Asymmetric epoxidation of fluoroolefins by chiral dioxirane. Fluorine effect on enantioselectivity

Article abstract of DOI:10.1021/jo901553t

(Chemical Equation Presented) The asymmetric epoxidation of various fluoroolefins has been studied using chiral ketone catalyst, and up to 93% ee was achieved with fructose-derived ketone 1.

Full text of DOI:10.1021/jo901553t

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state A, which is favored over spiro B due to the steric effect
Asymmetric Epoxidation of Fluoroolefins by Chiral
Dioxirane. Fluorine Effect on Enantioselectivity
and favored over planar C due to the stabilizing secondary
orbital interaction between the oxygen nonbonding orbital of
the dioxirane and the π* orbital of the olefin in the spiro
transition state (Figure 2).2,3,5 The stereodifferentiation for the
epoxidation with ketones 3 likely results from electronic inter-
actions.4 It appears that there exists an attraction between the
π substituent of the olefin and the oxazolidinone moiety of the
catalyst (spiro D is favored over spiro E) (Figure 3).4
O. Andrea Wong and Yian Shi*
Department of Chemistry, Colorado State University, Fort
Collins, Colorado 80523
yian@lamar.colostate.edu
Received July 17, 2009
FIGURE 1. Ketones 1-3.
The asymmetric epoxidation of various fluoroolefins has
been studied using chiral ketone catalyst, and up to 93%
ee was achieved with fructose-derived ketone 1.
FIGURE 2. Proposed transition states for the epoxidation with
ketones 1 and 2.
Chiral ketones represent an important class of organic
catalysts for asymmetric epoxidation.1 Our previous studies
have shown that ketones 1 and 2 are highly effective for the
epoxidation of trans- and trisubstituted olefins,2,3 and keto-
nes 3 are highly effective for the epoxidation of cis- and
related olefins (Figure 1).4 The electronic and steric proper-
ties of substituents on an olefin have an important impact on
the enantioselectivity for the epoxidation. The epoxidation
with ketones 1 and 2 proceeds mainly via spiro transition
FIGURE 3. Proposed transition states for the epoxidation with
ketones 3.
(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) For leading references on 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.;
Shi, Y. J. Org. Chem. 1997, 62, 2328. (c) Wang, Z.-X.; Tu, Y.; Frohn, M.;
Zhang, J.-R.; Shi, Y. J. Am. Chem. Soc. 1997, 119, 11224. (d) Shu, L.; Shi, Y.
Tetrahedron 2001, 57, 5213.
(3) For leading references on ketone 2, see: (a) Wu, X.-Y.; She, X.; Shi, Y.
J. Am. Chem. Soc. 2002, 124, 8792. (b) Wang, B.; Wu, X.-Y.; Wong, O. A.;
Nettles, B.; Zhao, M.-X.; Chen, D.; Shi, Y. J. Org. Chem. 2009, 74, 3986.
(4) For leading references on ketone 3, see: (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.; Shi, Y.
Angew. Chem., Int. Ed. 2006, 45, 4475. (l) Burke, C. P.; Shi, Y. J. Org. Chem.
2007, 72, 4093.
Fluorine has unique steric and electronic properties and is
widely used to alter the properties of organic molecules.6,7 It
is foreseeable that fluorinated olefins may display different
steric and electronic properties for the epoxidation with
chiral ketones as compared to their nonfluorinated counter-
parts. We decided to investigate the asymmetric epoxidation
of monofluorinated olefins using ketones 1-3 to explore the
effect of fluorine on reactivity and enantioselectivity. Herein,
we wish to report our studies on this subject.8-12
The syntheses of various fluoroolefins are outlined
in Schemes 1-4. Fluoroolefins 4, 5, 8, 9, and 11 were
(6) Chambers, R. D. Fluorine in Organic Chemistry; Blackwell Publishing:
Boca Raton, 2004.
(7) Smart, B. E. In Organofluorine Chemistry. Principles and Commercial
Applications; Banks, R. E., Smart, B. E., Tatlow, J. C., Ed.; Plenum Press:
New York, 1994; Chapter 3.
(5) For leading references on theoretic studies on transition states for the
ꢀ
dioxirane epoxidation, see: (a) Bach, R. D.; Andres, J. L.; Owensby, A. L.;
(8) For examples of asymmetric epoxidation of fluoroallylic alcohols and
^
nucleophilic epoxide opening, see: (a) Dubuffet, T.; Bidon, C.; Sauvetre, R.;
Normant, J.-F. J. Organomet. Chem. 1990, 393, 173. (b) Gosmini, C.;
Schlegel, H. B.; McDouall, J. J. W. J. Am. Chem. Soc. 1992, 114, 7207. (b)
Houk, K. N.; Liu, J.; DeMello, N. C.; Condroski, K. R. J. Am. Chem. Soc.
