Preparation of ethylene glycol abducts at 2,3-positions of indoles with hypervalent iodine

Article abstract of DOI:10.3987/com-07-s(w)25

An efficient method for protection-deprotection of the 2,3-bond of indoles was developed. Treatment of various indole derivatives with hypervalent iodine-ethylene glycol in the presence of ammonium chloride provided 2,3-ethylene glycol bridged adducts in excellent yields. The adducts, which possessed a masked form of pyrrole moiety in the indole nucleus, could be converted back to the mother indoles under mild reductive conditions.

Full text of DOI:10.3987/com-07-s(w)25

HETEROCYCLES, Vol. 74, 2007
461
HETEROCYCLES, Vol. 74, 2007, pp. 461 - 472. © The Japan Institute of Heterocyclic Chemistry
Received, 6th August, 2007, Accepted, 20th September, 2007, Published online, 21st September, 2007. COM-07-S(W)25
PREPARATION
OF
ETHYLENE
GLYCOL
ADDUCTS
AT
✝
2
,3-POSITIONS OF INDOLES WITH HYPERVALENT IODINE
Naoki Okada, Kaori Misawa, Mariko Kitajima, and Hiromitsu Takayama*
Graduate School of Pharmaceutical Sciences, Chiba University, 1-33 Yayoi-cho,
Chiba 263-8522, Japan
Abstract – An efficient method for protection–deprotection of the 2,3-bond of
indoles was developed. Treatment of various indole derivatives with hypervalent
iodine–ethylene glycol in the presence of ammonium chloride provided
2
,3-ethylene glycol bridged adducts in excellent yields. The adducts, which
possessed a masked form of pyrrole moiety in the indole nucleus, could be
converted back to the mother indoles under mild reductive conditions.
✝
Dedicated to Professor Ekkehard Winterfeldt on the occasion of his 75th birthday.
INTRODUCTION
In the course of our studies of potent opioid ligands having the Corynanthe skeleton, we recently found a
1
2
3
new reaction to mask the 2,3-π bond of an indole alkaloid, mitragynine (1), a major constituent of
4
Mitragyna speciosa, a rubiaceous plant that has long been used in Thailand and Malaysia for its
opium-like effect. Further, utilizing ethylene glycol (EG) adduct 2 that acted as a reactive aromatic
compound toward various electrophiles on the benzene ring, we succeeded in the preparation of highly
potent opioid agonist (3) having a fluorine function at C-10 (Scheme 1). Its potency was approximately
OMe
PhI(O CCF )
OMe
OMe
2
3 2
O
O
7
2
OH
F
7
HO
10
+
N
H
2
N
H
F
N
H
N
H
MeCN, 0 °C, 1.5 h
y. quant
N
H
N
O
O
H
OMe
OMe
OMe
MeO C
2
MeO C
MeO C
2
2
NaCNBH , AcOH, rt, 2 h
3
then add MeOH, 90 °C, 2 h
y. quant
mitragynine (1)
2
3 (potent opioid agonist)
Scheme 1

462
HETEROCYCLES, Vol. 74, 2007
2
1
8-fold higher than that of morphine. Here we describe the results of further examination of the
generality of the newly developed method, using various indole derivatives to construct the EG adduct.
RESULTS AND DISCUSSION
To inspect the scope and limitations of the reaction of indoles with a combination of hypervalent iodine,
such as phenyliodine bis(trifluoroacetate) (PIFA), and EG, which gives a 2,3-EG bridged adduct, we
initially applied this reaction to 2,3-dimethylindole (4), tetrahydrocarbazole (7), indoloquinolizidine (9),
dihydrocorynantheol (12), and yohimbine (17). Using the reaction conditions employed for mitragynine
(
1), the corresponding EG adducts were obtained in low yields, as shown in Scheme 2 [from 4 to 6,
condition a: PIFA, EG, MeCN, 0 °C, y. 49%] and in Scheme 3 [from 7 to 8, condition a: 18%; from 9 to
1
0 and 11, condition a: 10 (8%), 11 (13%); from 12 to 14, condition b: 33%; from 17 to 19, condition a:
3
5%]. Based on these results, it was apparent that the primarily found reaction conditions were not
suitable to indoles in general. Then, we attempted to improve the reaction conditions.
a) or b)
O
Me
Me
Me
Me
Me
Me
3
2
3
c)
d)
2
N
H
N
N
H O
TMS
4
6
5
e)
Me
Me
f) or g)
N
TMS
Scheme 2. Reagents and conditions; a) phenyliodine bis(trifluoroacetate) (PIFA),
ethylene glycol (EG), MeCN, 0 °C, 49%; b) PIFA, EG, NH Cl (5 equiv), MeCN, 0 °C,
4
7
9%; c)NaH, MeCN, 0 °C, then TMSCl, rt; d) PIFA, EG, 0 °C, 1.5 h, 68%; e) n-BuLi,
THF, -78 °C, then TMSCl, -40 °C, 4 h, 77%; f) PIFA, EG, MeCN, 0 °C, 2 h, 38%; g)
PIFA, EG, NaCl (2.5 equiv), MeCN, 0 °C, 3 h, 68%.
