New class of pyridine catalyst having a conformation switch system: Asymmetric acylation of various sec-alcohols

Article abstract of DOI:10.1021/jo060989t

We have developed a new class of pyridine catalyst for asymmetric acylation of sec-alcohols having a conformation switch system in which interconversion between self-complexation and uncomplexation is induced by acylation and deacylation steps, respectively. Kinetic resolution of various sec-alcohols is performed by the asymmetric acylation with isobutyric anhydride using 0.05 to 0.5 mol % catalyst 1a with s values of up to 30. In addition, dl-diols are also resolved in a similar manner in good selectivity. Moreover, asymmetric desymmetrization of meso-1,X-diols (X = 2-6) are achieved in the presence of 0.5-5 mol % catalyst 1a. A working model for the reaction mechanism is proposed on the basis of the ¹H NMR measurements, X-ray structural analyses, and AM1 and DFT calculations, where the conformation switch system governed by an intramolecular cation-π interaction between a pyridinium ring and a thiocarbonyl group would play a key role to attain both good selectivity and high catalytic activity.

Full text of DOI:10.1021/jo060989t

New Class of Pyridine Catalyst Having a Conformation Switch
System: Asymmetric Acylation of Various sec-Alcohols
Shinji Yamada,* Tomoko Misono, Yuko Iwai, Ayako Masumizu, and Yukiko Akiyama
Department of Chemistry, Ochanomizu UniVersity, Bunkyo-ku, Tokyo 112-8610, Japan
yamada@cc.ocha.ac.jp
ReceiVed May 12, 2006
We have developed a new class of pyridine catalyst for asymmetric acylation of sec-alcohols having a
conformation switch system in which interconversion between self-complexation and uncomplexation is
induced by acylation and deacylation steps, respectively. Kinetic resolution of various sec-alcohols is
performed by the asymmetric acylation with isobutyric anhydride using 0.05 to 0.5 mol % catalyst 1a
with s values of up to 30. In addition, dl-diols are also resolved in a similar manner in good selectivity.
Moreover, asymmetric desymmetrization of meso-1,X-diols (X ) 2-6) are achieved in the presence of
0.5-5 mol % catalyst 1a. A working model for the reaction mechanism is proposed on the basis of the
1H NMR measurements, X-ray structural analyses, and AM1 and DFT calculations, where the conformation
switch system governed by an intramolecular cation-π interaction between a pyridinium ring and a
thiocarbonyl group would play a key role to attain both good selectivity and high catalytic activity.
Introduction
and substituted aryl7 groups have been employed; however, a
nonaromatic system has not yet been reported.
4-(Dimethylamino)pyridine (DMAP) derivatives are one of
the most important organocatalysts for acyl-transfer reaction of
various alcohols.1 The chiral version of the DMAP derivatives
has been extensively developed over the past decade2 because
of the significant importance of asymmetric acylation of alcohols
for production of chiral alcohols. In the design of such chiral
DMAP catalysts, the key feature is selective blocking of the
pyridinium face by an aromatic moiety to discriminate enan-
tiomeric alcohols. A variety of aromatic moieties such as
pentaphenylcyclopentadienyl,3 naphthyl,4 binaphthyl,5 biaryl,6
We have recently found a new type of cation-π interaction8
between a pyridinium ring and a thiocarbonyl group.9 This
interaction enables nucleophiles to attack the less-hindered side
(4) Kawabata, T.; Nagato, M.; Takasu, K.; Fuji, K. J. Am. Chem. Soc.
1997, 119, 3169.
(5) Jeong, K.-S.; Kim, S.-H.; Park, H.-J.; Chang, K.-J.; Kim, K. S. Chem.
Lett. 2002, 1114.
(6) Spivey, A. C.; Leese, D. P.; Zhu, F.; Davey, S. G.; Jarvest, R. L.
Tetrahedron 2004, 60, 4513. (b) Spivey, A. C.; Zhu, F.; Mitchell, M. B.;
Davey, S. G.; Jarvest, R. L. J. Org. Chem. 2003, 68, 7379 and references
therein.
(1) Ho¨fle, G.; Steglich, W.; Vorbru¨ggen, Angew. Chem., Int.Ed. Engl.
1978, 17, 569. (b) Hassner, A.; Krepski, L. R.; Alexanian, V. Tetrahedron
1978, 34, 2069. (c) Scriven, E. F. Chem. Soc. ReV. 1983, 129.
(7) OÄ Da´laigh, C.; Hynes, S. J.; Maher, D. J.; Connon, S. J. Org. Biomol.
Chem. 2005, 3, 981. (b) Shaw, S. A.; Alemen, P.; Vedejs, E. J. Am. Chem.
Soc. 2003, 125, 13368. (c) Priem, G.; Pelotier, B.; Macdonald, S. J. F.;
Anson, M. S.; Campbell, I. B. J. Org. Chem. 2003, 68, 3844. (d) Pelotier,
B.; Priem, G.; Campbell, I. B.; Macdonald, S. J. F.; Anson, M. S. Synlett
2003, 679. (e) Kawabata, T.; Stragies, R.; Fukaya, T.; Nagaoka, Y.; Schedel,
H.; Fuji, K.Tetrahedron Lett. 2003, 44, 1545. (f) Naraku, G.; Shimomoto,
N.; Hanamoto, T.; Inanaga, J. Enantiomer 2000, 5, 135.
(8) Ma, J. C.; Dougherty, D. A. Chem. ReV. 1997, 97, 1303.
(9) Yamada, S.; Misono, T.; Tsuzuki, S. J. Am. Chem. Soc. 2004, 126,
9862. (b) Yamada, S.; Misono, T. Tetrahedron Lett. 2001, 42, 5497.
(2) For reviews, see: (a) Vedejs, E.; Jure, M. Angew. Chem., Int. Ed.
2005, 44, 3974. (b) Dalko, P. I.; Moisan, L. Angew. Chem., Int. Ed. 2004,
43, 5138. (c) Guerin, D. J.; Miller, S. J.; Lectka, T. Chem. ReV. 2003, 103,
2985. (d) Murugan, R.; Scriven, E. F. V. Aldrichimica Acta 2003, 36, 21.
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(3) For a review, see: Fu, G. C. Acc. Chem. Res. 2004, 37, 542.
10.1021/jo060989t CCC: $33.50 © 2006 American Chemical Society
Published on Web 08/04/2006
6872
J. Org. Chem. 2006, 71, 6872-6880

Pyridine Catalyst with a Conformation Switch System
SCHEME 1. Face-Selective Addition of a Nucleophile to a
Pyridinium Salt and Expected Kinetic Resolution of a
sec-Alcohol
SCHEME 3. Synthesis of New DMAP Catalysts
prepared in a similar manner using oxazolidine-2-thione or
oxazolidine-2-one as a chiral auxiliary. Compounds 5-7 are
reference compounds for structural studies of the catalysts.
SCHEME 2. New Class of DMAP Catalyst with a
Conformation Switch System
to give chiral 1,4-dihydropyridines as shown in Scheme 1.10
We expected that if a sec-alcohol is employed as a nucleophile,
it would attack the N-acyl group from the nonshielded side to
achieve enantiomer-selective acylation with recovery of a chiral
alcohol and the starting pyridine compound.
This prospect prompted us to develop a new DMAP catalyst
as shown in Scheme 2. The key feature is that the catalyst has
a conformation switch system based on the interconversion
between uncomplexed form I and self-complexed form II
induced by N-acylation and deacylation steps as outlined in
Scheme 2.11 The self-complexation by Py+‚‚‚SdC interaction
provides a chiral environment around the active site, which is
required for discrimination of the racemic sec-alcohols, although
the chiral center is apart from the active site. The recovered
uncomplexed catalyst undergoes smooth N-acylation with an
acid anhydride to form self-complex II repeatedly. This
conformation change in the catalyst would solve the selectivity-
reactivity dilemma4 similar to the induced-fit-type catalyst4,7a
developed by Kawabata. In this paper, we report a new class
of pyridine catalysts having a conformation switch system which
serve as asymmetric acylating catalysts for sec-alcohols.
