A formal [3 + 3] cycloaddition reaction. Improved reactivity using α,β-unsaturated iminium salts and evidence for reversibility of 6π-electron electrocyclic ring closure of 1-oxatrienes

Article abstract of DOI:10.1021/jo020688t

A detailed account regarding a formal [3 + 3] cycloaddition method using 4-hydroxy-2-pyrones and 1,3-diketones is described here. This formal cycloaddition reaction or annulation reaction is synthetically useful for constructing 2H-pyranyl heterocycles. T

Full text of DOI:10.1021/jo020688t

A F or m a l [3 + 3] Cycloa d d ition Rea ction . Im p r oved Rea ctivity
Usin g r,â-Un sa tu r a ted Im in iu m Sa lts a n d Evid en ce for
Rever sibility of 6π-Electr on Electr ocyclic Rin g Closu r e of
1-Oxa tr ien es
Hong C. Shen, J iashi Wang, Kevin P. Cole, Michael J . McLaughlin, Christopher D. Morgan,†
Christopher J . Douglas,† Richard P. Hsung,*,‡ Heather A. Coverdale, Aleksey I. Gerasyuto,
J uliet M. Hahn, J ia Liu, Heather M. Sklenicka, Lin-Li Wei, Luke R. Zehnder, and
Craig A. Zificsak
Department of Chemistry, University of Minnesota, Minneapolis, Minnesota 55455
hsung@chem.umn.edu
Received November 7, 2002
A detailed account regarding a formal [3 + 3] cycloaddition method using 4-hydroxy-2-pyrones
and 1,3-diketones is described here. This formal cycloaddition reaction or annulation reaction is
synthetically useful for constructing 2H-pyranyl heterocycles. The usage of R,â-unsaturated iminium
salts is significant in controlling competing reaction pathways to give exclusively 2H-pyrans. Most
significantly, experimental evidence is provided to support the mechanism of this reaction that
involves a sequential Knoevenagel condensation and a reversible 6π-electron electrocyclic ring-
closure of 1-oxatrienes.
SCHEME 1
In tr od u ction
Cycloaddition and annulation reactions are among the
most powerful methods in organic synthesis, owing to
their ability to provide multiple bond formations with
regio- and stereochemical control leading to polycyclic
carbocycles and heterocycles through a concerted, step-
wise, or sequential process.1 We encountered an annu-
lation reaction that was first cited by Link2 in 1944
specifically involving 4-hydroxycoumarins and later was
studied in detail by Moreno-Man˜as.3 This annulation
reaction involves condensation of 6-methyl-4-hydroxy-2-
pyrones 1 with R,â-unsaturated aldehydes 2 in the
presence of a secondary amine leading to 2H-pyrans 3
(Scheme 1). Mechanistically, it has been proposed to
involve a sequence that consists of a C-1,2-addition to
an iminium salt generate in situ followed by â-elimina-
tion that gives an 1-oxatriene 5 (or Knoevenagel conden-
sation) and a 6π-electron electrocyclic ring closure of 5.3-5
This results in the formation of two σ-bonds and a new
stereocenter adjacent to the oxygen atom, thereby con-
stituting a sequential anionic-pericyclic process that is
† UMN undergraduate research students from 1997 to 2000. Fund-
ing from Pharmacia-Upjohn is greatly appreciated.
‡ A recipient of 2001 Camille Dreyfus Teacher-Scholar and McK-
night New Faculty Awards. Author names after the corresponding
author are alphabetically ordered.
(4) For leading references on electrocyclic ring closures involving
1-oxatrienes, see: (a) Kametani, T.; Kajiwara, M.; Fukumoto, K.
Tetrahedron 1974, 30, 1053. (b) Shishido, K.; Ito, M.; Shimada, S.-I.;
Fukumoto, K.; Kametani, T. Chem. Lett. 1984, 1943. (c) Shishido, K.;
Shitara, E.; Fukumoto, K. J . Am. Chem. Soc. 1985, 107, 5810. (d)
Shishido, K.; Hiroya, K.; Fukumoto, K.; Kametani, T. Tetrahedron Lett.
1986, 27, 971.
(1) For some reviews, see: (a) Trost, B. M.; Fleming, I. In Compre-
hensive Organic Synthesis; Pergamon Press: Oxford and New York,
1991; Vols. 4 and 5. (b) Carruthers, W. In Cycloaddition Reactions in
Organic Synthesis; Pergamon Press: Oxford and New York, 1990. (c)
Padwa, A.; Schoffstall, A.; Curran, D. P. In Advances in Cycloaddition;
J AI Press: Greenwich, CT, 1990; pp 1-89.
