Diastereoselective Aldol Reactions of Enolates Generated from Vicinally Substituted Trimethylsilylmethyl Cyclopropyl Ketones

Article abstract of DOI:10.1021/ol035481g

(Equation presented) Vicinally substituted trimethylsilylmethyl cyclopropyl ketones undergo facile desilylative ring opening with Lewis acids under mild conditions. The enolates, thus generated, undergo aldol addition with aldehydes and ketones. The diast

Full text of DOI:10.1021/ol035481g

ORGANIC
LETTERS
2003
Vol. 5, No. 23
4281-4284
Diastereoselective Aldol Reactions of
Enolates Generated from Vicinally
Substituted Trimethylsilylmethyl
Cyclopropyl Ketones
Veejendra K. Yadav* and Rengarajan Balamurugan
Department of Chemistry, Indian Institute of Technology, Kanpur 208 016, India
Vijendra@iitk.ac.in
Received August 6, 2003
ABSTRACT
Vicinally substituted trimethylsilylmethyl cyclopropyl ketones undergo facile desilylative ring opening with Lewis acids under mild conditions.
The enolates, thus generated, undergo aldol addition with aldehydes and ketones. The diastereoselectivity of the reaction with aldehydes
depends on the nature of the Lewis acid used. The resulting aldol product is easily converted into a substituted tetrahydrofuran derivative.
The trimethylsilylmethyl function assists the ring-opening
of cyclopropane. This is due primarily to the â-effect of the
silicon atom.1 The ring-opening of substituted (cyclopropyl-
methyl)trimethylsilanes with a variety of electrophiles yields
substituted olefins with the extrusion of the silicon function.2
Cyclopropanes bearing trimethylsilylmethyl and an electron-
attracting group as vicinal substituents cause ring-opening
to take place under mild conditions either with reagents such
as CsF,3a BF3‚OEt2,3a BF3‚AcOH,3b,c and TBAF,3d or under
nucleophilic conditions.3e Surprisingly, however, sufficient
efforts were not made to trap the intermediate enolate to
make the reaction synthetically more meaningful. Only the
γ,δ-unsaturated carbonyl compounds were obtained from
these reactions. Attempts to trap the enolate formed from
the TBAF-induced ring-opening of methyl (2-trimethylsi-
lylmethyl)cyclopropylcarboxylate with MeI were unsuccess-
ful, as only methyl 4-pentenoate was isolated.3d
We planned to trap the intermediate enolate with electro-
philes by using a suitable ring-opening Lewis acid. From
our earlier exploration of the synthetic potential of cyclo-
propylmethylsilanes bearing bulky substituents on the sili-
con,4 we discovered TiCl4 to be an effective Lewis acid for
the ring-cleavage, and we used this in the synthesis of
substituted dihydrofurans.4a Since the aldol reaction is a
powerful tool for constructing carbon-carbon bonds in a
stereoselective manner and, moreover, new variants are being
developed currently,5 we wished to study the reactions of
the cyclopropane derivatives 1a-c6 with carbonyl com-
pounds under Lewis acid conditions. Related aldol-type
reactions of substituted cyclopropanes bearing stronger donor
substituents such as alkoxy and siloxy groups are known in
(1) (a) Sugawara, M.; Yoshida, J. Bull. Chem. Soc. Jpn. 2000, 73, 1253.
(b) Sugawara, M.; Yoshida, J. J. Org. Chem. 2000, 65, 3135 and references
cited therein. For reviews, see: (c) Lambert, J. B.; Zhao, Y.; Emblide, R.
W.; Salvador, L. A.; Liu, X.; So, J.-H.; Chelius, E. C. Acc. Chem. Res.
1999, 32, 183. (d) Lambert, J. B. Tetrahedron 1990, 46, 2677.
(2) (a) Landais, Y.; Rapado, L. P-. Tetrahedron Lett. 1996, 37, 1209.
(b) Ryu, I.; Hirai, A.; Suzuki, H.; Sonada, N.; Murai, S. J. Org. Chem.
1990, 55, 1409. (c) Ryu, I.; Suzuki, H.; Murai, S.; Sonada, N. Organome-
tallics 1987, 6, 212. (d) Dubois, M. G.; Dunogues, J. J. Organomet. Chem.
1986, 309, 35. (e) Dubois, M. G.; Calas, R. Can. J. Chem. 1981, 59, 802.
