An efficient synthesis of highly functionalized [5,6] aromatic spiroketals by hetero-diels-alder reaction

Article abstract of DOI:10.1021/ol7029068

A hetero-Diels-Alder reaction of vinyl sulfoxides with o-quinone methides precursor constructs highly functionalized [5,6] aromatic spiroketal skeletons in moderate to good yields with high regioselectivity. The two functional groups (ketone and olefin) c

Full text of DOI:10.1021/ol7029068

ORGANIC
LETTERS
2008
Vol. 10, No. 5
721-724
An Efficient Synthesis of Highly
Functionalized [5,6] Aromatic
Spiroketals by Hetero-Diels
−Alder
Reaction
Guanglian Zhou, Jianrong Zhu, Zhixiang Xie,* and Ying Li*
State Key Laboratory of Applied Organic Chemistry, College of Chemistry and
Chemical Engineering, Lanzhou UniVersity, Lanzhou 730000, P.R. China
xiezx@lzu.edu.cn; liying@lzu.edu.cn
Received December 3, 2007
ABSTRACT
A hetero-Diels−Alder reaction of vinyl sulfoxides with o-quinone methides precursor constructs highly functionalized [5,6] aromatic spiroketal
skeletons in moderate to good yields with high regioselectivity. The two functional groups (ketone and olefin) can be further subjected to
many synthetic transformations.
The [5,6] aromatic spiroketal skeleton is found in a wide
range of bioactive natural products such as heliquinomycin
(1) and its analogues (Figure 1).1 The interesting biological
activity and structures of these compounds have stimulated
many studies of [5,6] aromatic spiroketal skeleton construc-
tion. Even though there is progress that has been achieved
in this area in recent years,2 the synthesis of highly
functionalized [5,6] aromatic spiroketal skeletons remains
a formidable challenge.2c,d Our interest in these structures
has given rise to diverse methods for their expeditious
synthesis.
On the basis of our previous work on synthesis of [6,6]
aromatic spiroketal skeletons,3 we attempted to synthesize
highly functionalized [5,6] aromatic spiroketal skeletons
(Scheme 1) that would be applicable for most of the natural
products containing the [5,6] aromatic spiroketal skeletons.
To the best of our knowledge, there is no report of the
synthesis of functionalized [5,6] aromatic spiroketals using
a hetero-Diels-Alder reaction. In this letter, we report our
successful execution of this strategy.
(2) (a) Capecchi, T.; de Koning, C. B.; Michael, J. P. Tetrahedron Lett.
1998, 39, 5429. (b) Capecchi, T.; de Koning, C. B.; Michael, J. P. J. Chem.
Soc., Perkin Trans. 1 2000, 2681. (c) Qin, D.; Ren, R. X.; Siu, T.; Zheng,
C.; Danishefsky, S. J. Angew. Chem., Int. Ed. 2001, 40, 4709. (d) Siu, T.;
Qin, D.; Danishefsky, S. J. Angew. Chem., Int. Ed. 2001, 40, 4713. (e)
Tsang, K. Y.; Brimble, M. A.; Bremner, J. B. Org. Lett. 2003, 5, 4425. (f)
Waters, S. P.; Fennie, M. W.; Kozlowski, M. C. Tetrahedron Lett. 2006,
47, 5409. (g) Lindsey, C. C.; Wu, K. L.; Pettus, T. R. R. Org. Lett. 2006,
8, 2365. (h) Waters, S. P.; Fennie, M. W.; Kozlowski, M. C. Org. Lett.
2006, 8, 3243. (i) So¨1rgel, S.; Azap, C.; Reissig, H-U. Org. Lett. 2006, 8,
4875. (j) Tsang, K. Y.; Brimble, M. A. Tetrahedron 2007, 63, 6015. (k)
Akai, S.; Kakiguchi, K.; Nakamura, Y.; Kuriwaki, I.; Dohi, T.; Harada, S.;
Kubo, O.; Morita, N.; Kita, Y. Angew. Chem., Int. Ed. 2007, 46, 7458.
(3) Zhou, G. L.; Zheng, D. P.; Da, S. J.; Xie, Z. X.; Li, Y. Tetrahedron
Lett. 2006, 47, 3349.
(1) (a) Brockmann, H.; Lenk, W.; Schwantje, G.; Zeeck, A. Tetrahedron
Lett. 1966, 22, 3525. (b) Brockmann, H.; Lenk, W.; Schwantje, G.; Zeeck,
A. Chem. Ber. 1969, 102, 126. (c) Brockmann, H.; Zeeck, A. Chem. Ber.
1970, 103, 1709. (d) Coronelli, C.; Pagani, H.; Bardone, M. R.; Lancini,
G. C. J. Antibiot. 1974, 27, 161. (e) Bardone, M. R.; Martinelli, E.; Zerilli,
L. F.; Cornelli, C. Tetrahedron 1974, 30, 2747. (f) Stroshane, R. M.; Chan,
J. A.; Rubalcaba, E. A.; Garetson, A. L.; Aszalos, A. A.; Roller, P. P. J.
Antibiot. 1979, 32, 197. (g) Chino, M.; Nishikawa, K.; Umekia, M.; Hayashi,
C.; Yamazaki, T.; Tsuchida, T.; Sawa, T.; Hamada, M.; Takeuchi, T. J.
Antibiot. 1996, 49, 752. (h) Chino, M.; Nishikawa, K.; Tsuchida, T.; Sawa,
R.; Nakamura, H.; Nakamura, K. T.; Muraoka, Y.; Ikeda, D.; Naganawa,
H.; Sawa, T.; Takeuchi, T. J. Antibiot. 1997, 50, 143.
10.1021/ol7029068 CCC: $40.75
© 2008 American Chemical Society
Published on Web 02/12/2008