(2) (a) Ikawa, M.; Stahmann, M. A.; Link, K. P. J . Am. Chem. Soc.
1944, 66, 902. (b) Seidman, M.; Robertson, D. N.; Link, K. P. J . Am.
Chem. Soc. 1950, 72, 5193. (c) Seidman, M.; Link, K. P. J . Am. Chem.
Soc. 1952, 74, 1885.
(3) (a) de March, P.; Moreno-Man˜as, M.; Casado, J .; Pleixats, R.;
Roca, J . L.; Trius, A. J . Heterocycl. Chem. 1984, 21, 1369. (b) de March,
P.; Moreno-Man˜as, M.; Casado, J .; Pleixats, R.; Roca, J . L. J . Heterocycl.
Chem. 1984, 21, 85.
(5) For leading references on electrocyclic ring-closures involving
1-azatrienes, see: (a) Maynard, D. F.; Okamura, W. H. J . Org. Chem.
1995, 60, 1763. (b) de Lera, A. R.; Reischl, W.; Okamura, W. H. J . Am.
Chem. Soc. 1989, 111, 4501. (c) Okamura, W. H.; de Lera, A. R.;
Reischl, W. J . Am. Chem. Soc. 1988, 110, 4462. For an earlier account,
see: (e) Oppolzer, V. W. Angew. Chem. 1972, 22, 1108. For a recent
account similar to Okamura’s elegant studies, see: (f) Tanaka, K.; Mori,
H.; Yamamoto, M.; Katsumura, S. J . Org. Chem. 2001, 66, 3099.
10.1021/jo020688t CCC: $25.00 © 2003 American Chemical Society
Published on Web 02/06/2003
J . Org. Chem. 2003, 68, 1729-1735
1729

Shen et al.
formally the equivalent of a [3 + 3] cycloaddition,6-8
a
term described in Seebach’s carboannulation of nitroalk-
enes with enamines.9
The significance of tandem strategies in natural prod-
uct synthesis has been elegantly reviewed by Tietze.10
This particular formal cycloaddition strategy should
provide a unique approach to 1-oxadecalins and oxa-
spirocycles that are well represented in biologically
relevant natural products such as arisugacins (6),11
phomactin A (7),12,13 penostatin A (8),14 rhododarichr-
moanic acid A (9),15 pyripyropenes (10),16 and orevactaene
(11)17 (Figure 1). We became interested in this reaction
specifically because of arisugacin A (6a ) that was isolated
(6) Examples of [3 + 3] cycloaddition reactions in the truest sense
are extremely scarce. There are limited examples of metal mediated
[3 + 3] cycloaddition reactions. For recent reviews: a) Fru¨hauf, H.-W.
Chem. Rev. 1997, 97, 523. (b) Lautens, M.; Klute, W.; Tam, W. Chem.
Rev. 1996, 96, 49.
(7) For a review, see: Hsung, R. P.; Wei, L.-L.; Sklenicka, H. M.;
Shen, H. C.; McLaughlin, M. J .; Zehnder, L. R. In Trends Heterocycl.
Chem. 2001, 7, 1-24.
(8) For recent reviews on stepwise [3 + 3] formal cycloadditions
leading to bridged carbocycles, pyridines, or pyridones using enamines,
enaminones, enol ethers, or â-ketoesters, see: (a) Filippini, M.-H.;
Rodriguez, J . Chem. Rev. 1999, 99, 27. (b) Rappoport, Z. The Chemistry
of Enamines. In The Chemistry of Functional Groups; J ohn Wiley and
Sons: New York, 1994. (c) Filippini, M.-H.; Faure, R.; Rodriguez, J . J .
Org. Chem. 1995, 60, 6872 and refs 21-33 cited therein.
(9) (a) Seebach, D.; Missbach, M.; Calderari, G.; Eberle, M. J . Am.
Chem. Soc. 1990, 112, 7625. For related reactions, see: (b) Landesman,
H. K.; Stork, G. J . Am. Chem. Soc. 1956, 78, 5129. (c) Hendrickson, J .
B.; Boeckman, R. K. J r. J . Am. Chem. Soc. 1971, 93, 1307. (d) Alexakis,
A.; Chapdelaine, M. J .; Posner, G. H. Tetrahedron Lett. 1978, 19, 4209.
