A concise total synthesis of (±)-alantrypinone by a novel hetero-diels-alder reaction

Article abstract of DOI:10.1021/ol030070l

(Matrix presented) An efficient total synthesis of (±) -alantrypinone (1) and its 17-epi isomer (17) has been accomplished employing a novel aza-Diels-Alder reaction as the key step. The reaction sequence comprises 8 steps starting from anthranilic acid a

Full text of DOI:10.1021/ol030070l

ORGANIC
LETTERS
2003
Vol. 5, No. 18
3205-3208
A Concise Total Synthesis of
(±)-Alantrypinone by a Novel
Hetero-Diels−Alder Reaction
Andrew S. Kende,* Junfa Fan, and Zecheng Chen
Department of Chemistry, UniVersity of Rochester, Rochester, New York 14627
kende@chem.rochester.edu
Received June 3, 2003
ABSTRACT
An efficient total synthesis of (±)-alantrypinone (1) and its 17-epi isomer (17) has been accomplished employing a novel aza-Diels−Alder
reaction as the key step. The reaction sequence comprises 8 steps starting from anthranilic acid and proceeds in 13.5% overall yield. An
interesting anionic equilibration between 1 and its epimer 17 has also been discovered.
In 1998 Larsen et al. reported the first isolation and structure
elucidation of a hexacyclic alkaloid, (+)-alantrypinone (1),
from extracts of the fungus Penicillium thymicola.1 Three
years later, the same group described a second, minor
metabolite from this species, identified as the hydroxy
derivative (-)-serantrypinone (2).2 From the absolute con-
figuration of 1 as determined by X-ray crystallography it
was suggested that the alantrypinone molecule formally
incorporates D-tryptophan and L-alanine, as seems to be the
case for its congener, the known alkaloid fumiquinazoline
F (3).3
Both (+)-alantrypinone (1) and (-)-serantrypinone (2)
possess a tricyclic pyrazinoquinazolinedione base bridged
by a 3-methyleneoxindole substructure. The unusual molec-
ular architecture of these new compounds, and the claimed
biological activity of the related spiroquinazoline structure
Magomedov5 have recently reported a total synthesis of ent-
4,4 has led to speculation about their biosynthesis and to
alantrypinone (7) in 10 steps from isatoic anhydride in 12%
efforts toward their total synthesis. In particular, Hart and
(1) Larsen, T. O.; Frydenvang, K.; Frisvad, J. C.; Christophersen, C. J.
Nat. Prod. 1998, 61, 1154-1157.
(2) Ariza, M. R.; Larsen, T. O.; Petersen, B. O.; Duus, J. Q.; Christo-
phersen, C.; Barrero, A. F. J. Nat. Prod. 2001, 64, 1590-1592.
(3) Takahashi, C.; Matsushita, T.; Doi, M.; Minoura, K.; Shingu, T.;
Kumeda, Y.; Numata, A. J. Chem. Soc., Perkin Trans. 1 1995, 2345-
2353.
(4) (a) Barrow, C. J.; Sun, H. H. J. Nat. Prod. 1994, 57, 471-476. (b)
Cascieri, M. A.; Macleod, A. M.; Underwood, D.; Shiao, L.-L.; Ber, E.;
Sadowski, S.; Yu, H.; Merchant, K. J.; Swain, C. J.; Strader, C. D.; Fong,
T. M. J. Biol. Chem. 1994, 269, 6587-6591.
(5) (a) Hart, D. J.; Magomedov, N. A. J. Am. Chem. Soc. 2001, 123,
5892-5899. (b) Hart, D. J.; Magomedov, N. A. Tetrahedron Lett. 1999,
40, 5429-5432.
10.1021/ol030070l CCC: $25.00 © 2003 American Chemical Society
Published on Web 08/08/2003

