齊墩果酸衍生物的合成*

李群林, 顧 軍, 李靈芝,3

(1. 天津醫科大學 藥學院,天津 300070； 2. 中國人民武裝警察部隊醫學院, 天津 300162; 3. 天津市職業與環境危害生物標志物重點實驗室，天津 300162)

來自天然產物的齊墩果酸(1)其抗HIV活性EC50值為1.7μg·mL-1， TI值為12.8[1]，具有進一步改造提升活性的價值。

1的3-OH和28-CO2H是抗HIV活性最大的兩個潛在部位[2],本文以其為化學修飾對象，通過1的酯化、醚化和酰胺化反應合成了26個齊墩果酸衍生物。1的3-OH與芳香酸(Ⅰl～Ⅰp)在DCC/DMAP縮合成酯(2a～2k, Scheme 1);帶有酚羥基的芳香酸可用氯化芐保護后再與1的3-OH成酯(2l～2p, Scheme 1)。1的28-CO2H先與1,2-二氯乙烷在無水碳酸鉀作用下成酯得到中間體Ⅱ； Ⅱ再與六水合哌嗪同樣在無水碳酸鉀作用下形成氮醚4； 4的另一個哌嗪氮與芳香酸(Ⅰ)在EDC·HCl(1-3-二甲氨基丙基-3-乙基碳二亞胺鹽酸鹽)和HOBT(1-羥基苯并三唑)作用下形成酰胺(3a,3c～3f,3h,3l,3m,3q, Scheme 1)。其結構經1H NMR和MS確認，其中2b～2j,2m～2p, 3和4均未見文獻報道。

1 實驗部分

1．1 儀器與試劑

XCL-1顯微熔點儀(溫度未經校正)；Varian Inova 500型核磁共振儀(CDCl3為溶劑，TMS為內標)；Finnigan FINS 2000型質譜儀。

Scheme 1

1,純度98%,西安小草植物科技有限責任公司;硅膠,200目～300目，青島海洋化工廠；其余所用試劑均為分析純,溶劑經常規干燥處理。

1.2 合成

(1)2a～2k的合成(以2a為例)

在反應瓶中依次加入1 208 mg(0.46 mmol)的CH2Cl2(15 mL)溶液，苯甲酸(Ⅰa) 120 mg(0.99 mmol)和DMAP(對二甲氨基吡啶)54 mg(0.44 mmol),攪拌使其完全溶解,加入DCC(二環己基碳二亞胺)210 mg(1.02 mmol),于室溫反應(TLC跟蹤)。過濾，濾液經制備薄層分離得白色粉末3-O-苯甲酰基齊墩果酸(2a)。

用類似方法合成白色粉末2b～2k，實驗結果見表1。

(2)2l～2p的合成(以2l為例)

在反應瓶中加入對羥基苯甲酸(Ⅰl) 0.5 g(3.6 mmol)的丙酮(15 mL)溶液，無水K2CO31.5 g(10.8 mmol)和TBAB(四丁基溴化銨)115 mg(0.36 mmol),加熱至回流，攪拌下滴加氯化芐(BnCl) 0.85 mL(7.4 mmol),滴畢，回流反應(TLC跟蹤)。減壓蒸除大部分丙酮，殘液倒入水(100 mL)中，析出黃白色黏稠物，過濾，濾餅用無水乙醇洗至白色。

將白色濾餅加入0.1 g·mL-1氫氧化鉀甲醇溶液(10 mL)中，回流反應2 h。倒入水(200 mL)中，用10%鹽酸調至pH 3(溶液中出現大量白色固體)，過濾，濾餅真空干燥得對芐氧基苯甲酸(Ⅰl′) 0.726 g,產率88%。

在反應瓶中依次加入1 250 mg(0.548 mmol)的CH2Cl2(10 mL)溶液，Ⅰl′ 250 mg(1.096 mmol)和DMAP 67 mg(0.548 mmol)，攪拌至完全溶解，加入DCC 230 mg(1.117 mmol)，于室溫反應(TLC跟蹤)。過濾，濾液經硅膠柱層析[洗脫劑:A=V(石油醚) ∶V(乙酸乙酯)=10 ∶1]分離得白色粉末2l′ 185 mg，產率50%。

