CN108191944A - 海洋微生物来源的二倍半萜AsperterpinolB衍生物及合成方法与糖酶应用 - Google Patents

海洋微生物来源的二倍半萜AsperterpinolB衍生物及合成方法与糖酶应用 Download PDF

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CN108191944A
CN108191944A CN201810048404.6A CN201810048404A CN108191944A CN 108191944 A CN108191944 A CN 108191944A CN 201810048404 A CN201810048404 A CN 201810048404A CN 108191944 A CN108191944 A CN 108191944A
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naphthalen
asb
cycloocta
cyclopenta
hexamethyl
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CN108191944B (zh
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龙玉华
李婷妹
佘志刚
范炜隆
温世彤
颜樟元
郭惠娴
黄翠莹
蒋腊生
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South China Normal University
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Abstract

本发明公开了海洋微生物来源的二倍半萜Asperterpinol B衍生物及合成方法与糖酶应用。其化学结构如结构式Ⅰ的酯类衍生物、结构式Ⅱ的酰胺类衍生物、结构式Ⅲ的五元环脱水衍生物或结构式Ⅳ的八元环脱水酰胺类衍生物，或其药学上可接受的盐或立体异构体或其前药分子：R0：为X取代的碳原子数为1‑10的烷烃、烯烃、炔烃、环烷烃或苯基，X为H、Cl、Br、F、I、CN、NO2、CF3、OH、OCH3、COOH或COOCH3；R1、R2：为X取代的碳原子数为1‑10的烷烃、烯烃、炔烃、环烷烃、N/O/S杂环或苯基，X为H、Cl、Br、F、I、CN、NO2、CF3、OH、OCH3、COOH或COOCH3。本发明通过将Asperterpinol B结构修饰，得到一系列具有很好α‑葡萄糖苷酶活性的化合物，为临床治疗糖尿病提供了新候选药物分子。

Description

海洋微生物来源的二倍半萜AsperterpinolB衍生物及合成方 法与糖酶应用
技术领域
本发明涉及药物化学领域，具体地说，涉及海洋微生物来源的二倍半萜Asperterpinol B(Ze’en et al.,2013)衍生物的制备和其衍生物在α-葡萄糖苷酶抑制剂药物中的应用。
背景技术
糖尿病(DM)是一种与胰岛素产生和作用异常相关、以高血糖症为主要特征的代谢性疾病。糖尿病主要分为两大类：以胰岛素绝对缺乏为主的Ⅰ型糖尿病及以胰岛素相对缺乏和胰岛素抵抗为主的Ⅱ型糖尿病。随着人们生活水平的提高，糖尿病(DM)对人类健康的日益严重，成为全球性的公共卫生问题。据国际糖尿病联盟(IDF)有关统计表明，2015年全球糖尿病患者约4.15亿人，预计在2040年将达到6.42亿人，糖尿病已成为继肿瘤、心血管疾病之后第三位严重威胁人类健康问题的慢性疾病(IFD diabetes atlas 7th edtion，IDFreport 2014and 2015)。由于糖尿病还会导致多种慢性急并发症，造成肝、肾及心血管系统的损害，因此解决糖尿病疾病问题刻不容缓。
糖尿病与α-葡萄糖苷酶有密切关系。淀粉等碳水化合物类食物在摄入人体后并不能直接被吸收，而是在口腔及胃肠道等各种消化酶的作用下逐步水解成葡萄糖才能被小肠吸收。α-葡萄糖苷酶(AG)是存在于小肠上端粘膜上的消化酶，能水解二糖或者多糖的α-1,4糖苷键，进而将多糖水解成葡萄糖和其他寡糖。α -葡萄糖苷酶抑制剂(AGI)可以竞争性与AG的催化位点结合，抑制AG催化活性，延缓多糖水解成葡萄糖和其他可吸收寡糖，进而使血糖维持在正常水平，防止高血糖和其他并发症的发生(Azuma et al 2011)。某些AGI也可非竞争性的与 AG的其他位点结合来抑制AG的催化活性。目前市场上治疗糖尿病的药物已经开发，如阿卡波糖、二甲双胍、格列美脲和瑞格列奈等，但是这些药物存在膨胀，腹胀、肠胃气胀、腹泻、肠气囊肿胀的等不良反应，长期服用会导致患者体重增加，易发生低血糖不良反应(Kihara et al.,1997；Güemes et al.,2016)。糖尿病药物虽然能较好的控制空腹血糖含量，但是不能完全控制餐后血糖的升高。因此人们迫切需要一种能有效降低高血糖，能控制餐后血糖含量，无毒副作用的α-葡萄糖苷酶抑制剂。
海洋特殊生态环境中的生物，其代谢产物丰富新颖，是具有新药开发潜力的新领域，拓展新药的重要资源。人们从海洋生物中提取出的海洋天然产物代谢物如萜类、甾醇类、多糖、生物碱、脂肪酸和蛋白质，这些海洋天然产物具有良好的生物活性包括抗菌、抗真菌、抗原生生物、抗结核、抗病毒、抗炎、酶抑制剂等药理活性，对开发高效安全的α-葡萄糖苷酶抑制剂提供重要资源。人们发现萜类具有良好的α-葡萄糖苷酶抑制活性，如从Diospyros mespiliformis中分离的三萜羽扇豆醇(Mohamed et al.,2009)，从Alpinianigra中分离出的二萜化合物半日花烷二萜(Ghosh et al.,2015)，从海绵分离出来的dysidine(Li et al.,2009；Zhang et al.,2009)都有较好的α-葡萄糖苷酶抑制活性。
本专利的Asperterpinol B是一种结构稀有的的5/8/6/6的四环骨架，从红树林内生真菌曲霉菌085242中分离出来的二倍半萜。因此本发明对其进行结构修饰，得到一系列对α-葡萄糖苷酶有良好抑制活性的化合物，为临床治疗糖尿病症选择提供了新的药物。
发明内容
本发明的目的之一是提供一类对糖尿病症具有良好治疗效果的二倍半萜Asperterpinol B的衍生物或其药学上可接受的盐或立体异构体及其前药分子。
实现上述目的的技术方案如下：
通过与酸酐反应形成酯键或与胺反应形成酰胺键或五元环脱水或八元环脱水形成的二倍半萜Asperterpinol B的衍生物或者其药学上可接受的盐或立体异构体或其前药分子，具有式Ⅰ，Ⅱ，Ⅲ或Ⅳ的结构。
通过与酸酐类化合物构成酯键的二倍半萜Asperterpinol B的衍生物中，酸酐化合物优选地，酸酐化学结构可不同，包括，但不局限于，乙酸酐、丙酸酐、丁酸酐、异丁酸酐、正己酸酐、丁二酸酐、戊二酸酐、一氯二氟乙酸酐；通过与胺类化合物构成酰胺键的二倍半萜Asperterpinol B的衍生物中，胺类化学结构可不同，包括，但不局限于，正丙胺，环己胺，呋喃甲胺，苯乙胺，噻吩甲按，环己烯乙胺，噻吩乙胺，对溴苯胺，庚胺，呋喃乙胺，4-(2-氨乙基)吗啉，二烯丙氨，四氢吡咯烷，o-苄基羟胺，四氢异喹啉，N-(3-氨丙基)-吗啡啉，吗啡，1-三氟甲基环戊氨，对甲氧基苯胺，环丙氨，环戊胺，萘胺，3-溴-吡啶-2-氨，3-溴-1-氢吡唑-4-氨。
本发明的另一目的是提供二倍半萜Asperterpinol B衍生物的合成方法。
实现上述目的技术方案如下：
通过与酸酐反应形成酯键或与胺反应形成酰胺键或五元环脱水或八元环脱水形成的二倍半萜Asperterpinol B的衍生物。
1)二倍半萜Asperterpinol B与酰卤、羧酸、酸酐反应成具有式Ⅰ结构的酯类衍生物。
2)结构式为的二倍半萜Asperterpinol B衍生物与胺类化合物反应生成具有结构式Ⅱ的酰胺类衍生物。
3)二倍半萜Asperterpinol B在三氟化硼乙醚作用下五元环脱水生成具有式Ⅲ的衍生物。
4)结构为的二倍半萜Asperterpinol B先与无水二氯亚砜反应生成中间体酰氯再与胺类化合物反应生成具有式Ⅳ的衍生物。
所述胺类化合物为伯胺或仲胺。
本发明的另一目的是提供一种治疗糖尿病症的药用化合物。
实现上述目的技术方案如下：
一种治疗糖尿病症的药用衍生物，其药学活性成份通过与酸酐反应形成酯键或与胺反应形成酰胺键或五元环脱水或八元环脱水形成的二倍半萜Asperterpinol B的衍生物或者其药学上可接受的盐或立体异构体或其前药分子。
本发明的另一目的是提供上述二倍半萜Asperterpinol B的衍生物或者其药学上可接受的盐或立体异构体或其前药分子的应用。
实现上述目的技术方案如下：
上述通过通过与酸酐反应形成酯键或与胺反应形成酰胺键或五元环脱水或八元环脱水形成的二倍半萜Asperterpinol B的衍生物或者其药学上可接受的盐或立体异构体或其前药分子在制备对α-葡萄糖苷酶抑制剂药物中的应用。
本发明通过将二倍半萜Asperterpinol B进行衍生化，得到新的化学实体，得到的新化合物具有很好的治疗糖尿病症的效果，为临床治疗选择提供了新的药物。
具体实施方式
通过以下实施例对本发明具体实施方法进行描述，但该实施例并非用于限制本发明的保护范围。
实施例1
AsB-1:(2aS,6aS,6bS,12S,12aS,13R,13aS,Z)-2a,5,5,9,12,13a-hexamethyl-2,2a,3, 4,5,6,6a,6b,7,8,12,12a,13,13a-tetradecahydro-1H-cyclopenta[4,5]cycloocta[1,2-a]nap hthalen-13-ol的合成
实验步骤：
称取AsB(38.7mg，0.103mmol，1eq)于50ml的圆底烧瓶，加入2ml二氯甲烷溶解，1ml注射器滴加三氟化硼乙醚(质量分数为46.5％-49.5％)(50ul， 0.135mmol，1.3eq)于溶液中，室温搅拌反应半小时，半小时反应完加三乙胺停止反应，调节PH至中性，加饱和食盐水15ml及二氯甲烷(3×20ml)萃取，分离得有机相，加无水硫酸镁干燥，减压蒸馏得粗产品，石油醚/乙酸乙酯体系 (V:V＝1：10)柱层析得白色固体38.5mg，产率为95％。
白色固体,产率为95％,m.p.122.5-124.7℃.1H NMR(500MHz,CDCl3)δ5.60 (d,J＝11.3Hz,1H),5.15–4.68(m,1H),3.94(d,J＝5.8Hz,1H),3.16(s,1H),2.66 (dd,J＝18.5,5.5Hz,1H),2.41(dd,J＝11.1,9.8Hz,1H),2.26–2.17(m,1H),1.90 (dd,J＝13.9,10.4Hz,1H),1.85–1.76(m,2H),1.64(s,3H),1.42(ddd,J＝11.4,9.6, 3.7Hz,3H),1.34–1.21(m,4H),1.19–1.10(m,2H),1.08–1.02(m,2H),0.97(t,J ＝10.3Hz,1H),0.91(s,3H),0.89(s,3H),0.87(d,J＝5.4Hz,3H),0.83(s,3H),0.64 (d,J＝7.2Hz,3H).
EIMS:calcd for C25H40O:356.58.Found:356.
