Total synthesis of the marine alkaloid mansouramycin D

Article abstract of DOI:10.1021/ol4032396

Mansouramycin D, a cytotoxic alkaloid was isolated from a marine Streptomyces sp. in 2009. The first, simple, and concise route to the total synthesis of Mansouramycin D is reported. The core structure of the isoquinoline ring has been constructed from iminoannulation of 2-alkynylbenzaldehyde followed by oxidation/deprotection and oxidative amination via a three-step sequence from easily accessible starting materials.

Full text of DOI:10.1021/ol4032396

Letter
pubs.acs.org/OrgLett
Total Synthesis of the Marine Alkaloid Mansouramycin D
K. S. Prakash and Rajagopal Nagarajan*
School of Chemistry, University of Hyderabad, Hyderabad-500 046, India
S
* Supporting Information
ABSTRACT: Mansouramycin D, a cytotoxic alkaloid was isolated from a marine Streptomyces sp. in 2009. The first, simple, and
concise route to the total synthesis of Mansouramycin D is reported. The core structure of the isoquinoline ring has been
constructed from iminoannulation of 2-alkynylbenzaldehyde followed by oxidation/deprotection and oxidative amination via a
three-step sequence from easily accessible starting materials.
ansouramycin D (1), an isoquinoline quinone, was
isolated from the ethyl acetate extract of marine
cyclization.3 Synthesis of isoquinoline heterocycles has received
much attention due to the presence of the isoquinoline skeleton
in numerous alkaloids.5 Synthesis of isoquinoline systems by
various methods is known. The classical methods are, mainly,
the Bischler−Napieralski reaction,6 Pomeranz−Fritsch reac-
tion,7 Pictet−Spengler reaction, and Pictet−Games reaction.8
Numerous elegant protocols for isoquinoline synthesis have
been reported to date.9
M
Streptomyces sp. isolate Mei37 by Laatsch and co-workers in
2009 (Figure 1).1 The structure of compound 1 has been
Herein, we report the first successful and concise total
synthesis of Mansouramycin D (1) involving intramolecular
iminoannulation as a key ring closure step, which resulted in an
overall yield of 54.5% to 60.9%. The retrosynthetic
disconnection for the synthesis of 1 is depicted in Scheme 1.
Scheme 1. Retrosynthetic Approach to Mansouramycin D
(1)
Figure 1. Structure of Mansouramycin A−D.
confirmed as 3-(1H-indol-3-yl)-7-methylaminoisoquinoline-
5,8-dione by NMR and mass spectrometry. Marine isoquinoline
alkaloids have received substantial attention from the scientific
community due to their rich biological activities.1−4 Mansour-
amycin A−D (1−4) showed cytotoxicity against cancer cell
lines and strong antimicrobial activity. Mansouramycin A−D
(1−4) showed cytotoxicity against 36 cancer cell lines and were
found to have significant activity against nonsmall cell lung
cancer, breast cancer, melanoma, and prostate cancer cells.
Specifically, high cytotoxicity was shown against many human
cancer cell lines with an IC50 value up to 0.089 μM for lung
cancer.1
Considering the biological importance of Mansouramycin D
and the lack of synthetic methods to date, we focused our
interest on its synthesis. There was an unsuccessful attempt to
synthesize Mansouramycin D (1) involving Pictet−Spengler
Received: November 10, 2013
Published: December 9, 2013
© 2013 American Chemical Society
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Organic Letters
Letter
Scheme 2. Total Synthesis of Mansouramycin D (1)
The core structure of 1 contains an isoquinoline moiety
substituted with the indole at the third position. Among the
reported synthetic methods, iminoannulation (key step)
followed by subsequent deprotection, oxidation, and oxidative
amination would be the simplest and most concise route to the
synthesis of this valuable marine alkaloid, Mansouramycin D
(1).
At the outset, we focused on Sonogashira coupling of 2-
bromo-3,6-dihydroxybenzaldehyde and Boc protected 3-
ethynyl-1H-indole (11).11 Unfortunately, the expected product
was not formed. This might be due to the presence of free
hydroxy groups in 2-bromo-3,6-dihydroxybenzaldehyde. Then,
both hydroxyl groups of 2-bromo-3,6-dihydroxybenzaldehyde
