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Communication

Enantioselective 5-exo-Fluorocyclization of Ene-Oximes

by
Taiki Rouno
,
Tomoki Niwa
,
Kousuke Nishibashi
,
Nobuharu Yamamoto
,
Hiromichi Egami
and
Yoshitaka Hamashima
*
School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan
*
Author to whom correspondence should be addressed.
Molecules 2019, 24(19), 3464; https://doi.org/10.3390/molecules24193464
Submission received: 26 August 2019 / Revised: 19 September 2019 / Accepted: 23 September 2019 / Published: 24 September 2019
(This article belongs to the Special Issue Fabulous Fluorine in Organic and Medicinal Chemistry)
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Abstract

:
The enantioselective 5-exo-fluorocyclization of ene-oxime compounds was demonstrated under phase-transfer catalysis. Although deprotonative fluorinations competed, the chemical yields and the ee values of the desired isoxazoline products were generally moderate to good. The absolute stereochemistry of the major isomer was determined to be S by comparison with the literature after transformation of the product to the corresponding iodinated isoxazoline.

Graphical Abstract

1. Introduction

Isoxazoline framework has been recognized as a significant substructure of natural and unnatural compounds [1,2], which possess various biological activities including anticancer activity [3,4], FXa inhibitory activity [5], and antiparasitic activity [6,7,8,9]. Therefore, the construction of isoxazoline has been actively studied [10,11,12,13]. Among various methods for isoxazoline synthesis, a difunctionalization-type cyclization of ene-oxime is one of the major strategies. Cyclization reactions with concomitant introduction of a fluoroalkyl group [14,15,16,17], a hydroxyl group [18,19], a thiocyanate group [20], and an iodine group [21] have been reported so far.
Fluorine chemistry has contributed to pharmaceutical and agrochemical sciences, because an introduction of fluorine atom(s) at an appropriate position often improves the property of the parent compounds in terms of metabolic stability, lipophilicity, and so on [22,23,24,25,26,27]. Thus, a tremendous amount of fluorination reactions, including the asymmetric versions have been investigated [28,29,30]. Reflecting that alkene is a useful feedstock in organic chemistry and easy to prepare, asymmetric fluoro-functionalizations of alkenes have attracted increasing attention [31,32,33,34,35,36,37]. However, there is no report of the asymmetric fluorocyclization of ene-oximes, while its racemic version was recently reported in 2017 [38].
Our recent research interests include the asymmetric fluorofunctionalization of alkenes by phase-transfer catalysis. In 2015, we reported the first successful example of asymmetric fluorolactonization of ene-carboxylic acids using a hydroxymethyl carboxylate phase-transfer catalyst [39]. Based on this study, we recently developed a linked-binaphthyl dicarboxylic acid precatalyst 1, which was proven to be highly effective for the asymmetric fluorocyclization and the deprotonative fluorination of allylic amides (Scheme 1a) [40,41]. In these reactions, hydrogen bonding between the catalyst and the substrate was considered to be crucial for high asymmetric induction. Considering pKa values of amide and oxime, we anticipated that oxime could interact with our anionic phase-transfer catalyst through hydrogen bonds, which would define the conformation of the substrate and/or a fluorinated carbocation intermediate. Our previous study suggested that the fluorocyclization of alkenes proceeds via the formation of a fluoro-carbocation intermediate [40,41]. If this is the case, hydrogen bond interaction of the cationic intermediate with the catalyst seems essential, because the intramolecular cyclization step is an enantio-determining step. Herein, we report our effort to develop the enantioselective 5-exo-fluorocyclization of ene-oximes to provide fluorinated isoxazolines (Scheme 1b).

2. Results and Discussion

Ene-oxime 2a [21] was chosen as a test substrate to optimize the reaction conditions (Table 1). At first, the reaction was carried out with 1 under the previous cyclization conditions [40] and the desired product, 3a, was obtained with 58% ee (entry 1). In this reaction, undesired byproducts were simultaneously observed by 1H NMR analysis of the crude mixture. Although these byproducts could not be purified at this point, 1H and 19F NMR analyses suggested that the byproducts were deprotonative fluorination products 4a–6a. The enantioselectivity observed in chlorobenzene and benzene was almost the same with that in toluene, but the reaction rate became somewhat slower (entries 1–3). Use of CH2Cl2 and THF resulted in low chemical yield (entries 4 and 5). While Na2SO4 had a positive effect in improving the chemical yield in our previous case [40,41], it did not affect the reaction efficiency in the present reaction (entries 1 and 6). Among bases tested, Na3PO4 was found to be the base of choice in terms of the chemical yield of the desired product 3a (entries 6–11). The enantioselectivity was almost similar (59%–61%), irrespective of the basicity and counter cation. Proton sponge provided a low yield and a low enantioselectivity under the described conditions (entry 11). As seen in entry 12, the reaction rate became slower at 15 °C, but a better enantioselectivity was observed (69% ee). In all cases, the yields based on the recovered starting material were around 65%. Interestingly, the ee of 6a was as high as 77% under the optimized conditions (entry 12), albeit in only 4% yield. It should be noted that phosphoric acid 7, which is a commonly used precursor of anionic phase transfer catalysts [33], did not promote the present reaction (entry 14), confirming the better performance of our dicarboxylate catalyst.
To determine the absolute stereochemistry of the major isomer, the fluorinated isoxazoline 3a was transformed to the corresponding iodinated isoxazoline 8a with MgI2 using a sealed tube at 80 °C [42] (Scheme 2). Although the conversion was modest, 8a could be obtained without erosion of the ee value. The stereochemistry of the major isomer was determined to be S by comparing the retention time of HPLC analysis with that reported in the literature [21]. This result indicates that the major isomer of the present fluorocyclization is S.
Having optimized the reaction conditions, other ene-oximes were transformed to the corresponding fluorinated isoxazolines (Figure 1). Reactions of para- and meta-methylated substrates proceeded to give the corresponding isoxazoline products with good ee values (3b, 3c). However, ortho-substituent retarded the reaction completely, probably due to the steric repulsion (3d). meta-Chlorinated and para-fluorinated isoxazolines were formed with 77% ee and 73% ee, respectively (3e and 3f). An ene-oxime bearing a cyclohexyl group was less reactive for the fluorocyclization and 3g was obtained in only 12% yield, even at room temperature. The chemical structure on the oxime side did not have a significant impact on the enantioselectivity (3h and 3i). To our delight, a substrate having a thiophen group provided 3j in 69% with 84% ee. We additionally performed the SDE (self-disproportionation of enantiomer) test by achiral column chromatography [43]. The difference between the first and the last fractions was less than 1% ee, suggesting that SDE did not occur. As usual, all fractions were collected after the chromatographic purification.
To confirm the importance of hydrogen bond interaction between the oxime and the dianionic catalyst 1, the following control experiment was carried out. Thus, when O-methylated compound 9 was subjected to the described reaction conditions, no reaction occurred at all and the starting material 9 was just recovered (Scheme 3). Since even deprotonated products were not formed, it is likely that the hydrogen bond interaction has an important role in accelerating the fluorination step, in addition to the enantioselectivity control.