We deduced that the presence of an electron-donating group, such as a methoxy function on the indole
nucleus in 1, would facilitate this oxidative reaction. Then, we employed an N -silyl derivative of indoles
1
with the expectation that the reactivity toward oxidation would be increased due to the electropositive
nature of silicon. When 4 was treated successively with NaH and TMSCl and then with PIFA and EG
(
conditions c and d in Scheme 2), adduct (6) was obtained in 68% yield, which was somewhat higher than

HETEROCYCLES, Vol. 74, 2007
463
O
a)
c)
N
H
N
O
H
7
8
(a; 18%, c; 87%)
O
O
NH
N
a)
N
H
N
H
N
N
+
N
H
O
N
c)
O
H
H
H
O
H
O
NOE
9
d) y. quant
10 (a; 8%, c; 97%)
11 (a; 13%, c; 3%)
O
O
b)
c)
N
N
N
N
N
H
+
N
H O
H
O
H
H
H
R
R
R
OH
OH
OH
1
1
2 : R = Et
5 : R = vinyl
d) y. 12 (86%), 15 (68%)
14 : R = Et (b; 33%)
1
3 : R = Et (c; 87%)
16 : R = vinyl (c; 97%)
NH
N
R
OH
O
H
O
NOE
O
O
N
N
N
N
N
H
a)
c)
N
H
H
H
H
H
O
H
H
H
O
+
H
H
H
MeO C
MeO C
MeO C
2
2
2
OH
OH
OH
d) y. 86%
17
18 (c; 83%)
19 (a; 35%)
NOEs
H
H
H
O
NH
N
N
O
MeO C
O
2
OH
NH MeO C
2
H
O
OH
H
NOE
Scheme 3 Reagents and conditions; a) phenyliodine bis(trifluoroacetate) (PIFA),
ethylene glycol (EG), MeCN, 0 °C; b) phenyliodine diacetate (PIDA), EG, MeCN,
0
°C; c) PIFA, EG, NH Cl (1.3–5.0 equiv), MeCN; d) NaCNBH , AcOH, rt, then
4
3
add MeOH, 90 °C.

464
HETEROCYCLES, Vol. 74, 2007
that obtained by initial condition a (49% yield). To examine the effect of the N -silyl function, we
1
5
isolated N -silyl derivative (5) and treated it with PIFA and EG (condition f in Scheme 2), but this
1
resulted in a decrease of the yield (38%). Comparing the reaction conditions, i.e., one-pot experiment vs.
stepwise procedure, we found that the difference lies in the presence or absence of NaCl when I(III)/EG
reacted with indoles. Then, we reacted TMS derivative (5) with PIFA and EG in the presence of NaCl
(
condition g in Scheme 2), and this oxidative reaction afforded adduct (6) in 68% yield. Encouraged by
this result, we next investigated the additive to the reaction mixture. Several inorganic or organic salts,
such as NH Cl, LiCl, n-Bu NCl, NaBr, or NaI, were examined and the use of NH Cl in MeCN (condition
4
4
4
b in Scheme 2) was found to afford the best result (79% yield). Then, this condition was employed to
other indole substrates (7, 9, 12, 15 and 17). As shown in Scheme 3, the yields were dramatically
improved (8: 87%, 10: 97%, 13: 87%, 16: 97%, and 18: 83%) when NH Cl was added to the reaction
4
mixture (condition c).
Quite interestingly, under the reaction conditions in the presence of NH Cl, adducts (10, 13, 16, and 18)
4
having the syn structure, i.e., H-3 and EG bridge positioned on the same face were obtained. Their
stereochemistry was elucidated by nOe observation, as shown in Scheme 3. On the other hand, in the
absence of NH Cl, adducts (11, 14, and 19) with the anti structure were obtained as the main product, and
4
the chemical yields were low. To understand the reaction mechanisms and the role of chloride ion in the
reaction, we next attempted the preparation of EG adducts via chloroindolenine derivatives, which are a
candidate for the reaction intermediate in the presence of NH Cl.
4
6
We employed the well-studied chloroindolenine derivative of yohimbine (17). According to the literature,
t
yohimbine was treated with BuOCl in the presence of triethylamine to give 7α-chloroindolenine (20) and
its β-isomer in 67% and 28% yields, respectively. When 20 was treated with EG at rt to 40 °C in the
presence of trifluoroacetic acid, desired adduct 18 was obtained in 69% yield (Scheme 4). This result
indicated that unstable cationic intermediate (22) generated from 7-iodo-indolenine (21) was once trapped
as stable 7α-chloroindolenine derivative (20), which reacted gradually with EG to afford adduct (18). In
the transformation from 20 to 18, EG would attack the imine function from the α side, as described by
7
Borschberg and co-workers in their mechanistic studies of the rearrangement of 7-chloroyohimbine
–
derivatives, and successive Cl elimination–addition at the other terminal of EG would give adduct (18)
with syn stereochemistry. The present results, i.e., indole alkaloids 9, 12, 15, and 17 giving α-oriented EG
adducts, are in accordance with previously reported observations that indole alkaloids having a
trans-quinolizidine structure gave mainly 7α-substituted indolenine derivatives under various oxidative
t
6d
8
9
conditions, such as BuOCl, lead tetraacetate, or IBDA/alcohol, which respectively afforded
α-chloroindolenine, 7α-acetoxyindolenine, or 7α-alkoxyindolenine. However, the mechanism for the
production of β-adducts when the reaction was conducted in the absence of NH Cl is still unclear.
