Desymmetrization of meso -1,2-diols via the dynamic kinetic resolution of its monodichloroacetates

Article abstract of DOI:10.1021/jo100435f

Figure presented Enantioselective acylation catalyzed by the thioamide modified 1-methylhistidine methyl ester 1 in combination with DABCO-mediated racemization of the substrate led to the efficient dynamic kinetic resolution of meso-1,2-diol monodichloro

Full text of DOI:10.1021/jo100435f

pubs.acs.org/joc
Desymmetrization of meso-1,2-Diols via the Dynamic Kinetic
Resolution of Its Monodichloroacetates
Jin-Li Cao and Jin Qu*
State Key Laboratory and Institute of Elemento-organic Chemistry, Nankai University,
Tianjin 300071, China
qujin@nankai.edu.cn
Received March 9, 2010
Enantioselective acylation catalyzed by the thioamide modified 1-methylhistidine methyl ester 1 in
combination with DABCO-mediated racemization of the substrate led to the efficient dynamic
kinetic resolution of meso-1,2-diol monodichloroacetates. In this way, cyclic and acyclic meso-1,2-
diol monodichloroacetates can be transformed to the enantiomerically enriched (1S,2R)-heterosub-
stituted diol diesters which are stable in enantiomerically pure form and can be readily used for
further organic transformations.
Introduction
more reactive benzoyl chloride as the electrophile provided
higher enantioselectivities at low temperature with the high-
est ee value of 97%.3 The desymmetrization of cis-1,2-
cyclohexanediol can also be achieved by monoprotecting
one of the hydroxy groups to the corresponding silyl ether (er
96:4, 82% yield), but 20% catalyst loading is required.4
The nonenzymatic desymmetrization of meso-1,2-diols via
direct asymmetric monoacylation is an important methodol-
ogy for the synthesis of chiral building blocks. Previous
organocatalytic desymmetrizations of meso-1,2-diols such
as cis-1,2-cyclohexanediol with alkyl anhydrides as the elec-
trophile gave moderate ee values and moderate conversions.1
In 2009, Schreiner’s research group reported a desymmetri-
zation of meso-1,2-diols employing a 1-methylhistidine-con-
taining oligopeptide. By using this method, (1S,2R)-1,2-
cyclohexanediol monoacetate could be formed with an er
value of 94:6 by GC analysis of the reaction mixture. But the
er value of the isolated product decreased to 80:20 due to
partial racemization during the workup process.2 Organo-
catalytic desymmetrizations of cis-1,2-cyclohexanediol with
(4) (a) Zhao, Y.; Rodrigo, J.; Hoveyda, A. H.; Snapper, M. L. Nature
2006, 443, 67. (b) Zhao, Y.; Mitra, A. W.; Hoveyda, A. H.; Snapper, M. L.
Angew. Chem., Int. Ed. 2007, 46, 8471. (c) You, Z.; Hoveyda, A. H.; Snapper,
M. L. Angew. Chem., Int. Ed. 2009, 48, 547.
(5) (a) Sculimbrene, B. R.; Morgan, A. J.; Miller, S. J. Chem. Commun.
2003, 1781. (b) Miller, S. J. Acc. Chem. Res. 2004, 37, 601. (c) Miller, S. J.;
Copeland, G. T.; Papaioannou, N.; Horstmann, T. E.; Ruel, E. M. J. Am.
Chem. Soc. 1998, 120, 1629. (d) Copeland, G. T.; Jarvo, E. R.; Miller, S. J. J.
Org. Chem. 1998, 63, 6784. (e) Jarvo, E. R.; Copeland, G. T.; Papaioannou,
N.; Bonitatebus, P. J., Jr.; Miller, S. J. J. Am. Chem. Soc. 1999, 121, 11638. (f)
Sculimbrene, B. R.; Miller, S. J. J. Am. Chem. Soc. 2001, 123, 10125. (g)
Jarvo, E. R.; Evans, C. A.; Copeland, G. T.; Miller, S. J. J. Org. Chem. 2001,
66, 5522. (h) Sculimbrene, B. R.; Morgan, A. J.; Miller, S. J. J. Am. Chem.
Soc. 2002, 124, 11653. (i) Fierman, M. B.; O’Leary, D. J.; Steinmetz, W. E.;
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B. R.; Xu, Y.; Miller, S. J. Org. Lett. 2005, 7, 3021. (k) Lewis, C. A.; Chiu, A.;
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Hansen, K. B.; Miller, S. J. J. Am. Chem. Soc. 2006, 128, 16454. (l) Lewis, C.
A.; Gustafson, J. L.; Chiu, A.; Balsells, J.; Pollard, D.; Murry, J.; Reamer, R.
A.; Hansen, K. B.; Miller, S. J. J. Am. Chem. Soc. 2008, 130, 16358. (m) Fiori,
K. W.; Puchlopek, A. L. A.; Miller, S. J. Nat. Chem. 2009, 1, 630.
(1) (a) Kawabata, T.; Stragies, R.; Fukaya, T.; Nagaoka, Y.; Schedel, H.;
Fuji, K. Tetrahedron Lett. 2003, 44, 1545. (b) Spivey, A. C.; Zhu, F.; Mitchell,
M. B.; Davey, S. G.; Jarvest, R. L. J. Org. Chem. 2003, 68, 7379. (c) Vedejs,
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(2) Muller, C. E.; Zell, D.; Schreiner, P. R. Chem.;Eur. J. 2009, 15, 9647.
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39, 3529. (b) Mizuta, S.; Sadamori, M.; Fujimoto, T.; Yamamoto, I. Angew.
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DOI: 10.1021/jo100435f
r
Published on Web 05/07/2010
J. Org. Chem. 2010, 75, 3663–3670 3663
2010 American Chemical Society

Cao and Qu
JOCArticle
SCHEME 1. KR of Monoprotected Secondary Alcohols by
Catalyst 1
SCHEME 2. The Racemizing Intramolecular Transesterifica-
tion in 3a
monochloroacetates give optically active cis-1,2-diol hetero-
substituted diesters which actually accomplish the desymme-
trization of meso-1,2-diols. The racemization without a
reaction at the asymmetric center is an uncommon racemiza-
tion method and many of them are through multiple steps and
not an in situ racemization.11 It is also of interest to determine
if a racemizing intramolecular transesterification can work
together with an enantioselective acylation.
In a successful DKR, the reaction rate of the racemization
reaction should be fast enough to keep a 1:1 ratio of two
substrate enantiomers during the whole reaction otherwise
the er value of the product would decrease gradually as the
reaction proceeds as happens in a KR. The enantiomeric
purity of the acylated product 3b was monitored during the
DKR of 3a. The er value of 3b declined from 82:18 at the
beginning of the reaction to 61:39 at the end of the reaction,
which implied that the racemizing chloroacetoxy migration
in 3a was not fast enough. If the chloroacetoxy carbonyl is
made more electron deficient by attaching more electron-
withdrawing atoms to it, it is more susceptible to the
nucleophilic attack and thus the racemizing intramolecular
transesterification will be accelerated. On the other hand, an
electron-rich acetoxy group in the 1,2-diol substrate is
desired for the formation of a strong intermolecular hydro-
gen bond with the thioamide NH in catalyst 1. The electron-
withdrawing atoms substituted acetoxy group becomes a
worse hydrogen bond acceptor and this will deteriorate the
enantioselectivity of the resolution reaction. To find a sui-
table balance that can benefit both processes, five cis-cyclo-
hexane-1,2-diol monoacetates with one, two, or three halogen
atoms on the acetoxy group were synthesized and subjected to
the DKR condition.
