Stereocontrolled synthesis of an indole moiety of sespendole and stereochemical assignment of the side chain

Article abstract of DOI:10.1021/ol202895u

Two possible diastereomers of the indole moiety of sespendole were synthesized from 3-hydroxy-4-nitrobenzaldehyde in a highly stereoselective manner. Comparison of ¹H and ¹³C NMR spectra of the two synthetic materials with those sespendole leads us to propose that the relative stereochemistry of the epoxyalcohol is syn.

Full text of DOI:10.1021/ol202895u

ORGANIC
LETTERS
2012
Vol. 14, No. 1
114–117
Stereocontrolled Synthesis of an Indole
Moiety of Sespendole and Stereochemical
Assignment of the Side Chain
Masaatsu Adachi,† Keiko Higuchi,† Nopporn Thasana,‡ Hitomi Yamada,† and
Toshio Nishikawa*,†
Laboratory of Organic Chemistry, Graduate School of Bioagricultural Sciences, Nagoya
University, Chikusa, Nagoya 464-8601, Japan, and Laboratory of Medicinal Chemistry,
Chulabhorn Research Institute, Laksi, Bangkok 10210, Thailand
nisikawa@agr.nagoya-u.ac.jp
Received October 28, 2011
ABSTRACT
Two possible diastereomers of the indole moiety of sespendole were synthesized from 3-hydroxy-4-nitrobenzaldehyde in a highly stereoselective
1
manner. Comparison of H and 13C NMR spectra of the two synthetic materials with those sespendole leads us to propose that the relative
stereochemistry of the epoxyalcohol is syn.
Sespendole (1) was isolated from the culture broth of the
fungal strain Pseudobotrytis terrestris FKA-25 by Tomoda
and co-workers in 2004, and its structure including all
absolute configurations except C-31 was elucidated by
extensive spectroscopic analyses (Figure 1).1 This new
indole sesquiterpene alkaloid inhibits the synthesis of
cholesteryl ester and triacylglycerol by mouse macro-
phages with IC50 values of 4.0 and 3.2 μM, respectively.1b
The structural complexity as well as the important
biological activity prompted us to embark on the
synthesis of sespendole and its related compounds.2
Our synthetic strategy is a divergent manner based on
coupling between two highly functionalized seg-
ments, aromatic segment 2 and sesquiterpene segment
3 (Figure 1). We have already reported the synthesis of
the (() sesquiterpene segment 3 possessing all requi-
site functions for sespendole.3 We disclose herein the
stereocontrolled synthesis of two diastereomers of the
aromatic segment and construction of the indole
nucleus possessing the same side chains as those of
sespendole. We also compare the NMR data of these
two compounds with those of sespendole for stereo-
chemical assignment of the side chain.
† Nagoya University.
‡ Chulabhorn Research Institute.
(1) (a) Yamaguchi, Y.; Masuma, R.; Kim, Y.-P.;Uchida, R.; Tomoda,
H.; Omura, S. Mycoscience 2004, 45, 9–16. (b) Uchida, R.; Kim, Y.-P.;
Namatame, I.; Tomoda, H.; Omura, S. J. Antibiot. 2006, 59, 93–97.
(c) Uchida, R.; Tomoda, H.; Omura, S. J. Antibiot. 2006, 59, 298–302.
(d) Uchida, R.; Kim, Y.-P.; Nagamitsu, T.; Tomoda, H.; Omura, S. J.
Antibiot. 2006, 59, 338–344.
(2) For recent synthetic studies on indole diterpenes with a related
architectural ring system, see: (a) Smith, A. B.; Davulcu, A. H.; Cho,
Synthesis of the aromatic segment having two prenyl units
began with the addition of 2-methyl-1-propenylmagnesium
€
Y. S.; Ohmoto, K.; Kurti, L.; Ishiyama, H. J. Org. Chem. 2007, 72, 4596–
€
4610. (b) Smith, A. B.; Kurti, L.; Davulcu, A. H.; Cho, Y. S.; Ohmoto,
K. J. Org. Chem. 2007, 72, 4611–4620. (c) Churruca, F.; Fousteris, M.;
Ishikawa, Y.; von Wantoch Rekowski, M.; Hounsou, C.; Surrey, T.;
Giannis, A. Org. Lett. 2010, 12, 2096–2099.
(3) Sugino, K.; Nakazaki, A.; Isobe, M.; Nishikawa, T. Synlett 2011,
647–650.
r
10.1021/ol202895u
Published on Web 11/29/2011
2011 American Chemical Society

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
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
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.
Org. Lett., Vol. 14, No. 1, 2012
115

