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  波谱学杂志   2019, Vol. 36 Issue (1): 113-126.  DOI: 10.11938/cjmr20182655
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引用本文 [复制中英文]

尹田鹏, 罗智慧, 蔡乐, 等. 天然C19-二萜生物碱的研究进展及其核磁共振波谱特征[J]. 波谱学杂志, 2019, 36(1): 113-126. DOI: 10.11938/cjmr20182655.
[复制中文]
YIN Tian-peng, LUO Zhi-hui, CAI Le, et al. Research Progress and NMR Spectral Features of Natural C19-Diterpenoid Alkaloids[J]. Chinese Journal of Magnetic Resonance, 2019, 36(1): 113-126. DOI: 10.11938/cjmr20182655.
[复制英文]

基金项目

国家自然科学基金(31860095);贵州省科学技术基金(黔科合基础[2018]1193);云南省高校功能分子分析与生物转化重点实验开放基金

通讯联系人

丁中涛, Tel:0871-65032667, E-mail:ztding@ynu.edu.cn

文章历史

收稿日期:2018-05-23
在线发表日期:2018-06-21
天然C19-二萜生物碱的研究进展及其核磁共振波谱特征
尹田鹏 1,2, 罗智慧 1, 蔡乐 2, 丁中涛 2     
1. 遵义医科大学珠海校区, 珠海市中药基础及应用研究重点实验室, 广东 珠海 519041;
2. 云南大学 化学科学与工程学院, 云南省高校功能分子分析与生物转化重点实验室, 云南 昆明 650091
摘要: C19-二萜生物碱是二萜生物碱中数量最多的一类,主要分布于毛茛科的乌头属、翠雀属和飞燕草属植物中.C19-二萜生物碱结构复杂、生理活性显著,一直吸引着科研工作者的广泛关注.本文主要对2010~2018年报道的天然来源C19-二萜生物碱的研究进行总结,并归纳了C19-二萜生物碱各子类型的核磁共振(NMR)结构特征和解析方式,以期为C19-二萜生物碱的深入研究及开发提供参考依据.
关键词: C19-二萜生物碱    核磁共振(NMR)波谱    结构解析    乌头属    翠雀属    
Research Progress and NMR Spectral Features of Natural C19-Diterpenoid Alkaloids
YIN Tian-peng 1,2, LUO Zhi-hui 1, CAI Le 2, DING Zhong-tao 2     
1. Zhuhai Key Laboratory of Fundamental and Applied Research in Traditional Chinese Medicine, Zhuhai Campus of Zunyi Medical University, Zhuhai 519041, China;
2. Key Laboratory of Functional Molecules Analysis and Biotransformation of Universities in Yunnan Province, School of Chemical Science and Technology, Yunnan University, Kunming 650091, China
Abstract: Majority of diterpenoid alkaloids are C19-diterpenoid alkaloids found in the plants from the genera Aconitum, Delphinium and Consolida (Ranunculaceae). C19-diterpenoid alkaloids have attached lots of research interests due to their complex structures and remarkable pharmacological activities. This paper reviewed the structural features of natural C19-diterpenoid alkaloids reported in literature from 2010 to 2018, focusing on the NMR spectral characteristics of different subtypes of C19-diterpenoid alkaloids and how their structures could be elucidated from the NMR data. The work may provide a reference for the further research and development of C19-diterpenoid alkaloids.
Key words: C19-diterpenoid alkaloids    nuclear magnetic resonance (NMR)spectroscopy    structural elucidation    Aconitum    Delphinium    
引言

