Chiral Lewis acid catalyzed resolution of racemic enol ester epoxides. Conversion of both enantiomers of an enol ester epoxide to the same enantiomer of acyloxy ketone

Article abstract of DOI:10.1021/jo0108515

This paper describes an efficient kinetic resolution of racemic enol ester epoxides via a chiral Lewis acid catalyzed rearrangement. Both enantiomerically enriched enol ester epoxides and α-acyloxy ketones can be obtained through this resolution. A positive nonlinear effect is observed in this process. By taking advantage of the mechanistic duality in acid-catalyzed enol ester epoxide rearrangement, we can completely convert a racemic enol ester epoxide into an enantiomerically enriched α-acyloxy ketone by treatment with a catalytic amount of a chiral Lewis acid followed by a catalytic amount of an achiral protic acid.

Full text of DOI:10.1021/jo0108515

J . Org. Chem. 2002, 67, 2831-2836
2831
Ch ir a l Lew is Acid Ca ta lyzed Resolu tion of Ra cem ic En ol Ester
Ep oxid es. Con ver sion of Both En a n tiom er s of a n En ol Ester
Ep oxid e to th e Sa m e En a n tiom er of Acyloxy Keton e
Xiaoming Feng, Lianhe Shu, and Yian Shi*
Department of Chemistry, Colorado State University, Fort Collins, Colorado 80523
yian@lamar.colostate.edu
Received August 20, 2001
This paper describes an efficient kinetic resolution of racemic enol ester epoxides via a chiral Lewis
acid catalyzed rearrangement. Both enantiomerically enriched enol ester epoxides and R-acyloxy
ketones can be obtained through this resolution. A positive nonlinear effect is observed in this
process. By taking advantage of the mechanistic duality in acid-catalyzed enol ester epoxide
rearrangement, we can completely convert a racemic enol ester epoxide into an enantiomerically
enriched R-acyloxy ketone by treatment with a catalytic amount of a chiral Lewis acid followed by
a catalytic amount of an achiral protic acid.
The rearrangement of enol ester epoxides to R-acyloxy
ketones or aldehydes can be promoted by both protic and
Lewis acids.1-3 Studies of such rearrangements with
enantiomerically enriched enol ester epoxides have re-
vealed that the rearrangement can proceed either via
retention of configuration or inversion by judicious choice
of acid catalysts (Scheme 1).3 The strength of the acid
catalyst is an important factor for the stereochemical
outcome of the rearrangement, with strong acids favoring
retention of configuration and weak acids favoring inver-
sion. Recently, we have shown that a racemic enol ester
epoxide can be kinetically resolved to give an enantio-
merically enriched epoxide and R-acyloxy ketone when
a chiral Lewis acid catalyst is used (Scheme 2).4 In a
further study of this resolution, we observed a positive
nonlinear effect. Herein we wish to report our detailed
studies on this resolution process.
including Ti(OiPr)4, TiF4, Al(OiPr)3, Zr(OEt)4, Sc(OiPr)4,
SnCl4, and Cu(OAc)2, were used with the chiral ligands.
With almost every catalyst generated, less than 5%
conversion was obtained after the reaction was run for
20 h, except for a BINOL-Ti(OiPr)4 system,5 which was
found to be the most promising catalyst for the resolution
in terms of both reactivity and selectivity. Treating
epoxide 1 with 5 mol % [(R)-BINOL]2-Ti(OiPr)4 (16) in
Et2O at 0 °C for 0.5 h led to a 52% conversion, as judged
by 1H NMR assay of the crude reaction mixture. Analysis
of the unreacted epoxide and the rearranged product
using chiral HPLC (Chiralcel OD) revealed a 99% ee for
the epoxide and an 89% ee for 2-(benzoyloxy)cyclohex-
anone (2). Both the recovered epoxide and the rearranged
ketone were determined to be enriched in the R isomer,
revealing that the S isomer of epoxide 1 had rearranged
to the R isomer of 2. Therefore, the rearrangement
occurred with inversion of configuration.
Further studies showed that the ratio of ligand to
metal was important for both the reactivity and the
selectivity. The best results were obtained when 2 equiv
or more of BINOL was used per Ti.5e,6 The solvent study
indicated that Et2O and CH2Cl2 gave the best overall
Resu lts a n d Discu ssion
BINOL-Ti Ca ta lyzed Kin etic Resolu tion of En ol
Ester Ep oxid es. The kinetic resolution of enol ester
epoxides started with racemic 1-(benzoyloxy)-1,2-epoxy-
cyclohexane (1) as a test substrate (Scheme 3). A variety
of chiral Lewis acids were investigated. Chart 1 lists some
of the chiral ligands and acids. A wide variety of metals,
(5) For leading references on BINOL-Ti catalyzed asymmetric
processes see: (a) Mikami, K.; Terada, M.; Nakai, T. J . Am. Chem.
Soc. 1989, 111, 1940. (b) Terada, M.; Mikami, K.; Nakai, T. J . Chem.
Soc., Chem. Commun. 1990, 1623. (c) Komatsu, N.; Hashizume, M.;
Sugita, T.; Uemura, S. J . Org. Chem. 1993, 58, 4529. (d) Costa, A. L.;
Piazza, M. G.; Tagliavini, E.; Trombini, C.; Umani-Ronchi, A. J . Am.
Chem. Soc. 1993, 115, 7001. (e) Mikami, K.; Matsukawa, S. J . Am.
Chem. Soc. 1993, 115, 7039. (f) Keck, G. E.; Tarbet, K. H.; Geraci, L.
S. J . Am. Chem. Soc. 1993, 115, 8467. (g) Keck, G. E.; Krishnamurthy,
D.; Grier, M. C. J . Org. Chem. 1993, 58, 6543. (h) Komatsu, N.;
Hashizume, M.; Sugita, T.; Uemura, S. J . Org. Chem. 1993, 58, 7624.