实施例2
AsB-S1:(2aS,6aS,6bS,11R,12R,12aS,13R,13aS,Z)-13-hydroxy-2a,5,5,9,12,13a- hexamethyl-2,2a,3,4,5,6,6a,6b,7,8,10,11,12,12a,13,13a-hexadecahydro-1H-cyclopenta [4,5]cycloocta[1,2-a]naphthalen-11-yl acetate的合成
实验步骤：
称取AsB(42.3mg，0.11mmol，1eq)于50ml两口圆底烧瓶，加2ml无水吡啶溶解，加入酸酐(1.1mmol，10eq)，置于90℃油浴锅冷凝回流反应，TLC跟踪反应直至反应完全。冷却至室温加2M HCl溶液停反应，调节溶液PH至2，搅拌 15min，加饱和食盐水15ml和EA(3×15ml)萃取得有机相，无水硫酸镁干燥，减压蒸馏得粗产品，石油醚乙酸乙酯体系(V:V＝1:2)柱层析得纯白色固体。
白色固体,产率为67.6％,m.p.58.2-60.8℃.1H NMR(500MHz,CDCl3)δ 4.73(d,J＝6.5Hz,1H),4.57(d,J＝10.7Hz,1H),2.99(d,J＝2.1Hz,1H),2.79(dd, J＝17.7,6.6Hz,1H),2.61(t,J＝14.7Hz,1H),2.29–2.17(m,2H),2.03(s,3H), 1.68(ddd,J＝10.2,9.7,5.8Hz,2H),1.63(s,3H),1.60(dd,J＝13.1,6.0Hz,1H), 1.53(td,J＝11.4,3.8Hz,1H),1.40(td,J＝13.5,3.8Hz,2H),1.35–1.25(m,6H), 1.21–1.10(m,3H),1.09(s,3H),0.91(s,3H),0.90–0.84(m,6H),0.78(s,3H).
HRMS(ESI)for[M+Na]+:calcd for C27H44O3Na:439.31827.Found:439.31755.
实施例3
AsB-S2:(2aS,6aS,6bS,11R,12R,12aS,13R,13aS,Z)-13-hydroxy-2a,5,5,9,12,13a-h examethyl-2,2a,3,4,5,6,6a,6b,7,8,10,11,12,12a,13,13a-hexadecahydro-1H-cyclopenta[ 4,5]cycloocta[1,2-a]naphthalen-11-yl butyrate的合成
实验步骤：同实施例2
白色固体,产率为72.04％,m.p.51.7-54.7℃.1H NMR(500MHz,CDCl3)δ4.75 (d,J＝6.5Hz,1H),4.57(d,J＝10.7Hz,1H),3.01(d,J＝1.8Hz,1H),2.78(dd,J＝ 17.8,6.5Hz,1H),2.62(t,J＝14.8Hz,1H),2.22(ddd,J＝18.3,14.3,7.0Hz,4H), 1.73–1.65(m,3H),1.64(d,J＝0.5Hz,1H),1.63(s,3H),1.62–1.49(m,2H),1.43 –1.36(m,2H),1.35–1.24(m,6H),1.19–1.09(m,3H),1.08(s,3H),0.97–0.92(m, 3H),0.91(s,3H),0.88(d,J＝6.8Hz,6H),0.77(s,3H).
HRMS(ESI)for[M+Na]+:calcd for C29H48O3Na:467.34957.Found:467.3492.
实施例4
AsB-S3:4-(((2aS,6aS,6bS,11R,12R,12aS,13R,13aS,Z)-13-hydroxy-2a,5,5,9,12,1 3a-hexamethyl-2,2a,3,4,5,6,6a,6b,7,8,10,11,12,12a,13,13a-hexadecahydro-1H-cyclop enta[4,5]cycloocta[1,2-a]naphthalen-11-yl)oxy)-4-oxobutanoic acid的合成
实验步骤：同实施例2
白色固体，产率为81％；m.p.130.1-131.7℃；1H NMR(400MHz,CDCl3)δ4.77 (d,J＝6.5Hz,1H),4.55(d,J＝10.8Hz,1H),2.99(s,1H),2.77(dd,J＝17.7,6.5Hz, 1H),2.63(ddd,J＝26.4,11.6,7.3Hz,5H),2.21(dd,J＝20.9,13.6Hz,2H),1.67(d, J＝8.4Hz,2H),1.63(s,3H),1.61–1.46(m,2H),1.46–1.20(m,8H),1.14(dd,J＝ 17.8,14.0Hz,3H),1.07(s,3H),0.90(s,3H),0.88–0.82(m,6H),0.77(s,3H)；13C NMR(100MHz,CDCl3)δ:177.17,171.80,132.70,127.20,77.32,77.00,76.68, 47.66,43.00,42.00,40.20,38.56,38.47,37.49,36.69,36.25,33.98,33.80,33.41, 31.44,29.39,29.04,29.00,25.95,25.62,23.43,17.47,15.91,12.37；
HRMS(ESI)for[M-H]-:calcd for C29H45O5：473.32615.Found:473.32678.
实施例5
AsB-S4:(2aS,6aS,6bS,11R,12R,12aS,13R,13aS,Z)-13-hydroxy-2a,5,5,9,12,13a- hexamethyl-2,2a,3,4,5,6,6a,6b,7,8,10,11,12,12a,13,13a-hexadecahydro-1H-cyclopenta [4,5]cycloocta[1,2-a]naphthalen-11-yl propionate的合成
实验步骤：同实施例2
白色固体,产率为78.08％,m.p.108.8-109.4℃.1H NMR(400MHz,CDCl3)δ 4.74(d,J＝6.4Hz,1H),4.56(d,J＝10.7Hz,1H),2.99(s,1H),2.78(dd,J＝17.8, 6.5Hz,1H),2.61(t,J＝14.6Hz,1H),2.29(q,J＝7.6Hz,2H),2.25–2.14(m,2H), 1.73–1.64(m,2H),1.62(s,3H),1.61–1.47(m,3H),1.42–1.22(m,8H),1.18– 1.15(m,1H),1.15–1.11(m,3H),1.10(s,1H),1.07(s,3H),0.89(s,3H),0.89–0.83 (m,6H),0.76(s,3H).
HRMS(ESI)for[M+Na]+:calcd for C28H46O3Na:453.33392.Found:453.33326.
实施例6
AsB-S5:5-(((2aS,6aS,6bS,11R,12R,12aS,13R,13aS,Z)-13-hydroxy-2a,5,5,9,12, 13a-hexamethyl-2,2a,3,4,5,6,6a,6b,7,8,10,11,12,12a,13,13a-hexadecahydro-1H-cyclo penta[4,5]cycloocta[1,2-a]naphthalen-11-yl)oxy)-5-oxopentanoic acid的合成
实验步骤：同实施例2
白色固体，产率为86.69％；m.p.66.1-76.9℃；1H NMR(400MHz,CDCl3)δ4.74 (d,J＝6.4Hz,1H),4.56(d,J＝10.7Hz,1H),2.98(s,1H),2.78(dd,J＝18.0,6.6Hz, 1H),2.60(t,J＝14.9Hz,1H),2.42(t,J＝7.2Hz,2H),2.36(td,J＝7.3,2.4Hz,2H), 2.25–2.15(m,2H),1.99–1.90(m,2H),1.67(d,J＝8.3Hz,1H),1.63(s,3H),1.61 –1.47(m,2H),1.43–1.24(m,10H),1.18–1.08(m,3H),1.07(s,3H),0.90(s,3H), 0.87(d,J＝4.6Hz,5H),0.76(s,3H)；
HRMS(ESI)for[M-H]-:calcd for C30H47O5:487.3418.Found:487.34256
实施例7
AsB-S6:(2aS,6aS,6bS,11R,12R,12aS,13R,13aS,Z)-13-hydroxy-2a,5,5,9,12,13a-h examethyl-2,2a,3,4,5,6,6a,6b,7,8,10,11,12,12a,13,13a-hexadecahydro-1H-cyclopenta[ 4,5]cycloocta[1,2-a]naphthalen-11-yl hexanoate的合成
实验步骤：同实施例2
白色固体,产率为86.54％,m.p.74.8-75.9℃.1H NMR(400MHz,CDCl3)δ4.74 (d,J＝6.4Hz,1H),4.57(d,J＝10.7Hz,1H),3.00(s,1H),2.78(dd,J＝17.8,6.5Hz, 1H),2.61(t,J＝14.7Hz,1H),2.30–2.24(m,2H),2.24–2.14(m,2H),1.74–1.64 (m,3H),1.63(s,3H),1.62–1.48(m,4H),1.45–1.21(m,12H),1.20–1.09(m,3H), 1.08(s,3H),0.90(s,3H),0.87(t,J＝9.8Hz,8H),0.77(s,3H).
HRMS(ESI)for[M+Na]+:calcd for C31H52O3Na:495.38087.Found:495.38027.
实施例8
AsB-S9:(2aS,6aS,6bS,11R,12R,12aS,13R,13aS,Z)-13-hydroxy-2a,5,5,9,12,13a-h examethyl-2,2a,3,4,5,6,6a,6b,7,8,10,11,12,12a,13,13a-hexadecahydro-1H-cyclopenta[ 4,5]cycloocta[1,2-a]naphthalen-11-yl isobutyrate的合成
实验步骤:同实施例2
白色固体,产率为84.18％,m.p.104.6-106.1℃.1H NMR(400MHz,CDCl3)δ 4.72(d,J＝6.4Hz,1H),4.58(d,J＝10.7Hz,1H),3.02(s,1H),2.77(dd,J＝18.0, 6.4Hz,1H),2.62(t,J＝14.9Hz,1H),2.49(dq,J＝14.0,7.0Hz,1H),2.25–2.13(m, 2H),1.73–1.65(m,2H),1.63(s,3H),1.61–1.45(m,3H),1.44–1.22(m,9H),1.15 (d,J＝1.4Hz,3H),1.13(t,J＝2.1Hz,3H),1.11–1.09(m,1H),1.08(s,3H),0.90(s, 3H),0.89–0.83(m,6H),0.75(s,3H)
HRMS(ESI)for[M+Na]+:calcd for C29H48O3Na:467.34957.Found:467.34877.
实施例9
AsB-S10:(2aS,6aS,6bS,11R,12R,12aS,13R,13aS,Z)-13-hydroxy-2a,5,5,9,12,13a- hexamethyl-2,2a,3,4,5,6,6a,6b,7,8,10,11,12,12a,13,13a-hexadecahydro-1H-cyclopenta [4,5]cycloocta[1,2-a]naphthalen-11-yl 2-chloro-2,2-difluoroacetate的合成
实验步骤：同实施例2
白色固体,产率为89％,m.p.124.8-125.4℃.1H NMR(400MHz,CDCl3)δ6.28 (d,J＝11.1Hz,1H),4.95(d,J＝6.1Hz,1H),3.34(d,J＝10.5Hz,1H),2.87(dd,J＝ 18.4,6.0Hz,1H),2.74(t,J＝13.6Hz,1H),2.40(d,J＝18.4Hz,1H),2.35–2.25(m, 1H),1.88–1.71(m,3H),1.69(s,3H),1.66–1.58(m,1H),1.44–1.08(m,11H), 1.02(s,3H),0.91(s,3H),0.88(s,3H),0.77(s,3H),0.68(d,J＝6.9Hz,3H).
实施例10
AsB-n1:(2aS,6aS,6bS,11R,12R,12aS,13R,13aS,Z)-13-hydroxy-2a,5,5,9,12,13a-h examethyl-2,2a,3,4,5,6,6a,6b,7,8,10,11,12,12a,13,13a-hexadecahydro-1H-cyclopenta[ 4,5]cycloocta[1,2-a]naphthalen-11-yl 4-oxo-4-(propylamino)butanoate的合成
实验步骤：
称取AsB-COOH(67.4mg,0.142mmol,1eq)于20ml的螺纹口样品瓶，2ml无水二氯甲烷溶解化合物，再称取EDC(57.2mg,0.298mmol,2eq)，HoBt (75.2mg,0.5565mmol,4eq)于反应液中，室温反应4h后，再加胺(0.3mmol,2eq) 反应4h-12h，TLC跟踪反应。反应完后，室温减压旋蒸除去二氯甲烷，0.5M HCl 和EA(V:V＝1:1)萃取得有机相(50ml的分液漏斗萃取)，所得有机相再转移至 125ml的分液漏斗依次加饱和食盐水(2×20ml)，5％的碳酸氢钠溶液(2×20ml)，加饱和食盐水(3×20ml)，最后测萃取的那一次的饱和食盐水的PH，PH呈中性即可。加无水硫酸钠干燥有机相，45℃减压蒸馏得粗产品，乙酸乙酯石油醚体系柱层析得纯化合物。
白色固体,产率为60.9％,m.p.66.0-66.5℃.1H NMR(500MHz,CDCl3)δ5.68 (s,1H),4.75(d,J＝6.5Hz,1H),4.57(dd,J＝21.7,8.8Hz,1H),3.19(td,J＝13.6, 6.5Hz,2H),2.98(s,1H),2.78(dd,J＝17.8,6.5Hz,1H),2.70–2.54(m,3H),2.45(t, J＝6.8Hz,2H),2.31–2.14(m,2H),1.72–1.65(m,2H),1.63(s,3H),1.54(ddt,J＝ 29.1,14.5,7.2Hz,5H),1.39(td,J＝13.8,3.6Hz,2H),1.29(ddd,J＝14.0,11.9,3.1 Hz,6H),1.15(ddd,J＝23.4,12.7,7.5Hz,3H),1.08(s,3H),0.92(d,J＝7.4Hz,2H), 0.91(s,3H),0.87(dd,J＝11.8,8.4Hz,6H),0.78(s,3H).
