A Lewis acid-catalyzed formal [3 + 3] cycloaddition of α,β- unsaturated aldehydes with 4-hydroxy-2-pyrone, diketones, and vinylogous esters

Article abstract of DOI:10.1021/ol0523042

A Lewis acid-catalyzed formal cycloaddition of α,β-unsaturated aldehydes with 6-methyl-4-hydroxy-2-pyrone, 1,3-diketones, and vinylogous silyl esters is described here.

Full text of DOI:10.1021/ol0523042

ORGANIC
LETTERS
2006
Vol. 8, No. 2
191-193
A Lewis Acid-Catalyzed Formal [3
Cycloaddition of -Unsaturated
Aldehydes with 4-Hydroxy-2-Pyrone,
Diketones, and Vinylogous Esters
+ 3]
r,â
Aleksey V. Kurdyumov, Nan Lin, Richard P. Hsung,*,† Glen C. Gullickson,
Kevin P. Cole, Nadiya Sydorenko, and Jacob J. Swidorski
Department of Chemistry, UniVersity of Minnesota, Minneapolis, Minnesota 55455
rphsung@pharmacy.wisc.edu
Received September 22, 2005
ABSTRACT
A Lewis acid-catalyzed formal cycloaddition of
silyl esters is described here.
r,â-unsaturated aldehydes with 6-methyl-4-hydroxy-2-pyrone, 1,3-diketones, and vinylogous
Recently, we have been developing a formal cycloaddition
or annulation reaction involving R,â-unsaturated aldehydes
and 1,3-dicarbonyls,1-3 and have employed this strategy in
the synthesis of natural products.4-8 The tandem nature9 of
this annulation involves an initial condensation of 3 with
iminium ions 2 followed by 6π-electron electrocyclic ring-
closure of 1-oxatrienes 610,11 [Scheme 1]. It has become
increasingly evident from the literature12-14 that this bio-
inspired strategy is both useful and practical for constructing
(9) For reviews on sequential strategies, see: (a) Tietze, L. F. Chem.
ReV. 1996, 96, 115. (b) Tietze, L. F.; Beifuss, U. Angew. Chem., Int. Ed.
1993, 32, 131.
(10) For leading references on electrocyclic ring-closures of 1-oxatrienes
see: (a) Shishido, K.; Ito, M.; Shimada, S.-I.; Fukumoto, K.; Kametani, T.
Chem. Lett. 1984, 1943. (b) Shishido, K.; Shitara, E.; Fukumoto, K. J. Am.
Chem. Soc. 1985, 107, 5810. (c) Shishido, K.; Hiroya, K.; Fukumoto, K.;
Kametani, T. Tetrahedron Lett. 1986, 27, 971.
(11) For some examples of natural product syntheses employing elec-
trocyclic ring-closures of 1-oxatrienes, see: (a) Tambar, U. K.; Kano, T.;
Stoltz, B. M. Org. Lett. 2005, 7, 2413. (b) Li, C.; Johnson, R. P.; Porco, J.
A., Jr. J. Am. Chem. Soc. 2003, 125, 5095.
(12) For recent studies on related formal cycloaddition reactions in the
syntheses of pyranyl heterocycles, see: (a) Grecian, S.; Wrobleski, A. D.;
Aube, J. Org. Lett. 2005, 7, 3167. (b) Sagar, R.; Singh, P.; Kumar, R.;
Maulik, P. R.; Shaw, A. K. Carbohydr. Res. 2005, 340, 1287. (c) Itoh, K.;
Hasegawa, M.; Tanaka, J.; Kanemasa, S. Org. Lett. 2005, 7, 979. (d)
Pettigrew, J. D.; Cadieux, J. A.; So, S. S. S.; Wilson, P. D. Org. Lett. 2005,
7, 467.
† Current address: Division of Pharmaceutical Sciences and Department
of Chemistry, University of Wisconsin, Madison, WI 53705-2222.
(1) For reviews, see: (a) Harrity, J. P. A.; Provoost, O. Org. Biomol.
Chem. 2005, 3, 1349. (b) Hsung, R. P.; Kurdyumov, A. V.; Sydorenko, N.
Eur. J. Org. Chem. 2005, 1, 23.
(2) For a recent reference on the chemistry of 1,3-dicarbonyls, see:
Simon, C.; Constantieux, T.; Rodriguez, J. Eur. J. Org. Chem. 2004, 4957.
(3) For methodological developments, see: Shen, H. C.; Wang, J.; Cole,
K. P.; McLaughlin, M. J.; Morgan, C. D.; Douglas, C. J.; Hsung, R. P.;
Coverdale, H. A.; Gerasyuto, A. I.; Hahn, J. M.; Liu, J.; Wei, L.-L.;
Sklenicka, H. M.; Zehnder, L. R.; Zificsak, C. A. J. Org. Chem. 2003, 68,
1729.
(4) Cole, K. P.; Hsung, R. P. Org. Lett. 2003, 5, 4843.
(5) Kurdyumov, A. V.; Hsung, R. P.; Ihlen, K.; Wang, J. Org. Lett. 2003,
5, 3935.
(6) (a) Hsung, R. P.; Cole, K. P.; Zehnder, L. R.; Wang, J.; Wei, L.-L.;
Yang, X.-F.; Coverdale, H. A. Tetrahedron 2003, 59, 311. (b) Zehnder, L.
R.; Hsung, R. P.; Wang, J.; Golding, G. M. Angew. Chem., Int. Ed. 2000,
39, 3876.
(13) For some earlier studies, see: (a) Stevenson, R.; Weber, J. V. J.
Nat. Prod. 1988, 51, 1215. (b) Schuda, P. F.; Price, W. A. J. Org. Chem.
1987, 52, 1972. (c) de March, P.; Moreno-Man˜as, M.; Casado, J.; Pleixats,
R.; Roca, J. L. J. Hetrocycl. Chem. 1984, 21, 85.
(7) Cole, K. P.; Hsung, R. P. Tetrahedron Lett. 2002, 43, 8791.
(8) McLaughlin, M. J.; Hsung, R. P. J. Org. Chem. 2001, 66, 1049.
10.1021/ol0523042 CCC: $33.50
© 2006 American Chemical Society
Published on Web 12/16/2005

