Rational design of an L-histidine-derived minimal artificial acylase for the kinetic resolution of racemic alcohols

Article abstract of DOI:10.1021/ja045850j

This communication describes the rational design of an l-histidine-derived minimal artificial acylase. Our new artificial acylase, tert-butyldiphenylsilyl ether of N-(2,4,6-triisopropylbenzenesulfonyl)-π(Me)-l-histidinol, is a simple and small molecule (m

Full text of DOI:10.1021/ja045850j

Published on Web 09/11/2004
Rational Design of an L-Histidine-Derived Minimal Artificial Acylase for the
Kinetic Resolution of Racemic Alcohols
Kazuaki Ishihara,*,† Yuji Kosugi,† and Matsujiro Akakura‡
Graduate School of Engineering, Nagoya UniVersity, Furo-cho, Chikusa, Nagoya 464-8603, Japan, and
Department of Chemistry, Aichi UniVersity of Education, Igaya-cho, Kariya 448-8542, Japan
Received July 10, 2004; E-mail: ishihara@cc.nagoya-u.ac.jp
Table 1. Comparison of Catalytic Activities of Bases for the
The kinetic resolution of racemic secondary alcohols has
traditionally been achieved by using acylases.1 Recently, several
impressive examples of the nonenzymatic kinetic resolution of
racemic alcohols with achiral anhydrides have been reported using
nucleophilic chiral analogues of trialkylphosphine,2 4-(dimethyl-
amino)pyridine (DMAP),3 and 1-alkylimidazole (1-alkyl-IMD).4 In
particular, Miller’s biomimetic approach4 to the identification of
artificial acylases based on â-turn peptide fragments with defined
secondary structures that contain 1-alkyl-IMD residues prompted
our present study. In this communication, we report the rational
design of an L-histidine-derived minimal artificial acylase. The new
artificial acylase 1d is a simple and small molecule (molecular
weight ) 660) that contains only one chiral carbon center that
originates from natural L-histidine. Reusable polystyrene-bound
catalyst 2 was also developed to evaluate the practical usability of
1d (Chart 1).
Acetylation of Menthol with Acetic Anhydridea
catalyst (mol %)
time (h)
yield (%)
|µ| (D)b
|µx| (D)b
DMAP, 5
0.5
0.5
3.0
3.0
3.0
3.0
100
47
100
73
29
23
4.84
4.46
4.46
4.27
3.87
4.11
4.83
4.26
4.26
3.93
3.61
3.58
1,5-Me2-IMD, 5
1,5-Me2-IMD, 5
1-Me-IMD, 10
1,4-Me2-IMD, 10
1,2-Me2-IMD, 10
a Unless otherwise noted, menthol (1 mmol), Ac2O (1.5 mmol), i-Pr2EtN
(1.5 mmol), and MeCN (2 mL) were used. b µ ) µx + µy, dipole moment
of catalyst. |µ| was calculated at the B3LYP/6-311++G(d,p) level.
with (i-PrCO)2O (eq 2).3c Reactions were allowed to proceed for 3
h at room temperature in toluene under conditions using 5 mol %
of catalyst relative to 6a. As shown in Table 2, all of the L-histidine-
