The chemistry of trichlorosilyl enolates. Aldol addition reactions of methyl ketones

Article abstract of DOI:10.1021/ja001023g

Investigations on the aldol addition chemistry of trichlorosilyl enolates derived from methyl ketones are presented in full. These trichlorosilyl enolates are competent aldol reagents in the absence of additives, reacting with aldehydes at ambient temperature to provide high yields of aldol adducts. When either enol or aldehyde partner bears a stereogenic center, low diastereoselectivity is observed in this uncatalyzed aldol process. The aldol additions are dramatically accelerated by the addition of catalytic quantities of chiral phosphoramides, particularly one derived from N,N'-dimethylstilbene-1,2-diamine. In this catalyzed mode, good to high enantioselectivities are obtained with a variety of achiral trichlorosilyl enolates and aldehydes. When either partner bears a stereogenic center, high diastereoselectivities are obtained with one enantiomer of the catalyst (matched case), while the other enantiomer provides low diastereoselectivity (mismatched case). The reaction scope, optimization of conditions, and stereoselection events are also discussed.

Full text of DOI:10.1021/ja001023g

J. Am. Chem. Soc. 2000, 122, 8837-8847
8837
The Chemistry of Trichlorosilyl Enolates. Aldol Addition Reactions
of Methyl Ketones
Scott E. Denmark* and Robert A. Stavenger
Contribution from the Roger Adams Laboratory, Department of Chemistry, UniVersity of Illinois,
Urbana, Illinois 61801
ReceiVed March 22, 2000
Abstract: Investigations on the aldol addition chemistry of trichlorosilyl enolates derived from methyl ketones
are presented in full. These trichlorosilyl enolates are competent aldol reagents in the absence of additives,
reacting with aldehydes at ambient temperature to provide high yields of aldol adducts. When either enol or
aldehyde partner bears a stereogenic center, low diastereoselectivity is observed in this uncatalyzed aldol process.
The aldol additions are dramatically accelerated by the addition of catalytic quantities of chiral phosphoramides,
particularly one derived from N,N′-dimethylstilbene-1,2-diamine. In this catalyzed mode, good to high
enantioselectivities are obtained with a variety of achiral trichlorosilyl enolates and aldehydes. When either
partner bears a stereogenic center, high diastereoselectivities are obtained with one enantiomer of the catalyst
(matched case), while the other enantiomer provides low diastereoselectivity (mismatched case). The reaction
scope, optimization of conditions, and stereoselection events are also discussed.
Introduction
acyclic) ketones has recently appeared.4 Contemporaneously, a
relatively clear mechanistic view is emerging from studies of
the trichlorosilyl enolate derived from cyclohexanone.5
In recent years we have been engaged in a broadly based
program to explore the synthetic potential and mechanistic
underpinnings of asymmetric catalysis with chiral Lewis bases.1
The centerpiece of this program has involved the invention of
a new class of aldol reactions based on novel silicon reagents
(enoxytrichlorosilanes) which undergo spontaneous addition to
aldehydes at or below ambient temperature. More importantly,
the action of these reagents has been shown to be highly
responsive to catalysis by (chiral) phosphoramides.2,3 The
preparative aspects of both catalyzed and uncatalyzed reactions
of trichlorosilyl enolates derived from R-substituted (cyclic and
A significant component of our mission in developing this
new type of aldol process is to establish its scope with the
ultimate objective of creating a general synthetic method. This
mandates the investigation of the reactivity of a broad range of
trichlorosilyl enolates and aldehyde partners. Some of the more
useful members of the aldol reagent family are enolates derived
from methyl ketones. The utility of reagents capable of
delivering an RC(O)CH2 unit enantioselectively is self-evident,
yet such transformations have traditionally been among the most
challenging to accomplish.3i,6 While the reasons for the difficulty
are still in debate, one consensus view is the greater accessibility
of competing, diastereomeric transition structures resulting from
the reduced steric demand of the nucleophile. In view of our
discovery that the catalyzed reactions of trichlorosilyl enolates
derived from cyclic ketones proceed through closed, six-
membered transition structures and that the arrangement of
reactants is strongly influenced by the structure of the phos-
phoramide catalyst, we were encouraged to pursue this recal-
citrant class of aldol components. This report details our full
investigations of the trichlorosilyl enolates derived from achiral
and chiral methyl ketones, in both uncatalyzed and catalyzed
reaction with chiral and achiral aldehyde acceptors.7
(1) (a) Denmark, S. E.; Stavenger, R. A. Acc. Chem. Res. 2000, 33, 432-
440. (b) Denmark, S. E.; Stavenger, R. A. Angew. Chem., Int. Ed.
Manuscript in preparation.
(2) (a) Denmark, S. E.; Winter, S. B. D.; Su, X.; Wong, K.-T. J. Am.
Chem. Soc. 1996, 118, 7404-7405. (b) Denmark, S. E.; Winter, S. B. D.
Synlett 1997, 1087-1090. (c) Denmark, S. E.; Wong, K.-T.; Stavenger, R.
