Chinese Chemical Letters  2017, Vol. 28 Issue (3): 588-592   PDF    
A minor arcutine-type C20-diterpenoid alkaloid iminium constituent of "fu zi"
Xian-Hua Meng, Zhi-Bo Jiang, Qing-Lan Guo, Jian-Gong Shi     
State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China
Abstract: A rare arcutine-type C20-diterpenoid alkaloid, named aconicarmicharcutinium A and obtained as hydroxide (1) and trifluoroacetate (1a), was characterized as a minor constituent of "fu zi" (the lateral roots of Aconitum carmichaelii). The structures of 1 and 1a were elucidated by comprehensive analysis of spectroscopic data including 19F and 2D NMR experiments. Compounds 1 and 1a represent the first examples of the arcutine-type C20-diterpenoid alkaloid iminium.
Key words: Aconitum carmichaelii     Ranunculaceae     Arcutine-type C20-diterpenoid alkaloid     iminium     Aconicarmicharcutinium A    
1. Introduction

The lateral root of Aconitum carmichaelii Debx. (Ranunculaceae), named "fu zi" in Chinese, is an important ingredient of formulations for the treatment of cardianeuria, neuralgia, and rheumatalgia in China, Japan, and Korea [1-3]. Chemical and pharmacological studies have shown that aconitine C19-diterpenoid alkaloids are main toxic and active constituents of "fu zi" [4-7], while more than a hundred of diverse chemical constituents were isolated from extracts of A. carmichaelii [8, 9]. However, previous chemical studies were mainly carried out on the extracts obtained by extraction of raw or processed drug materials with less polar organic solvents (benzene, CHCl3, methanol, or ethanol) [2-8, 10-13], that differs from a practical application by decocting the formulations. Therefore, an aqueous decoction of the raw "fu zi" was investigated as part of a program to systematically study the chemical diversity of several common traditional Chinese medicines and their biological effects [14-32]. In previous papers, we reported four new hetisan-type and three napeline-type C20-and twenty-two new aconitane-type C19-diterpenoid alkaloids, two new 2-(quinonylcarboxamino) benzoates, and seven new aromatic acid derivatives [33-36]. A continuation of the study, focusing on the minor constituents, has led to characterization of a rare arcutine-type C20-diterpenoid alkaloid iminium, named aconicarmicharcutinium A and obtained as hydroxide (1) and trifluoroacetate (1a) forms (Fig. 1). Herein, we report details of the isolation and structure elucidation of 1 and 1a.

Figure 1. Structures of 1 and 1a.

2. Results and discussion

Compound 1 was isolated as a white amorphous powder with [α]20D +32.1 (c 0.07, MeOH). Its IR spectrum displayed absorption bands due to hydroxyl (3357 cm-1) and iminium (1683 cm-1) [36] functionalities. The 1H NMR spectrum of 1 in MeOH-d4 showed resonances assignable to a methylene of an exocyclic double bond at δH 5.10 (brs, 2H, H2-17), three oxygen-and/or nitrogen-bearing methylenes and one oxygen-bearing methine between δH 3.91 and 3.80 (partially overlapped m, 7H, H-15, H2-19, H2-21, and H2-22), and a tertiary methyl group at δH 1.23 (s, H3-18), as well as resonances due to several aliphatic methine and methylene units between δH 2.85 and 1.26. The 13C NMR and DEPT spectra showed 21 carbon resonances corresponding to the above units and four additional quaternary carbons, including an oxygen-bearing (δC 72.9, C-10) and three aliphatic (δC 61.7, C-5; 42.6, C-8; and 41.4, C-4) quaternary carbons, while the quaternary iminium carbon resonated at δC 203.7 (C-20) and the carbon resonances of seven methylenes and two methines were differentiated in the aliphatic region (Table 1). However, the 13C NMR spectrum showed one less methine carbon than that expected from HR-ESIMS at m/z 358.2377 (calcd. for C22H32NO3, 358.2377), and in the 1H NMR spectrum the multiple signal with a less integration than one proton at δH 2.85 (dd, 0.73H, J=13.2 and 6.0 Hz) was disappeared when the sample was stored in MeOH-d4. As compared with those of the previously isolated alkaloids from "fu zi" [33-36], these spectroscopic data suggest that 1 is an uncommon C20-diterpene alkaloid, of which the structure was further elucidated by 2D NMR data analysis.

