Synthetic studies on dragmacidin D: synthesis of the left-hand fragment

Article abstract of DOI:10.1016/j.tetlet.2008.10.020

We report a synthesis of a left-hand fragment of bis(indole)-class marine alkaloid, dragmacidin D. The synthesis features Suzuki-Miyaura reaction for the coupling of imidazolyl boronic acid and (4-indolyl)vinyl bromide.

Full text of DOI:10.1016/j.tetlet.2008.10.020

Tetrahedron Letters 49 (2008) 7197–7199
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Synthetic studies on dragmacidin D: synthesis of the left-hand fragment
*
Minoru Ikoma, Masato Oikawa , Makoto Sasaki
Laboratory of Biostructural Chemistry, Graduate School of Life Sciences, Tohoku University, Tsutsumidori-Amamiya, Aoba-ku, Sendai 981-8555, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
We report a synthesis of a left-hand fragment of bis(indole)-class marine alkaloid, dragmacidin D. The
synthesis features Suzuki–Miyaura reaction for the coupling of imidazolyl boronic acid and (4-indol-
yl)vinyl bromide.
Received 3 September 2008
Revised 25 September 2008
Accepted 1 October 2008
Available online 8 October 2008
Ó 2008 Elsevier Ltd. All rights reserved.
Dragmacidin D (1) is a bis(indole) alkaloid, isolated first from a
deep-water marine sponge of the genus Spongosorites by Wright
et al. in 1992.1 With other dragmacidins,2,3 1 receives considerable
attention because of the diverse biological spectrum of activities
such as potent inhibition of serine-threonine protein phosphatases
(PP1)3 and brain nitric oxide synthase (bNOS)4 (Fig. 1).
Structurally, dragmacidin D (1) contains two indoles with pyr-
azinone spacer between them. Among dragmacidin family, the
characteristic features of 1 are the presence of guanidine function-
ality and a stereogenic center at a benzylic position.
As for the chemical synthesis of 1, Jiang and co-workers have
reported some synthetic studies,5,6 and Stoltz’s group has accom-
plished the first total synthesis in 2002.7 Prompted by the
intriguing biological activities, we also started our own program
directed toward the total synthesis of 1, aiming for the develop-
ment of a route amenable to the analogue preparation.
1
dragmacidin D ( )
SPh
N
Ts
N
Br
MOM
N
O
2
B(OH)2
4
b
Cl
O
a
Br
c
CO2Et
NHBoc
N
Our synthetic strategy is shown in Scheme 1. Three advanced
intermediates 2–4 have retrosynthetically emerged as key frag-
ments, which would be assembled sequentially. It should be
emphasized here that the intermediates 2–4 may have structural
Ts
OMe
3
Scheme 1. Synthetic plan for dragmacidin D (1) amenable to analogue synthesis.
variants as branching points for diverted synthesis of analogues.8
Coupling reaction of the intermediates 2 and 3 is of significance,
since Suzuki–Miyaura reaction9 between imidazolyl boronic acid
and vinyl bromide (arrow a) was planned to be used for this pur-
pose.10 As shown by arrows b and c, it was envisioned that the cen-
tral pyrazinone ring would be constructed by successive reactions
between indole side chains.11 In this Letter, we report syntheses
and coupling of fragments 2 and 3 toward the suitably protected
left-hand fragment 17.
Synthesis of imidazolyl boronic acid fragment 2 is shown in
Scheme 2. Here, imidazole derivative 5, prepared from imidazole
in two steps (MOM protection and SPh group introduction),12
was used as a starting material. Deprotonation of 5 followed by
the addition of trimethyl borate gave the boronic acid 2 after acidic
work-up. The reaction was highly regioselective,13 giving rise to
the desired 2 as a sole product in 50% yield.
NH2
HN
NH
H
N
N
Br
N
H
O
HO
N
H
1
dragmacidin D ( )
Figure 1. Structure of dragmacidin D (1).
* Corresponding author. Tel./Fax: +81 22 717 8827.
E-mail address: mao@bios.tohoku.ac.jp (M. Oikawa).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.10.020