A. J. Am. Chem. Soc. 1997, 119, 2333-2334. (d) Denmark, S. E.; Stavenger,
R. A.; Wong, K.-T. Tetrahedron 1998, 54, 10389-10402. (e) Denmark, S.
E.; Stavenger, R. A.; Su, X.; Wong, K.-T.; Nishigaichi, Y. Pure Appl. Chem.
1998, 70, 1469-1476.
(3) For recent reviews on catalytic asymmetric aldol additions see: (a)
Nelson, S. G. Tetrahedron: Asymmetry 1998, 9, 357-389. (b) Gro¨ger, H.;
Vogl, E. M.; Shibasaki, M. Chem. Eur. J. 1998, 4, 1137-1141. (c) Carreira,
E. M. In ComprehensiVe Asymmetric Catalysis; Jacobsen, E. N., Pfaltz,
A., Yamamoto, H., Eds.; Springer-Verlag: Heidelberg, 1999; Vol. III,
Chapter 29.1 (d) Braun, M. In StereoselectiVe Synthesis, Methods of Organic
Chemistry (Houben-Weyl), E21 ed.; Helmchen, G., Hoffman, R., Mulzer,
J., Schaumann, E., Eds.; Thieme: Stuttgart, 1996; Vol. 3, pp 1730-1736.
For recent developments not covered in those reviews, see: (e) Yanagisawa,
A.; Matsumoto, Y.; Nakashima, H.; Asakawa, H.; Yamamoto, H. J. Am.
Chem. Soc. 1997, 119, 9319-9320. (f) Kru¨ger, J.; Carreira, E. J. Am. Chem.
Soc. 1998, 120, 837-838. (g) Evans, D. A.; Kozlowski, M.; Murry, J.;
Burgey, C.; Campos, K.; Connel, B.; Staples, T. J. Am. Chem. Soc. 1999,
121, 669-685. (h) Evans, D. A.; Burgey, C.; Kozlowski, M.; Tregay, S. J.
Am. Chem. Soc. 1999, 121, 686-699. For a review of aldol chemistry of
R-unsubstituted enolates, see: (i) Braun, M. Angew. Chem., Int. Ed. Engl.
1987, 26, 24-37.
(6) For examples of other catalytic asymmetric aldol additions of methyl
ketones, see: (a) Corey, E. J.; Cywin, C. L.; Roper, T. D. Tetrahedron
Lett. 1992, 33, 6907-6910. (b) Ishihara, K.; Maruyama, T.; Mouri, M.;
Gao, Q.; Furuta, K.; Yamamoto, H. Bull. Chem. Soc. Jpn. 1993, 66, 3483-
3491. (c) Mikami, K.; Matsukawa, S. J. Am. Chem. Soc. 1993, 115, 7039-
7040. (d) Carreira, E. M.; Lee, W.; Singer, R. A. J. Am. Chem. Soc. 1995,
117, 3649-3650. (e) Sodeoka, M.; Tokunoh, R.; Miyazaki, F.; Hagiwara,
E.; Shibasaki, M. Synlett 1997, 463-466. (f) Ando, A.; Miura, T.;
Tatematsu, T.; Shioiri, T. Tetrahedron Lett. 1993, 34, 1507-1510. (g)
Yamada, Y. M. A.; Yoshikawa, N.; Sasai, H.; Shibasaki, M. Angew. Chem.,
Int. Ed. Engl. 1997, 36, 1871-1873.
(4) Denmark, S. E.; Stavenger, R. A.; Wong, K.-T.; Su, X. J. Am. Chem.
Soc. 1999, 121, 4982-4991.
(5) (a) Denmark, S. E.; Su, X.; Nishigaichi, Y. J. Am. Chem. Soc. 1998,
120, 12990-12991. (b) Denmark, S. E.; Pham, S. M. HelV. Chim. Acta
2000, 83, 1846-1853.
(7) Portions of this work have been communicated: (a) Denmark, S. E.;
Stavenger, R. A.; Wong, K.-T. J. Org. Chem. 1998, 63, 918-919. (b)
Denmark, S. E.; Stavenger, R. A. J. Org. Chem. 1998, 63, 9524-9527.
10.1021/ja001023g CCC: $19.00 © 2000 American Chemical Society
Published on Web 09/02/2000

8838 J. Am. Chem. Soc., Vol. 122, No. 37, 2000
Denmark and StaVenger
Results
analytically pure compounds. The adduct (()-19 derived from
methyl vinyl ketone polymerized upon purification. The insta-
bility of this product precluded the further use of enolate 8 for
subsequent studies.
A. Synthesis of Enolates. The preparation of several classes
of trichlorosilyl enolates has been described in detail.8 The
methyl ketone enolates used in this study are shown in Chart
1. All of the enoxytrichlorosilanes (except for 1 which was
prepared by the method of Benkeser8b) were prepared via the
corresponding trimethylsilyl enol ethers by use of the mercury-
(II)-catalyzed trans-silylation reaction (with SiCl4) developed
in these laboratories.7a,8a It should be noted that although these
species are hydrolytically sensitive, they are otherwise stable
and can be stored for many weeks under an inert atmosphere
without noticeable degradation (as determined by spectroscopic
analysis and chemical reactivity).
