Enantioselective synthesis and stereoselective rearrangements of enol ester epoxides

Article abstract of DOI:10.1021/jo001593z

Enol esters can be epoxidized with high enantioselectivities using the fructose-derived chiral ketone 1 as catalyst and Oxone as oxidant. A detailed study of enantiomerically enriched enol ester epoxides has revealed that the acid-catalyzed rearrangement can proceed through two distinct pathways, one with retention of configuration and the other with inversion. The competition between the two pathways is highly dependent upon the nature of the acid catalyst. A strong acid favors retention of configuration and a weak acid favors inversion of configuration. Under thermal conditions, these epoxides rearrange highly stereoselectively with inversion of configuration. Either enantiomer of an α-acyloxy ketone can be formed from one enantiomer of an enol ester epoxide by judicious choice of reaction conditions.

Full text of DOI:10.1021/jo001593z

1818
J . Org. Chem. 2001, 66, 1818-1826
En a n tioselective Syn th esis a n d Ster eoselective Rea r r a n gem en ts of
En ol Ester Ep oxid es
Yuanming Zhu, Lianhe Shu, Yong Tu, and Yian Shi*
Department of Chemistry, Colorado State University, Fort Collins, Colorado 80523
yian@lamar.colostate.edu
Received November 9, 2000
Enol esters can be epoxidized with high enantioselectivities using the fructose-derived chiral ketone
1 as catalyst and Oxone as oxidant. A detailed study of enantiomerically enriched enol ester epoxides
has revealed that the acid-catalyzed rearrangement can proceed through two distinct pathways,
one with retention of configuration and the other with inversion. The competition between the two
pathways is highly dependent upon the nature of the acid catalyst. A strong acid favors retention
of configuration and a weak acid favors inversion of configuration. Under thermal conditions, these
epoxides rearrange highly stereoselectively with inversion of configuration. Either enantiomer of
an R-acyloxy ketone can be formed from one enantiomer of an enol ester epoxide by judicious choice
of reaction conditions.
Enol ester epoxides are synthetically useful intermedi-
We have found that chiral enol ester epoxides can be
efficiently prepared by asymmetric epoxidation of enol
esters using the fructose-derived ketone 1 as catalyst and
Oxone as oxidant. Furthermore these chiral epoxides can
undergo stereospecific rearrangements under both acidic
and thermal conditions to give enantiomerically enriched
R-acyloxy ketones (Scheme 1). Herein we report the
detailed study of both the synthesis and rearrangement
of chiral enol ester epoxides.4
ates. Among many synthetic transformations, these
epoxides can readily rearrange to R-acyloxy ketones or
aldehydes under thermal or acidic conditions.1,2 When
enol ester epoxides are chiral, enantiomerically enriched
R-acyloxy carbonyl intermediates could be derived. Asym-
metric oxidation of prochiral enol derivatives has been
well studied, and a variety of chiral R-hydroxy carbonyl
compounds can effectively be obtained.3 However, the
formation of chiral enol ester epoxides by asymmetric
epoxidation of enol esters has been elusive, presumably
due to their instability under many reaction conditions.
Asym m etr ic Ep oxid a tion of En ol Ester s. Our ep-
oxidation studies started with the enol acetate and enol
benzoate of cyclohexanone (Table 1, entries 1 and 2).
Subjecting these enol esters to the in situ epoxidation
conditions5 led to a smooth formation of product.6 In both
cases the epoxides were found to be relatively stable
under the reaction conditions and could be isolated
through a Et3N-buffered silica gel column. A 93% ee was
obtained for the epoxide of the enol benzoate (Table 1,
entry 2) while the enol acetate gave a lower ee (Table 1,
entry 1). Altering the electronics of the benzoate did not
lead to a large effect on the ee of the epoxide (Table 1,
entries 2-6). Enol pivaloate gave a similar ee to the
benzoate (Table 1, entry 7).
* 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 and thermal 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) Shine, H. J .; Hunt, G. E. J . Am. Chem. Soc. 1958, 80,
2434. (f) House, H. O.; Thompson, H. W. J . Org. Chem. 1961, 26, 3729.
(g) Williamson, K. L.; J ohnson, W. S. J . Org. Chem. 1961, 26, 4563.
(h) Nambara, T.; Fishman, J . J . Org. Chem. 1962, 27, 2131. (i) Draper,
A. L.; Heilman, W. J .; Schaeffer, W. E.; Shine, H. J .; Shoolery, J . N. J .
Org. Chem. 1962, 27, 2727. (j) Riehl, J .-J .; Lehn, J .-M.; Hemmert, F.
Bull. Soc. Chim. Fr. 1963, 224. (k) Rhone, J . R.; Huffman, M. N.
Tetrahedron Lett. 1965, 1395. (l) Williamson, K. L.; Coburn, J . I.; Herr,
M. F. J . Org. Chem. 1967, 32, 3934. (m) McDonald, R. N.; Tabor, T. E.
J . Am. Chem. Soc. 1967, 89, 6573. (n) Smith, S. C.; Heathcock, C. H.
J . Org. Chem. 1992, 57, 6379.
(3) For leading references on nonenzymatic synthesis of enantio-
merically enriched hydroxyketones 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) Davis, F. A.; Chen, B.-C. Chem. Rev. 1992, 92,
919. (d) Hashiyama, T.; Morikawa, K.; Sharpless, K. B. J . Org. Chem.
1992, 57, 5067. (e) Reddy, D. R.; Thornton, E. R. J . Chem. Soc., Chem.
Commun. 1992, 172. (f) D’Accolti, L.; Detomaso, A.; Fusco, C.; Rosa,
A.; Curci, R. J . Org. Chem. 1993, 58, 3600. (g) Chang, S.; Heid, R. M.;
J acobsen, E. N. Tetrahedron Lett. 1994, 35, 669. (h) Fududa, T.;
Katsuki, T. Tetrahedron Lett. 1996, 37, 4389. (i) Adam, W.; Fell, R.
T.; Stegmann, V. R.; Saha-Moller, C. R. J . Am. Chem. Soc. 1998, 120,
708.
Encouraged by these results, a number of cyclic and
acyclic enol esters were subsequently prepared and
epoxidized to further test the generality of the process
(Table 1, entries 8-14). In all cases the reactions were
relatively clean, the epoxides were isolated in good yields,
(4) For a preliminary report of a portion of this work, see: (a) Zhu,
Y.; Tu, Y.; Yu, H.; Shi, Y. Tetrahedron Lett. 1998, 39, 7819. (b) Zhu,
Y.; Manske, K. J .; Shi, Y. J . Am. Chem. Soc. 1999, 121, 4080.
(5) (a) Tu, Y.; Wang, Z.-X.; Shi, Y. J . Am. Chem. Soc. 1996, 118,
9806. (b) Wang, Z.-X.; Tu, Y.; Frohn, M.; Zhang, J .-R.; Shi, Y. J . Am.
Chem. Soc. 1997, 119, 11224. (c) Frohn, M.; Dalkiewicz, M.; Tu, Y.;
Wang, Z.-X.; Shi, Y. J . Org. Chem. 1998, 63, 2948. (d) Wang, Z.-X.;
Shi, Y. J . Org. Chem. 1998, 63, 3099. (e) Cao, G.-A.; Wang, Z.-X.; Tu,
Y.; Shi, Y. Tetrahedron Lett. 1998, 39, 4425.
(6) For examples of racemic epoxidation of enol esters using dim-
ethyldioxirane, see: (a) Adam, W.; Hadjiarapoglou, L.; J ager, V.; Seidel,
B. Tetrahedron Lett. 1989, 30, 4223. (b) Adam, W.; Hadjiarapohlou,
L.; J ager, V.; Klicic, J .; Seidel, B.; Wang, X. Chem. Ber. 1991, 124,
2361. (c) Reference 2n.
10.1021/jo001593z CCC: $20.00 © 2001 American Chemical Society
Published on Web 02/15/2001

Synthesis and Rearrangements of Enol Ester Epoxides
J . Org. Chem., Vol. 66, No. 5, 2001 1819
Sch em e 1
Ta ble 1. Asym m etr ic Ep oxid a tion of En ol Ester s by
Keton e 1a
Sch em e 2
Sch em e 3
(Table 1, entries 2-8, 10, and 11), while the five-
membered ring gave lower ee (Table 1, entry 9).
