Synthesis of ellipticine: A radical cascade protocol to aryl- and heteroaryl-annulated[b]carbazoles

Article abstract of DOI:10.1021/jo0519920

Imidoyl selanides, synthesized from amides, have been used as radical precursors of imidoyl radicals in cascade reactions. The novel radical cascade has been developed for the simple synthesis of the medicinally important aryl-annulated[b]-carbazoles. The protocol has been exemplified with the high-yielding total synthesis of the anticancer alkaloid ellipticine.

Full text of DOI:10.1021/jo0519920

Synthesis of Ellipticine: A Radical Cascade
Protocol to Aryl- and
Heteroaryl-Annulated[b]carbazoles
Jan M. Pedersen,† W. Russell Bowman,*,†
Mark R. J. Elsegood,† Anthony J. Fletcher,† and
Peter J. Lovell‡
Department of Chemistry, Loughborough University,
Loughborough, Leics. LE11 3TU, Great Britain, and
Psychiatry Medicinal Chemistry III, GlaxoSmithKline,
New Frontiers Science Park North, Harlow,
Essex CM19 5AW, Great Britain
annulated carbazoles have also received considerable
synthetic attention.1,4,6 However, few syntheses have been
high-yielding and regioselective, and few syntheses have
used mild conditions. Surprisingly, no radical methodolo-
gies have been reported, although biradicals have been
used to synthesize benzo[b]carbazoles.7 We report the
results of our studies of a new radical protocol using
imidoyl radical intermediates for the synthesis of aryl-
and heteroaryl-[b]carbazoles and ellipticine 1 which
meets the requirements of good yields, regioselectivity,
and moderate conditions.
w.r.bowman@lboro.ac.uk
Received September 23, 2005
We recently published a novel methodology for the
formation of imidoyl radicals 6 from amides via imidoyl
selanides 5 (Scheme 1)8 which has facilitated our new
synthetic protocol. Cyclizations of imidoyl radicals onto
alkynes have been previously used for radical cascade
reactions. In these synthetic protocols, isocyanides9 and
isothiocyanates10 were used as the imidoyl radical pre-
cursors. We envisaged that fused [b]carbazoles could be
synthesized in just two steps at room temperature from
easily available amides using our putative protocol
(Scheme 2).
Imidoyl selanides, synthesized from amides, have been used
as radical precursors of imidoyl radicals in cascade reactions.
The novel radical cascade has been developed for the simple
synthesis of the medicinally important aryl-annulated[b]-
carbazoles. The protocol has been exemplified with the high-
yielding total synthesis of the anticancer alkaloid ellipticine.
A range of amides 9 were synthesized in high yields
using amide and Sonogashira couplings.11 High yields
could be obtained by carrying out either the amide
(4) (a) Sainsbury, M. Synthesis 1977, 437-448. (b) Alvarez, M.;
Joule, J. A. In The Chemistry of Heterocyclic Compounds; Saxton, J.
E., Ed.; Wiley: Chichester, 1994; pp 261-278. (c) Kansal, V. K.; Potier,
P. Tetrahedron 1986, 42, 2389-2408. (d) Hewlins, M. J. E.; Oliveira-
Campos, A.-M.; Shannon, P. V. R. Synthesis 1984, 289-302.
(5) (a) Ishikura, M.; Hino, A.; Yaginuma, T.; Agata, I.; Katagiri, N.
Tetrahedron 2000, 56, 193-207; a good review of references to earlier
syntheses is included. Recent references include: (b) Mal, D.; Senapati,
B. K.; Pahari, P. Synlett 2005, 994-996. (c) Miki, Y.; Hachiken, H.;
Yanase, N. Org. Biomol. Chem. 2001, 2213-2216.
(6) Recent references include: (a) Tsuchimoto, T.; Matsubayashi,
H.; Kaneko, M.; Shirakawa, E.; Kawakami, Y. Angew. Chem., Int. Ed.
2005, 44, 1336-1340. (b) Martinez-Espero´n, M. F.; Rodr´ıguez, D.;
Castedo, L.; Saa´, C. Org. Lett. 2005, 7, 2213-2216.
