Highly regioselective synthesis of cyclic enol silyl ethers using ring-closing metathesis

Article abstract of DOI:10.1016/S0040-4039(01)01713-0

We developed the first highly regioselective synthesis of cyclic enol ethers from readily accessible acyclic alkenyl ketones or acyclic alkenyl silyl esters using ring-closing metathesis (RCM). The RCM of acyclic enol silyl ethers was examined using Tebbe

Full text of DOI:10.1016/S0040-4039(01)01713-0

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 8023–8027
Highly regioselective synthesis of cyclic enol silyl ethers using
ring-closing metathesis
Akihiro Okada, Takashi Ohshima and Masakatsu Shibasaki*
Graduate School of Pharmaceutical Sciences, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
Received 15 August 2001; revised 3 September 2001; accepted 7 September 2001
Abstract—We developed the first highly regioselective synthesis of cyclic enol ethers from readily accessible acyclic alkenyl ketones
or acyclic alkenyl silyl esters using ring-closing metathesis (RCM). The RCM of acyclic enol silyl ethers was examined using Tebbe
reagent 5 or Grubbs catalyst 6 or 7 and successfully proceeded using the second generation Grubbs catalyst 7 to afford the
corresponding cyclic enol ethers in high yield (up to 99%, two steps from alkenyl kenone). This process can be applied to syntheses
of a variety of cyclic enol ethers in a highly regioselective manner. © 2001 Elsevier Science Ltd. All rights reserved.
Despite their utility and versatility in organic synthesis,1
the regioselective synthesis of cyclic enol silyl ethers is
still a challenging transformation. For example, the
enolate formation of cyclic ketone with strong base
followed by trapping with silyl chloride, which is one of
the simplest and most conventional methods, often
produces a mixture of regioisomers.2 Poor regioselectiv-
ity is a common problem encountered in the course of
synthetic studies of bioactive natural and unnatural
compounds. Therefore, the development of efficient
methods to synthesize enol silyl ether in a highly
regioselective manner from a readily accessible starting
material is very desirable. We hypothesized that ring-
closing metathesis (RCM) between an acyclic enol silyl
ether and the internal terminal olefin might be exploited
in a novel way to regioselectively produce the desired
cyclic enol silyl ether under mild conditions. RCM is a
powerful strategy for organic synthesis.3 Despite the
successes of this general approach to ring construction,
there are few reports of the RCM of enol ethers. In
1996, Nicolaou et al. achieved direct conversion of
alkenyl esters to cyclic enol ethers with Tebbe reagent
5.4,5 However, no RCM of enol silyl ethers to cyclic
enol silyl ethers has been reported, probably due to the
instability of enol silyl ethers. Herein we present a new
strategy for the synthesis of a variety of cyclic enol silyl
ethers 3 by intramolecular RCM between the double
bond of the enol silyl ether moiety and the internal
terminal olefin (Scheme 1). Using this strategy, many
types of cyclic enol silyl ethers 3 can be synthesized in
a highly regioselective manner from readily accessible
acyclic alkenyl ketones 1 or acyclic alkenyl silyl esters 4
under mild conditions.
To explore the possibilities of this strategy, we first
examined RCM of enol silyl ether 10, which was pre-
pared in situ from the corresponding silyl ester 8.6
According to Nicolaou’s procedure, 8 was treated with
excess Tebbe reagent 5 (Fig. 1). Initially, acyclic enol
silyl ether 10 was formed at lower temperatures (−78°C
O
CH3
m
n
TMSO
RCM
TMSO
R R'
1
n
m
m
n
R R'
R R'
3
TMSO
O
2
m
n
R R'
4
Scheme 1.
PCy
Mes
Cl
N
N Mes
Ph
3 Ph
Cp
CH3
Cl
Cl
Ti Al
Ru
Ru
Cp Cl CH3
PCy3
Cl
PCy3
5
6
7
Keywords: ring-closing metathesis; enol silyl ether; Grubbs catalyst.