二萜生物碱(diterpenoid alkaloids)是四环或五环二萜的C-19或C-20与一分子β-氨基乙醇、甲胺或乙胺的氮原子联结而成的杂环化合物,可分为四种结构类型:C18-、C19-、C20-和双二萜生物碱[1].C19-二萜生物碱是其中数量最多的一类,主要分布在毛茛科(Ranunculaceae)的乌头属(Aconitum)、翠雀属(Delphinium)及飞燕草属(Consolida)植物中,具有显著的抗炎、镇痛和抗心律失常作用,目前有3-乙酰乌头碱和草乌甲素临床用作无成瘾性镇痛药[2, 3].C19-二萜生物碱结构复杂而生理作用显著,一直吸引着药学工作者的广泛关注.近年随着色谱学和波谱学等分离分析技术的发展,C19-二萜生物碱研究进展迅速,积累了丰富的基础数据.本文对2010 ~2018年国内外报道的天然C19-二萜生物碱的结构特点、核磁共振(nuclear magnetic resonance,NMR)波谱特征及解析方式进行总结,为C19-二萜生物碱的深入研究及合理开发利用提供参考依据.

1 化学成分研究进展

C19-二萜生物碱可分为六种子类型:乌头碱型(Aconitine type,Ⅰ)、牛扁碱型(Lycaconitine type,Ⅱ)、热解型(Pyro type,Ⅲ)、内酯型(Lactone type,Ⅳ)、7, 17-次裂型(7, 17-Seco type,Ⅴ)和重排型(Rearranged type,Ⅵ).表 1列出了2010~2018年报道的167个天然来源的C19-二萜生物碱.

表 1 2010~2018年报道的天然来源C19-二萜生物碱 Table 1 Natural C19-diterpenoid alkaloids reported from 2010 to 2018
1.1 乌头碱型和牛扁碱型

乌头碱型和牛扁碱型涵盖了绝大多数的C19-二萜生物碱,二者区别在于有无7-含氧取代:前者不含有7-含氧基;而后者含有.2010~2018年报道乌头碱型有105个(图 1),牛扁碱型有41个(图 2),它们大多数的区别在于常见取代基种类、数量和位置的不同.

图 1 2010~2018年报道的天然来源的C19-乌头碱型二萜生物碱 Fig. 1 Natural aconitine type C19-diterpenoid alkaloids reported from 2010 to 2018
图 2 2010~2018年报道的天然来源的C19-牛扁碱型二萜生物碱 Fig. 2 Natural lycaconitine type C19-diterpenoid alkaloids reported from 2010 to 2018

乌头碱型C19-二萜生物碱多见羟基、甲氧基、乙酰基(Ac)、苯甲酰基(Bz)、大茴香酰基(As)、藜芦酰基(Vr)取代[32, 35],也可见双键、酮羰基、亚胺(N=C(21))、氮杂缩醛、肉桂酸酯基(Cn)等基团取代;牛扁碱型C19-二萜生物碱多见邻氨基苯甲酸酯衍生物(Ant、Nsa)、7, 8-次甲二氧基、OMe-14等取代,而几乎不见Ac、Bz和As取代.乌头碱型和牛扁碱型C19-二萜生物碱几乎都含甲氧基取代,乌头碱型化合物16β-hydroxycardiopetaline是首个不含甲氧基的C19-二萜生物碱,其差向异构体1-epi-16β-hydroxycardiopetaline (68)近年也从黄草乌中分离得到,该化合物还具罕见的1β-含氧基[34].近年来,C19-二萜生物碱中也发现有新颖取代基.Meng等[51]从附子首次发现的乌头碱型C19-二萜生物碱苷aconicarmichosides A~D (108~111)分别取代有α-、β-的L -阿拉伯吡喃糖和L-阿拉伯呋喃糖;Zhang等[45]从伊犁翠雀花(D. iliense)发现的牛扁碱型iliensine A (94)取代有肉桂酸葡萄糖基;D. elatum中的牛扁碱型C19-二萜生物碱N-formyl-4, 19-secopacinine (69)首次发现具有CHO-19基团(甲酰胺)[35],而之前报道多为CHO-20基团,如乌头碱型化合物brachyaconitine (1)、alexhumboldtine (48)等.此外还有N-丁酮[5]、4-羟基丁酰基[55]、丁氧基[63]等取代基的报道.

乌头碱型C19-二萜生物碱常见取代基位置为C-1、C-3、C-6、C-8、C-14、C-16和C-18.牛扁碱型取代位置与乌头碱型类似,但其6-含氧基为β构型,而乌头碱型的多为α,仅极少数为β,本课题组从宾川乌头(A. duclouxii)分离的乌头碱型C19-二萜生物碱ducludine F (59)具有OCH3-6β取代[30].

