CN102276677A - 齐墩果烷型三萜皂苷及其制备方法与应用 - Google Patents
齐墩果烷型三萜皂苷及其制备方法与应用 Download PDFInfo
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Abstract
本发明属化学药物技术领域,涉及齐墩果烷型三萜皂苷及其制备方法与应用。本发明以齐墩果酸为母体,在其3位羟基和/或28位羧基上引入不同的糖单元制备结构式如下式的齐墩果烷型三萜皂苷。经检测,制得的齐墩果烷型三萜皂苷其水溶性得到了显著改善,且对胰脂肪酶显示出很好的抑制活性。本发明制得的齐墩果烷型三萜皂苷可以用于制备新的治疗肥胖症的药物。
Description
技术领域
本发明属化学药物技术领域,涉及齐墩果烷型三萜皂苷及其制备方法与应用。
背景技术
据统计,目前世界上肥胖症患者约有3亿,随着经济的发展,发病人群呈上升趋势。超重带来的并发症,Ⅱ型糖尿病、动脉粥样硬化、高脂血症、高血压、冠心病等已对人类的健康构成极大的威胁。肥胖症作为一种全身性内分泌代谢疾病,通常通过减少热能摄入和增加运动尚不能达到减肥的满意效果,而通过外科手术治疗风险又很大,不易为患者所接受。因此,药物治疗已成为肥胖症的首选治疗手段。
近年来,若干针对肥胖症的新作用靶点被发现和鉴定,从而促成了一些有治疗潜力的新药的研发。例如,瘦素(Leptin)及瘦素受体激动剂、瘦素增敏剂:蛋白质酪氨酸磷酸酯酶1B抑制剂(Protein tyrosine phosphatase 1B inhibitor)、睫状神经营养因子类似物、大麻素受体1拮抗剂、神经肽Y5受体拮抗剂、胰高血糖素样肽-1(Glucagon-like peptide-1)、β3-肾上腺素受体激动剂、甲状腺激素β受体激动剂、脂肪酶抑制剂、脂肪酸转运蛋白(fatty acid transport proteins,FATP)4抑制剂、单胺类神经递质再摄取抑制剂、过氧化物酶增殖体激活受体γ(peroxisomeproliferator activated receptor gamma,PPARγ)2受体激动剂等。
有关药理学研究表明,如无胰脂肪酶的参与,饮食中的脂肪不会直接从肠吸收。胰脂肪酶是一种关键的酶,它能将脂肪降解成脂肪酸从而被吸收。因此,抑制胰脂肪酶的活性是控制发胖的被认为是一种有效途径。目前已上市的减肥药奥利斯特(Orlistat),即是通过与胰脂肪酶的丝氨酸活性位点共价绑定来抑制胰脂肪酶活性从而达到治疗肥胖的目的。但是在后期的研究中发现此种减肥药具有明显的不良反应(如大便失禁等)。
现有技术以脂肪酶为靶标研究减肥的抑制剂很多,而关于齐墩果烷型皂苷对胰脂肪酶抑制活性的研究尚未见报道。
发明内容
本发明的目的是提供新的用于治疗肥胖症的药物,具体涉及齐墩果烷型三萜皂苷及其制备方法。
本发明的目的进一步目的是提供所述齐墩果烷型三萜皂苷在制备治疗肥胖症药物中的用途。
本发明以齐墩果酸为母体,在其3位羟基和/或28位羧基上引入不同的糖单元制备齐墩果烷型三萜皂苷。经检测,制得的齐墩果烷型三萜皂苷其水溶性得到了显著改善,且对胰脂肪酶显示出很好的抑制活性。本发明制得的齐墩果烷型三萜皂苷可以用于制备治疗肥胖症的药物。
本发明所述的齐墩果烷型三萜皂苷,其特征是它的结构式如下:
其中,
R1选自H,D-葡萄糖-(1→6)-D-葡萄糖基或L-鼠李糖-(1→4)-D-葡萄糖-(1→6)-D-葡萄糖基;
R2选自L-鼠李糖-(1→2)-D-木糖基,L-鼠李糖-(1→2)-L-阿拉伯糖基,L-鼠李糖-(1→2)-D-葡萄糖基,L-鼠李糖-(1→2)-D-半乳糖基,L-鼠李糖-(1→3)-D-葡萄糖基,L-鼠李糖-(1→3)-D-半乳糖基,L-鼠李糖-(1→3)-[L-鼠李糖-(2→3)]-D-葡萄糖基,L-鼠李糖-(1→3)-[L-鼠李糖-(2→3)1-4,6-苄叉基-D-半乳糖基,D-木糖-(1→3)-L-鼠李糖-(1→2)-D-木糖基,D-葡萄糖-(1→3)-L-鼠李糖-(1→2)-D-木糖基,D-葡萄糖-(1→4)-D-葡萄糖-(1→3)-L-鼠李糖-(1→2)-D-木糖基,L-鼠李糖-(1→3)-L-鼠李糖-(1→2)-D-木糖基,D-木糖-(1→3)-L-鼠李糖-(1→2)-L-阿拉伯糖基,D-葡萄糖-(1→3)-L-鼠李糖-(1→2)-L-阿拉伯糖基,D-葡萄糖-(1→4)-D-葡萄糖-(1→3)-L-鼠李糖-(1→2)-L-阿拉伯糖基,D-葡萄糖-(1→4)-D-木糖-(1→3)-L-鼠李糖-(1→2)-L-阿拉伯糖基或D-葡萄糖-(1→4)-D-葡萄糖-(1→3)-L-鼠李糖-(1→2)-[D-葡萄糖-(1→4)]-L-阿拉伯糖基。
优选的,其中所述的R1选自H,β-D-葡萄糖-(1→6)-β-D-葡萄糖基或α-L-鼠李糖-(1→4)-β-D-葡萄糖-(1→6)-β-D-葡萄糖基;
R2选自α-L-鼠李糖-(1→2)-β-D-木糖基,α-L-鼠李糖-(1→2)-α-L-阿拉伯糖基,β-L-鼠李糖-(1→2)-α-L-阿拉伯糖基,α-L-鼠李糖-(1→2)-β-L-阿拉伯糖基,α-L-鼠李糖-(1→2)-β-D-葡萄糖基,α-L-鼠李糖-(1→2)-β-D-半乳糖基,α-L-鼠李糖-(1→3)-β-D-葡萄糖基,α-L-鼠李糖-(1→3)-β-D-半乳糖基,α-L-鼠李糖-(1→3)-[α-L-鼠李糖-(2→3)]-β-D-葡萄糖基,α-L-鼠李糖-(1→3)-[α-L-鼠李糖-(2→3)]-4,6-苄叉基-β-D-半乳糖基,β-D-木糖-(1→3)-α-L-鼠李糖-(1→2)-β-D-木糖基,β-D-葡萄糖-(1→3)-α-L-鼠李糖-(1→2)-β-D-木糖基,β-D-葡萄糖-(1→4)-β-D-葡萄糖-(1→3)-α-L-鼠李糖-(1→2)-β-D-木糖基,α-L-鼠李糖-(1→3)-α-L-鼠李糖-(1→2)-β-D-木糖基,β-D-木糖-(1→3)-α-L-鼠李糖-(1→2)-α-L-阿拉伯糖基,β-D-葡萄糖-(1→3)-α-L-鼠李糖-(1→2)-α-L-阿拉伯糖基,β-D-葡萄糖-(1→4)-β-D-葡萄糖-(1→3)-α-L-鼠李糖-(1→2)-α-L-阿拉伯糖基,β-D-葡萄糖-(1→4)-β-D-木糖-(1→3)-α-L-鼠李糖-(1→2)-α-L-阿拉伯糖基或β-D-葡萄糖-(1→4)-β-D-葡萄糖-(1→3)-α-L-鼠李糖-(1→2)-[β-D-葡萄糖-(1→4)]-α-L-阿拉伯糖基。
本发明中,所述的R1和R2中的糖基为吡喃或呋喃型。
本发明中,优选的化合物为下述化合物中的任一种:
化合物1,其R1=β-D-葡萄糖-(1→6)-O-β-D-葡萄糖基,R2=β-D-木糖-(1→3)-O-α-L-鼠李糖-(1→2)-O-β-D-木糖基;
化合物2,其R1=β-D-葡萄糖-(1→6)-O-β-D-葡萄糖基,R2=β-D-葡萄糖-(1→3)-O-α-L-鼠李糖-(1→2)-O-β-D-木糖基;
化合物3,其R1=β-D-葡萄糖-(1→6)-O-β-D-葡萄糖基,R2=β-D-葡萄糖-(1→4)-O-β-D-葡萄糖-(1→3)-O-α-L-鼠李糖-(1→2)-O-β-D-木糖基;
化合物4,其R1=H,R2=β-D-葡萄糖-(1→4)-O-β-D-木糖-(1→3)-O-α-L-鼠李糖-(1→2)-O-β-D-木糖基;
化合物5,其R1=H,R2=β-D-木糖-(1→3)-O-α-L-鼠李糖-(1→2)-O-α-L-阿拉伯糖基;
化合物6,其R1=H,R2=β-D-葡萄糖-(1→3)-O-α-L-鼠李糖-(1→2)-O-α-L-阿拉伯糖基;
化合物7,其R1=H,R2=β-D-葡萄糖-(1→4)-O-β-D-葡萄糖-(1→3)-O-α-L-鼠李糖-(1→2)-O-α-L-阿拉伯糖基;
化合物8,其R1=H,R2=β-D-葡萄糖-(1→4)-O-β-D-葡萄糖-(1→3)-O-α-L-鼠李糖-(1→2)-[β-D-葡萄糖-(1→4)]-O-α-L-阿拉伯糖基;
化合物9,其R1=H,R2=β-D-木糖-(1→3)-O-α-L-鼠李糖-(1→2)-O-β-D-木糖基;
化合物10,其R1=H,R2=β-D-葡萄糖-(1→3)-O-α-L-鼠李糖-(1→2)-O-β-D-木糖基;
化合物11,其R1=H,R2=α-L-鼠李糖-(1→3)-O-α-L-鼠李糖-(1→2)-O-β-D-木糖基;
化合物12,其R1=H,R2=β-D-葡萄糖-(1→4)-O-β-D-葡萄糖-(1→3)-O-α-L-鼠李糖-(1→2)-O-α-L-阿拉伯糖基;
化合物13,其R1=H,R2=α-L-鼠李糖-(1→2)-O-α-L-阿拉伯糖基;化合物14的R1=H,R2=α-L-鼠李糖-(1→2)-O-β-D-木糖基;
化合物15,其R1=H,R2=α-L-鼠李糖-(1→2)-O-β-D-葡萄糖基;
化合物16的R1=H,R2=α-L-鼠李糖-(1→2)-O-β-D-半乳糖基;
化合物17,其R1=H,R2=β-L-鼠李糖-(1→2)-O-α-L-阿拉伯糖基;
化合物18,其R1=H,R2=α-L-鼠李糖-(1→2)-O-β-L-阿拉伯糖基;
化合物19,其R1=H,R2=2,3--α-L-鼠李糖-O-β-D-葡萄糖基;
化合物20,其R1=H,R2=α-L-鼠李糖-(1→3)-O-β-D-葡萄糖基;
化合物21,其R1=H,R2=2,3-二-α-L-鼠李糖-4,6-苄叉基-O-β-D-半乳糖基;
化合物22,其R1=H,R2=α-L-鼠李糖-(1→3)-O-β-D-半乳糖基;
化合物23,其R1=α-L-鼠李糖-(1→4)-O-β-D-葡萄糖-(1→6)-O-β-D-葡萄糖基,R2=α-L-鼠李糖-(1→2)-O-β-D-木糖基。
本发明将上述的齐墩果烷型三萜皂苷化合物进行胰脂肪酶的抑制活性测定,将三油酸脂(80mg),卵磷脂(10mg)和牛磺胆酸(5mg)悬浮于含有0.1M NaCl的0.1M TES生物缓冲液中超声波处理5分钟,然后将胰脂肪酶(50μL)分别与上述齐墩果烷型三萜皂苷(100μL)(以Orlistat为阳性对照,DMSO为空白对照)加入到超声处理过的底物中,在约37℃温度下培养30分钟;培养过的混合物加入到含有2%(v/v)甲醇的3mL氯仿和正庚烷(v∶v,1∶1)的混合溶液中,水平振荡10分钟后,离心10分钟,吸除上层水相,下层的有机相中加入1mL铜试剂,振荡10分钟,离心10分钟,取出0.5mL 0.1%(w/v)浴铜灵,在480nm处测量其吸收值。
结果显示,与阳性对照Orlistat比较,本发明的齐墩果烷型三萜皂苷化合物,对胰脂肪酶表现出了很好的抑制活性(如图1所示),并且水溶性好,本发明制备齐墩果烷型三萜皂苷化合物简单方便,所述的化合物能用于制备治疗肥胖症的药物。
为了便于理解,以下将通过具体的附图和实施例对本发明的齐墩果烷型三萜皂苷及其用途进行详细地描述。需要特别指出的是,具体实例和附图仅是为了说明,显然本领域的普通技术人员可以根据本文说明,在本发明的范围内对本发明做出各种各样的修正和改变,这些修正和改变也纳入本发明的范围内。
附图说明
图1是本发明的齐墩果烷型三萜皂苷化合物对胰脂肪酶的抑制活性。
具体实施方式
实施例1,按下式制备齐墩果烷型三萜皂苷4、5、6:
其中:
R1=2,3,4,6-四-苯甲酰基-β-D-葡萄糖-(1→4)-2,3-二-苯甲酰基-β-D-木糖-(1→3)-2,4-二-乙酰基-α-L-鼠李糖-(1→2)-3,4-异丙叉基-α-L-阿拉伯糖基,
R2=2,3,4-三-苯甲酰基-β-D-木糖-(1→3)-2,4-二-乙酰基-α-L-鼠李糖-(1→2)-3,4-异丙叉基-α-L-阿拉伯糖基,
R3=2,3,4,6-四-苯甲酰基-β-D-葡萄糖-(1→3)-2,4-二-乙酰基-α-L-鼠李糖-(1→2)-(1→2)-3,4-异丙叉基-α-L-阿拉伯糖基,
R4=2,3,4,6-四-苯甲酰基-β-D-葡萄糖-(1→4)-2,3-二-苯甲酰基-β-D-木糖-(1→3)-2,4-二-乙酰基-α-L-鼠李糖-(1→2)-α-L-阿拉伯糖基,
R5=2,3,4-三-苯甲酰基-β-D-木糖-(1→3)-2,4-二-乙酰基-α-L-鼠李糖-(1→2)-α-L-阿拉伯糖基,
R6=2,3,4,6-四-苯甲酰基-β-D-葡萄糖-(1→3)-2,4-二-乙酰基-α-L-鼠李糖-(1→2)-(1→2)-α-L-阿拉伯糖基,
R7=β-D-葡萄糖-(1→4)-β-D-木糖-(1→3)-α-L-鼠李糖-(1→2)-α-L-阿拉伯糖基,
R8=β-D-木糖-(1→3)-α-L-鼠李糖-(1→2)-α-L-阿拉伯糖基,
R9=β-D-葡萄糖-(1→3)-α-L-鼠李糖-(1→2)-α-L-阿拉伯糖基,
中间体30、31、32的合成:
将2-甲基-5叔丁基苯硫苷28(40mg,0.112mmol)和分子筛溶于二氯甲烷(5mL)中,氩气保护下室温搅拌反应30分钟,冷却至-78℃,滴加TMSOTf(0.2个当量),10分钟后分别加入三氯乙酰亚胺酯25、26、27(均为2.1个当量),保持在-78℃温度下反应30分钟,然后升至-10℃,依次添加化合物29(79mg,0.112mmol)和NIS(50mg,0.112mmol),反应完毕后,加入三乙胺终止反应,过滤除去分子筛,减压蒸除溶剂后,残渣经硅胶柱层析精制分别得白色泡沫状固体30、31、32。
所述中间体30:两步收率73%.[α]D 22+12.0°(c 1.10,CHCl3);IR(KBr)νmax 2934,1731,1455,1369,1260,1097,1058,1027,707cm-1;1H NMR(CDCl3,600MHz):δ7.27-7.98(m,35H,Ph-H),5.82(t,J=9.9Hz,1H,H-3″″),5.63(t,J=7.1Hz,1H,H-3′),5.47(dd,J=9.9,7.7Hz,1H,H-2″″),5.41(t,J=9.9Hz,1H,H-4″″),5.29(t,J=3.6Hz,1H,H-12),5.27(dd,J=3.3,1.7Hz,1H,H-2″),5.25(d,J=1.7Hz,1H,H-1″),5.13(dd,J=7.1,5.5Hz,1H,H-2′),5.11(d,J=12.1Hz,1H,PhCHH),5.07(d,J=12.1Hz,1H,PhCHH),5.02(t,J=9.9Hz,1H,H-4″),4.97(d,J=7.7Hz,1H,H-1″″),4.67(d,J=5.5Hz,1H,H-1′),4.27(d,J=7.7Hz,1H,H-1″′),4.20(dd,J=12.1,2.8Hz,1H,H-5″′-1),4.17(m,1H,H-4″′),4.09-4.13(m,2H,H-3″′,H-6″″-1),4.08(dd,J=9.9,3.3Hz,1H,H-6″),4.02-4.06(m,2H,H-4′,H-5″″),3.96-4.01(m,3H,H-5′-1,H-5″,H-6″″-2),3.68-3.72(m,2H,H-2″′,H-5′-2),3.36(dd,J=12.7,7.1Hz,1H,H-5″′-2),3.02(dd,J=12.1,4.4Hz,1H,H-3),2.89(dd,J=13.7,4.4Hz,1H,H-18),2.04,2.01(s each,3H each,Ac×2),1.49,1.29(s each,3H each,O-(CH3)2-O),1.10(d,J=6.0Hz,3H,H-6″),1.13,0.92,0.90,0.87,0.86,0.75,0.60(s each,3H each,CH3×7);13C NMR(CDCl3,150MHz):δ177.7(C-28),170.6,166.1,165.9,165.5,165.3,165.1,143.9(C-13),136.6,133.6,133.5,133.4,133.3,129.9,129.8,129.7,128.6,128.5,128.2,123.2(C-12),110.5((CH3)2 C),103.5(C-1″′),102.0(C-1′),101.8(C-1″″),95.0(C-1″),89.1(C-3),79.0,73.1,72.1,71.1,69.4,66.6,66.1,63.1,60.6,56.0,47.8,47.0,46.1,42.0,41.6,39.3,38.9,36.9,35.6,33.3,32.8,32.5,30.9,29.9,28.2,27.9,26.3,26.1,23.9,23.3,21.3,20.6,18.4,17.6,17.1,16.6,15.6,14.4;HRMALMS:Calcd for[M+Na+]C108H122O28Na:1889.8059;found:m/z 1889.8015。