Kinetic Resolution of Compound 8. Acylation of 1-(2-
naphthyl)ethanol (8) with isobutyric anhydride smoothly pro-
ceeded in the presence of 5 mol % catalysts 1-4 in toluene at
0 °C (Table 1, entries 1-6). The selectivity14 largely depends
on the substituent of the chiral auxiliary; 1a having a bulky
tert-butyl group provides the highest selectivity among 1a-1c.
2 and 3 also served as effective acylating catalysts, whereas 4
was less effective, suggesting the importance of the CdS 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.15
A survey of acylating reagents revealed that isobutyric
anhydride gave the most satisfactory results among the anhy-
drides that we have investigated. The solvents significantly affect
the s values14 (entries 7-11); use of acyclic ethers Et2O, i-Pr2O,
and t-BuOMe remarkably improved the selectivity (entries
9-11), whereas polar solvents were less effective (entries 7 and
8). The reaction temperature is also an important factor for the
stereoselectivity (entries 11-13); lowering the temperature
increases the s value. There have been known a variety of
acylation catalysts that show excellent levels of s values such
as chiral phosphines,17 diamines,18 dihydroimidazopyridines,19
and peptide-based catalysts.20,21 Since it has been well docu-
Results and Discussion
Synthesis of Catalysts. We prepared DMAP analogues 1
possessing chiral thiazolidine-2-thione.12 These catalysts can be
readily prepared from commercially available 4-chloronicotinic
acid as outlined in Scheme 3. Introduction of a dimethylamino
group at the 4-position13 gave potassium 4-(dimethylamino)-
3-carboxylate. After conversion into the corresponding acid
chloride with SOCl2, coupling with chiral thiazolidine-2-thione
derivatives afforded catalysts 1. Catalysts 2-4 were also
(14) Kagan, H. B.; Fiaud, J. C. Top. Stereochem. 1988, 18, 249.
(15) Brunner, H.; Kuerzinger, J. Organomet. Chem. 1988, 346, 413.
(16) Vedejs, E.; Daugulis, O. J. Am. Chem. Soc. 1999, 121, 5813.
(17) For a review, see: Vedejs, E.; Daugulis, O.; MacKay, J. A.; Rozners,
E. Synlett 2001, 1499.
(18) Sano, T.; Miyata, H.; Oriyama, T. Enantiomer 2000, 5, 119. (b)
Sano, T.; Imai, K.; Ohashi, K.; Oriyama, T. Chem. Lett. 1999, 265.
(19) Birman, V. B.; Uffman, E. W.; Jiang, H.; Li, X.; Kilbane, C. J. J.
Am. Chem. Soc. 2004, 126, 12226. (b) Birman, V. B.; Li, X.; Jiang, H.;
Uffman, E. W. Tetrahedron 2006, 62, 285.
(10) Yamada, S.; Misono, T.; Ichikawa, M.; Morita, C. Tetrahedron 2001,
57, 8939. (b) Yamada, S.; Ichikawa, M. Tetrahedran Lett. 1999, 40, 4231.
(11) Preliminary communication: Yamada, S.; Misono, T.; Iwai, Y.
Tetrahedron Lett. 2005, 46, 2239.
(12) Preparation of (S)-4-tert-butyl-1,3-thiazolidine-2-thione, see: (a)
Yamada, S.; Katsumata, H. J. Org. Chem. 1999, 64, 9365. (b) Yamada, S.;
Sugaki, T.; Matsuzaki, K. J. Org. Chem. 1996, 61, 5932. For an improved
method, see: Zhang, Y.; Phillips, A. J.; Sammakia, T. Org. Lett. 2004, 6,
23.
(20) For reviews, see: (a) Miller, S. J. Acc. Chem. Res. 2004, 37, 601.
(b) Sculimbrene, B. R.; Morgan, A. J.; Miller, S. J. Chem. Commun. 2003,
1781.
(13) Tono-oka, S. Bull. Chem. Soc. Jpn. 1982, 55, 1531.
J. Org. Chem, Vol. 71, No. 18, 2006 6873

Yamada et al.
TABLE 1. Kinetic Resolution of 1-Naphthylethyl Alcohol Catalyzed by 1-4a
cat.
(concn,
mol %)
temp
(°C)
time
(h)
convb
(%)
ee
(%)
entry
solv
sc
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
1a (5)
1a (5)
1c (5)
2 (5)
3 (5)
4 (5)
1a (5)
1a (5)
1a (5)
1a (5)
1a (5)
1a (5)
1a (5)
1a (0.5)
1a (0.05)
toluene
toluene
toluene
toluene
toluene
toluene
CH3CN
THF
0
0
0
0
0
0
0
0
0
3
3
3
3
3
3
3
3
3
3
3
3
5
12
72
59
55
58
61
57
53
61
60
61
50
57
64
56
57
55
87
74
73
88
82
37
68
80
96
78
95
99
97
92
87
11
9.1
7.0
9.8
11
2.7
5.0
7.6
15
19
24
18
30
17
17
Et2O
i-Pr2O
0
0
t-BuOMe
t-BuOMe
t-BuOMe
t-BuOMe
t-BuOMe
25
-30
25
25
a A 0.7 equiv sample of (i-PrCO)2O and an 0.8 equiv sample of collidine were used. b Conversion (%) ) (ee of recovered 8)/(ee of recovered 8 + ee of
ester); see ref 16. c Selectivity factor s ) k(fast-reacting enantiomer)/k(slow-reacting enantiomer); see ref 14.
TABLE 2. Kinetic Resolution of Various Alcohols Catalyzed by 1aa
a All reactions were conducted in the presence of 0.5 mol % 1a, 0.8 equiv of (i-PrCO)2O, and 0.9 equiv of Et3N at rt for 12 h unless otherwise noted.
b Determined by HPLC using chiral stationary phases. c The absolute configuration was determined by comparison of [R]D values with those reported:
compd 9, ref 23; compd 10, ref 24; compd 11, ref 25; compd 12, ref 26; compd 13, ref 26; compd 14, ref 27; compd 15, ref 28; compd 16, ref 29; compd
17, ref 30. d Selectivity factor s ) k(fast-reacting enantiomer)/k(slow-reacting enantiomer); see ref 14. e Conversion (%) ) (ee of recovered alcohol)/(ee of
recovered alcohol + ee of ester); see ref 16. f The reaction time is 72 h. g Temperature -30 °C, time 48 h. h The absolute configuration was not determined.
mented that one of the merits of DMAP catalysts is high
activity,1 we examined the influence of the catalyst amount on
the reactions (entries 12, 14, and 15). Reducing the catalyst
amount from 5 to 0.5 mol % had little effect on the s value,
and the reactions were completed within 12 h. Remarkable is
that further reducing the catalyst to 0.05 mol % resulted in the
same selectivity as in the case of entry 15, though the reaction
required 72 h to reach 55% conversion.
Kinetic Resolution of Various sec-Alcohols. This catalysis
is applicable to various sec-alcohols as shown in Table 2.
Acylation of 9-18 with isobutyric anhydride in the presence
of 0.5 mol % 1a and Et3N22 gave esters 9a-18a with recovery
of (S)-alcohol. The electron-donating and -withdrawing groups
(21) Ishihara, K.; Kosugi, Y.; Akakura, M. J. Am. Chem. Soc. 2004,
126, 12212. (b) Fierman, M. B.; O′Leary, D. J.; Steinmetz, W. E.; Miller,
S. J. J. Am. Chem. Soc. 2004, 126, 6967 and references therein.
(22) Triethylamine was used instead of collidine because of little
difference in the selectivities.
