Supporting Information. Mild Synthesis of Asymmetric 2 -Carboxyethyl-Substituted Fluoresceins. Eugeny A. Lukhtanov* and Alexei V.

Transcription

1 Supporting Information Mild Synthesis of Asymmetric 2 -Carboxyethyl-Substituted Fluoresceins Eugeny A. Lukhtanov* and Alexei V. Vorobiev Nanogen Inc., rd Drive SE, Suite 150 Bothell, WA elukhtanov@nanogen.com Table of Contents General information and instrumentation...s2 Experimental Procedures... S3-S6 2-[2-(2-Carboxyethyl)-4-chloro-6-hydroxy-3-oxo-3H-xanthen-9-yl]-4,5-dichlorobenzoic acid (1b) S3 2-[2-(2-Carboxyethyl)-4,7-dichloro-6-hydroxy-3-oxo-3H-xanthen-9-yl]-4,5-dichlorobenzoic acid (1c)...S3 2-[2-(2-Carboxyethyl)-4,7-dichloro-6-hydroxy-5-methyl-3-oxo-3H-xanthen-9-yl]-4,5-dichlorobenzoic acid (1d)...S3 2-[2-(2-Carboxyethyl)-7-chloro-6-hydroxy-3-oxo-4-phenyl-3H-xanthen-9-yl]-3,4,5,6-tetrachlorobenzoic acid (1f)...S3 2,6-Dimethoxybiphenyl-3-carbaldehyde (5b).. S3 3-(3-Chloro-2,4-dimethoxyphenyl)acrylic acid (6a)..... S3 3-(2,6-Dimethoxybiphenyl-3-yl)acrylic acid (6b)..S4 3-(3-Chloro-2,4-dimethoxyphenyl)propanoic acid (7a)... S4 3-(2,6-Dimethoxybiphenyl-3-yl)propanoic acid (7b). S4 Methyl 3-(3-chloro-2,4-dihydroxyphenyl)propanoate (8b).S4 Methyl 3-(2,6-dihydroxybiphenyl-3-yl)propanoate (8c).S5 2-[2,4-Dihydroxy-5-(3-methoxy-3-oxopropyl)benzoyl]benzoic acid (9a).. S5 4,5-Dichloro-2-[3-chloro-2,4-dihydroxy-5-(3-methoxy-3-oxopropyl)benzoyl]benzoic acid (9b) S5 2,3,4,5-Tetrachloro-6-[3-chloro-2,4-dihydroxy-5-(3-methoxy-3-oxopropyl)benzoyl]benzoic acid (9c)... S5 2-{[2,6-Dihydroxy-5-(3-methoxy-3-oxopropyl)biphenyl-3-yl]carbonyl}benzoic acid (9d) S5 4-Chloro-2-methylbenzene-1,3-diol (10c).. S6 1 H-, and 13 C-NMR Spectra..S7-S42 2-[2-(2-Carboxyethyl)-6-hydroxy-3-oxo-3H-xanthen-9-yl]benzoic acid (1a) S7-S8 2-[2-(2-Carboxyethyl)-4-chloro-6-hydroxy-3-oxo-3H-xanthen-9-yl]-4,5-dichlorobenzoic acid (1b). S9-S10 2-[2-(2-Carboxyethyl)-4,7-dichloro-6-hydroxy-3-oxo-3H-xanthen-9-yl]-4,5-dichlorobenzoic acid (1c).....S11-S12 S1