* Corresponding author. Fax: +81-3-5684-5206; e-mail: mshibasa@
mol.f.u-tokyo.ac.jp
Figure 1. Structures of Tebbe reagent 5, Grubbs catalyst 6,
and the second generation Grubbs catalyst 7.
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01713-0

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A. Okada et al. / Tetrahedron Letters 42 (2001) 8023–8027
O
OTMS
carbonyl
olefination
RCM
TMSO
R
TMSO
R
5
5
//
–78ºC to rt
>90%
rt to reflux
O
O
O
O
O
O
8: R = H
10: R = H
12
9: R = Me
11: R = Me
Scheme 2. Carbonyl olefination/RCM cascade reaction using Tebbe reagent 5.
Table 1. RCM of acyclic enol ether 10 using Grubbs catalyst 6 or 7
OTMS
O
CH3
TMSO
O
condition
O
O
O
O
O
O
O
O
O
O
10
12
13
14
15
Entry
Catalyst (mol%)
Solvent (conc.)
Temp.
Time (h)
Yield (%)
12a
13a
14b
15b
1c
2c
3d
4d
6 (40)
6 (37)
6 (10)
6 (80)
CH2Cl2 (0.01 M)
Benzene (0.01 M)
Benzene (0.01 M)
Benzene (0.01 M)
rt
rt
Reflux
72
120
48
0
23
10
17
3
68
65
Trace
0
10
rt
120
4
5d
6c
7c
7 (38)
7 (38)
7 (50)
CH2Cl2 (0.02 M)
CH2Cl2 (0.02 M)
Benzene (0.02 M)
Reflux
Reflux
45°C
1
1
1
73
\99
\99
a Yield was determined by 500 MHz 1H NMR (two steps from 8 or 15).
b Isolated yield (two steps from 8 or 15).
c 10 was prepared from 15 (LDA, TMSCl, THF, −78°C).
d 10 was prepared from 8 (Tebbe reagent, THF, −78°C).
to rt) in high yield.7 At higher temperatures (rt to reflux
in THF), however, only decomposition of 10 occurred
instead of RCM (Scheme 2). Even using silyl ester 9
corresponding to Nicolaou’s substrates, no desired
product 12 was obtained. Probably the Tebbe reagent
itself or a decomposed species promoted decomposition
of the enol silyl ethers at the high temperature. Thus,
we examined the use of Grubbs catalyst 68 and the
second generation Grubbs catalyst 79 (Fig. 1) because
of their high ability to promote the metathesis reaction.
The results are summarized in Table 1. Surprisingly, in
CH2Cl2 solution catalyst 6 promoted the migration of
the double bond of the enol silyl ether moiety from exo
to endo in preference to RCM to afford the undesired
cyclic alkene 14 as a major byproduct with desilylated
acyclic ketone 15 (entry 1). By changing the solvent
from CH2Cl2 to benzene, this undesirable tendency was
improved slightly and RCM proceeded to afford cyclic
compounds 12 (10%) and 13 (4%), although 80 mol%
of 6 was required (entry 4). In contrast, catalyst 7
successfully promoted RCM in both solvents to afford
the corresponding cyclic enol silyl ether 12 in high yield
(entries 5–7).
Further optimization of the reaction conditions was
performed using enol silyl ether 17a, which was readily
prepared from the corresponding ketone 16a (Table 2).
