Isolation and asymmetric total synthesis of a new Mitragyna indole alkaloid, (-)-mitralactonine

Full text of DOI:10.1021/jo9823644

1772
J . Org. Chem. 1999, 64, 1772-1773
The new compound 1,4 obtained as an orange amorphous
Isola tion a n d Asym m etr ic Tota l Syn th esis of
a New Mitr a gyn a In d ole Alk a loid ,
(-)-Mitr a la cton in e
1
powder, exhibited [R]18 -16.5 (c 0.17, CHCl3). The H and
D
13C NMR spectra of 1 showed the presence of the funda-
mental structural units in the common Corynanthe-type
monoterpenoid indole alkaloids, i.e., an indole nucleus, an
ethane-bridge at C5-C6, an ethyl group at C-20, and a
methoxycarbonyl group. The UV spectrum exhibited a long-
wavelength absorption at 460 nm, indicating a high degree
of unsaturation in the molecule. The 13C NMR and HMBC
spectra disclosed the presence of six conjugated sp2 carbons
including an ester and a lactone carbonyl carbon, besides
the aromatic carbons due to the indole nucleus. The quite
characteristic proton signal observed at δ 6.51 (1H, singlet)
was unambiguously assigned to be the proton at C14 by the
HMQC spectrum, and this signal has the HMBC connec-
tivities between the C2, C3, C15, C16, and C20 carbons. The
molecular formula (C21H20N2O4) obtained from a high-
resolution mass spectrum as well as the fact that the carbon
signal at C20 resonated at δ 77.4 ppm showed the presence
of a lactone function constructed between the oxygen atom
on C20 and the carbonyl group at the C22 position. All of
the above findings as well as biogenetic consideration
enabled us to compose the molecular structure of the new
alkaloid, now named mitralactonine, to be the formula 1
having a highly conjugated pentacyclic Corynanthe skeleton.
This is the first example of Corynanthe-type indole alkaloids
carrying an oxygen function at the C20 position.
Hiromitsu Takayama,*,† Mika Kurihara,†
Mariko Kitajima,† Ikram M. Said,‡ and Norio Aimi†
Faculty of Pharmaceutical Sciences, Chiba University,
1-33, Yayoi-cho, Inage-ku, Chiba 263-8522, J apan, and
Chemistry Department, Universiti Kebangsaan Malaysia,
43600 Bangi, Selangor, Malaysia
Received December 2, 1998
Mitragyna speciosa Korth. (Rubiaceae) is a tropical plant
indigenous to Thailand and the Malay Peninsula. The leaves
of this plant are known to produce narcotic-like actions when
smoked or chewed and have been used traditionally as a
stimulant like coca or as a substitute for opium. The unique
properties of this medicinal plant have attracted many
researchers over the last 50 years.1 In our recent chemical2
and pharmacological3 studies on the Mitragyna alkaloids,
potent analgesic activity due to the opioid agonistic property
of mitragynine, a major indole alkaloid of M. speciosa in
Thailand, and that of pseudoindoxyl derivatives2g has been
demonstrated. This prompted us to investigate the constitu-
ents in the leaves of M. speciosa native to Malaysia.2e From
the ethyl acetate extract of the young leaves of M. speciosa
collected in Malaysia, a new alkaloid (1) could be isolated
together with six known Corynanthe-type indole alkaloids.
In this paper, we describe the structure elucidation of the
novel monoterpenoid indole alkaloid 1 by means of spectro-
scopic analysis as well as racemic and asymmetric total
syntheses.
To establish the novel structure of mitralactonine, includ-
ing the absolute configuration due to one chiral center at
C20, we next planned the asymmetric total synthesis of 1.