HRMS(ESI)for[M+Na]+:calcd for C32H53O4NNa:538.38668.Found:538.38560.
实施例11
AsB-n2:(2aS,6aS,6bS,11R,12R,12aS,13R,13aS,Z)-13-hydroxy-2a,5,5,9,12,13a-h examethyl-2,2a,3,4,5,6,6a,6b,7,8,10,11,12,12a,13,13a-hexadecahydro-1H-cyclopenta[ 4,5]cycloocta[1,2-a]naphthalen-11-yl 4-(cyclohexylamino)-4-oxobutanoate的合成
实验步骤：同实施例10
白色固体，产率40.5％,m.p.69.1-69.7℃.1H NMR(500MHz,CDCl3)δ5.53(d, J＝6.9Hz,1H),4.75(d,J＝6.5Hz,1H),4.54(d,J＝10.7Hz,1H),3.82–3.66(m, 1H),2.98(s,1H),2.76(dt,J＝25.5,12.8Hz,1H),2.67–2.55(m,3H),2.42(t,J＝ 6.8Hz,2H),2.25–2.16(m,2H),1.93–1.84(m,2H),1.73–1.64(m,4H),1.62(s, 3H),1.54(ddd,J＝22.7,11.5,7.8Hz,3H),1.43–1.23(m,10H),1.21–1.09(m,6H), 1.08(s,3H),0.90(s,3H),0.86(dd,J＝10.9,7.1Hz,6H),0.77(s,3H)
HRMS(ESI)for[M+Na]+:calcd for C35H57O4NNa:578.41798；Found:578.41690
实施例12
AsB-n3:(2aS,6aS,6bS,9Z,11R,12R,12aZ,13aS)-2a,5,5,9,12,13a-hexamethyl-2,2 a,3,4,5,6,6a,6b,7,8,10,11,12,13a-tetradecahydro-1H-cyclopenta[4,5]cycloocta[1,2-a]n aphthalen-11-yl 4-oxo-4-(propylamino)butanoate的合成
实验步骤：
称取AsB-COOH(45.4mg，0.096mmol，1eq)于50ml圆底烧瓶中，2ml无水二氯甲烷溶解，冰浴下加入二氯亚砜(42ul，0.58mmol，6eq)，冰浴下反应 6h。待原料完全转化，35℃减压蒸馏二氯甲烷及SOCl2。继续加无水二氯甲烷，冰浴下加正丙胺(26ul，0.316mmol，3.3eq)及TEA，室温搅拌反应。TLC跟踪反应完后，加2M HCl溶液调至PH至中性，加二氯甲烷及饱和食盐水萃取的得有机相，加无水硫酸钠干燥，35℃减压蒸馏得粗产品，甲醇二氯甲烷体系(V:V＝1:200)柱层析得纯化合物。
白色固体,产率为56.3％；m.p.49.9-52.0℃；1H NMR(400MHz,CDCl3)δ5.72 (s,1H),5.59(d,J＝11.3Hz,1H),4.97–4.89(m,1H),4.81(d,J＝6.0Hz,1H),3.20 (dd,J＝13.5,6.6Hz,2H),3.00(s,1H),2.75–2.63(m,3H),2.45(t,J＝6.9Hz,2H), 2.33(dd,J＝24.3,14.8Hz,2H),1.97–1.82(m,2H),1.75(td,J＝13.4,4.1Hz,1H), 1.59(d,J＝13.9Hz,3H),1.52(dt,J＝14.5,7.4Hz,2H),1.47–1.36(m,3H),1.34– 1.10(m,5H),1.08–1.01(m,2H),0.93(t,J＝8.3Hz,2H),0.89(dd,J＝8.7,4.3Hz, 7H),0.86(s,3H),0.82(s,3H),0.68(d,J＝7.2Hz,3H)
HRMS(ESI)for[M+Na]+:calcd for C32H51O3NNa:520.37612；Found:520.37544
实施例13
AsB-n4:(2aS,6aS,6bS,11R,12R,12aS,13R,13aS,Z)-13-hydroxy-2a,5,5,9,12,13a-h examethyl-2,2a,3,4,5,6,6a,6b,7,8,10,11,12,12a,13,13a-hexadecahydro-1H-cyclopenta[ 4,5]cycloocta[1,2-a]naphthalen-11-yl 4-((furan-2-ylmethyl)amino)-4-oxobutanoate 的合成
实验步骤：同实施例10
白色固体，产率90.2％,m.p.76.1-78.0℃.1H NMR(400MHz,CDCl3)δ7.33(d, J＝1.3Hz,1H),6.35–6.26(m,1H),6.21(d,J＝3.2Hz,1H),6.01(s,1H),4.74(d,J ＝6.5Hz,1H),4.54(d,J＝10.7Hz,1H),4.46–4.36(m,2H),2.96(s,1H),2.76(dd,J ＝17.8,6.5Hz,1H),2.64(t,J＝6.8Hz,2H),2.58(d,J＝14.1Hz,1H),2.48(t,J＝6.8 Hz,2H),2.25–2.14(m,2H),1.66(dd,J＝16.7,8.4Hz,3H),1.62(s,3H),1.60– 1.45(m,3H),1.42–1.33(m,2H),1.31–1.22(m,5H),1.13(dd,J＝21.4,8.7Hz, 3H),1.07(s,3H),0.91(d,J＝11.7Hz,3H),0.86(t,J＝3.4Hz,5H),0.76(s,3H). HRMS(ESI)for[M+Na]+:calcd for C34H51O5NNa:576.36594；Found:576.36511.
实施例14
AsB-n5:(2aS,6aS,6bS,11R,12R,12aS,13R,13aS,Z)-13-hydroxy-2a,5,5,9,12,13a-he xamethyl-2,2a,3,4,5,6,6a,6b,7,8,10,11,12,12a,13,13a-hexadecahydro-1H-cyclopenta[4 ,5]cycloocta[1,2-a]naphthalen-11-yl-4-oxo-4-(phenethylamino)butanoate的合成
实验步骤：同实施例10
白色固体，产率为77％,m.p.60.1-62.1℃.1H NMR(400MHz,CDCl3)δ7.31(t, J＝7.3Hz,2H),7.25–7.12(m,3H),5.64(s,1H),4.73(d,J＝6.5Hz,1H),4.54(d,J ＝10.7Hz,1H),3.51(d,J＝5.9Hz,2H),2.97(s,1H),2.85–2.72(m,3H),2.68– 2.53(m,3H),2.41(t,J＝6.7Hz,2H),2.21(dd,J＝15.2,8.9Hz,2H),1.73–1.63(m, 2H),1.62(s,3H),1.60–1.47(m,3H),1.38(dd,J＝18.4,8.0Hz,2H),1.33–1.22(m, 6H),1.14(dd,J＝21.6,9.1Hz,3H),1.07(s,3H),0.90(s,3H),0.87(t,J＝3.4Hz, 5H),0.76(s,3H)
HRMS(ESI)for[M+Na]+:calcd for C37H55O4NNa:600.40233；Found: 600.40134
实施例15
AsB-n6:(2aS,6aS,6bS,11R,12R,12aS,13R,13aS,Z)-13-hydroxy-2a,5,5,9,12,13a-he xamethyl-2,2a,3,4,5,6,6a,6b,7,8,10,11,12,12a,13,13a-hexadecahydro-1H-cyclopenta[4 ,5]cycloocta[1,2-a]naphthalen-11-yl 4-oxo-4-((thiophen-2-ylmethyl)amino)butanoate 的合成
实验步骤：同实施例10
白色固体，产率85.13％,m.p.58.1-59.0℃.1H NMR(400MHz,CDCl3)δ7.20 (dd,J＝4.9,1.1Hz,1H),6.94(dd,J＝8.4,3.5Hz,2H),6.05(s,1H),4.74(d,J＝6.4 Hz,1H),4.59(d,J＝5.6Hz,2H),4.54(d,J＝10.7Hz,1H),2.96(s,1H),2.76(dd,J ＝17.8,6.5Hz,1H),2.68–2.53(m,3H),2.48(t,J＝6.8Hz,2H),2.25–2.15(m,2H), 1.67(dd,J＝15.1,6.8Hz,2H),1.62(s,3H),1.57(dd,J＝13.0,6.1Hz,1H),1.50(dd, J＝10.8,7.8Hz,2H),1.38(dd,J＝20.9,9.2Hz,2H),1.26(dd,J＝17.3,10.2Hz,6H), 1.13(dd,J＝21.1,8.5Hz,3H),1.07(s,3H),0.89(s,3H),0.86(t,J＝3.4Hz,5H), 0.76(s,3H)
HRMS(ESI)for[M+Na]+:calcd for C34H51O4NNaS:592.3431；Found:592.34214
实施例16
AsB-n7:(2aS,6aS,6bS,11R,12R,12aS,13R,13aS,Z)-13-hydroxy-2a,5,5,9,12,13a-he xamethyl-2,2a,3,4,5,6,6a,6b,7,8,10,11,12,12a,13,13a-hexadecahydro-1H-cyclopenta[4 ,5]cycloocta[1,2-a]naphthalen-11-yl-4-((2-(cyclohex-1-en-1-yl)ethyl)amino)-4-oxobut anoate的合成
实验步骤：同实施例10
白色固体，产率为83.69％,m.p.100.3-102.8℃.1H NMR(400MHz,CDCl3)δ5.61(s,1H),5.45(s,1H),4.74(d,J＝6.5Hz,1H),4.53(d,J＝10.8Hz,1H),3.30(dd, J＝12.5,6.5Hz,2H),2.97(s,1H),2.77(dd,J＝17.7,6.5Hz,1H),2.64–2.54(m, 3H),2.43(t,J＝6.9Hz,2H),2.26–2.16(m,2H),2.10(t,J＝6.7Hz,2H),1.99(s, 2H),1.90(s,2H),1.72–1.63(m,3H),1.61(s,3H),1.60–1.46(m,5H),1.39(dd,J＝ 22.3,10.2Hz,3H),1.26(dd,J＝19.1,10.1Hz,6H),1.18–1.08(m,3H),1.07(s,3H), 0.89(s,3H),0.86(t,J＝3.4Hz,5H),0.76(s,3H).
