Asymmetric Acylation of sec-Alcohols with Twisted Amides Possessing Axial Chirality Induced by the Adjacent Asymmetric Center

Article abstract of DOI:10.1021/jo990892p

This paper reports that axially chiral twisted amides serve as asymmetric acylating agents for sec-alcohols under neutral conditions. Kinetic resolution of various racemic sec-alcohols and desymmetrization of 1,2-, 1,3-, and 1,4-meso-diols were performed by using the twisted amides. The utility of this desymmetrization method was shown by the preparation of the synthetic intermediate 28 for macrolide antibiotic nodusmicin and 18-deoxynargenicin. The stereoselectivity of the acylation reactions is significantly dependent on the bulkiness of both the acyl group and the C-4 substituent of the chiral auxiliary. When an amide possessing an imidazolyl group at C-4 was employed, the stereoselectivity was reversed to give R esters. A possible working model of the acylation reaction is also described on the basis of the structural studies of the twisted amides by IR and ¹H and ¹³C NMR spectroscopies and AMI calculations. These studies suggested that rotamer II is thermodynamically more stable than the others. The rotamer II has an axial chirality about its C(O)-N linkage that is induced by the adjacent chiral center. This would enable discrimination of the two enantiomeric hydroxy groups of the racemic alcohols or meso-diols.

Full text of DOI:10.1021/jo990892p

J . Org. Chem. 1999, 64, 9365-9373
9365
Asym m etr ic Acyla tion of sec-Alcoh ols w ith Tw isted Am id es
P ossessin g Axia l Ch ir a lity In d u ced by th e Ad ja cen t Asym m etr ic
Cen ter
Shinji Yamada* and Hiroko Katsumata
Department of Chemistry, Faculty of Science, Ochanomizu University, 2-1-1 Otsuka,
Bunkyo-ku, Tokyo 112-8610, J apan
Received J une 2, 1999
This paper reports that axially chiral twisted amides serve as asymmetric acylating agents for
sec-alcohols under neutral conditions. Kinetic resolution of various racemic sec-alcohols and
desymmetrization of 1,2-, 1,3-, and 1,4-meso-diols were performed by using the twisted amides.
The utility of this desymmetrization method was shown by the preparation of the synthetic
intermediate 28 for macrolide antibiotic nodusmicin and 18-deoxynargenicin. The stereoselectivity
of the acylation reactions is significantly dependent on the bulkiness of both the acyl group and
the C-4 substituent of the chiral auxiliary. When an amide possessing an imidazolyl group at C-4
was employed, the stereoselectivity was reversed to give R esters. A possible working model of the
acylation reaction is also described on the basis of the structural studies of the twisted amides by
1
IR and H and 13C NMR spectroscopies and AM1 calculations. These studies suggested that rotamer
II is thermodynamically more stable than the others. The rotamer II has an axial chirality about
its C(O)-N linkage that is induced by the adjacent chiral center. This would enable discrimination
of the two enantiomeric hydroxy groups of the racemic alcohols or meso-diols.
In tr od u ction
Kinetic resolution of racemic sec-alcohols and desym-
metrization of meso-diols by way of acyl transfer reactions
are effective methods for obtaining chiral alcohols. To
achieve asymmetric acylation, enzymatic processes have
widely been used as the most effective approach1 and
have been applied to the preparation of a number of
F igu r e 1. Reported selective acylation of diols with a twisted
natural products and bioactive compounds. However,
since the substrate specificity of enzymes is very high,
as a result, structural variation of the substrates is often
limited. Recently, nonenzymatic methods have also been
extensively explored.2-4 While most nonenzymatic asym-
metric acylations are conducted at very low temperature
or in the presence of a metal salt for chelation control to
amide.
achieve high stereoselectivity, recent efforts have enabled
the acylation under very mild conditions.3a,h-j
Previously, we have reported that 3-pivaloyl-1,3-thi-
azolidine-2-thione possessing an extremely twisted amide
linkage5,6 serves as a selective acylating agent for diols
having primary and secondary hydroxy groups and those
having alcoholic and phenolic hydroxy groups under
neutral conditions (Figure 1).7 In the course of our studies
on the structure and reactions of twisted amides, we were
interested in the asymmetric acylation by utilizing axially
chiral twisted amides. If it is possible to control the
directionality of the amide bond twisting, axial chirality
will be induced in the C(O)-N bond (Figure 2). The
axially chiral twisted amides seem to discriminate enan-
tiomeric hydroxy groups during the acylating process and
would serve as asymmetric acylating agents. Although
the imides and amides possessing axial chirality about
the C-N8 and C-C(O)9 bonds have recently received
(1) For reviews, see: (a) J ones, J . B. Tetrahedron 1986, 42, 3351.
(b) Chen, C.-S.; Sih, C. J . Angew. Chem., Int. Ed. Engl. 1989, 28, 695.
(c) Klibanov, A. M. Acc. Chem. Res. 1990, 23, 114. (d) Wong, C.-H.;
Whitesides, G. M. Enzymes in Synthetic Organic Chemistry; Elsevier
Science Ltd.: Oxford, 1994. (e) Schoffers, E.; Golebiowski, A.; J ohnson,
C. R. Tetrahedron 1996, 52, 3769.
(2) For a review, see: Somfai, P. Angew. Chem., Int. Ed. Engl. 1997,
36, 2731.
(3) Recent nonenzymatic kinetic resolution, see: (a) Kawabata, T.;
Nagato, M.; Takasu, K.; Fuji, K. J . Am. Chem. Soc. 1997, 119, 3169.
(b) Vedejs, E.; Chen, X. J . Am. Chem. Soc. 1997, 119, 2584. (c) Ruble,
J . C.; Latham, H. A.; Fu, G. C. J . Am. Chem. Soc. 1997, 119, 1492. (d)
Chandrasekhar, S.; Ramachander, T.; Takhi, M. Tetrahedron Lett.
1998, 39, 3263. (e) Ruble, J . C.; Tweddell, J .; Fu, G. C. J . Org. Chem.
1998, 63, 2794. (f) Miller, S. J .; Copeland, G. T.; Papaioannou, N.;
Horstmann, T. E.; Ruel, E. M. J . Am. Chem. Soc. 1998, 120, 1629. (g)
Trost. B. M.; Patterson, D. E. J . Org. Chem. 1998, 63, 1339. (h)
Copeland, G. T.; J arvo, E. R.; Miller, S. J . J . Org. Chem. 1998, 63,
6784. (i) Garrett, C. E.; Fu, G. C. J . Am. Chem. Soc. 1998, 120, 7479.
(j) Vedejs, E.; Daugulis, O. J . Am. Chem. Soc. 1999, 121, 5813. (k) Sano,
T.; Imai, K.; Ohashi, K.; Oriyama, T. Chem. Lett. 1999, 265.
(4) For desymmetrization, see: (a) Mukaiyama, T.; Tomioka, I.;
Shimizu, M. Chem. Lett. 1984, 49. (b) Ichikawa, J .; Asami, M.;
Mukaiyama, T. Chem. Lett. 1984, 949. (c) Suzuki, T.; Uozumi, Y.;
Sibasaki, M. J . Chem. Soc., Chem. Commun. 1991, 1593. (d) Ishihara,
K.; Kubota, M.; Yamamoto, H. Synlett 1994, 611. (e) Vedejs, E.;
Daugulis, O.; Diver, S. T. J . Org. Chem. 1996, 61, 430. (f) Oriyama,
T.; Imai, K.; Sano, T.; Hosoya, T. Tetrahedron Lett. 1998, 39, 3529. (g)
Ruble, J . C.; Tweddell, J .; Fu, G. C. J . Org. Chem. 1998, 63, 2794.
(5) Yamada, S. Angw. Chem., Int. Ed. Engl. 1993, 32, 1083.
(6) Yamada, S. In The Amide Linkage: Selected Structural Aspects
in Chemistry, Biochemistry and Materials Science; Greenberg, A.,
Breneman, C. M., Liebman, J . F., Eds.; J ohn Wiley & Sons: New York,
2000; Chapter 8.
(7) Yamada, S.; Sugaki, T.; Matsuzaki, K. J . Org. Chem. 1996, 61,
5932.
(8) For example, see: (a) Kawamoto, T.; Tomishima, M.; Yoneda,
F.; Hayami, J . Tetrahedron Lett. 1992, 33, 3173. (b) Curran, D. P.; Qi,
H.; Geib, S. J .; DeMello, N. C. J . Am. Chem. Soc. 1994, 116, 3131. (c)
Curran, D. P.; Yu, H.; Liu, H. Tetrahedron 1994, 50, 7343. (d) Hughes,
10.1021/jo990892p CCC: $18.00 © 1999 American Chemical Society
Published on Web 12/02/1999

9366 J . Org. Chem., Vol. 64, No. 26, 1999
Yamada and Katsumata
Ta ble 1. IR (cm -1) a n d 1H a n d 13C NMR (p p m ) Sp ectr a l
Da ta for 1-8
ratio
amide νCdOa
δ1H4
δ
13CdOc 13CdSc ∆δ13CdOc (A/B)b
δ
b
1
2
3
1697
1696
1739
5.31
170.3
177.9
201.6
205.3
1.2
2.2
5.38
204.6
4.15e
158.8f
1:25e
6:1g
F igu r e 2. Generation of axial chirality by amide bond
twisting.
(1700)d
4
5
1737
(1726)d
1720
(1727)d
4.55
188.3
189.0
188.6
200.8
200.1
11.9
13.6
considerable attention in various asymmetric synthesis,
little is known about axial chirality based on the C(O)-N
bond.