1997, 119, 10147. (c) Jenson, C.; Liu, J.; Houk, K. N.; Jorgensen, W. L. J. Am.
Chem. Soc. 1997, 119, 12982. (d) Deubel, D. V. J. Org. Chem. 2001, 66, 3790.
(e) Singleton, D. A.; Wang, Z. J. Am. Chem. Soc. 2005, 127, 6679.
^
Dubuffet, T.; Sauvetre, R.; Normant, J.-F. Tetrahedron: Asymmetry 1991,
2, 223. (c) Gosmini, C.; Sauvetre, R.; Normant, J. F. Bull. Soc. Chim. Fr 1993,
^
130, 236.
DOI: 10.1021/jo901553t
r
Published on Web 10/01/2009
J. Org. Chem. 2009, 74, 8377–8380 8377
2009 American Chemical Society

Wong and Shi
JOCNote
SCHEME 1
SCHEME 4
TABLE 1. Asymmetric Epoxidation of Fluoroolefins with Ketones 1-3aa
SCHEME 2
SCHEME 3
synthesized by fluorobromination13 followed by HBr elimi-
nation using DBU14 or KOtBu15 (Scheme 1). (Z)-Fluoros-
tilbene (6) was synthesized by iodofluorination of cis-stil-
bene16 followed by the elimination of HI with KOtBu
(Scheme 2), and (E)-fluorostilbene (7) was synthesized via
Suzuki coupling of phenylboronic acid and the correspond-
ing bromide17 (Scheme 3). (1-Fluoro-2-methylprop-1-enyl)-
benzene (10) was synthesized in three steps from diethyl
phosphite via the fluorination of diethyl R-hydroxybenzyl-
phosphonate with DAST (Scheme 4).18
The epoxidations of fluoroolefins 4-11 were carried out
with 28-30 mol % of ketones 1, 2, and 3a (R=p-EtPh) in
MeCN/DMM (2:1 v/v) at 0 °C for 8 h (Table 1). Good to
(9) For additional examples of asymmetric epoxidation of fluoroolefins,
see: Bortolini, O.; Fogagnolo, M.; Fantin, G.; Maietti, S.; Medici, A.
Tetrahedron: Asymmetry 2001, 12, 1113.
(10) For examples of epoxidation of fluoroolefins, see: (a) Elkik, E.; Le
Blanc, M. Bull. Soc. Chim. Fr. 1971, 38, 870. (b) Camps, F.; Messeguer, A.;
aAll reactions were carried out with olefin (0.20 mmol), ketone 1, or 3a
(0.06 mmol) or hydrate of ketone 2 (0.056 mmol), Oxone (0.27-0.53
mmol), K2CO3 (0.81-2.12 mmol), and Bu4NHSO4 (0.012 mmol) in
MeCN/DMM (2:1 v/v) and buffer at 0 °C (bath temperature) for 8 h.
bIsolated yield. cThe ee’s were determined by chiral GC (Chiraldex
B-DM), except for entries 7-9 which were determined by chiral HPLC
(Chiralcel OD). dThe absolute configurations of entries 4-6 and 16-18
were determined using the VCD spectra by BioTools.
ꢀ
Sanchez, F.-J. Tetrahedron 1988, 44, 5161. (c) Dubuffet, T.; Sauvetre, R.;
Normant, J. F. Tetrahedron Lett. 1988, 29, 5923. (d) Lluch, A.-M.; Sanchez-
^
ꢀ
Baeza, F.; Messeguer, A.; Fusco, C.; Curci, R. Tetrahedron 1993, 49, 6299. (e)
Kornilov, A. M.; Sorochinsky, A. E.; Kukhar, V. P. Tetrahedron: Asymmetry
1994, 5, 1015. (f) Michel, D.; Schlosser, M. Tetrahedron 1996, 52, 2429. (g)
Tranel, F.; Haufe, G. J. Fluorine Chem 2004, 125, 1593.
(11) For examples of fluorinated epoxide synthesis by ring closure of
halogenated alcohols, see: (a) Kirrmann, A.; Nouri-Bimorghi, R. Bull. Soc.
Chim. Fr. 1972, 6, 2328. (b) Duhamel, P.; Leblond, B.; Poirier, J.-M. J. Chem.
