Asymmetric synthesis of cyclic alkenes via cyclization of enantioenriched allylsilanes

Article abstract of DOI:10.1055/s-2001-14656

Intramolecular cyclizations of optically active allylsilanes bearing electrophilic functional groups on their α-alkyl side chains were examined. The allylsilanes having aldehyde and enone functional groups underwent the intramolecular cyclizations in the presence of Lewis acid catalysts to give 6- and 7-membered cycloalkenes with high stereoselectivity in good yields. Reactions of the allylsilanes having α-hydroxyalkyl chain with aldehydes provided 6- and 7-membered oxacycloalk-4-enes stereoselectively in good yields. Use of highly enantioenriched allylsilanes furnished enantioenriched cyclic alkenes with almost perfect chirality transfer from the allylsilanes.

Full text of DOI:10.1055/s-2001-14656

1042
LETTER
Asymmetric Synthesis of Cyclic Alkenes via Cyclization of Enantioenriched
Allylsilanes
Michinori Suginome,* Taisuke Iwanami, Akihiko Yamamoto, Yoshihiko Ito*
Department of Synthetic Chemistry and Biological Chemistry, Graduate School of Engineering, Kyoto University, Kyoto 606-8501, Japan
Fax +81(75)7535668; E-mail: suginome@sbchem.kyoto-u.ac.jp
Received February 23, 2001
silane cyclization has been so far limited, due to the lack
Abstract: Intramolecular cyclizations of optically active allylsi-
of convenient synthetic access to the functionalized allyl-
lanes bearing electrophilic functional groups on their -alkyl side
silanes.
chains were examined. The allylsilanes having aldehyde and enone
functional groups underwent the intramolecular cyclizations in the
Recently, we have developed new methodology for the
presence of Lewis acid catalysts to give 6- and 7-membered cy-
general synthesis of highly enantioenriched allylsilanes,
cloalkenes with high stereoselectivity in good yields. Reactions of
in which palladium-catalyzed intramolecular bis-silyla-
the allylsilanes having -hydroxyalkyl chain with aldehydes pro-
tion of optically active allylic alcohols is involved as a key
vided 6- and 7-membered oxacycloalk-4-enes stereoselectively in
step (Scheme 2).4 Of particular interest is that the synthe-
good yields. Use of highly enantioenriched allylsilanes furnished
sis of (E)-allylsilanes was accomplished with nearly per-
fect 1,3-chirality transfer from the allylic alcohols. With
the practically useful method in our hands, we have suc-
ceeded in the synthesis of enantioenriched allylsilanes
having hydroxyalkyl groups at the -allylic carbon atoms.
The allylsilanes underwent Lewis acid-catalyzed cycliza-
tion with carbonyl compounds, giving optically active cy-
clic compounds through -type cyclization with nearly
perfect chirality transfer.5 Herein, we describe -type cy-
clization of enantioenriched allylsilanes bearing electro-
philic functional groups, which provide cyclic alkenes
stereoselectively with efficient chirality transfer.
enantioenriched cyclic alkenes with almost perfect chirality transfer
from the allylsilanes.
Key words: allylations, chirality transfer, Lewis acids, silicon, ste-
reoselective synthesis
Allylsilanes have been widely utilized in organic synthe-
sis owing to the highly regio- and stereoselective C-C
bond formations in their reactions with carbon electro-
philes. Besides the intermolecular allylations with allylsi-
lanes, intramolecular cyclization of allylsilanes bearing
electrophilic functional groups has enabled efficient syn-
thesis of cyclic compounds, including cycloalkenes, alky-
lidenecycloalkanes, and alkenylcycloalkanes, depending
upon the functionalized starting allylsilanes (Scheme 1).1
R1
R2
SiR3
R1
R2
OH
Si-O
elimination
disilanylation
1) α-type (functionalized α-chain)
+E
Ph2
Si
E
Pd-catalyzed
bis-silylation
SiR3
α
Ph
2Si
O
SiR3
R2
SiR3
O
R2
2) β-type (functionalized β-chain)
R1
R1
+E
SiR3
E
β
Scheme 2 Synthesis of Enantioenriched Allylsilanes via Bis-
Silylation
3) γ-type (functionalized γ-chain)
E+
E
γ
An outline of the synthesis of -functionalized allylsi-
lanes is shown in Scheme 3. The allylic alcohols bearing
an -tetrahydropyranyloxy group were transformed to the
corresponding disilanyl ethers and subjected to the in-
tramolecular bis-silylation reaction in the presence of a
palladium-isonitrile catalyst. Subsequent treatment of the
crude reaction mixture with n-BuLi followed by deprotec-
tion of the THP group with pyridinium p-toluene sul-
fonate afforded allylsilanes bearing hydroxyalkyl
-chains. According to the procedure, enantioenriched al-
lylsilanes were prepared stereoselectively with >99%
SiR3
Scheme 1 Classification of Lewis Acid-Promoted Allylsilane
Cyclization
The use of enantioenriched allylsilanes in the intramolec-
ular cyclization has been potentially useful for the asym-
metric synthesis of cyclic compounds, since the allylative
cyclization may proceed with stereoselective 1,3-chirality
transfer.2,3 However, the asymmetric version of the allyl-
Synlett 2001, SI, 1042–1045 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Asymmetric Synthesis of Cyclic Alkenes via Cyclization of Enantioenriched Allylsilanes
1043
chirality transfer from the starting optically active allylic
alcohols. Allylsilanes bearing aldehyde and enone func-
tional groups on the -alkyl side chains were prepared
from the corresponding alcohol precursors via Swern ox-
idation and subsequent Horner-Emmons olefination.
