Next Article in Journal
X-ray and Hydrogen-bonding Properties of 1-((1H-benzotriazol-1-yl)methyl)naphthalen-2-ol
Next Article in Special Issue
(+)-N-(2-Hydroxypropyl)lindcarpine: A New Cytotoxic Aporphine Isolated from Actinodaphne pruinosa Nees
Previous Article in Journal
Current Status of Older and New Purine Nucleoside Analogues in the Treatment of Lymphoproliferative Diseases
Previous Article in Special Issue
Total Syntheses of Telisatin A, Telisatin B and Lettowianthine
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:

Grandine A, a New Proaporphine Alkaloid from the Bark of Phoebe grandis

Centre for Natural Products and Drug Discovery, Block D, Department of Chemistry, Faculty of Science, University of Malaya, 50603 Kuala Lumpur, Malaysia
Institut de Chimie des Substances Naturelles, Centre Nationale de la Recherche Scientifique, UPR2301, 91198, Gif-sur-Yvette, Cedex, France
Department of Chemical Sciences, Faculty of Science and Technology, Universiti Malaysia Terengganu, 21030 Kuala Terengganu, Terengganu, Malaysia
Author to whom correspondence should be addressed.
Molecules 2009, 14(3), 1227-1233;
Submission received: 23 December 2008 / Revised: 13 February 2009 / Accepted: 18 February 2009 / Published: 23 March 2009
(This article belongs to the Special Issue Aporphines and Oxoaporphines)


The stem bark of Phoebe grandis afforded one new oxoproaporphine; (–)-grandine A (1), along with six known isoquinoline alkaloids: (–)-8,9-dihydrolinearisine (2), boldine, norboldine, lauformine, scortechiniine A and scortechiniine B. In addition to that of the new compound, complete 1H- and 13C-NMR data of the tetrahydroproaporphine (–)-8,9-dihydrolinearisine (2) is also reported. The alkaloids’ structures were elucidated primarily by means of high field 1D- and 2D-NMR and HRMS spectral data.

Graphical Abstract


The Phoebe species (Lauraceae) are producers of isoquinoline alkaloids such as aporphines and oxoaporphines and they are especially known to give proaporphine-tryptamines [1,2,3,4]. At present, only seventeen such dimers have been reported and five were isolated from Phoebe [4]. Ten Phoebe species have been investigated for their chemical constituents [5,6,7,8,9,10,11] and interestingly only two Malaysian species (P. grandis and P. scortechinii) produce the proaporphine-tryptamine dimers. In this communication, we report the isolation and characterization of one new oxoproaporphine; (+)-grandine A (1, Figure 1) and the complete 1H- and 13C-NMR spectroscopic data of (–)-8,9-dihydrolinearisine (2, Figure 1). In addition to these two compounds five other known alkaloids: (–)-boldine [1], (–)-norboldine [1], (+)-lauformine [6], (+)-scortechiniine A [11] and (+)-scortechiniine B 3 (Figure 1) [11] were also isolated from the bark of Phoebe grandis.
Figure 1. Structures of (+) –grandine A 1, (-)-8,9-dihydrolinearisine 2, (+)-scortechiniine B 3 and prooxocryptochine 4.
Figure 1. Structures of (+) –grandine A 1, (-)-8,9-dihydrolinearisine 2, (+)-scortechiniine B 3 and prooxocryptochine 4.
Molecules 14 01227 g001

