Total synthesis of(±)-neovibsanin b

Article abstract of DOI:10.1021/ol802973f

(±)-Neovibsanin B was synthesized based on a DMI-accelerated intramolecular Diels-Alder reaction followed by oxy-Michael addition- lactonization. The synthetic (±)-neovibsanin B induced similar morphological changes in NGF-mediated PC12 cells compared wit

Full text of DOI:10.1021/ol802973f

ORGANIC
LETTERS
2009
Vol. 11, No. 6
1253-1255
Total Synthesis of (()-Neovibsanin B
Hiroshi Imagawa,* Hayato Saijo, Takahiro Kurisaki, Hirofumi Yamamoto,
Miwa Kubo, Yoshiyasu Fukuyama, and Mugio Nishizawa*
Faculty of Pharmaceutical Sciences, Tokushima Bunri UniVersity,
Yamashiro-cyo, Tokushima 770
imagawa@ph.bunri-u.ac.jp; mugi@ph.bunri-u.ac.jp
Received December 27, 2008
ABSTRACT
(()-Neovibsanin B was synthesized based on a DMI-accelerated intramolecular Diels-Alder reaction followed by oxy-Michael
addition-lactonization. The synthetic (()-neovibsanin B induced similar morphological changes in NGF-mediated PC12 cells compared
with natural (+)-neovibsanin B.
Neovibsanin A (1) and its isomer neovibsanin B (2) are rarely
occurring natural products isolated from Viburnum
awabuki.1a Both compounds display neurotrophic activity in
PC12 cells as reported by Fukuyama’s group in 1996.1b Thus,
neovibsanin-type compounds, compact polyoxygenated natu-
ral products, are expected to act as lead compounds for the
development of novel therapeutic agents to treat Alzheimer’s
disease.2 However, to date, very few synthetic studies have
been reported.3 We describe herein the first total synthesis
of (()-2 (Figure 1) based on an intramolecular Diels-Alder
reaction accelerated with 1,3-dimethyl-2-imidazolidinone (7,
hereafter DMI) and a subsequent oxy-Michael addition-
lactonization reaction. We also describe the neurotrophic
activity of (()-2 on PC12 cells.
(1) (a) Fukuyama, Y.; Minami, H.; Takeuchi, K.; Kodama, M.; Kawazu,
K. Tetrahedron Lett. 1996, 37, 6767–6770. (b) Fukuyama, Y.; Esumi, T.
J. Org. Synth. Chem. Jpn. 2007, 65, 585–597.
(2) (a) Fukuyama, Y.; Minami, H.; Yamamoto, I.; Kodama, M.; Kawazu,
K. Chem. Pharm. Bull. 1998, 46, 545–547. (b) Kubo, M.; Minami, H.;
Hayashi, E.; Kodama, M.; Kawazu, K.; Fukuyama, Y. Tetrahedron Lett.
1999, 40, 6261–6265. (c) Kubo, M.; Chen, I.-S.; Fukuyama, Y. Chem.
Pharm. Bull. 2001, 49, 242–245. (d) Fukuyama, Y.; Kubo, M.; Minami,
H.; Yuasa, H.; Matsuo, A.; Fujii, T.; Morisaki, M.; Harada, K. Chem. Pharm.
Bull. 2005, 53, 72–80. (e) Fukuyama, Y.; Fujii, H.; Minami, H.; Takahashi,
H.; Kubo, M. J. Nat. Prod. 2006, 69, 1098–1100.
Figure 1. Structures of neovibsanins.
(3) (a) Esumi, T.; Zhao, M.; Kawakami, T.; Fukumoto, M.; Toyota, M.;
Fukuyama, Y. Tetrahedron Lett. 2008, 49, 2692–2696. (b) Gallen, M. J.;
Williams, C. M. Org. Lett. 2008, 10, 713–715. Chen, A. P.-J.; Williams,
C. M. Org. Lett. 2008, 10, 3441–3443.
Starting material, homogeranic acid (3), was prepared in
76% yield in three steps from geranyl bromide by Tamao’s
protocol4 and subsequent oxidations by Dess-Martin pe-
riodinane and NaClO2. After chlorination of 3 with oxalyl
chloride, the resulting chloride 4 was treated with lithium
(E)-1,3-butadien-1-olate prepared from (E)-trimethylsilyl
(4) Tamao, K.; Ishida, N.; Kumada, M. J. Org. Chem. 1983, 48, 2120–
2122.
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736.
10.1021/ol802973f CCC: $40.75
Published on Web 02/12/2009
2009 American Chemical Society