Our synthesis started with the preparation of the chiral
epoxy ketone 5, which is an essential synthon for the
construction of the functionalized tetracyclic compound 7
(Scheme 1). Attempts at the direct preparation of the highly
optically active epoxide 5 from the known R,â-unsaturated
ketone 25 utilizing the known asymmetric oxidation proce-
dures were unsuccessful. Thus, we synthesized the optically
pure 5 in a stepwise manner as follows. By the reduction of
the enone 2 using a chiral oxazaborolidine catalyst (0.7 equiv
of BH3, 0.2 equiv of (S)-5,5-diphenyl-2-methyl-3,4-propano-
1,3,2-oxazaborolidine, -20 °C),6 an optically active alcohol
(+)-3 [[R]23 +9.5 (c 0.35, CHCl3)] was obtained in 93% ee.
D
The enantiomeric excess of 3 was determined by chiral
HPLC analysis of the p-nitrobenzoate derivatives, and the
absolute configuration was deduced to be R by the proposed
reaction mechanism.6b Next, the allylic alcohol 3 (93% ee)
was subjected to the Sharpless asymmetric epoxidation
under the kinetic resolution conditions7 (1.0 equiv of Ti(O-
i-Pr)4, 1.2 equiv of diisopropyl D-tartrate, t-BuOOH, -40 °C,
40.5 h) to give the (-)-epoxide 4 [[R]23D -12.4 (c 0.56, CHCl3)]
† Chiba University.
‡ Universiti Kebangsaan Malaysia.
(1) (a) J ansen, K. L. R.; Prast, C. J . J . Ethnopharmacol. 1988, 23, 115-
119 and references cited therein. (b) Houghton, P. J .; Latiff, A.; Said, I. M.
Phytochem. 1991, 30, 347-350 and references cited therein.
(2) (a) Ponglux, D.; Wongseripipatana, S.; Takayama, H.; Kikuchi, M.;
Kurihara, M.; Kitajima, M.; Aimi, N.; Sakai, S. Planta Med. 1994, 60, 580-
581. (b) Takayama, H.; Yamamoto, R.; Kurihara, M.; Kitajima, M.; Aimi,
N.; Mao, L.; Sakai, S. Tetrahedron Lett. 1994, 35, 8813-8816. (c) Takayama,
H.; Maeda, M.; Ohbayashi, S.; Kitajima, M.; Sakai, S.; Aimi, N. Tetrahedron
Lett. 1995, 36, 9337-9340. (d) Takayama, H.; Kurihara, M.; Subhad-
hirasakul, S.; Kitajima, M.; Aimi, N.; Sakai, S. Heterocycles 1996, 42, 87-
92. (e) Takayama, H.; Kurihara, M.; Kitajima, M.; Said, I. M.; Aimi, N.
Tetrahedron 1998, 54, 8433-8440.
(4) Dark orange amorphous powder Rf value: 0.3 (SiO2, solvent system:
n-hexane/AcOEt ) 1:2). [R]26D: -16.5 (c 0.17, CHCl3). UV λmax
(log ꢀ):
MeOH
460 (4.49), 434 (sh, 4.37), 344 (3.78), 262 (sh, 3.79), 223 (4.24) nm. EI-MS
m/z: 364 (M+, 48), 335 (44), 320 (53), 289 (21), 262 (39), 261 (49), 220 (22),
219 (36), 97 (100). HR-FABMS: calcd for C21H21O4N2 (MH+) 365.1501, found
365.1474. 1H NMR (500 MHz, DMSO-d6) δ: 11.91 (1H, s, Na-H), 7.61 (1H,
d, J ) 7.9 Hz, H-9), 7.43 (1H, d, J ) 7.9 Hz, H-12), 7.28 (1H, dd, J ) 7.9,
7.9 Hz, H-11), 7.09 (1H, dd, J ) 7.9, 7.9 Hz, H-10), 6.51 (1H, s, H-14), 3.79
(1H, d, J ) 12.8 Hz, H-21), 3.73 (3H, s, 22-OCH3), 3.66 (1H, d, J ) 12.8 Hz,
H-21), 3.60-3.70 (2H, m, H-5), 3.08 (2H, m, H-6), 1.81 and 1.70 (2H, each
m, H-19), 0.83 (3H, dd, J ) 7.3, 7.3 Hz, H-18). 13C NMR (125 MHz, DMSO-
d6) δ: 169.87 (C-15), 168.56 (C-17), 163.08 (C-22), 149.27 (C-3), 138.67 (C-
13), 126.89 (C-2), 125.19 (C-11), 124.90 (C-8), 120.00 and 119.95 (C-9 and
C-10), 116.80 (C-7), 112.19 (C-12), 95.38 (C-16), 87.31 (C-14), 77.41 (C-20),
54.87 (C-21), 50.54 (22-OCH3), 50.37 (C-5), 29.59 (C-19), 19.88 (C-6), 7.13
(C-18). It is interesting to note that the sp2 carbons at C14 and C16 resonate
at unusually higher field.