C19-二萜生物碱酯化程度常见醇胺、单酯或双酯,具有三酯取代的C19-二萜生物碱如乌头碱型brachyaconitine B (2)、N-deethyl-3-O-acetylchasmaconitine (164)、N-deethyl-3-O-acetylyunaconitine (165)、N-deethyl-3-O-acetyljesaconitine (166)较为罕见[5, 68].

1.2 7, 17-次裂型

7, 17-次裂型C19-二萜生物碱是乌头碱型的C(7)-C(17)键经Grob裂解形成双键△7, 8,然后OH-6α进攻N+=C(17)亚胺盐形成C(17)-O-C(6)键而得,典型化合物为大渡乌碱类,目前报道的大渡乌碱型约有10个,近年发现有guiwuline (28)(图 3[17].部分化合物Grob裂解后保留N=C(17)亚胺结构,如brachyacintine C (3) [4];或形成C(3)-O-C(17)-N氮杂缩醛结构如secoaconitine (22)[12].本课题组从黄草乌和展毛黄草乌发现的vilmorine A (83)、vilmotenitines A和B (86, 87)具有△7, 8,但没有C(17)-O-C(6)键,且C(8)-C(9)键重排为C(8)-C(10)形成六元B环,是一类新颖的7, 17-次裂型骨架[42].

图 3 2010~2018年报道的天然来源的7, 17-次裂型、重排型、内酯型和热解型C19-二萜生物碱 Fig. 3 Natural 7, 17-seco type, rearranged type, lactone type and pyro type C19-diterpenoid alkaloids reported from 2010 to 2018
1.3 重排型

典型重排型C19-二萜生物碱acoseptine类由具有7, 8-邻二羟基牛扁碱型C19-二萜生物碱经纳咵醇重排成C(17)-C(8)键而得,目前约5个,近年发现的有D. yunnanense中的yunnanenseine A (25)[14].具B环C(8)-C(9)-C(10)三元环的vilmoraconitine类重排C19-二萜生物碱由谭宁华等[70]从黄草乌首次发现,同类化合物有aconitramine A (29)及本课题组从黄草乌分离的vilmorines B和C (84, 85) [18, 42].此外D. grandiflorum中的grandiflodine B (129)的N-C(19)和C(7)-C(17)键均断裂重排为N-C(7)键,是首次发现的重排型C19-二萜生物碱[58].

1.4 热解型和内酯型

热解型C19-二萜生物碱指具有△8, 15或15-酮结构的C19-二萜生物碱,源于乌头碱型消除8-OAc或15-含氧基而得.近年来发现的有保山乌头(A. nagarum)中的nagaconitine B (120)[55][49].

内酯型C19-二萜生物碱指具有六元内酯C环的C19-二萜生物碱,由乌头碱型14-酮经Bayer-Viliger氧化而得.天然来源的内酯型C19-二萜生物碱数量极少,目前报道的约为11个,近年仅有从A. heterophyllum分离的9β-dihydroxylheteratisine (118) [54].

2 C19-二萜生物碱的NMR波谱特征和结构解析 2.1 C18-、C19-、C20-和双二萜生物碱的区分

二萜生物碱结构复杂、解析困难,其1H NMR谱图高场区域重叠严重,而13C NMR谱图分辨率更高,而且结合DEPT技术可区分伯碳、仲碳、叔碳和季碳,对二萜生物碱的骨架解析极有帮助.C19-二萜生物碱的结构解析可首先根据其来源、母核碳原子数目、特征性季碳信号和取代基信号区分C18-、C19-、C20-和双二萜生物碱.