The results obtained from the DKR of 3a-8a were shown
in Table 1. The pKa values of the halogen-substituted acetic
acids representing the leaving abilities of the halogen-
substituted acetoxy groups were also listed for the understand-
ing of the experimental results. As anticipated, a low er value
of 70:30 was observed for the trifluoroacetoxy protected diol
4a with a poor hydrogen bond acceptor. The er value
increased with the increase of the pKa value and the highest
er value was obtained with the dichloroacetoxy protected
diol 6a. Then the er value decreased as the pKa value further
increased because the corresponding racemization reaction
slowed down. The er value of the acylated product 6b in the
DKR of 6a did not change as a function of percent conver-
sion of 6a, which suggested a satisfactory racemization rate
was reached.
Therefore, efficient and practical desymmetrization of meso-
1,2-diols is still highly desirable.
Results and Discussion
1-Methylhistidine-containing oligopeptides or 1-methyl-
histidinol derivatives as effective nucleophilic catalysts have
been successfully applied to the kinetic resolution (KR) and
the desymmetrization of alcohols.5-7 We recently reported
that a thioamide-modified 1-methylhistidine methyl ester 1,
which has a low molecular weight and can be readily
synthesized, could catalyze the kinetic resolution of the
secondary alcohols containing a hydrogen bond accepting
auxiliary with high selective factors (Scheme 1).8 During the
course of this work, we found that when using cis-cyclohexane-
1,2-diol monochloroacetate (3a) as the substrate, the ee value
of the product was 51% but the ee value of the starting
material was only 3% at 53% conversion of the starting
material (Scheme 1). The racemization of the unreacted
(1S,2R)-3a can be explained by an intramolecular chloro-
acetoxy migration process as shown in Scheme 2. The intra-
molecular acetoxy migration was observed before in enzy-
matic and nonenzymatic asymmetric acylations of 1,2-diols
or desymmetrizations of meso-1,2-diols via asymmetric acy-
lation and was considered as an harmful side reaction that
could cause partial racemization of the optically active product
(this problem can be avoided by protecting the hydroxy group
in the product immediately after the reaction).1c,2,9 We think
the fast racemizing chloroacetoxy migration in cis-1,2-diol
monochloroacetate can be utilized to enable a dynamic kinetic
resolution (DKR), which is highly valued for both economical
and environmental reasons.10 The DKR of meso-1,2-diol
(6) (a) Ishihara, K.; Kosugi, Y.; Akakura, M. J. Am. Chem. Soc. 2004,
126, 12212. (b) Kosugi, Y.; Akakura, M.; Ishihara, K. Tetrahedron 2007, 63,
6191. (c) Ishihara, K.; Sakakura, A.; Hatano, M. Synlett 2007, 686.
€
(7) (a) Muller, C. E.; Wanka, L.; Jewell, K.; Schreiner, P. R. Angew.
Chem., Int. Ed. 2008, 47, 6180. (b) Hrdina, R.; Muller, C. E.; Schreiner, P. R.
€
Chem. Commun. 2010, 46, 2689.
(8) Geng, X.-L.; Wang, J.; Li, G.-X.; Chen, P.; Tian, S.-F.; Qu, J. J. Org.
Chem. 2008, 73, 8558.
(9) (a) Hemmerle, H.; Gais, H.-J. Tetrahedron Lett. 1987, 28, 3471. (b)
Xie, Z.-F.; Nakamura, I.; Suemune, H.; Sakai, K. J. Chem. Soc., Chem.
Commun. 1988, 966. (c) Laumen, K.; Seemayer, R.; Schneider, M. P. J.
Chem. Soc., Chem. Commun. 1990, 49.
To obtain the information about the rate of the intramole-
cular dichloroacetoxy migration, we studied the dichlorace-
toxy migration in methyl-substituted cis-1,2-cyclohexanediol
monodichloroacetate 9 where the dichloroacetoxy migration
€
(10) For reviews on DKR, see: (a) Martın-Matute, B.; Backvall, J.-E.
´
Curr. Opin. Biotechnol. 2007, 11, 226. (b) Ahn, Y.; Ko, S.-B.; Kim, M.-J.;
Park, J. Coor. Chem. Rev. 2008, 252, 647. (c) Lee, W. K.; Park, Y. S.; Beak, P.
Acc. Chem. Res. 2009, 42, 224.
(11) Ebbers, E. J.; Ariaans, G. J. A.; Houbiers, J. P. M.; Bruggink, A.;
Zwanenburg, B. Tetrahedron 1997, 53, 9417.
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TABLE 1. Screening of the Monoester Group on cis-1,2-Cyclohexanediola
SCHEME 4. DKR of Monodichloroacetate 6a by Catalyst 13
R
time (h)
pKa of RCOOH
er of isobutyrate diester
CF3 (4a)
CCl3 (5a)
CHCl2 (6a)
CHBr2 (7a)
CH2Cl (3a)
CH2Br (8a)
5
4
3
3
3
2.5
0.50
0.52
1.26
1.39
2.87
2.90
70:30b
77:23c
83:17b
73:27c
61:39b
60:40b
TABLE 2. Screening of the Racemizing Basesa
aConditions: alcohol (0.2 mmol), catalyst (5 mol %), DIEA (0.2
mmol), and (i-PrCO)2O (0.2 mmol) in CCl4 (4 mL) were stirred at 0 °C.
bDetermined by GC analysis. cDetermined by HPLC analysis.
base
none
DIEA
amount (equiv)
time (h)
er of isobutyrate diesterb
SCHEME 3. Base-Catalyzed Dichloroacetoxy Migrations in
Compounds 9 and 11
0
1
2
1
1
1
1
1
1
1
1
1
5
3
3
4
4
2.5
3
2.5
3
3
65:35
83:17
83:17
79:21
78:22
80:20
80:20
82:18
83:17
85:15
59:41
84:16
DIEA
pyridine
collidine
Et3N
HMTA
TMEDA
PMP
DABCO
DBU
Cs2CO3
2
4
aConditions: alcohol (0.2 mmol), catalyst (5 mol %), (i-PrCO)2O
(0.2 mmol), and base in CCl4 (4 mL) were stirred at 0 °C. bDetermined by
GC analysis.
between two hydroxy groups in the molecule can be monitored
by 1H NMR analysis (Scheme 3). A 1H NMR spectrum was
taken immediately after the addition of 1 equiv of DABCO in
an NMR tube containing compound 9 in CDCl3. The reaction
reached equilibrium within 5 min and the ratio of compound 9
and compound 10 was 1:1 judging from the integration of their
1H NMR signals.12 This indicated that the dichloroacetoxy
migration proceeded very fast at room temperature. It took 9
days for the dichloroacetoxy migration to proceed 10% with-
out a base catalyst. The dichloroacetoxy migration in methyl-
substituted trans-1,2-cyclohexanediol monodichloroacetate 11
proceeded with a similar reaction rate. Nevertheless, the
dichloroacetoxy migration intrans-1,2-cyclohexanediol mono-
dichloroacetate is useless because the migration gave back the
original molecule.
has also been observed before by Prof. Ishihara’s research
group.6b
The base catalyzing the racemization reaction in the DKR
was screened by using 6a as the substrate (Table 2). A lower
er value of 65:35 was obtained when no base was added,
while using 2 equiv of DIEA gave a similar result compared
with using 1 equiv of DIEA. But the use of a weaker base
such as pyridine or collidine gave a lower er value. Trialkyl-
amines and solid base Cs2CO3 gave comparable results.
Using DABCO as the base provided a slightly higher er
value than using other bases. A strong base such as DBU
deteriorated the enantioselectivity significantly.
