Development of highly affine and selective fluorinated cannabinoid type 2 receptor ligands

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1 Development of highly affine and selective fluorinated cannabinoid type 2 receptor ligands Rareş-Petru Moldovan*, Kristin ausmann, Winnie Deuther-Conrad, Peter Brust elmholtz-zentrum Dresden-Rossendorf e. V., Institute of Radiopharmaceutical Cancer Research, Permoserstraße 15, Leipzig 04318, Germany Corresponding author. Rareş-Petru Moldovan Tel.: ; fa: ; r.moldovan@hzdr.de Supplementary Materials

2 Materials and methods General Unless otherwise noted, moisture sensitive reactions were conducted under dry nitrogen or argon. All chemicals and reagents were purchased from commercially available sources and used without further purification. Thin layer chromatography (TLC): Silica gel 60 F254 plates (Merck KGaA, Darmstadt, Germany). Flash chromatography (fc): Silica gel 60, μm (Merck). Room temperature (rt.) was 21 C. MS: MAT GCQ (Thermo Finnigan MAT Gmb, Bremen, Germany). 1, 13 C and 19 F MR spectra were recorded on VARIA "MERCURY plus" (300 Mz for 1 MR, 75 Mz for 13 C MR, 282 Mz for 19 F MR) and VARIA "MERCURY plus" and BRUKER DRX-400 (400 Mz for 1 MR, 100 Mz for 13 C MR, 377 Mz for 19 F MR); δ in ppm related to tetramethylsilane; coupling constants (J) are given with 0.1 z resolution. Multiplicities of MR signals are indicated as follows: s (singlet), d (doublet), t (triplet), m (multiplet), dd (doublet of doublets), dt (doublet of triplets). ESI/Ion trap mass spectra (LRMS) were recorded with a Bruker Esquire 3000 plus instrument (Billerica, MA, USA). igh resolution mass spectra were recorded on an FT-ICR APEX II spectrometer (Bruker Daltonics; Bruker Corporation, Billerica, MA, USA) using electrospray ionization (ESI) in positive ion mode. The purity of all the tested compounds was 95% as determined by PLC [Jasco, MD-2010Plus, LG S, DG , AS-2055Plus, LC-etII/ADC, λ = 254 nm, column ReproSil-Pur Basic C18-D ( mm, 5 μm, Dr. Maisch Gmb), gradient MeC/20mMAA from 10/90 to 95/5, (v/v) over 50 min, flowrate 1 ml/min]. General procedure 1 The respective fluoroaniline (3 mmol, 1.5 equiv) and trifluoroacetic acid (3 mmol, 1.5 equiv) were added to a solution of methyl 2-acetamido-3-oopentanoate (2 mmol, 1.0 equiv) in 5 ml butyronitrile and the reaction miture was reflued for 2 h. After evaporation of the solvent the resulting residue was taken up in dichloromethane (15 ml) and washed with an aq. K 2 C 3 sol. (215 ml). The organic layer was dried over sodium sulfate, filtered and concentrated in vacuum. The residue was purified by flash chromatography on silica gel. General procedure 2 The corresponding carboylic acid (1 mmol, 1 equiv), Et 3 (3 mmol, 3 equiv) and BP (1.3 mmol, 1.3 equiv) were added to a suspension of the corresponding adamantane amine (1 mmol, 1 equiv) in 5 ml DCM at 0 C, and the miture was stirred at room temperature for 20 hours. The reaction was quenched by addition of 2 ml water followed by a 10 ml aq. saturated sol. of ac 3 and 15 ml EA. The phases were separated and the aqueous phase was washed with 210 ml EA. The combined organic fractions were washed with 20 ml brine, dried over MgS 4 and concentrated by rotary evaporation. The obtained residue was purified by column chromatography on silica. General procedure 3 a (60% in mineral oil, 2 mmol, 2 equiv) was added to a sol. of alcohol 8 (1 mmol, 1 equiv), in 0.5 ml DMF, and the miture was stirred for 5 minutes at room temperature. Thereafter the alkylating agent RX (5 mmol, 5 equiv) was added, and the reaction miture was stirred overnight at room temperature. The reaction was quenched by addition of 2 (2 ml), followed by 15 ml aq. saturated sol. ac 3 and 20 ml EA while stirring. The phases were separated, the aqueous phase was washed with 20 ml EA and the combined organic fractions were dried over MgS 4 and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica. General procedure 4 Al(C 3 ) 3 (2M solution in heptane, 0.2 mmol, 1.3 equiv) was added to a solution of 1-adamantylamine (0.2 mmol, 1.3 equiv) in anhydrous dichloromethane (1.8 ml) and the reaction miture was magnetically stirred for 10 min at room temperature. The corresponding methylester (0.16 mmol, 1.0 equiv) was then added and the miture was stirred at 35 C for 22 h, poured into an aq. ac 3 sol. (10 ml) and stirred for 30 min at room temperature. After filtration over celite, the solution was etracted with dichloromethane (215 ml). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuum. Purification was performed by flash chromatography on silica gel. 5-Ethyl--(3-hydroyadamantan-1-yl)-2-methyl-1-phenyl-1-imidazol-4-carboamide (8) Compound 8 was obtained by General procedure 2, yield 68%, white solid; R f = 0.16 (EA); 1 -MR (300 Mz, ): δ (ppm) = (m, 3), (m, 2), 7.04 (s, 1), 2.79 (q, J = 7.5 z, 2), (m, 9), (m, 8), 0.97 (t, J = 7.4 z, 3); 13 C-MR (75 Mz, ): δ (ppm) = 163.2, 143.0, 139.0, 135.8, 129.7, 129.4, 127.7,