HRMS(ESI)for[M+Na]+:calcd for C37H59O4NNa:604.43363；Found:604.43275
实施例17
AsB-n8:(2aS,6aS,6bS,11R,12R,12aS,13R,13aS,Z)-13-hydroxy-2a,5,5,9,12,13a-h examethyl-2,2a,3,4,5,6,6a,6b,7,8,10,11,12,12a,13,13a-hexadecahydro-1H-cyclopenta[ 4,5]cycloocta[1,2-a]naphthalen-11-yl-4-oxo-4-((2-(thiophen-2-yl)ethyl)amino) butanoate的合成
实验步骤：同实施例10
淡粉色固体，产率79.3％,m.p.70.3-72.2℃.1H NMR(400MHz,CDCl3)δ7.15 (d,J＝5.1Hz,1H),6.94(dd,J＝5.0,3.5Hz,1H),6.83(d,J＝3.3Hz,1H),5.85(s, 1H),4.73(d,J＝6.5Hz,1H),4.54(d,J＝10.7Hz,1H),3.56–3.47(m,2H),3.02(t, J＝6.7Hz,2H),2.97(s,1H),2.77(dd,J＝17.8,6.5Hz,1H),2.69–2.53(m,3H), 2.43(t,J＝6.8Hz,2H),2.27–2.14(m,2H),1.67(dd,J＝16.4,8.1Hz,3H),1.62(s, 3H),1.61–1.44(m,3H),1.43–1.21(m,7H),1.21–1.08(m,3H),1.05(d,J＝19.9 Hz,3H),0.96–0.89(m,3H),0.87(t,J＝3.4Hz,5H),0.76(s,3H)
HRMS(ESI)for[M+Na]+:calcd for C35H53O4NNaS:606.35875；Found: 606.35734
实施例18
AsB-n9:(2aS,6aS,6bS,11R,12R,12aS,13R,13aS,Z)-13-hydroxy-2a,5,5,9,12,13a-he xamethyl-2,2a,3,4,5,6,6a,6b,7,8,10,11,12,12a,13,13a-hexadecahydro-1H-cyclopenta[4 ,5]cycloocta[1,2-a]naphthalen-11-yl 4-((4-bromophenyl)amino)-4-oxobutanoate的合成
实验步骤：同实施例10
白色固体，产率为75.69％,m.p.194.6-195.9℃.1H NMR(400MHz,CDCl3)δ7.89(s,1H),7.39(s,4H),4.76(d,J＝6.4Hz,1H),4.54(d,J＝10.7Hz,1H),2.97(s, 1H),2.83–2.67(m,3H),2.67–2.53(m,3H),2.27–2.16(m,2H),1.72–1.64(m, 2H),1.62(s,3H),1.60–1.44(m,3H),1.43–1.19(m,8H),1.13(dd,J＝20.4,8.2Hz, 3H),1.07(s,3H),0.89(s,3H),0.87(t,J＝3.4Hz,5H),0.76(s,3H).
HRMS(ESI)for[M+Na]+:calcd for C35H50O4NBrNa:650.28154；Found:650.28136.
实施例19
AsB-n10:(2aS,6aS,6bS,11R,12R,12aS,13R,13aS,Z)-13-hydroxy-2a,5,5,9,12,13a- hexamethyl-2,2a,3,4,5,6,6a,6b,7,8,10,11,12,12a,13,13a-hexadecahydro-1H-cyclopenta [4,5]cycloocta[1,2-a]naphthalen-11-yl 4-(heptylamino)-4-oxobutanoate的合成
实验步骤：同实施例10
白色油状物，产率为70.69％，m.p.1H NMR(400MHz,CDCl3)δ5.71(s,1H), 4.73(d,J＝6.5Hz,1H),4.53(d,J＝10.7Hz,1H),3.21(dd,J＝13.0,6.6Hz,2H), 2.96(s,1H),2.76(dd,J＝17.9,6.6Hz,1H),2.66–2.53(m,3H),2.43(t,J＝6.7Hz, 2H),2.27–2.14(m,2H),1.66(dd,J＝17.3,8.6Hz,4H),1.61(s,3H),1.59–1.42(m, 4H),1.42–1.18(m,15H),1.18–1.08(m,3H),1.06(s,3H),0.89(s,3H),0.85(d,J＝ 3.4Hz,8H),0.73(d,J＝22.3Hz,3H)
HRMS(ESI)for[M+Na]+:calcd for C36H61O4NNa:594.44928；Found:594.44892
实施例20
AsB-n11:(2aS,6aS,6bS,11R,12R,12aS,13R,13aS,Z)-13-hydroxy-2a,5,5,9,12,13a- hexamethyl-2,2a,3,4,5,6,6a,6b,7,8,10,11,12,12a,13,13a-hexadecahydro-1H-cyclopent a[4,5]cycloocta[1,2-a]naphthalen-11-yl-4-((2-(furan-2-yl)ethyl)amino)-4-oxobutanoat e的合成
实验步骤：同实施例10
白色固体，产率为79.75％,m.p.56.4-58.4℃.1H NMR(400MHz,CDCl3)δ 7.32(s,1H),6.29(s,1H),6.07(s,1H),5.85(s,1H),4.73(d,J＝6.4Hz,1H),4.54(d, J＝10.4Hz,1H),3.52(d,J＝5.9Hz,2H),2.97(s,1H),2.90–2.70(m,3H),2.70– 2.51(m,3H),2.44(t,J＝6.4Hz,2H),2.22(d,J＝17.6Hz,2H),1.65(s,4H),1.62(s, 3H),1.60–1.46(m,2H),1.38(t,J＝13.7Hz,2H),1.29(d,J＝13.3Hz,5H),1.18– 1.10(m,2H),1.07(s,3H),0.90(s,3H),0.89–0.79(m,6H),0.76(s,3H)；
HRMS(ESI)for[M+Na]+:calcd for C35H53O5NNa:590.38159；Found:590.38071
实施例21
AsB-n12:(2aS,6aS,6bS,11R,12R,12aS,13R,13aS,Z)-13-hydroxy-2a,5,5,9,12,13a- hexamethyl-2,2a,3,4,5,6,6a,6b,7,8,10,11,12,12a,13,13a-hexadecahydro-1H-cyclopenta [4,5]cycloocta[1,2-a]naphthalen-11-yl 4-((2-morpholinoethyl)amino)-4-oxobutanoate 的合成
实验步骤：同实施例10
白色固体,产率为51.77％,m.p.64.0-66.2℃.1H NMR(400MHz,CDCl3)δ6.21 (s,1H),4.71(d,J＝6.4Hz,1H),4.51(d,J＝7.3Hz,1H),3.76–3.60(m,4H),3.32 (dd,J＝11.1,5.5Hz,2H),2.94(s,1H),2.74(dd,J＝17.8,6.6Hz,1H),2.63–2.52 (m,3H),2.50–2.32(m,8H),2.18(dd,J＝19.5,12.4Hz,3H),1.70–1.61(m,2H), 1.59(s,3H),1.57–1.53(m,1H),1.52–1.44(m,1H),1.34(d,J＝13.8Hz,2H),1.26 (d,J＝14.8Hz,5H),1.15–1.06(m,3H),1.04(s,3H),0.87(s,3H),0.86–0.79(m, 6H),0.74(s,3H)
HRMS(ESI)for[M+H]+:calcd for C35H59O5N2:587.44185；Found:587.44143.
实施例22
AsB-n13:(2aS,6aS,6bS,11R,12R,12aS,13R,13aS,Z)-13-hydroxy-2a,5,5,9,12,13a-h examethyl-2,2a,3,4,5,6,6a,6b,7,8,10,11,12,12a,13,13a-hexadecahydro-1H-cyclopenta[ 4,5]cycloocta[1,2-a]naphthalen-11-yl 4-(diallylamino)-4-oxobutanoate的合成
实验步骤：同实施例10
白色固体，产率为71.68％,m.p.66.9-68.9℃.1H NMR(400MHz,CDCl3)δ5.75(dddd,J＝22.1,16.4,10.9,5.4Hz,2H),5.25–5.06(m,4H),4.74(d,J＝6.5Hz,1H), 4.52(d,J＝10.8Hz,1H),3.96(t,J＝7.7Hz,2H),3.89(d,J＝4.8Hz,2H),2.99(s, 1H),2.76(dd,J＝17.7,6.6Hz,1H),2.60(d,J＝9.4Hz,4H),2.20(dd,J＝19.7,12.7 Hz,2H),1.73–1.62(m,3H),1.61(s,3H),1.58(d,J＝6.0Hz,1H),1.51(td,J＝11.4, 3.6Hz,1H),1.43–1.21(m,8H),1.13(dd,J＝21.6,8.8Hz,3H),1.06(s,3H),0.89(s, 3H),0.88–0.82(m,6H),0.76(s,3H)
HRMS(ESI)for[M+Na]+:calcd for C35H55O4NNa:576.40233；Found:576.40181.
实施例23
AsB-n14:(2aS,6aS,6bS,11R,12R,12aS,13R,13aS,Z)-13-hydroxy-2a,5,5,9,12,13a- hexamethyl-2,2a,3,4,5,6,6a,6b,7,8,10,11,12,12a,13,13a-hexadecahydro-1H-cyclopent a[4,5]cycloocta[1,2-a]naphthalen-11-yl 4-oxo-4-(pyrrolidin-1-yl)butanoate的合成
实验步骤：同实施例10
白色固体，产率为64.65％,m.p.148.2-148.9℃.1H NMR(400MHz,CDCl3)δ 4.73(d,J＝6.6Hz,1H),4.51(d,J＝10.8Hz,1H),3.51–3.33(m,4H),2.98(s,1H), 2.75(dd,J＝17.8,6.6Hz,1H),2.64–2.58(m,2H),2.55(d,J＝5.9Hz,2H),2.27– 2.17(m,2H),1.98–1.90(m,2H),1.87–1.79(m,2H),1.66(dd,J＝14.6,7.8Hz, 3H),1.60(s,3H),1.59–1.44(m,2H),1.37(t,J＝13.2Hz,2H),1.25(t,J＝13.7Hz, 5H),1.16–1.08(m,2H),1.06(s,3H),0.88(s,3H),0.87–0.81(m,6H),0.72(d,J＝ 20.8Hz,3H)
HRMS(ESI)for[M+Na]+:calcd for C33H53O4NNa:550.38668；Found:550.38594
实施例24
AsB-n15:(2aS,6aS,6bS,11R,12R,12aS,13R,13aS,Z)-13-hydroxy-2a,5,5,9,12,13a- hexamethyl-2,2a,3,4,5,6,6a,6b,7,8,10,11,12,12a,13,13a-hexadecahydro-1H-cyclopent a[4,5]cycloocta[1,2-a]naphthalen-11-yl 4-((benzyloxy)amino)-4-oxobutanoate的合成
实验步骤：同实施例10
白色固体，产率为71.2％,m.p.69.8-71.5℃.1H NMR(400MHz,CDCl3)δ8.59 (s,1H),7.45–7.30(m,5H),4.88(s,2H),4.71(d,J＝5.2Hz,1H),4.53(d,J＝10.7 Hz,1H),2.95(s,1H),2.76(dd,J＝17.8,6.4Hz,1H),2.58(t,J＝10.3Hz,3H),2.36 –2.13(m,4H),1.72–1.64(m,2H),1.61(s,3H),1.59–1.54(m,1H),1.50(dd,J＝ 15.3,7.3Hz,1H),1.42–1.32(m,2H),1.31–1.20(m,6H),1.17–1.07(m,3H),1.06 (s,3H),0.89(s,3H),0.88–0.82(m,6H),0.75(s,3H)
HRMS(ESI)for[M+Na]+:calcd for C36H53O5NNa:602.38159；Found: 602.38068.
实施例25
AsB-n16:(2aS,6aS,6bS,11R,12R,12aS,13R,13aS,Z)-13-hydroxy-2a,5,5,9,12,13a- hexamethyl-2,2a,3,4,5,6,6a,6b,7,8,10,11,12,12a,13,13a-hexadecahydro-1H-cyclopent a[4,5]cycloocta[1,2-a]naphthalen-11-yl-4-(3,4-dihydroisoquinolin-2(1H)-yl)-4-oxobut anoate的合成
实验步骤：同实施例10
白色固体，产率为68.9％,m.p.66.5-67.4℃.1H NMR(500MHz,CDCl3)δ7.24 –7.04(m,4H),4.76(d,J＝6.6Hz,1H),4.71(s,1H),4.64(s,1H),4.54(d,J＝10.7 Hz,1H),3.81(t,J＝5.9Hz,1H),3.70(t,J＝6.0Hz,1H),3.01(s,1H),2.91(t,J＝5.8 Hz,1H),2.84(t,J＝5.8Hz,1H),2.78(dd,J＝17.7,6.6Hz,1H),2.75–2.68(m,2H), 2.68–2.63(m,2H),2.61(t,J＝12.0Hz,1H),2.24(dd,J＝14.8,8.8Hz,2H),1.77– 1.64(m,4H),1.62(s,3H),1.57(d,J＝7.3Hz,1H),1.56–1.48(m,1H),1.42–1.33 (m,2H),1.32–1.25(m,4H),1.25–1.22(m,1H),1.13(dd,J＝11.5,4.9Hz,2H), 1.08(s,3H),0.90(s,3H),0.87(dd,J＝8.7,5.1Hz,6H),0.76(d,J＝5.0Hz,3H).