Table 1
NMR spectroscopic data for 1 and 1a.a

The proton resonances and corresponding proton-bearing carbon resonances in the NMR spectra were assigned by HSQC data analysis. In the 1H1H COSY spectrum of 1, cross-peaks of H2-1/ H2-2/H2-3, H2-6/H2-7, H-9/H2-11/H-12/H2-13, H-15/H2-17, and H2-21/H2-22 revealed the presence of four vicinal and one allylic homonuclear coupling systems (Fig. 2, thick lines). In the HMBC spectrum of 1, two-and three-bond correlations (Fig. 2, arrows) from H3-18 to C-3, C-4, C-5, and C-19 and from H2-19 to C-3, C-4, C-5, and C-18, together with the chemical shifts of these proton and carbon resonances, demonstrated a linkage of C-4 with C-3, C-5, C-18, and C-19. The HMBC correlations from H2-6 to C-5, C-10, and C-20, in combination with their chemical shifts, revealed that C-6 connected via C-5 to both C-10 and C-20. The connection of C-8 with C-7, C-9, C-14, and C-15 was indicated by the HMBC correlations from H2-7 to C-8, C-9, and C-14; from H-9 to C-7, C-8, and C-14; and from H-15 to C-7, C-9, and C-14. The HMBC correlations of C-10 with H2-2, H-9, and H2-11, combined with the chemical shift of the C-10 resonance, suggested that the oxygenbearing C-10 was connected by C-1 and C-9, while the HMBC correlations from H-15 to C-12, C-16, and C-17 and from H2-17 to C-12 and C-15 revealed a location of the exocyclic double bond between C-12 and C-15. In addition, the HMBC correlations of C-20 with H2-13, H2-19, and H2-21 indicated that the quaternary iminium carbon C-20 connected via C-14 to C-13 and via the nitrogen atom to both C-19 and C-21 to give an iminium skeletal structure of the rare arcutine-type C20-diterpene alkaloid [37, 38] for 1. Three hydroxyl groups were located at C-10, C-15, and C-22 based on the chemical shifts of these carbons and their attaching protons, which was supported by the ESIMS and HR-ESIMS data. Because the proton resonances were partially overlapped in the 1H NMR spectrum of 1 in MeOH-d4 and because isomerization of several C20-diterpene alkaloid imines and iminiums under acidic and basic conditions was reported [39-41], to ensure the structural elucidation and to test stability of 1 in the basic solvent pyridine, the 1D NMR and 2D NMR spectra of 1 in pyrinde-d5 were acquired (Figs. S15-S21 in Supporting information). Subsequent data analysis confirmed the structure assignment and stability of the alkaloid iminium. However, it must be noted that, in the HMBC spectrum of 1 in MeOH-d4 or pyrinded5, the strong correlations from H2-7, H-9, H2-13, and H-15 to a resonated carbon around δC 36.8 in MeOH-d4 or δC 34.9 in pyrinded5 were observed though no signal was observed in the 13C NMR spectrum. This carbon resonance was assigned to C-14 in the above structural elucidation, which paired with the weak signal of H-14 at δH 2.85 in MeOH-d4 or at δH 3.26 in pyrinde-d5 in the 1H NMR spectrum and matched requirement of the cationic alkaloid formula as determined by HR-ESIMS. In particular, cross-peaks between H2-13 and H-14 were clearly observed in the 1H-1H COSY spectrum of 1 in pyrinde-d5 (Fig. S18 in Supporting information). The diminish and absence of the 1H and 13C resonances may be explained by a deuterium exchange and/or a dissociation of H-14 in MeOH-d4 or pyrinde-d5, since this proton is activated by an electron withdraw inductive effect of the germinal quaternary iminium unit. Accordingly, the planar structure of the alkaloid iminium in 1 was determined as shown in Fig. 2.

