Kinetic resolution of sec-alcohols by a new class of pyridine catalysts having a conformation switch system

Article abstract of DOI:10.1016/j.tetlet.2005.02.019

The catalysts having a conformation switch system induced by acylation and deacylation serve as asymmetric acylating catalysts of sec-alcohols. The kinetic resolution of various sec-alcohols resulted in good to excellent selectivities in the presence of 0.5 to 0.05 mol % of catalyst 1a. The conformation switch system plays a key role to attain both good selectivity and high catalytic activity.

Full text of DOI:10.1016/j.tetlet.2005.02.019

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 2239–2242
Kinetic resolution of sec-alcohols by a new class of
pyridine catalysts having a conformation switch system
*
Shinji Yamada, Tomoko Misono and Yuko Iwai
Department of Chemistry, Ochanomizu University, Bunkyo-ku, Tokyo 112-8610, Japan
Received 27 December 2004; revised 1February 2005; accepted 3 February 2005
Abstract—The catalysts having a conformation switch system induced by acylation and deacylation serve as asymmetric acylating
catalysts of sec-alcohols. The kinetic resolution of various sec-alcohols resulted in good to excellent selectivities in the presence of 0.5
to 0.05 mol % of catalyst 1a. The conformation switch system plays a key role to attain both good selectivity and high catalytic
activity.
Ó 2005 Elsevier Ltd. All rights reserved.
Kinetic resolution is an effective method for obtaining
chiral sec-alcohols. Various types of non-enzymatic
1
acyl-transfer organocatalysts such as chiral phos-
5
2
,3
4
phines, diamines, 4-aminopyridine analogues, pep-
6
,7
8
tide-based
catalysts,
dihydroimidazopyridines,
9
and N-heterocyclic carbenes have extensively been
explored, and the catalytic acylations are achieved by
them in high enantioselectivities. Nevertheless, further
development of a new class of acylating catalysts has
continued to be an important challenge in synthetic
organic chemistry.
Scheme 1.
alcohols and the uncomplexed form I causes smooth
N-acylation for the next catalytic cycle. This concept
seems to be related to an induced-fit process proposed
We have recently found a new type of cation–p interac-
tion between a pyridinium ring and a thiocarbonyl
1
3
1
0
by Kawabata et al.
1
1
group. This interaction was utilized for the selective
shielding of the pyridinium face by the thiocarbonyl
group, which enabled nucleophiles to attack the oppo-
Recently, several groups have extensively developed pyri-
dine catalysts for asymmetric acylation of alcohols. The
key feature of the catalytic reactions is selective blocking
of the pyridinium ring by an aromatic moiety such as
1
2
site side to give chiral 1,4-dihydropyridines. This result
suggests a new conformation switch system based on the
interconversion between uncomplexed form I and self-
complexed form II induced by N-acylation and deacyla-
tion steps as shown in Scheme 1. We planned to develop
new asymmetric acylating catalysts having this confor-
mation switch system because this system would play a
key role to attain both high catalytic activity and selec-
tivity in the kinetic resolution; the formation of cation–p
complex II enables discrimination of enantiomeric sec-
1
4
13
pentaphenylcyclopentadienyl,
naphthyl,
binaph-
1
5
16
17
thyl, biaryl, and substituted aryl group; however,
a non-aromatic system has not yet been reported. In this
letter, we report a new class of pyridine catalysts having
a conformation switch system, which serve as practical
asymmetric acylating catalysts for sec-alcohols.
We prepared 4-dimethylaminopyridine (DMAP) and 4-
pyrrolidinopyridine (PPY) analogues 1–4 possessing
chiral thiazolidine-2-thione, oxazolidine-2-thione or
oxazolidine-2-one. These catalysts can be readily pre-
pared from 4-aminonicotinic acid obtained from com-
mercially available 4-chloropyridine with the chiral
Keywords: Kinetic resolution; Cation–p interaction; Asymmetric acyl-
ation; Organocatalyst; Conformation switch system.
*
Corresponding author. Tel.: +813 5978 5349; fax: +813 5978
715; e-mail: yamada@cc.ocha.ac.jp
1
8
5
auxiliary. Acylation of 1-(2-naphthyl)ethanol (8) with
0
040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.02.019