7
4

HETEROCYCLES, Vol. 74, 2007
465
Cl
O
7
N
N
N
N
H
N
H H
t-BuOCl
N
EG, TFA
H O
H
H
H
H
Et N, CH Cl
3
2
2
MeCN
y. 69%
H
H
H
20 (67%)
MeO C
MeO C
MeO2C
2
2
OH
OH
OH
17
18
2
0
N
N
PIFA, EG, NH Cl, MeCN
4
MeO C
2
OH
H
Cl
Ph
N
O CCF
HO
2
3
I
OH
–
7
Cl
N
+
N
H
N
H
N
N
MeO C
2
H
O
OH
H
H
HO
MeO C
2
OH
22
21
Scheme 4
Next, we attempted the conversion of EG adducts back to the starting indoles. As has been proven using
2
10
mitragynine (1), a series of reactions, i.e., indole → EG adduct → regeneration of indole, enabled us to
modify the benzene ring of the indole nucleus in 1. According to the method discovered in 1, adducts 10,
1
3, 16, and 18 could be converted respectively into their starting indoles (9, 12, 15, and 17) in good yields
upon reduction with NaCNBH in AcOH at rt, followed by heating at 90 °C after the addition of MeOH
3
(
Scheme 3). In the case of compounds 6 and 8, the desired indoles could not be isolated in good yields,
probably due to the instability of compounds 4 and 7 under the present conditions. The developed
protocol, i.e., preparation of 2,3-EG adducts of indole derivatives to mask the pyrrole moiety in the indole
nucleus and conversion back to the mother indoles, would offer a new and general method to synthesize
various A-ring-modified indole derivatives. The application of this methodology to other indoles is under
way.
EXPERIMENTAL
UV: recorded in MeOH on a JASCO V-560 instrument. IR: recorded on a JASCO FT/IR-230
1
13
spectrophotometer. H and C NMR spectra: recorded on a JEOL JNM A-400, JNM A-500, JNM
ECP-400 or JNM ECP-600 spectrometer, J values are given in Hz. EI-MS: direct probe insertion at 70 eV
recorded on a JEOL JMS GC-mate spectrometer. FAB-MS: recorded on a JEOL JMS-AX500 or
JMS-HX110 mass spectrometer. Optical rotation: measured with a JASCO P-1020 polarimeter. Melting

466
HETEROCYCLES, Vol. 74, 2007
Point: Yanagimoto Micro Melting Point Apparatus 1631A. TLC: precoated Kieselgel 60 F254 plates
Merck, 0.25 mm thick). Column chromatography: Kieselgel 60 [Merck, 70-230 mesh (for open
(
chromatography) and 230-400 mesh (for flash chromatography)], Chromatorex NH [Fuji Silysia
Chemical, 100-200 mesh (for amino-silica gel column chromatography)]. Medium pressure liquid
chromatography (MPLC): C. I. G. prepacked column CPS-HS-221-05 (Kusano Kagakukikai, SiO2).
Preparation of EG adduct 6
To a stirred solution of 2,3-dimethylindole (4, 74.3 mg, 0.51 mmol) in dry MeCN (2.6 mL) and dry EG
(
2.6 mL) were successively added NH Cl (132.2 mg, 2.45 mmol) and PIFA (251.5 mg, 0.61 mmol) at
4
0
°C and the mixture was stirred for 1 h at 0 °C under argon atmosphere. After adding chilled aqueous
NaHCO solution, the mixture was extracted three times with CHCl . The combined extract was washed
3
3
with brine, dried over MgSO , and evaporated. The crude product was purified by pre-packed silica gel
4
column chromatography (EtOAc/n-hexane = 30:70) to give 83.1 mg (79%) of 6 as a yellowish amorphous
powder, a portion of which was recrystallized from n-hexane to give pale yellowish prisms (mp
-
1
7
3
7
9–81 °C). Compound 6: UV (MeOH) λmax nm: 290, 269, 241, 233, 220, 218, 104. IR (KBr) νmax cm :
1
329, 2979, 2960, 2864, 1612, 1468. H NMR (400 MHz, CDCl ) δ ppm: 7.21 (1H, d, J=7.3 Hz, H-5),
3
.15 (1H, ddd, J=7.7, 7.7, 1.3 Hz, H-7), 6.86 (1H, ddd, J=7.4, 7.4, 0.9 Hz, H-6), 6.71 (1H, d, J=7.9 Hz,
H-8), 4.11 (1H, br s, N -H), 3.72 (2H, m, H-1’ and H-2’), 3.65 (1H, m, H-2’), 3.58 (1H, m, H-1’), 1.56
a
1
3
(
(
(
3H, s, 2-CH ), 1.38 (3H, s, 3-CH ). C NMR (100 MHz, CDCl ) δ ppm: 147.6 (C-9), 131.1 (C-4), 129.0
3 3 3
C-7), 123.1 (C-5), 119.8 (C-6), 110.5 (C-8), 93.2 (C-2), 81.5 (C-3), 61.3 (C-2’), 61.1 (C-1’), 23.3
+
2-CH ), 18.0 (3-CH ). FAB-MS (NBA) m/z: 206 [M+H] . HR-FAB-MS (NBA/PEG): calcd. for
3
3
C H NO : 206.1181, found: 206.1180.