The absolute configurations of some of the epoxides
(Table 1, entries 10, 12-14) were determined by hydro-
lyzing the epoxides to R-hydroxy ketones and comparing
the measured optical rotations of the resulting R-hydroxy
ketones with reported ones (for details see Table 1). The
results in all these cases were consistent with the spiro
reaction mode (Scheme 2).5
Acid -Ca ta lyzed Rea r r a n gem en t of Ch ir a l En ol
Ester Ep oxid es. Enol ester epoxides can rearrange to
R-acyloxy ketones or aldehydes under acidic or thermal
conditions.1,2 Investigations of these rearrangements have
largely been carried out on conformationally rigid
steroids,2a,b,d,g,h,k,l,n and the mechanistic conclusions have
been based on the analysis of the diastereomeric prod-
ucts. Most of the reported acid-catalyzed rearrangements
occur with retention of configuration (Scheme 3).2b,h,k,l
While the proposed mechanisms have provided reason-
able explanations for the observed stereochemistry in
these cases, some uncertainty remains.7 The availability
of enantiomerically enriched enol ester epoxides provided
us an opportunity to further study the factors involved
in the rearrangements of these epoxides under acidic
conditions with the aim of developing a route to enan-
tiomerically enriched R-acyloxy ketones.3
a
All reactions were carried out at 0 °C (bath temperature) with
substrate (1 equiv), ketone (0.3 equiv), Oxone (1.38 equiv) and
K2CO3 (5.8 equiv) in organic solvent (15 mL) and aqueous buffer
solution (10 mL). The organic solvent used was either CH3CN
(entries 9, 11, and 13) or CH3CN-DMM (1/2, v/v) (entries 1-8,
10, 12, and 14). For entries 2, 9, 11, 12, and 13, 0.05 M Na2B4O7‚10
H2O of EDTA (4 × 10-4 M) was used as buffer; for others, AcOH-
b
0.1 M K2CO3 (1/250, v/v) was used as buffer. The epoxides were
purified on silica gel column (silica gel was pretreated with Et3N)
by flash chromatography and gave satisfactory spectroscopic
characterization. c Enantioselectivity was determined by 1H NMR
d
shift analysis of epoxide products directly with Eu(hfc)3. Enan-
tioselectivity was determined by chiral HPLC (Chiracel OD).
e Enantioselectivity was determined by chiral HPLC (Chiracel OJ ).
f Enantioselectivity was determined by chiral HPLC (Chiralpak
AD). The absolute configuration was tentatively assumed by
analogy based on the spiro reaction mode. The epoxides were
g
h
hydrolyzed under basic conditions to R-hydroxy ketones, and the
absolute configurations were determined by comparing the mea-
sured optical rotations of the R-hydroxy ketones with the reported
ones (for entry 10, see ref 13; for entry 12 see ref 14; for entries
13 and 14 see refs 3b and 3d, respectively).
(7) For example, it was observed that treating an enol ester epoxide
of epiandrosterone acetate with silicic acid at 50 °C for 17 h led to the
formation of a mixture R and â epimeric 16-acetoxy ketones with a
ratio of 1.8:1 in a 16.7% isolated yield (see ref 2d). The R isomer resulted
from a rearrangement with retention of configuration, and the â isomer
resulted from a rearrangement with inversion. On the basis of the
observation that the R and â isomers did not undergo isomerization
under the reaction conditions, it was suggested that these two isomers
came from two competing reactions. However, it is not clear whether
these two reactions were induced by acid alone or both acid and heat
since the reaction was carried out at 50 °C.
and the enantioselectivities were high in most cases.
Among the cyclic substrates, it was found that six-,
seven-, and eight-membered rings gave the highest ee’s

1820 J . Org. Chem., Vol. 66, No. 5, 2001
Zhu et al.
Sch em e 4
uration, thereby reducing the ee. To investigate the
existence of the competing pathway, more Lewis acids
were tested.9 Strikingly, it was found that the S isomer
(inverted product) actually became the major product
when certain Lewis acids were utlized (Table 2, entries
12-19). Good enantioselectivities (80-91% ee) were
obtained with YbCl3, ErCl3, AlMe3, and silica gel10 (Table
2, entries 12, 15, 16, and 19).
Ta ble 2. Effects of Differ en t Acid Ca ta lysts on th e
Rea r r a n gem en t of 1-Ben zoyloxy-1,2-ep oxycycloh exa n e
(5)a
The results presented in Table 2 clearly indicate that
there are two distinct pathways involved in the acid-
catalyzed rearrangement of enol ester epoxides, leading
to two different enantiomers. Although a full understand-
ing of the factors controlling this competition has not
been attained, the acidity of the catalyst seems to play
an important role. For example, when Yb(OTf)3 was used
as the catalyst, the R enantiomer of the rearranged
product was obtained in 66% ee (Table 2, entry 11). On
the other hand, when a notably weaker Lewis acid YbCl3
was used, the S enantiomer was obtained in 82% ee
(Table 2, entry 12). Pathways a and b outlined in Scheme
5 provide plausible mechanisms for the results. In
pathway a, the complexation of a strong acid to the
epoxide oxygen of 3 leads to cleavage of C1-O bond to
form carbocation intermediate 8. Subsequent acyloxy
migration with retention of configuration gives acyloxy
ketone 4. In pathway b, the complexation of a weak acid
to 3 weakens both epoxide bonds, facilitating acyloxy
migration with inversion of configuration (9) to give
acyloxy ketone ent-4.11,12
entry
acid
t (min) ee % (5)b ee % (6)b yield (%)c
1
2
3
4
5
6
7
8
p-TsOH
H2SO4
Sn(OTf)2
TMSOTf
Sc(OTf)3
FeCl3
TiF4
BF3‚Et2O
AlCl3
La(OTf)3
Yb(OTf)3
YbCl3
ZnBr2
VCl3(THF)3
ErCl3
10
3
93
93
93
93
93
93
93
93
92
93
92
93
93
93
90
91
91
91
92
90 (R)
87 (R)
85 (R)
82 (R)
80 (R)
71 (R)
69 (R)
67 (R)
26 (R)
15 (R)
66 (R)
82 (S)
12 (S)
15 (S)
80 (S)
87 (S)
67 (S)
30 (S)
91 (S)
89
57
84
90
74
63
44
52
74
88
67
76
48
58
73
85
54
41
83
10
10
10
10
5
1500
1
40
5
90
10
300
90
5
17
10
720
9
10
11
12
13
14
15
16
17
18
19
AlMe3
AlEt2Cl
AlEtCl2
silica gel
a
All reactions were carried out in nitromethane under anhy-
drous conditions at room temperature using 10 mol % acid
catalysts except entry 19 where 5-10 times (by weight) silica gel
(Davisil 35-60 mesh, pH 7.0) was used. Epoxide 5 was freshly
Among other possible pathways, it was also conceivable
that enol ester epoxide 5 could rearrange to (S)-6 with a
net inversion of configuration via a hydride shift mech-
anism (pathway c) (Scheme 6). To further differentiate
between pathways b and c, 1-benzoyloxy-1,2-epoxy-4,4-
dimethylcyclohexane (10) was then investigated (Scheme
7). As indicated in Scheme 7, two different structural
isomers 11 and 12 would arise from the two pathways.
Enol ester epoxide 10 was then treated with YbCl3,
AlMe3, and silica gel. In all these cases, compound 11
was formed predominately as judged by the NMR analy-
sis, suggesting that pathway c is not the major operating
pathway at least for enol ester epoxide 10.
b
made and stored at -20 °C to avoid decomposition. The enan-
tiomeric excess was determined by HPLC (Chiracel OD). The
absolute configuration of 6 was determined by comparing HPLC
chromatograms with the authentic sample prepared from com-
mercially available (R,R)-1,2-trans-cyclohexanediol. c Isolated yield.
Our studies started with (R,R)-1-benzoyloxy-1,2-ep-
oxycyclohexane (5) as a test substrate (Scheme 4). Treat-
ing epoxide 5 with a protic acid such as p-TsOH led to a
facile rearrangement with retention of configuration
(Table 2, entry 1). The reaction was complete within 10
min as monitored by TLC, and the product showed only
a 3% decrease in ee compared to the starting epoxide.8
In addition to protic acids, Lewis acids were also inves-
tigated as catalysts for this rearrangement. It was found
that the enantiomeric excess of the product varied
dramatically with the Lewis acids. For example, 85% and
80% ee were obtained, respectively, for the product when
Sn(OTf)2 and Sc(OTf)3 were used (Table 2, entries 3 and
5), but only 26% and 15% ee were obtained when AlCl3
and La(OTf)3 were used (Table 2, entries 9 and 10). The
low ee obtained with AlCl3 and La(OTf)3 was initially
thought to be due to the racemization of the rearranged
benzoyloxy ketone via enolization under the acidic reac-
tion conditions. However, in a control experiment, only
a 3% decrease of the ee was observed upon stirring
benzoyloxy ketone (R)-6 (91% ee) in nitromethane with
La(OTf)3 for 0.5 h. The results suggested that in the acid-
catalyzed rearrangement there was a competing pathway
which gave rise to the S isomer via inversion of config-
The discovery of the two different rearrangement
pathways prompted us to investigate more substrates to
test the generality. Of particular interest was the pos-
sibility of generating either enantiomer of an acyloxy
ketone in high ee from a single enantiomerically enriched
enol ester epoxide under mild conditions. As shown in
Table 3, p-TsOH proved to be an effective catalyst for
rearrangement via pathway a for a variety of epoxides,
giving products with retention of configuration in high
stereospecificity. In most cases, the resulting R-acyloxy
ketones were crystalline, and the enantiomeric excess
could be further enhanced by recrystallization. To test
the generality of the rearrangement via pathway b, silica
gel, YbCl3, and AlMe3 were used (Table 3). In most cases
the isomer with inverted configuration was the major
product, however, in two cases (Table 3, entries 7 and 8)
the rearrangement proceeded with retention of configu-
ration. The preference for pathway a with these benzylic
(8) Studies showed that the enantiomeric excess of the rearranged
product 6 was somewhat solvent dependent. Among a few solvents
tested, nitromethane was shown to be the best. The other solvents
tested include CHCl3 (83% ee), CH2Cl2 (83% ee), CH3CN (80% ee), Et2O
(80% ee), C6H6 (79% ee), DMF (no reaction).
