Synthesis of dragmacidin D via direct C-H couplings

Article abstract of DOI:10.1021/ja209945x

Dragmacidin D, an emerging biologically active marine natural product, has attracted attention as a lead compound for treating Parkinson's and Alzheimer's diseases. Prominent structural features of this compound are the two indole-pyrazinone bonds and the presence of a polar aminoimidazole unit. We have established a concise total synthesis of dragmacidin D using direct C-H coupling reactions. Methodological developments include (i) Pd-catalyzed thiophene-indole C-H/C-I coupling, (ii) Pd-catalyzed indole-pyrazine N-oxide C-H/C-H coupling, and (iii) acid-catalyzed indole-pyrazinone C-H/C-H coupling. These regioselective catalytic C-H couplings enabled us to rapidly assemble simple building blocks to construct the core structure of dragmacidin D in a step-economical fashion.

Full text of DOI:10.1021/ja209945x

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Synthesis of Dragmacidin D via Direct CÀH Couplings
Debashis Mandal, Atsushi D. Yamaguchi, Junichiro Yamaguchi,* and Kenichiro Itami*
Department of Chemistry, Graduate School of Science, Nagoya University, Chikusa, Nagoya 464-8602, Japan
S Supporting Information
b
Scheme 1. Dragmacidin D (1), E, and F, and Our CÀH
ABSTRACT: Dragmacidin D, an emerging biologically
active marine natural product, has attracted attention as a
lead compound for treating Parkinson’s and Alzheimer’s
diseases. Prominent structural features of this compound
are the two indoleÀpyrazinone bonds and the presence of
a polar aminoimidazole unit. We have established a concise
total synthesis of dragmacidin D using direct CÀH coupling
reactions. Methodological developments include (i) Pd-cat-
alyzed thiopheneÀindole CÀH/CÀI coupling, (ii) Pd-cat-
alyzed indoleÀpyrazine N-oxide CÀH/CÀH coupling, and
(iii) acid-catalyzed indoleÀpyrazinone CÀH/CÀH cou-
pling. These regioselective catalytic CÀH couplings enabled
us to rapidly assemble simple building blocks to construct the
core structure of dragmacidin D in a step-economical fashion.
Coupling Strategy for a Concise Total Synthesis of 1
he search for natural products in marine and terrestrial
T
environments has led to the discovery of a number of
biologically active bis(indole) alkaloids, which include the family
of dragmacidins. Dragmacidin D (1: Scheme 1), which has been
found to serve as a potent inhibitor of serineÀthreonine protein
phosphatases,1 has received particular attention as a lead com-
pound for treating Parkinson’s, Alzheimer’s, and Huntington’s
diseases.2,3 In addition to 1, closely related dragmacidin E and F
are also known within this family of natural products.4 These
compounds exhibit prominent structural features such as two
indoleÀpyrazinone bonds (shown in blue in Scheme 1) and an
aminoimidazole moiety. Becase of their unique chemical struc-
tures and promising biological activities, dragmacidins have been
synthetic targets for many chemists.5,6 In 2002, Stoltz and co-
workers reported the first, and only, synthesis of (()-1 using Pd-
catalyzed SuzukiÀMiyaura cross-coupling as a key reaction.5a Here-
in, we report a concise total synthesis of 1 utilizing direct CÀH
couplings as step-economical unit-assembling reactions (Scheme 1).
As exemplified by the work of Stoltz, the cross-coupling reaction is
one of the most reliable methods for carbonÀcarbon bond forma-
tions in total synthesis.7 However, several steps are required as both
of the coupling partners (organometallics and organic halides) must
be prefunctionalized prior to cross-coupling. Meanwhile, direct
CÀH functionalization has garnered significant attention from the
synthetic community as an “ideal” method for carbonÀcarbon and
carbonÀheteroatom bond formation.8,9 Although the development
of new reactions and catalysts continues to evolve at a rapid pace,
successful applications of this method to the synthesis of complex
natural products are still rare.10,11 Thus, as a part of our program
focusing on synthesis-oriented methodology development in cataly-
tic CÀH coupling,12 we set out to rapidly synthesize 1.
on the pyrazinone core is a CÀH/CÀH cross-coupling reaction.
