SUPPLEMENTARY NOTE COMPOUND CHARACTERIZATION
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1 SUPPLEMENTARY NOTE COMPOUND CHARACTERIZATION Cyclobutane-core antagonists prevent nuclear translocation of the androgen receptor Julie A. Pollock 1,5,6, Suzanne E. Wardell 2,6, Alexander A. Parent 1,6, David B. Stagg 2, Stephanie J. Ellison 2, Holly M. Alley 2, Christina A. Chao 2, Scott A. Lawrence 2, James P. Stice 2, Ivan Spasojevic 3,4, Jennifer G. Baker 2, Sung Hoon Kim 1, Donald P. McDonnell 2, John A. Katzenellenbogen 1, and John D. Norris 2 * 1 Department of Chemistry University of Illinois at Urbana-Champaign 600 South Mathews Avenue Urbana, IL Department of Pharmacology and Cancer Biology Duke University School of Medicine Durham, NC Department of Medicine Duke University Medical Center Durham, NC Duke Cancer Institute Pharmaceutical Research PK/PD Core Laboratory Durham, NC Present Address: Department of Chemistry University of Richmond 28 Westhampton Way Richmond, VA These authors contributed equally to the work. *Corresponding author: jdn001@duke.edu Nature Chemical Biology: doi: /nchembio.2131
2 Synthetic Procedures and Compound Characterization for CB1-21. General Synthetic Methods. All reagents were used as purchased. THF, Ether, CH 2 Cl 2, and DMF used in reactions were dried using a solvent delivery system (neutral alumina column). Solvents used for extraction and flash chromatography were reagent or ultima grade, purchased from either Aldrich or Fisher Scientific. All reactions were run under dry N 2 atmosphere except where noted. Flash column chromatography was performed on Silica P Flash Silica Gel (40-64 μm, 60 Å) from SiliCycle or using a Teledyne ISCO CombiFlash MPLC system equipped with Redisep Gold silica gel columns. 1 HNMR and 13 CNMR spectra were obtained on 400 or 500 MHz Varian FT-NMR spectrometers. Except where noted, both low and high resolution mass spectra were obtained using electrospray ionization on either a Micromass Q-Tof Ultima or Waters Quattro instrument. Scheme 1 The synthesis of (E)-2,4-dichloro-6-styrylpyrimidine, 22, has been reported previously. 19 The synthesis of 6,6'-((1R,2R,3S,4S)-2,4-diphenylcyclobutane-1,3-diyl)bis(2,4- dichloropyrimidine), CB9 (9), has been reported previously. 20 Representative example for the formation of compounds 1-5, 15-17: Nature Chemical Biology: doi: /nchembio.2131
3 6,6'-((1R,2R,3S,4S)-2,4-diphenylcyclobutane-1,3-diyl)bis(2,4-dimethoxypyrimidine), CB1 (1). Dissolved 100 mg (0.199 mmol) of CB9 in 4 ml of methanol. To this solution 200 mg (5.00 mmol) of NaH (60% dispersion in mineral oil) was added, and the resulting cloudy solution was heated at 80 C for 2 days. The reaction was allowed to cool to room temperature, diluted with saturated NaCl solution, and extracted three times with EtOAc. The combined organic layers were washed with brine and dried over MgSO 4. The solvent was removed using a rotary evaporator and the residue purified by Combiflash on a silica gel column (gradient elution 10 30% EtOAc/hex) to give 49 mg (0.096 mmol, 48% yield) of CB1 and 30 mg (0.062 mmol, 31% yield) of its diastereomer as shown in Scheme S1. 6,6'-((1R,2R,3S,4S)-2,4- diphenylcyclobutane-1,3-diyl)bis(2,4-dimethoxypyrimidine) CB1 (1). 1 H NMR (500 MHz, CDCl 3 ) δ 3.85 (s, 6 H), 3.85 (s, 6 H), 4.52 (m, J=9.86, 6.43 Hz, 2 H), 4.66 (dd, J=10.08, 6.86 Hz, 2 H), 6.13 (s, 2 H), (m, 2 H), (m, 8 H). 