C19-二萜生物碱是含19个碳原子母核的四环二萜与β-氨基乙醇联结成的杂环衍生物,其不含氧取代的季碳C-4、C-11和含氧取代的季碳C-8在骨架无变化情况下相对恒定(表 2),是C19-二萜生物碱结构类型判断的重要依据.C19-二萜生物碱氧化程度较高,通常有多个含氧取代(δH 3.0~5.0;δC 70~90);醇羟基易与醋酸、苯甲酸衍生物成酯,几乎都有甲氧基取代(δH 3.2~3.6,s;δC 55~59,q),可作为判断依据.

表 2 C19-二萜生物碱常见季碳化学位移范围(δC Table 2 Chemical shift (δC) ranges of common quaternary carbons in C19-diterpenoid alkaloids

C18-二萜生物碱为C19-二萜生物碱失去18-碳原子的降解产物,母核碳数为18,数目较少,多存在于牛扁亚属.C18-二萜生物碱根据C-7含氧取代的有无分为高乌碱型和冉乌碱型,分别对应C19-乌头碱型和牛扁碱型.C18-二萜生物碱取代方式和C19-相似,区别在于缺少C-18角甲基(δH 0.8~1.1,s;δC 21~28,q)或含氧亚甲基(δH 2.8~3.4,ABq;δC 72~80,t),C-4为含氧季碳或不含氧的次甲基.C18-二萜生物碱通常包含不含氧取代季碳C-11和含氧取代季碳C-8、C-4.此外3, 4-环氧取代仅存在于C18-二萜生物碱,而C19-和C20-二萜生物碱均不存在.

C20-二萜生物碱结构类型较多,主要可分为阿替生型、海替生型、海替定型、光翠雀碱型、维特钦型、纳哌啉型六类.母核碳数为20,其不含氧取代季碳C-4(δC 30~40,s)、C-8(δC 30~50,s)和C-10(δC 35~50,s)相对恒定,可能存在C-15含氧取代季碳,这是判断该类型结构的主要依据.与C19-二萜生物碱相比,C20-二萜生物碱的含氧取代较少,而且不含甲氧基取代,且大多数C20-二萜生物碱具有环外双键△16, 17δH ~5,brs;δC ~110,t;δC ~143,s).

双二萜生物碱数量极少,通常由1分子的C19-二萜生物碱与1分子或2分子的C20-二萜生物碱缩合而成,母核碳数为二者之和,解析可依据其组成单体的NMR特征进行.

2.2 C19-二萜生物碱子类型的确定

C19-二萜生物碱是乌头属、翠雀属和飞燕草属植物的特征成分,其种类与植物进化程度有密切关系.C19-二萜生物碱的结构解析,尤其是骨架类型的推测,首先应考虑植物来源:如牛扁碱型几乎全分布于翠雀属;内酯型几乎全分布于乌头亚属比较原始的类群,如甘青乌头系.C19-二萜生物碱子类型的区分主要根据季碳和特征性取代基NMR特征信号,其中季碳信号在C19-二萜生物碱的骨架推测中起关键作用(表 2).

乌头碱型C19-二萜生物碱常具有不含氧取代季碳C-4、C-11和含氧取代季碳C-8;而且因含氧取代的引入,可能存在季碳C-9、C-10和C-13(δC > 70).牛扁碱型C19-二萜生物除含有季碳C-4、C-11、C-8外,NMR谱图低场区域还可见C-7β取代季碳(δC 86~90,s)信号,若存在7, 8-次甲二氧基取代,则见于更低场区域(δC 91~93,s).受7β-含氧取代影响,与乌头碱型C19-二萜生物碱相比,牛扁碱型季碳C-8的NMR信号向低场位移,据此可区分二者.另外,也可利用取代基种类、位置和构型区分乌头碱型和牛扁碱型C19-二萜生物碱:乌头碱型C19-二萜生物碱常见的Ac、As和Bz取代几乎不出现在牛扁碱型中;而邻氨基苯甲酸酯衍生物和次甲二氧基(δH 3.2~3.6, s;δC 55~59, t)取代几乎都存在牛扁碱型C19-二萜生物碱中;乌头碱型C-14多为羟基或成酯,而牛扁碱型多为甲氧基;乌头碱型6-含氧基多为α构型,极少数为β构型,而牛扁碱型6-含氧基多为β构型;乌头碱型C-13、C-15常有羟基或醋酸酯取代,而牛扁碱型C-13、C-15则不含取代基.

