Total synthesis of (+)-sundiversifolide

Article abstract of DOI:10.1021/ol062960h

(Chemical Equation Presented) The first, enantiocontrolled total synthesis of (+)-sundiversifolide has been accomplished using the sequential ring-closing metathesis, [3,3]-sigmatropic rearrangement, and iodolactonization for the key assembly of the cis-f

Full text of DOI:10.1021/ol062960h

ORGANIC
LETTERS
2007
Vol. 9, No. 6
969-971
Total Synthesis of (+)-Sundiversifolide
Hiromasa Yokoe,† Hiroyuki Sasaki,† Tomoyuki Yoshimura,† Mitsuru Shindo,‡
Masahiro Yoshida,† and Kozo Shishido*,†
Graduate School of Pharmaceutical Sciences, The UniVersity of Tokushima,
1-78-1 Sho-machi, Tokushima 770-8505, Japan, and Institute for Materials Chemistry
and Engineering, Kyushu UniVersity, 6-1 Kasugakoen, Kasuga 816-8580, Japan
shishido@ph.tokushima-u.ac.jp
Received December 7, 2006
ABSTRACT
The first, enantiocontrolled total synthesis of (+)-sundiversifolide has been accomplished using the sequential ring-closing metathesis, [3,3]-
sigmatropic rearrangement, and iodolactonization for the key assembly of the cis-fused oxabicyclo[5.3.0]decene framework of the natural
product.
Sundiversifolide (1) was isolated from the exudates of
Helianthus annuus L., germinating sunflower seeds, by
Tomita-Yokotani and co-workers.1 This compound inhibited
shoot and root growth of cat’s-eye by about 50% at a
concentration of 30 ppm and also showed species-selective
activity in the shoot and root growth of various tested plants,
e.g., tomato, crabgrass, and barnyard grass. Although sun-
diversifolide has been recognized as having an allelopathic
function in sunflowers, interestingly, it did not inhibit shoot
growth of the sunflower itself. Because of its intriguing
structural features, interesting biological profiles, and limited
availability, sundiversifolide represents an attractive target
for total synthesis.
In this communication, we report the first, enantiocon-
trolled total synthesis of (+)-sundiversifolide (1). Our
strategy for sundiversifolide is shown in the retrosynthetic
analysis in Scheme 1. We anticipated that the regioselective
installation of the olefinic ethanol unit at C1 would be
achieved via the Wittig-type olefination-deconjugation-
reduction sequence of the ketone 2 or the carbonyl ene
reaction2 of the corresponding exo-methylene derivative of
2 with formaldehyde. Introduction of the methyl group at
C11 would give sundiversifolide (1). The bicyclic ketone 2
with the requisite three stereogenic centers would be as-
sembled via Claisen-type [3,3]-sigmatropic rearrangement
followed by iodo lactonization from 3, which would in turn
be constructed by sequential ring-closing metathesis (RCM)
of 4 and diastereoselective reduction of the resulting enone.
The diene 4 might be prepared from a diastereoselective
Evans aldol reaction of 6 with the aldehyde 5 (Scheme
1).
Scheme 1. Retrosynthetic Analysis
† University of Tokushima.
‡ Kyusyu 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) Taber, D. F. Intramolecular Diels-Alder and Alder Ene Reactions;
Springer-Verlag: Berlin, 1984. (b) Johnson, J. S.; Evans, D. A. Acc. Chem.
Res. 2000, 33, 325.
10.1021/ol062960h CCC: $37.00
© 2007 American Chemical Society
Published on Web 02/13/2007

