Total synthesis of (+)- and (-)-sundiversifolide via intramolecular acylation and determination of the absolute configuration

Article abstract of DOI:10.1021/ol8001333

Intramolecular acylation of an organolithium leads to an efficient stereocontrolled total synthesis of both enantiomers of sundiversifolide. The absolute configuration was determined by HPLC analysis and allelopathy assay. The y-lactone moiety resulted fr

Full text of DOI:10.1021/ol8001333

ORGANIC
LETTERS
2008
Vol. 10, No. 6
1247-1250
Total Synthesis of (
+)- and
(−)-Sundiversifolide via Intramolecular
Acylation and Determination of the
Absolute Configuration
Keiko Ohtsuki,† Kazumasa Matsuo,† Takashi Yoshikawa,† Chihiro Moriya,‡
|
Kaori Tomita-Yokotani,§ Kozo Shishido,‡ and Mitsuru Shindo*,
Institute for Materials Chemistry and Engineering, Kyushu UniVersity, 6-1,
Kasugako-en, Kasuga 816-8580, Japan, Interdisciplinary Graduate School of
Engineering Sciences, Kyushu UniVersity, Graduate School of Pharmaceutical
Sciences, The UniVersity of Tokushima, and Graduate School of Life and
EnVironmental Sciences, UniVersity of Tsukuba, Tsukuba, Ibaraki 305-8572, Japan
shindo@cm.kyushu-u.ac.jp
Received January 19, 2008
ABSTRACT
Intramolecular acylation of an organolithium leads to an efficient stereocontrolled total synthesis of both enantiomers of sundiversifolide. The
absolute configuration was determined by HPLC analysis and allelopathy assay. The -lactone moiety resulted from a butenolide was obtained
by the condensation of a bicyclic -hydroxyhemiacetal with Ph3P CMe(CO2R).
γ
r
d
Sundiversifolide (1) was isolated from the exudate of
germinating sunflowers (Helianthus annuus L.) as an allelo-
pathic compound,1 that is, a plant release chemical compound
that environmentally affects the germination or growth of
different plant species growing in their vicinity. At a
concentration of around 30 ppm, sundiversifolide inhibits
the root development of cat’s-eye seedlings by 50%. Sun-
diversifolide also reduced the conidial germination rate of
the fungus, Neurospora crassa, at approximate concentrations
of 30 µM when its conidia were incubated with the liquid
medium for 3 h.2 These promising results potentially could
lead to a naturally occurring herbicide or anti-microbial agent
that could become an important tool for chemical ecology
and/or the food industry as a food additive. Although the
structure elucidation of this novel dinorxanthane sesquiter-
pene bearing four stereocenters was established by analysis
of its IR, MS, and NMR spectra, the absolute configuration
has not been determined. Since this compound is available
in only tiny quantities from seeds and seems to partially
decompose or isomerize during purification by HPLC, it is
difficult to obtain enough of the pure form from nature, and
the optical rotation of the natural product has not been
reported. Owing to the few reports on the synthetic studies
† Interdisciplinary Graduate School of Engineering Sciences, Kyushu
University.
‡ The University of Tokushima.
§ University of Tsukuba.
| Institute for Materials Chemistry and Engineering, Kyushu University.
(1) Ohno, S.; Tomita-Yokotani, K.; Kosemura, S.; Node, M.; Suzuki,
T.; Amano, M.; Yasui, K.; Goto, T.; Yamamura, S.; Hasegawa, K.
Phytochemistry 2001, 56, 577.
(2) (a) Kato, T.; Tomita-Yokotani, K.; Suzuki, T.; Hasegawa, K. Weed
Biol. Manag. in press. (b) Tomita-Yokotani, K.; Suzuki, T.; Kato, T. In
Current Concepts in Botany; Mukerji, K. G., Manoharachary, C., Eds.; I.
K. International: India, 2006; pp 371-376.
10.1021/ol8001333 CCC: $40.75
© 2008 American Chemical Society
Published on Web 02/21/2008

