Dihydropyrones as dienophiles in the Diels-Alder reaction: Application to the synthesis of 1-oxadecalones

Full text of DOI:10.1021/jo982488g

1776
J . Org. Chem. 1999, 64, 1776-1777
Dih yd r op yr on es a s Dien op h iles in th e
Diels-Ald er Rea ction : Ap p lica tion to th e
Syn th esis of 1-Oxa d eca lon es
Deqi Chen, J unquan Wang, and Nancy I. Totah*
Department of Chemistry, University of Iowa,
Iowa City, Iowa 52242
Received December 29, 1998
The 1-oxadecalin unit serves as the structural core for a
number of naturally occurring compounds, including the
reduced furochroman phomactin A (1, Figure 1),1 as well as
a variety of diterpenoids such as forskolin (2),2 jamesoniellide
E (3),3 and scutorientalin D (4).4 Many of these compounds
exhibit intriguing biological properties, though the diverse
array of structural features present in these systems make
them challenging synthetic targets.
Our interest in the development of new strategies for the
synthesis of complex substrates, in particular toward the
preparation of the PAF antagonist phomactin A, led us to
consider a general approach to the synthesis of highly
functionalized 1-oxadecalone derivatives.5 Our goal in this
endeavor was to develop an expedient entry to the basic 6,6-
ring system, while at the same time providing sufficient
functionality to allow for subsequent synthetic manipulation.
Toward this end, we envisaged that the Diels-Alder reaction
of a suitably functionalized 2,3-dihydro-4-pyrone with a
diene would effectively meet these criteria. Though several
related examples have appeared using chromone6 and py-
rone7 derivatives as dienophiles in [4 + 2] cycloaddition
reactions, to the best of our knowledge, dihydropyrones of
this type have not previously been utilized in this applica-
tion. Herein we report the successful implementation of this
strategy for the synthesis of highly functionalized 1-oxade-
calone derivatives.
In practice, we chose to explore the reactivity of 2,3-
dihydro-4-pyrones that contain an electron-withdrawing
substituent at C5 (e.g., 5).8 We anticipated the need for this
functionality to enhance the reactivity of these substrates
as dienophiles relative to that of the parent dihydropyrones.9
As the C5 substituent of the dihydropyrone would ultimately
be located at the ring junction of the 1-oxadecalone unit,
incorporation of diverse functionality at this position would
provide added flexibility in the application of this method
to the synthesis of more complex systems. As shown,
F igu r e 1.
derivatives of this type react readily with electron-rich
dienes to provide highly functionalized 1-oxadecalone de-
rivatives (Table 1).
We first examined the reaction of the 5-carbethoxy dihy-
dropyrone derivative 5a with the tert-butyldimethylsilyl
derivative of Danishefsky′s diene 8 (entry 1). Here, Diels-
Alder reaction occurs in refluxing toluene to provide the
Diels-Alder adduct in 85% yield as a ca. 6:1 mixture of
diastereomers.10,11 In this case, stereochemistry is of little
consequence as the C5 stereocenter is subsequently de-
stroyed. Here, direct hydrolysis of the enol ether is compli-
cated by the facile degradation of the product 1-oxadecalone
(7, W ) CO2Et, X ) H) to give ethyl p-hydroxybenzoate.
Presumably, formation of this contaminant results from
hydration of the C4 ketone (e.g., 7), with subsequent retro-
Claisen reaction, elimination, and aromatization of the
carbocyclic ring (Figure 2).12 This process can be cleanly
circumvented by reduction at C4 prior to hydrolysis. Though
in certain cases derivatives of this type can be isolated with
the C4 ketone intact (entries 3, 4, and 7), in general,
1-oxadecalone derivatives (7) that lack a substituent at C5
are subject to this degredative aromatization pathway. Upon
incorporation of added functionality at C1 of the diene (and
hence at C5 of the 1-oxadecalone), direct hydrolysis of the
initially formed enol ethers occurs to give a stable product
(entries 8-14).13
A variety of functionalized 1-oxadecalones are accessible
by this method. As anticipated, a number of different
electron-withdrawing substituents can be utilized to activate
the dienophile toward Diels-Alder reaction. In addition to
the 5-carbethoxy derivative 5a , 5-cyano- (5b), 5-phenyl
sulfone- (5c), and 5-acetyl-2,3-dihydro-4-pyrones (5d ) par-
ticipate readily in the cycloaddition reaction. Though best
results are obtained in the reactions of the dihydropyrones
with unhindered, highly oxygenated dienes,14 even 1,1-
* To whom correspondence should be addressed. Tel: (319)335-1198.
Fax: (319) 335-1270. E-mail: nancy-totah@uiowa.edu.
(1) Sugano, M.; Sato, A.; Iijima, Y.; Oshima, T.; Furuya, K.; Kuwano,
H.; Hata, T.; Hanzawa, H. J . Am. Chem. Soc. 1991, 113, 5463. For
a
synthetic approach to the tricyclic furanochroman core of phomactin A,
see: Foote, K. M.; Hayes, C. J .; Pattenden, G. Tetrahedron Lett. 1996, 37,
275.
(2) Bhat, J . V.; Bajwa, B. S.; Dornauer, H.; de Souza, N. J .; Fehlhaber,
H. W. Tetrahedron Lett. 1977, 33, 1669. (b) Ueno, Y. Trichotheceness
Chemical, Biological, and Toxicological Aspects; Elsevier: Amsterdam, 1983;
Vol. 4.
(3) Tazaki, H.; Zapp, J .; Becker, H. Phytochemistry 1995, 39, 859.
(4) Malakov, P. Y.; Papanov, G. Y.; Spassov, S. L. Phytochemistry 1997,
44, 121.
(5) For the synthesis of simple 1-oxadecalins see: (a) Anzalone, L.; Hirsch,
J . A. J . Org. Chem. 1985, 50, 2608. (b) Dolmazon, R.; Gelin, S. J . Org. Chem.
1984, 49, 4003.
(10) The stereochemistry of the major diastereomer is tentatively as-
signed as that bearing an R-methoxy function at C5 (cf. 6). This stereo-
chemical assignment is based on the observation of long-range coupling
between protons on C5 and C8a of the major Diels-Alder adduct.
(11) Though 85% represents the yield of the purified Diels-Alder adduct,
routinely these compounds are utilized in subsequent transformations
without purification.
(6) (a) Cremins, P. J .; Saengchantara, S. T.; Wallace, T. W. Tetrahedron
1987, 43, 3075. (b) Sain, B.; Prajapati, D.; Mahajan, A. R.; Sandhu, J . S.
Bull. Chem. Soc. Fr. 1994, 131, 313. (c) Ohkata, K.; Kubo, T.; Miyamoto,
K.; Ono, M.; Yamamoto, J .; Akiba, K. Heterocycles 1994, 38, 1483. (d) Hsung,
R. P. J . Org. Chem. 1997, 62, 7904.
(12) Ethyl p-hydroxybenzoate can be isolated cleanly from the reaction
mixture.
(7) Groundwater, P. W.; Hibbs, D. E.; Hursthouse, M. B.; Nyerges, M. J .
Chem. Soc., Perkin Trans. 1 1997, 163.
(8) Totah, N. I.; Chen, D. Tetrahedron Lett. 1998, 39, 213.
(9) To date we have been unable to identify conditions under which the
parent 2,3-dihydro-2,2-dimethyl-4-pyranone will react, even with highly
activated dienes.
(13) Presumably, the presence of a substituent at C5 impedes hydration
of the C4 ketone due to an increase in steric hindrance.
(14) Petrzilka, M.; Grayson, J . I. Synthesis 1981, 753.
(15) Under thermal conditions, hydrolysis of the diene predominates,
particularly at elevated temperatures. Cf. Rathke, M. W.; Sullivan, D. F.
Synth. Commun. 1973, 67.
10.1021/jo982488g CCC: $18.00 © 1999 American Chemical Society
Published on Web 02/27/1999

