Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX
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Tabernabovines A−C: Three Monoterpenoid Indole Alkaloids from the Leaves of Tabernaemontana bovina Yang Yu,†,‡ Mei-Fen Bao,†,‡ Jing Wu,†,‡ Jing Chen,†,‡ Yu-Rong Yang,†,§ Johann Schinnerl,∥ and Xiang-Hai Cai*,†,§
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†
State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650201, China ‡ University of Chinese Academy of Sciences, Beijing 100049, China § Yunnan Key Laboratory of Natural Medicinal Chemistry, Kunming 650201, China ∥ Chemodiversity Research Group, Division of Systematic and Evolutionary Botany, University of Vienna, Rennweg 14, A-1030 Vienna, Austria S Supporting Information *
ABSTRACT: Three monoterpenoid indole alkaloids (MIAs), tabernabovines A−C (1−3), were isolated from Tabernaemontana bovina. They were elucidated by spectroscopic data and computational calculations. Unlike precursors of MIAs, strictosidine and alstrostine A, alkaloid 1 consists of tryptamine and secologanin in a 2:1 ratio. Alkaloid 2 is a cage compound, and 3 possesses a bridged ring. Tabernabovine A exhibited inhibitory activity against NO production with IC50 44.1 μM compared to L-NMMA with IC50 of 48.6 μM.
M
onoterpenoid indole alkaloids (MIAs) usually originate from strictosidine by the condensation of tryptamine and secologanin in a 1:1 ratio.1 The previously isolated alstrostine A consists of tryptamine and secologanin in a 1:2 ratio, which supports the possibilities of differentiations in the biosynthesis of MIAs.2 Furthermore, many MIAs are formed by postbiosynthetic modifications through skeletal rearrangements or degradation or extension processes. So, MIAs possess a vast structural diversity often linked with impressive bioactivities.3 In continuation of our previous investigation, we still focus on structurally complex MIAs from Tabernaemonatana species (Apocynaceae).4 This pantropical distributed genus is a well-known source of structurally complex MIAs which challenges structure elucidation5 as well as chemical synthesis.6 In the present study, we report the isolation and structure elucidation of three undescribed alkaloids (Figure 1) from Tabernaemontana bovina Lour. (Apocynaceae) (Supporting Information). Compounds 1−3 may be alkaloids as they exhibited a positive reaction with Dragendorff’s reagent on TLC plates. Compound 17 forms colorless crystals and possesses a molecular formula of C30H32N4O3 as established by HRESIMS at m/z 497.2545 [M + H]+ (calcd for 497.2547). Its UV © XXXX American Chemical Society
Figure 1. Structures of alkaloids 1−3.
spectra (203, 224, 258 nm) displayed the presence of benzene rings. The 1H NMR spectra of 1 indicated two sets of Received: June 15, 2019
A
DOI: 10.1021/acs.orglett.9b02060 Org. Lett. XXXX, XXX, XXX−XXX
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Organic Letters unsubstituted indole A rings based on the signals δH 7.10 (1H, t, J = 7.0 Hz), 7.14 (1H, t, J = 7.0 Hz), 7.19 (1H, d, J = 7.0 Hz), 7.45 (1H, d, J = 7.0 Hz) and δH 6.55 (1H, d, J = 7.3 Hz), 6.79 (1H, t, J = 7.3 Hz), 7.21 (1H, t, J = 7.3 Hz), 7.29 (1H, d, J = 7.3 Hz). Its 13C NMR and DEPT spectrum displayed 30 carbon resonances for 9 sp2 methines (δC 130.6 × 2, 124.1, 121.6, 120.3, 119.3, 118.5, 109.3, 109.1), 7 sp2 quaternary carbons (δC 151.2, 136.8, 135.9, 131.4, 129.0, 110.8, 106.4), 1 methyl (δc 22.6), 1 methoxyl ester [δC 170.3 (s), 51.8 (q)], 5 methylenes (δc 44.2, 22.3, 29.9, 51.2, 35.3), 5 sp3 methines (δC 52.2, 51.9, 40.4, 60.3, 78.3), and 1 sp3 quaternary carbon (δC 84.9) (Table 1), indicating the presence of independent indole Table 1. 1H and 13C NMR Spectroscopic Assignments of 1 (in CDCl3) (δ in ppm and J in Hz) δH 1
no. 2 3 5
δC 1
δH 1
δC 1
3.96, q, 6.8 5.72, s
51.9 d 110.8 s 130.6 d
2′
4.70, s
78.3 d
106.4 s
5′
51.2 t
129.0 s
6′
2.49, 3.40, 2.43, 2.54,
118.5 d 120.3 d 121.6 d 109.3 d 136.8 s 29.9 t
7′ 8′ 9′ 10′ 11′ 12′
40.4 d 60.3 d 22.6 q
13′ CO OMe
no.