(7) (a) Schmittel, M.; Steffen, J.-P.; AÄ ngel, M. AÄ . W.; Engels, B.;
Lennartz, C.; Hanrath, M. Angew. Chem. 1998, 110, 2531-2533;
Angew. Chem., Int. Ed. 1998, 37, 1562-1564. (b) Shi, C.; Wang, K. K.
J. Org. Chem. 1998, 63, 3517-3520. (c) Shi, C.; Zhang, Q.; Wang, K.
K. J. Org. Chem. 1999, 64, 925-932.
(8) (a) Bowman, W. R.; Fletcher, A. J.; Lovell, P. J.; Pedersen, J. M.
Synlett 2004, 1905-1908. (b) See also: Bachi, M. D.; Denenmark, D.
J. Am. Chem. Soc. 1989, 111, 1886-1888. (c) Fujiwara, S.-I.; Matsuya,
T.; Maeda, H.; Shin-Ike, T.; Kambe, N.; Sonoda, N. J. Org. Chem. 2001,
66, 2183-2185.
Aryl- and heteroaryl[b]carbazoles are an important
class of biologically active compounds that include no-
table alkaloids of pharmaceutical interest.1 Ellipticine 1
and its natural analogues 2 and 3, first isolated in 1959,2
have received a vast amount of attention because of their
anticancer properties due to interaction with DNA. The
synthetic analogue elliptinium 4 has been used clinically
as an anticancer drug, including treatment of breast
cancer, myeoblastic leukemia, and solid tumors.1,3a More
recent studies have also indicated activity against HIV.3b
Ellipticine has proved a popular target for synthesis,
and a wide variety of strategies have been reported.1,4,5
Similarly, the structurally related aryl- and heteroaryl-
* Corresponding author. Tel: +44 1509 222569. Fax: +44 1509 223
925.
† Loughborough University.
‡ GlaxoSmithKline.
(9) Leading references: (a) Du, W.; Curran, D. P. Org. Lett. 2003,
5, 1765-1768; Synlett 2003, 1299-1302. (b) Curran, D. P.; Ko, S.-B.;
Josien, H. Angew. Chem., Int. Ed. Engl. 1995, 34, 2683-2684. (c)
Review: Nanni, D. In Radicals in Organic Synthesis; Renaud, P., Sibi,
M. P., Eds.; Wiley-VCH: Weinheim, Germany, 2001; Vol. 2, pp 44-
61.
(1) (a) Gribble, G. W. In The Alkaloids; Brossi, A., Ed.; Academic
Press: San Diego, CA, 1990; pp 239-352. (b) Kno¨lker H.-J.; Reddy,
K. R. Chem. Rev. 2002, 102, 4303-4427.
(2) Goodwin, S.; Smith, A. F.; Horning, E. C. J. Am. Chem. Soc. 1959,
81, 1903-1908.
(3) (a) Stiborova´, M.; Bieler, C. A.; Wiessler, M.; Frei, E. Biochem.
Pharmacol. 2001, 62, 1675-1684. (b) Stiborova´, M.; Breuer, A.;
Aimova´, D.; Stiborova´-Rupertova´, M.; Wiessler, M.; Frei, E. Int. J.
Cancer 2003, 107, 885-890. (c) Mathe´, G.; Triana, K.; Pontiggia, P.;
Blanquet, D.; Hallard, M.; Morette, C. Biomed. Pharmacother. 1998,
52, 391-396.
(10) (a) Benati, L.; Calestani, G.; Leardini, R.; Minozzi, M.; Nanni,
D.; Spagnolo, P.; Strazzari, S.; Zanardi, G. J. Org. Chem. 2003, 68,
3454-3464. (b) Benati, L.; Leardini, R.; Minozzi, M.; Nanni, D.;
Spagnolo, P.; Zanardi, G. J. Org. Chem. 2000, 65, 8669-8674.
(11) Hiroya, K.; Itoh, S.; Sakamoto, T. J. Org. Chem. 2004, 69, 1126-
1136.