In this case, the choice of solvent was critical. In
CH2Cl2 solution even catalyst 7 promoted migration of
the double bond of the enol silyl ether moiety in high
preference to RCM to afford 19 (entries 1–3). Finally,
the use of benzene as a solvent under dilute condition
(0.005 M) afforded the desired cyclic enol ether 18a in
almost quantitative yield (entry 7).10
Having succeeded in developing an efficient synthesis of
cyclic enol silyl ether 18a from acyclic alkenyl ketone
16a, we examined the scope and limitation of different
substrates. As shown in Table 3, catalyst 7 promoted
RCM of a variety of acyclic enol silyl ethers 17a–e to
afford five- to seven-membered ring cyclic enol silyl
ethers 18a–e in good to excellent yield. In these cases,
no migration of the double bond of the resulting cyclic
enol silyl ethers 18 was observed, making this process a
novel alternative method for the synthesis of cyclic enol
silyl ethers in a highly regioselective manner. In addi-
tion, other types of substrates such as 19 and 22 were
also converted to the desired cyclic enol ether 21 (90%,

A. Okada et al. / Tetrahedron Letters 42 (2001) 8023–8027
8025
Table 2. RCM of acyclic enol ether 17a using Grubbs catalyst 7
CH3
OTMS
CH3
LDA
TMSCl
O
TMSO
TMSO
cat. 7
THF
–78ºC
MeO2C CO2Me
MeO2C CO2Me
17a
MeO2C CO2Me
MeO2C CO2Me
16a
18a
19
Entry
Catalyst (mol%)
Solvent (conc.)
Temp. (°C)
Time (h)
Yield (%)
18aa
19a
1
2
3
4
5
6
7
8
5
10
7
5
7
7
7
7
CH2Cl2 (0.1 M)
45
45
45
50
50
50
65
50
1.0
2.5
3.0
0.5
1.0
1.0
1.0
1.0
0
0
3
70
92
97
99
95
82
78
70
CH2Cl2 (0.01 M)
CH2Cl2 (0.001 M)
Benzene (0.05 M)
Benzene (0.01 M)
Benzene (0.005 M)
Benzene (0.005 M)
Toluene (0.01 M)
a Yield was determined by 500 MHz 1H NMR (two steps from 16a).
two steps) and 24 (92%, two steps), respectively. To the
best of our knowledge, this is the first example of a
synthesis of cyclic enol ethers from acyclic enol silyl
ethers by using RCM.11
regioselectivity (Scheme 3). Crude 18a, which was
almost pure after removal of the solvent under reduced
pressure, was treated with benzaldehyde dimethyl acetal
and a catalytic amount of trimethylsilyl triflate in
CH2Cl2 to afford the coupling product 25 in 93% yield
(three steps from 16a).12 In addition, an aldol reaction
with aqueous formaldehyde solution13 and bromination
Finally, further transformation of cyclic enol silyl ether
18a was demonstrated to confirm the yield and the
Table 3. RCM of a variety of acyclic enol ethers using Grubbs catalyst 7
TMSO
O
CH3
TMSO
LDA
TMSCl
7 (7 mol %)
m
n
m
n
m
n
THF
–78ºC
benzene
(0.005 M)
65ºC, 1 h
MeO2C CO2Me
MeO2C CO2Me
MeO2C CO2Me
16
17
18
Entry
1
Substrate (E = CO2Me)
Intermediate
Product
Yield (%)a
94
H3C
TMSO
16b
16c
17b
17c
18b
E
E
E E
O
TMSO
E
E
H3C
2
92
99
88
93
90
92
E
E
E
E E
18c
O
TMSO
TMSO
TMSO
TMSO
E
O
3
H3C
E
16a
16d
17a
17d
18a
E
E
E E
E
O
TMSO
E
4b
5b
6
H3C
TMSO
TMSO
E
E
E
E E
18d
H3C
E
E
E
E E
O
TMSO
16e
19
17e
20
18e
21
E
O
OTMS
OTMS
CH3
CH3
O
OTMS
O
OTMS
O
22
23
24
7
O
a Yield was determined by 500 MHz 1H NMR (2 steps from the corresponding acyclic ketone).
b The reaction was carried out in benzene (0.001 M) reflux condition.

