HETEROCYCLES

Paper | Regular issue | Vol. 89, No. 2, 2014, pp. 427-435
Received, 2nd December, 2013, Accepted, 27th December, 2013, Published online, 14th January, 2014.
DOI: 10.3987/COM-13-12906

■ The First Total Synthesis of the Antiplasmodial Alkaloid (±)-Cassiarin C Based on a Microwave-Assisted Thermal Azaelectrocyclic Reaction

Yoshinari Tazaki, Yuhta Tsuchiya, Tominari Choshi,* Takashi Nishiyama, Noriyuki Hatae, Hideo Nemoto, and Satoshi Hibino*

Faculty of Pharmacy and Pharmaceutical Sciences, Fukuyama University, Fukuyama, Hiroshima 729-0292, Japan

Abstract

A first total synthesis of the antiplasmodial alkaloid (±)-cassiarin C is described. The key step was a microwave-assisted thermal azaelectrocyclic reaction for the construction of the tricyclic pyrano[2,3,4-ij]isoquinoline core.

INTRODUCTION
The development of new chemotherapeutic agents against chloroquine-resistant and multiple-drug-resistant strains of malaria parasite is in high demand as more than two billion people living in tropical areas of high incidence according to the World Health Organization are exposed to the malaria parasite. Synthetic studies and evaluation of antimalarial natural products have been reported by many organic and/or medicinal chemists.1

Cassia siamea is widely used in traditional medicine for treatment of periodic fever and malaria in Indonesia. Cassiarins A (1) and B (2) were isolated from the leaves of Cassia siamea by Morita and co-workers in 2007.2 These alkaloids possess an unprecedented tricyclic skeleton and exhibit potent antiplasmodial activity. The total synthesis of cassiarins is reported by four groups to date.3 Honda’s group achieved the first total synthesis of cassiarin A (1) using alkynylation by Sonogashira coupling and 6-endo-dig-cyclization to alkynes as key steps.3a Morita’s group reported the synthesis and bioactivity of cassiarin A (1) and its derivatives derived from chromen-4-one.3c The total synthesis of cassiarin B (2) together with cassiarin A (1) from chromen-4-one was described by Yao’s group.3b Furthermore, Thamyongkit’s group achieved the synthesis of cassiarins A (1) and B (2) and their N-substituted derivatives by the condensation of barakol and amines.3d Three new closely related alkaloids, cassiarins C-E possessing a tricyclic 2,3-dihydro-pyrano[2,3,4-ij]isoquinoline core were recently isolated from the Cassia siamea flower by Morita and co-workers and also show antiplasmodial activity against Plasmodium falciparum 3D7.4 Cassiarin C (3) has one stereogenic center, but the absolute configuration is not yet known. In addition, its total synthesis has not been reported.
We are performing the synthetic studies of fused pyridine ring systems based on a thermal electrocyclic reaction of an aza 6π-electron system.5 To date, we have reported the construction of several fused pyridine ring systems, such as furo[3,2-h]isoquinoline,6a-c phenanthridine,6d benzo[c]phenanthridine,6e,f azaanthraquinone,6g and β-carboline alkaloids,6h using a microwave-assisted thermal electrocyclic reaction of a 1-aza 6π-electron system. We have also performed the synthetic studies of the antimalarial and antitumor alkaloids calothrixins A, B, and their derivatives.7 As a next target compound, we focused on the synthesis of cassiarine C (3), which has a unique tricyclic framework and the antiplasmodial activity. In this paper, we describe the first total synthesis of (±)-cassiarin C (3).

