Kinetic resolution of racemic alcohols using thioamide modified 1-methyl-histidine methyl ester

Article abstract of DOI:10.1021/jo801859m

(Chemical Equation Presented) The low-molecular-weight and easily prepared N-thiobenzoyl 1-methyl-histidine methyl ester 3k was utilized to efficiently catalyze the kinetic resolution of racemic secondary alcohols. Comparison of the conformations of amide

Full text of DOI:10.1021/jo801859m

Kinetic Resolution of Racemic Alcohols Using Thioamide Modified
1-Methyl-histidine Methyl Ester
Xue-Li Geng, Jia Wang, Guo-Xing Li, Peng Chen, Shu-Fang Tian, and Jin Qu*
The State Key Laboratory of Elemento-Organic Chemistry, Nankai UniVersity, Tianjin 300071, P. R. China
qujin@nankai.edu.cn
ReceiVed August 21, 2008
The low-molecular-weight and easily prepared N-thiobenzoyl 1-methyl-histidine methyl ester 3k was
utilized to efficiently catalyze the kinetic resolution of racemic secondary alcohols. Comparison of the
conformations of amide catalyst 3c and thioamide catalyst 3k was made to understand the origin of the
improvement of the enantioselectivity by thioamide modification.
Introduction
Owing to the great efforts of organic chemists, currently there
are numerous chiral structures one may choose to use in
enantioselective chemical reactions. Among them, some chiral
molecules producing excellent asymmetric induction can be
easily prepared from commercially available and inexpensive
starting materials. These catalysts are practical for users who
wish to prepare them in their own laboratories. Two typical
examples are TADDOLs1 (a group of versatile chiral auxiliaries)
and fructose-derived ketone2 (Shi epoxidation catalyst) that can
be readily synthesized via simple two-step transformations from
tartrate and fructose, respectively. Because of the good acces-
sibility, they are among the most frequently used chiral inductive
materials in organic chemistry laboratories. Our laboratory’s
long-term goal is to discover more such user-friendly chiral
molecules and use them in enantioselective organocatalytic
reactions.
FIGURE 1. Miller’s N-methyl-histidine based ꢀ-hairpin-like tetrapep-
tide catalyst 1 and Ishihara’s histidinol-derived catalyst 2.
The catalysts that have been utilized for nonenzymatic
enantioselective acylation3 were chiral analogs of trialkylphos-
phine,4 dialkylaminopyridine,5 and recently discovered ring-
fused imidazoline.6 In particular, Miller’s research group
developed N-methyl-histidine containing oligopeptides (Figure
1) that successfully catalyze the kinetic resolution of secondary
alcohols containing a hydrogen bond accepting auxiliary.7a-h
The efficiency of this strategy was further demonstrated by
Ishihara’s research group. They reported that histidinol deriva-
tive 2, containing only one chiral center, could catalyze the simi-
lar transformations with very impressive enantioselectivities.7j,k
In the X-ray structure of histidinol derivative 2, the amide
NH (H-bonding site) and the N-methyl imidazole ring (reactive
(1) Seebach, D.; Beck, A. K.; Heckel, A. Angew. Chem., Int. Ed. 2001, 40,
92.
(2) Shi, Y. Acc. Chem. Res. 2004, 37, 488.
(3) For excellent reviews on kinetic resolution using nonenzymatic catalysts,
see: (a) Kagan, H. B.; Fiaud, J. C. Top. Stereochem. 1988, 18, 294. (b) Spivey,
A. C.; Maddaford, A.; Redgrave, A. J. Org. Prep. Proced. Int. 2000, 32, 333.
(c) Keith, J. M.; Larrow, J. F.; Jacobsen, E. N. AdV. Synth. Catal. 2001, 343, 5.
(d) Robinson, D. E. J. E.; Bull, S. D. Tetrahedron: Asymmetry 2003, 14, 1407.
(e) Vedejs, E.; Jure, M. Angew. Chem., Int. Ed. 2005, 44, 3974.
(4) For a recent example of kinetic resolution employing trialkylphosphine
catalysts, see: (a) Vedejs, E.; Daugulis, O.; Harper, L. A.; MacKay, J. A.; Powell,
D. R. J. Org. Chem. 2003, 68, 5020. (b) Vedejs, E.; Daugulis, O. J. Am. Chem.
Soc. 2003, 125, 4166. (c) MacKay, J. A.; Vedejs, E. J. Org. Chem. 2006, 71,
498.