所述中间体31:两步收率73%.[α]D 22+3.68(c 2.88,CHCl3);Mp:137-139℃;IR(KBr)νmax2939,1719,1448,1255,1096,705cm-1;1H NMR(CDCl3,600MHz):δ7.25-8.03(m,20H,Ph-H),5.72(t-like,J=7.3,6.9Hz,1H,H-3′),5.35(dd,J=3.2,1.9Hz,1H,H-2″),5.31(d,J=1.9Hz,1H,H-1″),5.26-5.29(m,3H,H-12,H-2′,H-4′),5.11(d,J=12.9Hz,1H,PhCHH),5.08(d,J=12.7Hz,1H,PhCHH),5.07(t,J=10.1Hz,1H,H-4″),4.86(d,J=5.0Hz,1H,H-1′),4.36(dd,J=12.4,4.1Hz,1H,H-5′-1),4.31(d,J=7.3Hz,1H,H-1″′),4.21(dd,J=10.1,3.7Hz,1H,H-3″),4.15-4.19(m,2H,H-4″′,H-5″′-1),4.10-4.14(m,2H,H-3″′,H-5″′-2),4.01(dq,J=9.2,6.0Hz,1H,H-5″),3.72(m,1H,H-2″′),3.65(dd,J=12.4,6.4Hz,1H,H-5′-2),3.05(dd,J=11.9,4.6Hz,1H,H-3),2.91(dd,J=13.4,4.1Hz,1H,H-18),2.09,2.04(s each,3H each,Ac×2),1.57,1.31(s each,3H each,O-(CH3)2-O),1.12(d,J=6.4Hz,3H,H-6″),1.09,0.99,0.92,0.89,0.88,0.80,0.60(seach,3H each,CH3×7);13C NMR(CDCl3,150MHz):δ177.5(C-28),170.5,169.7,165.6,165.5,143.7(C-13),136.5,133.5,130.0,128.5,122.6(C-12),110.4((CH3)2 C),103.5(C-1″′),101.6(C-1′),94.9(C-1″),89.1(C-3),76.1,75.8,73.4,71.7,70.5,66.0,62.8,61.3,60.9,55.9,47.7,46.8,46.3,41.8,39.4,36.8,30.8,28.2,27.8,26.2,23.7,20.6,17.5,16.5,15.5,13.8;HRMALMS:Calcd for[M+Na+]C81H100O20Na:1415.6721;found:m/z 1415.6700。
所述中间体32:两步收率78%.[α]D 22+36.4°(c 2.88,CHCl3);Mp:132-134℃;IR(KBr)νmax2945,1731,1599,1451,1369,1256,1093,1069,1023,707cm-1;1H NMR(CDCl3,600MHz):δ7.27-8.04(m,25H,Ph-H),5.89(t-like,J=10.1,9.6Hz,1H,H-3″′),5.66(t-like,J=10.1,9.7Hz,1H,H-4″′),5.48(dd,J=10.1,7.8Hz,1H,H-2″′),5.34(dd,J=3.2,1.9Hz,1H,H-2″),5.30(s,1H,H-1″),5.29(t,J=3.2Hz,1H,H-12),5.10(d,J=12.9Hz,1H,PhCHH),5.07(d,J=12.8Hz,1H,PhCHH),5.01(t-like,J=10.1,9.6Hz,1H,H-4″),4.87(d,J=7.8Hz,1H,H-1″′),4.55(dd,J=12.4,3.7Hz,1H,H-6″′-1),4.50(dd,J=12.4,4.6Hz,1H,H-6″′-2),4.12-4.18(m,3H,H-1′,H-4′,H-3″),4.08-4.11(m,2H,H-3′,H-5″′),4.05(m,1H,H-5′-1),3.94(dq,J=9.6,5.9Hz,1H,H-5″),3.66-3.69(m,2H,H-2′,H-5′-2),2.97(dd,J=11.5,4.1Hz,1H,H-3),2.91(dd,J=13.4,4.1Hz,1H,H-18),2.09,2.04(s each,3H each,Ac×2),1.58,1.31(s each,3H each,O-(CH3)2-O),1.05(d,J=6.4Hz,3H,H-6″),1.14,0.98,0.93,0.91,0.88,0.76,0.62(s each,3H each,CH3×7);13C NMR(CDCl3,150MHz):δ177.6(C-28),170.4,169.4,166.0,164.8,143.8(C-13),136.6,133.1,130.0,129.3,128.5,128.4,122.6(C-12),110.3((CH3)2 C),103.4(C-1′),102.0(C-1″′),94.6(C-1″),88.9(C-3),78.1,75.6,74.3,74.0,73.5,72.0,69.6,66.0,63.1,60.5,55.9,53.5,46.9,46.0,41.5,41.3,39.4,39.2,36.8,33.2,27.8,26.2,26.0,23.8,21.1,17.4,16.5,15.4;HRMALMS:Calcd for[M+Na+]C89H106O22Na:1549.7084;found:m/z 1549.7068。
中间体33、34、35的合成:
分别将上述中间体30、31、32(各0.054mmol)溶于二氯甲烷和甲醇(V∶V=1∶2,5mL)的混合溶剂中,加入对甲苯磺酸(0.054mmol),室温搅拌反应。反应完毕后,加入三乙胺终止反应,减压蒸除溶剂后,残渣经硅胶柱层析精制分别得白色泡沫状固体33、34、35。
所述中间体33:收率90%;[α]D 22-0.6°(c 0.85,CHCl3);IR(KBr)νmax 3451,2922,1735,1447,1256,1093,1062,1023,711cm-1;1H NMR(CDCl3,600MHz):δ7.26-7.94(m,35H,Ph-H),5.82(t,J=9.9Hz,1H,H-3″″),5.61(t-like,J=7.7,7.1Hz,1H,H-3″′),5.47(dd,J=9.9,7.7Hz,1H,H-2″″),5.41(t,J=9.4Hz,1H,H-4″″),5.28(t-like,J=3.8,3.3Hz,1H,H-12),5.18(dd,J=3.4,1.1Hz,1H,H-2″),5.14(dd,J=7.7,5.5Hz,1H,H-2″′),5.10(d,J=12.6Hz,1H,PhCHH),5.06(d,J=12.7Hz,1H,PhCHH),5.01(t,J=9.9Hz,1H,H-4″),4.97(d,J=7.7Hz,1H,H-1″″),4.93(d,J=1.7Hz,1H,H-1″),4.74(d,J=5.5Hz,1H,H-1″′),4.70(d,J=2.8Hz,1H,H-1′),4.22(dd,J=11.6,1.6Hz,1H,H-6″″-1),4.03-4.08(m,2H,H-4″′,H-5″″),3.96-4.02(m,3H,H-3″,H-5″′-1,H-6″″-2),3.82-3.86(m,3H,H-2′,H-3′,H-4′),3.79(dq,J=9.9,6.6Hz,1H,H-5″),3.70(dd,J=11.5,8.8Hz,1H,H-5′-1),3.70(dd,J=11.5,4.9Hz,1H,H-5′-2),3.40(dd,J=12.1,7.7Hz,1H,H-5″′-2),3.08(dd,J=11.5,4.4Hz,1H,H-3),2.90(dd,J=13.7,3.8Hz,1H,H-18),2.04,2.01(seach,3H each,Ac×2),1.08(d,J=6.1Hz,3H,H-6″),1.10,0.91,0.90,0.89,0.87,0.76,0.59(seach,3H each,CH3×7);13C NMR(CDCl3,150MHz):δ177.4(C-28),170.4,169.6,165.9,165.8,165.7,165.1,165.0,164.8,143.7(C-13),136.4,133.4,133.2,133.0,129.7,129.6,129.5,129.4,129.2,128.9,128.5,128.3,127.9,127.8,122.4(C-12),101.6(C-1′),101.5(C-1″″),101.4(C-1″′),98.0(C-1″),90.4(C-3),75.7,75.3,72.9,72.3,71.8,71.6,70.7,70.5,70.0,69.4,67.1,65.9,62.9,61.9,60.1,55.4,47.6,46.7,45.9,41.7,41.3,39.2,39.0,38.4,36.7,33.8,33.1,32.6,30.7,29.7,28.1,27.6,25.8,25.6,23.6,23.4,23.0,20.9,20.4,18.2,17.3,16.8,16.4,15.3;HRMALMS:Calcd for[M+Na+]C105H118O28Na:1849.7706;found:m/z 1849.7702。
所述中间体34:收率95%;[α]D 23-17.6°(c 3.65,CHCl3);Mp:141-143℃;IR(KBr)νmax2945,1731,1451,1373,1260,1097,707cm-1;1H NMR(CDCl3,600MHz):δ7.27-8.04(m,20H,Ph-H),5.70(t-like,J=7.1,6.6Hz,1H,H-3″′),5.27-5.30(m,4H,H-12,H-3″,H-2″′,H-4″′),5.10(d,J=12.1Hz,1H,PhCHH),5.08(s,1H,H-2″),5.06(d,J=12.7Hz,1H,PhCHH),5.01(s,1H,H-1″),4.97(d,J=5.0Hz,1H,H-1″′),4.74(br s,1H,H-1′),4.35(dd,J=12.7,3.8Hz,1H,H-5″′-1),4.10(dd,J=9.9,3.8Hz,1H,H-5′-1),3.88-3.92(m,2H,H-3′,H-4′),3.83-3.87(m,2H,H-2′,H-5″),3.71-3.75(m,2H,H-4″,H-5′-2),3.61(dd,J=11.5,4.4Hz,1H,H-5″′-2),3.10(dd,J=11.5,4.4Hz,1H,H-3),2.91(dd,J=13.7,3.8Hz,1H,H-18),2.09,1.80(s each,3H each,Ac×2),1.12(d,J=6.6Hz,3H,H-6″),1.11,0.94,0.92,0.89,0.88,0.78,0.60(s each,3H each,CH3×7);13C NMR(CDCl3,150MHz):δ=177.5(C-28),170.5,169.8,165.6,165.5,165.0,143.8(C-13),136.5,133.5,133.4,130.0,129.9,128.5,128.4,128.1,122.5(C-12),101.7(C-1′),101.3(C-1″′),98.0(C-1″),90.5(C-3),75.8,75.6,71.9,71.8,70.2,70.1,69.9,68.9,67.3,66.0,64.9,61.1,60.4,55.5,47.7,46.8,46.0,41.8,41.5,39.4,39.2,38.6,36.8,33.9,33.2,32.7,32.5,30.8,29.8,28.2,27.7,25.9,25.8,23.7,23.5,23.1,21.1,20.6,18.3,17.5,16.9,16.5,15.4;HRMALMS:Calcd for[M+Na+]C78H96O20Na:1375.6371;found:m/z 1375.6387。
所述中间体35:收率94%;[α]D 23+21.8°(c 3.25,CHCl3);Mp:133-135℃;IR(KBr)νmax2934,1727,1451,1377,1260,1085,704cm-1;1H NMR(CDCl3,600MHz):δ7.28-8.05(m,25H,Ph-H),5.89(t-like,J=9.9,9.3Hz,1H,H-3″′),5.72(t-like,J=9.8,9.4Hz,1H,H-4″′),5.52(dd,J=9.9,7.7Hz,1H,H-2″′),5.31(br s,1H,H-3″),5.30(t,J=3.8Hz,1H,H-12),5.12(d,J=12.7Hz,1H,PhCHH),5.08(d,J=12.7Hz,1H,PhCHH),5.05(d,J=3.0Hz,1H,H-1′),5.02(s,1H,H-2″),4.99(d,J=7.7Hz,1H,H-1″′),4.69(d,J=1.7Hz,1H,H-1″),4.62(dd,J=12.1,1.7Hz,1H,H-6″′-1),4.49(dd,J=12.7,2.8Hz,1H,H-6″′-2),4.15(m,1H,H-5″′),4.12(dd,J=9.9,3.8Hz,1H,H-3′),3.92(m,1H,H-4′),3.82-3.85(m,3H,H-4″,H-5″,H-5′-1),3.77(t-like,J=3.6,3.2Hz,1H,H-2′),3.61(dd,J=12.1,4.4Hz,1H,H-5′-2),3.10(dd,J=11.5,3.8Hz,1H,H-3),2.91(dd,J=14.3,4.4Hz,1H,H-18),2.06,2.05(s each,3H each,Ac×2),1.08(d,J=6.0Hz,3H,H-6″),1.12,0.94,0.93,0.91,0.89,0.79,0.61(s each,3H each,CH3×7);13C NMR(CDCl3,150MHz):δ177.5(C-28),170.4,169.5,165.9,165.1,164.8,143.8(C-13),136.5,133.5,133.4,133.2,129.9,129.8,128.6,128.5,128.4,128.3,128.1,128.0,122.5(C-12),101.9(C-1″),101.7(C-1″′),98.0(C-1′),90.4(C-3),76.2,75.9,72.9,72.1,72.0,71.7,70.4,69.3,67.0,66.0,65.4,62.7,55.5,47.7,46.8,46.0,41.8,41.5,39.4,39.2,38.6,36.8,33.9,33.2,32.7,32.5,30.8,29.8,28.2,27.7,25.9,25.8,23.7,23.5,23.1,21.0,20.2,18.3,17.4,16.9,16.5,15.4;HRMALMS:Calcd for[M+Na+]C86H102O22Na:1509.6772;found:m/z 1509.6755。
合成化合物4、5、6:
将上述中间体33、34、35(各50mg)分别溶于二氯甲烷和甲醇(V∶V=1∶1,8mL)的混合溶剂中,加入10%Pd-C(30mg)和2滴醋酸,1个大气压氢气作用下反应4小时。反应完毕后,过滤除去Pd-C,减压浓缩得到白色固体,直接投入到下一步反应中。
将上一步所得白色固体分别溶于二氯甲烷和甲醇(V∶V=1∶2,8mL)的混合溶剂中,加入甲醇钠(40mg),室温反应8小时后,加入阳离子交换树脂终止反应,过滤,减压浓缩,所得残渣经硅胶柱层析精制分别得白色泡沫状固体4、5、6。