3. Materials and Methods

3.1. General Information

1H and 19F NMR spectra were measured on a JEOL ECX-500 spectrometer at 500 and 470 MHz, respectively. 13C NMR spectra were recorded on a JEOL JNM-ECX-500 spectrometer at 125 MHz. Chemical shifts were reported in parts per million (ppm) downfield from TMS (δ = 0) for 1H NMR. For 13C NMR, chemical shifts were reported in the scale relative to CDCl3. For 19F NMR, chemical shifts were reported in a scale relative to CFCl3 external standard (δ = 0 ppm). Column chromatography was performed with silica gel N-60 (40–100 μm) purchased from Kanto Chemical Co., Inc. TLC analysis was performed on Silica gel 60 F254-coated glass plates (Merck). Visualization was accomplished by means of ultraviolet (UV) irradiation at 254 nm or by spraying an ethanol solution of 12-molybdo(VI)phosphoric acid as a developing agent.
Dehydrated dichloromethane (CH2Cl2) and toluene were purchased from Wako Pure Chemical Industries, Ltd. Dehydrated tetrahydrofuran (THF), diethyl ether (Et2O), and benzene were purchased from Kanto Chemical Co., Inc. Selectfluor was purchased from Aldrich. Other reagents were purified by usual methods.
The substrates were synthesized according to the literature [21]. The catalysts were synthesized according to the literature [40]. The 1H, 13C and 19F NMR spectra and HPLC data of compounds 3 are available in the Supplementary Material.

