Solid-phase synthesis and asymmetric reactions of polymer-supported highly enantioenriched allylsilanes [11]

Full text of DOI:10.1021/ja005865r

4356
J. Am. Chem. Soc. 2001, 123, 4356-4357
Scheme 1. Synthesis of Polymer-Supported Enantioenriched
Solid-Phase Synthesis and Asymmetric Reactions of
Polymer-Supported Highly Enantioenriched
Allylsilanes
Allylsilanesa
Michinori Suginome,* Taisuke Iwanami, and Yoshihiko Ito*
Department of Synthetic Chemistry and Biological Chemistry
Graduate School of Engineering
Kyoto UniVersity, Kyoto 606-8501, Japan
ReceiVed December 8, 2000
There is an increasing demand for polymer-supported reagents
(PSR) in organic synthesis which enable not only the efficient
synthesis of target molecules but also effective collection of a
number of derivatives for chemical libraries.1 Furthermore, chiral
technologies with development of enantio-directing PSR in
organic synthesis, which produces enantiopure molecules stereo-
selectively in reaction with achiral molecules, seems to be highly
attractive and useful.2 Enantioenriched chiral allylsilanes attached
onto the polymer may be one of the most promising and attractive
candidates for such enantio-directing PSR, since a high degree
of chirality transfer from the silicon-bound allylic carbon to the
newly created stereogenic centers in the products has been
established in the solution-phase reactions.3
Recently, Panek and Zhu successfully demonstrated asymmetric
allylation of electrophiles with a polymer-supported allylsilane,
in which the allylic moiety was attached to the polymer support
through an ω-hydroxy group.4 Remarkably high yields and
diastereoselectivities comparable to those for the corresponding
solution-phase reaction were achieved by this strategy. However,
the particular polymer-supported allylsilane may not have taken
full advantage of immobilization, since the attachment through
the hydroxy group may considerably limit the structural variation
of the allylsilanes, and the requirement of solution-phase prepara-
tion of the enantioenriched allylsilanes bearing the hydroxy group
for the attachment may detract from synthetic efficiency. With
these in mind, we planned the solid-phase synthesis of new
enantioenriched allylsilanes attached onto the resin through the
silicon atom.5 Herein, we report on the synthesis of new polymer-
supported enantioenriched allylsilanes, of which synthetic utility
is demonstrated by the new asymmetric cyclization reaction giving
highly enantioenriched oxacycloheptene derivatives.
a Reagents and conditions: (a) 1,3-dichloro-5,5-dimethylhydantoin,
CH2Cl2, room temperature, 5 h; (b) Ph2(Et2N)SiLi, THF, room temper-
ature, 10 h; (c) AcCl, THF, room temperature, 4 h; (d) 7a-c (1 equiv),
imidazole, CH2Cl2, room temperature, 10 h; (e) Pd(acac)2 (6 mol %),
1,1,3,3-tetramethylbutyl isocyanide, toluene, 110 °C, 6 h; (f) PhLi or
n-BuLi, THF, 0 °C, 1 h; (g) TsOH, EtOH/THF (1/2), 50 °C, 5 h.
an intermolecular process (IBS), in which stereoselectivity may
hardly be affected by immobilization of substrate onto the polymer
support.
To apply our IBS protocol, we needed to establish a preparative
method for polymer-bound disilane carrying a chlorine atom on
the silicon for the attachment of allylic alcohols. Commercially
available PS-bound (PS: polystyrene) hydrosilane 3 (1.6 mmol/
g) was chosen as a starting material, of which transformation to
chlorosilane 4 has been reported already (Scheme 1).7 Reaction
of 4 with (diethylamino)diphenylsilyllithium8 (3 equiv) was
carried out at room temperature for 10 h. The reaction mixture
was treated with acetyl chloride for conversion of the diethylamino
group in 5 into chloride (6). The disilane formation was estimated
to be quantitative by GC quantification of N,N-diethylacetamide
formed in the chlorination step. This PS-bound chlorodisilane 6
was reacted with highly enantioenriched allylic alcohols 7a-c
in the presence of imidazole as a base in dichloromethane.
A feasible synthetic plan for the synthesis of polymer-bound
enantioenriched allylsilanes is based on the transformations
involving stereoselective intramolecular bis-silylation (IBS) of
optically active allylic alcohols, of which the solution-phase
variant has been established by us (eq 1).6 This protocol may be
Fortunately, we found that only 1 equiv of optically active alcohol
was needed for attaining reasonable chemical yields of 2 (ca. 80%)
and that use of more equivalents did not improve the yield at all.
The resulting resins 2a-c were treated with a catalyst generated
from Pd(acac)2/1,1,3,3-tetramethylbutyl isocyanide at 110 °C in
toluene.