HRMS(ESI)for[M+Na]+:calcd for C38H55O4NNa:612.40233；Found:612.40165.
实施例26
AsB-n17:(2aS,6aS,6bS,11R,12R,12aS,13R,13aS,Z)-13-hydroxy-2a,5,5,9,12,13a-h examethyl-2,2a,3,4,5,6,6a,6b,7,8,10,11,12,12a,13,13a-hexadecahydro-1H-cyclopenta[ 4,5]cycloocta[1,2-a]naphthalen-11-yl 7-morpholino-4-oxoheptanoate的合成
实验步骤：同实施例10
白色固体，产率为71.95％,m.p.68.6-70.9℃.1H NMR(500MHz,CDCl3)δ6.90 (s,1H),4.72(d,J＝6.5Hz,1H),4.52(d,J＝10.4Hz,1H),3.81–3.71(m,4H),3.37 –3.28(m,2H),2.96(s,1H),2.75(dd,J＝17.7,6.6Hz,1H),2.61(t,J＝6.8Hz,2H), 2.58–2.45(m,6H),2.42(t,J＝6.8Hz,2H),2.25–2.17(m,2H),1.75–1.63(m,4H), 1.61(s,3H),1.59–1.55(m,1H),1.50(td,J＝11.4,3.6Hz,1H),1.42–1.33(m,2H), 1.29(d,J＝4.0Hz,1H),1.26(d,J＝3.3Hz,3H),1.25–1.20(m,2H),1.18–1.08(m, 3H),1.06(s,3H),0.88(d,J＝8.0Hz,3H),0.85(d,J＝6.6Hz,5H),0.76(s,3H)
实施例27
AsB-n18:(2aS,6aS,6bS,11R,12R,12aS,13R,13aS,Z)-13-hydroxy-2a,5,5,9,12,13a-h examethyl-2,2a,3,4,5,6,6a,6b,7,8,10,11,12,12a,13,13a-hexadecahydro-1H-cyclopenta[ 4,5]cycloocta[1,2-a]naphthalen-11-yl 4-morpholino-4-oxobutanoate的合成
实验步骤：同实施例10
白色固体，产率为82.9％,m.p.63.8-65.8℃.1H NMR(500MHz,CDCl3)δ4.75 (d,J＝6.5Hz,1H),4.53(d,J＝10.7Hz,1H),3.69–3.43(m,8H),2.99(s,1H),2.77 (dd,J＝17.7,6.6Hz,1H),2.64–2.59(m,4H),2.28–2.17(m,2H),1.73–1.63(m, 4H),1.62(s,3H),1.59(d,J＝5.1Hz,1H),1.51(td,J＝11.4,3.7Hz,1H),1.38(dd,J ＝21.3,8.7Hz,2H),1.32–1.21(m,6H),1.18–1.08(m,3H),1.07(s,3H),0.90(s, 3H),0.86(d,J＝4.8Hz,6H),0.76(s,3H)
HRMS(ESI)for[M+Na]+:calcd for C33H53O5NNa:566.38159；Found:566.38068.
实施例28
AsB-n19:(2aS,6aS,6bS,11R,12R,12aS,13R,13aS,Z)-13-hydroxy-2a,5,5,9,12,13a- hexamethyl-2,2a,3,4,5,6,6a,6b,7,8,10,11,12,12a,13,13a-hexadecahydro-1H-cyclopent a[4,5]cycloocta[1,2-a]naphthalen-11-yl-4-oxo-4-(2-(trifluoromethyl)pyrrolidin-1-yl) butanoate的合成
实验步骤：同实施例10
白色固体，产率为62.75％,m.p162.3-163.4℃.1H NMR(500MHz,CDCl3)δ 4.92–4.64(m,2H),4.53(t,J＝11.0Hz,1H),3.80–3.43(m,2H),2.99(s,1H),2.86 –2.65(m,3H),2.65–2.49(m,3H),2.22(dd,J＝17.8,10.5Hz,2H),2.16(s,1H), 2.15–2.09(m,1H),2.00(dt,J＝19.6,9.5Hz,2H),1.72–1.63(m,3H),1.62(s,3H), 1.61–1.56(m,1H),1.55–1.48(m,1H),1.42–1.33(m,2H),1.32–1.28(m,2H), 1.26(s,2H),1.23(dd,J＝8.5,5.5Hz,1H),1.18–1.08(m,3H),1.07(s,3H),0.90(s, 3H),0.86(d,J＝6.9Hz,6H),0.76(s,3H).
HRMS(ESI)for[M+Na]+:calcd for C34H52O4NF3Na:618.37406；Found: 618.37329.
实施例29
AsB-n20:(2aS,6aS,6bS,11R,12R,12aS,13R,13aS,Z)-13-hydroxy-2a,5,5,9,12,13a-h examethyl-2,2a,3,4,5,6,6a,6b,7,8,10,11,12,12a,13,13a-hexadecahydro-1H-cyclopenta[ 4,5]cycloocta[1,2-a]naphthalen-11-yl 4-((4-methoxyphenyl)amino)-4-oxobutanoate 的合成
实验步骤：同实施例10
白色固体，产率为75.57％,m.p.90.5-92.5℃.1H NMR(400MHz,CDCl3)δ7.58 (s,1H),7.38(d,J＝8.8Hz,2H),6.83(d,J＝8.8Hz,2H),4.76(d,J＝6.4Hz,1H), 4.53(d,J＝10.7Hz,1H),3.77(s,3H),2.97(s,1H),2.77(dd,J＝17.9,6.5Hz,1H), 2.70(t,J＝6.4Hz,2H),2.60(dd,J＝18.0,11.2Hz,3H),2.21(t,J＝12.6Hz,2H), 1.74–1.62(m,3H),1.61(s,3H),1.60–1.51(m,2H),1.49(d,J＝11.1Hz,1H),1.42 –1.22(m,7H),1.19–1.08(m,3H),1.06(s,3H),0.88(s,3H),0.87(d,J＝6.4Hz, 5H),0.76(s,3H)
HRMS(ESI)for[M+Na]+:calcd for C36H53O5NNa:602.38159；Found:602.38147.
实施例30
AsB-n21:(2aS,6aS,6bS,11R,12R,12aS,13R,13aS,Z)-13-hydroxy-2a,5,5,9,12,13a-h examethyl-2,2a,3,4,5,6,6a,6b,7,8,10,11,12,12a,13,13a-hexadecahydro-1H-cyclopenta[ 4,5]cycloocta[1,2-a]naphthalen-11-yl 4-(cyclopropylamino)-4-oxobutanoate的合成
实验步骤：同实施例10
白色固体，产率为78％,m.p.138.4-141.7℃.
HRMS(ESI)for[M+Na]+:calcd for C32H51O4NNa:536.37103；Found: 536.37073.
实施例31
AsB-n22:(2aS,6aS,6bS,11R,12R,12aS,13R,13aS,Z)-13-hydroxy-2a,5,5,9,12,13a-he xamethyl-2,2a,3,4,5,6,6a,6b,7,8,10,11,12,12a,13,13a-hexadecahydro-1H-cyclopenta[4 ,5]cycloocta[1,2-a]naphthalen-11-yl 4-(cyclopentylamino)-4-oxobutanoate的合成
实验步骤：同实施例10
白色固体，产率为80.5％,m.p.73.7-75.1℃.1H NMR(600MHz,CDCl3)δ5.65 (d,J＝6.6Hz,1H),4.74(d,J＝6.5Hz,1H),4.53(d,J＝10.7Hz,1H),4.21–4.13(m, 1H),2.97(s,1H),2.76(dd,J＝17.8,6.6Hz,1H),2.67–2.54(m,3H),2.41(t,J＝6.9 Hz,2H),2.28–2.13(m,2H),1.96(td,J＝12.8,6.9Hz,2H),1.79–1.63(m,5H), 1.61(s,3H),1.57(ddd,J＝11.3,7.5,3.6Hz,2H),1.50(td,J＝11.5,3.5Hz,1H), 1.41–1.32(m,4H),1.31–1.23(m,6H),1.17–1.09(m,3H),1.07(s,3H),0.92– 0.88(m,3H),0.86(dd,J＝13.6,9.4Hz,6H),0.77(s,3H)
HRMS(ESI)for[M+Na]+:calcd for C34H55O4NNa:564.40233；Found:564.40198.
实施例32
AsB-n23:(2aS,6aS,6bS,11R,12R,12aS,13R,13aS,Z)-13-hydroxy-2a,5,5,9,12,13a-h examethyl-2,2a,3,4,5,6,6a,6b,7,8,10,11,12,12a,13,13a-hexadecahydro-1H-cyclopenta[ 4,5]cycloocta[1,2-a]naphthalen-11-yl 4-(naphthalen-1-ylamino)-4-oxobutanoate的合成
实验步骤：同实施例10
淡粉色固体，产率为42.12％,m.p.86.1-90.1℃.1H NMR(600MHz,CDCl3)δ 8.09(s,1H),7.94(dd,J＝15.7,7.8Hz,2H),7.86(d,J＝7.9Hz,1H),7.69(d,J＝8.0 Hz,1H),7.50(ddd,J＝26.5,15.2,7.3Hz,3H),4.82(d,J＝6.2Hz,1H),4.54(d,J＝ 10.6Hz,1H),2.98(s,1H),2.81(s,4H),2.60(t,J＝14.7Hz,1H),2.24(dd,J＝20.4, 12.9Hz,2H),1.70–1.63(m,2H),1.61(s,3H),1.59–1.47(m,3H),1.41–1.31(m, 2H),1.31–1.19(m,9H),1.15–1.07(m,3H),1.06(s,3H),0.92–0.87(m,6H),0.86 (s,3H),0.76(s,3H)
HRMS(ESI)for[M+Na]+:calcd for C39H53O4NNa:622.38668；Found: 622.38612.
实施例33
AsB-n24:(2aS,6aS,6bS,11R,12R,12aS,13R,13aS,Z)-13-hydroxy-2a,5,5,9,12,13a-he xamethyl-2,2a,3,4,5,6,6a,6b,7,8,10,11,12,12a,13,13a-hexadecahydro-1H-cyclopenta[4 ,5]cycloocta[1,2-a]naphthalen-11-yl 4-((3-bromopyridin-2-yl)amino)-4-oxobutanoate 的合成
实验步骤：同实施例10
白色固体，产率为55％,m.p.57.2-59.2℃.1H NMR(600MHz,CDCl3)δ8.34(d, J＝3.9Hz,1H),8.03(s,1H),7.86(dd,J＝7.9,1.4Hz,1H),6.99–6.88(m,1H),4.77 (d,J＝6.4Hz,1H),4.54(d,J＝10.7Hz,1H),3.11–2.94(m,3H),2.78(dd,J＝17.7, 6.6Hz,1H),2.75–2.70(m,2H),2.60(t,J＝14.4Hz,1H),2.28–2.19(m,2H),1.70 –1.64(m,2H),1.62(s,3H),1.57(dd,J＝13.5,4.6Hz,1H),1.51(td,J＝11.6,3.9Hz, 1H),1.40–1.31(m,2H),1.30–1.27(m,2H),1.23(ddd,J＝16.1,7.0,4.4Hz,5H), 1.16–1.08(m,3H),1.07(s,3H),0.89(s,3H),0.89–0.85(m,6H),0.74(s,3H)
HRMS(ESI)for[M+H]+:calcd for C34H50O4N2Br:629.29485；Found:629.29474.
