Six new indole alkaloids from Gelsemium sempervirens Ait. f.

Article abstract of DOI:10.1016/j.tetlet.2005.06.136

One new yohimbane and five new sarpagine-type indole alkaloids were isolated from the radix of Gelsemium sempervirens Ait. f., and their structures were determined by spectroscopic analysis, chemical conversion or total synthesis. It was found that 2-acyl sarpagine-type alkaloids possessing an N_b-methyl group take a keto-amino structure or a transannular form in solution depending on the solvent.

Full text of DOI:10.1016/j.tetlet.2005.06.136

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 5857–5861
Six new indole alkaloids from Gelsemium sempervirens Ait. f.
Noriyuki Kogure, Chika Nishiya, Mariko Kitajima and Hiromitsu Takayama*
Graduate School of Pharmaceutical Sciences, Chiba University, 1-33 Yayoi-cho, Inage-ku, Chiba 263-8522, Japan
Received 8 June 2005; revised 23 June 2005; accepted 24 June 2005
Available online 14 July 2005
Abstract—One new yohimbane and five new sarpagine-type indole alkaloids were isolated from the radix of Gelsemium sempervirens
Ait. f., and their structures were determined by spectroscopic analysis, chemical conversion or total synthesis. It was found that
2-acyl sarpagine-type alkaloids possessing an Nb-methyl group take a keto–amino structure or a transannular form in solution
depending on the solvent.
Ó 2005 Elsevier Ltd. All rights reserved.
9
6
3
In our recent study, we proved that the original plant of
ÔYakatsu,Õ one of the ancient medicines stored for more
than 1250 years in Shosoin repository in Japan, was
Gelsemium elegans Benth.1 The genus Gelsemium, which
belongs to Loganiaceae, comprises three species: G. ele-
gans Benth., G. sempervirens Ait. f., and G. rankinii
Small, from which more than fifty indole alkaloids have
been isolated.2–4 In the course of our chemical studies on
Gelsemium alkaloids, we investigated the constituents in
the radix of G. sempervirens, and this has resulted in the
isolation of one new yohimbane alkaloid (1) and five
new sarpagine-type alkaloids (2–6). In this paper, we
describe the structure elucidation of the new alkaloids
as well as an interesting spectroscopic observation in
the new sarpagine-type alkaloids.
5
8
7
2
10
11
N
O
N
21
13
N
H
N
12
21
20
14
19
18
15
16
17
sempervilam (1)
sempervirine (8)
O
17
O
RO
HO
9
6
16
16
5
8
7
5
10
11
OMe
OMe
2
Me
N
3
N
3
13
21
21
N
H
N
H
12
O
15
15
HO
14
20
18
18
19
19
The dried radix of G. sempervirens Ait. f. (413.7 g), that
was cultivated in the medicinal plant garden of our uni-
versity, was extracted with hot MeOH to give the
MeOH extract (50.2 g). The crude alkaloidal fraction
(4.88 g) obtained by a conventional procedure from
the MeOH extract was purified by SiO2 column chroma-
tography to afford six new alkaloids, sempervilam (1,
17.8 mg), gelsempervine-A (2, 20.7 mg), -B (3, 7.6 mg),
-C (4, 49.0 mg), -D (5, 5.3 mg), and 19Z-16-epi-voacar-
pine (6, 1.7 mg) (Fig. 1).
R=H, 19E : gelsempervine-A (2)
R=Ac, 19E : gelsempervine-B (3)
R=H, 19Z : gelsempervine-C (4)
R=Ac, 19Z : gelsempervine-D (5)
19Z : 19Z-16-epi-voacarpine (6)
19E : 16-epi-voacarpine (7)
Figure 1. Structures of new alkaloids (1–6) and known alkaloids (7, 8).