(f) Chan, T. H.; Fleming, I. Synthesis 1979, 761. (g) Dubois, M. G.;
Dunogues, J.; Calas, R. J. Chem. Res., Synop. 1979, 6. (h) Dubois, M. G.;
Pillot, J.-P.; Dunogues, J.; Calas, R. J. Organomet. Chem. 1977, 124, 135.
(3) (a) Hirao, T.; Misu, D.; Agawa, T. J. Chem. Soc., Chem. Commun.
1986, 26. (b) Ochiai, M.; Sumi, K.; Fujita, E. Chem. Lett. 1982, 79. (c)
Ochiai, M.; Sumi, K.; Fujita, E. Chem. Pharm. Bull. 1983, 31, 3931. (d)
Reichelt, I.; Reissig, H.-U. Liebigs Ann. Chem. 1984, 828. (e) Ochiai, M.;
Sumi, K.; Fujita, E. Tetrahedron Lett. 1982, 23, 5419. For exhaustive
reviews on the utilities of donor-acceptor-substituted cyclopropanes, see:
(f) Reissig, H.-U.; Zimmer, R.Chem. ReV. 2003, 103, 1151. (g) Reissig,
H.-U. Top. Curr. Chem. 1988, 144, 73.
(4) (a) Yadav, V. K.; Balamurugan, R. Org. Lett. 2001, 3, 2717. (b)
Yadav, V. K.; Balamurugan, R. Chem. Commun. 2002, 514.
10.1021/ol035481g CCC: $25.00 © 2003 American Chemical Society
Published on Web 10/11/2003

the literature.7 The aldol products formed from these reactions
serve as useful intermediates for the synthesis of substituted
tetrahydrofurans, γ-lactones, and γ-lactams. We present our
results herein and comment upon the stereochemical aspects.
Our investigation began with the phenyl ketone 1a (Table
1). 1a underwent smooth ring-opening at -78 °C with TiCl4
with different aliphatic, aromatic, and heteroaromatic alde-
hydes. The syn:anti ratios were generally g4:1 and as high
as 12:1 when trans-cinnamaldehyde (entry 5) was used.8
When the syn and anti isomers of 1a were reacted separately
with benzaldehyde under the above conditions, 5:1 and 4.7:1
syn:anti selectivity was observed, respectively. This dem-
onstrated that the geometry of the starting cyclopropane
derivative was not important in the overall diastereodeter-
mination. The reactions were sluggish with ketones at -78
°C and required warming to 25 °C to obtain the products in
decent yields.9 The reaction with ferrocene carboxaldehyde
was also slow at -78 °C. A 2.6:1 mixture of the trans and
cis isomers of the R,â-unsaturated ketone derived from
dehydration of the primary aldol product was formed on
warming the reaction mixture to 25 °C. More than 2-fold
increase in the syn selectivity was noticed when the tert-
butyl ketone 1b was employed as the nucleophilic partner.
The enhancement in the syn selectivity indicates the involve-
ment of the (Z)-enolate10 that results in the syn aldol.
To demonstrate the usefulness of the present protocol, we
examined the reactions of 1c as well. The enolate generated
from 1c is equivalent to the enolate formed from the
regioselective deprotonation of n-butyl homoallyl ketone, a
reaction that is generally difficult to achieve. The yields of
the aldol products were good with 1c as well. However, the
syn selectivity with butyraldehyde had diminished consider-
ably in comparison to those from 1a and 1b. This is not
surprising because the steric interactions of the n-butyl group
in the enolate and the n-propyl group in butyraldehyde will
not be significant in the transition state leading to the anti
product. The γ,δ-unsaturated ketones 5a-c were also isolated
in 10-15% and ∼35% yields from the above reactions with
aldehydes and ketones, respectively.
