7
904
J . Org. Chem. 1997, 62, 7904-7905
F ir st Ster eoselective [4 + 2] Cycloa d d ition
tems for exploring the potential of our strategy as well
as for investigating the scope (i.e., regio- and stereose-
lectivity) of γ-pyrones in [4 + 2] cycloadditions. In
addition, the aromatic ring of cyanochromone derivatives,
when appropriately substituted, could serve as a precur-
sor for constructing the D-ring of arisugacin, and more
importantly, analogues of arisugacin containing aromatic
D-rings could offer interesting biological activities. We
report here our initial success in achieving high stereo-
selectivities in the first [4 + 2] cycloaddition reactions
using 3-cyanochromone derivatives as dienophiles and
in demonstrating the synthetic application of this reac-
tion for constructing the ABC tricyclic core of arisugacin.
The reaction of 3-cyanochromone (5) with TBS-pro-
tected Danishefsky’s diene (6) in toluene proceeded well
at 200 °C in a sealed tube for 72 h to give the desired
cycloadduct 7 in 80% yield (Scheme 1) without observing
Rea ction s of 3-Cya n och r om on e Der iva tives
w ith Electr on -Rich Dien es: An Ap p r oa ch
to th e ABC Tr icyclic F r a m e of Ar isu ga cin 1
Richard P. Hsung
Department of Chemistry, University of Minnesota,
Minneapolis, Minnesota 55455
Received August 11, 1997
Our interest in arisugacin (1), a novel and selective
inhibitor of acetylcholine esterase that was isolated from
penicillium sp. Fo-4259,2 has led us to explore the
synthetic potential of γ-pyrones as dienophiles in [4 + 2]
cycloaddition reactions. Particularly, we envisioned that
if dienes such as 2 could be used, then such a cycload-
9
any inverse-electron demand [4 + 2] cycloadducts.
However, the endo:exo ratio was only 1.3:1 as determined
from 1H NMR, and the stereochemistry was assigned
according to NOE experiments.10 A strong electron-
withdrawing group at the C-3 position was essential and
the most effective in adjusting the electron density of the
γ-pyrone system of chromone derivatives and enhancing
the dienophilic reactivity. For examples, 3-bromo-
chromone (8)11 was found to be reactive only with 1,3-
cyclohexadiene giving the adduct 10 in <16% yield with
an isomeric ratio of 2:1 (stereochemistry not vigorously
assigned) after heating at 300 °C for 120 h. An acyl group
at the C-2 position rendered the compound 9 more
reactive providing 11 (1:1 endo:exo) in 25% yield after
dition would lead to a convergent approach for construct-
ing not only the tetracyclic frame of arisugacin, but also
of other structurally analogous natural products such as
pyripyropenes3 and forskolin.4 Given the significant
therapeutic potential of arisugacin in the treatment of
Alzheimer’s disease,2 this strategy could serve as a
useful entry to a wide range of structural analogues with
unique biological activities.
1
20 h at 270 °C, but the regioselectivity suffered in this
case since regioisomers were isolated in an equal amount.
The reactions of 5 with 1-methoxy-1,3-butadiene pro-
vided a much different stereochemical outlook giving the
cycloadduct 12 in 83% yield with an endo:exo ratio of 92:8
,5
(entry 1 in Table 1). This represents the first example
of a highly diastereoselective [4 + 2] cycloaddition reac-
tion involving a γ-benzopyrone dienophile.6b Subsequent
reactions of 5 with all other less oxygenated dienes were
found to be highly endo selective (Table 1, entries 2-4).
However, the rate of reaction was noticeably slower when
the electron density of the diene decreased. For nonoxy-
genated dienes, reactions had to be promoted by the use
of a Lewis acid (Table 1, entries 4 and 5). After screening
It was surprising to find that there have been very few
reports on [4 + 2] cycloaddition reactions using γ-pyrones
as dienophiles.6
,7
We have focused our interest on
3
-cyanochromone derivatives because to the best of our
knowledge, the dienophilic reactivity of these compounds
8
have gone unnoticed, and they could be excellent sys-
a variety of Lewis acids, TiCl
4
(1.0 equiv) was found to
(
1) The preliminary results of this work were carried out at
Columbia University.