(10) (a) Tietze, L. F.; Beifuss, U. Angew. Chem., Int. Ed. Engl. 1993,
32, 131. b) Tietze, L. F. J . Heterocycl. Chem. 1990, 27, 47.
(11) (a) O˜ mura, S.; Kuno, F.; Otoguro, K.; Sunazuka, T.; Shiomi,
K.; Masuma, R.; Iwai, Y. J . Antibiot. 1995, 48, 745. For biological
activities of arisugacin, see: (b) Kuno, F.; Otoguro, K.; Shiomi, K.; Iwai,
Y.; O˜ mura, S. J . Antibiot. 1996, 49, 742. (c) Kuno, F.; Shiomi, K.;
Otoguro, K.; Sunazuka, T.; O˜ mura, S. J . Antibiot. 1996, 49, 748. (d)
Otoguro, K.; Kuno, F.; O˜ mura, S. Pharmacol. Ther. 1997, 76, 45. For
C-H, see: (e) Otoguro, K.; Shiomi, K.; Yamaguchi, Y.; Arai, N.;
Sunazuka, T.; Masuma, R.; Iwai, Y.; O˜ mura, S. J . Antibiot. 2000, 53,
50.
(12) For phomactin A, see: (a) Sugano, M.; Sato, A.; Iijima, Y.;
Oshima, T.; Furuya, K.; Kuwano, H.; Hata, T.; Hanzawa, H. J . Am.
Chem. Soc. 1991, 113, 5463. (b) Sugano, M.; Sato, A.; Iijima, Y.; Furuya,
K.; Haruyama, H.; Yoda, K.; Hata, T. J . Org. Chem. 1994, 59, 564. (c)
Sugano, M.; Sato, A.; Iijima, Y.; Furuya, K.; Kuwano, H.; Hata, T. J .
Antibiot. 1995, 48, 1188.
(13) (a) Miyaoka, H.; Saka, Y.; Miura, S.; Yamada, Y. Tetrahedron
Lett. 1996, 37, 7107. (b) Foote, K. M.; Hayes, C. J .; Pattenden, G.
Tetrahedron Lett. 1996, 37, 275. (c) Foote, K. M.; J ohn, M.; Pattenden,
G. Synlett 2001, 365. (d) Kallan, N. C.; Halcomb, R. L. Org. Lett. 2000,
2, 2687. (e) Seth, P. P.; Totah, N. I. Org. Lett. 2000, 2, 2507. (f) Mi, B.;
Maleczka, R. E., J r. Org. Lett. 2001, 3, 1491. (g) Chemler, S. R.; Iserloh,
U.; Daneshefsky, S. J . Org. Lett. 2001, 3, 2949. (h) Houghton, T. J .;
Choi, S.; Rawal, V. H. Org. Lett. 2001, 3, 3615.
(14) For isolations of penostatins, see: (a) Takahashi, C.; Numata,
A.; Yamada, T.; Minoura, K.; Enmoto, Konishi, K.; Nakai, M.; Matsuda,
C.; Nomoto. K. Tetrahedron Lett. 1996, 37, 655. For synthesis, see:
(b) Snider, B. B.; Liu, T. J . Org. Chem. 2000, 65, 8490.
(15) For isolation of rhododaurichromanic acid: Kashiwada, Y.;
Yamzaki, K.; Ikeshiro, Y.; Yamagishi, T.; Fujioko, T.; Mihashi, K.;
Mizuki, K.; Cosentino, L. M.; Fowke, K.; Morris-Natschke, S. L.; Lee,
K.-H. Tetrahedron 2001, 57, 1559.
(16) (a) Tomoda, H.; Tabata, N.; Yang, D. J .; Namatame, I.; Tanaka,
H.; O˜ mura, S.; Kaneko, T. J . Antibiot. 1996, 49, 292. (b) b) Obata, R.;
Sunazuka, T.; Li, Z. R.; Tian, Z. M.; Harigava, Y.; Tabata, N.; Tomoda,
H.; O˜ mur, S. J . Antibiotics 1996, 49, 1133. For total synthesis of
pyripyropene A and E, see: (c) Smith, A. B., III; Kinsho, T.; Sunazuka,
T.; O˜ mura, S. Tetrahedron Lett. 1996, 37, 6461. (d) Nagamitsu, T.;
Sunazuka, T.; Obata, R.; Tomoda, H.; Tanaka, H.; Harigaya, Y.;
O˜ mura, S.; Smith, A. B., III. J . Org. Chem. 1995, 60, 8126. For
synthesis of a related natural product GERI-BP001, see: (d) Parker,
K. A.; Resnick, L. J . Org. Chem. 1995, 60, 5726. For a biosynthesis of
pyripyropene A, see: (e) Tomoda, H.; Tabata, N.; Nakata, Y.; Nishida,
H.; Kaneko, T.; Obata, R.; Sunzazuka, T.; O˜ mura, S. J . Org. Chem.