10.1021/jo0519920 CCC: $30.25 © 2005 American Chemical Society
Published on Web 11/16/2005
J. Org. Chem. 2005, 70, 10615-10618
10615

TABLE 2. Radical Cascade Reactions To Form
SCHEME 1. Formation of Imidoyl Radicals from
Amides via Imidoyl Selanides
Benzo[b]carbazoles
SCHEME 2. Retrosynthesis for Aryl- and
Heteroaryl-Annulated[b]carbazoles
entry
R1
R2
t (h)
product, yield (%)a
1
2
3
4
5
6
7
8
10a
10b
10c
10d
10e
10f
H
Ph
7b
24
48
48
72
48
6
11a, 33
H
Me
11b, 15
Me
Me
Me
Me
Me
Me
Ph
Me
11c, 55
11d, 54
CH2OAc
SiMe3
H
11e, 40
11f, 0 11g, 18 12f, 33
11g, 18
10g
10h
CO2Me
72
11h, 19 12h, 29
a Isolated yields. b Using AIBN/∆.
SCHEME 3. Proposed Mechanism for the Radical
Cascade Reaction
TABLE 1. Conversion of Amides to Imidoyl Selanides
entry
R1
R2
yield (%)a
1
2
3
4
5
6
7
8
9a
9b
9c
9d
9e
9f
H
Ph
10a
10b
10c
10d
10e
10f
22
41
67
61
71
44
46
57
H
Me
Me
Me
Me
Me
Me
Me
Ph
Me
CH2OAc
SiMe3
H
9g
9h
10g
10h
CO2Me
a Isolated yields.
coupling first, followed by the Sonogashira coupling, or
vice versa, which is useful for building in diversity if
required. The amides were converted to imidoyl selanides
in moderate to good unoptimized yields (Table 1).
Initial cyclization reactions were performed using Bu3-
SnH with AIBN as the initiator in refluxing toluene, but
poor yields were obtained. The best results were obtained
using Et3B and O2 for radical initiation at room temper-
ature. After some optimization, the best conditions were
found to be the addition of Et3B (10 equiv) to deoxygen-
ated solutions of the imidoyl selanides and Bu3SnH,
introduction of an O2 bleed, stirring normally for 24 h,
deoxygenation again, further addition of Et3B (10 equiv),
and stirring until the selanide 10 was consumed. The
second deoxygenation was required to lower the concen-
tration of O2 so that the second portion of Et3B was not
consumed too rapidly. The somewhat unorthodox proce-
dure successfully yielded the required cyclized products
in up to 55% yields (Table 2).
as well as the expected carbazole 11h. (Scheme 3). We
suggest that interception of the electrophilic vinyl radical
intermediate (14, R2 ) CO2Me) by the nucleophilic Bu3-
SnH competes with further cyclization. For the terminal
alkyne 10g (entry 7), the cyclization competes with the
addition of tributyltin radicals (Bu3Sn•) to the alkyne, and
only an 18% yield of the carbazole 11g was obtained.
HPLC analysis of the product mixtures indicated a large
number of very minor impurities but no other significant
products other than those indicated.
We propose the mechanism as shown in Scheme 3 for
the formation of the carbazoles. Although the (Z)-imidoyl
selanides should yield the trans-imidoyl radicals 13,
theoretical and EPR spectroscopic analysis also shows
that the trans-radicals are more stable.12 The imidoyl
radicals 13 undergo selective 5-exo-cyclization onto the
alkynes. Evidence9,10,13 suggests that the vinyl radical 14
undergoes a 5-exo-cyclization to 15 followed by a neophyl
rearrangement to 16, but a 6-endo-cyclization cannot be
Some of the reactions also gave monocyclized products.
For example, for 10f (entry 6) none of the desired
carbazole 11f was detected and the desilylated carbazole
11g and the 3-formylindole 12f were isolated (Scheme
3). Similarly, 10h (entry 8) also yielded the indole 12h
(12) Blum, P. M.; Roberts, B. P. J. Chem. Soc., Perkin Trans. 2 1978,
1313-1319.
10616 J. Org. Chem., Vol. 70, No. 25, 2005

SCHEME 4. Total Synthesis of Ellipticine
FIGURE 1. X-ray crystal structure of the imidoyl selanide
ruled out. Studies indicate that the mechanism of rearo-
matization of π-radical intermediates (e.g., 16) in Bu3-
SnH-mediated reactions is by H-abstraction by the
initiator or a breakdown fragment therefrom.14 In these
reactions, we propose that the hydrogen is abstracted by
ethyl radicals generated from the Et3B initiator. Rapid
tautomerism of the bicyclic products 17 yields the ben-
zocarbazoles 11.
