Total Syntheses of (-)-Fumiquinazolines C, E, and H

Article abstract of DOI:10.1021/ol017215d

matrix presented Total syntheses of the heptacyclic fumiquinazolines C and H have been accomplished efficiently using FmocNHCH(CH₂SePh)CO₂H as the precursor for the requisite dehydrofumiquinazoline.

Full text of DOI:10.1021/ol017215d

ORGANIC
LETTERS
2002
Vol. 4, No. 7
1087-1090
Total Syntheses of (−)-Fumiquinazolines
C, E, and H
Barry B. Snider* and Hongbo Zeng
Department of Chemistry, MS015, Brandeis UniVersity,
Waltham, Massachusetts 02454-9110
snider@brandeis.edu
Received December 12, 2001
ABSTRACT
Total syntheses of the heptacyclic fumiquinazolines C and H have been accomplished efficiently using FmocNHCH(CH SePh)CO H as the
2
2
precursor for the requisite dehydrofumiquinazoline.
Numata and co-workers isolated the moderately cytotoxic
fumiquinazolines A-G (1-3, 5) from a strain of Aserpgillus
fumigatus found in the gastrointestinal tract of the fish
Pseudolabrus japonicus.1 Belofsky, Ko¨ck, and co-workers
isolated the antifungal fumiquinazolines H (6) and I (4) from
a fungus Acremonium sp. isolated from the surface of the
Caribbean tunicate Ecteinascidia turbinata.2
are more highly oxidized with a methoxy group at C-3 in
fumiquinazoline E (3) and a seven-membered ring formed
between C-3 and the oxygen on C-17 in fumiquinazolines
C (5) and H (6).
The challenge for the syntheses of fumiquinazolines A (1),
B (2), and I (4) is the modification of the tryptophan indole
to introduce the imidazolinone ring and hydroxy group.3 We
recently reported syntheses of fumiquinazolines A, B, and
I,4 using indole modification chemistry initially developed
for the synthesis of asperlicin.5 Fumiquinazolines C (5), E
(3), and H (6) present an additional challenge because they
(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, 2345-2343.
(2) Belofsky, G. N.; Anguera, M.; Jensen, P. P.; Fenical, W.; Kock, M.
Chem. Eur. J. 2000, 6, 1355-1360.
(3) The simpler fumiquinazolines F and G, in which the indole ring of
tryptophan has not been modified, have been synthesized several times:
(a) He, F.; Snider, B. B. Synlett 1997, 483-484. (b) Wang, H.; Ganesan,
A. J. Org. Chem. 1998, 63, 2432-2433. (c) Wang, H.; Ganesan, A. J. Org.
Chem. 2000, 65, 1022-1030. (d) Snider, B. B.; Busuyek, M. V. Tetrahedron
2001, 57, 3301-3307. (e) Herna´ndez, F.; Lumetzberger, A.; Avendan˜o,
C.; So¨llhuber, M. Synlett 2001, 1387-1390.
(4) Snider, B. B.; Zeng, H. Org. Lett. 2000, 2, 4103-4106.
10.1021/ol017215d CCC: $22.00 © 2002 American Chemical Society
Published on Web 03/13/2002

Fumiquinazolines C (5) and E (3) are probably biosyn-
thesized by oxidation of fumiquinazoline A or B (1 or 2) to
form dehydrofumiquinazoline A (7a) (Scheme 1). Protona-
Scheme 2
Scheme 1
tion and cyclization will give fumiquinazoline C (5); pro-
tonation and reaction with MeOH will give fumiquinazoline
E (3). Such an oxidation is hard to carry out chemically, but
our synthetic route to 1 and 2 can be easily modified by use
of Fmoc-L-NHCH(CH2X)CO2H instead of Fmoc-L-alanine
to give 8. X can be any functional group that can be
eliminated to give Cbz-dehydrofumiquinazoline A (7b).
Numerous dehydroalanine precursors have been devel-
oped, including O-acetylserine, O-tosylserine, and S-meth-
ylcysteine,6,7 which has been used by Hart and Magomedov
for the syntheses of dehydrofumiquinazoline F and alantry-
pinone.7 van der Donk recently reported the synthesis of
FmocNHCH(CH2SePh)CO2H and its use as a dehydroalanine
precursor.8 The facile elimination by oxidation to the
selenoxide with NaIO4 in aqueous THF at 25 °C was
particularly appealing because these conditions were likely
to be compatible with the functionality in 8.
Reaction of fumiquinazoline A intermediate 94 with
FmocNHCH(CH2SePh)CO2H and EDAC in CH3CN affords
96% of 10 (Scheme 2). Mazurkiewicz-Ganesan cycliza-
tion,3bc,9,10 provides 81% of 11, which is treated with 10 equiv
of piperidine in EtOAc at 25 °C for 10 min to cleave the
Fmoc group and open the iminobenzoxazine to give amidine
12.
line C (14, 14% from 11) (Scheme 3). Under these reaction
conditions, 12 undergoes four sequential reactions. The
amidine amide cyclizes to form the quinazolinone. The amine
lactone reacts to give the piperazine ring. At this point,
benzeneselenol is eliminated without the need for oxidation
to the selenoxide. Finally, under the acidic conditions, the
double bond is protonated to give a cation that reacts with
the alcohol to form the seven-membered ether ring of
fumiquinazoline C.
Further heating of 7b in 100:1 CH3CN/HOAc at reflux
for 2 h affords 30% of 14 and 60% of recovered 7b, which
Scheme 3
We were delighted to find that heating crude 12 in 25:1
CH3CN/HOAc at reflux for 2 h forms Cbz-dehydro-
fumiquinazoline A (7b, 56% from 11) and Cbz-fumiquinazo-
(5) He, F.; Foxman B. M.; Snider, B. B. J. Am. Chem. Soc. 1998, 120,
6417-6418
(6) Chai, C. L. L.; King, A. R. J. Chem. Soc., Perkin Trans. 1 1999,
1173-1182. Miao, Z.; Tam, J. P. Org. Lett. 2000, 2, 3711-3713 and
references therein.
(7) (a) Freed, J. D.; Hart, D. J.; Magomedov, N. J. Org. Chem. 2001,
66, 839-852. (b) Hart, D. J.; Magomedov, N. A. J. Am. Chem. Soc. 2001,
123, 5892-5899.
(8) (a) Okeley, N. M.; Zhu, Y.; van der Donk, W. A. Org. Lett. 2000, 2,
3603-3606. (b) Gieselman, M. D.; Xie, L.; van der Donk, W. A. Org.
Lett. 2001, 3, 1331-1334.
(9) Mazurkiewicz, R. Monatsh. Chem. 1989, 120, 973-980.
(10) He, F.; Snider, B. B. J. Org. Chem. 1999, 64, 1397-1399.
1088
Org. Lett., Vol. 4, No. 7, 2002