(9) No rearrangement occurred with Lewis acids such as MgBr2,
Ti(OiPr)4, Zr(OEt)4, Pd(OAc)2, Cu(OAc)2, LaCl3, PrCl3.
(10) For examples of silica gel catalyzed rearrangements, see refs
2a, b, and d. Both inversion and retention of configuration were
reported.

Synthesis and Rearrangements of Enol Ester Epoxides
J . Org. Chem., Vol. 66, No. 5, 2001 1821
Sch em e 5
Sch em e 6
at this temperature for 2.0 h gave the rearranged product
with 11% isolated yield. It was found that the rearrange-
ment could be dramatically facilitated by raising the
temperature. For example, heating epoxide 13 at 153 °C
in a sealed tube for 2.0 h, the rearranged product was
obtained in 59% isolated yield with 86% ee. When the
reaction temperature was further raised to 195 °C, the
rearrangement was complete after 0.5 h and gave a
quantitative yield of the product (Table 4, entry 12). More
importantly, the product ee was determined to be 90%,
showing only a 4% decrease in ee compared with the
starting epoxide. It seems that shorter reaction time as
a result of higher reaction temperature is important to
obtain the high product ee. Further studies showed that
the rearranged product had the S configuration. As
anticipated, the rearrangement proceeded with inversion
of configuration. Upon demonstrating that thermal rear-
rangement of epoxide 13 proceeded with inversion of
configuration with high stereoselectivity, the process was
then extended to a wide range of epoxides (Table 4). For
those epoxides that can readily rearrange, the reaction
can be performed in a vial under N2 (Table 4, entries
1-3). However, for many other epoxides, the rearrange-
ment needs to be carried out at higher temperature and
in a sealed tube to obtain high stereoselectivity (Table
4, entry 5 vs 6). As shown in Table 4, all the epoxides
including benzylic epoxides (Table 4, entries 12-14)
underwent the rearrangement with a clean inversion of
configuration. Good yields and high ee’s were obtained
by careful control of the reaction temperature and time.15
This thermal rearrangement in combination with the
Sch em e 7
Sch em e 8
epoxides is probably due to a stabilized carbocation
intermediate 8.
Th er m a l R ea r r a n gem en t of Ch ir a l E n ol E st er
Ep oxid es. As shown above, in many cases the acid-
catalyzed rearrangement of chiral enol ester epoxides
could lead to the formation of R-acyloxy ketones with
either retention or inversion of configurations. In the case
of retention of configuration, all the examples presented
in Table 3 worked well. However, in the case of inversion
of configuration, the results were somewhat substrate
dependent. For example, with benzylic epoxides (Table
3, entries 7 and 8), the rearrangement with inversion of
configuration could not become the major pathway with
any of the acids tested.
It has been shown that rearrangements of steroid enol
ester epoxides under thermal conditions proceed diaste-
reoselectively via intramolecular migration of the acyloxy
group with inversion of configuration at the carbon to
which the acyloxy group migrates.2a,g,n The stereoselec-
tivity of thermal rearrangement demonstrated on these
systems prompted us to investigate the thermal rear-
rangement of chiral enol ester epoxides with the aim of
achieving the rearrangement with inversion of configu-
ration for a wider range of substrates.
(11) While the acidity of the catalyst is an important factor affecting
the competition of the two pathways, the size and the coordination
number of the Lewis acid could also be important. Full elucidation of
these factors is difficult at present.
(12) To test whether the rearrangements proceed intermolecularly
or intramolecularly, crossover experiments were carried out using a
mixture of 1-acetoxy-1,2-epoxycyclohexane and 1-benzoyloxy-1,2-ep-
oxycycloheptane as substrates under acidic conditions (p-TsOH, YbCl3,
AlMe3, silica gel) (Scheme 5). In the case of p-TsOH, small amounts of
crossover products were detected by GC and 1H NMR. The amounts
of these products were found to be concentration dependent (ca 6.8%
at substrate concentration of 0.64
M and ca. 1.7% at substrate
concentration of 0.018 M). In the cases of YbCl3, AlMe3, and silica gel,
the crossover products were found to be minimal (less than 0.5% at
substrate concentration of 0.64 M and less than 0.2% at substrate
concentration of 0.018 M). All of these results suggest that the acid-
catalyzed rearrangements proceed predominantly in an intramolecular
fashion, particularly for pathway b. Further experiments with enan-
tiomerically enriched enol ester epoxides showed that the enantiose-
lectivities of the rearranged products were not affected by the substrate
concentrations.
(13) (a) Nicolosi, G.; Patti, A.; Piattelli, M.; Sanfilippo, C. Tetrahe-
dron Asymmetry 1995, 6, 519. (b) Carnell, A. J .; Iacazio, G.; Roberts,
S. M.; Willetts, A. J . Tetrahedron Lett. 1994, 35, 331.
(14) Naemura, K.; Wakebe, T.; Hirose, K.; Tobe, Y. Tetrahedron
Asymmetry 1997, 8, 2585.
Our studies started with (1S,2R)-1-acetoxy-1-phenyl-
1,2-epoxypropane (13) (94% ee) as a test substrate
(Scheme 8). The thermal rearrangement was initially
performed in a sealed tube at 120 °C. Heating the epoxide
(15) It was found that the product ee was also affected by the purity
of the starting epoxide.

1822 J . Org. Chem., Vol. 66, No. 5, 2001
Ta ble 3. Exa m p les of Acid -Ca ta lyzed Rea r r a n gem en ts of En ol Ester Ep oxid esa
Zhu et al.
a
All reactions were carried out at room temperature with 10 mol % p-TsOH (dried by azeotropic removal of its hydrate) in dry CH3NO2,
or 5-10 times (by weight) silica gel (Davisil 35-60 mesh, pH 7.0) in CH3NO2, or 10 mol % YbCl3 in CH2Cl2, or 10 mol % AlMe3 in
d
CH3NO2 unless otherwise noted. b 100 mol % acid catalyst was used. c 20 mol % acid catalyst was used. Enantioselectivity was determined
by chiral HPLC (Chiralcel OD) except entries 3 and 4 where enantioselectivity was determined by 1H NMR shift analysis with Eu(hfc)3
or by chiral HPLC (Chiralpak AD), respectively. The values in parentheses are the ee’s after recrystallization. e The absolute configurations
were determined by comparing HPLC chromatograms (entries 1 and 2) or 1H NMR shift analysis using Eu(hfc)3 (entry 3) with the authentic
sample prepared from commercially available (R,R)-1,2-trans-cyclohexanediol. f The R-acyloxy ketones were hydrolyzed to R-hydroxy ketones,
and the absolute configurations were determined by comparing the measured optical rotations of the R-hydroxy ketones with the literature
h
(for entry 5 see ref 13; for entry 8 see ref 14). g The absolute configuration was tentatively assigned by analogy. The absolute configuration
i
j
was determined by comparing the measured optical rotation with the literature (see ref 3a). Isolated yield. Conversion determined by
k
the 1H NMR of the crude reaction mixture. No reaction was found with silica gel.
acid-catalyzed rearrangements allows the formation of
either enantiomer of R-acyloxy ketone from one enanti-
omer of an enol ester epoxide (Scheme 9).