2) For isolation of arisugacin see: (a) Omura, S.; Kuno, F.; Otoguro,
K.; Sunazuka, T.; Shiomi, K.; Masuma, R.; Iwai, Y. J . Antibiot. 1995,
8, 745. For biological activities of arisugacin see: (b) Kuno, F.;
Otoguro, K.; Shiomi, K.; Iwai, Y.; Omura, S. J . Antibiot. 1996, 49, 742.
c) Kuno, F.; Shiomi, K.; Otoguro, K.; Sunazuka, T.; Omura, S. J .
Antibiot. 1996, 49, 748.
3) (a) Tomoda, H.; Tabata, N.; Yang, D. J .; Namatame, I.; Tanaka,
be most suitable, and the stereoselectivity in these
reactions remained in favor of the endo products (Table
1, entry 4). When the diene 16, which bears an electron-
withdrawing group was used, no cycloadducts were
isolated under any conditions (Table 1, entry 6). In
comparison, the diene 16 reacted well with 2-cyclohex-
enone and methyl vinyl ketone under Lewis acid condi-
(
4
(
(
H.; Omura, S.; Kaneko, T. J . Antibiot. 1996, 49, 292. (b) Smith, A. B.,
III; Kinsho, T.; Sunazuka, T.; Omura, S. Tetrahedron Lett. 1996, 6461.
(
Soc. 1988, 110, 3672. (b) Ziegler, F. E.; J aynes, B. H.; Saindane, M. T.
Ibid. 1987, 109, 8115.
12
tions. This suggests that the lack of reactivity observed
4) (a) Corey, E. J .; J ardine, P. D. S.; Rohloff, J . C. J . Am. Chem.
here with 3-cyanochromone (5) is likely not due to the
steric nature (being 1,1-disubstituted) but rather the
(
5) (a) Alzheimer, A. Gesamte Psych. 1907, 64, 1264. Arisugacin’s
therapeutic potential was found on the basis of the cholinergic
hypothesis since it is a potent inhibitor of acetylcholine esterase
AChE). For a leading reference see: (b) J a e´ n, J . C.; Gregor, V. E.;
Lee, C.; Davis, R.; Emmerling, M. Bioorg. Med. Chem. Lett. 1996, 6,
37. For a leading reference on another potent inhibitor huperzine
see: (c) Kozikowski, A. P.; Ding, Q. J .; Saxena, A.; Doctor, B. P. Bioorg.
Med. Chem. Lett. 1996, 6, 259.
(8) 3-Cyano-4H-benzopyran-4-thione was reported to give xanthione
upon reacting with 1-(dimethylamino)-1,3-butadiene. An initial [4 +
2] cycloadduct, albeit never isolated, was postulated as the intermedi-
ate involved in providing xanthione after dehydroamination and
dehydrocyanation. See: Sain, B.; Prajapati, D.; Mahajan, A. R.;
Sandhu, J . S. Bull. Soc. Chim. Fr. 1994, 131, 313.
(
7
(9) Wallace, T. W.; Wardell, I.; Li, K.-D.; Leeming, P.; Redhouse, A.
D.; Chanlland, S. R. J . Chem. Soc., Perkin Trans. 1 1995, 2293.
(10) NOE enhancement was observed only for the tertiary allylic
hydrogen on the newly formed ring upon irradiation of the â-hydrogen
on the γ-pyrone ring in endo-7, whereas NOE enhancement was
observed only for methyl hydrogens upon irradiation of the same
â-hydrogen in exo-7.
(6) (a) Cremins, P. J .; Saengchantara, S. T.; Wallace, T. W. Tetra-
hedron 1987, 13, 3075. (b) Ohkata, K.; Kubo, T.; Miyamoto, K.; Ono,
M.; Yamamoto, J .; Akiba, K. Heterocycles 1994, 38, 1483.
(7) (a) Groundwater, P. W.; Hibbs, D. E.; Hursthouse, M. B.;
Nyerges, M. J . Chem. Soc., Perkin Trans. 1 1997, 163. (b) Chen, D.;
Totah, N. I. Abstracts of Papers, 213th National Meeting of the
American Chemical Society, San Francisco, CA, Spring 1997; American
Chemical Society: Washington, DC, 1997; ORGN-173.
(11) Gammill, R. B. Synthesis 1979, 901.
(12) Stork, G.; Hsung, R. P. Unpublished results.
S0022-3263(97)01479-5 CCC: $14.00 © 1997 American Chemical Society