The enantioselectivity for monodichloroacetate 6a is lower
than that for 2a in which a carbamate carbonyl serves as
the hydrogen bond acceptor. One technique for improving
the enantioselectivity for 6a is to reinforce the hydrogen
bond between the substrate and the catalyst. Catalyst 13 with
a hydroxy group forming an intramolecular hydrogen bond
with the thioamide and making the thioamide NH a better
hydrogen bond donor was synthesized. The more acidic
thioamide NH was supported by the evidence that the
chemical shift of the NH moved downfield to 9.5 ppm (the
chemical shift of the thioamide NH in 1 is at 8.1 ppm).8
Unfortunately, the observed er value in the DKR of 6a with
catalyst 13 was lower than that from the DKR with catalyst 1
(Scheme 4). We cannot explain why increasing the hydrogen
bond-forming ability of the amide NH does not improve the
enantioselectivity of the catalyst. The same phenomenon
Other organic solvents such as toluene and methylene
dichloride were also tested in the DKR of 6a. Running the
reaction in toluene at 0 °C afforded a slightly lower enantio-
selectivity and further decreasing the reaction temperature to
-78 °C greatly retarded the reaction. The corresponding
reaction in methylene dichloride constantly gave very slow
reaction rates and lower enantioselectivities. It was found
that carbon tetrachloride, the solvent used in our initial
study, was the best choice. Lowing the reaction temperature
to -20 °C could further increase the er value to 87:13, but a
longer reaction period was needed (Table 3).
The optimized reaction condition was then applied to the
DKR of various monodichloroacetates derived from meso-
1,2-diols (Table 4). All reactions were carried out at -20 °C
and went to completion within 24 h with the isolated yields
between 83% and 95%. Analogous enantioselectivities were
observed for all tested cyclic 1,2-diol monodichloroacetates
(12) See the Supporting Information for details.
J. Org. Chem. Vol. 75, No. 11, 2010 3665

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TABLE 3. Solvent and Temperature Effects on the DKRa
TABLE 4. Dynamic Kinetic Resolution of cis-Diol Monodichloroace-
tates by Catalyst 1 and DABCOa
er of isobutyrate
diesterb
solvent
temp (°C) time (h) conversion (%)
PhCH3
PhCH3
PhCH3
CH2Cl2
CH2Cl2
CCl4
0
-40
-78
0
-40
0
5
24
24
24
24
3
100
75
18
20
11
100
100
77:23
79:21
71:29
75:25
78:22
85:15
87:13
CCl4
-20
24
aConditions: alcohol (0 2 mmol), catalyst (5 mol %), DABCO (0.2
mmol), and (i-PrCO)2O (0.2 mmol)) in solvent (4 mL) were stirred at the
temperature indicated. bDetermined by GC analysis.
except in the case of cis-cyclododecane-1,2-diol mono-
dichloroacetate 17a. The flexible conformation of this sub-
strate led to the substantial lower er value. For 18a and 19a
having a double bond in their ring structure, the er values of
the products were slightly lower than those from 6a and 16a.
This further supported the conclusion we made in our
previous studies that catalyst 1 recognized the hydrogen
bond accepting auxiliary in the substrates rather than the
skeleton of the substrates.8 The enantioselectivities for acyc-
lic substrates such as 20a and 21a did not drop significantly
compared with those of the cyclic substrates. cis-1,3-Cyclo-
hexanediol monoacetates can also be racemized through
acetoxy migration13 and thus compound 22a was also tested
in the standard condition, but it turned out that 22a was not a
suitable substrate for the current system.
The dichloroacetoxy group in the heterosubstituted di-
ester product is more liable toward a basic deprotection and is
supposed to be selectively removed in the standard condition
(triethylamine in methanol). However, partial racemization
due to the facile acyl migration occurred during the deprotec-
tion. Using a milder base could largely avoid the racemization
problem. Treating 6b (er of 87:13) in methanol/water (4/1)
mixture solvent containing 1.1 equiv of collidine at room
temperature for 1.5 h gave (1S,2R)-diol monoisobutyrate 6c
(er of 86:14) in 93% isolated yield.14 The enantiomerically
enriched 6c is stable in aprotic solvents such as CH2Cl2
solution for at least 3 days at room temperature and this
period is long enough for carrying further organic transfor-
mations. When enantiomerically enriched cis-2-(2,2-dichloro-
acetoxy)cyclopentyl isobutyrate 14b (er of 83:17) was treated
with this deprotection system, the er ratio of the isolated 1,2-
diol monoisobutyrate 14c decreased to 60:40. Careful exam-
ination of the reaction mixture found that the er ratio of 14c
did not decline considerably after the reaction completed. The
severe racemization happened in the workup and column
chromatography processes owing to the facile acyl migration
in this product. Two other substrates including 18b and the
acyclic heterosubstituted diester 20b were not racemized sig-
nificantly during the above-mentioned deprotection proce-
dure (Table 5).
aConditions: alcohol (0.2 mmol), catalyst(5mol%), DABCO(0.2mmol),
and (i-PrCO)2O (0.2 mmol) in CCl4 (4 mL) were stirred at -20 °C.
bDetermined by GC analysis. cDetermined by HPLC analysis.
TABLE 5. Selective Deprotection of the Dichloroacetoxy Group in
Heterosubstituted Diestersa
isobutyrate
diester (er)
time
(h)
yield
(%)a
er of
monoisobutyrateb
6b (87:13)
14b (83:17)
18b (83:17)
20b (84:16)
1.5
1.5
1.5
1.0
93
91
91
90
86:14
60:40
81:19
81:19
aIsolated yield. bDetermined by GC analysis.
In summary, the desymmetrization of cyclic and acyclic
meso-1,2-diols was achieved via the DKR of their monodi-
chloroacetates. The resulting enantiomerically enriched
(1S,2R)-heterosubstituted diol diesters are stable in enantio-
merically pure form and can be readily used for further
€
(13) Edin, M.; Backvall, J.-E. J. Org. Chem. 2003, 68, 2216.
(14) Johnson, F.; Starkkovsky, N. A.; Paton, A. C.; Carlson, A. A. J. Am.
Chem. Soc. 1964, 86, 118.
3666 J. Org. Chem. Vol. 75, No. 11, 2010

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JOCArticle
organic transformations. The in situ racemization of the sub-
strate through the fast dichloroacetoxy migration enables the
dynamic kinetic resolution in which 90% of the starting mate-
rials are converted into the products, which is much higher than
the 50% theoretical yield in a kinetic resolution.
cis-2-(2,2,2-Trifluoroacetoxy)cyclohexyl isobutyrate (4b): yield
74%; 1H NMR (400 MHz, CDCl3) δ 5.25-5.28 (m, 1H),
5.04-5.08 (m, 1H), 2.53 (septet, J = 7.0 Hz, 1H), 1.94-2.01 (m,
1H), 1.80-1.88 (m, 1H), 1.63-1.79 (m, 4H), 1.43-1.54 (m, 2H),
1.15 (dd, J = 2.0, 7.0 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ
176.2, 156.8 (q, J = 42 Hz), 114.5 (q, J = 284 Hz), 75.5, 69.8, 34.0,
27.5, 27.1, 21.7, 20.9, 18.7, 18.6; HRMS (ESI) for C12H17F3O4
calcd for [M þ Na]þ m/z 305.0971, found 305.0972; [R]20 -1.5
Experimental Section
D
(c1.0, CH2Cl2) 70:30 er; GC analysis: Beta DEX 120 column (30 m ꢀ
0.25 mm ꢀ 0.25 μmfilmthickness), 100°C for 50 min, 1 deg/min to
190 °C, 11 psi, tR = 42.9 min (1S,2R, major), 44.2 min (1R,2S,
minor). The absolute stereochemistry was determined by analogy
with that of 6b.
cis-2-Hydroxycyclohexyl 2,2,2-trichloroacetate (5a): white so-
lid; mp 49 °C-51 °C ; 1H NMR (400 MHz, CDCl3) δ 5.11-5.14
(m, 1H), 3.91-3.93 (m, 1H), 2.01-2.10 (m, 1H), 1.71-1.74 (m,
4H), 1.58-1.69 (m, 2H), 1.34-1.49 (m, 2H); 13C NMR (100
MHz, CDCl3) δ 161.4, 90.2, 79.8, 69.3, 30.1, 27.0, 21.7, 21.0;
HRMS (ESI) for C8H11Cl3O3 calcd for [M þ Na]þ m/z 282.9666,
found 282.9666.