135.9 s 52.2 d 44.2 t
19 20 21
22.3 t
7 8
6
9 10 11 12 13 14 15 16 18
3.84, 3.09, 3.44, 2.71, 2.86,
dd, 11.0, 5.6 m m m m, overlap
7.45, 7.10, 7.14, 7.19,
d, 7.0 t, 7.0 t, 7.0 d, 7.0
1.80, 2.08, 2.86, 5.13, 1.54,
m q, 11.0 m, overlap d, 5.4 d, 6.8, (3H)
7.29, 6.79, 7.21, 6.55,
m m m m
d, 7.3 t, 7.3 t, 7.3 d, 7.3
35.3 t 84.9 s 131.4 s 124.1 d 119.3 d 130.6 d 109.1 d
Figure 2. 2D NMR correlations of 1 and 2.
to N′-4. The signal H3-18 (δH 1.54) showed the HMBC correlations to C-19 (δC 51.9, d) and C-20 (δC 110.8, s), indicating CH3-18/CH-19/C-20 connectivity. Further, the correlations of H-19 with C-13′ and C-21 (δC 130.6) suggested C-19/N-1′ connection. Considering the molecular formula of 1 and chemical shift of C-7′ (δC 84.9, s), a hydroxyl group should be located at C-7′. Thus, the second unit II was constructed. Both units I and II were connected via the C-15/ 20 from the key HMBC correlations of H-15 with C-20/21, H14 with C-20, and H-19 with C-21/15. The relative configuration of 1 was deduced from the ROESY spectra. The correlations of H-15, H-16, and H-3 showed them at the same side. In addition, the correlations between H-18 with H-2′ revealed their equal orientation. Its configuration was further supported by employing X-ray crystal diffraction (Figure 3). However, due to the tiny crystal form, the flack parameter (0.3) of 1 was too large, which would lead to an uncertain absolute configuration. Therefore, to establish the absolute configuration of 1, the calculated ECD data were
151.2 s 170.3 s 51.8 q
and dihydro-indole units. Consequently, the gross structure of compound 1 was further determined by 2D NMR spectra. In the HMBC spectrum of 1, the cross-peaks of H-9 (δH 7.45) with C-7 (δC 106.4)/C-13 (δC 136.8) and H-12 (δH 7.19) with C-8 (δC 129.0) supported the indole moiety. The HMBC correlations from a pair of protons (δH 2.71 and 2.86) to C-2 (δC 135.9)/C-8 (δC 129.0) assigned them to H2-6. In the 1 H−1H COSY spectrum, the protons of CH2 (δH 3.09 and 3.44, H-5) correlated with H-6 with an assignment to H2-5 (Figure 2). The HMBC correlations from H-5 to C-7/C-3 (δC 52.2) as well as from H-3 to C-2/C-7 disclosed a tetrahydropyrido[3,4-b]indole moiety (A/B/C-ring).8 Connectivity of H-3/14/15/16 was proven by the cross-peaks of δH 3.84/δH 1.80 and 2.08/δH 2.86/δH 5.13 in the 1H−1H COSY spectrum of 1. The HMBC cross-peaks of H2-14 (δH 1.80, 2.08) with C-2, H-15 (δH 2.86) with C-3, and H-16 (δC 5.13) with C-2 displayed another pyrido ring (D-ring). A methyl ester was located at C-16 by the HMBC correlations from both H-16/15 to the ester signal δC 170.3. With these signals, fraction I was constructed (black fraction). The coupled H-5′/6′ in the other unit showed the HMBC crosspeaks to the C-7′/2′, indicating a 1,2,3,3a,8,8ahexahydropyrrolo[2,3-b]indole moiety (A′/B′/C′-ring).2 The double bond H-21 (δH 5.72) showed the HMBC correlations to C-2′/5′, meaning the double bond C-20/21 was connected
Figure 3. X-ray structure and ECD of 1. B
DOI: 10.1021/acs.orglett.9b02060 Org. Lett. XXXX, XXX, XXX−XXX
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Organic Letters
correlations from H-17 to C-15, H-19 to C-15, H-3 to C-2, and H-21 to C-15 as well as 1H−1H COSY correlations of H-3 with H-15. Finally, the oxygen bridge between C-21 and C-14 (brown part) was determined from the HMBC correlations from H-21 to C-14 and H-14 to C-21 and the cross-peak of H3 with H-14 in the 1H−1H COSY spectrum (Figure 2). Finally, the HMBC correlations from H-3, H-16, and H-21 to C-2, H17 to C-7, and H-6 to C-3 confirmed the above presumption, as shown in Figure 2. Due to the rigid planar structure of 2, its ROESY correlations of H-15 with H-19/18/14 (Figure 4) presented two possible configurations, namely 2 and its enantiomer (2a) (S40).
