Structural Elucidation and NMR Spectral Assignments of Two C<sub>19</sub>-Diterpenoid Alkaloids

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YIN Tian-peng, CHEN Yang, LUO Ping, et al. Structural Elucidation and NMR Spectral Assignments of Two C₁₉-Diterpenoid Alkaloids[J]. Chinese Journal of Magnetic Resonance, 2018, 35(1): 90-97. DOI: 10.11938/cjmr20172583.

[复制英文]

尹田鹏, 陈阳, 罗萍, 等. 两个C₁₉-二萜生物碱的结构鉴定和NMR信号归属[J]. 波谱学杂志, 2018, 35(1): 90-97. DOI: 10.11938/cjmr20172583.

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Foundation item

The national natural science foundation of China (81460648); Graduate student quality curriculum of Yunnan university

Corresponding author

CAL Le, Tel:0871-65033719, E-mail:caile@ynu.edu.cn

Article History

Received date: 2017-05-30
Revised date: 2017-06-26

Contents Abstract Full text Figures/Tables PDF

Structural Elucidation and NMR Spectral Assignments of Two C₁₉-Diterpenoid Alkaloids

YIN Tian-peng^1,2, CHEN Yang¹, LUO Ping², CAL Le², DING Zhong-tao²

1. Zhuhai Key Laboratory of Fundamental and Applied Research in Traditional Chinese Medicine, Zunyi Medical University Zhuhai Campus, Zhuhai 519041, China;
2. Functional Molecules Analysis and Biotransformation Key Laboratory of Universities in Yunnan Province, School of Chemical Science and Technology, Yunnan University, Kunming 650091, China

Received date: 2017-05-30; Revised date: 2017-06-26

Foundation item: The national natural science foundation of China (81460648); Graduate student quality curriculum of Yunnan university

Corresponding author: CAL Le, Tel:0871-65033719, E-mail:caile@ynu.edu.cn

Abstract: Two C₁₉-diterpenoid alkaloids, homochasmanine (compound 1) and 14-debenzoylfranchetine (compound 2), were isolated from the roots of Aconitum handelianum. Their structures were elucidated by one-dimensional and two-dimensional nuclear magnetic resonance (NMR) techniques, including ¹H NMR, ¹³C NMR, DEPT, ¹H-¹H COSY, HSQC, HMBC and NOESY. The ¹H and ¹³C NMR signals of the compounds were completely assigned.

Key words: NMR elucidation assignment diterpenoid alkaloid Aconitum handelianum

两个C₁₉-二萜生物碱的结构鉴定和NMR信号归属

尹田鹏^1,2, 陈阳¹, 罗萍², 蔡乐², 丁中涛²

1. 遵义医学院珠海校区, 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: 从剑川乌头（Aconitum handelianum）的根中分离得到两个C₁₉-二萜生物碱：高展花乌头宁（homochasmanine，化合物1）和14-去苯甲酰大渡乌碱（14-debenzoylfranchetine，化合物2）.采用1D和2D核磁共振（NMR）技术（包括¹H NMR、¹³C NMR、DEPT、¹H-¹H COSY、HSQC、HMBC和NOESY）对其进行结构鉴定，完整归属了这两个化合物的¹H和¹³C NMR信号.

关键词: 核磁共振(NMR) 鉴定归属二萜生物碱剑川乌头(Aconitum handelianum)

Introduction

Aconitum handelianum Comber (Ranunculaceae), a perennial herb, is endemic to Jianchuan County in Yunnan Province of China. The roots of A. handelianum have long been utilized to treat various pains by the native^{[1, 2]}. Diterpenoid alkaloids, which possess complex structures and varied biological activities, have been reported to be the characteristic bioactive ingredients in this plant^{[3, 4]}. In recent years, the research of diterpenoid alkaloids has grown markedly due to the development and application of the nuclear magnetic resonance (NMR) techniques^[5]. This paper deals with the structural elucidation and NMR spectral assignments of two C₁₉-diterpenoid alkaloids isolated from the roots of A. handelianum (Fig. 1). Homochasmanine (compound 1) is an aconitine-type C₁₉-diterpenoid alkaloid with a methoxy group rarely substituted at C-8. To our knowledge, no complete NMR spectral assignment of compound 1 has been undertaken^[6-8]. 14-debenzoylfranchetine (compound 2) is a franchetine-type C₁₉-diterpenoid alkaloid, whose ¹³C NMR data had been assigned previously but the complete ¹H NMR data were not reported in literatures^{[9, 10]}. To provide more important NMR spectroscopic data for structure determination of diterpenoid alkaloids, the NMR signals of compounds 1 and 2 have been full assigned accurately by the extensive NMR spectroscopic analyses (i.e. ¹H NMR, ¹³C NMR, DEPT, ¹H-¹H COSY, HSQC, HMBC and NOESY)^{[11, 12]}.