所述化合物4:[α]D 25-17.9(c 0.80,CH3OH);IR(KBr)νmax 3412,2945,1693,1499,1071cm-1;1H NMR(C5D5N,500MHz):δ6.19(s,1H,H-1″),5.49(t,J=3.6Hz,1H,H-12),5.23(d,J=7.0Hz,1H,H-1″′),5.01(d,J=7.9Hz,1H,H-1″″),4.87(br s,1H,H-2″),4.85(d,J=5.0Hz,1H,H-1′),4.67(dd,J=9.5,3.0Hz,1H,H-3″),4.60(dq,J=9.3,5.5Hz,1H,H-5″),4.53-4.56(m,2H,H-4″,H-6″″-1),4.47(t,J=9.5Hz,1H,H-3″′),4.37(dd,J=12.5,2.7Hz,1H,H-6″″-2),4.24-4.33(m,5H,H-3′,H-4′,H-5′-1,H-4″′,H-3″″),4.18(t,J=9.6Hz,1H,H-4″″),3.97-4.06(m,4H,H-2″′,H-2″″,H-5″′-1,H-5″″),3.82(dd,J=12.1,2.3Hz,1H,H-5″′-2),3.63(m,1H,H-5′-2),3.28-3.31(m,2H,H-3,H-18),1.55(d,J=6.0Hz,3H,H-6″),1.29,1.26,1.10,0.99,0.96,0.94,0.82(s each,3H each,CH3×7);13C NMR(C5D5N,125MHz):δ180.2(C-28),145.0(C-13),122.7(C-12),106.8(C-1″′),104.9(C-1′),103.5(C-1″″),101.4(C-1″),88.7(C-3),82.9(C-3″),78.7,78.1,77.7,76.1,75.5,75.2,74.2,73.9,72.7,71.7,71.6,69.6,64.7,64.3,62.6,56.6,48.0,46.6,46.4,42.1,41.9,39.7,39.5,36.9,34.2,33.2,33.1,32.0,30.9,30.7,29.8,29.7,29.5,28.2,28.1,26.5,26.1,23.7,23.6,22.8,18.4,18.3,17.3,17.0,15.4,14.1;ESI-HRMS:m/z calcd for C52H83O20[M-H+]:1027.5478;found:1027.5460。
所述化合物5:两步收率74%;[α]D 25-4.30(c 0.80,CH3OH);Mp:219-221℃;IR(KBr)νmax3397,2941,1688,1455,1385,1046cm-1;1H NMR(C5D5N,600MHz):δ6.30(br s,1H,H-1″),5.49(t,J=3.6Hz,1H,H-12),5.39(d,J=7.4Hz,1H,H-1″′),4.95(br s,1H,H-2″),4.89(d,J=5.9Hz,1H,H-1′),4.77(dd,J=9.6,3.2Hz,1H,H-3″),4.67(dq,J=9.6,5.9Hz,1H,H-5″),4.62(t-like,J=6.9,6.4Hz,1H,H-2′),4.52(t-like,J=9.7,9.1Hz,1H,H-4″),4.32-4.35(m,2H,H-4′,H-5″′-1),4.26-4.30(m,2H,H-3′,H-5′-1),4.23(m,1H,H-4″′),4.19(t-like,J=8.7,8.3Hz,1H,H-3″′),4.11(t,J=8.2Hz,1H,H-2″′),3.84(d,J=10.9Hz,1H,H-5′-2),3.72(t,J=11.0Hz,1H,H-5″′-2),3.30-3.33(m,3H,H-3,H-18),1.57(d,J=6.0Hz,3H,H-6″),1.34,1.33,1.16,1.03,1.00,0.98,0.85(s each,3H each,CH3×7);13C NMR(C5D5N,150MHz):δ180.8(C-28),145.3(C-13),122.5(C-12),107.9(C-1″′),105.8(C-1′),101.9(C-1″),89.3(C-3),83.4(C-3″),78.9,76.1,75.9,73.5,72.5,71.6,70.2,67.9,66.1,56.5,48.6,47.2,47.0,42.7,42.5,40.3,40.1,39.4,37.6,34.8,33.8,33.7,31.5,30.5,28.8,28.7,27.2,26.7,24.3,18.9,17.9,17.7,16.1;ESI-HRMS:m/z calcd forC46H73O15[M-H+]:865.4949;found:865.4961。
所述化合物6:两步收率77%;[α]D 25-0.74(c 0.65,CH3OH);Mp:229-231℃;IR(KBr)νmax3393,2945,1692,1455,1389,1054cm-1;1H NMR(C5D5N,600MHz):δ6.19(br s,1H,H-1″),5.49(d,J=7.3Hz,1H,H-1″′),5.48(br s,1H,H-12),5.03(br s,1H,H-2″),4.86(d,J=6.0Hz,1H,H-1′),4.83(dd,J=9.0,3.2Hz,1H,H-3″),4.65(dq,J=9.6,5.9Hz,1H,H-5″),4.49-4.55(m,3H,H-2′,H-4″,H-6″′-1),4.37(dd,J=11.9,5.0Hz,1H,H-6″′-2),4.32(dd,J=10.1,3.8Hz,1H,H-5′-1),4.27-4.30(m,3H,H-3′,H-3″′,H-4″′),4.24(dd,J=7.8,3.7Hz,1H,H-4′),4.14(t,J=9.1,7.8Hz,1H,H-2″′),3.98(m,1H,H-5″′),3.83(dd,J=12.4,2.3Hz,1H,H-5′-2),3.29-3.33(m,3H,H-3,H-18),1.58(d,J=5.9Hz,3H,H-6″),1.35,1.33,1.15,1.03,0.99,0.98,0.85(s each,3H each,CH3×7);13C NMR(C5D5N,150MHz):δ180.8(C-28),145.1(C-13),123.8(C-12),107.0(C-1″′),105.7(C-1′),102.0(C-1″),89.1(C-3),83.5(C-3″),78.9,78.8,76.2,74.7,73.3,71.9,71.8,70.1,69.7,66.0,62.8,56.3,48.4,47.1,46.8,42.5,42.3,40.1,39.9,39.2,37.4,34.6,33.7,31.3,28.5,27.0,26.5,24.1,18.9,17.7,17.5,15.9;ESI-HRMS:m/z calcd for C47H75O16[M-H+]:895.5055;found:895.5072。
实施例2,按下式制备齐墩果烷型三萜皂苷9、10、11、12:
其中,
R1=2,3,4-三-苯甲酰基-β-D-木糖-(1→3)-2,4-二-乙酰基-α-L-鼠李糖-(1→2)-3,4-二-苯酰基-β-D-木糖基,
R2=2,3,4,6-四-苯甲酰基-β-D-葡萄糖-(1→3)-2,4-二-乙酰基-α-L-鼠李糖-(1→2)-3,4-二-苯酰基-β-D-木糖基,
R3=2,3,4-三-苯甲酰基-α-L-鼠李糖-(1→3)-2,4-二-乙酰基-α-L-鼠李糖-(1→2)-3,4-二-苯酰基-β-D-木糖基,
R4=2,3,4,6-四-苯甲酰基-β-D-葡萄糖-(1→4)-2,3,6-三-苯甲酰基-β-D-葡萄糖-(1→3)-2,4-二-乙酰基-α-L-鼠李糖-(1→2)-3,4-二-苯酰基-β-D-木糖基,
R5=β-D-木糖-(1→3)-α-L-鼠李糖-(1→2)-β-D-木糖基,
R6=β-D-葡萄糖-(1→3)-α-L-鼠李糖-(1→2)-β-D-木糖基,
R7=α-L-鼠李糖-(1→3)-α-L-鼠李糖-(1→2)-β-D-木糖基,
R8=β-D-葡萄糖-(1→4)-β-D-葡萄糖-(1→3)-α-L-鼠李糖-(1→2)-β-D-木糖基,
合成中间体39、40、41、42:
将2-甲基-5叔丁基苯硫苷28(40mg,0.112mmol)和分子筛溶于二氯甲烷(5mL)中,氩气保护下室温搅拌反应30分钟,冷却至-78℃,滴加TMSOTf(0.2个当量),10分钟后分别加入三氯乙酰亚胺酯26、27、36、37(均为2.1个当量)。保持在-78℃温度下反应30分钟,然后升至-10℃,依次添加化合物38(99mg,0.112mmol)和NIS(50mg,0.112mmol)。反应完毕后,加入三乙胺终止反应,过滤除去分子筛,减压蒸除溶剂后,残渣经硅胶柱层析精制分别得白色泡沫状固体39、40、41、42。
所述中间体39:收率67.5%;Mp:140-142℃;[α]D 25-28.1(c 2.04,CHCl3);IR(KBr)νmax2945,1731,1603,1451,1256,1093,711cm-1;1H NMR(CDCl3,600MHz):δ7.27-8.10(m,30H,Ph-H),5.59(t,J=7.1,6.6Hz,2H,H-3′,H-3″′),5.29(t,J=3.8Hz,1H,H-12),5.20-5.22(m,2H,H-2″,H-2″′),5.14-5.17(m,2H,H-4′,H-4″′),5.10(d,J=12.7Hz,1H,PhCHH),5.05(s,1H,H-1″),5.04(d,J=12.7Hz,1H,PhCHH),5.03(m,1H,H-4″),4.78(d,J=4.9Hz,1H,H-1′),4.60(d,J=5.0Hz,1H,H-1″′),4.37(dd,J=12.1,3.9Hz,1H,H-5′-1),4.11(dd,J=12.1,3.8Hz,1H,H-5″′-1),4.01-4.04(m,2H,H-3″,H-5″),3.97(t,J=5.5Hz,1H,H-2′),3.62(dd,J=12.1,6.6Hz,1H,H-5′-2),3.33(dd,J=12.1,6.6Hz,1H,H-5″′-2),3.15(dd,J=11.5,4.4Hz,1H,H-3),2.91(dd,J=13.2,4.4Hz,1H,H-18),1.92,1.77(s each,3H each,Ac×2),1.13(d,J=6.6Hz,3H,H-6″),1.12,0.95,0.92,0.90,0.89,0.74,0.60(s each,3H each,CH3×7);13C NMR(CDCl3,150MHz):δ177.6(C-28),169.9,169.5,165.8,165.6,165.5,165.4,165.2,143.8(C-13),136.5,133.5,133.4,129.9,129.8,128.6,128.5,128.4,122.6(C-12),103.1(C-1′),101.1(C-1″′),97.6(C-1″),89.4(C-3),75.9,74.1,71.4,71.2,70.3,69.5,69.1,67.2,66.0,60.9,55.7,47.7,46.8,46.0,41.8,41.5,39.4,39.2,38.8,36.8,33.9,33.2,32.8,32.5,30.8,28.1,27.7,26.0,25.9,23.7,23.5,23.1,20.9,20.6,18.3,17.5,16.9,16.4,15.5;HRMALMS:Calcd for[M+Na+]C92H104O22Na:1583.6952;found:m/z1583.6912。
所述中间体40:收率63.7%;Mp:140-142℃;[α]D 24+15.9(c 1.85,CHCl3);IR(KBr)νmax2945,1735,1451,1268,1093,707cm-1;1H NMR(CDCl3,600MHz):δ7.27-8.07(m,35H,Ph-H),5.62(t,J=9.3Hz,1H,H-3″′),5.58(t-like,J=7.7,7.2Hz,1H,H-3′),5.51(t-like,J=9.9,9.4Hz,1H,H-4″′),5.38(dd,J=9.9,8.3Hz,1H,H-2″′),5.29(t,J=3.8Hz,1H,H-12),5.11-5.24(m,2H,H-2″,H-4′),5.10(d,J=12.7Hz,1H,PhCHH),5.06(d,J=12.6Hz,1H,PhCHH),5.04(s,1H,H-1″),4.96(t,J=9.9Hz,1H,H-4″),4.66(d,J=5.5Hz,1H,H-1′),4.38(d,J=8.2Hz,1H,H-1″′),4.32-4.37(m,2H,H-5′-1,H-6″′-1),4.27(dd,J=12.1,3.3Hz,1H,H-6″′-2),3.93-3.98(m,2H,H-3″,H-5″),3.89(dd,J=7.1,5.5Hz,1H,H-2′),3.53(dd,J=12.1,7.7Hz,1H,H-5′-2),3.41(d,J=9.4Hz,1H,H-5″′),3.12(dd,J=11.6,4.4Hz,1H,H-3),2.91(dd,J=14.9,4.9Hz,1H,H-18),1.85,1.85(s each,3H each,Ac×2),1.05(d,J=6.1Hz,3H,H-6″),1.12,0.93,0.92,0.90,0.87,0.71,0.60(s each,3H each,CH3×7);13C NMR(CDCl3,150MHz):δ=177.7(C-28),170.1,169.7,166.2,166.1,165.7,165.6,164.9,164.8,143.9(C-13),136.6,133.6,133.5,133.4,133.3,133.2,130.0,129.9,129.8,128.7,128.6,128.5,122.7(C-12),103.6(C-1′),101.1(C-1″′),97.7(C-1″),89.2(C-3),76.5,75.4,72.9,72.0,71.9,70.2,70.0,69.0,67.1,66.1,62.6,55.9,47.8,47.0,46.1,41.9,41.6,39.5,39.3,38.9,36.9,34.1,33.3,32.9,32.6,30.9,29.9,28.1,27.8,26.2,26.1,23.8,23.6,23.2,20.8,20.3,18.4,17.5,17.1,16.4,15.6;HRMALMS:Calcd for[M+Na+]C100H110O24Na:1717.7242;found:m/z 1717.7279。
所述中间体41:收率70.2%;Mp:136-138℃;[α]D 24+36.9(c 2.10,CHCl3);IR(KBr)νmax2945,1727,1603,1451,1264,1093,707cm-1;1H NMR(CDCl3,600MHz):δ7.28-8.12(m,30H,Ph-H),5.57-5.62(m,3H,H-3′,H-3″′,H-4″),5.38(t-like,J=2.3,1.9Hz,1H,H-2″′),5.29(t,J=3.7Hz,1H,H-12),5.24(br s,1H,H-2″),5.13-5.19(m,2H,H-4′,H-4″),5.09(d,J=12.4Hz,1H,PhCHH),5.08(s,1H,H-1″),5.06(d,J=12.9Hz,1H,PhCHH),4.89(s,1H,H-1″′),4.81(d,J=4.6Hz,1H,H-1′),4.48(dd,J=12.4,4.1Hz,1H,H-5′-1),4.12-4.15(m,3H,H-3″,H-5″,H-5″′),4.00(t-like,J=6.0,5.0Hz,1H,H-2′),3.63(dd,J=11.9,6.4Hz,1H,H-5′-2),3.18(dd,J=11.9,4.6Hz,1H,H-3),2.90(dd,J=13.8,4.6Hz,1H,H-18),2.22,2.10(s each,3H each,Ac×2),1.23(d,J=5.9Hz,3H,H-6″),1.12,0.98,0.92,0.89,0.89,0.77,0.60(s each,3H each,CH3×7);13CNMR(CDCl3,150MHz):δ=177.6(C-28),170.4,170.0,165.8,165.9,165.8,165.4,143.8(C-13),136.5,133.7,133.4,133.1,129.9,128.8,128.5,128.1,122.6(C-12),102.9(C-1′),98.7(C-1″′),97.6(C-1″),89.5(C-3),74.7,73.8,72.5,71.6,71.0,69.5,67.5,67.2,66.0,60.8,55.7,47.7,46.8,46.0,41.8,41.5,39.4,39.3,38.8,36.8,33.9,33.2,32.7,30.8,28.1,27.7,26.1,26.0,23.7,23.1,21.0,20.9,18.3,17.7,17.4,16.9,16.5,15.5;HRMALMS:Calcd for[M+Na+]C93H106O22Na:1597.7089;found:m/z 1597.7068。
