A concise total synthesis of bruceolline e

Article abstract of DOI:10.1016/j.tetlet.2011.10.023

An efficient synthesis of bruceolline E was completed in three steps from the known ethyl indole-1-carboxylate (9d) in 60% overall yield, via a tandem acylation/Nazarov cyclization with 3,3-dimethyl acrylic acid followed by selenium dioxide oxidation to i

Full text of DOI:10.1016/j.tetlet.2011.10.023

Tetrahedron Letters 52 (2011) 6772–6774
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A concise total synthesis of bruceolline E
Jason A. Jordan a, Gordon W. Gribble b, Jeanese C. Badenock a,
⇑
a Department of Biological and Chemical Sciences, University of the West Indies, Cave Hill, Barbados
b Department of Chemistry, Dartmouth College, Hanover, NH 03755, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient synthesis of bruceolline E was completed in three steps from the known ethyl indole-1-car-
Received 10 August 2011
Revised 4 October 2011
Accepted 6 October 2011
Available online 14 October 2011
boxylate (9d) in 60% overall yield, via a tandem acylation/Nazarov cyclization with 3,3-dimethyl acrylic
acid followed by selenium dioxide oxidation to install the
a
-diketone functionality.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Indole
Bruceolline E
Cyclopenta[b]indolones
Nazarov cyclization
Selenium dioxide
Our continued interest in the synthesis of fused indoles has
emerged into a focus toward the cyclopenta[b]indolone natural
products and their analogues. These compounds, which include
the marine natural products scytonemin (1)1 and nostodione A
(2),2 have received little attention from the synthetic community,
and as such their potential benefits have not been fully explored.3
Our preliminary investigations of this class of indoles have led us
to the first synthesis of the structurally simple bruceolline E (3)
(Fig. 1). Bruceollines A, B,4 C,5 and D–F6 were isolated, in the
1990s, from the root wood of Bruceo mollis Wall. var. tonkinensis
Lecomte by Ohmoto and co-workers.
Unfortunately, in our hands we generated the C-4 cyclization
product 4—identified primarily by the presence of a doublet for
C-2 at d 7.73 in the 1H NMR—under both reaction conditions.16
The recent reports of direct acylation and annulation of pyrrole
under Nazarov conditions17 prompted us to investigate the use of a
similar strategy with indoles. Of particular interest was the reac-
tion of N-tosylpyrrole (7) with 3,3-dimethylacrylic acid in the pres-
ence of trifluoroacetic anhydride to yield the bicyclic ketone 8 in
fair yield (Scheme 2). Previous reports of Nazarov cyclizations18
of indoles have involved the expected divinyl ketone with the acyl
group at both the C-219 and C-320 positions of the indole ring.
While cyclopenta[b]indoles have been synthesized by numer-
ous methods including Fischer indolization,7 the Pauson–Khand
reaction,8 intramolecular Friedel–Crafts reaction,9 palladium-
catalyzed cyclization,10 and rhodium-catalyzed ring closure of
-diazoketones,11 the direct synthesis of cyclopenta[b]indol-1-
OH
a
ones12 has made fewer appearances in the literature.13,14 We envi-
sioned that the synthesis of bruceolline E could be reduced to the
formation of cyclopenta[b]indol-1-one, with the dimethyl func-
tionality intact, followed by oxidation of the remaining methylene
group. Bergman’s earlier exploration of the intramolecular ring clo-
N
O
O
O
sure of
a,b-unsaturated 3-acylindoles resulted in the synthesis of
O
O
O
benzo[cd]indol-3-one 4 by the thermally induced cyclization of
3-(3-methylbut-2-enoyl)indole (5) in an AlCl3–NaCl melt and
cyclopenta[b]indol-1-one 6 when 5 was heated in phosphoric acid
trimethylsilyl ester (PPSE) (Scheme 1).15
N
N
H
N
H
HO
HO
1
2
3
⇑
Corresponding author. Tel.: +1 246 417 4336; fax: +1 246 417 4325.
E-mail address: jeanese.badenock@cavehill.uwi.edu (J.C. Badenock).
Figure 1. Cyclopenta[b]indolone natural products.
