Catalytic enantioselective construction of all-carbon quaternary stereocenters: Synthetic and mechanistic studies of the C-acylation of silyl ketene acetals

Article abstract of DOI:10.1021/ja043832w

With the aid of an appropriate chiral catalyst, acyclic silyl ketene acetals react with anhydrides to furnish 1,3-dicarbonyl compounds that bear all-carbon quaternary stereocenters in good ee and yield. Mechanistic studies provide strong support for a catalytic cycle that involves activation of both the electrophile (anhydride → acylpyridinium) and the nucleophile (silyl ketene acetal → enolate).

Full text of DOI:10.1021/ja043832w

Published on Web 03/12/2005
Catalytic Enantioselective Construction of All-Carbon
Quaternary Stereocenters: Synthetic and Mechanistic Studies
of the C-Acylation of Silyl Ketene Acetals
Ara H. Mermerian and Gregory C. Fu*
Contribution from the Department of Chemistry, Massachusetts Institute of Technology,
Cambridge, Massachusetts 02139
Received October 10, 2004; E-mail: gcf@mit.edu
Abstract: With the aid of an appropriate chiral catalyst, acyclic silyl ketene acetals react with anhydrides
to furnish 1,3-dicarbonyl compounds that bear all-carbon quaternary stereocenters in good ee and yield.
Mechanistic studies provide strong support for a catalytic cycle that involves activation of both the electrophile
(anhydride f acylpyridinium) and the nucleophile (silyl ketene acetal f enolate).
number of groups.4 In contrast, to the best of our knowledge,
prior to our initial work in this area3a there had been no reports
Introduction
Within the area of asymmetric synthesis, the enantioselective
construction of all-carbon quaternary stereocenters (C*R1R2R3R4)
is a particularly difficult challenge.1 One obstacle is low
reactivity, due to steric congestion, which discourages the
targeted carbon-carbon bond formation from occurring. Of
course, even if this reactivity problem can be overcome, there
is yet another formidable barrier to success: high enantio-
selectivity requires that, in the transition state for the formation
of a new C-R4 bond, the three groups (R1, R2, and R3) already
attached to the central carbon must be very effectively distin-
guished.2
An even more daunting challenge is the development of
catalytic processes that generate highly enantioenriched all-
carbon quaternary stereocenters. As Overman summarized in a
recent review, few chiral catalysts have yet been able to
accomplish this difficult objective.1b In this report we establish
that a chiral nucleophilic catalyst can efficiently achieve the
asymmetric acylation of acyclic silyl ketene acetals to produce
all-carbon quaternary stereocenters (eq 1). Furthermore, we
describe mechanistic studies that elucidate the pathway and
origin of stereoselection for this process.3
of corresponding processes wherein an acyl compound such as
a halide or an anhydride had been employed as the electrophile.5
Attempts to employ nucleophiles to catalyze the acylation
of silylated enolates have nearly always resulted in the formation
of the O-acylated product (eq 2).6 Nevertheless, we decided to
explore the potential of planar-chiral DMAP and PPY deriva-
tives (e.g., 1; DMAP ) 4-(dimethylamino)pyridine; PPY )
4-(pyrrolidino)pyridine)7 as catalysts for enolate C-acylation.
This decision was motivated in part by our realization that, even
if the O-acylated compound is formed initially, complex 1 might
catalyze subsequent migration of the acyl group from oxygen
to carbon, thereby furnishing the target 1,3-dicarbonyl com-
pound.8
Results and Discussion
Catalytic asymmetric reactions of enolate derivatives with
aldehydes have been very extensively investigated by a large
We therefore initiated an investigation of the utility of chiral
DMAP and PPY derivatives as catalysts for the enantioselective
C-acylation of silyl ketene acetals with anhydrides.3a,9 The
(1) For very recent reviews with leading references, see: (a) Denissova, I.;
Barriault, L. Tetrahedron 2003, 59, 10105-10146. (b) Douglas, C. J.;
Overman, L. E. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 5363-5367.
(2) Clearly, not all processes fall within this analysis (e.g., asymmetric
cyclopropanations of olefins).
(3) (a) For a preliminary communication, see: Mermerian, A. H.; Fu, G. C. J.
Am. Chem. Soc. 2003, 125, 4050-4051. (b) For a study of the catalytic
asymmetric acylation of silyl ketene imines, see: Mermerian, A. H.; Fu,
G. C. Angew. Chem., Int. Ed. 2005, 44, 949-952.
(4) For reviews of catalytic asymmetric aldol reactions, see: (a) Carreira, 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.
