First enantiocontrolled formal synthesis of (+)-neovibsanin B, A neurotrophic diterpenoid

Article abstract of DOI:10.1021/ol902960n

(Figure Presented) An enantiocontrolled formal synthesis of (+)-neovibsanin B has been achieved by a sequence that applies an asymmetric 1,4-addition of (H₂C=CH)₂Cu(CN)Li₂ to trisubstituted α,β-carboxylic acid derivative 1 to induce the chirality at the C-11 all-carbon quaternary center. Together with a modified Negishi cyclic carbopalladation-carbonylative esterification tandem reaction for constructing the A-ring, the synthesis was completed.

Full text of DOI:10.1021/ol902960n

ORGANIC
LETTERS
2010
Vol. 12, No. 4
888-891
First Enantiocontrolled Formal Synthesis
of (+)-Neovibsanin B, A Neurotrophic
Diterpenoid
Tomoyuki Esumi,* Takehiro Mori, Ming Zhao, Masao Toyota, and
Yoshiyasu Fukuyama*
Faculty of Pharmaceutical Sciences, Tokushima Bunri UniVersity, Yamashiro-cho,
Tokushima 770-8514, Japan
fukuyama@ph.bunri-u.ac.jp
Received December 28, 2009
ABSTRACT
An enantiocontrolled formal synthesis of (+)-neovibsanin B has been achieved by a sequence that applies an asymmetric 1,4-addition of
(H2CdCH)2Cu(CN)Li2 to trisubstituted r,ꢀ-carboxylic acid derivative 1 to induce the chirality at the C-11 all-carbon quaternary center. Together
with a modified Negishi cyclic carbopalladation-carbonylative esterification tandem reaction for constructing the A-ring, the synthesis was
completed.
Neovibsanins A and B, vibsane-type diterpenoids, which
were isolated from the leaves of Viburnum awabuki by
Fukuyama et al.,1 have attracted considerable synthetic
attention because of their challenging structures combined
with interesting neurotrophic activity. They have been found
to significantly promote the neurite outgrowth of NGF-
mediated PC12 cells,2 and thus have shown potential as drugs
for the treatment of neurodegenerative diseases such as
Alzheimer’s disease.3 Recently, Nishizawa et al.4 achieved
the total synthesis of (()-neovibsanin B by utilizing an
intramolecular Diels-Alder reaction to construct the A-ring
system and a chelation-controlled diastereoselective alkyla-
tion at C-4 as two key steps, and the resultant synthetic (()-
neovibsanin B was shown to exhibit neurite outgrowth-
promoting activity in NGF-mediated PC12 cells comparable
to that of natural (+)-neovibsanin B. On the other hand,
Williams et al.5 reported a synthesis of (()-4,5-bis-epi-
neovibsanins A and B, which were also shown to accelerate
neurite outgrowth in NGF-mediated PC12 cells (Figure 1).
Figure 1. Structures of neovibsanins A and B.
(1) Fukuyama, Y.; Minami, K.; Takeuchi, M.; Kodama, M.; Kawazu,
K. Tetrahedron Lett. 1996, 37, 6767–6770.
However, no enantioselective synthetic study on neovibsanins
has been published. Herein, we wish to demonstrate the first
enantiocontrolled formal synthesis of (+)-neovibsanin B
(2) Fukuyama, Y.; Esumi, T. J. Org. Synth. Chem. Jpn. 2007, 65, 585–
597.
(3) Li, P.; Matsunaga, K.; Ohizumi, Y. Eur. J. Pharmacol. 2000, 406,
203–208.
(4) Imagawa, H.; Saijo, H.; Kurisaki, T.; Yamamoto, H.; Kubo, M.;
Fukuyama, Y.; Nishizawa, M. Org. Lett. 2009, 11, 1253–1255.
(5) Chen, A. P.-J.; Mu¨ller, C. C.; Cooper, H. M.; Williams, C. M. Org.
Lett. 2009, 11, 3758–3761.
10.1021/ol902960n  2010 American Chemical Society
Published on Web 01/21/2010

