4508
T. Ito et al. / Tetrahedron Letters 50 (2009) 4506–4508
Table 1
and HMBC) spectroscopy. However, significant differences were
noted between our NMR data (see Table 1) and those reported
1H and 13C NMR data for synthetic and natural2 eudistomidin B in CDCl3 + CF3CO2D
(10:1)
for the natural product (½a D22
ꢁ76.4 (c 0.3, CHCl3)). In particular,
ꢀ
the chemical shifts at H-10, 13, 14, and 18 in the 1H NMR spectra
and at C-10 and 18 in the 13C NMR spectra showed marked differ-
ences, as depicted in Scheme 4. Hence, we concluded that natural
eudistomidin B does not have structure 1, and inconsistencies in
the data reported for the natural product hindered us from propos-
ing a credible alternative structure.
Position
dH (500 MHz)
Natural
dC (125 MHz)
Synthetic
Synthetic
Natural
1
3
5.28 (s)
3.88 (m)
3.77 (br dd, 14.0, 4.0)
3.21 (2H, overlapped)
5.19 (d, 8.9)
3.28 (dd, 12.2, 5.3)
2.86 (m)
62.77
50.36
63.59
45.80
4
2.82 (m)
15.29
15.00
2.38 (dd, 15.6, 4.2)
4a
4b
5
6
7
8
8a
9
107.27
126.74
121.40
114.51
127.96
113.67
136.05
105.53
122.40
121.05
113.61
126.91
113.87
135.49
Acknowledgment
7.71 (d, 1.7)
7.52 (d, 1.6)
This work was supported by a Grant-in-Aid for Scientific Re-
search from the Japan Society for the Promotion of Science.
7.46 (dd, 8.7, 1.7)
7.34 (d, 8.7)
7.39 (dd, 8.7, 1.6)
7.42 (d, 8.7)
References and notes
11.08 (s)
9a
10
11
121.24
56.75
34.32
137.57
63.73
33.27
1. (a) Takayama, H.; Kitajima, M.; Kogure, N. Curr. Org. Chem. 2005, 9, 1445–1464;
(b) Takayama, H.; Misawa, K.; Okada, N.; Ishikawa, H.; Kitajima, M.; Hatori, Y.;
Murayama, T.; Wongseripipatana, S.; Tashima, K.; Matsumoto, K.; Horie, S. Org.
Lett. 2006, 8, 5705–5708; (c) Kitajima, M. J. Nat. Med. 2007, 61, 14–23; (d)
Nakayama, A.; Kogure, N.; Kitajima, M.; Takayama, H. Heterocycles 2008, 76,
861–865.
2. Kobayashi, J.; Cheng, J.-F.; Ohta, T.; Nozoe, S.; Ohizumi, Y.; Sasaki, T. J. Org. Chem.
1990, 55, 3666–3670.
3. Suzuki, K.; Takayama, H. Org. Lett. 2006, 8, 4605–4608.
4. Zhong, G. Angew. Chem., Int. Ed. 2003, 42, 4247–4250.
4.56 (br d, 9.8)
3.21 (overlapped)
3.09 (m)
4.18 (m)
3.23 (dd, 14.7, 3.1)
3.03 (dd, 14.7, 9.7)
12
128.69
128.58
130.49
139.47
20.72
134.10
128.87
128.52
134.10
32.42
13, 17
14, 16
15
18
19
6.97 (2H, d, 7.9)
7.12 (2H, d, 7.9)
7.05 (2H, d, 7.5)
6.59 (2H, d, 7.5)
2.29 (3H, s)
3.15 (3H, s)
2.88 (3H, s)
2.92 (3H, s)
42.54
39.75
5. 5-Bromotryptamine was prepared from 5-bromoindole via
a three-step
operation: (i) POCl3, DMF, 40 °C, y. 94%; (ii) NH4OAc, MeNO2, reflux, y. 74%;
(iii) NaBH4, BF3–Et2O, THF, reflux, y. 77%.
could be improved to 16:1 by using TMSCl as acid. The high diaste-
reoselectivity of the cyclization could be due to the plausible acyli-
minium intermediate, in which the indole nucleus would attack
from the less hindered side (anti from the side chain), as depicted
in Figure 1.