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10.1021/ja043832w CCC: $30.25 © 2005 American Chemical Society

C-Acylation of Silyl Ketene Acetals
A R T I C L E S
Table 1. Catalytic Asymmetric C-Acylations of Acyclic Silyl Ketene
Acetals: Effect of the R Group of the Ester on Enantioselectivitya
entry
R
isomer ratio
% ee
% yield
1
2
3
4
Me
CH2CMe3
i-Pr
1.5/1
1.1/1
1.8/1
1.5/1
70
79
85
93
87
75
92
47
i-Bu
a All data are the average of two runs.
interest. Consequently, we decided to investigate the enantio-
selective acylation of silyl ketene acetals derived from acyclic
esters.
There is a lack of general methods for producing geo-
metrically pure silyl ketene acetals from R,R-disubstituted esters,
and we were initially pessimistic about the prospects of obtaining
highly enantioenriched 1,3-dicarbonyl compounds from C-
acylations of E/Z mixtures of silyl ketene acetals. Thus, as
illustrated in eq 4, whereas silyl ketene acetal 5a might be
predicted, in analogy with the results outlined in eq 3, to furnish
1,3-dicarbonyl 6 with good enantioselectivity, the stereochemical
outcome of the acylation of 5b was more uncertain.
Figure 1. Possible Pathway for the Catalytic Asymmetric C-Acylation
of Silyl Ketene Acetals: Dual Activation of the Nucleophile and the
Electrophile.
mechanism that we envisioned for this process, which generates
an all-carbon quaternary stereocenter (4), is outlined in Figure
1.10 Of course, in order for this C-acylation to be highly
enantioselective, the ester enolate must react with much greater
facility with its chiral acylpyridinium counterion (see 3) than
with the much more abundant achiral anhydride.
For our initial study3a we chose to focus on acylations of
silyl ketene acetals that are derived from lactones, since this
avoids potential complications arising from the use of an E/Z
isomeric mixture of a silyl ketene acetal. For the (admittedly
limited) range of substrates depicted in eq 3, we were able to
provide proof-of-principle for our approachscomplex 1 not only
catalyzes the C-acylation of these silyl ketene acetals but does
so with good enantioselectivity. In addition, our preliminary
mechanistic work was consistent with the pathway outlined in
Figure 1.
Fortunately, we determined that isomeric mixtures of acyclic
silyl ketene acetals do in fact undergo C-acylation to afford 1,3-
dicarbonyl compounds with good enantioselectivity in the
presence of catalyst 1 and Ac2O (Table 1).11 In contrast to silyl
ketene acetals that are derived from lactones, for silyl ketene
acetals that are generated from acyclic esters, the R group of
the ester represents a parameter that can be varied in order to
enhance enantioselectivity (Table 1). We established that the
choice of R does indeed have a significant impact on stereo-
selection; specifically, as R becomes larger, the ee increases
(entries 1-4). Unfortunately, in the case of the very bulky tert-
At this stage we were pleased that we had accomplished our
objective of effecting catalytic asymmetric C-acylations of silyl
ketene acetals to generate all-carbon quaternary stereocenters.
On the other hand, we were not satisfied with the scope of the
process since (five-membered) lactone-derived silyl ketene
acetals comprise only a very small subset of the substrates of
(9) For examples of other methods for the catalytic asymmetric synthesis of
â-ketoesters that contain an all-carbon quaternary stereocenter in the R
position, see: (a) Nemoto, T.; Matsumoto, T.; Masuda, T.; Hitomi, T.;
Hatano, K.; Hamada, Y. J. Am. Chem. Soc. 2004, 126, 3690-3691. (b)
Ooi, T.; Miki, T.; Taniguchi, M.; Shiraishi, M.; Takeuchi, M.; Maruoka,
K. Angew. Chem., Int. Ed. 2003, 42, 3796-3798. (c) Hamashima, Y.; Hotta,
D.; Sodeoka, M. J. Am. Chem. Soc. 2002, 124, 11240-11241. (d) Yang,
D.; Gu, S.; Yan, Y.-L.; Zhu, N.-Y.; Cheung, K.-K. J. Am. Chem. Soc. 2001,
123, 8612-8613. (e) Trost, B. M.; Radinov, R.; Grenzer, E. M. J. Am.
Chem. Soc. 1997, 119, 7879-7880.
(10) For a recent review of catalytic asymmetric processes that exploit dual
activation of the electrophile and the nucleophile, see: Ma, J.-A.; Cahard,
D. Angew. Chem., Int. Ed. 2004, 43, 4566-4583.
(11) (a) One preliminary example of an asymmetric C-acylation of an acyclic
ketene acetal was described in our initial report (20% catalyst loading; ref
3a). (b) The ee of the product does not erode upon exposure to the catalyst
for an extended period of time, which establishes that C-acylation is
irreversible. (c) Silyl ketene acetals in which the aryl group is replaced
with an alkyl substituent are not suitable substrates, presumably due to a
reluctance to participate in acetate-induced desilylation to form an ester
enolate (vide infra).