(5) For recent examples of kinetic resolution using chiral dialkylaminopyridine
catalysts, see: (a) Wurz, R. P. Chem. ReV. 2007, 107, 5570. (b) Spivey, A. C.;
Zhu, F.; Mitchell, M. B.; Davey, S. G.; Jarvest, R. J. J. Org. Chem. 2003, 68,
7379. (c) Kawabata, T.; Stragies, R.; Fukaya, T.; Fuji, K. Chirality 2003, 15,
71. (d) Priem, G.; Pelotier, B.; Macdonald, S. J. F.; Anson, M. S.; Campbell,
´
I. B. J. Org. Chem. 2003, 68, 3844. (e) Da´laigh, C. O.; Hynes, S. J.; O’Brien,
J. E.; McCabe, T.; Maher, D. J.; Watson, G. W.; Connon, S. J. Org. Biomol.
´
Chem. 2006, 4, 2785. (f) Da´laigh, C. O.; Connon, S. J. J. Org. Chem. 2007, 72,
7066. (g) Yamada, S.; Misono, T.; Iwai, Y.; Masumizu, A.; Akiyama, Y. J.
Org. Chem. 2006, 71, 6872.
8558 J. Org. Chem. 2008, 73, 8558–8562
10.1021/jo801859m CCC: $40.75 2008 American Chemical Society
Published on Web 10/10/2008

Kinetic Resolution of Racemic Alcohols
TABLE 1. Kinetic Resolution of (()-4a by 3a-3ka
FIGURE 2. Newman projections of the three possible conformations
by rotating the CR-Cꢀ bond of histidine derivatives: the imidazole ring
and the amide NH are at the same side in rotamers I and III, whereas
they are at the opposite side in rotamer II.
site) are at the same side and parallel to each other, which is
probably forced by two very bulky groups at the N-terminal
and the C-terminal.7j,k An analysis of the X-ray structure of 2
revealed that it adopts the conformation of rotamer III (Figure
2), which exhibits steric hindrance at imidazole ring site. In a
series of studies about the side chain’s orientation of aromatic
8
1
amino acids using H NMR spectroscopy, it was found that
rotamer III is strongly preferred for N-acylated histidine ester
such as Ac-His-OMe in nonpolar solvent (the population of
rotamer III is more than 50% in chloroform at room temper-
ature). However, in polar organic solvent and aqueous solution,
the less steric hindered rotamer I is the most stable conformation.
We then questioned if an N-acylated histidine ester preferring
the conformation of rotamer III might be directly used to
catalyze asymmetric acylation in nonpolar solvents. In this paper,
we wish to report our attempts to use N-thiobenzoyl 1-methyl-
histidine methyl ester as catalyst for kinetic resolution of racemic
secondary alcohols.
catalyst
conv (%)
ee (%)b 5a
ee (%)b 4a
Sc
3a
3b
3c
3d
3e
3f
3g
3h
3i
48
49
50
51
53
50
49
51
49
48
52
28
44
54
53
50
5
44
53
77
13d
90
27
42
53
56
58
4
46
55
73
12
97
2.3
3.8
5.6
5.7
5.1
1.1
3.8
5.7
17
3j
3k
1.4
80
a Conditions: racemic 4a (0.25 mmol), catalyst (5 mol %), (iPrCO)2O
(0.125 mmol), DIEA (0.125 mmol), and CCl4 (2.5 mL), 0 °C. b HPLC
analysis. c Calculated according to the method of ref 3a. d The absolute
configuration was 1S,2R.
Results and Discussion
The first compound we evaluated was the simple N-benzoyl
1-methyl-L-histidine methyl ester 3a (Table 1), which gave an
encouraging selectivity factor (S ) 2.3) in the kinetic resolution
of (()-4a using (i-PrCO)2O as acylation reagent. Variations of
the group at the N-terminal, C-terminal, and imidazole ring of
3a were applied, and the resulting compounds were tested under
the same condition. Compounds 3a-3f were readily prepared
from the commercially available 1-methyl-L-histidine via stan-
dard N-terminal acylation and C-terminal esterification in high
yield. Better enantioselectivities of 3b and 3c were observed
by increasing the steric hindrance at the 3 and 5 positions of
the benzoxy ring. However, further enlargement of the tert-
butyl group in 3c to the trimethylsilyl group in 3d did not cause
any significant improvement in selectivity. No noticeable benefit
was observed by replacing the C-terminal methyl ester with a
bulkier isopropyl ester (3e). Changing the methyl ester with an
n-butyl ester (3f) made the resulting catalyst lose its selectivity.