实施例34
AsB-n25:(2aS,6aS,6bS,11R,12R,12aS,13R,13aS,Z)-13-hydroxy-2a,5,5,9,12,13a- hexamethyl-2,2a,3,4,5,6,6a,6b,7,8,10,11,12,12a,13,13a-hexadecahydro-1H-cyclopent a[4,5]cycloocta[1,2-a]naphthalen-11-yl-4-((4-bromo-1H-pyrazol-3-yl)amino)-4-oxob utanoate的合成
实验步骤：
称取AsB-COOH(67.4mg,0.142mmol,1eq)于50ml圆底烧瓶，2ml无水1,2-二氯乙烷溶解化合物，再称取EDC(57.2mg,0.298mmol,2eq)，HoBt (75.2mg,0.5565mmol,4eq)于反应液中，室温反应4h后，再胺(0.3mmol,2eq) 80℃冷凝回流反应12h，TLC跟踪反应。反应完后，冷凝室温减压旋蒸除去溶剂， 0.5M HCl和EA(V:V＝1:1)萃取得有机相(50ml的分液漏斗萃取)，所得有机相再转移至125ml的分液漏斗依次加饱和食盐水(2×20ml)，5％的碳酸氢钠溶液 (2×20ml)，加饱和食盐水(3×20ml)，最后测萃取的那一次的饱和食盐水的 PH，PH呈中性即可。加无水硫酸钠干燥有机相，45℃减压蒸馏得粗产品，乙酸乙酯石油醚体系柱层析得纯化合物。
白色固体，产率为60.5％.1H NMR(600MHz,CDCl3)δ8.06(s,1H),4.76(d,J ＝6.5Hz,1H),4.55(d,J＝10.7Hz,1H),4.16(dd,J＝31.0,26.6Hz,1H),3.29–3.19 (m,2H),2.97(d,J＝2.2Hz,1H),2.83–2.74(m,1H),2.70(t,J＝6.7Hz,2H),2.60(t, J＝14.7Hz,1H),2.21(dt,J＝17.1,14.3Hz,2H),1.71–1.64(m,2H),1.62(s,3H), 1.61–1.55(m,1H),1.51(td,J＝11.7,3.7Hz,1H),1.41–1.34(m,2H),1.32–1.24 (m,6H),1.17–1.08(m,3H),1.07(s,3H),0.89(d,J＝8.3Hz,3H),0.87(t,J＝3.5 Hz,6H),0.74(s,3H)；
HRMS(ESI)for[M+Na]+:calcd for C32H48O4N3BrNa:640.27204；Found:640.27167.
下面为本发明化合物对α-葡萄糖苷酶抑制活性的测定结果
实验材料：PBS,pNPG，α-葡萄糖苷酶酶，多通道移液器，涡旋振荡器，多孔酶标仪，恒温混旋仪，96孔板，PH计。
试验方法：
1.待测化合物和阳性对照阿卡波糖用DMSO溶解。加10ul的待测样品或阳性对照和20ulα-葡萄糖苷酶(1.25units/ml)至160ul磷酸钠缓冲液钠溶液(100mM， PH 6.8)
2.30℃恒温混旋仪充分混合10min，后加10ul的底物(pNPG,5mM)，在 37℃恒温混旋仪充分混合20min，最后功能酶标仪测试吸光度。
3.根据吸光值计算各种化合物对α-葡萄糖苷酶的抑制率：抑制率(％)＝1- (实验组-空白组)/(阴性对照组-空白组)。
表1化合物对α-葡萄糖苷酶活性分析体系表
阳性对照为阿卡波糖
下表为部分化合物的生物活性数据：
表2化合物的α-葡萄糖苷酶活性结果(IC50μM)
以上所述实施例仅表达了本发明的几种实施方式，其描述较为具体和详细，但并不能因此而理解为对本发明专利范围的限制。应当指出的是，对于本领域的普通技术人员来说，在不脱离本发明构思的前提下，还可以做出若干变形和改进，这些都属于本发明的保护范围。因此，本发明专利的保护范围应以所附权利要求为准。

Claims (8)

1.二倍半萜Asperterpinol B衍生物，其化学结构如结构式Ⅰ的酯类衍生物、结构式Ⅱ的酰胺类衍生物、结构式Ⅲ的五元环脱水衍生物或结构式Ⅳ的八元环脱水酰胺类衍生物，或其药学上可接受的盐或立体异构体或其前药分子：
R0：为X取代的碳原子数为1-10的烷烃、烯烃、炔烃、环烷烃或苯基，X为H、Cl、Br、F、I、CN、NO2、CF3、OH、OCH3、COOH或COOCH3；
R1、R2：为X取代的碳原子数为1-10的烷烃、烯烃、炔烃、环烷烃、N/O/S杂环或苯基，X为H、Cl、Br、F、I、CN、NO2、CF3、OH、OCH3、COOH或COOCH3。
2.根据权利要求1所述的二倍半萜Asperterpinol B衍生物，其特征是，
在结构式Ⅰ中，R0为CH2CH2CH2CH2CH3、CH2CH2CH3、CH2CH3、CH(CH3)2、CH3、CF2Cl、CH2CH2COOH或CH2CH2CH2COOH；
在结构式Ⅱ中，R1为H，R2为：
在结构式Ⅳ中，R1+R2为各种环胺，包括或R1＝R2为各种烯烃，包括
3.根据权利要求1所述的二倍半萜Asperterpinol B衍生物，其特征是，所述衍生化合物选自以下：
AsB-1:(2aS,6aS,6bS,12S,12aS,13R,13aS,Z)-2a,5,5,9,12,13a-hexamethyl-2,2a,3,4,5,6,6a,6b,7,8,12,12a,13,13a-tetradecahydro-1H-cyclopenta[4,5]cycloocta[1,2-a]naphthalen-13-ol.
AsB-S1:(2aS,6aS,6bS,11R,12R,12aS,13R,13aS,Z)-13-hydroxy-2a,5,5,9,12,13a-hexamethyl-2,2a,3,4,5,6,6a,6b,7,8,10,11,12,12a,13,13a-hexadecahydro-1H-cyclopenta[4,5]cycloocta[1,2-a]naphthalen-11-yl acetate.
AsB-S2:(2aS,6aS,6bS,11R,12R,12aS,13R,13aS,Z)-13-hydroxy-2a,5,5,9,12,13a-hexamethyl-2,2a,3,4,5,6,6a,6b,7,8,10,11,12,12a,13,13a-hexadecahydro-1H-cyclopenta[4,5]cycloocta[1,2-a]naphthalen-11-yl butyrate.
AsB-S3:4-(((2aS,6aS,6bS,11R,12R,12aS,13R,13aS,Z)-13-hydroxy-2a,5,5,9,12,13a-hexamethyl-2,2a,3,4,5,6,6a,6b,7,8,10,11,12,12a,13,13a-hexadecahydro-1H-cyclopenta[4,5]cycloocta[1,2-a]naphthalen-11-yl)oxy)-4-oxobutanoic acid.
AsB-S4:(2aS,6aS,6bS,11R,12R,12aS,13R,13aS,Z)-13-hydroxy-2a,5,5,9,12,13a-hexamethyl-2,2a,3,4,5,6,6a,6b,7,8,10,11,12,12a,13,13a-hexadecahydro-1H-cyclopenta[4,5]cycloocta[1,2-a]naphthalen-11-yl propionate.
AsB-S5:5-(((2aS,6aS,6bS,11R,12R,12aS,13R,13aS,Z)-13-hydroxy-2a,5,5,9,12,13a-hexamethyl-2,2a,3,4,5,6,6a,6b,7,8,10,11,12,12a,13,13a-hexadecahydro-1H-cyclopenta[4,5]cycloocta[1,2-a]naphthalen-11-yl)oxy)-5-oxopentanoic acid.
AsB-S6:(2aS,6aS,6bS,11R,12R,12aS,13R,13aS,Z)-13-hydroxy-2a,5,5,9,12,13a-hexamethyl-2,2a,3,4,5,6,6a,6b,7,8,10,11,12,12a,13,13a-hexadecahydro-1H-cyclopenta[4,5]cycloocta[1,2-a]naphthalen-11-yl hexanoate.
AsB-S9:(2aS,6aS,6bS,11R,12R,12aS,13R,13aS,Z)-13-hydroxy-2a,5,5,9,12,13a-hexamethyl-2,2a,3,4,5,6,6a,6b,7,8,10,11,12,12a,13,13a-hexadecahydro-1H-cyclopenta[4,5]cycloocta[1,2-a]naphthalen-11-yl isobutyrate.
AsB-S10:(2aS,6aS,6bS,11R,12R,12aS,13R,13aS,Z)-13-hydroxy-2a,5,5,9,12,13a-hexamethyl-2,2a,3,4,5,6,6a,6b,7,8,10,11,12,12a,13,13a-hexadecahydro-1H-cyclopenta[4,5]cycloocta[1,2-a]naphthalen-11-yl 2-chloro-2,2-difluoroacetate.
AsB-n1:(2aS,6aS,6bS,11R,12R,12aS,13R,13aS,Z)-13-hydroxy-2a,5,5,9,12,13a-hexamethyl-2,2a,3,4,5,6,6a,6b,7,8,10,11,12,12a,13,13a-hexadecahydro-1H-cyclopenta[4,5]cycloocta[1,2-a]naphthalen-11-yl 4-oxo-4-(propylamino)butanoate.
AsB-n2:(2aS,6aS,6bS,11R,12R,12aS,13R,13aS,Z)-13-hydroxy-2a,5,5,9,12,13a-hexamethyl-2,2a,3,4,5,6,6a,6b,7,8,10,11,12,12a,13,13a-hexadecahydro-1H-cyclopenta[4,5]cycloocta[1,2-a]naphthalen-11-yl 4-(cyclohexylamino)-4-oxobutanoate.
AsB-n3:(2aS,6aS,6bS,9Z,11R,12R,12aZ,13aS)-2a,5,5,9,12,13a-hexamethyl-2,2a,3,4,5,6,6a,6b,7,8,10,11,12,13a-tetradecahydro-1H-cyclopenta[4,5]cycloocta[1,2-a]naphthalen-11-yl 4-oxo-4-(propylamino)butanoate.
AsB-n4:(2aS,6aS,6bS,11R,12R,12aS,13R,13aS,Z)-13-hydroxy-2a,5,5,9,12,13a-hexamethyl-2,2a,3,4,5,6,6a,6b,7,8,10,11,12,12a,13,13a-hexadecahydro-1H-cyclopenta[4,5]cycloocta[1,2-a]naphthalen-11-yl 4-((furan-2-ylmethyl)amino)-4-oxobutanoate.
AsB-n5:(2aS,6aS,6bS,11R,12R,12aS,13R,13aS,Z)-13-hydroxy-2a,5,5,9,12,13a-hexamethyl-2,2a,3,4,5,6,6a,6b,7,8,10,11,12,12a,13,13a-hexadecahydro-1H-cyclopenta[4,5]cycloocta[1,2-a]naphthalen-11-yl 4-oxo-4-(phenethylamino)butanoate.
AsB-n6:(2aS,6aS,6bS,11R,12R,12aS,13R,13aS,Z)-13-hydroxy-2a,5,5,9,12,13a-hexamethyl-2,2a,3,4,5,6,6a,6b,7,8,10,11,12,12a,13,13a-hexadecahydro-1H-cyclopenta[4,5]cycloocta[1,2-a]naphthalen-11-yl 4-oxo-4-((thiophen-2-ylmethyl)amino)butanoate.
AsB-n7:(2aS,6aS,6bS,11R,12R,12aS,13R,13aS,Z)-13-hydroxy-2a,5,5,9,12,13a-hexamethyl-2,2a,3,4,5,6,6a,6b,7,8,10,11,12,12a,13,13a-hexadecahydro-1H-cyclopenta[4,5]cycloocta[1,2-a]naphthalen-11-yl
4-((2-(cyclohex-1-en-1-yl)ethyl)amino)-4-oxobutanoate.