用類似方法合成2m′～2p′ 。

在反應瓶加入2l′ 185 mg,混合溶劑CHCl3-CH3OH(等體積比，10 mL)，攪拌使其溶解后加入Pd/C 18.5 mg，置中壓氫化釜中反應8 h。過濾，濾液濃縮后經制備薄層分離得白色粉末3-O-對羥基苯甲酰基齊墩果酸(2l)。

用類似方法合成2m～2p,實驗結果見表1。

(3)3的合成(以3a為例)

在干燥三頸瓶中加入1 10 g(21.9 mmol),二氯乙烷10 mL，丙酮50 mL和無水K2CO34.5 g，攪拌下回流反應(TLC跟蹤)。減壓蒸除溶劑，濃縮物經硅膠柱層析(A=6 ∶1)分離得白色粉末Ⅱ。在反應瓶子中依次加入Ⅱ,六水合哌嗪20.9 g(107.9 mmol, 5eq)和DMF 50 mL，攪拌使其溶解，加入無水K2CO34.8 g，于80 ℃反應(TLC跟蹤)。傾入蒸餾水(200 mL)中，用乙酸乙酯(3×150 mL)萃取，合并有機層，減壓濃縮，濃縮物經柱層析[洗脫劑：V(二氯甲烷) ∶V(甲醇)=20 ∶1]分離得白色粉末4。

將4 0.35 mmol溶于適量二氯甲烷中，依次加入Ⅰa65 mg(0.53 mmol)， EDC·HCl 102 mg(0.53 mmol)和HOBT 72 mg(0.53 mmol)，攪拌下于室溫反應(TLC跟蹤)。用蒸餾水(2×10 mL)洗滌后經制備薄層分離得白色粉末3a。

表 1 2～4的實驗結果Table 1 The experimental results of 2～4

用類似方法合成白色粉末3b,3c,3d(棕色粉末),3e,3f,3h,3l,3m(黃色粉末)和3q,實驗結果見表1。

2a:1H NMRδ: 7.41～8.08(m, 5H, PhH), 5.31(s, 1H, 12-H), 4.70(dd,J=10.5 Hz, 5.5 Hz, 1H, 3-H), 2.95(d,J=10.0 Hz, 1H, 18-H), 2.84(d,J=10.0 Hz, 1H, 3-H), 2.18(m, 1H, 2-H),1.02(s, 3H, CH3), 0.99(s, 3H, CH3), 0.97(s, 3H, CH3), 0.95(s, 3H, CH3), 0.92(s, 3H, CH3), 0.88(s, 3H, CH3), 0.79(s, 3H, CH3)。

2b:1H NMRδ: 7.97(d,J=8.5 Hz, 2H, ArH), 7.47(d,J=8.5 Hz, 2H, ArH), 5.39(t,J=3.5 Hz, 1H, 12-H), 3.27(dd,J=11.0 Hz, 5.5 Hz, 1H, 3-H), 2.91(dd,J=13.5 Hz, 4.0 Hz, 1H,18-H), 1.18(s, 3H, CH3), 0.99(s, 3H, CH3), 0.95(s, 3H, CH3), 0.94(s, 3H, CH3), 0.91(s, 3H, CH3), 0.84(s, 3H, CH3), 0.78(s, 3H, CH3)。

2c:1H NMRδ: 8.23(d,J=4.0 Hz, 2H, ArH), 8.20(d, J=4.0 Hz, 2H, ArH), 5.34(t,J=3.3 Hz, 1H, 12-H), 4.79(dd,J=8.5 Hz, 6.0 Hz, 1H, 3-H), 2.85(dd,J=13.5 Hz, 4.0 Hz, 1H, 18-H), 1.18(s, 3H, CH3), 1.04(s, 3H, CH3), 1.00(s, 3H, CH3), 0.96(s, 3H, CH3), 0.95(s, 3H, CH3), 0.93(s, 3H, CH3), 0.84(s, 3H, CH3)。

2d:1H NMRδ: 9.23(t,J=2.0 Hz, 1H, ArH), 9.14(d,J=2.0 Hz, 2H, ArH), 5.31(t,J=3.7 Hz, 1H, 12-H), 4.88(dd,J=11.0 Hz, 5.5 Hz, 1H, 3-H), 2.84(dd,J=14.0 Hz, 3.5 Hz, 1H, 18-H), 1.17(s, 3H, CH3), 1.07(s, 3H, CH3), 1.03(s, 3H, CH3), 0.97(s, 3H, CH3), 0.95(s, 3H, CH3), 0.93(s, 3H, CH3), 0.80(s, 3H, CH3)。