The steric factor of the N-alkyl group on the imidazole ring
was also examined. The N-ethyl catalyst 3g gave slightly lower
selectivity and the N-benzyl catalyst 3h gave similar selectivity
as 3c. All of these catalysts preferred selectively acylating the
1R,2S configuration of 4a.
According to the conclusion of the Ishihara group’s
experiments,7j,k strengthening the H-bonding interaction between
the catalyst and the substrate by changing amide functionality
to sulfonamide dramatically enhanced the enantioselectivity
because sulfonamide amide NH is a better hydrogen bond donor.
Indeed, the sulfonamide 3i provided considerably improved
selectivity. Encouraged by this result, we decided to replace
amide functionality in 3c with amide isostere which was reported
to present more acidic NH in literature. Catalyst 3j bearing an
aminoxy acid amide NH, which has been proved to be a good
hydrogen bond donor,9 was tested. Unfortunately, catalyst 3j
afforded almost no selectivity, which might be due to distur-
bance of the conformation of the catalyst by introduction of an
extra oxygen atom. Thioamide NH was also found to be a better
hydrogen bond donor compared with normal amide NH (in a
similar way to thiourea compared with urea)10 and for this
reason, thioamide was frequently employed as an amide
surrogate to obtain stronger hydrogen bonding in bioactive
(6) For recent examples of kinetic resolution employing ring-fused imida-
zoline catalysts, see: (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.; Li, X. Org. Lett. 2006, 8, 1351. (d)
Birman, V. B.; Guo, L. Org. Lett. 2006, 8, 4859. (e) Birman, V. B.; Li, X. Org.
Lett. 2008, 10, 1115.
(7) For recent examples of kinetic resolution using histidine-based catalysts,
see: (a) Jarvo, E. R.; Evans, C. A.; Copeland, G. T.; Miller, S. J. J. Org. Chem.
2001, 66, 5522. (b) Copeland, G. T.; Miller, S. J. J. Am. Chem. Soc. 2001, 123,
6496. (c) Fierman, M. B.; O’Leary, D. J.; Steinmetz, W. E.; Miller, S. J. J. Am.
Chem. Soc. 2004, 126, 6967. (d) Evans, J. W.; Fierman, M. B.; Miller, S. J.;
Ellman, J. A. J. Am. Chem. Soc. 2004, 126, 8134. (e) Jarvo, E. R.; Miller, S. J.
Tetrahedron 2002, 58, 2481. (f) Miller, S. J. Acc. Chem. Res. 2004, 37, 601. (g)
Angione, M. C.; Miller, S. J. Tetrahedron 2006, 62, 5254. (h) Colby Davie,
E. A.; Mennen, S. M.; Xu, Y.; Miller, S. J. Chem. ReV. 2007, 107, 5759. (i)
Formaggio, F.; Barazza, A.; Bertocco, A.; Toniolo, C.; Broxterman, Q. B.;
Kaptein, B.; Brasola, E.; Pengo, P.; Pasquato, L.; Scrimin, P. J. Org. Chem.
2004, 69, 3849. (j) Ishihara, K.; Kosugi, Y.; Akakura, M. J. Am. Chem. Soc.
2004, 126, 12212. (k) Kosugi, Y.; Akakura, M.; Ishihara, K. Tetrahedron 2007,
63, 6191. (l) Ishihara, K.; Sakakura, A.; Hatano, M. Synlett 2007, 686. (m)
Ishihara, K.; Kosugi, Y.; Umemura, S.; Sakakura, A. Org. Lett. 2008, 10, 3191.
(8) (a) Kobayashi, J.; Higashijima, T.; Miyazawa, T. Int. J. Peptide Protein
Res 1984, 24, 40. (b) Kobayashi, J.; Nagai, U. Biopolymers 1978, 17, 2265. (c)
Kobayashi, J.; Higashijima, T.; Sekido, S.; Miyazawa, T. Int. J. Peptide Protein
Res 1981, 17, 486.
(9) Li, X.; Yang, D. Chem. Commun. 2006, 3367.
J. Org. Chem. Vol. 73, No. 21, 2008 8559

Geng et al.
