Kinetic Resolution of Racemic R-Arylalkanoic Acids
A R T I C L E S
Table 1. Kinetic Resolution of Racemic 2-Phenylpropanoic Acid
((()-1) Using Various Nucleophiles
determined that the kinetic resolution of (()-1 could be attained
effectively by employing bis(R-naphthyl)methanol (3) as the
achiral nucleophile, which produced the corresponding ester
(R)-2 and the recovered acid (S)-1 with good enantiomeric
excesses (81% ee; 80% ee) as shown in entry 10. Similar to
the kinetic resolution of racemic secondary alcohols in the
previous paper,5,6 PMBA as well as pivalic anhydride also
proved to be suitable coupling reagents, and the desired ester
(R)-2 was obtained in 86% and 89% ee’s, respectively (entries
11 and 12).
ester 2
yield [%]
(% ee)
acid 1
yield [%]
(% ee)
Furthermore, we screened phenol and several substituted
phenol derivatives for the kinetic resolution of (()-1 as listed
in entries 13-19. Although phenol itself provided poor ee’s in
the present reaction, it was determined that introduction of bulky
substituents at the o- and o′-positions on the aromatic rings was
effective in attaining good enantioselectivity of the formed
carboxylic ester 2. For example, the combined use of 2,6-bis(R-
naphthyl)phenol and PMBA produced the optically active ester
2 in 86% ee as demonstrated in entry 19. We succeeded in
discovering that there were two suitable nucleophiles, 3 and
2,6-bis(R-naphthyl)phenol, in this asymmetric esterification, and
the former was clearly superior to the latter in both chemical
yields and selectivities of the desired products based on the
above experimental results (compare entries 11 and 19).
We then tried to optimize the suitable structure of the chiral
acyl-transfer catalysts, and the results, including chemical yields
and selectivities of the produced esters and recovered carboxylic
acids, are listed in Table 2. New catalysts, (S)-R-Np-BTM and
(S)-ꢀ-Np-BTM used in entries in 9 and 10, were easily generated
from 2-amino-2-(R-naphthyl)-1-ethanol and 2-amino-2-(ꢀ-naph-
thyl)-1-ethanol, respectively. These amino alcohol derivatives
had already been utilized for the synthesis of chiral ligands,10
which were applied to the asymmetric cyclopropanation of 2,5-
dimethyl-2,4-hexadiene to produce several chrysanthemic acid
derivatives including pyrethroid chemicals. Other benzotetra-
misole-type catalysts, such as (S)-i-Pr-BTM, (S)-t-Bu-BTM, and
(S)-Bn-BTM, were prepared from the corresponding 1,2-amino
alcohols or R-amino acids according to the synthetic protocol
reported by Birman et al.7
When the reaction was carried out using 5 mol % of (R)-
BTM or (S)-BTM in the presence of 0.5 equiv of 3, 0.6 equiv
of PMBA, and 0.9 equiv of diisopropylethylamine, the enan-
tioselective esterification proceeded smoothly at room temper-
ature, and the corresponding chiral carboxylic ester 2 was
obtained in good yield (33% for (R)-2, 34% for (S)-2) with a
fairly good enantioselectivity (89% ee for (R)-2, 87% ee for
(S)-2). Furthermore, nearly half the amount of the unreacted
carboxylic acid (S)-1 or (R)-1 (49% or 58%) was also recovered
in moderate optical purity (41% or 38% ee) as shown in entry
1 or 2. On the other hand, the modified BTM derivatives, such
as (S)-i-Pr-BTM, (S)-t-Bu-BTM, and (S)-Bn-BTM, which have
aliphatic substituents instead of a phenyl group on the dihy-
droimidazole moiety of BTM, afforded poor results as depicted
entry
ROH
anhydride
time
1
2
3
4
5
6
7
8
TrOH
t-BuOH
c-HexOH
Bn2CHOH
PhCH2OH
Ph2CHOH
(4-MeOC6H4)2CHOH
(4-FC6H4)2CHOH
(ꢀ-Np)2CHOH
(R-Np)2CHOH (3)
(R-Np)2CHOH (3)
(R-Np)2CHOH (3)
PhOH
2,6-Me2C6H3OH
2,6-Ph2C6H3OH
2,6-(ꢀ-Np)2C6H3OH
2,6-(ꢀ-Np)2C6H3OH
2,6-(R-Np)2C6H3OH
2,6-(R-Np)2C6H3OH
Bz2O
Bz2O
Bz2O
Bz2O
Bz2O
Bz2O
Bz2O
Bz2O
Bz2O
Bz2O
PMBA
Piv2O
Bz2O
Bz2O
Bz2O
Bz2O
PMBA
Bz2O
PMBA
18 h
15 h
3 d
16 h
12 h
12 h
12 h
12 h
11 h
4 h
4 h
4 h
1 h
12 h
15 h
2.5 h
2.5 h
7.5 h
4 h
0 (nd)
0 (nd)
39 (0)
0 (nd)
0 (nd)
31 (3)
12 (3)
11 (0)
40 (33)
42 (33)
15 (12)
60 (27)
67 (31)
56 (81)
46 (86)
42 (89)
56 (24)
12 (44)
19 (58)
29 (64)
15 (67)
14 (77)
21 (86)
60 (23)
37 (19)
26 (0)
27 (35)
16 (41)
19 (80)
46 (60)
51 (27)
14 (28)
5 (9)
9
10
11
12
13
14
15
16
17
18
19
36 (8)
43 (23)
71 (11)
31 (15)
58 (17)
secondary alcohols (entries 3 and 4) afforded the desired esters
in 39% and 12% yields, respectively, but the produced car-
boxylates and the recovered carboxylic acids proved to be almost
racemic compounds. On the other hand, it was revealed that
benzyl alcohol and diphenylmethanol produced a relatively
improved enantioselectivity of the corresponding carboxylic
esters (33% ee in each case) as shown in entries 5 and 6.