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.10.023

J. A. Jordan et al. / Tetrahedron Letters 52 (2011) 6772–6774
6773
Table 2
Accordingly, we treated indole (9a) with 3,3-dimethylacrylic
Selenium dioxide oxidation of protected indolones
acid under identical conditions to those reported by Song. Unfortu-
nately, heating for up to 72 h still returned the starting material
unchanged. Undaunted by this result, we decided to utilize a pro-
tected indole and hence 1-(phenylsulfonyl)indole (9b)21 was
heated for 17 h under the same reaction conditions. Pleasingly,
we obtained the desired cyclopenta[b]indolone (10b),22 albeit in
a meager 14% yield. Increasing the reaction time to 72 h resulted
in a moderate increase in yield to 32%. Further investigation of in-
doles bearing less electron-withdrawing protecting groups (R = Ts
(9c), CO2Et (9d))23 produced higher yields of 10c24 and 10d,25
respectively, even at a reaction time of 17 h while ethyl carbamate
indole (9d) gave the highest yield of the corresponding indolone
10d after 72 h (Table 1).26
O
O
SeO2
O
aq. 1,4-dioxane
N
R
N
R
Δ, 16 h
10
11
Indolone
R
Product Yielda (%)
10b
10c
10d
SO2Ph
Ts
CO2Et
51
75
95
a
Yields are for isolated products after column chromatography.
Satisfied with the generation of the Nazarov adducts we then
sought to create the requisite
a-diketone functionality found in
bruceolline E. While oxidations of this type involving DMSO/I2,27
Me2S2/CuCl2,28 and others,29 have been reported with variable suc-
cess, selenium dioxide oxidation30 of the
a-position of carbonyl
O
O
compounds remains the most facile and consistent method used
to date. Following literature reports, we subjected indolone 10c to
reflux conditions with selenium dioxide in acetic anhydride and
in acetic acid under varied reaction times and were rewarded with
returned starting material or complete decomposition. However,
the initial solvation of the oxidant in 1,4-dioxane at reflux for 1 h
prior to the introduction of indolones 10b–d gave diketones
11b,31 11c,32 and 11d,33 in fair to excellent yields (Table 2).34,35
To our delight, deprotection of 11d was easily accomplished un-
der mild conditions using tetra-n-butylammonium fluoride provid-
TBAF
O
O
N
N
H
THF, Δ, 2 h
EtO C
2
97%
11d
3
Scheme 3. Synthesis of bruceolline E.
ing bruceolline E (3) in 97% yield (Scheme 3).23 Spectral analysis
gave identical results to the reported spectra of natural bruceolline
E and our material was confirmed by X-ray crystallography.36
In summary, we have described a concise synthesis of cyclo-
penta[b]indolone bruceolline E (3), which features a tandem acyl-
ation/Nazarov cyclization, in three steps with an overall yield of
60%.
O
O
O
PPSE, CH Cl
2
AlCl /NaCl
3
2
Δ
53%
Δ
25%
N
H
N
H
N
H
Acknowledgments
4
5
6
Scheme 1. Cyclizations of 3-(3-methylbut-2-enoyl)indole (5).15
Financial support from the UWI and the Government of Barba-
dos is gratefully acknowledged.
References and notes
CO H
2
1. (a) Nägeli, C. Neue Denkschrift. Allg. Schweiz. Nat. Ges. 1849, 10, 1; (b) Nägeli, C.;
Schwenderer, S. Das Mikroskop, 2 ed.; Willhelm Engelmann: Leipzig, 1877; (c)
Garcia-Pichel, F.; Castenholz, R. W. J. Phycol. 1991, 27, 395; (d) Garcia-Pichel, F.;
Sherry, N. D.; Castenholz, R. W. Photochem. Photobiol. 1992, 56, 17; (e) Proteau,
P. J.; Gerwick, W. H.; Garcia-Pichel, F.; Castenholz, R. Experientia 1993, 49, 825.
2. (a) Kobayashi, A.; Kajiyama, S.-I.; Inawaka, K.; Kanzaki, H.; Kawazu, K. Z. Z.
Naturforsch., C: Biosci. 1994, 49, 464; (b) Shim, S. H.; Chlipala, G.; Orjala, J. J.
Microbiol. Biotechnol. 2008, 18, 1655.
N
N
O
TFAA, ClCH CH Cl
2
2
Ts
Ts
54%
7
8
Scheme 2. In situ Nazarov cyclization of pyrrole.17
3. Ratni, H.; Blum-Kaelin, D.; Dehmlow, H.; Hartman, P.; Jablonski, P.; Masciadri,
R.; Maugeais, C.; Patiny-Adam, A.; Panday, N.; Wright, M. Bioorg. Med. Chem.
Lett. 2009, 19, 1654.