4.55-4.61
4.65
11:1
6
7
1720
1734
200.1
187.6
12.2
8.4
17:1
4.44-4.59g 184.8
12:1g
(1730)d
In this paper, we report that twisted amides 1-8,
which have axial chirality about the C(O)-N bond
induced by the adjacent asymmetric center, serve as
asymmetric acylating agents for racemic sec-alcohols and
meso-diols.10 Furthermore, a possible working model in
the acylating process was proposed by studying the
conformational structures of these amides on the basis
8
1734
4.60-4.66
184.2
186.2
7.8
a
b
KBr disk. 400 MHz in CDCl3 unless otherwise noted. c 100.4
MHz in CDCl3. In CHCl3. e In C6D5CD3. f This value is not for
CdS, but for CdN. In C6D6.
d
g
Sch em e 1
1
of the IR and H and 13C NMR spectral data and AM1
calculations.
Resu lts a n d Discu ssion
Amides 1-8 were readily prepared by the acylation of
the corresponding (S)-4-isopropyl-,11 (S)-4-isobutyl-,12 (S)-
4-tert-butyl-,7 and (S)-4-benzyl-1,3-thiazolidine-2-thiones
and (S)-4-tert-butyl-7 and (S)-4-(3-methyl-3H-imidazol-
4-yl)-1,3-oxazolidine-2-thiones,13 which were synthesized
from L-amino acids via several steps.
bonyl carbons of the amides except for amide 3 were
observed between δ170.3-189.0 and δ184.8-205.3, re-
spectively. The ∆δ13C values, which were determined by
comparing with those of the corresponding standard
N-acylpyrrolidines14 in order to evaluate the net twisting
effect, clearly show that the ∆δ13C values of 4-8 were
much higher than those of 1 and 2. This also supports
the significant amide bond twisting of 4-8.
1H NMR spectra show that 1, 2, and 8 exist as a single
isomer, whereas 3-7 are a mixture of two structural
isomers, which are considered to be the N-acyl form A
and the S-acyl form B as shown in Scheme 1. The isomer
ratio was determined by the 1H NMR spectra on the basis
of the integration of H-3 and H-4. These isomers are not
considered to be rotamers because the rotational barrier
of this type of compound is generally very small; for
example, the rotational barrier of diacetylamine is about
10.8 kcal/mol.15 The 13C NMR and IR spectral data of the
major isomer satisfied the twisted amide structure as
described above; the δ13C values of the carbonyl and
thiocarbonyl carbons and the νCdO values of 4-7 are
close to those of reported, structurally analogous twisted
amides.5 The structure of amide 5 has already been
confirmed to be the N-acyl form A by X-ray analysis.12
Therefore, the major isomers of 4-7 were determined to
be N-acyl form A. The minor isomers were considered to
be S-acyl form B. In the 13C NMR spectrum of 4, two
characteristic peaks for the minor isomer appeared at δ
158.8 and 201.2 in CDCl3. The signal at δ 158.8 was
assigned to the S-CdN carbon by comparison with
related compounds 2-benzyloxycarbonylthio-5-methyl-
1,3,4-thiadiazole (δ 157.3)16 and 2-benzylthio-∆2-1,3-
thiazoline (δ 164.3),17 and the other signal at δ 201.2 was
assigned to the thioester carbonyl carbon.18
1
The structures of the amides 1-8 were studied by H
and 13C NMR and IR spectroscopies. The data are shown
in Table 1. The carbonyl stretching bands of the amides
1 and 2 are observed at 1696-1697 cm-1. On the other
hand, those of 3-8 having a pivaloyl group appear at
1720-1739 cm-1 in solid or neat film, indicating that
these amide linkages are highly twisted compared to
those of 1 and 2.5,12 When they are measured in CHCl3,
only the carbonyl stretching band of 3 dramatically
shifted to lower frequency and was observed at 1700
cm-1. In the 13C NMR spectra, the carbonyl and thiocar-
A. D.; Price, D. A.; Shishkin, O.; Simpkins, N. S. Tetrahedron Lett.
1996, 37, 7607. (e) Kitagawa, O.; Izawa, H.; Sato, K.; Dobashi, A.;
Taguchi, T.; Shiro, M. J . Org. Chem. 1998, 63, 2634. (f) Kondo, K.;
Fujita, H.; Suzuki, T.; Murakami, Y. Tetrahedron Lett. 1999, 40, 5577.
(9) For reviews, see: (a) Clayden, J . Angw. Chem., Int. Ed. Engl.
1997, 36, 949. (b) Clayden, J . Synlett 1998, 810.
(10) Preliminary communications: (a) Yamada, S.; Ohe, T. Tetra-
hedron Lett. 1996, 37, 6777. (b) Yamada, S.; Katsumata, H. Chem. Lett.
1998, 995.
(11) Nagao, Y.; Hagiwara, Y.; Kumagai, T.; Ochiai, M.; Inoue, T.;
Hashimoto, K.; Fujita, E. J . Org. Chem. 1986, 51, 2391.
(12) Yamada, S. J . Org. Chem. 1996, 61, 941.
(13) Gonzalez, F. B.; Baz, J . P.; Espina, M. I. R. Tetrahedron Lett.
1989, 30, 2145.
(14) δ13C chemical shifts of N-acylpyrrolidines, N-acetylpyrroli-
dine: δ 169.1; N-isobutyrylpyrrolidine: δ 175.7; N-pivaloylpyrroli-
dine: δ 176.4.
(15) Noe, E. A.; Raban, M. J . Am. Chem. Soc. 1975, 97, 5811.
(16) Allainmat, M.; L’Haridon, P.; Toupet, L.; Plusquellec, D.
Synthesis 1990, 27.

Asymmetric Acylation of sec-Alcohols
J . Org. Chem., Vol. 64, No. 26, 1999 9367
Ta ble 2. En a n tioselective Acyla tion of Ra cem ic sec-Alcoh ols 9-14 w ith Tw isted Am id es 1-8
entry
alcohola
amide
solv
additivesb
T, °C
time, h
product
yieldc, %
ee, %
confign
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
9
9
9
9
9
9
9
9
10
10
10
10
10
10
10d
10
10
10
11
12
13
14
9
1
2
3
3
3
3
3
3
3
4
5
6
7
8
3
3
7
2
3
3
3
3
3
4
3
3
hexane
hexane
hexane
toluene
CH3COOEt
CHCl3
reflux
reflux
reflux
80
114
39
22
22
23
15
19
71
18
14
15
15
14
18
14
14
6 days
18
14
28
18
12
2
9a
9b
9c
9c
9c
9c
9c
9c
10c
10c
10c
10c
10c
10c
10c
10c
10c
10b
11c
12c
13c
14c
9c
79
84
92
97
94
89
70
72
92
99
98
97
91
51
92
87
93
92
90
94
93
98
49
74
58
53
34
39
49
37
36
35
33
26
80
57
38
44
75
16
70
84
79
64
46
45
50
56
19
39
20
42
S
S
S
S
S
S
S
S
S
S
S
S
S
R
S
S
S
S
S
S
S
S
R
R
R
R
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
rt
t-BuOH
THF
hexane
hexane
hexane
hexane
hexane
hexane
hexane
hexane
hexane
hexane
hexane
hexane
hexane
hexane
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
Et3N
Et3N
rt
reflux
reflux
reflux
reflux
reflux
0
0
rt
0
MeMgBr
MeMgBr
MgBr2/Et3N
MeMgBr
9
11
12
4
18
6
9c
11c
12c
a
b
Five equiv of alcohol was used unless otherwise noted. Five equiv of the reagent was added. c Isolated yields based on acylating
d
agents. Two equiv of alcohol was used.
On the other hand, amide 3 shows very different IR
and 13C NMR spectra compared to the others. The IR
spectrum exhibited strong absorption bands of 1739 and
1130 cm-1 for the carbonyl and thiocarbonyl groups in
the solid state. In contrast, a strong thioester carbonyl
absorption at 1700 cm-1 and no trace of CdS absorption
were detected in CHCl3 solution. In the 13C NMR data of
the amide 3, thioester carbonyl and the S-CdN carbon
were observed at δ 201.6 and 158.8, respectively, which
are very close to those of the minor isomer of amide 4
described above. Therefore, amide 3 mainly exists in the
S-acyl form B in solution and exists in the N-acyl form
A in the solid state. This suggests that the amides 3-7
would be in equilibrium between A and B.19 To the best
of our knowledge, the N to S acyl migration of N-
acylthioimides has not yet been reported, although S to
N acyl migration has been observed in the S-acylisothio-
urea20 and S-(2-benzoxazolyl)thioester.21
uration was performed by comparison of the specific
rotations of the hydrolyzed alcohols with those reported.23
Each acylation of 5 equiv of 1-indanol (9) with amides
1-3 was carried out in hexane at reflux temperature for
22-114 h under neutral conditions to give (S)-1-indanoyl
esters as major products in good yields. As the size of
the acyl group increased, both the reaction rate5 and the
stereoselectivity increased (Table 2, entries 1-3). These
observations may be due to the magnitude of the C(O)-N
twist angle; as the twist angle increases by steric repul-
sion, amide resonance is inhibited; as a result, the
reactivity increased. Since the twist angle determines the
relative geometry between the carbonyl and the thiocar-
bonyl groups, the magnitude of the twist angle may play
an important role in the stereoselectivity. Among the
various solvents employed, hexane was the most effective,
whereas tetrahydrofuran was the least effective, indicat-
ing that a less polar solvent is preferable in this reaction
(Table 2, entries 4-8). A similar solvent effect has also
been observed in the kinetic resolution of racemic amines.24
Table 2 shows the results of the kinetic resolution of
racemic sec-alcohols 9-14 with the amides 1-8 under
various reaction conditions. The enantiomeric excess of
the resulting esters was determined by HPLC analysis
using a chiral stationary phase22 after hydrolysis into the
starting alcohols. Determination of the absolute config-
(17) Fujita, E.; Nagao, Y.; Seno, K.; Takao, S.; Miyasaka, T.; Kimura,
M.; Watson, H. J . Chem. Soc., Perkin Trans. 1 1981, 914.