Next, several achiral diphenylmethanol derivatives were
examined as nucleophiles for the kinetic resolution of (()-1 as
depicted in entries 7-10. Substitution of the aryl ring of
diphenylmethanol diminished the selectivities (entries 7 and 8),
and the use of bis(ꢀ-naphthyl)methanol afforded relatively better
results compared with those of the reaction using bis(4-
fluorophenyl)methanol (entry 9; cf. entry 8). Fortunately, we
(8) Other related studies by Birman et al. for the kinetic resolution of
racemic alcohols: (a) Birman, V. B.; Uffman, E. W.; Jiang, H.; Li,
X.; Kilbane, C. J. J. Am. Chem. Soc. 2004, 126, 12226. (b) Birman,
V. B.; Jiang, H. Org. Lett. 2005, 7, 3445. (c) Birman, V. B.; Jiang,
H.; Li, X.; Guo, L.; Uffman, E. W. J. Am. Chem. Soc. 2006, 128,
6536. (d) Birman, V. B.; Li, X.; Jiang, H.; Uffman, E. W. Tetrahedron
2006, 62, 285. (e) Birman, V. B.; Li, X.; Han, Z. Org. Lett. 2007, 9,
37. (f) Zhang, Y.; Birman, V. B. AdV. Synth. Catal 2009, 351, 2525.
Carboxy group transfer reaction of azlactones using tetramisole
derivatives: (g) Joannesse, C.; Johnston, C. P.; Concello´n, C.; Simal,
C.; Philp, D.; Smith, A. D. Angew. Chem., Int. Ed. 2009, 48, 8914.
See also: (h) Kobayashi, M.; Okamoto, S. Tetrahedron Lett. 2006,
47, 4347. (i) Zhou, H.; Xu, Q.; Chen, P. Tetrahedron 2008, 64, 6494.
(9) (a) Shiina, I.; Kubota, M.; Oshiumi, H.; Hashizume, M. J. Org. Chem.
2004, 69, 1822. (b) Shiina, I. Chem. ReV. 2007, 107, 239. (c) Shiina,
I.; Katoh, T.; Nagai, S.; Hashizume, M. Chem. Rec. 2009, 9, 305, and
references therein.
(10) (a) Masumoto, K.; Itagaki, M. Jpn. Kokai Tokkyo Koho 2004 067,671,
2004; Chem. Abstr. 2004, 140, 217396. (b) Masumoto, K.; Itagaki,
M. Jpn. Kokai Tokkyo Koho 2004 051,604, 2004; Chem. Abstr. 2004,
140, 181222. (c) Itagaki, M.; Masumoto, K.; Yamamoto, Y. J. Org.
Chem. 2005, 70, 3292. See also other references for the reduction of
R-amino acids: (d) van Lingen, H. L.; van de Mortel, J. K. W.;
Hekking, K. F. W.; van Delft, F. L.; Sonke, T.; Rutjes, F. P. J. T.
Eur. J. Org. Chem. 2003, 317. (e) van Lingen, H. L.; van Delft, F. L.;
Storcken, R. P. M.; Hekking, K. F. W.; Klaassen, A.; Smits, J. J. M.;
Ruskowska, P.; Frelek, J.; Rutjes, F. P. J. T. Eur. J. Org. Chem. 2005,
4975.
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J. AM. CHEM. SOC. VOL. 132, NO. 33, 2010 11631