Kinetic resolution of racemic 1-heteroarylalkanols by asymmetric esterification using diphenylacetic acid with pivalic anhydride and a chiral acyl-transfer catalyst

Article abstract of DOI:10.1246/cl.2011.147

A variety of optically active 1-heteroarylalkanols and their esters, which include heteroaromatic moieties, such as 2-furyl, 2-thienyl, 3-thienyl, 2-thiazoyl, 2-benzothiazoyl, and 2-benzoxazoyl groups, are efficiently produced by a novel asymmetric esterification. The transition states that form the desired (R)- esters from the (R)-1-heteroarylalkanols are determined by DFT calculations, and the structural features of these transition states are systematically discussed.

Full text of DOI:10.1246/cl.2011.147

doi:10.1246/cl.2011.147
Published on the web January 8, 2011
147
Kinetic Resolution of Racemic 1-Heteroarylalkanols by Asymmetric Esterification
Using Diphenylacetic Acid with Pivalic Anhydride and a Chiral Acyl-transfer Catalyst
Isamu Shiina,* Keisuke Ono, and Kenya Nakata
Department of Applied Chemistry, Faculty of Science, Tokyo University of Science,
1-3 Kagurazaka, Shinjuku-ku, Tokyo 162-8601
(Received November 29, 2010; CL-101005; E-mail: shiina@rs.kagu.tus.ac.jp)
A variety of optically active 1-heteroarylalkanols and their
esters, which include heteroaromatic moieties, such as 2-furyl,
2-thienyl, 3-thienyl, 2-thiazoyl, 2-benzothiazoyl, and 2-benzox-
azoyl groups, are efficiently produced by a novel asymmetric
esterification. The transition states that form the desired (R)-
esters from the (R)-1-heteroarylalkanols are determined by DFT
calculations, and the structural features of these transition states
are systematically discussed.
Optically active 1-heteroarylalkanols are commonly utilized
Figure 1. Transition structures ts-(R)-A and ts-(R)-B derived
from methyl (R)-lactate and (R)-1-phenylethanol with the
intermediary zwitterionic species (int-II) (See also Scheme 1,
vide infra, and Supporting Information (SI)).7
as chiral building blocks in pharmaceutical and agrochemical
industries to provide valuable drugs via asymmetric synthesis.
Several useful enzymatic methods for preparing chiral 1-
heteroarylalkanols are available today for these purposes.1 To
the best of our knowledge, however, a general nonenzymatic
method for the kinetic resolution (KR) of the racemic 1-
heteroarylalkanols has not yet appeared until now. In order to
expand the synthetic utilities of the chiral 1-heteroarylalkanol
derivatives, we planned to develop a nonenzymatic method for
the production of the chiral molecules starting from racemic
substrates using the KR of (R)- and (S)-1-heteroarylalkanols.
We have reported the first asymmetric esterification2,3 of
racemic benzylic alcohols with free carboxylic acids via the
formation of the mixed anhydrides in situ using carboxylic
anhydrides as coupling reagents and chiral acyl-transfer cata-
lysts, such as (S)-tetramisole and (R)-benzotetramisole ((R)-
BTM), which were introduced by Birman et al.4 Recently, we
also achieved the KR of racemic 2-hydroxyalkanoates5 with
diphenylacetic acid using pivalic anhydride in the presence of
(R)-BTM. During our examination of solvent effects, it became
apparent that diethyl ether is a suitable media for the KR of
racemic alcohols to improve both the reactivity and the
selectivity.