TABLE 2. Kinetic Resolution of Racemic 4a-4g by Catalyst 3ka
time
(h)
conv
(%)
ee of isobutyrate
ester (%)b
ee of recovered
alcohol (%)
b
substrate
Sc
4a
4b
4c
4d
4e
4f
3
10
5
4
4
52
48
46
52
47
58
50
90
64
51
65
81
56
61
97
60
41
73
72
78
62
80
9
3
11
21
8
6
5
4g
8
FIGURE 3. Summary of NOEs observed in the NOE difference
spectroscopy of 3c and 3k (in the 3:1 solvent mixture of CCl4 and
CDCl3, 5 mM at room temperature; s ) strong NOE, m ) medium
NOE, w ) weak NOE) and X-ray structures of 3c and 3k.
a Conditions: substrate alcohol (0.25 mmol), catalyst (5 mol %),
(iPrCO)2O (0.125 mmol), DIEA (0.125 mmol), and CCl4 (2.5 mL), 0
°C. b HPLC analysis. c Calculated according to the method of ref 3a.
oligopeptides11 and anion receptors.12 The thioamide catalyst
3k was prepared by selective thionation of 3c using Lawesson’s
reagent.13 There was a big improvement of the enantioselectivity
when the acylation was performed using thioamide 3k as
catalyst, the enantioselectivity for recovered 4a was 97% ee at
52% of conversion and the selectivity factor was 80.
chain of catalyst 3k resembles rotamer III, and the imidazole
ring and the thioamide plane are parallel to each other on the
same side. The relative steric positions of the imidazole ring
and the amide NH are the same in 3k and histidinol derivative
2, though the other parts of the two molecules are rather
different. It appears that the parallel relationship of the amide
plane and the imidazole plane plus the rotamer III-like
conformation are important for high enantioselective histidine-
derived acylation catalysts.
The alteration of conformation by thioamide modification is
possibly due to the larger van der Waals radius of sulfur. The
imidazole side chain rotate 120° to adopt the conformation of
rotamer III owing to the steric repulsion between the sulfur
atom and the side chain. In the conformational studies of
oligopeptides by single substitution of amide with thioamide
along the peptide chain, it was found that the residues following
a thioamide are more restricted because thioamide plane would
be more difficult to rotate.14 It is possible that the thioamide
modification may also make 3k more rigid than 3c, and this
was another factor that contributed to the high enantioselectivity
observed for 3k.
Subsequently, it was found that both electronic and steric
factors of the auxiliary on alcohol substrates strongly influenced
the selectivity of the kinetic resolution. Replacing N-pyrrolodinyl
ring in 4a (Table 2) with cyclopentyl ring in 4b, both reactivity
and selectivity decreased because the carbonyl oxygen atom of
4b acts as a worse hydrogen bond acceptor and this weakens
the interaction between the catalyst and the substrate. The
carbonyl oxygen atom of 4c is expected to be an even better
hydrogen bond acceptor because it contains an urea type
auxiliary. However, 4c proved to be an inefficient substrate. In
addition, it was found that either a slight increase (4d) or a slight
The reason for the big improvement of the selectivity for 3k
is worth considering. It was asked whether the thioamide
modification only introduced a more acidic amide NH and
thereby strengthened the hydrogen bond between the substrate
and the catalyst or this modification caused subtle perturbation
of the conformation of catalyst 3c. The conformations of
catalysts 3c and 3k were compared by the use of X-ray analysis
1
and NMR spectroscopy. In the H NMR spectrum of 3k, the
thioamide modification made the amide proton downfield-shifted
to 8.1 ppm (the chemical shift of the amide NH in 3c was 6.8
ppm), reflecting a more acidic thioamide NH. The single crystals
grown in the mixture of carbon tetrachloride and n-hexane were
subjected to X-ray analysis. NOE difference spectroscopy of
3c and 3k were taken using a mixed solvent of carbon
tetrachloride and deuterochloroform, which was similar to the
real solvent environment employed in the kinetic resolution
reactions. The conformations found in solution coincided with
that observed by X-ray analysis (Figure 3).
The imidazole side chain’s orientation of catalyst 3c resembles
rotamer I rather than rotamer III (Figure 2) as suggested by
early NMR studies,8 probably owing to the presence of a large
substituent at its N-terminal. Meanwhile, the imidazole ring is
nearly perpendicular to the amide plane, although they are on
the same side. However, the orientation of the imidazole side
(10) (a) Alema´n, C. J. Phys. Chem. A 2001, 105, 6717. (b) Lee, H.-J.; Choi,
Y.-S.; Lee, K.-B.; Park, J.; Yoon, C.-J. J. Phys. Chem. A 2002, 106, 7010. (c)
Doyle, A. G.; Jacobsen, E. N. Chem. ReV. 2007, 107, 5713.