Typical Procedure for the Dynamic Kinetic Resolution of
Monoprotected meso-1,2-Diols Catalyzed by Catalyst 1 and
DABCO. To the CCl4 (4 mL) solution containing (()-6a
(45 mg, 0.2 mmol) and catalyst 1 (4 mg, 0.01 mmol) was added
DABCO (22 mg, 0.2 mmol) and isobutyric anhydride (33 uL,
0.2 mmol) at -20 °C under nitrogen atmosphere. After comple-
tion, the reaction mixture was quenched with water and extracted
with EtOAc. The organic phasewas washed withaqueous NH4Cl,
water, and brine, dried over anhydrous Na2SO4, and concentrated
under reduced pressure. The residue was purified by flash column
chromatography (eluent: 5% Et2O/petroleum ether) to afford
product 6b as a colorless oil (53 mg, 90%);
1H NMR Analysis of Dichloroacetoxy Migration in Com-
pounds 9 and 11.16 Compound 9 (6.0 mg, 0.025 mmol) in CDCl3
(0.5 mL) was added to a dry NMR tube. A 1H NMR spectrum
was taken at room temperature. Then DABCO (2.8 mg, 0.025
mmol) was added to the mixture and the mixture was monitored
by 1H NMR within 5 min.
cis-2-(2,2,2-Trichloroacetoxy)cyclohexyl isobutyrate (5b):
1
yield 81%; H NMR (400 MHz, CDCl3) δ 5.24-5.26 (m, 1H),
5.02 (dt, J = 3.0, 9.4 Hz, 1H), 2.53 (septet, J = 7.0 Hz, 1H), 2.00-
2.06 (m, 1H), 1.84-1.94 (m, 1H), 1.64-1.77 (m, 4H), 1.38-1.43
(m, 2H), 1.16 (dd, J = 2.4, 7.0 Hz, 6H); 13C NMR (100 MHz,
CDCl3) δ 176.1, 161.2, 90.1, 76.4, 70.7, 34.1, 27.9, 26.9, 22.3, 20.6,
18.9, 18.8; HRMS(ESI) for C12H17Cl3O4 calcd for [Mþ Na]þ m/z
Procedure for the Deprotection of the Dichloroacetoxy Group.14
cis-2-(2,2-dichloroacetoxy)cyclohexyl isobutyrate 6b (0.1 mmol,
30 mg, er 87:13) was dissolved in a mixture of 10 mL of MeOH and
3 mL of H2O. Collidine (0.11 mmol, 13 mg, 15 μL) in 2 mL of
MeOH was added to the mixture. The mixture was stirred at room
temperature for 1.5 h and diluted with EtOAc, washed by aqueous
solution of citric acid and brine, dried over anhydrous Na2SO4,
and concentrated under reduced pressure. The residue was
purified by flash column chromatography (eluent:15% EtOAc/
petroleum ether) to give the desired product 6c (18 mg, 93%,
er 86:14) as a colorless oil.
353.0085, found 353.0081; [R]20 -4.0 (c 1.0, CH2Cl2) 77:23 er;
D
HPLC (Chiralcel OJ-H, hexane:2-propanol = 99:1, flow rate =
0.3 mL/min) 210 nm; tR = 15.1 min (1S,2R, major), 16.0 min
(1R,2S, minor). The absolute stereochemistry was determined by
analogy with that of 6b.
1
cis-2-Hydroxycyclohexyl 2,2-dichloroacetate (6a): H NMR
(400 MHz, CDCl3) δ 5.99 (s, 1H), 5.05-5.07 (m, 1H), 3.91-3.93
(m, 1H), 1.94-2.02 (m, 1H), 1.63-1.83 (m, 6H), 1.35-1.48 (m,
2H); 13C NMR (100 MHz, CDCl3) δ 164.1, 77.6, 69.0, 64.5, 30.1,
26.8, 21.3, 21.2; HRMS (ESI) for C8H12Cl2O3 calcd for [M þ
Na]þ m/z 249.0056, found 249.0059.
cis-2-Hydroxycyclohexyl 2-chloroacetate (3a):17 white solid;
mp 59-62 °C; 1H NMR (400 MHz, CDCl3) δ 5.03 (dt, J = 2.8, 8.0
Hz, 1H), 4.11 (s, 2H), 3.89-3.92 (m, 1H), 1.87-1.96 (m, 1H), 1.74-
1.76 (m, 2H), 1.57-1.71(m, 4H), 1.34-1.45 (m, 2H); 13C NMR
(100 MHz, CDCl3) δ 167.0, 76.2, 69.0, 41.1, 30.2, 26.8, 21.7, 21.1.
cis-2-(2-Chloroacetoxy)cyclohexyl isobutyrate (3b): yield
cis- 2-(2,2-Dichloroacetoxy)cyclohexyl isobutyrate (6b):15 yield
90%; 1H NMR (400 MHz, CDCl3) δ 5.95 (s, 1H), 5.17-5.19 (m,
1H), 5.03 (dt, J = 2.8, 8.8 Hz, 1H), 2.54 (septet, J = 7.2 Hz, 1H),
1.82-1.99 (m, 2H), 1.65-1.75 (m, 4H), 1.43-1.51 (m, 2H), 1.16
(dd, J = 2.8, 7.2 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ 176.2,
163.8, 74.5, 70.4, 64.5, 34.1, 27.6, 27.2, 21.9, 21.0, 18.9, 18.8;
HRMS (ESI) for C12H18Cl2O4 calcd for [M þ Na]þ m/z
319.0474, found 319.0479; [R]20D -4.8 (c 1.0, CH2Cl2) for 87:13
er; GC analysis: Beta DEX 120 (30 m ꢀ 0.25 mm ꢀ 0.25 μm film
thickness), 152 °C for 100 min, 3 deg/min to 190 °C, 8.6 psi, tR =
90.1 min (1R,2S, minor), 91.6 min (1S,2R, major). The absolute
configuration of 6b was determined by comparing the optical
rotation value with reported (1R,2S)-2-hydroxycyclohexyl iso-
butyrate after removal of the dichloroacetoxy group.
1
93%; H NMR (400 MHz, CDCl3) δ 5.07-5.11 (m, 2H), 4.04
(s, 2H), 2.55 (septet, J = 7.0 Hz, 1H), 1.81-1.91 (m, 2H),
1.63-1.70 (m, 4H), 1.40-1.50 (m, 2H), 1.17 (dd, J = 3.6, 7.0 Hz,
6H); 13C NMR (100 MHz, CDCl3) δ 176.3, 166.6, 73.3, 70.0,
40.9, 34.1, 27.7, 27.3, 21.8, 21.3, 19.0, 18.9; HRMS (ESI) for
C12H19ClO4 calcd for [M þ Na]þ m/z 285.0864, found 285.0868;
[R]20D -0.8 (c 1.0, CH2Cl2) for 61:39 er; GC analysis: Beta DEX
120 column (30 m ꢀ 0.25 mm ꢀ 0.25 μm film thickness), 165 °C
for 50 min, 1 deg/min to 190 °C, 13.6 psi, tR = 24.7 min (1R,2S,
minor), 25.3 min (1S,2R major). The absolute stereochemistry
was determined by analogy with that of 6b.
cis-2-Hydroxycyclohexyl isobutyrate (6c):15 yield 93%; 1H
NMR (400 MHz, CDCl3) δ 4.93-4.95 (m, 1H), 3.84-3.87 (m,
1H), 2.60 (septet, J = 7.0 Hz, 1H), 1.82-1.87 (m, 2H), 1.73-1.79
(m, 1H), 1.64-1.70 (m, 2H), 1.54-1.58 (m, 2H), 1.32-1.42 (m,
2H), 1.19 (d, J = 7.0 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ
176.9, 73.6, 69.4, 34.2, 30.1, 27.1, 21.7, 21.3, 19.1, 18.9; GC
analysis: Gamma DEX 225 column (30 m ꢀ 0.25 mm ꢀ 0.25
μm film thickness), 115 °C for 45 min, 10 deg/min to 200 °C, 11 psi,
cis-2-Hydroxycyclohexyl 2,2,2-trifluoroacetate (4a):18 Com-
pound 4a was synthesized from cis-cyclohexane-1,2-diol and
trifluoroacetic anhydride catalyzed by DMAP in CH2Cl2: H
1
NMR (400 MHz, CDCl3) δ 5.14-5.18 (m, 1H), 3.92-3.95 (m,
1H), 1.94-2.05 (m, 1H), 1.57-1.83 (m, 6H), 1.37-1.48 (m, 2H);
13C NMR (100 MHz, CDCl3) δ 157.0 (q, J = 42 Hz), 114.5 (q,
J = 284 Hz), 78.7, 68.7, 29.9, 26.8, 21.3, 21.0.
t
R = 41.8 min (1R,2S, minor), 42.1 min (1S,2R major).
