Homobenzotetramisole-catalyzed kinetic resolution of α-Aryl-, α-Aryloxy-, and α-Arylthioalkanoic acids

Article abstract of DOI:10.1002/adsc.200900451

Effective kinetic resolutions of α-aryl-, αaryloxy-, and α-arylthioalkanoic acids have been achieved via in situ generation of their symmetrical anhydrides and enantioselective alcoholysis in the presence of homobenzotetramisole (HBTM) 3.

Full text of DOI:10.1002/adsc.200900451

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DOI: 10.1002/adsc.200900451
Homobenzotetramisole-Catalyzed Kinetic Resolution of a-Aryl-,
a-Aryloxy-, and a-Arylthioalkanoic Acids
Xing Yanga and Vladimir B. Birmana,*
a
Department of Chemistry, Washington University, Campus Box 1134, One Brookings Drive, St. Louis, Missouri 63130,
USA
Fax : (+1)-314-935-4481; phone: (+1)-314-935-9188; e-mail: birman@wustl.edu
Received: June 30, 2009; Published online: October 1, 2009
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.200900451.
Abstract: Effective kinetic resolutions of a-aryl-, a-
aryloxy-, and a-arylthioalkanoic acids have been
achieved via in situ generation of their symmetrical
anhydrides and enantioselective alcoholysis in the
presence of homobenzotetramisole (HBTM) 3.
(DCC) (Ishihara) or p-methoxybenzoic anhydride
(Shiina). We reasoned that since kinetic resolutions
are typically carried out to ca. 50% conversion, it
should be sufficient to activate only one half of a sub-
strate acid via in situ generation of its symmetrical an-
hydride. Treating racemic 2-phenylpropionic acid 4
with 0.53 equiv. of DCC in toluene, as expected, re-
sulted in rapid precipitation of dicyclohexylurea and
clean formation of the anhydride,[8] presumably as a
mixture of d,l- and meso-diastereomers. Alcoholysis
of this mixture in the presence of catalysts 1, 2 and 3
(Figure 1) was investigated next (Table 1).
Keywords: acylation; anhydrides; carboxylic acids;
kinetic resolution
Resolution of racemic carboxylic acids is commonly
Modest enantioselectivities were obtained using
accomplished via fractional crystallization of their dia- isopropyl alcohol (entries 1–3).[10] HBTM 3[7c] proved
stereomeric salts with chiral amines.[1] The need for to be clearly superior to Cl-PIQ 1[7a] and BTM 2,[7b] in
the trial-and-error optimization of conditions, utiliza- terms of both the reaction rate and enantioselectivity.
tion of stoichiometric amounts of chiral resolving Benzyl alcohol produced a lower selectivity factor
agents and repeated recrystallizations often detract than isopropyl alcohol (entry 4). On the other hand,
from the convenience of this approach. One of the al- diarylcarbinols, such as benzhydrol (entry 5) and espe-
ternatives to this so-called classical resolution is kinet- cially di-(1-naphthyl)-methanol (entry 6) employed in
ic resolution[2] (KR), which can be achieved via enan- Shiinaꢀs work,[6] led to significant improvements.
tioselective alcoholysis of activated carboxylic acid Under the same conditions, Cl-PIQ 1 displayed very
derivatives in the presence of chiral catalysts. Al- low enantioselectivity (entry 7), whereas BTM 2
though examples of this process have been known for (entry 8) produced a markedly lower reaction rate
some time, high selectivity factors[3] have been ob- than HBTM 3.
tained in relatively few cases.[4] In contrast to the ear-
Screening different solvents (Table 2, entries 1–5)
lier studies using preformed acyl donors as substrates, led us to conclude that the initially chosen toluene
two groups recently reported successful KR of car- was, in fact, optimal. Lowering the temperature to
boxylic acids activated in situ. Ishihara et al.[5] utilized 08C (entry 6) increased the selectivity factor by ca.
their histidine-derived enantioselective acylation cata-
lyst to resolve carboxylic acids bearing a pyrrolidino-
carboxy moiety at the a-position. Shiina et al.[6] suc-
cessfully resolved several 2-arylpropionic acids using
benzotetramisole (BTM, 2), previously developed in
our laboratory in the context of the KR of benzylic
alcohols.[7b]
In both previous studies, the free acids were activat-
ed using equimolar amounts of condensing agents,
such as pivaloyl chloride, dicycloheyxalcarbodiimide Figure 1. Amidine-based catalysts.
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Xing Yang and Vladimir B. Birman
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Table 1. Variation of the catalyst and alcohol substrate.
tivity factors (entries 7–9). It should be noted that the
non-enzymatic KR of this type of substrates has not
been previously reported.[11] On the other hand, the
geometrically similar acid 15 reacted with barely de-
tectable enantioselectivity (entry 10).