1996, 61, 882. (f) Obata, R.; Sunazuka, T.; Tian, Z.; Tomoda, H.;
Harigaya, Y.; Omura, S.; Smith, A. B., III. Chem. Lett. 1997, 935.
F IGURE 1.
from Penicillium sp. Fo-4259 by O˜ mura.11 Arisugacin A
(6a ) is identified as the most potent and selective
inhibitor known against acetylcholinesterase (AChE)
with an IC50 value of 1 nM,11 and thus, it possesses
therapeutic significance in treatment of dementia dis-
eases.18
Despite the obvious synthetic potential of this formal
cycloaddition or annulation reaction, its application has
remained little known because of the competing reaction
pathways due to 1,2- versus 1,4-addition and the C-
addition versus O-addition (Scheme 2). After Link’s first
report using 4-hydroxycoumarins and R,â-unsaturated
ketones,2 Moreno-Man˜as reported a detailed study fea-
turing reactions of 6-methyl-4-hydroxy-2-pyrone 12 and
crotyl aldehyde.3 A variety of products such as 13-17
were identified and isolated in various amounts, resulting
from these competing reaction pathways. The syntheti-
cally most useful product 13 was found in very low yields.
These discouraging preliminary studies seriously ham-
pered our efforts19-21 to achieve a total synthesis of
arisugacin A via this formal [3 + 3] cycloaddition
strategy. Although J onassohn22 and Hua23 reported the
use of cyclic enals to improve the overall product distri-
bution by suppressing the 1,4-addition pathway, a gen-
eral solution remained elusive until we communicated
(17) a) Shu, Y.-Z.; Ye, Q.; Li, H.; Kadow, K. F.; Hussain, R. A.;
Huang, S.; Gustavson, D. R.; Lowe, S. E.; Chang, L. P..; Pirnik, D. M.;
Kodukula, K. Bioorg. Med. Chem. Lett. 1997, 17, 22295. (b) Organ, M.
G.; Bratovanov, S. Tetrahedron Lett. 2000, 41, 6945.
(18) J ohn, V.; Lieberburg, I.; Thorsett, E. D. Ann. Rep. Med. Chem.
1993, 28, 197.
1730 J . Org. Chem., Vol. 68, No. 5, 2003

Formal [3 + 3] Cycloaddition Reaction
SCHEME 2
SCHEME 3
lem or to improve the pathway that would lead to the
2H-pyran 13 is an experimental one. Our solution
eventually involved the utilization of R,â-unsaturated
iminium salts because this reaction presumably involved
generation of iminium salts in situ.
the use of R,â-unsaturated iminium salts.24-26 We report
here a detailed account of our study to particularly
include various results on mechanistic support.
As shown in Scheme 3, 3-methyl-2-butenal (18) was
incubated in the presence of 1.0 equiv of piperidine and
1.0 equiv of Ac2O in EtOAc (added at -10 °C) at 85 °C in
a sealed flask for 45 min to 1 h. The solution containing
the iminium salt 19 was then transferred without cooling
to a solution of pyrone 2027 in EtOAc. After the solution
was stirred at 85 °C in a sealed flask for an additional
24-36 h, the 2H-pyran 2128 was obtained in 85% yield.
Without pregenerating the iminium salt 19, simply
mixing 3-methyl-2-butenal (18) and pyrone 20 in the
presence of L-proline22 or a secondary amine led to 2H-
pyran 21 in 47% as the best yield that was very difficult
to reproduce.
It was quickly evident that the usage of R,â-unsatur-
ated iminium salts is a general and efficient solution
leading to 2H-pyranyl products exclusively via the C-1,2-
addition pathway. This assertion was validated by a
recent account reported by Cravotto.26 In addition, reac-
tions of the pyrone 24 with several acyclic R,â-unsatur-
ated piperidine iminium salts 25-27 generated from the
corresponding enals with only one â-substituent could be
carried out to give pyranyl products 13 in much improved
yield and the previously unknown 28-29 (Scheme 4).
This further supports the significance of using R,â-
unsaturated iminium salts.