13 C NMR (500 MHz, CDCl 3 ) δ 45.1, 48.2, 53.6, 54.6, 100.7, 126.2, 127.7, 128.0, 139.9, 164.8, 170.7, HRMS (ESI + ) m/z calcd for C 28 H 29 N 4 O , found ,6'-((1R,2R,3S,4S)-2,4-diphenylcyclobutane-1,3-diyl)bis(2,4-diethoxypyrimidine) CB2 (2). As for the synthesis of CB1: 30 mg (0.060 mmol) CB9, 4 ml EtOH, 45 mg (1.12 mmol) NaH (60% dispersion in mineral oil), producing 15 mg (0.028 mmol, 47% yield) of CB2. 1 H NMR (500 MHz, CDCl 3 ) δ 1.30 (t, J=7.07 Hz, 6 H), 1.33 (t, J=7.07 Hz, 6 H), (m, 8 H), 4.48 (dd, J=9.97, 6.97 Hz, 2 H), 4.64 (dd, J=9.86, 7.93 Hz, 2 H), 6.09 (s, 2 H), (m, 2 H), (m, 8 H). 13 C NMR (500 MHz, CDCl 3 ) δ 14.3, 14.5, 45.2, 48.4, 62.1, 63.1, 100.8, 126.1, 127.8, 128.0, 140.1, 170.6, HRMS (ESI + ) m/z calcd for C 32 H 37 N 4 O , found ,6'-((1R,2R,3S,4S)-2,4-diphenylcyclobutane-1,3-diyl)bis(2,4-dipropoxypyrimidine) CB3 (3). As for the synthesis of CB1: 40 mg (0.080 mmol) CB9, 4 ml n-propanol, 60 mg (1.50 mmol) Nature Chemical Biology: doi: /nchembio.2131
4 NaH (60% dispersion in mineral oil), producing 18 mg (0.029 mmol, 37% yield) of CB3. 1 H NMR (500 MHz, CDCl 3 ) δ 0.94 (t, J=7.40 Hz, 6 H), 0.98 (t, J=7.50 Hz, 6 H), 1.71 (oct, J=7.30 Hz, 8 H), (m, 8 H), 4.48 (dd, J=9.86, 7.07 Hz, 2 H), 4.63 (dd, J=10.51, 7.50 Hz, 2 H), 6.10 (s, 2 H), (m, 2 H), (m, 8 H). 13 C NMR (125 MHz, CDCl 3 ) δ 10.4, 10.5, 22.03, 22.09, 45.1, 48.3, 67.9, 68.9, 100.6, 126.1, 127.7, 127.9, 140.0, 164.6, 170.5, HRMS (ESI + ) m/z calcd for C 36 H 45 N 4 O , found ,6'-((1R,2R,3S,4S)-2,4-diphenylcyclobutane-1,3-diyl)bis(2,4-diisopropoxypyrimidine) CB4 (4). As for the synthesis of CB1: 40 mg (0.080 mmol) CB9, 4 ml isopropanol, 60 mg (1.50 mmol) NaH (60% dispersion in mineral oil), producing 11 mg (0.019 mmol, 24% yield) of CB4. 1 H NMR (500 MHz, CDCl 3 ) δ 1.25 (dt, J=6.22, 1.50 Hz, 12 H), 1.30 (d, J=6.22 Hz, 12 H), 4.44 (dd, J=10.08, 7.07 Hz, 2 H), 4.63 (dd, J=10.18, 7.18 Hz, 2 H), 5.14 (spt, J=6.20 Hz, 2 H), 5.29 (spt, J=6.20 Hz, 2 H), 6.03 (s, 2 H), (m, 2 H), (m, 8 H). 13 C NMR (125 MHz, CDCl 3 ) δ 21.8, 21.9, 44.9, 48.3, 68.7, 69.7, 101.0, 126.0, 127.8, 127.9, 140.1, 164.1, 170.5, HRMS (ESI + ) m/z calcd for C 36 H 45 N 4 O , found ,6'-((1R,2R,3S,4S)-2,4-diphenylcyclobutane-1,3-diyl)bis(2,4-dibenzyloxypyrimidine) CB5 (5). As for the synthesis of CB1: 200 mg (0.398 mmol) CB9, 4 ml benzyl alcohol, 300 mg (7.5 mmol) NaH (60% dispersion in mineral oil), heated at 50 C for 16 h, producing 52 mg (0.066 mmol, 17% yield) of CB5. 1 H NMR (500 MHz, CDCl 3 ) δ 4.46 (dd, J=10.08, 7.08 Hz, 2 H), 4.62 (dd, J=9.86, 7.50 Hz, 2 H), (m, 8 H), 6.15 (s, 2 H), (m, 10 H), (m, 16 H), 7.43 (d, J=7.07 Hz, 4 H). 13 C NMR (500 MHz, CDCl 3 ) δ 45.0, 48.1, 68.0, 69.0, 101.2, 126.2, 127.7, 127.8, , , , , 128.4, 128.5, 136.1, 137.1, 139.7, 153.9, 164.1, 170.8, HRMS (ESI + ) m/z calcd for C 52 H 45 N 4 O , found Nature Chemical Biology: doi: /nchembio.2131
5 Scheme 2 6,6'-((1R,2R,3S,4S)-2,4-diphenylcyclobutane-1,3-diyl)bis(pyrimidine) CB6 (6). Dissolved 20 mg (0.04 mmol) of CB9 in 6 ml of MeOH. To this solution 10 mg of 10% Pd/C and 250 mg of NaHCO 3 were added. This suspension was stirred under 1 atm of H 2 for 24 hours. The solvent was removed using a rotary evaporator and the residue purified by Combiflash on a silica gel column (gradient elution 10 35% EtOAc/hex) to give CB6. 1 H NMR (500 MHz, CDCl 3 ) δ 4.67 (dd, J=10.18, 7.40 Hz, 2 H), 4.95 (dd, J=10.08, 7.93 Hz, 2 H), 6.96 (dd, J=5.36, 1.07 Hz, 2 H), (m, 2 H), (m, 8 H), 8.39 (d, J=4.93 Hz, 2 H), 9.06 (s, 2 H). 13 C NMR (500 MHz, CDCl 3 ) δ 44.8, 48.1, 121.1, 126.6, 127.8, 128.2, 138.9, 155.9, HRMS (ESI + ) m/z calcd for C 24 H 21 N , found Scheme 3 6,6'-((1R,2R,3S,4S)-2,4-diphenylcyclobutane-1,3-diyl)bis(2,4-dimethylpyrimidine) CB7 (7). Samples of CB9 (20 mg, mmol) and Fe(acac) 3 (10 mg, mmol) were dissolved in 3 Nature Chemical Biology: doi: /nchembio.2131
