Formal synthesis of optically active ingenol via ring-closing olefin metathesis

Article abstract of DOI:10.1021/jo048833l

The construction of strained carbon skeletons by ring-closing olefin metathesis (RCM) was investigated. With well-designed diene 4, RCM was found to be applicable to the formation of a highly strained inside-outside bicyclo[4.4.1]undecane skeleton of ingenol, a bioactive diterpenoid, and formal total synthesis of optically active ingenol (1) was achieved. The key features of this synthesis are construction of an A-ring by spirocyclization of the ketone with an allylic chloride unit, 26, and ring closure of a B-ring by olefin metathesis. Starting from Funk's keto ester 6, the key intermediate aldehyde 9 in Winkler's total synthesis was synthesized in eight steps in 12.5% overall yield. This strategy of direct cyclization of a strained inside-outside skeleton provided the first easy access to optically active ingenol.

Full text of DOI:10.1021/jo048833l

Formal Synthesis of Optically Active Ingenol via Ring-Closing
Olefin Metathesis
Kazushi Watanabe, Yuto Suzuki, Kenta Aoki, Akira Sakakura, Kiyotake Suenaga, and
Hideo Kigoshi*
Department of Chemistry, University of Tsukuba, Tennoudai, Tsukuba, Ibaraki 305-8571, Japan
kigoshi@chem.tsukuba.ac.jp
Received July 10, 2004
The construction of strained carbon skeletons by ring-closing olefin metathesis (RCM) was
investigated. With well-designed diene 4, RCM was found to be applicable to the formation of a
highly strained inside-outside bicyclo[4.4.1]undecane skeleton of ingenol, a bioactive diterpenoid,
and formal total synthesis of optically active ingenol (1) was achieved. The key features of this
synthesis are construction of an A-ring by spirocyclization of the ketone with an allylic chloride
unit, 26, and ring closure of a B-ring by olefin metathesis. Starting from Funk’s keto ester 6, the
key intermediate aldehyde 9 in Winkler’s total synthesis was synthesized in eight steps in 12.5%
overall yield. This strategy of direct cyclization of a strained inside-outside skeleton provided the
first easy access to optically active ingenol.
5
Introduction
fragmentation, the Ireland-Claisen rearrangement for
6
ring contraction, 1,5-H sigmatropy to change the intra-
bridgehead stereochemistry from out-out to in-out, and
the tandem cyclization-rearrangement reaction; direct
Ingenol (1) is a diterpenoid isolated from Euphorbia
ingens, possessing a bicyclo[4.4.1]undecane skeleton with
a highly strained inside-outside intrabridgehead stereo-
chemistry (Figure 1), and many derivatives have also
7
8
cyclization to the in,out-bicyclo[4.4.1]undecane system
has not been reported. Recently, two total syntheses in
a racemic form using the aforementioned strategies were
1
been isolated. Ingenol and its derivatives interest or-
ganic chemists not only because of their unique frame-
work, but also due to their biological activities such as
protein kinase C (PKC)-activating and anti-HIV activi-
reported by Winkler5 and Tanino-Kuwajima.
f
8b
2,3
4-8
Results and Discussion
ties. Several strategies for construction of the unique
in,out-bicyclo[4.4.1]undecane skeleton have been re-
ported, involving the de Mayo reaction and subsequent
We have previously9 developed a direct cyclization
method for the highly strained tricyclic skeleton of
ingenol via ring-closing olefin metathesis to synthesize
tricyclic compound 5, thus indicating the efficiency of
olefin metathesis in the construction of highly strained
carboskeletons (Scheme 1). Wood et al.10 also have
reported a similar strategy for synthesizing the tetra-
cyclic skeleton of ingenol. We describe herein the details
of the synthesis of inside-outside tricyclic compound 5
and easy access to the Winkler’s aldehyde 9, an important
intermediate of the total synthesis, utilizing ring-closing
olefin metathesis to achieve a formal total synthesis of
optically active ingenol (Scheme 2).
(1) (a) Zeichmeister, K.; Brandl, F.; Hoffe, W.; Hecker, E.; Opferkuch,
H. J.; Adolf, W. Tetrahedron Lett. 1970, 4075-4078. (b) Uemura D.;
Hirata, Y. Tetrahedron Lett. 1971, 3673-3676. (c) Opferkuch H.;
Hecker, E. Tetrahedron Lett. 1974, 261-264. (d) Uemura, D.; Ohwaki,
H.; Hirata, Y.; Chen, Y.-P.; Hsu, H.-Y. Tetrahedron Lett. 1974, 2527-
2
528. (e) Uemura, D.; Hirata, Y.; Chen Y.-P.; Hsu, H.-Y. Tetrahedron
Lett. 1974, 2529-2532. (f) Uemura, D.; Hirata, Y. Tetrahedron Lett.
1
975, 1701-1702. (g) Upadhyay, R. R.; Mohaddes, G. Curr. Sci. 1987,
5
6, 1058-1059. (h) Matsumoto, T.; Cyoun, J. C.; Yamada, H. Planta
Med. 1992, 58, 255-258. (i) Wang, L.-Y.; Wang, N.-L.; Yao, X.-S.;
Miyata, S.; Kitanaka, S. J. Nat. Prod. 2002, 65, 1246-1251.
(2) Hasler, C. M.; Acs, G.; Blumberg, M. Cancer Res. 1992, 52, 202-
2
08.
3) (a) Fujiwara, M.; Ijichi, K.; Tokuhisa, K.; Katsuura, K.; Shigeta,
(
S.; Konno, K.; Wang, G.-Y.-S.; Uemura, D.; Yokota, T.; Baba, M.
Antimicro. Agents Chemother. 1996, 40, 271-273. (b) Fujiwara, M.;
Ijichi, K.; Tokuhisa, K.; Katsuura, K.; Wang, G.-Y.-S.; Uemura, D.;
Shigeta, S.; Konno, K.; Yokota, T.; Baba, M. Antiviral Chem. Chemo-
ther. 1996, 7, 230-236.
