Synthetic studies toward neovibsanins A and B: construction of the neovibsanin core utilizing palladium(0)-catalyzed carbonylative cyclization with carbon monoxide

Article abstract of DOI:10.1016/j.tetlet.2008.02.168

The core A-ring of neovibsanins A (1) and B (2), which are potent neurotrophic agents isolated from the leaves of Viburnum awabuki, have been effectively constructed by the intramolecular palladium(0)-catalyzed carbonylative cyclization of alkenyl iodide

Full text of DOI:10.1016/j.tetlet.2008.02.168

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 2692–2696
Synthetic studies toward neovibsanins A and B: construction
of the neovibsanin core utilizing palladium(0)-catalyzed
carbonylative cyclization with carbon monoxide
Tomoyuki Esumi *, Ming Zhao, Taishi Kawakami, Mayuna Fukumoto,
Masao Toyota, Yoshiyasu Fukuyama *
Faculty of Pharmaceutical Sciences, Tokushima Bunri University, Yamashiro-cho, Tokushima 770-8514, Japan
Received 8 February 2008; revised 28 February 2008; accepted 29 February 2008
Available online 4 March 2008
Abstract
The core A-ring of neovibsanins A (1) and B (2), which are potent neurotrophic agents isolated from the leaves of Viburnum awabuki,
have been effectively constructed by the intramolecular palladium(0)-catalyzed carbonylative cyclization of alkenyl iodide with carbon
monoxide.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords: Neovibsanins A and B; Pd-catalyzed carbonylative cyclization; Neurotrophic activity
Neovibsanins A (1) and B (2), isolated from the leaves of
Viburnum awabuki by Fukuyama et al.,1 are classified into
rearranged vibsane-type diterpenes, which consist of more
complex and tricyclic structures than the other vibsane-
type members.2 Among a number of vibsane family mem-
bers, 1 and 2 have unusual structures based on the cyclo-
hexene core (A-ring) fused with two tetrahydrofurans
having five chiral carbons, including two quaternary cen-
ters and two side chains. In addition, 1 and 2 significantly
promote neurite outgrowth of NGF-mediated PC12 cells,2
and are therefore expected to be lead compounds for develo-
ping anti-Alzheimer’s disease drugs. Their architectural
complexity, outstanding neurotrophic activity, and extreme
scarcity have attracted the interest of our synthetic group.
In this Letter, we report our studies toward the construc-
tion of a core A-ring 4 for neovibsanins A (1) and B (2),
featuring palladium-catalyzed carbonylative cyclization
with carbon monoxide.
As seen in our synthetic strategy, outlined in Scheme 1,
we conceived that the cyclohexadienone 4 would serve as
the key intermediate for elaboration to precursor 3 that
O
H
Y
7
5
O
X
8
C
7
O
5
B
OH
O
HO
4
3
8
10 A
O
9
4
OHC
9
20
14
1
12
CHO
14
neovibsanin A (1): X = OCH3, Y = CH3
neovibsanin B (2): X = CH3, Y = OCH3
3
O
O
O
I
MgBr
CO, Pd(0)
base
OR
5
OR
OR
6
OR
4
*
Scheme 1. Synthetic plan targeting neovibsanins A and B, and the key
Corresponding authors. Tel.: +81 88 602 8435; fax: +81 88 655 3051.
synthetic intermediate 4.
E-mail address: fukuyama@ph.bunri-u.ac.jp (T. Esumi).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.02.168

T. Esumi et al. / Tetrahedron Letters 49 (2008) 2692–2696
2693
could be readily converted to neovibsanins A (1) and B (2),
because the enone moiety of 4 would be a competent scaf-
fold to introduce a variety of functionalities requisite to the
synthesis of 1 and 2. Namely, 3 would be derived from 4 by
a two-step operation involving C1 homologation at the C-9
position and the addition of the C4 unit with alkenylmag-
nesium reagent 5 to the C-4 ketone. Subsequent intramo-
lecular oxy-Michael addition at C-5 of 3, the formation
of acetal at C-7, the Wittig olefination at C-14, and the final
esterification with senecioyl chloride at C-8 would allow us
to achieve total synthesis of 1 and 2. Thus, we initially
focused on the synthesis of 4 corresponding to the neovi-
bsanin core A-ring. We employed palladium(0)-catalyzed
carbonylative cyclization with carbon monoxide to synthe-
size 4 for which precursor 6 would be suitable.
