Table 1. Importance of Silyl Group and Estera
Table 2. Aluminum-Based Lewis Acid Screeninga
a Reactions were run with 1.2 mmol of silyl enol ether and 1.0 mmol of
acrylate under a N2 atmosphere. b Isolated yield. c Determined by 1H NMR
of crude material.
a Reactions were run with 1.2 mmol of silyl enol ether and 1.0 mmol of
acrylate under a N2 atmosphere. b Isolated yield. c Determined by 1H NMR
of crude material. d Reaction run at room temperature.
hyde derived SEEs gave no [2 + 2] adducts, showing only
decomposition of the SEE (Table 1, entries 1 and 2).
To compensate for the instability of the cationic portion
in proposed intermediate A, an electron-donating substituent
that provides increased hyperconjugation was employed. Use
of the (dimethyl-trimethylsilyl)silyl-derived enol ether af-
forded the cyclobutane adduct in 7% yield (Table 1, entry
3). This represents the first example of a [2 + 2] condensa-
tion between an acetaldehyde silyl enol ether and an acrylic
ester. Realizing that the introduction of one trimethylsilyl
group was able to give the desired product, we next turned
our attention to the tris(trimethylsilyl)silyl (TTMSS) group,
which has three Si-Si bonds. It has been reported that the
group is of comparable steric size to tert-butyl5 and is among
the strongest electron donators to π systems, lone pair centers,
and molecular cations.6 Therefore, TTMSS should be an
excellent functional group for this reaction, and indeed
TTMSS-derived silyl enol ether gave the [2 + 2] adduct in
45% yield (Table 1, entry 4). The effect of the R group of
the ester was next investigated, and phenyl acrylate was
shown to give the best yield and diastereoselectivity (Table
1, entry 5). Encouraged by these results, various Lewis acids
were screened under identical reaction conditions as in Table
1; however, only the aluminum-based catalyst gave accept-
able results, while TiCl4, GaCl3, SnCl4, AgNTf2, TMSOTf,
and HNTf2 all gave <10% of the desired product. Previously,
we had observed that unwanted transfer of silyl groups during
attempted asymmetric aldol synthesis could be prevented by
using a bulky Lewis acid with the triflimide counteranion.7
Many aluminum-triflimide-based catalysts were examined,
and significant results are summarized in Table 2.
It was found that a catalyst loading of 3 mol % was
sufficient for good yields and a reasonable reaction time.
While Al(NTf2)3 gave better diastereoselectivity than EtAlCl2,
the reactivity was too high, giving lower yields of the desired
product, showing decomposition of the silyl enol ether (Table
2, entry 2). The use of EtAl(NTf2)2 and Et2AlNTf2 gave
similar diastereoselectivity, and the latter gave a comparable
yield with EtAlCl2, with a decrease in reaction time (Table
2, entries 3 and 4 vs 1). In an effort to further increase the
diastereoselectivity of the reaction, the use of bulky catalysts
based on the methylaluminum bis(2,6-diphenylphenoxide)
(MAPH)8 scaffold was investigated. While the previous use
of this catalyst was for the selective recognition of less
hindered aldehydes for the Mukaiyama aldol reaction,
implementation in this [2 + 2] reaction was imagined to
increase the yield by imposing a steric environment that could
concomitantly increase the diastereoselectivity during the
ring-closing (aldol) step. The best result was obtained with
bis(2,6-diphenylphenoxide) aluminum triflimide (BDAT)
(Table 2, entry 6), while bis(2,6-diphenylphenoxide) alumi-
num chloride was unable to give the cyclobutane adduct even
when warmed to room temperature (Table 2, entries 7 and
8).
To increase the scope and generality of the [2 + 2]
reaction,2c,d nucleophiles with substitution at the â-position
(aldehyde derived) as well as R-position (ketone derived)
were investigated. The reaction was found to proceed
smoothly in both cases at -40 °C with a 3 mol % catalyst
(5) Frey, J.; Schottland, E.; Rappoport, Z.; Bravo-Zhivotovskii, D.;
Nakash, M.; Botoshansky, M.; Kaftory, M.; Apeloig, Y. J. Chem. Soc.,
Perkin Trans. 2 1994, 2555.
(6) Bock, H.; Meuret, J.; Baur, R.; Ruppert, K. J. Organomet. Chem.
1993, 446, 113.
(7) Hiraiwa, Yukihiro, Ph.D. Thesis, Department of Chemistry, University
of Chicago, Chicago, IL, 2003.
(8) Marx, A.; Yamamoto, H. Angew. Chem., Int. Ed. 2000, 39, 178.
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