(6) (a) Funk, R. L.; Olmstead, T. A.; Parvez, M. J. Am. Chem. Soc.
1988, 110, 3298-3300. (b) Funk, R. L.; Olmstead, T. A.; Parvez, M.;
Stallman, J. B. J. Org. Chem. 1993, 58, 5873-5875.
(7) (a) Rigby, J. H.; de Sainte Claire, V.; Cuisiat, S. V.; Heeg, M. J.
J. Org. Chem. 1996, 61, 7992-7993. (b) Rigby, J. H.; Hu, J.; Heeg, M.
J. Tetrahedron Lett. 1998, 39, 2265-2268. (c) Rigby, J. H.; Bazin, B.;
Meyer, J. H.; Hohammadi, F. Org. Lett. 2002, 5, 799-801.
(8) (a) Nakamura, T.; Matsui, T.; Tanino, K.; Kuwajima, I. J. Org.
Chem. 1997, 62, 3032-3033. (b) Tanino, K.; Onuki, K.; Asano, K.;
Miyashita, M.; Nakamura, T.; Takahashi, Y.; Kuwajima, I. J. Am.
Chem. Soc. 2003, 125, 1498-1500.
(
4) Review: Kim, S.; Winkler, J. D. Chem. Soc. Rev. 1997, 26, 387-
3
99.
(
5) (a) Winkler, J. D.; Hey, J. P.; Williard, P. G. J. Am. Chem. Soc.
1
986, 108, 6425-6427. (b) Winkler, J. D.; Henegar, K. E.; Williard, P.
G. J. Am. Chem. Soc. 1987, 109, 2850-2851. (c) Winkler, J. D.;
Henegar, K. E.; Hong, B.-C.; Williard, P. G. J. Am. Chem. Soc. 1994,
1
16, 4183-4188. (d) Winkler, J. D.; Hong, B.-C.; Bahador, A.; Kaza-
nietz, M. G.; Blumberg, P. M. J. Org. Chem. 1995, 60, 1381-1390. (e)
Winkler, J. D.; Kim, S.; Harrison, S.; Lewin, N. E.; Blumberg, P. M. J.
Am. Chem. Soc. 1999, 121, 296-300. (f) Winkler, J. D.; Rouse, M. B.;
Greaney, M. F.; Harrison, S. J.; Jeon, Y. T. J. Am. Chem. Soc. 2002,
(9) Kigoshi, H.; Suzuki, Y.; Aoki, K.; Uemura, D. Tetrahedron Lett.
2000, 41, 3927-3930.
(10) Tang, H.; Yusulff, N.; Wood, J. L. Org. Lett. 2001, 3, 1563-
1566.
1
24, 9726-9728.
10.1021/jo048833l CCC: $27.50 © 2004 American Chemical Society
7802
J. Org. Chem. 2004, 69, 7802-7808
Published on Web 10/13/2004

Synthesis of Optically Active Ingenol
FIGURE 2. Grubbs catalysts.
SCHEME 3. Synthesis of Iodide 14a
FIGURE 1. Ingenol and the strained inside-outside bicyclic
skeleton.
SCHEME 1. Ring-Closing Olefin Metathesis in the
a
Synthesis of Ingenol Derivatives
a
Reagents and conditions: (a) DIBAL, toluene, -78 °C, 5 h;
(
b) Ph3PdCHCOOMe, benzene, 60 °C, 4 h, 59% (2 steps); (c) I2,
PPh3, imidazole, toluene, rt, 1.5 h, 81%; (d) DIBAL, toluene, -78
C, 1 h; (e) 3,4-dihydro-2H-pyran, TsOH, CH2Cl2, rt, 40 min, 94%
2 steps).
°
(
relatively close to one another. We therefore investigated
ring-closing olefin metathesis for bicyclic skeletons and
found that metathesis of trans-2,7-diallylcycloheptanone
(
2b) affords dimeric compounds rather than in,out-
bicyclo[4.4.1]undecene (3b) under conditions where cis-
,7-diallylcycloheptanone (2a) is converted into out,out-
2
bicyclo[4.4.1]undecene (3a) (Scheme 1). We therefore
chose spiro compound 4 as a key intermediate, in which
the distance between the two terminal olefins is closer,
approximately 3.6 Å based on a molecular mechanics
a
Reagents and conditions: (a) First generation Grubbs catalyst
I, benzene, reflux, 18 h, 45%; (b) same conditions as a.
SCHEME 2. Synthetic Plan for Optically Active
Ingenol (1) via Ring-Closing Olefin Metathesis
12
calculation, than that of trans-2,7-diallylcycloheptanone
(
2b, 3.8 Å).
The synthesis of 4 began with γ-butyrolactone as a
starting material (Scheme 3). γ-Butyrolactone was re-
duced with DIBAL to give hemiacetal 10, the Wittig
reaction of which afforded the unsaturated ester 11 (59%,
2
steps). Iodination of the hydroxy group in 11 and
subsequent reduction with DIBAL afforded the allylic
alcohol 13. The hydroxy group in 13 was protected to
provide the THP ether 14 (76%, 3 steps). The alkylation
reaction of cycloheptanone with 14 (LDA) afforded the
alkylated ketone 16 in a 43% yield (Scheme 4). This step
1
3
was improved by using the alkylation reaction of
cycloheptanone N,N-dimethylhydrazone with 14 (n-BuLi)
and subsequent hydrolysis with silica gel14 to give 16 in
a 92% yield. Deprotection of the THP group in 16 and
subsequent chlorination provided the allylic chloride 17
(
90%), which was then treated with t-BuOK in t-BuOH
to give the spiroketones 18a (28%) and 18b (43%).
The stereochemistry of 18a and 18b was determined
as follows (Scheme 5). The spiroketone 18b was reduced
The key reaction of this synthesis is the ring-closing
olefin metathesis with Grubbs’ ruthenium catalysts,
4
with NaBH in EtOH to give alcohol 19a (50%) and its
2 3 2 2 3
RuCl (dCHPh)(PCy ) and RuCl (dCHPh)(PCy )(bis-
diastereomeric alcohol 19b (21%). The stereostructures
of 19a and 19b were determined by the coupling constant
mesitylimidazolidinylidene) (Figure 2), which provides a
new strategy for the synthesis of cyclic natural products.11
In the ring-closing olefin metathesis, it is important that
the two olefins being attached to one another be located
(
12) The global minima were calculated in a Multiconformer con-
formational search with MacroModel (Version 6.0, MM2* force field).