3 69.3, 53.9, 49.5, 44.2, 40.6, 35.0, 30.7, 17.6, 14.0, 13.6; MS (ESI+): m/z ( %) = 380.2, calcd for C [M+] + ; PLC: t R = 27.5 min, purity 99.5 %. 5-Ethyl--(3-methoyadamantan-1-yl)-2-methyl-1-phenyl-1-imidazol-4-carboamide (9) Compound 9 was obtained by General procedure 3, yield 25%, white solid; R f = 0.36 (EA); 1 -MR (300 Mz, ): δ (ppm) = (m, 3), (m, 2), 7.07 (s, 1), 3.29 (s, 3), 2.82 (q, J = 7.4 z, 2), (m, 9), (m, 8), 1.00 (t, J = 7.4 z, 3); 13 C-MR (75 Mz, ): δ (ppm) = 163.1, 143.0, 138.9, 135.8, 129.7, 129.4, 127.7, 73.1, 53.8, 48.2, 44.6, 40.8, 40.3, 35.4, 30.4, 29.7, 17.6, 14.0, 13.6; RMS (ESI+): m/z ( %) = , calcd for C [M+] + ; PLC: t R = 33.3 min, purity 99.0 %. 5-Ethyl--(3-(4-fluorobutoy)adamantan-1-yl)-2-methyl-1-phenyl-1--imidazole-4-carboamide (10) Compound 10 was obtained by General procedure 3, yield 19%, pale yellow solid; R f = 0.67 (EA); 1 -MR (300 Mz, ): δ (ppm) = (m, 3), (m, 2), 4.39 (dt, J = 47.3,J = 6.1 z, 2), 3.40 (t, J = 6.2 z, 2), 2.74 (q, J = 7.4 z, 2), (m, 12), (m, 10), 0.91 (t, J = 7.4 z, 3); 13 C-MR (75 Mz, ): δ (ppm) = 142.9, 129.8, 129.6, 127.6, 85.2, 83.1, 72.9, 59.4, 54.0, 45.2, 40.8, 40.8, 35.4, 30.5, 29.7, 27.6, 27.3, 26.3, 26.2, 17.6, 14.0; RMS (ESI+): m/z ( %) = , calcd for C F 3 2 [M+] + ; PLC: t R = 38.3 min, purity 96.0 %. 5-Ethyl--(3-((4-fluorobenzyl)oy)adamantan-1-yl)-2-methyl-1-phenyl-1-imidazole-4-carboamide (11) Compound 11 was obtained by General procedure 3, yield 38%, white solid; R f = 0.55 (EA/PE 1:1); 1 MR (400 Mz, ): δ (ppm) = (m, 3), 7.33 (dd, J = 8.5, 5.6 z, 2), (m, 2), 7.02 (t, J = 8.8 z, 2), 4.52 (s, 2), 2.83 (q, J = 7.4 z, 2), (m, 17), 1.01 (t, J = 7.4 z, 3); 13 C MR (100 Mz, ): δ (ppm) = 160.8, 143.0, 135.5, 129.9, (d, J = 8.1 z), 127.6, (d, J = 21.3 z), 73.9, 62.0, 45.2, 40.9 (d, J = 7.7 z), 35.4, 30.5, 17.6, 13.9; RMS (ESI+): m/z ( %) = , calcd for C F 3 2 [M+] + ; PLC: t R = 38.8 min, purity 99.1 %. 5-Ethyl--(3-fluoroadamantan-1-yl)-2-methyl-1-phenyl-1-imidazole-4-carboamide (12) DAST (33µL, 0.25 mmol, 1.5 equiv) was added to a 78 C cold solution of 8 (65 mg, 0.16 mmol, 1 equiv) in 2 ml dry DCM. The reaction was allowed to warm up to rt. after which 10 ml 2 was added and the miture was washed 210 ml DCM. The combined organic solutions were dried over sodium sulfate and the volatiles were eliminated under reduced pressure. The