C O M M U N I C A T I O N S
Table 2. Evidence for Dual Activation: Reactivity of a Silyl Ketene
Acetal toward Several Potential Acetylating Agents
Institutes of Health (National Institute of General Medical Sciences,
R01-GM57034) and Novartis.
Supporting Information Available: Experimental procedures and
compound characterization data (PDF and CIF). This material is
entry
acetylating agent
Ac2O
t1/2 for reaction
References
1
2
3
4
<2% conversion (60 h)
0.3 h
<2% conversion (60 h)
<0.1 h
(1) For leading references, see: (a) Carriera, E. M. In ComprehensiVe
Asymmetric Catalysis; Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.;
Springer: New York, 1999; Chapter 29.1. (b) Machajewski, T. D.; Wong,
C.-H. Angew. Chem., Int. Ed. 2000, 39, 1352-1374.
Ac2O; 5% (-)-4
(+)-9
Ac2O; 5% [Me4N]OAc
(2) The effective use of chiral auxiliaries to achieve asymmetric acylations
of enolates has been described. For pioneering work, see: (a) Evans, D.
A.; Ennis, M. D.; Le, T.; Mandel, N.; Mandel, G. J. Am. Chem. Soc.
1984, 106, 1154-1156. (b) Ito, Y.; Katsuki, T.; Yamaguchi, M.
Tetrahedron Lett. 1984, 25, 6015-6016.
(3) (a) Fleming, I.; Iqbal, J.; Krebs, E.-P. Tetrahedron 1983, 39, 841-846
and references therein. (b) Le Roux, C.; Mandrou, S.; Dubac, J. J. Org.
Chem. 1996, 61, 3885-3887.
(4) For example, see: Olofson, R. A.; Cuomo, J. Tetrahedron Lett. 1980,
21, 819-822.
(5) (a) For an overview, see: Fu, G. C. Acc. Chem. Res. 2000, 33, 412-420.
(b) For more recent reports, see: Arai, S.; Bellemin-Laponnaz, S.; Fu, G.
C. Angew. Chem., Int. Ed. 2001, 40, 234-236. Hodous, B. L.; Fu, G. C.
J. Am. Chem. Soc. 2002, 124, 1578-1579.
(6) The synthesis of related â-ketoesters has been achieved by: (a) catalytic
asymmetric alkylation: Trost, B. M.; Radinov, R.; Grenzer, E. M. J. Am.
Chem. Soc. 1997, 119, 7879-7880. (b) catalytic asymmetric Michael
reaction: Hamashima, Y.; Hotta, D.; Sodeoka, M. J. Am. Chem. Soc. 2002,
124, 11240-11241.
(7) For an enantioselective rearrangement reaction catalyzed by 2, see: Ruble,
J. C.; Fu, G. C. J. Am. Chem. Soc. 1998, 120, 11532-11533.
(8) For overviews of the chemistry of DMAP, see: (a) Scriven, E. F. V. Chem.
Soc. ReV. 1983, 12, 129-161. (b) Hassner, A.; Krepski, L. R.; Alexanian,
V. Tetrahedron 1978, 34, 2069-2076. (c) Ho¨fle, G.; Steglich, W.;
Vorbru¨ggen, H. Angew. Chem., Int. Ed. Engl. 1978, 17, 569-583.
(9) For an example of another reaction that is initiated by complexation of
acetate to a SiMe3 group, see: Trost, B. M.; Chan, D. M. T. J. Am. Chem.
Soc. 1979, 101, 6432-6433.
(10) For a recent review of catalytic asymmetric methods that generate
quaternary stereocenters, see: Corey, E. J.; Guzman-Perez, A. Angew.
Chem., Int. Ed. 1998, 37, 388-401. See also: Christoffers, J.; Mann, A.
Angew. Chem., Int. Ed. 2001, 40, 4591-4597.
We have begun to pursue experiments designed to test the
mechanistic hypothesis outlined in Figure 1. Thus, we have
examined the reactivity of a silyl ketene acetal toward the various
acetylating systems illustrated in Table 2.14 In the absence of a
catalyst, treatment of the silyl ketene acetal with acetic anhydride
results in no detectable reaction after 60 h at room temperature
(entry 1). In contrast, the addition of 5% of catalyst 4 leads to very
rapid acetylation (t1/2 ) 0.3 h; entry 2). Activation of the electrophile
(Ac2O f acylpyridinium) is not sufficient for achieving efficient
acylation - the silyl ketene acetal does not react with salt 9 at
room temperature (entry 3). On the other hand, Me4N[OAc] is an
effective (non-enantioselective) catalyst for the reaction (entry 4).
Taken together, the data provided in Table 2 indicate that it is the
combination of the acylpyridinium ion and the acetate ion that is
responsible for the dramatic rate acceleration and high enantiose-
lectivity that we observe in the presence of catalyst 4.15
(11) Gem-dimethyl substitution is present for ease of synthesis (double
deprotonation of an arylacetic acid, followed by trapping with isobutylene
oxide). As shown in Table 1, these groups are not necessary for high
enantioselectivity.
(12) (a) DMAP derivative 4 also catalyzes the C-acylation of silyl ketene acetals
by reagents such as acid chlorides, albeit in lower enantiomeric excess.
(b) Use of isobutyric, rather than acetic, anhydride as the acylating agent
for the silyl ketene acetal illustrated in Table 1, entry 1, provides the
desired product in 83% ee, but the reaction is quite slow. (c) The
enantioselectivity is not very sensitive to temperature. (d) We observe
none of the product derived from O-acylation of the silyl ketene acetal.
(e) Currently, silyl ketene acetals in which the aryl group is replaced with
an alkyl or alkenyl substituent are not suitable substrates (low conversion).
In conclusion, we have developed a new process - a nucleophile-
catalyzed intermolecular C-acylation of silyl ketene acetals by
anhydrides. Through mechanistic studies, we have provided support
for the hypothesis that the reaction involves activation of both the
anhydride (formation of an acylpyridinium ion) and the silyl ketene
acetal (generation of an enolate). Furthermore, we have demon-
strated that a catalytic asymmetric variant of this new transformation
can be achieved, furnishing a new carbon-carbon bond and a
quaternary stereocenter with very good enantioselection. Additional
synthetic and mechanistic studies are underway.
(13) We have established through 1H NMR studies that the minor isomer of 8
is more reactive than the major isomer.
(14) Because these reactions were monitored by 1H NMR, CD2Cl2, rather than
a mixture of d10-Et2O/CD2Cl2, was employed. In CD2Cl2, the intermo-
lecular C-acylation that is illustrated in Table 2 proceeds in 87% ee
(vs 90% ee in Et2O/CH2Cl2).
(15) Consistent with the hypothesis that a silicon-free enolate is a key reactive
intermediate in these catalytic asymmetric acylations, the sense and level
of enantioselectivity is independent of the silyl group of the silyl ketene
acetal (e.g., SiMe3, SiMe2Ph, and Si(i-Pr)3).
Acknowledgment. We thank Ivory D. Hills for assistance with
X-ray crystallography. Support has been provided by the National
JA028554K
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J. AM. CHEM. SOC. VOL. 125, NO. 14, 2003 4051