Chart 1. Homo- and Heterogeneous Artificial Acylases 1d and 2
Table 2. Kinetic Resolution of (()-6a [R ) 4-(Me2N)C6H4] (eq 2)a
ee (%)b
Initially, the catalytic activity of Me2-IMD in the acetylation
of menthol with acetic anhydride was investigated (Table 1). 1,5-
Me2-IMD was the most active among 1,2-, 1,4-, and 1,5-Me2-
IMD and 1-Me-IMD, although it was less active than DMAP. The
catalytic activity increased in proportion to the intensity of the dipole
moment (µx) on the x-axis parallel to a lone pair at the 3-positon.
Thus, it was ascertained that Miller’s L-histidine-derived peptide
was suitable as an artificial acylase.
Our initial considerations for the design of new artificial acylases
focused on two functional groups derived from L-histidine: (i) a
1,5-dialkyl-IMD component as a nucleophilic catalytic moiety and
(ii) an amide component as a hydrogen-bonding domain.4 Thus,
sulfonamide 1 and carboxamide 5 were prepared from N(π)-Me-
L-histidiol (3)5 in two steps (eq 1).6
catalyst (S)-1, 4, or 5 (Ar, X)
6a
f
7a (%)c
6a
7a
Sc
5 (C6H5, OSiPh2t-Bu)
1a (C6H5, OSiPh2t-Bu)
1b (p-(CF3)C6H4, OSiPh2t-Bu)
1c (2,4,6-i-Pr3C6H2, OCOi-Pr)
4 (2,4,6-i-Pr3C6H2, OCOi-Pr)
1d (2,4,6-I-Pr3C6H2, OSiPh2t-Bu)
36
3
60
52
70
3
5
57
71
77
7
1
51
42
48
30
47
7
10
16
1
74
83
24
a Unless otherwise noted, (()-6a (1 equiv), (i-PrCO)2O (0.5 equiv),
i-Pr2EtN (0.5 equiv), catalyst (5 mol %), and toluene (2 mL) were used.
b HPLC analysis. c Calculated according to the method of ref 7.
derived catalysts examined resulted in the preferential acyltion of
(1R,2S)-6a. When 1d bearing two bulky groups, 2,4,6-i-Pr3C6H2-
SO2 and t-BuPh2SiO groups, was used, (1R,2S)-7a was obtained
in 83% ee at 47% conversion [S (kfast/kslow) ) 24]. The use of
sulfonamide 1a gave (1R,2S)-6a much more selectively and rapidly
than that of carboxamide 5. In addition, higher asymmetric induction
was observed with the use of a more acidic sulfonamide catalyst
(1a versus 1b). In contrast, aprotic catalyst 4 was less active and
showed almost no selectivity (S ) 1). These results suggest that
hydrogen bonding between 1d and 6a may be a key interaction for
attaining a high level of kinetic resolution.
1, 4, and 5 were evaluated as catalysts for the kinetic resolution
of (()-cis-1-[p-(dimethylamino)benzoyl]-2-hydroxyhexane (6a)
If hydrogen bonding between 1d and 6a is truly a key interaction,
then 6 bearing a more electron-donating group (R) should give better
† Nagoya University.
‡ Aichi University of Education.
9
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J. AM. CHEM. SOC. 2004, 126, 12212-12213
10.1021/ja045850j CCC: $27.50 © 2004 American Chemical Society