6874 J. Org. Chem., Vol. 71, No. 18, 2006

Pyridine Catalyst with a Conformation Switch System
SCHEME 4. Kinetic Resolution of Racemic 19 and 22
at the para-position on 10 and 11, respectively, had little effect
on the s values. These conditions are also effective for sterically
hindered alcohol 12. Kinetic resolution of 1-(1-naphthyl)ethanol
(13) gave a result similar to that of its isomer 8. This method
is applicable to heterocyclic sec-alcohol 14 and allylic and
propargylic alcohols 15 and 16; lowering the temperature to
-30 °C improved the selectivity. Acylation of aliphatic alcohols
17 and 18 resulted in much lower selectivities, suggesting the
importance of an aromatic moiety or π-electrons around the
hydroxy group to attain efficient resolution. In most cases the
s values are larger than 7, showing the practical usefulness of
this method.14
Kinetic Resolution of dl-Diols. Kinetic resolution of dl-diols
is also achieved by using this catalysis. Since C2-symmetric
chiral diols are useful as chiral auxiliaries,31 chiral ligands,32
and intermediates of a wide variety of chiral compounds,33
resolution of dl-diols is of significant importance in synthetic
organic chemistry. Various 1,2- and 1,3-diols have been resolved
by asymmetric acylation using transition-metal catalysts, whereas
1,X-diols (X > 3) are scarcely employed except for a few
examples3 due to the difficulty of the formation of a chelate
ring with a catalyst. Kinetic resolution of acyclic 1,4-diol 19
with 1.5 equiv of isobutyric anhydride in the presence of 5 mol
% catalyst gave a mixture of (R,R)-diester 20 and (S,S)-
monoester 21 with recovery of (S,S)-diol 1934 in excellent optical
purity (Scheme 4). Similar results were obtained for 1,5-diol
22; (R,R)-diester 23, (S,S)-monoester 24, and (S,S)-diol 2235 were
produced in good to excellent selectivities. The assignment of
the absolute configuration of 20 and 21, and 23 and 24, was
performed after hydrolysis into 19 and 22, respectively, by
comparison of the specific rotations with those reported.33,34
Desymmetrization of meso-Diols. Next, we turned our
attention to asymmetric desymmetrization of meso-diols36,37
because chiral hydroxy esters would be theoretically available
in quantitative yields. The product monoesters are valuable
synthetic intermediates due to having two different functional
groups, which are employed for the synthesis of crown ethers,38
acetals,31 polymers,39 and chiral ligands.32 Table 3 summarizes
the results for the desymmetrization of various meso-1,X-diols
using 5 mol % 1a. Catalytic desymmetrization of 1,2-diol 25
and 1,3-diol 26 with isobutyric anhydride in THF gave the
corresponding monoesters in 72% ee and 59% ee, respectively.
The lower yield of the monoester of 25 may be due to migration
of the acyl group and successive second acylation. Acylation
of 1,4-diol 27 afforded a monoester in much higher selectivity.
On the other hand, desymmetrization of cyclic 1,4-diol 28 gave
much lower selectivity despite having a partial structure similar
to that of 27. Optimized geometries of 27 and 28 predicted by
DFT calculations at the B3LYP/6-31G* level40 were signifi-
cantly different from each other; the two hydroxy groups of 28
occupy pseudoaxial and equatorial positions in the six-membered
ring, whereas both hydroxy groups of 27 are perpendicular to
the phenyl ring with formation of a hydrogen bond. This
conformational difference may have resulted in very different
selectivities. The absolute configuration of 27a was determined
after conversion into ketone 31; comparison of the specific
26.5
rotation of 31 {[R]D
+3.6 (c 0.95, CHCl3)} with that of
(23) The absolute configuration was assigned by comparison with the
HPLC retention time of a commercially available authentic sample.
(24) Ohkuma, T.; Ooka, H.; Hashiguchi, S.; Ikariya, T.; Noyori, R. J.
Am. Chem. Soc. 1995, 117, 2675.
authentic (R)-31 {[R]D26.5 +2.8 (c 1.42, CHCl3)} derived from
(R,R)-21 clarified the R,S configuration of 27a (Scheme 5).
(25) Akakabe, Y.; Takahashi, M.; Kamezawa, M.; Kikuchi, K.; Ta-
chibana, H.; Ohtani, T.; Naoshima, Y. J. Chem. Soc., Perkin Trans. 1 1995,
1295.
(26) Kasai, M.; Froussios, C.; Ziffer, H. J. Org. Chem. 1983, 48, 459.
(27) Takeshita, M.; Terada, K.; Akutsu, N.; Yoshida, S.; Sato, T.
Heterocycles 1987, 26, 3051.
(28) Goering, H. L.; Kantner, S. S.; Tseng, C. C. J. Org. Chem. 1983,
48, 715.
(29) Niwa, S.; Soai, K.. J. Chem. Soc., Perkin Trans. 1 1990, 937.
(30) Kashiwagi, Y.; Yanagisawa, Y.; Kurashima, F.; Anzai, J.; Osa, T.;
Bobbitt, J. M. Chem. Commun. 1996, 2745.
(31) Superchi, S.; Casarini, D.; Laurita, A.; Bavoso, A.; Rosini, C. Angew.
Chem., Int. Ed. 2001, 40, 451.
(32) Longmire, J. M.; Zhang, X. Tetrahedron Lett. 1997, 38, 1725.
(33) Asami, M.; Wada, M.; Furuya, S. Chem. Lett. 2001, 1110 and
references therein.
(34) Ramachandran, P. V.; Chen, G.-M.; Lu, Z.-H.; Brown, H. C.
Tetrahedron Lett. 1996, 37, 3795.
(35) Wallace, J. S.; Baldwin, B. W.; Morrow, C. J. J. Org. Chem. 1992,
57, 5231.
(36) Vedejs, E.; Daugulis, O.; Tuttle, N. J. Org. Chem. 2004, 69, 1389.
(b) Ku¨ndig, E. P.; Lomberget, T.; Bragg, R.; Poulard, C.; Bernardinelli, G.
Chem. Commun. 2004, 1548. (c) Trost, B. M.; Mino, T. J. Am. Chem. Soc.
2003, 125, 2410. (d) Kawabata, T.; Stragies, R.; Fukaya, T.; Nagaoka, Y.;
Schedel, H.; Fuji, K. Tetrahedron Lett. 2003, 44, 1545. (e) Spivey, A. C.;
Zhu, F.; Mitchell, M. B.; Davey, S. G.; Jarvest, R. L. J. Org. Chem. 2003,
68, 7379. (f) Mizuta, S.; Sadamori, M.; Fujimoto, T.; Yamamoto, I. Angew.
Chem., Int. Ed. 2003, 42, 3383. (g) Oriyama, T.; Imai, K.; Hosoya, T.;
Sano, T. Tetrahedron Lett. 1998, 39, 397. (h) Oriyama, T.; Imai, K.; Sano,
T.; Hosoya, T. Tetrahedron Lett. 1998, 39, 3529. (i) Vedejs, E.; Daugulis,
O.; Diver, S. T. J. Org. Chem. 1996, 61, 430.
(37) Matsumura, Y.; Maki, T.; Murakami, S.; Onomura, O. J. Am. Chem.
Soc. 2003, 125, 2052. (b) Ruble, J. C.; Tweddell, J.; Fu, G. C. J. Org.
Chem. 1998, 63, 2794.
(38) For a review, see: Naemura, K.; Tobe, Y.; Kaneda, T. Coord. Chem.
ReV. 1996, 148, 199.
(39) For a review, see: Kakuchi, T.; Obata, M.; Yokota, K. Yuki Gosei
Kagaku Kyokaishi 2000, 58, 306.
(40) DFT calculations were carried out by using PC Spartan pro ’02.
J. Org. Chem, Vol. 71, No. 18, 2006 6875

Yamada et al.
TABLE 3. Desymmetrization of Various meso-Diols Catalyzed by
1aa
FIGURE 1. ∆δ values for (a) 1a and (b) 5a in CDCl3.
1
Structural Studies of Intermediary Pyridinium Salts. H
NMR studies of 1a, 5a, 6, and 7 provided insight into the
geometrical differences between 1a and the pyridinium salt 5a.
Figure 1 shows ∆δ(1a) and ∆δ(5a) values, which are the
chemical shift differences of 1a and 5a with reference com-
pounds 6 and 7, respectively. These values reflect the effect of
the thiocarbonyl moiety on the chemical shifts of the pyridine
and pyridinium protons. Comparison of ∆δ(1a) and ∆δ(5a)
clearly shows significant differences between them. The ∆δH2
and ∆δH6 values for 5a are 1.09 and -0.44, respectively, the
absolute values of which are much larger than those of 1a (0.08
and -0.04). These observations are comparable to those of the
previously reported related cation-π complex.9 The significant
differences in the ∆δ values between 1a and 5a clarify that 5a
has a fixed conformation with close proximity of the CdS group
toward the pyridinium face, whereas the chiral auxiliary of the
Cs(CdO) bond of 1a rotates much faster.