Results and Discussion

The alkaloid grandine A (1), [ α ] D 23 + 55o (c= 1.0, CHCl3), was isolated as a brownish amorphous solid. The HRESI+ mass spectrum showed an [M+Na]+ peak at m/z 318.0768, thus suggesting a molecular formula of C17H13NO4 (calc. 318.0742 for C17H13NO4Na). Two major fragmentation peaks were observed at m/z 277 and m/z 249, which may be attributed to the loss of a water molecule, [M-H2O]+, and a carbonyl, [M-CO]+, respectively. The IR spectrum revealed absorption bands at 3,376 and 1,729 cm-1 due to the OH and the C=O stretching vibrations respectively. The 1H-NMR spectrum (Table 1) showed a pair of doublets (J = 5.4 Hz) typically found in oxoaporphines [9]. These signals are attributable to H-4 (δ 7.60) and H-5 (δ 8.68), respectively. A singlet ascribable to H-3 appeared at δ 7.19. Two broad singlets representing the methylenedioxy protons were apparent at δ 6.16 and 6.12, respectively. The respective protons in scortechiniine B 3, which lacks the C-8,9 double bond, gave a singlet at δ 6.13 corresponding to both protons (Table 1). The deshielded aliphatic proton, H-10, resonated as a broad singlet at δ 4.45. The olefinic protons, H-8 and H-9, resonated at δ 5.43 and 6.14 as a doublet and a doublet of doublets, similar to the resonances of the same protons in prooxocryptochine (4) (Figure 1, Table 1). However, H-8 appeared as a doublet in the former as compared to doublet of doublets in the latter.
Table 1. 1H-NMR (400 MHz) and 13C-NMR (100 MHz) spectral data of compounds 1, 3 and 4 in CDCl3 (δ in ppm, J in Hz) .
Table 1. 1H-NMR (400 MHz) and 13C-NMR (100 MHz) spectral data of compounds 1, 3 and 4 in CDCl3 (δ in ppm, J in Hz) .
Alkaloids1 3a4b
Position13Cδ 1H (J Hz)HMBCNOESY13Cδ 1H (J Hz)δ 1H (J Hz)
1154.59 154.43
1a118.11 120.15
1b136.78 136.39
2142.62 142.06
399.767.19 s1, 2, 3aOCH2O, H-499.667.04 s7.15 s
3a133.11 133.18
4121.667.60 d (5.4)3aH-5121.587.56 d (5.4)7.67 d (5.6)
5146.928.68 d (5.4)3a, 4, 6aH-4146.968.66 d (5.4)8.77 d (5.6)
6a150.86 151.23
7204.37 206.02
7a52.73 50.57
8126.285.43 d (10.0) 7a,10 H-929.381.85 m (1H) 2.08 m (1H)5.49 dd (10, 3.2)
9134.75 6.14 dd (10.0, 2.9)7a, 10H-8, H-1029.922.08 m6.25 dd (10, 3.2)
1065.05 4.45 br s H-9, H-1168.443.96 m4.44 m
1128.14 2.38 m 2.12 m10, 12H-1229.922.08 m2.29 m
1228.602.12 m (2H) 7, 7a, 11H-1129.381.85 m2.06 m 2.26 m
OCH2O102.376.16 br s 6.12 br s1, 2 102.116.13 s
2-OMe 4.02 s
a 1H- and 13C-NMR Data are reproduced from Mukhtar et al. [11]; b 1H-NMR data is reproduced from Wu et al. [17].
The 13C-NMR spectrum of grandine A (1) showed the presence of 17 carbons, which is in agreement with the molecular formula. The resonance of the quaternary spiro carbon, C-7a, at δ 52.7 implied the proaporphinic nature of compound 1. The C-7 carbonyl peak was observed at δ 204.4. The carbon bearing the hydroxyl group, C-10, resonated at δ 65.1. Thorough analysis of the COSY, HMQC, HMBC and NOESY spectrums allowed the complete assignments of all protons and carbons of grandine A 1 (Table 1).
(–)-8,9-Dihydrolinearisine (2), [ α ] D 23 –50.0o (c =0.1, MeOH) was isolated as a white amorphous solid. The HRESI+ mass spectrum showed the pseudomolecular ion peak, [M+H]+, at m/z 302.1707 (calc. 302.1756) thus indicating a molecular formula of C18H23NO3. The EIMS revealed two major fragments at m/z 300 [M-H]+ and at m/z 258, [M-CH2NCH3]+, indicative of an N-methylproaporphine or an N-methylaporphine skeleton [12,13]. The IR spectrum showed a strong carbonyl absorption at 1,712 cm-1. In addition, a broad absorption band at 3,345 cm-1 was attributed to the presence of a hydroxyl group.
The 1H-NMR spectrum (Table 2) displayed one methoxyl singlet at δ 3.76. In addition, one proton singlet was observed at δ 6.41, which may be ascribed to H-3. This observation also indicated that C-2 is substituted. The N-methyl group resonated at δ 2.38 and the aliphatic protons gave a multiplet between δ 1.82 to δ 3.27. H-6a resonated at δ 3.23 (dd, J, J’ = 11.0, 6.3 Hz) while H-7α appeared as a doublet of doublets at δ 2.72.
Table 2. 1H-NMR (400 MHz) and 13C-NMR (100 MHz) spectral data of compounds 2 in CDCl3 plus two drops of CD3OD (δ in ppm, J in Hz).
Table 2. 1H-NMR (400 MHz) and 13C-NMR (100 MHz) spectral data of compounds 2 in CDCl3 plus two drops of CD3OD (δ in ppm, J in Hz).
Positionδ 13Cδ 1H (Hz)DEPTHMBC
3114.326.41 sCH-31, 1b, 2, 4
426.72α 2.61 mCH2-41b, 5
β 2.55 m
554.76α 2.38 mCH2-53a, 6a, N-CH3
β 3.07 m
6a65.123.23 ddCH-61b, 7, 7a
(11.0, 6.3)
742.21α 2. 72 dd (11.0, 6.3)CH2-76a, 1b, 7a
β 1.65 dt (11.0)6a, 7a, 8, 12
833.70ax, 2.22 mCH2-87
eq, 1.98 m
938.582.48 mCH2-98, 10
1139.13ax, 2.48 mCH2-1110, 12
eq, 2.80 m
1236.23ax, 2.82 mCH2-127a, 7
eq, 1.82 m
1-OCH361.003.76 s 1
N-CH343.062.38 s 5, 6a
The 13C-NMR spectrum of 2 showed the presence of eighteen carbon atoms; two methyls, seven methylenes, two methines, one carbonyl carbon and six quarternary carbons. The quaternary C-7a resonated at δ 47.3, while the C-1 methoxyl group peak appeared at δ 61.0. The NOE differential experiment showed signal enhancements of H-7α and H-8eq upon irradiation of H-6a, therefore indicating that H-6a is syn to H-7α and H-8eq [11]. Irradiation of H-3 resulted in the enhancement of H-4 (δ 2.55), thus suggesting that the methoxyl group is attached to C-1. (–)-8,9-Dihydrolinearisine (2) adopts an S configuration at C-6a, based on its negative optical rotation value [ α ] D 23 –50.0o [12]. Alkaloid 2 is actually the enantiomer of (+)-N-methyltetrahydrocrotonosine, which occurred in Croton species [14].