resulting residue was subject of column chromatography purification on silica gel (EA/PE 2:8) to give 12 as white solid (83% yield). R f = 0.12 (EA/PE 1:4); 1 MR (400 Mz, ): δ (ppm) = (m, 3), (m, 2), 7.12 (s, 1), 2.80 (q, J = 7.4 z, 2), (m, 4), 2.15 (s, 3), 2.11 (s, 4), (m, 4), (m, 2), 0.99 (t, J = 7.4 z, 3); 13 C MR (100 Mz, ): δ (ppm) = 163.0, 143.0, 139.1, 135.7, 129.7, 129.4, 127.6, 93.5, 91.6, 54.4 (d, J = 12.1 z), 46.7 (d, J = 18.5 z), 41.8 (d, J = 17.4 z), 40.4, 34.8, 31.1 (d, J = 10.3 z), 17.6, 13.9, 13.5; RMS (ESI+): m/z ( %) = , calcd for C F 3 [M+] + ; PLC: t R = 36.1 min, purity 97.1 %. -(Adamantan-1-yl)-2-(bromomethyl)-5-ethyl-1-phenyl-1-imidazole-4-carboamide (13) BS (161 mg, 0.9 mmol, 1.1 equiv) and AIB (13 mg, 0.90 mmol, 0.1 equiv) were added to a solution of 5 (300 mg, 0.82 mmol, 1 equiv) in 5 ml CCl 4 at room temperature and the miture was reflued for 6 h. Upon cooling, ac 3 sat. aq. sol. (10 ml) was added and the solution was etracted with DCM (210 ml). The combined organic layers were dried over a 2 S 4, concentrated under reduced pressure and the resulting residue was subject to flash chromatography purification (silica, EA/PE 1:9 to EA/PE 1:4), to give 13 (110 mg, 0.24 mmol, 30%) as tan white solid. 1 -MR (400 Mz, ): δ (ppm) = (m, 3), (m, 2), 7.05 (s, 1), 4.29 (s, 2), (m, 2), (m, 9), 1.74 (q, J = 12.3 z, 6), 1.03 (t, J = 7.5 z, 3); 13 C MR (100 Mz, ): δ (ppm) = 162.6, 143.0, 135.1, 131.8, 130.2, 127.5, 74.9, 51.8, 41.9, 36.4, 29.5, 10.6; MS (ESI+): m/z ( %) = 442 (C Br 2 ). -(Adamantan-1-yl)-5-ethyl-2-((2-fluoroethoy)methyl)-1-phenyl-1-imidazole-4-carboamide (14) 2-Fluoroethanol (13 µl, 0.2 mmol, 2 equiv) was added to a solution of 13 (44 mg, 0.1 mmol, 1 equiv) and Cs 2 C 3 (65 mg, 0.2 mmol, 2 equiv) in 2 ml MeC and the reaction miture was warmed to 45 C for 60 min. Upon completion, the reaction was quenched by addition of ac 3 sat. aq. sol. (5 ml) and the resulting miture was etracted with DCM (25 ml). The combined organics were dried over a 2 S 4 and the product (14, 30 mg, 0.07 mmol, 72% yield) was obtained by flash chromatography (EA/PE 2:8). R f = 0.18 (EA/PE 1:4); 1 MR (400 Mz, ): δ (ppm) = (m, 3), (m, 2), 7.10 (s, 1), (m, 4), (m, 2), 2.84 (q, J = 7.5 z, 2), (m, 9), (m, 6), 1.00 (t, J = 7.4 z, 3); 13 C MR (100 Mz, ): δ (ppm) = 162.6, 142.0, 140.2,