(i) Terada, M.; Mikami, K. J . Chem. Soc., Chem. Commun. 1994, 833.
(j) Mikami, K.; Motoyama, Y.; Terada, M. J . Am. Chem. Soc. 1994,
116, 2812. (k) Keck, G. E.; Krishnamurthy, D. J . Am. Chem. Soc. 1995,
117, 2363. (l) Bedeschi, P.; Casolari, S.; Costa, A. L.; Tagliavini, E.;
Umani-Ronchi, A. Tetrahedron Lett. 1995, 36, 7897. (m) Faller, J . W.;
Sams, D. W. I.; Liu, X. J . Am. Chem. Soc. 1996, 118, 1217. (n) Gauthier,
D. R., J r.; Carreira, E. M. Angew. Chem., Int. Ed. Engl. 1996, 35, 2363.
(6) The 1H NMR showed that all OiPr groups on Ti had been
replaced by BINOL when 2 equiv of BINOL was used per Ti. However,
the actual structure of catalytic species responsible for the current
resolution is not very clear at the moment.
* To whom correspondence should be addressed. Phone: 970-491-
7424. Fax: 970-491-1801.
(1) For leading reviews on enol ester epoxide rearrangements see:
(a) McDonald, R. N. Mech. Mol. Migr. 1971, 3, 67. (b) Riehl, J .-J .;
Casara, P.; Fourgerousse, A. C.R. Acad. Sci. Paris, Ser. C 1974, 279,
79.
(2) For examples of acid-catalyzed rearrangements of enol ester
epoxides see: (a) Soloway, A. H.; Considine, W. J .; Fukushima, D. K.;
Gallagher, T. F. J . Am. Chem. Soc. 1954, 76, 2941. (b) Leeds, N. S.;
Fukushima, D. K.; Gallagher, T. F. J . Am. Chem. Soc. 1954, 76, 2943.
(c) Gardner, P. D. J . Am. Chem. Soc. 1956, 78, 3421. (d) J ohnson, W.
S.; Gastambide, B.; Pappo, R. J . Am. Chem. Soc. 1957, 79, 1991. (e)
Nambara, T.; Fishman, J . J . Org. Chem. 1962, 27, 2131. (f) Rhone, J .
R.; Huffman, M. N. Tetrahedron Lett. 1965, 1395. (g) Williamson, K.
L.; Coburn, J . I.; Herr, M. F. J . Org. Chem. 1967, 32, 3934.
(3) (a) Zhu, Y.; Manske, K. J .; Shi, Y. J . Am. Chem. Soc. 1999, 121,
4080. (b) Zhu, Y.; Shu, L.; Tu, Y.; Shi, Y. J . Org. Chem. 2001, 66, 1818.
(4) Feng, X.; Shu, L.; Shi, Y. J . Am. Chem. Soc. 1999, 121, 11002.
10.1021/jo0108515 CCC: $22.00 © 2002 American Chemical Society
Published on Web 03/30/2002

2832 J . Org. Chem., Vol. 67, No. 9, 2002
Feng et al.
Sch em e 1
Ta ble 1. Solven t Effects on Kin etic Resolu tion of
Sch em e 2
Ep oxid e 1a
recovered
SM ee, %c
product
ee, %c
entry
solvent
conv, %b
1
2
3
4
5
6
7
8
9
Et2O
50
56
46
6
95 (R)
89 (R)
86 (R)
0.5 (R)
3 (R)
94 (R)
17 (R)
78 (R)
21 (R)
87 (R)
69 (R)
90 (R)
13 (R)
46 (R)
86 (R)
71 (R)
80 (R)
69 (R)
tBuOMe
iPr2O
THF
THP
CH2Cl2
CHCl3
ClCH2CH2Cl
PhH
Sch em e 3
4
52
19
51
22
a
All reactions were carried out with substrate (0.5 mmol) and
b
catalyst (5 mol %) in solvent (3 mL) at 0 °C for 0.5 h. The
conversion was determined by 1H NMR of the crude reaction
mixture after workup. c Enantioselectivity was determined by
chiral HPLC (Chiralcel OD).
tries 13-15). In all these cases, the recovered enol ester
epoxides could be obtained with high ee’s and the pure
epoxides could be isolated in reasonable yields. However,
the current catalyst system is not effective for acyclic
epoxides (Table 2, entry 17). Many of these enol ester
epoxides can be obtained in high ee by the asymmetric
epoxidation of enol esters.3 However, a distinct feature
of current kinetic resolution is that, in principle, ex-
tremely high ee’s for enol ester epoxides can be obtained
by adjusting the reaction conversion.
Ch a r t 1
Non lin ea r Effect of th e Kin etic Resolu tion of
En ol Ester Ep oxid es. Asymmetric amplification has
been widely observed in asymmetric catalysis.7,8 High ee’s
can be obtained for the reaction products when catalysts
with marginal ee’s are employed. The nonlinear effects
of the BINOL-Ti system for various asymmetric pro-
cesses have been reported.5 To gain more insight about
the catalyst structure in this resolution, nonlinear effects
were then investigated. Table 3 lists the results for the
kinetic resolution of 1-(benzoyloxy)-1,2-epoxy-4,4-dim-
ethylcyclohexane (17) using the BINOL-Ti catalyst with
different ee’s. As shown in Table 3, high-resolution
efficiency can still be obtained with low ee’s of the
catalyst, suggesting that some asymmetric amplification
exists in this resolution.
Although nonlinear effects have been extensively stud-
ied in asymmetric catalysis,7 such studies for kinetic
results (Table 1). To test the effect of the ester group on
the reaction, a number of esters with different steric and
electronic properties were investigated. As shown in
Table 2 (entries 1-10), good reactivity and selectivity
were obtained in all cases except for acetate (entry 10),
suggesting that a wide range of esters can be tolerated.