(
13) Corey, E. J.; Enders, D. Tetrahedron Lett. 1976, 3-6.
(11) Review: Grubbs, R. H.; Chang, S. Tetrahedron 1998, 54, 4413-
(14) Kotsuki, H.; Miyazaki, A.; Kadota, I.; Ochi, M. J. Chem. Soc.,
Perkin 1 1990, 429-430.
4
450.
J. Org. Chem, Vol. 69, No. 23, 2004 7803

Watanabe et al.
SCHEME 4. Synthesis of Spiroketones 18a and
a
18b
FIGURE 3. Plausible transition states of spirocyclization of
1
8a.
SCHEME 6a. Synthesis of Tricyclic Ketone 5 and Its
Isomer 21
a
Reagents and conditions: (a) BuLi, THF, -5 °C, 1 h, 14, rt, 1
h; (b) SiO2, CH2Cl2, 19 h, 92% (after rehydration of the recovered
sm); (c) PPTS, EtOH, 55 °C, 12 h, 97%; (d) PPh3, CCl4, reflux, 5 h,
PPh3, reflux, 4 h, 93%; (e) NaH, Et3COH, xylene, reflux, 30 min,
7
9% (18a), 7% (18b).
SCHEME 5. Stereochemistry of 18ba
a
Reagents and conditions: (a) KHMDS, THF, -78 °C, 1 h; allyl
iodide, 0 °C, 3 h, 81% (4:20 ) 10:1); (b) first-generation Grubbs
catalyst I, toluene, reflux, 5.5 h, 27%; (c) first-generation Grubbs
catalyst I, toluene, reflux, 1.5 h, 62%; (d) H2, 10% Pd/C, EtOH, rt,
22 h, 55%; (e) H2, 10% Pd/C, EtOH, rt, 22 h, 69%.
3 3
with Et CONa in Et COH/xylene, coordination of the
chlorine atom to the sodium ion in the enolate possibly
stabilized the transition state A to 18a (Figure 3). The
addition of 18-crown-6, KI, or LiCl would interrupt the
coordination to give 18b predominantly.
Allylation of 18a with KHMDS and allyl iodide pro-
vided a 10:1 mixture of the allyl ketones 4 and 20 in an
a
Reagents and conditions: (a) NaBH4, EtOH, rt, 32 h, 50%
(
19a), 21% (19b).
8
1% yield, which were separated by silica gel column
J ) 10.0 Hz for 19b) and the half-height widths15 (W1/2
chromatography (Scheme 6). We could not determine the
stereochemistry of 4 and 20 by spectroscopic analysis;
however, we predicted that the allylation of 18a would
occur from the less hindered side of the corresponding
enolate, and that the allyl ketone 4 would be predomi-
nantly obtained.
(
)
10.8 Hz for 19a, 18.9 Hz for 19b) of oxymethine proton
1
in their H NMR spectra. Both alcohols 19a and 19b
exhibited an NOE between the oxymethine proton and
the allylic proton, suggesting that the oxymethine group
and the vinyl group in 19a and 19b are on opposite sides
of the cyclopentane ring. This finding indicates that the
carbonyl and vinyl groups in 18b are on opposite sides
of the cyclopentane ring, and thus 18a possesses the
desired stereochemistry for the synthesis of 4 and 5,
which was confirmed later by the fact that compound 18a
The ring-closing olefin metathesis of the allyl ketones
and 20 was investigated, respectively, and it was
4
proved that this reaction requires a relatively higher
temperature. The allyl ketone 4 reacted with the first-
generation Grubbs’ ruthenium catalyst I in boiling
toluene to give the tricycloketone 5 in 27% yield, whereas
the ring-closing olefin metathesis of 20 gave the tri-
cycloketone 21 in 62% yield. The use of a second-
generation catalyst II improved the formation of 5 to a
is converted into the known 22a5c through compounds 4
and 5.
The stereoselectivity of this spirocyclization was in-
vestigated (Table 1). The addition of 18-crown-6, KI, or
LiCl decreased the predominance of the desired 18a. The
3
1% yield. The tricycloketones 5 and 21 were catalytically
hydrogenated to afford the previously reported compound
2
use of a bulky base, Et
the stereoselectivity to give 18a predominantly. Further-
more, Et CONa in Et COH/xylene afforded the desired
8a stereoselectively. Under the less polar conditions
3 3
COK in Et COH/xylene, reversed
5c,16
16
2a
(55%) and compound 22b (68%), respectively.
Thus, the structures of 5 and 21 were confirmed.
After determining the applicability of ring-closing
olefin metathesis for synthesis of the highly strained
3
3
1
(
15) Hassner, A.; Heathcock, C. H. J. Org. Chem. 1964, 29, 1350-
1
355.
(16) Yields are not optimized.
7804 J. Org. Chem., Vol. 69, No. 23, 2004

Synthesis of Optically Active Ingenol
TABLE 1. Spirocyclization of Allylic Chloride 17
conditions
additive
product
yield/%
entry
base
solvent
temp/°C
time/h
18a:18b
1
2
3
4
5
6
t-BuOK
t-BuOK
t-BuOK
t-BuOK
Et3COK
t-BuOH
reflux
50
12
1.5
5
88
86
74
86
58
86
1:1.8
1:4.8
1:3.2
1:4.8
2.4:1
12:1
t-BuOH
18-crown-6
KI
LiCl
t-BuOH
t-BuOH
Et3COH/xylene
Et3COH/xylene
50
70
reflux
reflux
5
a
0.5
0.5
b
Et3CONa
a
Prepared from the alcohol and KH. b Prepared from the alcohol and NaH.