Table 1. Aldol Reactions of 1a-c with Aldehydes and
Ketones
The stereochemical outcome of the aldol reaction of a
Lewis acid enolate has been documented to be different from
that of the Lewis acid-mediated reaction of a silyl enol
ether.11 Our system, being typical of a Lewis acid enolate,
gave us an opportunity to examine the effect of different
Lewis acids on the reaction diastereoselectivity (Table 2).
a Isolated overall yield. b Diastereomeric ratio was estimated from the
1H integrals of the isomeric mixture. c Product was a 2.6:1 mixture of trans-
and cis-isomers of the R,â-unsaturated ketones formed from dehydration
of the primary aldol products. d Reactions required warming to room
temperature.
to give a deep red solution in anhydrous CH2Cl2. The aldol
products were formed in good yields on treatment of the
above titanium enolate with different aldehydes. Good syn
diastereoselectivity was maintained throughout in the adducts
Table 2. Effect of Lewis Acids on Reaction
Diastereoselectiona
entry
silane
Lewis acid
aldehyde
3:4 (%)
1
2
3
4
5
6
1a
1a
1b
1b
1a
1a
BF3‚OEt2
BF3‚OEt2
BF3‚OEt2
BF3‚OEt2
SnCl4
n-PrCHO
PhCHO
n-PrCHO
PhCHO
PhCHO
PhCHO
1.3:1 (44)
1:2.5 (52)
2.2:1 (32)
1:1.7 (34)
2.0:1 (40)
1.2:1 (94)
(5) (a) Palomo, C.; Oiarbide, M.; Garc´ıa, J. M. Chem. Eur. J. 2002, 8,
36. (b) Machajewski, T. D.; Wong, C.-H. Angew. Chem., Int. Ed. 2000,
39, 1352. (c) Mahrwald, R. Chem. ReV. 1999, 99, 1095. (d) Saito, S.;
Yamamoto, H. Chem. Eur. J. 1999, 5, 1959. (e) Nelson, S. G. Tetrahe-
dron: Asymmetry 1998, 357. (f) Gro¨ger, H.; Vogl, E. M.; Shibasaki, M.
Chem. Eur. J. 1998, 4, 1137.
Et2AlCl
(6) Cyclopropane derivatives 1a-c were prepared conveniently in good
yield by a rhodium-catalyzed carbene insertion reaction of the corresponding
diazo-compound with allyltrimethylsilane. 1a, 1b, and 1c were, respectively,
2.2:1, 1.5:1, and 1.7:1 mixtures of the anti and syn isomers and were used
as such for reactions.
a All reactions were carried out at -30 °C for 3 h, and all yields and
diastereomeric ratios are based on the isolated materials.
(7) (a) Sugita, Y.; Kawai, K.; Yokoe, I. Heterocycles 2001, 55, 1475.
(b) Shimada, S.; Hashimoto, Y.; Saigo, K. J. Org. Chem. 1993, 58, 5226.
(c) Shimada, S.; Hashimoto, Y.; Sudo, A.; Hasegawa, M.; Saigo, K. J. Org.
Chem. 1992, 57, 7126. (d) Saigo, K.; Shimada, S.; Hasegawa, M. Chem.
Lett. 1990, 905. (e) Reissig, H.-U.; Holzinger, H.; Glomsda, G. Tetrahedron
1989, 45, 3139.
For this, we chose BF3‚OEt2 since the syn selectivity was
expected to be enhanced due to a tighter transition state. To
our great surprise, there was a considerable erosion in the
syn selectivity of 1a with butyraldehyde (syn:anti ) 1.3:1,
4282
Org. Lett., Vol. 5, No. 23, 2003

entry 1). Even more surprisingly, the selectivity reversed
(syn/anti ) 1:2.5, entry 2) in reaction with benzaldehyde. A
similar trend was observed when the tert-butyl ketone 1b
was used (entries 3 and 4). The reactions involving BF3‚
OEt2 were carried out at -30 °C since the enolate formation
from the cyclopropane derivative was very slow at -78 °C.
The yields were generally low, and good amounts (35-45%)
of the corresponding γ,δ-unsaturated ketones 5a/5b were
obtained.
and (E)-enolates was estimated to be 2.1:1. The signal
assignments for the Ti-enolates were used to determine the
Z/E ratios of the other metal enolates. The Z/E ratios of the
different metal enolates after 0.5 and 4 h of mixing are given
in Table 3. These experiments reveal an equilibration of the
1
Table 3. Results of H NMR Study of Different Metal
Enolates of 1a at 25 °C
To understand the above discrepancies, we carried out
SnCl4- and Et2AlCl-assisted reactions of 1a with benzalde-
hyde (entries 5 and 6, Table 2) where reversal in selectivity
was observed with BF3‚OEt2. Poor syn selectivity was noted
with SnCl4 (2:1), which improved to 5.2:1 when the reaction
was warmed to 25 °C with a decrease in the yield.
