李群林, 顧 軍, 李靈芝,3

(1. 天津醫(yī)科大學(xué) 藥學(xué)院,天津 300070； 2. 中國(guó)人民武裝警察部隊(duì)醫(yī)學(xué)院, 天津 300162; 3. 天津市職業(yè)與環(huán)境危害生物標(biāo)志物重點(diǎn)實(shí)驗(yàn)室，天津 300162)

來(lái)自天然產(chǎn)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(jìn)一步改造提升活性的價(jià)值。

1的3-OH和28-CO2H是抗HIV活性最大的兩個(gè)潛在部位[2],本文以其為化學(xué)修飾對(duì)象，通過(guò)1的酯化、醚化和酰胺化反應(yīng)合成了26個(gè)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(hù)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(wú)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(wú)水碳酸鉀作用下形成氮醚4； 4的另一個(gè)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(jié)構(gòu)經(jīng)1H NMR和MS確認(rèn)，其中2b～2j,2m～2p, 3和4均未見(jiàn)文獻(xiàn)報(bào)道。

1 實(shí)驗(yàn)部分

1．1 儀器與試劑

XCL-1顯微熔點(diǎn)儀(溫度未經(jīng)校正)；Varian Inova 500型核磁共振儀(CDCl3為溶劑，TMS為內(nèi)標(biāo))；Finnigan FINS 2000型質(zhì)譜儀。

Scheme 1

1,純度98%,西安小草植物科技有限責(zé)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(jīng)常規(guī)干燥處理。

1.2 合成

(1)2a～2k的合成(以2a為例)

在反應(yīng)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(duì)二甲氨基吡啶)54 mg(0.44 mmol),攪拌使其完全溶解,加入DCC(二環(huán)己基碳二亞胺)210 mg(1.02 mmol),于室溫反應(yīng)(TLC跟蹤)。過(guò)濾，濾液經(jīng)制備薄層分離得白色粉末3-O-苯甲?；R墩果酸(2a)。

用類(lèi)似方法合成白色粉末2b～2k，實(shí)驗(yàn)結(jié)果見(jiàn)表1。

(2)2l～2p的合成(以2l為例)

在反應(yīng)瓶中加入對(duì)羥基苯甲酸(Ⅰl) 0.5 g(3.6 mmol)的丙酮(15 mL)溶液，無(wú)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(yīng)(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(guò)濾，濾餅用無(wú)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(yīng)2 h。倒入水(200 mL)中，用10%鹽酸調(diào)至pH 3(溶液中出現(xiàn)大量白色固體)，過(guò)濾，濾餅真空干燥得對(duì)芐氧基苯甲酸(Ⅰl′) 0.726 g,產(chǎn)率88%。

在反應(yīng)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(yīng)(TLC跟蹤)。過(guò)濾，濾液經(jīng)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(chǎn)率50%。

用類(lèi)似方法合成2m′～2p′ 。

在反應(yīng)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(yīng)8 h。過(guò)濾，濾液濃縮后經(jīng)制備薄層分離得白色粉末3-O-對(duì)羥基苯甲?；R墩果酸(2l)。

用類(lèi)似方法合成2m～2p,實(shí)驗(yàn)結(jié)果見(jiàn)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(wú)水K2CO34.5 g，攪拌下回流反應(yīng)(TLC跟蹤)。減壓蒸除溶劑，濃縮物經(jīng)硅膠柱層析(A=6 ∶1)分離得白色粉末Ⅱ。在反應(yīng)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(wú)水K2CO34.8 g，于80 ℃反應(yīng)(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(jī)層，減壓濃縮，濃縮物經(jīng)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(yīng)(TLC跟蹤)。用蒸餾水(2×10 mL)洗滌后經(jīng)制備薄層分離得白色粉末3a。

表 1 2～4的實(shí)驗(yàn)結(jié)果Table 1 The experimental results of 2～4

用類(lèi)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(shí)驗(yàn)結(jié)果見(jiàn)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(jié)果與討論