所述中间体42:收率66.2%;Mp:144-146℃;[α]D 24+26.2(c 1.92,CHCl3);IR(KBr)νmax2945,1731,1599,1451,1264,1085,707cm-1;1H NMR(CDCl3,600MHz):δ7.27-8.07(m,50H,Ph-H),5.65(t,J=9.4Hz,1H,H-3″′),5.51-5.54(m,2H,H-2″′,H-3′),5.40(t-like,J=9.9,3.3Hz,1H,H-3″″),5.27-5.31(m,2H,H-12,H-3″),5.25(dd,J=9.6,7.8Hz,1H,H-2″″),5.15(m,1H,H-4′),5.10(d,J=12.1Hz,1H,PhCHH),5.06(d,J=12.6Hz,1H,PhCHH),4.92-4.95(m,3H,H-1″,H-2″,H-4″),4.74(d,J=7.7Hz,1H,H-1″′),4.66(d,J=4.9Hz,1H,H-1′),4.34(dd,J=11.6,3.8Hz,1H,H-5′-1),4.28(dd,J=12.6,2.7Hz,1H,H-6″′-1),4.22(t,J=9.9Hz,1H,H-4″′),4.05(d,J=7.8Hz,1H,H-1″″),4.03(t,J=9.6Hz,1H,H-4″″),3.99(dd,J=12.1,2.8Hz,1H,H-6″″-1),3.89-3.92(m,1H,H-5″),3.85-3.87(m,1H,H-5″′),3.84(t,J=6.6Hz,1H,H-2′),3.67(m,1H,H-5″″),3.57(dd,J=12.1,5.5Hz,1H,H-6″″-2),3.51(dd,J=12.1,5.6Hz,1H,H-5′-2),3.12(dd,J=11.5,4.4Hz,1H,H-3),2.91(dd,J=13.7,3.8Hz,1H,H-18),2.71(t,J=10.5Hz,1H,H-6″′-2),1.74,1.74(s each,3H each,Ac×2),1.04(d,J=6.1Hz,3H,H-6″),1.12,0.92,0.90,0.89,0.86,0.67,0.59(s each,3H each,CH3×7);13C NMR(CDCl3,150MHz):δ=177.5(C-28),169.8,169.7,165.7,165.6,165.4,165.3,165.1,143.8(C-13),136.5,133.3,129.8,129.7,128.5,128.3,128.1,122.6(C-12),103.4(C-1′),100.9(C-1″′),100.5(C-1″″),97.9(C-1″),88.9(C-3),76.4,75.4,73.0,72.4,72.3,71.9,69.7,69.6,66.9,66.6,66.0,62.7,61.7,55.7,47.7,46.8,45.9,41.8,41.5,39.4,39.2,38.8,36.8,33.2,32.8,30.8,28.0,26.0,23.7,23.1,20.7,20.1,17.4,16.9,16.2,15.5;HRMALMS:Calcd for[M+Na+]C127H132O32Na:2191.8557;found:m/z 2191.8594。
合成化合物9、10、11、12:
将上述中间体39、40、41、42(各50mg)分别溶于二氯甲烷和甲醇(V∶V=1∶1,8mL)的混合溶剂中,加入10%Pd-C(30mg)和2滴醋酸,1个大气压氢气作用下反应4小时。反应完毕后,过滤除去Pd-C,减压浓缩得到白色固体,直接投入到下一步反应中。
将上一步所得白色固体分别溶于二氯甲烷和甲醇(V∶V=1∶2,8mL)的混合溶剂中,加入甲醇钠(40mg),室温反应8小时后,加入阳离子交换树脂终止反应,过滤,减压浓缩,所得残渣经硅胶柱层析精制分别得白色泡沫状固体9、10、11、12。
所述化合物9:两步收率78.3%;[α]D 25-3.82(c 0.50,CH3OH);IR(KBr)νmax 3412,2938,1696,1536,1455,1385,1046cm-1;1H NMR(C5D5N,600MHz):δ6.62(br s,1H,H-1″),5.50(brs,1H,H-12),5.44(d,J=7.8Hz,1H,H-1″′),5.06(br s,1H,H-2″),4.88(d,J=7.8Hz,1H,H-1′),4.83-4.87(m,2H,H-2′,H-5″),4.58(t,J=9.1Hz,1H,H-3′),4.36-4.39(m,2H,H-4′,H-4″′),4.30(t,J=8.8Hz,1H,H-4″),4.21-4.27(m,5H,H-3″′,H-4″,H-5′-1,H-5″′-1,H-5″′-2),4.14(dd,J=8.7,7.3Hz,1H,H-2″′),3.74-3.79(m,2H,H-3,H-5′-2),3.39(dd,J=11.5,4.1Hz,1H,H-18),1.69(d,J=5.9Hz,3H,H-6″),1.43,1.35,1.26,1.05,0.99,0.99,0.88(s each,3H each,CH3×7);13C NMR(C5D5N,150MHz):δ=176.9(C-28),145.8(C-13),123.8(C-12),108.3(C-1″′),106.9(C-1′),102.4(C-1″),89.4(C-3),83.8(C-3″),80.6,79.4,78.1,76.5,73.7,72.7,72.4,72.0,70.5,68.3,67.9,57.0,48.9,43.0,40.5,37.9,35.1,34.2,31.8,29.2,29.0,27.7,27.0,24.6,19.5,18.1,16.4;ESI-HRMS:m/z calcd for C46H73O15[M-H+]:865.4949;found:865.4980。
所述化合物10:两步收率78.3%;[α]D 25+3.67(c 0.45,CH3OH);IR(KBr)νmax 3381,2941,1696,1455,1042cm-1;1H NMR(C5D5N,600MHz):δ6.51(br s,1H,H-1″),5.53(d,J=7.3Hz,1H,H-1″′),5.48(br s,1H,H-12),5.09(br s,1H,H-2″),4.89(d,J=6.8Hz,1H,H-1′),4.80(m,1H,H-5″),4.56(t,J=9.1Hz,1H,H-3′),4.51(d,J=11.5Hz,1H,H-5′-1),4.41(m,1H,H-3″),4.28-4.35(m,3H,H-4′,H-4″′,H-6″′-1),4.13-4.22(m,5H,H-2′,H-3″′,H-4″,H-5′-2,H-6″′-2),4.00(br s,1H,H-2″′),3.72(m,1H,H-5″′),3.30-3.35(m,2H,H-3,H-18),1.67(d,J=5.5Hz,3H,H-6″),1.42,1.32,1.23,1.02,0.99,0.98,0.85(s each,3H each,CH3×7);13C NMR(C5D5N,150MHz):δ180.8(C-28),145.3(C-13),122.9(C-12),107.3(C-1″′),106.8(C-1′),102.1(C-1″),89.1(C-3),83.8(C-3″),79.9,79.1,79.0,77.8,76.4,73.5,72.1,71.9,70.3,67.5,62.9,56.6,48.5,47.2,42.6,42.5,40.2,40.1,39.4,37.5,33.8,31.4,28.8,28.7,27.4,26.7,24.3,19.1,19.0,17.9,17.8,16.1;ESI-HRMS:m/z calcd for C47H75O16[M-H+]:895.5055;found:895.5076。
所述化合物11:两步收率78.3%;[α]D 25-11.1(c 0.65,CH3OH);IR(KBr)νmax 3350,2922,1595,1544,1424,1042,704cm-1;1H NMR(C5D5N,600MHz):δ6.60(br s,1H,H-1″),6.11(br s,1H,H-1″′),5.47(br s,1H,H-12),4.99(br s,1H,H-2″),4.86(d,J=6.8Hz,1H,H-1′),4.78-4.84(m,3H,H-2″′,H-3″,H-5″′),4.74(dq,J=9.1,6.4Hz,1H,H-5″),4.67(dd,J=9.1,3.2Hz,1H,H-5′-1),4.49(t,J=9.6Hz,1H,H-4′),4.30-4.36(m,3H,H-3′,H-3″′,H-4″),4.27(dd,J=8.7,7.2Hz,1H,H-2′),4.19(m,1H,H-4′),3.74(t,J=11.0Hz,1H,H-5′-2),3.30-3.36(m,2H,H-3,H-18),1.69(d,J=6.4Hz,3H,H-6″′),1.62(d,J=6.4Hz,3H,H-6″),1.38,1.32,1.23,1.02,0.97,0.97,0.85(s each,3H each,CH3×7);13C NMR(C5D5N,150MHz):δ176.4(C-28),143.5(C-13),123.7(C-12),106.5(C-1′),104.7(C-1″′),101.9(C-1″),89.0(C-3),80.1(C-3″),80.0(C-3″′),78.7,74.7,73.1,72.8,72.6,72.4,70.0,68.5,56.6,49.3,42.5,40.1,39.9,37.4,33.7,31.3,30.3,28.7,26.5,24.2,19.0,17.6,15.9;ESI-HRMS:m/z calcd for C47H75O15[M-H+]:879.5106;found:879.5103。
所述化合物12:两步收率78.3%;[α]D 25-5.86(c 0.50,CH3OH);IR(KBr)νmax 3397,2945,1692,1459,1389,1042cm-1;1H NMR(C5D5N,600MHz):δ6.51(br s,1H,H-1″),5.49(d,J=7.3Hz,1H,H-1″′),5.47(br s,1H,H-12),5.05(br s,1H,H-2″),4.85(dd,J=9.6,3.5Hz,1H,H-3″),4.82(d,J=7.3Hz,1H,H-1′),4.79(dq,J=9.3,5.5Hz,1H,H-5″),4.54-4.58(m,3H,H-2′,H-4″,H-6″′-1),4.42(dd,J=12.1,5.2Hz,1H,H-6″″-1),4.33-4.37(m,2H,H-4″′,H-6″′-2),4.26-4.30(m,2H,H-3′,H-4′),4.13-4.22(m,5H,H-3″′,H-3″″,H-4″″,H-5′-1,H-6″″-2),4.10(t,J=8.3Hz,1H,H-2″′),4.07(t,J=8.3Hz,1H,H-2″″),4.10(m,1H,H-5″″),3.95(m,1H,H-5″′),3.72(m,1H,H-5′-2),3.32(m,2H,H-3,H-18),1.67(d,J=5.9Hz,3H,H-6″),1.39,1.32,1.22,1.03,0.98,0.98,0.86(s each,3H each,CH3×7);13C NMR(C5D5N,150MHz):δ178.9(C-28),145.5(C-13),122.9(C-12),107.0(C-1″′),106.7(C-1′),105.5(C-1″″),102.1(C-1″),89.0(C-3),83.9(C-3″),81.6,79.9,79.0,78.8,77.3,75.9,75.3,73.5,72.0,67.5,62.9,62.3,56.6,48.6,47.2,47.0,42.7,42.5,40.3,39.4,37.6,33.8,31.5,28.9,28.7,27.2,26.7,24.3,19.2,19.0,17.9,17.8,16.1;ESI-HRMS:m/z calcd forC53H85O21[M-H+]:1057.5583;found:1057.5569。
实施例3,按下式制备齐墩果烷型三萜皂苷14,15,16,19,20,21,22:
其中,
R1=3,4-二-苯甲酰基-O-β-D-木糖基,
R2=4,6-苄叉基-O-β-D-葡萄糖基,
R3=4,6-苄叉基-O-β-D-半乳糖基,
R4=2,3,4-三-苯甲酰基-O-α-L-鼠李糖-(1→2)-3,4-二-苯甲酰基-O-β-D-木糖基,
R5=2,3-二-(2,3,4-三-苯甲酰基-O-α-L-鼠李糖)-4,6-苄叉基-O-β-D-葡萄糖基,
R6=2,3,4-三-苯甲酰基-O-α-L-鼠李糖-(1→3)-4,6-苄叉基-O-β-D-葡萄糖基,
R7=2,3,4-三-苯甲酰基-O-α-L-鼠李糖-(1→2)-4,6-苄叉基-O-β-D-葡萄糖基,
R8=2,3-二-(2,3,4-三-苯甲酰基-O-α-L-鼠李糖)-4,6-苄叉基-O-β-D-半乳糖基,
R9=2,3,4-三-苯甲酰基-O-α-L-鼠李糖-(1→3)-4,6-苄叉基-O-β-D-半乳糖基,
R10=2,3,4-三-苯甲酰基-O-α-L-鼠李糖-(1→2)-4,6-苄叉基-O-β-D-半乳糖基,
R11=α-L-鼠李糖-(1→2)-O-β-D-木糖基,
R12=2,3-二-α-L-鼠李糖-O-β-D-葡萄糖基,
R13=α-L-鼠李糖-(1→3)-O-β-D-葡萄糖基,
R14=α-L-鼠李糖-(1→2)-O-β-D-葡萄糖基,
R15=2,3-二-α-L-鼠李糖-4,6-苄叉基-O-β-D-半乳糖基,
R16=α-L-鼠李糖-(1→3)-O-β-D-半乳糖基,
R17=α-L-鼠李糖-(1→2)-O-β-D-半乳糖基,
合成中间体45,46,47,48,49,50,51:
氩气保护下,将化合物36(0.13mmol)分别与化合物38、43、44(均为0.13mmol)溶解于干燥过的二氯甲烷(2mL)中,加入分子筛,室温搅拌30分钟后,滴加TMSOTf(2μL,0.1个当量),室温下继续反应30分钟。反应完毕后,加入三乙胺终止反应,过滤除去分子筛,减压蒸除溶剂后,残渣经硅胶柱层析精制分别得白色泡沫状固体45、46、47、48、49、50、51。
中间体45:收率90.8%;[α]D 20+63.2(c 0.52,CHCl3);1H NMR(CDCl3,600MHz):δ7.23-8.05(m,30H,Ph-H),5.82(dd,J=10.1,3.2Hz,1H,H-3″),5.71(t-like,J=7.3,6.9Hz,1H,H-3′),5.60(t-like,J=10.1,9.6Hz,1H,H-4″),5.56(dd,J=3.2,1.4Hz,1H,H-2″),5.34(d,J=1.8Hz,1H,H-1″),5.30(t-like,J=3.7,3.2Hz,1H,H-12),5.21-5.24(m,1H,H-4′),5.09(dd,J=34.4,12.8Hz,2H,CH2-Ph),4.87(d,J=5.5Hz,1H,H-1′),4.48-4.52(m,1H,H-5″),4.40(dd,J=12.4,4.6Hz,1H,H-5′-1),4.12(dd,J=6.9,6.0Hz,1H,H-2′),3.66(dd,J=12.4,7.4Hz,1H,H-5′-2),3.25(dd,J=11.9,4.6Hz,1H,H-3),2.91(dd,J=14.2,4.6Hz,1H,H-18),1.99(dt,J=13.2,4.1Hz,1H,H-16),1.31(d,J=5.9Hz,3H,H-6″),1.13,1.12,0.92,0.89,0.89,0.83,0.62(seach,3H each,CH3×7);13C NMR(CDCl3,150MHz):δ177.5(C-28),165.9,165.8,165.2,143.8(C-13),136.6,133.4,130.0,128.4,122.6(C-12),103.5(C-1′),97.7(C-1″),89.6(C-3),74.2,72.5,71.9,70.6,66.0,61.3,55.8,47.8,46.8,46.0,39.4,39.3,36.9,33.2,30.8,28.2,25.9,23.8,17.5,16.6,15.5;ESI-MS(m/z):1345.6(M+H+);HRMALMS:Calcd for[M+Na+]C83H92O16Na:1367.6309;found:m/z 1367.6278.