Dynamic NMR experiments for 1a and 5a were carried out
to investigate the differences in the behavior in solution between
them. Figure 2 depicts the 1H NMR spectra of them. The
spectrum of 1a at 253 K clearly shows two rotamers with respect
to the Cs(CdO) bond, the ratio of which is about 1:1. The
equilibrium state between the two rotamers was supported by
the fact that the 1H NMR spectrum at 293 K shows coalescence
of the two rotamers. On the other hand, only one rotamer appears
for the spectrum of 5a in the range of 193-323 K, strongly
suggesting that the equilibrium shifts toward one of the two
rotamers. This also indicates a higher rotational barrier in 5a
than 1a, which is in agreement with the larger ∆δ values of
5a.
a All reactions were conducted in the presence of 5 mol % 1a, 1.1 equiv
of (i-PrCO)2O, and 1.1 equiv of Et3N in TBME at rt unless otherwise noted.
b Isolated yield. c Determined by HPLC analysis; see the Supporting
Information. d The absolute configuration was determined by comparison
of [R]D values with those reported: compd 25a, ref 40. e THF was used as
a solvent due to the insolvability of the substrate. f The absolute configu-
ration was not determined. g The sign of the [R]D value of monoacetate is
the same as that reported; see ref 36b.
NOE experiments of the N-isobutyryl salt of 1a clarified that
the N-acyl carbonyl is close to H6. Irradiation of H2 resulted
in 17.6% NOE for the methine proton of the isobutyryl group,
whereas 0.5% NOE was observed between H6 and the methine
proton (Figure 3). In addition, irradiation of the methine proton
resulted in 8.1% and 0.9% enhancement for H2 and H6,
respectively. These NMR studies clarified that the conformation
of the pyridinium salt is much more fixed than that of catalyst
1a, suggesting that the CdS‚‚‚Py+ interaction governs the
conformation of both the pyridinium ring and the N-acyl group.
SCHEME 5. Determination of the Absolute Configuration
of 27a
The existence of intramolecular interaction between a thio-
carbonyl group and a pyridinium ring was confirmed by X-ray
structural analysis. Since crystals of 5a were unsuitable for X-ray
analysis, the X-ray structure of 5b was compared with that of
reference compound 1d. The intramolecular distances between
the sulfur atom of the thiocarbonyl group and C2, C3, and C4
are 3.491, 3.111, and 3.695 Å, respectively, while those of 1d
are 3.422, 3.214, and 4.071 Å, respectively. Superimposition
of their X-ray structures shown in Figure 4 clarified that the
thiocarbonyl group of 5b is closer to the pyridinium face than
1d. This is in agreement with our previous structural studies of
1,5-Diol 29 and 1,6-diol 30 are also good substrates for the
desymmetrization reaction; 88% ee and 96% ee and good yields
were obtained, respectively. The absolute configuration of the
monoester of 30 was determined after conversion into reported
24
4-(1-hydroxyethyl)acetophenone 32; comparison of the [R]D
value with that of the literature34 revealed the R configuration
of 30.
6876 J. Org. Chem., Vol. 71, No. 18, 2006

Pyridine Catalyst with a Conformation Switch System
FIGURE 2. 1H NMR spectra for (a) 1a at 253 and 293 K and (b) 5a at 193 and 323 K and their schematic equilibrium equations.
FIGURE 3. NOEs for salts of 1a.
FIGURE 5. Optimized geometries for the isobutyrylpyridinium of 1a
and their relative energies.
SCHEME 6. Plausible Catalytic Cycle for Acymmetric
Acylation of sec-Alcohols
FIGURE 4. Superimposition of the X-ray structures of 1d and 5b.
a similar system,9 strongly suggesting an intramolecular interac-
tion between CdS and Py+.
Structural optimization of the intermediary N-isobutyrylpy-
ridinium of 1a was carried out by DFT calculations at the
B3LYP/6-31G* level. Figure 5 shows two stable conformers,
A and B, and their energy difference is 1.02 kcal/mol. The A
side42 of conformer A is blocked by the CdS group. On the
other hand, the CdS group of conformer B blocks the B side
of the pyridinium plane, and the t-Bu group blocks the A side
of it. In both conformers, orientation of the N-acyl groups is in
agreement with that predicted by NOE experiments as described
above. The energy difference between the two conformers can
the two types of conformers, A and B, was predicted to be in
a ratio of 99.3:0.7 on the basis of the conformer distribution
calculated by the AM1 method, supporting the preference of
conformer A.
Working Model for the Reaction Mechanism. Scheme 6
outlines a plausible catalytic cycle. Acylation of the catalyst
with isobutyric anhydride gives conformationally fixed N-
acylpyridinium salt A as a result of an intramolecular cation-π
interaction. One of the enantiomers of racemic sec-alcohols
preferentially attacks the intermediate A from the B side42 to
give the corresponding ester with recovery of the catalyst. The
catalyst restored conformational freedom allows smooth N-
acylation of the next cycle.
1
explain the observation of equilibrium shifts in the H NMR
studies as indicated in Figure 2. Moreover, the population for
(41) Nicolosi, G.; Patti, A.; Piattelli, M.; Sanfilippo, C. Tetrahedron:
Asymmetry 1994, 5, 283.
(42) Bastiaansen, L. A. M.; Vermeulen, T. J. M.; Buck, H. M.; Smeets,
W. J. J.; Kanters, J. A.; Spek, A. L. J. Chem. Soc., Chem. Commun. 1988,
230.
J. Org. Chem, Vol. 71, No. 18, 2006 6877

Yamada et al.
residue was evaporated in vacuo at 50 °C to give potassium
4-(dimethylamino)nicotinate (1.3 g, pale brown powder). The
mixture was used in the next reaction without further purification.
General Procedure for the Synthesis of 4-(Dimethylamino)-
nicotinamides 1-4. A mixture of crude potassium 4-(dimethy-
lamino)nicotinate (408 mg), thionyl chloride (7 mL), and a catalytic
amount of dimethylformamide was heated at 78 °C for 12 h. The
reaction mixture was concentrated in vacuo to give crude acid
chloride. To a solution of the crude acid chloride in dry CH2Cl2 (8
mL) were added dropwise (S)-4-tert-butyl-1,3-thiazolidine-2-thione
(468 mg, 2.67 mmol) and Et3N (1.2 mL, 8.6 mmol) in dry CH2Cl2
under a nitrogen atmosphere at 0 °C. The reaction mixture was
stirred for 3 h at room temperature. Saturated aqueous NaHCO3
solution was added, and the reaction mixture was extracted twice
with CH2Cl2. The combined organic layer was washed with brine
and dried over anhydrous MgSO4. After removal of the solvent,
the residue was purified by silica gel column chromatography
(AcOEt:MeOH ) 20:1) to afford pure 4-(dimethylamino)nicoti-
namide (400 mg, 1.24 mmol, 70% for two steps). Recrystallization
from AcOEt/hexane gave an analytical specimen of 1a.
FIGURE 6. Schematic favored (TS-I) and disfavored (TS-II) transition
structures for acylation of (R)- and (S)-alcohols, respectively.
The R selectivity in the kinetic resolution can be explained
by comparing the two plausible transition-state models TS-I and
TS-II for the acylation of (R)- and (S)-2-phenylethyl alcohols,
respectively (Figure 6). Each hydroxy group would approach
the B side of the pyridinium in a face-to-face manner due to an
intermolecular cation-π interaction between the pyridinium and
the phenyl rings.43 While the (R)-alcohol can effectively attack
the N-acyl group, the (S)-hydroxy moiety receives considerable
steric repulsion with the chiral auxiliary; therefore, the acylation
would preferentially proceed through TS-I to give the (R)-ester
predominantly. A similar explanation can also be adapted for
the acylation of dl-diols and meso-diols.
The fact that the substituent at the aromatic ring did not affect
the s values as shown in Table 2 may suggest that the interaction
energy is enough to form a hypothetical transition structure even
if the alcohol has an electron-withdrawing group. The much
lower selectivities in the case of aliphatic alcohols 17 and 18
can be attributable to the absence of the intermolecular cation-π
interactions.