In summary, we have shown that enol esters can be
epoxidized with high ee’s using the fructose-derived chiral
ketone 1 as catalyst and Oxone as oxidant. The avail-
ability of the enantiomerically enriched enol ester ep-
oxides provided us the opportunities to study their
rearrangement under acidic and thermal conditions. Our
studies have shown that the acid-catalyzed rearrange-
ment of these epoxides operates through two distinct
pathways, one with retention of configuration and the
other with inversion. Acidity of the catalyst is one
important factor, with strong acids favoring retention of
configuration and weak acids favoring inversion. Under
thermal conditions, these epoxides rearrange highly
stereoselectively with inversion of configuration. In ad-
dition to the mechanistic significance, the current study

Synthesis and Rearrangements of Enol Ester Epoxides
J . Org. Chem., Vol. 66, No. 5, 2001 1823
Ta ble 4. Exa m p les of Th er m a l Rea r r a n gem en ts of En ol Ester Ep oxid es
a
b
Rearrangements were performed neat under N2. Rearrangements were performed neat under N2 in a sealed tube. c Enantioselectivity
was determined by chiral HPLC (Chiralcel OD). Enantioselectivity was determined by chiral HPLC (Chiralpak AD). e Enantioselectivity
was determined by 1H NMR shift analysis with Eu(hfc)3. f The absolute configurations were determined by comparing HPLC chromatograms
(entries 1-6) or 1H NMR shift analysis using Eu(hfc)3 (entries 7 and 8) with the authentic samples prepared from commercially available
d
g
(R,R)-1,2-trans-cyclohexanediol. The R-acyloxy ketones were hydrolyzed to R-hydroxy ketones, and the absolute configurations were
determined by comparing the measured optical rotations of the R-hydroxy ketones with the literature (for entry 10, see ref 13; for entry
13, see refs 3b and 3d; for entry 14, see ref 14). The absolute configuration was tentatively assigned by analogy. i The absolute configuration
h
j
was determined by comparing the measured optical rotation with the literature (see ref 3a). Isolated yield.
Oxone occasionally varies with different batches). All glass-
ware used for the epoxidation was carefully washed to be free
of any trace metals which catalyze the decomposition of Oxone.
Elemental analyses were performed by M-H-W Laboratories,
Phoenix, AZ.
Sch em e 9
P r ep a r a tion of En ol Ester s.
Meth od A.16 To a mixture of cyclohexanone (9.82 g, 100
mmol) and benzoic anhydride (90%, 28.9 g, 115 mmol) in
hexane (200 mL) was added HClO4 (0.2 mL). Upon stirring at
room temperature for 2 h, the mixture was filtered to remove
the formed solids. The filtrate was washed with 1 N NaOH
solution (100 mL), saturated NaHCO3 solution (2 × 100 mL),
and brine (2 × 100 mL), dried (Na2SO4), filtered, concentrated,
and purified by flash chromatography (hexanes-ether, 50:1,
v/v) to afford 1-benzoyloxy-1-cyclohexene6b,17 as a colorless
also provides the flexibility to synthesize either enanti-
omer of R-acyloxy ketone from one enantiomer of an enol
ester epoxide by judicious choice of reaction conditions.
liquid (11.9 g, 59%). IR (NaCl) 1730, 1690 cm-1 1H NMR δ
;
8.07 (m, 2H), 7.58 (m, 1H), 7.45 (m, 2H), 5.50 (m, 1H), 2.27
(m, 2H), 2.17 (m, 2H), 1.80 (m, 2H), 1.66 (m, 2H); 13C NMR δ
Exp er im en ta l Section
(16) Whitlock, H. W., J r.; Overman, L. E. J . Org. Chem. 1969, 34,
1962.
(17) Goldblum, A.; Mechoulam, R. J . Chem. Soc., Perkin Trans. 1
1977, 1889.
Gen er a l Meth od s. Oxone was purchased from Aldrich (it
has been found that the oxidation activity of the purchased

1824 J . Org. Chem., Vol. 66, No. 5, 2001
Zhu et al.
165.3, 148.8, 133.3, 130.3, 130.1, 128.6, 114.5, 27.2, 23.9, 22.9,
22.0.
Ep oxid e. [R]25D ) -23.6 (c 0.49, CHCl3) (90% ee). IR (NaCl)
1720, 1606, 1257 cm-1; 1H NMR δ 7.98 (m, 2H), 6.91 (m, 2H),
3.86 (s, 3H), 3.41 (m, 1H), 2.33 (dt, J ) 14.4, 6.9 Hz, 1H), 2.22
(dt, J ) 14.4, 6.3 Hz, 1H), 2.06-1.90 (m, 2H), 1.58-1.38 (m,
4H); 13C NMR δ 165.2, 163.9, 132.1, 121.9, 113.9, 83.5, 59.6,
55.6, 28.4, 24.9, 20.5, 19.0. Anal. Calcd for C14H16O4: C, 67.72;
H, 6.49. Found: C, 67.73; H, 6.34.
Meth od B.18 To a stirred suspension of KH (washed with
pentane) (2.4 g, 60.0 mmol) in DME (25 mL) under N2 at -5
°C was added a solution of cyclohexanone (4.9 g, 50 mmol) in
dry DME (5 mL). The resulting enolate solution was then
added by syringe to a mixture of p-toluoyl chloride (11.5 g,
75.0 mmol) and DMAP (0.30 g, 2.5 mmol) in DME (15 mL)
over a period of 10 min at room temperature. Upon stirring
for another 20 min at r.t., the mixture was poured into ice-
water, extracted with hexane, washed with saturated NaHCO3
and brine, dried (Na2SO4), filtered, concentrated, and purified
by flash chromatography (silica gel column was pretreated
with Et3N, 2-4% EtOAc in hexane was used as eluent) to
afford 1-(p-methylbenzoyloxy)cyclohexene as a colorless semi-
solid (5.72 g, 53%). IR (NaCl) 1729, 1677 cm-1; 1H NMR δ 7.96
(d, J ) 6.3 Hz, 2H), 7.24 (d, J ) 6.3 Hz, 2H), 5.48 (m, 1H),
2.42 (s, 3H), 2.25 (m, 2H), 2.17 (m, 2H), 1.79 (m, 2H), 1.66 (m,
2H); 13C NMR δ 165.3, 148.7, 143.9, 130.0, 129.2, 127.5, 114.3,
27.2, 24.0, 23.0, 22.0, 21.9.
1-(p-Ch lor oben zoyloxy)-1,2-ep oxycycloh exa n e (Ta ble
1, en tr y 5).
En ol Ester (Method B). IR (NaCl) 1731, 1684, 1590, 1272
cm-1; 1H NMR δ 8.00 (m, 2H), 7.43 (m, 2H), 5.50 (m, 1H), 2.24
(m, 2H), 2.17 (m, 2H), 1.80 (m, 2H), 1.66 (m, 2H); 13C NMR δ
164.3, 148.6, 139.7, 131.4, 128.9, 128.7, 114.6, 27.1, 23.9, 22.9,
21.9.
Ep oxid e. [R]25 ) -26.4 (c 1.1, CHCl3) (90% ee); IR (NaCl)
D
1
1728, 1594 cm-1; H NMR δ 7.92 (m, 2H), 7.37 (m, 2H), 3.38
(m, 1H), 2.32 (dt, J ) 14.1, 6.9 Hz, 1H), 2.17 (dt, J ) 14.1, 6.1
Hz, 1H), 2.03-1.87 (m, 2H), 1.51-1.37 (m, 4H); 13C NMR δ
164.5, 140.1, 131.3, 129.0, 128.1, 83.9, 59.5, 28.3, 24.8, 20.5,
19.0. Anal. Calcd for C13H13ClO3: C, 61.79; H, 5.19. Found:
C, 61.81; H, 5.47.
A Rep r esen ta tive Ep oxid a tion P r oced u r e. To an ice-
cold mixture of 1-benzoyloxy-1-cyclohexene (0.134 g, 0.67
mmol), 10 mL of CH3CN-DMM (v/v, 1/2), 6.7 mL of buffer
(0.05 M Na2B4O7 in 4 × 10-4 M aqueous Na2EDTA), Bu4NHSO4
(0.009 g, 0.027 mmol), and ketone 1 (0.0516 g, 0.20 mmol) were
added a solution of Oxone (0.567 g, 0.92 mmol) in 4.3 mL of
aqueous Na2EDTA (4 × 10-4 M) and a solution of K2CO3 (0.567
g, 3.87 mmol) in 4.3 mL of water simultaneously through two
syringes via syringe pump over a period of 1.5 h. The reaction
was quenched with hexane and brine. The mixture was
extracted with hexane, washed with brine, dried (Na2SO4),
filtered, concentrated, and purified by flash chromatography
(silica gel was buffered with Et3N, using 5% ether in hexane
as eluent) to afford 1-benzoyloxy-1,2-epoxycyclohexane6a,b,19 as
a colorless oil (0.12 g, 82% yield, 93% ee) (Table 1, entry 2).
1-(p-Nitr oben zoyloxy)-1,2-ep oxycycloh exa n e (Ta ble 1,
en tr y 6).
