Tetrahedron Letters 49 (2008) 4279–4281
Tetrahedron Letters
Synthesis of diversifolide and structure revision
c,
Kazumasa Matsuo a, Hiromasa Yokoe b, Kozo Shishido b, , Mitsuru Shindo
*
*
a Interdisciplinary Graduate School of Engineering Sciences, Kyushu University, 6-1, Kasugako-en, Kasuga 816-8580, Japan
b Graduate School of Pharmaceutical Sciences, The University of Tokushima, 1-78-1 Sho-machi, Tokushima 770-8505, Japan
c Institute for Materials Chemistry and Engineering, Kyushu University, 6-1, Kasugako-en, Kasuga 816-8580, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
The synthesis of diversifolide and its structural revision are reported. We synthesized the assigned struc-
ture of diversifolide via two methods, but the NMR spectra of the synthetic material did not match those
of the natural material. Through careful investigation, we found that the spectra were identical with
those of 11-epi-sundiversifolide.
Received 7 April 2008
Revised 23 April 2008
Accepted 25 April 2008
Available online 29 April 2008
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
Natural product
Structure revision
Sesquiterpene lactone
Stereoselective synthesis
Diversifolide is a novel dinorxanthane sesquiterpene lactone
that was isolated from Tithonia T. diversifolia (Hernsl.) A. Gray
(Compositae) by Kuo in 1999.1 Although its absolute configuration
was not defined in this Letter, the structure was assigned as shown
in Figure 1, using spectroscopic analyses including 1H and 13C
NMR, IR and HRMS.2 Sundiversifolide,3 its stereoisomer, is a potent
allelochemical, and related xanthanolides recently have been
found to exhibit intriguing biological profiles such as antimalarial4
and antitumor activity,5 inhibition of farnesylation of the human
lamin-B6 as well as allelopathic activity.3 Consequently, diversifo-
lide would also be expected to show some biological activity, even
allelopathy, although to date no bioassay of diversifolide has been
reported. Herein, we describe the revision of the structure of diver-
sifolide by total synthesis and the determination of its absolute
configuration.
Recently, we have reported the total synthesis of sundiversifo-
lide,7 which is a diastereomer of diversifolide at the C-8 and C-11
positions. We therefore commenced the synthesis from 3 isolated
as an isomeric side product in the hydrogenation of the butenolide
2.7b The key conversion of 3 to ‘diversifolide’ is thus the stereo-
chemical inversion at C-8. Dehydration of 3, followed by the regio-
selective reduction of the epoxide afforded 11-epi-sundiversifolide
(4).7a After protection of the alcohol as a TBDPS ether, the lactone
moiety was opened by diethylamine with aluminum trichloride
to give the hydroxy amide 5. Next, the alcohol at C-8 was oxidized
by TPAP, and the resulting ketone 6 was reduced by SmI2 to afford
HO
8
O
11
{[α]2D0 -12.5° (c 0.35, CHCl3)}
O
1
Figure 1. Kuo’s assigned structure of diversifolide (1).
the alcohol 7 with the desired configuration at C-8.8 After lacton-
ization by acid, followed by deprotection, the synthetic 1 was
obtained (Scheme 1). Alternatively, 1 was also prepared from the
bicyclic lactone 8, which has been utilized for the synthesis of
(ꢀ)-xanthatin.9 Thus, the lactone 8 was treated with LDA and
MeI to give the undesired isomer 9 as a single product, the struc-
ture of which was determined by NOE. Attempted inversion at
C-11 using kinetic protonation conditions produced a chromato-
graphically separable 1:1 mixture of diastereoisomers, the desired
isomer of which was desilylated to give 1 (Scheme 2). However, the
1H and 13C NMR spectra of 1 did not match those for the natural
material reported by Kuo.1 Since the stereochemistry was con-
firmed by the NOE spectra as shown in Figure 2, Kuo’s proposed
stereochemistry is incorrect.
We speculated that since their spectra indicated the same car-
bon framework, the correct structure should be the diastereomer
of 1. After careful examination of the NMR spectra of the synthetic
intermediates, we noticed that all the spectral data of the synthetic
intermediate 4, 11-epi-sundiversifolide (the C8-epimer of Kuo’s
* Corresponding authors.
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.04.141