can be recycled. Slow decomposition occurs on longer
heating, so that reaction for 12 h consumes all of 7b but
gives only 40-50% of 14. Treatment of 7b with 0.2 M HCl
in MeOH at 25 °C for 5 min provides 61% of Cbz-
fumiquinazoline E (13). Hydrogenolysis of 13 with Pd/C
under 1 atm of H2 for 30 min proceeds cleanly, giving 84%
of (-)-fumiquinazoline E (3).11 The additional ring of 14
forces the Cbz group into a more hindered environment.
Hydrogenolysis with Pd/C under 4 atm of H2 for 30 h affords
77% of (-)-fumiquinazoline C (5).11
as needed for fumiquinazolines H and I giving 50% of 18b
and only 34% of 16b after reduction. Lactonization of 18a
and 18b by stirring with SiO2 in CH2Cl2 gives lactones 19a
and 19b in 88% and 82% yield, respectively.
Elaboration of both 19a and 19b to Cbz-dehydro-
fumiquinazolines 21a and 21b by the procedure developed
for the preparation of 7b proceeds uneventfully as shown in
Scheme 5. To our surprise, cyclization of 21a by heating in
We next turned to the preparation of fumiquinazoline H
(6) by coupling FmocNHCH(CH2SePh)CO2H with the
aniline intermediate in our fumiquinazoline I synthesis.4 The
hydrogen and hydroxy substituents on the indoline ring are
cis to the alkyl substituent on the imidazoline ring in
fumiquinazoline I (4) rather than trans as in fumiquinazoline
A (1). Therefore on formation of the seven-membered ether
ring, the imidazoline ring is over the quinazolinone ring in
fumiquinazoline C (5), while the indoline is over the
quinazolinone in fumiquinazoline H (6). MM2 calculations
indicate that the fumiquinazoline H ring system is more
hindered by about 2 kcal/mol.
Scheme 5
Epoxidation of 15a4 with oxaziridine 2012 occurs selec-
tively on the bottom face, leading to the fumiquinazoline A,
B, C, and E precursors (Scheme 4). Ring opening by MeOH
Scheme 4
25:1 CH3CN/HOAc was slow. After heating for 12 h, we
obtain 22% of a 2:1 mixture of 22a and the enantiomer of
14, 33% of recovered 21a, and no Cbz-fumiquinazoline H
analogue. Epimerization at C-14 prior to cyclization leads
to the formation of 22a, while epimerization at both C-14
and C-20 leads to the enantiomer of 14. Cyclization of 21b
by heating in 25:1 CH3CN/HOAc for 12 h provides 27% of
22b and 33% of recovered 21b. Hydrogenolysis of 22a under
4 atm of H2 for 24 h gives 68% of 23a, while the isobutyl
group of 22b makes the Cbz group even more hindered so
that hydrogenolysis under 4 atm of H2 for 24 h yields only
17% of 23b. These experiments indicate that the additional
steric hindrance of the fumiquinazoline H ring system
prevents the cyclization of 21. Facile epimerization at C-141
leads to an intermediate that cyclizes more readily to give
22 with the fumiquinazoline C ring system.13
gives a mixture of methoxy alcohols. Reductive cleavage of
the methoxy group by NaBH(OAc)3 occurs by intramolecular
hydride delivery from the alkoxyborohydride4 to give 52%
of 16a and 18% of 18a, both of which have the hydrogen
and hydroxy groups cis. On the other hand, oxidation of 15b
with dimethyldioxirane proceeds selectively on the top face
MM2 calculations indicate that Cbz-fumiquinazoline H is
also 2 kcal/mol more hindered than Cbz-fumiquinazoline C.
Even though the Cbz group does not affect the relative
stability, examination of models indicates that it severely
hinders the approach of the hydroxy group to a cation at
(11) The spectral data, melting point, and optical rotation are identical
to those reported for the natural product.1
(12) 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) In fumiquinazoline C (5), 14, 22, and 23 there is an NOE between
H-2 and H-27. In fumiquinazoline H (6) there is an NOE between H-2 and
H-18. In Cbz-fumiquinazoline C (14) and 22, the Cbz benzyl protons are
shifted upfield to δ 4.40-4.25 as a result of shielding by the quinazolinone
ring.
Org. Lett., Vol. 4, No. 7, 2002
1089

