Screening chiral fluorinated binaphthyl ketone catalysts for asymmetric epoxidation

Article abstract of DOI:10.1016/S0040-4039(02)00173-9

A series of five chiral binaphthyl ketone catalysts 4-8 with variable distributions of fluorine atoms alpha to the carbonyl have been synthesized. These catalysts were screened in the asymmetric epoxidation of trans-β-methylstyrene. The best catalyst was

Full text of DOI:10.1016/S0040-4039(02)00173-9

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 1943–1946
Screening chiral fluorinated binaphthyl ketone catalysts for
asymmetric epoxidation
Chad J. Stearman and Victor Behar*
Department of Chemistry MS-60, Rice University, Houston, TX 77251-1892, USA
Received 7 December 2001; revised 23 January 2002; accepted 24 January 2002
Abstract—A series of five chiral binaphthyl ketone catalysts 4–8 with variable distributions of fluorine atoms alpha to the carbonyl
have been synthesized. These catalysts were screened in the asymmetric epoxidation of trans-b-methylstyrene. The best catalyst
was a,a%-difluoroketone 6 which catalyzed the epoxidation to trans-b-methylstyrene oxide with 100% conversion and 86% e.e. at
10 mol% catalyst loading. © 2002 Elsevier Science Ltd. All rights reserved.
The asymmetric epoxidation of unfunctionalized alke-
nes by dioxiranes derived from chiral ketones remains
an active area of research.1 As part of initial screens for
promising new catalysts we were interested in pursuing
structures containing the binaphthyl scaffold for three
reasons. First the binaphthyl system has a proven
record in asymmetric synthesis as a strong agent of
chirality induction.2 Secondly, the binaphthyl skeleton
is easily modified to change the shape and depth of a
chiral pocket by the introduction of vaulting sub-
stituents at the 3 and 3% positions.2b,3 Finally, and most
importantly, functionalization at the 6 and/or 6% posi-
tions has been utilized to anchor the binaphthyl nucleus
to various solid supports to facilitate catalyst recovery.4
between the ketone group and the binaphthyl chiral
element is too large for effective epoxidation of smaller
substrates. The Song catalyst 2 moves the carbonyl
closer to the chirality axis, but only modest enan-
tiomeric excesses are reported. This has been attributed
to the relatively unactivated carbonyl, which lacks
alpha electron-withdrawing groups critical to good cat-
alytic turnover.1b
Finally, during the course of our work, Denmark
reported in a review1a unpublished results on the epoxi-
dation of trans-disubstituted alkenes in good yields and
modest to high enantioselectivities with 10–30 mol% of
a closely related chiral biphenyl catalyst 3 (Fig. 1). The
carbonyl is not only in closer proximity to the biaryl
axis, but it also incorporates the necessary electron
withdrawing groups to ensure good catalytic turnover.
We felt a binaphthyl moiety should provide a more
prominent chiral element and the absence of inductively
electron-donating methyl groups as found in catalyst 3,
would further improve the performance of a biaryl-
Chiral ketone catalyst systems based on the binaphthyl
skeleton have been developed by Yang3,5 and Song6
(Fig. 1) for asymmetric epoxidation albeit with limited
success. The Yang catalyst 1 is effective in the epoxida-
tion of 4,4%-substituted trans-stilbenes, a rather limited
class of substrates and Shi1b suggested that the distance
X
O
F
F
O
O
O
O
O
O
O
O
X
1 Yang
2 Song
3 Denmark
Figure 1. Related biaryl ketone catalysts.
Keywords: asymmetric synthesis; epoxidation; dioxirane.
* Corresponding author. Tel.: 1-713-348-6159; fax: 1-713-348-6355; e-mail: behar@rice.edu
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00173-9

1944
C. J. Stearman, V. Behar / Tetrahedron Letters 43 (2002) 1943–1946
based ketone epoxidation catalyst. Examination of the
literature led us to consider chiral ketone 4 (Fig. 2),
which had been synthesized in optically pure form by
Mislow and co-workers.7 We report herein an improved
preparation of ketone 4 and novel fluorinated deriva-
tives 5–8 (Fig. 2) and their reactivity in the asymmetric
epoxidation of trans-b-methylstyrene.
to bis-bromide 11 (81%) by treatment with HBr in
acetic acid was followed by ring closure to ketone 4
with ketone synthon TosMIC9 in 82% yield. Ketone 4 is
thus readily available in gram quantities in both enan-
tiomeric forms.