used at the B3LYP/6-311g (2d, p) level in MeOH using the polarizable continuum model (PCM).9 The calculated ECD matched well with the experimental spectrum (S39), indicating the absolute configuration to be 3S,15S,16S,19S,2′S,7′S. Alkaloid 210 was purified as a yellow oil, and its positive HRESIMS gave the molecular formula of C20H26N2O4 from an ion peak at m/z 359.1962 [M + H]+ (calcd for 359.1965). The 1 H and 13C NMR data of 2 suggested the presence of a 9- or 12-substituted indole A ring based on the characteristic proton signals at δH 6.67 (t, J = 7.4 Hz), 6.78 (d, J = 7.4 Hz), and 6.86 (d, J = 7.4 Hz) as well as the carbon signals δC 114.3 (d), 117.6 (d), 119.9 (d), 133.9 (s), 138.0 (s), and 145.8 (s) in its NMR spectra (Table 2). In the 13C NMR and DEPT spectra of 2, Table 2. 1H and 13C NMR Spectroscopic Assignments of 2 and 3 (Acetone-d6) (δ in ppm, J in Hz) δH 2
no. 2 3 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19
3.05, 2.64, 2.72, 2.30,
td, 5.0, 3.5 m m m (2H)
6.86, d, 7.4 6.67, t, 7.4 6.78, d, 7.4
3.55, dd, 11.5, 5.0 3.73, dd, 11.5, 5.0 3.68, dd, 7.0, 3.5 1.73 (overlap) 2.36, m 1.06, m 1.93, m 0.98, t, 7.6 (3H) 1.44, m 1.74 (overlap)
δC 2 85.4 s 57.8 d 48.8 t 37.2 t 87.7 s 133.9 s 117.6 d 119.9 d 114.3 d 145.8 s 138.0 s 63.2 t 73.0 d 31.4 t 22.2 t 8.8 q 33.8 t
20 21
5.22, s
44.9 s 86.6 d
OMe
3.76, s (3H)
56.2 q
δH 3 2.68, br d 2.69, m, (overlap) 3.33, t, 8.4 2.02 m 2.93 m
7.29, 7.02, 7.20, 6.91,
d, 7.4 t, 7.4 t, 7.4 d, 7.7
2.03, m 1.55, dt, 13.6, 3.0 1.88, dt, 13.6, 3.0 2.20, 3.41, 0.93, 1.59,
dd, 17.8, 6.2 br.d, 17.8 t, 7.5 (3H) q, 7.5 (2H)
2.24, d, 11.5 3.12, d, 11.5
δC 3 180.6 s 79.0 d 54.4 t 36.6 t
Figure 4. Key ROESY correlations of alkaloids 2 and 3.
56.4 s 135.9 s 124.2 d 122.8 d 128.7 d 109.9 d 142.3 s 29.2 d
Subsequently, TDDFT calculations were performed to distinguish these enantiomers. The calculated ECD spectrum of 2 gave a 2R,3R,7R,15S,20R,21S-configuration, which was in good agreement with the experimental CD spectrum (Figure 5).