Scheme 1. A Formal oxa-[3 + 3] Annulation
Table 2. Screening of Lewis Acids for the Reaction of 11
temp
[°C]
time
[h]
yield
[%]a
entry
LA
equiv
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
BF3-Et2O
BF3-Et2O
BF3-Et2O
BF3-Et2O
BF3-Et2O
TiCl4
TiCl4
Ti(i-PrO)3Cl
SnCl4
Sn(OTf)2
AlCl3
FeCl3
Mg(OTf)2
CuCl
ZnBr2
0.50
0.50
0.50
0.10
0.05
0.10
0.01
0.10
0.10
0.10
0.10
0.10
0.10
0.10
0.10
0.01
0.10
0.10
rt
0
16
16
24
16
16
16
24
16
16
16
16
16
48
48
48
48
24
48
94
86
[50]b
80
65
95
70
35
81
83
79
77
65
74
72
48
71
95
-10
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
2H-pyrans 7 from rather simple and cost-effective starting
materials.
There remain two significant problems with this reaction:
(1) high temperatures are required [80-150 °C] and (2) in
many cases pregeneration of iminium intermediates 2 is
necessary prior to the addition of 3 to control the regio-
chemistry and enhance the overall yield.15
ZnBr2
Zn(OTf)2
In(OTf)3
This led us to explore if this annulation can be catalyzed
or promoted by a Lewis acid16,17 and proceed under a milder
reaction temperature. We report here a Lewis acid-catalyzed
formal [3 + 3] cycloaddition reaction.
A preliminary screening reveals that a range of Lewis acids
could be used to promote this formal cycloaddition as
summarized in Tables 1 and 2 with use of pyrone 8 and
diketone 11, respectively. Notable features are the follow-
ing: (1) Usage of Lewis acids did not alter the chemistry
and provide the same 2H-pyran as when using iminium salts;
2) Lewis acids could be employed at substoichiometric
a Isolated yields unless otherwise indicated. b Conversion.
amounts; (3) reaction temperatures could be lowered to room
temperature; (4) molecular sieves were needed to ensure the
efficiency; (5) reactions of pyrone 8 were more sluggish
given its lower solubility in CH2Cl2 at room temperature,
and thus, diketone 11 worked better for a wider range of
Lewis acids; and (6) BF3-Et2O and TiCl4 became the Lewis
acids of choice because their respective reactions were faster
than those employing weaker Lewis acids such as zinc,
copper halides, and In(OTf)3.
This protocol proved to be general in the preparation of
pyrans 13-21, 23, 24, and 27-30 as shown in Figure 1.
Particularly, we were able to effectively carry out the reaction
of Funk’s enal 2218 with pyrone 8 and diketone 11 to give
the desired pyrans 23 and 2419 in 71% and 77% yields,
respectively. Although the reaction temperature was quite
Table 1. Screening of Lewis Acids for the Reaction of 8
(14) For recent applications in natural product syntheses, see: (a) Olson,
B. S.; Trauner, D. J. Synlett 2005, 700. (b) Sunazuka, T.; Handa, M.; Nagai,
K.; Shirahata, T.; Harigaya, Y.; Otoguro, K.; Kuwajima, I.; O˜ mura, S.
Tetrahedron 2004, 60, 7845. (c) Hu, H.; Harrison, T. J.; Wilson, P. D. J.
Org. Chem. 2004, 69, 3782.
(15) This two-step protocol is necessary for many reactions to control
the regiochemistry as well as provide consistency in yields, although by
using appropriate amine salts, this reaction can be feasible as a one-step
protocol. See: References 3 and 13c, and also: Cravotto, G.; Nano, G.
M.; Tagliapietra, S. Synthesis 2001, 49.
(16) For an InCl3-catalyzed example, see: Lee, Y. R.; Kim, D. H.; Shim,
J.-J.; Kim, S. K.; Park, J. H.; Cha, J. S.; Lee, C.-S. Bull. Korean Chem.
Soc. 2002, 23, 998. Also see ref 12b.
(17) For an example with phenol, see: Cossy, J.; Rakotoarisoa, H.; Kahn,
P.; Desmurs, J.-R. Tetrahedron Lett. 1998, 39, 9671.
concn
[M]c
temp
[°C]
time
[h]
yield
[%]b
entry
LAa
equiv
1
2
3
4
5
6
7
8
9
BF3-Et2O
BF3-Et2O
BF3-Et2O
BF3-Et2O
TiCl4
SnCl4
AlCl3
In(OTf)3
ZnBr2
1.00
0.50
0.10
0.05
0.10
0.10
0.10
0.10
0.10
0.11
0.12
0.09
0.09
0.09
0.09
0.09
0.09
0.09
rt
rt
rt
rt
rt
rt
rt
rt
rt
24
16
24
24
22
24
48
48
24
69
68
11
5
80
38
8
3
48
(18) For the synthesis of aldehyde 22, see: Aungst, R. A., Jr.; Funk, R.
L. Org. Lett. 2001, 3, 3553.
(19) Details of procedures and characterizations can be found in the
Supporting Information.
a All reactions were carried out with 186 mg/mmol of 4 Å MS. b Isolated
yields. c Concentrations are based on aldehyde 9.
192
Org. Lett., Vol. 8, No. 2, 2006