Resu lts a n d Discu ssion
1. Syn th etic Scop e a n d Ap p lica tion s.
a . Th e Use of R,â-Un sa tu r a ted Im in iu m Sa lts. The
challenge to solve the competing reaction pathway prob-
(19) For our earlier efforts in total synthesis arisugacin A, see the
following references. 4-Pyrone Diels-Alder route: (a) Hsung, R. P. J .
Org. Chem. 1997, 62, 7904. (b) Granum, K. G.; Merkel, G.; Mulder, J .
A.; Debbins, S. A.; Hsung, R. P. Tetrahedron Lett. 1998, 39, 9597. (c)
Hsung, R. P. Heterocycles 1998, 48, 421. (d) Hsung R. P.; Zificsak, C.
A.; Wei, L.-L.; Zehnder, L. R.; Park, F.; Kim, M.; Tran, T.-T. T. J . Org.
Chem. 1999, 64, 8736. (e) Degen, S. J .; Mueller, K. L.; Shen, H. C.;
Mulder, J . A.; Golding, G. M.; Wei, L.-L.; Zificsak, C. A.; Neeno-Eckwall,
A.; Hsung, R. P. Bioorg. Med. Chem. Lett. 1999, 973, 3. For an acid
condensation approach: (f) Zehnder, L. R.; Dahl, J . W.; Hsung, R. P.
Tetrahedron Lett. 2000, 41, 1901.
(20) For our formal [3 + 3] cycloaddition approach, see: Zehnder,
L. R.; Hsung, R. P.; Wang, J .-S.; Golding, G. M. Angew. Chem., Int.
Ed. 2000, 39, 3876.
(21) For an identical route, see: Handa, M.; Sunazuka, T.; Nagai,
K.; Kimura, R.; Shirahata, T.; Tian, Z. M.; Otoguro, K.; Harigaya, Y.;
O˜ mura, S. J . Antibiot. 2001, 54, 382.
(22) J onassohn, M.; Sterner, O.; Anke, H. Tetrahedron 1996, 52,
1473.
(23) Hua, D. H.; Chen, Y.; Sin, H.-S.; Maroto, M. J .; Robinson, P.
D.; Newell, S. W.; Perchellet, E. M.; Ladesich, J . B.; Freeman, J . A.;
Perchellet, J .-P.; Chiang, P. K. J . Org. Chem. 1997, 62, 6888.
(24) Hsung, R. P.; Shen, H. C.; Douglas, C. J .; Morgan, C. D.; Degen,
S. J .; Yao, L. J . J . Org. Chem. 1999, 64, 690. For preliminary
communications on the formal [3 + 3] cycloaddition approach, see:
Shen, H. C.; Degen, S. J .; Mulder, J . A.; Hsung, R. P.; Douglas C. J .;
Golding, G. M.; J ohnson, E. W.; Mathias, D. S.; Morgan, C. D.; Mueller,
K. L.; Shih, R. A. Abstract No. ORGN-664, 216th ACS National
Meeting, Boston, MA, Fall 1998.
This improved protocol has been applied to prepara-
tions of a series of bicyclic and tricyclic pyranyl hetero-
cycles as shown in Schemes 5 and 6. These pyranyl
heterocycles are currently being evaluated as potential
structural analogues of arisugacin A (6a ) especially with
the compound 35 serving as the BCDE-ring analogue of
6a .
(25) For a recent citation in support the usage of R,â-unsaturated
iminium salts, see: Cravotto, G.; Nano, G. M.; Tagliapietra, S.
Synthesis 2001, 49.
(26) For recent related studies in this area: (a) Hua, D. H.; Chen,
Y.; Sin, H.-S.; Robinson, P. D.; Meyers, C. Y.; Perchellet, E. M.;
Perchellet, J .-P.; Chiang, P. K.; Biellmann, J .-P. Acta Crystallogr. 1999,
C55, 1698. (b) P. Benovsky, G. A. Stephenson, J . R. Stille, J . Am. Chem.
Soc. 1998, 120, 2493. (c) Moorhoff, C. M. Synthesis, 1997, 685. (d)
Krasnaya, Z. A.; Bogdanov, V. S.; Burova, S. A.; Smirnova, Y. V. Russ.
Chem. 1995, 44, 2118. (e) Heber, D.; Berghaus, Th. J . Heterocycl. Chem.
1994, 31, 1353. (f) Paulvannan,; K.; Stille, J . R. Tetrahedron Lett. 1993,
34. 6677. (g) Appendino, G.; Cravotto, G.; Tagliapietra, S.; Nano, G.
M.; Palmisano, G. Helv. Chim. Acta 1990, 73, 1865.