6 ml of THF. To this brown solution, MeMgBr (3 M in ether, 0.15 ml, 0.48 mmol) was added dropwise causing the solution to progress to a cloudy white followed by a cloudy orange-brown. After an hour of stirring at room temperature an additional 10 mg (0.028 mmol) of Fe(acac) 3 was added followed by another 0.2 ml of Grignard solution (0.60 mmol). After another hour the Fe(acac) 3 and Grignard addition was repeated once more. At this point the reaction turned from brown to a dark black. The reaction was quenched with saturated NaCl solution and extracted three times with ether. The combined organic layers were dried over anhydrous MgSO 4, and after removal of solvent by rotary evaporator the residue was purified by Combiflash (gradient elution 20 70%, EtOAc/hex) to give CB7. 1 H NMR (500 MHz, CDCl 3 ) δ 2.28 (s, 6 H), 2.57 (s, 6 H), 4.59 (dd, J=10.51, 7.50 Hz, 2 H), 4.76 (dd, J=10.08, 6.86 Hz, 2 H), 6.63 (s, 2 H), (m, 2 H), (m, 8 H). 13 C NMR (125 MHz, CDCl 3 ) δ 23.9, 25.9, 44.9, 47.9, 116.7, 126.3, 127.9, 127.9, 139.2, 166.0, 167.0, HRMS (ESI + ) m/z calcd for C 28 H 29 N , found ,6'-((1R,2R,3S,4S)-2,4-diphenylcyclobutane-1,3-diyl)bis(2,4-diethylpyrimidine) CB8 (8). Samples of CB9 (20 mg, mmol) and Fe(acac) 3 (10 mg, mmol) were dissolved in 3 ml of THF. To this brown solution, EtMgBr (1 M in THF, 0.60 ml, 0.60 mmol) was added dropwise causing the solution to progress to a cloudy white followed by a cloudy orange-brown. After an hour of stirring at room temperature an additional 10 mg (0.028 mmol) of Fe(acac) 3 was added followed by another 0.6 ml of Grignard solution (0.60 mmol). After the second addition of Grignard reagent, the reaction turned from brown to a dark black. The reaction was quenched with saturated NaCl solution and extracted three times with ether. The combined organic layers were dried over anhydrous MgSO 4, and after removal of solvent by rotary evaporator the residue was purified by Combiflash (gradient elution 0 20%, EtOAc/hex) to give 9 mg ( mmol, 48% yield) of CB8. 1 H NMR (500 MHz, CDCl 3 ) δ 1.10 (t, J=7.61 Hz, 6 H), 1.22 (t, J=7.61 Hz, 6 H), 2.56 (q, J=7.72 Hz, 4 H), 2.82 (qd, J=7.61, 2.47 Hz, 4 H), 4.61 (dd, J=10.18, 7.18 Hz, Nature Chemical Biology: doi: /nchembio.2131
7 2 H), 4.81 (dd, J=10.08, 7.29 Hz, 2 H), 6.64 (s, 2 H), 7.05 (tt, J=6.40, 2.10 Hz, 2 H), (m, 8 H). 13 C NMR (125 MHz, CDCl 3 ) δ 13.0, 13.1, 30.8, 32.7, 44.9, 48.2, 115.5, 126.1, 127.9, 127.9, 139.7, 168.2, 170.9, HRMS (ESI + ) m/z calcd for C 32 H 37 N , found Scheme 4 Representative example for the formation of compounds 23-26: (E)-2-chloro-4- styrylpyrimidine (23): Trans-2-phenylvinylboronic acid (0.5 g, 1 eq, 3.6 mmol) was dissolved in 20 ml THF. The catalyst, PdCl 2 (PPh 3 ) 2 (76 mg, 0.03 eq, 0.11 mmol) was added followed by potassium phosphate tribasic (1.5 g, 2 eq, 7.2 mmol). The 2,4-dichloropyrimidine (0.5 g, 1 eq, 3.6 mmol) was dissolved in 4 ml THF and then added to the stirred solution via syringe. Water (3 ml) was added. The flask was equipped with a condenser and brought to a reflux for 24 Nature Chemical Biology: doi: /nchembio.2131
