Total synthesis of a marine alkaloid from the tunicate Dendrodoa grossularia

Article abstract of DOI:10.1021/ol801375k

(Chemical Equation Presented) A short synthesis of an indole marine alkaloid (1) from the tunicate Dendrodoa grossularla is described. The key step in the synthesis involves a novel twist on an underutilized oxazole rearrangement, which produces the quaternary stereocenter in the molecule.

Full text of DOI:10.1021/ol801375k

ORGANIC
LETTERS
2008
Vol. 10, No. 17
3737-3739
Total Synthesis of a Marine Alkaloid
from the Tunicate Dendrodoa
grossularia
Christopher D. Hupp and Jetze J. Tepe*
Department of Chemistry, Michigan State UniVersity, East Lansing, Michigan 48824
tepe@chemistry.msu.edu
Received June 18, 2008
ABSTRACT
A short synthesis of an indole marine alkaloid (1) from the tunicate Dendrodoa grossularia is described. The key step in the synthesis
involves a novel twist on an underutilized oxazole rearrangement, which produces the quaternary stereocenter in the molecule.
Marine organisms have been a large source of synthetically
interesting and pharmacologically important natural prod-
ucts.1-4 Furthermore, the synthetic challenge of many natural
products often attracts the curious organic chemist. Even
some of the smaller marine natural products hold some
intriguing structural scaffolds as well as hidden utility.5
The tunicate Dendrodoa grossularia, a red marine organ-
ism that grows along the coasts of Brittany and in the Baltic
and North Seas, contains small heterocyclic alkaloids with
unique scaffolds.6-11 Biological studies on indole alkaloids
from this tunicate displayed moderate cytotoxicity toward
the L1210 leukemia cell line (4-10 µg/mL) and up to 10
ng/mL for the MCF7 and WiDr cell lines.11,12 The latest
compound (1) to come from this tunicate was isolated in
1998 and to the best of our knowledge has not been
synthesized to date.13
As a continuation of our laboratory’s focus on the
development of new heterocyclic methodologies for the
syntheses of pharmacologically significant scaffolds,14 we
report the racemic total synthesis of indole alkaloid 1.15
The key step in forming the quaternary stereocenter in the
alkaloid utilizes a novel oxazole rearrangement16,17 producing
an oxazolone intermediate, ultimately leading to a quaternary
hydantoin.
(1) Barsby, T. Trends Biotechnol. 2006, 24, 1–3
(2) Gul, W.; Hamann, M. T. Life Sci. 2005, 78, 442–453
(3) Jha, R. K.; Zi-rong, X. Mar. Drugs 2004, 2, 123–146
(4) Simmons, T. L.; Andrianasolo, E.; McPhail, K.; Flatt, P.; Gerwick,
W. H. Mol. Cancer Ther. 2005, 4, 333–342
(5) Baker, D. D.; Alvi, K. A. Curr. Opin. Biotechnol. 2004, 15, 576–
583.
(6) Guyot, M.; Meyer, M. Tetrahedron Lett. 1986, 27, 2621–2
(7) Heitz, S.; Durgeat, M.; Guyot, M.; Brassy, C.; Bachet, B. Tetrahedron
Lett. 1980, 21, 1457–8
(8) Moquin, C.; Guyot, M. Tetrahedron Lett. 1984, 25, 5047–8
(9) Loukaci, A.; Guyot, M. Magn. Reson. Chem. 1996, 34, 143–5
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(12) Helbecque, N.; Moquin, C.; Bernier, J. L.; Morel, E.; Guyot, M.;
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Henichart, J. P. Cancer Biochem. Biophys. 1987, 9, 271–9.
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(13) Loukaci, A.; Guyot, M.; Chiaroni, A.; Riche, C. J. Nat. Prod. 1998,
61, 519–522.
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(14) Fisk, J. S.; Mosey, R. A.; Tepe, J. J. Chem. Soc. ReV. 2007, 36,
1432–1440.
(15) The natural product (1) was derivatized and crystallized out as a
racemic mixture as described in ref 13.
.
(16) Engel, N.; Kubel, B.; Steglich, W. Angew. Chem., Int. Ed. 1977,
.
16, 394–396.
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(17) Kubel, B.; Hofle, G.; Steglich, W. Angew. Chem., Int. Ed. 1975,
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(18) (a) Kharasch, M. S.; Kane, S. S.; Brown, H. C. J. Am. Chem. Soc.
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2055–2060
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Soc. 2002, 124, 13179–13184.
10.1021/ol801375k CCC: $40.75
Published on Web 08/05/2008
2008 American Chemical Society