The hydrostannation6 of 13 on heating at 65 °C with n-tri-
butyltin hydride in the presence of AIBN (0.05 equiv) pro-
ceeded with complete regio and stereoselectivity to give rise
to (Z)-alkenylstannane 14 in moderate yield. Replacement
of butyltin in 14 by iodine afforded the cyclization precur-
sor 157 after TBS protection in 81% yield.
Palladium(0)-catalyzed carbonylative cyclization and
related reactions have been well investigated by Negishi
and co-workers.8 Three possible cyclic acylpalladium pro-
cesses in the absence of nucleophiles are summarized in
Scheme 3. The first organopalladium intermediate 17 is
generated via oxidative addition of x-alkenyliodide 16
X
Pd
First, the required precursor 15 for palladium(0)-cata-
lyzed carbonylative cyclization was prepared, starting with
4-penten-1-ol (7), as shown in Scheme 2. TBDPS protec-
tion of the hydroxy group in 7 followed by ozonolysis of
the terminal olefin yielded the aldehyde, which in turn
reacted with MeMgI and then the resulting hydroxy group
was oxidized with PCC, giving rise to methylketone 8 in
64% yield over four steps. The subsequent Horner–Wads-
worth–Emmons–Wittig reaction of 8 with (EtO)2P(O)CH2-
CO2Et gave 9 as an E/Z (4:1) isomeric mixture. Reduction
of 9 with DIBAL provided the allyl alcohol 10, which was
subjected to the Johnson–Claisen rearrangement3 with
excess triethyl orthoacetate in the presence of a catalytic
amount of n-propionic acid at 200 °C for 3 days to give
the rearranged compound 11 in 97% yield. Successive
reduction of the ester moiety of 11 with LiAlH4 yielded
the alcohol, which was homologated to a,a-dibromoalkene
12 by PCC oxidation and Corey–Fuchs dibromoolefin-
ation.4 Treatment of 12 with n-butyllithium gave lithium
acetylide,5 which was in situ trapped with paraformalde-
hyde to furnish the propargyl alcohol 13 in 89% yield.
I
n
base
17
n
16
CO
X
Pd
n
O
19
Pd(0)
X
O
n
O
Pd
O
O
18
base
n
n
23
22
CO
X
Pd
O
O
base
n
n
20
21
Scheme 3. Three possible pathways of intramolecular palladium(0)-
catalyzed carbonylative cyclization of x-terminal olefin-containing
iododienes in the absence of nucleophiles.
O
a–d
e
CO2Et
HO
75%
64% (4 steps)
OTBDPS
OTBDPS
4-pentene-1-ol (7)
8
9 (E : Z = 4 : 1)
Br
Br
OH
f
g
h-j
CO2Et
OTBDPS
99%
97%
66% (3 steps)
OTBDPS
OTBDPS
10
11
12
I
X
OTBS
OH
k
l
m,n
OH
55%
89%
81% (2 steps)
OTBDPS
OTBDPS
OTBDPS
15
13
14; X = SnBu3
Scheme 2. Reagents and conditions: (a) TBDPSCl, CH2Cl2, Et3N, DMAP; (b) O3, CH2Cl2/MeOH, NaHCO3, À78 °C, then Me2S; (c) MeMgI, THF, 0 °C;
(d) PCC on Celite, CH2Cl2; (e) (EtO)2P(O)CH2CO2Et, NaH, THF, À78 °C; (f) DIBAL, CH2Cl2; (g) (EtO)3CCH3, CH3CH2CO2H, 200 °C, 3 days;
(h) LiAlH4, THF, 0 °C; (i) PCC on Celite, CH2Cl2; (j) CBr4, PPh3, CH2Cl2; (k) n-BuLi, THF, À78 °C, then (CHO)n, rt; (l) Bu3SnH, AIBN, THF, 65 °C;
(m) TBSCl, Et3N, DMAP, CH2Cl2; (n) I2, CH2Cl2, 0 °C.