8 hours. The reaction was quenched with 20 ml water. The organic products were extracted with 3X25 ml Et 2 O. They were combined and washed with brine (30 ml), dried over MgSO 4 and concentrated under reduced pressure. The product was purified using 10% ethyl acetate in hexanes to yield pure g (64% yield) of off-white solid 23: 1 H NMR (500 MHz, CDCl 3 ) δ 8.62 (d, J = 5.1 Hz, 1H), 8.02 (d, J = 16.0 Hz, 1H), (m, 2H), (m, 2H), 7.31 (d, J = 5.1 Hz, 1H), 7.10 (d, J = 16.0 Hz, 1H). 13 C NMR (125 MHz, CDCl 3 ) δ 165.5, 161.5, 159.6, 139.3, 135.0, 129.9, 128.9, 127.9, 126.1, 124.0, 122.7, HRMS (ESI + ) m/z calcd for C 12 H 10 N 2 Cl , found (E)-4-chloro-6-styrylpyrimidine (24). As for the synthesis of 23: g trans-2- phenylvinylboronic acid (3.6 mmol), 70.6 mg PdCl 2 (PPh 3 ) 2 (0.11 mmol), g 4,6- dichloropyrimidine (3.6 mmol), g K 3 PO 4, 20 ml THF, and 3 ml water, producing g (66 % yield) of white solid H NMR (500 MHz, CDCl 3 ) δ 8.88 (d, J = 1.1 Hz, 1H), 7.88 (d, J = 16.0 Hz, 1H), 7.55 (dd, J = 7.9, 1.7 Hz, 2H), (m, 3H), 7.25 (d, J = 1.1 Hz, 1H), 6.95 (d, J = 15.9 Hz, 1H). 13 C NMR (125 MHz, CDCl 3 ) δ 163.9, 161.5, 158.5, 138.8, 135.0, 129.8, 128.8, 127.7, 124.0, HRMS (ESI + ) m/z calcd for C 12 H 10 N 2 Cl , found (E)-2-chloro-4-methyl-6-styrylpyrimidine (25): As for the synthesis of 23: g trans-2- phenylvinylboronic acid (3.6 mmol), 77.6 mg PdCl 2 (PPh 3 ) 2 (0.11 mmol), g 4,6-dichloro-6- methylpyrimidine (3.6 mmol), g K 3 PO 4, 20 ml THF, and 3 ml water, producing g (65 % yield) of white solid H NMR (500 MHz, CDCl 3 ) δ 7.83 (d, J = 15.9 Hz, 1H), (m, 2H), (m, 3H), 6.99 (s, 1H), 6.89 (d, J = 15.9 Hz, 1H), 2.45 (s, 3H). 13 C NMR (125 MHz, CDCl 3 ) δ 170.5, 164.8, 160.8, 138.5, 134.9, 129.6, 128.7, 127.6, 123.9, 116.3, 77.3, 77.0, 76.7, HRMS (ESI + ) m/z calcd for C 13 H 12 N 2 Cl , found Nature Chemical Biology: doi: /nchembio.2131
9 (E)-4-(2-([1,1'-biphenyl]-4-yl)vinyl)-2,6-dichloropyrimidine (26). As for the synthesis of 23: g trans-2-(4-biphenyl)vinylboronic acid (2.2 mmol), 47.7 mg PdCl 2 (PPh 3 ) 2 (0.07 mmol), 250 µl 2,4,6-trichloropyrimidine (2.2 mmol), g K 3 PO 4, 15 ml THF, and 2 ml water, producing g (34 % yield) of yellow solid H NMR (500 MHz, CDCl 3 ) δ 8.02 (d, J = 15.8 Hz, 1H), 7.67 (s, 4H), (m, 2H), (m, 2H), (m, 1H), 7.24 (s, 1H), 6.99 (d, J = 15.9 Hz, 1H). 13 C NMR (125 MHz, CDCl 3 ) δ 166.4, 162.6, 160.6, 143.0, 140.3, 139.9, 133.7, 130.2, 129.0, 128.9, 128.8, 128.6, 128.4, 127.9, 127.7, 127.6, 127.4, 127.3, 127.0, 122.8, 120.1, 116.9, HRMS (ESI + ) m/z calcd for C 18 H 13 N 2 Cl , found ,6'-((1R,2R,3S,4S)-2,4-diphenylcyclobutane-1,3-diyl)bis(2-chloropyrimidine) CB10 (10): 23 (179 mg, 1 mmol) was crushed between two borosilicate plates. The plate was placed about ½-1 inch below a water-cooled 450 W low pressure mercury immersion lamp and then irradiated for 1 h. The material was isolated and did not require any purification to yield 176 mg (98 % yield) of light yellow solid CB10. 1 H NMR (499 MHz, CDCl 3 ) δ 8.26 (d, J = 5.1 Hz, 2H), (m, 10H), 6.87 (d, J = 5.1 Hz, 2H), 4.90 (dd, J = 10.3, 7.3 Hz, 2H), 4.67 (dd, J = 10.3, 7.2 Hz, 2H). 