3.2. Asymmetric Fluorocyclization of Ene-Oximes

To a solution of 2a (23.7 mg, 0.1 mmol), 1 (9.7 mg, 10 mol %), and Na3PO4 (24.6 mg, 1.5 equiv) in toluene (1 mL), was added Selectfluor (53.1 mg, 1.5 equiv) at 15 °C under Ar atmosphere. After stirring for 72 h at 15 °C, the reaction mixture was diluted with EtOAc and filtrated through a pad of Celite. The filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel (n-hexane/ethyl acetate = 20/1 → 15/1 → 10/1) to provide 3a as a colorless solid (14.8 mg, 58%). The ee value was determined by chiral HPLC analysis.
5-(Fluoromethyl)-3,5-diphenylisoxazoline (3a). Colorless solid (58%, 14.8 mg). [α]27D = 29.7 (c = 0.47, CHCl3). The ee value (69% ee) was determined by HPLC analysis using a chiralpack IG-3 (n-hexane/i-PrOH = 80:20, flow rate = 1.0 mL/min, t(minor) = 11.4 min, t(major) = 20.6 min). 1H NMR (500 MHz, CDCl3) δ = 7.69–7.67 (m, 2H), 7.53–7.51 (m, 2H), 7.43–7.38 (m, 5H), 7.36–7.33 (m, 1H), 4.64 (dd, J = 9.7, 47.5 Hz, 1H), 4.60 (dd, J = 9.7, 47.5 Hz, 1H), 3.89 (d, J = 16.6 Hz, 1H), 3.53 (dd, J = 2.3, 16.6 Hz, 1H). 13C NMR (125 MHz, CDCl3) δ = 156.2, 140.1 (d, J = 3.6 Hz), 130.3, 129.3, 128.7, 128.7, 128.4, 126.7, 125.5, 88.9 (d, J = 18.0 Hz), 85.5 (d, J = 183.5 Hz), 42.9 (d, J = 3.6 Hz). 19F NMR (470 MHz, CDCl3) δ = −221.3 (t, J = 47.5 Hz, 1F). IR (neat): 2941, 1599, 1447, 1362, 1020, 980, 912 cm−1. HRMS (ESI) m/z calcd. for C16H15FNO [M + H+]: 256.1132, found: 256.1131.
5-(Fluoromethyl)-3-phenyl-5-(p-tolyl)isoxazoline (3b). Colorless solid (46%, 12.7 mg). [α]29D = 31.8 (c = 0.38, CHCl3). The ee value (47% ee) was determined by HPLC analysis using a chiralpack IG-3 (n-hexane/i-PrOH = 80:20, flow rate = 1.0 mL/min, t(minor) = 13.4 min, t(major) = 23.5 min). 1H NMR (500 MHz, CDCl3) δ = 7.67–7.66 (m, 2H), 7.42–7.37 (m, 5H), 7.21 (d, J = 8.0 Hz, 2H), 4.61 (dd, J = 10.0, 47.4 Hz, 1H), 4.57 (dd, J = 10.0, 47.4 Hz, 1H) 3.86 (d, J = 16.6 Hz, 1H), 3.51 (dd, J = 1.7, 16.6 Hz, 1H), 2.35 (s, 3H). 13C NMR (125 MHz, CDCl3) δ = 156.2, 138.2, 137.1 (d, J = 3.6 Hz), 130.2, 129.4, 129.3, 128.7, 126.6, 125.4, 88.9 (d, J = 18.0 Hz), 85.5 (d, J = 183.5 Hz), 42.8 (d, J = 3.6 Hz), 21.0. 19F NMR (470 MHz, CDCl3) δ = −220.9 (t, J = 47.4 Hz, 1F). IR (neat): 2922, 1570, 1514, 1447, 1358, 978, 906 cm−1. HRMS (ESI) m/z calcd. for C17H17FNO [M + H+]: 270.1289, found: 270.1287.
5-(Fluoromethyl)-3-phenyl-5-(m-tolyl)isoxazoline (3c). Colorless solid (48%, 12.9 mg). [α]28D = 21.4 (c = 0.50, CHCl3). The ee value (54% ee) was determined by HPLC analysis using a chiralpack IG-3 (n-hexane/i-PrOH = 80:20, flow rate = 1.0 mL/min, t(minor) = 8.7 min, t(major) = 12.4 min). 1H NMR (500 MHz, CDCl3) δ = 7.69–7.68 (m, 2H), 7.41–7.39 (m, 3H), 7.35 (s, 1H), 7.30–7.29 (m, 2H), 7.17-7.15 (m, 1H), 4.63 (dd, J = 10.0, 47.6 Hz, 1H), 4.60 (dd, J = 10.0, 47.6 Hz, 1H), 3.88 (d, J = 16.6 Hz, 1H), 3.53 (dd, J = 2.3, 16.6 Hz, 1H), 2.39 (s, 3H). 13C NMR (125 MHz, CDCl3) δ = 156.2, 140.0 (d, J = 3.6 Hz), 138.5, 130.2, 129.3, 129.1, 128.7, 128.6, 126.6, 126.1, 122.5, 88.9 (d, J = 18.0 Hz), 85.6 (d, J = 183.5 Hz), 42.8 (d, J = 3.6 Hz), 21.5. 19F NMR (470 MHz, CDCl3) δ = −221.1 (t, J = 47.6 Hz, 1F). IR (neat): 2955, 1600, 1487, 1447, 1364, 1011, 922 cm−1. HRMS (ESI) m/z calcd. for C17H17FNO [M + H+]: 270.1289, found: 270.1286.