(11) (a) Kessler, H.; Matter, H.; Geyer, A.; Diehl, H.-J.; Ko¨ck, M.; Kurz,
G.; Opperdoes, F. R.; Callens, M.; Wierenga, R. K. Angew. Chem., Int. Ed.
Engl. 1992, 31, 328–330. (b) Clausen, K.; Spatola, A. F.; Lemieux, C.; Schiller,
P. W.; Lawesson, S.-O. Biochem. Biophys. Res. Commun. 1984, 120, 305.
(12) Inoue, Y.; Kanbara, T.; Yamamoto, T. Tetrohedron Lett. 2003, 44, 5167.
(13) (a) Pedersen, B. S.; Scheibye, S.; Nilsson, N. H.; Lawesson, S.-O. Bull.
Soc. Chim. Belg. 1978, 87, 223. (b) Cava, M. P.; Levinson, M. I. Tetrahedron
1985, 41, 5061.
(14) (a) LaCour, T. F. M. Int. J. Peptide Protein Res 1987, 30, 564. (b)
Attis, D. R.; Lipton, M. A. J. Am. Chem. Soc. 1998, 120, 12200.
8560 J. Org. Chem. Vol. 73, No. 21, 2008

Kinetic Resolution of Racemic Alcohols
TABLE 3. Kinetic Resolution of Racemic 4h-4p
(R ) (CH2CH2)2N-) by Catalyst 3ka
(417 mg, 1.1 mmol) at 0 °C under N2 atmosphere. After stirring
for 10 min, (S)-methyl-2- amino-3-(1-methyl-1H-imidazol-5-yl)
propanoate dihydrochloride15 (257 mg, 1 mmol) and DIEA (0.42
mL, 3.1 mmol) were added. The reaction was stirred at 0 °C for
1 h and at room temperature overnight. After removal of DMF
under reduced pressure, the residue was dissolved in EtOAc and
the mixture was washed with aqueous NaHCO3, water and brine,
respectively. The organic layer was separated and dried over
anhydrous Na2SO4 and concentrated to give the crude product,
which was then purified by flash column chromatography (eluent:
5% MeOH/EtOAc) to afford pure product 3c as a white foam (339
mg, 85%). TLC (5% CH3OH/EtOAc), Rf ) 0.3; [R]20 ) +30.5
D
(c 1.0, CH2Cl2); mp 191-193 °C; IR (KBr) 3258, 2960, 2905, 2869,
1
2479, 2004, 1637, 1536, 1438, 1250, 843 cm-1; H NMR (600
time
(h)
conv
(%)
ee of isobutyrate
ester (%)b
ee of recovered
alcohol (%)b
substrate
Sc
MHz, CDCl3) δ 1.31 (s, 18H), 3.27-3.28 (m, 2H), 3.73 (s, 3H),
3.77 (s, 3H), 4.94 (dd, J ) 9.0, 9.6 Hz, 1H), 7.02 (s, 1H), 7.07 (d,
J ) 4.2 Hz, 1H), 7.58 (s, 3H), 7.95 (s, 1H); 13C NMR (150 MHz,
CDCl3) δ 26.1, 31.3, 31.4, 32.6, 35.0, 52.1, 53.0, 121.2, 122.6,
126.5, 129.2, 132.6, 136.7, 151.6, 168.6, 171.3; LRMS (ESI) [M
+ H]+ m/z 400.5. HRMS (ESI) for C23H33N3O3: calcd for [M +
H]+ 400.2595, found 400.2590.
4h
4i
4j
4k
4l
4m
4n
4o
4p
4
4
5
2
4
3
3
1
2
54
53
62
44
53
43
53
53
52
80 (1R,2S)
84 (1R,2S)
60 (1R,2S)
86 (1R,2S)
76 (R)
96
98
99.8
68
88
63
86
92
98
40
65
25
28
23
21
22
32
91
83 (R)
77 (R)
78 (R)
88 (R)
Step 2. (S)-Methyl-2-(3,5-di-tert-butylbenzamido)-3-(1-methyl-
1H-imidazol-5-yl)propanoate (3c, 200 mg, 0.5 mmol) was dissolved
in a solvent mixture of CH2Cl2 (2 mL) and toluene (6 mL).