Table 1 Stereoselective Synthesis of Cyclic Alkenes via Cycliza-
tion of Chiral Allylsilanesa
product
(%yield, cis:trans)
allylsilane
entry
acid
%ee
(enantiopurity)
O
HO
R
Me
Me
SiMe2Ph
2
1
OH
OTHP
OTHP
1
2
racemic
93.6%ee
TMSOTf
TiCl4
81%, 83:17
92%, 92:8
–
n
93.0%ee
e
Me
OH
S
a-d
HO
n
or
HO
O
Me
SiR3
n = 0-3
Me
SiMe2Ph
Me
Me
n
3
4
63%, <1:>99
trace
n = 1-3
O
3
4
TMSOTf
TiCl4
93.6%ee
racemic
94.8%ee
–
f
O
n
n
O
O
Me
SiR3
Me
SiR3
Me
Me
Me
SiMe2Ph
5
6
Scheme 3 Outline of the Synthesis of Chiral Allylsilanes Bearing
Functionalized -Chains
–
–
–
5
6
7
racemic
racemic
racemic
65%, 17:83
65%, 37:63
77%, 12:88
TMSOTf
TiCl4
AlCl3
O
O
Initially, we examined the Lewis acid-catalyzed intramo-
lecular cyclization of the aldehyde derivatives 1 and 3
(Table 1). Among the Lewis acids tested, trimethylsilyl
triflate (TMSOTf) was effective for both the cyclizations
to give the corresponding 2-methyl-3-cycloalken-1-ols 2
and 4 in moderate-to-good yield (entries 1 and 3).6 It is
noteworthy that the seven-membered ring formation took
place with almost complete trans-selectivity, whereas the
six-membered ring formation proceeded with moderate
cis-selectivity,7 which was improved to 92:8 by using
TiCl4 as Lewis acid under otherwise the same reaction
conditions (entry 2). Under the optimized reaction condi-
tions, enantioenriched (R)-allylsilanes 1 and 3 (both
93.6% ee) afforded the respective products (1R,2S)-2 and
(1S,2S)-4 with complete conservation of the enantiopurity
of the starting allylsilanes.10,11
Me
Me
Me
SiMe2Ph
8
7
8
9
10
racemic
racemic
racemic
–
–
–
TMSOTf
TiCl4
AlCl3
91%, 1:99
92%, <1:>99
68%, 5:95
a At 78 °C. For detailed reaction conditions, see
note 6.
bIsolated yield.
cDetermined by capillary GC.
dDetermined by chiral GC.
the high volatility of the silicon-containing by-products.
Thus, essentially pure 10 was obtained after extraction
and evaporation.
