8008 Journal of Medicinal Chemistry, 2010, Vol. 53, No. 22
Wei et al.
J2=4.8 Hz, 4H), 2.35 (s, 6H), 1.91 (s, 6H). 13C NMR (600 MHz,
CD3OD) δ 184.57, 183.70, 170.33, 152.01, 150.28, 147.04,
139.71, 139.24, 129.68, 129.41, 128.87, 127.33, 126.04, 126.00,
124.32, 113.21, 44.65, 21.66, 14.49. HPLC purity 99.0%, tR =
5.53 min (method A). HRMS calcd for C40H32N2O10 701.2130
(M þ H), found 701.2128.
organic layer was washed with water and brine and dried over
MgSO4. The solvent was concentrated in vacuo, and the residue
was purified by C-18 column chromatography (H2O/aceto-
nitrile) to give 350 mg of compound 6f (35%) as yellow solid.
1H NMR (600 MHz, CD3OD) δ 7.40 (s, 2H), 7.22 (d, J=7.8 Hz,
4H), 7.08 (d, J=7.2 Hz, 4H), 3.45 (m, 4H), 2.78 (t, J1=8.4 Hz,
J2=7.8 Hz, 4H), 2.30 (s, 6H), 1.93 (s, 6H). 13C NMR (600 MHz,
CD3OD) δ 185.65, 182.87, 149.35, 148.72, 146.61, 139.47,
138.20, 134.62, 131.79, 128.32, 128.14, 126.47, 123.95, 110.50,
34.44, 28.68, 19.69, 13.36. HPLC purity 99.0%, tR=17.53 min
(method A). HRMS calcd for C40H34O8 643.2326 (M þ H),
found 643.2326.
50
N5,N -Bis(4-ethylphenethyl)-6,60,7,70-tetrahydroxy-3,30-dimethyl-
1,10,4,40-tetraoxo-1,10,4,40-tetrahydro-2,20-binaphthyl-5,50-dicarbo-
xamide (8c). Yield, 52%. 1H NMR (600 MHz, CD3OD) δ 7.43
(s, 2H), 7.23 (d, J=6.6 Hz, 4H), 7.12 (d, J=6.6 Hz, 4H), 3.60
(m, 4H), 2.96 (t, J1 = J2 = 6.6 Hz, 4H), 2.50 (q, J1 = J2 =
6.6 Hz, 4H), 1.93 (s, 6H), 1.20 (t, J1= J2=6.6 Hz, 6H). 13C NMR
(600 MHz, CD3OD) δ 184.55, 183.68, 170.37, 151.99, 150.18,
147.01, 143.51, 140.73, 138.24, 130.09, 129.09, 127.38, 126.09,
124.31, 113.18, 43.03, 36.03, 29.68, 16.49, 14.51. HPLC purity
97.6%, tR = 6.99 min (method A). HRMS calcd for
C44H40N2O10 757.2756 (M þ H), found 757.2745.
Following above-mentioned procedure and the appropriate
starting materials and reagents used, compounds 6b-i, 6l and
6m were synthesized.
6,60,7,70-Tetrahydroxy-5,50-diisobutyl-3,30-dimethyl-2,20-bin-
aphthyl-1,10,4,40-tetraone (6b). Yield, 50%. 1H NMR (600 MHz,
CD3OD) δ 7.39 (s, 2H), 3.18 (m, 4H), 1.94 (m, 2H), 1.93 (s, 6H),
0.96 (d, J = 6.0 Hz, 6H). 13C NMR (600 MHz, (CD3)2SO))
δ 185.67, 182.75, 149.97, 149.53, 146.67, 138.38, 132.10, 126.65,
123.60, 111.39, 34.43, 29.18, 23.13, 23.11, 14.96. HPLC purity
96.7%, tR=13.68 min (method A). HRMS calcd for C30H30O8
519.2013 (M þ H), found 519.2012.
6,60,7,70-Tetrahydroxy-3,30-dimethyl-5,50-bis(2-phenylacetyl)-
2,20-binaphthyl-1,10,4,40-tetraone (7). Yield, 49%. 1H NMR (600
MHz, CD3OD) δ 7.32 (s, 2H), 7.28 (d, J=6.0 Hz, 4H), 7.22 (t,
J1=J2=6.0 Hz, 4H), 7.15 (t, J1=J2=6.0 Hz, 2H), 4.13 (m, 4H),
1.93 (s, 6H). 13C NMR (600 MHz, CD3OD) δ 204.02, 183.63,
181.97, 150.74, 147.30, 145.10, 139.75, 134.05, 130.14, 129.78,
127.70, 126.40, 125.69, 122.90, 111.65, 49.31, 12.84. HPLC
purity 99.0%, tR = 9.44 min (method A). HRMS calcd for
C38H26O10 643.1599 (M þ H), found 643.1601.