(3) (a) Matsumoto, K.; Mizowaki, M.; Thongpradichote, S.; Takayama,
H.; Sakai, S.; Aimi, N.; Watanabe, H. Life Sci. 1996, 59, 1149-1155. (b)
Matsumoto, K.; Mizowaki, M.; Thongpradichote, S.; Murakami, Y.; Takaya-
ma, H.; Sakai, S.; Aimi, N.; Watanabe, H. Eur. J . Pharmacol. 1996, 317,
75-81. (c) Tohda, M.; Thongpraditchote, S.; Matsumoto, K.; Murakami, Y.;
Sakai, S.; Aimi, N.; Takayama, H.; Tongroach, P. Watanabe, H. Biol. Pharm.
Bull. 1997, 20, 338-340. (d) Matsumoto, K.; Mizowaki, M.; Takayama, H.;
Sakai, S.; Aimi, N.; Watanabe, H. Pharmaco. Biochem. Behav. 1997, 57,
319-323. (e) Watanabe, K.; Yano, S.; Horie, S.; Yamamoto, L. T. Life Sci.
1997, 60, 933-942. (f) Thongpradichote, S.; Matsumoto, K.; Tohda, M.;
Takayama, H.; Aimi, N.; Sakai, S.; Watanabe, H. Life Sci. 1998, 62, 1371-
1378. (g) Yamamoto, L. T.; Horie, S.; Takayama, H.; Aimi, N.; Sakai, S.;
Yano, S.; Shan, J .; Pang, P. K. T.; Ponglux, D.; Watanabe, K. Gen.
Pharmacol., in press.
(5) Faulkner, D. J .; Petersen, M. R. J . Am. Chem. Soc. 1973, 95, 553-
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10.1021/jo9823644 CCC: $18.00 © 1999 American Chemical Society
Published on Web 02/25/1999

Communications
J . Org. Chem., Vol. 64, No. 6, 1999 1773
Sch em e 1a
F igu r e 1. Chiral HPLC analysis of natural mitralactonine
(conditions: Chiralcel OD; 20% EtOH/n-hexane; flow rate, 0.5 mL/
min; column temperature, 30 °C).
C3-14 position in 8 by a two-step operation ((i) t-BuOCl,
Et3N, (ii) ethanolic HCl then NaHCO3). The synthetic
compound was identified with the natural product by
a
Reagents and conditions: (i) 0.2 equiv of (S)-5,5-diphenyl-2-methyl-
3,4-propano-1,3,2-oxazaborolidine, BH3-THF complex, dry THF, -20
°C (65% after distillation); (ii) diisopropyl D-tartrate, Ti(i-PrO)4,
t-BuOOH, CH2Cl2, -40 °C (56% after distillation); (iii) (COCl)2, DMSO,
Et3N, CH2Cl2, -78 °C (41% after distillation); (iv) MeOH, reflux (7a
36%. 7b 9%); (v) dimethyl malonate, AcONH4, AcOH, dry toluene,
reflux (55%); (vi) (a) t-BuOCl, Et3N, CH2Cl2, 0 °C, (b) 5 N ethanolic
HCl, 0 °C, then alkaline workup (83%).