Intramolecular -type cyclization of enone allylsilanes 5
and 7 also proceeded in the presence of Lewis acids to
provide trans-3,4-disubstituted cycloalkenes 6 and 8 se-
lectively (entries 5-10). Although the six-membered ring
formation took place with moderate stereoselectivity up to
12:88 in the AlCl3-catalyzed reaction (entry 7), extremely
high stereoselectivity as well as high yield was attained in
the cyclization of 7 in the presence of TiCl4 or TMSOTf
(entries 8 and 9).12
+
HO
TMSOTf
R
O
+
RCHO
CH2Cl2
–78°C
Me
SiMe3
Me
SiMe3
9
(99.3%ee)
O
R
Me
Reaction of -hydroxyalkyl-substituted allylsilane 9 with
acetaldehyde was carried out in the presence of TMSOTf
at 78 °C (Scheme 4, Table 2, entry 1), affording trans-
3,4-disubstituted 5-oxacycloheptene 10a diastereoselec-
tively in good yield with perfect chirality transfer.13-15 An
-branched aliphatic aldehyde, an aromatic aldehyde, and
an , -unsaturated aldehyde also afforded the correspond-
ing oxacycloheptenes 10b-d with high enantiopurity in
high yields. It is noteworthy that the use of the trimethyl-
silyl derivative rather than higher alkyl-substituted silyl
derivatives made the isolation process simple because of
10
HO
R
O
Lewis acid
CH2Cl2
+
RCHO
Bu
SiMe3
Bu
11
12
(86.8-87.6%ee)
Scheme 4 Cyclization of Hydroxyalkyl-Substituted Allylsilanes
with Aldehydes
Synlett 2001, SI, 1042–1045 ISSN 0936-5214 © Thieme Stuttgart · New York

1044
M. Suginome et al.
LETTER
Table 2 TMSOTf-Promoted Reaction of (R)-9 (99.3% ee) with Al-
dehydes Giving 10.a
Table 3 Lewis Acid-Promoted Reaction of (S)-11 (86.8-87.6% ee)
with Aldehydes Giving 12.a
aAt 78 °C. For detailed reaction conditions, see note 13.
bIsolated yield unless otherwise noted.
cDetermined by capillary GC.
aAllylsilane (S)-11 of 86.8% ee (for entry 3) or 87.6%ee (for other
entries) was used. Reactions were conducted at 78 °C unless other-
wise noted. For detailed reaction conditions, see note 13.
bIsolated yield.
dDetermined by chiral capillary GC or HPLC.
eGC yield.
cDetermined by capillary GC.
d
78 °C–room temperature.
Then, reactions of the aldehydes with allylsilane 11 hav-
ing a shorter -chain were carried out under the same re-
action conditions as those for the seven-membered ring
formation (Scheme 4), providing trans-disubstituted ox-
acyclohexenes 12 in slightly lower yields and diastereose-
lectivities than the corresponding seven-membered ring
formation (Table 3). The lower yield may be due to the
minor formation of 1,3-pentadiene via acid-induced
Peterson-type elimination. On the other hand, non-
branched aliphatic aldehyde gave the cyclized product
with significantly lower ee (7% decrease) than that of the
starting allylsilane (entry 1). The decrease in ee may be at-
tributed to the minor syn-attack pathway, which has gen-
erally been considered unusual for the reaction of
allylsilanes.16 The involvement of the syn-attack pathway
has only recently been described by Panek et al. for the re-
lated oxacyclohexene formation using enantioenriched al-
References and Notes
(1) (a) Fleming, I.; Dunogues, J.; Smithers, R. Org. React. 1989,
37, 57. (b) Langkopf, E.; Schinzer, D. Chem. Rev. 1995, 95,
1375.
(2) For the stereochemical aspects in the reactions of
enantioenriched allylsilanes, see: (a) Hayashi, T.; Konishi,
M.; Kumada, M. J. Am. Chem. Soc. 1982, 104, 4963.
(b) Hayashi,T.; Konishi, M.; Kumada, M. J. Org. Chem. 1983,
48, 281.
(3) Examples of intramolecular cylization of enantioenriched
allylsilanes: (a) Mikami, K.; Maeda, T.; Kishi, Y.; Nakai, T.
Tetrahedron Lett. 1984, 25, 5151. (b) Denmark, S. E.;
Almsted, N. G. J. Org. Chem. 1997, 62, 9335. (c) Masse, C.
E.; Dakin, L. A.; Knight, B. S.; Panek, J. S. J. Org. Chem.
1997, 62, 9335. (d) Huang, H.; Panek, J. S. J. Am. Chem. Soc.
2000, 122, 9836.
(4) (a) Suginome, M.; Matsumoto, A.; Ito, Y. J. Am. Chem. Soc.
1996, 118, 3061. (b) Suginome, M.; Iwanami, T.; Matsumoto,
A.; Ito, Y. Tetrahedron: Asymmetry 1997, 8, 859.
(5) (a) Suginome, M.; Iwanami, T.; Ito, Y. J. Org. Chem. 1998,
63, 6096. (b) Suginome, M.; Iwanami, T.; Ito, Y. Chem.
Commun. 1999, 2357.
lylsilanes bearing hydroxyalkyl
-chain with an
additional stereogenic center.3d We found that the undes-
ired syn-attack pathway can be completely suppressed by
use of other Lewis acids such as TiCl2(OPr-i)2 and AlCl3.