5-(3-Chlorophenyl)-5-(fluoromethyl)-3-phenylisoxazoline (3e). Colorless oil (54%, 15.6 mg). [α]27D = 33.3 (c = 0.19, CHCl3). The ee value (77% ee) was determined by HPLC analysis using a chiralpack IG-3 (n-hexane/i-PrOH = 80:20, flow rate = 1.0 mL/min, t(minor) = 8.8 min, t(major) = 10.2 min). 1H NMR (500 MHz, CDCl3) δ = 7.68–7.66 (m, 2H), 7.53 (s, 1H), 7.41–7.39 (m, 4H), 7.36–7.31 (m, 2H), 4.62 (dd, J = 10.0, 47.0 Hz, 1H), 4.56 (dd, J = 10.0, 47.0 Hz, 1H), 3.88 (d, J = 16.6 Hz, 1H), 3.50 (dd, J = 2.3, 16.6 Hz, 1H). 13C NMR (125 MHz, CDCl3) δ = 156.2, 142.3 (d, J = 2.4 Hz), 134.8, 130.4, 130.1, 128.9, 128.8, 128.6, 126.7, 125.9, 123.7, 88.3 (d, J = 19.2 Hz), 85.1 (d, J = 183.5 Hz), 43.1 (d, J = 3.6 Hz). 19F NMR (470 MHz, CDCl3) δ = −221.6 (t, J = 47.0 Hz, 1F). IR (neat): 2940, 1597, 1572, 1447, 1358, 1034, 995, 910 cm−1. HRMS (ESI) m/z calcd. for C16H14ClFNO [M + H+]: 290.0742, found: 290.0743.
5-(Fluoromethyl)-5-(4-fluorophenyl)-3-phenylisoxazoline (3f). Colorless solid (54%, 14.8 mg). [α]28D = 27.6 (c = 0.40, CHCl3). The ee value (73% ee) was determined by HPLC analysis using a chiralpack IG-3 (n-hexane/i-PrOH = 80:20, flow rate = 1.0 mL/min, t(minor) = 10.1 min, t(major) = 17.1 min). 1H NMR (500 MHz, CDCl3) δ = 7.68–7.66 (m, 2H), 7.51–7.48 (m, 2H), 7.42–7.38 (m, 3H), 7.11–7.08 (m, 2H), 4.61 (dd, J = 9.7, 47.5 Hz, 1H), 4.57 (dd, J = 9.7, 47.5 Hz, 1H), 3.88 (d, J = 16.6 Hz, 1H), 3.49 (dd, J = 2.3, 16.6 Hz, 1H). 13C NMR (125 MHz, CDCl3) δ = 162.6 (d, J = 247.1 Hz), 156.2, 136.0 (t, J = 3.6 Hz), 130.4, 129.1, 128.8, 127.4 (d, J = 8.4 Hz), 126.7, 115.7 (d, J = 21.6 Hz), 88.4 (d, J = 19.2 Hz), 85.3 (d, J = 183.5 Hz), 43.1 (d, J = 3.6 Hz). 19F NMR (470 MHz, CDCl3) δ = −113.5–−113.6 (m, 1F), −221.1 (t, J = 47.5 Hz, 1F). IR (neat): 1601, 1508, 1447, 1360, 1221, 1159, 1028, 918 cm−1. HRMS (ESI) m/z calcd. for C16H14F2NO [M + H+]: 274.1038, found: 274.1034.
5-Cyclohexyl-5-(fluoromethyl)-3-phenylisoxazoline (3g). Colorless oil (12%, 3.1 mg). [α]29D = 45.8 (c = 0.34, CHCl3). The ee value (65% ee) was determined by HPLC analysis using a chiralpack IG-3 (n-hexane/i-PrOH = 80:20, flow rate = 1.0 mL/min, t(minor) = 8.2 min, t(minor) = 9.2 min). 1H NMR (500 MHz, CDCl3) δ = 7.68–7.66 (m, 2H), 7.41–7.39 (m, 3H), 4.53 (dd, J = 9.7, 47.0 Hz, 1H), 4.49 (dd, J = 9.7, 47.0 Hz, 1H), 3.22 (d, J = 1.7 Hz, 2H), 1.82–1.78 (m, 5H), 1.71–1.69 (m, 1H), 1.32–1.05 (m, 5H). 13C NMR (125 MHz, CDCl3) δ = 155.7, 130.0, 129.6, 128.7, 126.5, 90.2 (d, J = 16.8 Hz), 84.2 (d, J = 177.5 Hz), 42.6 (d, J = 2.4 Hz), 37.9 (d, J = 6.0 Hz), 27.2, 26.5, 26.2, 26.1, 26.1. 19F NMR (470 MHz, CDCl3) δ = −229.6 (t, J = 47.0 Hz, 1F). IR (neat): 2922, 1595, 1447, 1360, 1009, 926 cm−1. HRMS (ESI) m/z calcd. for C16H21FNO [M + H+]: 262.1602, found: 262.1609.
