Total Synthesis of the Quinazoline Alkaloids (-)-Fumiquinazoline G and (-)-Fiscalin B

Full text of DOI:10.1021/jo980360t

2432
J . Org. Chem. 1998, 63, 2432-2433
Tota l Syn th esis of th e Qu in a zolin e Alk a loid s
(-)-F u m iqu in a zolin e G a n d (-)-F isca lin B
Haishan Wang and A. Ganesan*
Institute of Molecular and Cell Biology, National University of
Singapore, 30 Medical Drive, Singapore 117609
Received February 26, 1998
In 1992, Numata et al. reported1 a series of cytotoxic
fungal metabolites obtained from a strain of Aspergillus
fumigatus isolated from the marine fish Pseudolabrus
japonicus. Fumiquinazoline G (1, Figure 1) is a prototypical
member, while others such as fumiquinazoline D (2) feature
further intramolecular cyclizations. The related alkaloid
fiscalin B (3), from the fungus Neosartorya fischeri, was
discovered2 at Sterling-Winthrop in the course of screening
for substance P antagonists and also independently isolated3
from the ascomycete Corynascus setosus. These examples
demonstrate that the pyrazino[2,1-b]quinazoline-3,6-dione
ring skeleton is used by nature as a scaffold for constrained
peptidomimetics, and it has also attracted considerable
attention4 among medicinal chemists.
F igu r e 1.
Retrosynthetically, dehydration of a peptide precursor
(Figure 2) represents a concise and biomimetic route to the
quinazoline ring of these natural products.5 However,
previous conditions for the dehydration have been fairly
harsh, and suitable only for unhindered 2,3-disubstituted
quinazolin-4-ones.6 Syntheses of natural products involving
more sterically demanding substrates have utilized indirect
methods such as thioamide formation (asperlicin C7), oxida-
tion of a dihydroquinazolinone (tryptoquivaline8), or aza-
Wittig reaction (ardeemin9). Snider’s recent synthesis10 of
ent-1 (reported shortly after we began our work) also
employed the aza-Wittig disconnection, requiring judicious
F igu r e 2.
Sch em e 1a
* To whom correspondence should be addressed. Tel.: (65) 874 3739.
Fax: (65) 779 1117. E-mail: mcbgane@imcb.nus.edu.sg.
(1) (a) Numata, A.; Takahashi, C.; Matsushita, T.; Miyamoto, T.; Kawai,
K.; Usami, Y.; Matsumura, E.; Inoue, M.; Ohishi, H.; Shingu, T. Tetrahedron
Lett. 1992, 33, 1621-1624. (b) Takahashi, C.; Matsushita, T.; Doi, M.;
Minoura, K.; Shingu, T.; Kumeda, Y.; Numata, A. J . Chem. Soc., Perkin
Trans. 1 1995, 2345-2353.
(2) Wong, S.-M.; Musza, L. L.; Kydd, G. C.; Kullnig, R.; Gillum, A. M.;
Cooper, R. J . Antibiot. 1993, 46, 545-553.
(3) Fujimoto, H.; Negishi, E.; Yamaguchi, K.; Nishi, N.; Yamazaki, M.
Chem. Pharm. Bull. 1996, 44, 1843-1848.
(4) For examples, see: (a) Malamas, M. S.; Millen, J . J . Med. Chem. 1991,
34, 1492-1503. (b) Yu, M. J .; McCowan, J . R.; Mason N. R.; Deeter, J . B.;
Mendelsohn, L. G. J . Med. Chem. 1992, 35, 2534-2542. (c) de Laszlo, S.