Although the use of the former resulted in moderate yield,
the latter afforded 12a in good yield with perfect chirality
transfer. Since the highly stereoselective anti-attack path-
way was demonstrated by Hayashi and Kumada,2 the pos-
sibility of the syn-attack pathway has not been taken into
consideration or examined carefully in the reactions of
enantioenriched allylsilanes. Our results suggest that the
appropriate use of Lewis acid is highly important to real-
ize perfect chirality transfer in the reactions of enantioen-
riched allylsilanes.
(6) General procedure for the Lewis-acid promoted cyclization of
1, 3, 5, and 7. To a solution of the allylsilanes (0.21 mmol) in
CH2Cl2 (4 mL) was added Lewis acid (0.23 mmol) in CH2Cl2
at 78 °C. The mixture was stirred for 30 min at 78 °C.
Aqueous NaOH (1 M) was added at 78 °C, and the mixture
was warmed to room temperature with stirring. Extractive
workup with ether followed by silica gel column
chromatography afforded the corresponding products 2, 4, 6,
and 8. Spectral data for the products: (1R,2S)-2-
Acknowledgement
Methylcyclohex-3-en-1-ol (2, Registry number: [81452-74-
6]). 1H NMR 1.03 (d, J = 7.4 Hz, 3H), 1.37-1.45 (m, 1H),
1.49-2.28 (m, 4H), 2.28-2.29 (m, 4H), 2.29-2.48 (m, 1H),
3.87-3.99 (m, 1H), 5.38-5.51 (m, 1H), 5.58-5.71 (m, 1H).
(1S,2S)-2-Methylcyclohept-3-en-1-ol (4): 1H NMR 1.12 (d,
J = 6.9 Hz, 3H), 1.37-1.78 (m, 4H), 1.94-2.19 (m, 3H), 2.35-
2.50 (m, 1H), 3.30-3.42 (m, 1H), 5.36 (ddd, J = 11.4, 7.8, 2.1
Hz, 1H), 5.82 (dddd, J = 11.4, 6.9, 5.7, 2.1 Hz); 13C NMR
18.3, 23.8, 28.0, 39.2, 40.6, 73.6, 132.6, 134.1. HRMS calcd
for C8H14O (M+): 126.1045. Found: 126.1043. (3S*,4R*)-3-
This work was supported by Grant-in-Aids from Ministry of Educa-
tion, Culture, Sports, Science, and Technology, Japan. T. I. acknow-
ledges fellowship support of the Japan Society for the Promotion of
Science for Japanese Young Scientists.
Synlett 2001, SI, 1042–1045 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Asymmetric Synthesis of Cyclic Alkenes via Cyclization of Enantioenriched Allylsilanes
1045
Methyl-4-(2-oxopropyl)cyclohex-1-ene (6): 1H NMR 0.99
and Lewis acid (0.25 mmol) at 78 °C. The mixture was
stirred for 1 h at 78 °C. Aqueous NaOH (2 M) was added at
78 °C, and the mixture was warmed to room temperature
with stirring. Extractive workup with ether followed by silica
gel column chromatography afforded the corresponding
products 10 and 12. Spectral data for the representative
products: 2-Cyclohexyl-3-methyl-2,3,6,7-tertahydrooxepine
(10b): 1H NMR 0.97 (d, J = 7.2 Hz, 3H), 1.09-1.34 (m, 4H),
1.40-1.53 (m, 3H), 1.56-1.81 (m, 4H), 2.11-2.24 (m, 1H),
2.27-2.42 (m, 1H), 2.43-2.60 (m, 1H), 2.92 (d, J = 9.3 Hz,
1H), 3.39 (ddd, J = 3.3, 9.3, 12.0 Hz, 1H), 4.02 (dt, J = 12.0,
4.5 Hz, 1H), 5.41-5.51 (m, 1H), 5.59-5.72 (m, 1H); 13C NMR
18.4, 25.2, 26.5, 26.6, 26.7, 30.8, 31.5, 38.1, 40.0, 70.1, 88.8,
127.4, 137.8. HRMS calcd for C13H22O (M+): 194.1671.
Found: 194.1671. 2-Cyclohexyl-3-methyl-3,6-dihydro-2H-
pyran (12b): 1H NMR 0.90 (t, J = 7.2 Hz, 3H), 1.06-1.88 (m,
17H), 2.13-2.26 (m, 1H), 3.05 (dd, J = 7.5, 3.6 Hz, 1H), 3.96-
4.18 (m, 2H), 5.66-5.80 (m, 2H); 13C NMR 14.0, 23.0, 26.4,
26.48, 26.51, 26.7, 28.4, 30.7, 31.7, 35.0, 38.3, 64.7, 81.8,
125.7, 129.2. HRMS calcd for C15H26O (M+): 222.1982.