Lawesson’s reagent (2,4-bis(p-methoxyphenyl)-1,3-dithiaphosphe-
tane 2,4-disulfide) (205 mg, 0.5 mmol) was added and the reaction
mixture was heated at 80 °C for 4 h. After removal of solvent, the
residue was dissolved in EtOAc and the mixture was washed with
aqueous NaHCO3, water and brine, respectively. The organic layer
was separated and dried over anhydrous Na2SO4 and concentrated
to give the crude product, which was then purified by flash column
chromatography (eluent: 5% MeOH/CH2Cl2) to afford pure product
3k as a light yellow foam (167 mg, 81%). TLC (5% CH3OH/
a Conditions: substrate alcohol (0.25 mmol), catalyst (5 mol %),
(iPrCO)2O (0.125 mmol), DIEA (0.125 mmol), and CCl4 (2.5 mL), 0
°C. b HPLC analysis. c Calculated according to the method of ref 3a.
decrease (4e) of spacial hindrance of the auxiliary resulted in
declined enantioselectivities. Employment of a simple methyl
(4f) or N, N-dimethyl phenyl group (4g) led to lower enanti-
oselectivities. These observations implied that the recognition
site on the substrate was the carbamate auxiliary rather than
the skeleton of the alcohol.
EtOAc), Rf ) 0.5; [R]20 ) +94.3 (c 1.0, CH2Cl2); mp 136-138
D
°C; IR (KBr) 3364, 3172, 2960, 2868, 1744, 1595, 1475, 1438,
1
1279, 1247, 1212, 1111, 1032, 981, 924, 897, 832, 762 cm-1; H
Several racemic alcohols were selected to test the asymmetric
acyl transfer efficiency of catalyst 3k (Table 3). Synthetically
useful S values of 40 and 65 were obtained for acylation of 4h
and 4i, though the enantioselectivities for 4h and 4i were even
higher with histidinol derivative 2. The ee value of the recovered
alcohol 4j was 99.8% at 62% conversion and the selectivity
factor was 25. For an acylic substrate 4k, the selectivity factor
was 28. A new type of secondary alcohol (4l-4p) was resolved
by 3k in good to excellent selectivity. The best enantioselectivity
was obtained for substrate 4p (S ) 91). This was the first
example of effective kinetic resolution of protected secondary
alcohol by acylating the adjacent primary alcohol.
In conclusion, the utilization of a thioamide as organocatalyst
to catalyze asymmetric reaction has been described. The low-
molecular-weight (MW ) 415) and user-friendly catalyst 3k
was found to be an efficient catalyst for the kinetic resolution
of monoprotected cis-diols and also the terminal vicinal diols.
NMR and X-ray studies proved that the thioamide modification
changes the conformation of the catalyst to the desired one and
also that this conformation became more rigid owing to the
relatively bulky sulfur atom. The current studies have shown
the possibility of achieving high enantioselectivity through
controlling the conformation of amino acid derivative by
thionation of the amide carbonyl.
NMR (600 MHz, CDCl3) δ 1.33 (s, 18H), 3.36 (dd, J ) 4.8, 10.8
Hz, 1H), 3.58 (s, 3H), 3.59 (dd, J ) 6.6, 10.8 Hz, 1H), 3.84 (s,
3H), 5.49 (dd, J ) 4.8, 6.6 Hz, 1H), 6.81 (s, 1H), 7.40 (s, 1H),
7.50 (s, 2H), 7.56 (s, 1H), 8.09 (d, J ) 4.2 Hz, 1H); 13C NMR
(150 MHz, CDCl3) δ 24.7, 31.3, 31.6, 35.0, 53.0, 57.7, 121.0, 126.1,
128.3, 138.6, 141.0, 151.4, 171.1, 200.6; LRMS (ESI) [M + H]+
m/z 416.4. HRMS (ESI) for C23H33N3O2S: calcd for [M+H]+ m/z
416.2366, found 416.2367.
