A concise and rapid approach to the marine natural product streptochlorin and its analogues

Full text of DOI:10.5012/bkcs.2013.34.2.357

Communications to the Editor
Bull. Korean Chem. Soc. 2013, Vol. 34, No. 2 357
http://dx.doi.org/10.5012/bkcs.2013.34.2.357
A Concise and Rapid Approach to the Marine Natural Product Streptochlorin and its
Analogues
Jong Seok Lee,†,* Junho Shin,†,‡ Hyi-Seung Lee,† Hee Jae Shin,† and Yeon-Ju Lee†
†Marine Natural Products Laboratory, Korea Institute of Ocean Science and Technology, Ansan 426-744, Korea
*E-mail: jslee@kiost.ac
‡Department of Chemistry and Applied Chemistry, Hanyang University, Ansan 426-791, Korea
Received October 6, 2012, Accepted November 1, 2012
Key Words : Marine natural product, Streptochlorin, van Leusen’s oxazole synthesis, Robinson-Gabriel cy-
clodehydration reaction, Regioselective chlorination
The rich chemical diversity of marine life is the inex-
haustible source of drug pipeline.1 Over the last few decades,
great strides have been made in our understanding of marine
natural products largely due to dramatic advances in the fields
of analytical technology, spectroscopy, synthetic chemistry,
and high-throughput screening. Nevertheless, it remains elu-
sive how to secure a supply of rare marine natural products
to ensure further study for their biomedical application. Con-
sequently it was driven to develop innovative methods
including aquaculture, semi-synthesis, and chemical synthesis
to ameliorate the material supply problem. Although the
chemical synthesis of natural products is still far from being
a mature or applied science, it is an important and reliable
tool to attain a target natural product and its analogues for
further systematic investigation.
which was easily prepared from the corresponding indole-3-
carboxaldehyde (not shown) in quantitative yield.7
Subsequently aldehyde 1a was reacted with tosylmethyl-
isocyanide (TosMIC) in the presence of 1.1 eq. of K2CO3 in
MeOH, namely, ‘van Leusen’s oxazole synthesis’, to pro-
vide the desired oxazole compound (not shown) with the
Boc protection group lost during this transformation.8 To
compensate the unwanted loss of a Boc protection group, it
was reintroduced to the N-1 position to give compound 2a in
11% yield (Scheme 1).
Having achieved the synthesis of the key intermediate 2a
on a comfortable scale, effectiveness of this synthetic
sequence was evaluated by applying it to the synthesis of
other analogues. Therefore compounds 2b and 2c which
Streptochlorin is a small molecule that was first isolated
in 1988 from the lipophilic extract of the mycelium of
Streptomyces sp. as a new antibiotic (Figure 1).2
Compared to other natural products, streptochlorin is a
simple molecule. In consequence, this feature can render
easy access to diverse analogues by chemical synthesis.
Other than the innate antibiotic effect of streptochlorin, it has
been revealed that streptochlorin significantly inhibits the
growth of cultured human cell lines,3 suppresses angiogenesis
in vitro by inhibition of NF-κB,4 and induces apoptosis in
human hepatocarcinoma cells through a reactive oxygen
species (ROS)-mediated mitochondrial pathway as well.5 In
addition, a recent study noted that streptochlorin is one of
the nine antibiotic substances which confer a potent anti-
microbial defense for the wasp larvae that parallels the
combination prophylaxis known from human medicine.6
Herein, we wish to present a preliminary account of our
synthetic efforts toward the marine natural product strepto-
chlorin and its analogues.
Scheme 1. van Leusen’s oxazole synthesis reaction of compound 1.
The synthesis of streptochlorin began with aldehyde 1a
Scheme 2. Analogue synthesis via Robinson-Gabriel cyclodehyd-
ration reaction.
Figure 1. Structure of streptochlorin.

358 Bull. Korean Chem. Soc. 2013, Vol. 34, No. 2
Communications to the Editor
have a substituent in the indole core structure were prepared
from compounds 1b and 1c in 15-25% yields over 2 steps
(Scheme 1).
To further broaden the substrate scope, our attention
turned to installing a substituent at the C2'-position of the
oxazole ring. Wipf’s variant of Robinson-Gabriel cyclo-
dehydration reaction was employed as the key reaction,
forming oxazole rings.9
Hence, amide coupling of tryptamine 3 with 1.1 eq. of
benzoic acid (Y' = Ph) in the presence of EDC (1.1 eq.) and
HOBt (1.1 eq.), afforded the corresponding amide 4a in 83%
yield.10 Two-step consecutive reaction of 4a with DDQ (2.3
eq.) in aqueous THF,11,9b followed by Wipf’s variant of
Robinson-Gabriel cyclodehydration smoothly transformed
compound 4a into the desired oxazole compound (not
shown) in 81% overall yield. Then Boc protection of the N-1
position of the indole core provided compound 6a in 87%
yield. Instead of phenyl group at the C2'-position of the
oxazole ring, other substituents including methyl, benzyl,
and isobutyl group were introduced via the previously
described synthetic sequence (Scheme 2).
As a result, compounds 6b-6d were prepared in yields of
11-26% over four steps, starting from the coupling reaction
of tryptamine 3 with corresponding coupling counterparts
such as acetic acid (Y' = Me), phenyl acetic acid (Y' = Bn),
and isovaleric acid (Y' = i-Bu).
The completion of the synthesis was accomplished through
the regioselective chlorination at the oxazole ring of compounds
2 and 6 using N-chlorosuccinimide (NCS) at room temper-
ature, followed by deprotection of the Boc group (Table 1).
For example, streptochlorin 7a was obtained in 50% yield
over two steps (entry 1, Table 1). Other analogues were pre-
pared from the above described sequential reactions. Thus
NCS-mediated chlorination of compounds 2, 6 and the sub-
sequent deprotection of the Boc group at the indole nucleus
(not shown) gave the target compounds (7b-7g) in 47-79%
yields (Table 1 and Table S2).
In summary, we have demonstrated a straightforward and
efficient synthesis of the marine natural product streptochlorin
and its analogues, starting from either 3-formylindole 1 or
tryptamine 3. Notably, our synthesis features a construction
of oxazole ring by van Leusen’s oxazole synthesis and Wipf’s
variant of Robinson-Gabriel cyclodehydration reaction de-
pending upon the substituent of the analogues (compounds 2
and 6). Regioselective halogenation was realized using NCS
to furnish compounds 7a-7g.
In order to construct a streptochlorin-based, focused library
and the screening for additional biological activities, we are
now focusing on the further extension of the scope of the
above described synthetic sequences and the evaluation for
additional biological activities.
Acknowledgments. This work was partially supported by
the KIOST (PE98833, PE98816, PE99161) and the Ministry
of Land, Transport and Maritime Affairs (PM57120),
Republic of Korea.
Supporting Information. Supplementary data associated
with this article can be found, in the online version, at http://
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2
3
aOverall isolated yields.