Structure revision of mitragynaline, an indole alkaloid in Mitragyna speciosa
Hiromitsu Takayama,a,* Hayato Ishikawa,a Mika Kurihara,a Mariko Kitajima,a Shin-ichiro Sakai,a Norio Aimi,a,b Hiroko Seki,b Kentaro Yamaguchi,b Ikram M. Saidc and Peter J. Houghtond Faculty of Pharmaceutical Sciences, Chiba University, 1 -33, Yayoi-cho, Inage-ku, Chiba 263 -8522, Japan Chemical Analysis Center of Chiba University, 1 -33, Yayoi-cho, Inage-ku, Chiba 263 -8522, Japan Chemistry Department, Universiti Kebangsaan Malaysia, 43600 Bangi, Selangor, Malaysia Department of Pharmacy, King’s College London, Franklin–Wilkins Building, 150 Stamford Street, London SE1 8WA, UK Received 13 November 2000; revised 13 December 2000; accepted 22 December 2000
The structure of mitragynaline, an indole alkaloid isolated from Malaysian Mitragyna speciosa, was revised as formula 3 by analysis of the NMR spectra measured at low temperature and by chemical transformation with DDQ oxidation from the known alkaloid mitragynine (5).
An indole alkaloid, mitragynaline, was first isolated from the young leaves of Malaysian Mitragyna speciosa Korth. (Rubiaceae),1 which is a plant used in traditional medicine in the Malay Peninsula, is used as a stimulant like coca or as a substitute for opium. The chemical structure of mitragynaline (1), proposed in 1991, has an unusual skeleton featuring the presence of a carbon function at the C-14 position, among the hitherto known indole alkaloids found in higher plants (Fig. 1). During the chemical and pharmacological studies on the Mitragyna alkaloids, we have had a keen interest in this structurally unique alkaloid from both synthetic and biological viewpoints. Along this line, we commenced a chemical study on the structure of nauclefidine, 5 whose UV spectrum had been used for the structure elucidation of mitragynaline. As a result, we have revised the structure of nauclefidine6 and, therefore, structure re-elucidation of mitragynaline became an urgent objective. In this communication, we propose a new structure of mitragynaline, revised by exhaustive NMR analysis and by partial synthesis from mitragynine (5)3a,b,7 via an abnormal oxidative reaction.
Mitragynaline (C22H24N2O4, [a]D 24 −4.3 (c 0.34, CHCl3)),8 which was obtained by reinvestigation of the young leaves of M. speciosa native to Malaysia, showed weak signals in the 1H and 13C NMR spectra when measured at ambient temperature in CDCl3. As shown in Fig. 2, some widely swollen signals in the downfield area were observed in the 1H NMR spectrum. In the 13C NMR spectrum, only 16 signals, including some tiny peaks, were observed although the presence of 22 carbons in the molecule was demonstrated by the highresolution MS spectrum. When the solvent was changed to DMSO-d6, two clear signals (d 11.7 and 9.8) appeared in the downfield region in the 1H NMR spectrum. Further, the 13C signals also sharpened generally, but only 7 and 13 signals were observed in the sp3 and sp2 areas, respectively.
Consequently, the NMR spectra of mitragynaline was measured at low temperature (−50°C) in CDCl3, resulting in the appearance of all the proton and carbon signals corresponding to the molecular formula. The presence of a 9-methoxyindole nucleus, an ethane bridge at C-5C-6, an ethyl group at C-20, an sp3
carbon at C-21, and a methoxycarbonyl group, all of which are the fundamental structural units in the common Corynanthe-type monoterpenoid indole alkaloids, has been clarified. The 13C NMR and HMBC spectra at low temperature disclosed the presence of six conjugated sp2 carbons including ester and aldehyde carbonyls, besides the aromatic carbons due to the indole nucleus. The UV spectrum, exhibiting an absorption at 486 nm, also indicated a high degree of unsaturation in the molecule. The quite characteristic proton signal observed at d 8.28 (1H, singlet), which was finally recognized at low temperature, was unambiguously assigned to be the proton at C-14 by the HMQC spectrum, since this signal has HMBC connectivities with the C-2, C-3, C-15, C-16 and C-20 carbons. The HMBC correlation between the aldehyde proton at d 10.0 and the carbons at C-15 and C-16 indicated the location of the aldehyde residue at C-17. All the above findings, as well as biogenetic considerations, enabled us to compose the molecular structure of the mitragynaline to be that of 3. The geometry at C-16 was elucidated by NOE observation between H-14 and the aldehyde proton.
Recently, we have demonstrated the potent opioid agonistic properties of mitragynine (5), a major indole alkaloid of this plant, and of mitragynine pseudoindoxyl, an oxidative derivative of mitragynine, whose analgesic activity is more potent than that of morphine. 9 Based on these results, we studied the preparation of various kinds of oxidative derivatives of mitragynine for the development of new and potent analgesic agents. When mitragynine (5) was treated with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ), we obtained unexpectedly mitragynaline in 13% yield as one of the oxidation products (Fig. 3). The semi-synthetic compound (mp 220–221°C) was identified with the natural product by comparison of their chromatographic behaviors, UV, 1H and 13C NMR, and mass spectra. The optical rotation of the semi-synthetic compound was levorotatory ([a]D 24 −2.4 (c 0.45, CHCl3)), establishing the absolute stereochemistry at the C-20 position. Although the DDQ oxidation of indole derivatives is generally known to produce 3-acylindole derivatives,10 the mechanism of this abnormal reaction, including the oxidative double bond formation at the C-3C-14 position, demethylation of the vinyl ether moiety in 5, and additional oxidation at the C-15C-16 position, remains obscure.
Corynantheidaline (2) has been simultaneously isolated from M. speciosa together with mitragynaline and the structure was proposed as a H-9 analogue of 1. Based on the spectroscopic comparison of these two compounds, here we propose the new structure 4 as corynantheidaline. H. Takayama et al. : Tetrahedron Letters 42 (2001) 1741–1743 1743
This work was supported in part by Grant-in-Aid (Nos. 10557229 and 10044325) for Scientific Research from the Ministry of Education, Science, Sports, and Culture, Japan.