Scheme 1. Synthetic Plan of (+)-Neovibsanin B
based on an asymmetric 1,4-addition, which was previously
developed by us,6 and a modified Negishi cyclic carbopal-
ladation-carbonylative esterification tandem reaction.7
Our synthetic plan of (+)-neovibsanin B is outlined in
Scheme 1. To achieve its synthesis in an enantiocontrolled
fashion, the enantioselective construction of the chiral all
carbon quaternary center at C-11 was a requirement. We
decided to employ the asymmetric 1,4-addition reaction of
(H2CdCH)2Cu(CN)Li2 to the trisubstituted R,ꢀ-carboxylic
acid derivative 1 of (R)-4-phenyl-2-oxazolidinone6 to prepare
(11S)-2. According to our previous report,8 removal of the
chiral auxiliary of (11S)-2 followed by the alkynylation and
selective iodination would lead to iodoalkene, (11S)-3.
Previously we reported that the modified Negishi pal-
ladium(0)-catalyzed carbonylative cyclization7 of (()-3
smoothly proceeded to give rise to the cyclohexen-1-one
derivative, (()-4.8 Therefore, (11S)-4 would be prepared
from (11S)-3 by employing the same reaction (Scheme 2).
After C1 extension from the exo-methylene group by a 1,4-
addition reaction, simple functional group manipulation
would lead to Nishizawa’s intermediate, (11S)-5 in optical
active form.
the hydroxy group with TBDPSCl. Subsequent palladium(0)-
catalyzed carbonylation-amidation of 6 with (R)-4-phenyl-
2-oxazolidinone afforded the trisubstituted R,ꢀ-carboxylic
acid derivative 1 in 68% yield. The asymmetric 1,4-addition
reaction of (H2CdCH)2Cu(CN)Li2 to 1 gave rise to 2 as a
diastereomeric mixture of 95 (11S):5 (11R) in good yield,
and each diastereomer was readily separated by column
chromatography over silica gel. The optically pure (11S)-
isomer of 2 was used for the subsequent reaction. Removal
of the oxazolidinone in 2 with 30% aqueous H2O2/LiOH10
followed by esterification with EtOH yielded the ester, which
was then reduced with LiAlH4 to the alcohol 7 in 87% yield
over three steps. PCC oxidation of 7, followed by Corey-
Fuchs dibromoolefination,11 provided 1,1-dibromoolefin 8
in 89% yield. The stereoselective conversion of 8 into the
cyclization precursor (2Z)-3 was achieved by the following
sequence. Treatment of 8 with n-BuLi generated the alkynyl
anion, which was trapped in situ with formaldehyde, giving
rise to the alkynyl alcohol. Regio- and stereoselective
hydrostannylation12 of its alkyne moiety with tributyltin
hydride in the presence of AIBN exclusively afforded
(2Z,11S)-3 after protecting the hydroxyl group as a TBS
group in 83% yield over four steps. Then, carbonylative
cyclization of (2Z)-3 in the presence of 10 mol % of
Negishi’s iodomethylation9 of 4-pentyn-1-ol gave the
alkenyl iodide 6, which was followed by the silylation of
Scheme 2. Synthesis of (11S)-4
Org. Lett., Vol. 12, No. 4, 2010
889