SCHEME 7. Synthesis of Winkler’s Aldehyde 9a
compound 23 (75%), which was transformed into com-
pound 24 by demethoxycarbonylation (78%). The THP
group of 24 was removed to give alcohol 25 (97%), which
was chlorinated to furnish allylic chloride 26 (95%).
The spirocyclization of 26 was investigated (Table 2).
The procedure applied to 17, t-BuOK in t-BuOH, did not
afford the desired compound 28 but tert-butyl ether 27
(
14%). To increase the steric hindrance of the base, we
used Et COK in the corresponding alcohol and found that
3
the desired compound 28 was obtained as a sole product
in 23% yield (entry 2). The stereochemistry of 28 was
determined by the NOESY correlation between the allylic
methine proton and the methine proton with a secondary
methyl group (Figure 4). The corresponding lithium
alkoxide and sodium tert-amyloxide were found to be less
effective. DBU was inappropriate as a base. Although the
addition of LiI or 18-crown-6 somehow enhanced the
reaction rate, it did not increase the yield. As in the
cyclization of 17, the use of xylene as a cosolvent
improved the yield to some extent (entry 8). The condi-
3 3
tions with Et CONa in Et COH/xylene afforded the best
results as in the case of cyclization of 17 (entry 9, 53%
yield). Replacement of the alcohol with tert-amyl alcohol
decreased the yield (entry 10).
Allylation of spiroketone 28 was effected by a standard
procedure (allyl iodide and LDA) to give ketone 29 as a
sole product in 83% yield. The bulky dimethylcyclopro-
pane ring would interfere with the alkylation from the
â-face. Ring-closing olefin metathesis of 29 was then
investigated (Table 3). The reaction was effected with a
a
Reagents and conditions: (a) NaH, DMF, rt, 1 h, 14, 100 °C,
6
3
h, 75%; (b) LiI, DMF, reflux, 4 h, 78%; (c) PPTS, EtOH, 55 °C,
h, 97%; (d) CCl4, PPh3, reflux, 7 h, 93%; (e) NaH, Et3COH, xylene,
reflux, 30 min, 53%; (f) LDA, HMPA, THF, 0 °C, 40 min; allyl
iodide, 0 °C, 6 h, 83%; (g) LDA, HMPA, THF, 0 °C, 40 min;
methallyl iodide, -10 °C, 2 h, 59%; (h) second-generation Grubbs
catalyst II, toluene, reflux, 30 min, 53%; (i) second-generation
Grubbs catalyst II, toluene, reflux, 30 min, 87%; (j) SeO2, dioxane,
reflux, 1 h, 85%.
0
.2 molar equiv of Grubbs catalyst in a boiling solvent
(1.5 mM). The first-generation Grubbs catalyst in toluene
gave tetracyclicketone 30 in only 14% yield (entry 1). The
second-generation catalyst in toluene worked better
(entry 2). The shorter reaction times provided the desired
compound 30 in the best yield (entry 3). Use of the other
hydrocarbon solvents, benzene and xylene, decreased the
yield (entries 4 and 5), probably because of insufficient
activation energy and decomposition of the catalyst or
ingenol skeleton, we attempted to synthesize the optically
active ingenol itself (Scheme 2). Although our compound
5
lacks the D-ring, this strategy would be applicable to
total synthesis of ingenol by starting from Funk’s keto
ester 6. Cyclization of methallyl compound 7 gives
trisubstituted olefin 8, which would be converted into the
corresponding aldehyde 9, a key intermediate in Win-
kler’s total synthesis.
the product. No cyclization was observed in CH
).
The methallyl compound 7 was prepared from ketone
2 2
Cl (entry
6
28 as above (59%). Ring-closing olefin metathesis of
methallyl compound 7 was achieved under the same
conditions described in entry 3 of Table 3 to give
tetracyclic compound 8 in 87% yield. The success of ring-
3
-Carene was converted into the keto ester 6 in five
6a
steps following the procedure of Funk (Scheme 7). The
keto ester 6 was alkylated with iodide 14 to give
J. Org. Chem, Vol. 69, No. 23, 2004 7805

Watanabe et al.
TABLE 2. Spirocyclization of Allylic Chloride 26
entry
base
solvent
additive
temp
time/h
yield/%d
1
2
3
4
5
6
7
8
9
t-BuOK
t-BuOH
reflux
reflux
reflux
reflux
reflux
reflux
rt
reflux
reflux
reflux
8
0e
23
0
13
0
12
5
46
53
11
a
Et3COK
Et3COH
12
24
13
10
0.5
1.5
0.5
0.5
15
b
Et3COLi
Et3COH
t-AmONa
t-AmOH
DBU
toluene
a
Et3COK
Et3COH
LiI
18-crown-6
a
Et3COK
Et3COH
a
Et3COK
Et3COH/xylene
Et3COH/xylene
t-AmOH/xylene
c
Et3CONa
a
10
t-AmOK
a
Prepared from the alcohol and KH. b Prepared from the alcohol and n-BuLi. Prepared from the alcohol and NaH. d Isolated yield.
c
e
Besides 28, an inseparable mixture of byproducts was obtained. An allylic tert-butyl ether 27 was obtained in 14% yield.
Winkler’s aldehyde. This synthesis provides the first
synthetic access to optically active ingenol. Application
of this strategy to the synthesis of natural ingenol
derivatives is now in progress in our laboratory.
Experimental Section
Alkylation of Funk’s Keto Ester 6. To a suspension of
NaH (60% in mineral oil, 238 mg, 6.0 mmol) in DMF (10 mL)
FIGURE 4. NOE in 28.
was added a solution of keto ester 6 (1.07 g, 4.8 mmol) in DMF
(
2 + 1 mL), and the mixture was stirred at room temperature
for 1 h. A solution of iodide 14 (1.72 g, 5.6 mmol) in DMF (3 ×
mL) was added, and the reaction mixture was stirred at 100
C for 6 h. After cooling to room temperature, the mixture was
diluted with water (10 mL) and extracted with ethyl acetate
3 × 15 mL). The combined extracts were washed with brine,
dried (Na SO ), and concentrated. The residual oil was chro-
TABLE 3. Ring-Closing Olefin Metathesis of Diene 29
1
°
(
2
4
matographed on silica gel (100 g, hexane-ether 10:1 to 5:1)
to give alkylated ketone 23 (1.46 g, 75%) as a colorless oil.