RESULTS AND DISCUSSION
To synthesize cassiarin C (3) according to the retro-synthetic scheme shown below (Scheme 1), we planned to construct a tricyclic pyranoisoquinoline core of 3 by a new bond formation between the C11 and N in 3 based on a microwave-assisted azaelectrocyclic reaction of a 1-azahexatriene 4. We assumed that a 1-azahexatriene 4 might be derived from the known compound, 5,7-dihydroxy-2-methyl-chroman-4-one 5.8

To synthesize a precursor, 1-azahexatriene 4, the known starting material, chroman-4-one 58,9 was prepared from phloroglucinol according to Rao’s method.9 Treatment of 5 with O-methylhydroxylamine in the presence of AcONa gave the oxime ether 6 in 97% yield (Scheme 2). Regioselective protection of the C-7 hydroxy group of 6 using MOMCl and/or TBDMSCl in the presence of amines afforded the 7-MOM ether 7a and the 7-TBDMS ether 7b in 92% and 98% yields, respectively. Sequential treatment of 7a or 7b with trifluoromethanesulfonic anhydride only yielded the corresponding triflate 8a (97%), which was used in the Stille coupling reaction with 1-propenylstannane in the presence of PdCl2(PPh3)2 to give the 5-propenylchromane 9 in 94% yield. The triflation of 7b failed, because desilylation occurred.

To obtain a tricyclic pyranoisoquinoline 10 from the 1-azahexatriene 9, we next investigated a thermal azaelectrocyclic reaction under microwave-assisted or conventional conditions. Electrocyclic reactions of 1-azahexatriene 9 were performed by various conditions using toluene (100 °C), bromobenzene (150 °C), or 1,2-dichrolobenzene (180 °C) as the solvent (Table 1). Microwave-assisted conditions (entries 1,3,5) were more effective than conventional conditions for increasing the yield and reducing the reaction time (entries 2,4,8,9). In particular, the best yield of the product 10 was obtained by performing the reaction in 1,2-dichlorobenzene at 180 °C under microwave irradiation (entry 5). Heating of 9 for 1.5 h under the same conditions as entry 5 did not increase the yield of 10 (entry 6). Similarly, heating of 9 at 200 °C decreased the yield of 10 compared with that of entry 6 (entry 7). As the result, the microwave irradiation under thermal conditions seems to be the effective tool for 6π-azaelectrocyclic reaction.

Finally, treatment of O-MOM cassiarin C 10 with 2 M HCl in MeOH afforded (±)-cassiarin C (3) (Scheme 3). The spectroscopic data of our synthetic (±)-cassiarin C (3) were identical with those of reported previously natural cassiarin C.4

CONCLUSION
The first total synthesis of (±)-cassiarin C (3) was established by constructing a pyrano[2,3,4-ij]isoquinoline ring with a microwave-assisted electrocyclic reaction of aza 6π-electron system as the key reaction. The target compound 3 was obtained in six steps in 60% overall yield from the readily accessible known starting material chroman-4-one 5. This synthetic strategy is applicable to a series of other pyranoisoquinoline alkaloids. An asymmetric synthesis of (−)-cassiarin C (3) is now in progress.

EXPERIMENTAL
Melting points were determined on a Yanagimoto micro-melting point apparatus MP-500D and are uncorrected. Infrared spectra were recorded with ATR method on a Shimadzu FTIR-8000 spectrometer. Proton nuclear magnetic resonance (1H NMR) spectra were recorded on a JEOL AL-300 at 300 MHz. Chemical shifts are reported relative to Me4Si (δ 0.00). NMR spectra was measured with CDCl3 unless otherwise noted. Multiplicity is indicated by one or more of the following: s (singlet); d (doublet); t (triplet); q (quartet); m (multiplet); br (broad). Carbon nuclear magnetic resonance (13C NMR) spectra were recorded on a JEOL AL-300 at 75 MHz. Chemical shifts are reported relative to CDCl3 (δ 77.0) and DMSO-d6 (δ 39.7). Low and high resolution mass spectra were recorded on JEOL JMS-700 and JMS-LCmate MS-MP30 spectrometers by direct inlet system. The reaction of microwave (MW) irradiation was carried out by Discover of CEM Co. Ltd. with 2450 MHz. Anhydrous THF, CH2Cl2, and DMF were used commercially available solvents (Cica reagents) for organic synthesis. 1,2-Dichlorobenzene, using for an MW-assisted electrocyclic reaction, was degassed before use. Silica gel 60N (63-210 µm, Kanto Ltd.) was used for column chromatography.

