DIRECT, HIGHLY EFFICIENT SYNTHESIS FROM (S)-(+)-PHENYLGLYCINE OF THE TAXOL AND TAXOTERE SIDE-CHAINS
DIRECT, HIGHLY EFFICIENT SYNTHESIS FROM (S)-(+)-PHENYLGLYCINE OF THE TAXOL AND TAXOTERE SIDE-CHAINS
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DOI：
10.1021/jo00024a044
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发表时间：
1991-11-22
影响因子：
3.6
通讯作者：
GREENE, AE
中科院分区：
文献类型：
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作者：
DENIS, JN;CORREA, A;GREENE, AE
4-[(2-甲氧基鸟嘌呤-8-基)乙炔]苯甲酰基]-谷氨酸二甲酯(7)。在1.1g(3.5 mmol)5a的20mLCH3CN和2mLET^N的溶液中加入82 mg(0.36 mmo1)Pd(OAc)2,108 mg(0.57 mmo1)CuL和213 mg(0.81 mmo1)ph3p的混合物，然后加入2.02 g(6.6 mmo1)[4-乙炔基苯甲酰基]谷氨酸二甲酯(6)e 20mLCH3CN中。所得溶液在70-80℃加热6h，然后在减压下浓缩，得到的固体用145g硅胶闪蒸层析纯化，使用CH2C12中的3%甲醇作为洗脱溶剂，得到0.91g固体，经核磁共振分析，其由60%的2-新戊酰基-8-溴鸟嘌呤5a和40%的7：核磁共振(二甲亚砜-de，300 MHz)1.22(S，9)，2.0(m，1)，2.1(m，1H)，2.48(t，2H，J=7.3赫兹)组成，CH2CH2CH)，3.57(S，3H，CH3)，3.64(S，3H，CH3)，4.45(m，1H，CtfCH2)，7.74(d，2H，J=8.0 Hz，C6H4)，7.96(d，2H，J=8.0 Hz，C6H4)，8.92(d，1H，J=7.3 Hz，NHCH)，11.09(S，1 H)，12.21(S，1 H)，13.68(br S，1，9-NH)。[4-[2-(2-甲氧基鸟嘌呤-8-基)乙基]苯甲酰基]-谷氨酸二甲酯(8)。将0.5g的3%炭上钯和0.7g(1.30 mmol)的上述5b和7的混合物加入40mL甲醇中，在50psi的氢气中搅拌16h。催化剂通过Celite垫过滤，用25mL5%的甲醇在CH2C12中洗涤。滤液浓缩成固体，在5%甲醇中溶解在CH2C12中。过滤除去少量白色固体(2-甲氧基鸟嘌呤)，滤液浓缩后得到0.58g橙色固体，经闪蒸层析(5%甲醇在CH2C12中)通过86g硅胶纯化，得黄色固体8得0.22g(31%)。分析样品MP175-176C由乙酸乙酯重结晶而成：IR(KBr3140,2940,1735,1660,1400,1155 cm~(-1))。主变构体：核磁共振氢谱(DMSO-De，300 MHz)1.22(S，9)，2.0和2.1(2M，2H，CH2CH)，2.42(t，2H，J=7.3H，CH2CH)，3.06(m，4H，CH2CH2)，3.55(S，3H，CH3)，3.61(S，3H，CH3)，4.41(m，1H，CHNH)，7.29(d，2H，J=8.0 Hz，C6H4)，7.75(d，2H，J=8.0 Hz，C6H4)，8.66(d，1H，J=7.3 Hz，CHNH)，11.02(S，1H)，12.16(S，1H)，13.08(S，1H)。对于次要互变异构体，上场区域(低于7ppm)与主要互变异构体的上场区域相同：*H核磁共振(DMSO-De，300 MHz)7.31(d，2 H，J=6.1 Hz，CeH4)，7.77(d，2 H，J=6.1 Hz，C6H4)，8.67(d，2 H，J=7.0 Hz，CHNH)，10.93(S，1 H)，12.03(S，1 H)，12.60(S，1 H)。MS(Fab，m/e)，541(MH+)，366；精确质量(Fab)为C26-33？07(MH+)541.2410，找到541.24049。肛门。C26H32Ne07：C，57.77；H，5.97；N，15.55。结果：C，57.56，H，5.78，N，15.32。[4-(2-鸟嘌呤-8-乙基)苯甲酰基]谷氨酸(2)。将0.14g(0.26 mmol)的酯8悬浮液加入2.5mL1N NaOH中，在RT下搅拌3d。得到的透明溶液用醋酸中和至pH 6，然后用10毫升水稀释，通过过滤收集得到的固体，用水、甲醇和乙醚洗涤，最后干燥得到50 mg(48%)的黄色固体，MP 20CH230 C DEC：IR(KBR)3350(Br)，1690,1630 cm“1；核磁共振(DMSO-d6,300 MHz)1.95和2.05(2M，2H，CH2CH)，2.32(S，2H，CH2CH)，2.9和3.34(2 br S，4H，CH2CH2)，4.37(m，1H，CHNH)，6.23(S，2H，NH_2)，7.29(d，2)，7.70(d，2)，8.51(d，1H，NHCH)，10.5(S，1)，12.1(S，1
Dimethyl [4-[(2-Pivaloylguanin-8-yl) ethynyl] benzoyl]-glutamate (7). To a solution of 1.1 g (3.5 mmol) of 5a in 20 mL of CH3CN and 2 mL of Et^ N was added a mixture of 82 mg (0.36 mmol) of Pd (OAc) 2,108 mg (0.57 mmol) of Cul, and 213 mg (0.81 mmol) of Ph3P followed by a solution of 2.02 g (6.6 mmol) of dimethyl [4-ethynylbenzoyl] glutamate (6) e in 20 mL of CH3CN. The resulting solution was heated at 70-80 C for 6 h and then concentrated under reduced pressure, and the resulting solid was purified by flash chromatography with 145 g of silica gel, using 