6. Compound 2: mp 219–221 °C (from EtOAc); ½a D25
ꢀ
+1.7 (c 0.87, CHCl3); 1H NMR
(400 MHz, CDCl3) d 7.53 (1H, d, J = 1.9 Hz, H-5), 7.38 (2H, d, J = 8.0 Hz, H-14, H-
16), 7.31 (2H, d, J = 8.0 Hz, H-13, H-17), 7.17 (1H, dd, J = 8.8, 1.9 Hz, H-7), 6.70
(1H, d, J = 8.8 Hz, H-8), 5.52 (1H, br s, N9-H), 4.80 (1H, d, J = 8.1, 1.8, 1.8 Hz, H-1),
4.46 (1H, ddd, J = 11.0, 8.1, 4.5 Hz, H-10), 4.26 (1H, dd, J = 13.5, 5.2 Hz, H-3), 3.61
(1H, dd, J = 13.0, 4.5 Hz, H-11), 3.09 (1H, ddd, J = 13.5, 11.5, 5.0 Hz, H-3), 2.98
(1H, dd, J = 13.0, 11.0 Hz, H-11), 2.78 (1H, dddd, J = 15.4, 11.5, 6.1, 2.2 Hz, H-4),
2.69 (1H, br dd, J = 15.4, 5.0 Hz, H-4), 2.53 (3H, s, H3-18); 13C NMR (100 MHz,
CDCl3) d 156.1 (C-19), 138.1 (C-15), 134.5 (C-8a), 131.6 (C-12), 130.5 (C-9a),
130.3 (C-14, C-16), 130.1 (C-13, C-17), 128.0 (C-4b), 125.2 (C-7), 121.2 (C-5),
112.9 (C-6), 112.1 (C-8), 108.5 (C-4a), 80.8 (C-10), 56.6 (C-1), 40.0 (C-11), 38.7
(C-3), 21.1 (C-18), 20.7 (C-4); UV (MeOH) kmax nm 300 (sh), 291, 229; IR (ATR)
To accomplish the total synthesis, we next investigated the intro-
duction of an amino function to the C-10 position, which is accompa-
nied by the inversion of stereochemistry. The carbonyl group in 2
was removed by alkaline hydrolysis and the resulting secondary
amine in 10 was protected as carbamate or sulfonamide (Scheme
4). All attempts to conduct the nucleophilic substitution of the free
alcohol in 11a or 11b under Mitsunobu conditions or of the C-10-
O-mesyl derivatives prepared from 11a or 11b with sodium azide
gave unsuccessful results. Then, we modified the cyclic sulfamate
strategy developed by White and Garst7 and applied it to the synthe-
sis. Treatment of amino alcohol 10 with 1.2 equiv of sulfuryl chloride
in DCM at ꢁ78 °C in the presence of Et3N for 2 h gave unstable cyclic
sulfamate 12. To this mixture was added 10 equiv of sodium azide in
DMF. The reaction mixture was heated at 60 °C to facilitate nucleo-
philic ring opening with the azide group at C-10. After cooling to
room temperature, the reaction mixture was treated with 10% aque-
ous sulfuric acid to hydrolyze resulting sulfamidic acid intermediate
13 to give azidoamine derivative 14 in 26% overall yield. By careful
treatment and column chromatography, unstable cyclic sulfamate
128 could be isolated in low yield (9–15%) and then transformed to
14 with the same procedure as above-mentioned in 64% yield. Final-
ly, reductive methylation of the secondary amine in 14 and succes-
sive reduction of the azide function with Red-Al furnished the
target molecule in 60% yield (2 steps).
m
max cmꢁ1 3230, 2363, 1715, 1417, 1233, 789; EIMS m/z (%) 412 (100, M++2), 410
(99, M+), 306 (98), 304 (92); HREIMS m/z 410.0629 (M+, calcd for
C21H19N2O279Br, 410.0629).