To enhance reactivity and to control regioselectivity in this
coupling, we planned to capitalize on the tautomeric switch
between pyrazinone and pyrazine N-oxide. Whereas pyrazine
N-oxide could be coupled with indole at the most acidic carbon
α to the NÀO moiety using Pd catalysts,13 the installation of indole
on the opposite carbon could be achieved in the pyrazinone form
by way of an oxidative FriedelÀCrafts-type reaction. This sequence
was designed so that the oxidation state of the central pyrazinone
moiety of 1 remains unaltered throughout the synthesis. We also
envisioned that a thiophene moiety with an oxygen substituent at
C3-position could be utilized as a four-carbon unit of the aminoi-
midazole side chain of 1. Thus, an indoleÀthiophene bond dis-
connection was conceived, resulting in the necessity of inventing
a C4-selective coupling reaction onto such a thiophene ring.
We began our study by investigating two sequential CÀH/
CÀH couplings to access the bis(indolyl)pyrazinone unit using
Our initial blueprint for the synthesis of 1 is shown in
Scheme 1. The most direct way to install the two indole moieties
Received: September 21, 2011
Published: November 10, 2011
r
2011 American Chemical Society
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dx.doi.org/10.1021/ja209945x J. Am. Chem. Soc. 2011, 133, 19660–19663
|

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Scheme 2. Construction of Bis(indolyl)pyrazinone Unit via
Scheme 3. C4-Selective Indolation of Thiophene Having
Oxygen Substituent at C3 Position
Two Sequential CÀH/CÀH Couplingsa
a Reagents and conditions: (a) 2 (1.0 equiv), 3 (4.0 equiv), Pd(OAc)2
(10 mol %), AgOAc (3.0 equiv), AcOH (1.0 equiv), 1,4-dioxane, 120 °C,
16 h, 45% (65% of unreacted 3 was recovered); (b) (CF3CO)2O
(4.0 equiv), DMF, 23 °C, 12 h, 60% (5a/5b = 1:1); (c) CF3SO3H
(0.5 equiv), 6 (2.0 equiv), 80 °C, air, 73% from 5a.
conditions,20 employing PdCl2 (10 mol %), P[OCH(CF3)2]3
(20 mol %), and Ag2CO3 (1.0 equiv) in m-xylene at 140 °C
(Scheme 3). Unfortunately, however, these conditions afforded
an equimolar and inseparable mixture of desired C4-arylated
product 10a and undesired C2-arylated product 10b in 22%
combined yield.
model substrates (Scheme 2). As our first step, we recently
reported that a CÀH/CÀH coupling reaction of indoles (or
pyrroles) and azine N-oxides can be catalyzed by the combina-
tion of Pd(OAc)2/2,6-lutidine/AgOAc.13a By modifying our
original conditions, regioselective and reasonably efficient cou-
pling of N-tosylindole (2) and pyrazine N-oxide (3) was
achieved. Thus, the treatment of 2 (1.0 equiv) and 3 (4.0 equiv)
in the presence of Pd(OAc)2 (10 mol %), AgOAc (3.0 equiv),
and AcOH (1.0 equiv) in 1,4-dioxane at 120 °C afforded the target
coupling product 4 in 45% yield (75% yield based on recovered
starting material) with 65% of unreacted 3 recovered.14 Upon
treatment of N-oxide 4 with (CF3CO)2O,15 a formal rearrange-
ment occurred to give two regioisomers of pyrazinones 5a and 5b
in 60% yield (5a/5b = 1:1).16 Subsequently, we found that a
CÀH/CÀH coupling reaction between 5a and 6-bromoindole (6)
could be achieved with CF3SO3H (0.5 equiv) in DMF under air. The
desired coupling product 7 was obtained from 5a in good yield,
whereas the regioisomer 5b17 did not react with 6 at all. The mole-
cular structure of 7 was determined by single-crystal X-ray diffraction
analysis (Scheme 2). The precise mechanism of this CÀH/CÀH
coupling is unclear at present, but we presume that the reaction
proceeds by a FriedelÀCrafts-type addition followed by oxidation.18