(18) Voss, J . In The Chemistry of Acid Derivatives; Patai, S., Ed.;
Wiley: Chichester, 1979; Suppl. B, Part 2, Chapter 18.
(19) The interconversion process may be an uncatalyzed process
because the recrystallized amides also showed the same 1H NMR
spectra.
(20) (a) Pratt, R. F.; Bruice, T. C. Biochemistry 1971, 10, 3178. (b)
Pratt, R. F.; Bruice, T. C. J . Am. Chem. Soc. 1972, 94, 2823.
(21) Ueda, M.; Seki, K.; Imai, Y. Synthesis 1981, 991.
(22) The analysis was carried out using a CHIRALCEL OB column
with a 9: 1 mixture of hexane and 2-propanol as an eluent solvent.
(23) Compd. 11: Kabuto, K.; Imuta, M.; Kempner, E. S.; Ziffer, H.
J . Org. Chem. 1978, 43, 2357. Compound 13: Carter, M. B.; Schiott,
B.; Gutierrez, A.; Buchwald, S. L. J . Am. Chem. Soc. 1994, 116, 11670.
Compound 14: Brunner, H.; Kurzinger, A. J . Organomet. Chem. 1988,
346, 413.

9368 J . Org. Chem., Vol. 64, No. 26, 1999
Yamada and Katsumata
Sch em e 3
Sch em e 2
Ta ble 3. Desym m etr iza tion of m eso-Diols 19-22 w ith
Tw isted Am id es 3-7
The kinetic resolution of racemic 1-tetralol (10) with
the amides 3-8 clearly shows the substituent effect at
C-4. Depending on the substituent at C-4 of the thiazoli-
dine-2-thione moiety, the selectivity was significantly
changed (Table 2, entries 9-14); as the steric bulkiness
of the substituent increased, the selectivity increased.
Although amide 3 mainly exists in the S-acyl form in
solution, the selectivity is 80% ee, which is the highest
among the amides.
Although each reaction gave (S)-ester as the major
product similar to the case of 1-indanol, only the reaction
with the amide 8 gave an (R)-ester (Table 2, entry 14).
Reducing the amount of 1-tetralol used from 5 to 2 equiv
resulted in a slight decrease in the enantiomeric purity
(Table 2, entry 15). Addition of triethylamine enhanced
the reaction rate sufficiently to enable it to proceed even
at room temperature and provided the highest enantio-
selectivity of 84% ee (Table 2, entries 16 and 17),
although the reactivity of 7 was much lower than that of
3.
This method was applicable to a variety of sec-alcohols.
Each acylation of 11-14 with 3 gave (S)-esters as major
products similar to the reactions described above. Com-
paring entry 19 with entries 3 and 9, the selectivity of
11 is close to that of 9, but much different from that of
10 despite the closely related structures; therefore, the
ring size exerts a significant effect on the stereoselectiv-
ity. Similar results were observed for isobutylation with
2 (Table 2, entries 2 and 18). On the other hand, the
selectivities for acyclic alcohols 12-14 are similar, al-
though their aromatic moieties are very different; there-
fore, the substituent on the aromatic part may not
contribute to the enantioselectivity (Table 2, entries 20-
22).
It is noteworthy that the addition of MeMgBr as a base
or MgBr2 as a Lewis acid reversed the stereoselectivity
to yield the (R)-isomers predominantly (Table 2, entries
23-26). This observation is closely related to the reported
kinetic resolution by Evans and his colleague25 where
asymmetric benzoylation of 1-tetralol with (S)-3-benzoyl-
oxazolidinones in the presence of MeMgBr or MgBr2 gave
(R)-benzoate as a major product. The reversal of stereo-
selectivity may be ascribed to the change in the transition
conformations around the amide bonds by chelation with
the magnesium reagents.
mono-
T, time, ester
eeb, diester
entry diola amide additives °C
h
(a )/%
%
(b), %
1
2
3
4
5
19
19
19
19
19
4
5
3
7
3
80
80
80
80
20 71c
71
27c
21d
17c
28c
0
20 69d (52)c 48
20 79c
20 69c
79
78
Et3N
(2 equiv)
Et3N
(5 equiv)
DMAP
(2 equiv)
rt 138 98d (34)c 88
6
7
19e
19
3
3
rt
rt
71 99d (41)c 82
0
0
48 84c
51
33
8
9
10
20
21
2e
3
3
3
80
80
50
14 78c
8c
0
0
14 92d (68)c 44
89 86d (37)c 56
Et3N
(2 equiv)
11
22
3
80
15 86d (55)c 42f
0
a
The reactions were conducted in toluene unless otherwise
noted. b S configuration. c Isolated yield. Conversion yield. e THF
was used as a solvent. f The ee was determined by 1H NMR in
the presence of Eu(hfc)3 and the absolute configuration is not
determined.
d
dl- and meso-dibromides, which were converted into
diacetates 15 with silver(I) acetate in 81% yield. After
hydrolysis with 2 N NaOH, fractional recrystallization
from the MeOH-ether afforded pure dl-diol 16 and meso-
diol 19.
The kinetic resolution of racemic dl-diol 16 with the
amide 3 gave the corresponding monopivalate 17 and
dipivalate 18 in 60% and 91% ee, respectively (Scheme
3). In this reaction, the ee of dipivalate 18 was higher
than that of monopivalate 17. This would be a result of
the sequential enantioselective processes. In fact, the
kinetic resolution of the isolated 17 afforded 18 with
much higher ee as expected. A similar sequential process
has been observed by Fu and co-workers.4g
Desymmetrization of meso-diols by way of a nonenzy-
matic acyl-transfer reaction has also been extensively
explored for the preparation of chiral alcohols.4 We
applied the present asymmetric acylation method to the
desymmetrization of meso-diols under very mild condi-
tions. Desymmetrization of meso-1,2-, -1,3-, and -1,4-diols
19-22 with twisted amides 3-5 and 7 as acylating
agents was investigated. The results are summarized in
Table 3. Although 1,2- and 1,3-diols have often been
employed as substrates for the nonenzymatic desymmet-
This method is also applicable to the kinetic resolution
of dl-diols. The racemic dl-diol 16 and meso-diol 1926 were
prepared from tetralin via three steps (Scheme 2).
Treatment of tetralin with NBS yielded a 1:1 mixture of
(24) Nagao, Y.; Yagi, M.; Ikeda, T.; Fujita, E. Tetrahedron Lett. 1982,
23, 201.
(25) Evans, D. A.; Anderson, J . C.; Taylor, M. K. Tetrahedron Lett.
1993, 34, 5563.
(26) Martan, M.; Manassen, J .; Vofsi, D. Tetrahedron 1970, 26, 3815.

Asymmetric Acylation of sec-Alcohols
J . Org. Chem., Vol. 64, No. 26, 1999 9369
Sch em e 4
rization, there are few examples of using sec-meso-1,4-
diols. The reactions of cis-tetrahydronaphthalene-1,4-diol
(19) with 1.1 equiv of amides 3-5 and 7 in toluene at 80
°C for 20 h gave the corresponding monopivalate in good
yields (Table 3, entries 1-4). Determination of the
enantiomeric excess was performed by HPLC analysis
using a chiral stationary phase. Among the amides, 3 and
7 are more effective for the stereoselective acylation than
4 and 5. Addition of triethylamine enhances the reaction
rate sufficiently to enable it to proceed even at room
temperature with higher selectivity than that attained
at 80 °C (Table 3, entries 5 and 6); however, amide 7 is
less reactive than 3 at room temperature. Addition of
DMAP decreases the enantioselectivity, although it very
effectively accelerates the reaction rate (Table 3, entry
7). In the case of cis-1,3-indandiol (20), the selectivity was
lower than that observed for 1,4-diol 19 (Table 3, entry
8), indicating the significant dependence of the structure
of the diols on the stereoselectivity. The absolute con-
figurations of the monoesters were determined by con-
verting them into the corresponding known 1-tetralol and
1-indanol. Acylation of diol 21 with 3 at 80 °C gave the
reported (S)-monopivalate27 in 44% ee (Table 3, entry 9).
Lowering the reaction temperature increased the selec-
tivity to 56% ee (Table 3, entry 10). The chiral monoester
of diol 21 and related compounds obtained by enzymatic
desymmetrization have been proven to be useful building
blocks for natural product synthesis.28 In addition to the
1,3- and 1,4-diols, the present method was also applicable
to a saturated 1,2-diol 22 (Table 3, entry 11).
Sch em e 5
Ta ble 4. Hea ts of F or m a tion s of th e Rota m er s of 1-8
a n d Th eir Tw ist An glesa
∆HfIa
,
∆HfIb
,
∆HfII
,
∆∆Hf,
amide kcal mol-1 kcal mol-1 kcal mol-1 kcal mol-1 τ, deg
3
4
5
6
7
8
-28.2
-28.8
-36.6
7.5
-29.0
-29.5
-37.6
5.9
-31.6
-30.8
-38.5
5.5
2.6
1.3
0.9
0.4
3.4
48.7
47.3
51.8
55.0
45.2
27.6
-65.6
-69.04
0.97
a
Predicted by AM1 method.