Figure 2. Main 1H-1H COSY (thick lines) and three-bond HMBC correlations (red arrows, from 1H to 13C) of the alkaloid iminium in 1 and 1a.

In the ROESY spectrum of 1 in pyridine-d5, the NOE correlations between H3-18 with both H-1a and H-3a; between H-9 with both H-1a and H-7a revealed that these protons were cofacial on one side of the ring system. In addition, the ROESY spectrum showed the NOE correlations between H-15 with H-7b and H-14, indicating these protons were cofacial on the other side of the ring system (Fig. 3). This demonstrates that the alkaloid iminium in 1 has the same relative configuration as that of arcutine which was determined by single-crystal X-ray diffraction [37]. Based on possible biogenetic transformations among the co-occurring C20- diterpenoid alkaloids (such as hetisans and hetidines), the absolute configuration of the arcutine nucleus is proposed to be consistent with those of the other type C20-diterpenoid alkaloids isolated from the same plant [9, 33, 36]. Therefore, the structure of the alkaloid iminium in 1 was determined as shown and named aconicarmicharcutinium A.

Figure 3. Main NOESY correlations (pink dashed double arrows) of the alkaloid iminium in 1 and 1a.

Compounds 1a (colorless gum and acetone soluble) and 1 (white amorphous and acetone insoluble) with respective Rf values of 0.40 and 0.18, were obtained from the same fraction by chromatography over silica gel eluting with CHCl3 (saturated by concentrated aqueous ammonia)-MeOH (5:1) (see Section 4). Although the two compounds possessed different properties, the 1D NMR spectra of 1a in MeOH-d4 exhibited the resonances overlapped with those of 1 except for the full appearance of the CH-14 resonances [δH 2.85 (dd, 1H, J=13.2 and 6.0 Hz) and δC 36.8] (Table 1 and Figs. S29-S31 in Supporting information). Further 2D NMR spectroscopic data analysis proved that the alkaloid iminium moiety in 1a were completely identical to that in 1. Especially, the 1H-1H COSY cross-peak of H2-13/H-14, the HSQC correlation of H-14/C-14, and the NOE correlations of H-15 with H-7b and H-14 in the spectra of 1a (Figs. S32, S33, and S35 in Supporting information) further proved the structure assignment. Considering purifications of 1 and 1a were contacted with ammonia and trifluoroacetic acid (TFA), respectively (see Section 4), identity of the alkaloid iminium moiety suggested that 1 and 1a differed in their anion counterparts, e.g. the two compounds were obtained as hydroxide (1) and trifluoroacetate (1a) forms of the same alkaloid iminium. This was supported by measurements of the 19F NMR spectra of 1 and 1a. The 19F NMR spectrum of 1a displayed a strong 19 F resonance at δF -76.5, whereas a similar but very weak signal was observed in the 19F NMR spectrum of 1. Subsequent quantitative 19F NMR analysis in MeOH-d4, using benzene (C6H6) and hexafluorobenzene (C6F6) as internal standards, determined that the molar ratios of alkaloid iminium cation and TFA anion in 1 and 1a were 1:0.1 and 1:1, respectively (Figs. S36-S39 in Supporting information). In addition, TLC and 19F NMR spectroscopic data analysis verified that 1 was transformed into 1a by treatment of 1 with the HPLC mobile phase containing TFA. The occurrence of a minor amount of TFA in 1 suggested that the ammonia used in the mobile phase of CC was not enough to completely transform 1a into 1. The different behavior of the CH-14 resonances in the NMR spectra of 1 and 1a in MeOH-d4 demonstrated that the iminium carbon germinated H-14 in the hydroxide was easier to be dissociated and/or substituted by deuterium than that in the trifluoroacetate (e.g. the dissociation and/or exchange reaction was accelerated under the basic condition and restricted under the acidic condition). As also observed in our previous studies [33, 36], the absence of the 13C resonances of TFA- in the 13C NMR spectrum of 1a may be explained by a combination of multiple reasons, including spin coupling-split of the 13C resonances by the 19F nucleus, conjugation between different anion species of TFA as commonly observed for carboxylic groups, and interaction of the anion species with the iminium and solvent. Thus, compounds 1 and 1a were determined as aconicarmicharcutinium A hydroxide and trifluoroacetate, respectively.