of xanthanolides, the development of an efficient synthetic
strategy is needed to supply the natural product.3,4 Herein,
we report the efficient total synthesis of both enantiomers
of sundiversifolide via a route of acylation of an organo-
lithium by a γ-lactone, and the absolute configuration
determination by HPLC analysis and allelopathy assay of
the synthetic molecules.
and selective deprotection of the primary TBDPS ether with
TBAF/acetic acid in THF/CH2Cl2,8 followed by iodination,
furnished the iodolactone 12 in good yield (Scheme 2).
Scheme 2. Asymmetric Synthesis of γ-Lactone12
Our synthetic strategy for sundiversifolide is illustrated
in Scheme 1. The γ-lactone moiety would be formed by an
Scheme 1. Retrosynthesis of Sundiversifolide (1)
The pivotal intramolecular acylation forming the seven-
membered ring was first attempted with SmI2 under various
conditions and resulted in no reaction. Instead, lithiation of
the iodide 12 using t-BuLi successfully provided the seven-
membered ring in excellent yield.9 The NMR spectra showed
that the product is in equilibrium between the hemiacetal
13 and the cycloheptanone 14 in CDCl3. Although MOMCl
reacted with both of the hydroxyl groups on 13 and 14,
TBDPSCl protected only the secondary alcohol of 14 to
afford 15 quantitatively (Scheme 3).
olefination-lactonization of the hydroxyketone 2, followed
by hydrogenation. The 2-hydroxyethyl side chain then would
be introduced by alkylation of the ketone 3. The seven-
membered ring construction, which is much more challenging
than the six-membered ring, would be achieved by an
intramolecular acylation of an organometallic species on the
γ-lactone 4.5 The asymmetric centers on 4 would be
obtained by stereocontrolled alkylation using a chiral ox-
azolidinone, followed by stereocontrolled dihydroxylation
of the resulting 5.
The stereocontrolled alkylation of Evans’ oxazolidinone
7 with 6, prepared from 3-butyn-1-ol in 72% yield for the
five steps, provided 8 in good yield with excellent stereo-
selectivity.6 The stereocontrolled dihydroxylation of 8 with
AD-mixâ7 was accompanied by spontaneous lactonization
of the intermediate diol to afford the lactone 9 as a single
isomer. The protection of the secondary alcohol with TBSCl
Scheme 3. Intramolecular Acylation of the Alkyllithium Giving
Cycloheptanone
(3) (a) Evans, M. A.; Morken, J. P. Org. Lett. 2005, 7, 3371. (b) Kummer,
D. A.; Brenneman, J. B.; Martin, S. F. Org. Lett. 2005, 7, 4621. (c) Kummer,
D. A.; Brenneman, J. B.; Martin, S. F. Tetrahedron 2006, 62, 11437. (d)
Rudler, H.; Alvarez, C.; Parlier, A.; Perez, E.; Denise, B.; Xu, Y.;
Vaissermann, J. Tetrahedron Lett. 2004, 45, 2409.
(4) For total synthesis of sundiversifolide, see; (a) (+)-form: H. Yokoe,
H.; Sasaki, H.; Yoshimura, T.; Shindo, M.; Yoshida, M.; Shishido Org.
Lett. 2007, 9, 969. (b) (()-form: Hashimoto, T.; Tashiro, T.; Sasaki, M.;
Takikawa, H. Biosci. Biotecnol. Biochem. 2007, 71, 2046.
(5) The relevant protocol has been reported by Molander using SmI2.
For a review, see: (a) Molander, G. A. Acc. Chem. Res. 1998, 31, 603.
See, also: (b) Kawamura, K.; Hinou, H.; Matsuo, G.; Nakata, T.
Tetrahedron Lett. 2003, 44, 5259.
With the seven-membered skeleton in hand, we next
attempted the introduction of the C2-C3 unit along with
the formation of the C1-C5 endo-olefin. The enol triflation
of the ketone 15 gave only recovered starting material, and
the Shapiro reaction of the corresponding p-toluenesulfonyl
(8) Without use of CH2Cl2 as a co-solvent, the diol was mainly generated.
See: Higashibayashi, S.; Shinko, K.; Ishizu, T.; Hashimoto, K.; Shirahama,
H.; Nakata, M. Synlett 2000, 1306.
(6) Evans, D. A.; Ennis, M. D.; Mathre, D. J. J. Am. Chem. Soc. 1982,
104, 1737.
(7) Sharpless, K. B.; Amberg, W.; Bennani, Y. L.; Crispino, G. A.;
Hartung, J.; Jeong, K.-S.; Kwong, H.-L.; Morikawa, K.; Wang, Z.-M.;
Zhang, X.-L. J. Org. Chem. 1992, 57, 2768.
(9) For cyclization of iodo esters with organolithiums, see: (a) Cooke,
M. P., Jr.; Houpis, I. N. Tetrahedron Lett. 1985, 26, 4987. (b) Saito, T.;
Takeuchi, T.; Matsuhashi, M.; Nakata, T. Heterocycles 2007, 72, 151.
1248
Org. Lett., Vol. 10, No. 6, 2008