Data for (S)-(4-tert-butyl-2-thioxothiazolidin-3-yl)[4-(dim-
ethylamino)pyridin-3-yl]methanone (1a): yellow crystals; 70%
yield for two steps; mp 159-160 °C; IR (KBr) 3437, 2955, 1674,
1
1593, 1544, 1313, 1230, 1199, 1130 cm-1; H NMR (400 MHz,
CDCl3, 50 °C) δ 8.22 (br, 1H), 8.18 (d, J ) 6.4 Hz, 1H), 6.59 (d,
J ) 6.4 Hz, 1H), 5.21 (br, 1H), 3.70 (t, J ) 8.8 Hz, 1H), 3.38 (d,
J ) 11.6 Hz, 1H), 2.99 (s, 6H), 1.17 (s, 9H); 13C NMR (100.4
MHz, CDCl3) δ 204.2, 167.7, 153.3, 149.9, 116.2, 108.8, 72.9, 60.3,
42.0, 38.1, 27.0; MS m/z 323 (M+, 60), 290 (30), 149 (100), 121
(30), 78 (27); HRMS m/z calcd for C15H21ON3S2 323.1126, found
24
323.1086; [R]D +644 (c 1.04, CHCl3).
(S)-[4-(Dimethylamino)pyridin-3-yl](4-isopropyl-2-thioxothia-
zolidin-3-yl)methanone (1b). Purification of 1b was performed
by column chromatography (silica gel, AcOEt:MeOH ) 10:1).
Recrystallization from CH2Cl2/hexane gave an analytical specimen
of 1b: yellow crystals; 34% yield for two steps; mp 163-164 °C;
IR (KBr) 2965, 1668, 1589, 1541, 1312, 1201, 808 cm-1; 1H NMR
(400 MHz, CDCl3, 50 °C) δ 8.19 (s, 1H), 8.18 (d, J ) 6.0 Hz,
1H), 6.59 (d, J ) 6.0 Hz, 1H), 5.08-5.02 (m, 1H), 3.61 (td, J )
9.6, 3.2 Hz, 1H), 3.23 (dd, J ) 11.6, 3.2 Hz, 1H), 2.98 (s, 6H),
2.62-2.54 (m, 1H), 1.15-1.07 (m, 6H); 13C NMR (100.4 MHz,
CDCl3) δ 202.8, 167.7, 153.5, 150.2, 116.6, 108.8, 71.8, 42.2, 19.3;
MS m/z 309 (M+, 75), 276 (53), 149 (100), 121 (40), 78 (32);
HRMS m/z calcd for C14H19ON3S2 309.0970; found 309.1003,
Conclusions
We have developed a new class of acylating catalyst having
a conformation switch system. The kinetic resolution of various
sec-alcohols and dl-diols and desymmetrization of meso-1,X-
diols (X ) 2-6) were achieved in good selectivities in the
presence of 0.05-5 mol % catalyst 1a. The structural studies
of the catalyst and its intermediate by 1H NMR measurements,
X-ray analysis, and AM1 and DFT calculations led to a working
model for the reaction mechanism. The key feature in this
catalytic acylation reaction is a conformation switch process
between self-complexation and uncomplexation induced by
N-acylation and deacylation steps, respectively, which would
play an important role in attaining both good stereoselectivity
and high catalyitic activity. Since this catalyst has a compact
structure with small molecular weight, and it can be readily
prepared from a commercially available pyridine compound with
a chiral auxiliary, it is of significant synthetic utility from a
practical point of view.
24
[R]D +354 (c 1.01, CHCl3).
(S)-(4-Benzyl-2-thioxothiazolidin-3-yl)[4-(dimethylamino)py-
ridin-3-yl]methanone (1c). Purification of 1c was performed by
column chromatography (silica gel, AcOEt:MeOH ) 10:1): yellow
oil; 41% yield for two steps; IR (neat) 3019, 2927, 1676, 1590,
1
1541, 1310, 1233, 1206, 965 cm-1; H NMR (270 MHz, CDCl3,
50 °C) δ 8.20 (d, J ) 6.4 Hz, 1H), 8.19 (s, 1H), 7.35-7.27 (m,
5H) 6.61 (d, J ) 6.4 Hz, 1H), 5.35-5.27 (m, 1H), 3.52 (td, J )
12, 3.7 Hz, 2H), 3.15-3.06 (m, 2H), 3.01 (s, 6H); 13C NMR (100.4
MHz, CDCl3) δ 200.9, 167.5, 153.4, 149.8, 136.0, 129.2, 128.8,
108.7, 68.4, 65.0, 42.2, 39.9, 38.1, 32.9; MS m/z 357 (M+, 19),
324 (19), 149 (100), 91 (29), 78 (17); HRMS m/z calcd for C18H19-
Experimental Section
24
ON3S2 357.0970, found 357.1012; [R]D +97.4 (c 1.00, CHCl3).
Preparation of Potassium 4-(Dimethylamino)nicotinate. A
mixture of 3-carboxy-4-chloropyridinium hydrochloride (1.1 g, 5.67
mmol) and Me2NH (40% aqueous solution, 4.0 mL) was stirred at
75 °C for 2 h in a sealed tube. After being cooled to room
temperature, the reaction mixture was concentrated. Saturated
K2CO3 (3.1 g, 22.4 mmol) aqueous solution was added, and the
mixture was stirred for 15 min. The reaction mixture was evaporated
in vacuo. EtOH was added to the residue, and the reaction mixture
was filtered through Celite. The filtrate was concentrated, and EtOH
was added. The solution was filtered through Celite again. The
(S)-(4-tert-Butyl-2-thioxothiazolidin-3-yl)(4-pyrrolidin-1-ylpy-
ridin-3-yl)methanone (2). Purification was performed by column
chromatography (silica gel, AcOEt:MeOH ) 10:1); yellow crystals;
84% yield for two steps; mp 149.5-151 °C; IR (KBr) 2968, 2864,
1673, 1592, 1534, 1514, 1373, 1313, 1298, 1262, 1246, 1190, 1146,
1021, 980, 821 cm-1; 1H NMR (400 MHz, CDCl3, 50 °C) δ 8.50-
7.50 (br s, 1H), 6.49 (d, J ) 4.8 Hz, 1H), 5.60-4.75 (br s, 1H),
3.71 (br, 1H), 3.38-3.20 (m, 5H), 1.99 (br s, 4H), 1.16 (s, 9H); 1H
NMR (400 MHz, CDCl3) δ 8.56 (br s, 0.5 H), 8.14 (br s, 1H),
7.92 (br s, 0.5 H), 6.50 (br s, 1H), 5.54 (br s, 0.5 H), 4.99 (br s, 0.5
H), 3.73 (br s, 1 H), 3.50-3.00 (m, 5H), 2.25-1.80 (m, 4H), 1.15
(s, 9H); 13C NMR (100.4 MHz, CDCl3) δ 205.9, 202.5, 167.3,
(43) Yamada, S.; Morita, C. J. Am. Chem. Soc. 2002, 124, 8184.
6878 J. Org. Chem., Vol. 71, No. 18, 2006

Pyridine Catalyst with a Conformation Switch System
152.3, 150.1, 149.7, 149.4, 147.4, 147.1, 115.9, 115.0, 108.7, 108.2,
73.4, 73.2, 72.7, 50.8, 50.0, 38.5, 38.3, 38.2, 32.7, 29.7, 29.6, 27.3,
29.7, 25.9, 25.8, 25.7, 25.5; MS m/z 349 (M+, 28), 316 (57), 175
(100), 174 (58), 157 (54), 156 (42), 146 (57); HRMS m/z calcd for
C17H23ON3S2 349.1283, found 349.1266; [R]D +666 (c 1.48,
CHCl3).
(i-PrOH:hexane ) 1:9). The optical purity of the ester was also
determined by HPLC analysis after hydrolysis with 2 N KOH/
MeOH.