Examination of aliquots drawn at -30 and 25 °C and at 3
and 5 h from reaching 25 °C by 1H NMR revealed
enhancement in syn selectivity. Further, a similar examina-
tion of the aliquots drawn at -30 and 25 °C of the TiCl4-
assisted reaction showed hardly any change in selectivity.
The yield, however, was somewhat reduced. These experi-
ments suggest a possible retro-aldol in the SnCl4-assisted
reaction upon being warmed to 25 °C. Even though the
selectivity observed with Et2AlCl was only marginally syn
(1.2:1), the yield of the reaction was excellent.12
Further, to understand the origin of the syn/anti diaste-
reoselectivity,13 the titanium enolate derived from 1a was
treated separately with Me3SiCl and (EtO)2P(O)Cl, 1.5 equiv
each, at -78 °C to discern the geometry of the enolate. Both
the attempts, however, were unsuccessful, as only 1-phe-
nylpent-4-en-1-one was obtained. Hence, 1H NMR study of
the different metal enolates derived from 1a was carried out
at 25 °C in CD2Cl2. The geometries of the Ti-enolates were
discerned from NOE experiments, and the ratio of the (Z)-
Lewis acid time (h) enolate ratio (Z:E) product ratio (syn:anti)
TiCl4
0.5
4.0
0.5
4.0
0.5
4.0
0.5
4.0
2.1:1
1.9:1
1:4.3
1:1.7
1:1
1:1.3
1:1.5
1:1.5
2.6:1
1.2:1
>1:10
1.5:1
BF3‚OEt2
Et2AlCl
SnCl4
enolates at 25 °C except for the tin-enolate. The boron enolate
existed predominantly in the (E)-form. After 4 h, the metal
enolates were treated with benzaldehyde for 1 h in the NMR
tube itself and the syn:anti ratios of the aldol products were
estimated from 1H NMR. The following observations could
be made from the above experiments: (a) the syn:anti ratios
are less at 25 °C compared to those at the lower temperatures
with TiCl4 and SnCl4, (b) the preferred anti selectivity (syn:
anti ) 1:2.5) observed at -30 °C is changed in favor of the
syn selectivity (syn:anti ) 1.2:1) at 25 °C with BF3‚OEt2,
and (c) with Et2AlCl, interestingly, the selectivity changed
from slightly syn (syn:anti ) 1.2:1) to largely anti (syn:anti
> 1:10) at 25 °C.
A closed chair transition state appears to be the most
probable transition structure to explain the syn selectivity
of the Ti-enolates (Scheme 1). Both BF3‚OEt2 and SnCl4
(8) Syn and anti relationships in the aldol products were assigned on
the basis of 1H chemical shifts of the hydrogen on the carbinol carbon. The
hydrogen resonated 0.06-0.12 ppm downfield in the syn isomer compared
to the hydrogen in the corresponding anti isomer. Furthermore, this hydrogen
appeared as a triplet (J ) 1.7-6.3 Hz) and a doublet (J ) 4.6-5.8 Hz) or
a broad singlet, respectively, in the anti and syn aldol products obtained
from arylaldehydes. For references related to the syn and anti assignments,
see: (a) Ohtsuka, Y.; Koyasu, K.; Ikeno, T.; Yamada, T. Org. Lett. 2001,
3, 2543. (b) Denmark, S. E.; Wong, K.-T.; Stavenger, R. A. J. Am. Chem.
Soc. 1997, 119, 2333. (c) Hasegawa, E.; Ishiyama, K.; Kato, T.; Horaguchi,
T.; Shimizu, T.; Tanaka, S.; Yamashita, Y. J. Org. Chem. 1992, 57, 5352.
(d) Noyori, R.; Nishida, I.; Sakata, J. J. Am. Chem. Soc. 1981, 103, 2106.
(e) House, H. O.; Crumrine, D. S.; Teranishi, A. Y.; Olmstead, H. D. J.
Am. Chem. Soc. 1973, 95, 3310.
Scheme 1
(9) Mukaiyama, T.; Banno, K.; Narasaka, K. J. Am. Chem. Soc. 1974,
96, 7603.
(10) Heathcock, C. H.; Buse, C. T.; Kleschick, W. A.; Pirrung, M. C.;
Sohn, J. E.; Lampe, J. J. Org. Chem. 1980, 45, 1066.