(5) The effective use of covalently bound chiral auxiliaries to achieve the
asymmetric acylation of enolates has been described. For pioneering studies,
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.
(6) At the outset of our investigation, we were aware of only one example of
a nucleophile-catalyzed C-acylation: the TBAF-catalyzed C-acylation of
silyl enol ethers with acyl cyanides. See: Wiles, C.; Watts, P.; Haswell, S.
J.; Pombo-Villar, E. Tetrahedron Lett. 2002, 43, 2945-2948.
(7) For an overview and leading references, see: Fu, G. C. Acc. Chem. Res.
2004, 37, 542-547.
(8) For examples of O-to-C rearrangements catalyzed by such complexes,
see: (a) Hills, I. D.; Fu, G. C. Angew. Chem., Int. Ed. 2003, 42, 3921-
3924. (b) Ruble, J. C.; Fu, G. C. J. Am. Chem. Soc. 1998, 120, 11532-
11533.
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A R T I C L E S
Mermerian and Fu
Table 2. Catalytic Asymmetric C-Acylations of Acyclic Silyl Ketene
Acetals: Scope with Respect to the Alkyl Substituenta
viability of the mechanism postulated in Figure 1. The first step
in this proposed catalytic cycle, the reaction of a pyridine
derivative with an anhydride to generate an acylpyridinium salt,
is well precedented in transformations such as the DMAP-
catalyzed acylation of alcohols.14
entry
R
isomer ratio
% ee
% yield
1
2
3
4
Me
Et
i-Bu
i-Pr
1.8/1
1.8/1
3.3/1
1.7/1
69
85
85
97
54
92
82
45
In the second step of the suggested catalytic cycle (Figure 1)
a carboxylate anion desilylates a silyl ketene acetal to produce
an ester enolate.15 Although we do not expect this elementary
step to be thermodynamically favorable, we anticipate that it
may be kinetically accessible. Relevant to this suggestion, we
observed that the C-acylation of silyl ketene acetals by
anhydrides is catalyzed by [Me4N]OAc (eq 6).3a Since it is less
clear how [Me4N]OAc might activate Ac2O, we believe that
the rate acceleration is likely due to activation of the silyl ketene
acetal through the generation of either an enolate (see ion pair
3 in Figure 1) or a hypervalent silicate (7).16,17
a All data are the average of two runs.
Table 3. Catalytic Asymmetric C-Acylations of Acyclic Silyl Ketene
Acetals: Scope with Respect to the Aryl Substituenta
a All data are the average of two runs. b The TBS-substituted silyl ketene
acetal was employed. c CH2Cl2 was employed as the solvent.
butyl group, high enantioselectivity is achieved at the price of
lower yield (entry 4; a high yield can be achieved by using
20% catalyst or a longer reaction time). Taking into consider-
ation both ee and reactivity, we chose to employ isopropyl-
substituted silyl ketene acetals for our subsequent investigations.
In our initial studies of the scope of this catalytic asymmetric
C-acylation of acyclic silyl ketene acetals we varied the bulk
of the alkyl substituent on the olefin. As illustrated in Table 2,
an array of E/Z mixtures of silyl ketene acetals react to generate
all-carbon quaternary stereocenters in good to excellent ee. An
increase in the steric demand of the alkyl group leads to higher
enantioselectivity.
With regard to distinguishing between these two possibilities,
we observed that the enantioselectivity for C-acylations cata-
lyzed by PPY derivative 1 is essentially independent of the
choice of the SiR3 group of the silyl ketene acetal (eq 7). This
observation is more readily accommodated by a mechanism that
involves a free enolate rather than a hypervalent silicate as an
intermediate.
We also examined the scope of these catalytic asymmetric
C-acylations with respect to the aromatic substituent on the
olefin (Table 3).12 For electron-rich (entries 2 and 3), electron-
poor (entry 4), and heteroaryl (entry 5) groups, PPY derivative
1 furnishes the desired quaternary stereocenter in good ee.
Significantly, a conformationally constrained indane-derived
silyl ketene acetal is also a suitable substrate (entry 6).
Furthermore, this nucleophile-catalyzed C-acylation process is
not limited to aryl-substituted compoundssan alkenyl-substi-
tuted silyl ketene acetal can also be acylated regioselectively,
albeit in modest ee (eq 5).13 The catalyst may generally be
recovered in high (>90%) yield at the end of these reactions.
In addition to the synthetically oriented studies described
above, we pursued investigations directed at determining the
With respect to the final step in the postulated catalytic cycle,
we generated the key intermediates (acylpyridinium and enolate)
independently and allowed them to react (eq 8). Acylation on
carbon does indeed occur, and the ee of the product is very
similar to the catalytic asymmetric process.18 It is worth noting
that the acylpyridinium salt depicted in eq 8 does not react with
(14) For leading references to the chemistry of DMAP, see: Spivey, A. C.;
Arseniyadis, S. Angew. Chem., Int. Ed. 2004, 43, 5436-5441.