C O M M U N I C A T I O N S
Table 3. Screening of R of (()-6 and Influence of Solvent on the
Kinetic Resolution of (()-6 Induced by 1d (eq 2)a
ee (%)b
entry
racemic alcohol (
±
)-6 [R-]
solvent
6
f
7 (%)c
6
7
Sc
1
2
3
4
6a[p-(Me2N)C6H4-]
6a[p-(Me2N)C6H4-]
6a[p-(Me2N)C6H4-]
6a[p-(Me2N)C6H4-]
6a[p-(Me2N)C6H4-]
6b[Me2N-]
CH3CN
THF
CH2Cl2
toluene
CCl4
CCl4
CCl4
CCl4
30
25
38
50
74
81
96
99
97
57
59
66
83
83
83
83
90
5
6
8
24
27
42
64
87
39
43
47
49
53
54
52
5
6
7d
8d
6b[Me2N-]
6c[(CH2CH2)2N-]
Figure 1. ORTEP plot of 1d (left) and a proposed transition-state assembly
(right). The figure is drawn with 50% probability, and hydrogen atoms
except for the SO2NH moiety are omitted for clarity (left).
a See footnote a in Table 2. b HPLC analysis. c See footnote c in Table
2. d The reaction was carried out at 0 °C for 3 h.
Table 4. Kinetic Resolution of Racemic Alcohols 8-15
[R ) (CH2CH2)2N-] Induced by 1d (A ) Alcohol; E )
Isobutyrate of A)a
2 (5 mol %) was reused more than 6 times for the acylation of
(()-6c (1 equiv) with (i-PrCO)2O (0.5 equiv) under shaking at 0
°C for 7 h in the presence of i-Pr2EtN (0.5 equiv) without any loss
of activity or selectivity ((1R,2S)-7c: ∼48-49% yield, ∼87-90%
ee; S value ) 37).
A
f
(%)b
E
ee (%)c
A, E
A
f
(%)b
E
ee (%)c
A, E
(
±
)-A
Sb
(±
)-A
Sb
In summary, we have designed a minimal artificial acylase 1d
derived from L-histidine by introducing a sulfonylamino group in
place of a polypeptide chain on the basis of the notion that
sulfonamide hydrogen bonding is much stronger than the corre-
sponding carboxamide interaction. In addition, we developed a
reusable organocatalyst 2, which should greatly contribute to green
and sustainable chemistry.
8d
49
50
47
44
90, 94
93, 92
82, 93
64, 82
93
83
68
19
12d
13e
14f
15d
49
42
39
50
80, 82
67, 93
51, 80
88, 86
25
51
15
39
9d
10d
11d
a See footnote a in Table 2. b See footnote c in Table 2. c HPLC or GC
analysis. d 0 °C, 3 h; CCl4. e 0 °C, 3 h; CHCl3-CCl4 (2:3). f 0 °C, 4 h;
CHCl3-CCl4 (1:5).
Acknowledgment. Financial support for this project was
provided by the JSPS. KAKENHI (15205021), the 21st Century
COE Program “Nature-Guided Materials Processing” of MEXT,
and the Ichihara International Scholarship Foundation.
results than 6a. As shown in Table 3, carbamates 6b and 6c were
more effective than 6a (entries 5-8). In particular, the S value for
the kinetic resolution of (()-6 was dramatically increased to 87 by
using 6c in place of 6a (entry 8). In addition, CCl4 and toluene
were more suitable solvents, probably because less polar solvents
did not inhibit hydrogen bonding interaction (entries 1-5).
To explore the generality and scope of the 1d-induced kinetic
resolution of secondary alcohols, the acylation of several structurally
diverse alcohols with (i-PrCO)2O was examined (Table 4). The
acylations of not only cyclic 1,2-diol derivatives 8 and 9 but also
acyclic 10 gave S values of more than 68. Hydroxycarboxylic acid
derivatives 11 and 12 and amino alcohol derivatives 13-16 were
also suitable substrates.
According to an X-ray structural analysis, a N-H bond and IMD
ring in 1d are parallel to each other on the same side, probably
due to steric limitations imposed by the two bulky substituents
(Figure 1). A transition-state assembly formed from 1d, (1R,2S)-
6c, and (i-PrCO)2O was proposed on the basis of this X-ray structure
(Figure 1). The conformation of the acyl group in the acylammo-
nium salt generated from 1d and (i-PrCO)2O would be fixed by
the attractive electrostatic interaction between its acyl oxygen and
imidazoyl-2-proton or the dipole minimization effect.8 Hydrogen
bonding between the sulfonylamino proton of acylammonium salt
and the carbamoyl oxygen of 6c preferentially promotes the
acylation of (1R,2S)-6c by a proximity effect. On the other hand,
similar hydrogen bonding with (1S,2R)-6c inhibits its acylation.
Polymer-bound catalyst 2 was easily prepared from commercially
available resin 166 and 1 (Ar ) 2,4,6-i-Pr3C6H2, X ) OH) (eq 3).3h
Supporting Information Available: Experimental procedures, full
characterization of new compounds, and crystallographic data for 1d
(PDF, CIF). This material is available free of charge via the Internet at
http://pubs.acs.org.
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