Enantioselective epoxidation of conjugated cis-enynes by chiral dioxirane

Article abstract of DOI:10.1021/jo070205r

(Chemical Equation Presented) This paper describes a highly chemo- and enantioselective epoxidation of conjugated cis-enynes using readily available glucose-derived ketone 2 as catalyst and Oxone as oxidant to form cis-propargyl epoxides in high ee's. The

Full text of DOI:10.1021/jo070205r

Enantioselective Epoxidation of Conjugated cis-Enynes by Chiral
Dioxirane
Christopher P. Burke and Yian Shi*
Department of Chemistry, Colorado State UniVersity, Fort Collins, Colorado 80523
yian@lamar.colostate.edu
ReceiVed February 2, 2007
This paper describes a highly chemo- and enantioselective epoxidation of conjugated cis-enynes using
readily available glucose-derived ketone 2 as catalyst and Oxone as oxidant to form cis-propargyl epoxides
in high ee’s. The interaction between the alkyne group of the substrate and the oxazolidinone moiety of
the ketone catalyst as well as the interactions between the substituents on enynes and the oxazolidinone
moiety of the ketone catalyst are important for the stereodifferentiation.
SCHEME 1
Introduction
Chiral propargyl epoxides are very useful synthetic intermedi-
ates which can undergo a variety of synthetic transformations,1
and enantioselective epoxidation of enynes provides a direct
approach to these epoxides.2,3 Enantioselective epoxidation of
conjugated cis-enynes using chiral (salen)Mn catalysts has been
shown to form trans-propargyl epoxides as major products in
high ee’s.3a-e Recently, it also has been reported that cis-1-
phenylpent-3-en-1-yne can be epoxidized stereospecifically
using chiral (salan)Ti catalysts, giving the cis-epoxide in high
ee.3f,g Previously, we reported that fructose-derived ketone 1
provides high ee’s for a wide variety of trans- and trisubstituted
olefins (Scheme 1).4,5 Conjugated trans- and trisubstituted
enynes have also been found to be effective substrates for this
ketone, giving trans-propargyl epoxides in high ee’s (eq 1).6
* Corresponding author. Phone: 970-491-7424. Fax: 970-491-1801.
(1) For some examples of synthetic applications of propargyl epoxides,
see: (a) Alexakis, A.; Marek, I.; Mangeney, P.; Normant, J. F. Tetrahedron
1991, 47, 1677. (b) Marshall, J. A.; DuBay, W. J. J. Am. Chem. Soc. 1992,
114, 1450. (c) Marshall, J. A.; Pinney, K. G. J. Org. Chem. 1993, 58, 7180.
(d) Marshall, J. A.; Tang, Y. J. Org. Chem. 1994, 59, 1457. (e) Mukai, C.;
Sugimoto, Y-i.; Ikeda, Y.; Hanaoka, M. Tetrahedron Lett. 1994, 35, 2183.
(f) Aurrecoechea, J. M.; Solay, M. Tetrahedron Lett. 1995, 36, 2501. (g)
Piotti, M. E.; Alper, H. J. Org. Chem. 1997, 62, 8484. (h) Aurrecoechea,
J. M.; Alonso, E.; Solay, M. Tetrahedron 1998, 54, 3833. (i) Aurrecoechea,
J. M.; Solay, M. Tetrahedron 1998, 54, 3851. (j) Bernard, N.; Chemla, F.;
Normant, J. F. Tetrahedron Lett. 1998, 39, 6715. (k) Klein, S.; Zhang, J.
H.; Holler, M.; Weibel, J-M.; Pale, P. Tetrahedron 2003, 59, 9793.
(2) For leading references on asymmetric epoxidation of enynes directed
by hydroxyl groups, see: (a) Johnson, R. A.; Sharpless, K. B. In Catalytic
Asymmetric Synthesis; Ojima, I. Ed.; VCH: New York, 1993; Chapter 4.1.
(b) Katsuki, T.; Martin, V. S. Org. React. 1996, 48, 1.