2 2-[2-(2-Carboxyethyl)-4,7-dichloro-6-hydroxy-5-methyl-3-oxo-3H-xanthen-9-yl]-4,5-dichlorobenzoic acid (1d)..S13-S14 2-[2-(2-Carboxyethyl)-4,7-dichloro-6-hydroxy-3-oxo-3H-xanthen-9-yl]-3,4,5,6-tetrachlorobenzoic acid (1e).. S15-S16 2-[2-(2-Carboxyethyl)-7-chloro-6-hydroxy-3-oxo-4-phenyl-3H-xanthen-9-yl]-3,4,5,6-tetrachlorobenzoic acid (1f)..S17-S18 2,6-Dimethoxybiphenyl-3-carbaldehyde (5b) S19-S20 3-(3-Chloro-2,4-dimethoxyphenyl)acrylic acid (6a) S21-S22 3-(2,6-Dimethoxybiphenyl-3-yl)acrylic acid (6b) S23-S24 3-(3-Chloro-2,4-dimethoxyphenyl)propanoic acid (7a).S25-S26 3-(2,6-Dimethoxybiphenyl-3-yl)propanoic acid (7b).S27-S28 Methyl 3-(3-chloro-2,4-dihydroxyphenyl)propanoate (8b) S29-S30 Methyl 3-(2,6-dihydroxybiphenyl-3-yl)propanoate (8c) S31-S32 2-[2,4-Dihydroxy-5-(3-methoxy-3-oxopropyl)benzoyl]benzoic acid (9a).S33-S34 4,5-Dichloro-2-[3-chloro-2,4-dihydroxy-5-(3-methoxy-3-oxopropyl)benzoyl]benzoic acid (9b)...S35-S36 2,3,4,5-Tetrachloro-6-[3-chloro-2,4-dihydroxy-5-(3-methoxy-3-oxopropyl)benzoyl]benzoic acid... (9c).. S37-S38 2-{[2,6-Dihydroxy-5-(3-methoxy-3-oxopropyl)biphenyl-3-yl]carbonyl}benzoic acid (9d)..S39-S40 4-Chloro-2-methylbenzene-1,3-diol (10c)..S41-S42 General information and instrumentation All reactions were conducted under argon atmosphere unless otherwise stated. Chemicals were obtained from commercial sources and used without further purification. 1 H-NMR spectra were recorded at 300 MHz using residual solvent signal as the internal standard: 2.50 ppm for DMSO-d 6 and 3.31 ppm for CD 3 OD with added 0.8% NaOD and 1.2% D 2 O. Chemical shifts are quoted in parts per million (ppm) and coupling constants are in hertz. When peak multiplicities are given, the following abbreviations are used: s, singlet; d, doublet; t, triplet; q, quartet; quin, quintet; dd, doublet of a doublet; m, multiplet; br, broad. 13 C-NMR spectra were proton decoupled and recorded at 75.5 MHz using the carbon signal of the deuterated solvent signal as the internal standard: ppm for DMSO-d 6 and 49.0 ppm for CD 3 OD with added 0.8% NaOD and 1.2% D 2 O. Flash column chromatographic purifications were conducted using silica gel 60 (40-63 µm). Thin layer analytical chromatography was performed on silica gel plates with F-254 indicator and visualization was achieved with UV lamp. HPLC analysis was performed on an instrument equipped with a photo diode array (PDA) detector and C 18 - column. The mobile phase was a gradient containing acetonitrile and 0.1 M triethylammonium acetate (ph=7.5). S2