(11) (a) Yamago, S.; Machii, D.; Nakamura, E. J. Org. Chem. 1991, 56,
2098. (b) Kuwajima, I.; Nakamura, E. Acc. Chem. Res. 1985, 18, 181. (c)
Mukaiyama, T.; Iwasawa, N.; Stevens, R. W.; Haga, T. Tetrahedron 1984,
40, 1281. (d) Mukaiyama, T.; Stevens, R. W.; Iwasawa, N. Chem. Lett.
1982, 353. (e) Yamamoto, Y.; Maruyama, K. Tetrahedron Lett. 1980, 21,
4607.
(12) Only marginal syn selectivity has been reported with similar
aluminium enolates; see: Maruoka, K.; Hashimoto, S.; Kitagawa, Y.;
Yamamoto, H.; Nozaki, H. J. Am. Chem. Soc. 1977, 99, 7705.
(13) For transition state models, see: (a) Zimmerman, H. E.; Traxler,
M. D. J. Am. Chem. Soc. 1957, 79, 1920. (b) Dubois, J. E.; Fellmann, P.
Tetrahedron Lett. 1975, 1225. (c) Fellmann, P.; Dubois, J. E. Tetrahedron
1978, 34, 1349. (d) Evans, D. A.; Nelson, J. V.; Taber, T. R. Topics in
Stereochemistry; Eliel, E. L., Wiley, S. H., Eds.; Wiley-Interscience: New
York, 1982; Vol. 13, p 1. (e) Also see ref 10.
show syn selectivity, although their enolates are more of the
(E)-configuration. This could be because of the difference
in the reactivities of the (Z)- and (E)-enolates; the (Z)-enolate
reacts faster than the (E)-enolate. The preferred anti selectivi-
ties of the boron enolates of 1a and 1b with benzaldehyde
at -30 °C may be because of a combination of the higher
Org. Lett., Vol. 5, No. 23, 2003
4283

concentration of the (E)-enolates and the better reactivity of
benzaldehyde. The reversal in selectivity with Et2AlCl at
room temperature may be due to the involvement of a
boatlike transition state13d that explains the (Z)-enolate switch
from the syn to the anti selectivity. However, more designed
experiments are needed to ascertain the transition structures
of the aldol reactions with BF3‚OEt2, Et2AlCl, and SnCl4.
To demonstrate the synthetic utility of the present protocol,
we have treated selected aldol products with m-CPBA
following a literature protocol14 to obtain the substituted
tetrahydrofuranylmethanol derivatives.15 The results are
collected in Table 4. The yields were excellent from the
ketone-derived aldol adducts. The stereorelationships of the
substituents in the products were discerned from a series of
NOE experiments for selected compounds and extended to
others by comparing the spectral data.
In summary, we have shown that the enolate generated
from the Lewis acid-assisted ring-opening of the vicinally
substituted trimethylsilylmethyl cyclopropyl ketones could
be effectively trapped with aldehydes and ketones. The aldol
additions of Ti-enolates are syn selective and proceed
possibly through a closed cyclic transition state. Importantly,
the aldol products are convenient precursors to the prepara-
tion of substituted tetrahydrofuranylmethanol derivatives. The
transition state structures of the present aldol reactions with
different Lewis acids and double stereodifferentiation are
interesting features to investigate in detail in the future.
Table 4. Conversion of Selected Aldol Products into
Tetrahydrofuranylmethanol Derivatives
Acknowledgment. The authors thank DST, Government
of India, for financial assistance and UGC, Government of
India, for a Senior Research Fellowship to R.B.
Supporting Information Available: Experimental pro-
cedures and spectroscopic data of all the products. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL035481G
(14) Panek, J. S.; Garbaccio, R. M.; Jain, N. F. Tetrahedron Lett. 1994,
35, 6453.
(15) For alternative syntheses of similar substituted tetrahydrofuranyl-
methanol derivatives, see: (a) Hopkins, M. H.; Overman, L. E. J. Am. Chem.
Soc. 1987, 109, 4748. (b) Hopkins, M. H.; Overman, L. E.; Rishton, G. M.
J. Am. Chem. Soc. 1991, 113, 5354.
a Diastereomeric ratio was estimated from the 1H integrals of the isomeric
mixture.
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