中间体46:收率20%;[α]D 20+37.9(c 0.64,CHCl3);1H NMR(CDCl3,600MHz):δ7.16-7.97(m,40H,Ph-H),5.86(dd,J=10.5,3.7Hz,1H,H-3″),5.79(dd,J=10.1,3.2Hz,1H,H-3″′),5.75(dd,J=3.2,1.3Hz,1H,H-2″),5.68(t,J=10.1Hz,1H,H-4″),5.63(dd,J=3.2,1.4Hz,1H,H-2″′),5.62(s,1H,H-1″′),5.58(s,1H,H-1″),5.50(t,J=10.1Hz,1H,H-4″′),5.37(s,1H,PhCH(O)),5.30(t,J=3.2Hz,1H,H-12),5.09(dd,J=34.3,12.4Hz,2H,CH 2-Ph),4.82(d,J=6.4Hz,1H,H-1′),4.64-4.69(dt,J=12.4,6.0Hz,1H,H-5″),4.49(dt,J=12.4,5.9Hz,1H,H-5″′),4.40(dd,J=10.5,5.0Hz,1H,H-6′’-1),4.24(dd,J=9.2,7.3Hz,1H,H-3′),4.10(t-like,J=7.3,6.9Hz,1H,H-2′’),3.96(t-like,J=9.5,9.2Hz,1H,H-4′),3.82-3.88(m,1H,H-6′-2),3.64(td,J=9.6,4.6Hz,1H,H-5′),3.32(dd,J=11.5,4.1Hz,1H,H-3),2.91(dd,J=13.7,4.6Hz,1H,H-18),1.37(d,J=6.0Hz,3H,H-6″),0.88(d,J=5.9Hz,3H,H-6″′),1.18,1.14,0.97,0.92,0.90,0.89,0.63(s each,3H each,CH3×7);13C NMR(CDCl3,150MHz):δ177.6(C-28),165.4,165.3,163.6,143.8(C-13),137.2,136.5,132.9,129.7,128.4,122.6(C-12),103.5(C-1′),102.2(C-1″),97.4(PhC(O)),97.1(C-1″′),91.9(C-3),89.1,78.7,77.5,71.8,70.0,68.9,67.1,66.0,55.9,47.8,46.9,41.8,39.2,36.9,33.2,30.8,28.3,26.1,25.8,23.7,17.5,17.1,15.5;HRMALMS:Calcd for[M+Na+]C104H112O22Na:1735.7564;found:m/z 1735.7538.
中间体47:收率35%;[α]D 20+35.9(c 1.04,CHCl3);1H NMR(CDCl3,600MHz):δ7.20-8.08(m,25H,Ph-H),5.83(dd,J=10.1,3.7Hz,1H,H-3″),5.72(dd,J=3.7,1.9Hz,1H,H-2″),5.63(s,1H,PhCH(O)),5.57(t-like,J=10.1,9.6Hz 1H,H-4″),5.53(d,J=1.4Hz,1H,H-1″),5.29(t,J=3.7Hz,1H,H-12),5.08(dd,J=31.1,12.8Hz,2H,CH 2-Ph),4.53(dt,J=12.4,6.4Hz,1H,H-5″),4.47(d,J=7.8Hz,1H,H-1′),4.35(dd,J=10.6,5.0Hz,1H,H-6′-1),4.01(t-like,J=9.2,9.1Hz,1H,H-3′),3.86(t,J=9.6Hz,1H,H-6′-2),3.74-3.77(m,1H,H-2′),3.72(t-like,J=9.7,9.1Hz,1H,H-4′),3.49(dt,J=9.6,5.0Hz,1H,H-5′),3.20(dd,J=11.5,4.6Hz,1H,H-3),2.9(dd,J=13.7,4.1Hz,1H,H-18),2.00(dt,J=13.7,4.1Hz,1H,H-16),1.00(d,J=6.0Hz,3H,H-6″),1.11,0.99,0.91,0.89,0.89,0.83,0.60(s each,3H each,CH3×7);13C NMR(CDCl3,150MHz):δ177.5(C-28),165.7,143.8(C-13),137.3,136.5,133.5,128.5,128.2,122.6(C-12),105.7(C-1′),101.8(PhC(O)),97.7(C-1″′),90.3(C-3),78.2,71.5,70.9,70.2,68.5,66.9,66.0,55.6,47.7,46.8,46.3,41.8,39.4,36.8,33.2,30.8,28.4,27.6,25.9,23.8,23.7,23.5,17.7,17.1,16.8,15.4;HRMALMS:Calcd for[M+Na+]C77H90O15Na:1277.6201;found:m/z 1277.6172.
中间体48:收率45%;[α]D 20+49.5(c 0.50,CHCl3);1H NMR(CDCl3,600MHz):δ7.29-8.09(m,25H,Ph-H),5.91(dd,J=10.1,3.2Hz,1H,H-3″),5.83(dd,J=5.0,1.8Hz,1H,H-2″),5.76(br s,1H,H-1″),5.69(t,J=10.1Hz,1H,H-4″),5.53(s,1H,PhCH(O)),5.30(t,J=3.6Hz,1H,H-12),5.09(dd,J=37.6,12.4Hz,2H,CH 2-Ph),4.67(d,J=7.3Hz,1H,H-1′),4.52-4.57(m,1H,H-5″),4.35(dd,J=10.5,5.5Hz,1H,H-6′-1),4.07(m,1H,H-3′),3.83-3.88(m,1H,H-2′),3.78(t,J=10.1Hz,1H,H-6′-2),3.56(t,J=9.6Hz,1H,H-4′),3.45(dt,J=10.1,5.0Hz,1H,H-5′),3.25(dd,J=11.9,4.6Hz,1H,H-3),2.91(dd,J=13.1,3.2Hz,1H,H-18),1.35(d,J=6.0Hz,3H,H-6″),1.14,0.94,0.93,0.92,0.91,0.89,0.63(s each,3H each,CH3×7);13C NMR(CDCl3,150MHz):δ177.6(C-28),165.9,165.7,143.8(C-13),137.1,136.5,133.4,129.8,128.4,122.6(C-12),104.7(C-1′),101.9(PhC(O)),97.7(C-1″′),89.9(C-3),80.8,75.1,72.5,70.7,69.5,67.2,66.1,65.8,56.0,47.8,46.8,46.0,41.8,41.5,39.4,38.5,34.1,33.2,30.8,28.1,26.0,25.9,23.8,22.9,21.6,19.2,17.6,16.6,15.5;HRMALMS:Calcd for[M+Na+]C77H90O15Na:1277.6210;found:m/z 1277.6172.
中间体49:收率7%;[α]D 20+64.1(c 0.65,CHCl3);1H NMR(CDCl3,600MHz):δ7.15-8.11(m,40H,Ph-H),5.90(dd,J=10.0,3.6Hz,1H,H-3″′),5.83(dd,J=10.1,3.7Hz,1H,H-3″),5.77(m,1H,H-4′),5.70(m,1H,H-4″′),5.62(t,J=10.1Hz,1H,H-4″),5.56(s,1H,PhCHO),5.32(d,J=1.9Hz,1H,H-1″′),5.30(t,J=3.6Hz,1H,H-12),5.08(dd,J=31.1,12.4Hz,2H,CH 2-Ph),4.48-4.50(m,1H,H-5″),4.44-4.47(m,1H,H-5″′),4.40(d,J=7.3Hz,1H,H-1′),4.35(d,J=3.2Hz,1H,H-1″),4.33(dd,J=11.5,1.6Hz,1H,H-6′-1),4.08-4.12(m,4H,H-2′,H-3′,H-5′,H-6′-2),3.75(dd,J=7.0,3.7Hz,1H,H-2″),3.17(dd,J=11.9,4.6Hz,1H,H-3),2.91(dd,J=12.8,4.1Hz,1H,H-18),1.44(d,J=5.0Hz,3H,H-6″′),1.34(d,J=5.9Hz,3H,H-6″),1.12,1.05,0.91,0.89,0.86,0.85,0.60(s each,3H each,CH3×7);13C NMR(CDCl3,150MHz):δ177.5(C-28),165.5,165.2,164.9,143.8(C-13),137.6,136.5,129.8,128.5,128.3,128.0,122.7,104.3(C-1′),101.2(C-1″),100.2(PhC(O)),97.7(C-1″′),89.6(C-3),85.8,72.5,71.6,70.9,66.0,56.3,47.9,46.9,46.0,41.5,39.5,39.3,33.2,30.8,28.3,26.0,23.8,17.5,17.1,15.6;HRMALMS:Calcd for[M+Na+]C104H112O22Na:1735.7533;found:m/z 1735.7538.
中间体50:收率29%;[α]D 20+80.8(c 0.55,CHCl3);1H NMR(CDCl3,600MHz):δ7.04-8.11(m,25H,Ph-H),5.96(dd,J=10.5,3.2Hz,1H,H-3″),5.83(t,J=10.1Hz,1H,H-4″),5.76(m,1H,H-2″),5.58(t,J=10.1Hz,1H,H-3′),5.53(s,1H,H-1″),5.38(s,1H,PhCHO),5.30(br s,1H,H-12),5.10(dd,J=34.4,12.5Hz,2H,CH 2-Ph),4.91(m,1H,H-5″),4.66(d,J=7.3Hz,1H,H-1′),4.55(m,1H,H-4′),4.43(t,J=8.7Hz,1H,H-2′),4.33(dd,J=11.5,5.0Hz,1H,H-6′-1),4.11(dd,J=9.2,6.8Hz,1H,H-6′-2),3.86(m,1H,H-5′),3.28(dd,J=11.4,4.4Hz,1H,H-3),2.92(dd,J=13.7,3.2Hz,1H,H-18),1.40(d,J=6.0Hz,3H,H-6″),1.14,0.93,0.93,0.92,0.92,0.90,0.63(s each,3H each,CH3×7);13C NMR(CDCl3,150MHz):δ177.5(C-28),165.8,165.5,163.4,143.8(C-13),137.8,136.5,133.3,129.8,128.3,122.7(C-12),105.3(C-1′),101.2(PhC(O)),99.9(C-1″′),89.9(C-3),81.8,70.9,70.3,70.1,66.0,60.5,55.8,47.8,46.8,46.0,41.8,39.2,36.9,33.2,30.8,28.3,26.0,23.8,19.2,17.8,16.8,15.4;HRMALMS:Calcd for[M+Na+]C77H90O15Na:1277.6173;found:m/z 1277.6172.