1
2
16
2
Preparation of EG adduct 8
To a stirred solution of tetrahydrocarbazole (8, 110.9 mg, 0.65 mmol) in dry MeCN (3.3 mL) and dry EG
(
3.3 mL) were added NH Cl (167.8 mg, 2.60 mmol) and PIFA (335.6 mg, 0.78 mmol) at 0 °C and the
4
mixture was stirred for 30 min at 0 °C under argon atmosphere. After adding chilled aqueous NaHCO3
solution, the mixture was extracted three times with CHCl . The combined extract was washed with brine,
3
dried over MgSO , and evaporated. The crude product was chromatographed on silica gel
4
(
EtOAc/n-hexane = 0:100 – 50:50) to give 129.5 mg (87%) of 8 as a colorless amorphous powder, a
portion of which was recrystallized from EtOAc to give colorless prisms (mp 156–157 °C). Compound
-
1
8
: UV (MeOH) λmax nm: 295, 275, 247, 223, 205. IR (KBr) νmax cm : 3311, 3035, 2958, 2933, 2864,
1
1
616. H NMR (400 MHz, CDCl ) δ ppm: 7.18 (1H, d, J=7.3Hz, H-9), 7.14 (1H, ddd, J=7.6, 7.6, 1.2Hz,
3
H-11), 6.85 (1H, dd, J=7.4, 7.4Hz, H-10), 6.71 (1H, d, J=7.6Hz, H-12), 4.01 (1H, br s, N -H), 3.81 (1H,
a

HETEROCYCLES, Vol. 74, 2007
467
m, H-1’, overlapped with H-2’), 3.65 (2H, m, H-1’, overlapped with H-2’), 2.12 (1H, ddd, J=10.4, 10.4,
1
3
2
.7), 2.00 (1H, m), 1.70 (2H, m), 1.52 (3H, m), 1.42 (1H, m). C NMR (100 MHz, CDCl ) δ ppm: 147.4
3
(
(
C-13), 131.6 (C-8), 128.8 (C-11), 122.4 (C-9), 119.7 (C-10), 111.1 (C-12), 92.3 (C-2), 80.6 (C-7), 61.4
+
C-1’), 61.0 (C-2’), 36.4, 29.4, 22.9, 20.6. FAB-MS (NBA) m/z: 231 [M] . HR-FAB-MS (NBA/PEG):
calcd. for C H NO : 231.1259, found: 231.1269.
1
4
17
2
Preparation of EG adducts 10 and 11
To a stirred solution of indoloquinolizidine (70.4 mg, 0.31 mmol) in dry MeCN (1.6 mL) and dry EG (1.6
mL) were added NH Cl (83.2 mg, 1.55 mmol) and PIFA (157.8 mg, 0.37 mmol) at rt and the mixture was
4
stirred for 2 h at 50 °C under argon atmosphere. After adding chilled aqueous NaHCO solution, the
3
mixture was extracted three times with CHCl . The combined extract was washed with brine, dried over
3
MgSO , and evaporated. The crude product was purified by pre-packed silica gel column chromatography
4
(
5% MeOH in CHCl ) to give 86.0 mg (97%) of 10 as a colorless amorphous powder, a portion of which
3
was recrystallized from acetone and n-hexane to give colorless prisms (mp 142–143 °C). Compound 10:
-1
UV (MeOH) λmax nm: 290, 262, 238, 221, 206. IR (ATR) νmax cm : 3313, 3033, 2964, 2939, 2924, 2910,
1
1
1
614. H NMR (500 MHz, CDCl ) δ ppm: 7.18 (1H, dd, J=7.2, 0.6 Hz, H-9), 7.14 (1H, ddd, J=7.6, 7.6,
3
.3 Hz, H-11), 6.86 (1H, ddd, J=7.4, 7.4, 0.9 Hz, H-10), 6.71 (1H, d, J=7.7 Hz, H-12), 4.20 (1H, br s,
N -H), 3.90 (2H, m, H-1’, overlapped with H-2’), 3.61 (1H, m, H-1’ or H-2’), 3.44 (1H, m, H-1’ or H-2’),
a
2
2
.99 (1H, d, J=11.0 Hz), 2.57 (1H, m), 2.50 (1H, dd, J=10.9, 2.1 Hz, H-3), 2.41 (1H, ddd, J=12.3, 12.3,
.5 Hz), 2.16 (1H, ddd, J=11.1, 11.1, 4.3 Hz), 2.05 (1H, d, J=10.3 Hz), 1.91 (2H, m), 1.80 (1H, ddd,
1
3
J=13.8, 13.8, 4.5 Hz), 1.68 (2H, m), 1.43 (1H, m), 1.33 (1H, m). C NMR (100 MHz, CDCl ) δ ppm:
3
1
6
46.8 (C-13), 130.8 (C-8), 128.6 (C-11), 122.0 (C-9), 119.9 (C-10), 111.8 (C-12), 91.1 (C-2), 80.4 (C-7),
+
2.0 (C-1’), 61.2 (C-2’), 59.5, 56.5, 50.6, 37.4, 25.5, 24.8, 24.6. FAB-MS (NBA) m/z: 287 [M+H] .