3 Experimental Procedures 2-[2-(2-Carboxyethyl)-4-chloro-6-hydroxy-3-oxo-3H-xanthen-9-yl]-4,5-dichlorobenzoic acid (1b). NMR (300 MHz, CD 3 OD + 0.8% NaOD +1.2% D 2 O): (br s, 1H), (br s, 1H), (br s, 1H), 8.29 (s, 1H), 7.80 (s, 1H), 6.67 (m, 4H), 2.66 (m, 2H), 2.34 (m, 2H). 13 C NMR (75.5 MHz, CD 3 OD + 0.8% NaOD +1.2% D 2 O): 182.4, 181.5, 176.5, 171.3, 159.2, 156.3, 154.3, 141.6, 137.1, 135.1, 134.2, 133.8, 132.9, 132.5, 131.3, 127.2, 123.8, 112.8, 112.3, 109.7, 104.7, 38.4, HRMS (FTMS) (m/z) calcd for C 23 H 14 3 O 7 (M+H) , found [2-(2-Carboxyethyl)-4,7-dichloro-6-hydroxy-3-oxo-3H-xanthen-9-yl]-4,5-dichlorobenzoic acid (1c). 1 H NMR (300 MHz, CD 3 OD + 0.8% NaOD +1.2% D 2 O): 8.22 (s, 1H), (s, 1H), 7.05 (s, 1H), 6.87 (s, 1H), 6.71 (s, 1H), 2.77 (m, 2H), 2.32 (m, 2H). 13 C NMR (75.5 MHz, CD 3 OD + 0.8% NaOD +1.2% D 2 O): 182.3, 177.0, 174.8, 171.1, 157.6, 155.5, 154.4, 141.4, 137.6, 134.8, 134.4, 134.1, 133.1, 132.5, 128.9, 128.2, 127.2, 113.2, 111.7, 109.8, 105.1, 38.4, HRMS (FTMS) (m/z) calcd for C 23 H 12 4 NaO 7 (M+Na) , found [2-(2-Carboxyethyl)-4,7-dichloro-6-hydroxy-5-methyl-3-oxo-3H-xanthen-9-yl]-4,5-dichlorobenzoic acid (1d). 1 H NMR (300 MHz, CD 3 OD + 0.8% NaOD +1.2% D 2 O): 8.20 (s, 1H), 7.41 (s, 1H), 7.01 (s, 1H), 6.86 (s, 1H), 2.80 (m, 2H), 2.38 (s, 3H), 2.36 (m, 2H). 13 C NMR (75.5 MHz, CD 3 OD + 0.8% NaOD +1.2% D 2 O): 182.4, 176.4, 174.2, 171.1, 155.5, 154.7, 154.3, 141.5, 137.1, 135.1, 143.3, 133.9, 133.0, 132.6, 128.2, 127.0, 126.8, 114.0, 112.5, 111.7, 109.9, 38.5, 29.4, 9.4. HRMS (FTMS) (m/z) calcd for C 24 H 15 4 O 7 (M+H) , found [2-(2-Carboxyethyl)-7-chloro-6-hydroxy-3-oxo-4-phenyl-3H-xanthen-9-yl]-3,4,5,6-tetrachlorobenzoic acid (1f). 1 H NMR (300 MHz, CD 3 OD, CD 3 OD + 0.8% NaOD +1.2% D 2 O): (m, 5H), 7.02 (s, 1H), 6.91 (s, 1H), 6.33 (s, 1H), 2.81 (m, 2H), 2.39 (m, 2H). 13 C NMR (75.5 MHz, CD 3 OD + 0.8% NaOD +1.2% D 2 O): 182.5, 182.2, 174.0, 169.9, 157.3, 155.7, 147.3, 144.2, 139.4, 135.5, 135.0, 132.7, 132.3, 132.2, 130.7, 129.5, 128.8, 128.4, 128.1, 127.7, 127.4, 118.2, 114.1, 110.5, 105.0, 38.6, HRMS (FTMS) (m/z) calcd for C 29 H 16 5 O 7 (M+H) , found ,6-Dimethoxybiphenyl-3-carbaldehyde (5b). Compound 5b was synthesized from 4b (Song, C.; Ma, Y.; Chai, Q.; Ma, Chanqin; J., Wei; A., Merritt B. Tetrahedron 2005, 61, ) in 95% yield using the procedure described for formylation of 4a to 5a (Plattner, J. J.; Fung, A.K.L.; Parks, J.A.; Pariza, R.J.; Crowley, S.R.; Pernet, A.G.; Bunnell, P.R.; Dodge, P.W. J. Med. Chem. 1984, 27(8), ). 1 H NMR (300 MHz, DMSO-d 6 ): (s, 1H), 7.82 (d, J = 8.7 Hz, 1H), (m, 5H), 7.10 (d, J = 8.7 Hz, 1H), 3.79 (s, 3H), 3.40 (s, 3H). 13 C NMR (75.5 MHz, DMSO-d 6 ): 188.6, 162.6, 161.4, 132.5, 130.4, 129.5, 128.0, 127.4, 124.2, 122.5, 108.0, 62.6, Anal. calcd for C 15 H 14 O 3 : C, 74.36; H, Found: C, 74.15; H, (3-Chloro-2,4-dimethoxyphenyl)acrylic acid (6a). A solution of 5a (Plattner, J. J.; Fung, A.K.L.; Parks, J.A.; Pariza, R.J.; Crowley, S.R.; Pernet, A.G.; Bunnell, P.R.; Dodge, P.W. J. Med. Chem. 1984, 27(8), ) (11.07 g, 55.2 mmol), malonic acid (8.639 g, 83 mmol) and piperidine (2 ml, g, 20.2 mmol) in 80 ml of anhydrous pyridine was refluxed (bath temperature110 o C) for 2 h. Reaction mixture was cooled, concentrated S3 1 H