Found: 222.1984.
(t, J = 7.0 Hz, 2H), 1.27 (ddt, J = 13.0, 5.9, 8.8 Hz, 1H), 1.78-
1.90 (m, 3H), 1.93-2.06 (m, 2H), 2.15 (s, 3H), 2.27 (dd,
J = 16.3, 8.4 Hz, 1H), 2.60 (dd, J = 16.3, 4.6 Hz, 1H), 5.46
(dq, J = 9.9, 2.4 Hz, 1H), 5.60-5.66 (m, 1H); 13C NMR 20.2,
24.0, 26.7, 30.4, 35.2, 36.2, 48.3, 126.1, 132.4, 209.3. HRMS
calcd for C10H16O (M+): 152.1201. Found: 152.1199.
(3S*,4R*)-3-Methyl-4-(2-oxopropyl)cyclohept-1-ene (8): 1H
NMR 1.04 (d, J = 6.9 Hz, 3H), 1.38-1.65 (m, 3H), 1.77-1.93
(m, 1H), 1.95-2.15 (m, 3H), 2.12 (s, 3H), 2.16-2.30 (m, 1H),
2.34 (dd, J = 16.2, 7.8 Hz, 1H), 2.54 (dd, J = 16.2, 6.0 Hz,
1H), 5.49 (dd, J = 11.4, 6.0 Hz, 1H), 5.70 (dt, J = 11.4, 5.7 Hz,
1H); 13C NMR 19.4, 23.8, 28.3, 30.4, 33.1, 37.5, 37.8, 48.5,
130.5, 136.1, 209.4. HRMS calcd for C11H18O (M+):
166.1358. Found: 166.1359. Note: CDCl3 was used for all the
NMR measurements (300 MHz for 1H and 75 MHz for 13C).
(7) Panek et al. reported that the cyclization of 1 under essentially
the same reaction condition as ours afforded trans-2 with high
(>30:1) diastereoselectivity.3c In sharp contrast to their result,
we established the stereochemistry of our product 2 was cis in-
stead of trans by comparison of NMR data reported by
Danheiser et al.8 as well as determination of the absolute
configuration of R at 1-position according to the
(14) The same transformation was reported with the allylsilane
supported on the polymer resin. Suginome, M.; Iwanami, T.;
Ito, Y. J. Am. Chem. Soc. 2001, 123, 4356.
methoxymanderate method.9
(8) Danheiser, R. L.; Davila, C.-M.; Sard, H. Tetrahedron 1981,
37, 3943.
(9) Trost, B. M.; Belletire, J. L.; Godleski, S.; McDougal, P. G.;
Balkovec, J. M. J. Org. Chem. 1986, 51, 2370.
(10) The enantiomeric excesses of 2 and 4 were determined by
chiral GC analyses with a Chrompack Cyclodextrine- -
236M-19 capillary column.
(11) The TiCl4-catalyzed reaction of 3 afforded only a trace
amount of 4 along with two silicon-containing compounds
which have been unidentifiable so far (entry 4).
(15) The enantiomeric excesses of the products 10a, b, and d were
determined by chiral GC analyses with a Chrompack
Cyclodextrine- -236M-19 capillary column. The compounds
10c and 11a-c were subjected to hydroboration with 9-BBN
followed by H2O2 oxidation. The resultant cycloalkanols
bearing a hydroxy group at 5-position were isolated by HPLC
(silica gel) and transformed into the corresponding 3,5-
dinitrophenylcarbamates, which were subjected to chiral
HPLC analyses with Sumichiral OA-4500 columns.
(16) Buckle, M. J. C.; Fleming, I.; Gil, S. Tetrahedron Lett. 1992,
33, 4479.
(12) We have so far not been able to establish the GC or HPLC
conditions for the ee determination of 6 and 8.
(13) General procedure for the Lewis-acid promoted cyclization of
9 and 11 with aldehydes. To a solution of the allylsilanes (0.23
mmol) in CH2Cl2 (4 mL) were added aldehydes (0.26 mmol)
Article Identifier:
1437-2096,E;2001,0,SI,1042,1045,ftx,en;Y06501ST.pdf
Synlett 2001, SI, 1042–1045 ISSN 0936-5214 © Thieme Stuttgart · New York