8026
CH3
A. Okada et al. / Tetrahedron Letters 42 (2001) 8023–8027
2. For example, the enolate formation of cyclic ketone 28
OTMS
LDA
TMSCl
with LDA followed by trapping with TMSCl gave a
mixture of 18d and 18e (1:2.3).
cat. 7
O
THF
–78ºC
O
OTMS
OTMS
MeO2C CO2Me
16a
MeO2C CO2Me
LDA
TMSCl
18a
+
THF
–78ºC
CO2Me
CO2Me
CO2Me
PhCH(OMe)2
cat. TMSOTf
CH2Cl2
HCHO aq
cat. Yb(OTf)3
THF
NBS
THF
MeO2C
MeO2C
18d
MeO2C
(1 : 2.3)
28
18e
O
OH
O
O
OMe
3. For representative reviews on RCM, see: (a) Fu¨rstner, A.
Angew. Chem., Int. Ed. 2000, 39, 3012; (b) Grubbs, R. H.;
Chang, S. Tetrahedron 1998, 54, 4413; (c) Grubbs, R. H.;
Miller, S. J.; Fu, G. C. Acc. Chem. Res. 1995, 28, 446; (d)
Schmalz, H.-G. Angew. Chem., Int. Ed. Engl. 1995, 34,
1833.
Br
Ph
MeO2C CO2Me
26
(75%, 3 steps)
MeO2C CO2Me
27
(89%, 3 steps)
MeO2C CO2Me
25
(93%, 3 steps)
4. Nicolaou, K. C.; Postema, M. H. D.; Claiborne, C. F. J.
Am. Chem. Soc. 1996, 118, 1565.
Scheme 3. Transformation of cyclic enol ether 18a.
5. RCM reactions of enol ethers using Ru and Mo catalysts
were also reported. For a representative example, see:
Rainier, J. D.; Cox, J. M.; Allwein, S. P. Tetrahedron
Lett. 2001, 42, 179 and references cited therein.
6. The alkenyl silyl esters 8 and 9 were prepared from the
corresponding alkenyl carboxylic acids in high yield
(>95%) according to the reported methods. See: Kita, Y.;
Haruta, J.; Segawa, J.; Tamura, J. Tetrahedron Lett.
1979, 20, 4311.
proceeded to afford the corresponding desired products
26 (75%, three steps) and 27 (89%, three steps), respec-
tively. Although overall yield of the transformation of
16a to 26 was moderate, the RCM process under mild
conditions appears to be a suitable candidate to synthe-
size b-hydroxy ketone instead of intramolecular nitrile
oxide cyclo addition followed by treatment with Raney
Ni.
7. The acyclic enol silyl ether 10 can be purified by quick
silica gel column chromatography (92% isolated yield).
8. (a) Pchwab, P.; France, M. B.; Ziller, J. W.; Grubbs, R.
H. Angew. Chem., Int. Ed. Engl. 1995, 34, 2039; (b)
Pchwab, P.; Grubbs, R. H.; Ziller, J. W. J. Am. Chem.
Soc. 1996, 118, 100.
In conclusion, we developed the first highly regioselective
synthesis of cyclic enol silyl ethers from readily accessible
acyclic alkenyl ketones or acyclic alkenyl silyl esters using
RCM. By changing the catalyst from Grubbs catalyst 6
to the second generation Grubbs catalyst 7 and the
solvent from CH2Cl2 to benzene, RCM of a variety of
acyclic enol silyl ethers proceeds smoothly to afford the
corresponding cyclic enol ethers in a highly regioselective
manner. The described method renders many types of
functionalized cyclic enol ethers readily available as a
pure form in terms of regiochemistry. Further investiga-
tion concerning applications of this strategy to other
kinds of metathesis and syntheses of complex bioactive
compounds are currently ongoing.
9. Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org.
Lett. 1999, 1, 953. Second generation Grubbs catalyst 7
was prepared from Grubbs catalyst 6 according to the
reference. We also used commercially available catalyst 7
(STREM Chemicals, Inc.), which had the same activity.