Furthermore, we successfully determined several preferable
transition states to form the desired chiral (R)-diesters from (R)-
2-hydroxyesters using (R)-BTM,5 and the optically active bis-
(1-naphthyl)methyl (R)-esters from (R)-2-arylpropanoic acids3b
using (R)-BTM based on theoretical calculations from density
functional theory (DFT).6 The transition state ts-(R)-A in
Figure 1 presents the most stable structure forming methyl
(R)-2-acetyloxypropanoate from methyl (R)-lactate by reaction
with acetic anhydride and (R)-BTM. It was revealed that this
transition state is strongly stabilized by the attractive interaction
between oxygen in the ester carbonyl group and the positive
electronic charge on the face of the dihydroimidazolium salt
during the bond-forming step. Based on our investigation of the
reaction mechanism during the BTM-mediated acyl-transfer
catalysis, we also disclosed the preferable transition state ts-(R)-
B to provide (R)-1-phenylethyl acetate from (R)-1-phenylethanol
by the reaction with acetic anhydride and (R)-BTM. It is
apparently observed that the aromatic ring in (R)-1-phenyl-
ethanol is almost parallel to the horizontal plane of the
conjugated aromatics in the dihydroimidazolium salt. The
spontaneous formation of this stable stacking structure due to
³-cation interaction is easily anticipated according to the
pioneering theoretical analysis of the transition state to provide
(R)-1-phenylethyl acetate using (R)-CF3-PIP, a chiral acyl-
transfer catalyst, reported by Houk, Birman, et al.8 The dihedral
angle ª(O1-C2-C3-C*cat) in ts-(R)-A is ¹12.5° and it clearly
suggests that the C=O group in the ester moiety and the plane
surface of the conjugated aromatics in the dihydroimidazolium
salt nearly cross at right angles.5 On the other hand, the dihedral
angle ª(C1-C2-C3-C*cat) in ts-(R)-B is 89.6°, so that the structure
of ts-(R)-B includes the stacking correlation between the
aromatic ring in (R)-1-phenylethanol and the plane surface of
the conjugated aromatics in the dihydroimidazolium salt.
In this communication, we report the novel KR of a variety
of racemic 1-heteroarylalkanols using diphenylacetic acid
by the promotion of pivalic anhydride and (R)-BTM, as an
application of our mixed anhydride formation technology for
enantioselective esterification. The peculiar transition structures
of several 1-heteroarylalkanols that will be converted into the
corresponding chiral esters in the stereo-discriminating reactions
are also discussed.
We first examined the KR of racemic 1-(2-furyl)ethanol
((«)-1a) with diphenylacetic acid (3) using pivalic anhydride
and a catalytic amount of (R)-BTM in diethyl ether at room
temperature for 12 h,5 which was the standard reaction con-
ditions established in our preliminary study (Table 1, Entry 1).
Fortunately, the reaction smoothly proceeded to afford the
corresponding ester (R)-2a (42% yield, 90% ee) and the
recovered alcohol (S)-1a (42% yield, 57% ee) with a good
s-value9 (s = 34). This desirable result encouraged us to expand
the scope of the substrate for the reaction, and we next examined
Chem. Lett. 2011, 40, 147-149
© 2011 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/

148
Table 1. Kinetic resolution of the racemic 1-(2-furyl)alkanols
(«)-1a-1d and 1-(2-thienyl)alkanols («)-4a-4d
Table 2. Kinetic resolution of the racemic 1-heteroarylalkanols
(«)-6-9
Yield/%
(10-13; 6-9) (10-13; 6-9)
ee/%
Yield/%
(2/5; 1/4) (2/5; 1/4)
ee/%
Entry Substrate
R
s
Entry
X
R
s
1
2
3
4
5a
6
7
8
9
10a
O
O
O
O
O
S
S
S
S
S
Me 1a 42; 42
Et 1b 39; 61
i-Pr 1c 41; 47
t-Bu 1d 31; 65
t-Bu 1d 42; 55b
Me 4a 45; 53
90; 57
89; 62
94; 67
91; 22
87; 67b
89; 69
93; 81
96; 82
96; 23
93; 70b
34
31
69
28
28
35
71
118
69
56
1
2
6
7
47; 44
48; 52
85; 88
87; 81
37
37
3
4
5
6
7
8a
Me 8a
Et 8b
i-Pr 8c
Me 9a
Et 9b
i-Pr 9c
49; 48
44; 52
47; 53
50; 46
48; 51
48; 51
91; 86
96; 71
96; 86
92; 99
94; 91
93; 94
57
93
142
122
100
96
Et
4b 42; 46
i-Pr 4c 45; 46
t-Bu 4d 21; 68
t-Bu 4d 43; 51b
aLess hindered carboxylic acid (Ph(CH2)2COOH; 0.5 equiv)
was used as an acyl donor instead of using Ph2CHCOOH (3;
0.5 equiv). The corresponding 3-phenylpropanoate ((R)-2e or
aReaction time; 18 h.