288.1272 [M]+ that corresponded to the molecular for-
mula C19H16N2O (m/z 288.1263). The UV spectrum of
1 was similar to that of sempervirine (8).6 The 1H
NMR spectrum5 that showed signals corresponding to
seven aromatic protons including one singlet and eight
aliphatic protons was very similar to that of sempervi-
rine (8) that possessed two singlet aromatic protons.
The 13C NMR spectrum5 showed 15sp2 carbons, includ-
ing one carbonyl carbon at d 58.8 and four sp3 methyl-
enes. Heteronuclear multiple bond connectivity
(HMBC) correlations between H-5 and the carbon at d
58.8 revealed that the carbonyl function existed at
The high-resolution (HR)-FAB-MS spectrum of new
alkaloid (1)5 gave a molecular ion peak at m/z
Keywords: Indole alkaloid; Gelsemium; Structure elucidation; NMR;
Total synthesis; Isomerization; Solvent effect.
*
Corresponding author. Tel./fax: +81 43 290 2901; e-mail: htakayam@
p.chiba-u.ac.jp
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.06.136

5858
N. Kogure et al. / Tetrahedron Letters 46 (2005) 5857–5861
b
a
N
O
N
O
N
N
H
N
H
N
H
11
10
9
C
C
N
O
N
O
N
O
c
d
N
H
N
N
H
+
H
Cl
13
12
sempervilam (1)
e
Scheme 1. Reagents and conditions: (a) cyclohexene-1-carboxylic acid, HOAT, EDCI, iPr2NEt, CH2Cl2, rt, 4 h, 87% ; (b) hm, benzene, rt, 1 h, 36%;
t
(c) DDQ, 1,4-dioxane, reflux, 20 min, 74%; (d) (1) BuOCl, Et3N, CH2Cl2, 0 °C, 1 h; (2) DBU, toluene, reflux, 2 h, 1: 28%, 14: 24%; (e) n-Bu3SnH,
AIBN, toluene, reflux, 5.5 h, 74%.
O
O
HO
C-21. The spectroscopic data led to the elucidation of
structure 1 for the new alkaloid, sempervilam.
HO
16
35% HCHO
Pd/C, H2
OMe
OMe
C
2
Me
3 N
N
rt, 31h, y. 48%
N
H
N
H
To confirm the structure, we planned the total synthesis
of 1 (Scheme 1). 3,4-Dihydroharman (9), which was pre-
pared from tryptamine by acetylation and subsequent
Bishler–Napieralski reaction, was condensed with cyclo-
hexene-1-carboxylic acid using HOAT and EDCI to
give amide 10 in 87% yield. Photocyclization7 of 10 gave
cycloadduct 11 in 36% yield together with the recovered
starting material (14% recovery). Oxidation of 11 with
DDQ gave pyridone 12 in 74% yield. Next, to aromatize
O
HO
19
gelsempervine-A (2)
16-epi-voacarpine (7)
Scheme 2. Chemical conversion from 16-epi-voacarpine (7) to gelsem-
pervine-A (2).
t
presence of catalytic Pd–C under H2 atmosphere.10
The product was completely identical with natural alka-
loid, gelsempervine-A, demonstrating the 3-oxo, that is,
2-acyl indole structure of 2 (Scheme 2).
the C-ring, 12 was treated with BuOCl and then with
DBU to afford 1 in 28% yield together with 14-chloro
derivative 13 (24% yield), the latter of which was treated
with n-Bu3SnH and AIBN to give 1 in 74% yield. The
spectroscopic data (1H NMR, 13C NMR, and UV) of
synthetic compound 1 were completely identical with
those of the natural product.