2e:1H NMRδ: 7.83(d,J=8.5 Hz, 2H, ArH), 6.64(d,J=8.5 Hz, 2H, ArH), 5.38(t,J=3.5 Hz, 1H, 12-H), 4.26(s, 2H, NH2), 3.21(dd,J=11.0 Hz, 4.0 Hz, 1H, 3-H), 2.92(dd,J=14.0 Hz, 4.2 Hz, 1H, 18-H), 1.18(s, 3H, CH3), 0.99(s, 3H, CH3), 0.95(s, 3H, CH3), 0.93(s, 3H, CH3), 0.91(s, 3H, CH3), 0.85(s, 3H, CH3), 0.78(s, 3H, CH3)。

2f:1H NMRδ: 8.00(d,J=9.0 Hz, 2H, ArH), 6.92(d,J=9.0 Hz, 2H, ArH), 5.33(s, 1H, 12-H), 4.71(dd,J=10.5 Hz, 5.5 Hz, 1H, 3-H), 3.86(s, 3H, CH3), 2.84(dd,J=13.5 Hz, 3.3 Hz, 18-H), 1.17(s, 3H, CH3), 1.01(s, 3H, CH3), 0.98(s, 3H, CH3), 0.95(s, 3H, CH3), 0.94(s, 3H, CH3), 0.93(s, 3H, CH3), 0.83(s, 3H, CH3)。

2g:1H NMRδ: 7.81(d,J=8.5 Hz, 2H, PhH), 7.53(m, 1H, PhH), 7.45(t,J=8.5 Hz, 2H, PhH), 6.68(t,J=4.8 Hz, 1H, NH), 5.32(t,J=3.5 Hz, 1H, 12-H), 4.62(dd,J=11.0 Hz, 5.5 Hz, 1H, 3-H), 4.25(d,J=5.0 Hz, 2H, CH2), 2.82(dd,J=13.5 Hz, 3.5 Hz, 1H, 18-H), 1.15(s, 3H, CH3), 0.94(s, 3H, CH3), 0.92(s, 3H, CH3), 0.90(s, 3H, CH3), 0.88(s, 3H, CH3), 0.81(s, 3H, CH3), 0.79(s, 3H, CH3)。

2h:1H NMRδ: 9.23(d,J=1.5 Hz, 1H, ArH), 8.78(dd,J=5.0 Hz, 1.5 Hz, 1H, ArH), 8.31(m,J=7.5 Hz, 5.0 Hz, 1.5 Hz, 1H, PyH), 7.41(dd,J=7.5 Hz, 5.0 Hz, 1H, ArH), 5.30(t,J=3.5 Hz, 1H, 12-H), 4.78(dd,J=10.5 Hz, 6.0 Hz, 1H, 3-H), 2.84(dd,J=14.0 Hz, 4.3 Hz, 1H, 18-H), 1.16(s, 3H, CH3), 1.02(s, 3H, CH3), 1.00(s, 3H, CH3), 0.95(s, 3H, CH3), 0.94(s, 3H, CH3), 0.92(s, 3H, CH3), 0.79(s, 3H, CH3)。

2i:1H NMRδ: 7.58(d,J=1.0 Hz, 1H, ArH), 7.14(d,J=3.5 Hz, 1H, ArH), 6.45(dd,J=3.5 Hz, 1.5 Hz, 1H, ArH), 5.32(t,J=3.3 Hz, 1H, 12-H), 4.73(dd,J=9.0 Hz, 7.5 Hz, 1H, 3-H), 2.84(dd,J=13.5 Hz, 4.0 Hz, 1H, 18-H), 1.16(s, 3H, CH3), 0.97(s, 3H, CH3), 0.97(s, 3H, CH3), 0.94(s, 3H, CH3), 0.93(s, 3H, CH3), 0.92(s, 3H, CH3), 0.82(s, 3H, CH3)。