This resolution process could also be extended to five-,
seven-, and eight-membered-ring systems (Table 2, en-
(7) For reviews see: (a) Noyori, R.; Kitamura, M. Angew. Chem.,
Int. Ed. 1991, 30, 49. (b) Avalos, M.; Babiano, R.; Cintas, P.; J imenez,
J . L.; Palacios, J . C. Tetrahedron: Asymmetry 1997, 8, 2997. (c) Girard,
C.; Kagan, H. B. Angew. Chem., Int. Ed. 1998, 37, 2922.
(8) (a) Ismagilov, R. F. J . Org. Chem. 1998, 63, 3772. (b) Luukas, T.
O.; Girard, C.; Fenwick, D. R.; Kagan, H. B. J . Am. Chem. Soc. 1999,
121, 9299. (c) J ohnson, D. W., J r.; Singleton, D. A. J . Am. Chem. Soc.
1999, 121, 9307. (d) Blackmond, D. G. J . Am. Chem. Soc. 2001, 123,
545. (e) Kagan, H. B. Synlett 2001, 888.

Resolution of Racemic Enol Ester Epoxides
J . Org. Chem., Vol. 67, No. 9, 2002 2833
a
Ta ble 2. Kin etic Resolu tion of En ol Ester Ep oxid es Ca ta lyzed by [(R)-BINOL]2-Ti(OiP r )4
a
All reactions were carried out with substrate (0.5 mmol) and catalyst (5 mol %) in solvent (2 mL) at 0 °C unless otherwise noted.
The conversion was determined by 1H NMR of the crude reaction mixture after workup. c Isolated yield. The relative rate was calculated
b
d
using the equation krel ) kf/ks ) ln[(1 - C)(1 - ee)]/ln[(1 - C)(1 + ee)], where C is the conversion and ee is the fractional enantiomeric
g
excess of the recovered starting material.13 e 2.5 mol % catalyst used. f 10 mol % catalyst used. 20 mol % catalyst used. For entry 17,
h
the reaction was carried out at room temperature. The conversion was calculated by applying the ee’s of the recovered starting material
i
and the product to the following equation: ee(SM)/ee(product) ) C/(1 - C). Enantioselectivity was determined by chiral HPLC (Chiralcel
j
k
OD). Enantioselectivity was determined by chiral HPLC (Chiralpak AD). Enantioselectivity was determined by chiral HPLC (Chiralcel
OJ ). l Enantioselectivity was determined by 1H NMR shift analysis with Eu(hfc)3. The absolute configurations were assigned by comparing
m
the measured optical rotations with the epoxides obtained by asymmetric epoxidation.3 The absolute configurations were assigned by
n
comparing HPLC chromatograms with the enol ester epoxide obtained by asymmetric epoxidation3 and the R-benzoyloxy ketone obtained
from a stereospecific rearrangement of the chiral enol ester epoxide.3 o The absolute configurations were determined by comparing the
p
measured optical rotations with the authentic samples prepared from commercially available (R,R)-1,2-trans-cyclohexanediol. The absolute
configurations were assigned on the basis of the epoxide configurations and the mechanistic deduction from the transformations of Scheme
q
5. The absolute configuration was determined by comparing the measured optical rotation with the reported one.3
resolutions are relatively few. A nonlinear effect for the
kinetic resolution of sulfoxides was reported by Uemura
and co-workers in 1993.5h In their studies, the positive
nonlinear effect was illustrated by the plots of the ee of
the sulfoxide and krel (kf/ks) versus the ee of BINOL.
Recently, various mathematical analyses for the kinetic
resolution using enantioimpure catalysts have been
reported by Ismagilov, Kagan, Singleton, and Black-
mond.8 For example, in the model presented by J ohnson
and Singleton, a plot of DKEE versus the ee of the
catalyst is used, where DKEE stands for differential
kinetic enantiomeric enhancement (DKEE ) (krel - 1)/
(krel + 1)). The nonlinear effect is defined for a process if
DKEE does not vary linearly with the ee of the catalyst.
This model was then applied to the kinetic resolution of
enol ester epoxide 17. As shown in Figure 1, a positive
nonlinear effect was indeed displayed when the DKEE
was plotted against the ee of the catalyst. A similar effect
was also observed for two additional substrates, 1-(ben-
zoyloxy)-1,2-epoxycyclohexane and 1-(benzoyloxy)-1,2-

2834 J . Org. Chem., Vol. 67, No. 9, 2002
Feng et al.
Ta ble 3. Stu d ies of th e Non lin ea r Effect of th e Kin etic
Resolu tion of En ol Ester Ep oxid e 17 Ca ta lyzed by
Sch em e 4
a
(BINOL)2-Ti(OiP r )4
catalyst
ee, %
recovered
SM ee, %c
product
ee, %c
entry
conv, %b
krel
1
2
3
4
5
6
7
8
9
100
90
70
50
40
30
20
10
0
52
54
54
56
57
69
65
82
67
98
99
98
95
93
92
68
42
0
92
84
87
72
68
40
33
10
0
91
61
50
25
19
7
4
2
1
a
All reactions were carried out with substrate (0.25 mmol) and
catalyst (5 mol %) in solvent (1 mL) at 0 °C. The BINOL ligand
with different ee’s was prepared by mixing (R)-BINOL with (()-
tion reaction was quenched at the desired conversion, the
chiral catalyst was removed by a rapid filtration through
a plug of silica gel. The resulting mixture was subse-
quently treated with 10% p-TsOH at room temperature
for 20 min,10 at which time the epoxide was completely
consumed and the 2-(benzoyloxy)cyclohexanone was then
isolated in 78% overall yield with 93% ee (Scheme 4). The
ee could be further enhanced to >99% by a single
recrystallization from Et2O. As shown in Scheme 4, this
sequential process could also be extended to other
substrates. The overall result is that a racemic enol ester
epoxide can be completely converted into an enantio-
merically enriched R-acyloxy ketone using a catalytic
amount of a chiral Lewis acid followed by a catalytic
amount of an achiral protic acid.11
b
BINOL. The ligand to metal ratio was 2.2:1. The conversion was
determined by 1H NMR of the crude reaction mixture after
workup. c Enantioselectivity was determined by chiral HPLC
(Chiralpak AD).
