Complete conversion of racemic enol ester epoxides into optically active α-acyloxy ketones [1]

Full text of DOI:10.1021/ja9928982

11002
J. Am. Chem. Soc. 1999, 121, 11002-11003
Communications to the Editor
Complete Conversion of Racemic Enol Ester
Epoxides into Optically Active r-Acyloxy Ketones
Table 1. Kinetic Resolution of Enol Ester Epoxides Catalyzed by
i a
[
2 4
(R)-BINOL] -Ti(O Pr)
Xiaoming Feng, Lianhe Shu, and Yian Shi*
Department of Chemistry, Colorado State UniVersity
Fort Collins, Colorado 80523
ReceiVed August 10, 1999
Enol ester epoxides can rearrange to R-acyloxy ketones or
1,2
aldehydes under acidic conditions. Both protic and Lewis acids
3
can catalyze this rearrangement. In a study of acid-catalyzed
rearrangements of enantiomerically enriched enol ester epoxides,
we found that this rearrangement operated through two distinct
pathways, one with retention of configuration and the other with
3
inversion (Scheme 1). Competition between the two pathways
depended on the nature of the acid catalyst. The discovery that
certain Lewis acids can catalyze the rearrangement in a stereospe-
cific fashion prompted us to explore the feasibility of kinetically
resolving a racemic enol ester epoxide using a chiral Lewis acid
catalyst (Scheme 2). Herein we report our preliminary studies in
this area.
Our studies started with racemic 1-benzoyloxy-1,2-epoxycy-
clohexane (1) as a test substrate (Scheme 3). Among many chiral
i
4
Lewis acids tested, a BINOL-Ti(O Pr)
4
system was found to be
the most promising catalyst for the envisioned resolution. Treating
i
epoxide 1 with 5 mol % [(R)-BINOL]
°
2 4 2
-Ti(O Pr) (3) in Et O at 0
1
C for 0.5 h led to a 52% conversion, as judged by H 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
a
All reactions were carried out with substrate (0.5 mmol) and catalyst
The
2-benzoyloxycyclohexanone (2). Both the recovered epoxide and
(5 mol %) in solvent (2 mL) at 0 °C unless otherwise noted.
b
1
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
conversion was determined by H NMR of the crude reaction mixture
after workup. c Isolated yield. d The relative rate was calculated using
the equation krel ) k
where C is the conversion and ee is the percent enantiomeric excess of
f s
/k ) ln[(1 - C)(1 - ee)]/ln[(1 - C)(1 + ee)],
8
e
f
the recovered starting material.
2.5 mol % catalyst used. 10 mol
catalyst used. g 20 mol % catalyst used. For entry 16, the reaction
%
h
was carried out at room temperature. The conversion was calculated
by applying the ee’s of the recovered starting material and the product
to the following equation: ee(SM)/ee(product) ) C/(1 - C). Enan-
tioselectivity was determined by chiral HPLC (Chiralcel OD). Enan-
tioselectivity was determined by chiral HPLC (Chiralpak AD). Enan-
tioselectivity was determined by chiral HPLC (Chiralcel OJ).
Enantioselectivity was determined by H NMR shift analysis with
Eu(hfc)3. The absolute configurations were assigned by comparing
i
per Ti. A solvent study showed that Et
2
O and CH
2
Cl
2
provided
j
the best overall results. To test the effect of the ester group on
the reaction, a number of ester groups with different steric and
k
l
1
*
Corresponding author. Phone: 970-491-7424. Fax: 970-491-1801. E-
mail: yian@lamar.colostate.edu.
m
(1) For leading reviews on enol ester epoxide rearrangements, see: (a)
the measured optical rotations with those of the epoxides obtained by
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.
asymmetric epoxidation.9 n The absolute configurations were assigned
by comparing HPLC chromatograms with those of the enol ester
epoxide obtained by asymmetric epoxidation and the R-benzoyloxy
(2) For examples of acid-catalyzed rearrangements of enol ester epoxides,
9
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) Johnson, W. S.; Gastambide, B.; Pappo, R. J.
Am. Chem. Soc. 1957, 79, 1991. (e) Nambara, T.; Fishman, J. J. Org. Chem.
ketone obtained from a stereospecific rearrangement of the chiral enol
ester epoxide.3 The absolute configurations were determined by
comparing the measured optical rotations with those of the authentic
samples prepared from commercially available (R,R)-1,2-trans-cyclo-
hexanediol. p The absolute configurations were assigned on the basis
of the epoxide configurations and the mechanistic deduction from the
transformations of Scheme 4. q The absolute configuration was deter-
o
1
1
3
962, 27, 2131. (f) Rhone, J. R.; Huffman, M. N. Tetrahedron Lett. 1965,
395. (g) Williamson, K. L.; Coburn, J. I.; Herr, M. F. J. Org. Chem. 1967,
2, 3934.
(
3) Zhu, Y.; Manske, K. J.; Shi, Y. J. Am. Chem. Soc. 1999, 121, 4080.
(4) For leading references on BINOL-Ti catalyzed asymmetric processes,
mined by comparing the measured optical rotation with the reported
see: (a) Mikami, K.; Terada, M.; Nakai, T. J. Am. Chem. Soc. 1989, 111,
1
one.3
940. (b) Costa, A. L.; Piazza, M. G.; Tagliavini, E.; Trombini, C.; Umani-
Ronchi, A. J. Am. Chem. Soc. 1993, 115, 7001. (c) Mikami, K.; Matsukawa,
S. J. Am. Chem. Soc. 1993, 115, 7039. (d) Keck, G. E.; Tarbet, K. H.; Geraci,
L. S. J. Am. Chem. Soc. 1993, 115, 8467. (e) Keck, G. E.; Krishnamurthy, D.
J. Am. Chem. Soc. 1995, 117, 2363. (f) Faller, J. W.; Sams, D. W. I.; Liu, X.
J. Am. Chem. Soc. 1996, 118, 1217. (g) Gauthier, D. R., Jr.; Carreira, E. M.
Angew. Chem., Int. Ed. Engl. 1996, 35, 2363.
electronic properties were investigated. As shown in Table 1
(entries 1-10), good reactivity and selectivity were obtained in
all cases except for acetate (entry 10), suggesting that a wide
range of ester groups can be tolerated.
1
0.1021/ja9928982 CCC: $18.00 © 1999 American Chemical Society
Published on Web 11/11/1999