However, perusal of the UV spectrum of 2 revealed typ-
ical absorptions of the indole nucleus in MeOH (kmax
,
290.5, 282, 220.5 nm). The 2-acyl indole alkaloids are
known to exhibit a characteristic absorption at around
310 nm.11 In order to investigate this unusual observa-
The HR-FAB-MS spectrum of new alkaloid (2),8 named
gelsempervine-A, gave a protonated molecular ion peak
at m/z 383.1935 ([MH]+) that corresponded to the
molecular formula C22H27N2O4 (m/z 383.1971). The
1H NMR spectrum (in CDCl3) showed significant sig-
nals characteristic of an ethylidene group at d 5.28
(ddd, H-19) and d 1.71 (3H, d, H3-18), together with
four aromatic protons of the indole system [d 7.69 (d,
H-9), 7.37 (d, H-12), 7.31 (dd, H-11), 7.15 (dd, H-10)],
an Nb-methyl group at d 2.29 (3H, s) and a carboxy-
methyl group at d 3.68 (3H, s). The 13C NMR data of
2 and the known sarpagine-type alkaloid, 16-epi-voacar-
pine (7),9 are highly similar but for two exceptions,
namely, the spectrum of 2 shows a signal due to the
Nb-methyl group at d 42.0 and does not exhibit a signal
at the C-3 position, which is indicative of the hemiami-
nal function in 7. Taking the molecular formula into
consideration, new alkaloid 2 was deduced to be the
Nb-methyl derivative of 7. To reveal the structure,
including the stereochemistry at C-16 and the geometry
of the ethylidene side chain, 7 was converted into the
Nb-methyl derivative by treating with formalin in the
Keto-amine Form (A)
Zwitter ionic Form (B)
O
O
HO
HO
5
5
OMe
OMe
Me
Me
N
3
N
3
21
21
N
H
N
H
O
O
14
14
221
Abs.
Abs.
311
281
290
300
200
300
400
200
400
in CH3CN
in MeOH
Figure 2. Two structural forms and UV spectra of gelsempervine-A
(2).

N. Kogure et al. / Tetrahedron Letters 46 (2005) 5857–5861
5859
Table 1. NMR data for 2
Position
2 in CDCl3
2 in CD3CN
2 in CD3OD
1Ha
13Cb
1Hc
13Cd
1He
13Cd
2
3
133.9
—
133.6
—
136.5
—
*
*
*
5
6
3.81 (d, 9.8)
3.63 (overlapped)
3.23 (overlapped)
57.7
20.3
3.59 (br s)
3.56 (d, 8.5)
3.12 (d, 15.1)
57.9
20.3
4.18 (d, 6.0)
3.39 (overlapped)
3.41 (overlapped)
62.5
21.0
7
8
9
10
11
12
13
14
117.0
128.1
120.5
120.3
126.0
112.1
135.9
41.0
119.0
128.3
120.7
120.1
125.6
112.3
136.3
40.0
112.2
128.3
120.7
120.7
125.2
112.9
138.1
42.4
7.69 (d, 7.7)
7.69 (d, 8.2)
7.52 (d, 8.1)
7.15 (dd, 7.7, 7.7)
7.31 (dd, 7.7, 7.7)
7.37 (d, 7.7)
7.05 (ddd, 8.2, 7.0, 1.2)
7.21 (ddd, 8.2, 7.0, 1.2)
7.35 (d, 8.2)
6.97 (ddd, 8.1, 7.0, 1.1)
7.10 (ddd, 8.1, 7.0, 1.1)
7.28 (d, 8.1)
3.20 (overlapped)
3.09 (br dd, 12.4, 11.3)
3.74 (br d, 11.3)
2.91 (dd, 14.3, 11.5)
3.28 (br d, 14.3)
3.65 (br d, 11.5)
2.51 (m)
2.89 (dd, 14.2, 3.1)
3.47 (dd, 7.1, 3.1)
15
16
17
30.5
57.1
64.7
29.5
57.1
64.1
33.1
57.8
64.9
3.90 (2H, m)
3.71 (d, 11.6)
3.65 (d, 11.0)
4.03 (d, 11.6)
3.86 (d, 11.0)
18
19
20
21
1.71 (3H, d, 6.6)
5.28 (ddd, 6.6, 6.6, 6.6)
12.8
120.5
133.8
54.2
1.57 (3H, d, 6.9)
5.08 (ddd, 6.9, 6.9, 6.9)
12.3
119.9
136.4
54.8
1.58 (3H, d, 7.0)
5.18 (ddd, 7.0, 7.0, 7.0)
13.0
120.4
133.6
56.3
3.00 (br d, 15.3)
2.92 (d, 15.3)
9.26 (br s)
2.71 (d, 14.8)
2.63 (br d, 14.8)
9.75 (br s)
3.38 (overlapped)
3.08 (d, 15.4)
Na-H
Nb-Me
CO2Me
CO2Me
2.29 (3H, s)
42.0
175.3
52.3
2.14 (3H, s)
41.8
174.7
51.4
2.36 (3H, s)
3.58 (3H, s)
42.3
176.0
52.8
3.68 (3H, s)
3.49 (3H, s)
* Not detected.