Although the mechanism of chiral recognition in
the process described above is not fully understood at
present, a preliminary analysis of the experimental re-
sults is possible. The enantioselectivity clearly de-
pends on the alcohol employed, which suggests that
the first step of the catalytic cycle is rapid and reversi-
Entry Catalyst
ROH
Conversion [%][a]
S
1
2
3
4
5
6
7
8
Cl-PIQ 1 i-PrOH
BTM 2 i-PrOH
HBTM 3 i-PrOH
HBTM 3 PhCH2OH
HBTM 3 Ph2CHOH
HBTM 3 1-Np2CHOH 46
Cl-PIQ 1 1-Np2CHOH 49
20
5
48
50
53
1.9
1.7
6.9
5.2
9.3
33
Table 3. Substrate scope.[a]
Entry (Æ)-Substrate[b]
%eeSM
%eePR
/
S (Conversion
[%])
2.6
24
BTM 2
1-Np2CHOH 17
[a]
Conversions [%] were calculated from the ee values of
the ester (6) and the unreacted acid (4).[2a,9]
1
2
3
72/88
67/90
76/91
36 (45)
37 (43)
48 (46)
Table 2. Solvent and temperature effects.[a]
Entry Solvent Temp. [8C] Time [h] Conversion [%]
S
1
2
3
4
5
6
7
8
PhMe
CHCl3 23
CH2Cl2 23
THF
MeCN 23
PhMe
PhMe
PhMe
23
10
10
10
10
10
24
24
24
46
39
42
28
26
45
43
39
33
24
21
20
11
36
36
29
23
4[c]
80/86
54/71
75/79
33 (48)
10 (43)
19 (49)
0
À20
À40
[a]
5
Conditions: 1.0 equiv. (Æ)-4 in the specified solvent was
treated with 0.53 equiv. DCC at room temperature for
15 min, then with 0.05 equiv. of 3, 0.50 equiv. 1-
Np2CHOH, and 1.0 equiv. (i-Pr)2NEt.
6
10%. Further cooling, however, did not lead to any
improvement (entries 7 and 8).
7
76/90
61/95
41/93
5/7
42 (45)
74 (39)
39 (31)
1.2 (40)
Having thus optimized the reaction conditions, we
proceeded to investigate the substrate scope of the
new method (Table 3). Racemic forms of the non-ster-
oidal anti-inflammatory drugs ibuprofen 7, naproxen
8, and flurbiprofen 9 were successfully resolved using
the optimized set of conditions (entries 2–4). Increas-
ing the size of the a-substituent from methyl to ethyl
led to lower selectivities (entry 5). A similar observa-
tion was made in the case of a-methoxyphenylacetic
acid 11 (entry 6). However, much to our surprise, the
absolute stereochemistry of the fast-reacting enantio-
mer in this case proved to be the opposite of that ob-
served in all previous cases. Intrigued by these find-
ings, we investigated substrates 12–14 bearing an aryl-
8
9[d]
10
[a]
Conditions: Same as in Table 2, entry 6, unless specified
otherwise.
[b]
The absolute configuration of the fast-reacting enantio-
mer is shown.
Reaction time 2 d.
Reaction time 3 d.
[c]
[d]
ACHTUNGTRENNUNGoxy or an arylthio group and obtained excellent selec-
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Homobenzotetramisole-Catalyzed Kinetic Resolution
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Experimental Section
Optimized Procedure
N,N’-Dicyclohexylcarbodiimide (22 mg, 0.11 mmol) was
added to a stirring solution or suspension of the specified
racemic acid substrate (0.20 mmol) in 1 mL of toluene at
room temperature. In the case of poorly soluble substrates,
sonication was used to facilitate the reaction. After 15 min,
(i-Pr)2NEt (35 mL, 0.20 mmol), and di-(1-naphthyl)methanol
(28 mg, 0.10 mmol) were added, and the mixture was cooled
in an ice bath to 08C for 5 min before adding HBTM (50 mL
of 0.20M stock solution in toluene). After stirring for 24 h
at 08C (except for substrates 9 and 14, requiring 2 and 3
days, respectively), the reaction mixture was quenched by
adding 1 mL of saturated aqueous NH4Cl. The aqueous
layer was extracted with CH2Cl2 (3ꢂ2 mL). The organic
layer was extracted with 1M NaHCO3, dried with Na2SO4,
concentrated, and then subjected to flash column chroma-
tography (hexanes/EtOAc, 20:1) to give the pure ester prod-
uct. Acidification of the aqueous NH4Cl layer and/or the
NaHCO3 extract to pH 2 gave the unreacted acid substrate.
The ee values of the ester and the unreacted acid were ob-
tained by chiral stationary phase HPLC analysis and used to
calculate the % conversion and the selectivity factor accord-
ing to Ref.[2a] The results reported in each entry in Table 3
are averages of two runs.
Figure 2. Proposed catalytic cycle.