In summary, we have observed that Phoebe grandis produces alkaloids similar to those of Phoebe scortechinii [2,3]. Both plants yielded proaporphines, aporphines and proaporphine-tryptamines. Earlier work on the barks of Phoebe grandis, collected from the northern part of Peninsular Malaysia, had indicated only aporphine alkaloids [1] while another study on the same plant species collected from Pahang, on the east coast of Peninsular Malaysia, has shown the presence of aporphines and proaporphines. This could be due to either seasonal variations or a difference in the soil types (the former was collected from a lowland area while the latter was collected from a highland area). The occurrence of the new proaporphine in Phoebe grandis is of special interest, in view of the fact that this type of alkaloid is a precursor of aporphines [15, 16] and proaporhine–tryptamines, found in Phoebe species. To the knowledge of the authors, only two oxoproaporphines have been previously reported; scortechiniine B (3) [11] and prooxocryptochine (4) [17]. Grandine A (1) and scortechiniine B (3) occurred in the Phoebe species, while prooxocryptochine (4) was isolated from the wood of Cryptocarya chinensis [17]. Incidently, both Phoebe and Cryptocarya belong to the family Lauraceae.



The optical rotations were recorded on s Jasco (Japan) P1010 instrument equipped with a tungsten lamp. HRMS was obtained on a Thermo Finnigan Automass Multi. The ultraviolet spectra were obtained in MeOH on a Shimadzu UV-160A ultraviolet-visible spectrometer. The infrared spectra were taken on a Perkin Elmer 1600 Double-Beam recording spectrometer, using chloroform as solvent. The 1H-NMR and 13C-NMR spectra were recorded in deuterated chloroform on a JEOL 400 MHz (unless stated otherwise); chemical shifts are reported in ppm on δ scale, and the coupling constants are given in Hz. Silica gel 60, 70-230 mesh ASTM (Merck 7734) and silica gel 60, 230-400 Mesh ASTM (Merck 9385) were used for column and flash chromatography, respectively. Mayer’s reagent was used for alkaloid screening.