b
(R)-5e) was obtained instead of diphenylacetate ((R)-2d or (R)-
5d).
other various racemic 1-(2-furyl)alkanols («)-1b-1d and 1-(2-
thienyl)alkanols («)-4a-4d involving several aliphatic substitu-
ents at the C-1 positions. As shown in Entries 2-4, the KR of the
1-(2-furyl)alkanol derivatives («)-1b-1d effectively took place
to produce a variety of the optically active carboxylic esters (R)-
2b-2d with high selectivities (s = 28-69). When 1-(2-furyl)-2-
methylpropanol ((«)-1c; R = i-Pr, Entry 3) was employed under
the above conditions, the chemical yield and enantiopurity of
the desired ester (R)-2c reached the highest values (41% yield,
94% ee, s = 69). On the other hand, the reaction of 1-(2-furyl)-
2,2-dimethylpropanol ((«)-1d; R = t-Bu, Entry 4) provided a
relatively lower yield of (R)-2d with a high enantiopurity. We
could obtain an improved yield of the desired ester (R)-2e with
the same s-value when using 3-phenylpropanoic acid as a less
hindered acyl donor for («)-1d instead of using diphenylacetic
acid (3) in this case (Entry 5). We observed better selectivities
for the KR of 1-(2-thienyl)alkanol derivatives («)-4a-4d
compared to those of the KR of the racemic 1-(2-furyl)alkanols
(«)-1a-1d (Entries 6-10; s = 35-118 versus Entries 1-5; s =
28-69).
We further examined a variety of examples of the KR of 1-
heteroarylalkanols 6-9 under the standard reaction conditions,
and the generality of this protocol is demonstrated as shown in
Table 2. The reaction of 1-(3-thienyl)ethanol ((«)-6), a position-
al isomer of 1-(2-thienyl)ethanol ((«)-4a), afforded nearly the
same good s-value as that of the reaction of («)-4a irrespective
of the substitution pattern (Entry 1). It was revealed that the
reaction of the racemic 1-(1,3-thiazol-2-yl)ethanol ((«)-7) and 1-
(benzothiazol-2-yl)ethanol ((«)-8a) showed almost the same
reactivity, whether or not an extra aromatic ring on («)-7 exists
(Entries 2 and 3). On the other hand, we found that the
selectivities depend on the structures of the ring systems of the
aromatic moieties of («)-7 and («)-8a, and a better result was
Scheme 1. Transition structure ts-(R)-1a derived from (R)-1-(2-
furyl)ethanol ((R)-1a) with the intermediary zwitterionic species
(int-II) (See also SI).7
obtained in the latter case (Entry 2; s = 37 versus Entry 3;
s = 57). As shown in Entry 6, the reaction of 1-(benzoxazol-2-
yl)ethanol ((«)-9a) provided the desired chiral ester (R)-13a in
quantitative yield with good selectivity (50%, 92% ee), and the
remaining alcohol (S)-9a was also recovered in very high yield
and selectivity (46%, 99% ee) to afford an overall excellent
selectivity (s = 122). It is noteworthy that all the derivatives
of benzothiazoles 8a-8c and benzoxazoles 9a-9c in Table 2
(Entries 3-8) were successfully converted into the corresponding
chiral esters (R)-12a-12c/13a-13c with excellent selectivities
(s = 57-142) regardless of the aliphatic substituent R (R = Me;
8a/9a, R = Et; 8b/9b, R = i-Pr; 8c/9c).