13 C NMR (126 MHz, CDCl 3 ) δ 171.7, 161.1, 158.5, 137.9, 128.4, 127.8, 127.0, 119.2, 47.7, HRMS (ESI + ) m/z calcd for C 24 H 19 N 4 Cl , found ,6'-((1R,2R,3S,4S)-2,4-diphenylcyclobutane-1,3-diyl)bis(4-chloropyrimidine) CB11 (11): 24 (105.5 mg, 0.5 mmol) was crushed between two borosilicate plates. The plate was placed about ½-1 inch below a water-cooled 450 W low pressure mercury immersion lamp and then irradiated for 1 h. The material was isolated and purified using Combiflash (gradient elution 0 10%, EtOAc/hex) to give 48.0 mg (45 % yield) of light yellow solid CB11 and 21.1 mg of the regioisomer illustrated in Scheme S4. 1 H NMR (499 MHz, CDCl 3 ) δ 8.79 (d, J = 1.2 Hz, 1H), (m, 10H), (m, 2H), 4.87 (dd, J = 10.2, 7.1 Hz, 2H), 4.64 (dd, J = 10.3, Nature Chemical Biology: doi: /nchembio.2131
10 7.1 Hz, 2H). 13 C NMR (126 MHz, CDCl 3 ) δ 170.4, 161.0, 158.6, 138.3, 128.7, 127.8, 127.2, 121.3, 48.1, HRMS (ESI + ) m/z calcd for C 24 H 19 N 4 Cl , found ,6'-((1R,2R,3S,4S)-2,4-diphenylcyclobutane-1,3-diyl)bis(2-chloro-4-methylpyrimidine) CB12 (12): 25 (207 mg, 0.9 mmol) was crushed between two borosilicate plates. The plate was placed about ½-1 inch below a water-cooled 450 W low pressure mercury immersion lamp and then irradiated for 1 h. The material was isolated and purified using Combiflash (gradient elution 0 20%, EtOAc/hex) to give mg (76 % yield) of off-white solid CB12 and 52.2 mg of the regioisomer illustrated in Scheme S4. 1 H NMR (499 MHz, CDCl 3 ) δ (m, 10H), 6.72 (s, 2H), 4.82 (dd, J = 10.2, 7.3 Hz, 2H), (m, 2H), 2.30 (s, 6H). 13 C NMR (126 MHz, CDCl 3 ) δ 171.2, 169.5, 160.5, 138.0, 128.2, 128.1, 127.8, 127.7, 126.8, 118.6, 47.5, 44.8, HRMS (ESI + ) m/z calcd for C 26 H 23 N 4 Cl , found ,6'-((1R,2R,3S,4S)-2,4-di(4-phenyl)phenylcyclobutane-1,3-diyl)bis(2,4dichloropyrimidine) CB13 (13): 26 (12.4 mg, 0.03 mmol) was crushed between two borosilicate plates. The plate was placed about ½-1 inch below a water-cooled 450 W low pressure mercury immersion lamp and then irradiated for 1 h. The material was isolated and purified using Combiflash (gradient elution 0 20%, EtOAc/hex) to give 1.6 mg (13 % yield) of yellow solid CB13 and 0.8 mg of the regioisomer illustrated in Scheme S4. 1 H NMR (500 MHz, CDCl 3 ) δ (m, 4H), 7.49 (d, J = 8.1 Hz, 4H), 7.43 (t, J = 7.6 Hz, 4H), (m, 2H), (m, 12H), 6.99 (s, 2H), 4.90 (dd, J = 10.2, 7.2 Hz, 2H), 4.69 (dd, J = 10.2, 7.2 Hz, 2H). 13 C NMR (126 MHz, CDCl 3 ) δ 172.9, 162.2, 160.5, 140.4, 136.4, 128.9, 128.3, 127.6, 127.4, 127.2, 119.5, 109.9, 47.9, HRMS (ESI + ) m/z calcd for C 36 H 25 N 4 Cl , found Nature Chemical Biology: doi: /nchembio.2131
11 Scheme 5 (E)-2,4-dichloro-6-(2-(thiophen-3-yl)vinyl)pyrimidine (27): g, 32 %, off-white solid. NaH (19.7 mg, 0.8 mmol) was suspended in THF (5 ml) and 2,4-dichloro-6-methylpyrimidine (124 mg, 0.7 mmol) was added. 3-Thiophenecarboxylic acid was added via syringe dropwise. The reaction was brought to a reflux for 18 h. The reaction was quenched with water (2 ml) and the organic products extracted with Et 2 O (3X 4 ml), washed with MgSO 4 and concentrated under reduced pressure. Flash chromatography (10% ethyl acetate in hexanes) was used to isolate 12.8 mg (8 % yield) of H NMR (400 MHz, CDCl 3 ) δ 7.95 (d, J = 15.7 Hz, 1H), 7.54 (t, J = 2.1 Hz, 1H), (m, 2H), 7.17 (s, 1H), 6.75 (d, J = 15.7 Hz, 1H). 13 C NMR (100 MHz, CDCl 3 ) δ 166.7, 162.5, 160.5, 138.0, 134.3, 128.4, 127.2, 124.9, 122.6, HRMS (ESI + ) m/z calcd for C 10 H 7 N 2 SCl , found ,6'-((1R,2R,3S,4S)-2,4-dithiophen3-ylcyclobutane-1,3-diyl)bis(2,4-dichloropyrimidine) CB14 (14): 27 (12.2 mg, 0.05 mmol) was crushed between two borosilicate plates. The plate was placed about ½-1 inch below a water-cooled 450 W low pressure mercury immersion lamp Nature Chemical Biology: doi: /nchembio.2131