3. Conclusion

An arcutine-type C20-diterpenoid alkaloid iminium, named aconicarmicharcutinium A, was characterized as the minor component of A. carmichaelii and obtained as trifluoroacetate (1) and hydroxide (1a) forms from the aqueous extract of "fu zi". In this C20-diterpenoid alkaloid category, only two known natural products arcutine and arcutinine were reported from a species of the same genus A. arcuatum [37-39]. Although the imine structure of arcutine was established by X-ray crystallographic analysis [37], subsequent NMR spectroscopic data analysis showed that the crystal was a crystalline mixture containing arcutine and arcutinine in a 2:1 ratio, and the structure of arcutinine was elucidated on the basis of spectroscopic data of the mixture and its saponification product arcutinidine [38]. Therefore, compounds 1 and 1a represent the first examples of the arcutine-type C20- diterpenoid alkaloid iminium paired with different anions, while A. carmichaelii is the second plant producing the arcutine-type C20- diterpenoid alkaloids. Since the anion counterparts OH- or TFA- in 1 and 1a are obviously induced by using concentrated aqueous ammonia and TFA in the experiments and since a number of organic and inorganic anions exist in the complex bio-systems [34], the positively charged alkaloid iminium in the bio-system would be paired with a variety of organic and inorganic anions to increase their solubility, bioavailability, and transportations, as well as to play and/or manipulate potential biological functions. Although biological activity of 1 and 1a was not assayed due to limitation of the sample amounts, the rare structure enriched the diversity of the diterpene alkaloid constituents of "fu zi", and provide a clue for future in-depth studies of chemical transformation, structural modification, biomimetic and total synthesis, and biosynthesis of the diterpene alkaloids to obtain enough amount of the samples for biological evaluation. In addition, this study, along with our previous observation of TFA- induced conformational variations of ring A in the C19-diterpenoid alkaloids, as well as solvent-/base-/acid-dependent transformation and equilibration between alcohol iminium and aza acetal forms of the C20- diterpenoid alkaloids [33, 36, 42, 43], demonstrates the presence of different forms/species of the diterpenoid alkaloids under the experimental and biological conditions. Because the different forms/species possess different properties, which are critical for their solubility, bioavailability, transportations, and biological functions in the bio-systems, in-depth chemical and biological studies on a case by case basis are required and of considerably interesting to reveal multiple faces of the diterpenoid alkaloids.

4. Experimental 4.1. General experimental procedures

Optical rotations were measured on a P-2000 polarimeter (JASCO, Tokyo, Japan). UV spectra were recorded on a V-650 spectrometer (JASCO). CD spectra were measured on a JASCO J-815 CD spectrometer (JASCO). IR spectra were recorded on a Nicolet 5700 FT-IR Microscope spectrometer (FT-IR Microscope Transmission) (Thermo Electron Corporation, Madison, WI, USA). 1D-and 2D-NMR spectra were obtained at 600 MHz for 1H, 150 MHz for 13C, and 470 MHz for 19F, respectively, on a SYS 600 MHz (Varian Associates Inc., Palo Alto, CA, USA) or a WNMR-I 500 MHz (Wuhan Zhongke Niujin Magnetic Resonance Technology Co., Ltd., Wuhan, China) spectrometer with solvent or TMS peaks as references. ESIMS and HR-ESIMS data were obtained on Agilent 1100 Series LC-MSD-Trap-SL and Agilent 6520 Accurate-Mass QTOFL CMS spectrometers (Agilent Technologies, Ltd., Santa Clara, CA, USA), respectively. Column chromatography (CC) was performed with silica gel (200-300 mesh, Qingdao Marine Chemical Inc., China) and Sephadex LH-20 (Pharmacia Biotech AB, Uppsala, Sweden). HPLC separation was performed on a system consisting of a Waters 600 controller, a Waters 600 pump, and a Waters 2487 dual absorbance (Waters Corporation, Milford, MA, USA) or a Smartline RI detector (KNAUER, Berlin, Germany) detector, using using an Ultimate XB-Phenyl column (250 × 10 mm i.d.) packed with phenyl-silica gel (5 μm) (Welch, Shanghai, China) or a YMCPack Ph column (250 × 10 mm i.d.) packed with phenyl-silica gel (5 mm) (YMC Co., Ltd, Kyoto, Japan). TLC was conducted on precoated silica gel GF254 plates. Spots were visualized under UV light (254 or 356 nm) or by spraying with 7% H2SO4 in 95% EtOH followed by heating or with a Dragendorff's reagent. Unless otherwise noted, all chemicals were obtained from commercially available sources and were used without further purification.