The next task was to determine a convenient way to
introduce fluorine atoms sequentially about the ketone
alpha positions. Ketone 4 was thus treated with 1
equiv. of potassium hydride and the resultant enolate
quenched with N-fluorobenzosulfonimide (NFSI)10 to
give monofluorinated ketone 511 in 77% yield as shown
in Scheme 1. Assignment of the stereochemistry of the
fluorination was made by literature comparison of pro-
ton–fluorine coupling constants.12 Furthermore, AM1
calculations revealed the equatorial fluorinated product
was 3.6 kcal/mol more stable than the axial fluorinated
product.
Synthesis of the parent catalyst 4 (Scheme 1) com-
menced with known diester 9, prepared by the method
of Takaya.8 Reduction of the ester groups with DibalH
proceeded in 85% yield to provide diol 10. Conversion
3
6
R2
R1
4: R1, R2, R3, R4 = H
5: R1, R3, R4 = H, R2 = F
6: R1, R3 = H, R2, R4 = F
7: R1, R2, R3 = F, R4 = H
8: R1, R2, R3, R4 = F
O
R4
R3
6'
3'
Further fluorination could be effected by treatment of
ketone 5 with various equivalents of LDA and quench-
ing with NFSI.13 Although it proved difficult to opti-
mize the yield for installing each fluorine atom
sequentially beyond the first, each of the fluorinated
products were readily separable by conventional flash
chromatography. This gave us the opportunity to
screen all the catalysts without concern for optimization
of the synthesis until the most efficient catalyst was
identified.
Figure 2. Novel ketone catalysts for asymmetric epoxidation.
X
X
c
X
O
4 X= H
5 X= F
9 X= CO2Me
10 X= CH2OH
11 X= CH2Br
a
b
d
Attention therefore turned to the catalyst screening
process to determine the effects of fluorination on the
efficiency of epoxidation. We chose as our standard of
comparison the epoxidation of trans-b-methylstyrene.
The results are summarized in Table 1 below. A direct
comparison with the Song system 2 showed that even
stoichiometric quantities of catalyst 2 gave only 29%
e.e. of the trans-b-methylstyrene oxide product.6 The
Denmark catalyst 3 gave only 55% conversion to trans-
Scheme 1. Synthesis of parent ketone 4 and a-fluoroketone 5.
(a) DibalH (4.4 equiv., 1.0 M toluene), CH2Cl2, −67°C–rt,
(85%); (b) HBr/AcOH (10 equiv., 30% soln), AcOH, rt,
(81%); (c) TosMIC (1.1 equiv.), NaOH (5 equiv.), TBAI (5
mol%), CH2Cl2–H2O, rt (82%); (d) i. KH, rt, ii. NFSI, −78°C
to rt (77%).
Table 1. Epoxidation of trans-b-methylstyrene with catalysts 2–8
10 mol % (S )-6
Ph
Ph
O
Oxone , K2CO3
DME-H2O
-15o C
Catalyst
Mol%
Time (h)
Temp. (°C)
Yield (%)
e.e.
29b
–
88
2
3
3
4
5
6
7
8
100
10
30
10
10
10
10
10
1
10
10
4
25
0
0
−15
−15
−15
−15
−15
95a
55
80
c
35d
57d
100d
100d
32d
46e
80e
86e
83e
40e
4
3.5
3.5
3.5
a Yield determined by GC.
b Determined by 1H NMR using chiral shift reagent Eu(hfc)3.
c Enantiomeric excess was not reported.
d Percent conversion was determined by 1H NMR at 400 MHz.
e Enantioselectivity was determined by HPLC (Chiralcel OD).