2
1
[
R]
1202, 1118, 1023 cm ; H NMR (270 MHz, CDCl
J ) 15.4, 5.6 Hz, 1 H), 5.57 (dt, J ) 15.4, 5.4 Hz, 1 H), 4.62
dd, J ) 4.1, 2.7 Hz, 1 H), 4.17 (dd, J ) 11.3, 5.6 Hz, 1 H),
D
+95.4 (c 1.0, CHCl ); IR (neat) 2942, 1739, 1703, 1642,
3
-
1 1
conditions
product
3
) δ 5.66 (dt,
entry
catalyst
solvent
time
yield/%
(
1
2
3
4
5
6
Ia
toluene
toluene
toluene
benzene
xylene
3 h
14
44
53
32
39
0
3
3
1
1
3
8
.90 (dd, J ) 11.3, 5.6 Hz, 1 H), 3.86 (m, 1 H), 3.71 (s, 3 H),
.50 (m, 1 H), 2.66 (dd, J ) 14.7, 8.3 Hz, 1 H), 2.27 (dd, J )
4.7, 8.9 Hz, 1 H), 2.10-1.99 (m, 3 H), 1.88-1.35 (m, 11 H),
.22 (m, 1 H), 1.12 (d, J ) 6.8 Hz, 3 H), 1.06 (s, 3 H), 1.02 (s,
H), 0.78 (ddd, J ) 8.5, 8.5, 6.8 Hz,1 H), 0.64 (ddd, J ) 8.9,
b
II
6 h
b
II
30 min
2 h
10 min
3 h
b
II
b
II
b
II
CH2Cl2
+
.5, 8.3 Hz, 1 H); MS (FAB) m/z 407 (M + H) ; HRMS (ESI)
a
b
+
RuCl2(dCHPh)(PCy3)2.
imidazolidinylidene).
RuCl2(dCHPh)(PCy3)(bismesityl-
m/z calcd for C24
H
38NaO
5
(M + Na) 429.2617, found 429.2599
(∆ -1.8 mmu).
Demethoxycarbonylation of Alkylated Ketone 23. A
solution of alkylated ketone 23 (130.6 mg, 0.32 mmol) and LiI
closing olefin metathesis of the methallyl compound
might be due to (1) stability of the trisubstituted double
bond in the product under the reaction conditions and
(
650 mg, 4.9 mmol) in DMF (6 mL) was refluxed for 4 h. After
being cooled to room temperature, the reaction mixture was
diluted with triethylamine (0.1 mL) and water (10 mL) and
extracted with hexane (3 × 10 mL). The combined extracts
(
2) a high-frequency factor in encountering the two
olefins. Allylic oxidation of compound 8 with SeO
2
af-
2 4
were washed with brine, dried (Na SO ), and concentrated.
The residual oil was chromatographed on silica gel (30 g,
forded the desired aldehyde 9 (85%), which was a key
hexane-ether 8:1 to 5:1) to give ketone 24 (87.3 mg, 78%) as
intermediate of Winkler’s total synthesis.
2
1
a colorless oil. [R]
D
3
+74.7 (c 0.96, CHCl ); IR (neat) 2939,
-
1 1
1
704, 1454, 1381, 1200, 1118, 1076, 1023, 969 cm ; H NMR
Conclusions
(270 MHz, CDCl ) δ 5.69 (br dt, J ) 15.5, 6.2 Hz, 1 H), 5.56
3
(
4
ddd, J ) 15.6, 6.2, 5.8 Hz, 1 H), 4.63 (br t, J ) 4.0 Hz, 1 H),
We found the ring-closing olefin metathesis to be
effective in the synthesis of highly strained ring systems,
and to be a key step in synthesizing optically active
.17 (dd, J ) 11.9, 5.8 Hz, 1 H), 3.91 (dd, J ) 11.9, 6.2 Hz, 1
H), 3.85 (m, 1 H), 3.49 (m, 1 H), 2.50 (dd, J ) 11.5, 7.2 Hz, 1
H), 2.41 (m, 1 H), 2.10-2.02 (m, 4 H), 1.86-1.52 (m, 8 H),
7806 J. Org. Chem., Vol. 69, No. 23, 2004

Synthesis of Optically Active Ingenol
1
.43-1.16 (m, 4 H), 1.08 (s, 3 H), 1.07 (s, 3 H), 0.81 (d, J ) 6.5
2 4
were washed with brine, dried (Na SO ), and concentrated.
Hz, 3 H), 0.68 (m, 1 H), 0.55 (m, 1 H); MS (FAB) m/z 349 (M
The residue was chromatographed on silica gel (4 g, hexane-
+
+
+
H) ; HRMS (ESI) m/z calcd for C22
71.2562, found 371.2569 (∆ +0.7 mmu).