Plant material

Phoebe grandis (Lauraceae), collected in May 2001 from Kuala Tahan Forest Reserve, Pahang, Malaysia was identified by Mr Teo Leong Eng. A voucher specimen (KL 4994) is deposited at the Herbarium of Department of Chemistry, University of Malaya, Kuala Lumpur, Malaysia and at the Herbarium of the Forest Research Institute, Kepong, Malaysia.

Extraction and isolation of the alkaloids

The dried stem bark (1.0 kg) of Phoebe grandis was ground and extracted exhaustively with hexane followed by CH2Cl2 by Soxhlet extractor for 17 hours. Extraction of alkaloids was carried out in the usual manner, which has been described in detail [1, 2] and gave 4.02 g of crude alkaloid. CH2Cl2-extracted crude alkaloid (1.0 g) was subjected to column chromatography. The isolation and purification of compound 1 and 2 were carried out by chromatography on a small column and preparative TLC (Silica gel 60F254) yielding 4.2 mg of grandine A (1) (CH2Cl2: MeOH, 98:2) and 7.4 mg of (–)-8,9-dihydrolinearisine (2) (CH2Cl2: MeOH, 95:5).
Grandine A (1): Isolated as a brown amorphous solid; [ α ] D 23 +55o (c = 1.0, CHCl3); UV: λethanol: 250, 320 nm; IR νmax (liquid film): 3376, 1927, 2922 cm-1; HREIMS m/z: [M+Na]+, 318.0768 (calc. 318.0742 for C17H13NO4Na); 1H- and 13C-NMR see Table 1.
(-)-8,9-Dihydrolinearisine (2): Isolated as a white amorphous solid; [ α ] D 23 –50.0 (c = 0.1, MeOH); UV λethanol: 226, 283 and 302 nm; IR νmax (liquid film) : 1672, 3345, 945.4(OCH2O) cm-1; HRESI+ m/z: [M+H]+ 302.1707 (calc. 302.1756 for C18H24NO3); EIMS: m/z (rel. int. %): 301, 300 (100); 1H- and 13C-NMR see Table 2.


The authors would like to thank the Malaysian Government through the vots: PPF/FP092/2005C, ScienceFund 12-02-03-2063 (UM) and the grant from Centre Nationale de la Recherche Scientifique (France).