HR-FAB-MS (NBA/PEG): calcd. for C H N O : 287.1760, found: 287.1762.
1
7
23
2
2
Under the reaction conditions above without the addition of NH Cl, compounds 10 and 11 were obtained
4
in 13% and 8% yields, respectively. Compound 11: UV (MeOH) λmax nm: 298, 243, 205. IR (ATR) νmax
-
1
1
cm : 3310, 2922, 1613, 1466. H NMR (400 MHz, CDCl ) δ ppm: 7.20 (2H, m), 6.83 (1H, dd, J=7.4, 7.4
3
Hz), 6.74 (1H, d, J=7.5 Hz), 4.36 (1H, ddd, J=11.6, 11.6, 2.8 Hz, H-1’ or H-2’), 4.10 (1H, br s, N -H),
a
4
.05 (1H, ddd, J=11.8, 11.8, 2.7 Hz, H-1’ or H-2’), 3.65 (1H, dd, J=11.4, 2.4 Hz, H-1’ or H-2’), 3.49 (1H,
dd, J=11.9, 2.7 Hz, H-1’ or H-2’), 2.92 (1H, d, J=11.0 Hz), 2.83 (1H, d, J=12.1 Hz), 2.69 (1H, ddd,
J=13.4, 13.4, 4.6 Hz), 2.12 (1H, ddd, J=13.5, 2.6, 2.6 Hz), 1.97 (1H, dd, J=11.2, 11.2 Hz), 1.82-1.56 (7H,
13
overlapped), 1.11 (1H, m). C NMR (100 MHz, CDCl ) δ ppm: 148.7, 130.1, 129.5, 123.1, 119.5, 110.8,
3
9
2
2.2 (C-2), 75.6 (C-7), 68.3 (C-3), 60.6 (C-1’ or C-2’), 58.2 (C-1’ or C-2’), 56.4, 53.7, 25.2, 24.3, 23.9,
+
3.8. FAB-MS (NBA) m/z: 287 [M+H] . HR-EI-MS: calcd. for C H N O : 286.1681, found: 286.1683.
17
22
2
2

468
HETEROCYCLES, Vol. 74, 2007
Preparation of EG adducts 13 and 14
To a stirred solution of dihydrocorynantheol (229 mg, 0.77 mmol) in dry MeCN (4.0 mL) and dry EG
4.0 mL) was added NH Cl (55.4 mg, 1.04 mmol), and then PIFA was added portionwise to the stirred
(
4
mixture at rt under argon atmosphere in the following manner: 0 min, 157.6 mg (0.37 mmol); 1 h, 175.7
mg (0.41 mmol); 4 h, 37.5 mg (0.08 mmol). The reaction mixture was stirred at the same temperature for
further 3 h under argon atmosphere. After adding chilled aqueous NaHCO solution, the mixture was
3
extracted three times with CHCl . The combined extract was washed with brine, dried over MgSO , and
3
4
evaporated. The crude product was chromatographed on amino-silica gel (EtOAc/CHCl = 30:70) to give
3
2
38.7 mg (87%) of 13 as a colorless amorphous powder, a portion of which was recrystallized from
EtOAc and n-hexane to give colorless prisms (mp 108-111 °C). Compound 13: UV (MeOH) λmax nm:
-1
1
2
92, 264, 239, 221, 205. IR (ATR) νmax cm : 3313, 2958, 2866, 1614, 1466. H NMR (500 MHz, CDCl )
3
δ ppm: 7.17 (1H, d, J=7.0 Hz, H-9), 7.13 (1H, ddd, J=7.6, 7.6, 1.2 Hz, H-11), 6.86 (1H, ddd, J=7.3, 7.3,
.9 Hz, H-10), 6.71 (1H, d, J=7.6 Hz, H-12), 4.23 (1H, br s, N -H), 3.89 (2H, m, H-1’, overlapped with
0
a
H-2’), 3.75 (2H, m, H -17), 3.61 (1H, m, H-1’), 3.44 (1H, m, H-2’), 3.05 (1H, dd, J=11.3, 3.6 Hz, H-21),
2
2
1
1
.60 (1H, dddd, J=11.6, 2.2, 2.2, 2.2 Hz, H-5), 2.51 (1H, dd, J=11.1, 1.9 Hz, H-3), 2.39 (1H, ddd, J=12.4,
2.4, 2.4 Hz, H-5), 2.15 (1H, ddd, J=12.0, 2.8, 2.8 Hz, H-14), 1.96 (2H, m, H-6, overlapped with H-16),
.88 (1H, dd, J=11.3, 11.3 Hz, H-21), 1.80 (1H, ddd, J=13.8, 13.8, 4.4 Hz, H-6), 1.67 (1H, m, H-19), 1.38
(
3H, m, H-15, overlapped with H-16 and H-20), 1.24 (1H, ddd, J=11.6, 11.6, 11.6 Hz, H-14), 1.11 (1H, m,
1
3
H-19), 0.89 (3H, dd, J=7.5, 7.5 Hz, H -18). C NMR (100 MHz, CDCl ) δ ppm: 146.7 (C-13), 130.8
3
3
(
C-8), 128.7 (C-11), 122.0 (C-9), 119.9 (C-10), 111.8 (C-12), 91.1 (C-2), 80.3 (C-7), 62.0 (C-1’), 61.3
C-2’), 61.0 (C-21), 60.5 (C-17), 59.1 (C-3), 50.3 (C-5), 41.5 (C-20), 37.4 (C-6), 37.0 (C-15), 35.8 (C-16),
(
2
5
+
3
1
0.5 (C-14), 23.3 (C-19), 11.0 (C-18). [α]D -72 (c 1.1, CHCl ). EI-MS m/z (%): 358 (100, M ), 313 (20),
3
69 (95), 156 (41). HR-FAB-MS (NBA/PEG): calcd. for C H N O : 359.2335, found: 359.2344.
