Enantioselective epoxidation of nonconjugated cis-olefins by chiral dioxirane

Article abstract of DOI:10.1021/ol901724v

A variety of nonconjugated cis-olefins has been enantioselectively epoxidized with chiral ketones 2, and up to 92% ee has been obtained. The two prochiral faces of an olefin are likely stereodifferentiated by the relative hydrophobicity of the olefin substituents and/or allylic oxygen functionality.

Full text of DOI:10.1021/ol901724v

ORGANIC
LETTERS
2009
Vol. 11, No. 22
5150-5153
Enantioselective Epoxidation of
Nonconjugated cis-Olefins by Chiral
Dioxirane
Christopher P. Burke and Yian Shi*
Department of Chemistry, Colorado State UniVersity, Fort Collins, Colorado 80523
yian@lamar.colostate.edu
Received July 27, 2009
ABSTRACT
A variety of nonconjugated cis-olefins has been enantioselectively epoxidized with chiral ketones 2, and up to 92% ee has been obtained. The
two prochiral faces of an olefin are likely stereodifferentiated by the relative hydrophobicity of the olefin substituents and/or allylic oxygen
functionality.
Chiral ketones have been shown to be effective catalysts for
asymmetric epoxidation of olefins.1 In our own studies,
fructose-derived ketone 1 (Figure 1) has been shown to be
a very effective catalyst for the epoxidation of trans- and
trisubstituted olefins.2 It has also been found that oxazoli-
dinone-bearing ketones 2 can give high ee’s for olefins such
as conjugated aromatic cis-olefins,3a,c-e,g conjugated cis-
Figure 1. Ketones 1 and 2.
dienes,3k enynes,3a,c,l styrenes,3b-d,f and certain trisubsti-
tuted3h,j and tetrasubstituted olefins.3i,j,4 For epoxidation of
cis-olefins with ketones 2, the reacting C-C double bond
has usually been conjugated with an aromatic group, an
alkene, or an alkyne which directs the enantioselective
epoxidation via an apparent attraction with the spiro-
oxazolidinone of the ketone catalyst (Figure 2). For asym-
metric epoxidation of nonconjugated cis-olefins, 67% ee was
(1) For leading reviews, 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. (e) Wong,
O. A.; Shi, Y. Chem. ReV. 2008, 108, 3958.
(2) (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) Shu, L.; Shi, Y. Tetrahedron 2001, 57, 5213.
(3) (a) Tian, H.; She, X.; Shu, L.; Yu, H.; Shi, Y. J. Am. Chem. Soc.
2000, 122, 11551. (b) Tian, H.; She, X.; Xu, J.; Shi, Y. Org. Lett. 2001, 3,
1929. (c) Tian, H.; She, X.; Yu, H.; Shu, L.; Shi, Y. J. Org. Chem. 2002,
67, 2435. (d) Shu, L.; Wang, P.; Gan, Y.; Shi, Y. Org. Lett. 2003, 5, 293.
(e) Shu, L.; Shi, Y. Tetrahedron Lett. 2004, 45, 8115. (f) Goeddel, D.;
Shu, L.; Yuan, Y.; Wong, O. A.; Wang, B.; Shi, Y. J. Org. Chem. 2006,
71, 1715. (g) Wong, O. A.; Shi, Y. J. Org. Chem. 2006, 71, 3973. (h)
Shen, Y.-M.; Wang, B.; Shi, Y. Angew. Chem., Int. Ed. 2006, 45, 1429. (i)
Shen, Y.-M.; Wang, B.; Shi, Y. Tetrahedron Lett. 2006, 47, 5455. (j) Wang,
B.; Shen, Y.-M.; Shi, Y. J. Org. Chem. 2006, 71, 9519. (k) Burke, C. P.;
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72, 6320.
(4) For leading reviews on metal-catalyzed asymmetric epoxidation of
unfunctionalized olefins, see: (a) Jacobsen, E. N. In Catalytic Asymmetric
Synthesis; Ojima, I., Ed.; VCH: New York, 1993; Chapter 4.2. (b) Collman,
J. P.; Zhang, X.; Lee, V. J.; Uffelman, E. S.; Brauman, J. I. Science 1993,
261, 1404. (c) Mukaiyama, T. Aldrichim. Acta 1996, 29, 59. (d) Katsuki,
T. In Catalytic Asymmetric Synthesis; Ojima, I., Ed.; VCH: New York,
2000; Chapter 6B. (e) McGarrigle, E. M.; Gilheany, D. G. Chem. ReV. 2005,
105, 1563. (f) Xia, Q.-H.; Ge, H.-Q.; Ye, C.-P.; Liu, Z.-M.; Su, K.-X. Chem.
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Tetrahedron 2007, 63, 6075. (h) Matsumoto, K.; Sawada, Y.; Katsuki, T.
Pure Appl. Chem. 2008, 80, 1071.
10.1021/ol901724v CCC: $40.75
Published on Web 10/13/2009
 2009 American Chemical Society