中间体51:收率51%;[α]D 20+70.8(c 0.62,CHCl3);1H NMR(CDCl3,600MHz):δ7.23-8.07(m,25H,Ph-H),5.90(dd,J=10.6,3.7Hz,1H,H-3″),5.85(d,J=1.8Hz,1H,H-3′),5.81(m,1H,H-4′),5.65(t,J=10.1Hz,1H,H-4″),5.55(s,1H,PhCHO),5.30(t,J=3.6Hz,1H,H-12),5.09(dd,J=40.8,12.8Hz,2H,CH 2-Ph),4.61-4.64(m,1H,H-5″),4.52(d,J=7.3Hz,1H,H-1′),4.32(dd,J=10.2,1.8Hz,1H,H-6′-1),4.18(d,J=2.8Hz,1H,H-1″),4.08-4.10(m,2H,H-5′,H-6′-2),3.96(m,2H,H-2′,H-2″),3.20(dd,J=11.9,4.1Hz,1H,H-3),2.91(dd,J=13.3,3.7Hz,1H,H-18),1.1.36(d,J=6.4Hz,3H,H-6″),1.14,0.97,0.93,0.92,0.90,0.89,0.63(s each,3H each,CH3×7);13C NMR(CDCl3,150MHz):δ177.5(C-28),165.9,165.6,143.8(C-13),137.5,136.5,133.0,128.3,128.0,122.7(C-12),104.0(C-1′),101.3(PhC(O)),97.2(C-1″′),89.9(C-3),72.1,70.7,70.1,66.5,56.1,47.8,46.9,46.0,41.5,39.5,39.3,33.2,30.8,28.3,26.0,23.8,17.6,17.0,16.9;HRMALMS:Calcd for[M+Na+]C77H90O15Na:1277.6202;found:m/z 1277.6172.
合成化合物14、15、16、19、20、21、22:
将上述中间体45、46、47、48、49、50、51(均为0.08mmol)分别溶于二氯甲烷和甲醇(V∶V=1∶1,16mL)的混合溶剂中,加入10%Pd-C(50mg)和4滴醋酸,1个大气压氢气作用下反应4小时。反应完毕后,过滤除去Pd-C,减压浓缩得到白色固体,直接投入到下一步反应中。
将上一步所得白色固体分别溶于二氯甲烷和甲醇(V∶V=1∶2,16mL)的混合溶剂中,加入甲醇钠(60mg),室温反应8小时后,加入阳离子交换树脂终止反应,过滤,减压浓缩,所得残渣经硅胶柱层析精制分别得白色泡沫状固体14、19、20、15、21、22、16。
所述化合物14:两步收率65.7%;[α]D 20+5.96(c 0.62,CH3OH);1H NMR(CD3OD,600MHz):δ5.35(s,1H,H-1″),5.27(br s,1H,H-12),4.41(d,J=6.1Hz,1H,H-1′),3.95-3.98(m,2H,H-2″,H-5″′),3.87(dd,J=11.6,5.5Hz,1H,H-5′-1),3.25(dd,J=9.9,3.3Hz,1H,H-3″),3.48-3.51(m,1H,H-4′),3.39-3.46(m,3H,H-2′,H-3′,H-5′-2),3.20(t,J=9.9Hz,1H,H-4″),3.14(dd,J=12.1,4.4Hz,1H,H-3),2.88(dd,J=13.7,4.4Hz,1H,H-18),1.25(d,J=6.0Hz,3H,H-6″),1.19,1.07,0.97,0.97,0.94,0.89,0.85(s each,3H each,CH3×7);13C NMR(CD3OD,150MHz):δ143.9(C-13),122.3(C-12),104.9(C-1′),100.6(C-1″),88.8(C-3),77.5,77.3,72.7,70.8,70.3,68.7,55.9,41.6,40.9,39.3,38.9,36.6,32.7,32.3,30.3,27.2,25.1,22.7,18.0,16.7,15.8,14.7;ESI-HRMS:m/z calcd for[M+Na]+C41H66O11Na:757.4503;found:757.4509.
所述化合物19:两步收率57.2%;[α]D 20-1.49(c 0.75,CH3OH);1H NMR(CD3OD,600MHz):δ5.24(br s,1H,H-12),5.13(s,1H,H-1″),4.92(s,1H,H-1″′),4.48(d,J=7.1Hz,1H,H-1′),3.99(br s,1H,H-2″),3.90-3.96(m,3H,H-2″′,H-5′,H-5″′),3.84-3.86(m,2H,H-3″′,H-4′),3.64-3.71(m,3H,H-4″,H-5′,H-6′-1),3.58(t-like,J=8.8,8.3Hz,1H,H-3″),3.42-3.49(m,3H,H-2′,H-4″′,H-6′-2),3.39(t-like,J=9.9,9.4Hz,1H,H-3′),3.22(dd,J=12.1,4.4Hz,1H,H-3),2.87(dd,J=13.2,3.3Hz,1H,H-18),1.27(d,J=6.6Hz,3H,H-6″),1.22(d,J=6.1Hz,3H,H-6″′),1.16,1.05,0.95,0.94,0.91,0.87,0.82(s each,3H each,CH3×7);13C NMR(CD3OD,150MHz):δ144.2(C-13),122.2(C-12),104.0(C-1′),102.2(C-1″′),100.7(C-1″),88.8(C-3),86.9,77.4,76.1,72.2,71.9,70.8,70.5,69.8,68.9,63.0,61.3,56.0,41.6,39.3,39.0,36.6,32.5,32.3,30.3,27.2,25.1,23.2,22.7,16.7,16.5,15.8,14.7;ESI-HRMS:m/z Calcd for[M+Na]+C48H78O16Na:933.5188;found:933.5175.
所述化合物20:两步收率53.7%;[α]D 20+2.90(c 0.65,CH3OH);1H NMR(CD3OD,600MHz):δ5.27(br s,1H,H-12),5.17(s,1H,H-1″),4.35(d,J=8.2Hz,1H,H-1′),4.01(dq,J=9.4,6.6Hz,1H,H-5″),3.97(br s,1H,H-2″),3.86(dd,J=10.9,3.5Hz,1H,H-6′-1),3.71(ddd,J=9.4,5.0,3.3Hz,1H,H-5′),3.49(t,J=8.8Hz,1H,H-3′),3.42(t-like,J=9.9,9.3Hz,1H,H-4″),3.36(t-like,J=9.4,9.3Hz,1H,H-2′),3.28-3.32(m,2H,H-4′,H-6′-2),3.21(dd,J=11.6,4.4Hz,1H,H-3),2.89(dd,J=12.1,3.3Hz,1H,H-18),1.27(d,J=6.1Hz,3H,H-6″),1.19,1.08,0.98,0.97,0.93,0.87,0.84(s each,3H each,CH3×7);13C NMR(CD3OD,150MHz):δ143.9(C-13),122.3(C-12),105.2(C-1′),101.6(C-1″),89.6(C-3),83.7,74.8,72.9,71.1,70.9,69.0,68.8,61.4,55.7,41.6,39.3,38.8,38.5,36.6,32.3,30.3,27.3,25.1,23.2,22.7,18.0,16.6,15.7,14.6;ESI-HRMS:m/z Calcd for[M+H]+ C42H69O12Na:765.4789;found:765.4806.
所述化合物15:两步收率55.1%;[α]D 20+5.95(c 1.00,CH3OH);1H NMR(CD3OD,600MHz):δ5.37(s,1H,H-1″),5.24(t,J=3.6Hz,1H,H-12),4.41(d,J=7.7Hz,1H,H-1′),3.98(td,J=9.4,6.1Hz,1H,H-5″),3.95(dd,J=3.4,1.6Hz,1H,H-2″),3.83(dd,J=11.5,1.6Hz,1H,H-6′-1),3.74(dd,J=9.3,3.3Hz,1H,H-3″),3.66(dd,J=12.1,5.5Hz,1H,H-6′-2),3.46(t,J=8.8Hz,1H,H-3′),3.41(t-like,J=8.8,7.7Hz,1H,H-2′),3.38(t-like,J=9.8,9.4Hz,1H,H-4″),3.29(t,J=8.8Hz,1H,H-1-4′),3.21-3.24(m,1H,H-5′),3.18(dd,J=12.1,4.4Hz,1H,H-3),2.86(dd,J=14.3,3.8Hz,1H,H-18),1.21(d,J=6.6Hz,3H,H-6″),1.16,1.05,0.95,0.94,0.91,0.86,0.82(s each,3H each,CH3×7);13C NMR(CD3OD,150MHz):δ143.9(C-13),122.3(C-12),104.3(C-1′),100.5(C-1″),88.9(C-3),78.2,77.6,76.3,70.8,70.7,68.7,61.5,56.0,41.6,39.3,38.9,36.6,32.3,30.3,27.5,25.9,25.1,22.7,16.7,16.4,15.9,14.7;ESI-HRMS:m/z Calcd for[M+Na]+C42H68O12Na:787.4608;found:787.4584.
所述化合物21:两步收率58.7%;[α]D 20-2.72(c 0.75,CH3OH);1H NMR(CD3OD,600MHz):δ5.56(br s,1H,PhCHO),5.24(t,J=3.8Hz,1H,H-12),5.13(d,J=1.1Hz,1H,H-1″),4.90(s,1H,H-1″′),4.53(d,J=7.7Hz,1H,H-1′),4.38(d,J=3.3Hz,1H,H-4′),3.97(dq,J=9.4,6.1Hz,1H,H-5″),3.91(dd,J=3.3,1.2Hz,1H,H-2″′),3.88(br s,1H,H-2″),3.83-3.86(m,2H,H-2′,H-5″′),3.77(dd,J=9.9,3.3Hz,1H,H-3′),3.68(dd,J=9.4,3.3Hz,1H,H-3″),3.66(dd,J=9.4,3.3Hz,1H,H-3″′),3.54(br s,1H,H-6′-2),3.39(t,J=9.9Hz,1H,H-4″′),3.36(t,J=9.3Hz,1H,H-4″),3.20(dd,J=12.1,4.4Hz,1H,H-3),2.86(dd,J=13.7,3.8Hz,1H,H-18),1.21(d,J=6.0Hz,3H,H-6″),1.19(d,J=6.1Hz,3H,H-6″′),1.17,1.08,0.96,0.94,0.91,0.89,0.82(s each,3Heach,CH3×7);13C NMR(CD3OD,150MHz):δ182.6(C-28),162.7,145.4(C-13),139.7,130.0,129.2,127.6,123.7(C-12),106.0(C-1′),104.9(C-1″′),102.7(C-1″),102.4(PhCHO),90.8(C-3),84.4(C-3″),77.6(C-3″′),75.6,74.0,73.7,72.5,72.4,71.9,70.7,70.5,67.7,57.6,43.1,42.9,40.7,40.5,40.3,38.1,35.1,34.2,33.8,31.8,29.0,28.6,27.4,26.6,24.7,24.2,19.5,18.3,18.2,18.0,17.2,16.2;HRMALMS:Calcd for[M+Na+]C55H82O16Na:1021.5507;found:m/z 1021.5495.
所述化合物22:两步收率57.5%;[α]D 20+5.43(c 0.56,CH3OH);1H NMR(CD3OD,600MHz):δ5.37(s,1H,H-1″),5.27(t,J=3.6Hz,1H,H-12),4.40(d,J=7.7Hz,1H,H-1′),3.98-4.03(m,2H,H-2″,H-5″),3.80(d,J=3.3Hz,1H,H-4′),3.78(dd,J=9.9,3.3Hz,1H,H-3′),3.74(dd,J=5.5,2.8Hz,1H,H-3″),3.70(t-like,J=8.8,7.7Hz,1H,H-2′),3.60-3.63(m,2H,H-6′-1,H-6′-2),3.50(t-like,J=6.6,6.1Hz,1H,H-5′),3.41(t-like,J=9.9,9.3Hz,1H,H-4″),3.20(dd,J=12.1,4.4Hz,1H,H-3),2.87(dd,J=13.5,3.2Hz,1H,H-18),1.24(d,J=6.6Hz,3H,H-6″),1.19,1.08,0.97,0.97,0.94,0.89,0.84(s each,3H each,CH3×7);13C NMR(CD3OD,150MHz):δ143.9(C-13),122.3(C-12),105.9(C-1′),102.6(C-1″),89.5(C-3),80.5,74.8,72.8,71.4,70.8,68.8,60.8,55.8,41.4,39.3,38.3,36.6,32.3,27.3,25.7,25.1,23.2,22.7,16.7,16.4,15.7,14.6;ESI-HRMS:m/z Calcd for[M+Na]+C42H68O12Na:787.4608;found:787.4595.
所述化合物16:两步收率55.8%;[α]D 20-11.6(c 0.64,CH3OH);1H NMR(CD3OD,600MHz):δ5.24(t,J=3.7Hz,1H,H-12),5.05(d,J=1.9Hz,1H,H-1″),4.31(d,J=7.8Hz,1H,H-1′),3.96(dd,J=3.8,1.4Hz,1H,H-2″),3.92(d,J=3.2Hz,1H,H-4′),3.75-3.79(m,2H,H-3″,H-5″),3.69-3.73(m,2H,H-6′-1,H-6′-2),3.65(dd,J=9.7,7.8Hz,1H,H-2′),3.51(dd,J=9.6,3.2Hz,1H,H-3′),3.49(t-like,J=6.4,5.9Hz,1H,H-5′),3.39(t-like,J=9.7,9.1Hz,1H,H-4″),3.18(dd,J=11.5,4.1Hz,1H,H-3),2.86(dd,J=13.3,3.2Hz,1H,H-18),2.01(dt,J=14.2,3.7Hz,1H,H-16),1.24(d,J=6.4Hz,3H,H-6″),1.16,1.06,0.95,0.94,0.91,0.84,0.81(s each,3H each,CH3×7);13C NMR(CD3OD,150MHz):δ144.0(C-13),122.3(C-12),104.8(C-1′),100.7(C-1″),88.9(C-3),75.0,74.9,72.7,70.7,69.7,61.1,60.9,56.1,41.6,39.3,36.6,32.7,32.3,30.3,27.2,25.1,23.2,22.7,18.0,16.7,15.9,14.7;ESI-HRMS:m/z calcd for[M+H]+C42H69O12:765.4789;found:765.4783.