To obtain mechanistic information, structural optimi-
zation of the amides 3-8 was performed by the AM1
method.30 The calculations predicted three stable rota-
mers Ia , Ib, and II (Scheme 5). The number of rotamers
depends on the structure of the amides: one rotamer for
8, two rotamers for 7, three rotamers for 3-6. Rotamers
Ia and Ib have the conformation where the R and R′
groups are on opposite sides of the thiazolidine-2-thione
plane, whereas the R and R′ of rotamer II are on the
same side. The ∆Hf, ∆∆Hf, and twist angle τ are sum-
marized in Table 4.
It is clear that rotamers II have lower energy than Ia
or Ib in all cases, indicating the thermodynamic prefer-
ence of rotamer II. The X-ray geometry of amide 513 is
almost in agreement with that of the corresponding
rotamer II. The values of the twist angle τ,31 which were
determined on the basis of the rotamer II, show that the
amide bond of 3-8 is extremely twisted. The twist angle
of 65.5° of the amide 5 determined by X-ray analysis is
almost in agreement with that of the predicted value of
51.8°, suggesting the validity of the results of the calcula-
tions. The ∆∆Hf values, which are the difference in the
∆Hf values between I and II, are influenced by the C-4
substituent. The order of magnitude of the ∆∆Hf is in
agreement with that of the stereoselectivity. In fact, the
stereoselectivities in the kinetic resolution of 10 and
meso-1,4-Diol 23 has been used as the starting material
for the synthesis of a macrolide antibiotic nodusmicin and
its analogue 18-deoxynargenicin.29 In the synthesis, it has
been reported that attempts to generate the chiral
monoacetate by esterification of 23 or hydrolysis of the
diacetate of 23 with several enzymes failed.29 These
observations prompted us to study the desymmetrization
of 23 by the present method. When diol 23 and 1.1 equiv
of amide 3 in heptane were heated at reflux for 96 h, (R)-
monoester 24a was produced as a major isomer (61% ee)
in 45% yield with diester 24b. Determination of the
absolute configuration was performed by converting 24a
to the reported monosilyl ether 2829 as described in
Scheme 4, which is the intermediate for the synthesis of
nodusmicin and 18-deoxynargenicin. After protection of
the hydroxy group of 24a with ethyl vinyl ether, hydroly-
sis of the pivalate gave a hydroxyether 26 in 78% yield.
Protection of the resulting hydroxy group with tert-
butyldimethylsilyl triflate and deprotection of the ethoxy-
ethyl ether moiety yielded alcohol 28 (48%). The absolute
configuration was in agreement with that reported in the
literature.
(27) Takano, S.; Higashi, Y.; Kamikubo, T.; Moriya, M.; Ogasawara,
K. Synthesis 1993, 948.
(28) For example: (a) Takano, S.; Moriya, M.; Hayashi, Y.;
Ogasawara, K. J . Chem. Soc., Chem. Commun. 1993, 177. (b) Ka-
mikubo, T; Hiroya, K.; Ogasawara, K. Tetrahedron Lett. 1996, 37, 499.
(29) Go¨ssinger, E.; Graupe, M.; Kratky, C.; Zimmermann, K.
Tetrahedron 1997, 53, 3083.
(30) AM1 calculations were performed by using CS MOPAC Pro with
MMOK empirical amide correction factor.
(31) Winkler, F. K.; Dunitz, J . D. J . Mol. Biol. 1971, 59, 169.

9370 J . Org. Chem., Vol. 64, No. 26, 1999
Yamada and Katsumata
amide is postulated to be a transition-state intermediate
of a peptide substrate during enzymatic hydrolysis.34
Exp er im en ta l Section
Melting points are uncorrected. Column chromatography
was carried out using Merck silica gel 60, Merck silica gel 60
PF254, or Florisil (100-200 mesh). HPLC was carried out using
a Daicel CHIRALPAK OB column (25 cm × 4.6 mm) or AS
column (25 cm × 4.6 mm). IR spectra were obtained as neat
films between NaCl plates, as KBr pellets, or as a CHCl3
solution using a NaCl chamber. 1H NMR spectra were recorded
at 270 or 400 MHz as dilute solutions in CDCl3, CD3OD, C6D6,
or C6D5CD3, and the chemical shifts were reported relative to
internal TMS. 13C NMR spectra were recorded at 67.9 or 100.4
MHz as dilute solutions in CDCl3, and the chemical shifts were
reported relative to internal TMS. High- and low-resolution
mass spectra were recorded at an ionizing voltage of 70 eV by
electron impact.
F igu r e 3. Nucleophilic attack from less hindered side.
desymmetrization of 19 with amides 3-7 increased with
increasing ∆∆Hf (entries 9-13 in Tables 2 and entries
1-4 in Table 3).
Although the mechanism for the generation of the
stereoselectivity in this reaction is still unclear, the
experimental results described above suggest that the
conformation of the twisted amide plays an important
role. Thus, since rotamers I and II have opposite axial
chirality, the rotamer ratio would exert a significant
effect on the stereoselectivity in this reaction. In fact, the
relationships between the ∆∆Hf and the stereoselectivity
were observed in the kinetic resolution of 10 and desym-
metrization of 19 with amides 3-7. This observation
strongly suggests that the reaction proceeds from the
rotamer II.32 Since nucleophiles attack the amide carbo-
nyl from the less hindered side, they will approach from
the side of the thiocarbonyl group as shown in Figure 3.
Although this working model cannot be applied directly
to amide 3 that mainly exists as the S-acyl form in
solution, one possible explanation may be given as
follows: if the reactivity of the N-acyl form is significantly
higher than that of the S-acyl form and the rate of the S
to N acyl migration is faster than that of the acylation,
the reaction proceeds from the N-acyl form according to
the above working model.
In contrast to the reaction with amides 3-7, that of
amide 8 resulted in a reversal of stereoselectivity despite
the conformational preference of rotamer II. This can be
ascribed to the difference in the substituent at C-4. Thus,
since the 3-methyl-3H-imidazol-4-yl group of 8 can effect
hydrogen bonding with an alcohol, the alcohol would
approach from the side of the imidazolyl group and attack
the amide carbonyl as shown in Figure 3. This difference
in the direction of attack by the alcohol may cause the
reversal of the stereoselectivity.
The role of the asymmetric center at the 4-position is
to control the directionality of the amide bond twisting
and to induce axial chirality, which would enable dis-
crimination of the two hydroxy groups of racemic sec-
alcohols and meso-diols. Similar induced axial chirality
has been postulated in the diastereoselective Diels-Alder
reaction of 2-(â-substituted R,â-unsaturated)acyl-3-phen-
yl-l-menthopyrazoles.33 In the latter reaction, the direc-
tionality of the phenyl group rotation is controlled by the
adjacent chiral center, which causes the face-selectivity
in the Diels-Alder reaction.
In summary, these asymmetric acylations were at-
tained by taking advantage of the following two impor-
tant characteristic features of the twisted amides: (1)
high reactivity of the amide carbonyl due to inhibition
of amide resonance, which enables the acylation reaction
under neutral and mild conditions, and (2) axial chirality
induced by the adjacent chiral center, which enables
discrimination of the two enantiomeric hydroxy groups.
It is interesting to note that an axially chiral twisted
P r ep a r a t ion of (4S)-4-ter t-Bu t yl-1,3-t h ia zolid in e-2-
th ion e a n d (4S)-4-ter t-Bu tyl-1,3-oxa zolid in e-2-th ion e.7
Concentrated sulfuric acid (2.6 mL) was added dropwise to a
round-bottom flask containing L-tert-leucinol (2.14 g, 15.2
mmol), which was derived from L-tert-leucine35 at 0 °C, and
the mixture was vigorously stirred for 1.5 h. Then, potassium
O-ethyl dithiocarbonate (3.67 g, 22.9 mmol), 2 M NaOH (34
mL), and water (15 mL) were added to the reaction mixture,
and the solution was heated at 50 °C for 2 h. Potassium
O-ethyl dithiocarbonate (3.67 g, 22.9 mmol) and 2 M NaOH
(4 mL) were again added to the reaction mixture, and the
solution was heated at 50 °C further 15.5 h. After being cooled
to room temperature, the solution was acidified with 2 M HCl
and extracted with CHCl3 (35 mL × 3). The combined extracts
were washed with water and dried over anhydrous MgSO4.
Evaporation of the solvent gave a crude mixture of products,
which was subjected to column chromatography (silica gel)
using 5:2-1:0 mixture of CHCl3 and hexane as eluent solvents
to give two crystalline compounds. The less polar fraction was
(4S)-4-tert-butyl-1,3-thiazolidine-2-thione (1.44 g, 54% from
L-tert-leucine) The spectroscopic data was in agreement with
those reported:7 mp 143-144 °C; [R]27 ) -33.2° (c 1.03,
D
CHCl3). The polar fraction was (4S)-4-tert-butyl-1,3-oxazoli-
dine-2-thione (0.166 g, 7% from L-tert-leucine): mp 153-156
°C; [R]27 ) -11.8° (c 0.982, CHCl3).