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T. Esumi et al. / Tetrahedron Letters 49 (2008) 2692–2696
containing a terminal vinyl group. The insertion of CO to
17 leads to acylpalladium(II) intermediate 18. The
generated acylpalladium(II) species 18 then undergoes
intramolecular cyclic acylpalladation to produce cyclic
palladium(II) intermediate 20, which is decomposed to 21
by reductive b-elimination of Pd(0). This mechanistic pro-
cess is necessary for realizing the preparation of 4. How-
ever, this reaction is also accompanied not only by the
formation of the cyclic Heck reaction product 19 through
17, but also by the formation of the enol lactone 23 via
the homologated acylpalladium intermediate 22 derived
from 20 under carbonylative conditions.
zation with CO to realize specific synthesis of the desired
cyclohexadienone 24.
First, we focused on the effect of catalysts and ligands.
All reactions were carried out in the presence of
10 mol % Pd catalysts with K3PO4 (3 equiv) in 1,4-dioxane
at 70 °C for 12 h (Table 2). When using Pd2(dba)3, no reac-
tion occurred (entry 1). In contrast, the use of Pd(dppf)2
was found to dramatically enhance reactivity and selectiv-
ity in this reaction to provide the desired compound 24 as
the major product in moderate yield (entry 2). On the other
hand, the steric bulk of the ligand was also preferred for
the formation of 24 when Pd(OAc)2 was used as the cata-
lyst (entries 3–7). Although these reaction conditions could
substantially suppress the formation of the competing
Heck-type product 25, carboxylic acid 2711 that was not
observed under other catalytic conditions occurred in sig-
nificant amounts. This side reaction is most likely to be
explained presumably by trapping the acylpalladium inter-
mediate with OHÀ.
After a number of trials, we were pleased to find that
10 mol % PdCl2(PPh3)2 as a catalyst not only improved
the ratio in favor of the formation of 24 over other prod-
ucts but also brought about the highest isolation yield
(55%) of 24 (entry 8).12 If the reaction was employed under
the same catalytic conditions at room temperature, 24 was
solely obtained in 10% yield along with the recovery start-
ing material 15, which is recyclable (entry 9). After various
bases were examined (entries 10–13), 3 equiv of K3PO4
were found to be the most effective base suitable for the
10 mol % PdCl2(PPh3)2 catalytic system in the specific
Pd(0)-catalyzed carbonylative cyclization.
Thus, the reaction conditions8a–c must be carefully set
up so as not only to produce the desired products but also
to suppress competing side reactions. In addition, the scope
of this reaction of terminal vinyl-containing iododienes 16
is thought to be essentially limited to the synthesis of five-
membered enones, and neither small ring ketones nor
larger rings such as six- and seven-membered enones have
been observed in useful yields. With the general outcome
of this reaction in mind, our attention was focused on
applying Pd(0)-catalyzed carbonylative cyclization to
specifically produce the neovibsanins core A ring 4.