In summary, we have shown that the kinetic resolution
of racemic enol ester epoxides using a chiral Lewis acid
catalyst is feasible. High resolution efficiency was ob-
tained for a number of cyclic systems. Both enantiomeri-
cally enriched enol ester epoxides and R-acyloxy ketones
can be obtained. A positive nonlinear effect was observed
in this resolution, suggesting that multiple ligands are
F igu r e 1. Plot of DKEE against ee (%) of BINOL: (A)
1-(benzoyloxy)-1,2-epoxy-4,4-dimethylcyclohexane; (B) 1-(ben-
zoyloxy)-1,2-epoxycyclohexane; (C) 1-(benzoyloxy)-1,2-epoxy-
cycloheptane.
(10) In the case of the five-membered ring, the transformation was
carried out at 0 °C for 6 min. Higher temperature and longer reaction
time could lead to partial racemization of 2-(benzoyloxy)cyclopen-
tanone.
(11) For examples of synthesis of enantiomerically enriched hydroxy
ketones and their derivatives see: (a) Enders, D.; Bhushan, V.
Tetrahedron Lett. 1988, 29, 2437. (b) Davis, F. A.; Sheppard, A. C.;
Chen, B.-C.; Haque, M. S. J . Am. Chem. Soc. 1990, 112, 6679. (c)
DeNinno, M. P.; Perner, R. J .; Lijewski, L. Tetrahedron Lett. 1990,
31, 7415. (d) Davis, F. A.; Chen, B.-C. Chem. Rev. 1992, 92, 919. (e)
Hashiyama, T.; Morikawa, K.; Sharpless, K. B. J . Org. Chem. 1992,
57, 5067. (f) Reddy, D. R.; Thornton, E. R. J . Chem. Soc., Chem.
Commun. 1992, 172. (g) Duh, T.-H.; Wang, Y.-F.; Wu, M.-J . Tetrahe-
dron: Asymmetry 1993, 4, 1793. (h) D’Accolti, L.; Detomaso, A.; Fusco,
C.; Rosa, A.; Curci, R. J . Org. Chem. 1993, 58, 3600. (i) Chang, S.;
Heid, R. M.; J acobsen, E. N. Tetrahedron Lett. 1994, 35, 669. (j) Gala,
D.; DiBenedetto, D. J .; Clark, J . E.; Murphy, B. L.; Schumacher, D.
P.; Steinman, M. Tetrahedron Lett. 1996, 37, 611. (k) Adam, W.; Diaz,
M. T.; Fell, R. T.; Saha-Moller, C. R. Tetrahedron: Asymmetry 1996,
7, 2207. (l) Fududa, T.; Katsuki, T. Tetrahedron Lett. 1996, 37, 4389.
(m) Naemura, K.; Wakebe, T.; Hirose, K.; Tobe, Y. Tetrahedron:
Asymmetry 1997, 8, 2585. (n) Adam, W.; Fell, R. T.; Stegmann, V. R.;
Saha-Moller, C. R. J . Am. Chem. Soc. 1998, 120, 708. (o) Adam, W.;
Fell, R. T.; Saha-Moller, C. R.; Zhao, C.-G. Tetrahedron: Asymmetry
1998, 9, 397. (p) Kajiro, H.; Mitamura, S-i.; Mori, A.; Hiyama, T.
Tetrahedron: Asymmetry 1998, 9, 907. (q) Demir, A. S.; Hamamci, H.;
Tanyeli, C.; Akhmedov, I. M.; Doganel, F. Tetrahedron: Asymmetry
1998, 9, 1673. (r) Kajiro, H.; Mitamura, S.; Mori, A.; Hiyama, T.
Tetrahedron Lett. 1999, 40, 1689. (s) Adam, W.; Saha-Moller, C. R.;
Zhao, C.-G. J . Org. Chem. 1999, 64, 7492.
epoxycycloheptane (Figure 1). These nonlinear effects
suggest that the active catalyst contains two or more
BINOL ligands.9
Com p lete Con ver sion of Ra cem ic En ol Ester
Ep oxid es in to Op tica lly Active r-Acyloxy Keton es.
In the current kinetic resolution, the remaining epoxide
and the rearranged R-acyloxy ketone had the same
configuration at C2, since the rearrangement of the enol
ester epoxide occurred with inversion of configuration
(Scheme 3). It would be possible that a high yield (>50%)
of enantiomerically enriched R-acyloxy ketone could be
obtained if the proper achiral acid is used to convert the
remaining epoxide into the R-acyloxy ketone with reten-
tion of configuration.3 This hypothesis was tested with
1-(benzoyloxy)-1,2-epoxycyclohexane (1). After the resolu-
(9) Caution needs to be taken with regard to this nonlinear effect
due to the possible kinetic partitioning effect (for a detailed discussion,
see ref 8d).