Table 3. Lewis Acid-Catalyzed [3 + 3] Cycloaddition of
Vinylogous Esters
temp time yield
entry
R
SM Lewis acida equiv
[°C]
[h]
[%]b
1
2
3
4
5
Me
31
BF3-Et2O
BF3-Et2O
ZnBr2
BF3-Et2O
TiCl4
1.00
1.00
1.00
0.50
1.00
0-rt
0
rt
rt
rt
120
48
24
16
24
15
48
10
45
95
TMS 32
TIPS 33
TIPS 33
TIPS 33
a All reactions were carried out with 80 mg/mmol of 4 Å MS. b Isolated
yields.
such as 31-33. As shown in Table 3, TIPS vinylogous ester
33 appears to work the best, leading to pyran 35 in 95%
yield, although 1.0 equiv of TiCl4 was preferred, or the
reaction was rather slow [entry 5]. The reaction of methyl
vinylogous ester 31 was very slow [entry 1], whereas TMS
vinylogous ester 32 is feasible. This finding is significant
because it allows one to protect diketones as vinylogous
esters while carrying out other transformations, and subse-
quently pursue the formal cycloaddition without the concern
of having to hydrolyze vinylogous esters back to diketones.4
We have described here a Lewis acid-catalyzed formal
oxa-[3 + 3] cycloaddition of R,â-unsaturated aldehydes with
6-methyl-4-hydroxy-2-pyrone, 1,3-diketones, and vinylogous
silyl esters. Given the recent interest, this report should have
an impact on applications of this method in the natural
product synthesis.
Figure 1. The Scope of Lewis acid-catalyzed [3 + 3] annulation.
high here, it has been very difficult using R-oxygenated enals
in this annulation reaction under the iminium salt conditions
despite the potential of 23 and 24 in synthetic applications.
In addition, by using chiral enals 25 [(S)-(-)-perillaldehyde]
and 26 [(R)-(-)-myrtenal], Lewis acid-promoted formal
cycloadditions with pyrone 8 and 11 gave the respective
pyrans 27 and 28, and 29 and 30 in good yields as well as
high diastereoselectivity.20
Acknowledgment. R.P.H. thanks the NIH [N.S.38049]
for funding. K.P.C. thanks the ACS-Organic Division for a
Graduate Fellowship sponsored by the Schering-Plough
Research Institute. We thank Professors Scott Denmark and
Tony Barrett for invaluable discussions.
Supporting Information Available: Experimental and
1H NMR spectral and characterizations for all new com-
pounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
A major advantage in employing Lewis acids would be
the success in promoting cycloadditions of vinylogous esters
(20) The major diastereomers in all cases appear to be the more stable
isomer with ∆E ranging from 0.40 to 1.11 kcal mol-1
.
OL0523042
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