D
P r ep a r a t ion of (4S)-4-ter t-Bu t yl-3-isob u t yr yl-1,3-t h i-
a zolid in e-2-th ion e (2). To a solution of (4S)-4-tert-butyl-1,3-
thiazolidine-2-thione (300 mg, 1.71 mmol) and triethylamine
(600 µL, 4.30 mmol) in dry CH2Cl2 (6 mL) was added dropwise
isobutyryl chloride (270 µL, 2.58 mmol) at 0 °C, and the
solution was stirred at room temperature for 1 h. The reaction
mixture was washed with water, dried over anhydrous MgSO4,
and concentrated to give a crude product. This was subjected
to column chromatography (Florisil) using a 2:1 mixture of
hexane and CHCl3 as an eluent solvent to give amide 2 (421
mg, 100%). Recrystallization from hexane gave analytical
specimen of 2: mp 69.0-71.0 °C; [R]28D ) +595° (c 1.11, CHCl3);
IR (KBr) 2963, 1691, 1250, 1133 cm-1; IR (CHCl3) 1696 cm-1
;
1H NMR (400 MHz, CDCl3) δ 1.03 (s, 9H), 1.15 (d, J ) 6.7 Hz,
3H), 1.28 (d, J ) 6.7 Hz, 3H), 3.09 (d, J ) 12.0 Hz, 1H), 3.52
(dd, J ) 8.2, 12.0 Hz, 1H), 4.52 (sept, J ) 6.7 Hz, 1H), 5.38 (d,
J ) 8.2 Hz, 1H); 13C NMR (100.4 MHz, CDCl3) δ 18.9, 20.8,
26.9, 30.3, 33.0, 38.0, 72.5, 177.9, 204.6; MS m/z 245 (M+, 77),
146 (100), 118 (45), 71 (47); HRMS calcd for C11H19NOS2
245.0908, found 245.0906.
P r ep a r a tion of (4S)-4-ter t-Bu tyl-3-p iva loyl-1,3-th ia zol-
id in e-2-th ion e (3). To a solution of (4S)-4-tert-butyl-1,3-
thiazolidine-2-thione (781 mg, 4.46 mmol) and triethylamine
(4.35 µL, 11.2 mmol) in dry CH2Cl2 (16 mL) was added
dropwise pivaloyl chloride (825 µL, 6.7 mmol) at 0 °C, and the
(34) (a) Lipscomb, W. N. Tetrahedron 1974, 30, 1725. (b) Walsh, C.
Enzymatic Reaction Mechanisms; Freeman and Company: New York,
1979; Chapter 2, pp 24-48. (c) Fersht, A. Enzyme Structure and
Mechanism, 2nd ed.; Freeman: New York, 1984; pp 331-344.
(35) McKennon, M. J .; Meyers, A. I. J . Org. Chem. 1993, 58, 3568.
(32) This hypothesis is more valid than our previous one, which
assumed rotamer I was the major isomer (ref 10a).
(33) Kashima, C.; Fukusaka, K.; Takahashi, K.; Yokoyama, Y. J .
Org. Chem. 1999, 64, 1108.

Asymmetric Acylation of sec-Alcohols
J . Org. Chem., Vol. 64, No. 26, 1999 9371
solution was stirred at room temperature for 2 h. The reaction
mixture was washed with water, dried over anhydrous MgSO4,
and concentrated to give a crude product, which was recrystal-
lized from hexane to yield a pure amide 3 (984 mg, 85%): mp
disulfide (906 µL, 14.9 mmol), and the solution was stirred at
80 °C for 4 h. After being cooled to room temperature, the
solution was neutralized with 2 M HCl. Evaporation of the
solvent gave a crude product, which was subjected to column
chromatography (silica gel) using a 4:1 mixture of CHCl3 and
MeOH as an eluent solvent to yield (4S)-4-[(3-Methyl-3H-
imidazol-4-yl)methyl]-1,3-oxazolidine-2-thione (945 mg, 61%).
Recrystallization from MeOH-ether afforded an analytical
78.5-79.5 °C; [R]28 ) -85.6° (c 1.02, CHCl3); IR (KBr) 1739,
D
1387, 1249. 1130, 1004 cm-1; IR (CHCl3) 1700 cm-1; 1H NMR
(400 MHz, CDCl3) δ 1.01 (s, 9H), 1.28 (s, 9H), 3.17 (t, J ) 10.8
Hz, 1H), 3.28 (dd, J ) 9.0, 10.8 Hz, 1H), 4.15 (dd, J ) 9.0,
10.8 Hz, 1H); 13C NMR (100.4 MHz, CDCl3) δ 26.7, 27.1, 34.4,
35.0, 47.6, 86.1, 158.8, 201.6; MS m/z 259 (M+, 2), 118 (16), 85
(14), 57 (100); HRMS calcd for C12H21NOS2 259.1064, found
259.1057.
specimen: mp 181-183 °C; [R]27 ) -17.3° (c 0.968, MeOH);
D
IR (KBr) 3129, 1550, 1509, 1288, 1181 cm-1
;
1H NMR (270
MHz, CD3OD) δ 2.83 (d, J ) 5.9 Hz, 2H), 3.56 (s, 3H), 4.22-
4.34 (m, 1H), 4.28 (dd, J ) 8.6, 11.7 Hz, 1H), 4.62 (t, J ) 8.6
Hz, 1H), 6.76 (s, 1H), 7.51 (s, 1H); MS m/z 197 (M+, 5), 96
(100); HRMS calcd for C8H11N3OS 197.0623, found 197.0641.
P r ep a r a t ion of (4S)-4-[(3-Met h yl-3H -im id a zol-4-yl)-
m eth yl]-3-p iva loyl-1,3-oxa zolid in e-2-th ion e (8). To a solu-
tion of (4S)-4-[(3-methyl-3H-imidazol-4-yl)methyl]-1,3-oxazol-
idine-2-thione (50.3 mg, 0.255 mmol) and triethylamine (160
µL, 1.15 mmol) in dry CH2Cl2 (2.5 mL) was added dropwise
pivaloyl chloride (48 µL, 0.39 mmol) at 0 °C, and the solution
was stirred at room temperature for 2.5 h. The reaction
mixture was washed with water, dried over anhydrous MgSO4,
and concentrated to give a crude product. This was subjected
to column chromatography (Florisil) using a 10:1 mixture of
CHCl3 and MeOH as an eluent solvent to give amide 8 (51.6
P r ep a r a tion of (4S)-4-Isop r op yl-3-p iva loyl-1,3-th ia zol-
id in e-2-th ion e (4). To a solution of (4S)-4-isopropyl-1,3-
thiazolidine-2-thione (1.00 g, 6.21 mmol) and triethylamine
(1.73 mL, 12.4 mmol) in dry CH2Cl2 (50 mL) was added
dropwise pivaloyl chloride (0.92 mL, 7.45 mmol) at 0 °C, and
the solution was stirred at room temperature for 24 h. The
reaction mixture was washed with water, dried over anhydrous
MgSO4, and concentrated to give a crystalline product, which
was recrystallized from hexanes-ether to afforded a pure 4
(1.42 mg, 93%): mp 117.5-119.5 °C; [R]28 ) -27.1° (c 1.02,
D
CHCl3); IR (KBr) 2970, 1735, 1414, 1125 cm-1; IR (CHCl3) 1726
cm-1; 1H NMR (400 MHz, CDCl3) δ 0.98 (d, J ) 6.8 Hz, 0.6H),
0.98 (d, J ) 6.8 Hz, 2.4H), 1.06 (d, J ) 6.8 Hz, 0.6H), 1.07 (d,
J ) 6.8 Hz, 2.4H), 1.28 (s, 0.2H), 1.41 (s, 0.8H), 2.02-2.13 (m,
1H), 3.11 (dd, J ) 10.3, 11.2 Hz, 0.2H), 3.35 (dd, J ) 9.3, 11.2
Hz, 0.2H), 3.40 (d, J ) 9.8 Hz, 1.6H), 4.24 (td, J ) 6.3, 9.8 Hz,
0.2H), 4.55 (td, J ) 3.4, 8.3 Hz, 0.8H); 13C NMR (67.8 MHz,
CDCl3, major isomer) δ 15.4, 19.1, 27.9, 29.7, 30.9, 44.5, 74.1,
188.0, 200.4; 13C NMR (67.8 MHz, CDCl3, minor isomer) δ 18.8,
19.5, 27.0, 32.8, 35.7, 47.6, 82.1, 158.8, 201.2; MS m/z 245 (M+,
18), 118 (4), 85 (10), 55 (100); HRMS calcd for C11H19NOS2
245.0908, found 245.0893.
mg, 72%): [R]22 ) +59.2° (c 1.05, CH2Cl2); IR (neat) 2973,
D
1734, 1507, 1481, 1395, 1367, 1283, 1194 cm-1; 1H NMR (400
MHz, CDCl3) δ 1.50 (s, 9H), 2.86 (dd, J ) 10.7, 14.9 Hz, 1H),
3.13 (dd, J ) 3.4, 14.9 Hz, 1H), 3.63 (s, 3H), 4.34 (dd, J ) 5.8,
9.1 Hz, 1H), 4.52 (dd, J ) 7.6, 9.1 Hz, 1H), 4.60-4.66 (m, 1H),
6.84 (s, 1H), 7.45 (s, 1H); 13C NMR (100.4 MHz, CDCl3) δ 26.6,
28.0, 31.5, 44.1, 60.7, 72.1, 125.4, 128.1, 139.0, 184.2, 186.2;
MS m/z 281 (M+, 55), 57 (100); HRMS calcd for C13H19N3O2S
281.1198, found 281.1219.
P r ep a r a tion of (4S)-4-isobu tyl-3-p iva loyl-1,3-th ia zoli-
Gen er a l P r oced u r e for th e Kin etic Resolu tion of
Ra cem ic sec-Alcoh ols w ith Tw isted Am id es 1-8. A mix-
ture of an amide (0.18 mmol) and 5 equiv of an alcohol in an
appropriate solvent (3 mL) was heated under reflux for 15-
138 h. The reaction mixture was concentrated and separated
by preparative TLC using a 5:1 mixture of hexane and ethyl
acetate as an eluent solvent to yield esters. After hydrolysis
of the esters with 2 M NaOH, the enantiomeric excess of the
product was determined by HPLC analysis using a Daicel
CHIRALPAK OB column with a 10:1 mixture of hexane and
i-PrOH as an eluent solvent.
d in e-2-th ion e (5):12 mp 89.0-91.0 °C (lit.13 mp 88.5-91.5 °C);
[R]28 ) -0.971° (c 1.03, CHCl3).
