Efficient synthesis of ningalin C

Article abstract of DOI:10.1021/ol026074s

(Matrix presented) A concise and efficient synthesis of the permethyl derivative of the marine alkaloid ningalin C (2) has been accomplished. The key step involves the formation of a pyrrolinone fron an aminoquinone in one pot. An efficient route for the

Full text of DOI:10.1021/ol026074s

ORGANIC
LETTERS
2002
Vol. 4, No. 16
2633-2635
Efficient Synthesis of Ningalin C
Anucha Namsa-aid† and Somsak Ruchirawat*
,†,‡,§
Department of Chemistry, Faculty of Science, Mahidol UniVersity, Rama 6 Road,
Bangkok 10400, Thailand, Laboratory of Medicinal Chemistry, Chulabhorn Research
Institute, VipaVadee Rangsit Highway, Bangkok 10210, Thailand, and Program on
Research and DeVelopment of Synthetic Drugs, Institute of Science and Technology for
Research and DeVelopment, Mahidol UniVersity, Salaya Campus, Thailand.
somsak@tubtim.cri.or.th
Received April 24, 2002 (Revised Manuscript Received July 10, 2002)
ABSTRACT
A concise and efficient synthesis of the permethyl derivative of the marine alkaloid ningalin C (2) has been accomplished. The key step
involves the formation of a pyrrolinone from an aminoquinone in one pot. An efficient route for the synthesis of the key aminoquinone has
also been developed.
In 1997, Kang and Fenical1 reported the isolation of four
novel aromatic alkaloids, ningalin A-D (Figure 1), from an
northwest cape of western Australia. These ningalin deriva-
tives, as well as lukianols, polycitrins, and lamellarins,
appeared to be derived from the condensation of 3,4-
dihydroxyphenylalanine (DOPA) in the biosynthetic path-
way.3
The first total syntheses of ningalin A and B were re-
ported by Boger et al. in 1999, utilizing the application of
the versatile heteroaromatic azadiene Diels-Alder re-
action.4 Steglich has recently reported an efficient synthesis
of ningalin C using an intramolecular Friedel-Crafts acyl-
ation.5
In this paper, we report a new and efficient method for
the synthesis of ningalin C as a continuation of our synthetic
(1) Kang, H.; Fenical, W. J. Org. Chem. 1997, 62, 3254.
(2) (a) Lindquist, N.; Fenical, W.; Van Duyne, G. D.; Clady, J. J. Org.
Chem. 1988, 53, 4570. (b) Carrol, A. R.; Bowden, B. F.; Coll, J. C. Aust.
J. Chem. 1993, 46, 489. (c) Urban, S.; Hobbs, L.; Hooper, J. N. A.; Capon,
R. J. Aust. J. Chem. 1996, 49, 711. (d) Urban, S.; Capon, R. J. Aust. J.
Chem. 1995, 48, 1491.
(3) For a review see: Bowden, B. F. In Studies in Natural Products
Chemistry; Rahman, A., Ed.; Elsevier Science: New York, 2000; Vol. 23,
pp 233-283.
Figure 1. Structures of ningalin A, B, C, and D.
unidentified ascidian of the genus Didemnum2 collected in
ascidia-rich habitats near Ningaloo Reef region at the
(4) (a) Boger, D. L.; Boyce, C. W.; Labroli, M. A.; Sehon, C. A.; Jin,
Q. J. Am. Chem. Soc. 1999, 121, 54. (b) Boger, D. L.; Soenen, D. R.; Boyce,
C. W.; Hedrick, M. P., Jin, Q. J. Org. Chem. 2000, 65, 2479.
(5) Peschko, C.; Steglich, W. Tetrahedron Lett. 2000, 41, 9477.
† Mahidol University.
‡ Chulabhorn Research Institute.
§ Mahidol University, Salaya Campus.
10.1021/ol026074s CCC: $22.00 © 2002 American Chemical Society
Published on Web 07/18/2002