To examine the scope of the reaction with respect to the
aldehyde component, a representative enolate, 2, was then
combined with a variety of acceptors (Chart 2). A marked effect
of the aldehyde structure on the rate of the addition was noted
(Table 2) in that aliphatic and hindered aldehydes were less
reactive. In the extreme, almost no reaction took place with
trimethylacetaldehyde (i) and after a period of days only the
Claisen-Schmidt product was isolated. With the knowledge that
these additions could be accelerated by Lewis bases, the reaction
was repeated using 10 mol % of HMPA as catalyst, Table 2,
entry 7. Now the reaction with i proceeded rapidly (1 h) and
the aldol adduct (()-26 could be isolated in good yield.
Chart 1
Chart 2
Table 2. Uncatalyzed Aldol Additions of 2a
Table 1. Uncatalyzed Aldol Additions of Trichlorosilyl Enolates to
Benzaldehydea
entry
RCHO
time, h
product
yield,b %
1
2
3
4
5
6
7c
b
c
d
e
g
h
i
7
14
4
4
12
9
(()-20
(()-21
(()-22
(()-23
(()-24
(()-25
(()-26
91
92
92
91
84
93
86
entry
enolate
time, h
product
yield,b %
1
2
3
4
5
6
7
1
2
3
4
6
7
8
4
4
4
5
4
6
6
(()-12
(()-13
(()-14
(()-15
(()-17
(()-18
(()-19
92
95
94
93
91
93
97c
1
a Reactions performed at 0.5 M. b Analytically pure material. c 10
mol % HMPA added.
Although these reactions were found to be sluggish at room
temperature, it was nonetheless imperative to determine the
extent of uncatalyzed reaction that took place under standard
conditions for the catalyzed process. This would provide crucial
information for the optimization of the enantioselective, cata-
lyzed reaction by minimizing the competitive (achiral) pathway.
Accordingly, enolate 2 was allowed to react with biphenyl
carboxaldehyde (e) at -78 °C for 2 h (standard conditions for
the catalyzed reactions, vide infra), Scheme 1. After isolation
and purification, the aldol adduct (()-23 was isolated in 4%
yield, along with a 95% recovery of the starting aldehyde. Thus,
the background reaction is of little concern in this system.
2. Catalyzed Reactions. 2.1. Reaction Optimization. Having
established that the methyl ketone trichlorosilyl enolates were
viable aldolization reagents in uncatalyzed reactions, we turned
a Reactions performed at 0.5 M. b Analytically pure material.
c Chromatographically homogeneous material, decomposed after initial
purification.
B. Reactions of Achiral Enolates and Achiral Aldehydes.
1. Uncatalyzed Reactions. Initial experiments were carried out
to determine the inherent reactivity of these trichlorosilyl
enolates with respect to aldehydes. The results, summarized in
Table 1, clearly show that the trichlorosilyl enolates 1-8 all
reacted rapidly with benzaldehyde at ambient temperature in
CH2Cl2 solution. Standard aqueous workup and purification
provided the racemic â-hydroxy ketones in excellent yields as
(8) (a) Denmark, S. E.; Stavenger, R. A.; Winter, S. B. D.; Wong, K.-
T.; Barsanti, P. A. J. Org. Chem. 1998, 63, 9517-9523. (b) Benkeser, R.
A.; Smith, W. E. J. Am. Chem. Soc. 1968, 90, 5307-5309.

The Chemistry of Trichlorosilyl Enolates
J. Am. Chem. Soc., Vol. 122, No. 37, 2000 8839
Scheme 1
affording both the highest yield and er of all solvents tested.
Moving to either more polar or less polar solvent dramatically
decreased the enantioselectivity of the process. However, the
use of propionitrile did provide the aldol adduct in good, albeit
reduced, enantioselectivity relative to CH2Cl2. The rate of the
reaction (as judged by isolated yield of the aldol adduct) was
also attenuated in Et2O, THF, and toluene, while the use of
trichloroethylene and propionitrile still provided good yields of
purified aldol adducts.
our attention to additions under the influence of chiral catalysts.
On the basis of our previous experience with other trichlorosilyl
enolates we surveyed a collection of phosphoramide-based
catalysts (Chart 3),9 in the aldol addition of the acetone-derived
trichlorosilyl enolate 1 to benzaldehyde under the standard con-
ditions (10 mol % phosphoramide, 0.1 M in CH2Cl2, -78 °C),
Table 3. We were pleased to observe that these reactions were
highly susceptible to catalysis by the chiral Lewis bases. The
results in Table 3 clearly show that the stilbenediamine-derived
phosphoramide (S,S)-27 was both the most selective catalyst
and the most effective in promoting the reaction.10
Table 4. Solvent Effects in Addition of Enolate 1 Catalyzed by
(S,S)-27a
entry
solvent
CH2Cl2
trichloroethylene
Et2O
toluene
THF
erb
yield,c %
1
2
3
4
12.5/1
4.03/1
2.25/1
1.85/1
3.37/1
1/8.71
92
88
37
48
59
88
Chart 3
5
6d
CH3CH2CN
a Reactions performed at 0.1 M/2 h. b Ratio of the S/R isomer;
determined by CSP HPLC analysis of the dinitrophenyl carbamates.
c Chromatographically homogeneous material. d Performed with 10 mol
% (R,R)-27.