(3) For leading references on asymmetric epoxidations of cis-enynes using
chiral salen-type catalysts, see: (a) Lee, N. H.; Jacobsen, E. N. Tetrahedron
Lett. 1991, 32, 6533. (b) Brandes, B. D.; Jacobsen, E. N. J. Org. Chem.
1994, 59, 4378. (c) Hamada, T.; Irie, R.; Katsuki, T. Synlett 1994, 479. (d)
Sasaki, H.; Irie, R.; Hamada, T.; Suzuki, K.; Katsuki, T. Tetrahedron 1994,
50, 11827. (e) Hamada, T.; Daikai, K.; Irie, R.; Katsuki, T. Synlett 1995,
407. (f) Matsumoto, K.; Sawada, Y.; Saito, B.; Sakai, K.; Katsuki, T. Angew.
Chem., Int. Ed. 2005, 44, 4935. (g) Sawada, Y.; Matsumoto, K.; Kondo,
S.; Watanabe, H.; Ozawa, T.; Suzuki, K.; Saito, B.; Katsuki, T. Angew.
Chem., Int. Ed. 2006, 45, 3478.
However, generally speaking, an efficient synthesis of optically
active cis-propargyl epoxides is still challenging and highly
desirable.
(4) For leading reviews on chiral ketone catalyzed asymmetric epoxi-
dations, see: (a) Denmark, S. E.; Wu, Z. Synlett 1999, 847. (b) Frohn, M.;
Shi, Y. Synthesis 2000, 1979. (c) Shi, Y. Acc. Chem. Res. 2004, 37, 488.
(d) Yang, D. Acc. Chem. Res. 2004, 37, 497.
10.1021/jo070205r CCC: $37.00 © 2007 American Chemical Society
Published on Web 04/26/2007
J. Org. Chem. 2007, 72, 4093-4097
4093

Burke and Shi
SCHEME 2
SCHEME 3
Recently, we found that oxazolidinone-containing ketones 2
can provide high ee’s for substrates which are not effective with
ketone 1 (Scheme 1).7 N-Aryl substituted oxazolidinone-
containing ketones such as 2b and 2c, readily prepared in large
quantities from D-glucose and anilines in four steps (Scheme
2),8 are particularly promising for practical use. Studies have
shown that ketone 2 can give high ee’s for olefins such as
conjugated aromatic cis-olefins (eqs 2 and 3),9a,b styrenes (eq
4),8b certain trisubstituted and tetrasubstituted olefins (eqs 5 and
6)9c,d,e and conjugated cis-dienes (eq 7).9f
The origin of enantioselectivity of ketone 2 appears to arise
from an attraction between the Rπ group and the oxazolidinone
moiety of the ketone catalyst, causing spiro transition state A
to be favored over spiro B (Scheme 3),7,8,10 To further
understand the factors influencing the enantioselectivity of the
epoxidation and expand the scope of the reaction, we decided
to explore the epoxidation of conjugated cis-enynes with readily
available ketones 2b and 2c.8 Herein we wish to report our
efforts on this subject.11
can be effectively epoxidized with high enantioselectivities (80-
97% ee). The reactions were generally clean, as judged by the
1H NMR spectra of the crude reaction mixtures.12 The reactions
were stereospecific in that cis-olefins yielded only cis-epoxides
with no isomerization observed. Among the solvents screened,
DME gave the best combination of ee and conversion. Very
nonpolar substrates show markedly decreased reactivity presum-
ably due to poor solubility in the reaction mixture (e.g., Table
1, entry 5). For these substrates, dioxane was used as solvent,
which has the effect of raising conversion while slightly
lowering ee’s with respect to DME. For these and other less
reactive substrates, conversion can also usually be improved
with a slower addition of Oxone and/or higher reaction
temperature (0 °C). The slow addition of Oxone lowers its
concentration in solution, thus reducing the undesired reaction
processes such as Oxone self-decomposition (pathway e),
consumption of the dioxirane by Oxone (pathway h), and
racemic epoxidation of olefin by Oxone itself (pathway i)
(Scheme 4).13
As shown in Table 1, the ee’s are highly dependent upon the
substituents on the olefin and alkyne (R1 and R2). This could
(5) For examples of asymmetric epoxidation mediated by fructose-
derived ketone 1, see: (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) Warren, J. D.; Shi, Y. J. Org.