Typical Procedure for the Kinetic Resolution of Racemic
Secondary Alcohols Catalyzed by Histidine Derivatives. To the
solution of (()-4a (53 mg, 0.25 mmol) and catalyst 3k (5 mg,
0.0125 mmol) in CCl4 (2.5 mL) were added DIEA (22 µL, 0.125
mmol) and isobutyric anhydride (21 µL, 0.125 mmol) at 0 °C. After
completion, the reaction mixture was quenched by water and
extracted with EtOAc. The organic layer was washed with aqueous
NaHCO3, water and brine, respectively, dried over anhydrous
Na2SO4, and concentrated under reduced pressure. The residue was
then purified by flash column chromatography (eluent: 20% EtOAc/
Petroleum ether). Enantiometic excess (ee) values of the acylated
product 5a (90%) and the recovered alcohol 4a (97%) were
determined by HPLC analysis. The conversion (c ) 52%) and the
S value (80) were estimated using the method of Kagan.3a
cis-N-(2-Isobutyryloxycyclohexanoxycarbonyl)pyrrolidine (5a).
1
[R]20 ) -21.4 (c 1.0, CHCl3) for 90% ee; H NMR (600 MHz,
D
CDCl3) δ 1.16 (d, J ) 4.2 Hz, 3H), 1.20 (d, J ) 3.6 Hz, 3H),
1.34-1.50 (m, 2H), 1.51-1.72 (m, 4H), 1.78-1.95 (m, 6H), 2.57
(septet, J ) 3.6 Hz, 1H), 3.31 (t, J ) 6.6 Hz, 2H), 3.38 (t, J ) 6.6
Hz, 2H), 4.85-4.92 (m, 1H), 5.01-5.08 (m, 1H); 13C NMR (150
MHz, CDCl3) δ 18.9, 19.0, 21.2, 22.2, 24.9, 25.6, 27.8, 28.1, 34.2,
45.6, 46.0, 70.8, 71.7, 154.3, 176.1; HPLC (Daicel Chiralpack AS-
Experimental Section
Preparation of (S)-Methyl-2-(3,5-di-tert-butylphenylthioa-
mido)-3-(1-methyl-1H-imidazol-5-yl) propanoate (3k). Step 1.
To a solution of 3,5-di-tert-butylbenzoic acid (257 mg, 1.1 mmol)
in DMF (10 mL) were added HOBt (150 mg, 1.1 mmol) and HBTU
(15) Chandana, P.; Nayyar, A.; Jain, R. Synth. Commun. 2003, 33, 2925.
J. Org. Chem. Vol. 73, No. 21, 2008 8561

Geng et al.
H, hexane/2-propanol ) 90:10, flow rate ) 0.8 mL/min) 210 nm,
tR ) 7.0 min (1S,2R, minor), 7.5 min (1R,2S, major).
Ministry of Science and Technology of China (2006AA020502).
We thank Prof. Chi Zhang for helpful discussions. We also thank
Dr. Lu Shan in Bruker (Beijing) Technologies & Service Co., Ltd.
for conducting the 1D selective NOE spectroscopy of compound
3c and 3k.
cis-N-(2-Hydroxycyclohexanoxycarbonyl)pyrrolidine (4a). [R]20
D
1
) - 2.7 (c 1.0, CHCl3) for 97% ee; H NMR (600 MHz, CDCl3)
δ 1.33-1.34 (m, 2H), 1.55-1.58 (m, 2H), 1.65-1.70 (m, 3H),
1.85-1.93 (m, 5H), 2.62 (s, 1H), 3.40 (t, J ) 6.6 Hz, 4H),
3.83-3.84 (m, 1H), 4.92 (dt, J ) 3.6, 6.6 Hz, 1H); 13C NMR (150
MHz, CDCl3) δ 21.5, 22.0, 24.9, 25.6, 28.2, 30.0, 45.8, 46.2, 70.2,
74.3, 155.2; HPLC (Daicel Chiralpack AD-H, hexane/2-propanol
) 92:8, flow rate ) 1.0 mL/min) 210 nm, tR ) 14.1 min (1S,2R,
major), 16.2 min (1R,2S, minor).
Supporting Information Available: Experimental proce-
1
dures, H NMR, 13C NMR, and HRMS spectra of catalyst
3a-3k, secondary alcohols and their isopropyl esters in Table
2 and Table 3, HPLC data, X-ray structural analysis data of 3c
and 3k (CIF). This material is available free of charge via the
Internet at http://pubs.acs.org.
Acknowledgment. This work was financially supported by The
National Natural Science Foundation of China (20402007 and
20421202), the 111 Project (B06005) and the 863 Project of the
JO801859M
8562 J. Org. Chem. Vol. 73, No. 21, 2008