Total syntheses of (-)-fumiquinazolines A, B, and I.

Article abstract of DOI:10.1021/ol0067686

[structure] The first total syntheses of (-)-fumiquinazolines A, B, and I have been accomplished efficiently using the Pd-catalyzed cyclization of an iodoindole carbamate to construct the imidazoindolone moiety and the dehydrative cyclization of a diamide

Full text of DOI:10.1021/ol0067686

ORGANIC
LETTERS
2000
Vol. 2, No. 25
4103-4106
Total Syntheses of (−)-Fumiquinazolines
A, B, and I
Barry B. Snider* and Hongbo Zeng
Department of Chemistry MS015, Brandeis UniVersity, Waltham, Massachusetts
02454-9110
snider@brandeis.edu
Received October 23, 2000
ABSTRACT
The first total syntheses of (−)-fumiquinazolines A, B, and I have been accomplished efficiently using the Pd-catalyzed cyclization of an
iodoindole carbamate to construct the imidazoindolone moiety and the dehydrative cyclization of a diamide followed by rearrangement through
an amidine to construct the quinazolone moiety.
We recently reported the first synthesis of the potent
cholecystokinin antagonist asperlicin (1).1 The key steps in
to the fused quinazolinone ring system without the use of
protecting groups.3 Finally, epoxidation of 8 with the
saccharine-derived oxaziridine in MeOH affords 9 with the
desired R-hydroxy group in 75-92% selectivity depending
on the R group. Directed reduction of 9 with NaBH(OAc)3
proceeds through 10, which leads exclusively to 11 with the
desired cis H and OH substituents on the less hindered
R-face.
Numata and co-workers isolated the moderately cytotoxic
fumiquinazolines A (2) and B (3) from a strain of Aspergillus
fumigatus isolated from the gastrointestinal tract of the fish
Pseudolabrus japonicus.4 The imidazoindolone moieties of
the fumiquinazolines can be constructed using the protocol
developed in our asperlicin synthesis. However, the Eguchi
this synthesis include the use of the Buchwald palladium-
catalyzed cyclization2 of iodoindole carbamate 4 to form the
novel imidazoindolone 5 (see Scheme 1). Selective acylation
of the more acidic anilide nitrogen of 6 with azidobenzoyl
chloride and cyclization to quinazolone 7 by the Eguchi aza
Wittig protocol (see Scheme 1) provides an efficient route
(3) Takeuchi, H.; Hagiwara, S.; Eguchi, S. Tetrahedron 1989, 45, 6375-
6386.
(4) (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.
(5) Wang, H.; Ganesan, A. J. Org. Chem. 1998, 63, 2432-2433. (b)
Wang, H.; Ganesan, A. J. Org. Chem. 2000, 65, 1022-1030.
(6) He, F.; Snider, B. B. J. Org. Chem. 1999, 64, 1397-1399. See also:
Hart, D. J.; Magomedov, N. Tetrahedron Lett. 1999, 40, 5429-5432.
(7) Mazurkiewicz, R. Monatsh. Chem. 1989, 120, 973-980.
(1) He, F.; Foxman B. M.; Snider, B. B. J. Am. Chem. Soc. 1998, 120,
6417-6418.
(2) Wolfe, J. P.; Rennels, R. A.; Buchwald, S. L. Tetrahedron 1996, 52,
7525-7546.
10.1021/ol0067686 CCC: $19.00 © 2000 American Chemical Society
Published on Web 11/22/2000