SCHEME 5
ꢀ
Soc., Chem. Commun. 1993, 476. (c) Duhamel, P.; Leblond, B.; Bidois-Sery,
L.; Poirier, J.-M. J. Chem. Soc., Perkin Trans. 1 1994, 2265. (d) Shimizu, M.;
Takebe, Y.; Kuroboshi, M.; Hiyama, T. Tetrahedron Lett. 1996, 37, 7387. (e)
Hollenstein, H.; Luckhaus, D.; Pochert, J.; Quack, M.; Seyfang, G. Angew.
Chem. 1997, 109, 136. (f) Shimizu, M.; Yamada, N.; Takebe, Y.; Hata, T.;
Kuroboshi, M.; Hiyama, T. Bull. Chem. Soc. Jpn. 1998, 71, 2903.
(12) For an example of fluorinated epoxide synthesis by halogen sub-
stitution of chlorinated or brominated epoxides, see: Leroy, J.; Bensoam, J.;
Humiliere, M.; Wakselman, C.; Mathey, F. Tetrahedron 1980, 36, 1931.
(13) Haufe, G.; Alvernhe, G.; Laurent, A.; Ernet, T.; Goj, O. Org. Synth.
1999, 76, 159.
(14) Wolkoff, P. J. Org. Chem. 1982, 47, 1944.
(15) Suga, H.; Hamatani, T.; Guggisberg, Y.; Schlosser, M. Tetrahedron
1990, 46, 4255.
(16) Olah, G. A.; Welch, J. T.; Vankar, Y. D.; Nojima, M.; Kerekes, I.;
Olah, J. J. Org. Chem. 1979, 44, 3872.
(17) (a) Eddarir, S.; Francesch, C.; Mestdagh, H.; Rolando, C. Bull. Soc.
Chim. Fr. 1997, 134, 741. (b) Chen, C.; Wilcoxen, K.; Huang, C. Q.; Strack,
N.; McCarthy, J. R. J. Fluorine Chem. 2000, 101, 285.
(18) (a) Taylor, W. P.; Zhang, Z.-Y.; Widlanski, T. S. Bioorg. Med. Chem.
1996, 4, 1515. (b) Tsai, H.-J.; Lin, K.-W.; Ting, T.-h.; Burton, D. J. Helv.
Chem. Acta. 1999, 82, 2231.
high ee’s (74-93%) were obtained for the epoxidation of
olefins 4 and 5 with ketones 1 and 2 (Table 1, entries 1-2,
4-5). Modest ee (41%) was obtained for the epoxidation of
olefin 5 with ketone 3a (Table 1, entry 6) and the configura-
tion of the resulting epoxide is opposite to that of epoxides
resulting from ketones 1 and 2. The epoxidation of olefins 6-9
8378 J. Org. Chem. Vol. 74, No. 21, 2009

Wong and Shi
JOCNote
SCHEME 6
SCHEME 7
generally gave good to high ee’s (65-91%) with ketones 1
and 2 (Table 1, entries 7-8, 10-11, 13-14, 16-17). How-
ever, the ee’s obtained for these olefins with ketone 3a are
generally low (6-56% ee) (Table 1, entries 12, 15, 18) except
in the case of olefin 6 (85% ee) (Table 1, entry 9). The ee’s for
the epoxidation of (1-fluoro-2-methylprop-1-enyl)benzene
(10) and R-fluorostyrene (11) are generally modest
(27-62% ee) as these are not effective substrates for the
ketones tested (Table 1, entries 19-24).19
SCHEME 8
In order to determine the absolute configuration of the
fluorinated epoxides, the epoxides obtained from olefins 8
and 9 with ketone 2 (Table 1, entries 14 and 17) were treated
with anhydrous TsOH-MeOH at rt for 2 h, giving (-)-(S)-
6-methoxydecan-5-one (12) in both cases (Scheme 5).20 The
absolute configuration of 6-methoxydecan-5-one was deter-
mined by comparing the absolute configuration of the
methoxy ketone synthesized from the epoxide (13) with
known configuration (Scheme 6).2c When the deuterated
(E)-5-fluorodec-5-ene oxide (14) was treated with anhydrous
TsOH-MeOH at rt for 2 h, deuterated 6-methoxydecan-
5-one (15) was obtained, suggesting that MeOH attacks on
the nonfluorinated carbon to form the corresponding ketone
(Scheme 7). The absolute configuration determined by the
above reaction sequence confirmed the absolute configura-
tion obtained with the VCD data from BioTools (Table 1,
entry 17).
When the epoxide obtained from olefins 8 and 9 was
treated with acetic acid in THF-H2O at 60 °C for 20 h,
(S)-6-hydroxydecan-5-one (16) was obtained with only a
slight loss of ee (Scheme 8).21 When deuterated epoxide 17
was subjected to the same conditions (acetic acid in
THF-H2O at 60 °C for 20 h), (S)-deuterated-6-hydroxyde-
can-5-one (18) was obtained in 89% ee, which further
supports that nucleophilic attack occurs on the nonfluori-
nated carbon (Scheme 9).