Subsequently, the reaction mixtures were treated with PhLi (for
2a) or n-BuLi (for 2b and 2c) at 0 °C in THF to give PS-bound
allylsilanes including 1a and 1b. For the preparation of 1c bearing
the ω-hydroxy group on the allylic moiety, the THP protection
was removed with a catalytic amount of p-toluenesulfonic acid
in EtOH/THF at 50 °C. It is worth mentioning that the optimized
condition using PPTS for the solution-phase deprotection of the
highly suitable for the application to the solid-phase synthesis
(R ) polymer support), since the stereo-determining step involves
(1) Reviews: (a) James, I. W Tetrahedron 1999, 55, 4855. (b) Guillier, F.
G.; Orain, D.; Bradley, M. Chem. ReV. 2000, 100, 2091.
(3) (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. (c) Review: Masse, C. E.; Panek, J. S. Chem. ReV. 1995, 95, 1293.
(4) Panek, J. S.; Zhu, B. J. Am. Chem. Soc. 1997, 119, 12022.
(5) For the synthesis and reactions of achiral allylsilanes attached onto the
resin at the silicon atom, see: Schuster, M.; Lucas, N.; Blechert, S. Chem.
Commun. 1997, 823.
(2) For polymer-supported chiral catalysts for asymmetric synthesis, see:
(a) Reger, T. S.; Janda, K. D. J. Am. Chem. Soc. 2000, 122, 6929. (b)
Kobayashi, S.; Kusakabe, K.; Ishitani, H. Org. Lett. 2000, 2, 1225. (c)
Kobayashi, S.; Endo, M.; Nagayama, S. J. Am. Chem. Soc. 1999, 121, 11229.
(d) Fan, Q.-h.; Ren, C.-y.; Yeung, C.-h.; Hu, W.-h.; Chan, A. S. C. J. Am.
Chem. Soc. 1999, 121, 7407. (e) Huang, W.-S.; Hu, Q.-S.; Pu, L. J. Org.
Chem. 1999, 64, 7940. (f) Nozaki, K.; Itoi, Y.; Shibahara, F.; Shirakawa, E.;
Ohta, T.; Takaya, H.; Hiyama, T. J. Am. Chem. Soc. 1998, 120, 4051. (g) Ha,
H.; Janda, K. D. J. Am. Chem. Soc. 1996, 118, 7632. (h) Kamahori, K.; Ito,
K.; Itsuno, S. J. Org. Chem. 1996, 61, 8321.
(6) Suginome, M.; Matsumoto, A.; Ito, Y. J. Am. Chem. Soc. 1996, 118,
3061.
(7) Hu, Y.; Porco, J. A., Jr.; Labadie, J. W.; Gooding, O. W.; Trost, B. M.
J. Org. Chem. 1998, 63, 4518.
(8) Tamao, K.; Kawachi, A.; Ito, Y. J. Am. Chem. Soc. 1992, 114, 3989.
10.1021/ja005865r CCC: $20.00 © 2001 American Chemical Society
Published on Web 04/12/2001

Communications to the Editor
J. Am. Chem. Soc., Vol. 123, No. 18, 2001 4357
Table 1. Allylation of Aldehydes with PS-Bound Enantioenriched
Allylsilanes 1a and 1ba
Table 2. Asymmetric Synthesis of Disubstituted Oxacycloheptenes
10 via Reactions of PS-Bound Enantioenriched Allylsilane 1c with
Aldehydes and Acetala
allylsilane
(R)
aldehyde
(R1CHO)
product
entry
electrophile
product (R) %yieldc trans:cisd %eee
entry
(% yield)c syn:antid % eee
1
2
3
4
5
n-HexCHO
n-HexCH(OEt)2 10a
MeCHO
c-HexCHO
PhCHO
10a (n-Hex)
64
67
92:8
93:7
91:9
91:9
92:8
97.9
97.9
1
2
3
4
1a (Ph)
1a
1a
MeCHO
n-HexCHO
i-PrCHO
8a (54)
8b (44)
8c (40)
8d (34)
96:4
93:7
97:3
99:1
98.6
99.0
93.0
95.6
10b (Me)
10c (c-Hex)
10d (Ph)
(70)
59
70
>97.2f
98.1
98.1
1b (n-Hex) i-PrCHO
a 1, aldehyde (2.0 (for 1a) or 1.0 equiv (for 1b)), and TiCl4 (2.0
equiv) were stirred at -78 °C for 0.5-2 h. b Enantiomeric excesses
determined for the starting allylic alcohols. c Isolated yield based on 2
(3 steps). d Determined by capillary GC (for entries 1, 3, and 4) or 1H
NMR (entry 2). e Determined by chiral HPLC.
a 1c, aldehyde (1.0 equiv), and TMSOTf (2.0 equiv) were stirred at
-78 °C for 2 h. b Enantiomeric excesses determined for the starting
allylic alcohols. c Isolated yield based on 2c (4 steps). GC yield in
parentheses. d Determined by capillary GC (for entries 1-4) or 1H NMR
(entry 5). e Determined by chiral GC or HPLC. f Incomplete separation
in the chiral GC analysis.