5,7-Dihydroxy-2-methylchroman-4-one O-methyloxime (6)
A mixture of the chroman-4-one 5 (200 mg, 1.03 mmol), MeONH2•HCl (430 mg, 5.15 mmol), and AcONa (148 mg, 1.80 mmol) in EtOH (10 mL) was stirred at 80 °C for 2 h. After removal of solvent followed by addition of water, the mixture was extracted with EtOAc. The EtOAc layer was washed with water and brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by column chromatography using EtOAc-hexane (3:7 v/v) as an eluent to give the O-methyloxime 6 (218 mg, 95%), mp 120-121 °C (EtOH). IR (ATR) ν: 3386 cm-1. 1H NMR (300 MHz, CDCl3) δ: 1.43 (3H, d, J = 6.2 Hz), 2.34 (1H, dd, J = 17.1, 11.6 Hz), 3.22 (1H, dd, J = 17.1, 3.1 Hz), 3.94 (3H, s), 4.11-4.22 (1H, m), 5.14 (1H, br s), 5.95 (1H, d, J = 2.6 Hz), 6.04 (1H, d, J = 2.6 Hz), 10.88 (1H, s). 13C NMR (75 MHz, CDCl3) δ: 20.8, 30.1, 62.3, 71.2, 95.6, 96.9, 98.0, 153.8, 158.5, 158.9, 159.6. MS (EI) m/z: 223 (M+). HRMS (EI) calcd for 11H13NO4 223.0845; found 223.0841.

5-Hydroxy-7-methoxymethyloxy-2-methylchroman-4-one O-methyloxime (7a)
A suspention of O-methyloxime 6 (180 mg, 0.81 mmol), K2CO3 (250 mg, 1.77 mmol), and chloromethyl methyl ether (0.15 mL, 1.77 mmol) in DMF (20 mL) was stirred at rt for 12 h. The reaction mixture was quenched with water, and then the mixture was extracted with EtOAc. The EtOAc layer was washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (silica gel, 20 g) using EtOAc-hexane (3:7 v/v) as an eluent to give the MOM ether 7a (210 mg, 97%), mp 68-70 °C (Et2O). IR (ATR) ν: 2935 cm-1. 1H NMR (300 MHz, CDCl3) δ: 1.43 (3H, d, J = 6.2 Hz), 2.34 (1H, dd, J = 17.3, 11.7 Hz), 3.23 (1H, dd, J = 17.3, 3.0 Hz), 3.46 (3H, s), 3.94 (3H, s), 4.11-4.23 (1H, m), 5.12 (1H, d, J = 6.6 Hz), 5.15 (1H, J = 6.6 Hz), 6.15 (1H, d, J = 2.6 Hz), 6.24 (1H, d, J = 2.6 Hz), 10.8 (1H, s). 13C NMR (75 MHz, CDCl3) δ: 20.8, 30.1, 56.1, 62.3, 71.1, 94.0, 95.9, 97.4, 98.8, 153.7, 158.2, 159.4, 160.1. MS (EI) m/z: 267 (M+). HRMS (EI) calcd for C13H17NO5 267.1107; found 267.1092.