D
P r ep a r a tion of (4S)-4-Ben zyl-3-p iva loyl-1,3-th ia zoli-
d in e-2-th ion e (6). To a solution of (4S)-4-benzyl-1,3-thiazol-
idine-2-thione (1.00 g, 4.80 mmol) and triethylamine (0.8 mL,
5.7 mmol) in dry CH2Cl2 (50 mL) was added dropwise pivaloyl
chloride (0.71 mL, 5.7 mmol) at 0 °C, and the solution was
stirred at room temperature for 19 h. The reaction mixture
was washed with water, dried over anhydrous MgSO4, and
concentrated to give a crystalline product, which was recrys-
tallized from hexanes-ether to yield pure 6 (1.26 mg, 89%):
mp 119-121 °C; [R]28D ) -6.31° (c 1.07, CHCl3); IR (KBr) 2979,
1721, 1264, 1169, 1011 cm-1; IR (CHCl3) 1727 cm-1; 1H NMR
(400 MHz, CDCl3) δ 1.46 (s, 9H), 2.88 (dd, J ) 11.0, 12.9 Hz,
1H), 3.21-3.32 (m, 3H), 4.65 (quint, J ) 3.7 Hz, 1H), 7.18-
7.35 (m, 5H); 13C NMR (100.4 MHz, CDCl3) δ 27.97, 28.03,
28.06, 36.3, 38.4, 44.6, 70.3, 127.4, 128.99, 129.03, 135.5, 188.6,
200.1; MS m/z 293 (M+, 12), 202 (17), 118 (31), 85 (14), 55 (100);
HRMS calcd for C15H19NOS2 293.0959, found 293.0934.
P r ep a r a tion of (4S)-4-ter t-Bu tyl-3-p iva loyl-1,3-oxa zol-
id in e-2-th ion e (7). To a solution of (4S)-4-tert-butyl-1,3-
oxazolidine-2-thione (1.00 g, 6.30 mmol) and triethylamine
(1.75 mL, 12.6 mmol) in dry CH2Cl2 (20 mL) was added
dropwise pivaloyl chloride (930 µL, 7.55 mmol) at 0 °C, and
the solution was stirred at room temperature for 4 h. The
reaction mixture was washed with water, dried over anhydrous
MgSO4, and concentrated to yield a crystalline product, which
was washed with hexane to give pure amide 7 (1.44 g, 94%).
Recrystallization from hexane-CH2Cl2 gave an analytical
specimen of 7: mp 176-178 °C; [R]28D ) -43.7° (c 1.09, CHCl3);
IR (KBr) 1734, 1374, 1286, 1205, 920 cm-1; IR (CHCl3) 1730
1-In d a n oyl p iva la te (9c): IR (neat) 3032, 2971, 1726, 1282,
1
1149 cm-1; H NMR (400 MHz, CDCl3) δ 1.20 (s, 9H), 1.98-
2.06 (m, 1H), 2.50-2.58 (m, 1H), 2.88 (ddd, J ) 6.1, 8.5, 16.0
Hz, 1H), 3.09 (ddd, J ) 5.4, 8.8, 16.0 Hz, 1H), 6.18 (dd, J )
4.6, 7.1 Hz, 1H), 7.20-7.35 (m, 4H); MS m/z 218 (M+, 0.2),
117 ([M - OCOBut]+, 100), 55 (39); HRMS calcd for C9H9 ([M
- OCOBut]]+) 117.0704, found 117.0676.
1-Tetr a loyl isobu tyla te (10b): IR (neat) 2939, 1733, 1191,
1151, 765 cm-1; 1H NMR (270 MHz, CDCl3) δ 1.16 (d, J ) 2.0
Hz, 3H), 1.19 (d, J ) 2.0 Hz, 3H), 1.78-2.02 (m, 4H), 2.55
(sept., J ) 6.9 Hz, 1H), 2.70-2.92 (m, 2H), 5.98 (t, J ) 4.6 Hz,
1H), 7.10-7.25 (m, 4H); MS m/z 218 (M+, 4), 148 (35), 131 (91),
130 (100), 115 (21), 91 (22), 43 (9); HRMS calcd for C14H18O2
218.1307, found 218.1299.
1-Tetr a loyl p iva la te (10c): IR (neat) 3032, 2936, 1724,
1
1281, 1148 cm-1; H NMR (400 MHz, CDCl3) δ 1.20 (s, 9H),
1.80-2.04 (m, 4H), 2.73-2.90 (m, 2H), 5.95 (d, J ) 4.6 Hz,
1H), 7.11-7.26 (m, 4H); MS m/z 232 (M+, 9), 148 (6), 131 (100),
115 (2), 91 (4), 55 (16); HRMS calcd for C15H20O2 232.1464,
found 232.1420.
5-P ivaloyloxy-6,7,8,9-tetr ah ydr o-5H-ben zocycloh epten -
5-on e (11c): IR (neat) 2931, 1729, 1480, 1456, 1369, 1157,
1
cm-1; H NMR (270 MHz, CDCl3) δ 0.95 (s, 9H), 1.53 (s, 9H),
4.46 (dd, J ) 2.4, 4.9 Hz, 1H), 4.49-4.53 (m, 2H); 13C NMR
(67.9 MHz, CDCl3) δ 25.7, 28.7, 35.0, 44.6, 69.4, 70.1, 184.8,
187.6; MS m/z 243 (M+, 43), 186 (36), 158 (11), 85 (58), 57 (100);
HRMS calcd for C12H21NO2S 243.1293, found 243.1298.
P r ep a r a t ion of (4S)-4-[(3-Met h yl-3H -im id a zol-4-yl)-
m eth yl]-1,3-oxa zolid in e-2-th ion e. To a solution of Nπ-meth-
yl-L-histidinol dihydrochloride13 (1.79 g, 7.85 mmol) in EtOH
(35 mL) and 0.9 M KOH (35 mL) was added dropwise carbon
1033, 759 cm-1 1H NMR (270 MHz, CDCl3) δ 1.26 (s, 9H),
;
1.59-1.80 (m, 2H), 1.83-2.03 (m, 4H), 2.76 (m, 1H), 2.99 (dd,
J ) 10.9, 14.2 Hz, 1H), 5.91 (d, J ) 7.9 Hz, 1H), 7.14 (m, 3H),
7.31 (m, 1H); MS m/z 246 (M+, 3), 162 (2), 145 (59), 144 (49),
57 (13), 28 (100); HRMS calcd for C16H22O2 246.1620, found
246.1587.
1-P h en yl-1-eth a n oyl p iva la te (12c): IR (neat) 3032,
2978, 1730, 1281, 1158, 1063 cm-1; 1H NMR (90 MHz, CDCl3)

9372 J . Org. Chem., Vol. 64, No. 26, 1999
Yamada and Katsumata
δ 1.20 (s, 9H), 1.51 (d, J ) 6.6 Hz, 3H), 5.85 (q, J ) 6.6 Hz,
1H), 7.30-7.39 (m, 5H); MS m/z 206 (M+, 26), 122 (3), 105
(100), 55 (45); HRMS calcd for C13H18O2 206.1307, found
206.1305.
IR (KBr) 2958, 1730, 1154, 1119, 753 cm-1; 1H NMR (400 MHz,
CDCl3) δ 1.20 (s, 18H), 1.90 (dd, J ) 2.4, 3.5 Hz, 1H), 1.93
(dd, J ) 1.2, 3.5 Hz, 1H), 2.26 (dd, J ) 1.2, 2.4 Hz, 1H), 2.29
(t, J ) 2.4 Hz, 1H), 6.02 (t, J ) 2.4 Hz, 2H), 7.28-7.33 (m,
4H); MS m/z 231 ([M - OCOBut]+, 6), 230 ([M - t-BuCOOH]+,
34), 146 (50), 129 (100), 57 (30); HRMS calcd for C15H18O2 ([M
- t-BuCOOH]+) 230.1307, found 230.1338. After hydrolysis
of 18 into corresponding diol 16 with 2 mol dm-3 NaOH, the
enantiomeric excess was determined by HPLC analysis using
a Daicel CHIRALPAK OB column with a 4:1 mixture of hexane
and i-PrOH as an eluent solvent.
Kin etic Resolu tion of 17 w ith Tw isted Am id e 3. A
mixture of 3 and 17 in dry toluene (1 mL) was stirred at 80
°C for 16-17 h. The reaction mixture was concentrated and
separated by preparative TLC using a 5:1 mixture of hexane
and ethyl acetate as an eluent solvent to yield 18. After
hydrolysis of 18, the enantiomeric excess of the corresponding
diol was determined in a similar manner as described above.
Gen er a l P r oced u r e for th e Desym m etr iza tion of m eso-
Diols w ith Tw isted Am id es 3-5 a n d 7. A mixture of a meso-
diol (0.2 mmol), 1.1 equiv of an amide, and additives in
appropriate solvent (3 mL) was stirred at room temperature
to refluxing temperature for 14-138 h. The reaction mixture
was concentrated and separated by preparative TLC to yield
monoesters and diesters.
1-(3,4-Dim eth oxyp h en yl)-1-eth a n oyl p iva la te (13c): IR
(neat) 2977, 1726, 1595, 1520, 1463, 1264, 1030, 809 cm-1; 1H
NMR (270 MHz, CDCl3) δ 1.20 (s, 9H), 1.51 (d, J ) 6.6 Hz,
3H), 3.87 (s, 3H), 3.88 (s, 3H), 5.80 (q, J ) 6.6 Hz, 1H), 6.78-
6.92 (m, 3H); MS m/z 266 (M+, 94), 182 (7), 165 (100), 57 (24);
HRMS calcd for C15H22O4 266.1518, found 266.1472.