2
1
31
2
3
To a stirred solution of dihydrocorynantheol (12, 11 mg, 0.04 mmol) in dry MeCN (0.3 mL) and dry EG
0.3 mL) was added PIDA (12.7 mg, 0.04 mmol) to the stirred mixture at 0 °C under argon atmosphere.
(
The reaction mixture was stirred at the same temperature for further 12 h under argon atmosphere. After
adding chilled aqueous NaHCO solution, the mixture was extracted three times with CHCl . The
3
3
combined extract was washed with brine, dried over MgSO , and evaporated. The crude product was
4
purified by pre-packed silica gel column chromatography (7% MeOH in CHCl ) to give 4.4 mg (33%) of
3
1
4 as a colorless amorphous powder together with 5.5 mg of the starting material (12). Compound 14:
1
UV (MeOH) λmax nm: 298, 242, 227, 204. H NMR (400 MHz, CDCl ) δ ppm: 7.22-7.18 (2H,
3
overlapped), 6.83 (1H, ddd, J=7.5, 7.5, 1.1 Hz), 6.76 (1H, d, J=7.5 Hz), 4.35 (1H, ddd, J=11.6, 11.6, 2.7
Hz, H-1’ or H-2’), 4.04 (1H, ddd, J=11.9, 11.9, 2.8 Hz, H-1’ or H-2’), 3.79-3.70 (3H, overlapped), 3.64
(
1H, dd, J=11.4, 2.4 Hz, H-1’ or H-2’), 3.49 (1H, dd, J=11.9, 2.6 Hz, H-1’ or H-2’), 2.96 (1H, dd, J=11.4,

HETEROCYCLES, Vol. 74, 2007
469
3
2
.7 Hz), 2.85 (1H, m), 2.69 (1H, ddd, J=13.4, 13.4, 4.8 Hz), 2.13 (1H, ddd, J=14.1, 2.5, 2.5 Hz),
.00-1.88 (3H, overlapped), 1.73-1.52 (4H, overlapped), 1.40-1.32 (3H, overlapped), 1.31 (1H, m), 1.00
+
(
1H, m), 0.82 (3H, dd, J=7.4, 7.4 Hz). EI-MS m/z (%): 358 (M , 100), 313 (20), 169 (95). HR-EI-MS:
calcd. for C H N O : 358.2256, found: 358.2261.
2
1
30
2
3
Preparation of EG adduct 16
To a stirred solution of corynantheol (15, 302 mg, 1.02 mmol) in dry MeCN (15.0 mL) and dry EG (15.0
mL) was added NH Cl (107.4 mg, 2.01 mmol), and then PIFA was added portionwise to the stirred
4
mixture at 0 °C under argon atmosphere in the following manner: 0 min, 139.1 mg (0.32 mmol); 10 min ,
1
42.3 mg (0.33 mmol); 20 min, 175.5 mg (0.41 mmol); 30 min, 100.5 mg (0.23 mmol). The reaction
mixture was stirred at rt for further 15 h under argon atmosphere. After adding chilled aqueous NaHCO3
solution, the mixture was extracted three times with CHCl . The combined extract was washed with brine,
3
dried over MgSO , and evaporated. The crude product was chromatographed on amino-silica gel
4
(
EtOAc/CHCl = 30:70) to give 352.9 mg (97%) of 16 as an yellowish amorphous powder, a portion of
3
which was recrystallized from EtOAc and n-hexane to give colorless prisms (mp 105–110 °C).