7-(tert-Butyldimethylsilyloxy)-5-hydroxy-2-methylchroman-4-one O-methyloxime (7b)
A solution of O-methyloxime 6 (24 mg, 0.11 mmol), imidazole (29 mg, 0.43 mmol), and TBDMSCl (28 mg, 0.19 mmol) in CH2Cl2 (5 mL) was stirred at rt for 12 h. The reaction mixture was quenched with water, and then the mixture was extracted with EtOAc. The EtOAc layer was washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (silica gel, 20 g) using EtOAc-hexane (3:7 v/v) as an eluent to give the oily TBDMS ether 7b (36 mg, 98%). mp 71-72 °C (Et2O). IR (ATR) ν: 2931 cm-1. 1H NMR (300 MHz, CDCl3) δ: 0.21 (6H, s), 0.96 (9H, s), 1.43 (3H, d, J = 6.3 Hz), 2.33 (1H, dd, J = 17.5, 11.7 Hz), 3.22 (1H, dd, J = 17.5, 3.1 Hz), 3.94 (3H, s), 4.11-4.19 (1H, m), 5.95 (1H, d, J = 2.3 Hz), 6.05 (1H, d, J = 2.3 Hz), 10.8 (1H, s). 13C NMR (75 MHz, CDCl3) δ: -4.4, -4.4, 18.2, 20.9, 25.6, 30.2, 62.3, 71.1, 98.6, 100.1, 101.6, 153.9, 158.1, 159.1, 159.4. MS (EI) m/z: 337 (M+). HRMS (EI) calcd for C17H27NO4Si 337.1709; found 337.1693.

7-Methoxymethyloxy-2-methyl-5-(trifluoromethylsulfonyloxy)chroman-4-one O-methyloxime (8a)
A solution of MOM ether 7a (208 mg, 0.78 mmol) in THF (10 mL) was added to an ice-cooled suspention of NaH (47 mg, 1.17 mmol) in THF (10 mL) under an N2 atmosphere, and then stirred at the same temperature for 30 min. A solution of N-phenylbis(trifluoromethane-sulfonamide) (418 mg, 1.17 mmol) in THF (5 mL) was added to the reaction mixture at the same temperature. After being stirred at rt for 12 h, the mixture was quenched with water. The mixture was extracted with EtOAc. The EtOAc layer was washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by column chromatography using EtOAc-hexane (3:7 v/v) as an eluent to give the oily triflate 8a (302 mg, 97%). IR (ATR) ν: 1627 cm-1. 1H NMR (300 MHz, CDCl3) δ: 1.43 (3H, d, J = 6.9 Hz), 2.32 (1H, dd, J = 17.1, 11.3 Hz), 3.26 (1H, dd, J = 17.1, 3.5 Hz), 3.47 (3H, s), 4.03 (3H, s), 4.14-4.27 (1H, m), 5.15 (2H, s), 6.57 (1H, d, J = 2.5 Hz), 6.64 (1H, d, J = 2.5 Hz). 13C NMR (75 MHz, CDCl3) δ: 20.7, 30.1, 56.3, 62.3, 72.0, 94.5, 104.6, 105.4, 107.1, 120.8, 146.6, 147.3, 158.3, 158.9. MS (EI) m/z: 399 (M+). HRMS (EI) calcd for C14H16F3NO7S 399.0600; found 399.0607.