1-(2-Na p h th yl)-1-eth a n oyl p iva la te (14c): mp 72.5-73.4
°C; IR (KBr) 2960, 1715, 1603, 1508, 1159, 1047, 825, 753 cm-1
;
1H NMR (270 MHz, CDCl3) δ 1.23 (s, 9H), 1.60 (d, J ) 6.6 Hz,
3H), 6.01 (q, J ) 6.6 Hz, 1H), 7.47 (m, 3H), 7.81 (m, 4H); MS
m/z 256 (M+, 5), 172 (3), 155 (18), 57 (6), 28 (100); HRMS calcd
for C17H20O2 256.1463, found 256.1447.
Syn th esis of a Mixtu r e of m eso- a n d d l-1,2,3,4-Tet-
r a h yd r on a p h th a len e-1,4-d ia ceta te (15). A solution of tet-
ralin (5.00 g, 37.9 mmol), NBS (14.8 g, 75.8 mmol), and AIBN
(186 mg, 1.13 mmol) in CCl4 (50 mL) was refluxed for 20 min.
After the solution was cooled to room temperature, an insoluble
material was filtered off and the filtrate was concentrated to
give a crude dibromide. To a solution of the dibromide in acetic
acid (40 mL) and dry DMF (12 mL) was added silver(I) acetate
(12.6 g, 75.7 mmol) at 0 °C, and the solution was stirred at
room temperature for 2 h. The resulting precipitate of silver
bromide was filtered off, and the filtrate was concentrated.
After the residue was neutralized with saturated NaHCO3, the
solution was extracted three times with ethyl acetate. The
combined organic layer was washed twice with 5% Na2S2O3
and dried over anhydrous MgSO4. Concentration of the solution
to give a crystalline product, which was washed with hexane
cis-1,2,3,4-Tetr a h yd r o-1-p iva loyloxy-4-n a p h th ol (19a ).
The enantiomeric excess was determined by HPLC analysis
using a Daicel CHIRALPAC AS column with a 10:1 mixture
of hexane and i-PrOH as an eluent solvent: IR (neat) 3420,
1736, 1284, 1161, 1150, 1042, 773, 734 cm-1 1H NMR (400
;
MHz, CDCl3) δ 1.21 (s, 9H), 1.99-2.11 (m, 4H), 4.75 (dd, J )
3.7, 4.6 Hz, 1H), 5.89 (br s, 1H), 7.23 (d, J ) 7.6 Hz, 1H), 7.28
(td, J ) 1.5, 7.6 Hz, 1H), 7.34 (td, J ) 1.5, 7.4 Hz, 1H), 7.34
(d, J ) 7.6 Hz, 1H); MS m/z 248 (M+, 0.1), 230 ([M - H2O]+,
26), 146 (32), 129 (51), 57 (18), 28 (100); HRMS calcd for
1
to give a 1:1.75 mixture of dl- and meso-15 (7.62 g): H NMR
(400 MHz, CDCl3) for dl-15 δ 1.95-1.99 (m, 2H), 2.07 (s, 6H),
2.27-2.30 (m, 2H), 6.05 (t, J ) 2.1 Hz, 2H), 7.34 (br s, 4H); 1H
NMR (400 MHz, CDCl3) for meso-15 δ 2.09-2.12 (m, 4H), 2.13
(s, 6H), 5.96 (m, 2H), 7.32 (br s, 4H); MS m/z 188 ([M - CH3-
COOH]+, 11), 148 (100); HRMS calcd for C12H12O2 ([M - CH3-
COOH]+) 188.0838, found 188.0832.
C
15H18O2 ([M - H2O]+) 230.1307, found 230.1335.
cis-1,4-Dip iva loyloxy-1,2,3,4-t et r a h yd r on a p h t h a len e
(19b). Recrystallization from hexane gave analytical specimen
of 19b: mp 67.0-68.5 °C; IR (KBr) 1725, 1281, 1155, 764 cm-1
1H NMR (400 MHz, CDCl3) δ 1.24 (s, 18H), 2.00-2.16 (m, 4H),
5.91 (t, J ) 5.6 Hz, 2H), 7.25-7.32 (m, 4H); MS m/z 231 ([M
- OCO-t-Bu]+, 2), 230 ([M - t-BuCCOOH]+, 14), 146 (20), 129
(41), 57 (13), 28 (100); HRMS calcd for C15H18O2 ([M -
t-BuCCOOH]+) 230.1307, found 230.1337.
;
Syn th esis of d l-1,2,3,4-Tetr a h yd r on a p h th a len e-1,4-d iol
(16) a n d m eso-1,2,3,4-Tet r a h yd r on a p h t h a len e-1,4-d iol
(19).23 To a solution of 1:1 mixture of dl- and m eso-15 (1.36 g,
5.48 mmol) in MeOH (30 mL) was added 2 M NaOH (7 mL),
and the solution was stirred at room temperature for 2 h. Then
the solution was acidified with 2 M HCl and concentrated in
vacuo. The residue was dissolved in EtOH-CHCl3, and the
insoluble inorganic salt was filtered off. The filtrate was
concentrated to give a mixture of 16 and 19, which was
separated by fractional crystallization using MeOH-ether to
yield pure 16 and 19.26 dl-Diol 16: mp 141-142 °C; IR (KBr)
3278, 2866, 1507, 1050, 761 cm-1; 1H NMR (400 MHz, CDCl3)
δ 1.83 (m, 2H), 2.31 (dt, J ) 2.5, 11.0 Hz, 2H), 4.84 (br s, 2H),
7.33 (m, 2H), 7.46 (m, 2H); MS m/z 164 (M+, 0.6), 146 ([M -
H2O]+ 100), 145 (98), 131 (72), 128 (20); HRMS calcd for
cis-1-P iva loyloxy-3-in d a n ol (20a ): IR (neat) 2971, 1727,
1158, 757 cm-1; 1H NMR (270 MHz, CDCl3) δ 1.22 (s, 9H), 1.93
(dt, J ) 5.4, 14.1 Hz, 1H), 3.03 (dt, J ) 6.8, 14.1 Hz, 1H), 5.13
(m, 1H), 6.01 (dd, J ) 5.4, 6.8 Hz, 1H), 7.34-7.43 (m, 3H),
7.49 (d, J ) 7.3 Hz, 1H); MS m/z 216 ([M - H2O]+, 11), 133
(47), 115 (26), 57 (46), 28 (100); HRMS calcd for C14H16O2 ([M
- H2O]+) 216.1150, found 216.1135.
cis-1,3-Dip iva loyloxyin d a n e (20b): IR (neat) 2974, 1730,
1
1147 cm-1; H NMR (270 MHz, CDCl3) δ 1.22 (s, 18H), 1.98
10H12O ([M - H2O]+) 146.0731, found 146.0686.
Gen er a l P r oced u r e for th e Kin etic Resolu tion of 16
(dt, J ) 4.6, 14.4 Hz, 1H), 3.06 (dt, J ) 7.1, 14.4 Hz, 1H), 6.09
(dd, J ) 4.6, 7.1 Hz, 2H), 7.39 (s, 4H); MS m/z 216 ([M -
t-BuCCOOH]+, 31), 132 (29), 115 (100), 85 (20), 57 (40), 28
(66); HRMS calcd for C14H16O2 ([M - t-BuCCOOH]+) 216.1150,
found 216.1176.
C
w ith Tw isted Am id e 3. A mixture of 3 and 16 in appropriate
solvent (3 mL) was stirred at 80 °C to refluxing temperature
for 18-20 h. The reaction mixture was concentrated and
separated by preparative TLC using a 10:1 mixture of CHCl3
and ethyl acetate as an eluent solvent to yield trans-1,2,3,4-
tetrahydro-1-pivaloyloxy-4-naphthol (17) and trans-1,2,3,4-
tetrahydronaphthalene-1,4-dipivalate (18). Analytical crys-
talline 17 was obtained by recrystallization from hexane: mp
(1R,2S,3S,6R,7S,8S)-Tr icyclo-3-p iva loyloxy[6.2.1.02,7]-
u n d eca -4-en -6-ol (21b). Recrystallization from hexane gave
analytical specimen of 21b: mp 113-115 °C; IR (KBr) 2968,
1
1726, 1480, 1396, 1282, 1156, 716 cm-1; H NMR (270 MHz,
CDCl3) δ 1.18-1.38 (m, 2H), 1.26 (s, 18H), 2.84 (t, J ) 1.7 Hz,
2H), 3.05 (dd, J ) 1.7, 5.6 Hz, 2H), 5.33 (br s, 2H), 5.33-5.37
(m, 2H), 5.83 (t, J ) 1.7 Hz, 2H); MS m/z 346 (M+, 2), 245 (6),
179 (26), 146 (58), 129 (100), 52 (66); HRMS calcd for C21H30O4
346.2144, found 346.2137.