The ee increased when the other substituent on the olefin
became more hydrophilic (Table 1, entries 2-5) likely due
to spiro C being further favored over spiro D (Figure 3).9
Figure 2. Transition states for the epoxidation with ketone 2.
obtained for cis-1-cyclohexyl-1-propene, and 94-97% ee
was obtained for 3,3-ethylenedioxycycloalkenes with ketone
2a (Scheme 1).3a,c,5,6 To expand the substrate scope of chiral
Figure 3. Stereodifferentiation via hydrophobicity.
Up to 91% ee was obtained for cis-dec-4-enoic acid (entry
4). For entries 4 and 5, the products were obtained as five-
and six-membered lactones, respectively.10 The lactone in
entry 4 is the enantiomer of a natural product isolated from
Streptomyces griseus and has been the subject of several
synthetic investigations.11 The high enantioselectivity ob-
served for entries 4 and 5 (Table 1) is likely due to the
extreme difference in hydrophilicity between the two olefin
substituents. The carboxylic acids are presumably deproto-
nated under the basic reaction conditions to give the
corresponding carboxylates which are charged polar groups.
Good ee’s can also be obtained for certain allylic ethers
(Table 1, entries 6-8). An allylic acetal was a very effective
substrate (Table 1, entry 10), but an acyclic allylic ketal
(entry 11) was not, in contrast to the cyclic ketals previously
studied (Scheme 1). All-carbon analogues of an aromatic
ether and a cyclic ketal gave much lower ee’s than their
oxygen-containing counterparts (Table 1, entries 9 and 12),
indicating the oxygen atoms are important for stereodiffer-
entiation. The absolute configurations of the epoxides from
3,3-ethylenedioxycyclohexene (Scheme 1) and the allylic
ethers of entries 6 and 8 (Table 1) indicate that ketal and
ether substituents prefer to be proximal to the oxazolidinone
of 2a during the transition states (Figure 4) (for methods
Scheme 1
ketone-catalyzed epoxidation of nonconjugated cis-olefins
and gain better understanding of stereodifferentiation factors,
we undertook further investigations on asymmetric epoxi-
dation of this class of olefins with glucose-derived ketones
2. Herein we report our studies on this subject.
During our studies on asymmetric epoxidation of conju-
gated cis-dienes and enynes with ketones 2, it became
apparent that the relative hydrophobicity of the olefin
substituents had a significant effect on enantioselectivity.3k,l
To further probe this hydrophobic effect on stereodifferen-
tiation, cis-2-nonene was epoxidized with ketones bearing
different N-substituents, giving 44%, 56%, 58%, 64% (Table
1, entry 1), and 54% ee, respectively, for ketones 2a-e.7
The ee initially increased with increasing length of the p-alkyl
chain on the aryl ring of catalysts 2b-d (from Me to n-Bu)
but decreased with further increasing length of the alkyl chain
(n-C10H21) (2e). The epoxidations are run in aqueous solvent
mixtures, and although the absolute configuration of the
epoxide8a could not be unambiguously determined yet, the
results suggest that the enantioselectivity is likely derived
from hydrophobic interactions between the substrate and the
catalyst with the hydrophobic n-hexyl group of the olefin
aligned adjacent to the N-aryl group of the catalyst in the
transition state (spiro C favored over spiro D) (Figure 3, X
) H, n ) 6).
(8) (a) Asami, M.; Kanemaki, N. Tetrahedron Lett. 1989, 30, 2125. (b)
Utaka, M.; Konishi, S.; Takeda, A. Tetrahedron Lett. 1986, 27, 4737. (c)
Zaks, A.; Dodds, D. R. J. Am. Chem. Soc. 1995, 117, 10419.
(9) For leading references on asymmetric epoxidation of allylic and
homoallylic alcohols, see: (a) Katsuki, T.; Martin, V. S. Org. React. 1996,
48, 1. (b) Johnson, R. A.; Sharpless, K. B. In Catalytic Asymmetric
Synthesis; Ojima, I. Ed.; VCH: New York, 2000; Chapter 6A. (c) Zhang,
W.; Basak, A.; Kosugi, Y.; Hoshino, Y.; Yamamoto, H. Angew. Chem.,
Int. Ed. 2005, 44, 4389. (d) Zhang, W.; Yamamoto, H. J. Am. Chem. Soc.
2007, 129, 286.
(10) For entry 5, the epoxide did not completely cyclize under the
reaction conditions; a mixture of epoxy acid and lactone were isolated from
the crude reaction mixture. Refluxing this crude mixture overnight in
cyclohexane gave the lactone product in overall 88% yield; see: Ochiai,
M.; Ukita, T.; Iwaki, S.; Nagao, Y.; Fujita, E. J. Org. Chem. 1989, 54,
4832.
(5) For leading references on metal- and enzyme-catalyzed asymmetric
epoxidation of nonconjugated cis-olefins, see: (a) Jacobsen, E. N.; Zhang,
W.; Muci, A. R.; Ecker, J. R.; Deng, L. J. Am. Chem. Soc. 1991, 113,
7063. (b) Jacobsen, E. N.; Deng, L.; Furukawa, Y.; Mart´ınez, L. E.
Tetrahedron 1994, 50, 4323. (c) Hamada, T.; Irie, R.; Katsuki, T. Synlett
1994, 479. (d) Mikame, D.; Hamada, T.; Irie, R.; Katsuki, T. Synlett 1995,
827. (e) Sawada, Y.; Matsumoto, K.; Katsuki, T. Angew. Chem., Int. Ed.
2007, 46, 4559. (f) Allain, E. J.; Hager, L. P.; Deng, L.; Jacobsen, E. N.
(11) For leading references, see: (a) Gra¨fe, U.; Reinhardt, G.; Schade,
W.; Krebs, D.; Eritt, I.; Fleck, W. F.; Hienrich, E.; Radics, L. J. Antibiot.
1982, 35, 609. (b) Gra¨fe, U.; Eritt, I. J. Antibiot. 1983, 36, 1592. (c) Cooper,
R. D.; Jigajinni, V. B.; Wightman, R. H. Tetrahedron Lett. 1984, 45, 5215.
(d) Mori, K.; Otsuka, T. Tetrahedron 1985, 41, 3253. (e) Sato, F.;
Kobayashi, Y.; Takahashi, O.; Chiba, T.; Takeda, Y.; Kusakabe, M. J. Chem.
Soc., Chem. Commun. 1985, 1636. (f) Fujisawa, T.; Kojima, E.; Itoh, T.;
Sato, T. Chem. Lett. 1985, 1751. (g) Kotsuki, H.; Kadota, I.; Ochi, M. J.
Org. Chem. 1990, 55, 4417. (h) Wang, Z.-M.; Zhang, X.-L.; Sharpless,
K. B.; Sinha, S. C.; Sinha-Bagchi, A.; Keinan, E. Tetrahedron Lett. 1992,
33, 6407.
J. Am. Chem. Soc. 1993, 115, 4415
(6) 94% ee has been obtained for 3,3-ethylenedioxycyclohexene with
chiral (salen)Mn(III) catalyst; see refs 5a and 5b.
.
(7) For a recent report on Ti-catalyzed asymmetric epoxidation of
nonactivated cis-olefins (70-97% ee), see ref 5e.
Org. Lett., Vol. 11, No. 22, 2009
5151