Figure 1 Structures of homochasmanine (compound 1) and 14-debenzoylfranchetine (compound 2)

1 Experimental section 1.1 Instruments and reagents

¹H NMR (400.13 MHz, CDCl₃) and ¹³C NMR (100.06 MHz, CDCl₃) spectra were acquired with a Bruker AM-400 spectrometer using tetramethylsilane (TMS) as the internal reference, and 2D NMR (400.13 MHz, CDCl₃) spectra were recorded at standard conditions.

High resolution mass spectrum with electronic spray ionizer (HR-ESI-MS) were recorded with Agilent G3250AA (Agilent, Santa Clara, USA) and Auto Spec Premier P776 spectrometer (Waters, Milford, USA). Silica gel (300~400 mesh; Qingdao Haiyang, Qingdao, China) and Sephadex LH-20 (GE Healthcare, Fairfield, USA) were used for column chromatography (CC).

Fractions were monitored by thin layer chromatography (TLC) and visualized by spraying with modified Dragendorff's reagent.

A Nicolet Magna-IR 550 spectrometer was used for scanning IR spectroscopy with KBr pellets.

1.2 Plant material

Roots of A. handelianum were collected from Jianchuan County in Yunnan Province of China in September 2013 and identified by professor Lu Shu-gang, School of Life Sciences, Yunnan University. A voucher specimen (2013-hcw-1) is deposited in the Key Laboratory of Medicinal Chemistry for Natural Resources, Ministry of Education, School of Chemical Science and Technology, Yunan University.

1.3 Extraction and isolation

Air-dried and powdered roots (2.0 kg) of A. handelianum were percolated with 0.5% HCl. The aqueous acidic solution was basified with 10% ammonia to pH 9.0 and then extracted with ethyl acetate. Removal of the solvent under reduced pressure afforded the total crude alkaloids (15.0 g) as yellowish amorphous powder. The total alkaloids were subjected to silica gel CC eluted with CHCl₃/CH₃OH gradient system [V(CHCl₃):V(CH₃OH)=100:1~1:1] to give eight fractions (FrA~FrH). FrA (0.4 g) was further subjected to silica gel CC [V(petroleum ether):V(acetone):V(diethylamine)=100:2:1~100:10:1) to yield compound 1 (12 mg). FrG (1.3 g) was subjected to silica gel CC [V(CHCl₃):V(CH₃OH)=20:1~5:1) to yield compound 2 (23 mg).

2 Results and discussion 2.1 Structural elucidation and NMR spectral assignment of homochasmanine (compound 1)

Compound 1 was isolated as a white powder and its molecular formula was deduced to be C₂₆H₄₃NO₆ by HR-ESI-MS at m/z of 466.316 3 [M+H]⁺ (calculated for C₂₆H₄₃NO₆, 466.316 9) with an unsaturation degree of six. IR (KBr, cm⁻¹): ν_max 3 454, 2 972, 2 818, 1 621, 1 454, 1 377, 1 098.

The NMR spectra displayed signals of an N-ethyl group [δ_H 1.05 (3H, t, J = 7.2 Hz); δ_C 13.7 (q), 49.2 (t)] and five methoxy groups [δ_H 3.22 (3H, s), 3.24 (3H, s), 3.29 (3H, s), 3.31 (3H, s), 3.35 (3H, s); δ_C 48.8 (q), 56.3 (q), 56.5 (q), 58.9 (q), 59.2 (q)]. The ¹³C NMR, DEPT and HSQC spectra revealed compound 1 contains nineteen carbons except for the N-ethyl and methoxyl groups, including six methylenes, ten methines and three quaternary carbons. The data summarized above, in combination with biogenetic consideration, suggested that compound 1 might be an aconitine-type C₁₉-diterpenoid alkaloid^{[13, 14]}.