Resolution of Racemic Enol Ester Epoxides
J . Org. Chem., Vol. 67, No. 9, 2002 2835
g) (pretreated with 5% Et3N in hexane and thoroughly washed
with hexane to remove Et3N before use). The silica gel was
further washed with Et2O (10 mL). The combined ether
solutions were concentrated to give a residue. After it was
dried under vacuum for 1 h, the mixture was dissolved in CH2-
Cl2 (4 mL) followed by addition of anhydrous p-TsOH (8.6 mg,
0.05 mmol). After it was stirred at room temperature for 20
min, the mixture was rapidly filtered through a plug of silica
gel (ca. 10 g) (without Et3N treatment) followed by washing
with ether (2 × 10 mL). The combined solutions were concen-
trated to give (R)-2-(benzoyloxy)cyclohexanone as a white solid
(0.0845 g, 78% yield, 93% ee) (Scheme 4).
interacting with the Lewis acid. These results are also
supported by observation that a 2/1 ligand/metal ratio
gave the best results. By taking advantage of the
mechanistic duality of the acid-catalyzed enol ester
epoxide rearrangement, a racemic enol ester epoxide can
be completely converted into an enantiomerically en-
riched R-acyloxy ketone by sequential treatment with a
catalytic amount of a chiral Lewis acid and a catalytic
amount of an achiral protic acid.12
Exp er im en ta l Section
1-(Ben zoyloxy)-1,2-ep oxycycloh exa n e (Ta ble 2, En tr y
1).3,15,16 [R]25 ) -36.3° (c 0.49, CHCl3) (97% ee).
D
The general experimental information is similar to those
recently described.14
1-((p-Meth ylben zoyl)oxy)-1,2-epoxycycloh exan e (Table
2, En tr y 2).3 [R]25 ) -30.7° (c 0.45, CHCl3) (99% ee).
D
Rep r esen ta tive P r oced u r es for Kin etic Resolu tion . A.
P r ep a r a tion of En a n tiom er ica lly En r ich ed En ol Ester
Ep oxid e. (Note: the reaction is moisture sensitive and needs
to be carried out under rigorously anhydrous conditions.) To
a solution of (R)-(+)-binaphthol (7.9 mg, 0.0275 mmol) in CH2-
Cl2 (0.5 mL) was added a solution of Ti(OiPr)4 (3.8 uL, 3.6 mg,
0.0125 mmol) in CH2Cl2 (0.5 mL). After it was stirred at room
temperature for 5-10 h, the reaction mixture was concen-
trated and dried using a vacuum pump (ca. 0.5 h). The catalyst
was then dissolved in Et2O (1 mL) and cooled in an ice bath.
To this was added a solution of racemic 1-(benzoyloxy)-1,2-
epoxycyclohexane (0.109 g, 0.5 mmol) in Et2O (1 mL). After it
was stirred at 0 °C for 1 h, the reaction mixture was quenched
with saturated NaHCO3 (4 mL) and poured into a mixture of
ether (20 mL) and saturated NaHCO3 (10 mL). The organic
layer was washed with water and brine, dried (Na2SO4) (ca.
10 min), and then rapidly filtered through a plug of silica gel
(ca. 10 g) (pretreated with 5% Et3N in hexane and washed
thoroughly with hexane to remove Et3N before use). The silica
gel was further washed with Et2O (10 mL). The combined ether
solutions were concentrated to give a mixture of (R)-1-
(benzoyloxy)-1,2-epoxycyclohexane and (R)-2-(benzoyloxy)cy-
clohexanone. After a sample was taken for the determination
of the conversion and ee’s, the mixture was purified by flash
chromatography (silica gel was pretreated with 5% Et3N) using
hexane-CH2Cl2-EtOAc (84:10:6) as eluent to afford (R)-1-
(benzoyloxy)-1,2-epoxycyclohexane as a colorless oil (0.0365 g,
34% yield, 97% ee) (Table 2, entry 1) (Note: for the isolation
of the enol ester epoxides, Et3N is used to buffer the silica gel
to prevent any decomposition and rearrangement of the
epoxides. Under these isolation conditions, the R-acyloxy
ketones undergo partial racemization. Therefore, a better way
to prepare these R-acyloxy ketones is through kinetic resolu-
tion, followed by conversion, as illustrated in the following
procedure.)
B. P r ep a r a tion of En a n tiom er ica lly En r ich ed R-Acy-
loxy Keton e. (Note: the reaction is moisture sensitive and
needs to be carried out under rigorously anhydrous conditions.)
To a solution of (R)-(+)-binaphthol (7.9 mg, 0.0275 mmol) in
CH2Cl2 (0.5 mL) was added a solution of Ti(OiPr)4 (3.8 uL, 3.6
mg, 0.0125 mmol) in CH2Cl2 (0.5 mL). After it was stirred at
room temperature for 5-10 h, the reaction mixture was
concentrated and dried using a vacuum pump (ca. 0.5 h). The
catalyst was then dissolved in Et2O (1 mL) and cooled in an
ice bath. To this was added a solution of racemic 1-(benzoy-
loxy)-1,2-epoxycyclohexane (0.109 g, 0.5 mmol) in Et2O (1 mL).
After it was stirred at 0 °C for 1 h, the reaction mixture was
quenched with saturated NaHCO3 (4 mL) and poured into a
mixture of ether (20 mL) and saturated NaHCO3 (10 mL). The
organic layer was washed with water and brine, dried (Na2-
SO4), and rapidly filtered through a plug of silica gel (ca. 10
1-((m-Meth ylben zoyl)oxy)-1,2-epoxycycloh exan e (Table
2, En tr y 3). [R]25 ) -31.3° (c 0.44, CHCl3) (97% ee). IR
D
(NaCl): 1725 cm-1. 1H NMR: δ 7.86-7.79 (m, 2H), 7.40-7.28
(m, 2H), 3.41 (m, 1H), 2.39 (s, 3H), 2.34 (dt, J ) 14.4, 6.6 Hz,
1H), 2.22 (dt, J ) 14.4, 6.3 Hz, 1H), 2.07-1.86 (m, 2H), 1.58-
1.49 (m, 2H), 1.48-1.38 (m, 2H). 13C NMR: δ 165.5, 138.4,
134.3, 130.4, 129.5, 128.5, 127.1, 83.6, 59.6, 28.4, 25.0, 21.5,
20.6, 19.1. Anal. Calcd for C14H16O3: C, 72.38; H, 6.95.