The influence of both lower temperatures and different
catalyst loadings was investigated to improve enantioselectivity
(Table 5). Comparison of entries 1-3 in Table 5 reveals that
performing the reaction at -90 °C had no beneficial effects,
and though there was an increase in selectivity when 20 mol %
of the catalyst was used, the difference was not substantial. At
the other end, initial experimentation at 1 mol % catalyst loading
led to low yields. Increasing the reaction concentration to 0.5
M reduced reaction times to 2 h for consumption of the aldehyde
(Table 5, entries 4-8). Whereas the use of 5 mol % catalyst
did not alter the selectivity, dropping the loading to 3 mol %
and below afforded the adduct with significantly lower enan-
tioselectivity.
Table 3. Survey of Phosphoramide Catalysts with Enolate 1a
Table 5. Effect of Catalyst Loading on Aldol Additions with
Enolate 1a
entry
catalyst
erb
yield,c%
1
2
3
4
(S,S)-27
(R,R)-29
(R)-30
12.5/1
1/3.31
4.29/1
1.70/1
92
76
71
79
(S,S)-28
mol %
(S,S)-27
a Reactions performed at 0.1 M for 2 h. b Ratio of the S/R isomer;
determined by CSP HPLC analysis of the dinitrophenyl carbamates.
c Chromatographically homogeneous material.
entry
concn, M
erb
yield,c %
1
2
3
4
5
6
7
8
10
10d
20
10e
5
3
2
0.1
0.1
0.1
0.5
0.5
0.5
0.5
0.5
11.3/1
9.99/1
12.3/1
1/11.7
11.5/1
8.60/1
7.77/1
5.10/1
90
89
82
87
88
86
88
92
The optimization of the aldol addition continued with an
investigation of solvent and stoichiometry effects on the same
transformation using catalyst (S,S)-27. The solvents selected for
study (Table 4) represented a wide spectrum of polarities and
donicites, but were obviously limited by the compatibility with
the trichlorosilyl enolates.11 Several trends were apparent from
the yields and er values of (-)-12 in Table 4. First, CH2Cl2
was clearly the solvent of choice for this transformation
1
a Reaction time, 2 h. b Ratio of the S/R isomer; determined by CSP
HPLC analysis of the dinitrophenyl carbamates. c Chromatographically
homogeneous material. d Reaction performed at -90 °C. e Performed
with 10 mol % (R,R)-27.
(9) Denmark, S. E.; Su, X.; Nishigaichi, Y.; Coe, D. M.; Wong, K.-T.;
Winter, S. B. D.; Choi, J.-Y. J. Org. Chem. 1999, 64, 1958-1967.
(10) The absolute configuration of adducts 12-22, 24-26, and 43 were
assigned by analogy to (-)-23, see below.
(11) Reichardt, C. SolVents and SolVent Effects in Organic Chemistry,
2nd ed.; VCH: Weinheim, 1988.
2.2. Survey of Substrates. With optimized conditions in
hand, we investigated the effect of substitution on the ketone
donor in the catalyzed aldol addition (Table 6).10 The size and
electronic character of the spectator substituent had little role

8840 J. Am. Chem. Soc., Vol. 122, No. 37, 2000
Denmark and StaVenger
in the chemical efficiency of the process; all of the enolates
provided high yields of aldol adducts with benzaldehyde. The
enantioselectivity of the process, however, was very sensitive
to the enolate structure, with larger groups providing lower
enantioselectivities, as illustrated by the trend from R ) methyl
through R ) t-Bu, (entries 1-5). In addition, a phenyl
substituent also led to low enantioselectivity, entry 6. The
success of the functionalized enolate (7) underscored the
important feature that the silyloxy group had no deleterious
effect on either the yield or enantioselectivity of the process.
and enantioselectivities associated with the catalyzed reactions
of trichlorosilyl enolates provided the motivation to develop a
more practical protocol for the preparation and handling of these
reactive species. The mercury(II)-catalyzed trans-silylation of
the trimethylsilyl enol ethers with SiCl4 provided an ideal
opportunity to engineer a “one-pot” method for the generation
and reaction of the enolates. For this process to be successful
we had to determine if the mercury(II) salts and excess SiCl4
would interfere with the subsequent aldolization. These questions
were first addressed by the use of a minimal loading (1 mol %)
of Hg(OAc)2 and only 1 equiv of SiCl4 (sub-optimal for
formation of the desired mono(enoxy)trichlorosilanes8a). Treat-
ment of the TMS enol ether of acetone (32) under these
conditions (to form enolate 1) followed by cooling and addition
of the catalyst and benzaldehyde provided a 65% yield of the
adduct with moderate enantioselectivity (er 6.87/1, compared
to 14.6/1), Scheme 2. A similar protocol starting with the TMS
enol ether of methyl isobutyl ketone (33) provided higher yield
(71%) though even further reduction in enantioselectivity
relative to the case with preformed enolate (er 3.67/1, compared
to 9.75/1).