2j:1H NMRδ: 8.13(s, 1H, NH), 7.62(d,J=7.5 Hz, 1H, ArH), 7.35(d,J=7.5 Hz, 1H, ArH), 7.19(dd,J=4.0 Hz, 2.5 Hz, 2H, ArH), 7.14(d,J=7.0 Hz, ArH), 5.26(t,J=3.5 Hz, 1H, 12-H), 4.51(m, 1H, 3-H), 3.77(s, 2H, CH2), 3.09(dd,J=14.0 Hz, 4.5 Hz, 1H, 18-H), 1.12(s, 3H, CH3), 0.93(s, 3H, CH3), 0.91(s, 3H, CH3), 0.87(s, 3H, CH3), 0.79(s, 3H, CH3), 0.77(s, 3H, CH3), 0.75(s, 3H, CH3)。

2k:1H NMRδ: 7.54(m, 2H, PhH), 7.38(m, 3H, PhH), 7.67(d,J=16.0 Hz, 1H, =CH), 6.45(d,J=16.0 Hz, 1H, =CH), 5.33(t,J=3.5 Hz, 1H, 12-H), 4.65(t,J=8.0 Hz, 1H, 3-H), 2.84(dd,J=13.5 Hz, 3.75 Hz, 1H, 18-H), 1.26(s, 3H, CH3), 1.16(s, 3H, CH3), 0.97(s, 3H, CH3), 0.95(s, 3H, CH3), 0.95(s, 3H, CH3), 0.92(s, 3H, CH3), 0.82(s, 3H, CH3)。

2l:1H NMRδ: 7.92(d,J=8.5 Hz, 2H, ArH), 6.89(d,J=9.0 Hz, 2H, ArH), 5.38(t,J=3.5 Hz, 1H, 12-H), 3.26(dd,J=11.0 Hz, 4.5 Hz, 1H, 3-H), 2.92(dd,J=13.5 Hz, 4.0 Hz, 1H, 18-H), 1.17(s, 3H, CH3), 0.99(s, 3H, CH3), 0.95(s, 3H, CH3), 0.93(s, 3H, CH3), 0.90(s, 3H, CH3), 0.83(s, 3H, CH3), 0.79(s, 3H, CH3)。

2m:1H NMRδ: 7.59(s, 1H, ArH), 7.53(d,J=8.0 Hz, 1H, ArH), 6.92(d,J=8.0 Hz, 1H, ArH), 5.39(s, 1H, 12-H), 3.25(dd,J=11.0 Hz, 4.3 Hz, 1H, 3-H), 2.92(dd,J=14.0 Hz, 3.75 Hz, 1H, 18-H), 1.18(s, 3H, CH3), 0.99(s, 3H, CH3), 0.95(s, 3H, CH3), 0.93(s, 3H, CH3), 0.90(s, 3H, CH3), 0.82(s, 3H, CH3), 0.78(s, 3H, CH3)。

2n:1H NMRδ: 7.15(d,J=8.5 Hz, 2H, ArH), 6.78(d,J=8.5 Hz, 2H, ArH), 5.27(t,J=3.8 Hz, 1H, 12-H), 4.48(dd,J=9.0 Hz, 7.0 Hz, 1H, 3-H), 3.54(s, 2H, CH2), 2.81(dd,J=9.0 Hz, 4.3 Hz, 1H, 18-H), 1.12(s, 3H, CH3), 0.92(s, 3H, CH3), 0.91(s, 3H, CH3), 0.90(s, 3H, CH3), 0.78(s, 3H, CH3), 0.75(s, 3H, CH3), 0.74(s, 3H, CH3)。

2o:1H NMRδ: 6.78(d, 2H, ArH),6.69(d, 1H, ArH), 5.27(t,J=3.5 Hz, 1H, 12-H), 4.49(t,J=8.0 Hz, 1H, 3-H), 3.49(s, 2H, CH2), 2.82(dd,J=14.0 Hz, 4.0 Hz, 1H, 18-H), 1.12(s, 3H, CH3), 0.92(s, 3H, CH3), 0.91(s, 3H, CH3), 0.90(s, 3H, CH3), 0.80(s, 3H, CH3), 0.76(s, 3H, CH3), 0.73(s, 3H, CH3)。