Found: C, 72.39; H, 6.96.
1-((p-Ch lor oben zoyl)oxy)-1,2-epoxycycloh exa n e (Ta ble
2, En tr y 4).3 [R]25 ) -28.9° (c 0.67, CHCl3) (99% ee).
D
1-((p-Nitr oben zoyl)oxy)-1,2-ep oxycycloh exa n e (Ta ble
2, En tr y 5).3 [R]25 ) -29.8° (c 0.45, CHCl3) (96% ee).
D
1-((3,5-Dim et h ylb en zoyl)oxy)-1,2-ep oxycycloh exa n e
(Ta ble 2, En tr y 6). [R]25 ) -33.1° (c 0.36, CHCl3) (99% ee).
D
1
IR (NaCl): 1725 cm-1. H NMR: δ 7.64 (s, 2H), 7.20 (s, 1H),
3.41 (m, 1H), 2.35 (s, 6H), 2.33 (m, 1H), 2.21 (dt, J ) 14.1, 6.3
Hz, 1H), 2.02-1.95 (m, 2H), 1.59-1.50 (m, 2H), 1.47-1.40 (m,
2H). 13C NMR: δ 168.7, 138.4, 135.3, 129.4, 127.7, 83.6, 59.7,
28.4, 24.9, 21.3, 20.5, 19.0. Anal. Calcd. for C15H18O3: C, 73.13;
H, 7.37. Found: C, 73.21; H, 7.17.
1-((2,6-Dim et h ylb en zoyl)oxy)-1,2-ep oxycycloh exa n e
(Ta ble 2, En tr y 7). [R]25 ) -12.0° (c 0.75, CHCl3) (98% ee).
D
IR (NaCl): 1736 cm-1
.
1H NMR: δ 7.18 (t, J ) 7.2 Hz, 1H),
7.01 (d, J ) 7.2 Hz, 2H), 3.44 (m, 1H), 2.43 (m, 1H), 2.33 (s,
6H), 2.30 (m, 1H), 2.10-1.90 (m, 2H), 1.60-1.52 (m, 2H), 1.49-
1.41 (m, 2H). 13C NMR: δ 168.6, 135.0, 129.7, 128.1, 127.8,
83.7, 59.5, 28.4, 24.9, 20.6, 19.9, 19.1. Anal. Calcd for
C
15H18O3: C, 73.13; H, 7.37. Found: C, 73.32; H, 7.22.
1-(1-Naph th oyloxy)-1,2-epoxycycloh exan e (Table 2, En -
tr y 8). [R]25 ) -42.3° (c 0.22, CHCl3) (98% ee). IR (NaCl):
D
1
1720 cm-1. H NMR: δ 8.98 (d, J ) 9.0 Hz, 1H), 8.25 (dd, J )
7.2, 1.0 Hz, 1H), 8.04 (d, J ) 8.4 Hz, 1H), 7.88 (d, J ) 8.4 Hz,
1H), 7.63 (m, 1H), 7.58-7.45 (m, 2H), 3.52 (m, 1H), 2.44 (dt,
J ) 14.1, 6.6 Hz, 1H), 2.31 (dt, J ) 14.1, 6.3 Hz, 1H), 2.14-
1.94 (m, 2H), 1.65-1.54 (m, 2H), 1.53-1.43 (m, 2H) 13C NMR:
δ 166.2, 134.3, 131.7, 131.2, 128.8, 128.3, 126.5, 125.9, 125.8,
124.6, 83.8, 59.7, 28.5, 25.0, 20.6, 19.1. Anal. Calcd for
C
17H16O3: C, 76.09; H, 6.01. Found: C, 76.18; H, 6.09.
1-(P iva loyloxy)-1,2-ep oxycycloh exa n e (Ta ble 2, En tr y
9).3,15 [R]25 ) -42.4° (c 0.50, CHCl3) (97% ee).
D
1-Acetoxy-1,2-ep oxycycloh exa n e (Ta ble 2, En tr y 10).3,15
1-(Benzoyloxy)-1,2-epoxy-4,4-dimethylcyclohexane (Table
2, En tr y 11).3 [R]25 ) -16.4° (c 0.47, CHCl3) (98% ee).
D
4-(Ben zoyloxy)-3,4-ep oxytetr a h yd r o-4H-p yr a n (Ta ble
2, En tr y 12). [R]25 ) -51.2° (c 0.60, CHCl3) (99% ee). IR
D
(NaCl): 1728 cm-1. 1H NMR: δ 8.04 (m, 2H), 7.60 (tt, J ) 7.2,
1.5 Hz, 1H), 7.46 (m, 2H), 4.09 (dd, J ) 13.5, 2.4 Hz, 1H), 3.98
(d, J ) 13.5 Hz, 1H), 3.67 (m, 2H), 3.48 (d, J ) 2.4 Hz, 1H),
2.55 (dt, J ) 14.4, 6.0 Hz, 1H), 2.32 (dt, J ) 14.4, 5.4 Hz, 1H)
13C NMR: δ 133.9, 130.0, 129.1, 128.7, 81.0, 65.0, 62.6, 56.9,
29.3. Anal. Calcd for C12H12O4: C, 65.43; H, 5.50. Found: C,
65.30; H, 5.37.
