Formation of an unusual dimeric compound by lead tetraacetate oxidation of a Corynanthe-type indole alkaloid, mitragynine

Article abstract of DOI:10.1248/cpb.50.960

Lead tetraacetate oxidation of a Corynanthe-type indole alkaloid, mitragynine, produced mainly 7-acetoxyindolenine derivative (2) together with a dimeric compound (4) as a minor product. The novel structure having a bridge between the C-11′ and C-7 positions in the respective indolenine parts and its formation mechanism were studied.

Full text of DOI:10.1248/cpb.50.960

960
Chem. Pharm. Bull. 50(7) 960—963 (2002)
Vol. 50, No. 7
Formation of an Unusual Dimeric Compound by Lead Tetraacetate
Oxidation of a Corynanthe-Type Indole Alkaloid, Mitragynine
Hiromitsu TAKAYAMA,* Hayato ISHIKAWA, Mariko KITAJIMA, and Norio AIMI
Graduate School of Pharmaceutical Sciences, Chiba University; 1–33 Yayoi-cho, Inage-ku, Chiba 263–8522, Japan.
Received March 22, 2002; accepted May 1, 2002
Lead tetraacetate oxidation of a Corynanthe-type indole alkaloid, mitragynine, produced mainly 7-ace-
toxyindolenine derivative (2) together with a dimeric compound (4) as a minor product. The novel structure hav-
ing a bridge between the C-11؅ and C-7 positions in the respective indolenine parts and its formation mechanism
were studied.
Key words indole alkaloid; oxidation; dimerization; lead tetraacetate; indolenine; reaction mechanism
In the recent chemical1—9) and pharmacological10—15) stud-
ies on the Rubiaceous plant, Mitragyna speciosa,16—20) which
has been traditionally used in tropical areas as a substitute for
opium,21) we have found that mitragynine (1), a major Cory-
nanthe-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.
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 in-
dicated 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 1H-detected
heteronuclear multiple-bond correlation (HMBC) spectrum,
clear long-range connectivities were observed between both
two meta-coupled protons (d 6.07, 7.35) and a newly formed
quaternary carbon (d 61.7), which could be assigned as C-7
based on the fact that this carbon showed long-range cou-
pling with the protons on C-3, C-5 and C-6. All the above
spectroscopic analyses enabled us to construct the dimeric
structure that had a bridge between C-7 in one indolenine
part and C-11Ј on the aromatic part in theother indolenine
unit. The stereochemistry at C-7 and C-7Ј was respectively
deduced by the nuclear Overhauser effect (NOE) observa-
tions between H-10Ј and H-3 and H-6a, and between H-3Ј
and the protons on the acetyl group as shown in Fig. 1.
Results and Discussion
In general, 7-acetoxyindolenine derivatives are prepar-
ed 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 quantita-
tive yield. However, in the case of mitragynine (1) the yield
of the desired indolenine (2) was up to 50%, and the pres-
ence of side products was shown on thin-layer chromatogra-
phy. By careful purification of the reaction residue, we iso-
lated 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 (C48H60O10N4) obtained from high-resolution FAB-
MS spectrum indicated the presence of two units of indole-
nine chromophore derived from mitragynine (1). The 1H- and
13C-NMR spectra of 4 clearly showed the presence of two
sets of the fundamental structural units in the mother com-
pound, 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
For the carbon–carbon bond formation between C-7 and
C-11Ј to produce the dimeric compound (4), two possible
mechanisms can be considered, i.e., an electrophilic aromatic
substitution at C-11 on the indole ring (Type I) or a common
1
acetoxy group was shown by the H-NMR (d 2.09, 3H, s)
and 13C-NMR (d 168.3, 20.8) spectra. In the 13C-NMR spec-
trum, 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 ob-
served. Therefore, it became clear that compound (4) had the
1
usual acetoxyindolenine unit in the molecule. In the H-
Chart 1
To whom correspondence should be addressed. e-mail: htakayam@p.chiba-u.ac.jp
© 2002 Pharmaceutical Society of Japan