36.3 t 170.7 s 31.3 t 7.3 q 31.9 t 79.1 s 62.8 t
Figure 5. Calculated and experimental and ECDs of 2 and 3.
The molecular formula of alkaloid 3,11 a pale yellow amorphous powder, was established as C19H22N2O3 on the basis of the Na+-liganded molecular ion at m/z 349.1521 in its HRESIMS. The typical 2 aromatic quaternary carbons (δC 135.9, 142.3) and 4 aromatic methines (δC 109.9, 122.8, 124.2, 128.7) as well as 4 aromatic protons at δH 7.29 (d, J = 7.4 Hz), 7.20 (t, J = 7.4 Hz), 7.02 (t, J = 7.4 Hz), and 6.91 (d, J = 7.7 Hz) indicated an unsubstituted indole A-ring (Table 2). In the HMBC spectrum, the observed correlation of H-9 with δC 56.4 (s) was attributed to the latter signal as C-7. The methylene protons (δH 2.93, 2.02) showed HMBC correlations to C-8 (δC 135.9), assigning themselves to CH2−6. In the 1H−1H COSY spectrum, a pair of signals (δH 2.69 and 3.33) correlated with H-6 was assigned to H2-5. Furthermore, the signal δH 2.68 (H-3) showed the HMBC correlations to C-5/6/8, establishing a 5/5-spirane ring. The carbonyl signal δC 180.6 (s) was attributed to C-2 based on its HMBC correlations from H-3 and H-6. On the basis of these signals, fraction A was constructed. The connectivity of H-3/14/15 and H-14/16 was
two prominent quaternary carbons signals at δC 85.4 and 87.7 reminded us of the existence of a pyrrolo[2,3-b]indole like 1. This was further confirmed by the HMBC correlations from H-9 to C-7, H-5 to C-2/8, and H-6 to C-2/7 as well as the 1 H−1H COSY correlations of H-5/H-6 (fragment 2-I, Figure 2). The monosubstituted A-ring was determined as 12-OMe based on the HMBC correlations from δH 3.76 (3H, s, OCH3) to δC 145.8 (s) and from δH 6.86 (H-9) to δC 87.7 (s, C-7) together with the coupling of aromatic hydrogens. The unit II was established again through analysis of 2D NMR spectra. First, the cross-peaks of H-16 with H-17 and H-18 with H-19 in the 1H−1H COSY spectrum together with the HMBC correlations from H-17 to C-2/19/21, H-16 to C-2/20, H-19 to C-17, H-21 to C-2/19, and H-18 to C-20 indicated the sixmembered ring of C2−N1-C21−C20−C17−C16. Furthermore, the seven-membered ring C2−N1−C21−C20−C15−C13−N4 (blue part) was established based on the key HMBC C
DOI: 10.1021/acs.orglett.9b02060 Org. Lett. XXXX, XXX, XXX−XXX
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Organic Letters Scheme 1. Plausible Biogenetic Pathway of Compound 2
Scheme 2. Plausible Biogenetic Pathway of Compound 3
drawn by their 1H−1H COSY correlations. Both H-5/3 showed HMBC correlations to δC 62.8, assigning this signal to C-21. Additionally, H-19 displayed the HMBC correlations to C-21, C-15 (δC 36.3, t), and C-20 (δC 79.1, s), disclosing a tetrahydropyrrol ring. The HMBC correlations from H-14/16 to δC 170.7 assigned the carbon signal to C-17. Considering the 10 degrees of unsaturation of 3, a lactone moiety was necessary. Thus, the structure of 3 including the fragments A and B was assigned. Its ROESY correlations of H-21 with H-3/15 and H-15 with H-3/19 assigned them on same side (Figure 4). Also due to rigid structure of 3, there were present four possible relative configurations (3, 3b, 3c, 3d) (S44). The calculated 13C NMR data for 3 possessed the highest R2 value and lowest RMSD. In addition, DP4+ analysis based on all NMR data also exhibited 3 as the correct structure with 100% probability (S44). Like 2, calculated ECD of 3 (S41) further assigned the absolute configuration as 3S,7R,14S,20S other than its enantiomer (3a) (Figure 5). Unlike traditional MIAs which originate from strictosidine with condensation of tryptamine with secologanin in a 1:1 ratio and our previously discovered alstrostines A/B with a 1:2 ratio, 1 possesses the new