Table 1. Negishi’s Pd(0)-Catalyzed Cyclic Carbopalladation-Carbonylative Tandem Reaction of (2Z,11S)-3
entry
base (1.5 equiv)
solvent
MeOH (equiv)
CO (MPa)
temp. (°C)
9 (10R:10S)a
10
4
3 (%)
1
2
3
4
5
6
7
8
9
10
a
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
K3PO4
i-Pr2NEt
DABCO
MeCN/PhH (1:1)
MeCN/PhH (1:1)
MeCN/PhH (1:1)
MeCN/PhH (1:1)
MeCN/PhH (1:1)
1,4-dioxane
4
48
48
48
24
4
-
4
4
4
4
4
8
4
4
4
4
4
4
4
100
100
100
60
11 (1.1:1)
54 (2.4:1)
41 (2.3:1)
49 (2.7:1)
69 (2.6:1)
0
6 (1.4:1)
16 (1.4:1)
0
0
10
9
13
14
0
13
18
0
6
52
0
0
21
0
90
52
3
2
12
0
0
0
4
0
0
9
60
100
100
100
100
100
MeOH
MeCN/PhH (1:1)
MeCN/PhH (1:1)
MeCN/PhH (1:1)
85
0
24 (1.6:1)
0
1
Ratio was determined by H NMR spectroscopy in CDCl3 (300 MHz).
PdCl2(PPh3)2 under a carbon monoxide atmosphere (0.4
MPa) smoothly proceeded to give rise to the desired
cyclohexenone derivative (11S)-4 in 56% yield. In order to
produce (10R,11S)-5 from (11S)-4, we tried the C1-extension
from the exo-methylene moiety of (11S)-4 by using 1,4-
addition reaction of a CN- species. However, all these
attempts were fruitless due to the poor electrophilicity of
the conjugated exo-methylene moiety, which was diminished
by the additional conjugated endocyclic olefin. This result
prompted us to explore alternative routes to the key
intermediate 5 with an extended C1 unit.
In principle, compound 3 could be obtained by Negishi
palladium(0)-catalyzed cyclic carbopalladation-carbonylative
tandem reaction in the presence of MeOH.7b The desired
product 9, which has a methyl ester group, would be directly
formed instead of the exo-methylene type compound 4. Thus,
we examined this reaction. First, the reaction was performed
using 5 mol % PdCl2(PPh3)2 and Et3N (1.5 equiv) in MeCN/
PhH (1:1) containing 4 equiv of MeOH at 100 °C in an
autoclave, which gave rise to the desired diastereomeric
mixture of 9 in 11% yield along with ca. 50% of the starting
material containing a small amount of 4 (6%) (Table 1, entry
1). On the other hand, the addition of an excess amount (48
equiv) of MeOH to this reaction system dramatically
increased the yield of 9 to 54%, contaminated with 10% of
the noncyclic ester 10 (entry 2). The use of high pressure (8
MPa) was found to be ineffective at suppressing the
generation of 10 (entry 3), but low temperature (60 °C) was
able to decrease the generation of 4 (entry 4). After several
trials, we were pleased to find that the following reaction
conditions of 24 equiv of MeOH, 4 MPa CO and a
temperature of 60 °C, led to the formation of 9 alone in ca.
70% yield as a diastereomeric mixture (10R:10S ) 2.6:1)
(entry 5). Each diastereomer of 9 was readily separated by
silica gel column chromatography to give (10R,11S)-9 and
(10S,11S)-9. Furthermore, treatment of the undesired isomer,
(10S,11S)-9 with MeOLi in MeOH gave the equilibrating
diastereomers (10R,11S)-9 and (10S,11S)-9 in a ratio of 1.5:
1. Thus, repeating this operation enabled the conversion of
the undesired isomer (10S,11S)-9 to the desired isomer
(10R,11S)-9. This was due to the 1,3-diaxial interaction
between the side chain at the C10 position and the proton at
the C1 position as depicted in Scheme 3.
(6) Esumi, T.; Shimizu, H.; Kashiyama, A.; Sasaki, C.; Toyota, M.;
Fukuyama, Y. Tetrahedron Lett. 2008, 49, 6846–6849.
Scheme 3. Equilibrium between (10R,11S)-9 and (10S,11S)-9
(7) (a) In Handbook of Palladium Chemistry for Organic Synthesis;
Negishi, E., Ed.; Wiely-Interscience: New York, 2002; Vol. 2, pp
2309-2691. (b) Negishi, E.; Ma, S.; Amanfu, J.; Cope´ret, C.; Miller, J. A.;
Tour, J. M. J. Am. Chem. Soc. 1996, 118, 5919–5931. (c) Negishi, E.;
Cope´ret, C.; Sugihara, T.; Shimoyama, I.; Zhang, Y.; Wu, G.; Tour, J. M.
Tetrahedron 1994, 50, 425–436. (d) Zhang, Y.; O’Connor, B.; Negishi, E.
J. Org. Chem. 1988, 53, 5590–5592. (e) Tour, J.; Negishi, E. J. Am. Chem.
Soc. 1985, 107, 8289–8291. (f) Negishi, E.; Miller, J. A. J. Am. Chem.
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(8) Esumi, T.; Zhao, M.; Kawakami, T.; Fukumoto, M.; Toyota, M.;
Fukuyama, Y. Tetrahedron Lett. 2008, 49, 2692–2696.
With (10R,11S)-9 in hand, we focused on the last few steps
for the synthesis of Nishizawa’s intermediate 5 (Scheme 4).
Treatment of (10R,11S)-9 with n-Bu4NF containing acetic
acid gave 11, and the resultant hydroxy group was oxidized
by Swern oxidation to its aldehyde, which was subjected to
(9) (a) Ichige, T.; Okano, Y.; Kanoh, N.; Nakata, M. J. Org. Chem.
2009, 74, 230–243. (b) Negishi, E.; Van Horn, D. E.; King, A. O.; Okukado,
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890
Org. Lett., Vol. 12, No. 4, 2010