  1. Mukhtar, M.R.; Martin, M.T.; Domansky, M.; Pais, M.; Hadi, A.H.A.; Awang, K. Phoebegrandines A and B, Proaporphine-Tryptamine Dimers, from Phoebe grandis. Phytochemistry 1997, 45, 1543–1546. [Google Scholar]
  2. Mukhtar, M.R.; Hadi, A.H.A.; Sevenet, T.; Martin, M.T.; Awang, K. Phoebegrandine C, A Novel Proaporphine-Tryptamine Dimer from Phoebe grandis (Nees) Merr. Nat. Prod. Res. 2004, 18, 163–167. [Google Scholar] [CrossRef]
  3. Awang, K.; Mukhtar, M.R.; Hadi, A.H.A.; Litaudon, M.; Latip, J.; Abdullah, N.R. New Alkaloids from Phoebe grandis (Nees) Merr. Nat. Prod. Res. 2006, 20, 567–572. [Google Scholar] [CrossRef]
  4. Awang, K.; Mukhtar, M.R.; Mustafa, M.R.; Litaudon, M.; Shaari, K.; Mohamad, K.; Hadi, A.H.A. New Alkaloids from Phoebe scortechinii. Nat. Prod. Res. 2007, 21, 704–709. [Google Scholar] [CrossRef]
  5. Johns, S.R.; Lamberton, J. A. Alkaloids of Phoebe clemensii Allen (family Lauraceae). Aust. J. Chem. 1967, 20, 1277–1281. [Google Scholar] [CrossRef]
  6. Lu, S.T.; Tsai, I.L. Two Hexahydroproaporphine Alkaloids, Lauformine and N-Methyllauformine from Phoebe formosana. Heterocycles 1984, 22, 1031–1033. [Google Scholar] [CrossRef]
  7. Stermitz, F.R.; Castro, C.O. Pentasubstituted Aporphine Alkaloids from Phoebe molicella. J. Nat. Prod. 1983, 46, 913–916. [Google Scholar] [CrossRef]
  8. Oscar-Castro, C.; José-López, V.; Armando-Vergara, G. Aporphine alkaloids from Phoebe pittieri. Phytochemistry 1985, 24, 203–204. [Google Scholar]
  9. Martínez, E.; de Díaz, A.M.P.; Nathan, P. J. Oxoaporphine Alkaloids from the Wood of Phoebe cinnamofolia. Planta Med. 1988, 361–362. [Google Scholar]
  10. Hegde, V.R.; Dai, P.; Ladislaw, C.; Patel, M.G.; Puar, M.S.; Pachter, J.A. ID4 Dopamine Receptor-Selective Compounds From the Chinese Plant Phoebe chekiangensis. Bioorg. Med. Chem. Lett. 1997, 7, 1207–1212. [Google Scholar]
  11. Mukhtar, M.R.; Hadi, A.H.A; Rondeau, D.; Richomme, P.; Litaudon, M.; Mustafa, M.R.; Awang, K. New proaporphines from the bark of Phoebe scortechinii. Nat. Prod. Res. 2008, 22, 921–926. [Google Scholar] [CrossRef] [Green Version]
  12. Haynes, L.J.; Stuart, K.L.; Barton, D.H.R.; Kirby, G.W. Alkaloids from Croton species. Part III. The Constitution of the Proaporphines Crotonosine, “Homolinearine”, Base A, and the Dihydro-proaporphine linearisine. J. Chem. Soc. C 1966, 19, 1676–1679. [Google Scholar]
  13. Haynes, L.J.; Husbands, G.E.M.; Stuart, K.L. Alkaloids from Croton species. IV. The isolation and structure of a new proaporphine. J. Chem. Soc. C 1966, 19, 1680–1681. [Google Scholar]
  14. Snatzke, G.; Wollenberg, G. Alkaloids from Croton species. V. Configuration of linearisine and circular dichroism of proaporphine-type alkaloids. J. Chem. Soc. C 1966, 19, 1681–1685. [Google Scholar] [CrossRef]
  15. Kametani, T.; Yagi, H. Total syntheses of (±)-Glaziovine and (±)-Pronuciferine by Phenolic Oxidative coupling. J. Chem. Soc. C 1967, 20, 2182–2184. [Google Scholar] [CrossRef]
  16. Gözler, B.; Guinaudeau, H.; Shamma, M.; Sariyar, G. The photolysis of proaporphines Tetrahedron Lett. 1986, 27, 1899–1902. [Google Scholar]
  17. Wu, T.-S.; Lin, F.-W. Alkaloids of the Wood of Cryptocarya chinensis. J. Nat. Prod. 2001, 64, 1404–1407. [Google Scholar] [CrossRef]
  • Sample Availability: Samples of all the compounds are available from the authors.

Share and Cite

MDPI and ACS Style

Mukhtar, M.R.; Aziz, A.N.; Thomas, N.F.; Hadi, A.H.A.; Litaudon, M.; Awang, K. Grandine A, a New Proaporphine Alkaloid from the Bark of Phoebe grandis. Molecules 2009, 14, 1227-1233.

AMA Style

Mukhtar MR, Aziz AN, Thomas NF, Hadi AHA, Litaudon M, Awang K. Grandine A, a New Proaporphine Alkaloid from the Bark of Phoebe grandis. Molecules. 2009; 14(3):1227-1233.

Chicago/Turabian Style

Mukhtar, Mat Ropi, Ahmad Nazif Aziz, Noel F. Thomas, A. Hamid A. Hadi, Marc Litaudon, and Khalijah Awang. 2009. "Grandine A, a New Proaporphine Alkaloid from the Bark of Phoebe grandis" Molecules 14, no. 3: 1227-1233.

Article Metrics

Back to TopTop