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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
 
J Org Chem. Author manuscript; available in PMC 2010 November 6.
Published in final edited form as:
PMCID: PMC2784290
NIHMSID: NIHMS150607

Asymmetric Epoxidation of Fluoroolefins by Chiral Dioxirane. Fluorine Effect on Enantioselectivity

Abstract

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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.

Chiral ketones represent an important class of organic catalysts for asymmetric epoxidation.1 Our earlier studies have shown that ketones 1 and 2 are highly effective for the epoxidation of trans- and trisubstituted olefins,2,3 and ketones 3 are highly effective for the epoxidation of cis- and related olefins (Figure 1).4 The electronic and steric properties 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 state A, which is favored over spiro B due to the steric effect and favored over planar C due to the stabilizing secondary orbital interaction between the oxygen non-bonding 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 interactions.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

Figure 1
Ketones 1–3
Figure 2
Proposed transition states for the epoxidation with ketones 1 and 2.
Figure 3
Proposed transition states for the epoxidation with ketones 3.

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 non-fluorinated counterparts. We decided to investigate the asymmetric epoxidation of mono-fluorinated 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.812

The syntheses of various fluoroolefins are outlined in Scheme 1Scheme 4. Fluoroolefins 4–5, 8–9, and 11 were synthesized by fluorobromination13 followed by HBr elimination using DBU14 or KOtBu15 (Scheme 1). (Z)-Fluorostilbene (6) was synthesized by iodofluorination of cis-stilbene16 followed by the elimination of HI with KOtBu (Scheme 2), and (E)-fluorostilbene (7) was synthesized via Suzuki coupling of phenyl boronic acid and the corresponding bromide17 (Scheme 3). (1-Fluoro-2-methylprop-1-enyl)benzene (10) was synthesized in three steps from diethylphosphite via the fluorination of diethyl-α-hydroxybenzylphosphonate with DAST (Scheme 4).18

The epoxidation of fluoroolefins 4–11 were carried out with 28–30 mol% 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 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 configuration of the resulting epoxide is opposite to that of epoxides resulting from ketones 1 and 2. The epoxidation of olefins 6–9 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). However, 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 α-fluorostyrene (11) are generally modest (27–62% ee) as these are not effective substrates for the ketones tested (Table 1, entries 19–24).19

Table 1
Asymmetric Epoxidation of Fluoroolefins with Ketones 1–3aa

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 determined by comparing the absolute configuration of the methoxyketone 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 non-fluorinated carbon to form the corresponding ketone (Scheme 7). The absolute configuration determined by the above reaction sequence confirmed the absolute configuration obtained with the VCD data from BioTools (Table 1, entry 17).

When the epoxide obtained from olefins 8 and 9 were 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-hydroxydecan-5-one (18) was obtained in 89% ee, which further supports that nucleophilic attack occurs on the non-fluorinated carbon (Scheme 9).

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). 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) indicates that fluorine is not as effective in disfavoring spiro I as phenyl group in disfavoring spiro G (Figure 4 and Figure 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 additional beneficial interactions between the F and/or Ph group of the olefin and the acetate group of the catalyst in transition state spiro H (R = Ac), thus increasing the ee’s (Figure 5).3b

Figure 4
Proposed transition states for the epoxidation of olefins 4 and 6 with ketones 1 and 2.
Figure 5
Proposed transition states for the epoxidation of olefins 5 and 7 with ketones 1 and 2.

Higher ee’s obtained for the epoxidation of olefin 9 than that of olefin 8 with ketones 1 and 2 suggests 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.

Figure 6
Proposed transition states for the epoxidation of olefins 8 and 9 with ketones 1 and 2.

Lower ee obtained for the epoxidation of olefin 8 with ketone 1 (Table 1, entry 13) as compared to its non-fluorinated 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 non-bonding orbital of the dioxirane in spiro J, thus leading to more competition from planar C-like transition state and decreasing 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 non-fluorinated 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.

Figure 7
Proposed transition states for the epoxidation of olefins 5 and 11 with ketone 3a.

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.

Experimental Section

Representative asymmetric epoxidation procedure with ketone 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 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 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). Colorless oil; IR (film): 2960, 1468 cm−1; [α]20D = +12.8 (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.

Representative asymmetric epoxidation procedure with ketone 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 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 (0.027 g, 77% yield, 91% ee).

Representative asymmetric epoxidation procedure with ketone 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 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 (0.028 g, 80% yield, 6% ee).

Supplementary Material

1_si_001

Acknowledgement

We are grateful to the generous financial support from the General Medical Sciences of the National Institutes of Health (GM59705-08).

Footnotes

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 (71 pages). This material is available free of charge via the Internet at http://pubs.acs.org.

References

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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.
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22. The van der Waals’ radii of fluorine is larger than hydrogen (1.47 Å vs 1.20 Å) (see ref. 7)