General Procedure for the Kinetic Resolution of Racemic
Diols 19 and 22. To a solution of racemic diol (0.180 mmol) in
t-BuOMe (1.0 mL) were added 5 mol % catalyst 1a (2.9 mg,
0.00897 mmol) and Et3N (0.270 mmol). Isobutyric anhydride (0.270
mmol) was added to the solution at 0 °C and the resulting solution
stirred for 3 h. After addition of methanol, the solution was further
stirred for 20 min. Concentration of the reaction mixture gave a
crude product, which was purified by column chromatography
(hexane:ethyl acetate ) 3:1) to afford (R,R)-diester, (S,S)-monoester,
and (S,S)-diol. The optical purity of the alcohol was determined
by HPLC analysis with Daicel Chiralcel OB-H or AD (i-PrOH:
hexane ) 1:9). The optical purity of the esters was also determined
by HPLC analysis after hydrolysis into diols with 2 N KOH/MeOH.
Data for 1,2-bis[(1R)-(isobutyryloxy)ethyl]benzene (20): IR
(neat) 3036, 2977, 1736, 1470, 1388, 1259, 1158, 1058, 761 cm
-1; 1H NMR (400 Hz, CDCl3) δ 1.13 (d, J ) 7.0 Hz, 6H), 1.17 (d,
J ) 7.0 Hz, 6H), 1.60 (d, J ) 6.4 Hz, 6H), 2.57 (sept, J ) 7.0 Hz,
2H), 6.11 (q, J ) 6.4 Hz, 2H), 7.26-7.28 (m, 2H), 7.37-7.39 (m,
2H); MS m/z 306 (M+, 0.5), 218 (71), 175 (56), 148 (100), 131
(75), 71 (81); HRMS m/z calcd for C18H26O4 (M+) 306.1831, found
306.1859.
24
(S)-(4-tert-Butyl-2-thioxooxazolidin-3-yl)[4-(dimethylamino)-
pyridin-3-yl]methanone (3). Purification of 3 was performed by
column chromatography (silica gel, AcOEt): colorless amorphous;
34% yield for two steps; IR (KBr) 2967, 1683, 1591, 1539, 1362,
1
1334, 1317, 1246, 1206, 1178, 963 cm-1; H NMR (400 MHz,
CDCl3, 50 °C) δ 8.47 (br s, 1H), 8.23 (d, J ) 6.4 Hz, 1H), 6.65 (d,
J ) 6.4 Hz, 1H), 4.91 (br s, 1H), 4.55 (m, 2H), 3.01 (s, 6H), 1.05
(s, 9H); 13C NMR (100.4 MHz, CDCl3) δ 187.2 168.6, 153.8, 151.9,
150.4, 115.3, 108.9, 69.7, 64.5, 42.4, 36.3, 26.7, 25.8; MS m/z 307
(M+, 15), 274 (17), 149 (100), 148 (44), 121 (12); HRMS m/z calcd
for C15H21N3O2S 307.1355, found 307.1339; [R]D24 +164 (c 1.39,
CHCl3).
(S)-4-tert-Butyl-3-[[4-(dimethylamino)pyridin-3-yl]carbonyl]-
oxazolidin-2-one (4). Purification of 4 was performed by column
chromatography (silica gel, AcOEt:MeOH ) 10:1); light yellow
oil; 27% yield; IR (KBr) 2958, 1767, 1673, 1589, 1539, 1519, 1333,
1310, 1267, 1219, 1072, 964 cm-1; 1H NMR (400 MHz, CDCl3) δ
8.46 (s, 1H), 8.26 (d, J ) 5.6 Hz, 1H), 6.69 (d, J ) 5.6 Hz, 1H),
4.70 (s, 1H), 4.37 (m, 2H), 2.94 (s, 6H), 0.96 (s, 9H); 13C NMR
(100.4 MHz, CDCl3) δ 168.0, 153.9, 151.3, 150.7, 114.5, 109.0,
64.9, 60.2, 41.9, 36.2, 25.6; mp 143-144 °C; MS m/z 291 (M+,
16.1), 149 (91), 148 (100), 121 (18), 119 (11); HRMS m/z calcd
Data for 1-[(1S)-(isobutyryloxy)ethyl]-2-[(1S)-hydroxyethyl]-
benzene (21): IR (neat) 3423, 3035, 2976,1735, 1589, 1453, 1375,
1261, 1159, 1060, 761 cm-1; 1H NMR (400 Hz, CDCl3) δ 1.13 (d,
J ) 7.0 Hz, 3H), 1.16 (d, J ) 7.0 Hz, 3H), 1.56 (d, J ) 6.4 Hz,
3H), 1.57 (d, J ) 6.4 Hz, 3H), 2.39 (br, 1H), 2.55 (sept, J ) 7.0
Hz, 1H), 5.21 (q, J ) 6.4 Hz, 1H), 6.11 (q, J ) 6.4 Hz, 1H), 7.28-
7.30 (m, 2H), 7.41-7.45 (m, 2H); MS m/z 236 (M+, 0.4), 218 (2.5)
148 (73), 133 (100), 131 (59); HRMS m/z calcd for C14H18O2 (M+
24
for C15H21O3N3 291.1583, found 291.1559; [R]D +280 (c 1.03,
CHCl3).
General Procedure for the Synthesis of Pyridinium Salts 5
and 7. Gaseous MeBr was bubbled into a solution of 4-(alkylami-
no)nicotinamide (0.31 mmol) in dry CH3CN (3 mL), and the
solution was stirred for 2 h at room temperature. After evaporation
of the solvent, a yellow oily product was yielded quantitatively.
Data for (S)-3-[(4-tert-butyl-2-thioxothiazolidin-3-yl)carbo-
nyl]-4-(dimethylamino)-1-methylpyridinium bromide (5): yellow
oil; IR (neat) 2958, 1682, 1653, 1559, 1290, 1219, 1180 cm-1; 1H
NMR (400 MHz, CDCl3) δ 9.55 (s, 1H), 8.08 (d, J ) 6.8 Hz, 1H),
6.87 (d, J ) 6.8 Hz, 1H), 5.19-5.12 (m, 1H), 4.15 (s, 3H), 3.31-
3.23 (m, 8H), 1.12 (s, 9H); 13C NMR (100.4 MHz, CDCl3) δ 208.1,
162.7, 154.2, 142.0, 118.1, 109.8, 74.6, 44.9, 38.4, 34.5, 31.6, 27.5,
22.7, 14.1; MS m/z 323 (M+ - 95, 18), 290 (17), 221(18), 175
(29), 149 (96), 129 (100), 57 (29); HRMS m/z calcd for C15H21-
-
H2O) 218.1307, found 218.1284.
Data for 1,3-bis[(1R)-(isobutyryloxy)ethyl]benzene (23): IR
(neat) 2979, 1734, 1612, 1472, 1387, 1258, 1156, 1066, 706 cm
-1; 1H NMR (400 Hz, CDCl3) δ 1.16 (d, J ) 7.2 Hz, 6H), 1.18 (d,
J ) 7.2 Hz, 6H), 1.52 (d, J ) 6.4 Hz, 6H), 2.58 (sept, J ) 7.2 Hz,
2H), 5.87 (q, J ) 6.4 Hz, 2H), 7.23-7.35 (m, 4H); MS m/z 219
(M+ - 87, 100), 218 (41), 148 (68), 131 (81), 71 (44); HRMS m/z
calcd for C14H19O2 (M+ - C4H8O2) 219.1385, found 219.1382.
Data for 1-[(1S)-(isobutyryloxy)ethyl]-3-[(1S)-hydroxyethyl]-
benzene (24): IR (neat) 3449, 2979, 1735, 1610, 1388, 1261, 1158,
1
1065, 707 cm -1; H NMR (400 Hz, CDCl3) δ 1.16 (d, J ) 6.8
Hz, 3H), 1.18 (d, J ) 6.8 Hz, 3H), 1.50 (d, J ) 6.4 Hz, 3H), 1.52
(d, J ) 6.4 Hz, 3H), 1.80 (s, 1H), 2.57 (sept, J ) 6.8 Hz, 1H),
4.91 (q, J ) 6.4 Hz, 1H), 5.87 (q, J ) 6.4 Hz, 1H), 7.24-7.36 (m,
4H); MS m/z 236 (M+, 0.2), 219 (29), 218 (41), 166 (22), 149
24
ON3S2 323.1126, found 323.1125; [R]D +603 (c 1.00, CHCl3).