Table 6. Aldol Additions of Trichlorosilyl Enolates to
Benzaldehyde Catalyzed by (S,S)-27a
entry
enolate
R
product
erb
yield,c %
1
2
3
4
5
6
7
1
2
3
4
5
6
7
Me
n-Bu
i-Bu
i-Pr
t-Bu
(-)-12
(-)-13
(-)-14
(-)-15
(-)-16
(-)-17
(-)-18
14.6/1d
12.0/1
10.1/1
9.75/1
3.17/1
2.92/1
13.5/1
98
98
95
97
95
93
94
Scheme 2
Ph
TBSOCH2
a Reactions performed at 0.5 M for 2 h. b Ratio of the S/R isomer;
determined by CSP HPLC analysis. c Analytically pure material.
d Determined by CSP HPLC analysis of the dinitrophenyl carbamate.
The generality of the catalyzed reaction was evaluated by
combination of the trichlorosilyl enolate of 2-hexanone (2) with
a variety of aldehydes in the presence of 5-10 mol % of (S,S)-
27 (Table 7).10,12 Unsaturated aldehydes reacted quickly and
cleanly to provide the corresponding adducts in high enantio-
selectivity. Initial rates with the branched aldehydes h and i
were disappointing, though further experimentation showed that
using 10 mol % of the catalyst and increasing the reaction time
to 6 h consistently led to acceptable yields and high enantiose-
lectivities. Unfortunately, unbranched aliphatic aldehydes (such
as hydrocinnamaldehyde (g)) did not afford aldol products in
the catalyzed additions.
The overall process was measurably improved if an additional
step, namely removal of the volatiles (presumably only CH2Cl2,
SiCl4, and TMSCl), was incorporated into the reaction protocol.
Initial experiments employing the standard stoichiometry (1.1
equiv of TMS enol ether 34, 2.2 equiv of SiCl4, 1.0 equiv of
R-methylcinnamaldehyde (c), and 5 mol % of (S,S)-27) provided
the adduct (-)-21 in 75% yield with high enantioselectivity.
As the low yield was probably due to the formation of unreactive
bis(enoxy)dichlorosilane, excess TMS enol ether was employed
in a subsequent experiment, Scheme 3. When 1.3 equiv of 34
were used, 89% yield of the adduct (-)-21 was obtained, with
excellent enantioselectivity (er 23.4/1, compared to 21.7/1) thus
demonstrating that such in situ reactions can indeed be carried
out without problem if the enol ether can be used in slight
excess.
Table 7. Aldol Additions of Enolate 2 Catalyzed by (S,S)-27a
mol %
entry RCHO (S,S)-27 time, h product
erb
yield,c %
1
2
3
4
5
6
b
c
d
e
h
i
5
5
5
5
10
10
2
2
2
2
6
6
(-)-20 11.5/1
(-)-21 21.7/1
(-)-22 13.1/1
(-)-23 12.7/1
(-)-25 17.5/1d
(-)-26 24.0/1d
94
95
92
95
79
81
Scheme 3
a Reactions performed at 0.5 M. b Ratio of the S/R isomer; determined
by CSP HPLC analysis. c Analytically pure material. d Determined by
CSP HPLC analysis of the dinitrophenyl carbamate.
2.3. Development of Conditions for in Situ Generation and
Reaction of Trichlorosilyl Enolates. The high chemical yields
C. Reactions of Achiral Enolates and Chiral Aldehydes.
1. Uncatalyzed Reactions. To extend this technology to more
synthetically interesting (and challenging) substrates, we pursued
the reactions of simple trichlorosilyl enolates of methyl ketones
with the chiral aldehydes (S)-3513 and (S)-37,14 Scheme 4.15 In
orienting experiments, uncatalyzed reactions with the TBS-
(12) The absolute configuration of (-)-23 was determined by single-
crystal X-ray analysis of the corresponding 4-bromobenzoate. The crystal
structure data have been deposited in the Cambridge Crystallographic Data
Center as supporting publication 111714. All other adducts were assigned
by analogy.

The Chemistry of Trichlorosilyl Enolates
J. Am. Chem. Soc., Vol. 122, No. 37, 2000 8841
protected aldehyde (S)-35 and enolate 2 in various solvents at
0.5 M afforded only modest yield and stereoselectivity (for
determination of relative configuration, see below).16 Side
reactions, particularly elimination, over the long reaction times
required for the aldolization, appeared to be a major contributor
to the low yields of these reactions. Performing the reaction at
higher concentration (1 M) alleviated these problems by
shortening reaction times (5 h) and thus providing an excellent
yield of the aldol adducts 36 as a mixture of diastereomers
(syn/anti, 1/2.4), Scheme 4. The benzyloxy aldehyde (S)-37
responded similarly under these conditions, affording a high
yield and low (syn/anti, 1/2.7) diastereoselectivity.
diastereomers) by hydrogenolysis then provided a mixture of
diols 41 (syn/anti, 1/3), as correlated to the above materials.