amino group in 9a-9c was then substituted with benzenthiol
(1.1 equiv benzenethiol in toluene), giving rise to the
thioethers 10a-10c. Oxidation of 10a-10c with m-CPBA
(1.0 equiv in CH2Cl2 under -78 °C) afforded the vinyl
sulfoxides 11a-11c6 efficiently (good yield for three steps)
(Scheme 2).
Scheme 2. Synthesis of Dienophiles
Figure 1. Spirocyclic natural products.
As shown in Scheme 1, the [5,6] aromatic spiroketal
skeleton A could arise from a cycloaddition between the enol
ethers B and o-quinone methides C. The 2-methylene-2,3-
dihydrobenzofuran structure in B is readily isomerized to
2-methylbenzofurans,3 so a suitable functional group was
required at the 3 position of B to stabilize the exocyclic
double bond. Considering the hydroxyl in 2 and 5-7, the
carbonyl group could be the ideal choice in the dienophile.
With the enol ether dienophile B in hand, we began the
study of hetero-Diels-Alder cycloadditions, choosing 11a
as a model dienophiles. These reactions were performed
under a range of conditions, and the results are shown in
Table 1. The o-quinone methides precursor 12a3 and the enol
Scheme 1. Proposed Retrosynthesis of the [5,6] Aromatic
Spiroketal Skeletons
Table 1. Cycloaddition of o-Quinone Methides Precursor with
Vinyl Sulfoxides
A sulfoxide group on the dienophile has been found to
control the regiochemistry of its Diels-Alder cycloadditions
with a wide range of cyclic and acyclic dienes.4 The domino
Diels-Alder reaction/pyrolytic sulfoxide elimination as a
general one-pot strategy was reported by Carren˜o.4 We
therefor chose a sulfoxide group for R3 in dienophile B.
The dienophiles corresponding to B were synthesized from
the commercially available 3(2H)-benzofuranones 8a-8c5
in a three-step sequence. Ketones 8a-8c were first trans-
formed to 9a-9c, respectively, according to the method
reported by Merour et al.5 The newly introduced dimethyl-
entry time (h) solvent temp. (°C) catalysis yield (%)
1
2
3
4
5
6
7
8
9
39
39
40
39
50
47
39
39
39
PhHa
PhHb
PhHb
PhHb
PhHb
PhCH3
PhHb
PhHb
PhHb
110
110
100
120
120
120
110
110
110
no
no
no
no
no
no
AlCl3
BF3·Et2O
TiCl4
10
55
26
51
53
9
22
0
0
b
a Analytical PhH without purification. b Solvent was dried by distillation
over Na/K.
(4) For selected reports on Diels-Alder reactions of vinyl sulfoxides,
see: (a) Carren˜o, M. C. Chem. ReV. 1995, 95, 1717. (b) Carren˜o, M. C.;
Garc´ıa Ruano, J. L.; Toledo, M. A.; Urbano, A.; Remor, C. Z.; Stefani, V.;
Fischer, J. J. Org. Chem. 1996, 61, 503. (c) Carren˜o, M. C.; He´rnandez-
Sa´nchez, R.; Mahugo, J.; Urbano, A. J. Org. Chem. 1999, 64, 1387. (d)
Carren˜o, M. C.; Susana, G-C.; Urbano, A,; Vitta, C. D. J. Org. Chem. 2000,
65, 4355.
ether 11a reacted in analytical benzene at 110 °C in a sealed
tube giving the desired spiroketal product 13 as a single
(5) Merour, J. Y.; Cossais, F. J. Heterocycl. Chem. 1991, 28, 1875.
(6) Olsen, R. K.; Shao, R-l. J. Org. Chem. 1996, 61, 5852.
Org. Lett., Vol. 10, No. 5, 2008
722