Scheme 2. Synthesis of Aromatic Segments 10β and 10r
Scheme 3. Synthesis of Epoxyindoles 14β and 14r by
MigitaÀStille Coupling and Castro-Type Indole Synthesis
provided arylacetylene 11 in a low yield, along with
a significant amount of the recovered 10 and 9 as
a byproduct. The reason might be due to steric
hindrance around the triflate group exerted by two
ortho substituents. In contrast, MigitaÀStille coupl-
ing reaction10 with tributyl[(trimethylsilyl)ethynyl]-
stannane proceeded smoothly to afford 11 in good
yield. Reduction of the nitro group with the ZnÀCu
couple afforded alkynylaniline 12. Unexpectedly, in-
dole synthesis of 12 under the conventional conditions
used for the Castro reaction11 proved to be problem-
atic. We reasoned that the trimethylsilylacetylene
and the oxygenated prenyl groups may be unstable
under these conditions. After screening conditions
for the indole synthesis, we found that CuI in DMF
without a base was optimal for the cyclization of
syn-alkynylaniline 12β. Surprisingly, these conditions
were not applicable for the diastereomer 12r; expo-
sure of 12r to the same conditions gave a complex
mixture of products. Finally, Cu(OAc)2 in dichloroethane12
was found to be the optimal reagent for production of the
anti-alkynylaniline 12r. Desilylation of 13 with TBAF
furnished epoxyindole 14.
With the two diastereomers of the indole moiety of
sespendole (1) in hand, 1H and 13C NMR spectra of these
synthetic indoles 14β and 14r were compared. The cou-
pling constants between H-30 and H-31 of 14β/14r were
very close (J30,31 = 7.5 Hz for 14β and J30,31 = 8.0 Hz for
14r, respectively) and in good agreement with that re-
ported previously (J30,31 = 8.0 Hz for sespendole). On the
other hand, the chemical shifts of the synthetic compounds
14β and 14r were significantly different, which indicates
1
Figure 2. Chemical shift differences (Δδ) of H and 13C NMR
spectra for syn- and anti-epoxyindoles 14. Δδ = δ(synthetic) À
δ(natural). Bars represent the deviation in ppm between individual
chemical shifts observed for 14 and those reported for the sespendole
(1) (400 MHz, C5D5N).
(12) Hiroya, K.; Itoh, S.; Sakamoto, T. J. Org. Chem. 2004, 69, 1126–
1136.
116
Org. Lett., Vol. 14, No. 1, 2012

the possibility of stereochemical assignment of the side
1
enantioselective synthesis of the aromatic segment and
the total synthesis of sespendole (1) are now in progress.
chain. Selected comparative H and 13C NMR data are
shown in Figure 2. The resonances corresponding to the
benzylic and epoxide protons at C-30 and C-31 were
distinctly different in chemical shift. The syn-epoxyindole
14β exhibitedsmaller chemical shift differences (Δδ = 0.02
and À0.09 ppm, respectively), whereas the anti-epoxy-
indole 14r showed larger differences (Δδ = 0.12 and
À0.40 ppm, respectively). In the 13C NMR spectra, 14β
also exhibited smaller chemical shift differences than
14r in the carbons of epoxyalcohol between C-30 and
C-34. These results strongly suggest that the relative
stereochemistry of the epoxyalcohol moiety is syn in
sespendole (1).
Acknowledgment. This work was financially supported
by Grants-in-Aid for Scientific Research, the Naito Founda-
tion, the Nagase Science and Technology Foundation, a
SUNBOR GRANT from the Suntory Institute for Bioor-
ganic Research, the Global COE program from MEXT, the
Japan Society for Promotion of Science-Asian Core Program
(JSPS-ACP) on Cutting-Edge Organic Chemistry in Asia,
the National Research Council of Thailand (NRCT), and the
Chulabhorn Research Institute (CRI). We are grateful to Mr.
K. Yoza (Bruker AXS) for the X-ray crystallographic ana-
lysis. We gratefully acknowledge Prof. H. Tomoda and Dr.
R. Uchida (Kitasato University) for providing the NMR
spectra of sespendole.
In conclusion, we have stereoselectively synthesized two
diastereomers 10β and 10r of the aromatic segment of
sespendole (1), which were transformed into epoxyindoles
14β and 14r, respectively, according to our synthetic plan.
Supporting Information Available. Experimental pro-
cedures, characterization data, copies of 1H and 13C
NMR spectra for all new compounds, and crystallo-
graphic data for 7β (CIF). This material is available free
of charge via the Internet at http://pubs.acs.org.
1
Comparison of the H and 13C NMR spectra of these
epoxyindoles with those of sespendole (1) leads us to
propose that the epoxy group has a syn relationship
to the hydroxyl group. Continuing efforts toward the
Org. Lett., Vol. 14, No. 1, 2012
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