Communications
J . Org. Chem., Vol. 64, No. 6, 1999 1777
Ta ble 1. Syn th esis of 1-Oxa d eca lon es
derivative 5a occurs readily to provide the desired Diels-
Alder adduct as a 2.3:1 mixture of diastereomers.
In conclusion, we have demonstrated for the first time that
2,3-dihydro-4-pyrones can serve effectively as dienophiles in
the Diels-Alder reaction. In this way, a variety of highly
functionalized 1-oxadecalins are readily available under
relatively mild conditions. Furthermore, by modifying the
electron-withdrawing group at C5 of the dihydropyrone a
variety of functionalities can be incorporated at the ring
junction. This ability should allow for added flexibility in
the synthesis of more complex substrates. Further studies
aimed at expanding the scope and application of this method
are currently underway. These results will be reported in
due course.
F igu r e 2.
disubstituted dienes such as 11 and 12 (entries 12-14) react
to give reasonable yields of 1-oxadecalone derivatives in the
two-step Diels-Alder/hydrolysis sequence.
Ack n ow led gm en t. We thank the National Science
Foundation (CHE-9700141) and the Carver Charitable
Trust for support of this work.
Conversely, 1-(tert-butyldimethylsilyloxy)-1-methoxy-3-
methyl-1,3-butadiene 13 reacts only slowly with dihydropy-
rones of these types, and little of the cycloadduct is observed
under thermal conditions, even in the presence of a large
excess of diene.15 However, in the presence of a catalytic
amount of Lewis acid, Diels-Alder reaction of the cyano
Su p p or tin g In for m a tion Ava ila ble: Experimental proce-
dures, compound characterization data, and copies of spectra for
compounds 14-19.
J O982488G