12 and then irradiated for 1 h. The material was isolated and no purification was required to give 10.7 mg (88 % yield) of yellow solid CB14. 1 H NMR (400 MHz, CDCl 3 ) δ 7.18 (dd, J = 5.0, 2.9 Hz, 1H), 7.02 (dd, J = 3.0, 1.3 Hz, 1H), 6.91 (s, 1H), 6.80 (dd, J = 5.0, 1.3 Hz, 1H), 4.85 (dd, J = 9.9, 7.2 Hz, 1H), 4.43 (dd, J = 9.9, 7.2 Hz, 1H). 13 C NMR (101 MHz, CDCl 3 ) δ 172.5, 162.0, 160.3, 138.3, 126.8, 126.5, 122.2, 119.1, 48.8, HRMS (ESI + + ) m/z calcd for C 30 H 13 N 4 S 2 Cl , found Scheme 6 6,6'-((1R,2R,3S)-2,4-diphenylcyclobutane-1,3-diyl)bis(2-methoxy-4-methylpyrimidine) CB15 (15). As for the synthesis of CB1: 92.6 mg (0.2 mmol) CB12, 5 ml methanol, mg (5.4 mmol) NaH, producing 56.1 mg (62% yield) of CB15 as an almost equal mixture of the two stereoisomers illustrated in Scheme S6. All attempts to purify the single diastereomer were not successful. 1 H NMR (500 MHz, CDCl 3 ) δ 7.46 (dd, J = 7.9, 1.4 Hz, 1H), (m, 1H), 7.25 (d, J = 10.2 Hz, 1H), 7.15 (d, J = 4.9 Hz, 6H), (m, 1H), (m, 3H), 6.49 (d, J = 3.9 Hz, 3H), 5.22 (t, J = 10.8 Hz, 1H), 4.76 (dd, J = 10.3, 7.0 Hz, 1H), (m, 2H), (m, 1H), 4.03 (d, J = 11.2 Hz, 1H), 3.87 (s, 4H), 3.86 (s, 4H), 2.26 (s, 4H), 2.24 (s, 4H). 13 C NMR (126 MHz, CDCl 3 ) δ 170.6, 170.2, 169.2, 169.1, 165.3, 165.2, 143.4, Nature Chemical Biology: doi: /nchembio.2131
13 139.9, 137.1, 129.8, 128.7, 128.2, 127.9, 127.7, 127.2, 127.0, 126.8, 126.5, 126.4, 114.1, 113.3, 54.7, 54.6, 49.0, 48.8, 48.3, 45.2, 43.1, 24.0, 239. DPM (JAPI-185) CB 15: HRMS (ESI + ) m/z calcd for C 28 H 29 N 4 O , found ,6'-((1R,2R,3S,4S)-2,4-diphenylcyclobutane-1,3-diyl)bis(4-methoxypyrimidine) CB16 (16). As for the synthesis of CB1: 45.5 mg (0.10 mmol) CB11, 2 ml methanol, 3.7 mg (0.15 mmol) NaH, producing 18.2 mg (41% yield) of CB16. 1 H NMR (499 MHz, CDCl 3 ) δ (m, 2H), 7.18 (d, J = 4.3 Hz, 7H), 7.09 (q, J = 4.4 Hz, 2H), 6.42 (d, J = 1.1 Hz, 2H), 4.77 (dd, J = 10.2, 7.2 Hz, 2H), 4.59 (dd, J = 10.4, 7.0 Hz, 2H), 3.86 (d, J = 0.7 Hz, 5H). 13 C NMR (126 MHz, CDCl 3 ) δ 169.4, 168.8, 157.7, 139.3, 128.1, 127.8, 126.4, 107.0, 53.5, 48.1, HRMS (ESI + ) m/z calcd for C 26 H 25 N 4 O , found ,6'-((1R,2R,3S,4S)-2,4-dithiophen3-ylcyclobutane-1,3-diyl)bis(2,4-dimethoxypyrimidine) CB17 (17). As for the synthesis of CB1: 10.1 mg (0.02 mmol) CB14, 2 ml methanol, 1.3 mg (0.03 mmol) NaH, producing 3.4 mg (33% yield) of CB17. 1 H NMR (500 MHz, CDCl 3 ) δ (m, 2H), (m, 2H), 6.82 (dd, J = 4.9, 1.3 Hz, 2H), 6.11 (s, 2H), 4.71 (dd, J = 9.9, 7.1 Hz, 2H), 4.33 (dd, J = 9.9, 7.2 Hz, 2H), 3.92 (s, 6H), 3.87 (s, 6H). 13 C NMR (126 MHz, CDCl 3 ) δ 171.6, 170.5, 164.9, 140.8, 127.5, 125.1, 121.0, 100.5, 54.7, 53.6, 49.3, HRMS (ESI + ) m/z calcd for C 24 H 25 N 4 O 4 S , found Scheme S7 Nature Chemical Biology: doi: /nchembio.2131