E.; Quagliato, C. S.; Greenlee, W. J .; Patchett, A. A.; Chang, R. S. L.; Lotti,
V. J .; Chen, T.-B.; Scheck, S. A.; Faust, K. A.; Kivlighn, S. S.; Schorn, T. S.;
Zingaro, G. J .; Siegl, P. K. S. J . Med. Chem. 1993, 36, 3207-3210. (d)
Hutchinson, J . H.; Cook, J . J .; Brashear, K. M.; Breslin, M. J .; Glass, J . D.;
Gould, R. J .; Halczenko, W.; Holahan, M. A.; Lynch, R. J .; Sitko, G. R.;
Stranieri, M. T.; Hartman, G. D.; J . Med. Chem. 1996, 39, 4583-4591. (e)
Sa´nchez, J . D.; Ramos, M. T.; Avendan˜o, C. Tetrahedron 1998, 54, 969-
980.
(5) For recent reviews on quinazoline alkaloids, see: (a) Michael, J . P.
Nat. Prod. Rep. 1997, 14, 605-618. (b) J ohne, S. In Supplements to the
2nd Edition of Rodd’s Chemistry of Carbon Compounds; Ansell, M. F., Ed.;
Elsevier: Amsterdam, 1995; Vol. IV I/J , pp 223-240.
(6) Brown, D. J . Quinazolines. Supplement I; Wiley: New York, 1996.
For examples related to the synthesis of tryptoquivalines (R ) H or Me),
see: (a) Bu¨chi, G.; DeShong, P. R.; Katsumura, S.; Sugimura, Y. J . Am.
Chem. Soc. 1979, 101, 5084-5086. (b) Ohnuma, T.; Kimura, Y.; Ban, Y.
Tetrahedron Lett. 1981, 22, 4969-4972. (c) Nakagawa, M.; Taniguchi, M.;
Sodeoka, M.; Ito, M.; Yamaguchi, K.; Hino, T. J . Am. Chem. Soc. 1983, 105,
3709-3710.
a
Reagents and conditions: (a) 1-ethyl-3-[3-(dimethylamino)propyl]-
carbodiimide‚HCl (2.2 equiv), anthranilic acid (2.0 equiv), MeCN, rt,
3 h, 90%; (b) Fmoc-D-Ala-Cl (1.2 equiv), CH2Cl2/aqueous Na2CO3, rt, 1
h, 86%; (c) Ph3P (5.0 equiv), I2 (4.9 equiv), EtN(i-Pr)2 (10.1 equiv), rt,
2.5 h, 65%; (d) (i) 20% piperidine in CH2Cl2, rt, 12 min, (ii) SiO2 (75%).
manipulation of protecting groups and a total of 12 steps
from Cbz-L-tryptophan.
Assuming a suitable means for peptide dehydration could
be found, we proceeded with a synthesis of 1 along these
lines. Tripeptide 7 (Scheme 1) was prepared in two steps
from D-tryptophan methyl ester11 by standard methods. At
this stage, we became aware of Wipf’s protocol12 (tri-
phenylphosphine, iodine, triethylamine) for the dehydration
of â-keto amides to oxazoles. Among the amides in 7, the
anilide NH is the most acidic, suggesting that it can enolize
(7) Bock, M. G.; DiPardo, R. M.; Pitzenberger, S. M.; Homnick, C. F.;
Springer, J . P.; Friedinger, R. M. J . Org. Chem. 1987, 52, 1644-1646.
(8) Nakagawa, M.; Ito, M.; Hasegawa, Y.; Akashi, S.; Hino, T. Tetra-
hedron Lett. 1984, 25, 3865-3868.
(9) Marsden, S. P.; Depew, K. M.; Danishefsky, S. J . J . Am. Chem. Soc.
1994, 116, 11143-11144.
(10) He, F.; Snider, B. B. Synlett 1997, 483-484.
(11) Our initial studies used the cheaper L-tryptophan methyl ester,
eventually leading to ent-1. Details will be reported in a full paper, together
with syntheses of fumiquinazoline F and glyantrypine.
(12) Wipf, P.; Miller, C. P. J . Org. Chem. 1993, 58, 3604-3606.