(12) For leading reviews on dynamic resolution see: (a) Noyori, R.;
Tokunaga, M.; Kitamura, M. Bull. Chem. Soc. J pn. 1995, 68, 36. (b)
Ward, R. S. Tetrahedron: Asymmetry 1995, 6, 1475. (c) Caddick, S.;
J enkins, K. Chem. Soc. Rev. 1996, 25, 447. (d) Strecher, H.; Faber, K.
Synthesis 1997, 1, 1.
(15) Amos, R. A.; Katzenellenbogen, J . A. J . Org. Chem. 1977, 42,
2537.
(13) Kagan, H. B.; Fiaud, J . C. Top. Stereochem. 1988, 18, 249.
(14) Wang, Z.-X.; Tu, Y.; Frohn, M.; Zhang, J .-R.; Shi, Y. J . Am.
Chem. Soc. 1997, 119, 11224.
(16) (a) Adam, W.; Hadjiarapoglou, L.; J ager, V.; Seidel, B. Tetra-
hedron Lett. 1989, 30, 4223. (b) Adam, W.; Hadjiarapoglou, L.; J ager,
V.; Klicic, J .; Seidel, B.; Wang, X. Chem. Ber. 1991, 124, 2361.

2836 J . Org. Chem., Vol. 67, No. 9, 2002
Feng et al.
1-(Ben zoyloxy)-1,2-ep oxycyclop en ta n e (Ta ble 2, En tr y
1H NMR: δ 8.91 (d, J ) 8.1 Hz, 1H), 8.27 (dd, J ) 7.2, 1.2 Hz,
1H), 8.02 (d, J ) 8.1 Hz, 1H), 7.87 (d, J ) 7.8 Hz, 1H), 7.64-
7.47 (m, 3H), 5.53 (m, 1H), 2.64-2.40 (m, 3H), 2.18-1.62 (m,
5H). 13C NMR: δ 204.7, 166.8, 133.9, 133.6, 131.5, 130.6, 128.6,
127.9, 127.0, 126.4, 126.0, 124.7, 77.3, 41.0, 33.4, 27.4, 24.0.
Anal. Calcd for C17H16O3: C, 76.09; H, 6.01. Found: C, 75.99;
H, 6.00.
13).3 [R]25 ) -31.7° (c 0.55, CHCl3) (98% ee).
D
1-(Ben zoyloxy)-1,2-ep oxycycloh ep ta n e (Ta ble 2, En tr y
14).3 [R]25 ) -32.8° (c 0.50, CHCl3) (98% ee).
D
1-(Ben zoyloxy)-1,2-ep oxycycloocta n e (Ta ble 2, En tr y
15).3 [R]25 ) +9.3° (c 0.31, CHCl3) (98% ee).
D
1-(Ben zoyloxy)-1,2-epoxytetr ah ydr on aph th alen e (Table
2-(P iva loyloxy)cycloh exa n on e (Ta ble 2, En tr y 9).3,19
2, En tr y 16).3 [R]25 ) -227.0° (c 0.20, CHCl3) (99% ee).
D
[R]25 ) +47.4° (c 0.49, CHCl3) (92% ee).
D
2-(Ben zoyloxy)-1,3-d ip h en yl-1,2-ep oxyp r op a n e (Ta ble
2, En tr y 17). IR (NaCl): 1729 cm-1. 1H NMR: δ 7.78 (m, 2H),
7.50 (m, 1H), 7.39-7.26 (m, 9H), 7.21-7.16 (m, 3H), 3.95 (s,
1H), 3.71 (d, J ) 14.7 Hz, 1H), 3.52 (d, J ) 14.7 Hz, 1H). 13C
NMR: δ 164.7, 133.5, 133.0, 130.3, 129.8, 129.2, 128.7, 128.5,
128.4, 128.1, 127.4, 127.1, 88.2, 62.4, 39.4. Anal. Calcd for
2-Acetoxycycloh exa n on e (Ta ble 2, En tr y 10).3,18
2-(Ben zoyloxy)-4,4-d im eth ylcycloh exa n on e (Ta ble 2,
En tr y 11).3 [R]25 ) +18.4° (c 0.45, CHCl3) (92% ee).
D
3-(Ben zoyloxy)tetr a h yd r o-4H-p yr a n -4-on e (Ta ble 2,
En tr y 12). [R]25 ) +12.0° (c 0.75, CHCl3) (97% ee). IR
D
(NaCl): 1724 cm-1. 1H NMR: δ 8.07 (dd, J ) 8.4, 1.5 Hz, 2H),
7.59 (m, 1H), 7.45 (m, 2H), 5.52 (ddd, J ) 10.8, 6.9, 1.0 Hz,
1H), 4.46 (ddd, J ) 10.8, 6.9, 1.5 Hz, 1H), 4.32 (ddt, J ) 11.2,
7.2, 1.5 Hz, 1H), 3.73 (m, 2H), 2.85 (m, 1H), 2.60 (m, 1H). 13C
NMR: δ 200.6, 165.2, 133.7, 130.1, 129.2, 128.6, 74.2, 70.7,
68.7, 42.4. Anal. Calcd for C12H12O4: C, 65.43; H, 5.50.
Found: C, 65.21; H, 5.49.
C
22H18O3: C, 79.97; H, 5.50. Found: C, 80.17; H, 5.55.
2-(Ben zoyloxy)cycloh exa n on e (Ta ble 2, En tr y 1).3,17,18
[R]25 ) +18.4° (c 0.43, CHCl3) (93% ee).
D
2-((p-Meth ylben zoyl)oxy)cycloh exa n on e (Ta ble 2, En -
tr y 2).3 [R]25 ) +9.7° (c 0.48, CHCl3) (91% ee).
D
2-((m -Meth ylben zoyl)oxy)cycloh exa n on e (Ta ble 2, En -
tr y 3). [R]25 ) +13.2° (c 0.41, CHCl3) (92% ee). IR (NaCl):
D
2-(Ben zoyloxy)cyclop en ta n on e (Ta ble 2, En tr y 13).