5,50-Bis(cyclopentylmethyl)-6,60,7,70-tetrahydroxy-3,30-dimethyl-
2,20-binaphthyl-1,10,4,40-tetraone (6c). Yield, 40%. 1H NMR
(600 MHz, (CD3)2SO) δ 10.99 (s, br, 2H), 9.54 (s, br, 2H),
7.34 (s, 2H), 3.23 (dd, J1 = 7.2 Hz, J2=4.8 Hz, 2H), 3.15 (dd, J1=
7.2 Hz, J2=4.8 Hz, 2H), 2.10 (m, 2H), 1.87 (s, 6H), 1.61 (m, 8H),
1.45 (m, 4H), 1.26 (m, 4H). 13C NMR (600 MHz, (CD3)2SO)) δ
185.25, 182.29, 149.36, 149.00, 146.23, 137.95, 132.26, 126.19,
123.05, 110.84, 40.26, 32.00, 30.65, 24.50, 14.52. HPLC purity
99.0%, tR=16.80 min (method A). HRMS calcd for C34H34O8
571.2326 (M þ H), found 571.2323.
1,10,6,60,7,70-Hexamethoxy-3,30-dimethyl-5,50-bis(4-methylp-
henethyl)-2,20-binaphthyl (15f). To a freshly prepared 4-methyl-
benzylmagnesium chloride (30.85 mmol) solution at room tem-
perature was added a solution of 11 (2.0 g, 3.86 mmol) in anhy-
drous tetrahydrofuran (30 mL), and the reaction mixture was
heated at 30 °C for 18 h. The reaction mixture was poured onto
saturated ammonium chloride solution, and the aqueous layer
was extracted twice with diethyl ether, washed with brine, and
dried over MgSO4. Filtration followed by evaporation of the
ether gave yellow oil 13. To a solution of the yellow oil 13 (1.4 g,
1.929 mmol) in 25 mL of TFA was added 3.1 mL of triethylsilane
dropwise. The solution was heated at 75 °C for 1 h followed by
stirring at room temperature for 18 h. The solution was con-
centrated in vacuo followed by silica gel column chromatogra-
phy to give 660 mg compound 15f as colorless oil (50% from 11).
1H NMR (600 MHz, CDCl3) δ 7.64 (s, 2H), 7.44 (s, 2H), 7.26 (d,
J=7.8 Hz, 4H), 7.15 (d, J=7.8 Hz, 4H), 3.99 (s, 6H), 3.94 (s,
6H), 3.60 (s, 6H), 3.37 (t, J1=J2=8.40 Hz, 4H), 2.98 (t, J1=J2=
8.4 Hz, 4H), 2.35 (s, 6H), 2.20 (s, 6H).
5,50-Bis(2-cyclohexylethyl)-6,60,7,70-tetrahydroxy-3,30-dimethyl-
2,20-binaphthyl-1,10,4,40-tetraone (6d). Yield, 50%. 1H NMR (600
MHz, (CD3)2SO) δ 10.88 (s, br, 2H), 9.51 (s, br, 2H), 7.30 (s, 2H),
3.08 (m, 4H), 1.85 (s, 6H), 1.80 (d, J=12.0 Hz, 4H), 1.68 (d, J=
12.6 Hz, 4H), 1.61 (d, J=11.4 Hz, 2H), 1.35 (m, 6H), 1.23 (q, J1=
24.6 Hz, J2=12.6 Hz, 4H), 1.16 (m, 2H), 0.96 (m, 4H). 13C NMR
(600 MHz, (CD3)2SO)) δ 185.20, 182.22, 148.95, 148.85, 146.16,
138.00, 133.20, 125.96, 123.03, 110.72, 38.02, 36.26, 32.87, 26.32,
25.91, 23.93, 14.44. HPLC purity 98.5%, tR=14.76 min (method B).
HRMS calcd for C38H42O8 627.2952 (M þ H), found 627.2952.
6,60,7,70-Tetrahydroxy-3,30-dimethyl-5,50-diphenethyl-2,20-
binaphthyl-1,10,4,40-tetraone (6e). Yield, 38%. 1H NMR (600
MHz, CD3OD) δ 7.41 (s, 2H), 7.36 (d, J = 7.8 Hz, 4H), 7.28
(t, J1=7.8 Hz, J2=7.2 Hz, 4H), 7.16 (t, J1=7.8 Hz, J2=7.2 Hz,
2H), 3.47 (m, 4H), 2.84 (t, J1=8.4 Hz, J2=7.8 Hz, 4H), 1.95 (s,
6H). HPLC purity 99.0%, tR=15.48 min (method A). HRMS
calcd for C38H30O8 615.2013 (M þ H), found 615.2015.