The ¹³C NMR spectrum revealed six oxygenated carbons [δ_C 75.2 (d), 78.6 (s), 80.4(t), 82.5 (d), 83.1 (d), 85.8 (d)], corresponding to the molecular formula, which indicated the presence of one hydroxyl and five methoxy groups. The characteristic methylene [δ_H 3.67, 3.09 (ABq, J = 8.0 Hz)] was undoubtedly attributed to H-18, indicating a methoxy group substituted at C-18, which was confirmed by HMBC correlation of OCH₃-18/C-18 (Fig. 2). The HMBC correlations of OCH₃-1/C-1, H-1/C-5, H-1/C-10, H-1/C-11 suggested a methoxy group was placed at C-1 (Fig. 3). Besides, the chemical shift of C-1 [δ_C 85.8 (d)] was in accordance with the typical OCH₃-1α compounds chasmanine [δ_C 86.2 (d)] or talatisamine [δ_C 86.1 (d)]. Another two methoxy groups were placed at oxygenated methines C-6 and C-16 on the basis of HMBC correlations of OCH₃-6/C-6 and OCH₃-16/C-16, respectively. In addition, NOESY correlations of H-1β/H-5β, H-6β/H-9β, and H-13β/OCH₃-16 demonstrated the α-orientation of OCH₃-1, α-orientation of OCH₃-6, and β-orientation of OCH₃-16, respectively. A methoxy group substituted at oxygenated quaternary carbon C-8 was confirmed by the HMBC correlations of OCH₃-8/C-8 and H-10/C-8, which was supported by the chemical shift of OCH₃-8 [δ_C 48.8 (q)], which was upfield approximately δ 8~10 when compared with methoxy groups substituted at methines. Finally, the signal at δ_H 4.12 (m) was attributed to H-14β, suggesting the presence of α-orientation of OH ^[15], which was further supported by the NOESY correlation of H-10β/H-14β. Therefore, the structure of compound 1 was determined.

Figure 2 Key ¹H-¹H COSY (

), HMBC (

) and NOESY (

) correlations of compounds 1 and 2

Figure 3 HMBC spectrum of compound 1

All ¹H and ¹³C NMR signals of compound 1 were assigned based on its 2D NMR spectra (Table 1).

Table 1 ¹H NMR, ¹³C NMR, HSQC, ¹H-¹H COSY, HMBC and NOESY data of compound 1 in CDCl₃

Position	δ_H (J/Hz)	δ_C	HSQC	¹H-¹H COSY	HMBC	NOESY
1^*	2.98 (1H, dd, J=10.0/6.4 Hz)	85.8	+	H-2a, H-2b	C-10, C-11, C-17, OCH₃-1	H-2b, H-3, H-5, H-10, OCH₃-1
2^*	2.30 (1H, m, H-2a) 1.91 (1H, m, H-2b)	26.4	+	H-1, H-3 H-1	C-1, C-3 C-4	H-3 H-1, H-3
3^*	1.60 (2H, m)	35.4	+	H-2a	C-2, C-4, C-5, C-19	H-1, H-2a, H-2b, H-5, H-18, H-19
4^*	/	39.2	/	/	/	/
5^*	2.07 (1H, d, J=6.8 Hz)	49.1	+	H-6	C-4, C-7, C-10, C-11, C-17, C-18, C-19	H-1, H-3, H-6, H-10
6^*	4.11 (1H, d, J=6.8 Hz)	83.1	+	H-5, H-7	C-4, C-7, C-8, OCH₃-6	H-5, H-9, OCH₃-6
7^*	2.39 (1H, brs)	48.4	+	H-6	C-6, C-8, C-11, C-15, C-17	H-15, OCH₃-8
8^*	/	78.6	/	/	/	/
9^*	2.13 (1H, m)	48.1	+	H-10	C-7, C-8, C-12	H-6, H-10
10^*	1.77 (1H, m)	45.4	+	H-9, H-12a, H-12b	C-8, C-9, C-11, C-12, C-17	H-1, H-5, H-9, H-14
11^*	/	50.6	/	/	/	/
12^*	2.13 (1H, m, H-12a) 1.83 (1H, m, H-12b)	29.5	+	H-10 H-10, H-13	C-8, C-9, C-10, C-13, C-14, C-16 C-13, C-16	H-10 H-13, H-17
13^*	2.26 (1H, m)	38.9	+	H-14, H-12b	C-9, C-10, C-12, C-14, C-15, C-16	H-12b, H-14, H-16
14^*	3.99 (1H, m)	75.2	+	H-13, H-9	C-8, C-16	H-10, H-13
15^*	2.11 (2H, m)	34.1	+	H-16	C-7, C-8, C-9	H-7, H-16, H-17
16^*	3.28 (1H, m)	82.5	+	H-15	C-12, C-14, OCH₃-16	H-13, H-15, OCH₃-16
17^*	2.83 (1H, brs)	62.0	+	/	C-5, C-6, C-19, C-21	H-12b, H-15, H-21a, H-21b
18^*	3.67, 3.09 (2×1H, ABq, J=8.0 Hz)	80.4	+	/	C-3, C-4, C-5, C-19, OCH₃-18	H-3, H-5, H-19, OCH₃-18
19^*	2.52, 2.46 (2×1H, ABq, J=10.8 Hz)	53.8	+	/	C-3, C-4, C-17, C-21	H-3, H-17, H-22
21^*	2.52 (1H, m, H-21a) 2.46 (1H, m, H-21b)	49.2	+	H-22a, H-22b H-22a, H-22b	C-17, C-19, C-22 C-17, C-19, C-22	H-17, H-22 H-17, H-22
22^*	1.05 (3H, t, J=7.2 Hz)	13.7	+	H-21	C-21	H-19, H-21a, H-21b
OCH₃-1^*	3.22 (3H, s)	56.3	+	/	C-1	H-1
OCH₃-6^*	3.31 (3H, s)	58.9	+	/	C-6	H-6
OCH₃-8^*	3.24 (3H, s)	48.8	+	/	C-8	/
OCH₃-16^*	3.35 (3H, s)	56.5	+	/	C-16	H-16
OCH₃-18^*	3.29 (3H, s)	59.2	+	/	C-18	H-18
^* uncertain signals in references [6-8]