En ol Ester 17 (Method B). IR (NaCl) 1737, 1690, 1527 cm-1
;
1H NMR δ 8.30 (m, 2H), 8.24 (m, 2H), 5.54 (m, 1H), 2.27 (m,
2H), 2.19 (m, 2H), 1.82 (m, 2H), 1.68 (m, 2H); 13C NMR δ 163.3,
150.7, 148.6, 135.7, 131.1, 123.7, 115.0, 26.9, 23.8, 22.8, 21.8.
Ep oxid e. [R]25D ) -30.6 (c 0.33, CHCl3) (90% ee); IR (NaCl)
1714, 1527 cm-1 1H NMR δ 8.30 (dt, J ) 8.8, 1.8 Hz, 2H),
;
8.20 (dt, 8.8, 1.8 Hz, 2H), 3.45 (m, 1H), 2.40 (dt, J ) 14.2, 6.6
Hz, 1H), 2.22 (dt, J ) 14.2, 6.3 Hz, 1H), 2.00 (m, 2H), 1.61-
1.40 (m, 4H); 13C NMR δ 163.3, 150.8, 134.8, 130.9, 123.6, 84.3,
59.3, 28.1, 24.7, 20.4, 18.9. Anal. Calcd for C13H13NO5: C,
59.31; H, 4.98; N, 5.32. Found: C, 59.09; H, 5.18; N, 5.26.
1-P iva loyloxy-1,2-ep oxycycloh exa n e (Ta ble 1, en tr y 7).
[R]25 ) -39.2 (c 0.53, CHCl3); IR (NaCl) 1728, 1267 cm-1; 1H
D
En ol Ester (Method A). IR (NaCl) 1746, 1690 cm-1 1H
;
NMR δ 8.00 (d, J ) 7.8 Hz, 2H), 7.54 (t, J ) 7.8 Hz, 1H), 7.40
(t, J ) 7.8 Hz, 2H), 3.39 (m, 1H), 2.32 (dt, J ) 14.3, 6.9 Hz,
1H), 2.20 (dt, J ) 14.3, 6.2 Hz, 1H), 2.10-1.86 (m, 2H), 1.58-
1.36 (m, 4H); 13C NMR δ 165.4, 133.6, 129.9, 129.6, 128.6, 83.7,
59.5, 28.3, 24.8, 20.5, 19.0. Anal. Calcd for C13H14O3: C, 71.54;
H, 6.46. Found: C, 71.82; H, 6.31.
NMR δ 5.29 (m, 1H), 2.07 (m, 4H), 1.70 (m, 2H), 1.57 (m, 2H),
1.20 (s, 9H); 13C NMR δ 177.3, 148.7, 113.8, 38.9, 27.3, 26.8,
23.8, 22.8, 21.9.
Ep oxid e.19 [R]25 ) -40.5 (c 0.60, CHCl3) (91% ee); IR
D
(NaCl) 1740, 1142 cm-1; 1H NMR δ 3.25 (m, 1H), 2.22 (dt, J )
14.1, 6.8 Hz, 1H), 2.03 (dt, J ) 14.1, 6.3 Hz, 1H), 1.92 (m, 2H),
1.62-1.32 (m, 4H), 1.19 (s, 9H); 13C NMR δ 177.6, 83.1, 59.5,
38.8, 28.2, 27.0, 24.8, 20.4, 18.9. Anal. Calcd for C11H18O3: C,
66.64; H, 9.15. Found: C, 66.67; H, 9.50.
1-Acetoxy-1,2-ep oxycycloh exa n e (Ta ble 1, en tr y 1).19
En ol Ester . The enol ester was prepared by the method
described in ref 19. IR (NaCl) 1751, 1686 cm-1; 1H NMR δ 5.36
(m, 1H), 2.11 (s, 3H), 2.20-2.05 (m, 4H), 1.74 (m, 2H), 1.59
(m, 2H); 13C NMR δ 169.7, 148.6, 114.2, 27.0, 23.8, 22.8, 21.9,
21.3.
1-Ben zoyloxy-1,2-epoxy-4,4-dim eth ylcycloh exan e (Table
1, en tr y 8).
;
En ol Ester (Method A). IR (NaCl) 1724, 1685 cm-1 1H
Ep oxid e. [R]25D ) -51.9 (c 1.12, CHCl3) (75% ee); IR (NaCl)
NMR δ 8.08 (m, 2H), 7.58 (m, 1H), 7.45 (m, 2H), 5.40 (m, 1H),
2.27 (m, 2H), 1.95 (m, 2H), 1.55 (t, J ) 6.6 Hz, 2H), 1.02 (s,
6H); 13C NMR δ 165.3, 147.8, 133.2, 130.2, 130.0, 128.5, 113.3,
37.9, 35.7, 29.0, 28.2, 24.9.
1
1747, 1231 cm-1; H NMR δ 3.30 (ddd, J ) 2.7, 1.8, 0.9 Hz,
1H), 2.24 (dtd, J ) 14.5, 6.6, 0.9 Hz, 1H), 2.09 (dt, J ) 14.5,
6.3 Hz, 1H), 2.06 (s, 3H), 1.92 (m, 2H), 1.51-1.32 (m, 4H); 13
C
NMR δ 169.7, 83.0, 59.4, 28.1, 24.8, 21.3, 20.4, 18.9. Anal.
Calcd for C8H12O3: C, 61.52; H, 7.74. Found: C, 61.72; H, 8.11.
1-(p-Meth ylben zoyloxy)-1,2-ep oxycycloh exa n e (Ta ble
1, en tr y 3). [R]25D ) -30.6 (c 0.51, CHCl3) (90% ee). IR (NaCl)
Ep oxid e. [R]25D ) -15.1 (c 0.45, CHCl3) (95% ee); IR (NaCl)
1724 cm-1 1H NMR δ 8.04 (m, 2H), 7.58 (m, 1H), 7.44 (m,
;
2H), 3.41 (d, J ) 5.1 Hz, 1H), 2.33 (m, 2H), 1.86 (ddd, J )
15.9, 5.1, 2.1 Hz, 1H), 1.62 (d, J ) 15.9 Hz, 1H), 1.42 (ddd, J
) 13.5, 11.4, 5.7 Hz, 1H), 1.29 (m, 1H), 1.16 (s, 3H), 0.93 (s,
3H); 13C NMR δ 165.2, 133.6, 129.9, 129.5, 128.6, 83.7, 58.9,
38.4, 33.2, 31.2, 28.4, 26.9, 24.2. Anal. Calcd for C15H18O3: C,
73.13; H, 7.37. Found: C, 73.16; H, 7.18.
1
1725, 1611, 1269 cm-1; H NMR δ 7.91 (d, J ) 8.1 Hz, 2H),
7.23 (d, J ) 8.1 Hz, 2H), 3.41 (m, 1H), 2.40 (s, 3H), 2.34 (dt, J
) 14.1, 6.9 Hz, 1H), 2.22 (dt, J ) 14.1, 6.6 Hz, 1H), 2.07-1.89
(m, 2H), 1.61-1.49 (m, 2H), 1.49-1.38 (m, 2H); 13C NMR δ
165.5, 144.3, 130.0, 129.3, 126.8, 83.5, 59.5, 28.4, 24.9, 21.8,
20.5, 19.0. Anal. Calcd for C14H16O3: C, 72.39; H, 6.94.
Found: C, 72.23; H, 7.19.
1-Ben zoyloxy-1,2-ep oxycyclop en ta n e (Ta ble 1, en tr y
9).
En ol Ester 17 (Method A). IR (NaCl) 1736, 1665, 1267 cm-1
;
1-(p-Meth oxyben zoyloxy)-1,2-epoxycycloh exan e (Table
1, en tr y 4).
1H NMR δ 8.08 (m, 2H), 7.59 (tt, J ) 7.2, 1.5 Hz, 1H), 7.46
(m, 2H), 5.56 (dt, J ) 4.2, 2.1 Hz, 1H), 2.58 (m, 2H), 2.44 (m,
2H), 2.02 (m, 2H); 13C NMR δ 164.4, 151.3, 133.4, 130.1, 129.9,
128.6, 113.5, 31.2, 28.9, 21.3.
En ol Ester (Method B). IR (NaCl) 1723, 1685 cm-1 1H
;
NMR δ 8.00 (dt, J ) 9.0, 2.4 Hz, 2H), 6.93 (dt, J ) 9.0, 2.4 Hz,
2H), 5.45 (tt, J ) 3.9, 1.5 Hz, 1H), 3.83 (s, 3H), 2.23 (m, 2H),
2.14 (m, 2H), 1.76 (m, 2H), 1.63 (m, 2H); 13C NMR δ 165.0,
163.7, 148.8, 132.1, 122.7, 114.3, 113.8, 55.6, 27.2, 23.9, 22.9,
22.0.
