The formal total synthesis of dragmacidin B, trans-dragmacidin C, and cis- and trans-dihydrohamacanthins A

Article abstract of DOI:10.1016/j.tetlet.2005.02.054

A facile formal total synthesis of dragmacidin B, trans-dragmacidin C, and cis- and trans-dihydrohamacanthins A is presented. Our approach to these bis(indole) alkaloids involves a one-pot, four-step cross-coupling/deprotection sequence where complete hal

Full text of DOI:10.1016/j.tetlet.2005.02.054

Tetrahedron
Letters
Tetrahedron Letters46 (2005) 2423–2426
The formal total synthesis of dragmacidin B, trans-dragmacidin C,
and cis- and trans-dihydrohamacanthins A
Neil K. Garg and Brian M. Stoltz*
The Arnold and Mabel Beckman Laboratory for Chemical Synthesis, Division of Chemistry and Chemical Engineering,
California Institute of Technology, Pasadena, CA 91125, USA
Received 7 February 2005; revised 9 February 2005; accepted 9 February 2005
Abstract—A facile formal total synthesis of dragmacidin B, trans-dragmacidin C, and cis- and trans-dihydrohamacanthinsA ispre-
sented. Our approach to these bis(indole) alkaloids involves a one-pot, four-step cross-coupling/deprotection sequence where com-
plete halogen selectivity is observed. A related approach to access the dihydrohamacanthins is also described.
ꢀ 2005 Elsevier Ltd. All rights reserved.
Over the past several decades, biologically active natural
products isolated from marine organisms have served as
promising leads in the area of drug discovery.1 The
dragmacidin family of bis(indole) alkaloids represents
an emerging class of cytotoxic natural products ob-
tained from deep-water marine sponges.2 In 2002, we
described the total synthesis of dragmacidin D (1,
Scheme 1).3 Our route to 1 featured a series of thermally
controlled, halogen-selective Suzuki cross-couplings
of 2, 3, and 4 to construct the bis(indole)pyrazine
framework of the natural product. Importantly, the
6-bromoindole moiety could be maintained throughout
these reactions. Herein, we report an extension of this
approach to achieve the formal total synthesis of several
related bis(indole) alkaloids.
A retrosynthetic strategy for the preparation of dragma-
cidin B (5) and trans-dragmacidin C (6) isshown below
in Scheme 2. Based on conditions reported by Horne,
each of the bis(indole) alkaloids can be accessed from
unsaturated derivative 7 in a single step.4 Pyrazine 7,
Scheme 1.
Keywords: Suzuki; Heterocycles; Bis(indole); Dragmacidin; Palladium.
*
Corresponding author. Tel.: +1 626 395 6064; fax: +1 626 564
9297; e-mail: stoltz@caltech.edu
Scheme 2.
0040-4039/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.02.054

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N. K. Garg, B. M. Stoltz / Tetrahedron Letters 46 (2005) 2423–2426
in turn, would be obtained from two halogen-selective
Suzuki cross-coupling reactions of boronic acid 8 with
a dihalogenated pyrazine (9). We anticipated that the
boronic acid fragment employed in our synthesis of
dragmacidin D (i.e., 4) could be utilized asa surrogate
for 8 in order to achieve our current goals. However,
the success of our plan would depend highly on the
choice of halogensfor pyrazine 9.
cross-coupling conditions. Following quenching with
KOH/ethanol, the deprotected pyrazine product (7)
wasobtained in 54% yield. 6 Notably, although four bro-
mideswere introduced in the reaction mixture, only the
two pyrazinyl bromideswere reactive in the presence of
Pd(0) at 50 ꢁC. This rapid synthesis of bis(indole) pyr-
azine 7 constitutes a formal total synthesis of both
dragmacidin B (5) and trans-dragmacidin C (6).4,7,8
In order to probe the limitsof our halogen-eslective
Suzuki cross-coupling methodology, we chose to use
known dibromide 105 asthe critical pyrazine fragment
(Scheme 3). In a one-pot, four-step transformation,
an excess of 6-bromoindoloboronic acid (4) was
exposed to dibromopyrazine 10 under our standard
These halogen-selective Suzuki couplings also have great
potential for assembling a related family of natural
products, the dihydrohamacanthins (Scheme 4).9 In this
scenario, the desired alkaloids (11 and 12) would be ob-
tained from their pyrazinone counterparts( 13 and 14),
using the method established by Horne and co-work-
ers.10 Intermediates 13 and 14, in turn, would arise via
cross-coupling chemistry using indole fragments 15
and 16, aswell aspyrazine fragments 17 and 18, in a
manner similar to that describe above. Halogen-selective
cross-couplings will be crucial to prepare all of the halo-
genation patterns present in this series of natural prod-
ucts( 11a–d, 12a–d).
To demonstrate the feasibility of this approach, we pre-
pared one of the dihydrohamacanthin natural products
(11c, Scheme 5). In the first Suzuki coupling, dihalopyr-
azine 3 and bromoindole 4 were treated with Pd(0) at
23 ꢁC to afford coupled indolopyrazine 19.3 Dibromide
19, in turn, was subjected to boronic ester 20 in the pres-
ence of Pd(0) at 50 ꢁC to produce bis(indole)pyrazine 21
in 53% yield. In both cases, complete halogen-selectivity
wasobesrved. Subesquent removal of all protecting
groupsfurnished pyrazinone 22,11 which haspreviously
Scheme 3.
Scheme 4.

