A one-step synthesis of 2,3-dihydro-4H-pyran-4-ones from 3-ethoxy α,β-unsaturated lactones

Article abstract of DOI:10.1021/ol050702z

(Chemical Equation Presented) Addition of diverse nucleophiles to the unsaturated lactone 2 that results from hetero Diels-Alder reaction of Brassard's diene 1 with aldehydes leads to an efficient and general approach to the synthesis of 2,3-dihydro-4H-py

Full text of DOI:10.1021/ol050702z

ORGANIC
LETTERS
2
005
Vol. 7, No. 12
421-2423
A One-Step Synthesis of
2
2
,3-Dihydro-4H-pyran-4-ones from
-Ethoxy -Unsaturated Lactones
3
r,â
Jeffrey D. Winkler* and Kyungsoo Oh
Department of Chemistry, The UniVersity of PennsylVania,
Philadelphia, PennsylVania 19104
winkler@sas.upenn.edu
Received April 1, 2005
ABSTRACT
Addition of diverse nucleophiles to the unsaturated lactone 2 that results from hetero Diels−Alder reaction of Brassard’s diene 1 with aldehydes
leads to an efficient and general approach to the synthesis of 2,3-dihydro-4H-pyran-4-ones 3.
Dihydropyranones are ubiquitous functionalities in molecules
of Nature. They also represent important intermediates in
the synthesis of a variety of different structures, many of
Scheme 1
1
biological and medicinal significance. While several groups
have examined the preparation of the dihydropyranone ring
via aldol reaction of the dianion derived from a â-diketone
2
with an aldehyde, followed by cyclization of the resulting
hydroxydiketone to the dihydropyranone, we have developed
an alternative protocol for the synthesis of this ring system
as outlined in Scheme 1. Addition of a series of nucleophiles
to 2, the product of hetero Diels-Alder reaction of Brassard’s
diene with an aldehyde, leads to the formation of dihydro-
pyranone 3. This approach allows for considerable flexibility
in the nature of both the aldehyde R group and the
the cycloaddition is more efficient with a polymer-bound
diene moiety. We have examined the reaction of a series
of Lewis acids with the ethyl analogue 1 of Brassard’s diene
as outlined in Scheme 1. With 1 equiv of diene, the
cycloaddition reaction proceeds efficiently using 100 mol
nucleophile, facilitating the preparation of a diverse array
of dihydropyranones.
4
The reaction of Brassard’s diene with aldehydes was first
3
reported by Midland, although it was recently reported that
(1) Jorgensen, K. A. Angew. Chem., Int. Ed. 2000, 39, 3558. Faul, M.
%
diethylaluminum chloride or 5 mol % yitterbium triflate
M.; Huff, B. E. Chem. ReV. 2000, 100, 2407. Fleming, I.; Barbero, A.;
Walter, D. Chem. ReV. 1997, 97, 2063. Danishefsky, S. J.; Biolodeau, M.
T. Angew. Chem., Int. Ed. Engl. 1996, 35, 1380.
to give 2a in 56 and 48% yield, respectively.
These results were then applied to a series of aldehydes
and to cyclohexanone (entry 2f) as outlined in Table 2. Under
(
2) Voight, E. A.; Roethle, P. A.; Burke, S. D. J. Org. Chem. 2004, 69,
4
2
1
534. Henryon, V.; Liu, L. W.; Lopez, R.; Prunet, J.; Ferezou, J.-P. Synthesis
001, 2401. Molander, G. A.; Cameron, K. O. J. Am. Chem. Soc. 1993,
15, 830. Brownbridge, P.; Chan, T. H.; Brook, M. A.; Kang, G. J. Can. J.
(3) Midland, M. M.; Graham, R. S. J. Am. Chem. Soc. 1984, 106, 4294.
(4) Pierres, C.; George, P.; Hijfte, L.; Ducep, J.-B.; Hilbert, M.; Mann,
A. Tetrahedron Lett. 2003, 44, 3645.
Chem. 1983, 61, 688. For oxidative cyclization of the â-hydroxyeneone,
see: Reiter, M.; Ropp, S.; Gouverneur, V. Org. Lett. 2004, 6, 91.
1
0.1021/ol050702z CCC: $30.25
© 2005 American Chemical Society
Published on Web 05/11/2005