An important experimental improvement since we first
communicated this reaction24 is that amine salts can be
(27) Douglas C. J .; Sklenicka, H. M.; Shen, H. C.; Golding, G. M.;
Mathias, D. S.; Degen, S. J .; Morgan, C. D.; Shih, R. A.; Mueller, K.
L.; Seurer, L. M.; J ohnson, E. W.; Hsung, R. P. Tetrahedron 1999, 55,
13683.
J . Org. Chem, Vol. 68, No. 5, 2003 1731

Shen et al.
SCHEME 4
SCHEME 7
SCHEME 5
60% and 70% yields, respectively. This simplifies the
formal [3 + 3] cycloaddition reaction experimentally,
although most reactions can be carried out using either
conditions.
b. Oth er â-Dik eto System s. This formal [3 + 3]
cycloaddition reaction could be extended to include 1,3-
diketones leading to a facile construction of 1-oxadecalins.
In comparison with 4-hydroxy-2-pyrones, reactions of 1,3-
diketones with R,â-unsaturated iminium salts appear to
be slower.29 Upon raising the temperature to 100-150
°C and using the solvent system consisting of a toluene/
EtOAc mixture, the reaction of 1,3-cyclohexanedione
proceeded in a synthetically useful manner.
SCHEME 6
As shown in Scheme 7, 1,3-diketones 36 and 37 were
reacted with the iminium salt 26 generated from 2-hex-
enal under the standard conditions to give the formal
cycloadducts 38 and 39 in 65% and 69% yields, respec-
tively. Attempts to generate any reasonable diastereo-
selectivity by desymmetrizing the symmetric diketones
36 and 37 were not successful. The reaction of diketone
40 with 19 did lead to the 2H-pyrans 41 and 4229c in 82-
90% overall yield with a ratio ranged from 4:1 to 7:3 in
favor of 41, thereby suggesting that the steric interaction
of the two geminal dimethyl groups propelled the regio-
selectivity to favor 41.
We also observed an intriguing contrast between 1,3-
cyclopentanedione and 1,3-cyclohexandione. When 1,3-
cyclopentanedione 43 was reacted with a variety of R,â-
used to generate R,â-unsaturated iminium salts in a
highly efficient manner. Specifically as shown in Scheme
6, utilization of 0.1-1.0 equiv piperidinium acetate salts
not only could facilitate the reaction in the formation of
R,â-unsaturated iminium salts, but more significantly,
it renders the reaction to be carried out in one-pot. By
mixing the pyrone 24 or 34 directly with R,â-unsaturated
aldehyde 31 in the presence of piperidinium acetate, the
desired formal cycloadducts 32 and 35 were isolated in
(28) See the Supporting Information for preparations of all relevant
new compounds and details of their full characterizations along with
their 1H NMR spectra.
(29) For earlier studies, see: a) Schuda, P. F.; Price, W. A. J . Org.
Chem. 1987, 52, 1972. (b) Tietze, L. F.; v. Kiedrowski, G.; Berger, B.
Synthesis 1982, 683. (c) de Groot, A.; J ansen, B. J . M. Tetrahedron
Lett. 1975, 16, 3407. There were some disagreements in these citations
regarding reaction yields and conditions.
1732 J . Org. Chem., Vol. 68, No. 5, 2003

Formal [3 + 3] Cycloaddition Reaction
SCHEME 8
SCHEME 9
SCHEME 10
unsaturated iminium salts, no desired formal cycloadduct
44 (Scheme 7) was found. Instead, in one specific case,
the diketone 45 was isolated (68% yield) and vigorously
characterized using iminium salt 19. Formation of 45
could be derived from dehydration of the intermediate
48, which was the product of a second 1,4-addition of 1,3-
cyclopentanedione to the intermediate 46 or 47. This
implies that for reactions of 1,3-cyclopentanedione, the
electrocyclic ring-closure step is either very slow or is
arrested and that a second 1,4-addition either occurred
faster or is more favored.
When the δ-lactone 49 was used as a â-diketo equiva-
lent and condensed with 19, the desired cycloadduct 50
was obtained in 56% yield (Scheme 8). However, at higher
temperatures than 85 °C, decarboxylation of the starting
δ-lactone 49 occurred to give 51 as the competing side
product. Intriguingly, tetronic acid 52 did not yield any
desired formal cycloadduct 53, while Meldrum’s acid 54
did condense with 25 to give the Knoevenagel condensa-
tion product 5530 with no additional 1,4-additions but also
with the electrocyclic ring-closure step again arrested.