Table 1. Asymmetric Epoxidation of Non-conjugated cis-Olefinsa
a For ketone 2d: unless otherwise stated, all reactions were carried out with olefin (1.0 equiv), catalyst (0.25 equiv), Oxone (1.6 equiv), and K2CO3 (6.7
equiv) in DME/DMM (3:1, v/v) and buffer (0.1 M K2CO3-AcOH in 4 × 10-4 M aq EDTA, pH 9.3) (1.5:1, v/v). For ketone 2a: unless otherwise stated,
all reactions were carried out with olefin (1.0 equiv), catalyst (0.25 equiv), Oxone (1.6 equiv), and K2CO3 (3.8 equiv) in DME/DMM/n-BuOH (3:1:2, v/v/v)
and buffer (0.1 M K2CO3-AcOH in 4 × 10-4 M aq EDTA, pH 8.0) (4:1, v/v). In both cases, Oxone and K2CO3 were added separately and simultaneously
over the time and temperature specified. b Isolated yield. c DME was used as solvent. d The ee was determined by chiral GC (Chiraldex B-DM column).
e The ee was determined by chiral GC (Chiraldex B-DM column) of the methyl ether derivative. f Absolute stereochemistry was determined by comparing
the optical rotation of the epoxide or its derivate with the reported one. g Relative stereochemistry indicated. The ee was determined by chiral HPLC (Chiralpak
AD column) of the benzoate derivative. h Absolute stereochemistry was determined by converting a compound of known configuration to the epoxide of
interest and comparing the optical rotation and chiral GC elution order. i 0.30 equiv catalyst was used. j 2.9 equiv of Oxone and 6.9 equiv of K2CO3 were
used. k DME/DMM (3:1, v/v) was used as solvent; the solvent/buffer ratio was 1.5:1 (v/v). l The ee was determined by chiral HPLC (Chiralcel OD column).
used to determine absolute configuration, see the Supporting
Information).
ketone 2a is most effective when this mechanism dominates.
In the case of an allylic alcohol (Table 1, entry 2), both
mechanisms might be operating in competition with each
other. In this case, the free hydroxyl group is apparently
hydrophilic enough to override the second mechanism to give
the observed epoxide configuration. Based purely on hydro-
phobic considerations, cis-3-nonen-1-ol (Table 1, entry 3)
would be expected to give lower ee than cis-2-nonen-1-ol
(entry 2) since the alkyl substituent is one carbon shorter
All these results suggest that there are two main mecha-
nisms of stereodifferentiation operating for these olefins. For
substrates in entries 1-5 (Table 1), the relative hydrophobic-
ity of the olefin substituents is the dominant mechanism of
stereodifferentiation, and ketone 2d is most effective. The
second mechanism differentiates substituents that contain an
allylic oxygen functionality from those that do not, and
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Org. Lett., Vol. 11, No. 22, 2009