3% MeOH in CH2C12 as the eluting solvent, to give 0.91 g of a solid which (by NMR) consisted of 60% of 2-pivaloyl-8-bromoguanine 5a and 40% of 7: NMR (DMSO-de, 300 MHz) 1.22 (s, 9), 2.0 (m, 1), 2.1 (m, 1 H), 2.48 (t, 2 H, J= 7.3 Hz, CH2CH2CH), 3.57 (s, 3 H, CH3), 3.64 (s, 3 H, CH3), 4.45 (m, 1 H, CtfCH2), 7.74 (d, 2 H, J= 8.0 Hz, C6H4), 7.96 (d, 2H, J= 8.0 Hz, C6H4), 8.92 (d, 1 H, J= 7.3 Hz, NHCH), 11.09 (s, 1 H), 12.21 (s, 1 H), 13.68 (br s, 1, 9-NH). Dimethyl [4-[2-(2-Pivaloylguanin-8-yl) ethyl] benzoyl]-glutamate (8). A suspension of 0.5 g of 3% palladium-on-charcoal and 0.7 g (1.30 mmol) of the above mixture of 5b and 7 in 40 mL of MeOH was stirred at rt under 50 psi of hydrogen for 16 h. The catalyst was removed by filtration through a pad of Celite, which was washed with 25 mL of 5% MeOH in CH2C12. The filtrate was concentrated to give a solid which was dissolved in 5% MeOH in CH2C12. Filtration removed a small amount of a white solid (2-pivaloylguanine), and concentration of the filtrate then gave 0.58 g of an orange solid which was purified byflash chromatography (5% MeOH in CH2C12) through 86 g of silica gel, yield 0.22 g (31%) of 8 as a yellow solid. The analytical sample, mp 175-176 C, was prepared by recrystallization from ethyl acetate: IR (KBr) 3140, 2940, 1735, 1660, 1400, 1155 cm" 1. For the major tautomer:* H NMR (DMSO-de, 300 MHz) 1.22 (s, 9), 2.0 and 2.1 (2m, 2 H, CH2CH), 2.42 (t, 2 H, J= 7.3 H, CH2CH2CH), 3.06 (m, 4 H, CH2CH2), 3.55 (s, 3 H, CH3), 3.61 (s, 3 H, CH3), 4.41 (m, 1 H, CHNH), 7.29 (d, 2 H, J= 8.0 Hz, C6H4), 7.75 (d, 2 H, J= 8.0 Hz, C6H4), 8.66 (d, 1 H, J= 7.3 Hz, CHNH), 11.02 (s, 1 H), 12.16 (s, 1 H), 13.08 (s, 1 H). For the minor tautomer, the upper field region (lower than 7 ppm) is the same as that of the major tautomer:* H NMR (DMSO-de, 300 MHz) 7.31 (d, 2 H, J= 6.1 Hz, CeH4), 7.77 (d, 2 H, J= 6.1 Hz, C6H4), 8.67 (d, 2 H, J= 7.0 Hz, CHNH), 10.93 (s, 1 H), 12.03 (s, 1 H), 12.60 (s, 1 H). MS (FAB, m/e), 541 (MH+), 366; exact mass (FAB) caled for C26-33 ß07 (MH+) 541.2410, found 541.24049. Anal. Caled for C26H32Ne07: C, 57.77; H, 5.97; N, 15.55. Found: C, 57.56; H, 5.78; N, 15.32.[4-(2-Guanin-8-ylethyl) benzoyl] glutamic Acid (2). A suspension of 0.14 g (0.26 mmol) of the ester 8 in 2.5 mL of 1 N NaOH was stirred at rt for 3 days. The resulting clear solution was neutralized with acetic acid until pH 6 and then diluted with 10 mL of water, and the resulting solid was collected by filtration, washed throughly with water, MeOH, and ether, and finally dried to give 50 mg (48%) of a yellow solid, mp 20CH230 C dec: IR (KBr) 3350 (br), 1690, 1630 cm" 1; NMR (DMSO-d6, 300 MHz) 1.95 and 2.05 (2m, 2 H, CH2CH), 2.32 (s, 2 H, CH2CH2CH), 2.9 and 3.34 (2 br s, 4 H, CH2CH2), 4.37 (m, 1 H, CHNH), 6.23 (s, 2 H, NH2), 7.29 (d, 2), 7.70 (d, 2), 8.51 (d, 1 H, NHCH), 10.5 (s, 1), 12.1 (s, 1