First, we examined the typical Negishi’s conditions.8d,e
Namely, 15 was reacted with 10 mol % Pd(PPh3)4 in the
presence of Et3N in THF at 100 °C under CO (4 MPa)
atmosphere, resulting in the formation of an inseparable
complex mixture along with a trace amount of Heck-type
1
compound 259 that could be detected by H NMR of the
crude product (Table 1, entry 1), and neither the desired
cyclohexadienone 24 nor bicyclic compound 26 were
observed as anticipated. To our surprise, however, the
same reaction was carried out under reduced CO pressure
(0.4 MPa) to yield 2410 and 25 in 15% and 36% yield,
respectively, in addition to recovered starting material
(49%). With 1,4-dioxane as a solvent, the reaction rate
was remarkably accelerated, thereby inducing the starting
material 15 to disappear in 12 h (entries 3 and 4 in Table
1) to give 24 in 14% yield along with 25 as the main product
(86%). These results encouraged us to further explore the
potential scope of the Pd(0)-catalyzed carbonylative cycli-
In conclusion, we constructed the core A-ring 24 of neo-
vibsanins A (1) and B (2) by applying Pd(0)-catalyzed carb-
onylative cyclization with carbon monoxide to 15 under the
following reaction conditions: 10 mol % PdCl2(PPh3)2 with
K3PO4 (3 equiv) in 1,4-dioxane under ambient CO atmo-
sphere (0.4 MPa) at 70 °C for 12 h. To the best of our
knowledge, this is the first example of Pd(0)-catalyzed car-
bonylative cyclization with carbon monoxide to afford
cyclohexadienone derivative in practical yield. Further
development of this type of reaction and studies toward
Table 1
Palladium(0)-catalyzed carbonylative cyclization of 15 under Negishi’s conditions
O
O
O
10 mol% Pd(PPh3)4
base (3 eq), solv.
OTBS
OTBS
OTBS
15
temp., CO (press), 12 h
OTBDPS
OTBDPS
OTBDPS
24
25
Temp. (°C)
26
Entry
Base
Solv.
Press. (MPa)
Ratioa (15:24:25)
1
2
3
4
a
Et3N
Et3N
Et3N
K3PO4
THF
THF
1,4-Dioxane
1,4-Dioxane
100
72
100
100
4
(—:—:—)b
(49:15:36)
(0:14:86)
(0:13:87)
0.4
0.4
0.4
The ratio was determined by 1H NMR (300 MHz).
The condition resulted in complex mixture.
b

T. Esumi et al. / Tetrahedron Letters 49 (2008) 2692–2696
2695
Table 2
Palladium(0)-catalyzed carbonylative cyclization of 15
HO2C
10 mol% catalyst, ligand, CO (0.4 MPa)
base (3 eq), 1,4-dioxane, 70 °C, 12 h
OTBS
15
24
+
25
+
OTBDPS
27
Entry
Catalyst
Ligand (equiv)
Base
Isolation yield of 24
Ratioa (15:24:25:27)
b
1
2
3
4
5
6
7
8
9d
10
11
12
13
a
Pd2(dba)3
Pd(dppf)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
—
—
PBu3 (3)
PPh3 (3)
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
i-Pr2NEt
Na2CO3
t-BuOK
AcOK
—
(—:—:—:—)
(0:60:40:0)
(17:23:46:14)
(13:30:39:18)
(35:20:5:40)
(0:49:5:46)
(0:66:8:26)
(0:77:23:0)
(79:21:0:0)
(77:19:4:0)
(71:22:7:0)
(0:22:78:0)
(—:—:—:—)
40
19
23
14
38
47
55
10
18
15
16
P(p-tol)3 (3)
PCy3 (3)c
PCy3 (0.3)c
—
—
—
—
—
—
e
—
The ratio was determined by 1H NMR (300 MHz).
The condition resulted in complex mixture.
Toluene solution (0.48 M) of PCy3 was used.
The reaction was carried out at room temperature for 24 h.
No reaction was observed.
b
c
d
e
5.89 (t, J = 6.9 Hz, 1H), 5.70 (dd, J = 10.8, 17.4 Hz, 1H), 5.01 (dd,
J = 0.9, 10.8 Hz, 1H), 4.91 (dd, J = 0.9, 17.4 Hz, 1H), 4.25 (br s, 2H),
3.63 (t, J = 6.0 Hz, 2H), 2.20 (d, J = 6.9 Hz, 2H), 1.54–1.44 (m, 2H),
1.40–1.34 (m, 2H), 1.06 (s, 9H), 0.98 (s, 3H), 0.91 (s, 9H), 0.08 (s, 6H);
13C NMR (75 MHz, CDCl3) d 146.3, 135.6, 134.1, 130.5, 129.5, 127.6,
112.4, 108.8, 71.6, 64.5, 46.3, 39.9, 36.8, 27.4, 26.9, 25.8, 22.8, 19.2,
18.3, À5.2; HRMS m/z (CI+): [M+H]+ calcd for C33H52O2Si2I,
663.2551; found, 663.2553.
total synthesis of neovibsanins A (1) and B (2) from the key
intermediate 24 are currently in progress.