THP group only resulted in sluggish removal of the protection in
the solid-phase synthesis.
membered-ring formation proceeded with perfect chirality transfer.
Under the same reaction conditions, the resin-bound 1c afforded
10a in 64% yield based on the loaded alcohol 7c (Table 2, entry
1). In addition to the high degree of chirality transfer, the high
overall yield for the four steps was remarkable. The overall yield
was slightly better than that for the solution-phase synthesis, which
was calculated to be 60%. The corresponding diethyl acetal was
similarly used as electrophile to give 10a (entry 2). Application
of this resin 1c to the synthesis of some other oxacycloheptenes
was found to be fruitful. Thus, acetaldehyde, cyclohexanecar-
boxaldehyde, and benzaldehyde afforded the corresponding seven-
membered-ring ethers in good yields with a high degree of
chirality transfer (entries 3-5). It is worth mentioning that the
reactions of resin 1c with aldehydes proceeded so selectively that
essentially no byproducts derived from either the aldehydes or
the resin were contained in the crude products.11
In summary, we have demonstrated that resin-bound enan-
tioenriched allylsilanes, which serve as convenient enantio-
directing PSR in organic synthesis, are prepared on the solid phase
by the palladium-catalyzed intramolecular bis-silylation protocol.
The structurally well-defined allylsilanes on the polymer support
are ready not only for highly enantioselective reactions with
electrophiles, but also further transformation on the solid support
to more elaborated ones. Investigation along this line, as well as
optimization of the polymer support, is currently underway in
this laboratory
With these PS-bound allylsilanes 1a and 1b in our hands, we
examined some reactions with aldehydes under the typical reaction
conditions using TiCl4 at -78 °C (Table 1).9 Acetaldehyde
afforded the corresponding syn-homoallylic alcohol 8a with good
diastereoselectivity comparable to the corresponding solution-
phase reactions (entry 1). The chemical yield (54%) based on
the loaded allylic alcohol 7a on resin 2a indicated that each of
the three steps was accomplished in high yield (>80% in average).
More importantly, formation of allylsilanes possessing not only
high enentiopurity but also complete trans olefin geometry was
unambiguously evidenced by the nearly perfect chirality transfer
from the allylic alcohol. The resin 1a was also reacted with
heptanal and isobutyraldehyde under the same reaction conditions
(entries 2 and 3). Although the yield decreased with the increase
of the bulkiness of the aldehydes, a high level of diastereoselec-
tivity and chirality transfer has been attained in these reactions.
Resin-bound allylsilane 1b served similarly as an enantioselective
allylation reagent, giving the corresponding homoallyl alcohol
8d with good stereoselectivity (entry 4).
Next, we examined the reactions of ω-hydroxylated allylsilane
1c with aldehydes in the presence of TMSOTf.10 The correspond-
ing solution-phase reaction was tested prior to the resin-bound
counterpart (eq 2). Reaction of (R)-1c′ (99.3% ee) prepared from
Acknowledgment. This work was supported by a Grant-in-Aid for
Scientific Research from the Ministry of Education, Science, Sports, and
Culture, Japan. T.I. thanks fellowship support from the Japan Society of
Promotion of Science for Young Scientists.
(S)-7c with hexanal proceeded in the presence of TMSOTf at
-78 °C, giving trans-disubstituted oxacycloheptene 10a in high
yield. The observed high ee (99.2%) revealed that the seven-
Supporting Information Available: Experimental procedures, char-
acterization data for the new compounds, and 1H NMR charts of the crude
10 obtained in the reactions of (S)-1c with electrophiles (PDF). This
material is available free of charge via the Internet at http://pubs.acs.org.
(9) Hayashi, T.; Konishi, M.; Kumada, M. J. Am. Chem. Soc. 1982, 104,
4964.
(10) (a) Suginome, M.; Iwanami, T.; Ito, Y. J. Org. Chem. 1998, 63, 6097.
(b) Suginome, M.; Iwanami, T.; Ito, Y. Chem. Commun. 1999, 2537. (c)
Huang, H.; Panek, J. S. J. Am. Chem. Soc. 2000, 122, 9836.
JA005865R
1
(11) See H NMR charts in the Supporting Information.