1
55.0-57.0 °C; IR (KBr) 3264, 2971, 1719, 1156, 765 cm-1; H
NMR (400 MHz, CDCl3) δ 1.20 (s, 9H), 1.83-1.93 (m, 2H),
2.20-2.39 (m, 2H), 4.88 (br s, 1H), 5.98 (t, J ) 4.8 Hz, 1H),
7.26 (d, J ) 7.6 Hz, 1H), 7.30 (td, J ) 1.5, 7.6 Hz, 1H), 7.36
(td, J ) 1.5, 7.6 Hz, 1H), 7.48 (d, J ) 7.6 Hz, 1H); MS m/z 248
(M+, 0.1), 230 ([M - H2O]+, 8), 131(100); HRMS calcd for
cis-1-P iva loyloxy-2-cycloh exa n ol (22a ). The enantio-
meric excess was determined by 1H NMR in the presence of
C
15H18O2 ([M - H2O]+) 230.1307, found 230.1338. The enan-
Eu(hfc)3: IR(neat) 3452, 2940, 1727, 1481, 1287, 1169 cm-1
;
tiomeric excess of 18 was determined by HPLC analysis using
a Daicel CHIRALPAK AS column with a 10:1 mixture of
hexane and i-PrOH as an eluent solvent. Recrystallization
from hexane gave analytical specimen of 18: mp 58.0-59.5 °C;
1H NMR (270 MHz, CDCl3) δ 1.23 (s, 9H), 1.18-1.90 (m, 8H),
3.82 (m, 1H), 4.95 (dt, J ) 3.0, 6.9 Hz, 1H); MS m/z 182 ([M -
H2O]+, 0.5), 98 ([M - t-BuCCOOH]+, 100), 57 (90); HRMS calcd
for C6H10O ([M - t-BuCCOOH]+) 98.0731, found 98.0704.

Asymmetric Acylation of sec-Alcohols
J . Org. Chem., Vol. 64, No. 26, 1999 9373
(1S,2S,3R,6S,7R,8R)-1,8,9,10-Tetr a ch lor o-11,11-d im eth -
oxy-3-p iva loyloxyt r icyclo[6.2.1.02,7]u n d eca -4,9-d ien -6-
ol (24). The enantiomeric excess was determined by HPLC
analysis after oxidation of 24 with PCC into the corresponding
ketone using a Daicel CHIRALPAC AS column with a 10:1
mixture of hexane and i-PrOH as an eluent solvent. Recrys-
tallization from hexane gave analytical specimen of 24: mp
62.0-64.0 °C; IR(KBr) 3538, 2960, 1718, 1195, 1151, 1099, 770
cm-1; 1H NMR (270 MHz, CDCl3) δ 1.26 (s, 9H), 3.34 (m 1H),
3.48 (m, 1H), 3.54 (s, 3H), 3.62 (s, 3H), 4.57 (m, 1H), 5.36 (dd,
J ) 2.7, 7.3 Hz, 1H), 5.60 (d, J ) 10.0 Hz, 1H), 5.83 (d, J )
10.3 Hz, 1H); MS m/z 321/323/325/327 ([M - Cl - t-Bu-
COOH]+, 11/9/4/2), 253/255/257/259 (1-dimethoxycarbonium-
2,3,4-trichlorobenzene, 100/96/35/8). Anal. Calcd for C18H22O4Cl4:
C, 48.67; H, 4.99; Cl, 31.93. Found: C, 48.58; H, 5.05; Cl, 32.18.
(1S,2S,3R,6S,7R,8R)-1,8,9,10-Tetr a ch lor o-11,11-d im eth -
oxy-3,6-d ip iva loyloxyt r icyclo[6.2.1.02,7]u n d e ca -4,9-d i-
en e (24 b): IR (neat) 3005, 1715, 1420, 1363, 1223, 1148, 1093
combined extracts were dried over anhydrous MgSO4. Evapo-
ration of the solvent gave a crude product, which was sepa-
rated by preparative TLC using a 3:1 mixture of hexane and
ethyl acetate as an eluent solvent to yield pure 26 (147 mg,
76%): IR (neat) 3460, 2981, 1184, 1123, 752 cm-1 1H NMR
;
(270 MHz, CDCl3) δ 1.16 (t, J ) 7.1 Hz, 3H), 1.33 (d, J ) 5.3
Hz, 3H), 2.85 (dd, J ) 4.8, 11.2 Hz, 1H), 3.00 (dd, J ) 5.3,
11.2 Hz, 1H), 3.34-3.65 (m, 2H), 3.56 (s, 3H), 3.59 (s, 3H),
4.38 (t, J ) 5.3 Hz, 1H), 4.43 (m, 1H), 4.79 (q, J ) 5.3 Hz,
1H), 6.32 (dd, J ) 5.3, 9.6 Hz, 1H), 6.42 (dd, J ) 5.9, 9.6 Hz,
1H); MS m/z 253/255/257/259 (1-dimethoxycarbonium-2,3,4-
trichlorobenzene, 92/89/32/7), 73 (100); HRMS calcd for C9H8O2-
Cl3 (1-dimethoxycarbonium-2,3,4-trichlorobenzene) 252.9590,
found 252.9600.
(1S,2S,3R,6S,7R,8R)-1,8,9,10-Tetr a ch lor o-11,11-d im eth -
oxy-3-t er t -b u t yld im e t h ylsilyloxy-6-(1-e t h oxye t h oxy)-
tr icyclo[6.2.1.02,7]u n d eca -4,9-d ien e (27). Alcohol 26 (25 mg,
0.056 mmol) was dissolved in 0.5 mL of dry DMF and cooled
to 0 °C. To this solution were added 2,6-lutidine (19 µL, 0.16
mmol) and TBDMS triflate (19 µL, 0.083 mmol), and the
reaction mixture was stirred at 0 °C for 2.5 h. The reaction
was quenched by saturated aqueous NaHCO3 and diluted with
water. After extraction with ether, the organic layers were
washed once with water and once with brine and dried over
anhydrous MgSO4. Evaporation of the solvent gave a crude
product that was purified by column chromatography (Florisil)
using a 10:1 mixture of hexane and ether as an eluent solvent
to give pure 27 (25 mg, 80%): mp 103.6-105.2 °C; IR (KBr)
1
cm-1; H NMR (270 MHz, CDCl3) δ 1.27 (s, 18H), 3.46-3.55
(m, 2H), 3.54 (s, 3H), 3.59 (s, 3H), 5.38 (d, J ) 5.3 Hz, 2H),
5.61 (s, 2H); MS m/z 507/509/511/513 ([M - Cl]+, 19/19/6/1),
43 (100); HRMS calcd for C23H30O6Cl3 ([M - 35Cl]+) 507.1108,
found 507.1090.
(1S,2S,3R,6S,7R,8R)-1,8,9,10-Tetr a ch lor o-11,11-d im eth -
oxy-6-(1-eth oxyeth oxy)-3-p iva loyloxytr icyclo[6.2.1.02,7]-
u n d eca -4,9-d ien e (25). To a solution of monopivalate (250
mg, 0.543 mmol) and pyridinium p-toluenesulfonate (40 mg)
in dry CH2Cl2 (5 mL) was added dropwise ethyl vinyl ether
(156 µL, 1.63 mmol) at room temperature. The solution was
stirred at room temperature for 45 min. The solution was then
washed with water and dried over anhydrous MgSO4. Con-
centration of the reaction mixture gave a crude product that
was purified by column chromatography (Florisil) using a 1:1
mixture of CHCl3 and hexane as an eluent solvent to give pure
25 (284 mg, 98%): IR (neat) 2978, 1733, 1197, 1151, 1052, 786,
2953, 1195, 1124, 1082, 796, 777 cm-1 1H NMR (270 MHz,
;
CDCl3) δ 0.06 (s, 3H), 0.09 (s, 3H), 0.93 (s, 9H), 1.19 (t, J )
7.1 Hz, 3H), 1.34 (d, J ) 5.3 Hz, 3H), 3.14 (m, 1H), 3.25 (m,
1H), 3.46-3.71 (m, 2H), 3.54 (s, 3H), 3.61 (s, 3H), 4.43 (m, 2H),
4.93 (q, J ) 5.3 Hz, 1H), 5.57 (br s, 2H); MS m/z 525/527/529/
531 ([M - Cl]+, 2/2/0.8/0.2), 253 (100); HRMS calcd for
C
23H36O5Cl3Si ([M - 35Cl]+) 525.1398, found 525.1350.
1
772 cm-1; H NMR (270 MHz, CDCl3) δ 1.18 (td, J ) 3.0, 6.9
Hz, 3H), 1.27 (s, 9H), 1.36 (dd, J ) 5.5, 10.1 Hz, 3H), 3.24-
3.39 (m, 2H), 3.43-3.67 (m, 2H), 3.54 (s, 3H), 3.60 (s, 3H), 4.49
(m, 1H), 4.88 (dq, J ) 5.5, 23.6 Hz, 1H), 5.35 (m, 1H), 5.55 (m,
1H), 5.72 (m, 1H); MS m/z 495/497/499/501 ([M - Cl]+, 3/3/1/
0.2), 73 (100); HRMS calcd for C22H30O6Cl3 ([M - 35Cl]+)
495.1108, found 495.1137.
Ack n ow led gm en t. This work was financially sup-
ported by a Grant-in-Aid for Scientific Research from
the Ministry of Education, Science, and Culture of
J apan and Mitsubishi Chemical Cooperation Fund.
1
Su p p or tin g In for m a tion Ava ila ble: Copies of H NMR
(1R,2R,3S,6R,7S,8S)1,8,9,10-Tetr a ch lor o-11,11-d im eth -
oxy-3-(1-eth oxyeth oxy)tr icyclo[6.2.1.02,7]u n d eca -4,9-d ien -
6-ol (26). To a solution of 26 (230 mg, 0.432 mmol) in MeOH
(4 mL) was added 2 M NaOH (1 mL), and the solution was
stirred at 50 °C for 64.5 h. Then the solution was neutralized
with 2 M HCl and extracted three times with CHCl3. The
spectra for compounds 2-4, 6-8, 9c, 10b,c, 11c, 13c, 14c, 15-
18, 19a ,b, 20a ,b, 21b, 22a , 24b, and 24-27 and 13C NMR
spectra for compounds 3 and 4. This material is available free
of charge via the Internet at http://pubs.acs.org.
J O990892P