1
comparison of their chromatographic behavior, UV, H and
13C NMR, and mass spectra. The observed optical rotation
of the synthetic compound was levorotatory as in the natural
product; however, the specific rotation was very different
[[R]24 -892 (c 0.63, CHCl3)] from that of natural 1. Then,
D
we synthesized racemic mitralactonine starting from the
achiral epoxy ketone 5 and analyzed the enantiomeric purity
of both the synthetic (()-1 and (-)-1 and of the natural
product using chiral column chromatography. As a result,
it was found that the natural mitralactonine contained the
(-)-enantiomer slightly dominant over the (+)-enantiomer
in a ratio of 54:46 (Figure 1).
In conclusion, a novel Corynanthe-type indole alkaloid,
mitralactonine (1), having a highly conjugated pentacyclic
skeleton was isolated from the Malaysian medicinal plant,
Mitragyna speciosa, and the structure, including the abso-
lute configuration, was elucidated by spectroscopic analysis
and chiral total synthesis. It is interesting to note that
natural mitralactonine comprises of a mixture slightly
enriched with (-)-enantiomer. Further chemical investiga-
tion on the components in Malaysian M. speciosa and the
pharmacological evaluation of these compounds are in
progress in our laboratories.
with >99% ee. The enantiomeric excess of 4 was determined
by chiral HPLC analysis of the p-bromobenzoate derivatives,
and the absolute configuration of the quaternary center was
assigned as S by using the well-established enantioselec-
tivity principle.7b The secondary carbinol in 4 was then
converted to a ketone by Swern oxidation to give the (-)-
epoxy ketone 5 [bp 44-81 °C (82-96 mmHg); [R]24 -57.7
D
(c 0.54, CHCl3)].
The thus-obtained epoxide (-)-5 and 3,4-dihydro-â-car-
boline (6)8 were condensed9 in heated MeOH to afford two
diastereomeric tetracyclic compounds (7a and 7b) in 36%
and 9% yields, respectively. The C3 configurations of the
major and minor products was deduced by comparison of
their CD spectra.10 The major isomer 7a was subjected to
Knoevenagel condensation with dimethyl malonate in re-
fluxing toluene in the presence of AcONH4 and AcOH to give
directly the pentacyclic product 8 having a lactone residue
in 55% yield. Finally, the double bond was introduced to the
Ack n ow led gm en t. This work was supported in part
by a Grant-in-Aid (Nos. 10557229 and 10044325) for
Scientific Research from the Ministry of Education, Science,
Sports, and Culture, J apan.
(7) (a) Martin, V. S.; Woodard, S. S.; Katsuki, T.; Yamada, Y.; Ikeda, M.;
Sharpless, K. B. J . Am. Chem. Soc. 1981, 103, 6237-6240. (b) J ohnson, R.
A.; Sharpless, K. B. In Comprehensive Organic Synthesis; Trost, B. M.,
Fleming, I., Ed.; Pergamon Press: Oxford, 1991; Vol. 7, pp 389-436.
(8) Onda, M.; Sasamoto, M. Chem. Pharm. Bull. 1957, 5, 305-310.
(9) Szantay, C.; Toeke, L.; Honty, K.; Klaus, G. J . Org. Chem. 1967, 32,
423-427.
(10) (a) Lee, C. M.; Trager, W. F.; Beckett, A. H. Tetrahedron 1967, 23,
375-385. (b) Blaha, K.; Koblicova, Z.; Trojanek, J . Collect. Czech. Chem.
Commun. 1974, 39, 3168-3176.
Su p p or tin g In for m a tion Ava ila ble: Experimental proce-
1
dures, characterization data, and H and 13C NMR spectra for new
compounds.
J O9823644