iminobenzoxazine. Heating the crude product in CH3CN at
reflux for 1 h effects ring closure of the amidine to the
quinazolinone, formation of the piperazine ring, and elimina-
tion of benzeneselenol to give dehydrofumiquinazoline I.14
In the absence of the bulky Cbz group, cyclization proceeds
spontaneously without epimerization at C-14 to give 34%
of (-)-fumiquinazoline H (6).11 The conversion of 25b to 6
involves seven distinct chemical steps! A similar sequence
converts 18a to iminobenzoxazine 25a, which rearranges to
give 41% of fumiquinazoline H analogue 26.
Scheme 6
Fumiquinazoline D,1 which has a bridge from the imida-
zolinone nitrogen to C-3, is now the only unsynthesized
member of this family. We were not optimistic about
preparing it by cyclization of its biogenetic precursor
dehydrofumiquinazoline A (7a) since this would require the
preparation of a cation at C-3 by protonation of the double
bond without protonation of the amine. Nevertheless, we
investigated this cyclization since the requisite iminoben-
zoxazine can be prepared easily from 16a analogously to
the preparation of 25. Treatment of the iminobenzoxazine
with piperidine in EtOAc for 10 min and then heating at
reflux in CH3CN for 1.5 h affords 7a, which cyclizes to give
40% of fumiquinazoline C (5) and no fumiquinazoline D.
In conclusion, we have completed efficient 13-step syn-
theses of (-)-fumiquinazolines C (5) and E (3) and a 14-
step synthesis of (-)-fumiquinazoline H (6) using Fmoc-
NHCH(CH2SePh)CO2H as a dehydroalanine precursor that
spontaneously eliminates benzeneselenol without oxidation
under the cyclization conditions.15,16
C-3 to form the fumiquinazoline H ring system. Finally, the
isobutyl group of 22b retards hydrogenolysis, suggesting that
even if we could obtain Cbz-fumiquinazoline H, deprotection
would be difficult. Nature does cyclize dehydrofumiquinazo-
line I to fumiquinazoline H. Therefore we decided to adapt
our route to prepare unprotected dehydrofumiquinazoline I,
with the expectation that it would cyclize to fumiquinazoline
H without epimerization.
Replacement of the Cbz of 18 with an Fmoc group should
lead to iminobenzoxazine 25. Both Fmoc groups should be
deprotected during the rearrangement with piperidine. Hy-
drogenolysis of 18b with Pd/C under 1 atm H2 for 30 min
followed by lactonization with silica gel in CH2Cl2 gives
65% of the tetracyclic lactone. Reaction with FmocCl and
i-Pr2NEt affords 70% of 24b. Conversion of 24b to 25b
proceeds analogously to the preparation of 11 in the yields
indicated in Scheme 6.
Acknowledgment. We are grateful to the National
Institutes of Health (GM-51051) for financial support.
Supporting Information Available: Spectral data and
full experimental procedures. This material is available free
of charge via the Internet at http://pubs.acs.org.
OL017215D
(14) The rearrangements of Cbz-protected amidines such as 12 are best
carried out in CH3CN containing 2-5 equiv of HOAc to prevent
epimerization at C-14. These conditions will reduce the epimerization that
was observed in our syntheses of fumiquinazolines A, B, and I.4 The
rearrangement of the unprotected amidine from 25 proceeds much more
cleanly in CH3CN without HOAc.
(15) We previously acylated the indole by a three-step sequence involving
reduction to the indoline, acylation, and reoxidation. This can be ac-
complished in a single step in 90-95% yield by reaction of TrocNHtry-
pOMe with CbzNHalaOPhNO2 or CbzNHLeuOPhNO2, KF, 18-crown-6,
and i-Pr2NEt in CH3CN.16
Treatment of 25b with 10 equiv of piperidine in EtOAc
for 10 min cleaves both Fmoc groups and opens the
(16) Nakagawa, M.; Sodeoka, M.; Yamaguchi, K.; Hino, T. Chem.
Pharm. Bull. 1984, 32, 1373-1384.
1090
Org. Lett., Vol. 4, No. 7, 2002