overall yield. Their elegant sequence is based on a biomi-
metic motif that employs as key steps the transannular
iminium ion cyclization of indole 5 to 6 and subsequent
NBS-mediated oxidative rearrangement6 of the fused indole
system in 6 to the spirocyclic structure of ent-alantrypinone
(7).
Scheme 1
in deprotection and cyclization to give the key intermediate
13 in 41% overall yield from anthranilic acid.
A fresh examination of the synthetic problem led us to
explore whether alantrypinone (1) might be constructed by
a hetero-Diels-Alder reaction of the hypothetical azadiene
8 with the known 3-methyleneoxindole 9.7
Dehydroaromatization of the dihydropyrazinone ring of
dione 13 proved to be somewhat refractory. Treatment of
13 under diverse oxidative conditions (e.g. Br2, NBS, SeO2)
led to mixtures or destruction of the molecule. An attempted
oxidative chlorination with PCl5 gave small amounts of a
chloro derivative, which appeared to be the 3-chloro analogue
of the desired 8, but this substance was unstable and the
process was not reproducible. Success in this transformation
was finally achieved (Scheme 2) by reaction of dione 13
Scheme 2
To our knowledge, the fully conjugated 6H-pyrazino-
[2,1-b]quinazoline-6-one system represented by structure 8
had not been reported in the literature. Its stability was
unclear, and its propensity to serve as a diene in a Diels-
Alder reaction was uncertain. To exploit this opportunity,
we explored synthetic access to this interesting azadiene
system. Our proposed key intermediate was the tricyclic
dione 13, previously described by Hernandez et al.8 In a
modification of their published route, anthranilic acid was
condensed with ethyl glycinate, using EDCI to give the amide
10 (Scheme 1). A second coupling with Fmoc-L-ala-OH and
EDCI in CH3CN yielded the protected diamide 11. Dehy-
drative cyclization of this diamide was achieved by using
Ph3P and Br2 at room temperature to produce the imino
benzoxazine 12,9 which on reaction with piperidine10 resulted
with triethyloxonium fluoborate in CH2Cl2 to give the imino
ether 14, which was gently oxidized by DDQ in benzene to
produce the new azadiene 8 in 71% overall yield.11 Diene 8
was purified by flash chromatography and obtained as a
reasonably stable crystalline substance melting at 148-149
°C.
The dienophile 3-methyleneoxindole (9) was synthesized
by the method of Rossiter.12 To obtain pure 9 in high yield
we found it essential to repeatedly wash a methylene chloride
(6) Pellegrini, C.; Strassler, C.; Weber, M.; Borschberg, H.-J. Tetra-
hedron: Asymmetry 1994, 5, 1979-1982.
(7) A possible Diels-Alder approach to the synthesis of 1 is alluded to
in a footnote to the full paper by Hart and Magomedov cited as ref 5 above.
(8) Hernandez, F.; Buenadicha, F. L.; Avendano, C.; Sollhuber, M.
Tetrahedron: Asymmetry 2001, 12, 3387-3398.
(10) (a) Snider, B. B.; Zeng, H. Org Lett. 2000, 2, 4103-4106. (b) He,
H.; Snider, B. B. J. Org Chem. 1999, 64, 1397-1399.
(11) For a related aromatization see: Blake, K. W.; Porter, A. E. A.;
Sammes, P. G. J. Chem. Soc., Perkin Trans. 1 1972, 2494-2497.
(12) Rossitter, S. Tetrahedron Lett. 2002, 43, 4671-4673.
(9) Mazurkiewicz, R. Monatsh. Chem. 1989, 120, 973-980.
3206
Org. Lett., Vol. 5, No. 18, 2003