2p:1H NMRδ: 6.77(d, 1H, ArH), 6.73(d, 1H, ArH), 6.64(dd,J=8.0 Hz, 2.0 Hz, 1H, ArH), 5.31(t,J=3.5 Hz, 1H, 12-H), 4.49(t,J=8.0 Hz, 1H, 3-H), 2.85(t,J=7.5 Hz, 2H, CH2), 2.59(t,J=7.5 Hz, 2H, CH2), 1.26(s, 3H, CH3), 1.14(s, 3H, CH3), 0.94(s, 3H, CH3), 0.92(s, 3H, CH3), 0.83(s, 3H, CH3), 0.79(s, 3H, CH3), 0.79(s, 3H, CH3)。

3a:1H NMRδ: 7.40(m, 5H, PhH), 5.25(t,J=3.0 Hz, 1H, 12-H), 4.16(m, 2H, CH2), 3.78(s, 2H, H in piperazine), 3.41(s, 2H, H in piperazine), 3.20(dd,J=11.0 Hz, 4.0 Hz, 1H, 3-H), 2.84(dd,J=13.5 Hz, 4.0 Hz, 1H, 18-H), 2.65(t,J=5.5 Hz, 2H, CH2), 2.60(s, 2H, H in piperazine),2.45(s, 2H, H in piperazine), 1.12(s, 6H, CH3), 0.98(s, 6H, CH3), 0.91(s, 3H, CH3), 0.89(s, 3H, CH3), 0.88(s, 3H, CH3), 0.77(s, 3H, CH3), 0.71(s, 3H, CH3)。

3c:1H NMRδ: 8.28(d,J=9.0 Hz, 2H, ArH), 7.57(d,J=9.0 Hz, 2H, ArH), 5.25(t,J=3.5 Hz, 1H, 12-H), 4.16(m, 2H, CH2), 3.79(s, 2H, H in piperazine), 3.35(s, 2H, H in piperazine), 3.21(dd,J=11.0 Hz, 5.0 Hz, 1H, 3-H), 2.84(dd,J=14.0 Hz, 4.3 Hz, 1H, 18-H), 2.66(t,J=5.5 Hz, 2H, CH2), 2.62(s, 2H, H in piperazine), 2.46(s, 2H, H in piperazine), 1.13(s, 3H, CH3), 0.98(s, 3H, CH3), 0.91(s, 3H, CH3), 0.90(s, 3H, CH3), 0.89(s, 3H, CH3), 0.77(s, 3H, CH3), 0.71(s, 3H, CH3)。

3d:1H NMRδ: 9.09(d,J=2.0 Hz, 1H, ArH), 8.59(d,J=2.0 Hz, 2H, ArH), 5.25(t,J=3.0 Hz, 1H, 12-H), 4.16(m, 2H, CH2), 3.82(s, 2H, H in piperazine), 3.41(s, 2H, H in piperazine), 3.19(dd,J=11.0 Hz, 4.0 Hz, 1H, 3-H), 2.84(dd,J=13.5 Hz, 4.0 Hz, 1H, 18-H), 2.68(t,J=5.5 Hz, 2H, CH2), 2.68(s, 2H, H in piperazine), 2.52(s, 2H, H in piperazine), 1.13(s, 3H, CH3), 0.98(s, 3H, CH3), 0.91(s, 3H, CH3), 0.89(s, 3H, CH3), 0.89(s, 3H, CH3), 0.77(s, 3H, CH3), 0.72(s, 3H, CH3)。

3e:1H NMRδ: 7.25(d,J=8.0 Hz, 2H, ArH), 6.65(d,J=8.0 Hz, 2H, ArH), 5.26(t,J=3.3 Hz, 1H, 12-H), 4.16(m, 2H, CH2), 3.88(s, 2H, H in piperazine), 3.61(s, 2H, H in piperazine), 3.21(dd,J=11.0 Hz, 4.0 Hz, 1H, 3-H), 2.84(dd,J=13.5 Hz, 3.8 Hz,1H, 18-H), 2.65(t,J=5.5 Hz, 2H, CH2), 2.52(s, 4H, H in piperazine), 1.13(s, 3H, CH3), 0.98(s, 3H, CH3), 0.91(s, 3H, CH3), 0.90(s, 3H, CH3), 0.89(s, 3H, CH3), 0.78(s, 3H, CH3), 0.72(s, 3H, CH3)。