Allylic Alcohol 25. A solution of ketone 24 (1.03 g, 3.0
3
H36NaO (M + Na)
benzene 100:1) to give allyl spiro ketone 29 (42.8 mg, 83%) as
2
1
3
a colorless oil. [R]
695, 1638, 1458, 1378, 995, 909 cm ; H NMR (500 MHz,
) δ 5.67 (m, 1 H), 5.60 (dt, J ) 17.0, 9.9 Hz, 1 H), 5.01
m, 1 H), 4.98 (m, 1 H), 4.97 (m, 1 H), 4.94 (m, 1 H), 2.73 (m,
D
+93.4 (c 0.79, CHCl ); IR (neat) 2955,
3
-
1 1
1
CDCl
3
mmol) and pyridinium p-toluenesulfonate (55 mg, 0.22 mmol)
in ethanol (50 mL) was stirred at 55 °C for 10 h. After the
addition of pyridinium p-toluenesulfonate (20.8 mg, 0.083
mmol), the mixture was stirred at the same temperature for
a further 10 h. The mixture was concentrated, and the residual
oil was chromatographed on silica gel (30 g, hexane-ether 1:1)
(
1
H), 2.31 (m, 2 H), 2.15 (m, 1 H), 2.03-1.80 (m, 5 H), 1.71
(
m, 1 H), 1.63 (m, 1 H), 1.56-1.49 (m, 2 H), 1.02 (s, 3 H), 1.0
s, 3 H), 0.91 (d, J ) 6.8 Hz, 3 H), 0.70 (ddd, J ) 10.2, 9.3, 6.3
(
1
3
Hz, 1 H), 0.14 (dd, J ) 9.5, 9.5 Hz, 1 H); C NMR (67.8 MHz,
21
3
CDCl ) δ 212.0, 140.6, 136.5, 115.4, 114.7, 68.4, 49.8, 47.5, 35.7,
to give allylic alcohol 25 (761 mg, 97%) as a colorless oil. [R]
104 (c 1.01, CHCl ); IR (neat) 3420, 2931, 1699, 1457, 969
cm ; H NMR (270 MHz, CDCl ) δ 5.73-5.57 (m, 2 H), 4.08
m, 2 H), 2.51 (dd, J ) 11.3, 7.0 Hz, 1 H), 2.41 (dt, J ) 8.6, 4.3
Hz, 1 H), 2.11-1.99 (m, 4 H), 1.83 (m, 1 H), 1.64 (m, 1 H),
.42-1.15 (m, 5 H), 1.08 (s, 3 H), 1.07 (s, 3 H), 0.81 (d, J ) 6.8
Hz, 3 H), 0.69 (ddd, J ) 10.9, 10.6, 5.9 Hz, 1 H), 0.56 (ddd, J
D
3
4.6, 30.8, 28.9, 28.7, 27.0, 26.4, 22.9, 21.0, 20.9, 16.0, 14.6;
+
3
+
-
1
1
MS (FAB) m/z 287 (M + H) ; HRMS (ESI) m/z calcd for
3
+
(
20
C H
31O (M + H) 287.2375, found 287.2379 (∆ +0.4 mmu).
Ring-Closing Olefin Metathesis of 29. A solution of allyl
1
spiro ketone 29 (21.9 mg, 0.077 mmol) and the second-
generation Grubbs catalyst, RuCl (dCHPh)(PCy )(bismesityl-
2
3
+
)
10.6, 9.2, 7.0 Hz, 1 H); MS (FAB) m/z 287 (M + Na) ; HRMS
imidazolidinylidene) (13.6 mg, 0.016 mmol), in toluene (45 mL)
was refluxed for 30 min. The mixture was filtered through a
pad of silica gel (3 g), and the pad was washed with benzene.
The filtrate and washings were combined and concentrated
to give an oil, which was chromatographed on silica gel (4 g,
benzene) to give tetracyclic ketone 30 (10.6 mg, 53%) as a
+
(
29 2
ESI) m/z calcd for C17H O (M + H) 265.2167, found
2
65.2177 (∆ +1.0 mmu).
Chloride 26. A solution of allylic alcohol 25 (46.5 mg, 0.176
mmol) and triphenylphosphine (96.3 mg, 0.37 mmol) in CCl
1 mL) was refluxed for 7 h. After being cooled to room
4
(
2
1
temperature, the reaction mixture was filtered through a
cotton plug to remove triphenylphosphine oxide. The filtrate
was concentrated, and the residue was chromatographed on
silica gel (4 g, hexane-ether 20:1) to give chloride 26 (47.1
colorless oil. [R]
D
+74.0 (c 0.128, CHCl
3
); IR (neat) 3006, 2956,
2873, 1716, 1459, 1434, 1380, 1366, 1337, 1210, 1192, 1138,
944 cm ; H NMR (600 MHz, CDCl ) δ 5.56 (ddd, J ) 12.0,
-
1 1
3
5.8, 3.3 Hz, 1 H), 5.14 (ddd, J ) 12.0, 4.4, 2.1 Hz, 1 H), 3.17
(ddd, J ) 12.5, 11.8, 3.1 Hz, 1 H), 3.13 (m, 1 H), 2.40 (m, 1 H),
2.36 (m, 1 H), 2.09 (dddd, J ) 16.8, 5.8, 3.1, 3.1 Hz, 1 H), 1.91
(m, 1 H), 1.87 (m, 1 H), 1.81 (ddd J ) 15.3, 10.0, 1.9 Hz, 1 H),
1.68 (dddd, J ) 10.0, 10.0, 5.0, 5.0 Hz, 1 H), 1.58 (m, 1 H),
1.52 (ddd, J ) 10.0, 4.4, 1.0 Hz, 1 H), 1.43 (m, 1 H), 1.28 (ddd,
J ) 13.4, 10.3, 7.6 Hz, 1 H), 1.12 (s, 3 H), 1.03 (s, 3 H), 0.94 (d,
J ) 6.9 Hz, 3 H), 0.69 (ddd, J ) 10.0, 8.5, 6.1 Hz, 1 H), 0.62
2
1
mg, 95%) as a colorless oil. [R]
D
+95.9 (c 0.95, CHCl
3
); IR
neat) 2938, 2864, 1703, 1455, 1380, 1249, 966 cm ; H NMR
270 MHz, CDCl ) δ 5.73 (dt, J ) 15.3, 6.3 Hz, 1 H), 5.70 (dt,
-
1 1
(
(
3
J ) 15.3, 6.9 Hz, 1 H), 4.02 (d, J ) 6.9 Hz, 2 H), 2.51 (dd, J )
1.5, 6.8 Hz, 1 H), 2.41 (dt, J ) 8.8, 4.4 Hz, 1 H), 2.10-2.01
m, 3 H), 1.85 (m, 1 H), 1.65 (m, 1 H), 1.42-1.10 (m, 5 H),
1
(
1
.08 (s, 3 H), 1.07 (s, 3 H), 0.81 (d, J ) 7.0 Hz, 3 H), 0.69 (ddd,
1
3
J ) 9.9, 9.4, 5.9 Hz, 1 H), 0.56 (ddd, J ) 10.7, 9.4, 6.8 Hz, 1
3
(dd, J ) 11.8, 8.5 Hz, 1 H); C NMR (67.8 MHz, CDCl ) δ
+
H); MS (FAB) m/z 283 (M + H) ; HRMS (ESI) m/z calcd for
C
211.2, 137.3, 132.3, 72.0, 46.0, 45.6, 39.6, 34.8, 31.9, 29.5, 28.7,
+
17
H
28ClO (M + H) 283.1828, found 283.1801 (∆ -2.7 mmu).