enolate according to Stork’s protocol,5 giving rise to tetraene
5 in 79% yield. Successful Diels-Alder reactions of trisub-
stituted nonconjugated olefins as dienophiles are not well-
known.6 Therefore, we explored conditions suitable for the
intramolecular Diels-Alder reaction of 5. Among the
solvents and reaction temperatures examined, an 82:18
mixture of cycloadducts 6a and 6b was obtained in 18%
yield by heating 5 in mesitylene at 200 °C for 10 h using a
sealed tube. Furthermore, we found that the reaction in DMI
(7) as solvent resulted in both an improved yield of up to
58% within a shorter reaction period and an improved endo-
selectivity of up to 90:10 of 6a and 6b by heating at 200 °C
for 3 h (Scheme 1). It is particularly noteworthy that a sealed
tube is not required for this reaction, making it suitable for
scale-up. The observed acceleration of the reaction rate may
be due to a solvophobic packing effect of DMI based on its
aprotic polar properties. General applicability of this solvent
effect is currently under investigation.7
achieved by Baylis-Hillman reaction with formaldehyde using
tributylphosphine.9 The resulting hydroxy group of 10 was
protected by TBS to give 11 (Scheme 2).
Scheme 2. Preparation of Cyclopentenone 11
Scheme 1. Synthesis of Lactone 6
The reaction of the ketone 11 with 15 equiv of lithio ethyl
propiolate (12) in toluene took place successfully to give
the alkylated product 13 in 87% yield as a single diastere-
omer.10 We concluded that the newly generated stereochem-
istry of 13 was completely controlled to give the desired
ꢀ-configuration based upon the coordination effect of the
2,4-DMPM group with nucleophile 12 as shown in 14
(Scheme 3).11 Red-Al reduction of 13 afforded 15 in 89%
Scheme 3. Synthesis of Tricyclic Lactone 16
The reduction of 6a and 6b with DIBAL led to diols 8a and
8b in 89% yield. Selective protection of the primary alcohol of
8a and 8b by 2,4-DMPM (2,4-dimethoxybenzyl)8 followed by
oxidation of the secondary alcohol moiety resulted in the
formation of a single cyclohexenone 9 in 70% yield (three
steps). Introduction of a hydroxymethyl group into 9 was
(6) The examples for Diels-Alder reactions of sterically hindered diene
or dienophile: (a) Sugiyama, S.; Tsuda, T.; Mori, A.; Takeshita, H.; Kodama,
M. Bull. Chem. Soc. Jpn. 1987, 60, 3633–3638. (b) Boger, D. L.; Robarge,
K. D. J. Org. Chem. 1988, 53, 3377–3379. (c) Nicolaou, K. C.; Hwang,
C.-K.; Sorensen, E. J.; Claiborne, C. F. J. Chem. Soc., Chem. Commun.
1992, 1117–1118. (d) Engler, T. A.; Sampath, U.; Vander, D. V.;
Takusagawa, F. Tetrahedron 1992, 48, 9399–16. (e) Gacem, B.; Jenner,
G. J. Phys. Org. Chem. 2004, 17, 221–225. (f) Jung, M. E.; Ho, D.; Chu,
H. V. Org. Lett. 2005, 7, 1649–1651. The examples for Diels-Alder
reactions of isolated-trisubstituted olefin: (g) Begue, J.-P.; Bonnet-Delpon,
D.; Lequeux, T.; Angelo, J.; Guingant, A. Synlett 1992, 146–149. (h) Heiner,
T.; Michalski, S.; Gerke, K.; Kuchta, G.; Buback, M.; Meijere, A. Synlett
1995, 355–357. (i) Shrestha, K. S.; Honda, K.; Asami, M.; Inoue, S. Bull.
Chem. Soc. Jpn. 1999, 72, 73–83. (j) Wada, E.; Kumaran, G.; Kanemasa,
S. Tetrahedron Lett. 2000, 41, 73–76.
(7) The pioneering work for Diels-Alder reaction in water. Rideout,
D. C.; Breslow, R. J. Am. Chem. Soc. 1980, 102, 7816–7817. Organic
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yield.12 The R,ꢀ-unsaturated ester 15 was then treated with
TBAF to cleave the TBS group; however, subsequent oxy-
(8) Guibe, F. Tetrahedron 1997, 53, 13509–13556.
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Org. Lett., Vol. 11, No. 6, 2009

Michael addition and lactonization took place giving rise to
a tricyclic lactone 16 in 87% yield (Scheme 3). The
stereochemistry of 16 was confirmed by NOE experiments.
The 2,4-DMPM was cleaved by using DDQ under a two-
phase system of CH2Cl2 and NaCl saturated-phosphate buffer
to give a desired alcohol 17 in 83% yield.13 After protection
of the alcohol as the TBS ether, the resulting 18 was treated
with Tebbe reagent affording 19.14 Treatment of the crude
enol ether 19 with PPTS in methanol provided acetals 20a
and 20b in 91% yield (two steps) in a 1:4.5 ratio (Scheme
4). After separation of 20a and 20b by HPLC, the TBS group
of the major isomer 20b was removed with TBAF quanti-
tatively, and the resulting alcohol was oxidized with SO3-
pyridine-DMSO to give the aldehyde 21 in 89% yield.15
Finally, a potassium enolate derived from 21 with KHMDS
was trapped with 3,3-dimethylacryloyl chloride completing
the first total synthesis of (()-2 in 60% yield (Scheme 4).
(2) significantly promoted neurite outgrowth in NGF (10 ng/
mL)-mediated PC12 cells at concentrations ranging from 10
to 40 µM (Figure 2C, D). This is similar to the degree of
activity observed for natural (+)-2 (Figure 2B).
Scheme 4. Syntheses of Neovibsanins
Figure 2. Morphological changes of PC12 cells after treatment of
NGF with natural or synthetic neovibsanin B. A: No clear neurite
outgrowth was observed. B: The clear neurite outgrowth was
observed. (positive control). C: Some neurite outgrowth was
observed. D: The similar degree of activity compared with natural
(+)-2 was observed.
Acknowledgment. This study was financially supported
by a Grant-in-Aid from the Ministry of Education, Culture,
Sports, Science and Technology of the Japanese Government
(20590028), and the Open Research Center program of
MEXT.
Supporting Information Available: Experimental pro-
cedures and spectral data for all new compounds and detail
of assay for neurotrophic activity. This material is available
free of charge via the Internet at http://pubs.acs.org.
OL802973F
(11) Reaction of nonchelating 4-MPM protected ketoalcohol resulted
in low yield.
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The neurotrophic activity of (()-2 was confirmed by an
assay using PC12 cells (JCRB0733).16 (()-Neovibsanin B
(13) Reaction in CH2Cl2 resulted in giving a complex mixture due to
the acidity of in situ formed DDQH.
(14) Pine, H. S.; Pettit, R. J.; Geib, G. D.; Cruz, S. G.; Gallego, C. H.;
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