conditions needed to rearrange the iminobenzoxazine to the
quinazolone, we introduced the hydroxy group by epoxida-
tion and reduction prior to quinazolinone formation and
protected it intramolecularly as the lactone of 12.
Scheme 1
Reduction of protected D-tryptophan 158 with BH3‚THF
in TFA9 provides 92% of the indoline, which is acylated
with N-CBZ-L-alanine and DCC to afford 79% of N-
acylindole 16a after oxidation with DDQ10 (see Scheme 3).
Scheme 3
aza Wittig procedure is not attractive since selective acylation
of diketopiperazine 13 will not be selective (see Scheme 2).
Mercuration11 of 16a with Hg(OTFA)2, addition of KI, and
iodination give 85% of iodoindole 17a and 10% of recovered
16a. The Buchwald palladium-catalyzed cyclization2 of 17a
affords 64% of 14a and 11% of indole 16a, which can be
recycled.
Scheme 2
Epoxidation of 14a with the saccharine-derived oxaziri-
dine12 yields 65% of 18a as a mixture of diastereomers with
an R-hydroxy group and 23% of 19a as a mixture of
diastereomers with a â-hydroxy group (see Scheme 4).
Reduction of 18a with NaBH(OAc)3 provides exclusively
the isomer with an R-hydrogen as described above for the
conversion of 9 to 11.13 Lactonization to give 66% of 20a is
accomplished by stirring with silica gel in CH2Cl2 for 12 h.
Mild conditions are necessary since the lactone is easily
epimerized.14 A similar sequence converts 19a to 70% of
21a.
Reductive deprotection of 20a with Zn in AcOH affords
the amine, which is coupled with anthranilic acid and EDAC
(8) Prepared in >95% yield by reaction of D-tryptophan methyl ester
hydrochloride with Troc chloride in a two-phase system of ether and aqueous
NaHCO3 for 4 h: Vedejs, E.; Wang, J. Org. Lett. 2000, 2, 1031-1032.
(9) Maryanoff, B. E.; McComsey, D. F.; Nortey, S. O. J. Org. Chem.
1981, 46, 355-360.
Dehydrative cyclization of diamide 12 should form the
quinazolone of 2 and 3. Wang and Ganesan reported that
treatment of analogous simpler anthranilamides with Ph3P,
I2, and Et(i-Pr)2N affords the desired quinazolinones.5 We
showed6 that this procedure actually gives an iminobenzox-
azine,7 e.g., 23, which is converted to an amidine, e.g., 24,
by the piperidine used to deprotect the Fmoc group. The
desired quinazolinone is formed during TLC purification.
Diamide 12 can be prepared easily from imidazoindolone
14a. Since the amide bond of 14a is not stable to the basic
(10) Preobrazhenskaya, M. N. Russ. Chem. ReV. 1967, 36, 753-771.
(11) Mingoia, Q. Gazz. Chim. Ital. 1930, 60, 509-515.
(12) (a) Davis, F. A.; Sheppard, A. C. Tetrahedron Lett. 1988, 29, 4365-
4368. (b) Davis, F. A.; Towson, J. C.; Vashi, D. B.; ThimmaReddy, R.;
McCauley, J. P., Jr.; Harakal, M. E.; Gosciniak, D. G. J. Org. Chem. 1990,
55, 1254-1261.
(13) (a) Saksena, A. K.; Manglaracina, P. Tetrahedron Lett. 1983, 24,
273-276. (b) Hoveyda, A. Evans, D. A.; Fu, G. Chem. ReV. 1993, 93,
1307-1368.
(14) Michl, K.; Liebigs Ann. Chem. 1981, 33-39.
4104
Org. Lett., Vol. 2, No. 25, 2000

