bromide to 3-hydroxy-4-nitrobenzaldehyde 4, a com-
mercially available starting material (Scheme 1).4
Protection of the two hydroxy groups as TBS ethers
followed by selective deprotection of the phenol
TBS ether gave 5. Copper-catalyzed alkylation of
5 with 3-chloro-3-methyl-1-butyne5 and subsequent
deprotection of the TBS group afforded allylic alco-
hol 6. Epoxidation of 6 with MCPBA gave syn-
epoxyalcohol 7β as a single diastereomer, whose
stereochemistry was unambiguously determined to
be syn by single-crystal X-ray diffraction.6 The cor-
responding anti-epoxyalcohol 7r was synthesized
by inversion of the hydroxy group at the C-30 posi-
tion of 7β; oxidation of 7β with MnO2 afforded
ketone, which was used to search conditions for
stereoselective reduction. An extensive examination
led us to conclude that LiAlH(O-t-Bu)3 was the best
reductant to give 7r with a high stereoselectivity
(dr = 15:1).
of the acetylenic moiety with Lindlar’s catalyst
yielded reverse prenyl ether 8β, a precursor for ortho
Claisen rearrangement. For the synthesis of bis-
prenylated nitrophenol 9β, however, the Claisen
rearrangement7 was particularly challenging because
of the highly functionalized precursor 8β, which
included an acid-sensitive epoxide. After extensive
examination, we were pleased to find that the rear-
rangement of 8β proceeded in the presence of NaH-
CO3 at 110 °C to give the desired bis-prenylated
nitrophenol 9β in a moderate yield. Treatment of
9β with Tf2O afforded the aryltriflate 10β, an aro-
matic segment of sespendole. The corresponding ar-
yltriflate 10r having the anti-epoxide was synthesized
from 7r by the same procedure used for the synthesis
of 10β.
Scheme 1. Synthesis of syn-Epoxyalcohol 7β and anti-Epoxyal-
cohol 7r
We next investigated the construction of the indole nu-
cleus to validate our synthetic plan (Scheme 3). Sonogashira
coupling reaction8,9 of 10 with trimethylsilylacetylene
Figure 1. Structure and synthetic strategy of sespendole (1).
Synthesis of the aromatic segments 10β and 10r is
shown in Scheme 2. Protection of the benzylic alcohol
of 7β as TBS ether followed by partial hydrogenation
(7) (a) Castro, A. M. M. Chem. Rev. 2004, 104, 2939–3002. (b)
Nicolaou, K. C.; Pfefferkorn, J. A.; Cao, G.-Q. Angew. Chem., Int.
Ed. 2000, 39, 734–739. (c) Pettus, T. R. R.; Inoue, M.; Chen, X.-T.;
Danishefsky, S. J. J. Am. Chem. Soc. 2000, 122, 6160–6168.
(8) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett.
1975, 16, 4467–4470.
(4) These synthetic compounds were numbered according to
sespendole.
ꢀ
(9) Chinchilla, R.; Najera, C. Chem. Rev. 2007, 107, 874–922.
(5) (a) Godfrey, J. D., Jr.; Mueller, R. H.; Sedergram, T. C.;
Soundararajan, N.; Colandrea, V. Tetrahedron Lett. 1994, 35,
6405–6408. (b) Bell, D.; Davies, M. R.; Geen, G. R.; Mann, I. S.
Synthesis 1995, 707–712.
(6) CCDC 837239 (7β) contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge from The
data_request/cif.
(10) (a) Scott, W. J.; Crisp, G. T.; Stille, J. K. J. Am. Chem. Soc. 1984,
106, 4630–4632. (b) Scott, W. J.; Stille, J. K. J. Am. Chem. Soc. 1986, 108,
3033–3040. (c) Kosugi, M.; Sasazawa, K.; Shimizu, Y.; Migita, T. Chem.
Lett. 1977, 301–302. (d) Stille, J. K. Angew. Chem., Int. Ed. Engl. 1986,
25, 508–524.
(11) Castro, C. E.; Gaughan, E. J.; Owsley, D. C. J. Org. Chem. 1966,
31, 4071–4078.
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