27.9, 25.3, 23.6, 23.2. 22.8, 15.5, 15.2; MS (FAB) m/z 281 (M
+
+
+
2
Na) ; HRMS (ESI) m/z calcd for C18H26NaO (M + Na)
Spirocyclization of Chloride 26. To a solution of chloride
6 (24.2 mg, 0.086 mmol) in xylene (1.5 mL) and 3-ethyl-3-
pentanol (0.07 mL, 0.50 mmol) was added a mixture of NaH
60% in mineral oil, 9.3 mg, 0.23 mmol), and the mixture was
quickly heated to reflux. After 30 min, the mixture was cooled
to room temperature. diluted with saturated aqueous NH Cl
1 mL), and extracted with hexane (3 × 5 mL). The extract
81.1883, found 281.1882 (∆ -0.1 mmu).
2
Methallylation of Spiro Ketone 28. Spiro ketone 28 (21.7
(
mg, 0.090 mmol) was methallylated with methallyl iodide (37
mg, 0.20 mmol) by the same procedure used in the preparation
of 29 to give methallyl spiro ketone 7 (15.7 mg, 59%) as
colorless crystals. Mp 87.0-91.0 °C (hexane-ether-MeOH);
4
(
2
1
was washed with brine, dried (Na
2 4
SO ), and concentrated. The
[R]
D
+44.5 (c 0.26, CHCl
3
); IR (neat) 2954, 1685, 1454, 1377
-
1 1
residual xylene solution was chromatographed on silica gel (2
cm ; H NMR (270 MHz, CDCl ) δ 5.61 (ddd, J ) 16.9, 9.9,
3
g, hexane-ether 200:1 to 100:1) to give spiro ketone 28 (11.1
9.8 Hz, 1 H), 5.05 (dd, J ) 16.9, 1.9 Hz, 1 H), 4.97 (dd, J )
9.9, 1.9 Hz, 1 H), 4.75 (br s, 1 H), 4.68 (br s, 1 H), 2.75 (br t,
J ) 7.4 Hz, 1 H), 2.42 (ddd, J ) 10.9, 9.9, 3.0 Hz, 1 H), 2.29
(dd, J ) 12.1, 10.9 Hz, 1 H), 2.07 (dd, J ) 12.1, 3.0 Hz, 1 H),
2.01-1.43 (m, 9 H), 1.65 (s, 3 H), 0.98 (s, 3 H), 0.95 (s, 3 H),
0.91 (d, J ) 6.5 Hz, 3 H), 0.67 (ddd, J ) 9.5, 9.4, 6.1 Hz, 1 H),
21
mg, 53%) as a colorless oil. [R]
D
3
+135 (c 1.0, CHCl ); IR (neat)
-
1 1
2
954, 1696, 1634, 1456, 1378, 1286, 1160, 993, 912 cm ; H
NMR (500 MHz, CDCl ) δ 5.59 (ddd, J ) 16.9, 10.0, 8.7 Hz, 1
H), 5.00 (dd, J ) 16.9, 1.6 Hz, 1 H), 4.92 (dd, J ) 10.0, 1.6 Hz,
3
1
6
1
1
H), 2.69 (ddd, J ) 8.7, 7.5, 2.0 Hz, 1 H), 2.30 (dd, J ) 11.8,
.8 Hz, 1 H), 2.21 (dd, J ) 11.8, 10.7 Hz, 1 H), 1.99 (m, 1 H),
.97 (dd, J ) 9.9, 4.1 Hz, 1 H), 1.89 (m, 1 H), 1.85 (dt, J )
4.7, 6.2 Hz, 1 H), 1.78 (td, J ) 6.7, 2.2 Hz, 1 H), 1.71 (m, 1
1
3
3
0.10 (dd, J ) 9.9, 9.5 Hz, 1 H); C NMR (67.8 MHz, CDCl ) δ
212.1, 143.3, 140.7, 114.9, 112.1, 68.5, 49.8, 46.6, 39.4, 34.6,
31.1, 29.7, 28.9, 28.6, 27.8, 26.7, 23.1, 22.9, 20.9, 16.0, 14.7;
+
H), 1.65 (dd, J ) 14.7, 10.2 Hz, 1 H), 1.54 (dd, J ) 4.9, 3.0 Hz,
H), 1.51 (m, 1 H), 1.07 (s, 3 H), 1.05 (s, 3 H), 0.91 (d, J ) 6.8
Hz, 3 H), 0.69 (ddd, J ) 10.2, 9.6, 6.2 Hz, 1 H), 0.55 (ddd, J )
HRMS (FAB) m/z calcd for C21
found 323.2372 (∆ +2.1 mmu).
H
32NaO (M + Na) 323.2351,
1
Ring-Closing Olefin Metathesis of 7. Methallyl spiro
ketone 7 (6.3 mg, 0.021 mmol) was cyclized with second-
generation Grubbs catalyst, RuCl (dCHPh)(PCy )(bismesityl-
2 3
1
1
2
0.7, 9.6, 6.8 Hz, 1 H); 13C NMR (67.8 MHz, CDCl
3
) δ 211.1,
40.5, 114.9, 68.8, 50.1, 39.4, 34.8, 30.8, 28.8, 28.7, 26.3, 23.1,
+
1.2, 21.1, 20.7, 15.3, 14.8; MS (FAB) m/z 247 (M + H) ; HRMS
imidazolidinylidene) (4.5 mg, 5.3 µmol), in boiling toluene (13
mL) for 0.5 h by the same procedure used in the preparation
of 30 to give tetracyclic ketone 8 (5.0 mg, 87%) as a colorless
+
(
ESI) m/z calcd for C17
H
26NaO (M + Na) 269.1881, found
2
69.1861 (∆ -2.0 mmu).