Ep oxid e. [R]25D ) -26.8 (c 0.41, CHCl3) (80% ee); IR (NaCl)
1
1722, 1272 cm-1; H NMR δ 8.02 (m, 2H), 7.57 (m, 1H), 7.43
(m, 2H), 3.78 (s, 1H), 2.43 (dd, J ) 13.2, 8.4 Hz, 1H), 2.11 (ddd,
J ) 13.2, 9.9, 9.0 Hz, 1H), 1.93 (m, 2H), 1.73 (m, 1H), 1.54 (m,
1H); 13C NMR δ 165.2, 133.8, 130.1, 129.3, 128.7, 90.0, 62.8,
28.4, 26.3, 20.2. Anal. Calcd for C12H12O3: C, 70.57; H, 5.92.
Found: C, 70.35; H, 6.00.
(18) Riehl, J . J .; Ladjama, D. Synthesis 1979, 504.
(19) Amos, R. A.; Katzenellenbogen, J . A. J . Org. Chem. 1977, 42,
2537.

Synthesis and Rearrangements of Enol Ester Epoxides
J . Org. Chem., Vol. 66, No. 5, 2001 1825
1-Ben zoyloxy-1,2-ep oxycycloh ep ta n e (Ta ble 1, en tr y
10).
(s, 3H); 13C NMR δ 168.7, 146.8, 135.7, 134.5, 128.8, 127.8,
124.9, 117.0, 116.9, 21.3.
En ol Ester 17 (Method A). IR (NaCl) 1725, 1691, 1269 cm-1
1H NMR δ 8.06 (m, 2H), 7.57 (tt, J ) 7.3, 1.7 Hz, 1H), 7.45
(m, 2H), 5.60 (t, J ) 6.4 Hz, 1H), 2.46 (m, 2H), 2.16 (m, 2H),
1.61-1.80 (m, 6H); 13C NMR δ 165.6, 153.5, 133.2, 130.3, 130.0,
128.5, 118.4, 33.4, 31.2, 27.2, 25.5, 25.4.
;
Ep oxid e.6b [R]25 ) +85.0 (c 0.70, CHCl3) (90% ee); IR
D
(NaCl) 1767 cm-1; 1H NMR δ 7.50-7.34 (m, 10H), 4.17 (s, 1H),
1.92 (s, 3H); 13C NMR δ 169.0, 135.6, 133.3, 129.3, 128.8, 128.7,
128.3, 127.1, 125.9, 85.8, 65.8, 20.9. Anal. Calcd for C16H14O3:
C, 75.57; H, 5.55. Found: C, 75.95; H, 5.92.
Ep oxid e. [R]25D ) -29.9 (c 0.70, CHCl3) (91% ee); IR (NaCl)
1720, 1275 cm-1; 1H NMR δ 8.01 (m, 2H), 7.57 (tt, J ) 7.4, 1.6
Hz, 1H), 7.43 (m, 2H), 3.38 (d, J ) 5.4 Hz, 1H), 2.48 (ddd, J )
15.2, 11.9, 3.2 Hz, 1H), 2.38 (m, 1H), 2.22 (m, 1H), 2.02 (dddd,
J ) 15.2, 11.9, 3.0, 1.2 Hz, 1H), 1.85-1.59 (m, 3H), 1.49-1.22
(m, 2H), 1.09 (m, 1H); 13C NMR δ 165.6, 133.5, 130.0, 129.9,
128.6, 87.9, 63.4, 31.8, 30.0, 27.5, 24.1. Anal. Calcd for
C14H16O3: C, 72.39; H, 6.94. Found: C, 72.28; H, 6.89.
1-Ben zoyloxy-1,2-ep oxycyclooct a n e (Ta b le 1, en t r y
11).
Rep r esen ta tive P r oced u r es for Acid -Ca ta lyzed Rea r -
r a n gem en t of En ol Ester Ep oxid es.
p-TsOH a s Ca ta lyst. To a solution of (1R,2R)-2-benzoyloxy-
1,2-epoxycyclohexane (0.030 g, 93% ee) in anhydrous ni-
tromethane (0.4 mL) was added p-TsOH (0.0024 g, 0.0137
mmol). Upon stirring at room temperature for 10 min, the
reaction mixture was quenched with saturated NaHCO3
solution, extracted with ether, dried (Na2SO4), filtered, con-
centrated, and purified by flash column chromatography (silica
gel buffered with 0.5-1% Et3N)[EtOAc-CH2Cl2-hexane (3:
7:40)] to afford (R)-2-benzoyloxycyclohexanone (0.0267 g, 89%
yield, 90% ee) (Table 3, entry 1).
YbCl3 a s Ca ta lyst. To a solution of (1R,2R)-2-benzoyloxy-
1,2-epoxycyclohexane (0.030 g, 93% ee) in anhydrous CH2Cl2
(0.4 mL) was added YbCl3 (0.0038 g, 0.0137 mmol). Upon
stirring at room temperature for 30 min, the reaction mixture
was quenched with saturated NaHCO3 solution, extracted with
ether, dried (Na2SO4), filtered, concentrated, and purified by
flash column chromatography (silica gel buffered with 0.5-
1% Et3N)[EtOAc-CH2Cl2-hexane (3:7:40)] to afford (S)-2-
benzoyloxycyclohexanone (0.022 g, 73% yield, 88% ee) (Table
3, entry 1).21
En ol Ester (Method A). IR (NaCl) 1729, 1687, 1273 cm-1
;
1H NMR δ 8.08 (m, 2H), 7.57 (tt, J ) 7.7, 1.8 Hz, 1H), 7.45
(m, 2H), 5.42 (t, J ) 8.4 Hz, 1H), 2.44 (m, 2H), 2.20 (m, 2H),
1.64 (m, 8H); 13C NMR δ 165.8, 150.7, 133.3, 130.4, 130.1,
128.6, 116.7, 29.8, 29.5, 28.1, 26.5, 26.0, 25.1.
Ep oxid e. [R]25 ) +7.2 (c 0.62, CHCl3) (95% ee); IR (NaCl)
D
1731, 1275 cm-1; 1H NMR δ 8.01 (m, 2H), 7.57 (tt, J ) 7.4, 1.6
Hz, 1H), 7.43 (m, 2H), 3.20 (ddd, J ) 10.0, 4.6, 0.8 Hz, 1H),
2.88 (m, 1H), 2.27 (ddd, J ) 13.8, 7.8, 4.5 Hz, 1H), 1.92-1.20
(m, 10H); 13C NMR δ 165.2, 133.5, 130.1, 129.9, 128.6, 86.0,
60.5, 28.1, 28.0, 26.2, 25.2, 24.9. Anal. Calcd for C15H18O3: C,
73.15; H, 7.37. Found: C, 73.38; H, 7.27.
1-Ben zoyloxy-1,2-ep oxytetr a h yd r on a p h th a len e (Ta ble
1, en tr y 12).
Rep r esen ta tive P r oced u r e for Th er m a l Rea r r a n ge-
m en t of En ol Ester Ep oxid es.
En ol Ester 17 (Method A). IR (NaCl) 1738, 1658, 1264 cm-1
;
In a Via l. A 4 mL vial containing 1-benzoyloxy-1,2-epoxy-
cyclohexane (0.10 g) was flushed with N2 and then placed into
an oil-bath (120 °C) for 30 min. The vial was then taken out
and cooled to room temperature by air flow. The reaction
mixture was directly purified by flash chromatography to
afford (S)-2-benzoyloxycyclohexanone (0.092 g, 92% yield, 90%
ee) (Table 4, entry 1).
1H NMR δ 8.21 (m, 2H), 7.62 (tt, J ) 7.5, 1.8 Hz, 1H), 7.51
(m, 2H), 7.15 (m, 4H), 5.84 (t, J ) 4.5 Hz, 1H), 2.93 (t, J ) 8.1
Hz, 2H), 2.52 (td, J ) 8.1, 4.5 Hz, 2H); 13C NMR δ 165.1, 146.0,
136.6, 133.7, 130.7, 130.3, 129.7, 128.8, 128.1, 127.8, 126.6,
121.0, 115.9, 27.7, 22.3.
Ep oxid e.17 [R]25 ) -204.1 (c 0.44, CHCl3) (88% ee); IR
D
(NaCl) 1735, 1271 cm-1; 1H NMR δ 8.18 (m, 2H), 7.64 (m, 1H),
7.51 (t, J ) 8.1 Hz, 2H), 7.44 (d, J ) 7.5 Hz, 1H), 7.32-7.15
(m, 3H), 3.98 (d, J ) 2.7 Hz, 1H), 2.81 (m, 1H), 2.68 (dd, J )
15.3, 5.7 Hz, 1H), 2.46 (m, 1H), 2.11 (ddd, J ) 13.8, 13.5, 5.7
Hz, 1H); 13C NMR δ 165.0, 136.3, 134.0, 131.3, 130.3, 129.2,
129.0, 128.8, 128.7, 126.6, 125.6, 80.7, 62.4, 25.3, 21.9. Anal.