Reduction of oxime 4 using zinc and acetic acid led to
amine 5 (Scheme 3), which was treated with commercially
Scheme 1. Retrosynthesis of Indole Alkaloid (1)
Scheme 3. Synthesis of Akaloid (1): Formation of Hydantoin (7)
Scheme 1 illustrates our retrosynthetic strategy for the total
synthesis of indole alkaloid 1. It was envisioned that the
imidazolone moiety of the natural product could be accessed
from the hydantoin intermediate 7. Through an underutilized
oxazole rearrangement, first described by Steglich and co-
workers,16,17 hydantoin 7 was thought to be formed from
thiourea 6. In turn, thiourea 6 could be obtained from keto
allyl ester 2 after a few functional group manipulations.
available ethoxy carbonyl isothiocyanate to yield thiourea
6. Subsequent treatment of thiourea 6 with EDCI followed
by sodium methoxide yielded hydantoin 7 in 71% yield,
resulting from an oxazole rearrangement.
The proposed mechanism for the formation of hydantoin
7 is highlighted in Scheme 4. Initially, the thiourea moiety
Scheme 2. Synthesis of Alkaloid (1): Formation of Oxime (4)
Scheme 4. Proposed Mechanism for Novel Rearrangement
Keto allyl ester 2 (Scheme 2) was synthesized through an
esterification of 2-(1H-indol-3-yl)-2-oxoacetyl chloride with
2-methyl-2-propen-1-ol, which is the product of a known
reaction between indole and oxalyl chloride.18 Subsequent
protection of the indolic nitrogen with p-toluene sulfonyl
chloride gave keto ester 3, which when treated with hy-
droxylamine and pyridine in dioxane produced oxime 4 in
96% yield as a mixture of E and Z isomers.
was likely converted into a carbodiimide intermediate using
EDCI.19-21 Subsequently, a 5-exo-dig cyclization occurred
(22) Herdeis, C.; Gebhard, R. Heterocycles 1986, 24, 1019–1024.
(23) Scheibye, S.; Pedersen, B. S.; Lawesson, S. O. Bull. Soc. Chim.
Belg. 1978, 87, 229–238.
(19) Martin, N. I.; Woodward, J. J.; Marletta, M. A. Org. Lett. 2006, 8,
4035–4038.
(20) Katritzky, A. R.; Rogovoy, B. V. ARKIVOC 2005, 4, 49–87.
(21) Evindar, G.; Batey, R. A. Org. Lett. 2003, 5, 1201–1204.
(24) Pappo, R.; Allen, D. S., Jr.; Lemieux, R. U.; Johnson, W. S. J.
Org. Chem. 1956, 21, 478–9.
3738
Org. Lett., Vol. 10, No. 17, 2008

between the carbonyl oxygen of the ester and the carbodi-
imide to form a transient oxazole intermediate. Through a
Claisen-type rearrangement, the oxazole was transformed into
a quaternary oxazolone intermediate. Upon completion of the
rearrangement, as indicated by TLC, a solution of sodium
methoxide in methanol was added to complete the transforma-
tion from the oxazolone to hydantoin 7.22
The final steps for the total synthesis of 1 (Scheme 6)
began with the deprotection of the indole nitrogen using
potassium ethoxide and ethanol under refluxing conditions
to produce imidazolone 11 in 86 % yield. Finally, oxidation
of the terminal alkene was achieved through a two-step/
one-pot modified Johnson-Lemieux24 reaction to give indole
alkaloid 1,25 whose crystal structure is shown in Figure 1.
Treatment of hydantoin 7 with Lawesson’s reagent23
produced thiohydantoin 8 (Scheme 5), which was selectively
Scheme 5
.
Synthesis of Alkaloid (1): Formation of Imidazolone
(10)
Figure 1. X-ray crystal structure of indole alkaloid 1.
In short, we reported a concise total synthesis of a new
indole alkaloid from the tunicate Dendrodoa grossularia. The
key step utilized a new twist on a rarely used oxazole
rearrangement to afford the quaternary stereocenter in the
molecule.
methylated at the thiocarbonyl using methyl iodide, DMAP,
and diisopropylethylamine to furnish imidazolone 9. After
heating imidazolone 9 with dimethylamine in a sealed tube,
imidazolone 10 was produced in 94% yield.
Acknowledgment. We gratefully acknowledge the finan-
cial support provided by the American Cancer Society (RSG
CDD-106972) and Michigan State University. Additional
thanks go to Dr. Miche`le Guyot from the Museum National
D’Histoire Naturelle for providing original spectra on the
natural product, Dr. Richard J. Staples from MSU for X-Ray
analysis, Dr. Rui Huang from MSU for elemental analyses,
and Mr. Rahman Saleem from MSU for high resolution mass
spectrometry.
Scheme 6. Synthesis of Indole Alkaloid (1)
Supporting Information Available: Experimental pro-
cedures and characterizations for all new compounds (1-11).
This material is available free of charge via the Internet at
http://pubs.acs.org.
OL801375K
(25) The final product is spectroscopically identical to the isolated natural
product. See Supporting Information for a tabulated comparison of spectra.
Org. Lett., Vol. 10, No. 17, 2008
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