(15) The presence of an R-aryl substituent facilitates this process, since the aryl
group allows delocalization of the enolate anion.
(16) For a closely related process, see: Pfaltz, A.; Lautens, M. In ComprehensiVe
Asymmetric Catalysis; Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.;
Springer: New York, 1999; pp 858-859.
(12) The presence of a bulky aryl group (e.g., 1-naphthyl) leads to significant
(sometimes exclusive) O-acylation, presumably due to steric hindrance to
acylation at carbon.
(13) We have not pursued a separate optimization of the ee for this family of
substrates.
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C-Acylation of Silyl Ketene Acetals
A R T I C L E S
a silyl ketene acetal at room temperature, establishing that
activation of the electrophile alone is not sufficient to achieve
effective C-acylation. Thus, all of the mechanistic data that we
accumulated are consistent with the dual-activation pathway
illustrated in Figure 1.19
silyl ketene acetals. As illustrated in eq 10, treatment of two
separate isomeric mixtures of silyl ketene acetals with [Me4N]-
OAc does not lead to equilibration. Thus, it is likely that the
high ee’s that are obtained in C-acylations of acyclic silyl ketene
acetals catalyzed by 1 are due to stereoselective reactions of
both enolate isomers, presumably through an open transition
state in which the relative position of the O- vs the OR is
inconsequential (eq 9).21
C-Acylations of E/Z mixtures of acyclic silyl ketene acetals
proceed in high ee and yield (e.g., Tables 1-3), which
establishes that both isomers of the substrate are transformed
into the same enantiomer of the product with good selectivity.
Two of the scenarios by which this could occur are: (1) enolates
8a and 8b each undergo C-acylation with a strong preference
for generating the same enantiomer of the product or (2) enolates
8a and 8b interconvert under the reaction conditions20 and the
product arises primarily from the enantioselective acylation of
the more reactive enolate.
Finally, we established that the minor isomer of the silyl
ketene acetal is more reactive than the major isomer and that
the ee of the product is essentially constant throughout the course
of the reaction, suggesting that the two enolates are reacting
with virtually identical enantioselectivity.
Conclusions
With the aid of a chiral catalyst an array of E/Z isomeric
mixtures of acyclic silyl ketene acetals react with an anhydride
to generate all-carbon quaternary stereocenters in good ee and
yield. Mechanistic studies provide strong support for a catalytic
cycle that involves activation of both the electrophile (anhydride
f acylpyridinium) and the nucleophile (silyl ketene acetal f
enolate).
To distinguish between these two possibilities, we investigated
whether a carboxylate anion can induce the interconversion of
Acknowledgment. Support has been provided by the National
Institutes of Health (National Institute of General Medical
Sciences: R01-GM57034; National Cancer Institute: training
grant CA009112), Merck, and Novartis. Funding for the MIT
Department of Chemistry Instrumentation Facility has been
furnished in part by NSF CHE-9808061 and NSF DBI-9729592.
(17) For early studies of fluoride-catalyzed aldol reactions of silyl enol ethers,
see: (a) Noyori, R.; Yokoyama, K.; Sakata, J.; Kuwajima, I.; Nakamura,
E.; Shimizu, M. J. Am. Chem. Soc. 1977, 99, 1265-1267. (b) Nakamura,
E.; Shimizu, M.; Kuwajima, I.; Sakata, J.; Yokoyama, K.; Noyori, R. J.
Org. Chem. 1983, 48, 932-945. (c) Nakamura, E.; Yamago, S.; Machii,
D.; Kuwajima, I. Tetrahedron Lett. 1988, 29, 2207-2210. (d) Yamago,
S.; Machii, D.; Nakamura, E. J. Org. Chem. 1991, 56, 2098-2106. (e)
Denmark, S. E.; Lee, W. J. Org. Chem. 1994, 59, 707-709.
Supporting Information Available: Experimental procedures
and compound characterization data. This material is available
free of charge via the Internet at http://pubs.acs.org.
(18) A control experiment has established that the presence of [Me4N]SbF6 does
not affect the enantioselectivity of C-acylations of silyl ketene acetals
catalyzed by 1.
(19) A 1H NMR study has shown that the resting state of the catalyst during
the catalytic cycle is the unacylated species (i.e., structure 1).
(20) The aromatic substituent is expected to lower the barrier to interconversion,
relative to an enolate that bears only alkyl groups.
JA043832W
(21) For a discussion of open transition states in the context of Mukaiyama
aldol reactions, see ref 4a.
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