S0022-3263(98)00360-0 CCC: $15.00 © 1998 American Chemical Society
Published on Web 03/26/1998

Communications
J . Org. Chem., Vol. 63, No. 8, 1998 2433
Sch em e 2a
Ta ble 1. Exa m p les of Deh yd r a tive Qu in a zolin on e
Syn th esisa
reaction
time (h)
product
yield (%)
recovered
substrate (%)
substrate
R
R’
5a
5b
5c
5d
Me
Ph
i-Pr
OMe
OMe
OMe
7
3.5
6
4a
4b
4c
4d
99
93
88
17
0
2
12
83
t-Bu OMe
6
a
All substrates were prepared from L-tryptophan methyl ester.
Reactions were carried out in CH2Cl2 solutions with Ph3P (5.0
equiv), I2 (5.0 equiv), EtN(i-Pr)2 (10 equiv), and substrate (final
concentrations were ca. 0.03 M) at rt.
analogously to the ketone in the oxazole cyclization. To our
delight, treatment of 7 under Wipf’s conditions furnished
the desired product 8 in 65% yield. Following removal of
the Fmoc protecting group, attempted chromatographic
purification of the free amine induced intramolecular cy-
clization, directly yielding (-)-fumiquinazoline G in a total
of four steps and 38% overall yield.
Next, we investigated the sensitivity of the Wipf procedure
to steric hindrance (Table 1). The successful quinazolinone
formation with 4c (R ) i-Pr) is notable, as a previous
attempt6b using phosphorus trichloride failed when R ) i-Bu.
Only the extremely hindered pivalamide 4d did not provide
a satisfactory yield of the quinazolinone. Even in this case,
unreacted starting material was recovered intact, testifying
to the mildness of the reaction conditions.
The synthesis of (-)-fiscalin B (Scheme 2) proceeded
uneventfully up to and including Wipf dehydration of
tripeptide 9. However, amine 11 did not undergo spontane-
ous cyclization, and considerable experimentation was re-
quired for this transformation. Presumably, the increased
bulk of the isopropyl side chain disfavors the desired reactive
conformer. Success was finally realized by refluxing 11 in
acetonitrile, providing (-)-fiscalin B in a total of five steps
and 48% overall yield from D-tryptophan methyl ester.13
In summary, we have demonstrated that the Wipf oxazole
synthesis is also applicable to quinazolinones and provides
a
Reagents and conditions: (a) Fmoc-L-Val-Cl (1.4 equiv), CH2Cl2/
aqueous Na2CO3, rt, 2 h, 90%; (b) Ph3P (5.0 equiv), I2 (4.9 equiv), EtN(i-
Pr)2 (10.4 equiv), rt, 8 h, 82%; (c) 20% piperidine in CH2Cl2, rt, 12 min;
(d) MeCN, DMAP (1.3 equiv), reflux 19 h, 72%.
a powerful entry to this ring system. We are presently
adapting the methodology to the combinatorial synthesis14
of quinazolinone libraries for biological evaluation.
Ack n ow led gm en t. This work was supported by grants
from the National Science and Technology Board of
Singapore.
Su p p or tin g In for m a tion Ava ila ble: Experimental proce-
dures and compound characterization data for the total synthesis
of 1 and 3 (5 pages).
J O980360T
(13) Synthetic 1 and 3 matched the spectroscopic data reported for the
natural products. 1 had an optical rotation [R]26D ) -456.2° (c 0.59, CHCl3)
(14) For other approaches to the solid-phase synthesis of quinazolinones,
see: (a) Chucholowski, A.; Masquelin, T.; Obrecht, D.; Stadlwieser, J .;
Villalgordo, J . M. Chimia 1996, 50, 525-530. (b) Mayer, J . P.; Lewis, G. S.;
Curtis, M. J .; Zhang, J . Tetrahedron Lett. 1997, 38, 8445-8448.
[lit.1 [R]D ) -462.8° (c 0.61, CHCl3)], while 3 had an optical rotation [R]26
D
) -504° (c 0.64, MeOH) [lit.3 [R]D ) -124° (c 0.021, MeOH)].