Scheme 4. Completion of Enantiocontrolled Formal Synthesis of (+)-Neovibsanin B
22
Wittig olefination to give the dimethyl olefin 12 in 69% yield
over two steps. Reduction of 12 with DIBAL-H provided
the cyclic hemiacetal 13 and diol 14 in 29 and 26% yields,
respectively. The cyclic hemiacetal 13 was transformed to
14 by reduction with NaBH4. Unfortunately, the selective
protection of the primary alcohol in 14 using the reaction
conditions, 2,4- DMPMCl and Bu2SnO, utilized by Nish-
izawa et al.4,13 did not succeed in our hands. However, when
14 was reacted with freshly prepared 2,4-DMPM-trichloro-
acetoimidate14 in the presence of 10 mol % CSA, the desired
2,4-DMPM-ether 15 was obtained in 45% yield. Finally
Dess-Martin oxidation15 of 15 afforded the Nishizawa’s
intermediate 5 as an optically active form ([R]D +20.1 (c
1.05, MeOH)) in 95% yield. The spectroscopic data (MS,
IR, 1H NMR, 13C NMR) of our synthetic 5 were identical to
those of Nishizawa’s intermediate.4
In conclusion, the first enantiocontrolled formal syn-
thesis of (+)-neovibsanin B was accomplished in 1.1%
overall yield over 20 steps. Our formal synthesis of (+)-
neovibsanin B not only demonstrates a useful application
of the asymmetric 1,4-addition of the trisubstituted R,ꢀ-
carboxylic acid derivative 1, but also emphasizes the
potential use of the Negishi’s cyclic carbopalladation-
carbonylative esterification tandem reaction for construct-
ing the neovibsanin skeleton. Work is now in progress to
achieve total synthesis of (+)-neovibsanin B.
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Acknowledgment. This work was supported by a Grant-
in-Aid for Scientific Research from the Ministry of Educa-
tion, Culture, Sports, Science, and Technology of Japan
(20590029, 18032085) and the Open Research Fund for the
Promotion and Mutual Corporation of Private Schools of
Japan.
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Supporting Information Available: Experimental pro-
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available free of charge via the Internet at http://pubs.acs.org.
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