July 2002
961
Fig. 2. Possible Mechanisms for the Formation of Dimeric Compound 4
Fig. 1. Selected HMBC Data for Compound 4 and Selected NOE Data for
Compound 4
electrophilic substitution at the b-position (C-7) of the indole
nucleus (Type II) as shown in Fig. 2.
To formulate the reaction mechanism, Pb(OAc)4 oxidation
of mitragynine (1) was performed in the presence of 1,3-
dimethoxybenzene, which has high ability to react as a nu-
cleophile. The formation of 1,3-dimethoxybenzene adducts
(5) or (6) could be anticipated, if the reaction would respec-
tively proceed under the mechanisms Type-I or -II. As the re-
sult, we obtained the adduct (5) in 6% yield along with the 7-
acetoxyindolenine (2) and dimeric compound (4), indicating
that the mechanism of Type-I would be plausible for this
dimerization process. The indolenine residue of the upper
part in 4 would be formed by subsequent Pb(OAc)4 oxidation
of the indole portion in the dimer produced by the first step
(Type-I mechanism). Hereupon, a possibility of Type-II
mechanism could not be excluded entirely, if 1,3-dimethoxy-
benzene would function as an electrophilic species, as de-
picted in Chart 2, that would be generated by the contact
with Pb(OAc)4.27) But, when 1,3-dimethoxybenzene was
treated with one equivalent of Pb(OAc)4 under the same reac-
tion conditions above (CH2Cl2, 0 °C, 1.5 h), more than 90%
of the starting material was recovered. This fact would sup-
port our mechanistic consideration described above. Quite
recently, the production of the dimers and trimers of 1-
trimethylacetylindole in the presence of aluminum chloride
was reported,28) in which nucleophilicity of the benzene part
Chart 2
Fig. 3. Selected HMBC Data for Compound 5 ( ) and Selected NOE
(C-6) in the indole ring under the particular condition was Data for Compound 5 (→)