14 6,6'-((1R,2R,3S,4S)-2,4-diphenylcyclobutane-1,3-diyl)bis(2,4-dimethylmercaptopyrimidine) CB18 (18). Dissolved 100 mg (0.199 mmol) of CB9 in 4 ml THF. To this solution 112 mg (1.60 mmol) of sodium methylthiolate was added. The resulting suspension was stirred at reflux for 4 days. The reaction was allowed to cool to room temperature, and extracted from H 2 O three times with EtOAc. The combined organic layers were washed with brine, dried over anhydrous MgSO 4, and the solvent removed by rotary evaporator. The resulting residue was purified by Combiflash on a silica gel column (gradient elution 0 10%, EtOAc/hex) to give 45 mg (0.082 mmol, 41% yield) of CB18. 1 H NMR (500 MHz, CDCl 3 ) δ 2.43 (s, 6 H), 2.44 (s, 6 H), 4.45 (dd, J=10.25, 7.08 Hz, 2 H), 4.65 (dd, J=10.01, 7.32 Hz, 2 H), 6.50 (s, 2 H), (m, 6 H), 7.20 (t, J=7.10 Hz, 4 H). 13 C NMR (125 MHz, CDCl 3 ) δ 12.3, 14.0, 45.1, 48.1, 112.9, 126.4, 127.8, 128.1, 139.4, 166.0, 169.7, HRMS (ESI + ) m/z calcd for C 28 H 29 N 4 S , found ,6'-((1R,2R,3S,4S)-2,4-diphenylcyclobutane-1,3-diyl)bis(2,4-diethylmercaptopyrimidine) (28). Samples of 200 mg (5.0 mmol, 60% dispersion in mineral oil) of NaH and 0.2 ml (2.7 mmol) of EtSH were dissolved in 5 ml of THF. To the resulting cloudy solution, 100 mg (0.199 mmol) of CB9 were added. The reaction was stirred in a sealed tube at 80 C for 15h. After cooling to room temperature, the reaction mixture extracted from H 2 O three times with EtOAc. The combined organic layers were washed with brine, dried over anhydrous MgSO 4, and the solvent removed by rotary evaporator. The resulting residue was purified by Combiflash on a Nature Chemical Biology: doi: /nchembio.2131
15 silica gel column (gradient elution 0 15%, EtOAc/hex) to give 53 mg (0.087 mmol, 44% yield) of H NMR (500 MHz, CDCl 3 ) δ 1.28 (t, J=7.40 Hz, 6 H), 1.32 (t, J=7.29 Hz, 6 H), (m, 8 H), 4.42 (dd, J=10.08, 6.86 Hz, 2 H), 4.66 (dd, J=9.97, 7.40 Hz, 2 H), 6.46 (s, 2 H), (m, 6 H), 7.20 (t, J=7.30 Hz, 4 H). 13 C NMR (500 MHz, CDCl 3 ) δ14.3, 14.7, 23.6, 25.1, 45.0, 48.1, 113.4, 126.4, 128.0, 128.0, 139.4, 166.1, 169.3, HRMS (ESI + ) m/z calcd for C 32 H 37 N 4 S , found ,6'-((1R,2R,3S,4S)-2,4-diphenylcyclobutane-1,3-diyl)bis(2,4-diethylsulfonylpyrimidine) CB19 (19). Samples of 28 (35 mg, mmol) and mcpba (77%, 300 mg, 1.34 mmol) were dissolved in 2 ml of CHCl 3 and allowed to sit at room temperature for 2 days. The solvent was removed in vacuo, and the residue purified by Combiflash on a silica gel column (gradient elution 0 15%, EtOAc/CH 2 Cl 2 followed by a second column eluted with 20 80% EtOAc/hex) to give 20 mg (0.028 mmol, 48% yield) of CB19. 1 H NMR (500 MHz, CDCl 3 ) δ 1.18 (t, J=7.40 Hz, 6 H), 1.29 (t, J=7.50 Hz, 6 H), (m, 8 H), 4.99 (dd, J=10.08, 6.43 Hz, 2 H), 5.10 (dd, J=9.86, 6.43 Hz, 2 H), (m, 6 H), 7.21 (t, J=7.30 Hz, 4 H), 7.82 (s, 2 H). 13 C NMR (125 MHz, CDCl 3 ) δ 6.6, 6.7, 45.6, 45.9, 48.5, 119.6, , , 128.9, 136.7, 165.2, 165.4, HRMS (ESI + ) m/z calcd for C 32 H 37 N 4 O 8 S , found Scheme S8 Nature Chemical Biology: doi: /nchembio.2131
16 6,6'-((1R,2R,3S,4S)-2,4-diphenylcyclobutane-1,3-diyl)bis(2,4-dimethylaminopyrimidine) CB20 (20). Dissolved 30 mg (0.060 mmol) of CB9 in 2 ml of 2.0 M methylamine in THF. The resulting solution was heated with stirring in a sealed tube at 100 C for 16 h. After cooling to room temperature, the methylamine/thf was removed in vacuo and the resulting residue redissolved in 5 ml of 2.0 M methylamine in THF. The solution was again heated in a sealed tube at 100 C for 2 days. After cooling to room temperature, the solvent was removed in vacuo and the resulting residue dissolved and extracted from water three times with EtOAc. The combined organic layers were washed with brine and dried over anhydrous MgSO 4. The solvent was removed by rotary evaporator and the resulting solid purified by flash chromatography on silica gel (1% TEA in a 1:1 solution of EtOAc:hex) to give 16 mg (0.033 mmol, 55% yield) of CB20. 