program on lamellarins and other bioactive pyrrole alkaloids.6
Our retrosynthetic analysis of this compound is outlined in
Scheme 1.
Scheme 2a
Scheme 1
a Reagents and conditions: (a) Pd(PPh3)4, NaHCO3, DMF, reflux,
24 h, 65%; (b) 2 equiv of LDA, THF, -78 °C, 2 h, then rt 2 h,
76%; (c) H2O2, I2, H2SO4, MeOH, 62%; (d) homoveratrylamine
(9), EtOH, rt, 24 h, 80%
THF at -78 °C to give naphthol 4 (76%), which has recently
been obtained by a different route.10
Oxidation11 of naphthol 4 with 30% hydrogen peroxide
containing a trace amount of iodine and sulfuric acid in
methanol afforded the desired naphthoquinone 3 in 62% yield
as a red solid.
On the basis of the synthetic plan proposed in Scheme 1,
the key aminoquinone intermediate could be prepared via
the nucleophilic addition of amine to naphthoquinone deriva-
tive 3. Indeed, it was found that treatment of naphthoquinone
3 with homoveratrylamine 9 in ethanol12 at room temperature
furnished the homologous amide, aminonaphthoquinone 1,
as a deep red solid in 80% yield (Scheme 2).
Similarly, the aminonaphthoquinone 10 was readily pre-
pared by the addition of homoveratrylamine 9 to com-
mercially available menadione 8 in ethanol at room temper-
ature for 24 h. The aminoquinone derivatives have recently
been shown to be versatile intermediates in the synthesis of
various natural products.13
The construction of the pyrrolinone moiety in the ningalin
skeleton was initially investigated using this readily available
aminoquinone derivative 10.
It was planned that the pyrrolinone system of the target
ningalin compound 2 could be synthesized from naphtho-
quinone 1 via addition of the enolate derived from methyl
homoveratrate and subsequent lactam bond formation. This
aminoquinone could be synthesized by addition of an amine
to quinone 3 derived from the oxidation of naphthol
derivative 4. It was expected that an allyl carbanion prepared
from 5 would undergo intramolecular acylation to give
compound 4. The alkene 5 could conceivably be prepared
by the reaction of eugenol methyl ether 6 with bromo
compound 7 via the Heck reaction.7
In practice, the palladium-catalyzed coupling reaction8
between the methyl 2-bromoveratrate 7 and commercially
available eugenol methyl ether 6 gave ester 5 in 65% yield.
(Scheme 2).
Further cyclization9 of methyl ester 5 was accomplished
by treatment with 2 equiv of lithium diisopropylamide in
It was reasoned that the presence of the amino group would
render the C-1 carbonyl less electrophilic and thus the
(6) Ruchirawat, S.; Mutarapat, T. Tetrahedron Lett. 2001, 42, 1205.
(7) For some recent reviews, see: (a) Ikeda, M.; El Bialy, S. A. A.;
Yakura, T. Heterocycles 1999, 51, 1957. (b) Amatore, C.; Jutand, A. Acc.
Chem. Res. 2000, 33, 314. (c) Beletskaya, I. P.; Cheprakov, A. V. Chem.
ReV. 2000, 100, 3009. (d) Poli, G.; Giambastiani, G.; Heumann, A.
Tetrahedron 2000, 56, 5959.
(8) Amorese, A.; Arcadi, A.; Bernocchi, E.; Cacchi, S.; Cerini, S.; Fedili,
W.; Ortar, G. Tetrahedron 1989, 45, 813.
(9) (a) Sibi, M. P.; Dankwardt, J. W.; Snieckus, V. J. Org. Chem. 1986,
51, 273. (b) de Koning, C. B.; Michael, J. P.; Rosseau, A. L. Tetrahedron
Lett. 1997, 38, 893. (c) Hattori, T.; Takeda, A.; Suzuki, K.; Koike, N.;
Koshiishi, E.; Miyano, S. J. Chem. Soc., Perkin Trans. 1 1998, 3661.
(10) Estevez, R. J.; Martinez, E.; Martinez, L.; Treus, M. Tetrahedron
2000, 56, 6023.
(11) Minisci, F.; Citterio, A.; Vsaimara, E.; Fontana, F.; De Bernardinis,
S. J. Org. Chem. 1989, 54, 728.
(12) (a) Barret, R.; Roue, N. Tetrahedron Lett. 1999, 40, 3889. (b)
Tohma, H.; Harayama, Y.; Hashizumi, M.; Iwata, M.; Egi, M.; Kita, Y.
Angew. Chem., Int. Ed. 2002, 41, 348.
(13) Nicolaou, K. C.; Sugita, K.; Baran, P. S.; Zhong, Y.-L. Angew.
Chem., Int. Ed. 2001, 40, 207 and references therein.
2634
Org. Lett., Vol. 4, No. 16, 2002