2240
S. Yamada et al. / Tetrahedron Letters 46 (2005) 2239–2242
isobutyric anhydride smoothly proceeded in the pres-
ence of 5 mol % of catalysts 1–4 in toluene at 0 °C
temperature is also an important factor to attain high
stereoselectivity (entries 11–13); lowering the tempera-
ture increases the s value. We next studied the effect of
the catalyst amount on the reactions (entries 12, 14,
and 15). Reducing the catalyst amount from 5 mol %
to 0.5 mol % had little effect on the s value, and the reac-
tions were completed within 12 h. Remarkable is that
the further reducing of the catalyst to 0.05 mol % re-
sulted in the same selectivity as in the case of entry 14,
though the reaction required 72 h to reach 55%
conversion.
1
9
(
Table 1, entries 1–6). The selectivity largely depends
on the substituent of the catalysts; compound 1a having
a bulky tert-butyl group provides the highest selectivity
among 1a–c. Compounds 2 and 3 also served as effective
acylating catalysts, whereas 4 was less effective, suggest-
ing the importance of the C@S group to attain high
enantioselectivity. The absolute configuration of the
recovered alcohol was assigned to be S by comparison
of the specific rotation with that of the literature.
This method is applicable to various sec-alcohols as
shown in Table 2. Acylation of 1-phenylethanol (9) with
isobutyric anhydride in the presence of 0.5 mol % of 1a
2
1
and Et N gave good selectivity. The electron-donating
3
and withdrawing groups at the p-position on 10 and 11,
respectively, had little effect on the s values. This indi-
cates that the intermolecular interaction described later
is so stronger that the selectivities do not receive the
substituent effect. These conditions are also effective
for sterically hindered alcohol 12. Kinetic resolution of
1-(1-naphthyl)ethanol (13) gave a similar result to that
of its isomer 8. This method is applicable for hetero-
cyclic sec-alcohol 14, and allylic and propargylic alco-
hols 15 and 16; lowering the temperature to À30 °C
much improved the selectivities. In most cases the s
values are larger than 7, showing the practical usefulness
1
9
of this method.
1
H NMR studies of 1a, 5–7 and N-isobutyryl form of 1a
provided insight into the reaction mechanism. Figure 1
A survey of acylating reagents revealed that isobutyric
anhydride afforded the highest selectivity among the
anhydrides that we have investigated. The solvents sig-
nificantly affect the s values (entries 7–11); use of acyclic
ethers Et O, i-Pr O, and t-BuOMe remarkably im-
2
2
shows Dd1a and Dd5, which are differences between
d1a and d6 and d5 and d7, respectively. These values
reflect the effect of the thiocarbonyl moiety on the
pyridine and the pyridinium protons. Comparison of
the Dd1a and the Dd5 clarified significant differences
between them. The DdH2 and DdH6 values for 5 are
2
2
proved the selectivities (entries 9–11), whereas polar sol-
vents were less effective (entries 7 and 8). The reaction
a
Table 1. Kinetic resolution of 1-naphthylethyl alcohol catalyzed by 1–4
b
Conv (%)
c
s
Entry
Cat (mol%)
Solvent
Temp (°C)
Time (h)
ee (%)
1
2
3
4
5
6
7
8
9
1a (5)
1b (5)
1c (5)
2 (5)
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
0
0
3
3
59
55
87
74
73
11
9.1
7.0
0
3
58
0
3
6188
57
9.8
3 (5)
4 (5)
0
3
82
37
11
0
3
53
2.7
1a (5)
1a (5)
1a (5)
1a (5)
1a (5)
1a (5)
1a (5)
1a (0.5)
1a (0.05)
CH
THF
Et
i-Pr
3
CN
0
3
6168
60
5.0
80
0
3
7.6
2
O
0
3
6 15 96
50
1
10
11
12
13
14
15
2
O
0
3
78
95
99
97
92
87
1
9
t-BuOMe
t-BuOMe
t-BuOMe
t-BuOMe
t-BuOMe
0
3
57
64
24
18
30
17
17
25
À30
25
25
3
5
56
57
12
72
55
a
b
c
0
.7 equiv of (i-PrCO)
Conversion (%) = ee of recovered 8/(ee of recovered 8 + ee of ester), see Ref. 20.
Selectivity factor s = k(fast-reacting enantiomer)/k(slow-reacting enantiomer), see Ref. 19.
2
O and 0.8 equiv of collidine were used.