hydrazone resulted in the alkenyl iodide 1610 in moderate
yield after trapping of the alkenyl lithium with iodine. While
the keto group on 15 was inert to olefinations, such as the
Wittig or the Peterson reactions, vinyl magnesium bromide
effectively added to the ketone to afford the adduct 17 in
excellent yield as a single isomer. Since dehydration of the
tertiary alcohol giving the endo-olefin was unsuccessful at
this stage, we decided to assemble the lactone first. The
selective deprotection of the TBS group, TPAP oxidation,
and removal of the TBDPS group provided the hydroxy
hemiacetal 20 nearly quantitatively.
We next tried to construct the lactone moiety from 20,
which is equivalent to an R-hydroxyketone. Olefination of
20 with the Wittig reagent (Ph3PdC(CH3)CO2C2H5) under
reflux in xylene for 9 h directly provided the butenolide 22
in 91% yield, the structure of which was unambiguously
assigned by X-ray diffraction study. In contrast to Garner’s
report on the Wittig reaction of R-hydroxy ketones giving
(E)-olefins,11 this reaction was exclusively (Z)-selective. The
mechanism of this direct lactonization could be postulated
as transesterification giving the intermediate 21, followed
by intramolecular olefination, because the ketone on 20 was
masked by hemiacetalization. The reaction using the Wittig
reagent with the trifluoroethyl ester (Ph3PdC(CH3)CO2CH2-
CF3) was completed in only 4 h (92% yield), also suggesting
that the intramolecular olefination had occurred (Scheme 4).
pound. Since the double bond on the allylic alcohol had to
be protected prior to dehydration, 22 was treated with
mCPBA to give the epoxide 23, which was subjected to
hydrogenation with the nickel boride derived from NiCl2 and
12
NaBH4 to afford a separable mixture of 24 (81%) and its
C11-epimer (14%). After numerous attempts, the best results
for a kinetically controlled dehydration of 24 were obtained
using a protocol involving slow addition of a solution of
freshly distilled SOCl2 (2 equiv) and pyridine (4 equiv) in
CH2Cl2 at -20 °C. Under these conditions, the desired endo-
alkene 25 was successfully obtained in yields ranging from
∼68-87%. Finally, the epoxide in 25 was regioselectively
reduced with NaBH3CN in the presence of ZnI213 to provide
sundiversifolide (1) in 85% yield. The synthetic 1 {[R]22
D
) +33.0 (c 0.44, CHCl3)} was found to be identical to the
natural 1 according to spectroscopic properties (1H and 13C
NMR, IR, and MS) (Scheme 5).
Scheme 5. Completion of the Total Synthesis of
(+)-Sundiversifolide 1
Scheme 4. Synthesis of Lactone 22
The enantiomer ent-1 {[R]22 ) -33.7 (c 0.46, CHCl3)}
D
was also synthesized in a similar manner, using the chiral
oxazolidinone derived from L-Phe in the asymmetric alky-
lation and ADmix-R in the asymmetric dihydroxylation,
which also gave a single isomer. The HPLC analysis using
chiral column (Daicel Chiralpak IA, hexane/isopropanol 93:
7) indicated that the natural 1 is identical with the synthetic
(+)-1. This study therefore determined that the absolute
configuration of the naturally occurring sundiversifolide
isolated from the sunflower is that shown in 1.
The effect of sundiversifolide on the growth of cat’s-eye
seedlings and the germination rate in a model microbe,
Neurospora crassa, were tested. (+)-Sundiversifolide (1)
inhibited the elongation of root growth of cat’s-eye seedlings
at a concentration of 100 µM. The compound also reduced
the conidial germination rate of Neurospora crass by 50%
of the control at concentrations greater than 20 µM when its
conidia were incubated with liquid medium for 2.5 h. On
the other hand, (-)-sundiversifolide (ent-1) did not show
significant inhibition.
With the carbon skeleton in hand, we then investigated
the less substituted endo-alkene formation. Dehydration using
MsCl/Et3N gave SN2′ products and not the desired com-
(12) Kido, F.; Tsutsumi, K.; Maruta, R.; Yoshikoshi, A. J. Am. Chem.
Soc. 1979, 101, 6420.
(13) Finkielsztein, L. M.; Aguirre, J. M.; Lantano, B.; Alesso, E. N.;
Moltrasio Iglesias, G. Y. Synth. Commun. 2004, 34, 895.
(10) The methyl group on the TBS ether was also lithiated by the Shapiro
reaction.
(11) Garner, P.; Ramakanth, S. J. Org. Chem. 1987, 52, 2629.
Org. Lett., Vol. 10, No. 6, 2008
1249

In conclusion, we have achieved an efficient asymmetric
total synthesis of (+)- and (-)-sundiversifolide in 25%
overall yield, using a strategy involving a seven-membered
ring construction via intramolecular acylation of an organo-
lithium and a one-pot lactonization with a Wittig reagent.
We also determined the absolute configuration of the natural
product by HPLC analysis using a chiral column. Biological
tests also show its potential as an allelochemical. Work is
underway to synthesize xanthanolide families and their
analogues in order to find novel allelochemicals and other
medicinal resources.
Acknowledgment. This work was supported by a Grant-
in-Aid for Scientific Research on Priority Areas “Advanced
Molecular Transformations of Carbon Resources” from the
Ministry of Education, Culture, Sports, Science and Technol-
ogy, Japan
Supporting Information Available: Synthetic proce-
dures, spectroscopic data for new compounds, and crystal-
lographic data for 22. This material is available free of charge
via the Internet at http://pubs.acs.org.
OL8001333
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Org. Lett., Vol. 10, No. 6, 2008