实施例4,按下式制备齐墩果烷型三萜皂苷17:
其中,
R1=3,4-丙叉基-O-α-L-阿拉伯糖基,
R2=2,3,4-三-苄基-O-β-L-鼠李糖-(1→2)-3,4-丙叉基-O-α-L-阿拉伯糖基,
R3=2,3,4-三-苄基-O-β-L-鼠李糖-(1→2)-O-α-L-阿拉伯糖基,
R4=β-L-鼠李糖-(1→2)-O-α-L-阿拉伯糖基,
合成中间体53:
氩气保护下,将化合物29(0.14mmol)与化合物52(0.21mmol)溶解于干燥过的二氯甲烷(5mL)中,加入分子筛,室温搅拌30分钟后,加入NIS(0.22mmol)和AgOTf(0.02mmol)。反应完毕后,加入三乙胺终止反应,过滤除去分子筛,滤液依次用5%Na2S2O3,饱和食盐水洗涤,无水硫酸钠干燥,过滤减压蒸除溶剂后,残渣经硅胶柱层析精制分别得白色泡沫状固体53。收率86.8%;[α]D 23+5.92(c 1.18,CHCl3);1H NMR(CDCl3,600MHz):δ7.27-7.34(m,20H,Ph-H),5.33(d,J=1.1Hz,1H,H-1″),5.29(t,J=3.6Hz,1H,H-12),5.11(d,J=12.7Hz,1H,PhCHH),5.05(d,J=12.7Hz,1H,PhCHH),5.01(d,J=15.4Hz,1H,PhCHH),4.95(d,J=13.5Hz,1H,PhCHH),4.76(d,J=12.7Hz,1H,PhCHH),4.67(d,J=11.0Hz,1H,PhCHH),4.64(d,J=10.4Hz,1H,PhCHH),4.56(d,J=12.7Hz,1H,PhCHH),4.31(d,J=7.2Hz,1H,H-1′),4.21(dd,J=10.4,4.4Hz,1H,H-5′-1),3.99-4.02(m,2H,H-4′,H-4″),3.95(dq,J=9.1,6.6Hz,1H,H-5″),3.88(dd,J=9.4,2.8Hz,1H,H-5′-2),3.69-3.72(m,2H,H-2′,H-3″),3.61(dd,J=9.6,3.8Hz,1H,H-3′),3.01(dd,J=12.1,4.9Hz,1H,H-3),2.91(dd,J=13.7,3.8Hz,1H,H-18),1.48,1.33(s each,3H each,O-(CH3)2C-O),1.28(d,J=6.6Hz,3H,H-6″),1.11,0.92,0.91,0.89,0.88,0.81,0.61(s each,3H each,CH3×7);13C NMR(CDCl3,150MHz):δ177.7(C-28),143.9(C-13),138.9,138.6,136.6,128.6,128.4,128.3,128.2,122.8(C-12),110.4,103.3(C-1′),96.7(C-1″),88.9(C-3),80.1,80.0,79.3,75.3,74.9,73.5,72.3,68.7,68.5,66.1,55.9,47.8,46.9,46.2,41.7,41.5,40.0,39.3,38.2,36.9,33.6,33.3,30.9,28.0,26.3,23.9,23.6,18.1,17.1,15.9,15.6;HRMALDIMS:Calcd for[M+Na+]C72H94O11Na:m/z 1157.6686;found:m/z 1157.6688.
合成中间体54:
将上述中间体53(0.09mmol)溶于二氯甲烷和甲醇(V∶V=1∶2,6mL)的混合溶剂中,加入对甲苯磺酸(0.09mmol),室温搅拌反应。反应完毕后,加入三乙胺终止反应,加压蒸除溶剂后,残渣经硅胶柱层析精制分别得白色泡沫状固体54。收率82.8%;[α]D 23-21.1(c 0.64,CHCl3);1H NMR(CDCl3,600MHz):δ7.27-7.34(m,20H,Ph-H),5.28(t,J=3.3Hz,1H,H-12),5.10(d,J=12.7Hz,1H,PhCHH),5.05(d,J=12.6Hz,1H,PhCHH),4.95(d,J=11.0Hz,1H,PhCHH),4.82(d,J=1.1Hz,1H,H-1″),4.78(d,J=12.1Hz,1H,PhCHH),4.76(d,J=6.8Hz,1H,H-1′),4.68(d,J=12.6Hz,1H,PhCHH),4.66(d,J=11.9Hz,1H,PhCHH),4.62(d,J=12.1Hz,1H,PhCHH),4.60(d,J=12.7Hz,1H,PhCHH),3.84(br s,1H,H-2″),3.81(dd,J=9.4,2.8Hz,1H,H-3″),3.70-3.75(m,4H,H-2′,H-4′,H-5′-1,H-5″),3.56-3.64(m,3H,H-3′,H-4″,H-5′-2),3.01(dd,J=11.5,4.4Hz,1H,H-3),2.91(dd,J=13.7,4.4Hz,1H,H-18),1.28(d,J=6.1Hz,3H,H-6″),1.11,0.92,0.91,0.90,0.87,0.77,0.59(s each,3H each,CH3×7);13C NMR(CDCl3,150MHz):δ177.5(C-28),143.8(C-13),138.6,138.5,138.1,136.5,128.5,128.1,128.0,127.9,127.8,127.7,122.5(C-12),101.2(C-1′),98.7(C-1″),90.4(C-3),80.4(C-3″),75.4,74.2,73.3,72.6,68.9,66.0,64.1,59.2,55.4,47.6,46.8,46.0,41.8,41.5,39.4,39.1,38.5,36.8,33.9,33.2,32.7,32.5,30.8,28.2,27.7,25.9,25.6,23.7,23.5,23.1,18.3,18.0,16.9,16.5,15.4;ESI-MS:m/z1118.0(M+Na+).
合成化合物17:
将上述中间体54(0.05mmol)分别溶于二氯甲烷和甲醇(V∶V=1∶1,12mL)的混合溶剂中,加入10%Pd-C(50mg),1个大气压氢气作用下反应5小时。反应完毕后,过滤除去Pd-C,减压蒸除溶剂后,残渣经硅胶柱层析精制分别得白色泡沫状固体17。收率78.0%;[α]D 20+3.19(c 0.84,CH3OH);1H NMR(CD3OD,600MHz):δ5.24(t,J=3.6Hz,1H,H-12),5.10(d,J=1.1Hz,1H,H-1″),4.54(d,J=5.0Hz,1H,H-1′),3.89(dd,J=3.3,1.7Hz,1H,H-2″),3.84(dd,J=11.6,6.1Hz,1H,H-5′-1),3.81(qd,J=9.4,6.1Hz,1H,H-5″),3.76-3.79(m,2H,H-3′,H-4′),3.72(dd,J=7.1,3.8Hz,1H,H-2′),3.69(dd,J=9.4,3.3Hz,1H,H-3″),3.48(dd,J=11.6,2.8Hz,1H,H-5′-2),3.38(t,J=9.4Hz,1H,H-4″),3.11(dd,J=12.1,4.4Hz,1H,H-3),2.84(dd,J=13.7,3.8Hz,1H,H-18),1.22(d,J=6.1Hz,3H,H-6″),1.16,1.02,0.95,0.94,0.91,0.84,0.82(seach,3H each,CH3×7);13C NMR(CD3OD,150MHz):δ182.1(C-28),145.3(C-13),123.7(C-12),105.0(C-1′),102.2(C-1″),90.3(C-3),77.0,74.0,73.3,72.3,70.3,68.6,64.4,64.0,57.2,43.0,42.9,40.7,40.4,40.0,38.1,35.0,34.1,34.0,33.7,31.8,30.9,29.0,28.8,27.2,26.6,24.7,24.2,24.1,19.5,18.2,17.9,17.2,16.1;ESI-HRMS:m/z calcd for[M-H+]C41H65O11:733.4527;found:733.4515.
实施例5,按下式制备齐墩果烷型三萜皂苷18:
其中,
R1=2,3,4-三-苯甲酰基-O-α-L-鼠李糖基,
R2=2,3,4-三-苯甲酰基-O-α-L-鼠李糖基-(1→2)-3,4-丙叉基-O-β-L-阿拉伯糖基,
R3=2,3,4-三-苯甲酰基-O-α-L-鼠李糖基-(1→2)-O-β-L-阿拉伯糖基,
R4=α-L-鼠李糖基-(1→2)-O-β-L-阿拉伯糖基,
合成中间体56:
氩气保护下,将化合物55(0.34mmol)与化合物36(0.51mmol)溶解于干燥过的二氯甲烷(5mL)中,加入分子筛,室温搅拌30分钟后,于-78℃条件下加入TMSOTf(0.02mmol)。反应完毕后,加入三乙胺终止反应,过滤除去分子筛,减压蒸除溶剂后,残渣经硅胶柱层析精制分别得白色泡沫状固体56。收率86.5%;[α]D 23+77.9(c 0.95,CHCl3);1H NMR(CDCl3,600MHz):δ7.13-8.09(m,19H,Ph-H),5.81(dd,J=9.9,3.3Hz,1H,H-3′),5.74(dd,J=3.3,1.6Hz,1H,H-2′),5.66(t-like,J=9.9,9.8Hz,1H,H-4′),5.49(d,J=1.7Hz,1H,H-1′),4.82(d,J=8.3Hz,1H,H-1),4.55(dq,J=9.9,6.1Hz,1H,H-5′),4.32(m,1H,H-4),4.29(t,J=6.1Hz,1H,H-3),4.20(dd,J=13.2,3.8Hz,1H,H-5-1),3.98(dd,J=8.3,6.1Hz,1H,H-2),3.80(dd,J=12.7,3.8Hz,1H,H-5-2),2.33(s,3H,STol-CH 3),1.52,1.35(s each,3H each,O-(CH3)2C-O),1.32(d,J=6.6Hz,3H,H-6′);13C NMR(CDCl3,150MHz):δ166.0,165.8,165.7,138.1,133.7,133.5,133.3,132.8,130.2,130.0,129.9,129.8,129.7,129.6,128.8,128.7,128.6,128.5,110.7(C-1),96.8(C-1′),86.9(C-3′),78.5,76.0,72.8,71.9,70.9,70.3,67.7,65.1,28.0,26.3,21.4,17.7;HRMALDIMS:Calcd for[M+Na+]C42H42O11SNa:m/z 777.2359;found:m/z 777.2340.
合成中间体58:
氩气保护下,将化合物56(0.22mmol)与化合物57(0.15mmol)溶解于干燥过的二氯甲烷(5mL)中,加入分子筛,室温搅拌30分钟后,加入NIS(0.23mmol)和AgOTf(0.02mmol)。反应完毕后,加入三乙胺终止反应,过滤除去分子筛,滤液依次用5%Na2S2O3,饱和食盐水洗涤,无水硫酸钠干燥,过滤减压蒸除溶剂后,残渣经硅胶柱层析精制分别得白色泡沫状固体58。收率85.9%;[α]D 23+131.7(c 0.50,CHCl3);1H NMR(CDCl3,600MHz):δ7.10-8.10(m,20H,Ph-H),5.84(dd,J=9.9,3.3Hz,1H,H-3″),5.77(dd,J=3.3,1.7Hz,1H,H-2″),5.64(t,J=9.9Hz,1H,H-4″),5.34(d,J=1.7Hz,1H,H-1″),5.29(t-like,J=3.8,3.3Hz,1H,H-12),5.11(d,J=12.7Hz,1H,PhCHH),5.10(d,J=3.3Hz,1H,H-1′),5.06(d,J=12.7Hz,1H,PhCHH),4.44(dd,J=7.7,6.0Hz,1H,H-3′),4.27-4.30(m,2H,H-4′,H-5″),4.11(m,1H,H-5′-1),3.97(d,J=12.7Hz,1H,H-5′-2),3.90(dd,J=7.7,3.3Hz,1H,H-2′),3.29(dd,J=11.5,3.8Hz,1H,H-3),2.90(dd,J=14.3,3.8Hz,1H,H-18),1.55,1.36(s each,3H each,O-(CH3)2C-O),1.35(d,J=6.4Hz,3H,H-6″),1.13,1.05,0.95,0.92,0.92,0.90,0.62(s each,3Heach,CH3×7);13C NMR(CDCl3,150MHz):δ177.7(C-28),165.8,143.9(C-13),136.6,133.7,133.5,130.0,129.5,128.6,128.5,128.3,128.2,122.6(C-12),109.2,99.3(C-1″),93.5(C-1′),88.8(C-3),81.1(C-3″),71.0,70.4,70.2,69.9,69.3,67.2,66.1,62.7,55.7,47.8,46.9,41.9,41.7,39.5,38.9,38.1,37.8,33.3,33.1,32.8,32.7,31.5,31.3,31.2,30.0,29.9,28.7,28.0,23.8,23.7,23.5,23.3,23.2,18.0,17.9,16.5,15.5,14.2,11.6;HRMALDIMS:Calcd for[M+Na+]C72H88O14Na:m/z1199.6078;found:m/z 1199.6066.
合成中间体59:
将上述中间体58(0.09mmol)溶于二氯甲烷和甲醇(V∶V=1∶2,6mL)的混合溶剂中,加入对甲苯磺酸(0.09mmol),室温搅拌反应。反应完毕后,加入三乙胺终止反应,减压蒸除溶剂后,残渣经硅胶柱层析精制分别得白色泡沫状固体59。收率83.8%;[α]D 23+156.2(c 0.40,CHCl3);1H NMR(CDCl3,600MHz):δ7.27-8.07(m,20H,Ph-H),5.80(dd,J=9.9,3.3Hz,1H,H-3″),5.75(dd,J=2.8,1.6Hz,1H,H-2″),5.66(t,J=9.9Hz,1H,H-4″),5.28(br s,2H,H-1″,H-12),5.22(d,J=3.8Hz,1H,H-1′),5.12(d,J=12.7Hz,1H,PhCHH),5.05(d,J=12.7Hz,1H,PhCHH),4.38(dq,J=9.9,6.0Hz,1H,H-5″),4.20(d,J=8.8Hz,1H,H-3′),4.09(m,1H,H-4′),4.02(dq,J=9.3,3.3Hz,1H,H-2′),3.91(d,J=12.6Hz,1H,H-5′-1),3.75(d,J=12.1Hz,1H,H-5′-2),3.31(dd,J=11.6,3.9Hz,1H,H-3),2.89(dd,J=13.7,4.4Hz,1H,H-18),1.35(d,J=6.0Hz,3H,H-6″),1.13,1.07,0.97,0.91,0.89,0.87,0.61(s each,3H each,CH3×7);13C NMR(CDCl3,150MHz):δ177.7(C-28),171.4,165.8,144.0(C-13),136.7,133.7,133.6,133.3,130.1,129.9,128.8,128.6,128.5,128.2,122.6(C-12),99.3(C-1″),93.5(C-1′),88.7(C-3),81.2(C-3″),71.9,70.8,70.2,69.9,68.5,67.2,66.1,62.7,60.6,55.7,47.8,46.9,46.1,41.9,41.6,39.5,38.9,38.3,37.1,34.1,33.3,32.9,32.5,30.9,28.7,27.8,26.1,23.8,23.6,23.2,21.3,21.1,18.5,17.9,17.1,16.9,15.5,14.4;ESI-MS:m/z 1159.7(M+Na+).