6,60,7,70-Tetrahydroxy-3,30-dimethyl-5,50-bis(3-phenylpropyl)-
2,20-binaphthyl-1,10,4,40-tetraone (6g). Yield, 42%. 1H NMR
(600 MHz, CD3OD) δ 7.39 (s, 2H), 7.26 (m, 8H), 7.14 (m,
2H), 3.27 (m, 4H), 2.81 (t, J1=J2=7.8 Hz, 4H), 1.97 (s, 6H), 1.90
(p, J1 = J2 = 7.8 Hz, 4H). 13C NMR (600 MHz, CD3OD) δ
185.90, 183.4, 149.40, 148.80, 146.70, 142.80, 138.22, 132.54,
127.96, 127.75, 126.61, 125.11, 123.67, 110.42, 36.15, 30.73,
26.21. HPLC purity 98.0%, tR=16.20 min (method A). HRMS
calcd for C40H34O8 643.2326 (M þ H), found 643.2334.
6,60,7,70-Tetrahydroxy-3,30-dimethyl-5,50-bis(3-methyl-3-phe-
nylbutyl)-2,20-binaphthyl-1,10,4,40-tetraone (6h). Yield, 50%.
1H NMR (600 MHz, CD3OD) δ 7.52 (d, J=7.8 Hz, 4H), 7.36
(s, 2H), 7.32 (t, J1=J2=7.8 Hz, 4H), 7.16 (t, J1=7.2 Hz, J2=
7.8 Hz, 2H), 3.04 (t, J1=7.8 Hz, J2=8.4 Hz, 4H), 1.96 (s, 6H),
1.91 (m, 4H), 1.47 (s, 12H). HPLC purity 98.0%, tR=13.5 min
(method B). 13C NMR (600 MHz, CD3OD) δ 185.36, 182.93,
149.38, 148.47, 146.58, 138.18, 133.24, 131.96, 127.47, 126.47,
125.66, 124.84, 123.69, 110.29, 42.15, 37.51, 35.48, 28.19,
22.01. HRMS calcd for C44H42O8 699.2952 (M þ H), found
699.2964.
3,30-Dimethyl-5,50-bis(4-methylphenethyl)-2,20-binaphthyl-1,10,-
6,60,7,70-hexaol (2f). BBr3 solution (2.1 mL, 5.56 g, 22.2 mmol)
was added dropwise into a solution of 15f (1.23 g, 1.76 mmol) in
60 mL of anhydrous CH2Cl2 at -78 °C. Stirring was continued
at -78 °C for 1 h, 0 °C for 1 h, and ambient temperature for 1 h,
respectively. Ice (300 g) containing 30 mL of 6 M HCl was added
to the mixture and stirred for 0.5 h at room temperature. The
aqueous layer was extracted with dichloromethane (3ꢀ100 mL).
The combined organic layer was washed with water and brine
and dried over MgSO4. The solvent was concentrated in vacuo,
and the residue was purified by C-18 column chromatography
(H2O/acetonitrile) to give 1.1 g of compound 2f (90%) as white
solid. Yield, 45%. 1H NMR (600 MHz, CD3OD) δ 7.45 (s, 2H),
7.34 (s, 2H), 7.20 (d, J=7.2 Hz, 4H), 7.08 (d, J=7.2 Hz, 4H),
3.27 (m, 4H), 2.87 (m, 4H), 2.31 (s, 6H), 2.03 (s, 6H). HPLC
purity 96.6%, tR = 17.00 min (method A). HRMS calcd for
C40H38O6 615.2741 (M þ H), found 615.2720.
6,60,7,70-Tetrahydroxy-3,30-dimethyl-5,50-bis(4-methylphenethyl)-
2,20-binaphthyl-1,10,4,40-tetraone (6f). A solution of compound
2f (1.0 g, 1.55 mmol) in 50 mL of acetone and 80 mL of acetic
acid was heated on an oil bath (60-67 °C) during the addition of
68 mL of a 10% aqueous solution of ferric chloride and for
several minutes longer. The solution was cooled, and 50 mL of
water was added, followed by 30 mL of aqueous 20% sulfuric
acid. The solution was extracted twice with diethyl ether, and the