Reaction of 23a with 10 equiv of piperidine in EtOAc at 25
°C for 10 min gives crude amidine amine 24a, which is
refluxed in CH3CN for 2 h to give 65% of Cbz-fumiquinazo-
line A (25a) and 19% of the readily separable isomer 26a
resulting from epimerization of the sensitive lactone14 prior
to formation of the diketopiperazine. Cyclization at lower
temperatures proceeds with less epimerization but gives a
lower yield of 25a. Hydrogenolysis of 25a affords 90% of
fumiquinazoline A (2) with spectral data and optical rotation
identical to that reported for the natural product.4 Hydro-
genolysis of 26a gives 90% of 27a with spectral data
identical to that reported for a base-catalyzed rearrangement
product of fumiquinazolines A and B.4,16
Scheme 4
A similar sequence coupling the aniline formed from 20a
with FMOC-D-alanine provides 90% of 22b. Dehydrative
cyclization affords 71% of iminobenzoxazine 23b, which is
rearranged via amidine 24b to give 69% of Cbz-fumiquinazo-
line B (25b) and 18% of epimer 26b. Hydrogenolysis of 25b
affords 90% of fumiquinazoline B (3) with spectral data and
optical rotation identical to that reported for the natural
product.4,17 Hydrogenolysis of 26b gives 90% of 27b with
spectral data identical to that reported for a base-catalyzed
rearrangement product of fumiquinazolines A and B.4,16
Belofsky, Ko¨ck, and co-workers recently reported the
isolation of the antifungal fumiquinazoline I (30) from a
fungus Acremonium sp. isolated from the surface of the
Caribbean tunicate Ecteinascidia turbinata.18 Fumiquinazo-
line I differs from fumiquinazoline A in two respects. The
substituent on the imidazolinone ring is an isobutyl group
from leucine, rather than a methyl substituent from alanine.
More significantly, the hydrogen and hydroxyl substituents
on the indoline ring are cis to the alkyl substituent on the
imidazolinone ring, rather than trans as in fumiquinazoline
A. In our model study for the asperlicin synthesis, we found
that epoxidation of imidazoindolone 8, R ) Me, with
dimethyldioxirane,19 rather than the saccharine-derived ox-
aziridine, affords a 2:1 mixture rich in the isomer required
for fumiquinazoline I with the hydroxy group cis to the
isobutyl substituent.1 It was therefore a simple matter to adapt
the synthesis of fumiquinazoline A to the synthesis of
fumiquinazoline I.
in CH3CN to yield 85% of the aniline (see Scheme 5). A
second coupling with Fmoc-L-alanine yields 89% of 22a.
Treatment of 22a with Ph3P, Br2, and Et3N in CH2Cl2 at
room temperature provides 76% of iminobenzoxazine 23a.5-7,15
Scheme 5
Imidazoindolone 14b derived from Cbz-L-leucine is pre-
pared analogously to 14a in the yields indicated in Scheme
3. Epoxidation of 14b with dimethyldioxirane in 15:4:1
(15) Longer reaction times were required with I2 instead of Br2 so that
more FMOC cleavage occurs with either Et3N or Et(i-Pr)2N as the base.
(16) The spectral data for 27a correspond exactly to those reported for
6 in ref 4b, while those for 27b correspond exactly to those reported for 5.
The stereochemistry of 5 and 6 is switched in this reference.
(17) The 1H NMR spectrum of fumiquinazoline B is concentration
dependent. The spectrum of a 0.08 M solution in CDCl3 matches that
reported,4 while the spectrum of a 0.01 M solution is shifted by as much as
0.1 ppm.
(18) Belofsky, G. N.; Anguera, M.; Jensen, P. R.; Fenical, W.; Ko¨ck,
M. Chem. Eur. J. 2000, 6, 1355-1360.
(19) (a) Adam, W.; Bialas, J.; Hadjiarapoglou, L. Chem. Ber. 1991, 124,
2377. (b) Adam, W.; Reinhardt, D.; Reissig, H.-U.; Paulini, K. Tetrahedron
1995, 51, 12257-12262.
(20) The melting point for synthetic fumiquinazoline I, 169-171 °C, is
much higher than that reported for the natural product, 116-120 °C.
Similarly, the optical rotation [R]D for synthetic fumiquinazoline I, -222,
is larger than that for the natural product, -138, suggesting that the natural
product is contaminated with minor impurities.
Org. Lett., Vol. 2, No. 25, 2000
4105

acetone/MeOH/CH2Cl2 provides 55% of the desired alcohol
19b with the hydroxy group cis to the isobutyl group and
only 38% of the alcohol 18b, which is the major product
with the saccharine-derived oxaziridine (see Scheme 6).
Reduction of 19b with NaBH(OAc)3 and lactonization
with silica gel in CH2Cl2 yields 72% of 21b. Diamide 28 is
prepared analogously to 22a in the yields indicated. Dehy-
drative cyclization of 28 with Ph3P, Br2, and Et3N in CH2-
Cl2 affords 77% of the iminobenzoxazine. Deprotection and
ring opening of the iminobenzoxazine with piperidine and
cyclization in CH3CN at reflux give 70% of Cbz-fumiquinazo-
line I (29) and 10% of the impure epimer corresponding to
26a. Hydrogenolysis of 29 affords 96% of fumiquinazoline
I (30) with spectral data identical to those reported.20
Scheme 6
In conclusion, we have completed the first syntheses of
(-)-fumiquinazolines A, B, and I which proceed in 16 steps
from protected tryptophan, leucine, and alanine in 7% overall
yield, making this family of compounds and a wide variety
of analogues readily available. The oxidation of 14a with
the saccharine-derived oxaziridine for fumiquinazolines A
and B and of 14b with dimethyldioxirane for fumiquinazoline
I selectively forms the appropriate imidazoindolone stereo-
isomer. Application of these methods to the syntheses of the
more highly oxidized fumiquinazolines C, D, E and H is
currently in progress.
Acknowledgment. We are grateful to the National
Institutes of Health (GM-50151) for generous financial
support. We thank Dr. Feng He for technical advice,
Professor Numata for helpful discussions, and Prof. Belofsky
for copies of the spectral data of fumiquinazoline I.
Supporting Information Available: Full experimental
procedures for the preparation of 2, 3, and 30. This material
is available free of charge via the Internet at http://pubs.acs.org.
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