Table 1 ¹H NMR, ¹³C NMR, HSQC, ¹H-¹H COSY, HMBC and NOESY data of compound 1 in CDCl₃

2.2 Structural elucidation and NMR spectral assignment of 14-debenzoylfranchetine (compound 2)

Compound 2 was isolated as a white powder, whose molecular formula was deduced to be C₂₄H₃₇NO₅ by HR-ESI-MS at m/z of 420.274 4 [M+H]⁺ (calculated for C₂₄H₃₇NO₅, 420.275 0) with an unsaturation degree of seven. IR (KBr, cm⁻¹): ν_max 3 432, 2 927, 2 316, 1 723, 1 454, 1 371, 1 097.

The NMR spectra displayed signals of an N-ethyl group [δ_H 1.00 (3H, t, J = 7.2 Hz); δ_C 13.3 (q), 49.3 (t)], three methoxy groups [δ_H 3.29 (3H, s), 3.32 (3H, s), 3.33 (3H, s); δ_C 56.4 (q), 57.4 (q), 59.7 (q)], a characteristic trisubstituted double bond [δ_H 5.69 (1H, brs); δ_C 128.6 (d), 137.6 (s)] and an N, O-mixed ketal moiety [δ_H 4.33 (1H, s); δ_C 92.6 (d)]. The double bond accounts for one degree of unsaturation, indicating the presence of six rings in compound 2. The ¹³C NMR, DEPT and HSQC spectra revealed compound 2 contains nineteen carbons except for the N-ethyl and methoxyl groups, including six methylenes, ten methines and three quaternary carbons. The data summarized above, in combination with biogenetic consideration, suggested that compound 2 might be a franchetine-type C₁₉-diterpenoid alkaloid^[16].

The HMBC correlations of H-17/C-1 and H-6/C-17 further confirmed the presence of N, O-mixed ketal moiety (Fig. 2). The trisubstituted double bond was placed at C-7 and C-8 on the basis of HMBC correlations of H-5/C-7, H-6/C-7, H-10/C-8 and H-15/C-8 (Fig. 4). The ¹³C NMR spectrum revealed six oxygenated carbons [δ_C 85.0 (d), 75.1 (d), 77.5 (d), 85.0 (d), 92.6 (d), 79.4 (t)], which indicated the presence of one hydroxyl group except for the methoxy groups and N, O-mixed ketal moiety. Three methoxy groups were located at C-1, C-16 and C-18 on the basis of HMBC correlations of OCH₃-1/C-1, OCH₃-16/C-16 and OCH₃-18/C-18, respectively. The NOESY correlations of H-1β/H-5β and H-13β/OCH₃-16 demonstrated the α-orientation of OCH₃-1 and β-orientation of OCH₃-16, respectively. Finally, the broad singlet at δ_H 4.17 was attributed to H-14β, suggesting the presence of α-orientation of OH-14, which was further supported by the NOESY correlation of H-10β/H-14β^{[17, 18]}. Therefore, the structure of compound 2 was determined.