Determination of the transition state forming the optically
active (R)-ester from (R)-1-(2-furyl)ethanol ((R)-1a) with the
intermediary zwitterionic species (int-II), which was generated
from acetic anhydride and (R)-BTM, was carried out using DFT
calculations according to the former report on the KR of the
racemic 2-hydroxyalkanoates.5,10 Among the several calculated
transition state models forming the desired ester from the alcohol
(R)-1a with int-II, the most stable structure ts-(R)-1a is depicted
in Scheme 1. All of the three-dimensional structures of the
transition states in Scheme 1 and Figure 2 are shown in the SI.7
We noted the stacking correlation between the furan ring and the
plane surface of the conjugated aromatics in the dihydro-
Chem. Lett. 2011, 40, 147-149
© 2011 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/

149
category, because the value of the dihedral angle ª(N1-C2-C3-C*cat)
of ts-(R)-9a is very small (ª = ¹24.8°). The value of the
dihedral angle of ts-(R)-9a is very close to that of ts-(R)-A
(ª = ¹12.5°) consisting of acetic anhydride, (R)-BTM, and
methyl (R)-lactate. Hence, the observed strong coordination of
nitrogen to the cationic center of ts-(R)-9a might be crucial to
stabilizing the structure of ts-(R)-9a. It is deduced that the
effective KR of the 1-(benzoxazol-2-yl)ethanol via ts-(R)-9a was
attained from this structural effect in the transition state, because
the similar transition state ts-(R)-A also includes the strong
coordination of oxygen to the cationic center and the successful
KR of the racemic 2-hydroxyesters was attained in prior
experiments to produce remarkably high selectivity factors
(s = 47-202).5
In summary, we have achieved the first efficient non-
enzymatic method for providing the optically active 1-hetero-
arylalkanol derivatives by the KR of the racemic 1-hetero-
arylalkanols with diphenylacetic acid using pivalic anhydride in
the presence of (R)-benzotetramisole ((R)-BTM). Further studies
of the present method to provide chiral materials and other
applications of this novel protocol are now in progress in our
laboratory.
Figure 2. Transition structures ts-(R)-4a, ts-(R)-6, ts-(R)-8a,
and ts-(R)-9a derived from (R)-1-(2-thienyl)ethanol ((R)-4a),
(R)-1-(3-thienyl)ethanol ((R)-6), (R)-1-(benzothiazol-2-yl)etha-
nol ((R)-8a), and (R)-1-(benzoxazol-2-yl)ethanol ((R)-9a) with
the intermediary zwitterionic species (int-II).
This study was partially supported by a Research Grant from
Toray Science Foundation.
imidazolium salt because the value of the dihedral angle
ª(C1-C2-C3-C*cat) in ts-(R)-1a is very large (ª = 66.2°). This
transition structure belongs to the ts-(R)-B type category similar
to the reaction of the benzylic alcohols (cf. Figure 1 and SI);7
and therefore, the strong coordination of oxygen in the furan
ring to the positive electronic charge on the face of dihydro-
imidazolium salt is not observed in ts-(R)-1a.
Based on the former systematic studies of the reactions of
(R)-4a, (R)-6, (R)-8a, and (R)-9a with int-II generated from acid
anhydride with (R)-BTM, the corresponding transition structures
were also determined as shown in Figure 2. The calculated
results (upper two figures) showed that the dihedral angles
ª(C1-C2-C3-C*cat) of the transition states ts-(R)-4a and ts-(R)-6,
which were derived from (R)-1-(2-thienyl)ethanol ((R)-4a) and
(R)-1-(3-thienyl)ethanol ((R)-6), are very large (ª = 79.5 and
66.6°, respectively); consequently, it was proven that the
thiophene groups function as ³-electron donors to the plane
surface of the conjugated aromatics in the dihydroimidazolium
salt to form the ts-(R)-B type transition structures.