N. K. Garg, B. M. Stoltz / Tetrahedron Letters 46 (2005) 2423–2426
2425
Collins, E.; Sim, A. T. R.; Rostas, J. A. P.; Butler, M. S.;
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3. Garg, N. K.; Sarpong, R.; Stoltz, B. M. J. Am. Chem. Soc.
2002, 124, 13179–13184.
4. Miyake, F. Y.; Yakushijin, K.; Horne, D. A. Org. Lett.
2000, 2, 3185–3187.
5. Ellingson, H. J. Am. Chem. Soc. 1949, 71, 2798–
2800.
6. A vial charged with dibromopyrazine 10 (15.1 mg,
0.0635 mmol), boronic acid 4 (75 mg, 0.190 mmol), and
tetrakis(triphenylphosphine)palladium(0) (11 mg, 0.0095
mmol), wasevacuated and purged with N 2. Deoxygenated
benzene (1.2 mL), deoxygenated methanol (250 lL), and
deoxygenated 2 M aq Na2CO3 (105 lL) were then added.
The reaction mixture wasps arged with argon for 3 min.
The vial wasthen esaled, heated to 50 ꢁC for 84 h, and
cooled to 23 ꢁC. EtOH (7 mL) and KOH (500 mg) were
added. The reaction mixture washeated to 50 ꢁC for 20 h,
cooled to 23 ꢁC, then quenched by pouring into 10% (w/v)
aq citric acid (20 mL). EtOAc (30 mL) wasadded, and the
layerswere partitioned. The aqueousphaes wasfurther
extracted with EtOAc (2 · 30 mL). The combined organic
Scheme 5.
layerswere washed with brine (15 mL), dried over MgSO
,
4
and evaporated under reduced pressure. The crude prod-
uct waspurified by flahs chromatography (10:1 CH 2Cl2/
MeOH eluent), then further purified by preparative thin
layer chromatography (2:1 EtOAc/hexaneseluent) to
afford known bis(indole) 74 (16 mg, 54% yield) asa yellow
powder.
been converted to the natural product (11c) in a single
step.10,12
In summary, we have completed the formal total synthe-
sis of dragmacidin B and trans-dragmacidin C. Our
route features a one-pot, four-step halogen-selective
cross-coupling/deprotection sequence to construct the
bis(indole) scaffold of our targets. In addition, we have
applied thismethodology to the formal ysntheissof a
dihydrohamacanthin natural product.
7. Treatment of 7 with NaBH3CN in formic acid leadsto the
formation of dragmacidin B (5), while the analogous
reaction conducted in acetic acid results in production of
trans-dragmacidin C (6)4.
8. Kawasaki, T.; Ohno, K.; Enoki, H.; Umemoto, Y.;
Sakamoto, M. Tetrahedron Lett. 2002, 43, 4245–
4248.
9. Casapullo, A.; Bifulco, G.; Bruno, I.; Riccio, R. J. Nat.
Prod. 2000, 63, 447–451.
10. Miyake, F. Y.; Yakushijin, K.; Horne, D. A. Org. Lett.
2002, 4, 941–943.
Acknowledgements
11. A reaction tube charged with indolopyrazine 19 (125 mg,
0.335 mmol), boronic ester 20 (90 mg, 0.168 mmol), and
tetrakis(triphenylphosphine)palladium(0) (35 mg, 0.030
mmol), wasevacuated and purged with N 2. Deoxy-
genated benzene (3.5 mL), deoxygenated methanol