1718 cm-1. 1H NMR: δ 7.92-7.86 (m, 2H), 7.40-7.30 (m, 2H),
5.41 (dd, J ) 11.4, 6.0 Hz, 1H), 2.62-2.42 (m, 3H), 2.40 (s,
3H), 2.19-1.58 (m, 5H). 13C NMR: δ 204.4, 165.8, 138.2, 136.6,
134.0, 130.4, 128.3, 127.1, 77.1, 41.0, 33.4, 27.4, 24.0, 21.5.
Anal. Calcd for C14H16O3: C, 72.38; H, 6.95. Found: C, 72.51;
H, 6.84.
[R]25D ) -58.1° (c 0.73, CHCl3) (92% ee). IR (NaCl): 1758, 1712
cm-1 1H NMR: δ 8.06 (m, 2H), 7.57 (m, 1H), 7.44 (m, 2H),
.
5.31 (m, 1H), 2.61-2.28 (m, 3H), 2.22-1.85 (m, 3H). 13C
NMR: δ 212.3, 165.8, 133.4, 130.0, 129.5, 128.5, 76.3, 35.2,
28.8, 17.5. Anal. Calcd for C12H12O3: C, 70.57; H, 5.92.
Found: C, 70.72; H, 6.02.
2-((p-Ch lor oben zoyl)oxy)cycloh exa n on e (Ta ble 2, En -
2-(Ben zoyloxy)cycloh eptan on e (Table 2, En tr y 14).3,17,18
tr y 4).3 [R]25 ) +15.0° (c 0.46, CHCl3) (89% ee).
D
[R]25 ) -36.2° (c 0.60, CHCl3) (87% ee).
D
2-((p-Nitr oben zoyl)oxy)cycloh exa n on e (Ta ble 2, En tr y
2-(Ben zoyloxy)cyclooct a n on e (Ta ble 2, E n t r y 15).3,18
5).3 [R]25 ) +23.5° (c 0.43, CHCl3) (94% ee).
[R]25 ) -33.9° (c 0.31, CHCl3) (99% ee).
D
D
2-(Ben zoyloxy)-1-tetr a lon e (Ta ble 2, En tr y 16).3
1-(Ben zoyloxy)-1,3-d ip h en yl-2-p r opa n on e (Ta ble 2, En -
tr y 17). IR (NaCl): 1723 cm-1. 1H NMR: δ 8.09 (m, 2H), 7.56
(m, 1H), 7.49-7.38 (m, 7H), 7.29-7.19 (m, 3H), 7.06 (m, 2H),
6.30 (s, 1H), 3.80 (s, 2H). 13C NMR: δ 201.4, 165.9, 133.6,
133.3, 133.0, 130.1, 129.8, 129.6, 129.4, 129.3, 128.7, 128.6,
128.5, 127.2, 80.8, 46.0. Anal. Calcd for C22H18O3: C, 79.97;
H, 5.50. Found: C, 80.22; H, 5.62.
2-((3,5-Dim eth ylben zoyl)oxy)cycloh exa n on e (Ta ble 2,
En tr y 6). [R]25 ) +6.5° (c 0.87, CHCl3) (92% ee). IR (NaCl):
D
1717 cm-1. 1H NMR: δ 7.71 (s, 2H), 7.19 (s, 1H), 5.40 (dd, J )
12.0, 6.3 Hz, 1H), 2.60-2.36 (m, 3H), 2.35 (s, 6H), 2.20-1.57
(m, 5H). 13C NMR: δ 204.5, 166.0, 138.1, 134.9, 129.6, 127.6,
77.0, 41.0, 33.4, 27.5, 24.0, 21.3. Anal. Calcd for C15H18O3: C,
73.13; H, 7.37. Found: C, 72.91; H, 7.25.
2-((2,6-Dim eth ylben zoyl)oxy)cycloh exa n on e (Ta ble 2,
En tr y 7). [R]25 ) +23.0° (c 1.12, CHCl3) (85% ee). IR (NaCl):
D
1
1727 cm-1. H NMR: δ 7.18 (t, J ) 7.6 Hz, 1H), 7.04 (d, J )
Ack n ow led gm en t. We are grateful to the generous
financial support from the National Science Foundation
CAREER Award program (Grant No. CHE-9875497),
the General Medical Sciences of the National Institutes
of Health (Grant No. GM59705-03), the Arnold and
Mabel Beckman Foundation, the Camille and Henry
Dreyfus Foundation, the Alfred P. Sloan Foundation,
DuPont, Eli Lilly, GlaxoWellcome, and Merck.
7.6 Hz, 2H), 5.42 (dd, J ) 12.0, 6.0 Hz, 1H), 2.63-2.32 (m,
3H), 2.42 (s, 6H), 2.24-1.55 (m, 5H). 13C NMR: δ 204.0, 168.8,
135.5, 133.2, 129.6, 127.7, 77.0, 41.0, 33.3, 27.3, 24.0, 20.0.
Anal. Calcd for C15H18O3: C, 73.13; H, 7.37. Found: C, 73.33;
7.14.
2-(1-Na p h th oyloxy)cycloh exa n on e (Ta ble 2, En tr y 8).
[R]25D ) +29.4° (c 0.50, CHCl3) (95% ee). IR (NaCl): 1713 cm-1
.
(17) Goldblum, A.; Mechoulam, R. J . Chem. Soc., Perkin Trans. 1
1977, 1889.
J O0108515
(18) Rubottom, G. M.; Mott, R. C.; J uve, H. D., J r. J . Org. Chem.
1981, 46, 2717.
(19) Cummins, C. H.; Coates, R. M. J . Org. Chem. 1983, 48, 2070.