-
1
Compound 16: UV (MeOH) λmax nm: 291, 265, 239, 222, 205. IR (KBr) νmax cm : 3315, 2924, 2866,
1
2
7
821, 1614, 1466. H NMR (500 MHz, CDCl ) δ ppm: 7.18 (1H, d, J=7.3 Hz, H-9), 7.14 (1H, ddd, J=7.6,
3
.6, 1.3 Hz, H-11), 6.87 (1H, dd, J=7.3, 7.3 Hz, H-10), 6.72 (1H, d, J=7.6 Hz, H-12), 5.58 (1H, ddd,
J=17.2, 10.2, 8.9 Hz, H-19), 5.12 (1H, dd, J=17.2, 1.7 Hz, H-18), 5.09 (1H, dd, J=10.2, 1.7 Hz, H-18),
4
3
.23 (1H, br s, N -H), 3.89 (2H, m, H-1’, overlapped with H-2’), 3.75 (2H, m, H -17), 3.61 (1H, m, H-1’),
a 2
.44 (1H, m, H-2’), 2.89 (1H, dd, J=11.1, 3.7 Hz, H-21), 2.57 (2H, m, H-3, overlapped with H-5), 2.40
(
1H, ddd, J=12.4, 12.4, 2.4 Hz, H-5), 2.19 (2H, m, H-14, overlapped with H-20), 2.07 (1H, dd, J=11.1,
1.1 Hz, H-21), 1.92 (2H, m, H-6, overlapped with H-16), 1.79 (1H, ddd, J=13.9, 13.9, 4.6 Hz, H-6), 1.46
1
1
3
(
1H, m, H-15), 1.35 (1H, m, H-16), 1.24 (1H, ddd, J=11.4, 11.4, 11.4 Hz, H-14). C NMR (100 MHz,
CDCl ) δ ppm: 146.7 (C-13), 139.5 (C-19), 130.7 (C-8), 128.7 (C-11), 122.1 (C-9), 120.0 (C-10), 116.9
3
(
(
C-18), 111.8 (C-12), 91.0 (C-2), 80.3 (C-7), 61.9 (C-1’), 61.7 (C-21), 61.3 (C-2’), 60.4 (C-17), 58.9
24
C-3), 50.0 (C-5), 46.8 (C-20), 37.3 (C-6), 36.8 (C-16), 36.7 (C-15), 30.1 (C-14). [α]D -81 (c 1.0,
+
CHCl ). EI-MS m/z (%): 356 (100, M ), 166 (76), 154 (37). HR-FAB-MS (NBA/PEG): calcd. for
3
C H N O : 459.2495, found: 459.2515.
2
5
35
2
6
Preparation of EG adducts 18 and 19
To a stirred solution of yohimbine (17, 117.4 mg, 0.33 mmol) in dry MeCN (1.7 mL) and dry EG (1.7
mL) were added NH Cl (69.8 mg, 1.29 mmol) and PIFA (157.0 mg, 0.36 mmol) at rt and the mixture was
4
stirred for 3h at 40 °C under argon atmosphere. After adding chilled aqueous NaHCO solution, the
3

470
HETEROCYCLES, Vol. 74, 2007
mixture was extracted three times with CHCl . The combined extract was washed with brine, dried over
3
MgSO , and evaporated. The crude product was chromatographed on silica gel (10% MeOH in CHCl ) to
4
3
give 113.2 mg (83%) of 18 as a pale yellowish amorphous powder, a portion of which was recrystallized
from acetone and n-hexane to give colorless prisms (mp 231–234 °C). Compound 18: UV (MeOH) λmax
-
1
1
nm: 292, 265, 239, 222, 205. IR (KBr) νmax cm : 3381, 2924, 1726, 1616, 1468. H NMR (500 MHz,
CDCl ) δ ppm: 7.17 (1H, d, J=6.8 Hz, H-9), 7.13 (1H, ddd, J=7.6, 7.6, 1.3 Hz, H-11), 6.87 (1H, dd, J=7.3,
3
7
.3 Hz, H-10), 6.72 (1H, d, J=7.8 Hz, H-12), 4.19 (1H, br s, N -H), 4.18 (1H, m, H-17), 3.87 (2H, m, H-1’,
a
overlapped with H-2’), 3.76 (3H, s, 22-OCH ), 3.60 (1H, d, J=9.3 Hz, H-1’), 3.42 (1H, d, J=9.5 Hz, H-2’),
3
3
.27 (1H, br s, 17-OH), 2.88 (1H, dd, J=11.1, 3.1 Hz, H-21), 2.61 (1H, d, J=11.5 Hz, H-3), 2.57 (1H, m,
H-5), 2.42 (1H, ddd, J=12.3, 12.3, 2.4 Hz, H-5), 2.31 (1H, dd, J=11.1, 1.8 Hz, H-16), 2.02 (1H, dd,
J=10.9, 10.9 Hz, H-21), 1.99 (1H, m, H-18), 1.90 (3H, m, H-6, overlapped with H-14 and H-15), 1.77
(
1H, ddd, J=13.8, 13.8, 4.4 Hz, H-6), 1.50 (3H, m, H-18, overlapped with H-19 and H-20), 1.39 (1H, m,
1
3
H-19), 1.24 (1H, ddd, J=12.1, 12.1, 12.1 Hz, H-14). C-NMR (100 MHz, CDCl ) δ ppm: 176.1 (C-22),
3
1
6
4
46.6 (C-13), 130.7 (C-8), 128.7 (C-11), 122.1 (C-9), 120.1 (C-10), 111.8 (C-12), 90.9 (C-2), 80.2 (C-7),
6.6 (C-17), 61.9 (C-1’), 61.8 (C-21), 61.3 (C-2’), 59.2 (C-3), 52.3 (C-16), 51.9 (22-OCH ), 50.1 (C-5),
3
25
0.3 (C-20), 37.4 (C-6), 36.8 (C-15), 31.1 (C-18), 29.3 (C-14), 23.2 (C-19). [α]D -44 (c 0.98, CHCl ).