SCHEME 9
FIGURE 4. Proposed transition states for the epoxidation of
olefins 4 and 6 with ketones 1 and 2.
High enantioselectivities were obtained for Z-olefins 4
and 6 with ketones 1 and 2 (Table 1, entries 1-2, 7-8),
suggesting that spiro F is favored over spiro G due to
steric interaction between the phenyl ring on the olefin and
the spiro ketal group of the catalyst (Figure 4). The lower
ee’s obtained for E-olefins 5 and 7 with ketone 1 as compared
to that of olefins 4 and 6 (Table 1, entry 4 vs 1 and 10 vs 7)
indicate that fluorine is not as effective in disfavoring spiro
I as phenyl group in disfavoring spiro G (Figures 4 and 5,
R = CMe2). Higher ee’s obtained for the epoxidation of
olefins 5 and 7 with ketone 2 compared to that of ketone 1
(Table 1, entry 5 vs 4 and 11 vs 10) could be due to addi-
tional beneficial interactions between the F and/or Ph
group of the olefin and the acetate group of the catalyst in
FIGURE 5. Proposed transition states for the epoxidation of
olefins 5 and 7 with ketones 1 and 2.
transition state spiro H (R = Ac), thus increasing the ee’s
(Figure 5).3b
The higher ee’s obtained for the epoxidation of olefin 9
than that of olefin 8 with ketones 1 and 2 suggest that the
fluorine atom may be more effective in disfavoring spiro M
than the n-butyl group is in disfavoring spiro K (Figure 6).
High ee (91%) obtained for olefin 9 with ketone 2 again
suggests that there may be beneficial interactions between
the fluorine of the olefin and the OAc group of the catalyst in
transition state spiro L (R=Ac) as in the case of spiro H
(Figure 5), thus increasing the ee.
Lower ee obtained for the epoxidation of olefin 8 with
ketone 1 (Table 1, entry 13) as compared to its nonfluori-
nated counterpart (77% ee for 8 vs 91% ee (E)-dec-5-ene
with ketone 12c) could be due to the fact that the lone pair of
the fluorine substituent raises the π* orbital of the olefin
causing the weakening of the secondary orbital interaction
between the π* orbital of the olefin and the nonbonding
(19) The fluoroepoxides are reasonably stable except the epoxide from
olefin 7, which readily decomposes on silica gel. The epoxides from olefins 4,
5, and 11 are extremely volatile.
(20) The determination of the ee of compound 12 was attempted, but with
no success.
(21) The absolute configuration of 6-hydroxydecan-5-one is reported in:
Curci, R.; D’Accolti, L.; Dinoi, A.; Fusco, C.; Rosa, A. Tetrahedron Lett.
1996, 37, 115.
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JOCNote
mmol, 0.004 g) in MeCN/DMM (2:1, v/v) (3.0 mL) was added
buffer (0.05 M solution of Na2B4O7 10H2O in 4 ꢀ 10-4 M aq
3
Na2EDTA, pH 9.3) (2.0 mL) with stirring. Upon cooling to
0 °C, a solution of Oxone (0.27 mmol, 0.21 M in 4 ꢀ 10-4 M aq
Na2EDTA, 1.30 mL) and a solution of K2CO3 (1.16 mmol,
0.89 M in 4 ꢀ 10-4 M aq EDTA, 1.30 mL) were added dropwise
separately and simultaneously via syringe pump over 8 h. The
reaction was quenched by addition of pentane and extracted
with pentane. The combined organic layers were dried over
Na2SO4, filtered, concentrated, and purified by flash column
chromatography (pentane to pentane-Et2O, 40:1, v/v) to give
the epoxide as a colorless oil (0.029 g, 83% yield, 80% ee):
IR (film) 2960, 1468 cm-1; [R]20D=þ12.8 (c 0.86, CHCl3, 80%
ee); 1H NMR (300 MHz, CDCl3) δ 3.23-3.20 (m, 1H),
1.91-1.73 (m, 2H), 1.67-1.26 (m, 10H), 0.96-0.85 (m, 6H);
13C NMR (75 MHz, CDCl3) δ 100.3, 96.9, 62.9, 62.6, 29.6, 29.2,
28.2, 28.0, 25.8, 22.7, 22.6, 14.0. 19F NMR (376 MHz, CDCl3)
δ -129.2 (t, J=19.9 Hz). Anal. Calcd for C10H19FO: C, 68.93;
H, 10.99. Found: C, 68.69; H, 10.87.