a Measured at 500 MHz.
b Measured at 125 MHz.
c Measured at 400 MHz.
d Measured at 150 MHz.
e Measured at 600 MHz.
tion in the UV spectrum, we next measured the UV as
well as NMR spectra in protic or aprotic solvents. As
a result, we found that 2 exhibited the typical absorption
patterns of indole and 2-acyl indole alkaloids in MeOH
and CH3CN, respectively, as shown in Figure 2. Quite
interestingly, the signals of the protons and carbons at
C-5 and C-21 in CD3OD were observed in the low field
compared with those in CD3CN (see Table 1). On the
other hand, the signals of H2-14 were observed in the
lower field in CD3CN than in CD3OD. These spectro-
scopic data suggest that as shown in Figure 2, gelsem-
pervine-A (2) existed exclusively as a C/D ring-opening
structure with the keto–amine form (A) in such aprotic
solvents as CD3CN, and as a transannular structure
with the zwitter ionic form (B) in such protic solvents
as CD3OD.
Table 2. 13C NMR data for 3–7 in CDCl3 (at 125 MHz)
Position
3
4
5
6
7
2
3
133.2
—
135.5**
—
134.2
—
136.9
80.7
137.1
80.5
*
*
*
5
6
57.5
20.5
57.9
21.4
58.4
21.4
57.4
21.4
57.5
21.3
7
8
9
10
11
12
13
14
118.2
128.4
120.7
120.5
126.4
112.1
135.8
40.7
111.6
127.3
119.9
119.9
124.6
111.9
135.6**
44.9
113.3
127.7
120.1
120.2
125.3
112.1
135.9
43.5
107.1
125.8
118.6
119.6
122.2
110.9
136.3
36.7
107.0
125.7
119.5
115.7
122.0
110.9
136.3
36.5
15
29.9
39.3
37.5
40.9
33.7
53.2
63.3
16
55.2
56.4
54.7
54.0
17
65.8
64.8
65.9
63.1
18
19
20
21
Nb-Me
CO2Me
CO2Me
OCOMe
OCOMe
12.9
12.6
12.6
12.6
12.7
The other three new alkaloids, gelsempervine-B (3),12 -C
(4),13 and -D (5),14 are the analogues of gelsempervine-A
(2), that is, 3 is an acetyl derivative of the hydroxyl
group at C-17 in 2, 4 is a 19Z isomer of 2, and 5 is an
acetyl derivative of the hydroxyl group at C-17 in 4,
and were elucidated by comparison of the 1H NMR
and 13C NMR data (Table 2) and differential NOE
experiments, as shown in Figure 3. In these compounds,
the above-described phenomena in the UV and NMR
spectra for compound 2 were also observed.
121.2
133.8
53.9
42.2
173.9
52.2
120.3
133.4
51.2
41.1
175.4
52.5
121.7
132.6
51.1
42.0
173.9
52.5
116.5
136.3
46.0
118.5
135.4
48.1
175.8
52.5
175.8
52.1
170.5
20.7
170.1
20.7
* Not detected.