4 under vacuum and acidified with 250 ml of 5% aqueous citric acid to a ph of 3. The resultant heterogeneous mixture was sonicated for a few minutes. The precipitated material was collected by filtration, washed with water (2x100 ml) and dried under vacuum over KOH to give 12.7 g (52.3 mmol, 95% yield) of pure (HPLC, 1 H NMR) cinnamic acid analog 6a as a white solid. 1 H NMR (300 MHz, DMSO-d 6 ): (s, 1H), 7.77 (d, J = 8.7 Hz, 1H), 7.67 (d, J = 16.2 Hz, 1H), 7.01 (d, J = 9.0 Hz, 1H), 6.51 (d, J = 16.2 Hz, 1H), 3.90 (s, 3H), 3.77 (s, 3H). 13 C NMR (75.5 MHz, DMSO-d 6 ): 167.7, 157.3, , 137.4, , 121.4, 118.9, 115.7, 108.9, 61.4, Anal. calcd for C 11 H 11 O 4 : C, 54.45; H, 4.57;, Found: C, 54.20; H, 4.17;, (2,6-Dimethoxybiphenyl-3-yl)acrylic acid (6b). Compound 6b was synthesized from 5b in 96% yield using the procedure described for 6a. 1 H NMR (300 MHz, DMSO-d 6 ): 12.3 (br s, 1H), 7.81 (d, J = 9.0 Hz, 1H), 7.74 (d, J = 16.2 Hz, 1H), (m, 5H), 6.97 (d, J = 9.0 Hz, 1H), 6.47 (d, J = 16.2 Hz, 1H), 3.73 (s, 3H), 3.25 (s, 3H). 13 C NMR (75.5 MHz, DMSO-d 6 ) 168.0, 159.2, 157.3, 138.4, 133.3, 130.4, 128.3, 127.9, 127.1, 124.2, 120.2, 117.8, 108.0, 61.1, Anal. calcd for C 17 H 16 O 4 : C, 71.82; H, Found: C, 71.33; H, (3-Chloro-2,4-dimethoxyphenyl)propanoic acid (7a). A suspension of 6a (12.57 g, mmol) in a mixture of MeOH (50 ml) and THF (200 ml) was hydrogenated at 50 psi in the presence of 10% Pd/C (0.3g) for 4 h. The catalyst was removed by filtration through Celite and the filtrate was concentrated to afford 12.6 g (51.5 mmol, 99% yield) of analytically pure (HPLC, 1 H NMR) 7a as a white solid. 1 H NMR (300 MHz, DMSO-d 6 ): (br s, 1H), 7.16 (d, J = 8.4 Hz, 1H), 6.86 (d, J = 8.7 Hz, 1H), 3.81 (s, 3H), 3.76 (s, 3H), 2.79 (t, J = 7.5 Hz, 2H), 2.49 (t, J = 7.5 Hz, 2H). 13 C NMR (75.5 MHz, DMSO-d 6 ): 173.8, 154.6, 154.2, 128.0, 127.1, 115.2, 108.1, 60.4, 56.2, 34.3, Anal. calcd for C 11 H 13 O 4 : C, 54.00; H, 5.36;, Found: C, 53.71; H, 5.18;, (2,6-Dimethoxybiphenyl-3-yl)propanoic acid (7b). Compound 7b was synthesized from 6b in 98% yield using the procedure described for 7a. 1 H NMR (300 MHz, DMSO-d 6 ): (m, 2H), (m, 3H), 7.18 (d, J = 8.7 Hz, 1H), 6.80 (d, J = 8.7 Hz, 1H), 3.64 (s, 3H), 3.18 (s, 3H), 2.79 (t, J = 7.5 Hz, 2H), 2.50 (t, J = 7.5 Hz, 2H). 13 C NMR (75.5 MHz, DMSO-d 6 ): 174.1, 156.1, 155.8, 134.2, 130.5, 129.1, 127.7, 126.8, 125.9, 123.7, 107.1, 60.0, 55.7, 34.8, Anal. calcd for C 17 H 18 O 4 : C, 71.31; H, Found: C, 70.91; H, Compound 8a was synthesized as previously described (Gonzalez-Gomez, J.C.; Santana, L.; Uriarte, E. Synthesis 2003, 1, 27-29; Blickenstaff, R.T.; Tao, I.Y.C. Tetrahedron, 1968, 24(6), ). Methyl 3-(3-chloro-2,4-dihydroxyphenyl)propanoate (8b). A solution of 7a (10.0 g, 40.9 mmol) in a mixture of acetic acid (75 ml, g, 1.3 mol) and 48% aqueous hydrobromic acid (75 ml, g, 0.66 mol) was refluxed (bath temperature +120 C) for 15 h. Reaction mixture was cooled and concentrated under vacuum. The obtained solid material was dried by co-evaporation with toluene (3x100 ml) and dissolved in 100 ml of methanol. Hydrogen chloride was bubbled for 5 min. The resultant hot solution was allowed to cool to room temperature and then concentrated. The crude product was chromatographed on silica gel eluting with 1:4 EtOAc-hexane. Concentration of the pure product fractions afforded 9.2 g (98%) of the title compound 8b as a pale tan oil, which slowly solidified during drying in vacuo. 1 H NMR (300 MHz, DMSO-d 6 ): 9.79 (s, 1H), 8.94 (s, 1H), 6.81 (d, J = 8.4 Hz, 1H), 6.38 (d, J = 8.4 Hz, 1H), 3.57 (s, 3H), 2.73 (t, J = 7.5 Hz, 2H), 2.50 (t, J = 7.5 S4