Scheme 6
Scheme 4
2. Catalyzed Reaction. 2.1. Catalyst Survey. Although
aldehydes (S)-35 and (S)-37 have been used extensively in
double diastereoselective aldol additions,15 the lack of precedent
in these new aldol processes prompted us to survey catalyst
structure broadly to establish if the phosphoramide could control
the facial selectivity of addition, regardless of the inherent bias
in the aldehyde. The results of an initial study with enolate 2
and the silyloxy aldehyde (S)-35 are collected in Table 8. The
yields of these catalyzed reactions were modest. However, while
HMPA and (R)-30 were rather unselective, a number of the
reactions proceeded with high anti-diastereoselectivity. Interest-
ingly, the achiral phosphoramide 31b provided moderate levels
of stereoselection, suggesting that the intrinsic selectivity due
to the aldehyde was not insignificant. Once again, the stilbene-
diamine-derived phosphoramide 27 provided the most interesting
results. Whereas (S,S)-27 provided only a weak syn-preference,
the use of (R,R)-27 provided very high (>15/1) levels of anti-
selectivity, though still in modest yield. Changing the solvent
(entries 7-9) did not improve the yield or selectivity.
1.1. Determination of Relative Configuration. The relative
configuration of adducts 36 and 38 was assigned by correlation
to (()-syn-41, synthesized unambiguously by the OsO4-
catalyzed dihydroxylation of the corresponding alkene (E)-40,
Scheme 5. Addition of a cuprate derived from (E)-1-propenyl-
lithium17 to 1-hexene oxide (39)18 led to the desired alcohol in
76% yield. Swern oxidation,19 followed by dihydroxylation,
provided authentic (()-syn-41, which could be compared to the
(deprotected) products from the aldol additions, vide infra.
Scheme 5
Attempts to optimize the yield of this highly diastereoselective
aldol addition focused on those variations which were beneficial
in related additions of trichlorosilyl enolates. These included
slow addition of aldehyde (known to suppress unfavorable
monophosphoramide-catalyzed pathways2d,4), inclusion of 1.2
equiv of tetrabutylammonium triflate (known to increase the
rate of the catalyzed reaction5a), higher temperature, excess
enolate, and higher (25 mol %) catalyst loading. All attempts
provided only modest yield (35-45%), accompanied by roughly
(15) For previous studies on the diastereoselective addition of simple
achiral methyl ketone enolates to chiral R-oxygenated aldehydes see: (a)
Gennari, C. In ComprehensiVe Organic Synthesis, Vol. 2, Additions to C-X
π Bonds, Part 2; Heathcock, C. H., Ed.; Pergamon Press: Oxford, 1991;
pp 639-647. (b) Braun, M. In StereoselectiVe Synthesis, Methods of Organic
Chemistry (Houben-Weyl), E21 ed.; Hoffmann, R., Mulzer, J., Schaumann,
E., Eds.; Thieme: Stuttgart, 1996; Vol. 3, pp 1713-1722. (c) Hagiwara,
H.; Kimura, K.; Uda, H. J. Chem. Soc., Perkin Trans. 1 1992, 693-700.
(d) Heathcock, C. H.; Davidsen, S. K.; Hug, K. T.; Flippin, L. A. J. Org.
Chem. 1986, 51, 3027-3037. (e) Lodge, E. P.; Heathcock, C. H. J. Am.
Chem. Soc. 1987, 109, 3353-3361.
Deprotection of diastereomerically pure20 adducts 36 (to
compare with the authentic (()-syn-41) was hampered by the
sensitivity of the substrates: acidic media led to retro-aldoliza-
tion, while basic media led to elimination. However, the use of
1 equiv of TBAF in THF at 0 °C, in combination with careful
monitoring of the reaction, led to modest yields of the
diastereomerically pure diols syn-41 and anti-41, Scheme 6.
Deprotection of the benzyloxy adduct 38 (as a 1/2.7 mixture of
(16) Selected results: Et2O, 59% yield, syn/anti 1/2; toluene, 66% yield,
syn/anti 1/2; hexane, 31% yield, syn/anti 1/2.
(17) Neumann, H.; Seebach, D. Tetrahedron Lett. 1976, 4839-4842.
(18) Tang, P. W.; Williams, J. M. J. Chem. Soc., Perkin Trans. 1 1984,
1199-1203.
(13) Massad, S. K.; Hawkins, L. D.; Baker, D. C. J. Org. Chem. 1983,
(19) Tidwell, T. T. Org. React. 1990, 39, 297-572.
48, 5180-5182.
(20) Though inseparable by simple column chromatography, pure samples
of syn-36 and anti-36 were available from repeated preparative HPLC, see
Supporting Information for details.
(14) Solladie´-Cavallo, A.; Bonne, F. Tetrahedron: Asymmetry 1996, 7,
171-180.

8842 J. Am. Chem. Soc., Vol. 122, No. 37, 2000
Denmark and StaVenger
30% of recovered aldehyde; the balance of the material could
not be identified. Although enolization is perhaps the most likely
explanation, in one experiment, the recovered aldehyde was still
enantiomerically enriched suggesting that aldehyde enolization
may not be the only problem.