(690 lL), and deoxygenated 2 M aq Na2CO3 (180 lL)
were then added. The reaction mixture wassparged with
argon for 2 min. The tube wasthen sealed, heated to 50 ꢁC
for 48 h, cooled to 23 ꢁC, and quenched by the addition of
Na2SO4 (200 mg). The reaction mixture wasfiltered over a
plug of SiO2 (CH2Cl2 eluent) and the solvents were
evaporated under reduced pressure. The crude product
waspurified by flahs chromatography (2:1 CH 2Cl2/hex-
aneseluent), to afford bi(sindole) 21 (62 mg, 53% yield),
which was used immediately in the subsequent reaction.
Bis(indole) 21 (30 mg, 0.043 mmol) was dissolved in 1.0 M
TBAF in THF (1 mL, 1 mmol) and heated to 65 ꢁC for
16 h. After cooling to 23 ꢁC, the solvent was removed
under reduced pressure and CH2Cl2 (5 mL) wasadded.
The organic layer waswahs ed with H 2O (2 · 1 mL) and
brine (1 mL), concentrated to dryness, then purified by
flash chromatography (CH2Cl2 eluent) to give the inter-
mediate bis-N-deprotected product (16 mg, 89% yield). A
mixture of thisintermediate (1.5 mg, 0.0034 mmol), LiI
(100 mg, 0.75 mmol), and collidine (1 mL) washeated to
The authorsthank the NIH-NIGMS (R01 GM65961-
01), the NDSEG (predoctoral fellowship to N.K.G.),
AstraZeneca, Boehringer Ingelheim, Johnson & John-
son, Pfizer, Merck, Amgen, Research Corporation,
Roche, and GlaxoSmithKline for generousfunding.
References and notes
1. (a) Aygun, A.; Pindur, U. Curr. Med. Chem. 2003, 10,
¨
1113–1127; (b) Faulkner, D. J. Nat. Prod. Rep. 2002, 19,
1–48; (c) Pindur, U.; Lemster, T. Curr. Med. Chem. 2001,
8, 1681–1698; (d) Yang, C.-G.; Huang, H.; Jiang, B. Curr.
Org. Chem. 2004, 8, 1691–1720.
2. For the isolation of the piperazine-containing dragmaci-
dins, see: (a) Kohmoto, S.; Kashman, Y.; McConnell, O.
J., Jr.; Rinehart, K. L., Jr.; Wright, A.; Koehn, F. J. Org.
Chem. 1988, 53, 3116–3118; (b) Morris, S. A.; Andersen,
R. J. Tetrahedron 1990, 46, 715–720; (c) Fahy, E.; Potts, B.
C. M.; Faulkner, D. J.; Smith, K. J. Nat. Prod. 1991, 54,
564–569. For the isolation of the pyrazinone-containing
dragmacidins, see: (d) Wright, A. E.; Pomponi, S. A.;
Cross, S. S.; McCarthy, P. J. Org. Chem. 1992, 57, 4772–
4775; (e) Capon, R. J.; Rooney, F.; Murray, L. M.;

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N. K. Garg, B. M. Stoltz / Tetrahedron Letters 46 (2005) 2423–2426
under reduced pressure to afford known pyrazone 2210
130 ꢁC for 4 days. After cooling to 23 ꢁC, the reaction
mixture wasdiluted with EtOAc (5 mL), washed with H 2O
(3 · 5 mL), and brine (2 mL), then dried by passage over a
plug of SiO2 (EtOAc eluent). The solvent was removed
(1.0 mg, 69% yield).
12. Reduction of 22 with NaBH3CN leadsto the production
of a 11c.