C. J. Stearman, V. Behar / Tetrahedron Letters 43 (2002) 1943–1946
1945
b-methylstyrene oxide at 10 mol% catalyst loading.
Unfortunately, no measure of the enantiomeric excess
was reported. Increasing the catalyst loading to 30
mol% gave 80% conversion and 88% e.e.1a The reac-
tions with catalysts 4–8 were all run under the same
conditions with 10 mol% catalyst at pH 9.3 and −15°C.
Parent ketone 4 epoxidized trans-b-methylstyrene to
35% conversion with 46% e.e. This was encouraging
since the non-fluorinated version of Denmark’s catalyst
3 only proceeded to about 5% conversion under similar
conditions. This was the first indication that we had a
more reactive catalyst.
oxide as a colorless to slightly yellow liquid. Conversion
of trans-b-methylstyrene to trans-b-methylstyrene oxide
1
was measured by H NMR at 400 MHz. Enantioselec-
tivity was determined by HPLC (Chiralcel OD).
Acknowledgements
We gratefully acknowledge financial support from the
Robert A. Welch Foundation (Grant C-14189), the
donors of the Petroleum Research Fund, administered
by the ACS, and William Marsh Rice University.
Monofluorinated ketone 5 drove the reaction to 57%
conversion, and further increased the enantiomeric
excess to 80%. The trend continued with the a,a%-
difluorinated catalyst 6 completely converting the sub-
strate to epoxide with 86% e.e. The effect of additional
fluorination leveled off and trifluoroketone catalyst 7
offered no improvement in the enantiomeric excess
though the conversion to epoxide was still complete.
Denmark had previously shown that fluorinated cyclo-
hexanone derivatives that were conformationally con-
strained showed a dramatic stereoelectronic effect, with
axial fluorination resulting in little activation of the
ketone moiety.11 This is consistent with the third
fluorine atom in catalyst 7 presumably occupying a
pseudoaxial position, thus offering no advantage com-
pared to difluorinated catalyst 6. Tetrafluorinated
ketone 8, which exists almost exclusively as the hydrate,
gave results similar to parent ketone 4. The strong
preference for formation of the hydrate makes catalyst
8 less available for dioxirane formation and hence the
drop in conversion and enantiomeric excess.
References
1. (a) Denmark, S. E.; Wu, Z. Synlett 1999, S1, 847–859; (b)
Frohn, M.; Shi, Y. Synthesis 2000, 1979–2000; (c) Tian,
H. Q.; She, X. G.; Xu, J. X.; Shi, Y. Org. Lett. 2001, 3,
1929–1931; (d) Wang, Z. M.; Miller, S. M.; Anderson, O.
P.; Shi, Y. J. Org. Chem. 2001, 66, 521–530; (e) Tian, H.
Q.; She, X. G.; Shi, Y. Org. Lett. 2001, 3, 715–718; (f)
Yang, D.; Jiao, G.-S.; Yip, T.-C.; Lai, T.-H.; Wong,
M.-K. J. Org. Chem. 2001, 66, 4619–4624.
2. (a) Imai, Y.; Zhang, W.; Kida, T.; Nakatsuji, Y.; Ikeda,
I. Tetrahedron Lett. 1998, 39, 4343–4346; (b) Kobayashi,
S.; Kusakabe, K.; Ishitani, H. Org. Lett. 2000, 2, 1225–
1227; (c) Miyashita, A.; Yasuda, A.; Takaya, H.; Tori-
umi, K.; Ito, T.; Souchi, T.; Noyori, R. J. Am. Chem.
Soc. 1980, 102, 7932–7934; (d) Ogasawara, M.; Yoshida,
K.; Kamei, H.; Kato, K.; Uozumi, Y.; Hayashi, T.
Tetrahedron: Asymmetry 1998, 9, 1779–1787; (e) Pfaltz,
A.; Pretot, R. Angew. Chem., Int. Ed. 1998, 37, 323–325;
(f) Rosini, C.; Franzini, L.; Raffaelli, A.; Salvadori, P.