Acknowledgments
This work was supported by a Grant-in-Aid for Scien-
tific Research from the Ministry of Education, Science,
and Technology of Japan (Priority Area, 18032085). Ming
Zhao is grateful to the Open Research Center Fund from
the Promotion and Mutual Aid Corporation for Private
Schools of Japan for a postdoctoral fellowship.
8. (a) 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.; Coperet, C.; Miller, J. A.; Tour, J.
´
M. J. Am. Chem. Soc. 1996, 118, 5919–5931; (c) Negishi, E.; Coperet,
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. Soc. 1983, 105, 6761–6763.
References and notes
9. Data for 25: Rf = 0.44 (EtOAc/hexane = 1:20); IR m 3072 cmÀ1 1H
;
1. Fukuyama, Y.; Minami, K.; Takeuchi, M.; Kodama, M.; Kawazu, K.
Tetrahedron Lett. 1996, 37, 6767–6770.
2. Fukuyama, Y.; Esumi, T. J. Org. Synth. Chem. Jpn. 2007, 65, 585–
597.
3. (a) Srikrishna, A.; Nagaraju, S.; Kondaiah, P. Tetrahedron 1995, 51,
1809–1816; (b) Johnson, W. S.; Werthemann, L.; Bartlett, W. R.;
Brocksom, T. J.; Li, T.; Faulkner, D. J.; Paterson, M. R. J. Am.
Chem. Soc. 1970, 92, 741–743.
4. Corey, E. J.; Fuchs, P. L. Tetrahedron Lett. 1972, 36, 3769–3772.
5. (a) Esumi, T.; Iwabuchi, Y.; Irie, H.; Hatakeyama, S. Tetrahedron
Lett. 1998, 39, 877–880; (b) Marshall, J. A.; Bartley, G. S.; Wallace, E.
M. J. Org. Chem. 1996, 61, 5729–5735.
NMR (300 MHz, CDCl3) d 7.67–7.63 (m, 4H), 7.41–7.33, (m, 6H),
5.96 (br s, 1H), 4.71 (s, 1H), 4.53 (br s, 1H), 4.31 (br d, J = 2.4 Hz,
2H), 3.60 (t, J = 4.7 Hz, 2H), 2.33 (br dd, J = 2.4, 17.7 Hz, 1H), 2.12
(br dd, J = 2.4, 17.7 Hz, 1H), 1.43–1.37 (m, 4H), 1.06 (s, 3H), 1.02 (s,
9H), 0.91 (s, 9H), 0.08 (s, 6H); 13C NMR (75 MHz, CDCl3) d 160.6,
143.2, 135.6, 134.1, 131.2, 129.5, 127.5, 99.1, 64.5, 60.0, 45.0, 44.1,
38.1, 28.9, 28.0, 26.9, 25.9, 19.2, 18.4, À5.3; HRMS m/z (CI+):
[M+H]+ calcd for C33H51O2Si2, 535.3427; found, 535.3409.