Finally, acyclic â-diketo equivalents such as ethyl ac-
etoacetate, dimethyl malonate, and 1,3-pentanediones
were all unsuccessful in this reaction, limiting the scope
of this reaction at this moment to the formation of fused
bicyclic oxygen heterocycles.
c. Sim p le Ap p lica tion s. Since these formal cycload-
ducts represent unique cyclic dienes, we pursued their
utility in Diels-Alder cycloaddition reactions, and di-
methyl acetylenic dicarboxylate (DMAD) was found to be
a suitable dienophile. Reactions of DMAD with 2H-
pyrans (30a , 39, and 56) in toluene at 150 °C in a sealed
tube led to aromatic compounds 57,31 58, and 60 in
modest yields after thermal deformylation or decarbon-
ylation of the initially bridged cycloadducts. Intriguingly
as a comparison, the dihydropyridine 5932 also underwent
Diels-Alder cycloaddition with DMAD to give 60 in 50%
yield after loss of N-benzyl cyclohexyl ketimine under the
thermal conditions. It is noteworthy that this would
represent an alternative route to synthesis of substituted
tetralones.
Moreover, DDQ oxidation of the 2H-pyrans such as 61
in dioxane led to the formation of chromene 62 in 25%
yield (Scheme 9). Although this reaction is not particu-
larly efficient, this oxidative aromatization could be
readily achieved in a stepwise manner via R-selenization
and oxidative elimination.29a,b This application showcases
the potential of this formal [3 + 3] cycloaddition method
in synthesis of substituted chromenes.
Mech a n ism
a . R egioch em ica l Assign m en t . The regiochemical
issue of this formal [3 + 3] cycloaddition reaction was
resolved unambiguously via an X-ray structural analysis
of 30c (Scheme 10). This regiochemical assignment is
significant for endeavors in syntheses of the aforemen-
tioned natural products. Mechanistically, it supports
again that the reaction could involve a C-1,2-addition to
an iminium salt followed by â-elimination leading to an
1-oxatriene 64a or 64b (Knoevenagel condensation) and
that the subsequent 6π-electron electrocyclic ring-closure
of 64b would lead the desired formal cycloadduct. The
preference for 64b to undergo ring closure is an interest-
ing observation. Since both the Knoevenagel condensa-
(30) Stevenson, R.; Weber, J . V. J . Nat. Prod. 1988, 51, 1215.
(31) The compound 57 has been made before via a Diels-Alder
reaction of DMAD with dioxolane of 4-oxo-4,5,6,7-tetrahydrobenzo[b]-
furans. See: (a) Tochtermann, W.; Heinke, T. Tetrahedron Lett. 1978,
19, 2145. (b) Tochtermann, W.; Heinke, K. Chem Ber. 1980, 113, 3249.
(32) Hsung, R. P.; Wei, L.-L.; Sklenicka, H. M.; Douglas, C. J .;
McLaughlin, M. J .; Mulder, J . A.; Yao, L. J . Org. Lett. 1999, 1, 509.
J . Org. Chem, Vol. 68, No. 5, 2003 1733

Shen et al.
SCHEME 11
SCHEME 12
SCHEME 13
tion and electrocyclic ring-closure are reversible (see
below), such a preference could simply be a reflection that
stability of respective products is in favor of 30c.
b. Evid en ce for a 1-Oxa tr ien e In ter m ed ia te. While
there are not definitive protocols to rule out other
mechanistic pathways that could also logistically lead to
the final outcome of this formal [3 + 3] cycloaddition
reaction, we have experimental information to support
the pathway involving the Knoevenagel condensation and
electrocyclic ring-closure.
As shown in Scheme 11, reaction of the R,â-unsatur-
ated iminium ion 65 derived from camphylidene acetal-
dehyde33 with the pyrone 66 at 110 °C for 96 h led to the
spirocycle 67a in 29% yield with a diastereomeric ratio
of 10:1 as assigned using NOE experiments. The major
product isolated in 68% yield was spectroscopically
assigned as the 1-oxatriene 67b. Although only one
isomer of 67b was observed, stereochemistry of the olefin
exocyclic to the pyrone moiety could not be easily distin-
guished.