1
cis-2-Hydroxycyclohexyl 2,2-dibromoacetate (7a): H NMR
(400 MHz, CDCl3) δ 5.87 (s, 1H), 5.04 (dt, J = 2.6, 7.2 Hz, 1H),
3.91 (dt, J = 2.8, 8.0 Hz, 1H), 1.94-2.02 (m, 1H), 1.70-1.84 (m,
4H), 1.60-1.65 (m, 2H), 1.34-1.47 (m, 2H); 13C NMR (100
MHz, CDCl3) δ 164.2, 77.6, 69.1, 32.9, 30.2, 26.7, 21.4, 21.3;
HRMS (ESI) for C8H12Br2O3 calcd for [M þ Na]þ m/z
336.9045, found 336.9045.
(15) Kawabata, T.; Nagato, M.; Takasu, K.; Fuji, K. J. Am. Chem. Soc.
1997, 119, 3169.
(16) Robinson, P. L.; Evans, S. A., Jr. J. Org. Chem. 1985, 50, 3860.
(17) Clarke, P. A.; Kayaleh, N. E.; Smith, M. A.; Baker, J. R.; Bird, S. J.;
Chan, C. J. Org. Chem. 2002, 67, 5226.
(18) Cambie, R. C.; Lindsay, B. G.; Rutledge, P. S.; Woodgate, P. D. J.
Chem. Soc., Chem. Commun. 1978, 21, 919.
J. Org. Chem. Vol. 75, No. 11, 2010 3667

Cao and Qu
JOCArticle
cis-2-(2,2-Dibromoacetoxy)cyclohexyl isobutyrate (7b): yield
95%; 1H NMR (400 MHz, CDCl3) δ 5.82 (s, 1H), 5.16-5.17 (m,
1H), 5.02 (dt, J = 3.0, 9.2 Hz, 1H), 2.54 (septet, J = 7.0 Hz, 1H),
1.84-1.99 (m, 2H), 1.66-1.74 (m, 4H), 1.42-1.54 (m, 2H), 1.17
(dd, J = 2.8, 7.0 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ 176.2,
163.9, 74.4, 70.6, 34.1, 32.7, 27.7, 27.1, 22.1, 20.9, 19.0, 18.9;
HRMS (ESI) for C12H18Br2O4 calcd for [M þ Na]þ m/z
128.1, 125.9, 123.1, 118.7, 56.6, 53.1, 35.4, 34.3, 31.6, 31.3, 29.5,
24.6; HRMS (ESI) for C23H33N3O3S calcd for [M þ H]þ m/z
432.2315, found 432.2321.
cis-2-Hydroxycyclopentyl 2,2-dichloroacetate (14a): white so-
lid; mp 46-49 °C; 1H NMR (400 MHz, CDCl3) δ 6.01 (s, 1H),
5.09-5.13 (m, 1H), 4.25-4.29 (m, 1H), 1.84-2.06 (m, 5H),
1.69-1.78 (m, 1H), 1.58-1.65 (m, 1H); 13C NMR (100 MHz,
CDCl3) δ 164.3, 80.0, 73.3, 64.4, 30.6, 27.8, 19.3; HRMS (ESI)
for C7H10Cl2O3 calcd for [M þ Na]þ m/z 234.9899, found
234.9902.
cis-2-(2,2-Dichloroacetoxy)cyclopentyl isobutyrate (14b): yield
85%; 1H NMR (400 MHz, CDCl3) δ 5.93 (s, 1H), 5.27-5.31 (m,
1H), 5.14-5.19 (m, 1H), 2.53 (septet, J = 7.0 Hz, 1H), 2.01-2.08
(m, 2H), 1.77-1.98 (m, 3H), 1.63-1.72 (m, 1H), 1.16 (d, J = 7.0
Hz, 6H); 13C NMR (100 MHz, CDCl3) δ 176.4, 163.8, 77.5, 73.8,
64.3, 33.9, 29.7, 28.1, 27.8, 19.1, 18.8; HRMS (ESI) for C11H16-
406.9464, found 406.9458; [R]20 -6.8 (c 1.0, CH2Cl2) 73:27
D
er; HPLC (Chiralcel OD-H, hexane:2-propanol = 93:7, flow
rate = 0.4 mL/min) 210 nm, tR = 12.6 min (1S,2R, major), 13.5
min (1R,2S, minor). The absolute stereochemistry was deter-
mined by analogy with that of 6b.
cis-2-Hydroxycyclohexyl 2-bromoacetate (8a): 1H NMR (400
MHz, CDCl3) δ 5.00 (dt, J = 3.0, 8.0 Hz, 1H), 3.88-3.91 (m,
3H), 1.89-1.95 (m, 1H), 1.75-1.82 (m, 2H), 1.60-1.71 (m, 4H),
1.13-1.44 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 166.9, 76.2,
69.0, 30.2, 26.8, 26.1, 21.7, 21.1; HRMS (ESI) for C8H13BrO3
calcd for [M þ Na]þ m/z 258.9940, found 258.9941.
Cl2O4 calcd for [M þ Na]þ m/z 305.0318, found 305.0323; [R]20
D
-4.2 (c 1.0, CH2Cl2) for 83:17 er; GC analysis: Beta DEX 120
column (30 m ꢀ 0.25 mm ꢀ 0.25 μm film thickness), 152 °C for 100
min, 1 deg/min to 190 °C, 11 psi, tR = 63.5 min (1R,2S, minor),
64.8 min (1S,2R, major). The absolute stereochemistry was deter-
mined by analogy with that of 6b.
cis-2-(2-Bromoacetoxy)cyclohexyl isobutyrate (8b): yield 94%;
1H NMR (400 MHz, CDCl3) δ 5.05-5.09 (m, 2H), 3.82 (s, 2H),
2.55 (septet, J = 7.0 Hz, 1H), 1.82-1.91 (m, 2H), 1.64-1.70 (m,
4H), 1.44-1.49 (m, 2H), 1,17 (dd, J = 3.6, 7.0 Hz, 6H); 13C NMR
(100 MHz, CDCl3) δ 176.3, 166.5, 73.2, 70.1, 34.1, 27.6, 27.4, 25.9,
21.6, 21.5, 19.0, 18.9; HRMS (ESI) for C12H19BrO4 calcd for
cis-2-Hydroxycyclopentyl isobutyrate (14c): yield 91%; 1H
NMR (400 MHz, CDCl3) δ 4.97 (q, J = 5.4, 10.8 Hz, 1H), 4.19
(q, J = 4.8, 9.6 Hz, 1H), 2.60 (septet, J = 7.2 Hz, 1H), 1.96-2.04
(m, 1H), 1.83-1.94 (m, 2H), 1.67-1.78 (m, 2H), 1.52-1.61 (m,
2H), 1.19 (dd, J = 2.4, 7.2 Hz, 6H); 13C NMR (100 MHz, CDCl3)
δ 177.0, 76.4, 73.2, 34.0, 30.6, 28.1, 19.4, 19.0, 18.9; HRMS (ESI)
for C9H16O3 calcd for [M þ Na]þ m/z 195.0992, found 195.0994;
GC analysis: Gamma DEX 225 column (30 m ꢀ 0.25 mm ꢀ 0.25
μm film thickness), 120 °C for 28 min, 11 psi, tR = 20.1 min
(1R,2S, minor), 20.8 min (1S,2R, major).