7-Methoxymethyloxy-2-methyl-5-(prop-1-en-1-yl)chroman-4-one O-methyloxime (9)
A mixture of triflate 8a (305 mg, 0.76 mmol), propenylstannane (444 mg, 1.34 mmol), Et4NCl (253 mg, 1.53 mmol), and PdCl2(PPh3)2 (9 mg, 0.013 mmol) in DMF (10 mL) was stirred at 80 °C for 1.5 h under N2 atmosphere. The reaction mixture was quenched with aqueous solution of KF (30%), and then the mixture was stirred at rt for 2 h. The mixture was filtered off through Celite pad and the filtrate was extracted with EtOAc. The EtOAc layer was washed with water and brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by column chromatography using EtOAc-hexane (3:7 v/v) as an eluent to give the oily 5-propenyl-chromanone 9 (210 mg, 95%). 1H NMR (300 MHz, CDCl3) δ: 1.42 (3H, d, J = 6.1 Hz), 1.81 (3H, dd, J = 7.1, 1.6 Hz), 2.35 (1H, dd, J = 16.7, 11.7 Hz), 3.22 (1H, dd, J = 16.7, 2.9 Hz), 3.47 (3H, s), 3.94 (3H, s), 4.17-4.08 (1H, m), 5.14 (1H, d, J = 6.8 Hz), 5.17 (1H, d, J = 6.8 Hz), 5.69 (1H, dq, J = 11.7, 7.1 Hz), 6.52 (1H, d, J = 2.7 Hz), 6.58 (1H, d, J = 2.7 Hz), 6.9 (1H, dd, J = 11.7, 1.6 Hz). 13C NMR (75 MHz, CDCl3) δ: 14.6, 20.9, 29.7, 31.4, 56.1, 61.9, 71.4, 94.2, 103.1, 113.0, 124.0, 132.2, 137.9, 150.4, 157.5, 158.8. MS (EI) m/z: 291 (M+). HRMS (ESI) calcd for C16H22NO4 [M+H]+ 292.1549; found 292.1536.

7-Methoxymethyloxy-2,11-dimethyl-2,3-dihydropyrano[2,3,4-ij]isoquinoline (10)
An each mixture of the 5-propenylchromanone 9 (110 mg, 0.38 mmol) in 1,2-dichlorobenzene (15 mL) was stirred at 180 °C (external) under N2 atmosphere under microwave irradiation. After removal of solvent, the residue was purified by column chromatography (silica gel) using EtOAc-hexane (1:1 v/v) as an eluent to give the oily 2,3-dihydropyranoisoquinoline 10 (76 mg, 78%). 1H NMR (300 MHz, CDCl3) δ: 1.58 (3H, d, J = 6.2 Hz), 2.61 (3H, s), 3.26-3.08 (2H, m), 3.50 (3H, s), 4.57-4.48 (1H, m), 5.27 (2H, s), 6.67 (1H, d, J = 2.2 Hz), 6.83 (1H, d, J = 2.2 Hz), 7.21 (1H, s). 13C NMR (75 MHz, CDCl3) δ: 21.2, 24.4, 39.3, 56.3, 74.1, 94.2, 100.5, 102.3, 111.6, 116.3, 138.3, 151.9, 153.8, 156.5, 160.0 MS (EI) m/z: 259 (M+). HRMS (EI) calcd for C15H17NO3 259.1208; found 259.1186.

Cassiarin C (3)
To a solution of 2,3-dihydropyranoisoquinoline 10 (50 mg, 0.19 mmol) in MeOH (5 mL) was added 2 M HCl (5 mL), and then heated at 50 °C for 12 h. After removal of solvent, the residue was adjusted to pH 8 with 2 M aqueous K2CO3, and the extracted with EtOAc. The EtOAc layer was washed with water and brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by column chromatography using EtOAc-hexane (2:3 v/v) as an eluent to give the cassiarin C (3) (38 mg, 93%). mp 159-160 °C (CHCl3). IR (ATR) ν: 2924 cm-1. 1H NMR (300 MHz, CD3OD) δ: 1.54 (3H, d, J = 6.2 Hz), 2.52 (3H, s), 2.27-3.18 (2H, m), 4.41-4.53 (1H, m), 6.47 (1H, d, J = 2.0 Hz), 6.57 (1H, d, J = 2.0 Hz), 7.19 (1H, s). 13C NMR (75 MHz, CD3OD) δ: 21.3, 23.4, 39.1, 75.1, 101.4, 103.3, 111.5, 117.1, 140.5, 151.1, 155.1, 158.4, 163.6. MS (EI) m/z: 215 (M+). HRMS (EI) calcd for C13H13NO2 215.0946; found 215.0956.

ACKNOWLEDGEMENTS
This work was partly supported by JSPS Grant Number 24590040.

References

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