962
Vol. 50, No. 7
39.1 (C-15), 35.3 (C-6Ј), 32.0 (C-6), 26.3 (C-14), 25.8 (C-14Ј), 20.8 (7Ј-
O2CCH3), 19.1 (C-19Ј), 18.9 (C-19), 12.8 (C-18, C-18Ј). FAB-MS (NBA)
m/z: 853 ([Mϩ1]ϩ). High resolution (HR)-FAB-MS: Calcd for C48H61O10N4
[MHϩ]: 853.4388, Found 853.4349. CD (0.13 mM, MeOH, 24 °C), nm
(Del): 330 (0), 257 (ϩ22.5), 233 (Ϫ44.3), 218 (ϩ2.0), 200 (ϩ38.0).
Pb(OAc)4 Oxidation of Mitragynine (1) in the Presence of 1,3-
Dimethoxybenzene To a stirred mixture of mitragynine (1) (100 mg,
0.25 mmol) and 1,3-dimethoxybenzene (173 mg, 1.25 mmol) in dry CH2Cl2
(1 ml) was added Pb(OAc)4 (230 mg, 91% purity, 0.38 mmol) at 0 °C under
argon atmosphere. After the reaction mixture was stirred for 1.5 h, the reac-
tion mixture was poured onto chilled water and was extracted with CH2Cl2
three times. The combined organic layer was washed with brine, dried over
MgSO4 and evaporated. The residue was separated by SiO2 column chro-
matography (45% AcOEt/n-hexane) to give 7-acetoxyindolenine (2) (34 mg,
29%), dimer (4) (3.2 mg, 3%), and the adduct (5) (8.0 mg, 6%) as an amor-
phous powder. UV lmax (MeOH) nm: 286 (sh), 235, 205. 1H-NMR (CDCl3)
d: 7.60 (1H, br d, H-5Ј), 7.45 (1H, s, H-17), 7.30 (1H, dd, Jϭ7.6, 0.6, H-12),
7.20 (1H, dd, Jϭ7.9, 7.9, H-11), 6.61 (1H, d, Jϭ7.6, H-10), 6.57 (1H, dd,
Jϭ8.5, 2.4, H-4Ј), 6.29 (1H, d, Jϭ2.4, H-2Ј), 3.84 (3H, s, 17-OCH3), 3.80
(3H, s, 3Ј-OCH3), 3.68 (3H, s, 22-OCH3), 3.62 (3H, s, 9-OCH3), 3.40 (1Ј-
OCH3), 3.25 (1H, br d, Jϭ14.3, H-6a), 3.02 (1H, br dd, Jϭ13.4, 11.0, H-
14), 2.93 (1H, br d, Jϭ9.5, H-21), 2.89 (1H, ddd, Jϭ13.7, 3.4, 3.4, H-15),
2.68 (1H, br d, Jϭ2.4, H-3), 2.61 (1H, br d, Jϭ11.6, H-5b), 2.42 (1H, br dd,
Jϭ11.3, 11.3, H-5a), 2.21 (1H, br d, Jϭ2.8, H-21), 1.88 (1H, br d, Jϭ13.4,
H-14), 1.76 (1H, m, H-19), 1.53 (1H, m, H-20), 1.50 (1H, m, H-20), 1.34
(1H, br ddd, Jϭ12.8, 12.8, 3.7, H-6b), 1.23 (1H, m, H-19), 0.78 (3H, dd,
Jϭ4.0, 3.4, H-18). 13C-NMR (CDCl3) d: 188.7 (C-2), 169.6 (C-22), 160.9
(C-17), 159.7 (C-3Ј), 158.3 (C-1Ј), 156.7 (C-13), 155.5 (C-9), 130.6 (C-8),
128.5 (C-11), 117.8 (C-6Ј), 114.0 (C-12), 111.4 (C-16), 108.3 (C-10), 104.8
(C-4Ј), 99.1 (C-2Ј), 62.5 (C-3), 61.9 (17-OCH3), 58.7 (C-7), 57.9 (C-21),
55.6 (9-OCH3), 55.3 (1Ј-OCH3, 3Ј-OCH3), 51.3 (C-5), 51.1 (22-OCH3), 40.7
(C-20), 39.6 (C-15), 34.7 (C-6), 26.6 (C-14), 19.1 (C-19), 12.9 (C-18). FAB-
MS (NBA) m/z: 535 ([Mϩ1]ϩ). HR-FAB-MS: Calcd for C31H39O6N2
[MHϩ]: 535.2808, Found 535.2816. CD (0.14 mM, MeOH, 24 °C), nm
(Del): 350 (0), 251 (ϩ9.5), 234 (Ϫ33.8), 219 (ϩ17.2), 203 (ϩ15.9), 200
(ϩ14.5).
Fig. 4. CD Spectra of Compounds 4 and 5
proposed. An interesting dimerization of the simple indole
derivatives with anodic oxidation is also reported.29) The
structure of 5 was elucidated by spectroscopic analysis. Par-
ticularly, the HMBC correlation between H-6 and C-6Ј on the
benzene ring and the NOE observations depicted in Fig. 3
made clear the proposed structure. The dimeric compound 4
and the 1,3-dimethoxybenzene adduct (5) displayed almost
the same CD curves as shown in Fig. 4.
Further studies on the coupling reactions of indole deriva-
tives are in progress in our laboratory to develop new meth-
ods for the synthesis of biologically active dimeric natural al-
kaloids or their derivatives.
Experimental
General UV: recorded in MeOH, JASCO V-560. 1H- and 13C-NMR
spectra: recorded at 500 and 125.65 MHz, respectively, [ppm, J in Hz with
tetramethylsilane (TMS) as internal standard], JEOL JNM A-500. Electron
impact (EI)-MS: direct probe insertion at 70 eV, JEOL JMS-AM20. FAB-
MS: JEOL JMS-HX110. CD: JASCO J-720WI. TLC: precoated Kieselgel
Acknowledgements This work was supported in part by Grant-in-Aid
(No. 14370718) for Scientific Research from the Ministry of Education, Sci-
ence, Sports, and Culture, Japan, and JSPS Research Fellowship for Young
Scientists to HI.
60 F254 plates (Merck, 0.25 mm thick). Column Chromatography: Kieselgel References and Notes
60 [Merck, 70—230 (for open chromatography) and 230—400 mesh (for
flash chromatography)].
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