[M þ Na]þ m/z 329.0359, found 329.0357; [R]20 -1.3 (c 1.0,
D
CH2Cl2) 60:40 er; GC analysis: Beta DEX 120 column (30 mꢀ
0.25 mm ꢀ 0.25 μm film thickness), 177 °C for 40 min, 3 deg/min to
190 °C, 11 psi, tR = 20.9 min (1R,2S, minor), 21.3 min (1S,2R,
major). The absolute stereochemistry was determined by analogy
with that of 6b.
cis-2-Hydroxy-trans-6-methylcyclohexyl 2,2-dichloroacetate
(9):16 white solid; mp 70-72 °C; 1H NMR (400 MHz, CDCl3)
δ 6.00 (s, 1H), 4.65 (dd, J = 2.6, 10.0 Hz, 1H), 4.09-4.11 (m,
1H), 2.10-2.21 (m, 1H), 1.90-1.96 (m, 1H), 1.75-1.81 (m, 2H),
1.64-1.72 (m, 1H), 1.44-1.54 (m, 2H), 1.04-1.16 (m, 1H), 0.95
(d, J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 164.1, 83.8,
67.3, 64.5, 32.5, 31.0, 30.7, 18.7, 17.7; HRMS (ESI) for
C9H14Cl2O3 calcd for [M þ Na]þ m/z 263.0212, found 263.0219.
cis-2-Hydroxy-trans-3-methylcyclohexyl 2,2-dichloroacetate
(10):16 Compound 9 was crystallized from the mixture of
compounds 9 and 10. But pure compound 10 was inseparable
from the mixture of compounds 9 and 10. The NMR data of
compound 10 were deduced from the mixture’s NMR spectrum.
1H NMR (400 MHz, CDCl3) δ 6.01 (s, 1H), 5.22 (br s, 1H),
3.16-3.43 (m, 1H), 2.05-2.10 (m, 1H), 1.76-1.78 (m, 1H),
cis-2-Hydroxycycloheptyl 2,2-dichloroacetate (15a): 1H NMR
(400 MHz, CDCl3) δ 5.99 (s, 1H), 5.09 (dt, J = 2.6, 9.0 Hz, 1H),
4.03-4.06 (m, 1H), 2.03-2.12 (m, 1H), 1.68-1.90 (m, 6H),
1.56-1.64 (m, 2H), 1.42-1.54 (m, 2H); 13C NMR (100 MHz,
CDCl3) δ 164.0, 81.2, 72.0, 64.5, 31.4, 27.0, 26.6, 22.1, 21.7;
HRMS (ESI) for C9H14Cl2O3 calcd for [M þ Na]þ m/z
263.0212, found 263.0210.
cis-2-(2,2-Dichloroacetoxy)cycloheptyl isobutyrate (15b): yield
91%; 1H NMR (400 MHz, CDCl3) δ5.95 (s, 1H), 5.22 (dt, J=2.6,
7.6 Hz, 1H), 5.10 (dt, J= 2.6, 9.0 Hz, 1H), 2.54 (septet, J=7.0 Hz,
1H), 1.93-2.04 (m, 2H), 1.52-1.85 (m, 8H), 1.16 (dd, J = 1.8, 7.0
Hz, 6H); 13C NMR (100 MHz, CDCl3) δ 176.2, 163.7, 78.1, 73.7,
64.5, 34.1, 28.5, 28.3, 26.4, 22.4, 22.1, 18.9, 18.8; HRMS (ESI) for
C13H20Cl2O4 calcd for [M þ Na]þ m/z 333.0631, found 333.0634;
1.49-1.68 (m, 5H), 1.26 (br s, 1H), 1.05 (d, J = 6.4 Hz, 3H); 13
C
NMR (100 MHz, CDCl3) δ 164.2, 77.3, 75.9, 64.6, 34.4, 32.3,
28.7, 19.5, 18.3.
[R]20 -5.4 (c 1.0, CH2Cl2) 87:13 er; HPLC (Chiralcel OD-H,
D
hexane:2-propanol = 96:4, flow rate = 0.15 mL/min) 210 nm,
tR = 29.7 min (1S,2R, major), 31.4 min (1R,2S, minor). The
absolute stereochemistry was determined by analogy with that of 6b.
trans-2-Hydroxy-cis-6-methylcyclohexyl 2,2-dichloroacetate
(11):16 1H NMR (400 MHz, CDCl3) δ 6.00 (s, 1H), 4.81 (dd,
J = 4.0, 6.4 Hz, 1H), 3.94-3.97 (m, 1H), 2.26-2.31 (m, 1H),
2.05-2.19 (m, 1H), 1.90 (br s, 1H), 1.46-1.64 (m, 5H), 0.96 (d,
J = 7.0 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 164.2, 81.2,
67.0, 64.5, 30.5, 30. 4, 29.2, 18.8, 14.9; HRMS (ESI) for
C9H14Cl2O3 calcd for [M þ Na]þ m/z 263.0212, found 263.0221.
trans-2-Hydroxy-trans-3-methylcyclohexyl 2,2-dichloroacetate
(12):16 1H NMR (400 MHz, CDCl3) δ 5.96 (s, 1H), 4.96-4.98
(m, 1H), 3.75 (br s, 1H), 2.03-2.08 (m, 1H), 1.92-1.97 (m, 1H),
1.76 (br s, 1H), 1.54-1.58 (m, 3H), 1.47-1.49 (m, 2H), 1.0 (d, J =
6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 162.3, 76.6, 71.9,
64.5, 32.6, 28.4, 26.5, 19.3, 14.9; HRMS (ESI) for C9H14Cl2O3
calcd for [M þ Na]þ m/z 263.0212, found 263.0220.
1
cis-2-Hydroxycyclooctyl 2,2-dichloroacetate (16a): H NMR
(400 MHz, CDCl3) δ 5.98 (s, 1H), 5.16 (dt, J = 2.4, 9.6 Hz, 1H),
4.05 (br s, 1H), 2.12-2.21 (m, 1H), 2.02 (br s, 1H), 1.82-1.93 (m,
2H), 1.48-1.79 (m, 9H); 13C NMR (100 MHz, CDCl3) δ 163.9,
80.8, 71.2, 64.5, 30.2, 26.9, 26.8, 25.3, 24.2, 21.7; HRMS (ESI)
for C10H16Cl2O3 calcd for [M þ Na]þ m/z 277.0369, found
277.0371.
cis-2-(2,2-Dichloroacetoxy)cyclooctyl isobutyrate (16b): yield
93%; 1H NMR (400 MHz, CDCl3) δ 5.93 (s, 1H), 5.23-5.26 (m,
1H), 5.17-5.19 (m, 1H), 2.53 (septet, J = 6.8 Hz, 1H),
2.01-2.09 (m, 2H), 1.61-1.83 (m, 10H), 1.16 (dd, J = 2.4, 6.8
Hz, 6H); 13C NMR (100 MHz, CDCl3) δ 176.2, 163.8, 77.5, 72.7,
64.5, 34.1, 28.1, 27.9, 26.3, 25.9, 23.2, 22.4, 18.9, 18.8; HRMS
(ESI) for C14H22Cl2O4 calcd for [M þ Na]þ m/z 347.0787, found
347.0788; [R]20D -2.0 (c 1.0, CH2Cl2) for 85:15 er; HPLC (Chiralcel
OJ-H, hexane:2-propanol = 96:4, flow rate = 0.2 mL/min) 210 nm,
tR = 23.5 min (1S,2R, major), 26.1 min (1R,2S, minor). The
absolute stereochemistry was determined by analogy with that of 6b.