S. Yamada et al. / Tetrahedron Letters 46 (2005) 2239–2242
2241
a
Table 2. Kinetic resolution of various alcohols catalyzed by 1a
b
% ee (config)
c
d
s (% conv)
e
Substrate
8
9
9 (S)
7 (S)
7.6 (65)
10 (68)
9
8
9
8 (S)
8.9 (72)
9.6 (62)
13 (65)
f
8 (S)
Figure 2. Plausible catalytic cycle.
Figure 2 shows a plausible catalytic cycle. Acylation of
the catalyst with isobutyric anhydride gives conforma-
tionally locked N-acylpyridinium salt A as a result
of an intramolecular cation–p interaction. This confor-
7 (S)
2
3
mation is clarified by NOE experiments and DFT
e
8.1 (66)
24
9
9
2 (S)
4 (S)
calculations. One of two enantiomers of racemic
sec-alcohols preferentially attacks the intermediate A
2
5
from B-side to give the corresponding ester with recov-
ery of the catalyst. The catalyst restored conformational
freedom undergoes smooth N-acylation of the next
cycle.
e
9.8 (65)
The stereoselectivity can be explained by comparison of
the two transition state models TS-I and TS-II for the
acylation of (R)- and (S)-alcohols, respectively, as
shown in Figure 3. Both alcohols would approach the
pyridinium ring from B-side with face to face orienta-
tion due to a cation–p interaction between the pyridi-
e
6.6 (61)
7
8 (S)
a
All reactions were conducted in the presence of 0.5 mol % of 1a,
i
.8 equiv of (Pr CO)
0
2 3
O and 0.9 equiv of Et N at rt for 12 h unless
otherwise noted.
26
nium ring and the phenyl ring. While (R)-alcohol can
b
c
Determined by HPLC using chiral stationary phases.
Conversion (%) = ee of recovered alcohol/(ee of recovered alco-
hol + ee of ester), see Ref. 20.
effectively approach the N-acyl group, (S)-alcohol
receives significant steric repulsion with the amide
moiety during approaching the N-acyl group; therefore,
the acylation preferentially proceeds through TS-I to
give (R)-ester predominantly.
d
Selectivity factor s = k(fast-reacting enantiomer)/k(slow-reacting
enantiomer), see Ref. 19.
e
f
À30 °C, 48 h.
The reaction time is 72 h.
In summary, we have developed a new class of acylating
catalysts having a conformation switch system. The cata-
lytic kinetic resolution of various sec-alcohols resulted
in good to excellent selectivities in the presence of 0.5–
0.05 mol % of catalyst. These catalysts have compact
structures with small molecular weights. In addition,
they are easily prepared from a commercially available
Figure 1. (a) Dd1a values and (b) Dd5 values.
1
.09 and À0.44, respectively, the absolute values of
which are much larger than those of 1a (0.08 and
.04). These observations are comparable with those of
a previously reported cation–p complex having a thio-
0
1
1
carbonyl group and a pyridinium ring, strongly sug-
gesting the existence of an intramolecular interaction
in pyridinium salt 5.
Figure 3. Schematic favored (TS-I) and disfavored (TS-II) transition
structures for acylation of S and R alcohols, respectively.

2242
S. Yamada et al. / Tetrahedron Letters 46 (2005) 2239–2242
pyridine compound with a chiral auxiliary. These fea-
tures clearly show a significant synthetic utility of these
catalysts from a practical point of view.
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Acknowledgements
This work was supported by a Grant-in-Aid for Explor-
atory Research (No. 16655034) from the Japan Society
for the Promotion of Science.
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6
7
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