Synthesis 1992, 503–517; (g) Uozumi, Y.; Kato, K.;
Hayashi, T. J. Am. Chem. Soc. 1997, 119, 5063–5064.
3. Yang, D.; Yip, T.-C.; Wang, X.-C.; Tang, M.-W.; Zheng,
J.-H.; Cheung, K.-K. J. Am. Chem. Soc. 1998, 120,
5943–5952.
4. (a) Nogami, H.; Matsunaga, S.; Kanai, M.; Shibasaki,
M. Tetrahedron Lett. 2001, 42, 279–283; (b) Huang,
W.-S.; Hu, Q.-S.; Pu, L. J. Org. Chem. 1999, 64, 7940–
7956; (c) Bayston, D. J.; Fraser, J. L.; Ashton, M. R.;
Baxter, A. D.; Polywka, M. E. C.; Moses, E. J. Org.
Chem. 1998, 63, 3137–3140.
5. (a) Yang, D.; Wang, X.-C.; Wong, M.-K.; Yip, T.-C.;
Tang, M.-W. J. Am. Chem. Soc. 1996, 118, 11311–11312;
(b) Yang, D.; Tang, M.-W.; Wong, M.-K.; Zheng, J.-H.;
Cheung, K.-K. J. Am. Chem. Soc. 1996, 118, 491–492.
6. Song, C. E.; Lee, K. C.; Lee, S.; Jin, B. W. Tetrahedron:
Asymmetry 1997, 8, 2921–2926.
In the screening process we have identified a,a%-difluori-
nated ketone 6 to contain the optimal degree of fluori-
nation for catalytic asymmetric epoxidation. The
activity of this catalyst in the epoxidation of trans-b-
methylstyrene is the highest to date for biaryl-based
ketone epoxidation catalysts. The next goal is to define
the scope of substrates accepted by this catalyst system.
Additionally, attachment to a solid support to facilitate
catalyst recycling is under active investigation.
General epoxidation procedure: To a 10 mL round-bot-
tomed flask were added tetrabutylammonium hydrogen
sulfate (1.0 mg, 0.002 mmol), trans-b-methylstyrene
(0.250 mL, 0.05 mmol, 0.2 M in DME) and a solution
of ketone (4–8) (0.250 mL, 0.005 mmol, 0.02 M in
DME) followed by 0.4 mL buffer (prepared: 0.5 mL
acetic acid added to 100 mL 0.1 M aqueous K2CO3).
Using a well salted ice bath, the reaction mixture was
cooled to −15°C. While vigorously stirring the above
solution, solutions of K2CO3 (0.2 mL, 1.44 M in water)
and Oxone (0.2 mL, 0.34 M in 1×10−4 M aq.
Na2EDTA) were delivered simultaneously via separate
syringes over a 3.5 h period using a syringe pump.
Immediately following the addition, the reaction was
quenched by dilution with ether and water. The water
layer was extracted with ether three times. The com-
bined organics were dried (Na2SO4), filtered and con-
centrated in vacuo to afford trans-b-methylstyrene
7. Mislow, K.; McGinn, F. A. J. Am. Chem. Soc. 1958, 80,
6036–6037.
8. Ohta, T.; Ito, M.; Inagaki, K.; Takaya, H. Tetrahedron
Lett. 1993, 34, 1615–1616.
9. (a) Possel, O.; van Leusen, A. M. Tetrahedron Lett. 1977,
4229–4232; (b) Tichy, M.; Holanova, J.; Zavada, J. Tet-
rahedron: Asymmetry 1998, 9, 3497–3504.
10. (a) Differding, E.; Lang, R. W. Tetrahedron Lett. 1988,
29, 6087–6090; (b) Enders, D.; Potthoff, M.; Raabe, G.;
Runsink, J. Angew. Chem., Int. Ed. Engl. 1997, 36, 2362–
2364.

1946
C. J. Stearman, V. Behar / Tetrahedron Letters 43 (2002) 1943–1946
11. (S)-a Fluoro ketone 5: To a suspension of KH (240 mg, 6
mmol) in THF (3 mL) was added a solution of (S)-
ketone 4 (183 mg, 0.6 mmol) in THF (3 mL) via cannula.