与乌头碱型相比较,虽然大渡乌碱类7, 17-次裂型C19-二萜生物碱也具有较为恒定的季碳C-4(δC 37~38,s)和C-11(δC 50~51,s),但△7, 8(C-8,δC 137~139)替代了C-8含氧取代季碳.此外,7, 17-次裂型常具有N=C(17)亚胺、C(17)-O-C(6)等基团.与大渡乌碱型7, 17-次裂型C19-二萜生物碱相比较,Vilmorine A类7, 17-次裂型则多出不含氧取代季碳C-10(δC 44~45,s),此外,C-14酮羰基取代(δC 216~218)也是该类化合物的特征信号.

Acoseptine类重排型C19-二萜生物碱除含有季碳C-4、C-11外,C-8由于重排变为不含氧取代季碳(δC 54~55,s).具有C(8)-C(9)-C(10)三元环结构的重排型C19-二萜生物碱与乌头碱型相比,除C-4、C-11外,多出不含氧季碳C-8和C-10,而且与vilmorine A类7, 17-次裂型C19-二萜生物碱类似,具有C-14酮羰基.内酯型C19-二萜生物碱的季碳和乌头碱型一致,区别在于结构中多出内酯键(δC 175,s).热解型C19-二萜生物碱中△8, 15替代了C-8含氧取代季碳.

2.3 C19-二萜生物碱结构解析

通过季碳及取代基确定C19-二萜生物碱子类型后,需综合利用1H、13C和2D NMR进行结构解析,确定取代基种类、数目、位置及构型.取代基种类主要通过取代基的特征1H和13C NMR信号确定(表 3).取代基数目可通过13C NMR谱中δC 70~90含氧取代碳数、1H NMR谱中δH 3.0~5.0含氧取代质子数,结合高分辨质谱(high revolution mass spectrum,HR-MS)所得分子式来确定[71].

表 3 C19-二萜生物碱常见取代基特征核磁共振波谱信号 Table 3 Chemical shifts of common substituent groups in C19-diterpenoid alkaloids

取代位置主要根据含氧取代碳的级数和化学位移、取代质子化学位移和耦合常数等,参照文献类似化合物的NMR数据判断.应充分利用不同取代基产生的化学位移效应进行取代位置的判断,如C-8取代羟基或乙酰基化学位移相差6~8.首先考虑常见取代位置,如乌头碱型常见取代顺序为C-8/C-16/C-14→C-18→C-1→C-3/C-13→C-15.2D HMBC谱在取代位置判断中作用极大,如甲氧基位置可根据取代位置甲基质子与13C核相关峰确定,酯基取代可根据取代位置质子与羰基的相关峰确定.

取代构型可根据取代位置13C核化学位移判断,如乌头碱型C19-二萜生物碱含1β-含氧基时,C-1向高场位移4~5,C-6含氧基取代构型不同亦有明显化学位移差异.值得注意的是,利用化学位移判断取代构型时,需排除溶剂效应[72].NOESY谱在取代基构型判断中作用较大,如C-1取代构型可通过NOESY中H-1/H-5、H-1/H-11相关确定,C-6取代构型可通过NOESY中H-6/H-9相关确定.而化合物的绝对构型则一般通过X-单晶衍射实验确定.

3 总结

近年来,二萜生物碱的研究进展迅速,许多结构新颖的化合物被报道,反映了C19-二萜生物碱丰富的结构多样性,具有巨大的研究潜力与价值.C19-二萜生物碱结构复杂、鉴定困难,本文对其化学结构和NMR波谱特征进行了总结,为该类化合物的快速鉴定提供了参考依据.随着高分辨NMR波谱仪及多维NMR技术的推广与应用[73],C19-二萜生物碱的鉴定将更加快速而准确,且微量二萜生物碱的鉴定也将更加方便.因此可预见将有愈来愈多的C19-二萜生物碱新结构被发现,为药物研发提供更多的活性先导化合物.


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