Table 1
Tandem acylation/Nazarov cyclization of indoles
4. Ouyang, Y.; Koike, K.; Ohmoto, T. Phytochemistry 1994, 36, 1543.
5. Ouyang, Y.; Mitsunaga, K.; Koike, K.; Ohmoto, T. Phytochemistry 1995, 39, 911.
6. Ouyang, Y.; Koike, K.; Ohmoto, T. Phytochemistry 1994, 37, 575.
7. (a) Bhattacharya, D.; Gammon, D. W.; van Steen, E. Catal. Lett. 1999, 61, 93; (b)
Iwama, T.; Birman, V. B.; Kozmin, S. A.; Rawal, V. H. Org. Lett. 1999, 1, 673; (c)
Abramovitch, R. A.; Bulman, A. Synlett 1992, 795; (d) Rebeiro, G. L.; Khadilkar, B.
M. Synthesis 2001, 370; (e) Thummel, R. P.; Hegde, V. J. Org. Chem. 1989, 54,
1720.
O
CO2H
TFAA, ClCH2CH2Cl
N
N
R
10
Δ
R
9
8. Dominguez, G.; Casarrubios, L.; Rodriguez-Noriega, J.; Perez-Castells, J. Helv.
Chim. Acta 2002, 85, 2856.
Indole
R
Reaction time (h)
Yielda (%)
9. Bunce, R. A.; Nammalwar, B. J. Heterocycl. Chem. 2009, 46, 172.
10. Sorensen, U. S.; Pombo-Villar, E. Helv. Chim. Acta 2004, 87, 82.
11. (a) Franceschetti, L.; Garzon-Aburbeh, A.; Mahmoud, M. R.; Natalini, B.;
Pellicciari, R. Tetrahedron Lett. 1993, 34, 3185; (b) Danheiser, R. L.; Miller, R.
F.; Brisbois, R. G.; Park, S. Z. J. Org. Chem. 1990, 55, 1959; (c) Salim, M.; Capretta,
A. Tetrahedron 2000, 56, 8063.
9a
9b
9b
9c
9c
9d
H
72
17
72
17
72
72
0
14
32
25
42
66
SO2Ph
SO2Ph
Ts
Ts
CO2Et
12. This nomenclature refers to cyclopenta[b]indoles with
a carbonyl group
adjacent to the C-3 position of the indole.
13. Martinez, S. J.; Dalton, L.; Joule, J. A. Tetrahedron 1984, 40, 3339.
a
Yields are for isolated products after column chromatography.

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J. A. Jordan et al. / Tetrahedron Letters 52 (2011) 6772–6774
14. The most common strategy used to access cyclopenta[b]indol-1-ones involves
the selective oxidation of the cyclopenta[b]indoles using DDQ in aq THF as seen
in: Oikawa, Y.; Yonemitsu, O. J. Org. Chem. 1977, 42, 1213.
15. (a) Bergman, J.; Venemalm, L. Tetrahedron 1990, 46, 6061; (b) Bergman, J.;
Venemalm, L.; Gogoll, A. Tetrahedron 1990, 46, 6067.
28. Gregoire, B.; Carre, M. C.; Caubere, P. J. Org. Chem. 1986, 51, 1419.
29. (a) Nagao, Y.; Kaneko, K.; Kawabata, K.; Fujita, E. Tetrahedron Lett. 1978, 19,
5021; (b) Trost, B. M.; Massiot, G. S. J. Am. Chem. Soc. 1977, 99, 4405; (c) Tada,
N.; Shomura, M.; Nakayama, H.; Miura, T.; Itoh, A. Synlett 2010, 1979; (d)
Wendler, N. L.; Taub, D.; Graber, R. P. Tetrahedron 1959, 7, 173.
16. The cyclization of 5 in PPSE was only attempted once and indole 4 was the only
product isolated and characterized.
17. Song, C.; Knight, D. W.; Whatton, M. A. Org. Lett. 2006, 8, 163.
18. For recent reviews, see: (a) Frontier, A. J.; Collison, C. Tetrahedron 2005, 61,
7577; (b) Pellissier, H. Tetrahedron 2005, 61, 6479.
19. (a) Cheng, K.-F.; Chan, K.-P.; Lai, T.-F. J. Chem. Soc., Perkin Trans. 1 1991, 2461;
(b) Bergman, J.; Venemalm, L. Tetrahedron 1992, 48, 759; (c) Ishikura, M.
Heterocycles 1995, 41, 1385; (d) Ishikura, M.; Imaizumi, K.; Katagiri, N.
Heterocycles 2000, 53, 2201; (e) Miki, Y.; Hachiken, H.; Kawazoe, A.; Tsuzaki,
Y.; Yanase, N. Heterocycles 2001, 55, 1291; (f) Miki, Y.; Hachiken, H.; Sugimoto,
Y.; Yanase, N. Heterocycles 1997, 45, 1759.