Dibutylboron triflate mediated aldol reaction of 5 with the
Evans propionate 6 provided the aldol product 7 in 92% yield
as a single diastereomer. The conversion of 7 into the
corresponding Weinreb amide 8 was carried out under
standard Me3Al-mediated conditions.3 Protection of the
alcohol moiety as a TBS ether followed by treatment with
vinylmagnesium chloride furnished the diene 4 in 90% yield
for the two steps. RCM was performed by treatment of 4
with the second-generation Grubbs catalyst 9 (5 mol %) in
refluxing CH2Cl2 to give the cycloheptenone 10 smoothly
in 95% yield (Scheme 2).
Scheme 3
Scheme 2
or Horner-Emmons olefination of 2 did not give 14,
Peterson olefination6 cleanly produced the compound in
excellent yield. It was then exposed to deconjugation
conditions7 to give a separable mixture of the desired
deconjugated ester 15 and the starting ester 14 in a ratio of
Scheme 4
We examined the diastereoselective reduction of the ketone
in 10 under various conditions. The best result was obtained
when Red-Al was used as a reducing agent to give the
alcohol 3 as a chromatographically separable mixture in a
ratio of 67:1 in 75% yield. The absolute configuration of
the major diastereomer was confirmed to be the desired S
by the Kusumi-Mosher method.4 Attempted [3,3]-sigmat-
ropic rearrangements to construct the γ-lactone moiety
provided unsatisfactory results; e.g., the Johnson-Claisen
rearrangement of 3 gave a 2.3:1 mixture of the diastereoi-
somers in 81% yield. Although the Ireland-Claisen protocol
produced the corresponding carboxylic acid diastereoselec-
tively, the yield, however, was only 52%. The best result
was obtained by employing the Eschenmoser rearrangement.5
Thus, treatment of 3 with N,N-dimethylacetamide dimethyl
acetal in refluxing toluene produced the amide 11 in 96%
yield as a single product. Treatment of 11 with iodine in
aqueous THF afforded diastereoselectively the iodolactone
in 92% yield, which was exposed to radical deiodination
conditions to provide 12 quantitatively. Sequential DIBAL-H
reduction and acetalization with p-TsOH in MeOH provided
the alcohol 13, which was oxidized with Dess-Martin
periodinane to give the bicyclic ketone 2 in good overall
yield (Scheme 3).
1.8:1 quantitatively. The deconjugated ester 15 thus prepared
was reduced with DIBAL-H to provide 16. Although the
requisite 16 was obtained, we still hoped to find a more
efficient route. Sequential treatment of 2 with trimethylsi-
lylmethylmagnesium chloride and potassium hydride8 af-
forded the exo-methylene compound 17 which was exposed
to the methylaluminum bis(2,6-diphenylphenoxide) (MAPH)-
To install the olefinic ethanol appendage at C1, we initially
prepared the exocyclic unsaturated ester 14. Although Wittig
(3) (a) Levin, J. I.; Turos, E.; Weinreb, S. M. Synth. Commun. 1982, 12,
989. (b) Evans, D. A.; Black, W. C. J. Am. Chem. Soc. 1993, 115, 4497.
(4) Ohtani, I.; Kusumi, T.; Kashman, Y.; Kakisawa, H. J. Am. Chem.
Soc. 1991, 113, 4092.
(6) Peterson, D. J. J. Org. Chem. 1968, 33, 780.
(5) (a) Eschenmoser, A.; Wick, A. E.; Felix, D.; Steen, K. HelV. Chim.
Acta 1964, 47, 2425. (b) Mulzer, J.; Galkina, A.; Gilbert, M. W. Synlett
2004, 14, 2558.
(7) Winfield, C. J.; Al-Mahrizy, Z.; Gracestock, M.; Bugg, T. D. H. J.
Chem. Soc., Perkin Trans. 1 2000, 3277.
(8) Vazquez, A.; Williams, R. M. J. Org. Chem. 2000, 65, 7865.
970
Org. Lett., Vol. 9, No. 6, 2007

mediated carbonyl ene reaction9 conditions using trioxane
to provide 16 in 70% yield from 2. After protection of the
primary hydroxyl function and regeneration of the lactone
moiety, the resulting 18 was methylated using lithium
tetramethylpiperizide and methyl iodide in HMPA and THF
to give 19 diastereoselectively in 95% yield. The stereo-
chemistry at C11 was determined by NOESY experiments
and turned out to be the undesired R-configuration. After
deprotection of the silyl ether, the resulting ketoalcohol 20
was subjected to kinetic protonation conditions using LDA
and phenol at -78 °C to produce a chromatographically
separable 1:2.8 mixture of 20 and (+)-sundiversifolide 1
{[R]D +34 (c 0.4, CHCl3)} in 97% yield. The spectral
properties (1H and 13C NMR) of the synthetic material were
identical with those of the natural product. Because the
optical rotation for the natural product has never been
reported, the absolute structure could not be determined
(Scheme 4).
diastereoselective reduction, Eschenmoser rearrangement,
and iodolactonization to furnish the cis-fused oxabicyclo-
[5.3.0]decene framework of the natural product. A key
installation of the olefinic ethanol functionality at C1 was
realized regioselectively employing the MAPH-mediated
carbonyl ene reaction. The synthetic route developed here
is general and efficient and can also be applied to the
synthesis of other related natural products, e.g., diversifolide
and xanthatin.
Acknowledgment. We thank Dr. Kaori Tomita-Yokotani
of the University of Tsukuba for providing us with the
spectral data of natural sundiversifolide. This work was
supported financially by a Grant-in-Aid for Scientific
Research (A) (No.16209001) from the Japan Society for the
Promotion of Science.
Supporting Information Available: Experimental pro-
cedures and spectroscopic and analytical data for all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
In summary, we have completed the first, enantiocontrolled
total synthesis of (+)-sundiversifolide using sequential RCM,
(9) Maruoka, K.; Concepcion, A. B.; Murase, N.; Oishi, M.; Hirayama,
N.; Yamamoto, H. J. Am. Chem. Soc. 1993, 115, 3943.
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