FIGURE 6. Proposed transition states for the epoxidation of
olefins 8 and 9 with ketones 1 and 2.
Representative Asymmetric Epoxidation Procedure with Ke-
tone 2 (Table 1, Entry 17). To a solution of olefin 9 (0.20 mmol,
0.032 g), hydrate of ketone 2 (0.056 mmol, 0.018 g), and TBAHS
(0.012 mmol, 0.004 g) in MeCN/DMM (2:1, v/v) (3.6 mL) was
added buffer (0.05 M aq Na2HPO4-0.05 M aq KH2PO4, pH
7.0) (1.2 mL) with stirring. Upon cooling to 0 °C, a solution of
Oxone (0.40 mmol, 0.21 M in 4 ꢀ 10-4 M aq EDTA, 1.92 mL)
and a solution of K2CO3 (0.81 mmol, 0.42 M in 4 ꢀ 10-4 M aq
EDTA, 1.92 mL) were added dropwise separately and simulta-
neously via syringe pump over 8 h. The reaction was quenched
by addition of pentane and extracted with pentane. The com-
bined organic layers were dried over Na2SO4, filtered, concen-
trated, and purified by flash column chromatography (pentane
to pentane-Et2O, 40:1, v/v) to give the epoxide as a colorless oil
(0.027 g, 77% yield, 91% ee).
Representative Asymmetric Epoxidation Procedure with Ke-
tone 3 (Table 1, entry 18). To a solution of olefin 9 (0.20 mmol,
0.032 g), ketone 3a (0.06 mmol, 0.021 g), and TBAHS (0.012
mmol, 0.004 g) in MeCN/DMM (2:1, v/v) (3.0 mL) was added
buffer (0.1 M K2CO3-AcOH in 4 ꢀ 10-4 M aq Na2EDTA, pH
9.3) (2.0 mL) with stirring. Upon cooling to 0 °C, a solution of
Oxone (0.53 mmol, 0.21 M in 4 ꢀ 10-4 M aq EDTA, 2.52 mL)
and a solution of K2CO3 (2.12 mmol, 0.84 M in 4 ꢀ 10-4 M aq
EDTA, 2.52 mL) were added dropwise separately and simulta-
neously via syringe pump over 8 h. The reaction was quenched
by addition of pentane and extracted with pentane. The com-
bined organic layers were dried over Na2SO4, filtered, concen-
trated, and purified by flash column chromatography (pentane
to pentane-Et2O, 40:1, v/v) to give the epoxide as a colorless oil
(0.028 g, 80% yield, 6% ee).
FIGURE 7. Proposed transition states for the epoxidation of
olefins 5 and 11 with ketone 3a.
orbital of the dioxirane in spiro J, thus leading to more
competition from planar C-like transition state and decrea-
sing the ee.
The fluorine atom did not show a beneficial effect on the
epoxidation with ketone 3a. In fact, in most cases, lower ee’s
were obtained for fluorinated olefins than nonfluorinated
olefins (Table 1).4 For example, only 41% and 32% ee were
obtained, respectively, for olefins 5 and 11 with ketone 3a
(Table 1, entries 6 and 24). Compared to spiro D (Figure 3),
spiro N (Figure 7) is disfavored by the fluorine possibly via
steric22 and/or electronic repulsion.
In conclusion, a series of fluoroolefins were epoxidized
with ketones 1-3a, and up to 93% ee was obtained. In some
cases, the fluorine can act as an effective directing group via
its steric and/or electronic interactions with ketone catalysts.
In other cases, however, the fluorine is detrimental to the
enantioselectivity for the epoxidation. These results provide
us better understanding of the effect of the olefin substituent
on the chiral ketone-catalyzed epoxidation.
Acknowledgment. We are grateful to the generous finan-
cial support from the General Medical Sciences of the
National Institutes of Health (GM59705-08).
Experimental Section
Representative Asymmetric Epoxidation Procedure with Ke-
tone 1 (Table 1, Entry 16). To a solution of olefin 9 (0.20 mmol,
0.032 g), ketone 1 (0.06 mmol, 0.015 g), and TBAHS (0.012
Supporting Information Available: The synthesis and
characterization of olefins and epoxides along with the data
for the determination of the enantiomeric excess of the epoxides
and the VCD data. This material is available free of charge via
the Internet at http://pubs.acs.org.
(22) The van der Waals’ radii of fluorine is larger than hydrogen (1.47 vs
˚
1.20 A) (see ref 7).
8380 J. Org. Chem. Vol. 74, No. 21, 2009