1 H NMR (500 MHz, CDCl 3 ) δ 2.74 (d, J=5.13 Hz, 6 H), 2.84 (d, J=5.13 Hz, 6 H), 4.31 (t, J=8.55 Hz, 2 H), 4.46 (br. s., 2 H), 4.52 (dd, J=9.89, 7.45 Hz, 2 H), 4.84 (br. s., 2 H), 5.42 (s, 2 H), 7.09 (tt, J=7.08, 1.71 Hz, 2 H), 7.18 (t, J=7.69 Hz, 4 H), 7.24 (d, J=7.32 Hz, 4 H). 13 C NMR (125 MHz, CDCl 3 ) δ 28.3, 44.9, 125.7, 127.7, HRMS (ESI + + ) m/z calcd for C 28 H 33 N , found Scheme S9 (E)-2-chloro-4-{(2,3,4,5,6-d 5 )styryl}pyrimidine (29). The mixture of styrene-2,3,4,5,6-d 5 (C/D/N Isotope Inc., Quebec, Canada H9R 1H1) (112 mg, 1.03 mmol), 2,4-dichloropyrimidine (147 mg, 1.00 mmol), and triethanolamine (300 mg, 2.10 mmol) in DMF (0.5 ml) was purged with argon for 5 min before adding palladium diacetate (10 mg, mmol). The mixture was Nature Chemical Biology: doi: /nchembio.2131
17 heated up in a sealed reaction vial at 95 o C for 12 hr. The consumption of dichloropyrimidine was monitored by TLC and then the DMF was evaporated with a nitrogen stream. Water was added (2 ml), the organic products extracted with EtOAc (1 ml x 3), and dried over MgSO 4. After removal of solvent by a rotary evaporator, the resulting residue was purified through preparative SiO 2 TLC (20 x 20 cm, Merck) with a mixture of 10% ethyl acetate and n-hexane (v/v, Rf 0.4) to afford 75 mg (0.34 mmol, 33% yield) of 29 as a colorless powder. 1 H NMR (500 MHz, CDCl 3 ) δ 6.99 (d, J =16.0, 1H), 7.20 (d, J = 3.5 Hz, 1H), 7.91 (d, J =16.0, 1H), 8.51 (d, J = 3.5 Hz, 1H). 13 C NMR (126 MHz, CDCl 3 ) δ , , , , (t, J = Hz), (t, J = Hz), (t, J = Hz), , , , , , MS (ESI) m/z (M + +1, 100%) and (M + +3, 35%). HRMS (ESI+) m/z calcd for C 12 N 2 ClH 5 D 5 (M + +1) , found ,6'-((1R,2R,3S,4S)-2,4-diphenyl(d5)cyclobutane-1,3-diyl)bis(2-chloropyrimidine) (21). Finely ground 29 (55 mg, 0.25 mmol) was placed between two borosilicate glass plates and was irradiated with a 68 W compact fluorescent light bulb (TCP 300 Watt Incandescent Equivalent, 68 Watt, 120 Volt Warm White Spiral CFL Bulb, 2700 K color temperature) inside a hood with aluminum foil surrounding the irradiated area for 48 hr. Once the starting material was completely consumed, the irradiation was terminated. The material was collected by scraping the glass surface with a sharp blade to provide 53 mg (0.12 mmol) of 21 as a colorless powder. 1 H NMR (500 MHz, CDCl 3 ): δ 4.67 (dd, J =10.0, 6.5 Hz, 2H), 4.91 (dd, J = 10.0, 6.5 Hz, 2H), 6.88 (d, J =5.0 Hz, 1H), 8.27 (d, J =5.0 Hz, 1H). 13 C NMR (126 MHz, CDCl 3 ) δ 45.00, 47.99, , (t, J = Hz), (t, J = Hz), (t, J = Hz), , , , MS (ESI) m/z (M + +1, 100%) and (M + +3, 70%). HRMS (ESI+) m/z calcd for C 24 N 4 Cl 2 H 9 D 10 (M + +1) , found Nature Chemical Biology: doi: /nchembio.2131
18 NMR Spectra Nature Chemical Biology: doi: /nchembio.2131
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44 References 1. Parent, A.A., Gunther, J.R. & Katzenellenbogen, J.A. Blocking Estrogen Signaling After the Hormone: Pyrimidine-Core Inhibitors of Estrogen Receptor-Coactivator Binding. J. Med. Chem. 51, (2008). 2. Parent, A.A., Ess, D.H. & Katzenellenbogen, J.A. pi-pi interaction energies as determinants of the photodimerization of mono-, di-, and triazastilbenes. J Org Chem 79, (2014). Nature Chemical Biology: doi: /nchembio.2131
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