interaction between the ketal of the olefin and the oxazoli-
dinone of the catalyst due to A1,3 strain.
The origin of enantioselectivity for substrates which rely
on differences in hydrophobicity of the olefin substituents
is fairly straightforward (Figure 3). However, the origin of
the apparent attraction for allylic oxygen functionality to the
oxazolidinone of the catalyst is not clear, and there are several
possible rationales. One possibility is that there is an
attraction between the electron lone pairs on the oxygen
atoms and a partial or transient positive charge on the
oxazolidinone (Figure 5) which would favor spiro G (Figures
Figure 4. Transition states for ether/ketal-containing olefins.
and the alcohol substituent is one carbon longer. However,
higher ee is observed (82% vs 79% ee). This result indicates
that the apparent attraction between oxygen-containing
functionality and the oxazolidinone of the catalyst is
significantly weakened when the oxygen-containing func-
tionality is not in the allylic position.
Figure 5. Possible electronic interactions in transition states.
Entry 6 is another case where both mechanisms of
stereodifferentiation appear to be operating in competition
with each other. However, in this case, the methyl ether
substituent is not hydrophilic enough to override the apparent
ether-oxazolidinone attraction with ketone 2a, so the (2R,3S)
enantiomer predominates. With ketone 2c hydrophobic
properties again dominate, but only slightly, giving 14% ee
of the (2S,3R) enantiomer.16 The high enantioselectivity
observed in the epoxidation of the allylic acetal of entry 10
(Table 1) along with the previous observations of high ee
with spirocyclic ketals (Scheme 1) indicate that two allylic
oxygens on the same side of the olefin create an even stronger
apparent attraction to the oxazolidinone of the catalyst than
one. The allylic ketal of entry 11 (Table 1) was an ineffective
substrate possibly because the olefin is too hindered or
because it cannot adopt the optimal conformation for the
4 and 5). Another possibility is that repulsion exists between
the electron lone pairs of the oxygen atoms of the substrate
and the fused ketal of the catalyst in spiro H, thus disfavoring
this transition state. A better understanding awaits further
studies.
In summary, the scope of the ketone-catalyzed asymmetric
epoxidation reaction has been expanded to include several
types of nonconjugated cis-olefins, and good to high ee’s
have been obtained for a number of substrates. If the two
substituents of nonconjugated cis-olefins have substantially
different hydrophobic or electronic properties, this system
could provide a good opportunity for asymmetric induction.
This study opens up a new avenue for this system that will
be valuable for further studies and designing new ketone
catalysts in the future.
Acknowledgment. We are grateful for the generous
financial support from the General Medical Sciences of the
National Institutes of Health (GM59705-08). We thank Drs.
Xuegong She, Hongqi Tian, and David Goeddel (Colorado
State University) for some previous studies.
(12) (a) Kanerva, L. T.; Va¨nttinen, E. Tetrahedron: Asymmetry 1993,
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.
Supporting Information Available: Synthesis and char-
acterization of olefins and epoxides, as well as the data for
the determination of the enantiomeric excess and the NMR
spectra of the epoxides. This material is available free of
charge via the Internet at http://pubs.acs.org.
.
.
(16) It was found that ketone 2a was the most effective catalyst. No ee
was obtained with ketone 2b, and 14% ee of the opposite enantiomer was
obtained with ketone 2c for cis-1-methoxy-2-nonene using DME/DMM
(3:1, v/v) as solvent.
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