nucleophile would preferentially attack C-4 carbonyl group.14
This prediction was indeed found to be the case. When
aminonaphthoquinone 10 was treated with the carbanion
derived from the reaction of methyl homoveratrate and 2
equiv of lithium diisopropylamide in tetrahydrofuran at -78
°C, the desired ningalin C skeleton 11 was obtained (69%)
as an orange solid together with hydrated product 12, isolated
as a white solid in 9% yield (Scheme 3). It was gratifying
of aminoquinone 1 with methyl homoveratrate and 2 equiv
of LDA gave the required permethyl ningalin C 2 (73%)
and the hydrated compound 13 (15%) in a straightforward
manner (Scheme 4). The hydrated compounds 12 and 13
Scheme 4a
Scheme 3a
a Reagents and conditions: (a) 2 equiv of LDA, THF, -78 °C;
(b) 1 equiv of methyl homoveratrate, THF, -78 °C, 2 h then rt 2
h, 73% (2), 15%(13); (d) 2 M HCl, CH2Cl2, rt, 5 h.
could be readily dehydrated by treatment with 2 M hydro-
chloric acid in dichloromethane at room temperature for 5 h
to give the ningalin compound 11 and permethyl ningalin C
2 in quantitative yield. Permethyl ningalin C 2 was de-
methylated5 by BBr3 in methylene chloride to give ningalin
1
C in 72% yield. The spectral data (IR, UV, H NMR, 13C
NMR, MS) of our synthetic ningalin C are in full agreement
with the published data for the natural product.1,5
In conclusion, our synthetic approach to ningalin C
demonstrates the utility of the one-pot reaction for the
preparation of the pyrrolinone system, the core moiety of
ningalin C. The synthesis of the quinone and aminoquinone
also shows great promise for application in the synthesis of
related quinone derivatives.
a Reagents and conditions: (a) EtOH, rt, 24 h, 82%; (b) 2 equiv
of LDA, THF, -78 °C; (c) 1 equiv of methyl homoveratrate, THF,
-78 °C, 2 h then rt 2 h, 69%(11), 9%(12); (d) 2 M HCl, CH2Cl2,
rt, 5 h
to see that not only was the addition of the anionic species
to the right ketone group of compound 10 but also the lactam
cyclization took place to generate the ultimate pyrrolinone
system in one pot. We were unable to carry out the
intermolecular amide bond formation by the reaction of
aminonaphthoquinone 10 with homoveratroyl chloride in the
presence of various bases (Na2CO3, K2CO3, NaH, Et3N). This
is presumably due to the fact that the lone pair of electrons
on nitrogen is not readily available because the nitrogen is
part of a vinylogous amide. It was thus concluded that in
the key formation of the pyrrolinone the formation of the
carbon-carbon bond preceded the intramolecular amide
bond formation.
Acknowledgment. We gratefully thank the Thailand
Research Fund (TRF) for generous financial support and the
award of Senior Research Scholar to S.R. and the Golden
Jubilee Scholarship to A.N. We acknowledge the facilities
in the Department of Chemistry, Mahidol University, pro-
vided by the Postgraduate Education and Research in
Chemistry (PERCH) program. We are grateful to Professor
W. Steglich for copies of NMR spectra of permethyl ningalin
C and ningalin C and the procedure for the demethylation.
Supporting Information Available: Detailed experi-
mental procedures and characterization data for new com-
With the starting material 1 and an efficient method for
the synthesis of pyrrolinones in hand, the synthesis of
permethyl ningalin C 2 was then investigated. The reaction
1
pounds and spectra (IR, UV, H NMR, 13C NMR, MS) of
the synthetic ningalin C. This material is available free of
charge via the Internet at http://pubs.acs.org.
(14) Knolker, H.-J.; Frohner, W.; Reddy, K. R. Synthesis 2002, 557.
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