Formation of an Unusual Dimeric Compound by Lead Tetraacetate Oxidation of a Corynanthe-Type Indole Alkaloid, Mitragynine.

Abstract

In the recent chemical [1][2][3][4][5][6][7][8][9] and pharmacological [10][11][12][13][14][15] studies on the Rubiaceous plant, Mitragyna speciosa, [16][17][18][19][20] which has been traditionally used in tropical areas as a substitute for opium, 21) we have found that mitragynine (1), a major Corynanthe-type indole alkaloid of this plant, exhibited potent analgesic activity mediated by m-and d-opioid receptors. 22)Further, 7-hydroxymitragynine (3), 23) an oxidative derivative of 1, was found as a novel opioid agonist with higher potency than that of morphine.24) This remarkable opioid ligand was prepared from mitragynine (1) by conventional procedure, i.e., oxidation of 1 with lead tetraacetae [Pb(OAc) 4 ] followed by alkaline hydrolysis of the resultant 7-acetoxyindolenine (2). In investigating the first oxidation step in detail, we found a structurally and mechanistically novel dimerization product, as described in this publication. Results and DiscussionIn general, 7-acetoxyindolenine derivatives are prepared from the corresponding indoles by oxidation with Pb(OAc) 4 . 25,26) When yohimbine was treated with Pb(OAc) 4 , we obtained the 7-acetoxyindolenine derivative in a quantitative yield. However, in the case of mitragynine (1) the yield of the desired indolenine (2) was up to 50%, and the presence of side products was shown on thin-layer chromatography. By careful purification of the reaction residue, we isolated 2 together with an unusual compound (4) in 3% yield, which showed molecular weight of 852 by mass spectrum. The UV absorption curve of 4 exhibited close resemblance to that of 7-acetoxyindolenine derivative (2), but the large log e value at 234 nm (log eϭ4.68) together with the molecular formula (C 48 H 60 O 10 N 4 ) obtained from high-resolution FAB-MS spectrum indicated the presence of two units of indolenine chromophore derived from mitragynine (1). The 1 H-and 13 C-NMR spectra of 4 clearly showed the presence of two sets of the fundamental structural units in the mother compound, mitragynine (1), i.e., two b-methoxyacrylic acid methyl ester residues, two ethyl groups and two 9-methoxy groups on the aromatic ring. Further, the presence of one acetoxy group was shown by the 1 H-NMR (d 2.09, 3H, s) and 13 C-NMR (d 168.3, 20.8) spectra. In the 13 C-NMR spectrum, two characteristic signals due to indolenine carbons at C-2 or C-2Ј (d 187.1, 181.1) as well as two newly formed quaternary carbons at C-7 or C-7Ј (d 61.7, 84.5) were observed. Therefore, it became clear that compound (4) had the usual acetoxyindolenine unit in the molecule. In the 1 H-NMR spectrum, a set of three aromatic protons at d 6.65 (doublet), 7.22 (doublet of doublet), and 7.32 (doublet) same as those of 1 and a set of meta-coupled protons at d 6.07 (singlet-like) and 7.35 (singlet-like) were observed. This indicated that one of the two indolenine units had a substituent at the C-11 position and the other one was intact as regards the substituent mode on the benzene ring. In the 1 H-detected heteronuclear multiple-bond correlati...

Chemistry and Pharmacology of Analgesic Indole Alkaloids from the Rubiaceous Plant, Mitragyna speciosa

“…12). 49) In order to prepare 7-hydroxymitragynine (5) more conveniently, mitragynine (1) was exposed to a hypervalent iodine(III) reagent, PIFA, in aqueous CH 3 CN, expecting the introduction of a hydroxyl group at C7, to give the desired product 5 in 50% yield. 50) Investigation of the minor products in the residue led to the isolation of a novel dimeric compound 63 in 6% yield (Fig.…”

Mitragynine/Corynantheidine Pseudoindoxyls As Opioid Analgesics with Mu Agonism and Delta Antagonism, Which Do Not Recruit β-Arrestin-2

“…It is currently legal in many parts of the world, and kratom leaves are available for purchase over the Internet. Case studies of fatalities resulting from overdose have been published, although the risk posed by mitragynine remains uncertain, given that simultaneous use or contamination with other substances (including opioids) that may have been involved in the reported deaths. − Both mitragynine ( 1 ) and its naturally occurring oxidation product, 7-OH mitragynine (indolenine core) ( 2 ), are opioid antinociceptive agents that have been examined both in vitro and in vivo. − Mitragynine pseudoindoxyl ( 3 ), a rearrangement product of 2 with a spiro-pseudoindoxyl core, was first isolated in 1974 by Zarembo et al as a microbial metabolite of 1 by the fungus Helminthosporum sp . Yamamoto et al reported that it acted nonselectively on mu- and delta opioid receptors, while its kappa opioid receptor affinity was negligible .…”

Chemistry of Indole Alkaloids Related to the Corynanthe-Type from Uncaria, Nauclea and Mitragyna Plants

“…From the young leaves of M. speciosa, mitragynine (89) was obtained as the major constituent (66.2% based on the crude base) together with its analogues, speciogynine (90), speciociliatine (91), and paynantheine (92). In addition, a new alkaloid, 7α-hydroxy-7H-mitragynine (93), was isolated as a minor constituent, the structure of which was elucidated by spectroscopic analysis and chemical transformation from mitragynine (89) [71].…”

“…In the 13 C-NMR spectrum, the signals corresponding to sp 2 carbons at C14 and C16 resonated at unusually high positions, δ 87.08 and 94.91 ppm, 19 18 Speciogynine (90) Speciociliatine (91) Paynantheine (92) 9 7α-Hydroxy-7H-mitragynine (93) respectively. This unusual phenomenon as well as the novel chemical structure of 102 prompted us to synthesize the new alkaloid in a chiral manner in order to confirm the structure including the absolute configuration due to one chiral center at the C20 position.…”

“…However, in the case of mitragynine (89), the yield of desired indolenine 122 was 50% at most, and the presence of by-products was shown on thin-layer chromatography. By careful purification of the reaction residue, we isolated 122 together with unusual dimeric compound 123 in 3% yield [93]. 7-Acetoxyindolenine (122) could be converted into 93 by conventional alkaline hydrolysis in good yield.…”