** Interchangeable.

5860
N. Kogure et al. / Tetrahedron Letters 46 (2005) 5857–5861
7.6 Hz, H-10), 6.91 (1H, br s, H-14), 2.93 (2H, dd, J = 6.4,
3.3% OH
OAc
17
H
6.4 Hz, H2-19), 2.52 (2H, dd, J = 6.1, 6.1 Hz, H2-16), 1.68
(2H, m, H2-17), 1.59 (2H, m, H2-18). 13C NMR (125 MHz,
pyridine-d5): d 158.8 (C-21), 146.0 (C-15), 140.6 (C-13),
131.7 (C-2), 131.2 (C-3), 126.2 (C-11), 123.0 (C-8*), 120.9
(C-10), 120.7 (C-9), 119.1 (C-5), 117.8 (C-20), 116.8 (C-7),
112.4 (C-12), 108.1 (C-6), 98.1 (C-14), 30.0 (C-16), 25.0
(C-19), 23.0 (C-17), 22.5 (C-18). *: under C5D5N signal.
6. (a) Woodward, R. B. J. Am. Chem. Soc. 1949, 71, 379; (b)
Gribble, G. W.; Barden, T. C.; Johnson, D. A. Tetra-
hedron 1988, 44, 3195–3202; (c) Chatterjee, A.; Sahu, A.;
Saha, M.; Banerji, J. Monatsh. Chem. 1996, 127, 1259–
1262.
O
O
17
5.0%
4.7%
OMe
OMe
Me
Me
N
N
N
3.2%
N
1.7%
O
O
H
H
H
H
H
H
H
H
19
19
5.4%
10.1%
Me
Me
9.0%
gelsempervine-A (2) in CD3OD
gelsempervine-B (3) in CD3OD
4.7% OH
OAc
6.4%
H
H
O
O
17
17
7. Ninomiya, I.; Tada, Y.; Kiguchi, T.; Yamamoto, O.;
Naito, T. Heterocycles 1978, 9, 1527–1531.
5.1%
5.3%
OMe
OMe
2.7%
Me
Me
Me
8. Gelsempervine-A (2), colorless amorphous powder, EI-
MS m/z (%): 382 (M+, 17), 180 (100). HRFAB-MS (NBA/
PEG) m/z: 383.1935 (MH+, calcd for C22H27N2O4
383.1971). UV (MeOH) kmax nm (loge): 290.5 (3.65),
282.0 (3.71), 220.5 (4.44). UV (CH3CN) kmax nm (loge):
311.5 (3.99), 224.5 (4.17). IR (ATR, cmÀ1): 3492, 3385,
2923, 1720, 1648. IR (CHCl3, cmÀ1): 3451, 3342, 2951,
1732, 1639. CD (c = 0.262 mM, MeOH, 23 °C) De (k nm):
0 (396), +1.91 (321), 0 (299), À1.51 (282), 0 (265), +1.12
(257), 0 (243), À10.32 (224), 0 (210), +3.55 (203).
9. Ponglux, D.; Wongseripipatana, S.; Subhadhirasakul, S.;
Takayama, H.; Yokota, M.; Ogata, K.; Phisalaphong, C.;
Aimi, N.; Sakai, S. Tetrahedron 1988, 44, 5075–5094.
10. Gorman, M.; Sweeny, J. Tetrahedron Lett. 1964, 5, 3105–
3111.
N
N
N
N
6.0%
O
O
H
H
Me
H
H
4.8%
H
H
19
19
10.8%
7.6%
H
H
gelsempervine-C (4) in CD3OD gelsempervine-D (5) in CDCl3
Figure 3. NOE experiments in 2–5.