Table 2. Cycloaddition of Dienophiles 11a-11c, 20 with o-Quinone Methides Precursor 12a, 12ba
a All reactions were carried out in a sealed tube, PhH (dried by distillation over Na/K) as solvent, 110 °C for 39 h. b Yields were calculated after column
chromatography.
regioisomer (entry 1) in 10% yield. As expected, the
elimination of the sulfoxide group took place spontaneously
following the cycloaddition. No intermediate cycloadducts
were detected. The use of dry benzene as solvent improved
the yield to 55% (entry 2). Reducing the reaction temperature
to 100 °C decreased the yield to 26% (entry 3). Raising the
reaction temperature to 120 °C resulted in a little decrease
in the yield to 51% (entry 4). The better result (53% yield)
was obtained when the reaction time was extended to 50 h
(entry 5). When dry toluene was used as the solvent, the
yield was reduced to 9% (entry 6). The effect of some Lewis
acids was also examined. It was found that the yield of
spiroketal product 13 decreased greatly in the presence of
catalytic amount of AlCl3 (entry 7). Additon of BF3‚Et2O
and TiCl4 turned the reaction mixture red, and no spiroketal
product was detected (entries 8-9).
12a and 12b.7 As shown in Table 2, entries 1-6, substituents
on the aryl ring of the benzofuranone had no apparent effect
on the hetero-Diels-Alder reaction. In contrast, a 4-bromo
electron-withdrawing substituent of the o-quinone methide
precursor 12b increased the yield to a great extent (entries
4-6). When there was no sulfoxide moiety in dienophile
such as compound 20,8 the yield of the corresponding
spiroketal product 19 was reduced to 46% (entry 7). It is
noteworthy that the spiroketal products 13-18 were obtained
in moderate to good yield without any isomeric impurities.
The sulfoxide moiety served not only as a good leaving group
to form the styrene but also increased the yield (entries 1-7)
and ensured high regioselectivity.
In conclusion, we have developed a facile and effective
strategy for the synthesis of highly functionalized [5,6]
The hetero-Diels-Alder cycloaddition was further exam-
ined between the enol ethers 11a-c and o-quinone methides
(7) Prepared the compound 12b; see Supporting Information.
(8) Prepared the compound 20; see Supporting Information.
Org. Lett., Vol. 10, No. 5, 2008
723

aromatic spiroketal products. A sulfoxide proved to be a good
precursor of the styrene in our model compounds. Synthetic
studies toward natural spiroketal products employing this
newly developed hetero-Diels-Alder reaction method are
underway in this laboratory.
thank Dr. Scott McN. Sieburth of Temple University for
helpful discussions.
Supporting Information Available: Experimental pro-
cedures and NMR spectral data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
Acknowledgment. We are grateful for the financial
support of the National Natural Science Foundation of China
(Grant Nos. 20272020, 20672050, and 20621091). We also
OL7029068
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Org. Lett., Vol. 10, No. 5, 2008