On the other hand, it was found that the sulfur in
benzothiazole firmly coordinates to the cationic center in the
most stable transition state ts-(R)-8a (Figure 2, left column,
bottom figure), which was derived from (R)-1-(benzothiazol-2-
yl)ethanol ((R)-8a) with int-II. The value of the dihedral angle
ª(S1-C2-C3-C*cat) of the transition states ts-(R)-8a is relatively
small (ª = 38.2°), so that this structure could be classified in the
ts-(R)-A type category, and we can observe the stabilization of
ts-(R)-8a due to the attractive interaction between sulfur in the
benzothiazole moiety and the positive electronic charge on the
face of the dihydroimidazolium salt in this bond-forming step.
Furthermore, we could determine the transition structure of
the reaction of (R)-9a with int-II.11 The peculiar form of ts-(R)-
9a is also depicted in Figure 2 (right column, bottom figure), in
which the nitrogen in the oxazole coordinates to the cation
center of int-II. This structure also belongs to the ts-(R)-A type
References and Notes
1
a) J. Kaminska, I. Górnicka, M. Sikora, J. Góra, Tetrahedron:
Asymmetry 1996, 7, 907. b) A. Ghanem, V. Schurig, Tetrahedron:
Asymmetry 2001, 12, 2761. c) L. Zhu, A. Talukdar, G. Zhang, J. P.
Kedenburg, P. G. Wang, Synlett 2005, 1547. d) M. Toşa, S.
Pilbák, P. Moldovan, C. Paizs, G. Szatzker, G. Szakács, L. Novák,
F.-D. Irimie, L. Poppe, Tetrahedron: Asymmetry 2008, 19, 1844.
a) I. Shiina, K. Nakata, Tetrahedron Lett. 2007, 48, 8314. b) I.
Shiina, K. Nakata, M. Sugimoto, Y. Onda, T. Iizumi, K. Ono,
Heterocycles 2009, 77, 801. c) K. Nakata, I. Shiina, Heterocycles
2010, 80, 169.
2
3
Kinetic resolution of («)-carboxylic acids: a) I. Shiina, K. Nakata,
Y. Onda, Eur. J. Org. Chem. 2008, 5887. b) I. Shiina, K. Nakata,
K. Ono, Y. Onda, M. Itagaki, J. Am. Chem. Soc. 2010, 132,
11629.
4
5
6
a) V. B. Birman, X. Li, Org. Lett. 2006, 8, 1351. b) V. B. Birman,
L. Guo, Org. Lett. 2006, 8, 4859.
I. Shiina, K. Nakata, K. Ono, M. Sugimoto, A. Sekiguchi,
Chem.®Eur. J. 2010, 16, 167.
All calculations were performed with the program package
Spartan ’08 1.1.1 of Wavefunction Inc. (http://www.wavefun.
com).
7
Supporting Information is also available electronically on the
CSJ-Journal Web site, http://www.csj.jp/journals/chem-lett/index.
html.
8
9
X. Li, P. Liu, K. N. Houk, V. B. Birman, J. Am. Chem. Soc. 2008,
130, 13836.
H. B. Kagan, J. C. Fiaud, Top. Stereochem. 1988, 18, 249.
10 Energy difference between transition states to form (R)-2a and
(S)-2a from (R)-1a and (S)-1a with the 2nd intermediate (int-II),
which was generated from diphenylacetic acid (3) and pivalic
¹1
anhydride was calculated to be 3.92 kcal mol at the B3LYP/6-
311+G**// B3LYP/6-31G* level. See the SI.7
11 Energy difference between transition states to form (R)-13a and
(S)-13a from (R)-9a and (S)-9a with the 2nd intermediate (int-II),
which was generated from diphenylacetic acid (3) and pivalic
¹1
anhydride was calculated to be 4.76 kcal mol at the B3LYP/6-
311+G**// B3LYP/6-31G* level. See the SI.7
Chem. Lett. 2011, 40, 147-149
© 2011 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/