product 15 corresponds to an exo cycloaddition, a preference
consistent with the observations of Langlois and Ghosez14and
calculation by Sustmann and Sicking.15 This exo stereo-
chemistry of 15, which corresponds to that of alantrypinone,
Scheme 3
1
is readily differentiated by H NMR from that of its endo
isomer 16 by the chemical shift of the C(24) aromatic proton
ortho to the spirocyclic center. Whereas in 15 this signal
comes at δ 6.81, in 16 that signal is at δ 5.87 because of the
anisotropic shielding by the quinazoline π system. These
structural assignments were confirmed by mild acid hydroly-
sis of adduct 15 and adduct 16 to yield respectively (()-
alantrypinone (1) and (()-17-epi-alantrypinone (17). Our
synthetic (()-alantrypinone showed 1H NMR and 13C NMR
spectra in agreement with the data reported in the literature.1,5
The 1H NMR of the 17-epimer again displayed the diagnostic
upfield signal of H(24) at δ 5.95, in contrast to that of
alantrypinone at δ 7.16.
Although the stereochemical ratio of 16 to 15 in our
Diels-Alder sequence thus favored the natural series, we
envisioned the possibility that this ratio could be enhanced
by thermal equilibration of 17-epi-alantrypinone to the natural
isomer. When a dioxane or d6-DMSO solution of 17 was
heated overnight to 100 °C, no conversion to 1 was observed.
However, when 17 in d6-DMSO was treated with 0.1 equiv
of DBU and held at 100 °C for 45 min, approximately
60% of 17 was converted into 1, and after 1.5 h some 75%
of 1 was produced. Likewise, when (()-alantrypinone was
heated for 2.5 h under the same conditions, a 3:1 ratio of 1
to 17 was again generated. This DBU-catalyzed equilibration
did not occur at 100 °C in dioxane, and the reaction in d6-
DMSO was not inhibited by the addition of excess N-
phenylmaleimide. These data appear to exclude a retro-
Diels-Alder process for the equilibration. We conclude that
this interesting epimerization is an intramolecular rearrange-
ment involving an anionic retro-Mannich reaction, which
probably proceeds by the mechanism described in Scheme
4.16
extract of the final reaction mixture with saturated aqueous
sodium bicarbonate to neutralize traces of acid. The aza-
Diels-Alder reaction between diene 8 and dienophile 9
proceeded smoothly in chloroform at room temperature to
produce a chromatographically separable mixture of adduct
15 in 55% yield and adduct 16 in 18% yield (Scheme 3).
The regiochemistry of the Diels-Alder reaction was indi-
cated by the presence in the 1H NMR of a triplet near δ 6.1
for the bridgehead proton in each isomer, consistent with
the presence of a vicinal CH2 unit. The observed regiochem-
istry in adducts 15 and 16 paralleled that observed for some
related cycloadditions,13 and is consonant with the predomi-
nant direction of postulated dipolar contributors to the Diels-
Alder transition state. It is of further interest that the major
Scheme 4
Org. Lett., Vol. 5, No. 18, 2003
3207

We have thus achieved a concise total synthesis of (()-
alantrypinone by a hetero-Diels-Alder strategy leading from
anthranilic acid to racemic 1 in 8 steps and 13.5% overall
yield. The regioselective and exo-selective cycloaddition of
3-methyleneoxindole and the novel azadiene 8 has been
observed, and the facile anionic equilibration between 1 and
17 has been demonstrated. Further studies on the scope of
Diels-Alder additions to 8 and extensions of the epimer-
ization reaction at C(17) are under investigation.
(13) (a) Jnoff, E.; Ghosez, L. J. Am. Chem. Soc. 1999, 121, 2617-2618.
(b) Rivera, M.; Lamy-Schelkens, H.; Sainte, F.; Mbiya, K.; Ghosez, L.
Tetrahedron Lett. 1988, 29, 4573-4576.
(14) Pouilhes, A.; Langlois, Y.; Nshimyumukiza, P.; Mbiya, K.; Ghosez,
L. Bull. Soc. Chim. Fr. 1993, 130, 304-309.
(15) Sustmann, R.; Sicking, W. Tetrahedron 1992, 48, 10293-10300.
(16) For a somewhat related retroaldol epimerization in a synthesis of
(()-gelsemine see: Atarashi, S.; Choi, J.-K.; Ha, D.-C.; Hart, D. J.;
Kuzmich, D.; Lee, C.-S.; Ramesh, S.; Wu, S. C. J. Am. Chem. Soc. 1997,
119, 6226-6241. We thank Prof. N. Magomedov for calling this reference
to our attention.
1
Supporting Information Available: Data including H
NMR and 13C NMR spectra for 1, 8, 13, 15, 16, and 17.
This material is available free of charge via the Internet at
http://pubs.acs.org.
OL030070L
3208
Org. Lett., Vol. 5, No. 18, 2003