20. (a) Churruca, F.; Fousteris, M.; Ishikawa, Y.; von Wantoch Rekowski, M.;
Hounsou, C.; Surrey, T.; Giannis, A. Org. Lett. 2010, 12, 2096; (b) Cheng, K.-F.;
Cheung, M.-K. J. Chem. Soc., Perkin Trans. 1 1996, 1213.
30. (a) Stallcup, W. D.; Hawkins, J. E. J. Am. Chem. Soc. 1942, 64, 1807; (b) Corey, E.
J.; Schaefer, J. P. J. Am. Chem. Soc. 1960, 82, 918; (c) Schaefer, J. P. J. Am. Chem.
Soc. 1962, 84, 717; (d) Schaefer, J. P. J. Am. Chem. Soc. 1962, 84, 713; (e) Belsey,
S.; Danks, T. N.; Wagner, G. Synth. Commun. 2006, 36, 1019; (f) Rabjohn, N.
Organic Reactions; John Wiley & Sons, Inc., 2004; (g) Xu, P.-F.; Chen, Y.-S.; Lin,
S.-I.; Lu, T.-J. J. Org. Chem. 2002, 67, 2309.
31. Compound 11b: yellow amorphous solid; 1H NMR (300 MHz, CDCl3) d 8.05–
7.92 (m, 4H), 7.70–7.65 (m, 1H), 7.58–7.39 (m, 4H), 1.76 (s, 6H); 13C NMR
(75 MHz, CDCl3) d 204.2, 177.8, 170.2, 138.7, 137.8, 135.3, 130.0, 129.4, 127.7,
127.2, 126.1, 122.3, 122.0, 114.8, 46.5, 23.5; IR
m (film) 1765, 1711, 1483, 1447,
1227, 1146, 1086, 1022 cmꢀ1; UV kmax (95% MeOH) 238, 255, 276, 335 nm.
HRMS (ESI): m/z calcd for C19H15NO4S: 354.0800 (M++H). Found: 354.0795.
32. Compound 11c: yellow solid; mp 159–160 °C; 1H NMR (300 MHz, CDCl3) d
7.98–7.93 (dd, J0 = 8.1 Hz, J00 = 20.7 Hz, 2H), 7.79–7.77 (d, J = 8.6 Hz, 2H), 7.43–
7.36 (dt, J0 = 8.1 Hz, J00 = 15.2 Hz, 2H), 7.30–7.28 (d, J = 8.1 Hz, 2H), 2.37 (s, 3H),
1.74 (s, 6H); 13C NMR (75 MHz, CDCl3) d 204.3, 177.8, 170.3, 146.9, 138.7,
134.7, 130.6, 127.6, 127.4, 127.3, 126.0, 122.4, 122.1, 114.9, 46.6, 23.5, 21.9; IR
21. Illi, V. O. Synthesis 1979, 136.
22. Compound 10b: yellow oil; 1H NMR (300 MHz, CDCl3) d 7.97–7.94 (m, 1H),
7.91–7.84 (m, 3H), 7.64–7.58 (m, 1H), 7.52–7.46 (m, 2H), 7.34–7.31 (m, 2H),
2.96 (s, 2H), 1.74 (s, 6H); 13C NMR (75 MHz, CDCl3) d 196.5, 173.0, 141.6, 138.9,
134.8, 130.0, 127.4, 127.1, 126.2, 125.4, 122.0, 121.4, 115.1, 60.2, 40.8, 28.3; IR
m
(KBr) 1762, 1708, 1484, 1445, 1229, 1160, 1113, 1036 cmꢀ1; UV kmax (95%
MeOH) 246, 256, 274, 332 nm. Anal. calcd for C20H17NO4S: C, 65.38; H, 4.66; N,
3.81; S, 8.73. Found: C, 65.41; H, 4.69; N, 3.84; S, 8.57.
m
(film) 1628, 1458, 1188, 1140, 1090, 1022 cmꢀ1; UV kmax (95% MeOH) 211,
232, 270 nm. HRMS (ESI): m/z calcd for C19H17NO3S (M++Na): 362.0827. Found:
362.0821.