10. General procedure: To a solution of i-Pr2NH (0.14 mL,
1.0 mmol) in THF (10 mL) was added 1.54 M hexane
solution of n-BuLi (0.65 mL, 1.0 mmol) at 0°C. After 30
min, the reaction mixture was cooled to −78°C, to which
TMSCl (0.32 mL, 2.46 mmol) and a solution of 16a
(198.7 mg, 0.82 mmol) in THF (5 mL) were added in
order. After stirring at the same temperature for 2 h, the
reaction was quenched by addition of saturated NaHCO3
aqueous solution, allowed to warm to room temperature
(rt), and concentrated in vacuo. The residue was treated
with Et2O and water, extracted with Et2O twice. The
combined organic layers were washed with water and
brine, dried over Na2SO4 to afford the crude acyclic enol
silyl ether 17a (255 mg) (>99% yield determined by 1H
NMR): 1H NMR (500 MHz) (benzene-d6) l 0.15 (s, 9 H),
2.19 (m, 2 H), 2.43 (m, 2 H), 2.83 (d, J=7.3 Hz, 2 H),
3.29 (s, 6 H), 4.13 (s, 1 H), 4.16 (s, 1 H), 4.97 (d, J=10.7
Hz, 1 H), 5.01 (d, J=17.4 Hz, 1 H), 5.74 (m, 1 H); 13C
NMR (125 MHz) (benzene-d6) l 0.0, 30.6, 31.9, 37.7,
51.9, 57.6, 90.2, 118.9, 132.9, 158.9, 171.3. To a solution
of the crude 17a (20.3 mg, 64.6 mmol) in benzene (13 mL,
0.005 M) was added catalyst 7 (3.8 mg, 4.5 mmol) under
argon. The reaction mixture was stirred at 65°C for 1 h,
then cooled to rt, and concentrated in vacuo to afford the
Acknowledgements
This research was supported by CREST, The Japan
Science and Technology Corporation (JST), RFTF of
Japan Society for the Promotion of Science, and a
Grant-in-Aid for Scientific Research on Priority Areas
(A) ‘Exploitation of Multi-Element Cyclic Molecules’
from the Ministry of Education, Culture, Sports, Science
and Technology, Japan.
References
1. For recent reviews, see: (a) Fleming, I.; Barbero, A.;
Walter, D. Chem. Rev. 1997, 97, 2063; (b) Carreira, E. M.
In Comprehensive Asymmetric Catalysis; Jacobsen, E. N.;
Pfaltz, A.; Yamamoto, H., Eds.; Springer: Berlin, 1999;
Vol. 3, pp. 998–1065.

A. Okada et al. / Tetrahedron Letters 42 (2001) 8023–8027
8027
crude cyclic enol ether 18a (22.2 mg) (99% yield deter-
gawa, M., independently. See: 18th International Congress
of Heterocyclic Chemistry (Yokohama, Japan) Abstracts
2001, 130.
1
1
mined by H NMR): H NMR (500 MHz) (benzene-d6) l
0.14 (s, 9 H), 2.19 (m, 2 H), 2.27 (t, J=6.7 Hz, 2 H), 2.78
(m, 2 H), 3.31 (s, 6 H), 4.88 (m, 1 H); 13C NMR (125
MHz) (benzene-d6) l 0.2, 27.5, 28.6, 30.0, 52.1, 53.3,
101.2, 150.0, 171.6.
12. (a) Murata, S.; Suzuki, M.; Noyori, R. Tetrahedron Lett.
1980, 21, 2527; (b) Murata, S.; Suzuki, M.; Noyori, R. J.
Am. Chem. Soc. 1980, 102, 3248.
11. Recently, RCM of an acyclic enol silyl ether was achieved
by: Arisawa, M.; Theeraladanon, C.; Nishida, A.; Naka-
13. (a) Kobayashi, S. Chem. Lett. 1991, 2087; (b) Kobayashi,
S.; Hachiya, I. J. Org. Chem. 1994, 59, 3590.