Although the regioselectivity problem in the pyrazinone forma-
tion remained unsolved, we nevertheless moved on to the greater
challenge of synthesizing dragmacidin D (1). The synthesis
begins with iodoindole derivative 8, which was easily synthesized
in three steps from commercially available 7-benzyloxyindole.19
At first, the coupling of iodoindole 8 and 3-methoxythiophene
(9) was conducted using our original thiophene arylation
As the C2-position is the most electronically reactive position
in 9 (α to the sulfur atom and ortho to the methoxy group), com-
plete suppression of C2-arylated product is a formidable task. On
the basis of our mechanistic analyses,20b the complexation of
C2ÀC3 and C4ÀC5 π-bonds to palladium species would lead to
the formation of C2- and C4-arylated products, respectively
(Scheme 3). An important ramification of this mechanistic
picture is that the suppression of C2ÀC3 complexation might
be achieved by a large substituent at the C3 position of the thio-
phene ring, thereby increasing the C4-regioselectivity in the
thiophene indolation. However, the replacement of the methoxy
group of 9 with benzoate, pivalate, and phenoxy groups gave
mixtures of regioisomers in low yield. Upon further investigation,
we found that when the 3-triisopropylsilyloxy-substituted thio-
phene 11 (prepared in two steps from commercially available
3-thienylboronic acid)19 was used as a substrate, C4-arylated
product 12a was obtained in 23% yield with virtually complete
regioselectivity. The effective shielding of C2ÀC3 π-bond by
triisopropylsilyl group can be easily understood by the space-
filling models (Scheme 3). Encouraged by this finding, we further
screened the conditions and found that the use of Pd(OAc)2 as a
catalyst and 1,4-dioxane as a solvent increased the yield of 12a to
a 60%, maintaining perfect regioselectivity (Scheme 3). Gratifyingly,
more than 6 g of 12a was prepared under these conditions.21
With a critical hurdle overcome, we subsequently moved forward
to the synthesis of 1 (Scheme 4). Removal of the triisopropylsilyl
group from 12a with Bu4NF/AcOH, followed by treatment with
Raney Ni, allowed the concomitant reduction of thiophene and
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dx.doi.org/10.1021/ja209945x |J. Am. Chem. Soc. 2011, 133, 19660–19663

Journal of the American Chemical Society
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Scheme 4. Synthesis of Dragmacidin D (1)a
a Reagents and conditions: (a) 8 (1.0 equiv), 11 (3.0 equiv), Pd(OAc)2 (10 mol %), P[OCH(CF3)2]3 (20 mol %), Ag2CO3 (1.0 equiv), 1,4-dioxane,
140 °C, 16 h, 60% (86% of unreacted 11 was recovered); (b) Bu4NF (1.1 equiv), AcOH (1.1 equiv), THF, 23 °C, 10 min; then Raney Ni, 23 °C, 30 min,
77%; (c) Mg(OMe)2, MeOH, 23 °C, 30 min, 95%; (d) methoxymethyl chloride (2.0 equiv), NaH (2.0 equiv), DMF/THF = 1:2, 0À23 °C, 15 min, 96%;
(e) 3 (4.0 equiv), Pd(OAc)2 (10 mol %), AgOAc (3.0 equiv), 1,4-dioxane, 120 °C, 16 h, 50% (one recycle); (f) (CF3CO)2O (4.0 equiv),
DMF/THF =1:1, 23 °C, 16 h; (g) 6 (1.2 equiv), CF3SO3H (0.5 equiv), DMF, air, 80 °C, 3 h, 57% (2 steps); (h) i-Pr2NEt (10 equiv), Me3SiOTf
(10 equiv), CH2Cl2, 23 °C, 30 min; then N-bromosuccinimide (10 equiv), 0 °C, 1 h, 73%; (i) Boc-guanidine (3.0 equiv), THF, 55 °C, 16 h; then
CF3CO2H/CH2Cl2, 23 °C, 20 min, 51%.
debenzylation to afford the corresponding methyl ketone in a
one-pot process (77% yield). After the protecting group ex-
change from tosyl to methoxymethyl (MOM), the thus-obtained
bis-MOM-protected indole 13 was then primed for the Pd-
catalyzed CÀH/CÀH coupling reaction with pyrazine N-oxide (3).