3-(4-Bromophenyl)-5-(fluoromethyl)-5-phenylisoxazoline (3h). Colorless solid (37%, 12.4 mg). [α]28D = 22.5 (c = 0.39, CHCl3). The ee value (56% ee) was determined by HPLC analysis using a chiralpack IG-3 (n-hexane/i-PrOH = 80:20, flow rate = 1.0 mL/min, t(minor) = 12.9 min, t(major) = 20.4 min). 1H NMR (500 MHz, CDCl3) δ = 7.55–7.49 (m, 6H), 7.43–7.40 (m, 2H), 7.36–7.33 (m, 1H), 4.63 (dd, J = 10.3, 47.1 Hz, 1H), 4.59 (dd, J = 10.3, 47.1 Hz, 1H), 3.86 (d, J = 16.6 Hz, 1H), 3.50 (dd, J = 2.3, 16.6 Hz, 1H). 13C NMR (125 MHz, CDCl3) δ = 155.3, 139.8 (d, J = 4.8 Hz), 131.9, 128.8, 128.5, 128.2, 128.1, 125.4, 124.5, 89.3 (d, J = 18.0 Hz), 85.5 (d, J = 184.7 Hz), 42.6 (d, J = 3.6 Hz). 19F NMR (470 MHz, CDCl3) δ = −221.2 (t, J = 47.1 Hz, 1F). IR (neat): 2951, 1589, 1489, 1447, 1396, 1356, 1246, 989 cm−1. HRMS (ESI) m/z calcd. for C16H14BrFNO [M + H+]: 334.0237, found: 334.0237.
3-(3-Chlorophenyl)-5-(fluoromethyl)-5-phenylisoxazoline (3i). Colorless oil (58%, 16.8 mg). [α]28D = 43.5 (c = 0.30, CHCl3). The ee value (79% ee) was determined by HPLC analysis using a chiralpack IG-3 (n-hexane/i-PrOH = 80:20, flow rate = 1.0 mL/min, t(minor) = 8.1 min, t(major) =9.7 min). 1H NMR (500 MHz, CDCl3) δ = 7.66 (s, 1H), 7.57 (d, J = 7.5 Hz, 1H), 7.50 (d, J = 8.0 Hz, 2H), 7.43–7.40 (m, 2H), 7.38–7.31 (m, 3H), 4.64 (dd, J = 10.3, 47.1 Hz, 1H), 4.60 (dd, J = 10.3, 47.1 Hz, 1H), 3.87 (d, J = 16.6 Hz, 1H), 3.51 (dd, J = 2.3, 16.6 Hz, 1H). 13C NMR (125 MHz, CDCl3) δ = 155.2, 139.7 (d, J = 3.6 Hz), 134.7, 131.0, 130.2, 130.0, 128.8, 128.5, 126.7, 125.4, 124.7, 89.4 (d, J = 18.0 Hz), 85.5 (d, J = 184.7 Hz), 42.5 (d, J = 3.6 Hz). 19F NMR (470 MHz, CDCl3) δ = −221.2 (t, J = 47.1 Hz). IR (neat): 3063, 2947, 1595, 1560, 1429, 1344, 1028, 918 cm−1. HRMS (ESI) m/z calcd. for C16H14ClFNO [M + H+]: 290.0742, found: 290.0724.
5-(fluoromethyl)-5-phenyl-3-(3-thiophen-2-yl)isoxazoline (3j). Colorless solid (69%, 18.0 mg). [α]28D = 14.3 (c = 0.25, CHCl3). The ee value (84% ee) was determined by HPLC analysis using a chiralpack IG-3 (n-hexane/i-PrOH = 80:20, flow rate = 1.0 mL/min, t(minor) = 11.8 min, t(major) = 21.6 min). 1H NMR (500 MHz, CDCl3) δ = 7.52–7.50 (m, 2H), 7.43–7.38 (m, 3H), 7.36–7.33 (m, 1H), 7.21–7.20 (m, 1H), 7.06–7.04 (m, 1H), 4.63 (dd, J = 10.3, 47.5 Hz, 1H), 4.59 (dd, J = 10.3, 47.5 Hz, 1H), 3.90 (d, J = 16.2 Hz, 1H), 3.53 (dd, J = 2.6, 16.2 Hz, 1H). 13C NMR (125 MHz, CDCl3) δ = 152.0, 139.8 (d, J = 3.6 Hz), 131.7, 128.8, 128.5, 128.5, 128.4, 127.3, 125.5, 89.1 (d, J = 18.1 Hz), 85.3 (d, J = 183.5 Hz), 43.6 (d, J = 3.6 Hz). 19F NMR (470 MHz, CDCl3) δ = −221.1 (t, J = 47.5 Hz). IR (neat): 3084, 2943, 1600, 1491, 1437, 1024, 982, 907 cm−1. HRMS (ESI) m/z calcd. for C14H13FNOS [M + H+]: 262.0696, found: 262.0695.