5 Hz, 2H). 13 C NMR (75.5 MHz, DMSO-d 6 ): 172.9, 152.5, 151.4, 127.5, 119.2, 108.4, 106.9, 51.3, 33.7, Anal. calcd for C 10 H 11 O 4 : C, 52.08; H, 4.81;, Found: C, 51.95; H, 4.65;, Methyl 3-(2,6-dihydroxybiphenyl-3-yl)propanoate (8c). BBr 3 (4.72 g, 1.78 ml, 18.9 mmol) was added through a syringe over 5 min to a stirred solution of dimethoxy derivative 7b (1.35 g, 4.7 mmol) in anhydrous CH 2 2 (20 ml). The resulting mixture was magnetically stirred for 8 h and concentrated under vacuum. The residue was co-evaporated with toluene (2x20 ml), dissolved in methanol (20 ml) and H gas was bubbled into the solution for 2 min. The material obtained after evaporation of the solvent was partitioned between cold water (30 ml) and ethyl acetate (100 ml). The organic phase was washed with saturated NaHCO 3 (2x10 ml), brine (20 ml), dried over MgSO 4 and concentrated. The resultant crude product was chromatographed on silica eluting with ethyl acetate. Pure product fractions were concentrated to afford 1.2 g (94%) of 8c as a tan oil. 1 H NMR(300 MHz, DMSO-d 6 ): 8.95 (s, 1H), 7.82 (s, 1H), (m, 5H), 6.84 (d, J = 8.4 Hz, 1H), 6.38 (d, J = 8.4 Hz, 1H), 3.59 (s, 3H), 2.76 (t, J = 8.0 Hz, 2H), 2.52 (t, J = 8.0 Hz, 2H). 13 C NMR (75.5 MHz, DMSO-d 6 ): 173.2, 153.8, 152.4, 134.9, 131.1, 128.5, 127.6, 126.3, 118.5, 117.5, 107.1, 51.3, 34.0, Anal. calcd for C 16 H 16 O 4 : C, 70.58; H, Found: C, 70.33; H, Compounds 9a, b, d were synthesized from 8a, b, c using the procedure described for 9c. 2-[2,4-Dihydroxy-5-(3-methoxy-3-oxopropyl)benzoyl]benzoic acid (9a). 1 H NMR (300 MHz, DMSO-d 6 ): (br s, 1H), (s, 1H), (s, 1H), 8.00 (dd, J = 7.8, 1.2 Hz, 1H), 7.68 (m, 2H), 7.39 (dd, J = 7.5, 1.2 Hz, 1H), 6.77 (s, 1H), 6.38 (s, 1H), 3.45 (s, 3H), 2.56 (t, J = 7.5 Hz, 2H), 2.38 (t, J = 7.5 Hz, 2H). 13 C NMR (75.5 MHz, DMSO-d 6 ): 200.4, 172.6, 166.8, , , 140.0, 133.7, 132.2, 130.0, 129.7, 129.5, 127.5, 119.1, 112.8, 102.2, 51.2, 33.2, HRMS (FTMS) (m/z) calcd for C 18 H 16 NaO 7 (M+Na) , found ,5-Dichloro-2-[3-chloro-2,4-dihydroxy-5-(3-methoxy-3-oxopropyl)benzoyl]benzoic acid (9b). 1 H NMR (300 MHz, DMSO-d 6 ): (br s, 1H), (s, 1H), (br s, 1H), 8.16 (s, 1H), 7.87 (s, 1H), 6.90 (s, 1H), 3.49 (s, 3H), 2.70 (t, J = 7.3 Hz, 2H), 2.42 (t, J = 7.3 Hz, 2H). 13 C NMR (75.5 MHz, DMSO-d 6 ): 198.0, 172.5, 164.8, 158.2, 158.0, 139.4, 135.6, 132.7, 131.8, 131.6, 129.7, 129.6, 120.3, 113.2, 107.7, 51.2, 33.2, HRMS (FTMS) (m/z) calcd for C 18 H 13 3 NaO 7 (M+Na) , found {[2,6-Dihydroxy-5-(3-methoxy-3-oxopropyl)biphenyl-3-yl]carbonyl}benzoic acid (9d). 1 H NMR (300 MHz, DMSO-d 6 ): (br s, 1H), 9.84 (br s, 1H), (m, 5H), 7.16 (s, 1H), 3.54 (s, 3H), 2.76 (t, J = 7.4 Hz, 2H), 2.46 (t, J = 7.5 Hz, 2H). 13 C NMR (75.5 MHz, DMSO-d 6 ): 193.8, 172.6, 164.5, 161.1, 160.8, 135.7, 134.1, 134.0, 133.5, 133.2, 132.1, 131.0, 129.1, 129.0, 128.2, 127.4, 120.8, 116.9, 112.0, 51.3, 33.5, HRMS (FTMS) (m/z) calcd for C 24 H 16 4 NaO 7 (M+Na) , found ,3,4,5-Tetrachloro-6-[3-chloro-2,4-dihydroxy-5-(3-methoxy-3-oxopropyl)benzoyl]benzoic acid (9c). Tetrachlorophthalic anhydride (17.4 g, 60.8 mmol) was suspended in 160 ml of anhydrous 1,2-dichloroethane and stirred for 30 min to dissolve most of the solid. Al 3 (21.0 g, 158 mmol) was added in one portion followed by addition of ester 8b (14.0 g, 60.7 mmol) as a solution in anhydrous 1,2-dichloroethane (80 ml) (light exotherm). The mixture was stirred for min to give a clear solution. After being stirred at room temperature for another 20 h, the reaction was concentrated and the resulting gummy residue was partitioned between ethyl acetate (500 ml) and cold 5 N H (500 ml). The aqueous phase was extracted with more ethyl S5