Chem. 1999, 64, 7675. (f) Frohn, M.; Zhou, X.; Zhang, J-R.; Tang, Y.;
Shi, Y. J. Am. Chem. Soc. 1999, 121, 7718-7719. (g) Zhu, Y.; Shu, L.;
Tu, Y.; Shi, Y. J. Org. Chem. 2001, 66, 1818. (h) Shu, L.; Shi, Y.
Tetrahedron 2001, 57, 5213. (i) Tu, Y.; Frohn, M.; Wang, Z-X.; Shi, Y.
Org. Synth. 2003, 80, 1. (j) Wang, Z-X.; Shu, L.; Frohn, M.; Tu, Y.; Shi,
Y. Org. Synth. 2003, 80, 9. (k) Lorenz, J. C.; Frohn, M.; Zhou, X.; Zhang,
J-R.; Tang, Y.; Burke, C.; Shi, Y. J. Org. Chem. 2005, 70, 2904.
(6) (a) Cao, G.-A.; Wang, Z.-X.; Tu, Y.; Shi, Y. Tetrahedron Lett. 1998,
39, 4425. (b) Wang, Z.-X.; Cao, G.-A.; Shi, Y. J. Org. Chem. 1999, 64,
7646.
(7) For asymmetric epoxidation with ketone 2a, see: (a) Tian, H.; She,
X.; Shu, L.; Yu, H.; Shi, Y. J. Am. Chem. Soc. 2000, 122, 11551. (b) Tian,
H.; She, X.; Yu, H.; Shu, L.; Shi, Y. J. Org. Chem. 2002, 67, 2435.
(8) (a) Shu, L.; Wang, P.; Gan, Y.; Shi, Y. Org. Lett. 2003, 5, 293. (b)
Goeddel, D.; Shu, L.; Yuan, Y.; Wong, O. A.; Wang, B.; Shi, Y. J. Org.
Chem. 2006, 71, 1715. (c) Zhao, M.-X.; Goeddel, D.; Li, K.; Shi, Y.
Tetrahedron 2006, 62, 8064.
(9) (a) Shu, L.; Shi, Y. Tetrahedron Lett. 2004, 45, 8115. (b) Wong, O.
A.; Shi, Y. J. Org. Chem. 2006, 71, 3973. (c) Shen, Y.-M.; Wang, B.; Shi,
Y. Angew. Chem., Int. Ed. 2006, 45, 1429. (d) Shen, Y.-M.; Wang, B.;
Shi, Y. Tetrahedron Lett. 2006, 47, 5455. (e) Wang, B.; Shen, Y-M.; Shi,
Y. J. Org. Chem. 2006, 71, 9519. (f) Burke, C.P.; Shi, Y. Angew. Chem.,
Int. Ed. 2006, 45, 4475.
(10) (a) Tian, H.; She, X.; Xu, J.; Shi, Y. Org. Lett. 2001, 3, 1929. (b)
Hickey, M.; Goeddel, D.; Crane, Z.; Shi, Y. Proc. Natl. Acad. Sci. U.S.A.
2004, 101, 5794.
(11) Two examples of conjugated cis-enynes (cis-1-phenyl-3-penten-1-
yne and cis-2-undecen-4-yne) were previously examined with ketone 2a
(91% and 87% ee obtained repectively) (ref 7).
(12) For the substrates with a TMS group on the alkyne (Table 1, entries
6 and 7), some cleavage of the TMS group occurred during the reaction.
(13) For a detailed discussion, see: ref 4b.