ratio 2:1. This new isolate together with the reported homogeneous roxburghine D in literature12 support the diversity of biosynthetic steps leading to MIAs. Structural similarities of 2 and 3 suggested that both compounds belonged to Iboga and Aspidosperma type, respectively. Alkaloid 2 might be derived from simultaneously isolated new alkaloid 4 with the same stereoconfiguration (S42). An oxidation of the double bond C-2/7 in alkaloid 4 may lead to 2,7-epoxy. Subsequently, the next oxidations of N4/C-21 opened this bond and formed an aldehyde group at C21. Nucleophilic attack from N-4 to 2,7-epoxy formed the key tetrahydropyrrolo[2,3-b]indole moiety. Next to that, the aldehyde group of C-21 was attacked by N-1, and subsequent dehydration gave an imine N1C21. Present oxidation of the vicinal diol at C-14/15 formed two aldehyde groups at C-14/ 15. Then, a nucleophilic attack from C-3 to C-15 constructed a new bond C-3/15. C-14 aldehyde group was reduced to
hydroxy, and this OH attacked the imine N-1/C-21, giving 2 (Scheme 1). Compound 3 is structurally closely related to the simultaneously isolated pandoline (5)13 (S43). First, oxidation of 5 led to the imine N1C2. Then, the imine transformed into enamine N1−C2C16. Subsequently, the enamine was cleaved by oxidation, which led to the oxindole (C-2) and a carboxylic acid at C-16. An intramolecular esterification reaction between the carboxylic acid and 20-OH led to 3 (Scheme 2). Inspiringly, alkaloids 1−3 may be attractive for synthesis and biosynthetic studies, especially 2 because it is a rarely occurring bird-caged MIA. In accordance with the plant source, 1−3 were named as tabernabovines A−C. Compounds 1−3 showed no cytotoxicities (40 μM)14 and also no inhibitory activities (50 μg/mL) of xanthine oxidase (50 μg/mL) (S2) and acetylcholine esterase as reported methods.15 Only 1 exhibited inhibitory activities against nitric oxide production in LPS-activated RAW264.7 macrophages with IC50 values of 44.1 μM compared to the positive control L-NMMA with an IC50 of 48.6 μM (S2).
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ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.9b02060. 1D and 2D NMR, MS spectra, and ECD and NMR calculations of 1−3 (PDF) Accession Codes
CCDC 1916676 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, by emailing data_
[email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033. D
DOI: 10.1021/acs.orglett.9b02060 Org. Lett. XXXX, XXX, XXX−XXX
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Organic Letters
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Hz) NMR data (acetone-d6), Table 2; HRESIMS m/z 349.1521 [M + Na]+ (calcd for C19H22N2O3Na, 349.1523). (12) Merlini, L.; Mondelli, R.; Nasini, G. Tetrahedron 1970, 26, 2259−2279. (13) Hoizey, M. J.; Sigaut, C.; Jacquier, M. J.; Le Men-Olivier, L.; Levy, J.; Lemen, J. Tetrahedron Lett. 1974, 15, 1601−1603. (14) Zhang, B. J.; Lu, J. S.; Bao, M. F.; Zhong, X. H.; Ni, L.; Wu, J.; Cai, X. H. Phytochemistry 2018, 152, 125−133. (15) Tang, Y.; Fu, Y.; Xiong, J.; Li, M.; Ma, G. L.; Yang, G. X.; Wei, B. G.; Zhao, Y.; Zhang, H. Y.; Hu, J. F. J. Nat. Prod. 2013, 76, 1475− 1484.
AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Yu-Rong Yang: 0000-0001-6874-109X Johann Schinnerl: 0000-0003-4494-8736 Xiang-Hai Cai: 0000-0002-6723-6988 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS This project was supported by the Applied Basic Research Project of Yunnan Province (no. 2016FA030). Computational resources used in this work were supported in part by SciGrid, Chinese Academy of Sciences.
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REFERENCES
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