6 acetate, the combined organic solution was washed with 1 N H (300 ml), saturated Na (300 ml) and dried over MgSO 4. Concentration of the solution gave a pale yellow solid; it was triturated with CH 2 2 (200 ml), cooled to 0 C and then collected by filtration. Washing with CH 2 2 (2x50 ml) and drying under vacuum afforded 21.0 g of the desired benzophenone 9c as a white solid. The mother liquor afforded an additional 2.1 g of the product. Total yield was 23.1 g (74%). 1 H NMR (300 MHz, DMSO-d 6 ): (bs, 1H), (bs, 1H), 7.21 (s, 1H), 3.54 (s, 3H), 2.75 (t, J = 7.4 Hz, 2H), 2.45 (t, J = 7.5 Hz, 2H). 13 C NMR (75.5 MHz, DMSO-d 6 ): 193.3, 172.5, 164.5, 159.3, 158.0, 135.9, 134.2, 134.1, 133.0, 132.1, 129.4, 128.9, 121.3, 112.7, 107.9, 51.3, 33.5, HRMS (FTMS) (m/z) calcd for C 18 H 11 5 NaO 7 (M+Na) , found Chloro-2-methylbenzene-1,3-diol (10c). To a solution of 2-methylresorcinol (40 g, 322 mmol) in 750 ml of methanol was added N-chlorosuccinimide (45.17 g, mol). The mixture was stirred for 6 hours and concentrated. The resulting solid was triturated in 500 ml of a 2:1 mixture of hexane and ethyl acetate. The brown crystalline precipitate (succinimide) was filtered off and rinsed with a little extra solvent. The filtrate was concentrated to give the crude product, which was further purified on silica eluting with 4:1 hexane-ethyl acetate. Appropriate fractions were combined and evaporated. The product was crystallized from 1:8 ether/hexanes to afford 33.1 g (65%) of the desired resorcinol analog 10c. 1 H NMR (300 MHz, DMSO-d 6 ): O9.39 (s, 1H), 8.83 (s, 1H), 6.92 (d, J = 8.7 Hz, 1H), 6.34 (d, J = 8.7 Hz, 1H), 2.00 (s, 3H). 13 C NMR (75.5 MHz, DMSO-d 6 ): 155.0, 151.2, 125.9, 113.1, 110.8, 107.4, 9.5. Anal. calcd for C 7 H 7 O 2 H 2 O: C, 47.61; H, 5.14;, Found: C, 47.65; H 5.08; S6