3
+
FAB-MS (NBA) m/z: 415 [M+H] . HR-FAB-MS (NBA/PEG): calcd. for C H N O : 415.2233, found:
2
3
31
2
5
4
15.2202.
Under the reaction conditions above without the addition of NH Cl, compound 19 was obtained in 35%
4
-
1
yields. Compound 19: UV (MeOH) λmax nm: 297, 242, 206. IR (KBr) νmax cm : 3399, 2927, 1727, 1615.
1
H NMR (500 MHz, CDCl ) δ ppm: 7.20 (1H, ddd, J=7.4, 7.4, 1.2 Hz, H-9), 7.19 (1H, d, J=7.6 Hz, H-11),
3
6
2
.83 (1H, ddd, J=7.5, 7.5, 0.8 Hz, H-10), 6.76 (1H, dd, J=8.4, 1.1 Hz, H-12), 4.34 (1H, ddd, J=11.6, 11.6,
.8 Hz, H-2’), 4.16 (1H, m, H-17), 4.07 (1H, br s, N -H), 4.02 (1H, ddd, J=11.9, 11.9, 2.8 Hz, H-1’), 3.78
a
(
3H, s, 16-CO CH ), 3.63 (1H, dd, J=11.4, 2.4 Hz, H-2’), 3.49 (1H, dd, J=11.9, 2.4 Hz, H-1’), 2.83 (1H,
2 3
m, H-5), 2.80 (1H, dd, J=11.8, 2.6 Hz, H-21), 2.66 (1H, ddd, J=13.4, 13.4, 4.8 Hz, H-6), 2.28 (1H, dd,
J=11.3, 2.1 Hz, H-16), 2.12 (1H, ddd, J=13.7, 2.4, 2.4 Hz, H-6), 1.98 (1H, ddd, J=12.5, 12.5, 2.6 Hz,
H-5), 1.91 (1H, dd, J=13.7, 3.1 Hz, H-18), 1.83 (1H, dd, J=10.8, 2.6 Hz, H-3), 1.66 (2H, overlapped,
H-15, and H-21), 1.58 (1H, m, H-14), 1.50 (1H, m, H-18), 1.46 (1H, ddd, J=12.7, 2.7, 2.7 Hz, H-14),
1
3
1
.38-1.34 (2H, overlapped, H-19, and H-20), 1.31-1.26 (1H, m, H-19). C NMR (125 MHz, CDCl ) δ
3
ppm: 175.6 (16-CO CH ), 148.4 (C-13), 130.2 (C-9), 129.1 (C-8), 123.0 (C-11), 119.6 (C-10), 111.1
2
3
(
C-12), 92.0 (C-2), 75.6 (C-7), 68.0 (C-3), 66.8 (C-17), 61.7 (C-21), 60.6 (C-2’), 58.1 (C-1’), 53.1 (C-5),
2.4 (C-16), 51.9 (16-CO CH ), 39.7 (C-20), 35.7 (C-15), 31.3 (C-18), 28.7 (C-14), 23.7 (C-6), 23.0
5
2
3
+
(
C-19). EI-MS m/z (%): 414 (M , 67), 225 (100). HR-EI-MS: calcd. for C H N O : 414.2154, found:
23 30 2 5
4
14.2142.

HETEROCYCLES, Vol. 74, 2007
471
Preparation of EG adduct 18 from 7-chloroindolenine 20
To a stirred solution of 20 (34.7 mg, 0.0 mmol) in dry MeCN (0.5 mL) and dry EG (0.5 mL) was added
trifluoroacetic acid (0.1 mL) at 0 °C and the mixture was stirred at rt for 3 h and then at 40 °C for 6 h
under argon atmosphere. After adding chilled aqueous NaHCO solution, the mixture was extracted three
3
times with CHCl . The combined extract was washed with brine, dried over MgSO , and evaporated. The
3
4
crude product was chromatographed on silica gel (10% MeOH in CHCl ) to give 25.5 mg (69%) of 18 as
3
a pale yellowish amorphous powder, which was identical with the product prepared directly from 17.
Conversion of EG adduct 10 into indoloquinolizidine 9
To a stirred solution of 10 (21.4 mg, 0.08 mmol) in dry AcOH (0.8 mL) was added NaCNBH (24.8 mg,
3
0
.50 mmol) at rt and the mixture was stirred for 4 h at rt under argon atmosphere. MeOH (100 µL) was
added to the reaction mixture, which was then heated under reflux at 90 °C for 4 h. The reaction mixture
was poured into cold aqueous NH OH solution, and this mixture was extracted three times with CHCl .
4
3
The combined extract was washed with brine, dried over MgSO , and evaporated to give a residue that
4
was purified by silica gel column chromatography (10% MeOH in CHCl ) to give 19.9 mg (quantitative)
3
of indoloquinolizidine (9), which was completely identical with the authentic sample.
ACKNOWLEDGEMENTS
This work was supported by Grants-in-Aid for Scientific Research from the Japan Society for the
Promotion of Science and the Japan Science and Technology Agency, and by the Uehara Memorial
Foundation.
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