After 3 h the resulting orange potassium enolate was then
transferred to a solution of NFSI in THF at −78°C via
cannula. The solution was allowed to warm slowly to
room temperature. After 12 h the reaction was quenched
with aqueous NH4Cl. The reaction was partitioned
between water and CH2Cl2 and extracted three times with
CH2Cl2. Organic layers were combined and concentrated
in vacuo. Flash chromatography (EtOAc/hexanes, 1:3)
aqueous NH4Cl. The reaction was partitioned between
water and CH2Cl2. The aqueous layer was extracted with
CH2Cl2 (3 mL×2). Organic layers were combined and
concentrated. Successive flash chromatography (EtOAc/
benzene, 0.1:1.0 followed by EtOAc/hexanes 0.1:1.0)
afforded 4 (18%), 5 (26%), 6 (3%), 7 (26%) and 8 (16%).
1
Compound 6 H NMR (500 MHz, CDCl3): l 8.05–8.02
(d, 2H), 7.94–7.92 (d, 2H), 7.75–7.73 (d, 2H), 7.50–7.44
(m, 2H), 7.36–7.34 (d, 2H), 7.30–7.25 (m, 2H), 5.93 (dm,
2H, CHF, J=45.7 Hz). 19F NMR (470 MHz, CDCl3): l
−208.41 (dm, J=46 Hz). IR (NaCl, thin film) 1764 cm−1
.
HRMS (EI) calcd for (M+): 344.10127, found: 344.10178.
1
afforded a-fluoro ketone 5 (135 mg, 70%). H NMR (500
1
Compound 7 H NMR (500 MHz, CDCl3): l 8.15–7.25
MHz, CDCl3): l 8.05–7.25 (m, 12H), 5.98 (d, CHF,
J=47 Hz), 3.71 (s, 2H). 19F NMR (470 MHz, CDCl3): l
−208.05 (dm, J=47 Hz). IR (NaCl plate, thin film) 1741
cm−1. HRMS (CI) calcd for (M+H+): 327.11852, found:
327.11813.
(m, 12H), 6.23 (dd, CFH, doublet J=46.3 Hz, doublets
J=4.75 Hz), hydrate 5.47 (d, CHF, J=46.8 Hz). 19F
NMR (470 MHz, CDCl3) l −83.7 (dd, J1=283.8 Hz,
J2=4.59 Hz), −121.10 (ddd, J1=284 Hz, J2=8.84 Hz,
J3=0.86 Hz), −208.6 (ddd, J1=46.3 Hz, J2=8.75 Hz,
12. Denmark, S. E.; Crudden, C. M.; Matsuhashi, H. J. Org.
J3=1.15 Hz). IR (NaCl plate, thin film) 1769 cm−1
.
Chem. 1997, 62, 8288–8289.
HRMS (CI) calcd for (M+H+): 363.09967, found:
13. Fluorinated derivatives 6–8: To a solution of LDA (0.54
mL of a 0.93 M soln) in 2.3 mL THF at 0°C was added
a solution of (S)-ketone 5 (150 mg, 0.46 mmol) in 2.3 mL
THF via cannula. After 1 h the resulting lithium enolate
was transferred to NFSI (160 mg, 0.506 mmol) in 2.3 mL
THF at −78°C via cannula dropwise over a period of 15
min. The reaction was allowed to warm slowly to room
temperature. After 12 h the reaction was quenched with
1
363.09964. Compound 8 H NMR (500 MHz, CDCl3): l
8.37–7.23 (Ar, 12H), 4.1 (s (br), OH. 19F NMR (470
MHz, CDCl3): l −82.89 (dd, J1=269 Hz, J2=7 Hz),
−121.10 (ddd, J1=273 Hz, J2=6 Hz, J3=3 Hz), hydrate
−97.68 (d, J=250 Hz), −125.92 (dd, J1=241.5 Hz, J2=9
Hz). HRMS (CI) calcd for (M+H+): 381.09025, found:
381.09037.