The molecular formula of new alkaloid (6)15 was estab-
lished to be C21H24N2O4, which was the same as that of
16-epi-voacarpine (7), from the HR-FAB-MS spectrum
(m/z 369.1828 [MH]+). The H NMR and 13C NMR
1
spectra showed the existence of an ethylidene group, a
carboxymethyl group and an indole skeleton (Table 2).
A hemiaminal carbon was observed at d 80.7 (C-3) in
the 13C NMR spectrum similar to 16-epi-voacarpine
(7). The chemical shifts of C-15 (7.2 ppm lower field
than that of 7) and C-21 (2.1 ppm higher field than that
of 7) indicated that the double bond has a Z-configura-
tion, which was confirmed by NOE experiments. From
these data, new alkaloid (6) was concluded to be 19Z-
16-epi-voacarpine.
11. (a) Dolby, L. J.; Sakai, S. Tetrahedron 1967, 23, 1–9; (b)
Sakai, S.; Yamanaka, E.; Dolby, L. Yakugaku Zasshi
1977, 97, 309–319.
12. Gelsempervine-B (3), colorless amorphous powder, EI-MS
m/z (%): 424 (M+, 96), 365 (56), 192 (100), 180 (96).
HRFAB-MS (NBA/PEG) m/z: 425.2113 (MH+, calcd for
C24H29N2O5 425.2076). UV (MeOH) kmax nm (loge):
316.5 (3.65), 290.5 (3.72), 282.0 (3.74), 219.5 (4.46). UV
(CH3CN) kmax nm (loge): 312.5 (3.92), 221.0 (4.07). 1H
NMR (500 MHz, CDCl3): d 8.96 (1H, br s, Na-H), 7.73
(1H, dd, J = 8.2, 0.6 Hz, H-9), 7.35 (2H, overlapped, H-
11, H-12), 7.17 (1H, ddd, J = 8.2, 6.4, 1.7 Hz, H-10), 5.29
(1H, ddd, J = 6.9, 6.9, 6.9 Hz, H-19), 4.59 (1H, d,
J = 11.9 Hz, H-17), 4.29 (1H, d, J = 11.9 Hz, H-17), 3.80
(1H, br dd, J = 11.8, 2.4 Hz, H-15), 3.75 (1H, dd,
J = 15.9, 9.2 Hz, H-6b), 3.69 (1H, br d, J = 9.2 Hz, H-
5), 3.65 (3H, s, CO2Me), 3.26 (1H, overlapped, H-14a),
3.23 (1H, overlapped, H-6a), 3.16 (1H, dd, J = 14.3,
11.8 Hz, H-14b), 2.90 (1H, d, J = 15.0 Hz, H-21b), 2.79
(1H, br d, J = 15.0 Hz, H-21a), 2.29 (3H, s, Nb-Me), 2.02
(3H, s, OCOMe), 1.75 (3H, dd, J = 6.9, 1.2 Hz, H3-18). IR
(ATR, cmÀ1): 3313, 2925, 1742, 1640. CD (c = 0.210 mM,
MeOH, 23 °C) De (k nm): 0 (396), +2.29 (318), 0 (302),
À1.64 (286), 0 (264), +1.24 (252), 0 (246), À8.38 (223), 0
(205).
Acknowledgments
This work was supported by a Grant-in-Aid for
Scientific Research (C) (No. 16510156) from the Japan
Society for the Promotion of Science.
References and notes
1. Kitajima, M.; Arai, Y.; Takayama, H.; Aimi, N. Proc.
Jpn. Acad. 1998, 74, 159–163.
2. Takayama, H.; Sakai, S. In The Alkaloids; Cordell, G. A.,
Ed.; Academic Press: San Diego, 1997; Vol. 49, Chapter 1,
and references cited therein.
13. Gelsempervine-C (4), colorless amorphous powder, FAB-
MS (NBA) m/z: 383 (MH+). HRFAB-MS (NBA/PEG)
m/z: 383.1939 (MH+, calcd. for C22H27N2O4 383.1971).