The benzyloxy aldehyde (S)-37 was examined as well in a
more limited survey. As was the case with (S)-35, the yields
obtained were modest and the selectivity trends closely mirrored
the results with the silyloxy aldehyde. Although the selectivity
provided by (S,S)-27 (mismatched case) was higher than that
with the silyloxy aldehyde (S)-35 above (syn/anti 4/1 vs 2/1),
the matched case catalyzed by (R,R)-27 was not as selective as
that previously observed with the TBS derivative (syn/anti, 1/6
vs 1/15.6).
trichlorosilyl enolates, the aldol addition of chiral enolates to
achiral aldehydes was investigated.21 Whereas orienting studies
with these enolates were conducted with isolated, distilled
compounds 9-11 (Chart 1), all of the preparative experiments
described below were performed with enolates that were
prepared and used in situ starting from the corresponding TMS
enol ethers 44-46, Chart 4. As mentioned previously, the
formation of bis(enoxy)dichlorosilanes in the mercury-catalyzed
trans-silylation reaction leads to low yield of the aldol adduct
unless excess TMS enol ether is employed. However, in the
cases at hand, the enol donor should be considered precious
and therefore used as the limiting reagent. Hence, all of the in
situ reactions with chiral ketone enolates were performed with
equivalent amounts of TMS enol ether and aldehyde.
Table 8. Catalyzed Aldol Additions with Aldehyde (S)-35a
Chart 4
entry
catalyst
solvent
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
Et2O
syn/antib
yield,c %
1
2
3
4
5
6
7
8
9
HMPA
31b
(R,R)-29
(R)-30
(S,S)-27
(R,R)-27
(R,R)-27
(R,R)-27
(R,R)-27
1/1.3
1/6.7
1/10.1
1/1.8
2.7/1
1/15.6
1/9.0
1/6.7
1/11.5
41
37
51
54
47
50
45
40
43
1. Uncatalyzed Reactions. The addition of the oxygenated
enolates to benzaldehyde proceeded in good yield with weak
anti-selectivity (for determination of relative configuration, see
below), Table 9. A modest dependence of selectivity on the
O-protecting group was noted; the smaller group on the enolate
(Bn > Piv > TBS) provided higher anti-selectivity in combina-
tion with benzaldehyde (entries 1-3). When other aldehyde
acceptors were investigated (entries 4-6) the yields were
generally lower, especially for the reaction with hydro-
cinnamaldehyde, where elimination under the reaction conditions
again seemed to be problematic. In addition, only slight
diastereoselectivity was observed though perhaps this is not
surprising given the very low diastereoselectivity observed with
the TBS substrate 44 and benzaldehyde. Interestingly, crotonal-
dehyde (f) provided slight syn-selectivity in this reaction, unlike
other substrates investigated.
toluene
CH3CH2CN
a Reactions performed at 0.5 M for 6 h. b Determined by GC analysis.
c Chromatographically homogeneous material.
2.2. Test of R-Oxygen. To gain insight into the cause of the
moderate yields for catalyzed additions to (S)-35 and (S)-37, a
test substrate was designed to determine if the oxygen substituent
on the aldehyde acceptor was inherently problematic, or if the
R-hydrogen was the culprit. To this end, the tertiary silyloxy
aldehyde 42 was synthesized in four steps from 2-hydroxy-2-
methylpropanoic acid, Scheme 7. This material proved to be a
very capable substrate in the aldol addition of enolate 2 catalyzed
by 10 mol % of (S,S)-27, and provided the corresponding aldol
adduct (-)-43,10 in 88% yield with a good enantiomeric ratio
(6.75/1), Scheme 7. Clearly, the presence of oxygen functionality
on the acceptor is not detrimental to the operation of the
phosphoramide-catalyzed aldol addition, though selectivity was
attenuated relative to the all carbon analogue (er 6.75/1
compared to 24.0/1, Table 7, entry 6).
Table 9. Uncatalyzed Aldol Additions of Trichlorosilyl Enolates
Generated in Situa
entry
R1
enol R2CHO products syn/antib yield,c %
1
2
3
4
5
6
TBS
Piv
Bn
TBS
TBS
TBS
44
45
46
44
44
44
PhCHO
PhCHO
PhCHO
g
h
f
47
48
49
50
51
52
1/1.2d
1/2.4
1/3.4
1/1
82
71
75
35
55
66
Scheme 7
1/3
2.3/1e
a Conditions: (1) 1 mol % of Hg(OAc)2/2 equiv of SiCl4/1 M/1 h.
1
(2) Reactions performed at 1 M. b Determined by H NMR analysis.
c Analytically pure material. d Determined by CSP SFC analysis.
e Determined by CSP SFC analysis of the benzoates.