由于1的3-OH位阻較大，與芳香酸酯化時(shí)投料比例、底物結(jié)構(gòu)、反應(yīng)溶劑等條件對(duì)反應(yīng)收率有一定影響。(1)若按等比例投料，酯化產(chǎn)率較低，當(dāng)芳香酸的量增加一倍時(shí)，羧基與羥基接觸幾率加大，產(chǎn)物收率也明顯提高。(2)含有酚羥基的芳香酸酯化時(shí)，TLC檢測(cè)發(fā)現(xiàn)1始終未發(fā)生變化，卻出現(xiàn)含有芳香酸結(jié)構(gòu)的新點(diǎn)，這說(shuō)明在DCC/DMAP條件下不易與芳香酸發(fā)生酯化反應(yīng)，過(guò)量的芳香酸發(fā)生了分子間反應(yīng)。(3)在酚羥基保護(hù)過(guò)程中，首先選用了乙酸酐，但乙酰化保護(hù)的芳香酸與1反應(yīng)僅得3-O-乙?；R墩果酸。Deng[3]和曲峰等認(rèn)為采用羥基乙?；Ｗo(hù)糖基進(jìn)行糖苷化反應(yīng)時(shí)，在反應(yīng)過(guò)程中乙?；装l(fā)生轉(zhuǎn)移[4]。推測(cè)本實(shí)驗(yàn)中生成3-O-乙酰基齊墩果酸的原因可能是乙?；c酚羥基形成的酯不穩(wěn)定，在DCC/DMAP弱堿性反應(yīng)條件下易裂解，產(chǎn)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(hù)后產(chǎn)率提高，催化氫化脫保護(hù)也較容易且不會(huì)破壞酯鍵。文獻(xiàn)[5]報(bào)道先將芳香酸的羧基與甲醇在對(duì)甲基苯磺酸作用下形成甲酯，用芐基保護(hù)羥基，然后在氫氧化鉀的甲醇溶液中水解甲酯得芐基保護(hù)酚羥基的芳香酸，但該法酯化反應(yīng)需較長(zhǎng)時(shí)，且產(chǎn)率只有75%。本文直接用芳香酸(Ⅰl～Ⅰp)與過(guò)量氯化芐反應(yīng)，在氫氧化鉀的甲醇溶液中水解脫芐酯得芐基保護(hù)酚羥基的芳香酸(Ⅰl′～Ⅰp′, Scheme 2)，反應(yīng)時(shí)間縮短，產(chǎn)率提高到85%。

在1的28-CO2H改造過(guò)程中，(1)與1,2-二氯乙烷反應(yīng)時(shí)，首先以丙酮作為溶劑，由于丙酮沸點(diǎn)較低，反應(yīng)需要很長(zhǎng)時(shí)間，且反應(yīng)不完全；后改用DMF為溶劑，但DMF沸點(diǎn)較高，反應(yīng)后不易除去；1,2-二氯乙烷沸點(diǎn)是83.5 ℃，在回流狀態(tài)下對(duì)1有較好的溶解性，因此以1,2-二氯乙烷既作反應(yīng)物又作溶劑，不僅縮短了反應(yīng)時(shí)間，同時(shí)提高了產(chǎn)率。(2)哌嗪的另一個(gè)氮與芳香酸形成酰胺后，哌嗪上靠近酰胺的碳上的兩個(gè)氫發(fā)生裂分，且偶合常數(shù)非常大(J=180 Hz)。肖志會(huì)等[6]對(duì)大量的苯基哌嗪類(lèi)衍生物進(jìn)行NMR研究時(shí)，發(fā)現(xiàn)所有化合物都出現(xiàn)這種情況。本文也證實(shí)該現(xiàn)象，且認(rèn)為靠近酰胺的碳上的兩個(gè)氫由于在芳香酰基的共軛作用影響下發(fā)生化學(xué)不等價(jià)，導(dǎo)致出現(xiàn)偶合常數(shù)非常大的裂分。

本實(shí)驗(yàn)合成反應(yīng)條件溫和，產(chǎn)率較高，能夠得到較多類(lèi)型的齊墩果酸衍生物，為測(cè)試抗HIV活性和研究構(gòu)效關(guān)系提供了較為可靠的實(shí)驗(yàn)依據(jù)。

Scheme 2

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[2] Chaomei Ma, Norio Nakamura, Hirotsugu Miyashiro,etal. Inhibitory effects of constituents from cynomorium songaricum and related triterpene derivatives on HIV-1 protease[J].Chemical & Pharmaceutical Bulletin,1999,47(2):141-145.

[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(jī)化學(xué),2003,23(2):249-257.

[5] 段新方,張站斌,段新紅. 5,3′,4′-三羥基-6,7-二甲氧基黃酮的另法全合成[J].有機(jī)化學(xué),2003,23(4):353-355.

[6] 肖志會(huì),袁牧,黃建設(shè),等. 苯基哌嗪衍生物的NMR波譜研究[J].波譜學(xué)雜志,2004,21(3):365-369.