activating µ-opioid receptors. Development of tolerance to
its antinociceptive effect and cross-tolerance to morphine
antinociception were observed, indicating that 1 acts on
Scheme 1
5
µ-opioid receptors. Furthermore, 1 induces constipation less
6
potently than morphine at antinociceptive doses. These
interesting properties of 1, which has a chemical structure
different from that of morphine, have enabled us to pursue
further investigations for the development of novel analge-
sics. To develop a more potent opioid receptor agonist based
on 1, we have initially planned the synthesis of compounds
by modifying the benzene ring in 1 and the evaluation of
their potency to opioid receptors. In the present study, we
found a new method to protect the 2,3-π bond of indole
alkaloids, which was applied to the preparation of derivatives
having various substituents at the C-10 position in 1. Among
the synthetic derivatives, compound 11 showed the highest
potency: 4-fold and 18-fold higher than that of 1 and
morphine, respectively. In this communication, we report
these chemical findings as well as the preliminary pharma-
cological results on the opioid agonistic effect of Corynanthe-
type indole alkaloids.
ature, followed by heating at 90 °C after addition of MeOH.
Indoline 3 was put to practical use for the preparation of
several benzene-substituted derivatives for the study of opioid
receptor ligands, as described below.
Using other indole alkaloids, we examined the generality
of the newly developed method to mask the pyrrole moiety
in the indole nucleus. Among the tested compounds, 2,3-
dimethylindole, tetrahydrocarbazole, indoloquinolizidine,
corynantheol, dihydrocorynantheol, and yohimbine, the cor-
responding EG adducts (4-9), were obtained in moderate
yields. However, the best results (the yields are shown in
4
Figure 1) were obtained when NH Cl was added to the
Attempts at the direct introduction of electrophilic sub-
1
0
reaction mixture (see Supporting Information). In the case
of reserpine, it was found that phenyliodine diacetate (PIDA)
was a more suitable reagent than PIFA for the formation of
the EG-bridged adduct (10), which was also useful as a
starting material for the preparation of various kinds of
stituents on the benzene ring in 1 or in its parent compound,
7
mitragynine (2), were unsuccessful as expected. Then, we
8
devised a method to protect the 2,3-π bond of indoles,
producing the aniline structure that should act as a reactive
aromatic compound toward various electrophiles. When 2
1
1
A-ring-modified reserpine analogues.
was treated with 1 equiv of phenyliodine bis(trifluoroacetate)
Using EG adduct 3 derived from mitragynine (2), various
kinds of substituents were introduced onto the benzene ring,
as shown in Scheme 2. Treatment of 3 with N-fluoro-2,6-
9
(
PIFA) in the presence of ethylene glycol (EG) in MeCN
at 0 °C, a 2,3-ethylene glycol bridged indoline derivative
3) was obtained in quantitative yield. The structure of the
adduct including the stereochemistry was determined from
spectroscopic data, as shown in Scheme 1. Indoline 3 could
be converted into starting indole 2 in almost quantitative yield
(
1
2
dichloropyridinium triflate (FP-T800) gave compound 11
fluorinated at the C-10 position in 53% yield. Exposure of
3
to NCS in AcOH afforded two chlorinated derivatives 12a
(10-Chloro) and 12b (12-Chloro) in 88% and 11% yields,
3
upon reduction with NaCNBH in AcOH at room temper-
respectively. Using NBS in DMF, 10-bromo and 12-bromo
derivatives (13a and 13b) were obtained in 75% and 24%
yields, respectively. To introduce the nitro group, a combina-
(
5) Matsumoto, K.; Horie, S.; Takayama, H.; Ishikawa, H.; Aimi, N.;
Ponglux, D.; Murayama, T.; Watanabe, K. Life Sci. 2005, 78, 2-7.
6) Matsumoto, K.; Hatori, Y.; Murayama, T.; Tashima, K.; Wongseripi-
1
3
(
2 4
tion of CAN and concentrated H SO in DCM was used
patana, S.; Misawa, K.; Kitajima, M.; Takayama, H.; Horie, S. Eur. J.
Pharmacol. Available online 16 August 2006.
to give 14a in 52% yield together with its 12-isomer (14b)
(
7) (a) Takayama, H.; Maeda, M.; Ohbayashi, S.; Kitajima, M.; Sakai,
S.; Aimi, N. Tetrahedron Lett. 1995, 36, 9337-9340. (b) Matsumoto, K.;
Mizowaki, M.; Suchitra, T.; Takayama, H.; Sakai, S.; Aimi, N.; Watanabe,
H. Life Sci. 1996, 59, 1149-1155.
(10) We found that treatment of 7-chloroindolenine derivatives, which
were prepared by oxidation of indoles with tBuOCl, with ethylene glycol
in the presence of TFA also afforded EG adducts, although the yields were
inferior to those of the PIFA-EG-NH4Cl method. The reaction mechanism
for the formation of EG adducts with hypervalent iodines is still unclear.
(11) The preparation of various A-ring-modified reserpines will be
published in due course.
(12) Umemoto, T.; Fukami, S.; Tomizawa, G.; Harasawa, K.; Kawada,
K.; Tomita, K. J. Am. Chem. Soc. 1990, 112, 8563-8575.
(13) Mellor, J. M.; Mittoo, S.; Parkes, R.; Miller, R. W. Tetrahedron
2000, 56, 8019-8024.
(
8) A method for protection-deprotection of the indole 2,3-bond using
MTDA was reported. (a) Baran, P. S.; Guerrero, C. A.; Corey, E. J. Org.
Lett. 2003, 5, 1999-2001. (b) Baran, P. S.; Guerrero, C. A.; Corey, E. J.
J. Am. Chem. Soc. 2003, 125, 5628-5629.
(
9) (a) Wirth, T. Angew. Chem., Int. Ed. 2005, 44, 3656-3665. (b)
Moriarty, R. M. J. Org. Chem. 2005, 70, 2893-2903. (c) Dohi, T.;
Morimoto, K.; Maruyama, A.; Kita, Y. Org. Lett. 2006, 8, 2007-2010 and
references cited therein.
5706
Org. Lett., Vol. 8, No. 25, 2006
Takayama, Hiromitsu
