%. For (+)-6b: mp 153–160 °C; [a]D +6.9
(c 0.5, MeOH); nmax(Nujol)/cm21 3275 (OH); Calc. for C8H20ONBr: C,
42.49; H, 8.91; N, 6.19. Found: C, 42.19; H, 8.91; N, 6.33%. For 6c: mp
153–156 °C; [a]D +18.0 (c 0.5, MeOH); nmax(Nujol)/cm21 3290 (OH);
Calc. for C9H22ONBr: C, 52.56; H, 7.35; N, 5.11. Found: C, 52.49; H, 7.09;
6
5
a R = Me
b R = Pri
c R = Bui
d R = Bus
Scheme 1 Reagents: i, LiAlH4; ii, HCO2H, HCHO; iii, MeBr
Chem. Commun., 1997
1087