33. Compound 11d: yellow feathery solid; mp 162–163 °C; 1H NMR (300 MHz,
CDCl3) d 8.18–8.17 (d, J = 8.6 Hz, 1H), 8.05–8.04 (d, J = 7.8 Hz, 1H), 7.50–7.47 (t,
J = 7.9 Hz, 1H), 7.44–7.41 (t, J = 7.3 Hz, 1H), 4.68–4.65 (q, J = 7.2 Hz, 2H), 1.61 (s,
6H), 1.60–1.58 (t, J = 7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3) d 204.9, 178.1,
170.3, 149.8, 138.4, 127.6, 127.3, 125.8, 122.1, 122.0, 116.6, 65.5, 46.0, 22.5,
23. Jacquemard, U.; Bénéteau, V.; Lefoix, M.; Routier, S.; Mérour, J.-Y.; Coudert, G.
Tetrahedron 2004, 60, 10039.
24. Compound 10c: yellow oil; 1H NMR (300 MHz, CDCl3) d 7.97–7.93 (m, 1H),
7.90–7.87 (m, 1H), 7.76–7.73 (d, J = 9.0 Hz, 2H), 7.34–7.26 (m, 4H), 2.94 (s, 2H),
2.37 (s, 3H), 1.74 (s, 6H); 13C NMR (75 MHz, CDCl3) d 196.5, 172.7, 146.0, 141.6,
136.3, 130.5, 127.2, 126.1, 125.7, 125.2, 122.6, 121.5, 115.1, 60.2, 40.8, 28.3,
14.4; IR
m
(KBr) 1752, 1713, 1474, 1424, 1227, 1150, 1111, 1007 cmꢀ1; UV kmax
(95% MeOH) 252, 260, 272, 342 nm. Anal. calcd for C16H15NO4: C, 67.36; H,
5.30; N, 4.91. Found: C, 67.36; H, 5.37; N, 4.83.
22.2; IR
m
(film) 1636, 1458, 1254, 1152, 1089, 1022 cmꢀ1; UV kmax (95%
34. Gribble, G. W.; Barden, T. C.; Johnson, D. A. Tetrahedron 1988, 44, 3195.
35. In all cases, the products were signaled in part to the disappearance of 2H
MeOH) 211, 231, 275 nm. HRMS (ESI): m/z calcd for C20H19NO3S (M++H):
354.1164. Found: 354.1158.
singlet at approximately 2.95 ppm in the 1H NMR while the structures of
a-
25. Compound 10d: yellow oil; 1H NMR (300 MHz, CDCl3)
d
8.13–8.10 (d,
diketones 11c and 11d were also confirmed by X-ray crystallography.
J = 8.2 Hz, 1H), 7.92–7.90 (d, J = 7.6 Hz, 1H), 7.39–7.30 (m, 2H), 4.63–4.56 (q,
J = 7.2 Hz, 2H), 2.92 (s, 2H), 1.63 (s, 6H), 1.58–1.53 (t, J = 7.2 Hz, 3H); 13C NMR
(75 MHz, CDCl3) d 196.8, 173.0, 151.1, 141.6, 126.1, 125.1, 124.9, 122.5, 121.1,
36. Bruceolline E (3) was obtained as a yellow solid (0.42 g, 97%): mp 289–290
(dec) °C. Lit. mp5 289–291 (dec) °C. 1H NMR (600 MHz, DMSO-d6) d 12.9
(bs,1H), 7.85–7.84 (d, J = 8.0 Hz, 1H), 7.62–7.61 (d, J = 8.1 Hz, 1H), 7.42–7.39 (t,
J = 7.4 Hz, 1H), 7.34–7.31 (t, J = 7.7 Hz, 1H), 1.44 (s, 6H). 13C NMR (150 MHz,
DMSO-d6) d 206.6, 175.2, 171.0, 140.0, 125.4, 123.4, 121.5, 121.1, 121.0, 113.6,
117.0, 64.9, 59.9, 40.3, 27.5, 14.9; IR
1016 cmꢀ1; UV kmax (95% MeOH) 210, 232, 270 nm. HRMS (ESI): m/z calcd for
16H17NO3 (M++H): 272.1287. Found: 272.1281.
m (film) 1734, 1453, 1211, 1152, 1082,
C
41.6, 22.9; IR
1013 cmꢀ1
UV kmax (95% MeOH) 256, 264, 272, 342 nm. Anal. calcd for
13H11NO2: C, 73.22; H, 5.20; N 6.57. Found: C, 72.48; H, 5.30; N 6.40.
m (KBr) 3418, 1750, 1665, 1469, 1453, 1210, 1152, 1094,
26. Deprotection—KOH, aq THF,
respectively.
D
—of 10b and 10c generated 6 in 41% and 71%,
;
C
27. Bauer, D. P.; Macomber, R. S. J. Org. Chem. 1975, 40, 1990.