AsB-n8:(2aS,6aS,6bS,11R,12R,12aS,13R,13aS,Z)-13-hydroxy-2a,5,5,9,12,13a-hexamethyl-2,2a,3,4,5,6,6a,6b,7,8,10,11,12,12a,13,13a-hexadecahydro-1H-cyclopenta[4,5]cycloocta[1,2-a]naphthalen-11-yl
4-oxo-4-((2-(thiophen-2-yl)ethyl)amino)butanoate.
AsB-n9:(2aS,6aS,6bS,11R,12R,12aS,13R,13aS,Z)-13-hydroxy-2a,5,5,9,12,13a-hexamethyl-2,2a,3,4,5,6,6a,6b,7,8,10,11,12,12a,13,13a-hexadecahydro-1H-cyclopenta[4,5]cycloocta[1,2-a]naphthalen-11-yl 4-((4-bromophenyl)amino)-4-oxobutanoate.
AsB-n10:(2aS,6aS,6bS,11R,12R,12aS,13R,13aS,Z)-13-hydroxy-2a,5,5,9,12,13a-hexamethyl-2,2a,3,4,5,6,6a,6b,7,8,10,11,12,12a,13,13a-hexadecahydro-1H-cyclopenta[4,5]cycloocta[1,2-a]naphthalen-11-yl 4-(heptylamino)-4-oxobutanoate.
AsB-n11:(2aS,6aS,6bS,11R,12R,12aS,13R,13aS,Z)-13-hydroxy-2a,5,5,9,12,13a-hexamethyl-2,2a,3,4,5,6,6a,6b,7,8,10,11,12,12a,13,13a-hexadecahydro-1H-cyclopenta[4,5]cycloocta[1,2-a]naphthalen-11-yl 4-((2-(furan-2-yl)ethyl)amino)-4-oxobutanoate.
AsB-n12:(2aS,6aS,6bS,11R,12R,12aS,13R,13aS,Z)-13-hydroxy-2a,5,5,9,12,13a-hexamethyl-2,2a,3,4,5,6,6a,6b,7,8,10,11,12,12a,13,13a-hexadecahydro-1H-cyclopenta[4,5]cycloocta[1,2-a]naphthalen-11-yl 4-((2-morpholinoethyl)amino)-4-oxobutanoate
AsB-n13:(2aS,6aS,6bS,11R,12R,12aS,13R,13aS,Z)-13-hydroxy-2a,5,5,9,12,13a-hexamethyl-2,2a,3,4,5,6,6a,6b,7,8,10,11,12,12a,13,13a-hexadecahydro-1H-cyclopenta[4,5]cycloocta[1,2-a]naphthalen-11-yl 4-(diallylamino)-4-oxobutanoate.
AsB-n14:(2aS,6aS,6bS,11R,12R,12aS,13R,13aS,Z)-13-hydroxy-2a,5,5,9,12,13a-hexamethyl-2,2a,3,4,5,6,6a,6b,7,8,10,11,12,12a,13,13a-hexadecahydro-1H-cyclopenta[4,5]cycloocta[1,2-a]naphthalen-11-yl 4-oxo-4-(pyrrolidin-1-yl)butanoate.
AsB-n15:(2aS,6aS,6bS,11R,12R,12aS,13R,13aS,Z)-13-hydroxy-2a,5,5,9,12,13a-hexamethyl-2,2a,3,4,5,6,6a,6b,7,8,10,11,12,12a,13,13a-hexadecahydro-1H-cyclopenta[4,5]cycloocta[1,2-a]naphthalen-11-yl 4-((benzyloxy)amino)-4-oxobutanoate.
AsB-n16:(2aS,6aS,6bS,11R,12R,12aS,13R,13aS,Z)-13-hydroxy-2a,5,5,9,12,13a-hexamethyl-2,2a,3,4,5,6,6a,6b,7,8,10,11,12,12a,13,13a-hexadecahydro-1H-cyclopenta[4,5]cycloocta[1,2-a]naphthalen-11-yl
4-(3,4-dihydroisoquinolin-2(1H)-yl)-4-oxobutanoate.
AsB-n17:(2aS,6aS,6bS,11R,12R,12aS,13R,13aS,Z)-13-hydroxy-2a,5,5,9,12,13a-hexamethyl-2,2a,3,4,5,6,6a,6b,7,8,10,11,12,12a,13,13a-hexadecahydro-1H-cyclopenta[4,5]cycloocta[1,2-a]naphthalen-11-yl 7-morpholino-4-oxoheptanoate
AsB-n18:(2aS,6aS,6bS,11R,12R,12aS,13R,13aS,Z)-13-hydroxy-2a,5,5,9,12,13a-hexamethyl-2,2a,3,4,5,6,6a,6b,7,8,10,11,12,12a,13,13a-hexadecahydro-1H-cyclopenta[4,5]cycloocta[1,2-a]naphthalen-11-yl 4-morpholino-4-oxobutanoate.
AsB-n19:(2aS,6aS,6bS,11R,12R,12aS,13R,13aS,Z)-13-hydroxy-2a,5,5,9,12,13a-hexamethyl-2,2a,3,4,5,6,6a,6b,7,8,10,11,12,12a,13,13a-hexadecahydro-1H-cyclopenta[4,5]cycloocta[1,2-a]naphthalen-11-yl
4-oxo-4-(2-(trifluoromethyl)pyrrolidin-1-yl)butanoate.
AsB-n20:(2aS,6aS,6bS,11R,12R,12aS,13R,13aS,Z)-13-hydroxy-2a,5,5,9,12,13a-hexamethyl-2,2a,3,4,5,6,6a,6b,7,8,10,11,12,12a,13,13a-hexadecahydro-1H-cyclopenta[4,5]cycloocta[1,2-a]naphthalen-11-yl 4-((4-methoxyphenyl)amino)-4-oxobutanoate.
AsB-n21:(2aS,6aS,6bS,11R,12R,12aS,13R,13aS,Z)-13-hydroxy-2a,5,5,9,12,13a-hexamethyl-2,2a,3,4,5,6,6a,6b,7,8,10,11,12,12a,13,13a-hexadecahydro-1H-cyclopenta[4,5]cycloocta[1,2-a]naphthalen-11-yl 4-(cyclopropylamino)-4-oxobutanoate
AsB-n22:(2aS,6aS,6bS,11R,12R,12aS,13R,13aS,Z)-13-hydroxy-2a,5,5,9,12,13a-hexamethyl-2,2a,3,4,5,6,6a,6b,7,8,10,11,12,12a,13,13a-hexadecahydro-1H-cyclopenta[4,5]cycloocta[1,2-a]naphthalen-11-yl 4-(cyclopentylamino)-4-oxobutanoate.
AsB-n23:(2aS,6aS,6bS,11R,12R,12aS,13R,13aS,Z)-13-hydroxy-2a,5,5,9,12,13a-hexamethyl-2,2a,3,4,5,6,6a,6b,7,8,10,11,12,12a,13,13a-hexadecahydro-1H-cyclopenta[4,5]cycloocta[1,2-a]naphthalen-11-yl 4-(naphthalen-1-ylamino)-4-oxobutanoate.
AsB-n24:(2aS,6aS,6bS,11R,12R,12aS,13R,13aS,Z)-13-hydroxy-2a,5,5,9,12,13a-hexamethyl-2,2a,3,4,5,6,6a,6b,7,8,10,11,12,12a,13,13a-hexadecahydro-1H-cyclopenta[4,5]cycloocta[1,2-a]naphthalen-11-yl 4-((3-bromopyridin-2-yl)amino)-4-oxobutanoate.
AsB-n25:(2aS,6aS,6bS,11R,12R,12aS,13R,13aS,Z)-13-hydroxy-2a,5,5,9,12,13a-hexamethyl-2,2a,3,4,5,6,6a,6b,7,8,10,11,12,12a,13,13a-hexadecahydro-1H-cyclopenta[4,5]cycloocta[1,2-a]naphthalen-11-yl-4-((4-bromo-1H-pyrazol-3-yl)amino)-4-oxobutanoate。
4.根据权利要求3所述的二倍半萜Asperterpinol B衍生物，其特征是，所述衍生化合物选自以下至少一种：
AsB-1:(2aS,6aS,6bS,12S,12aS,13R,13aS,Z)-2a,5,5,9,12,13a-hexamethyl-2,2a,3,4,5,6,6a,6b,7,8,12,12a,13,13a-tetradecahydro-1H-cyclopenta[4,5]cycloocta[1,2-a]naphthalen-13-ol.
AsB-S1:(2aS,6aS,6bS,11R,12R,12aS,13R,13aS,Z)-13-hydroxy-2a,5,5,9,12,13a-hexamethyl-2,2a,3,4,5,6,6a,6b,7,8,10,11,12,12a,13,13a-hexadecahydro-1H-cyclopenta[4,5]cycloocta[1,2-a]naphthalen-11-yl acetate.
AsB-S2:(2aS,6aS,6bS,11R,12R,12aS,13R,13aS,Z)-13-hydroxy-2a,5,5,9,12,13a-hexamethyl-2,2a,3,4,5,6,6a,6b,7,8,10,11,12,12a,13,13a-hexadecahydro-1H-cyclopenta[4,5]cycloocta[1,2-a]naphthalen-11-yl butyrate.
AsB-S3:4-(((2aS,6aS,6bS,11R,12R,12aS,13R,13aS,Z)-13-hydroxy-2a,5,5,9,12,13a-hexamethyl-2,2a,3,4,5,6,6a,6b,7,8,10,11,12,12a,13,13a-hexadecahydro-1H-cyclopenta[4,5]cycloocta[1,2-a]naphthalen-11-yl)oxy)-4-oxobutanoic acid.
AsB-S4:(2aS,6aS,6bS,11R,12R,12aS,13R,13aS,Z)-13-hydroxy-2a,5,5,9,12,13a-hexamethyl-2,2a,3,4,5,6,6a,6b,7,8,10,11,12,12a,13,13a-hexadecahydro-1H-cyclopenta[4,5]cycloocta[1,2-a]naphthalen-11-yl propionate.
AsB-S5:5-(((2aS,6aS,6bS,11R,12R,12aS,13R,13aS,Z)-13-hydroxy-2a,5,5,9,12,13a-hexamethyl-2,2a,3,4,5,6,6a,6b,7,8,10,11,12,12a,13,13a-hexadecahydro-1H-cyclopenta[4,5]cycloocta[1,2-a]naphthalen-11-yl)oxy)-5-oxopentanoic acid.
AsB-S6:(2aS,6aS,6bS,11R,12R,12aS,13R,13aS,Z)-13-hydroxy-2a,5,5,9,12,13a-hexamethyl-2,2a,3,4,5,6,6a,6b,7,8,10,11,12,12a,13,13a-hexadecahydro-1H-cyclopenta[4,5]cycloocta[1,2-a]naphthalen-11-yl hexanoate.
AsB-S9:(2aS,6aS,6bS,11R,12R,12aS,13R,13aS,Z)-13-hydroxy-2a,5,5,9,12,13a-hexamethyl-2,2a,3,4,5,6,6a,6b,7,8,10,11,12,12a,13,13a-hexadecahydro-1H-cyclopenta[4,5]cycloocta[1,2-a]naphthalen-11-yl isobutyrate.
AsB-S10:(2aS,6aS,6bS,11R,12R,12aS,13R,13aS,Z)-13-hydroxy-2a,5,5,9,12,13a-hexamethyl-2,2a,3,4,5,6,6a,6b,7,8,10,11,12,12a,13,13a-hexadecahydro-1H-cyclopenta[4,5]cycloocta[1,2-a]naphthalen-11-yl 2-chloro-2,2-difluoroacetate.
AsB-n1:(2aS,6aS,6bS,11R,12R,12aS,13R,13aS,Z)-13-hydroxy-2a,5,5,9,12,13a-hexamethyl-2,2a,3,4,5,6,6a,6b,7,8,10,11,12,12a,13,13a-hexadecahydro-1H-cyclopenta[4,5]cycloocta[1,2-a]naphthalen-11-yl 4-oxo-4-(propylamino)butanoate.