Although the yield of this reaction was not superb, a 50% yield was
achieved by recycling 13.19 Despite its moderate yield, the reaction
furnished the coupling product 14 regioselectively. Treatment
of 14 with (CF3CO)2O then furnished pyrazinone 15. Notably,
the ratio of the desired 15 over the undesired regioisomeric
pyrazinone was 5:1. The increase in selectivity compared to that
of the model study might be due to the presence of a sterically
demanding side chain at the 4-position of the indole core,
blocking the C3 attack of trifluoroacetate ion to the pyrazine core
(Scheme 2). An oxidative CÀH/CÀH coupling reaction of
pyrazinone 15 and 6-bromoindole (6) under the influence of
CF3SO3H afforded the corresponding coupling product 16 with
simultaneous removal of the two MOM groups.
route to 1 in hand, asymmetric synthesis of 1 and the feasibility to
transform 1 into dragmacidin E and F5b are currently ongoing in
our laboratory.24 As exemplified by the present work, assembling
simple building blocks with least prefunctionalization by means
of CÀH coupling is what we consider to be an ideal approach to
rapidly increase molecular complexity in organic synthesis.10 In
addition to executing such complex molecule syntheses, we
concomitantly continue our synthesis-oriented catalyst develop-
ment campaign along this line. Such endeavors will surely unlock
opportunities for markedly different connection/disconnection
strategy in the construction of organic molecules.
’ ASSOCIATED CONTENT
S
Supporting Information. Detailed experimental proce-
b
dures, and spectral data for all compounds, including scanned
image of 1H and 13C NMR spectra. This material is available free
of charge via the Internet at http://pubs.acs.org.
During these studies, we found that a solution of bis(indolyl)-
pyrazinone 16 is very sensitive to light, even though 16 is stable in
a solid form. Therefore, the subsequent reactions were con-
ducted in the dark using a small amount of 16. The final tran-
sformation from 16 to dragmacidin D (1) necessitated the
following two steps;22,23 (i) treatment with i-Pr2NEt/Me3SiOTf
and then N-bromosuccinimide, and (ii) aminoimidazole forma-
tion from the resultant α-bromoketone and (Boc)guanidine,
followed by deprotection of the Boc group using CF3CO2H and
purification via reverse-phase preparative liquid chromatography.
The 1H and 13C NMR spectra of the synthetic sample of (()-1
were in complete agreement with those previously reported.1a,5a
As such, the total synthesis of (()-1 has been accomplished in a
total of 15 synthetic operations.
In conclusion, a concise total synthesis of dragmacidin D (1)
has been achieved using three direct CÀH coupling reactions,
Pd-catalyzed regioselective thiopheneÀindole CÀH/CÀI coupling
(8+11), Pd-catalyzed regioselective indoleÀpyrazine N-oxide
CÀH/CÀH coupling (3+13), and acid-catalyzed indoleÀ
pyrazinone CÀH/CÀH coupling (6+15), as step-economical
unit-assembling reactions. With an efficient synthetic platform en
’ AUTHOR INFORMATION
Corresponding Author
junichiro@chem.nagoya-u.ac.jp; itami.kenichiro@a.mbox.nagoya-u.
ac.jp
’ ACKNOWLEDGMENT
We thank Dr. Yasutomo Segawa for assistance in X-ray crystal
structure analysis, Kirika Ueda for experimental assistance and
fruitful discussions. Prof. Cathleen M. Crudden (Queen’s Uni-
versity, Canada) is greatly acknowledged for valuable comments
and discussion. This work was supported by the Funding Program
for Next Generation World-Leading Researchers from JSPS
(220GR049 to K.I.), Grants-in-Aid for Scientific Research (B)
(22750037 to J.Y.) and Grants-in-Aid for Scientific Research on
Innovative Areas “Molecular Activation Directed toward Straight-
forward Synthesis” (23105517 to J.Y.) from MEXT. D.M. thanks
the Nagoya University Global COE program of Elucidation and
Design of Materials and Molecular Functions for fellowship.
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(23) No guanidination product was obtained when we used DMF
instead of THF as a solvent.5a
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references therein.
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dx.doi.org/10.1021/ja209945x |J. Am. Chem. Soc. 2011, 133, 19660–19663