4 129.5, 129.5, 127.8, 110.0, 82.6 (d, J = z), 69.4 (d, J = 19.8 z), 41.7, 36.4, 29.6, 29.6, 17.5, 13.8; RMS (ESI+): m/z ( %) = , calcd for C F 3 2 [M+] + ; PLC: t R = 40.2 min, purity 96.2 %. -(Adamantan-1-yl)-5-ethyl-2-((3-fluoropropoy)methyl)-1-phenyl-1-imidazole-4-carboamide (15) 3-Fluoropropanol (16 µl, 0.2 mmol, 2 equiv) was added to a solution of 13 (44 mg, 0.1 mmol, 1 equiv) and Cs 2 C 3 (65 mg, 0.2 mmol, 2 equiv) in 2 ml MeC and the reaction miture was warmed to 45 C for 60 min. Upon completion, the reaction was quenched by addition of ac 3 sat. aq. sol. (5 ml) and the resulting miture was etracted with DCM (25 ml). The combined organics were dried over a 2 S 4 and the product (15, 30 mg, 0.07 mmol, 69% yield) was obtained by flash chromatography (EA/PE 2:8). R f = 0.18 (EA/PE 1:4); 1 MR (400 Mz, ): δ (ppm) = (m, z, 3), (m, 2), 7.11 (s, 1), (m, 4), (m, 2), 2.84 (q, J = 7.4 z, 2), (m, 9), 1.90 (dd, J = 12.1, 6.1 z, 2), (m, 6), 1.00 (t, J = 7.4 z, 3); 13 C MR (100 Mz, ): δ (ppm) = 162.6, , , , , , , (d, J = z), (d, J = 19.8 z), 41.79, 36.48, 29.67, 29.61, 17.53, 13.88; RMS (ESI+): m/z ( %) = , calcd for C F 3 2 [M+] + ; PLC: t R = 39.5 min, purity 97.8 %. Ethyl-5-methyl-1-phenyl-1--imidazole-4-carboylate (17a) Phenyl boronic acid (3.16 g, mmol, 1.6 equiv) and CuI (308 mg, 0.81 mmol, 0.10 equiv) were added to a solution of ethyl-5-methyl-1-imidazole-4-carboylate 16 (2.50 g, 16.2 mmol, 1.0 equiv) in ethanol/water (100 ml, 1/1 (v/v)) and the miture was stirred at 85 C for 60 h. After cooling to room temperature the solvent was evaporated in vacuum. The two regioisomers were separated by flash chromatography (EA/PE 1:1 to EA) to give 17a (0.90 g, 3.89 mmol, 24%) as beige solid. R f = 0.48 (EA); 1 -MR (400 Mz, ) δ (ppm) = 7.59 (s, 1), (m, 3), (m, 2), 4.40 (q, J = 7.0 z, 2), 2.46 (s, 3), 1.41 (t, J = 7.1 z, 3). 1, 2 -(Adamantan-1-yl)-5-methyl-1-phenyl-1--imidazole-4-carboamide (18) Compound 18 was obtained according to General Procedure 4, 40% yield, beige solid. R f = 0.75 (EA); 1 -MR (300 Mz, ): δ (ppm) = (m, 3), 7.38 (s, 1), (m, 2), 6.95 (s, 1), 2.42 (s, 3), (m, 9), (m, 6); 13 C-MR (100 Mz, ): δ (ppm) =162.8, 135.4, 134.5, 132.5, 132.2, 129.7, 129.1, 126.0, 51.6, 41.8, 36.5, 29.5, 10.2; RMS (ESI+): m/z ( %) = , calcd for C [M+] +. -(Adamantan-1-yl)-2-bromo-5-methyl-1-phenyl-1--imidazole-4-carboamide (19) -bromosuccinimide (291 mg, 1.6 mmol, 1.1 