Figure 3. Proposed transition state model. The carboxylate
anion is omitted for clarity.
Acknowledgements
This study was supported in part by NIGMS (NIH R01
GM072682). Mass spectrometry was provided by the Wash-
ington University Mass Spectrometry Resource, an NIH Re-
search Resource (Grant No. P41RR0954).
ble and that the enantiodiscrimination occurs in the
second step (Figure 2).
By analogy with the previously proposed transition
state for the KR of secondary benzylic alcohols,[12] the
model shown in Figure 3 may be envisioned. The References
structure-selectivity trends observed so far are consis-
tent with a Felkin–Anh-like model (17b).[13] In the
case of arylalkanoic acids (4, 7–10), R1 =Ar, R2 =Me
or Et. However, when a small, electron-withdrawing
substituent is introduced (cf. substrate 11), the situa-
tion is reversed: R1 =OMe, R2 =Ph. The reversed se-
lectivity is increased further when R2 becomes smaller
and R1 becomes larger and/or more electron-deficient
(cf. 11 vs. 12–14).
[1] F. Faigl, E. Fogassy, M. Nꢃgrꢄdi, E. Pꢄlovics, J. Schin-
dler, Tetrahedron: Asymmetry 2008, 19, 519.
[2] a) H. B. Kagan, J. C. Fiaud, Top. Stereochem. 1988, 18,
249; b) E. Vedejs, M. Jure, Angew. Chem. 2005, 117,
4040; Angew. Chem. Int. Ed. 2005, 44, 3974.
[3] Selectivity factor is defined as S=k(fast-reacting enan-
tiomer)/k(slow-reacting enantiomer).[2a] S values ꢀ20
are considered practically useful.[2b].
[4] a) K. Narasaka, F. Kanai, M. Okudo, N. Miyoshi,
Chem. Lett. 1989, 1187; b) S.-K. Tian, Y. Chen, J. Hang,
L. Tang, P. McDaid, L. Deng, Acc. Chem. Res. 2004, 37,
621; c) G. T. Notte, T. Sammakia, P. J. Steel, J. Am.
Chem. Soc. 2005, 127, 13502; d) G. T. Notte, T. Samma-
kia, J. Am. Chem. Soc. 2006, 128, 4230.
In conclusion, we have developed a new protocol
for the non-enzymatic KR of carboxylic acids via
their symmetrical anhydrides, which compares favora-
bly with previous methods[5,6] in terms of cost, experi-
mental convenience, and enantioselectivity. Further
investigations aimed at expanding the scope of this
methodology and probing the validity of the proposed
TS model are underway and will be reported in due
course.
[5] K. Ishihara, Y. Kosugi, S. Umemura, A. Sakakura, Org.
Lett. 2008, 10, 3191.
[6] I. Shiina, K. Nakata, Y. Onda, Eur. J. Org. Chem. 2008,
5887.
[7] a) V. B. Birman, H. Jiang, Org. Lett. 2005, 7, 3445;
b) V. B. Birman, X. Li, Org. Lett. 2006, 8, 1351; c) V. B.
Birman, X. Li, Org. Lett. 2008, 10, 1115.
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Xing Yang and Vladimir B. Birman
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[8] F. M. F. Chen, K. Kuroda, N. L. Benoiton, Synthesis
1978, 928.
[9] The possibility of racemization/epimerization of inter-
mediates under the reaction conditions has been ruled
out by a control experiment. See Supporting Informa-
tion.
[10] A modified protocol using 1.2 equiv. of DCC to pro-
duce the O-acylisourea instead of the anhydride proved
to be much less effective. The conversion to the ester
was low, presumably as a consequence of the N-acyl-
za, F. Fringuelli, M. Stillitano, Tetrahedron: Asymmetry
1999, 10, 4599; b) S. Koul, J. L. Koul, B. Singh, M.
Kapoor, R. Parshad, K. Manhas, S. C. Taneja, G. N.
Qazi, Tetrahedron: Asymmetry 2005, 16, 2575.
[12] a) V. B. Birman, E. W. Uffman, H. Jiang, X. Li, C. J.
Kilbane, J. Am. Chem. Soc. 2004, 126, 12226; b) X. Li,
L. Peng, K. N. Houk, V. B. Birman, J. Am. Chem. Soc.
2008, 130, 13836.
[13] a) M. Cherest, H. Felkin, N. Prudent, Tetrahedron Lett.
1968, 2199; b) N. T. Anh, O. Eisenstein, Nouv. J. Chim.
1977, 1, 61; c) N. T. Anh, Top. Curr. Chem. 1980, 88,
145.
ACHTUNGTRENNUNGurea formation (detected in the mixture after the reac-
tion).
[11] For examples of the enzymatic KR of a-aryloxy- and a-
arylthiopropionic acids, see: a) A. Cipiciani, F. Bellez-
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