Communications to the Editor
J. Am. Chem. Soc., Vol. 121, No. 47, 1999 11003
Scheme 1
Scheme 4
Scheme 2
Scheme 3
ketone using a catalytic amount of a chiral Lewis acid, followed
by a catalytic amount of an achiral acid.6
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 obtained for a number
of cyclic systems. Both enantiomerically enriched enol ester
epoxides and R-acyloxy ketones could be obtained through this
resolution. 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 enantiomeri-
cally enriched R-acyloxy ketone by sequential treatment with a
catalytic amount of a chiral Lewis acid and a catalytic amount of
an achiral acid.7 Future efforts will be devoted to further
understanding the difference between cyclic and acyclic epoxides
and searching for effective catalysts for acyclic systems.
Encouraged by the result obtained for the six-membered ring
epoxides (Table 1, entries 1-11), we prepared and investigated
a number of other enol ester epoxides to probe their behavior
under the current catalyst conditions. As shown in Table 1, this
resolution process could be extended to five-, seven-, and eight-
membered ring systems (Table 1, entries 12-14). 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. Compared to the other ring systems, the eight-membered
system was substantially less reactive, requiring more catalyst
and a longer reaction time. In contrast to the cyclic epoxides, the
current catalyst system is not effective for acyclic epoxides (Table
Acknowledgment. We are grateful for the generous financial support
from the Beckman Young Investigator Award Program, the General
Medical Sciences of the National Institutes of Health (GM59705-01),
National Science Foundation CAREER Award program (CHE-9875497),
the Camille and Henry Dreyfus New Faculty Award program, the Camille
Dreyfus Teacher-Scholar Award Program, the DuPont Young Faculty
Award Program, and the Alfred P. Sloan Foundation.
1, entry 16).
As discussed above (Scheme 3), the rearrangements occurred
with inversion of configuration. As a result, the remaining epoxide
and the rearranged R-acyloxy ketone had the same configuration
2
at C . It was envisioned that the remaining epoxide might be
Supporting Information Available: Characterization of enol ester
epoxides and R-acyloxy ketones along with the NMR spectral and HPLC
data for the determination of the enantiomeric excess of these compounds
further converted into the rearranged R-acyloxy ketone using an
achiral acid which would catalyze the rearrangement with
3
retention of configuration. This could then provide a high yield
(PDF). This material is available free of charge via the Internet at
(>50%) of enantiomerically enriched R-acyloxy ketone. To test
http://pubs.acs.org.
this hypothesis, 1 was again used as a substrate. After the
resolution reaction was quenched at the desired conversion, the
chiral catalyst was removed by a rapid filtration through a plug
JA9928982
(6) For leading references on nonenzymatic 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) 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.; Jacobsen, 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.
of silica gel. The resulting mixture was subsequently treated with
5
1
0% p-TsOH at room temperature for 20 min, at which time the
epoxide was completely consumed, and the 2-benzoyloxycyclo-
hexanone 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 Et O. As shown in Scheme 4, this
2
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 enantiomerically enriched R-acyloxy
(7) For leading reviews on dynamic resolution, see: (a) Noyori, R.;
Tokunaga, M.; Kitamura, M. Bull. Chem. Soc. Jpn. 1995, 68, 36. (b) Ward,
R. S. Tetrahedron: Asymmetry 1995, 6, 1475. (c) Caddick, S.; Jenkins, K.
Chem. Soc. ReV. 1996, 25, 447. (d) Strecher, H.; Faber, K. Synthesis 1997, 1.
(8) Kagan, H. B.; Fiaud, J. C. Top. Stereochem. 1988, 18, 249.
(
5) 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-benzoyloxycyclopentanone.
(9) Zhu, Y.; Tu, Y.; Yu, H.; Shi, Y. Tetrahedron Lett. 1998, 39, 7819.