4. Conclusions

In this paper, we have demonstrated the enantioselective 5-exo-fluorocyclization of ene-oximes using the linked-binaphthyl dicarboxylic acid precatalyst 1. The corresponding fluorinated isoxazolines were obtained with up to 84% ee, and the stereochemistry of the major isomers were determined to be S after transformation to known isoxazoline 8a with an iodomethyl unit. A control experiment revealed that hydrogen bond interaction of the oxime group is extremely important for the reaction acceleration and the enantioselectivity control. Further applications of the present fluorinating system are underway in our laboratory.

Supplementary Materials

The following are available online, 1H, 13C, and 19F NMR spectra of compounds 3 and HPLC data of compounds 3.

Author Contributions

H.E. and Y.H. conceived and directed this project. T.R., T.N., K.N., N.Y., and H.E. performed the experiments. H.E. and Y.H. wrote the paper.

Funding

This work was supported by a Grant-in-Aid for Scientific Research (Nos. 18K06585, and 19H03353) from JSPS, Basis for Supporting Innovative Drug Discovery and Life Science Research (BINDS) from Japan Agency for Medical Research and Development (AMED), The Uehara Memorial Foundation and Nagase Science and Technology Foundation.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Kaur, K.; Kumar, V.; Sharma, A.K.; Gupta, G.K. Isoxazoline containing natural products as anticancer agents: A review. Eur. J. Med. Chem. 2014, 77, 121–133. [Google Scholar] [CrossRef]
  2. Schorderet-Weber, S.; Noack, S.; Selzer, P.M.; Kaminsky, R. Blocking transmission of vector-borne diseases. Int. J. Parasitol. Drugs Drug Resist. 2017, 7, 90–109. [Google Scholar] [CrossRef] [PubMed]
  3. Kamal, A.; Reddy, J.S.; Ramaiah, M.J.; Dastagiri, D.; Bharathi, E.V.; Azhar, M.A.; Sultana, F.; Pushpavalli, S.; Pal-Bhadra, M.; Juvekar, A.; et al. Design, synthesis and biological evaluation of 3,5-diaryl-isoxazoline/isoxazole-pyrrolobenzodiazepine conjugates as potential anticancer agents. Eur. J. Med. Chem. 2010, 45, 3924–3937. [Google Scholar] [CrossRef]
  4. Kamal, A.; Bharathi, E.V.; Reddy, J.S.; Ramaiah, M.J.; Dastagiri, D.; Reddy, M.K.; Viswanath, A.; Reddy, T.L.; Shaik, T.B.; Pushpavalli, S.; et al. Synthesis and biological evaluation of 3,5-diaryl isoxazoline/isoxazole linked 2,3-dihydroquinazolinone hybrids as anticancer agents. Eur. J. Med. Chem. 2011, 46, 691–703. [Google Scholar] [CrossRef] [PubMed]
  5. Quan, M.L.; Ellis, C.D.; Liauw, A.Y.; Alexander, R.S.; Knabb, R.M.; Lam, G.; Wright, M.R.; Wong, P.C.; Wexler, R.R. Design and Synthesis of Isoxazoline Derivatives as Factor Xa Inhibitors. 2. J. Med. Chem. 1999, 42, 2760–2773. [Google Scholar] [CrossRef] [PubMed]
  6. Ozoe, Y.; Asahi, M.; Ozoe, F.; Nakahira, K.; Mita, T. The antiparasitic isoxazoline A1443 is a potent blocker of insect ligand-gated chloride channels. Biochem. Biophys. Res. Commun. 2010, 391, 744–749. [Google Scholar] [CrossRef]
  7. Gracia-Reynaga, P.; Zhao, C.; Sarpong, R.; Casida, J.E. New GABA/Glutamate Receptor Target for [3H]Isoxazoline Insecticide. Chem. Res. Toxicol. 2013, 26, 514–516. [Google Scholar] [CrossRef] [PubMed]
  8. Shoop, W.L.; Hartline, E.J.; Gould, B.R.; Waddell, M.E.; McDowell, R.G.; Kinney, J.B.; Lahm, G.P.; Long, J.K.; Xu, M.; Wagerle, T.; et al. Discovery and mode of action of afoxolaner, a new isoxazoline parasiticide for dogs. Vet. Parasitol. 2014, 201, 179–189. [Google Scholar] [CrossRef] [Green Version]
  9. Zhang, Y.-K.; Plattner, J.J.; Easom, E.E.; Zhou, Y.; Akama, T.; Bu, W.; White, W.H.; Defauw, J.M.; Winkle, J.R.; Balko, T.W.; et al. Discovery of an orally bioavailable isoxazoline benzoxaborole (AN8030) as a long acting animal ectoparasiticide. Bioorg. Med. Chem. Lett. 2015, 25, 5589–5593. [Google Scholar] [CrossRef]
  10. Madavu, K.; Rai, L. Heterocycles via Oxime Cycloadditions. In Synthesis of Heterocycles via Cycloadditions II; Springer: Berlin/Heidelberg, Germany, 2008; Volume 13, pp. 1–69. [Google Scholar]
  11. Kawai, H.; Shibata, N. Attractive Trifluoromethylated Dihydroxazoles and Related Compounds under Organocatalysis. Chem. Rec. 2014, 14, 1024–1040. [Google Scholar] [CrossRef]
  12. Kumer, V.; Kaur, K. Fluorinated isoxazolines and isoxazoles: A synthetic perspective. J. Fluor. Chem. 2015, 180, 55–97. [Google Scholar] [CrossRef]
  13. Yoshimura, A.; Zhdankin, V.V. Oxidative cyclizations of oximes using hypervalent iodine reagents. Arkivoc 2017, i, 99–116. [Google Scholar] [CrossRef]
  14. Zhu, M.; Fun, W.; Guo, W.; Tian, Y.; Wang, Z.; Xu, C.; Ji, B. Visible-Light-Induced Radical Di- and Trifluoromethylation of β,γ-Unsaturated Oximes: Synthesis of Di- and Trifluoromethylated Isoxazolines. Eur. J. Org. Chem. 2019, 2019, 1614–1619. [Google Scholar] [CrossRef]