4.2. Plant material

See Refs. [33, 34, 36].

4.3. Extraction and isolation

For extraction and preliminary fractionation of the extract, see Refs. [33, 34, 36]. Fraction C2-2 (200 g) was chromatographed over Sephadex LH-20 using MeOH:H2O (1:1) as the mobile phase to afford C2-2-1-C2-2-8. Fraction C2-2-4 (9.5 g) was separated by CC over silica gel (150 g) eluting with petroleum ether:acetone: diethylamine (5:2:1-2:2:1) to give C2-2-4-1-C-2-2-4-7. Further separation of C2-2-4-6 (2.65 g) by CC over silica gel, eluting with CHCl3 (saturated with ammonia water):MeOH (30:1-5:1), to yield C2-2-4-6-1-C-2-2-4-6-11, of which C2-2-4-6-9 (400 mg) was separated by RP HPLC (YMC-Pack Ph column, 35% MeOH in H2O, containing 0.1% TFA, 2 mL/min) to afford C2-2-4-6-9-1-C2-2-4-6-9-6. Fraction C2-2-4-6-9-4 was further isolated by CC over silica gel eluting with CHCl3 (saturated with concentrated aqueous ammonia):MeOH (5:1) to afford C2-2-4-6-9-4-1-C2-2-4-6-9-4-3. Fraction C2-2-4-6-9-4-1 was purified by CC over Sephadex LH-20 (MeOH) yielded 1 (1 mg, 0.000002%), and C2-2-4-6-9-4-3 was purified by RP HPLC (Ultimate XB-Phenyl column, 35% MeOH in H2O, containing 0.1% TFA, 2 mL/min) to obtain 1a (1.5 mg, tR=27 min, 0.000003%).

4.3.1. Aconicarmicharcutinium A hydroxide (1)

White amorphous powder (MeOH); [α]20D +32.1 (c 0.07, MeOH); UV (MeOH) λmax (log ε): 202 (3.29), 221 (2.76), 256 (2.29) nm; CD (MeOH) 216 (△ε +4.35); IR vmax 3406, 1684, 1451, 1378, 1207, 1147, 849, 802, 728 cm-1; 1H NMR (MeOH-d4, 600 MHz) data, see Table 1; 13C NMR (MeOH-d4, 150 MHz) data, see Table 1; (+)-ESIMS m/z 358; (+)-HR-ESIMS m/z 358.2377 (calcd. for C22H32NO3, 358.2377).

4.3.2. Aconicarmicharcutinium A trifluoroacetate (1a)

Colorless gum; [α]20D +29.4 (c 0.10, MeOH); UV (MeOH) λmax (log ε): 203 (3.10), 222 (2.57) nm; CD (MeOH) 219 (△ε +1.96); IR vmax 3360, 2921, 2851, 1683, 1468, 1448, 1423, 1210, 1142, 1068, 844, 802, 725 cm-1; 1H NMR (MeOH-d4, 600 MHz) data, see Table 1; 13C NMR (MeOH-d4, 150 MHz) data, see Table 1; (+)-ESIMS m/z 358; (+)-HR-ESIMS m/z 358.2384 (calcd. for C22H32NO3, 358.2377).

Appendix A. Supplementary data

Supplementary data associated with this article can be found, in the online version, at


Financial support from the National Natural Science Foundation of China (NNSFC; Nos. 81630094 and 30825044) is acknowledged.

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