UV (MeOH) kmax nm (loge): 290.0 (3.70), 281.0 (3.80),
221.0 (4.54). UV (CH3CN) kmax nm (loge): 309.5 (4.02),
3. Kitajima, M.; Kogure, N.; Yamaguchi, K.; Takayama, H.;
Aimi, N. Org. Lett. 2003, 5, 2075–2078.
4. Kitajima, M.; Urano, A.; Kogure, N.; Takayama, H.;
Aimi, N. Chem. Pharm. Bull. 2003, 51, 1211–1214.
5. Sempervilam (1), ocherous amorphous powder, EI-MS
m/z (%): 288 (M+, 100). HRFAB-MS (NBA/PEG) m/z:
288.1272 (M+, calcd for C19H16N2O 288.1263). UV
(MeOH) kmax nm (loge): 409.0 (4.32), 387.5 (4.17), 349.0
(3.69), 319.0 (3.97), 255.0 (4.24), 221.5 (4.37). 1H NMR
(500 MHz, pyridine-d5): d 13.25 (1H, s, Na-H), 9.21 (1H, d,
J = 7.4 Hz, H-5), 8.16 (1H, d, J = 7.6 Hz, H-9), 7.65 (1H,
d, J = 7.6 Hz, H-12), 7.63 (1H, d, J = 7.4 Hz, H-6), 7.48
(1H, dd, J = 7.6, 7.6 Hz, H-11), 7.37 (1H, dd, J = 7.6,
1
227.5 (4.27). H NMR (500 MHz, CDCl3): d 9.17 (1H, br
s, Na-H), 7.61 (1H, d, J = 7.7 Hz, H-9), 7.36 (1H, d,
J = 7.7 Hz, H-12), 7.27 (1H, dd, J = 7.7, 7.7 Hz, H-11),
7.13 (1H, dd, J = 7.7, 7.7 Hz, H-10), 5.36 (1H, ddd,
J = 6.7, 6.7, 6.7 Hz, H-19), 4.02 (1H, d, J = 7.2 Hz, H-5),
3.99 (1H, d, J = 11.2 Hz, H-17), 3.93 (1H, d, J = 11.2 Hz,
H-17), 3.70 (3H, s, CO2Me), 3.43 (1H, dd, J = 17.6,
7.2 Hz, H-6b), 3.31 (1H, d, J = 17.6 Hz, H-6a), 3.12 (1H,
overlapped, H-21b), 3.10 (1H, overlapped, H-15), 3.09

N. Kogure et al. / Tetrahedron Letters 46 (2005) 5857–5861
5861
(1H, overlapped, H-21a), 3.01 (1H, d, J = 13.9 Hz, H-
14b), 2.78 (1H, dd, J = 13.9, 8.2 Hz, H-14a), 2.22 (3H, s,
Nb-Me), 1.45 (3H, d, J = 6.7 Hz, H3-18). IR (ATR, cmÀ1):
3308, 2947, 1728, 1633. IR (CHCl3, cmÀ1): 3454, 3324,
2952, 1733, 1639. CD (c = 0.225 mM, MeOH, 23 °C) De (k
nm): 0 (377), +1.21 (320), 0 (301), À1.42 (289), À1.61
(281), 0 (263), +0.56 (252), 0 (247), À13.12 (226), 0 (216),
+5.01 (209). In the 1D 13C NMR spectrum, the signal due
to C-3 in compounds 2–5 could not be observed under
various experimental conditions (high or low temperature
in various solvents; using prolonged pulse delay time).
However, in the case of gelsempervine-C, HMBC corre-
lations between the protons at H-21 and H-5 and the
signal at d 125.5 were observed in CD3OD. These
correlations enabled us to assign the chemical shift of C-
3 in 4, and the HMBC connectivities supported the
transannular form in the protic solvent.