were protected by a MOM group using MOM chloride and
diisopropylethylamine (DIPEA) as a base.10 To our advantage
after this modification, the Sonogashira reaction with MOM
ether 10 of 2-bromo-3,6-dihydroxybenzaldehyde10 and N-Boc
protected 3-ethynyl-1H-indole (11)11 using PdCl2 (5 mol %),
PPh3 (10 mol %), CuI (10 mol %), and triethylamine as solvent
proceeded smoothly at 60 °C and yielded 92% of coupled
product 12 as a brown oil (Scheme 2). If the reaction was
carried out at more than 60 °C, the yield of the product was
decreased.
The isoquinoline ring closure was accomplished from
product 12 via intramolecular iminoannulation. Iminoannula-
tion can be performed in two ways: (i) Larock annulation with
tBuNH2 and (ii) with aqueous ammonia. In method A (Scheme
2), iminoalkyne 13 was synthesized by the treatment of
alkynylaldehyde 12 at room temperature with excess tert-
butylamine for 6 h. After evaporation of tert-butylamine, the
obtained crude imine 13 was then dissolved in DMF and 10
mol % copper iodide was added as a catalyst. To our delight,
the expected product 14 was achieved in 85% yield. In method
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Organic Letters
Letter
2009. URL:http://ediss.uni-goettingen.de/handle/11858/00-1735-
0000-0006-AD4C-2?locale-attribute=en.
B, isoquinoline core 15 was synthesized via ammonia mediated
ring closure of 12 with treatment of excess aqueous ammonia
and 1.5 equiv of potassium carbonate. A new polar spot was
observed by TLC. Surprisingly, during this reaction, the Boc
group was removed and the product 15 was obtained in 76%
yield.
(4) (a) Milanowski, D. J.; Gustafson, K. R.; Kelley, J. A.; McMahon, J.
B. J. Nat. Prod. 2004, 67, 70. (b) Alagille, D.; Baldwina, R. M.;
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2011, 28, 196.
At this juncture, having the core structure 14 and 15 in hand,
we further performed functional group modification, consisting
of removal of MOM or Boc using a THF, H2O, and cond HCl
(6:4:1) mixture heating at 50 °C. It is also to be noted that, for
15 having the MOM groups and in the case of 14 having both
MOM and Boc groups, the groups are removed under the same
conditions. To our surprise, the product 16 underwent
oxidation in situ without the use of any oxidizing agents and
with the complete conversion of the starting material (TLC). It
furnished the oxidized product 5, and we utilized the
compound without further purification. Finally, the amino-
methylation was accomplished using an ethanolic solution of
methylamine (33 wt %) in 1,2-dimethoxyethane at 0 °C. It is
noteworthy to mention that the reaction proceeded in a
regioselective manner and gave only the final targeted molecule
in 78% yield.
Thus, we have completed the first total synthesis of
Mansouramycin D in three steps with an overall yield of
54.5% to 60.9%. Spectral data of 1 are fully consistent with
those of Mansouramycin D isolated from the natural source.1
So the structure of 1 is rigorously verified by the present total
synthesis.
In summary, we accomplished a concise, first total synthesis
of Mansouramycin D in an overall yield of 54.5% to 60.9%. The
core isoquinoline ring has been constructed by iminoannulation
in two different methods. It will likely find applications for
other related alkaloids and provide an inroad to further
biological surveys.
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ASSOCIATED CONTENT
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Lett. 2013, 15, 3306. (b) Trost, B. M.; Dyker, G.; Kulawiec, R. J. J. Am.
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■
S
* Supporting Information
Details of experimental procedures, copies of 1H, 13C NMR and
HRMS spectra for compounds 12, 14, 15, and 1. This material
is available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: rnsc@uohyd.ernet.in; naga_indole@yahoo.co.in.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors thank DST, New Delhi for financial assistance
(Project Number: SR/S1/OC-70/2008). K.S.P. thanks UGC,
India for a Senior Research Fellowship.
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