LETTER
Synthesis of the Bisbenzannelated Spiroketal Core of Rubromycins
943
(10) For syntheses of the isocoumarin subunit, see: (a) Thrash,
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Chem. Rev. 2007, 107, 3180.
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279. (h) Harkat, H.; Weibel, J.-M.; Pale, P. Tetrahedron
Lett. 2007, 48, 1439.
In conclusion, a novel and efficient method for the con-
struction of the bisbenzannelated 5,6-spiroketal core of
rubromycins has been developed, which allows for the
synthesis of various substituted 5,6-aromatic spiroketal
skeletons under the catalysis of gold reagents. A compar-
ative study on the formatioan of aliphatic and of aromatic
spiroketals was also conducted. A tandem cyclization
mechanism was proposed. The process would serve as a
good complement to the existing methodologies and its
mild reaction conditions must be useful in synthesis of na-
ture products with such skeletons. The development of an
asymmetric version of this reaction and the extension of
this methodology to other functionalized 2-alkynyl phe-
nols are currently under investigation in our laboratory.
Acknowledgment
We are grateful for the financial support of the National Natural Sci-
ence Foundation of China (Grant Nos. 20672050 and 20272020).
(13) For a synthesis of alkyne 5, see: Trost, B. M.; Shen, H. C.;
Li, D.; Surivet, J. P.; Sylvain, C. J. Am. Chem. Soc. 2004,
126, 11966.
(14) For syntheses of o-iodophenols, see: (a) Edgar, K. J.;
Falling, S. N. J. Org. Chem. 1990, 55, 5287. (b) Schreiber,
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References and Notes
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(16) On the basis of the protocol described by Uitimoto,17
palladium reagents were tried initially but spiroketal 7a was
isolated in very low yields. Treatment of 6a with 5 mol% of
PdCl2 in refluxing MeCN for 2 d afforded spiroketal 7a in
only 5% yield. Even with 1.0 equiv of PdCl2 or the reaction
was performed in sealed tube at 120 °C, the yield of 7a was
still as low as 20% and 10%, respectively. Only trace of 7a
was isolated by using PdCl2(PhCN)2 and PdCl2(MeCN)2 in
Et2O at r.t.
(17) Utimoto, K. Pure Appl. Chem. 1983, 55, 1845.
(18) We treated 6a with 10 mol% of Ph3PAuCl/AgOTf and 20
mol% of PTSA in CH2Cl2 at r.t. for 2 d provided the aromatic
spiroketal 7a in 61% yield.
(6) For a review on the rubromycins, see: Brasholz, M.; Sörgel,
S.; Azap, C.; Reissig, H.-U. Eur. J. Org. Chem. 2007, 3801.
(7) (a) Qin, D.; Ren, R. X.; Siu, T.; Zheng, C.; Danishefsky, S.
J. Angew. Chem. Int. Ed. 2001, 40, 4709. (b) Siu, T.; Qin,
D.; Danishefsky, S. J. Angew. Chem. Int. Ed. 2001, 40,
4713. (c) 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.
(19) General Procedure for Gold-Catalyzed Spiroketalization
Under argon, PPh3AuCl (9.5 mg, 0.02 mmol) and AgOTf
(5.2 mg, 0.02 mmol) were added to a stirred solution of 6a
(48.0 mg, 0.2 mmol) in CH2Cl2 (4 mL). After the reaction
mixture had been stirred at r.t. for 2 d, the solvent was
removed and the residue purified by flash chromatography
on silica gel (hexane–EtOAc, 8:1 v/v) to give the
bisspiroketal 7a (30.0 mg, 62%) as a white solid.
(8) (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) Tsang, K. Y.; Brimble, M. A.; Bremner, J. B.
Org. Lett. 2003, 5, 4425. (d) Tsang, K. Y.; Brimble, M. A.
Tetrahedron 2007, 63, 6015. (e) Waters, S. P.; Fennie, M.
W.; Kozlowski, M. C. Tetrahedron Lett. 2006, 47, 5409.
(f) Waters, S. P.; Fennie, M. W.; Kozlowski, M. C. Org. Lett.
2006, 8, 3243. (g) Sörgel, S.; Azap, C.; Reissig, H.-U. Org.
Lett. 2006, 8, 4875.
(9) (a) Lindsey, C. C.; Wu, K. L.; Pettus, T. R. R. Org. Lett.
2006, 8, 2365. (b) For a synthesis of bisbenzannelated 6,6-
spiroketals, see: Zhou, G.; Zheng, D.; Da, S.; Xie, Z.; Li, Y.
Tetrahedron Lett. 2006, 47, 3349.
(20) Spectral Data for Selected Compounds (Table 2)
Compound 7b: white solid; mp 115–117 °C. 1H NMR (300
MHz, CDCl3): d = 7.13–7.07 (m, 2 H), 7.04 (s, 1 H), 6.95–
6.88 (m, 2 H), 6.78 (d, J = 8.4 Hz, 1 H), 6.68 (d, J = 8.1 Hz,
1 H), 3.40 (d, J = 16.5 Hz, 1 H), 3.30–3.18 (m, 2 H), 2.81
(ddd, J = 16.5, 6.0, 2.4 Hz, 1 H), 2.35–2.29 (m, 4 H), 2.17
(td, J = 12.6, 6.3 Hz, 1 H). 13C NMR (75 MHz, CDCl3):
d = 155.8, 152.3, 130.4, 129.1, 128.4, 127.4, 125.4, 125.3,
121.4, 121.1, 117.1, 109.4, 109.0, 41.9, 30.4, 21.9, 20.8. IR:
n = 3020 (CH, arom.), 2925 (CH), 1584, 1489 (ArC=C),
1080, 1045 (CO) cm–1. ESI-HRMS: m/z calcd for
C17H16O2Na [M + Na]+: 275.1043; found: 275.1046.
Compound 7c: pale yellow solid; mp 173–175 °C. 1H NMR
(300 MHz, CDCl3): d = 7.26 (s, 1 H), 7.19–7.08 (m, 3 H),
Synlett 2008, No. 6, 940–944 © Thieme Stuttgart · New York