Data for 4-(dimethylamino)-3-(dimethylcarbamoyl)-1-meth-
ylpyridinium bromide (7): brown oil; IR (neat) 2937, 1652, 1563,
1404, 1225, 1165, 1082, 822 cm-1; 1H NMR (270 MHz, CDCl3) δ
8.52 (dd, J ) 7.4, 1.9 Hz, 1H), 8.46 (s, 1H), 7.11 (d, J ) 7.4 Hz,
1H), 4.24 (s, 3H), 3.23 (s, 6H), 3.19 (s, 3H), 3.12 (s, 3H); 13C
NMR (100.4 MHz, CDCl3) δ 165.2, 154.1, 142.9, 142.5, 118.0,
110.6, 45.5, 42.2, 40.1, 35.4; MS m/z 193 (M+ - 95, 70), 176
(14), 149 (100), 121 (45), 78 (28); HRMS m/z calcd for C10H15-
ON3 193.1215, found 193.1218.
-
(100), 105 (67), 71 (29); HRMS m/z calcd for C14H19O2 (M+
OH) 219.1385, found 219.1341.
General Procedure for Desymmetrization of meso-Diols. To
a solution of a meso-diol (0.15 mmol) and 1a (0.0077 mmol) in 1
mL of t-BuOMe were added Et3N (17 µL, 0.23 mmol) and
isobutyric anhydride (38 µL, 0.23 mmol) at 0 °C. The mixture was
stirred for 3 h at 0 °C, and after addition of MeOH, the reaction
mixture was further stirred for 30 min. After concentration of the
solution, the residue was purified by column chromatography
(hexane:AcOEt ) 3:1) to give monoester, diester, and recovered
meso-diol. The optical purity was determined by HPLC analysis
with Daicel Chiralpak AD (i-PrOH:hexane ) 1:9).
General Procedure for the Kinetic Resolution of Racemic sec-
Alcohols 8-18. To a solution of racemic alcohol (1.24 mmol) was
added 73 µL (0.00621 mmol) of a CH2Cl2 solution of catalyst 1a
(55.0 mg of catalyst in 2.0 mL of CH2Cl2). The mixture was
concentrated, and t-BuOMe (6.2 mL) and Et3N (138 µL, 0.992
mmol) were added to the residue. Isobutyric anhydride (144 µL,
0.868 mmol) was added to the solution at 0 °C and the resulting
solution stirred for 12 h at 0 °C. After addition of a saturated
NaHCO3 solution, the reaction mixture was extracted twice with
Et2O. The combined organic layer was washed with brine and dried
over anhydrous MgSO4. This was filtered, and the filtrate was
concentrated to give a crude product, which was purified by column
chromatography (hexane:ethyl acetate ) 3:1) to afford (S)-alcohol
and a corresponding ester. The optical purity of the alcohol was
determined by HPLC analysis with Daicel Chiralcel OB-H or OD-H
Data for (1R,2S)-1,2-bis(isobutyryloxy)-1,2-diphenylethane
(25b): IR (KBr) 3068, 2975, 1727, 1606, 1458, 1346, 1256, 1156,
1
1078, 700 cm -1; H NMR (400 MHz, CDCl3) δ 7.37 (m, 10H),
6.07 (s, 2H), 2.48 (sept, J ) 6.8 Hz, 2H), 1.06 (d, J ) 6.8 Hz,
6H), 1.03 (d, J ) 6.8 Hz, 6H); MS m/z 267 (M+ - 87, 6.3), 196
(11), 177 (68), 105 (11), 71 (100); HRMS m/z calcd for C18H19O2
(M+ - C4H7O2) 267.1385, found 267.1361.
Data for (1R,3S)-1,3-diphenyl-1-(isobutyryloxy)-3-propanol
(26a): IR (neat) 3447, 2975, 1733, 1604, 1456, 1387, 1258, 1156,
1
1068, 700 cm -1; H NMR (400 Hz, CDCl3) δ 1.13 (d, J ) 7.0
J. Org. Chem, Vol. 71, No. 18, 2006 6879

Yamada et al.
Hz, 3H), 1.17 (d, J ) 7.0 Hz, 3H), 1.21 (d, J ) 7.0 Hz, 1H), 2.10-
2.17 (m, 1H), 2.43-2.48 (m, 1H), 2.53 (sept, J ) 7.0 Hz, 1H),
4.63 (dd, J ) 5.0HZ, 7.0 Hz, 1H), 5.84 (t, J ) 6.8HZ, 1H), 7.28-
(d, J ) 6.4 Hz, 6H), 1.18 (d, J ) 6.8 Hz, 3H), 1.15 (d, J ) 6.8 Hz,
3H); MS m/z 334 (M+, 1.1), 246 (96), 159 (100), 158 (96); HRMS
m/z calcd for C16H22O2 (M+ - C4H8O2) 246.1620, found 246.1586.
Data for 1-[(1R)-(isobutyryloxy)ethyl]-4-[(1S)-hydroxyethyl]-
benzene (30a): colorless oil; 69% yield; IR (neat) 3449, 2977, 1735,
7.36 (m, 10H); MS m/z 298 (M+, 0.2), 280 (7.0), 237 (7.4), 210
-
(85), 104 (100); HRMS m/z calcd for C19H20O2 (M+
H2O)
1
280.1463, found 280.1493.
1513, 1470, 1388, 1261, 1158, 1061, 833 cm-1; H NMR (400
Data for (1R,3S)-1,3-bis(isobutyryloxy)-1,3-diphenylpropane
(26b): IR (neat) 3035, 2975, 1737, 1587, 1470, 1387, 1252, 1153,
1067, 700 cm-1; 1H NMR (400 Hz, CDCl3) δ 1.13 (d, J ) 7.3 Hz,
6H), 1.18 (d, J ) 7.3 Hz, 6H), 2.17-2.23 (m, 1H), 2.54 (sept, J )
7.3 Hz, 2H), 2.57-2.63 (m, 1H), 5.63 (t, J ) 6.8 Hz, 2H), 7.34-
7.34 (m, 10H); MS m/z 368 (M+, 0.7), 280 (40), 237 (35), 210
(94), 105 (60) 104 (49), 71 (100); HRMS m/z calcd for C23H28O4
(M+) 368.1988, found 368.1941.
MHz, CDCl3) δ 7.34 (s, 1H), 7.26 (s, 1H), 6.02 (q, J ) 6.8 Hz,
1H), 5.10 (q, J ) 6.4 Hz, 1H), 2.58 (sept, J ) 6.8 Hz, 1H), 2.32
(s, 3H), 2.29 (s, 3H), 1.50 (d, J ) 6.4 Hz, 3H), 1.47 (d, J ) 6.4
Hz, 3H) 1.20 (d, J ) 6.8 Hz, 3H), 1.17 (d, J ) 6.8 Hz, 3H); MS
m/z 236 (M+, 31), 148 (38) 43 (100); HRMS m/z calcd for C14H20O3
236.1412, found 236.1380.
Data for 1-[(1R)-(isobutyryloxy)ethyl]-4-[(1S)-(isobutyryloxy)-
ethyl]benzene (30b): colorless oil; 24% yield; IR (neat) 2079, 1734,
1
Data for 1-[(1R)-(isobutyryloxy)ethyl]-2-[(1S)-hydroxyethyl]-
benzene (27a): IR (neat) colorless oil; 87% yield; 3475, 2977, 1734,
1472, 1387, 1258, 1157, 1021, 831 cm-1; H NMR (400 MHz,
CDCl3) δ 7.32 (s, 2H), 5.86 (q, J ) 6.8 Hz, 2H), 2.56 (sept, J )
6.8 Hz, 2H), 1.50 (d, J ) 6.8 Hz, 6H) 1.18 (d, J ) 6.8 Hz, 3H),
1.16 (d, J ) 6.8 Hz, 3H); MS m/z 306 (M+, 2.0), 218 (137) 148
(100), 130 (14); HRMS m/z calcd for C14H18O2 (M+ - C4H8O2)
218.1307, found 218.1277.