AsB-n2:(2aS,6aS,6bS,11R,12R,12aS,13R,13aS,Z)-13-hydroxy-2a,5,5,9,12,13a-hexamethyl-2,2a,3,4,5,6,6a,6b,7,8,10,11,12,12a,13,13a-hexadecahydro-1H-cyclopenta[4,5]cycloocta[1,2-a]naphthalen-11-yl 4-(cyclohexylamino)-4-oxobutanoate.
AsB-n3:(2aS,6aS,6bS,9Z,11R,12R,12aZ,13aS)-2a,5,5,9,12,13a-hexamethyl-2,2a,3,4,5,6,6a,6b,7,8,10,11,12,13a-tetradecahydro-1H-cyclopenta[4,5]cycloocta[1,2-a]naphthalen-11-yl 4-oxo-4-(propylamino)butanoate.
AsB-n4:(2aS,6aS,6bS,11R,12R,12aS,13R,13aS,Z)-13-hydroxy-2a,5,5,9,12,13a-hexamethyl-2,2a,3,4,5,6,6a,6b,7,8,10,11,12,12a,13,13a-hexadecahydro-1H-cyclopenta[4,5]cycloocta[1,2-a]naphthalen-11-yl 4-((furan-2-ylmethyl)amino)-4-oxobutanoate.
AsB-n5:(2aS,6aS,6bS,11R,12R,12aS,13R,13aS,Z)-13-hydroxy-2a,5,5,9,12,13a-hexamethyl-2,2a,3,4,5,6,6a,6b,7,8,10,11,12,12a,13,13a-hexadecahydro-1H-cyclopenta[4,5]cycloocta[1,2-a]naphthalen-11-yl 4-oxo-4-(phenethylamino)butanoate.
AsB-n6:(2aS,6aS,6bS,11R,12R,12aS,13R,13aS,Z)-13-hydroxy-2a,5,5,9,12,13a-hexamethyl-2,2a,3,4,5,6,6a,6b,7,8,10,11,12,12a,13,13a-hexadecahydro-1H-cyclopenta[4,5]cycloocta[1,2-a]naphthalen-11-yl 4-oxo-4-((thiophen-2-ylmethyl)amino)butanoate.
AsB-n7:(2aS,6aS,6bS,11R,12R,12aS,13R,13aS,Z)-13-hydroxy-2a,5,5,9,12,13a-hexamethyl-2,2a,3,4,5,6,6a,6b,7,8,10,11,12,12a,13,13a-hexadecahydro-1H-cyclopenta[4,5]cycloocta[1,2-a]naphthalen-11-yl
4-((2-(cyclohex-1-en-1-yl)ethyl)amino)-4-oxobutanoate.
AsB-n8:(2aS,6aS,6bS,11R,12R,12aS,13R,13aS,Z)-13-hydroxy-2a,5,5,9,12,13a-hexamethyl-2,2a,3,4,5,6,6a,6b,7,8,10,11,12,12a,13,13a-hexadecahydro-1H-cyclopenta[4,5]cycloocta[1,2-a]naphthalen-11-yl
4-oxo-4-((2-(thiophen-2-yl)ethyl)amino)butanoate.
AsB-n9:(2aS,6aS,6bS,11R,12R,12aS,13R,13aS,Z)-13-hydroxy-2a,5,5,9,12,13a-hexamethyl-2,2a,3,4,5,6,6a,6b,7,8,10,11,12,12a,13,13a-hexadecahydro-1H-cyclopenta[4,5]cycloocta[1,2-a]naphthalen-11-yl 4-((4-bromophenyl)amino)-4-oxobutanoate.
AsB-n10:(2aS,6aS,6bS,11R,12R,12aS,13R,13aS,Z)-13-hydroxy-2a,5,5,9,12,13a-hexamethyl-2,2a,3,4,5,6,6a,6b,7,8,10,11,12,12a,13,13a-hexadecahydro-1H-cyclopenta[4,5]cycloocta[1,2-a]naphthalen-11-yl 4-(heptylamino)-4-oxobutanoate.
AsB-n11:(2aS,6aS,6bS,11R,12R,12aS,13R,13aS,Z)-13-hydroxy-2a,5,5,9,12,13a-hexamethyl-2,2a,3,4,5,6,6a,6b,7,8,10,11,12,12a,13,13a-hexadecahydro-1H-cyclopenta[4,5]cycloocta[1,2-a]naphthalen-11-yl 4-((2-(furan-2-yl)ethyl)amino)-4-oxobutanoate.
AsB-n12:(2aS,6aS,6bS,11R,12R,12aS,13R,13aS,Z)-13-hydroxy-2a,5,5,9,12,13a-hexamethyl-2,2a,3,4,5,6,6a,6b,7,8,10,11,12,12a,13,13a-hexadecahydro-1H-cyclopenta[4,5]cycloocta[1,2-a]naphthalen-11-yl 4-((2-morpholinoethyl)amino)-4-oxobutanoate
AsB-n13:(2aS,6aS,6bS,11R,12R,12aS,13R,13aS,Z)-13-hydroxy-2a,5,5,9,12,13a-hexamethyl-2,2a,3,4,5,6,6a,6b,7,8,10,11,12,12a,13,13a-hexadecahydro-1H-cyclopenta[4,5]cycloocta[1,2-a]naphthalen-11-yl 4-(diallylamino)-4-oxobutanoate.
AsB-n14:(2aS,6aS,6bS,11R,12R,12aS,13R,13aS,Z)-13-hydroxy-2a,5,5,9,12,13a-hexamethyl-2,2a,3,4,5,6,6a,6b,7,8,10,11,12,12a,13,13a-hexadecahydro-1H-cyclopenta[4,5]cycloocta[1,2-a]naphthalen-11-yl 4-oxo-4-(pyrrolidin-1-yl)butanoate.
AsB-n15:(2aS,6aS,6bS,11R,12R,12aS,13R,13aS,Z)-13-hydroxy-2a,5,5,9,12,13a-hexamethyl-2,2a,3,4,5,6,6a,6b,7,8,10,11,12,12a,13,13a-hexadecahydro-1H-cyclopenta[4,5]cycloocta[1,2-a]naphthalen-11-yl 4-((benzyloxy)amino)-4-oxobutanoate.
AsB-n16:(2aS,6aS,6bS,11R,12R,12aS,13R,13aS,Z)-13-hydroxy-2a,5,5,9,12,13a-hexamethyl-2,2a,3,4,5,6,6a,6b,7,8,10,11,12,12a,13,13a-hexadecahydro-1H-cyclopenta[4,5]cycloocta[1,2-a]naphthalen-11-yl
4-(3,4-dihydroisoquinolin-2(1H)-yl)-4-oxobutanoate.
AsB-n17:(2aS,6aS,6bS,11R,12R,12aS,13R,13aS,Z)-13-hydroxy-2a,5,5,9,12,13a-hexamethyl-2,2a,3,4,5,6,6a,6b,7,8,10,11,12,12a,13,13a-hexadecahydro-1H-cyclopenta[4,5]cycloocta[1,2-a]naphthalen-11-yl 7-morpholino-4-oxoheptanoate
AsB-n18:(2aS,6aS,6bS,11R,12R,12aS,13R,13aS,Z)-13-hydroxy-2a,5,5,9,12,13a-hexamethyl-2,2a,3,4,5,6,6a,6b,7,8,10,11,12,12a,13,13a-hexadecahydro-1H-cyclopenta[4,5]cycloocta[1,2-a]naphthalen-11-yl 4-morpholino-4-oxobutanoate.
AsB-n19:(2aS,6aS,6bS,11R,12R,12aS,13R,13aS,Z)-13-hydroxy-2a,5,5,9,12,13a-hexamethyl-2,2a,3,4,5,6,6a,6b,7,8,10,11,12,12a,13,13a-hexadecahydro-1H-cyclopenta[4,5]cycloocta[1,2-a]naphthalen-11-yl
4-oxo-4-(2-(trifluoromethyl)pyrrolidin-1-yl)butanoate.
AsB-n20:(2aS,6aS,6bS,11R,12R,12aS,13R,13aS,Z)-13-hydroxy-2a,5,5,9,12,13a-hexamethyl-2,2a,3,4,5,6,6a,6b,7,8,10,11,12,12a,13,13a-hexadecahydro-1H-cyclopenta[4,5]cycloocta[1,2-a]naphthalen-11-yl 4-((4-methoxyphenyl)amino)-4-oxobutanoate.
AsB-n21:(2aS,6aS,6bS,11R,12R,12aS,13R,13aS,Z)-13-hydroxy-2a,5,5,9,12,13a-hexamethyl-2,2a,3,4,5,6,6a,6b,7,8,10,11,12,12a,13,13a-hexadecahydro-1H-cyclopenta[4,5]cycloocta[1,2-a]naphthalen-11-yl 4-(cyclopropylamino)-4-oxobutanoate
AsB-n22:(2aS,6aS,6bS,11R,12R,12aS,13R,13aS,Z)-13-hydroxy-2a,5,5,9,12,13a-hexamethyl-2,2a,3,4,5,6,6a,6b,7,8,10,11,12,12a,13,13a-hexadecahydro-1H-cyclopenta[4,5]cycloocta[1,2-a]naphthalen-11-yl 4-(cyclopentylamino)-4-oxobutanoate.
AsB-n23:(2aS,6aS,6bS,11R,12R,12aS,13R,13aS,Z)-13-hydroxy-2a,5,5,9,12,13a-hexamethyl-2,2a,3,4,5,6,6a,6b,7,8,10,11,12,12a,13,13a-hexadecahydro-1H-cyclopenta[4,5]cycloocta[1,2-a]naphthalen-11-yl 4-(naphthalen-1-ylamino)-4-oxobutanoate.
AsB-n24:(2aS,6aS,6bS,11R,12R,12aS,13R,13aS,Z)-13-hydroxy-2a,5,5,9,12,13a-hexamethyl-2,2a,3,4,5,6,6a,6b,7,8,10,11,12,12a,13,13a-hexadecahydro-1H-cyclopenta[4,5]cycloocta[1,2-a]naphthalen-11-yl 4-((3-bromopyridin-2-yl)amino)-4-oxobutanoate.
AsB-n25:(2aS,6aS,6bS,11R,12R,12aS,13R,13aS,Z)-13-hydroxy-2a,5,5,9,12,13a-hexamethyl-2,2a,3,4,5,6,6a,6b,7,8,10,11,12,12a,13,13a-hexadecahydro-1H-cyclopenta[4,5]cycloocta[1,2-a]naphthalen-11-yl
4-((4-bromo-1H-pyrazol-3-yl)amino)-4-oxobutanoate。
5.权利要求1-4任一项所述二倍半萜Asperterpinol B衍生物的合成方法，其特征是，该合成方法为：
1)二倍半萜Asperterpinol B与酰卤、羧酸、酸酐反应成具有式Ⅰ结构的酯类衍生物；
2)结构式为的二倍半萜Asperterpinol B衍生物与胺类化合物反应生成具有结构式Ⅱ的酰胺类衍生物；
3)二倍半萜Asperterpinol B在三氟化硼乙醚作用下五元环脱水生成具有式Ⅲ的衍生物；
4)结构为的二倍半萜Asperterpinol B先与无水二氯亚砜反应生成中间体酰氯再与胺类化合物反应生成具有式Ⅳ的衍生物。
6.根据权利要求5所述的合成方法，其特征是，所述胺类化合物为伯胺或仲胺。
7.一种治疗糖尿病症的药用组合物，其药学活性成份包括有权利要求1-4任一项所述二倍半萜Asperterpinol B衍生物或者其药学上可接受的盐或立体异构体或其前药分子。
8.权利要求1-4任一项所述的二倍半萜Asperterpinol B衍生物或者其药学上可接受的盐或立体异构体或其前药分子在制备α-葡萄糖苷酶抑制剂药物中的应用。
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