2
1
Allylation of Spiro Ketone 28. To a ice-cooled solution of
oil. [R]
D
+24.4 (c 0.16, CHCl
3
); IR (neat) 2950, 1724, 1455,
-
1 1
spiro ketone 28 (45.1 mg, 0.18 mmol) in THF (0.2 mL) were
added HMPA (0.04 mL, 0.23 mmol) and LDA (0.71 mmol)
solution in THF-hexane (0.6 mL). After 40 min, allyl iodide
1379 cm ; H NMR (500 MHz, CDCl ) δ 4.88 (br s, 1 H), 3.19
3
(ddd, J ) 12.5, 12.2, 3.2 Hz, 1 H), 3.13 (br s, 1 H), 2.33 (m, 1
H), 2.30 (m, 1 H), 2.06 (br d, J ) 16.7 Hz, 1 H), 1.89 (m, 1 H),
1.85 (m, 1 H), 1.80 (ddd, J ) 14.7, 9.4, 2.6 Hz, 1 H), 1.65 (m,
1 H), 1.64 (s, 3 H), 1.58 (m, 1 H), 1.47 (m, 1 H), 1.44 (m, 1 H),
1.26 (ddd, J ) 13.3, 10.1, 7.6 Hz, 1 H), 1.12 (s, 3 H), 1.03 (s, 3
H), 0.94 (d, J ) 6.8 Hz, 3 H), 0.69 (ddd, J ) 9.4, 8.8, 6.2 Hz,
(
0.07 mL, 0.77 mmol) was added, and the mixture was stirred
at 0 °C for 6 h. The mixture was diluted with saturated
aqueous Na (2 mL) and saturated aqueous NH Cl (2 mL)
and extracted with ether (3 × 5 mL). The combined extracts
S O
2 2 3
4
J. Org. Chem, Vol. 69, No. 23, 2004 7807

Watanabe et al.
1
H), 0.60 (dd, J ) 12.2, 8.8 Hz, 1 H); 13C NMR (67.8 MHz,
CDCl ) δ 211.3, 139.4, 132.3, 71.9, 45.7, 45.5, 39.6, 36.1, 35.0,
9.5, 28.7, 27.8, 26.2, 25.3, 23.6, 23.2. 22.8, 15.4, 15.3; HRMS
Acknowledgment. We would like to thank Prof.
Daisuke Uemura (Nagoya University) for his helpful
discussion and Ms. Satomi Omura for her technical
assistance. We appreciate Prof. J. D. Winkler (The
University of Pennsylvania) for providing the spectral
data for racemic aldehyde 9. This work has been
supported in part by the 21st Century COE program
and a Grant-in-Aid for Scientific Research (Ministry of
Education, Culture, Sports, Science and Technology,
Japan). Financial support from the Suntory Institute
for Bioorganic Research, Shorai Foundation for Science
and Technology, Yamada Science Foundation, the Fujisa-
wa Foundation, the Naito Foundation, University of
Tsukuba Research Projects, and Wako Pure Chemical
Industries, Ltd. is also acknowledged. The IR and NMR
spectra were recorded at the Chemical Analysis Center,
University of Tsukuba.
3
2
+
(
FAB) m/z calcd for C19
95.2023 (∆ -1.5 mmu).
Allylic Oxidation of 8. A solution of tetracyclic ketone 8
1.8 mg, 6.6 µmol) and SeO (11.8 mg, 0.11 mmol) in dioxane
0.5 mL) was refluxed for 1 h. The mixture was cooled to room
H28NaO (M + Na) 295.2038, found
2
(
(
2
temperature and filtered through a pad of Celite, and the
residue was washed with dioxane. The filtrate and washings
were concentrated, and the residue was diluted with ether (5
mL), washed with saturated aqueous NaHCO
Na SO ), and concentrated. The residue was chromatographed
on silica gel (0.5 g, ether 5:1) to give aldehyde 9 (1.6 mg, 85%)
3
and brine, dried
(
2
4
2
1
as colorless prisms. Mp 145.5-147.5 °C (hexane); [R]
D
+29.5
-
1
(
c 0.078, CHCl
3
); IR (neat) 2940, 1722, 1687, 1594, 1458 cm
;
1
3
H NMR (500 MHz, CDCl ) δ 9.28 (s, 1 H), 6.23 (d, J ) 1.9
Hz, 1 H), 3.36 (br s, 1 H), 3.09 (ddd, J ) 14.0, 10.9, 3.1 Hz, 1
H), 2.58 (dddd, J ) 17.1, 13.4, 3.7, 1.7 Hz, 1 H), 2.38 (m, 1 H),
2
1
.30 (m, 1 H), 2.02 (m, 1 H), 1.94 (ddd, J ) 15.6, 5.3, 5.3 Hz,
H), 1.85 (m, 1 H), 1.79 (m, 1 H), 1.70 (m, 1 H), 1.45-1.25
Supporting Information Available: General experimen-
tal procedures, experimental procedures, and spectral data for
(
m, 3 H), 1.10 (s, 3 H), 1.05 (s, 3 H), 0.98 (d, J ) 6.9 Hz, 3 H),
1
13
the synthesis of tricyclic ketone 5, as well as H and/or
C
13
0
1
2
.72 (m, 2 H); C NMR (100 MHz, C
46.5, 72.0, 46.9, 45.0, 39.8, 34.6, 29.6, 29.0, 28.4, 28.1, 25.8,
26
3.7, 23.3, 22.8, 15.4, 15.0; HRMS (FAB) m/z calcd for C19H -
6 6
D ) δ 208.1, 193.8, 159.3,
NMR charts for all new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
+
NaO
2
(M + Na) 309.1831, found 309.1853 (∆ +2.2 mmu).
JO048833L
7808 J. Org. Chem., Vol. 69, No. 23, 2004