7 O O OH COOH COOH Compound (1a) 1 H NMR (CD 3OD+0.8% NaOD+1.2% D2O) S7

8 O O OH COOH COOH Compound (1a) 13 C NMR (CD3OD+0.8% NaOD+1.2% D2O) S8

9 O O OH COOH COOH Compound (1b) 1 H NMR (CD 3OD+0.8% NaOD+1.2% D2O) S9

10 O O OH COOH COOH Compound (1b) 13 C NMR (CD3OD+0.8% NaOD+1.2% D2O) S10

11 O O OH COOH COOH Compound (1c) 1 H NMR (CD 3OD+0.8% NaOD+1.2% D2O) S11

12 O O OH COOH COOH Compound (1c) 13 C NMR (CD3OD+0.8% NaOD+1.2% D2O) S12

13 Me O O OH COOH COOH Compound (1d) 1 H NMR (CD 3OD+0.8% NaOD+1.2% D2O) S13

14 Me O O OH COOH COOH Compound (1d) 13 C NMR (CD3OD+0.8% NaOD+1.2% D2O) S14

15 O O OH COOH COOH Compound (1e) 1 H NMR (CD 3OD+0.8% NaOD+1.2% D2O) S15

16 O O OH COOH COOH Compound (1e) 13 C NMR (CD3OD+0.8% NaOD+1.2% D2O) S16

17 Ph O O OH COOH COOH Compound (1f) 1 H NMR (CD 3OD+0.8% NaOD+1.2% D2O) S17

18 Ph O O OH COOH COOH Compound (1f) 13 C NMR (CD3OD+0.8% NaOD+1.2% D2O) S18

19 Ph MeO OMe CHO Compound (5b) 1 H NMR (dmso-d 6) S19

20 Ph MeO OMe CHO Compound (5b) 13 C NMR (dmso-d6) S20

21 MeO OMe CO 2 H Compound (6a) 1 H NMR (dmso-d 6) S21

22 MeO OMe CO 2 H Compound (6a) 13 C NMR (dmso-d6) S22

23 Ph MeO OMe CO 2 H Compound (6b) 1 H NMR (dmso-d 6) S23

24 Ph MeO OMe CO 2 H Compound (6b) 13 C NMR (dmso-d6) S24

25 MeO OMe CO 2 H Compound (7a) 1 H NMR (dmso-d 6) S25

26 MeO OMe CO 2 H Compound (7a) 13 C NMR (dmso-d6) S26

27 Ph MeO OMe CO 2 H Compound (7b) 1 H NMR (dmso-d 6) S27

28 Ph MeO OMe CO 2 H Compound (7b) 13 C NMR (dmso-d6) S28

29 HO OH CO 2 Me Compound (8b) 1 H NMR (dmso-d 6) S29

30 HO OH CO 2 Me Compound (8b) 13 C NMR (dmso-d6) S30

31 Ph HO OH CO 2 Me Compound (8c) 1 H NMR (dmso-d 6) S31

32 Ph HO OH CO 2 Me Compound (8c) 13 C NMR (dmso-d6) S32

33 HO OH O CO 2 H CO 2 Me Compound (9a) 1 H NMR (dmso-d 6) S33

34 HO OH O CO 2 H CO 2 Me Compound (9a) 13 C NMR (dmso-d6) S34

35 HO OH O CO 2 H CO 2 Me Compound (9b) 1 H NMR (dmso-d 6) S35

36 HO OH O CO 2 H CO 2 Me Compound (9b) 13 C NMR (dmso-d6) S36

37 HO OH O CO 2 Me CO 2 H Compound (9c) 1 H NMR (dmso-d 6) S37

38 HO OH O CO 2 Me CO 2 H Compound (9c) 13 C NMR (dmso-d6) S38

39 Ph HO OH O CO 2 Me CO 2 H Compound (9d) 1 H NMR (dmso-d 6) S39

40 Ph HO OH O CO 2 Me CO 2 H Compound (9d) 13 C NMR (dmso-d6) S40

41 Me HO OH Compound (10c) 1 H NMR (dmso-d 6) S41

42 Me HO OH Compound (10c) 13 C NMR (dmso-d6) S42