21.
important class of compounds in just two steps from
easily available amides. The protocol was successfully
applied to the total synthesis of the anticancer alkaloid
ellipticine 1. The protocol allows for easy incorporation
of diversity for the synthesis of libraries of analogues.
Further studies are aimed at adapting the protocol for
the synthesis of other biologically active heteroarenes.
The new protocol was applied to a total synthesis of
ellipticine 1 from ethyl 2-(4-pyridyl)acetate in five steps
with an overall yield of 19% (Scheme 4). Trimethylalu-
minum was used to synthesize amide 19. While the last
two steps have good rather than excellent yields, the
overall yield is higher and the number of steps is smaller
than almost all reported syntheses. Our synthesis avoids
high-temperature reactions and indole protection/depro-
tection problems of previous syntheses and also facilitates
the easy application of diversity. The pharmaceutical
industry is reluctant to use Bu3SnH because of its
toxicity. Therefore, we repeated the radical cascade using
the nontoxic tributylgermanium hydride (Bu3GeH).15 The
yield was not optimized, but our preliminary result
showed that similar yields (49% unoptimized yield) could
be obtained using the nontoxic germanium alternative
reagent. Bu3GeH also has the advantages of long shelf
life and clean reaction workups.15
A crystal structure of imidoyl selanide 21 was obtained
showing the Z-configuration of the CdN bond (Figure 1).
Therefore, abstraction of the phenylselanyl group yields
an imidoyl radical with the correct stereochemistry (as
shown in 13, Scheme 3) for cyclization and does not
require isomerization of the radical intermediate. Model-
ing studies showed that the SH2 transition state for the
homolytic cleavage of the carbon-selenium bond (e.g.,
10 to 13, Scheme 3) is sterically hindered, which probably
accounts for the unusually slow reactions observed for
the cascade cyclizations.
Experimental Section
General Procedure for the Conversion of Amides to
Imidoyl Selanides. The amide (3.00 mmol) was dissolved in
dry DCM (50 mL) followed by addition of DMF (6 drops) and
dropwise addition of a 20% phosgene solution in toluene (4.76
mL, 9.00 mmol) at 0 °C. The reaction mixture was stirred
overnight at room temperature and evaporated under reduced
pressure. This residue was immediately dissolved in anhydrous
THF (50 mL) and transferred into a suspension of (PhSe)2 (0.47
g, 1.50 mmol) and K-selectride (1 M solution in THF) (3.30 mL,
3.30 mmol) in THF (20 mL). The reaction mixture was stirred
until homogeneous at room temperature and evaporated under
reduced pressure. The residue was dissolved in DCM, washed
with water, dried, and evaporated under reduced pressure. The
residue was purified by column chromatography on silica gel
with EtOAc in light petroleum (20%) as eluent to yield the
required imidoyl selanide.
Typical Experiment: (Z)-Phenyl N-2-(Prop-1-ynyl)phe-
nyl-2-(pyridin-4-yl)propaneselenoimidate 21. Yellow crys-
tals (48%), mp 90-92 °C. (Found: C, 68.52; H, 4.87; N, 6.70.
C23H20N2Se requires C, 68.48; H, 5.00; N, 6.94%). νmax(film)/cm-1
3052, 2982, 2926, 1630. 742, 692; δH (CDCl3, 400 MHz) 1.51 (3
H, d, J ) 6.9), 2.07 (3 H, s), 3.91 (1 H, q, J ) 6.9), 6.87 (1 H, bd,
J ) 7.9), 7.04-7.06 (2 H, m), 7.10 (1 H, dd, J ) 7.7, 1.3), 7.20-
7.31 (3 H, m), 7.35-7.40 (3 H, m), 7.45 (1 H, dd, J ) 8.1, 1.4,),
8.41-8.43 (2 H, m); δC (CDCl3, 100 MHz) 4.7 (CH3), 21.8 (CH3),
48.3 (CH), 77.3, 90.0 (C), 114.2 (C), 118.8, 123.1, 124.5 (CH),
126.9 (C), 128.4, 129.2, 129.3, 133.0, 137.6, 149.6 (CH), 151.4,
152.0 (C), 167.7 (C); m/z (LSIMS) 405.0866 [(M + H)+, C23H21N2-
Se requires 405.0864], 405 (41%), 249 (85), 108 (100). The
structure of 18 was confirmed by X-ray crystallography.