When 67b was heated in toluene at 250 °C in a sealed
tube for 96 h, the cyclized product 67a was obtained in
21% yield with a ratio of 10:1 in favor of the same major
isomer. Some decomposition of 67b was also observed,
but the two major compounds in the reaction mixture
were unreacted 67b and the cyclized product 67a . While
this result supports the structural assignment of 67b,
the high temperature and long reaction time also suggest
that the ring-closure could be impeded with the steric
encumbrance of the camphor group.
as a minor byproduct initially when the reaction was
terminated in 2 h, the yield of 71 could be as high as
60-70% if the reaction time for 68 with 34 was extended
to 18-24 h. The unambiguous assignment of 71 via X-ray
structural analysis suggests the formation of the 1-ox-
atriene intermediate 69. Two consecutive intramolecular
trappings of 69 by two hydroxyl groups in 1,6- and 1,4-
additions should lead to 71 through the initial intermedi-
ate 70. Given that the hexacycle 71 was formed as a
single diastereomer, it is also very reasonable to suggest
that the stereochemical predisposition of two hydroxyl
groups in 69 control the stereochemical outcome of the
two conjugate additions.
In addition, in our efforts in the total synthesis of
arisugacin A [6a ],34 we isolated the hexacycle 71 from
reaction of the enal 68 with the pyrone 34 using piperi-
dinium acetate salt (Scheme 12). Although 71 was found
(33) (a) Milas, N. A.; Priesing, C. P. J . Am. Chem. Soc. 1957, 79,
6298. (b) Dauben, W. G.; Michno, D. M. J . Org. Chem. 1977, 42, 682.
(c) Keegan, G. S.; Midland, M. M.; Werley, R. T.; McLoughlin, J . I. J .
Org. Chem. 1991, 56, 1185. (d) Kagawa, M. Chem. Pharm. Bull. 1959,
7, 751.
(34) (a) Cole, K. P.; Hsung, R. P. Tetrahedron Lett. 2002, 43, 8791.
(b) Wang, J .; Cole, K. P.; Wei, L. L.; Zehnder, L. R.; Hsung, R. P.
Tetrahedron Lett. 2002, 43, 3337. (c) Cole, K. P.; Hsung, R. P.; Yang,
X.-F. Tetrahedron Lett. 2002, 43, 3341.
c. Rever sibility of 6π-Electr on Electr ocyclic Rin g
Closu r e. The best evidence for the reversibility of this
ring closure is described in Scheme 13. In our efforts
toward the total synthesis of arisugacin A (6a ),34 we were
able to isolate both the desired major isomer 74 and the
1734 J . Org. Chem., Vol. 68, No. 5, 2003

Formal [3 + 3] Cycloaddition Reaction
minor isomer 75 from the formal cycloaddition reaction
of the iminium salt 7234 with the pyrone 34. With a pure
minor isomer 75 in hand, it was possible to equilibrate
75 quantitatively to the desired major isomer 74. This
successful equilibration strongly suggests the reversibil-
ity of the ring-closure via the 1-oxatriene intermediate
73, thereby leading to the final product 74 that is
thermodynamically more stable than 75 by about 2.40
kcal mol-1 from PM3 calculations using Spartan Model.
The reversibility of this ring closure is also supported
by another experiment. When the pure minor isomer 42
(Scheme 7) was heated at 150 °C for 26 h, the major
isomer 41 was found in addition to some decomposition
products without reaching the original ratio of 4:1 or 7:3.
reactions can be readily extended to 1,3-diketones. Most
significantly, we have provided experimental evidence to
support the mechanism of this reaction that involves a
sequential Knoevenagel condensation and 6π-electorn
electrocyclic ring-closure, and to support that the latter
pericyclic ring closure is reversible for these 1-oxatrienes.
Ack n ow led gm en t. R.P.H. thanks the National In-
stitutes of Health (Grant No. NS38049) and the Ameri-
can Chemical Society Petroleum Research Fund (Type-
G) for financial support. We thank Mr. William W.
Brennessel and Dr. Maren Pink for providing X-ray
structural analysis and Dr. Letitia Yao for performing
1
2D H NMR experiments. We thank David S. Mathias,
Kristen L. Mueller, Lisa M. Seurer, and Shane J . Degen
for some preliminary work involving Scheme 6.
Con clu sion
We have described here a detailed account regarding
a formal [3 + 3] cycloaddition strategy that is syntheti-
cally useful for constructing 2H-pyranyl heterocycles. We
have shown that R,â-unsaturated iminium salts are
useful in controlling competing reaction pathways to give
exclusively 2H-pyrans and demonstrated that these
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures as well as H NMR spectral and characterization data
are given for all new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
1
J O020688T
J . Org. Chem, Vol. 68, No. 5, 2003 1735