Calcd for C17H14O3: C, 76.68; H, 5.30. Found: C, 76.69; H,
5.47.
In a Sea led Tu be. A 1 mL ampule containing freshly
prepared 1-phenyl-1-acetoxy-1,2-epoxypropane (0.040 g) was
sealed under vacuum. After being immersed in a hot oil-bath
(195 °C) for 30 min, the ampule was taken out and cooled to
room temperature by air flow. Upon opening the ampule, the
reaction mixture was directly purified by flash chromatography
to afford 2-acetoxy propiophenone (0.040 g, 100% yield, 90%
ee) (Table 4, entry 12).
1-Acetoxy-1-p h en yl-1,2-ep oxyp r op a n e (Ta ble 1, en tr y
13).
Syn t h esis of (R)-2-Acyloxy Cycloh exa n on es fr om
(1R,2R)-tr a n s-1,2-Cycloh exa n ed iol for th e Deter m in a -
tion of th e Absolu te Con figu r a tion s of r-Acyloxy Cyclo-
h exa n on es.
En ol Ester . The enol ester was prepared by a method
similar to that described in ref 20. A mixture of propiophenone
(6.70 g, 50 mmol), acetic anhydride (10.2 g, 100 mmol), and
p-toluenesulfonic acid monohydrate (0.060 g, 0.31 mmol) was
heated in an oil bath (160-170 °C) for 7 h, and acetic acid
formed during the reaction was distilled off (ca. 3 mL). Upon
cooling, the reaction mixture was poured into cold saturated
NaHCO3, extracted with hexane, dried (K2CO3), filtered,
concentrated, and purified by flash chromatography (hexane)
to afford Z-1-acetoxy-1-phenylpropene as a colorless liquid
(R)-2-Ben zoyloxycycloh exa n on e.17,22 To an ice-cold solu-
tion of (1R,2R)-trans-1,2-cyclohexanediol (0.077 g, 0.667 mmol)
and pyridine (0.158 g, 2.0 mmol) in CH2Cl2 (7.0 mL) was added
dropwise a solution of benzoyl chloride (0.103 g, 0.735 mmol)
in CH2Cl2 (2.0 mL) over a period of 2 h. The ice bath was
removed, and the reaction mixture was stirred until the
reaction was completed as monitored by TLC. The reaction
mixture was washed with water and brine, dried (Na2SO4),
filtered, concentrated, and purified by flash chromatography
(EtOAc-CH2Cl2-hexane 3:1:7 v/v) to afford (R,R)-2-benzoyloxy-
1-cyclohexanol23 (0.066 g, 45%). [R]25D ) -55.5 (c 1.56, CHCl3);
IR (NaCl) 3532, 1693, 1278 cm-1; 1H NMR δ 8.06 (m, 2H), 7.57
(tt, J ) 7.5, 1.7 Hz, 1H), 7.44 (m, 2H), 4.85 (ddd, J ) 10.3, 8.5,
4.7 Hz, 1H), 3.74 (ddd, J ) 10.3, 8.3, 4.5 Hz, 1H), 2.14 (m,
3H), 1.77 (m, 2H), 1.52-1.25 (m, 4H); 13C NMR: 166.9, 133.2,
130.5, 129.8, 128.5, 78.9, 73.0, 33.2, 30.2, 24.1, 23.9.
(5.89 g, 61%). IR (NaCl) 1757, 1670, 1207 cm-1 1H NMR δ
;
7.41-7.21 (m, 5H), 5.89 (q, J ) 7.2 Hz, 1H), 2.29 (s, 3H), 1.70
(d, J ) 7.2 Hz, 3H); 13C NMR δ 168.8, 147.1, 135.2, 128.7,
128.2, 124.4, 112.8, 20.8, 11.8.
Ep oxid e. [R]25D ) +11.4 (c 0.65, CHCl3) (91% ee). IR (NaCl)
1
1763, 1211 cm-1; H NMR δ 7.39-7.34 (m, 5H), 3.21 (q, J )
5.4 Hz, 1H), 2.17 (s, 3H), 1.49 (d, J ) 5.4 Hz, 3H); 13C NMR δ
169.3, 136.3, 129.0, 128.7, 125.8, 85.1, 61.6, 21.2, 14.0. Anal.
Calcd for C11H12O3: C, 68.74; H, 6.29. Found: C, 68.76; H,
6.37.
(21) It was observed that small amounts of 2-chlorocyclohexanone
was also formed in this reaction. The amount of this byproduct
increased if the rearrangement was run at higher substrate concentra-
tion and/or if the reaction conditions were not completely dry.
(22) Rubottom, G. M.; Mott, R. C.; J uve, H. D., J r. J . Org. Chem.
1981, 46, 2717.
1-Acetoxy-1,2-d ip h en yl-1,2-ep oxyeth a n e (Ta ble 1, en -
tr y 14).
En ol ester 6b (Method A). IR (NaCl) 1757, 1645, 1198 cm-1
;
1H NMR δ 7.52 (m, 4H), 7.39-7.22 (m, 6H), 6.70 (s, 1H), 2.30
(23) J acobsen, E. N.; Kakiuchi, F.; Konsler, R. G.; Larrow, J . F.;
Tokunaga, M. Tetrahedron Lett. 1997, 38, 773.
(20) House, H. O.; Kramar, V. J . Org. Chem. 1963, 28, 3362.

1826 J . Org. Chem., Vol. 66, No. 5, 2001
Zhu et al.
To a solution of (R,R)-2-benzoyloxy-1-cyclohexanol (0.036 g,
0.16 mmol) in CH2Cl2 (3.0 mL) was added pulverized dry
molecular sieves (0.37 g, 4 Å) and pyridinium chlorochromate
(0.185 g, 0.86 mmol) at room temperature. After the reaction
was completed as monitored by TLC, the reaction mixture was
diluted with hexane (2.0 mL) and directly loaded onto a silica
gel column. The column was eluted with EtOAc-hexane (2:3,
v/v) to afford (R)-2-benzoyloxycyclohexanone (0.035 g, 98%)
(99% ee). [R]25D ) +19.9 (c 0.87, CHCl3); IR (NaCl) 1732, 1712,
(ddd, J ) 13.2, 6.3, 0.9 Hz, 1H), 2.65 (m, 1H), 2.44 (ddd, J )
14.4, 4.5, 2.6 Hz, 1H), 2.12 (ddd, J ) 12.9, 6.3, 3.3 Hz, 1H),
1.91 (t, J ) 12.9 Hz, 1H), 1.79 (m, 1H), 1.72 (td, J ) 13.5, 4.2
Hz, 1H), 1.34 (s, 3H), 1.12 (s, 3H); 13C NMR δ 204.9, 165.7,
133.2, 129.9, 129.8, 128.4, 74.3, 45.4, 39.8, 37.2, 32.2, 31.6, 24.9.
Anal. Calcd for C15H18O3: C, 73.13; H, 7.37. Found: C, 73.13;
H, 7.15.
2-Ben zoyloxycycloh ep ta n on e.17,22 [R]25D ) +44.5 (c 1.36,
CHCl3) (99% ee, Table 4, entry 10); IR (NaCl) 1730, 1708 cm-1
;
1272 cm-1; H NMR δ 8.09 (m, 2H), 7.57 (tt, J ) 7.3, 1.7 Hz,
1H NMR δ 8.08 (m, 2H), 7.57 (tt, J ) 7.5, 1.6 Hz, 1H), 7.44
(m, 2H), 5.46 (dd, J ) 9.3, 3.3 Hz, 1H), 2.71 (m, 1H), 2.50 (m,
1H), 2.13 (m, 1H), 1.99-1.66 (m, 6H), 1.44 (m, 1H); 13C NMR
δ 207.5, 165.9, 133.4, 130.0, 129.8, 128.5, 79.2, 40.9, 30.6, 28.6,
26.6, 23.2.
1
1H), 7.44 (m, 2H), 5.41 (dd, J ) 11.1, 6.3 Hz, 1H), 2.62-2.39
(m, 3H), 2.18-1.60 (m, 5H); 13C NMR δ 204.6, 165.8, 133.4,
130.1, 129.9, 128.6, 77.3, 41.0, 33.5, 27.5, 24.0. Anal. Calcd
for C13H14O3: C, 71.54; H, 6.46. Found: C, 71.66; H, 6.52.