General Procedure for Radical Cascade Reactions.
Ellipticine 1. (Z)-Phenyl N-2-(prop-1-ynyl)phenyl-2-(pyridin-4-
yl)propane selenoimidate 21 (0.25 g, 0.62 mmol) and tributyltin
hydride (0.36 mL, 1.36 mmol) were dissolved in toluene (20 mL),
and the solution was flushed with argon for 15 min. Triethylbo-
rane (18.6 mL, 18.6 mmol) was added in three portions, once
every 24 h (preceded by deoxygenation). The reaction mixture
was stirred for 72 h, allowing oxygen (in air) to bleed in through
a needle. The solution was evaporated under reduced pressure,
the residue was dissolved in DCM, extracted three times with
dilute HCl, and washed with petrol, and the aqueous phase was
basified using concentrated NaOH. The resulting dispersion was
In conclusion, we have demonstrated a novel radical
cascade protocol for the synthesis of aryl- and heteroaryl-
fused[b]carbazoles, thereby enabling the synthesis of this
(13) (a) Bowman, W. R.; Cloonan, M. O.; Fletcher, A. J.; Stein, T.
Org. Biomol. Chem. 2005, 3, 1460-1467. (b) Bowman, W. R.; Bridge,
C. F.; Brookes, P.; Cloonan, M. O.; Leach, D. C. J. Chem. Soc., Perkin
Trans. 1 2002, 58-68.
(14) Beckwith, A. L. J.; Bowry, V. W.; Bowman, W. R.; Mann, E.;
Parr, J.; Storey, J. M. D. Angew. Chem., Intl. Ed. 2004, 43, 95-98.
(15) Bowman, W. R.; Krintel, S. L.; Schilling, M. B. Org. Biomol.
Chem. 2004, 585-592; Synlett 2004, 1215-1218.
J. Org. Chem, Vol. 70, No. 25, 2005 10617

extracted five times with DCM, and the organic phase was
evaporated under reduced pressure. The resulting residue was
purified using column chromatography using silica gel as
absorbent and THF/EtOAc (1:1) as eluent to give ellipticine 1
(93 mg, 61%) as yellow crystals, mp 310-314 °C (Lit.,16 311-
315 °C) IR 3422, 3153, 3090, 2925, 2870, 2363, 2341, 1600, 1463,
1407, 1383, 1262, 1242, 1027, 811, 743, 604 cm-1; 1H NMR (400
MHz, d6-DMSO) δ 11.42 (1 H, s), 9.70 (1 H, s), 8.43 (1 H, d, J )
6.0 Hz), 8.39 (1 H, d, J ) 8.0 Hz), 7.92 (1 H, d, J ) 6.0 Hz),
7.51-7.59 (2 H, m), 7.27 (1 H, ddd, J ) 8.0, 6.9, 1.4 Hz), 3.26 (3
H, s), 2.79 (3 H, s); 13C NMR (100 MHz, DMSO) δ 149.6, 142.6,
140.5, 140.4, 132.4, 128.0, 127.1, 123.8, 123.3, 123.1, 121.9, 119.1,
115.9, 110.7, 108.0, 14.3, 11.9. The data were identical to those
reported in the literature.16
Acknowledgment. We thank GlaxoSmithKline and
Loughborough University for a postgraduate student-
ship (J.M.P.), EPSRC for a research associate (A.J.F.),
and GlaxoSmithKline for generous support.
Supporting Information Available: Experimental pro-
cedures and analytical data for all compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
(16) Saulnier, M. G.; Gribble, G. W. J. Org. Chem. 1982, 47, 2810-
2812.
JO0519920
10618 J. Org. Chem., Vol. 70, No. 25, 2005