7198
M. Ikoma et al. / Tetrahedron Letters 49 (2008) 7197–7199
coupling product 12 was found to be obtained only in unsatisfac-
SPh
N
SPh
N
tory yield (30%). The reaction with (4-indolyl)vinyl bromide 13,
which is analogous to 3 but had been prepared independently,18
was found to be sluggish at rt. However, at elevated temperature,
cross-coupling product 14 was obtained in 59% yield after deacet-
ylation (run 2). Since hydrolytic protodeboronation of 2 was ob-
served as an undesired side reaction in runs 1 and 2, addition of
water was supposed to be inconvenient for this coupling. We,
therefore, determined to use non-aqueous conditions for the cou-
pling reaction between 2 and 3 in run 3. Thus, when NaOEt
(150 mol %)19 was used in combination with Pd(PPh3)4 (10 mol %)
and Cs2CO3 (300 mol %) in 1,4-dioxane at 100 °C, we gratifyingly
found that the desired product 15 was obtained in >90% yield from
1H NMR analysis,20 and was cleanly isolated in 74% yield after
reduction of the ethyl ester (compound 16, see Scheme 4). As ex-
pected, no protodeboronation was observed in this reaction.10
a
MOM
N
MOM
N
B(OH)2
5
2
Scheme 2. Synthesis of the imidazolyl boronic acid fragment 2. Reagents and
conditions: (a) n-BuLi, B(OMe)3, THF, À78 °C rt, 1.5 h, then hydrochloric acid (1 M),
50%; MOM = methoxymethyl.
4-Bromo-7-methoxy-1H-indole (7), used for the synthesis of
indole fragment 3, was prepared in 73% by Batcho–Leimgruber in-
dole synthesis14 with slight modification of a reported procedure6
using zinc metal in AcOH, in place of Raney-Ni and hydrazine
(Scheme 3). The amino ester side chain was introduced to 7 by
three-component, Mannich-type Friedel–Crafts reaction in the
presence of MgSO4 to provide 8 in 76% yield.15 Protecting group
manipulation was then carried out on 8 (N-tosylation, MP-depro-
tection, and N-Boc formation) to give 9 in 22% overall yield. For
the preparation of vinyl halide 3, acetylene group was initially
introduced to 9 employing Sonogashira cross-coupling reaction.16
Thus, when 9 was reacted with TIPS-acetylene in the presence of
Pd(PPh3)4 (10 mol %), CuI (5 mol %), and triethylamine at 100 °C,
10 was cleanly obtained in 47% yield. Unreacted 9 was recovered
in 50% yield and reused. TIPS group of 10 was removed by Bu4NF
(88% yield), and treatment with HBrÁAcOH gave the desired indole
fragment 3 in 100% yield, ready for coupling with the imidazolyl
fragment 2.
Table 1
Suzuki–Miyaura cross-coupling reaction of imidazolyl boronic acid
halides
2 with vinyl
X
Ar
SPh
SPh
N
vinyl halide
(1 equiv)
MOM
MOM
N
N
N
Pd(PPh3)4 (10 mol%)
Cs2CO3 (300 mol%)
Suzuki–Miyaura cross-coupling reaction9 of imidazolyl boronic
acid 2 with three vinyl halides, including 3, was next examined
(Table 1). Here, 3 equiv of boronic acid 2 was used. As shown in
run 1, 1-(1-iodovinyl)benzene (11)17 was employed first under
standard conditions (Pd(PPh3)4, aqueous Cs2CO3, THF, rt), and the
B(OH)2
Ar
2
(3 equiv)
Run Vinyl halide
Additive
and
Product
(isolated yield)
reaction
conditions
I
SPh
Br
Br
MOM
Me
a, b
c
N
N
N
1
THF/H2O
(10:1),
rt, 10 h
N
H
NO2
OMe
Br
OMe
11
6
7
12 (30%)
CO2Et
CO2Et
Br
SPh
N
OAc
OAc
Br
d–f
MOM
NH
MP
NH
Boc
OAc
OAc
N
H
N
Ts
2
1,4-
OMe
g
OMe
h, i
8
9
N
dioxane/
H2O (10:1),
95 °C, 4 h
Ts
OMe
13
TIPS
N
Ts
14 (59%)a
OMe
CO2Et
NH
Br
SPh
N
Br
Boc
CO2Et
MOM
N
N
Ts
3
NHBoc
OMe
10
CO2Et
3
NaOEt
(150 mol %),
1,4-
dioxane,
100 °C,
2.5 h
N
NHBoc
Scheme 3. Synthesis of the (4-indolyl)vinyl bromide fragment 3. Reagents and
conditions: (a) HC(OMe)2–NMe2, pyrrolidine, DMF, 110 °C, 4.5 h; (b) Zn, AcOH,
85 °C, 1.5 h, 73% (two steps); (c) 4-methoxyaniline, ethyl glyoxalate, MgSO4, CH2Cl2,
rt, 10 h, 76%; (d) TsCl, triethylamine, 4-dimethylaminopyridine, THF, 65 °C, 24 h,
60%; (e) Ce(NH4)2(NO3)6, CH3CN, À15 °C, 15 min, 62%; (f) Boc2O, CH2Cl2, rt, 2 h, 60%;
(g) (triisopropylsilyl)acetylene, Pd(PPh3)4 10 mol %), CuI (5 mol %), 1,4-dioxane/
triethylamine (1:1), 100 °C, 10 h, 47% (50% recovery); (h) Bu4NF, THF, H2O, 0 °C,
30 min, 88%; (i) HBrÁAcOH, THF, 0 °C, 0.5 h, 100%; Boc = tert-butoxycarbonyl,
MP = 4-methoxyphenyl, TIPS = triisopropylsilyl, Ts = 4-tolylsulfonyl.
Ts
OMe
N
3
Ts
15 (>90%)b
OMe
a
Yield determined after removal of two acetyl groups (K2CO3, MeOH, rt).
After reduction of ethyl ester, the cross-coupling product was cleanly isolated in
74% yield (two steps), see text, Ref. 20, and Scheme 4.
b