(R)-2-(p-Meth ylben zoyloxy)cycloh exan on e. [R]25D ) +9.3
(c 1.07, CHCl3) (99% ee); IR (NaCl) 1732, 1718, 1271 cm-1; 1H
NMR δ 7.98 (m, 2H), 7.24 (m, 2H), 5.40 (ddd, J ) 10.8, 6.3,
1.2 Hz, 1H), 2.62-2.39 (m, 3H), 2.41 (s, 3H), 1.62-2.18 (m,
5H); 13C NMR δ 204.7, 165.8, 144.0, 130.1, 129.2, 127.1, 77.0,
41.0, 33.4, 27.4, 24.0, 21.9. Anal. Calcd for C14H16O3: C, 72.39;
H, 6.94. Found: C, 72.30; H, 6.69.
2-Ben zoyloxycycloocta n on e.22 [R]25 ) +32.8 (c 2.0,
D
CHCl3) (93% ee, Table 4, entry 11); IR (NaCl) 1714 cm-1; H
1
NMR δ 8.07 (m, 2H), 7.57 (tt, J ) 7.2, 1.8 Hz, 1H), 7.44 (m,
2H), 5.42 (dd, J ) 8.7, 3.9 Hz, 1H), 2.75 (ddd, J ) 14.1, 9.3,
3.6 Hz, 1H), 2.43 (ddd, J ) 14.1, 9.0, 3.6 Hz, 1H), 2.34 (m,
1H), 2.13-1.82 (m, 4H), 1.74-1.48 (m, 4H), 1.28 (m, 1H); 13
C
NMR δ 211.8, 166.2, 133.4, 130.0, 129.8, 128.6, 77.5, 40.7, 31.5,
27.7, 24.8, 24.7, 22.0. Anal. Calcd for C15H18O3: C, 73.15; H,
7.37. Found: C, 72.92; H, 7.33.
(R)-2-(p-Meth oxyben zoyloxy)cycloh exa n on e. [R]25
)
D
-21.4 (c 0.66, C6H6) (99% ee); IR (NaCl) 1731, 1713, 1257 cm-1
;
2-Acetoxyp r op iop h en on e.3a,25 [R]25 ) -29.7 (c 1.06,
1H NMR δ 8.00 (m, 2H), 6.86 (m, 2H), 5.33 (ddd, J ) 10.9, 6.1,
0.9 Hz, 1H), 3.81 (s, 3H), 2.55-2.32 (m, 3H), 2.12-1.57 (m,
5H); 13C NMR δ 204.8, 165.5, 163.7, 132.1, 122.3, 113.7, 77.0,
55.6, 41.0, 33.5, 27.4, 24.0. Anal. Calcd for C14H16O4: C, 67.72;
H, 6.49. Found: C, 67.53; H, 6.56.
D
C6H6) (90% ee, Table 4, entry 12); IR (NaCl) 1742, 1698, 1231
1
cm-1; H NMR δ 7.91 (m, 2H), 7.57 (tt, J ) 7.4, 1.7 Hz, 1H),
7.46 (m, 2H), 5.95 (q, J ) 7.2 Hz, 1H), 2.13 (s, 3H), 1.51 (d, J
) 7.2 Hz, 3H); 13C NMR δ 197.1, 170.6, 134.6, 133.8, 129.0,
128.7, 71.6, 21.0, 17.4.
(R)-2-(p -Ch lor ob en zoyloxy)cycloh exa n on e. [R]25
)
D
2-Acetoxy-2-p h en yla cetop h en on e.3a [R]25 ) +172 (c
D
+14.1 (c 0.45, CHCl3) (99% ee); IR (NaCl) 1717, 1593, 1271
cm-1; 1H NMR δ 8.03 (m, 2H), 7.42 (m, 2H), 5.40 (dd, J ) 11.8,
6.3 Hz, 1H), 2.62-2.39 (m, 3H), 2.21-1.61 (m, 5H); 13C NMR
δ 204.3, 164.9, 139.8, 131.4, 128.9, 128.3, 77.4, 40.9, 33.3, 27.4,
24.0. Anal. Calcd for C13H13ClO3: C, 61.79; H, 5.19. Found:
C, 61.42; H, 5.58.
(R)-2-(p-Nitr oben zoyloxy)cycloh exa n on e. [R]25D ) +24.8
(c 0.84, CHCl3) (99% ee); IR (NaCl) 1732, 1712, 1273 cm-1; 1H
NMR δ 8.32-8.23 (m, 4H), 5.43 (dd, J ) 11.8, 6.4 Hz, 1H),
2.64-2.42 (m, 3H), 2.21-1.63 (m, 5H); 13C NMR δ 203.8, 163.9,
150.8, 135.3, 131.2, 123.7, 78.0, 40.9, 33.2, 27.3, 24.0; HRMS
Calcd for C13H14NO5 (M+ + 1) 264.0872. Found 264.0877.
(R)-2-P iva loyloxycycloh exa n on e.24 [R]25D ) +50.7 (c 0.56,
CHCl3) (99% ee); IR (NaCl) 1739, 1726, 1157 cm-1; 1H NMR δ
5.12 (ddd, J ) 11.5, 6.4, 0.75 Hz, 1H), 2.54-2.23 (m, 3H), 2.13-
1.91 (m, 2H), 1.85-1.55 (m, 3H), 1.25 (s, 9H); 13C NMR δ 204.7,
177.8, 76.4, 40.9, 38.9, 33.1, 27.4, 23.9. Anal. Calcd for
0.81, CHCl3) (87% ee, Table 4, entry 13); IR (NaCl) 1739, 1696,
1
1229 cm-1; H NMR δ 7.93 (m, 2H), 7.54-7.33 (m, 8H), 6.86
(s, 1H), 2.20 (s, 3H); 13C NMR δ 193.9, 170.7, 134.8, 133.8,
133.7, 129.5, 129.4, 129.0, 128.9, 128.8, 77.8, 21.0.
2-Ben zoyloxy-1-tetr a lon e.17 [R]25D ) -29.4 (c1.90, CHCl3)
(88% ee, Table 4, entry 14); IR (NaCl) 1725, 1698, 1267 cm-1
;
1H NMR: 8.15 (m, 2H), 8.06 (dd, J ) 7.5, 1.5 Hz, 1H), 7.58
(tt, J ) 7.4, 1.9 Hz, 1H), 7.51 (td, J ) 7.5, 1.5 Hz, 1H), 7.46
(m, 2H), 7.35 (t, J ) 7.5 Hz, 1H), 7.29 (d, J ) 7.5 Hz, 1H),
5.79 (dd, J ) 12.8, 5.2 Hz, 1H), 3.30 (ddd, J ) 17.2, 12.8, 4.8
Hz, 1H), 3.13 (ddd, J ) 17.2, 4.8, 3.3 Hz, 1H), 2.53 (m, 1H),
2.43 (m, 1H); 13C NMR δ 193.1, 166.0, 143.3, 134.2, 133.4,
131.9, 130.2, 130.0, 128.9, 128.6, 128.1, 127.2, 75.2, 29.5, 28.2.
Ack n ow led gm en t. We are grateful to the generous
financial support from the General Medical Sciences of
the National Institutes of Health (GM59705-02), the
Arnold and Mabel Beckman Foundation, the Camille
and Henry Dreyfus Foundation, Alfred P. Sloan Foun-
dation, DuPont, Eli Lilly, GlaxoWellcome, and Merck.
C
11H18O3: C, 66.64; H, 9.15. Found: C, 66.80; H, 8.95.
2-Acetoxycycloh exa n on e.22 [R]25D ) -61.7 (c 1.37, CHCl3)
(75% ee, Table 4, entry 8); IR (NaCl) 1732, 1721 cm-1; 1H NMR
δ 5.17 (m, 1H), 2.52 (m, 1H), 2.41 (ddd, J ) 13.2, 6.0, 0.6 Hz,
1H), 2.31 (m, 1H), 2.16 (s, 3H), 2.14-1.92 (m, 2H), 1.85-1.54
(m, 3H); 13C NMR δ 204.7, 170.2, 76.7, 40.9, 33.2, 27.3, 23.9,
20.9.
2-Ben zoyloxy-4,4-dim eth ylcycloh exan on e. [R]25D ) -18.5
(c 0.34, CHCl3) (94% ee, Table 4, entry 9); IR (NaCl) 1734, 1709
cm-1; 1H NMR δ 8.08 (m, 2H), 7.57 (m, 1H), 7.44 (m, 2H), 5.56
Su p p or tin g In for m a tion Ava ila ble: The NMR spectral
and HPLC data for the determination of the enantiomeric
excess of the enol ester epoxides and R-acyloxyketones.
J O001593Z
(25) (a) Duh, T.-H.; Wang, Y.-F.; Wu, M.-J . Tetrahedron Asymmetry
1993, 4, 1793. (b) Adam, W.; Diaz, M. T.; Fell, R. T.; Saha-Moller, C.
R. Tetrahedron Asymmetry 1996, 7, 2207.
(24) Cummins, C. H.; Coates, R. M. J . Org. Chem. 1983, 48, 2070.