Preparation of (R)-1-[2-[1-(Isobutyryloxy)ethyl]phenyl]etha-
none (31). To a solution of monoester 27a (37 mg, 0.156 mmol)
in dry CH2Cl2 (3.2 mL) was added Dess-Martin periodinane (79.7
mg, 0.188 mmol). The solution was stirred for 1 h, and the
precipitate was filtered. Concentration of the filtrate gave a crude
product, which was purified by preparative TLC (hexane:AcOEt
1
1471, 1374, 1262, 1198, 1061, 762 cm-1; H NMR (400 MHz,
CDCl3) δ 7.52 (d, J ) 6.8 Hz, 1H), 7.39 (d, J ) 6.8 Hz, 1H), 7.30
(m, 2H), 6.13 (q, J ) 6.4 Hz, 1H), 5.33 (q, J ) 6.4 Hz, 1H), 2.53
(sept, J ) 6.8 Hz, 1H), 1.55 (d, J ) 6.8 Hz, 6H), 1.14 (d, J ) 6.8
Hz, 3H), 1.10 (d, J ) 6.8 Hz, 3H); MS m/z 236 (M+, 6.5), 148
(37) 133 (100); HRMS m/z calcd for C14H20O3 236.1412, found
236.1387.
Data for 1-[(1R)-(isobutyryloxy)ethyl]-2-[(1S)-(isobutyryloxy)-
ethyl]benzene (27b): colorless oil; 13% yield; IR (CHCl3) 2977,
1
1734, 1472, 1387, 1260, 1157, 1056, 761 cm -1; H NMR (400
MHz, CDCl3) δ 7.42 (m, 2H), 7.34 (m, 2H), 6.19 (q, J ) 6.8 Hz,
2H), 2.56 (sept, J ) 6.8 Hz, 2H), 1.55 (d, J ) 5.4 Hz, 6H), 1.19
(d, J ) 6.8 Hz, 6H), 1.15 (d, J ) 6.8 Hz, 6H); MS m/z 306 (M+,
) 4:1) to afford pure 31 (36 mg): oil; IR (neat) 2976, 1735, 1686,
-1
1573, 1487, 1356, 1252, 1060, 763 cm
;
1H NMR (400 Hz,
CDCl3) δ 1.13 (d, J ) 6.8 Hz, 3H), 1.15 (d, J ) 6.8 Hz, 3H), 1.57
(d, J ) 6.4 Hz, 3H), 2.54 (sept, J ) 6.8 Hz, 1H) 2.64 (s, 3H), 6.22
(q, J ) 6.4 Hz, 1H), 7.33 (dt, J ) 1.2, 6.8 Hz, 1H), 7.49 (dt, J )
1.2, 6.8 Hz, 1H), 7.56 (dd, J ) 1.2, 6.8 Hz, 1H), 7.64 (dd, J ) 1.2,
4.3), 218 (7.3) 43 (100); HRMS m/z calcd for C14H18O2 (M+
-
C4H8O2) 218.1307, found 218.1277.
Data for isobutyric acid (1R,4S)-4-hydroxy-1,2,3,4-tetrahy-
dronaphthalen-1-yl ester (28a): IR (CHCl3) 3419, 3020, 2976,
6.8 Hz, 1H); MS m/z 163 (M+ - 71, 100), 147 (51), 146 (32), 129
1
-
1720, 1456, 1388, 1259, 1198, 1041, 756 cm-1; H NMR (400
(25), 71 (15); HRMS m/z calcd for C10H11O2 (M+
C4H7O)
26.5
MHz, CDCl3) δ 7.55 (m, 1H), 7.38-7.26 (m, 3H), 5.93 (m, 1H),
4.77 (m, 1H), 2.59 (sept, J ) 6.8 Hz, 1H), 2.12-2.01 (m, 4H),
1.21 (d, J ) 7.3 Hz, 3H), 1.19 (d, J ) 6.8 Hz, 3H); MS m/z 216
(M+ - 18, 7.3), 147 (14), 146 (100), 129 (56), 71 (22); HRMS m/z
calcd for C14H16O2 (M+ - H2O) 216.1150, found 216.1090.
Data for isobutyric acid (1R,4S)-4-(isobutyryloxy)-1,2,3,4-
tetrahydronaphthalen-1-yl ester (28b): IR (neat) 3036, 2874,
3036, 2975, 1733, 1471, 1387, 1254, 1154, 993, 775 cm-1; 1H NMR
(400 MHz, CDCl3) δ 7.33-7.27 (m, 4H), 5.95 (m, 2H), 2.61 (sept,
J ) 6.8 Hz, 2H), 2.16-2.03 (m, 2H), 1.21 (d, J ) 7.37 Hz, 12H);
MS m/z 216 (M+ - 88, 21), 146 (100), 129 (90), 71 (33); HRMS
m/z calcd for C14H16O2 (M+ - C4H8O2) 216.1150, found 216.1082.
Data for 1-[(1R)-(isobutyryloxy)ethyl]-3-[(1S)-hydroxyethyl]-
2,4-dimethylbenzene (29a): colorless oil; 87% yield; IR (neat)
163.0759, found 163.0685; [R]D +3.6 (c 0.95, CHCl3).
Preparation of (R)-1-[4-(1-Hydroxyethyl)phenyl]ethanone
(32). To a solution of monoester 30a (22 mg, 0.1 mmol) in CH2-
Cl2 (4 mL) was added Dess-Martin periodinane (43 mg, 0.1 mmol).
After being stirred for 30 min, the reaction mixture was concen-
trated. The residue was purified by preparative TLC (hexane:AcOEt
) 3:1) to give 1-[4-[1-(isobutyryloxy)ethyl]phenyl]ethanone (20
mg), which was hydrolyzed with 2 N NaOH/MeOH to give 32:
colorless oil; 91% yield for two steps; 1H NMR (400 MHz, CDCl3)
δ 7.95 (d, J ) 6.8 Hz, 1H), 7.47 (d, J ) 7.8 Hz, 1H), 4.98 (q, J )
24
6.8 Hz, 1H), 2.61 (s, 3H), 151 (d, J ) 6.8 Hz, 3H); [R]D +41.7
(c 0.69, CHCl3).
Acknowledgment. This work was supported by a Grant-
in-Aid for Scientific Research (B) (No. 17350046) from the
Japan Society for the Promotion of Science.
3447, 2975, 1734, 1506, 1456, 1387, 1259, 1159, 1079, 870 cm-1
;
1H NMR (400 MHz, CDCl3) δ 7.34 (s, 1H), 7.26 (s, 1H), 6.02 (q,
J ) 6.8 Hz, 1H), 5.10 (q, J ) 6.4 Hz, 1H), 2.58 (sept, J ) 6.8 Hz,
1H), 2.32 (s, 3H), 2.29 (s, 3H), 1.50 (d, J ) 6.4 Hz, 3H), 1.47 (d,
J ) 6.4 Hz, 3H) 1.20 (d, J ) 6.8 Hz, 3H), 1.17 (d, J ) 6.8 Hz,
3H); MS m/z 264 (M+, 1.5), 176 (87), 161 (100), 133 (33); HRMS
Supporting Information Available: Details of the kinetic
1
resolution of sec-alcohols, H NMR spectra for 1a-1d, 2-4, 5a,
5b, 6, 7, 20, 21, 23, 24, 25b, 26a-30a, 26b-30b, and 31, 1H NMR
1
chemical shift data for 1a, 5, 6, and 7 and ∆δ values, H NMR
24
m/z calcd for C16H24O3 264.1725, found 264.1707; [R]D +49.9
spectra for NOE experiments, X-ray crystallographic data and CIF
files for 1d and 5b, Cartesian coordinates of conformers A and B
from optimized DFT calculations, and conformer distribution
predicted by AM1 calculations. This material is available free of
charge via the Internet at http://pubs.acs.org.
(c 1.0, MeOH).
Data for 1-[(1R)-(isobutyryloxy)ethyl]-3-[(1S)-(isobutyryloxy)-
ethyl]-2,4-dimethylbenzene (29b): colorless oil; 11% yield; IR
-1
(CHCl3) 2976, 1735, 1473, 1388, 1259, 1158, 1044, 871 cm
;
1H NMR (400 MHz, CDCl3) δ 7.42 (s, 1H), 6.93 (s, 1H), 6.02 (q,
J ) 6.8 Hz, 2H), 2.54 (sept, J ) 6.8 Hz, 2H), 2.32 (s, 6H), 1.49
JO060989T
6880 J. Org. Chem., Vol. 71, No. 18, 2006