M. Ikoma et al. / Tetrahedron Letters 49 (2008) 7197–7199
7199
demonstrated, leading to the suitably protected left-hand fragment
of 1. Coupling of 17 with the second indole fragment 4 toward the
total synthesis is currently underway in our laboratory and will be
reported in due course.
SPh
N
SPh
N
MOM
MOM
N
N
OH
a
CO2Et
NHBoc
NHBoc
References and notes
N
N
1. Wright, A. E.; Pomponi, S. A.; Cross, S. S.; McCarthy, P. J. Org. Chem. 1992, 57,
4772–4775.
Ts
Ts
OMe
OMe
2. Kohmoto, S.; Kashman, Y.; McConnell, O. J.; Rinehart, K. L.; Wright, A.; Koehn, F.
J. Org. Chem. 1988, 53, 3116–3118; Morris, S. A.; Andersen, R. J. Tetrahedron
1990, 46, 715–720; Fahy, E.; Potts, B. C. M.; Faulkner, D. J.; Smith, K. J. Nat. Prod.
1991, 54, 564–569; Cutignano, A.; Bifulco, G.; Bruno, I.; Casapullo, A.; Gomez-
Paloma, L.; Riccio, R. Tetrahedron 2000, 56, 3743–3748.
15
16
SPh
N
3. Capon, R. J.; Rooney, F.; Murray, L. M.; Collins, E.; Sim, A. T. R.; Rostas, J. A. P.;
Butler, M. S.; Carroll, A. R. J. Nat. Prod. 1998, 61, 660–662.
MOM
N
OTs
4. Longley, R. E.; Isbrucker, R. A.; Wright, A. E. U.S. Patent, 6,087,363, 2000.
5. Yang, C. G.; Liu, G.; Jiang, B. J. Org. Chem. 2002, 67, 9392–9396.
6. Yang, C. G.; Wang, J.; Jiang, B. Tetrahedron Lett. 2002, 43, 1063–1066.
7. Garg, N. K.; Sarpong, R.; Stoltz, B. M. J. Am. Chem. Soc. 2002, 124, 13179–13184.
8. For diverted total synthesis of natural products, see: Wilson, R. M.;
Danishefsky, S. J. J. Org. Chem. 2006, 71, 8329–8351.
b
NHBoc
N
Ts
9. For a recent review, see: Doucet, H. Eur. J. Org. Chem. 2008, 2013–2030.
17
OMe
10. Suzuki–Miyaura reaction of
a related imidazolyl boronic acid has been
reported to be unsuccessful in the synthesis of topsentin, see: Kawasaki, I.;
Katsuma, H.; Nakayama, Y.; Yamashita, M.; Ohta, S. Heterocycles 1998, 48,
1887–1901.
Scheme 4. Synthesis of the left-hand fragment of dragmacidin D (1). Reagents and
conditions: (a) LiBH4, THF, 40 °C, 1 h, 74% (two steps from 3); (b) TsCl, triethyl-
amine, 4-dimethylaminopyridine, CH2Cl2, rt, 1 h, 92%.
11. For a related strategy, see: Kawasaki, T.; Enoki, H.; Matsumura, K.; Ohyama, M.;
Inagawa, M.; Sakamoto, M. Org. Lett. 2000, 2, 3027–3029.
12. Tang, C. C.; Davalian, D.; Huang, P.; Breslow, R. J. Am. Chem. Soc. 1978, 100,
3918–3922.
13. Iddon, B.; Lim, B. L. J. Chem. Soc., Perkin Trans. 1 1983, 279–283; Achab, S.;
Guyot, M.; Potier, P. Tetrahedron Lett. 1995, 36, 2615–2618.
14. Batcho, A. D.; Leimgruber, W. Org. Synth. 1985, 63, 214–225.
15. Jiang, B.; Huang, Z. G. Synthesis 2005, 2198–2204.
16. For a recent review, see: Chinchilla, R.; Najera, C. Chem. Rev. 2007, 107, 874–
922.
Finally, the coupling product 15, thus obtained successfully, was
converted into the left-hand domain of dragmacidin D (1). Thus,
the ester 15 was reduced with LiBH4, giving rise to alcohol 16 in
74% yield for two steps (from 3), which in turn was tosylated to
provide the desired left-hand fragment 17 in 92% yield, ready for
coupling with the second indole fragment 4.
In summary, we have established the route to two fragments 2
and 3 as advanced intermediates for the diverted synthesis of
dragmacidin D (1) and analogues. Furthermore, Suzuki–Miyaura
reaction for the coupling of these fragments has been successfully
17. Lee, K.; Wiemer, D. F. Tetrahedron Lett. 1993, 34, 2433–2436.
18. The synthesis of 13 will be published in a full account of this work.
19. Miyaura, N.; Ishiyama, T.; Sasaki, H.; Ishikawa, M.; Satoh, M.; Suzuki, A. J. Am.
Chem. Soc. 1989, 111, 314–321.
20. The yield was evaluated from 1H NMR spectrum, since the coupling product 15
was contaminated with small quantities of reactants, which could not be
completely removed by chromatographic purification.