  15. Wei, Q.; Chen, J.-R.; Hu, X.-Q.; Yang, X.-C.; Lu, B.; Xiao, W.-J. Photocatalytic Radical Trifluoromethylation/Cyclization Cascade: Synthesis of CF3-Containing Pyrazolines and Isoxazolines. Org. Lett. 2015, 17, 4464–4467. [Google Scholar] [CrossRef]
  16. Li, X.-T.; Lv, L.; Gu, Q.-S.; Liu, X.-Y. Copper-catalyzed radical oxytrifluoromethylation of alkenyl oximes at ambient temperature. Tetrahedron 2018, 74, 6041–6046. [Google Scholar] [CrossRef]
  17. Li, X.-T.; Gu, Q.-S.; Dong, X.-Y.; Meng, X.; Liu, X.-Y. A Copper Catalyst with a Cinchona-Alkaloid-Based Sulfonamide Ligand for Asymmetric Radical Oxytrifluoromethylation of Alkenyl Oximes. Angew. Chem. Int. Ed. 2018, 57, 7668–7672. [Google Scholar] [CrossRef]
  18. Zhu, M.-K.; Zhao, J.-F.; Loh, T.-P. Palladium-Catalyzed Oxime Assisted Intramolecular Dioxygenation of Alkenes with 1 atm of Air as the Sole Oxidant. J. Am. Chem. Soc. 2010, 132, 6284–6285. [Google Scholar] [CrossRef]
  19. Yamamoto, D.; Oguro, T.; Tashiro, Y.; Soga, M.; Miyashita, K.; Aso, Y.; Makino, K. Manganese-Promoted Oxidative Cyclization of Unsaturated Oximes Using Molecular Oxygen in Air under Ambient Conditions. Eur. J. Org. Chem. 2016, 2016, 5216–5219. [Google Scholar] [CrossRef]
  20. Ji, F.; Fan, Y.; Yang, R.; Yang, Y.; Yu, D.; Wang, M.; Li, Z. Regioselective synthesis of thiocyanate-containing isoxazolines via Fe(III)/K2S2O8-mediated radical thiocyanation/cyclization cascade reaction of β,γ-unsaturated oximes. Asian J. Org. Chem. 2017, 6, 682–685. [Google Scholar] [CrossRef]
  21. Tripathi, C.B.; Mukherjee, S. Catalytic Enantioselective Iodoetherification of Oximes. Angew. Chem. Int. Ed. 2013, 52, 8450–8453. [Google Scholar] [CrossRef]
  22. Kirsch, P. Modern Fluoroorganic Chemistry: Synthesis, Reactivity, Applications, 2nd ed.; Wiley-VHC: Weinheim, Germany, 2013. [Google Scholar]
  23. Ojima, I. Fluorine in Medicinal Chemistry and Chemical Biology; Wiley-Blackwell: Oxford, UK, 2009. [Google Scholar]
  24. Gouverneur, V.; Müller, K. Fluorine in Pharmaceutical and Medicinal Chemistry: From Biophysical Aspects to Clinical Applications; Imperial College Press: London, UK, 2012. [Google Scholar]
  25. Wang, J.; Sánchez-Roselló, M.; Aceña, J.L.; del Pozo, C.; Sorochinsky, A.E.; Fustero, S.; Soloshonok, V.A.; Liu, H. Fluorine in Pharmaceutical Industry: Fluorine-Containing Drugs Introduced to the Market in the Last Decade (2001–2011). Chem. Rev. 2014, 114, 2432–2506. [Google Scholar] [CrossRef] [PubMed]
  26. Gillis, E.P.; Eastman, K.J.; Hill, M.D.; Donnelly, D.J.; Meanwell, N.A. Applications of Fluorine in Medicinal Chemistry. J. Med. Chem. 2015, 58, 8315–8359. [Google Scholar] [CrossRef] [PubMed]
  27. Haranahalli, K.; Honda, T.; Ojima, I. Resent progress in the strategic incorporation of fluorine into medicinally active compounds. J. Fluor. Chem. 2019, 217, 29–40. [Google Scholar] [CrossRef] [PubMed]
  28. Liang, T.; Neumann, C.N.; Ritter, T. Introduction of Fluorine and Fluorine-Containing Functional Groups. Angew. Chem. Int. Ed. 2013, 52, 8214–8264. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  29. Champagne, P.A.; Desroches, J.; Hamel, J.-D.; Vandamme, M.; Paquin, J.-F. Monofluorination of Organic Compounds: 10 Years of Innovation. Chem. Rev. 2015, 115, 9073–9174. [Google Scholar] [CrossRef] [PubMed]
  30. Zhu, Y.; Han, J.; Wang, J.; Shibata, N.; Sodeoka, M.; Soloshonok, V.A.; Coelho, J.A.S.; Toste, F.D. Modern Approaches for Asymmetric Construction of Carbon–Fluorine Quaternary Stereogenic Centers: Synthetic Challenges and Pharmaceutical Needs. Chem. Rev. 2018, 118, 3887–3964. [Google Scholar] [CrossRef]
  31. Wolstenhulme, J.R.; Gouverneur, V. Asymmetric Fluorocyclizations of Alkenes. Acc. Chem. Res. 2014, 47, 3560–3570. [Google Scholar] [CrossRef]
  32. Ishimaru, T.; Shibata, N.; Horikawa, T.; Yasuda, N.; Nakamura, S.; Toru, T.; Shiro, M. Cinchona Alkaloid Catalyzed Enantioselective Fluorination of Allyl Silanes, Silyl Enol Ethers, and Oxindoles. Angew. Chem. Int. Ed. 2008, 47, 4157–4161. [Google Scholar] [CrossRef]
  33. Rauniyar, V.; Lackner, A.D.; Hamilton, G.L.; Toste, F.D. Asymmetric Electrophilic Fluorination Using an Anionic Chiral Phase-Transfer Catalyst. Science 2011, 334, 1681–1684. [Google Scholar] [CrossRef]
  34. Kong, W.; Feige, P.; de Haro, T.; Nevado, C. Regio- and Enantioselective Aminofluorination of Alkenes. Angew. Chem. Int. Ed. 2013, 52, 2469–2473. [Google Scholar] [CrossRef]
  35. Wolstenhulme, J.R.; Rosenqvist, J.; Lozano, O.; Ilupeju, J.; Wurz, N.; Engle, K.M.; Pidgeon, G.W.; Moore, P.R.; Sandford, G.; Gouverneur, V. Asymmetric Electrophilic Fluorocyclization with Carbon Nucleophiles. Angew. Chem. Int. Ed. 2013, 52, 9796–9800. [Google Scholar] [CrossRef] [PubMed]
  36. Mennie, K.M.; Banik, S.M.; Reichert, E.C.; Jacobsen, E.N. Catalytic Diastero- and Enantioselective Fluoroamination of Alkenes. J. Am. Chem. Soc. 2018, 140, 4797–4802. [Google Scholar] [CrossRef] [PubMed]