(S)-Methyl 2-(3,5-di-tert-butyl-2-hydroxyphenylthioamido)-
1
3-(1-methyl-1H-imidazol-5-yl)propanoate (13):8. H NMR (400
MHz, CDCl3) δ 7.45 (s, 1H), 7.38 (s, 1H), 7.01 (s, 1H), 6.80 (s,
1H), 5.44-5.48 (m, 1H), 3.85 (s, 3H), 3.56-3.61 (m, 4H), 3.38 (d,
J = 15.6 Hz, 1H), 1.42 (s, 9H), 1.27 (s, 9H); 13C NMR (100
MHz, CDCl3) δ 196.7, 170.7, 154.8, 141.2, 138.7, 138.6, 128.5,
3668 J. Org. Chem. Vol. 75, No. 11, 2010

Cao and Qu
JOCArticle
cis-2-Hydroxycyclododecyl 2,2-dichloroacetate (17a): 1H NMR
(400 MHz, CDCl3) δ 5.98 (s, 1H), 5.19 (t, J = 6 Hz, 1H),
3.96 (dq, J = 3.6, 6.4 Hz, 1H), 1.93 (br s, 1H), 1.31 (d, J = 6.4
Hz, 3H), 1.23 (d, J = 6.4 Hz, 3H); 13C NMR (100 MHz, CDCl3)
δ 164.0, 78.0, 69.0, 64.4, 17.9, 13.8; HRMS (ESI) for
C6H10Cl2O3 calcd for [M þ Na]þ m/z 222.9899, found 222.9903.
cis-3-(2,2-Dichloroacetoxy)butan-2-yl isobutyrate (20b): yield
83%; 1H NMR (400 MHz, CDCl3) δ 5.94 (s, 1H), 5.13 (dq, J =
3.5, 6.6 Hz, 1H), 5.04 (dq, J = 3.5, 6.6 Hz, 1H), 2.54 (septet, J = 7.0
Hz, 1H), 1.32 (d, J = 6.6 Hz, 3H), 1.26 (d, J = 6.6 Hz, 3H), 1.16
(dd, J = 3.4, 7.0 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ 176.2,
163.8, 74.9, 70.4, 64.4, 34.1, 18.9, 18.8, 14.9, 14.5; HRMS (ESI) for
C10H16Cl2O4 calcd for [M þ Na]þ m/z 293.0318, found 293.0321;
[R]20D -1.3 (c 1.0, CH2Cl2) for 84:16 er; HPLC (Chiralcel OD-H,
hexane:2-propanol = 96:4, flow rate = 0.3 mL/min) 210 nm, tR =
14.8 min (major), 15.9 min (minor).
3.91-3.94 (m, 1H), 1.62-1.84 (m, 5H), 1.35-1.63 (m, 16H); 13
C
NMR (400 MHz, CDCl3) δ 164.6, 79.5, 71.1, 64.5, 29.6, 28.8, 24.5,
24.4, 24.2, 23.6, 23.5, 21.7, 21.6, 21.1; HRMS (ESI) for
C14H24Cl2O3 calcd for [M þ Na]þ m/z 333.0995, found 333.0990.
cis-2-(2,2-Dichloroacetoxy)cyclododecyl isobutyrate (17b):
1
yield 95%; white solid; mp 30-33 °C; H NMR (400 MHz,
CDCl3) δ 5.93 (s, 1H), 5.16-5.21 (m, 2H), 2.53 (septet, J = 7.0
Hz, 1H), 1.80-1.86 (m, 2H), 1.61-1.67 (m, 2H), 1.25-1.52 (m,
16H), 1.16 (dd, J = 2.5, 7.0 Hz, 6H); 13C NMR (400 MHz,
CDCl3) δ 176.8, 164.1, 77.3, 71.5, 71.4, 64.5, 34.1, 29.7, 24.42,
24.38, 24.3, 23.6, 23.5, 21.7, 21.6, 21.0, 18.9, 18.8; HRMS (ESI)
for C18H30Cl2O4 calcd for [M þ Na]þ m/z 403.1413, found
403.1407; [R]20 -4.5 (c 1.0, CH2Cl2) for 77:23 er; HPLC
cis-3-Hydroxybutan-2-yl isobutyrate (20c): yield 90%; 1H
NMR (400 MHz, CDCl3) δ 4.87 (dq, J = 3.2, 6.4 Hz, 1H),
3.86-3.91 (m, 1H), 2.56 (septet, J = 6.8 Hz, 1H), 1.97 (br s, 1H),
1.16-1.22 (m, 12H); 13C NMR (100 MHz, CDCl3) δ 176.9, 74.0,
69.7, 34.1, 19.0, 18.9, 17.8, 14.2; GC analysis: Gamma DEX 225
column (30 m ꢀ 0.25 mm ꢀ 0.25 μm film thickness), 120 °C for
10 min, 11 psi, tR = 8.5 min (minor), 8.8 min (major).
D
(Chiralcel OD-H, hexane:2-propanol = 99:1, flow rate = 0.4
mL/min) 210 nm, tR = 10.5 min (1S,2R, major), 11.1 min
(1R,2S, minor). The absolute stereochemistry was determined
by analogy with that of 6b.
cis-6-Hydroxycyclohex-3-enyl 2,2-dichloroacetate (18a): 1H
NMR (400 MHz, CDCl3) δ 6.00 (s, 1H), 5.59-5.66 (m, 2H),
5.19-5.21 (m, 1H), 4.12-4.15 (m, 1H), 2.45-2.48 (m, 3H),
2.29-2.34 (m, 1H), 2.02 (br s, 1H); 13C NMR (100 MHz, CDCl3)
δ 164.4, 123.8, 122.7, 75.7, 66.8, 64.4, 31.3, 27.5; HRMS (ESI) for
C8H10Cl2O3 calcd for [M þ Na]þ m/z 246.9899, found 246.9902.
cis-6-(2,2-Dichloroacetoxy)cyclohex-3-enyl isobutyrate (18b):
yield 87%; 1H NMR (400 MHz, CDCl3) δ 5.95 (s, 1H), 5.60-5.68
(m, 2H), 5.34 (t, J = 5 Hz, 1H), 5.20 (t, J = 6.4 Hz, 1H), 2.51-2.58
(m, 2H), 2.39-2.41 (m, 3H), 1.16 (t, J = 6 Hz, 6H); 13C NMR (100
MHz, CDCl3) δ 176.4, 164.0, 123.9, 122.6, 72.5, 68.3, 64.4, 34.1,
28.6, 27.8, 18.9, 18.8; HRMS (ESI) for C12H16Cl2O4 calcd for
[MþNa]þ m/z317.0318, found 317.0315; [R]20D -5.5 (c1.0, CH2Cl2)
for 83:17 er; GC analysis: Beta DEX 120 column (30 m ꢀ 0.25 mm ꢀ
0.25 μm film thickness), 148 °C for 100 min, 1 deg/min to 200 °C,
12 psi, tR = 80.1 min (1R,2S, minor), 81.9 min (1S,2R, major).