Results and Discussion
The enyne substrates were generally readily prepared from
vinyl halides and alkynes via Sonogashira coupling (see
Supporting Information for details). The epoxidation of enynes
was carried out using ketones 2b or 2c as catalyst and Oxone
as oxidant. As shown in Table 1, a variety of enyne substrates
4094 J. Org. Chem., Vol. 72, No. 11, 2007

Epoxidation of Conjugated cis-Enynes
TABLE 1. Asymmetric Epoxidation of Enynes by Ketones 2b and 2ca
a Unless stated otherwise, all reactions were carried out with enyne (1.0 eq.), catalyst (0.25 eq.), Oxone (1.6 eq.), and K2CO3 (6.7 eq.) in DME and buffer
(0.1 M K2CO3-AcOH in 4 × 10-4 aq EDTA, pH 9.3) (1.5:1, v/v). Oxone and K2CO3 were added separately and simultaneously over the time and temperature
1
specified. b Unless stated otherwise, the conversion was determined by GC of the crude reaction mixture. c The conversion was determined by H NMR of
the crude reaction mixture. d 0.20 equiv catalyst used. e Dioxane used as solvent. f Solvent-buffer (2:1, v/v). g 2.4 equiv Oxone/10.1 equiv. K2CO3 were
used. h Enantioselectivity was determined by chiral HPLC (Chiralcel OD column). i Enantioselectivity was determined by Chiral GC (Chiraldex B-DM
column). j Enantioselectivity was determined using the corresponding benzoate by chiral HPLC (Chiralpak AD column). k Enantioselectivity was determined
using the corresponding acetate by Chiral GC (Chiraldex B-DM column). l Enantioselectivity was determined by chiral HPLC (Chiralcel OJ column). m Oxone
was added over 8 h, and then the mixture was allowed to stir for an additional 4 h at 0 °C. n Enantioselectivity was determined using the corresponding
benzoate by chiral HPLC (Chiralcel OD column). o 0.30 equiv. catalyst used. p With DME/dioxane (1:1) as solvent.
be rationalized by spiro transition states C and D (Scheme 5).
Spiro C should be favored due to the apparent attractive
interaction between the alkyne group and the oxazolidinone
moiety of the catalyst. Moreover, it appears that there exist
J. Org. Chem, Vol. 72, No. 11, 2007 4095

Burke and Shi
SCHEME 4
determined by reducing the alkyne with excess diimide15 to the
known saturated compound and comparing the optical rotation
with the reported one (eq 9).16 In all these cases, the obtained
configurations are consistent with spiro transition state C being
favored. The stereochemistry of the remaining epoxides in Table
1 is tentatively assigned based on this model.
SCHEME 5
additional interactions such as hydrophobic interactions between
the R1 and R2 groups of the substrate and the oxazolidinone
moiety of the catalyst (possibly the N-aryl group). Thus, the
competition between spiro C and D is significantly influenced
by the nature of the R1 and R2 groups. Generally, increasing
the hydrophobicity of R1 group will enhance the competition
of spiro D, thus lowering ee’s (entry 5 vs entry 1, entry 7 vs
entry 6). Favorable substrates have more polar R1 groups and
less polar R2 groups (entries 11 and 12). Likewise, unfavorable
substrates contain less polar R1 groups and more polar R2 groups
(entry 9 vs entry 10). For entry 13, the lactone resulting from
the opening of the epoxide was obtained (eq 8). Further studies
have shown that a cis-endiyne is also an effective substrate
(Table 1, entry 15). This transformation is potentially useful
since several of this type of epoxides have been shown to be
biologically active compounds.14
Besides cis-enynes, ketone 2 also gave higher ee’s than ketone
1 for certain trisubstituted enynes. For example, 94% ee was
obtained for 4-methyl-1-phenyl-3-penten-1-yne (Table 1, entry
16) as compared to 55% ee with ketone 1. The low ee’s obtained
for this class of enyne with ketone 1 is likely due to a significant
competition from planar transition state F because the acetylene
group is a sterically small group (Scheme 6).5b On the other
hand, the desired spiro transition state G for ketone 2 is further
favored over the competing planar transition state such as H
due to the attractive interaction between the alkyne group of
the olefin and the oxazolidinone moiety of the ketone catalyst
(Scheme 7),7,8,9,10 thus giving higher enantioselectivities.