Table 1. Hetero Diels-Alder Reactions of Brassard’s Diene 1
with n-Heptaldehyde in the Presence of a Lewis Acid
Table 3. Hetero Diels-Alder Reactions of Brassard Diene 1
with n-Heptaldehyde in the Presence of Chiral Lewis Acids
entry
Lewis acid (mol %)
reaction time (h)
yield (%)
entry
Lewis acid (mol %)
yield (%)
ee (%)
1
2
3
4
5
6
7
Ti(i-PrO)4 (100)
BF3‚OEt2 (100)
ZnCl2 (100)
Et2AlCl (100)
Yb(OTf)3 (5)
Sc(OTf)3 (5)
18
18
18
18
48
48
48
2
7
11
56
48
3
1
2
3
Feng’s catalyst (10)
(+)-Eu(hfc)3 (5)
Jacobsen’s catalyst (1.5)
14
39
14
8.0
6.5
4.5
lanthanide catalysts (entry 2) proved to be unsuccessful. The
control of the absolute stereochemistry of the reaction
remains an unsolved problem.
In(OTf)3 (5)
8
Stork has described the utility of vinylogous esters for the
synthesis of â-substituted cyclohexenones via nucleophilic
addition and acid rearrangement. We reasoned that the
analogous reaction of vinylogous carbonate 2a could lead
our optimized conditions, 2.5 equiv of the diene 1 was
necessary to give the cycloadducts, 2a-f, in good to excellent
yields. These results indicate that diethylaluminum chloride
efficiently mediates the cycloaddition of carbonyl dienophiles
with Brassard’s diene 1.
7
to a general approach to the synthesis of dihydro-
8
pyranones 3a-g. In contrast to the results of Anand and
9
Firth , who reported that reactions of vinylogous carbonates
with excess of Grignard reagents lead to ring opened double
addition products, we find that, at low temperature, the
monoaddition of diverse nucleophiles occurs to generate the
requisite dihydropyranones (Table 4).
Table 2. Hetero Diels-Alder Reactions of Brassard’s Diene 1
with Carbonyl Dienophiles
Table 4. Preparation of 2,3-Dihydro-4H-pyran-4-ones from
Nucleophilic Addition to 3-Ethoxy R,â-Unsaturated Lactone
entry
R1
R2
yield (%)
2a
2b
2c
2d
2e
2f
H
H
H
H
H
(CH2)5CH3
Ph
c-Hexyl
t-Bu
CH2CH2OBn(CH2)5CH3
-CH2(CH2)3CH2-
68
79
83
96
33
97
Feng and Zhang recently reported the reaction of Bras-
sard’s diene 1 with aldehydes to give dihydropyranones
mediated by the use of a tridentate titanium catalyst with
5
high enantioselectivities. We examined a series of chiral
catalysts for the cycloaddition as shown in Table 3. While
Feng’s catalyst gives very high enantiomeric excess with
aromatic aldehydes as reported, the analogous reaction of
aliphatic aldehydes proceeds in low yield with poor enan-
tiocontrol (entry 1). We have also found that the Jacobsen
catalyst, which mediates the reaction of furan nucleophiles
6
with aldehydes with very high enantioselectivity, leads to
modest selectivity in this system. Similarly, the use of
We have now demonstrated that coupling the hetero
Diels-Alder reaction of Brassard’s diene and aldehydes with
nucleophilic addition to the resulting vinylogous carbonate
(5) Fan, Q.; Lin, L.; Liu, J.; Huang, Y.; Feng, X.; Zhang, G. Org. Lett.
2
004, 6, 2185.
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Org. Lett., Vol. 7, No. 12, 2005

leads to a general approach to the synthesis of dihydropy-
ranones. The application of this methodology to the synthesis
of dihydropyranone-containing natural products is currently
underway in our laboratory, and our results will be reported
in due course.
Acknowledgment. We would like to thank the National
Institutes of Health (GM065941), GlaxoSmithKline, and
Amgen for their generous support of this program.
Supporting Information Available: Experimental pro-
cedures and spectral data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(6) Winkler, J. D.; Oh, K.; Asselin, S. M. Org. Lett. 2005, 7, 387. Also
see Supporting Information.
(
(
(
7) Stork, G.; Danheiser, R. J. Org. Chem. 1973, 38, 1775.
8) Anand, R. C.; Ranjan, H. Indian J. Chem., Sect. B 1985, 24B, 560.
9) Firth, J. W.; Livingstone, R. J. Chem. Res., Miniprint. 2000, 7, 308.
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