The absolute stereochemistry was determined by analogy with that
of 6b.
cis-5-Hydroxyoctan-4-yl 2,2-dichloroacetate (21a): 1H NMR
(400 MHz, CDCl3) δ 5.98 (s, 1H), 4.98 (dt, J = 3.4, 9.6 Hz, 1H),
3.77-3.80 (m, 1H), 1.75-1.79 (m, 1H), 1.71-1.72 (m, 1H),
1.53-1.64 (m, 2H), 1.28-1.48 (m, 5H), 0.92-0.97 (m, 6H); 13
C
NMR (100 MHz, CDCl3) δ 164.4, 80.9, 72.4, 64.5, 34.1, 30.5,
18.9, 18.6, 13.9, 13.8; HRMS (ESI) for C10H18Cl2O3 calcd for
[M þ Na]þ m/z 279.0523, found 279.0520.
cis-5-(2,2-Dichloroacetoxy)octan-4-yl isobutyrate (21b): yield
90%; 1H NMR (400 MHz, CDCl3) δ 5.93 (s, 1H), 5.12 (dt, J =
3.4, 9.6 Hz, 1H), 5.03 (dt, J = 3.4, 10.0 Hz, 1H), 2.54 (septet, J =
7.0 Hz, 1H), 1.51-1.74 (m, 4H), 1.27-1.47 (m, 4H), 1.16 (dd,
J = 1.6, 7.0 Hz, 6H), 0.91-0.96 (m, 6H); 13C NMR (100 MHz,
CDCl3) δ 176.6, 164.1, 77.9, 73.1, 64.5, 34.1, 31.4, 30.8, 18.9, 18.8,
18.7, 18.6, 13.8, 13.7; HRMS (ESI) for C14H24Cl2O4 calcd for
[MþNa]þ m/z349.0944, found 349.0943; [R]20 -1.0 (c1.0, CH2Cl2)
D
for 81:19 er; HPLC (Chiralcel OD-H, hexane:2-propanol = 99:1,
flow rate = 0.4 mL/min) 210 nm, tR = 9.8 min (major), 10.3 min
(minor).
cis-6-Hydroxycyclohex-3-enyl isobutyrate (18c): yield 91%;
1H NMR (400 MHz, CDCl3) δ 5.57-5.63 (m, 2H), 5.06-5.09
(m, 1H), 4.05 (t, J = 6.4 Hz, 1H), 2.60 (septet, J = 6.8 Hz, 1H),
2.32-2.44 (m, 3H), 2.28-2.30 (m, 1H), 2.19 (br s, 1H), 1.18 (dd,
J = 3.6, 6.8 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ 177.2,
123.7, 123.3, 71.7, 67.4, 34.1, 31.3, 28.0, 19.0, 18.9; HRMS (ESI)
for C10H16O3 calcd for [M þ Na]þ m/z 207.0992, found
207.0991; GC analysis: Beta DEX 120 column (30 m ꢀ 0.25
cis-3-Hydroxycyclohexyl 2,2-dichloroacetate (22a): 1H NMR
(400 MHz, CDCl3) δ 5.93 (s, 1H), 4.82-4.90 (m, 1H), 3.71-3.77
(m, 1H), 2.29-2.32 (m, 1H), 2.12-2.14 (m, 1H), 1.86-1.99
(m, 3H), 1.25-1.56 (m, 4H); 13C NMR (100 MHz, CDCl3)
δ 163.8, 74.7, 68.1, 64.4, 39.8, 34.0, 30.0, 19.6; HRMS (ESI)
for C8H12Cl2O3 calcd for [M þ Na]þ m/z 249.0056, found
249.0057.
mm ꢀ 0.25 μm film thickness), 155 °C for 18 min, 10.6 psi, tR
14.4 min (1S,2R, major), 14.7 min (1R,2S, minor).
=
cis-3-(2,2-Dichloroacetoxy)cyclohexyl isobutyrate (22b):19 yield
91%; H NMR (400 MHz, CDCl3) δ 5.91 (s, 1H), 4.85-4.92
cis-8-Hydroxycyclooct-4-enyl 2,2-dichloroacetate (19a): 1H
NMR (400 MHz, CDCl3) δ 5.98 (s, 1H), 5.70-5.81 (m, 2H),
5.16 (dd, J = 3.8, 8.6 Hz, 1H), 4.11 (t, J = 6.2 Hz, 1H), 2.49-2.64
(m, 2H), 2.26 (br s, 1H), 1.98-2.26 (m, 3H), 1.78-1.90 (m, 3H);
13C NMR (100 MHz, CDCl3) δ 164.6, 130.9, 129.6, 83.1, 73.3,
64.5, 33.1, 29.2, 21.6, 21.3; HRMS (ESI) for C10H14Cl2O3 calcd for
[M þ Na]þ m/z 275.0212, found 275.0213.
1
(m, 1H), 4.74-4.81 (m, 1H), 2.52 (septet, J = 7.0 Hz, 1H),
2.29-2.33 (m, 1H), 2.01-2.03 (m, 1H), 1.87-1.96 (m, 2H),
1.56-1.64 (m, 1H), 1.30-1.48 (m, 3H), 1.16 (dd, J = 1.0, 7.0
Hz, 6H); 13C NMR (100 MHz, CDCl3) δ 176.3, 163.7, 74.1,
69.5, 64.4, 36.3, 34.0, 30.4, 30.1, 19.6, 18.9, 18.8; HRMS (ESI)
for C12H18Cl2O4 calcd for [M þ Na]þ m/z 319.0479, found
319.0471; [R]20 -0.6 (c 1.0, CH2Cl2) for 20% ee (60:40 er);
cis-8-(2,2-Dichloroacetoxy)cyclooct-4-enyl isobutyrate (19b):
yield 89%; 1H NMR (400 MHz, CDCl3) δ 5.97 (s, 1H), 5.76 (t,
J = 5 Hz, 2H), 5.23 (dd, J = 4, 7.6 Hz, 1H), 5.19 (dd, J = 4.8, 8.4
Hz, 1H), 2.52-2.63 (m, 3H), 1.99-2.09 (m, 4H), 1.75-1.91 (m,
2H), 1.18 (dd, J = 3.2, 6.8 Hz, 6H); 13C NMR (100 MHz,
CDCl3) δ 176.3, 163.8, 130.1, 129.8, 79.8, 74.6, 64.5, 34.1, 29.9,
29.8, 21.4, 21.2, 18.9, 18.8; HRMS (ESI) for C14H20Cl2O4 calcd
D
HPLC (Chiralpeak AD-H, hexane:2-propanol = 97:3, flow
rate = 0.4 mL/min) 210 nm, tR = 21.6 min (1R,3S, minor),
23.2 min (1S,3R, major). The absolute configuration was
determinded by comparing the optical rotation value with that
reported for (1S,3R)-3-hydroxycyclopentyl acetate after re-
moval of the dichloroacetoxy group.
for [M þ Na]þ m/z 345.0631, found 345.0631; [R]20 -4.4 (c 1.0,
D
CH2Cl2) for 80:20 er; HPLC (Chiralcel OJ-H, hexane:2-propa-
nol = 98:2, flow rate = 0.5 mL/min) 210 nm, tR = 10.9 min
(1S,2R, major), 12.5 min (1R,2S, minor). The absolute stereo-
chemistry was determined by analogy with that of 6b.
Acknowledgment. This work was financially supported by
The National Natural Science Foundation of China (20402007,
(19) Borcherding, D. R.; Peet, N. P.; Randall Munson, H.; Zhang, H.;
Hoffman, P. F.; Bowlin, T. L.; Edwards, C. K., III J. Med. Chem. 1996, 39,
2615.
cis-3-Hydroxybutan-2-yl 2,2-dichloroacetate (20a): 1H NMR
(400 MHz, CDCl3) δ 5.97 (s, 1H), 4.97 (dq, J = 3.6, 6.4 Hz, 1H),
J. Org. Chem. Vol. 75, No. 11, 2010 3669

Cao and Qu
JOCArticle
20772065), Program for New Century Excellent Talents
in University, and the 111 Project (B06005) and the 863
Project of the Ministry of Science and Technology of
China (2006AA020502). We thank Prof. Chi Zhang for
helpful discussions.
Supporting Information Available: General procedure for the
synthesisofsubstratesand products inSchemes3 and 4and Tables1,
4, and 5, 1H NMR, 13C NMR, and HRMS spectra, and 1H NMR
analysis of the dichloroacetoxy migration. This material is available
free of charge via the Internet at http://pubs.acs.org.
3670 J. Org. Chem. Vol. 75, No. 11, 2010