Figure 4 HMBC spectrum of compound 2

All ¹H and ¹³C NMR signals of compound 2 were assigned based on its 2D NMR spectra (Table 2).

Table 2 ¹H NMR, ¹³C NMR, HSQC, ¹H-¹H COSY, HMBC and NOESY data of compound 2 in CDCl₃

Position	δ_H (J/Hz)	δ_C	HSQC	¹H-¹H COSY	HMBC	NOESY
1^*	3.23 (1H, m)	85.0	+	H-2a, H-2b	C-10, C-17, OCH₃-1	H-2b, H-5, H-10, OCH₃-1
2^*	2.57 (1H, m, H-2a) 1.91 (1H, m, H-2b)	24.5	+	H-1, H-3a, H-3b H-1, H-3a, H-3b	C-1 C-1, C-3	H-3a, H-3b H-1, H-3a, H-3b
3^*	1.76 (1H, m, H-3a) 1.50 (1H, m, H-3b)	32.9	+	H-2a, H-2b H-2a, H-2b	C-1	H-1, H-2a, H-2b, H-2a, H-2b, H-5
4^*	/	37.5	/	/	/	/
5^*	2.25 (1H, m)	48.3	+	/	C-4, C-6, C-7, C-10, C-18, C-19	H-1, H-3b, H-9
6	4.38 (1H, d, J=6.0 Hz)	75.1	+	H-7	C-4, C-7, C-8, C-11	H-7, H-18, H-19
7	5.69 (1H, brs)	128.6	+	H-6	C-5, C-6, C-9, C-15	H-6, H-15b
8^*	/	137.6	/	/	/	/
9^*	2.77 (1H, m)	44.5	+	H-10, H-14		H-5
10^*	2.17 (1H, m)	49.3	+	H-9, H-12a, H-12b	C-8	H-1, H-9, H-12a, H-14
11^*	/	50.5	/	/	/	/
12^*	1.91 (1H, m, H-12a) 1.50 (1H, m, H-12b)	29.5	+	H-10, H-13 H-10, H-13	C-16 C-10, C-13, C-16	H-10
13^*	2.27 (1H, m)	40.7	+	H-16	C-9, C-16	H-12a, H-12b, H-14, H-16
14	4.17 (1H, brs)	77.5	+	H-9, H-13		H-9, H-10, H-13
15^*	2.91 (1H, dd, J=12.0/7.2 Hz, H-15a) 2.58 (1H, m, H-15b)	38.9	+	H-16 H-16	C-16	H-7
16^*	3.37 (1H, m)	85.0	+	H-13, H-15a	C-12, C-14, OCH₃-16	H-12a, H-13, H-15b, OCH₃-16
17	4.33 (1H, s)	92.6	+	/	C-5, C-6, C-10, C-19, C-21	H-12a, H-21
18^*	3.16, 3.06 (2×1H, ABq, J=8.8 Hz)	79.4	+	/	C-3, C-4, C-5, C-19, OCH₃-18	H-5, H-6, OCH₃-18
19^*	2.44, 2.03 (2×1H, ABq, J=11.2 Hz)	52.8	+	/	C-3, C-4, C-5, C-17	H-6
21	2.59 (1H, m, H-21a) 2.44 (1H, m, H-21b)	49.3	+	H-22 H-22	C-17, C-19, C-22 C-17, C-19, C-22	H-17, H-22 H-22
22	1.00 (3H, t, J=7.2 Hz)	13.3	+	H-21a, H-21b	C-22	H-21a, H-21b
OCH₃-1	3.33 (3H, s)	57.4	+	/	C-1	H-1
OCH₃-16	3.32 (3H, s)	56.4	+	/	C-16	H-16
OCH₃-18	3.29 (3H, s)	59.7	+	/	C-18	H-18
^* uncertain signals in references [9, 10]

Table 2 ¹H NMR, ¹³C NMR, HSQC, ¹H-¹H COSY, HMBC and NOESY data of compound 2 in CDCl₃

3 Conclusion

The structural elucidation and full NMR spectral assignments of two C₁₉-diterpenoid alkaloids homochasmanine (1) and 14-debenzoylfranchetine (2), which were isolated from the roots of A. handelianum, were accomplished by extensive spectroscopic analyses (¹H NMR, ¹³C NMR, DEPT, ¹H-¹H COSY, HSQC, HMBC and NOESY). The present study provides important references for the structure determination of diterpenoid alkaloids.

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