10. Data for 24: Rf = 0.48 (EtOAc/hexane = 1:10); IR m 3072, 1664 cmÀ1
;
1H NMR (300 MHz, CDCl3) d 7.64–7.61, (m, 4H), 7.41–7.34 (m, 6H),
6.89 (tt, J = 2.1, 4.2 Hz, 1H), 6.01 (d, J = 1.2 Hz, 1H), 5.22 (d,
J = 1.2 Hz, 1H), 4.39 (br d, J = 2.1 Hz, 2H), 3.58 (t, J = 4.8 Hz, 2H),
2.35 (br d, J = 4.2 Hz, 2H), 1.49–1.34 (m, 4H), 1.15 (s, 3H), 1.02 (s,
9H), 0.91 (s, 9H), 0.07 (s, 6H); 13C NMR (75 MHz, CDCl3) d 188.8,
151.3, 141.7, 128.4, 137.9, 135.6, 133.9, 129.6, 127.6, 118.8, 64.0, 60.0,
40.4, 38.9, 35.2, 27.5, 26.9, 25.9, 25.2, 19.2, 18.4, À5.4; HRMS m/z
(CI+): [M+H]+ calcd for C34H51O3Si2, 563.3377; found, 563.3368.
6. (a) Han, X.; Stoltz, B. M.; Corey, E. J. J. Am. Chem. Soc. 1999, 121,
7600–7605; (b) Kazmaier, U.; Schauss, D.; Pohlman, M. Org. Lett.
´
1999, 1, 1017–1019; (c) Zhang, H. X.; Guibe, F.; Balavone, G. J. Org.
Chem. 1990, 55, 1857–1867; (d) Jung, M. E.; Light, L. A. Tetrahedron
Lett. 1982, 23, 3851–3854; (e) Corey, E. J.; Ulrich, P.; Fitzpatrick, J.
M. J. Am. Chem. Soc. 1976, 98, 222–224.
7. Data for 15: Rf = 0.45 (EtOAc/hexane = 1:20); IR m 3072 cmÀ1 1H
;
11. Data for 27: Rf = 0.46 (EtOAc/hexane = 1:5); IR m 3072, 1689 cmÀ1
1H NMR (300 MHz, CDCl3) d 7.68–7.65 (m, 4H), 7.44–7.35, (m, 6H),
;
NMR (300 MHz, CDCl3) d 7.70–7.66 (m, 4H), 7.43–7.35 (m, 6H),

2696
T. Esumi et al. / Tetrahedron Letters 49 (2008) 2692–2696
6.49 (t, J = 6.9 Hz, 1H), 5.69 (dd, J = 10.8, 17.4 Hz, 1H), 5.05 (d,
(97.7 mg, 0.460 mmol) in 1,4-dioxane (1.5 mL) was stirred at 70 °C
under CO (0.4 MPa) atmosphere. After 10 min, the solution of 15
(101.8 mg, 0.154 mmol) in 1,4-dioxane (2.0 mL) was added to the
orange reaction mixture via a cannula, and stirred for 12 h at the same
temperature. The resulting black mixture was poured into satd NaCl–
water (3:20, 23 mL), and extracted with ether (3 Â 20 mL). Ether
extracts were dried over MgSO4, and concentrated. Purification of the
residue by silica gel column chromatography (SiO2 = 6 g, hexane/
Et3N = 100:1) gave 24 (47.9 mg, 0.0850 mmol, 55%) and 25 (11.4 mg,
0.0213 mmol, 14%).
J = 10.8 Hz, 1H), 4.94 (d, J = 17.4 Hz, 1H), 4.33 (s, 2H), 3.62 (t,
J = 6.0 Hz, 2H), 2.71 (dd, J = 6.9, 16.2 Hz, 1H), 2.58 (dd, J = 6.9,
16.2 Hz, 1H), 1.53–1.33 (m, 4H), 1.06 (s, 9H), 0.98 (s, 3H), 0.91 (s,
9H), 0.08 (s, 6H); 13C NMR (75 MHz, CDCl3) d 171.3, 146.0, 142.6,
135.6, 134.0, 130.1, 129.5, 127.6, 112.8, 64.5, 63.3, 39.9, 39.8, 37.0,
27.4, 26.9, 25.9, 22.5, 19.3, 18.3, À5.4; HRMS m/z (FAB+): [M+Na]+
calcd for C34H52O4Si2Na, 603.3302; found, 603.3313.
12. Typical procedure for carbonylative cyclization: The suspension of
PdCl2(PPh3)2 (11.0 mg, 0.0156 mmol) and anhydrous K3PO4