7. White, G. J.; Garst, M. E. J. Org. Chem. 1991, 56, 3177–3178.
8. Compound 12: ½a D25
ꢀ
+35.2 (c 0.18, CHCl3); 1H NMR (400 MHz, CDCl3) d 7.54 (1H,
d, J = 1.8 Hz, H-5), 7.39 (2H, d, J = 8.0 Hz), 7.31 (2H, d, J = 8.0 Hz), 7.18 (1H, dd,
J = 8.6, 1.8 Hz, H-7), 6.63 (1H, d, J = 8.6 Hz, H-8), 5.45 (1H, br s, N9-H), 4.91 (1H, d,
J = 7.8 Hz, H-1), 4.74 (1H, ddd, J = 10.9, 7.8, 4.6 Hz), 3.64 (2H, overlapped), 3.48
(1H, ddd, J = 12.8, 7.9, 4.7 Hz), 3.16 (1H, dd, J = 13.1, 10.9 Hz), 2.97 (1H, m), 2.74
(1H, m), 2.55 (3H, s, H3-18); 13C NMR (100 MHz, CDCl3) d 136.6, 134.7, 134.3,
133.9, 129.41, 129.36, 128.7, 124.6, 120.8, 112.5, 112.3, 110.0, 67.2, 54.3, 41.6,
37.1, 22.5, 21.1 (C-18); UV (MeOH) kmax nm 299 (sh), 291 (sh), 282, 229; IR (ATR)
m
max cmꢁ1 3384, 2920, 2850, 1715, 1518, 1441, 1317, 1312, 1176; EIMS m/z (%)
448 (32, M++2), 446 (30, M+), 368 (9), 366 (10), 250 (96), 248 (100); HREIMS m/z
446.0300 (M+, calcd for C20H19N2O3S79Br, 446.0299).
9. Synthetic 1: as free base ½a D25
ꢀ
+42.0 (c 0.57, CHCl3); 1H NMR (500 MHz, CDCl3) d
9.42 (1H, br s, N9-H), 7.62 (1H, d, J = 1.7 Hz, H-5), 7.19 (1H, dd, J = 8.5, 1.7 Hz, H-
7), 7.18 (1H, d, J = 8.5 Hz, H-8), 7.13 (2H, d, J = 8.1 Hz, H-14, H-16), 7.12 (2H, d,
J = 8.1 Hz, H-13, H-17), 3.41 (1H, dd, J = 13.7, 2.7 Hz, H-11), 3.38 (1H, br d,
J = 8.9 Hz, H-1), 3.22 (1H, ddd, J = 13.7, 8.5, 5.1 Hz, H-3), 3.10 (2H, overlapped, H-
3, H-10), 2.83 (1H, m, H-4), 2.60 (1H, br d, J = 15.3 Hz, H-4), 2.49 (1H, dd, J = 13.7,
9.5 Hz, H-11), 2.47 (3H, s, H3-19), 2.34 (3H, s, H3-18); 13C NMR (125 MHz, CDCl3)
d 135.93, 135.80, 135.27, 134.20, 129.37, 129.31, 128.92, 123.87 (C-7), 120.63
(C-5), 112.31 (C-8), 112.16, 107.44, 63.46 (C-1), 55.98 (C-10), 47.88 (br, C-3),
41.51 (C-11), 39.81 (br, C-19), 21.01 (C-18), 16.36 (C-4); UV (MeOH) kmax nm
300 (sh), 291, 230; IR (ATR) m
max cmꢁ1 2920, 2844, 1576, 1440, 1305, 1020; EIMS
The structure of synthetic compound 19 (½a D25
ꢀ
free base: +42.0 (c
0.57, CHCl3), TFA salt: +63.4 (c 0.78, CHCl3)) was confirmed by de-
m/z (%) 399 (1, M++2), 397 (1, M+), 265 (97), 263 (100); HREIMS m/z 397.1153
(M+, calcd for C21H24N379Br, 397.1153). As TFA salt ½a D25
ꢀ
+63.4 (c 0.78, CHCl3); 1
H
and 13C NMR data, see Table 1; UV (MeOH) kmax nm 301 (sh), 292, 229; IR (ATR)
mmax cmꢁ1 2925, 2855, 1668, 1444, 1139, 797.
tailed spectroscopic analyses, including 2D-NMR (COSY, HMQC,