  37. Scheidt, F.; Schäfer, M.; Sarie, J.C.; Daniliuc, C.G.; Molloy, J.J.; Gilmour, R. Enantioselective, Catalytic Vicinal Difluorination of Alkenes. Angew. Chem. Int. Ed. 2018, 57, 16431–16435. [Google Scholar] [CrossRef]
  38. Zhao, J.; Jiang, M.; Liu, J.-T. Synthesis of Fluoromethyl-Substituted Isoxazolines via Transition Metal-Free Oxyfluorination of Alkenyl Oximes. Adv. Synth. Catal. 2017, 359, 1626–1630. [Google Scholar] [CrossRef]
  39. Egami, H.; Asada, J.; Sato, K.; Hashizume, D.; Kawato, Y.; Hamashima, Y. Asymmetric Fluorolactonization with a Bifunctional Hydroxyl Carboxylate Catalyst. J. Am. Chem. Soc. 2015, 137, 10132–10135. [Google Scholar] [CrossRef] [PubMed]
  40. Egami, H.; Niwa, T.; Sato, H.; Hotta, R.; Rouno, D.; Kawato, Y.; Hamashima, Y. Dianionic Phase-Transfer Catalyst for Asymmetric Fluorocyclization. J. Am. Chem. Soc. 2018, 140, 2785–2788. [Google Scholar] [CrossRef]
  41. Niwa, T.; Ujiie, K.; Sato, H.; Egami, H.; Hamashima, Y. Asymmetric Fluorination of Cyclic Tetrasubstituted Alkenes with a Pendant Amide Groups under Dianionic Phase-Transfer Catalysis. Chem. Pharm. Bull. 2018, 66, 920–922. [Google Scholar] [CrossRef] [Green Version]
  42. Begum, S.A.; Terao, J.; Kambe, N. Conversion of (sp3)C–F Bonds of Alkyl Fluorides to (sp3)C–Heteroaton (Heteroatom = I, SR, SeR, TeR) Bonds by the Use of Magnesium Reagents Having Heteroatom Substituents. Chem. Lett. 2007, 36, 196–197. [Google Scholar] [CrossRef]
  43. Sorochinsky, A.E.; Aceña, J.L.; Soloshonok, V.A. Self-Disproportionation of Enantiomers of Chiral. Non-Racemic Fluoroorganic Compounds: Role of Fluorine as Enabling Element. Synthesis 2013, 45, 141–152. [Google Scholar] [CrossRef]
Sample Availability: Samples of the compounds 3 are available from the authors.
Molecules 24 03464 sch001 550
Scheme 1. Fluorofunctionalizations of alkenes with linked-binaphthyl dicarboxylic acid 1 and Selectfluor: (a) Asymmetric 6-endo-type fluorocyclization of allylic amides; (b) Asymmetric 5-exo-fluorocyclization of ene-oximes.
Scheme 1. Fluorofunctionalizations of alkenes with linked-binaphthyl dicarboxylic acid 1 and Selectfluor: (a) Asymmetric 6-endo-type fluorocyclization of allylic amides; (b) Asymmetric 5-exo-fluorocyclization of ene-oximes.
Molecules 24 03464 sch001
Molecules 24 03464 sch002 550
Scheme 2. Conversion of 3a to 8a to determine the stereochemistry of the major product.
Scheme 2. Conversion of 3a to 8a to determine the stereochemistry of the major product.
Molecules 24 03464 sch002
Molecules 24 03464 g001 550
Figure 1. Fluorocyclization of ene-oximes.
Figure 1. Fluorocyclization of ene-oximes.
Molecules 24 03464 g001
Molecules 24 03464 sch003 550
Scheme 3. Reaction of O-methylated compound.
Scheme 3. Reaction of O-methylated compound.
Molecules 24 03464 sch003
Table
Table 1. Optimization of the reaction conditions. 1
Table 1. Optimization of the reaction conditions. 1
Molecules 24 03464 i001
EntryPrecatalystSolventBaseYield (%) 2Ee (%) 3
1 41tolueneNa3PO43958
2 41chlorobenzeneNa3PO42658
3 41benzeneNa3PO43057
4 41CH2Cl2Na3PO411-
5 41THFNa3PO43-
61tolueneNa3PO44259
71tolueneNa2HPO41961
81tolueneNa2CO33561
91tolueneK3PO42459
101tolueneK2CO33-
111tolueneproton sponge177
12 51tolueneNa3PO463 (58) 669
13 51tolueneNa2CO362 (58) 665
14 57tolueneNa3PO42-
1 The reactions were carried out with 2a (0.1 mmol), precatalyst (10 mol %), Selectfluor (1.5 equiv), and base (1.5 equiv) at 25 °C, unless otherwise mentioned. 2 The yields were determined by 1H NMR analysis using 1,1,2,2-tetrabromoethane as an internal standard. 3 The ee values were determined by HPLC analysis using a chiral stationary column. 4 Run with Na2SO4. 5 Run at 15 °C for 72 h. 6 Isolated yield.

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Rouno, T.; Niwa, T.; Nishibashi, K.; Yamamoto, N.; Egami, H.; Hamashima, Y. Enantioselective 5-exo-Fluorocyclization of Ene-Oximes. Molecules 2019, 24, 3464. https://doi.org/10.3390/molecules24193464

AMA Style

Rouno T, Niwa T, Nishibashi K, Yamamoto N, Egami H, Hamashima Y. Enantioselective 5-exo-Fluorocyclization of Ene-Oximes. Molecules. 2019; 24(19):3464. https://doi.org/10.3390/molecules24193464

Chicago/Turabian Style

Rouno, Taiki, Tomoki Niwa, Kousuke Nishibashi, Nobuharu Yamamoto, Hiromichi Egami, and Yoshitaka Hamashima. 2019. "Enantioselective 5-exo-Fluorocyclization of Ene-Oximes" Molecules 24, no. 19: 3464. https://doi.org/10.3390/molecules24193464

APA Style

Rouno, T., Niwa, T., Nishibashi, K., Yamamoto, N., Egami, H., & Hamashima, Y. (2019). Enantioselective 5-exo-Fluorocyclization of Ene-Oximes. Molecules, 24(19), 3464. https://doi.org/10.3390/molecules24193464

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