J = 7.8 Hz, H-5), 3.67 (3H, s, CO2Me), 3.59 (1H, dd,
J = 17.1, 7.8 Hz, H-6b), 3.36 (1H, br d, J = 7.0 Hz, H-15),
3.20 (2H, overlapped, H-6a, H-21b), 3.14 (1H, dd,
J = 14.0, 2.9 Hz, H-14b), 2.95 (2H, overlapped, H-14a,
H-21a), 2.35 (3H, s, Nb-Me), 2.04 (3H, s, OCOMe), 1.44
(3H, d, J = 6.9 Hz, H3-18). IR (ATR, cmÀ1): 3344, 2923,
1736, 1636. IR (CHCl3, cmÀ1): 3451, 3316, 2928, 1737,
1641. CD (c = 0.224 mM, MeOH, 23 °C) De (k nm): 0
(392), +1.46 (318), 0 (301), À1.36 (282), 0 (265), +1.10
(251), 0 (244), À6.99 (224), 0 (214), +3.15 (204).
15. 19Z-16-epi-Voacarpine (6), colorless amorphous powder,
EI-MS m/z (%): 368 (M+, 100), 265 (61), 184 (78).
HRFAB-MS (NBA/PEG) m/z: 369.1828 (MH+, calcd for
C21H25N2O4 369.1814). UV (MeOH) kmax nm (loge):
290.5 (3.71), 282.5 (3.79), 225.5 (4.49). 1H NMR
(600 MHz, CDCl3): d 8.00 (1H, br s, Na-H), 7.10 (1H, d,
J = 8.0 Hz, H-12), 7.05 (1H, overlapped, H-11), 7.04 (1H,
overlapped, H-9), 6.90 (1H, ddd, J = 8.0, 6.9, 1.1 Hz, H-
10), 5.25 (1H, m, H-19), 4.46 (1H, d, J = 5.7 Hz, H-5),
4.16 (1H, d, J = 17.6, H-21), 3.70 (3H, s, CO2Me), 3.43
(2H, m, H2-17), 3.38 (1H, br d, J = 17.6 Hz, H-21), 2.86
(1H, dd, J = 16.3, 5.7 Hz, H-6a), 2.75 (1H, d, J = 16.3 Hz,
H-6b), 2.69 (1H, br dd, J = 2.9, 2.9 Hz, H-15), 2.08 (1H,
dd, J = 14.1, 2.9 Hz, H-14b), 1.84 (1H, dd, J = 14.1,
2.9 Hz, H-14a), 1.53 (3H, d, J = 6.9 Hz, H3-18). IR (ATR,
cmÀ1): 3330, 2925, 1731. CD (c = 0.272 mM, MeOH,
23 °C) De (k nm): 0 (319), +0.79 (271), 0 (244), À13.02
(230), 0 (215), +1.12 (211), +2.16 (206).
14. Gelsempervine-D (5), colorless amorphous powder, FAB-
MS (NBA) m/z: 425 (MH+). HRFAB-MS (NBA/PEG)
m/z: 425.2059 (MH+, calcd for C24H29N2O5 425.2076).
UV (MeOH) kmax nm (loge): 315.0 (3.36), 290.5 (3.71),
282.0 (3.77), 220.0 (4.48). UV (CH3CN) kmax nm (loge):
1
311.5 (4.01), 221.5 (4.21). H NMR (500 MHz, CDCl3): d
9.40 (1H, br s, Na-H), 7.65 (1H, d, J = 7.7 Hz, H-9), 7.40
(1H, d, J = 7.7 Hz, H-12), 7.31 (1H, dd, J = 7.7, 7.7 Hz,
H-11), 7.16 (1H, dd, J = 7.7, 7.7 Hz, H-10), 5.44 (1H, ddd,
J = 6.9, 6.9, 6.9 Hz, H-19), 4.61 (1H, d, J = 11.6 Hz, H-
17), 4.33 (1H, d, J = 11.6 Hz, H-17), 3.95 (1H, br d,