equiv) was added in one portion to a solution of 18 (500 mg, 1.5 mmol, 1.0 equiv) in MeC (8 ml) and the reaction miture was stirred for 4 h at room temperature. After evaporation of the solvent, the residue was taken up in EA (10 ml) and washed with an aq. ac 3 -sol. (15 ml). The organic layer was dried over sodium sulfate, filtered and concentrated in vacuum. Purification by flash chromatography on silica gel (EA/PE 1:5) yielded 19 (519 mg, 1.3 mmol, 85%) as a beige solid. R f = 0.52 (EA/PE 1:3); 1 -MR (400 Mz, ): δ (ppm) = (m, 3), (m, 2), 6.92 (s, 1), 2.38 (s, 3), 2.13 (d, J = 13.0 z, 9), (m, 6); 13 C-MR (100 Mz, ): δ (ppm) = 162.2, 136.0, 135.3, 133.1, 130.1, 129.9, 128.1, 118.0, 52.0, 42.0, 36.7, 29.7, 11.3; RMS (ESI+): m/z ( %) = , calcd for C Br 3 [M+] +. -(Adamantan-1-yl)-2-(hydroymethyl)-5-methyl-1-phenyl-1-imidazole-4-carboamide (20) LDA (2M in TF, 1 ml, 2 mmol, 2 equiv) was added to a 78 C cold solution of 19 (400 mg, 1 mmol, 1 equiv) in 5 ml TF, and the reaction miture was maintained at this temperature for 30 min after which DMF (300 µl, 9.6 mmol, 10 equiv) was added. The cooling bath was removed and the miture was allowed to react for one hour at room temperature after which a saturated aq. sol. of 4 Cl (10 ml) and DCM (10 ml) were added. The phases were separated and the aqueous phase was etracted once with DCM. The combined organic solutions were dried over a 2 S 4 and concentrated under reduced pressure. The resulting residue was subject to flash chromatography purification on silica gel (EA/PE 1:9; R f = 0.3). The aldehyde was obtained as white solid (100 mg, 0.3 mmol 30%). ab 4 (7 mg, 0.2 mmol, 1 equiv) was added to a 0 C cold Me (2 ml) solution of aldehyde (70 mg, 0.2 mmol, 1 equiv), and the miture was stirred for 30 min at 0 C. The reaction was quenched by addition of 4 Cl (5 ml) and the whole was etracted twice with 5 ml DCM. The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. Compound 20 (70 mg, 0.2 mmol, 1 equiv) was obtained as white solid and used without further purification in the net step. R f = 0.3 (EA/PE 1:1); 1 MR (400 Mz, ): δ (ppm) = (m, 3), (m, 2), 7.03 (s, 1), 4.46 (s, 2), 3.33 (s, 1), 2.39 (s, 3), (m, 9), (m, 6); 13 C MR (100 Mz, ): δ (ppm) = 162.7, 145.4, 134.6, 134.0, 130.4, 129.7, 129.6, 127.4, 56.3, 51.7, 41.8, 36.5, 29.5, (Adamantan-1-yl)-2-(fluoromethyl)-5-methyl-1-phenyl-1-imidazole-4-carboamide (21)