SCHEME 6
In summary, we report an effective method for the asymmetric
epoxidation of conjugated cis-enynes with readily available
The absolute configurations of the epoxides in entries 1 and
2 were determined by comparing the optical rotations with those
previously determined. For entry 11, the configuration was
(15) Denmark, S. E.; Yang, S.-M. J. Am. Chem. Soc. 2002, 124, 2102.
(16) Gao, Y.; Hanson, R. M.; Klunder, J. M.; Ko, S. Y.; Masamune, H.;
Sharpless, K. B. J. Am. Chem. Soc. 1987, 109, 5765.
(17) Mukai, C.; Sugimoto, Y-i.; Ikeda, Y.; Hanaoka, M. Chem. Commun.
1994, 1161.
(14) Grandjean, D.; Pale, P.; Chuche, J. Tetrahedron 1993, 49, 5225
and references therein.
(18) Nakata, K.; Takeda, T.; Mihara, J.; Hamada, T.; Irie, R.; Katsuki,
T. Chem. Eur. J. 2001, 7, 3776.
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Epoxidation of Conjugated cis-Enynes
SCHEME 7
g, 0.5 mmol) and ketone 2c (0.035 g, 0.10 mmol) in DME (7.5
mL) were added buffer (0.1 M K2CO3-AcOH in 4 × 10-4
M
aqueous EDTA, pH ) 9.3) (5.0 mL) and Bu4NHSO4 (0.0075
g, 0.02 mmol) with stirring (in order to maximize the conversion,
efficient stirring is required, but excessive splashing of the
reaction mixture should be avoided). After the mixture was
cooled to -10 °C (bath temperature) via NaCl-ice bath, solutions
of Oxone (0.20 M in 4 × 10-4 M aqueous EDTA, 4 mL) (0.49
g, 0.80 mmol) and K2CO3 (0.84 M in 4 × 10-4 M aqueous
EDTA, 4 mL) (0.46 g, 3.36 mmol) were added dropwise
separately and simultaneously over a period of 8 h via syringe
pump. The reaction was then quenched with the addition of
petroleum ether and extracted with petroleum ether. The
combined organic layers were washed with water, brine, dried
(Na2SO4), filtered, concentrated, and purified by flash chroma-
tography [the silica gel was buffered with 1% Et3N in petroleum
ether; petroleum ether was used as eluent] to give the cis-epoxide
as a colorless oil (0.062 g, 78% yield, 93% ee).
chiral ketones 2b and 2c as catalyst and Oxone as oxidant. The
reactions are highly chemo- and enantioselective and are
stereospecific, allowing exclusive formation of cis-propargyl
epoxides from cis-enynes in high ee’s. This method should
provide a valuable route to this useful class of compounds.
Studies have shown that while the interaction between the alkyne
group of the substrate and the oxazolidinone moiety of the
ketone catalyst plays an important role in stereodifferentiation,
the interactions (likely hydrophobic) between the substituents
on the enyne and the oxazolidinone moiety of the ketone catalyst
(possibly N-aryl group) also significantly influence the enan-
tioselectivity. The information obtained will be useful for the
prediction of the stereochemical outcome for a given substrate
and the design of more effective catalysts in the future.
Acknowledgment. We are grateful to the generous financial
support from the General Medical Sciences of the National
Institutes of Health (GM59705-08).
Supporting Information Available: Synthesis and character-
ization of conjugated cis-enynes and epoxides as well as the data
for the determination of the enantiomeric excess of the epoxides
and the NMR spectra of selected epoxides. This material is available
free of charge via the Internet at http://pubs.acs.org.
Experimental Section
Representative procedure for asymmetric epoxidation (Table
1, entry 1). To a solution of cis-1-phenyl-3-penten-1-yne (0.071
JO070205R
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