3f:1H NMRδ: 7.38(d,J=8.5 Hz, 2H, ArH), 6.91(d,J=8.5 Hz, 2H, ArH), 5.26(t,J=3.0 Hz, 1H, 12-H), 4.16(m, 2H, CH2), 3.83(s, 3H, OCH3), 3.68(s, 2H, H in piperazine), 3.51(s, 2H, H in piperazine), 3.20(dd,J=11.0 Hz, 4.0 Hz, 1H, 3-H), 2.84(dd,J=13.5 Hz, 4.0 Hz, 1H, 18-H), 2.65(t,J=5.5 Hz, 2H, CH2), 2.52(s, 4H, H in piperazine), 1.13(s, 3H, CH3), 0.98(s, 3H, CH3), 0.91(s, 3H, CH3),0.90(s, 3H, CH3), 0.89(s, 3H, CH3), 0.77(s, 3H, CH3), 0.72(s, 3H, CH3)。

3h:1H NMRδ: 8.67(d,J=1.5 Hz, 1H, ArH), 8.66(s, 1H, ArH), 7.75(dd,J=6.0 Hz, 2.0 Hz, ArH), 7.37(dd,J=8.0 Hz, 5.0 Hz, ArH), 5.26(s,J=3.0 Hz, 1H, 12-H), 4.16(m, 2H, CH2), 3.79(s, 2H, ArH), 3.43(s, 2H, H in piperazine), 3.21(dd,J=11.0 Hz, 4.0 Hz, 1H, 3-H), 2.84(dd,J=14.0 Hz, 4.0 Hz, 1H, 18-H), 2.66(t,J=5.5 Hz, 2H, CH2), 2.63(d,J=5.0 Hz, 2H, H in piperazine), 2.48(t,J=5.0 Hz, 2H, H in piperazine), 1.13(s, 3H, CH3), 0.98(s, 3H, CH3), 0.91(s, 3H, CH3), 0.90(s, 3H, CH3), 0.89(s, 3H, CH3), 0.78(s, 3H, CH3), 0.72(s, 3H, CH3)。

3l:1H NMRδ: 7.22(d,J=8.0 Hz, 2H, ArH), 6.73(d,J=8.0 Hz, 2H, ArH), 5.25(s, 1H, 12-H), 4.16(m, 2H, CH2), 3.75(s, 2H, ArH), 3.51(s, 2H, ArH), 3.22(dd,J=11.0 Hz, 4.0 Hz, 1H, 3-H), 2.84(dd,J=13.0 Hz, 3.3 Hz, 1H, 18-H), 2.66(t,J=5.3 Hz, 2H, CH2), 2.53(s, 4H, H in piperazine), 1.12(s, 3H, CH3), 0.98(s, 3H, CH3), 0.91(s, 3H, CH3), 0.89(s, 3H, CH3), 0.88(s, 3H, CH3), 0.77(s, 3H, CH3), 0.71(s, 3H, CH3)。

3m:1H NMRδ: 9.12(s, 1H,J=), 6.73(d,J=3.0 Hz, 2H, ArH), 5.26(t,J=3.0 Hz, 1H, 12-H), 4.16(m, 2H, CH2), 3.75(s, 2H, H in piperazine), 3.50(s, 2H, H in piperazine), 3.22(dd,J=11.0 Hz, 4.0 Hz, 1H, 3-H), 2.84(dd,J=13.8 Hz, 3.8 Hz, 1H, 18-H), 2.65(t,J=5.5 Hz, 2H, CH2), 2.58(s, 2H, H in piperazine), 2.47(s, 2H, H in piperazine), 1.13(s, 3H, CH3), 0.98(s, 3H, CH3), 0.91(s, 3H, CH3), 0.90(s, 3H, CH3), 0.89(s, 3H, CH3), 0.77(s, 3H, CH3), 0.72(s, 3H, CH3)。

3q:1H NMRδ: 7.33(t,J=7.0 Hz, 1H, ArH), 7.29(dd,J=7.0 Hz, 1.2 Hz, 1H, ArH), 7.03(dd,J=7.0 Hz, 1.2 Hz, 1H, ArH), 5.28(t,J=3.4 Hz, 1H, 12-H), 4.20(m, 2H, CH2), 3.75(t,J=4.8 Hz, 4H, H in piperazine), 3.22(t, 1H, 3-H),2.897(dd, 1H, 18-H), 2.68(t,J=5.4 Hz, 2H, CH2), 2.59(t,J=4.8 Hz, 4H, H in piperazine), 1.19(s, 3H, CH3), 1.00(s, 3H, CH3), 0.94(s, 3H, CH3), 0.92(s, 3H, CH3), 0.91(s, 3H, CH3), 0.793(s, 3H, CH3), 0.74(s, 3H, CH3)。