5 DAST (9 µl, 0.07 mmol, 1 equiv) was added to a 78 C cold solution of 20 (25 mg, 0.07 mmol, 1 equiv) in dry DCM (1 ml) and the miture was stirred a this temperature for 30 min. Aq. ac 3 sol. (5 ml) was then added for quenching and the reaction was etracted once with DCM (5 ml). The organic solution was dried over sodium sulfate and concentrated under reduced pressure. The product was purified by flash chromatography (silica, EA/PE 1:4), and obtained as white solid (23 mg, 0.06 mmol, 91%). R f = 0.15 (EA/PE 1:4); 1 MR (400 Mz, ): δ (ppm) = (m, 3), (m, 2), 7.08 (s, 1), 5.14 (d, J = 48.9 z, 2), 2.42 (d, J = 2.1 z, 3), (m, 9), (m, 6); 13 C MR (100 Mz, ): δ (ppm) = 162.6, (d, J = 19.5 z), (d, J = 51.5 z), 131.6, (d, J = 4.1 z), 127.5, 74.8 (d, J = z), 51.7, 41.8, 36.5, 29.5, 10.6; RMS (ESI+): m/z ( %) = , calcd for C F 3 a [M+a] + ; PLC: t R = 39.0 min, purity 97.3 %. -(adamantan-1-yl)-2-((2-fluoroethoy)methyl)-5-methyl-1-phenyl-1-imidazole-4-carboamide (22) Compound 22 was obtained according to General procedure 3 as white solid, 83% yield. R f = 0.65 (EA/PE 1:1); 1 MR (400 Mz, ): δ (ppm) = (m, 3), (m, 2), 7.06 (s, 1), (m, 2), 4.36 (s, 2), (m, 2), 2.39 (s, 3), 2.16 (d, J = 19.4 z, 8), (m, 4), 0.89 (dt, J = 10.5, 6.4 z, 3); 13 C MR (100 Mz, ): δ (ppm) = 163.1, 142.1, 134.9, 134.3, 129.5, 129.3, 127.6, 83.5, 81.8, 69.3 (d, J = 19.8 z), 64.3, 51.6, 41.8, 36.5, 29.6 (d, J = 13.3 z), 22.7, 14.1, 10.6; RMS (ESI+): m/z ( %) = , calcd for C F 3 2 [M+] + ; PLC: t R = 37.6 min, purity 96.8 %. -(Adamantan-1-yl)-5-ethyl-1-(2-fluorophenyl)-2-methyl-1-imidazole-4-carboamide (26) Compound 26 was obtained by General procedure 1, yield 31%, beige solid; R f = 0.63 (EA/PE 1:1); 1 -MR (400 Mz, ): δ (ppm) = (m, 1), (m, 4), 2.73 (ddq, J = 20.7, 13.6, 6.8 z, 2), (m, 11), (m, 7), 0.91 (t, J = 7.5 z, 3); 13 C-MR (100 Mz, ): δ (ppm) = 143.4, 129.9, 125.3, 117.4, 42.0, 36.7, 29.9, 29.7, 17.7, 13.8; RMS (ESI+): m/z ( %) = , calcd for C F 3 [M+] + ; PLC: t R = 40.1 min, purity 97.3 %. -(Adamantan-1-yl)-5-ethyl-1-(3-fluorphenyl)-2-methyl-1-imidazol-4-carboamide (27) Compound 27 was obtained by General procedure 1, yield 47%, beige solid; R f = 0.63 (EA/PE 1:1); 1 -MR (300 Mz, ): δ (ppm) = (m, 1), (m, 1), (m, 3), 2.82 (q, J = 7.5 z, 2), (m, 12), (m, 6), 0.98 (t, J = 7.4 z, 3); 13 C-MR (75 Mz, ): δ (ppm) = 164.7, 161.4, 142.8, 138.8, 131.3, 131.2, 123.8, 123.8, 117.1, 116.8, 115.7, , 51.7, 42.0, 36.7, 29.8, 29.7, 17.7, 14.2, 13.6; RMS (ESI+): m/z ( %) = , calcd for C F 3 [M+] + ; PLC: t R = 40.3 min, purity 95.0 %. -(Adamantan-1-yl)-5-ethyl-1-(4-fluorophenyl)-2-methyl-1--imidazole-4-carboamide (28) Compound 28 was obtained by General procedure 1, yield 33%, beige solid; R f = 0.63 (EA/PE 1:1); 1 -MR (400 Mz, ): δ (ppm) = (m, 4), (m, 1), 2.73 (q, J = 7.4 z, 2), (m, 12), (m, 6), 0.91 (t, J = 7.4 z, 3); 13 C-MR (100 Mz, ): δ (ppm) = 164.2, 161.7, 143.1, 139.0, 129.7, 129.6, 117.2, 116.9, 51.7, 42.0, 36.7, 29.8, 29.7, 17.7, 14.2, RMS (ESI+): m/z ( %) = , calcd for C F 3 [M+] + ; PLC: t R = 39.9 min, purity 98.9 %.

6 1 MR spectra of compounds 5, 8, 9, 10, 11, 12, 14, 15, 18, 19, 20, 21, 22, 26, 27 and

7 9 F 10

8 11 12

9 F 14 F 15

10 18 19

11 CDCl CDCl F

12 F 22 26

13 27 F 28

14 1. Lange, J.. M.; van der eut, M. A. W.; Wals,. C.; Kuil, G. D.; Borst, A. J. M.; Mulder, A.; den artog, A. P.; Zilaout,.; Goutier, W.; van Stuivenberg,..; van Vliet, B. J. Synthesis and SAR of novel imidazoles as potent and selective cannabinoid CB 2 receptor antagonists with high binding efficiencies. Bioorg. Med. Chem. Lett. 2010, 20, Lange, J.; van Stuivenberg,.; Van Vliet, B. 1-Imidazole derivatives as cannabinoid CB 2 receptor modulators. US A1, 2006.

Supporting Information. Copyright Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim, 2009

Supporting Information. Copyright Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim, 2009 Supporting Information Copyright Wiley-VC Verlag Gmb & Co. KGaA, 69451 Weinheim, 2009 A Stereodivergent Strategy to Both Product Enantiomers from the Same Enantiomer of a Stereoinducing Catalyst: Agelastatin