合成化合物18:
将上述中间体59(0.04mmol)分别溶于二氯甲烷和甲醇(V∶V=1∶1,10mL)的混合溶剂中,加入10%Pd-C(50mg)和2滴醋酸,1个大气压氢气作用下反应4小时。反应完毕后,过滤除去Pd-C,减压浓缩得到白色固体,直接投入到下一步反应中。
将上一步所得白色固体分别溶于二氯甲烷和甲醇(V∶V=1∶2,10mL)的混合溶剂中,加入甲醇钠(100mg),室温反应8小时后,加入阳离子交换树脂终止反应,过滤,减压浓缩,所得残渣经硅胶柱层析精制分别得白色泡沫状固体18。收率73.8%;[α]D 20+78.3(c 0.84,CH3OH);IR(KBr)νmax 3420,2941,1688,1455,1139,1066cm-1;1H NMR(CD3OD,600MHz):δ5.24(t,J=3.3Hz,1H,H-12),5.05(d,J=3.3Hz,1H,H-1′),4.95(d,J=1.1Hz,1H,H-1″),3.95(dd,J=3.3,1.6Hz,1H,H-2″),3.91(dd,J=9.9,3.3Hz,1H,H-3′),3.87(m,2H,H-2′,H-4′),3.85(dd,J=9.8,3.3Hz,1H,H-5′-1),3.75(qd,J=9.9,6.0Hz,1H,H-5″),3.66(dd,J=9.4,3.3Hz,1H,H-3″),3.57(dd,J=12.1,1.6Hz,1H,H-5′-2),3.40(t-like,J=9.9,9.3Hz,1H,H-4″),3.20(dd,J=12.1,4.4Hz,1H,H-3),2.84(dd,J=12.1,3.8Hz,1H,H-18),1.26(d,J=6.0Hz,3H,H-6″),1.16,1.03,0.96,0.94,0.91,0.85,0.82(s each,3H each,CH3×7);13C NMR(CD3OD,150MHz):δ182.1(C-28),145.4(C-13),123.7(C-12),103.8(C-1″),96.0(C-1′),83.3(C-3),77.3,73.9,72.5,72.2,71.4,70.3,64.8,64.4,57.2,47.8,47.4,43.0,42.9,40.7,39.8,39.5,38.3,35.1,34.2,34.0,33.7,31.8,29.4,29.0,26.6,24.7,24.2,24.1,22.8,19.6,18.2,17.9,17.4,16.1;ESI-HRMS:m/zcalcd for[M-H+]C41H65O11:733.4527;found:733.4543.
实施例6,化合物1~23的脂肪酶抑制活性实验:
上述的化合物1~23进行对胰脂肪酶的抑制活性测定,将三油酸脂(80mg),卵磷脂(10mg)和牛磺胆酸(5mg)悬浮于含有0.1M NaCl的0.1M TES生物缓冲液中超声波处理5分钟,然后将胰脂肪酶(50μL)分别与上述齐墩果烷型三萜皂苷(100μL)(以Orlistat为阳性对照,DMSO为空白对照)加入到超声处理过的底物中,在约37℃温度下培养30分钟;培养过的混合物加入到含有2%(v/v)甲醇的3mL氯仿和正庚烷(v∶v,1∶1)的混合溶液中,水平振荡10分钟后,离心10分钟,吸除上层水相,下层的有机相中加入1mL铜试剂,振荡10分钟,离心10分钟,取出0.5mL 0.1%(w/v)浴铜灵,在480nm处测量其吸收值。结果显示,与阳性对照Orlistat比较,本发明的齐墩果烷型三萜皂苷化合物,对胰脂肪酶表现出了很好的抑制活性(如图1所示),并且水溶性好,能用于制备治疗肥胖症的药物。
其中,化合物1的R1=β-D-葡萄糖-(1→6)-O-β-D-葡萄糖基,R2=β-D-木糖-(1→3)-O-α-L-鼠李糖-(1→2)-O-β-D-木糖基;化合物2的R1=β-D-葡萄糖-(1→6)-O-β-D-葡萄糖基,R2=β-D-葡萄糖-(1→3)-O-α-L-鼠李糖-(1→2)-O-β-D-木糖基;化合物3的R1=β-D-葡萄糖-(1→6)-O-β-D-葡萄糖基,R2=β-D-葡萄糖-(1→4)-O-β-D-葡萄糖-(1→3)-O-α-L-鼠李糖-(1→2)-O-β-D-木糖基;化合物4的R1=H,R2=β-D-葡萄糖-(1→4)-O-β-D-木糖-(1→3)-O-α-L-鼠李糖-(1→2)-O-β-D-木糖基;化合物5的R1=H,R2=β-D-木糖-(1→3)-O-α-L-鼠李糖-(1→2)-O-α-L-阿拉伯糖基;化合物6的R1=H,R2=β-D-葡萄糖-(1→3)-O-α-L-鼠李糖-(1→2)-O-α-L-阿拉伯糖基;化合物7的R1=H,R2=β-D-葡萄糖-(1→4)-O-β-D-葡萄糖-(1→3)-O-α-L-鼠李糖-(1→2)-O-α-L-阿拉伯糖基;化合物8的R1=H,R2=β-D-葡萄糖-(1→4)-O-β-D-葡萄糖-(1→3)-O-α-L-鼠李糖-(1→2)-[β-D-葡萄糖-(1→4)]-O-α-L-阿拉伯糖基;化合物9的R1=H,R2=β-D-木糖-(1→3)-O-α-L-鼠李糖-(1→2)-O-β-D-木糖基;化合物10的R1=H,R2=β-D-葡萄糖-(1→3)-O-α-L-鼠李糖-(1→2)-O-β-D-木糖基;化合物11的R1=H,R2=α-L-鼠李糖-(1→3)-O-α-L-鼠李糖-(1→2)-O-β-D-木糖基;化合物12的R1=H,R2=β-D-葡萄糖-(1→4)-O-β-D-葡萄糖-(1→3)-O-α-L-鼠李糖-(1→2)-O-α-L-阿拉伯糖基;化合物13的R1=H,R2=α-L-鼠李糖-(1→2)-O-α-L-阿拉伯糖基;化合物14的R1=H,R2=α-L-鼠李糖-(1→2)-O-β-D-木糖基;化合物15的R1=H,R2=α-L-鼠李糖-(1→2)-O-β-D-葡萄糖基;化合物16的R1=H,R2=α-L-鼠李糖-(1→2)-O-β-D-半乳糖基;化合物17的R1=H,R2=β-L-鼠李糖-(1→2)-O-α-L-阿拉伯糖基;化合物18的R1=H,R2=α-L-鼠李糖-(1→2)-O-β-L-阿拉伯糖基;化合物19的R1=H,R2=2,3-二-α-L-鼠李糖-O-β-D-葡萄糖基;化合物20的R1=H,R2=α-L-鼠李糖-(1→3)-O-β-D-葡萄糖基;化合物21的R1=H,R2=2,3-二-α-L-鼠李糖-4,6-苄叉基-O-β-D-半乳糖基;化合物22的R1=H,R2=α-L-鼠李糖-(1→3)-O-β-D-半乳糖基;化合物23的R1=α-L-鼠李糖-(1→4)-O-β-D-葡萄糖-(1→6)-O-β-D-葡萄糖基,R2=α-L-鼠李糖-(1→2)-O-β-D-木糖基。
Claims (7)
1.齐墩果烷型三萜皂苷,其特征是,其结构式如下示:
其中,
R1选自H,D-葡萄糖-(1→6)-D-葡萄糖基或L-鼠李糖-(1→4)-D-葡萄糖-(1→6)-D-葡萄糖基;
R2选自L-鼠李糖-(1→2)-D-木糖基,L-鼠李糖-(1→2)-L-阿拉伯糖基,L-鼠李糖-(1→2)-D-葡萄糖基,L-鼠李糖-(1→2)-D-半乳糖基,L-鼠李糖-(1→3)-D-葡萄糖基,L-鼠李糖-(1→3)-D-半乳糖基,L-鼠李糖-(1→3)-[L-鼠李糖-(2→3)]-D-葡萄糖基,L-鼠李糖-(1→3)-[L-鼠李糖-(2→3)]-4,6-苄叉基-D-半乳糖基,D-木糖-(1→3)-L-鼠李糖-(1→→2)-D-木糖基,D-葡萄糖-(1→3)-L-鼠李糖-(1→2)-D-木糖基,D-葡萄糖-(1→4)-D-葡萄糖-(1→3)-L-鼠李糖-(1→2)-D-木糖基,L-鼠李糖-(1→3)-L-鼠李糖-(1→2)-D-木糖基,D-木糖-(1→3)-L-鼠李糖-(1→2)-L-阿拉伯糖基,D-葡萄糖-(1→3)-L-鼠李糖-(1→2)-L-阿拉伯糖基,D-葡萄糖-(1→4)-D-葡萄糖-(1→3)-L-鼠李糖-(1→2)-L-阿拉伯糖基,D-葡萄糖-(1→4)-D-木糖-(1→3)-L-鼠李糖-(1→2)-L-阿拉伯糖基或D-葡萄糖-(1→4)-D-葡萄糖-(1→3)-L-鼠李糖-(1→2)-[D-葡萄糖-(1→4)]-L-阿拉伯糖基。
2.按权利要求1所述的齐墩果烷型三萜皂苷,其特征是,其中所述的
R1选自H,β-D-葡萄糖-(1→6)-β-D-葡萄糖基或α-L-鼠李糖-(1→4)-β-D-葡萄糖-(1→6)-β-D-葡萄糖基;
R2选自α-L-鼠李糖-(1→2)-β-D-木糖基,α-L-鼠李糖-(1→2)-α-L-阿拉伯糖基,β-L-鼠李糖-(1→2)-α-L-阿拉伯糖基,α-L-鼠李糖-(1→2)-β-L-阿拉伯糖基,α-L-鼠李糖-(1→2)-β-D-葡萄糖基,α-L-鼠李糖-(1→2)-β-D-半乳糖基,α-L-鼠李糖-(1→3)-β-D-葡萄糖基,α-L-鼠李糖-(1→3)-β-D-半乳糖基,α-L-鼠李糖-(1→3)-[α-L-鼠李糖-(2→3)]-β-D-葡萄糖基,α-L-鼠李糖-(1→3)-[α-L-鼠李糖-(2→3)]-4,6-苄叉基-β-D-半乳糖基,β-D-木糖-(1→3)-α-L-鼠李糖-(1→2)-β-D-木糖基,β-D-葡萄糖-(1→3)-α-L-鼠李糖-(1→2)-β-D-木糖基,β-D-葡萄糖-(1→4)-β-D-葡萄糖-(1→3)-α-L-鼠李糖-(1→2)-β-D-木糖基,α-L-鼠李糖-(1→3)-α-L-鼠李糖-(1→2)-β-D-木糖基,β-D-木糖-(1→3)-α-L-鼠李糖-(1→2)-α-L-阿拉伯糖基,β-D-葡萄糖-(1→3)-α-L-鼠李糖-(1→2)-α-L-阿拉伯糖基,β-D-葡萄糖-(1→4)-β-D-葡萄糖-(1→3)-α-L-鼠李糖-(1→2)-α-L-阿拉伯糖基,β-D-葡萄糖-(1→4)-β-D-木糖-(1→3)-α-L-鼠李糖-(1→2)-α-L-阿拉伯糖基或β-D-葡萄糖-(1→4)-β-D-葡萄糖-(1→3)-α-L-鼠李糖-(1→2)-[β-D-葡萄糖-(1→4)]-α-L-阿拉伯糖基。
3.按权利要求1所述的齐墩果烷型三萜皂苷,其特征是,其中所述的R1和R2中的糖基为吡喃或呋喃型。
4.按权利要求1或2所述的齐墩果烷型三萜皂苷,其特征是,所述的齐墩果烷型三萜皂苷化合物为下述化合物中的任一种:
化合物1,其R1=β-D-葡萄糖-(1→6)-O-β-D-葡萄糖基,R2=β-D-木糖-(1→3)-O-α-L-鼠李糖-(1→2)-O-β-D-木糖基;
化合物2,其R1=β-D-葡萄糖-(1→6)-O-β-D-葡萄糖基,R2=β-D-葡萄糖-(1→3)-O-α-L-鼠李糖-(1→2)-O-β-D-木糖基;
化合物3,其R1=β-D-葡萄糖-(1→6)-O-β-D-葡萄糖基,R2=β-D-葡萄糖-(1→4)-O-β-D-葡萄糖-(1→3)-O-α-L-鼠李糖-(1→2)-O-β-D-木糖基;
化合物4,其R1=H,R2=β-D-葡萄糖-(1→4)-O-β-D-木糖-(1→3)-O-α-L-鼠李糖-(1→2)-O-β-D-木糖基;
化合物5,其R1=H,R2=β-D-木糖-(1→3)-O-α-L-鼠李糖-(1→2)-O-α-L-阿拉伯糖基;
化合物6,其R1=H,R2=β-D-葡萄糖-(1→3)-O-α-L-鼠李糖-(1→2)-O-α-L-阿拉伯糖基;
化合物7,其R1=H,R2=β-D-葡萄糖-(1→4)-O-β-D-葡萄糖-(1→3)-O-α-L-鼠李糖-(1→2)-O-α-L-阿拉伯糖基;
化合物8,其R1=H,R2=β-D-葡萄糖-(1→4)-O-β-D-葡萄糖-(1→3)-O-α-L-鼠李糖-(1→2)-[β-D-葡萄糖-(1→4)]-O-α-L-阿拉伯糖基;
化合物9,其R1=H,R2=β-D-木糖-(1→3)-O-α-L-鼠李糖-(1→2)-O-β-D-木糖基;
化合物10,其R1=H,R2=β-D-葡萄糖-(1→3)-O-α-L-鼠李糖-(1→2)-O-β-D-木糖基;
化合物11,其R1=H,R2=α-L-鼠李糖-(1→3)-O-α-L-鼠李糖-(1→2)-O-β-D-木糖基;
化合物12,其R1=H,R2=β-D-葡萄糖-(1→4)-O-β-D-葡萄糖-(1→3)-O-α-L-鼠李糖-(1→2)-O-α-L-阿拉伯糖基;
化合物13,其R1=H,R2=α-L-鼠李糖-(1→2)-O-α-L-阿拉伯糖基;化合物14的R1=H,R2=α-L-鼠李糖-(1→2)-O-β-D-木糖基;
化合物15,其R1=H,R2=α-L-鼠李糖-(1→2)-O-β-D-葡萄糖基;
化合物16的R1=H,R2=α-L-鼠李糖-(1→2)-O-β-D-半乳糖基;
化合物17,其R1=H,R2=β-L-鼠李糖-(1→2)-O-α-L-阿拉伯糖基;
化合物18,其R1=H,R2=α-L-鼠李糖-(1→2)-O-β-L-阿拉伯糖基;
化合物19,其R1=H,R2=2,3-二-α-L-鼠李糖-O-β-D-葡萄糖基;
化合物20,其R1=H,R2=α-L-鼠李糖-(1→3)-O-β-D-葡萄糖基;
化合物21,其R1=H,R2=2,3-二-α-L-鼠李糖-4,6-苄叉基-O-β-D-半乳糖基;
化合物22,其R1=H,R2=α-L-鼠李糖-(1→3)-O-β-D-半乳糖基;
化合物23,其R1=α-L-鼠李糖-(1→4)-O-β-D-葡萄糖-(1→6)-O-β-D-葡萄糖基,R2=α-L-鼠李糖-(1→2)-O-β-D-木糖基。
5.权利要求1的齐墩果烷型三萜皂苷在制备治疗肥胖症药物中的应用。
6.权利要求2所述的齐墩果烷型三萜皂苷在制备治疗肥胖症药物中的应用。
7.权利要求4的任一种化合物在制备治疗肥胖症药物中的应用。
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