4:1H NMRδ: 5.26(t,J=3.5 Hz, 1H, 12-H), 4.16(m, 2H, CH2), 3.21(dd,J=11.0 Hz, 4.0 Hz, 1H, 3-H), 2.91(s, 4H, H in piperazine), 2.85(dd,J=14.0 Hz, 4.5 Hz, 1H, 18-H), 2.61(t,J=6.0 Hz, 2H, CH2), 2.52(s,4H, H in piperazine), 1.13(s, 3H, CH3), 0.98(s, 3H, CH3), 0.91(s, 3H, CH3), 0.90(s, 6H, CH3), 0.78(s, 3H, CH3), 0.72(s, 3H, CH3)。

2 結果與討論

由于1的3-OH位阻較大，與芳香酸酯化時投料比例、底物結構、反應溶劑等條件對反應收率有一定影響。(1)若按等比例投料，酯化產率較低，當芳香酸的量增加一倍時，羧基與羥基接觸幾率加大，產物收率也明顯提高。(2)含有酚羥基的芳香酸酯化時，TLC檢測發現1始終未發生變化，卻出現含有芳香酸結構的新點，這說明在DCC/DMAP條件下不易與芳香酸發生酯化反應，過量的芳香酸發生了分子間反應。(3)在酚羥基保護過程中，首先選用了乙酸酐，但乙酰化保護的芳香酸與1反應僅得3-O-乙酰基齊墩果酸。Deng[3]和曲峰等認為采用羥基乙酰化保護糖基進行糖苷化反應時，在反應過程中乙酰基易發生轉移[4]。推測本實驗中生成3-O-乙酰基齊墩果酸的原因可能是乙酰基與酚羥基形成的酯不穩定，在DCC/DMAP弱堿性反應條件下易裂解，產生的活性中間體乙酰基易與1的3-OH成酯。我們改用芐基保護后產率提高，催化氫化脫保護也較容易且不會破壞酯鍵。文獻[5]報道先將芳香酸的羧基與甲醇在對甲基苯磺酸作用下形成甲酯，用芐基保護羥基，然后在氫氧化鉀的甲醇溶液中水解甲酯得芐基保護酚羥基的芳香酸，但該法酯化反應需較長時，且產率只有75%。本文直接用芳香酸(Ⅰl～Ⅰp)與過量氯化芐反應，在氫氧化鉀的甲醇溶液中水解脫芐酯得芐基保護酚羥基的芳香酸(Ⅰl′～Ⅰp′, Scheme 2)，反應時間縮短，產率提高到85%。

在1的28-CO2H改造過程中，(1)與1,2-二氯乙烷反應時，首先以丙酮作為溶劑，由于丙酮沸點較低，反應需要很長時間，且反應不完全；后改用DMF為溶劑，但DMF沸點較高，反應后不易除去；1,2-二氯乙烷沸點是83.5 ℃，在回流狀態下對1有較好的溶解性，因此以1,2-二氯乙烷既作反應物又作溶劑，不僅縮短了反應時間，同時提高了產率。(2)哌嗪的另一個氮與芳香酸形成酰胺后，哌嗪上靠近酰胺的碳上的兩個氫發生裂分，且偶合常數非常大(J=180 Hz)。肖志會等[6]對大量的苯基哌嗪類衍生物進行NMR研究時，發現所有化合物都出現這種情況。本文也證實該現象，且認為靠近酰胺的碳上的兩個氫由于在芳香酰基的共軛作用影響下發生化學不等價，導致出現偶合常數非常大的裂分。

本實驗合成反應條件溫和，產率較高，能夠得到較多類型的齊墩果酸衍生物，為測試抗HIV活性和研究構效關系提供了較為可靠的實驗依據。

Scheme 2

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[3] Shaojiang Deng, Biao Yu, Jianming Xie,etal. Highly efficient glycosylation of sapogenins[J].J Org Chem,1999,64:7265-7266.

[4] 曲峰,李英霞,張一純,等. 幾種齊墩果酸糖綴合物的合成[J].有機化學,2003,23(2):249-257.

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