2. Catalyzed Reactions. The rate and diastereoselectivity of
the additions in the presence of phosphoramides 31a, (S,S)-27,
and (R,R)-27 were investigated next, Table 10. Achiral catalyst
31a served to establish the internal22 diastereofacial selectivity
in the catalyzed process. This reaction proceeded smoothly with
5 mol % of 31a to provide 47 with a modest syn preference
(1.2/1) and in good yield. With 5 mol % of catalyst (S,S)-27
D. Reactions of Chiral Enolates and Achiral Aldehydes.
To further explore the synthetic utility of methyl-ketone derived

The Chemistry of Trichlorosilyl Enolates
J. Am. Chem. Soc., Vol. 122, No. 37, 2000 8843
the reactions were rapid and provided good yields of adducts
but the diastereoselectivity of the process was low, marginally
favoring the syn diastereomer. Because catalyst (S,S)-27 typi-
cally provides aldol adducts with the S-configuration at the
hydroxyl-bearing center (opposite to that found in the major
syn-diastereomer) it was not surprising that the selectivity was
attenuated compared to that obtained from 31a. Moreover, it
was reasonable to suspect that use of (R,R)-27 as catalyst would
provide higher syn-selectivities in an overall matched case of
double diastereoselection. This was indeed found to be the case
(entries 5-8); good to excellent syn-diastereoselectivity was
observed. The TBS-protected enol ether 44 provided the adducts
in the highest yield (85%) and selectivity (73/1 syn/anti).
Scheme 8
Table 10. Catalyzed Additions of Trichlorosilyl Enolates
Generated in Situ Using (S,S)-27a
entry R1 enol aldehyde catalyst products syn/antib yield,c %
1
2
3
4
5
6
7
8
9
TBS 44 PhCHO 31ad
TBS 44 PhCHO (S,S)-27
47
47
48
49
52
47
48
49
52
1.2/1
1.5/1e
3.4/1
1/1.1
1.3/1f
73/1e
20/1
81
85
78
78
80
85
78
77
81
Piv
Bn
TBS 44
45 PhCHO (S,S)-27
46 PhCHO (S,S)-27
of diastereomers (from the reaction catalyzed by (R,R)-27) which
provided a 12/1 mixture of diols syn- and anti-53 in moderate
yield.
f
(S,S)-27
TBS 44 PhCHO (R,R)-27
Piv
Bn
TBS 44
45 PhCHO (R,R)-27
46 PhCHO (R,R)-27
11/1
6.2/1f
Discussion
f
(R,R)-27
a Conditions: (1) 1 mol % of Hg(OAc)2/2 equiv of SiCl4/1 M/1 h.
A. Uncatalyzed Reactions. 1. Reactivity Trends. The
reactivity of trichlorosilyl enolates and the mechanism of their
direct aldolization is believed to involve initial coordination of
the aldehyde to the Lewis acidic silicon center forming a trigonal
bipyramidal (tbp) silicon species.1a,2d,e,4 It has been suggested24
(and demonstrated computationally25) that such associative aldol
additions of enoxysilanes undergo carbon-carbon bond forma-
tion through a closed transition structure that resembles a boat.
In the absence of obvious steric interactions in either the boat
or chairlike arrangements, the underlying reasons for the
preference for tbp silicon enolates to react preferentially through
a boatlike structure are unclear. Although many factors (O-
M-O bond angles, M-O bond lengths, overall coordination
geometry around M, spectator ligands on M, and substitution
pattern on enol donor)26 have been implicated in the relative
stability of chair- and boatlike transition structures involving
metal enolates, there seem to be no clear-cut rules governing
such predictions a priori. As the present additions involve
R-unsubstituted enolates, there is no stereochemical reporter
1
(2) Reactions performed at 0.5 M for 2 h. b Determined by H NMR
analysis. c Chromatographically homogeneous material. d 5 mol % of
catalyst employed at 0.1 M for 4.5 h. e Determined by CSP SFC
analysis. f Determined by CSP SFC analysis of the benzoates.
3. Determination of Relative Configuration. The relative
configuration of the pivaloate 48 was established by crystallizing
a sample (obtained from the reaction catalyzed by (R,R)-27,
initial dr 20/1) to diastereomeric purity, followed by single-
crystal X-ray analysis.23 Diastereomerically pure syn-48 was
then deprotected with aqueous methylamine in methanol to
provide pure syn-53 in modest yield, Scheme 8. The major
diastereomer (dr 70/1) from the reaction of 44 with benzalde-
hyde in the presence of the (R,R)-27 catalyst was then
deprotected with aqueous HF in acetonitrile to also give syn-
1
53 (as compared to the above material by TLC and H NMR
analysis) in high yield as essentially one diastereomer. In
addition, a 1.5/1 mixture of diastereomers 47 (obtained from
the reaction catalyzed by (S,S)-27) was similarly deprotected
to give a 2/1 mixture of syn- and anti-diols 53. Finally, the
relative configurations of the benzyloxy adducts 49 were
determined by hydrogenolytic deprotection of an 11/1 mixture
(23) The crystal structure of (+)-syn-48 has been deposited in the
Cambridge Crystallographic Data Center as supplemental publication CCDC
111712.
(24) See refs 1a, 2d, 2e, and 4. The reactions of enoxysilacyclobutanes
are also thought to proceed through boatlike transition structures involving
tbp silicon species, see: (a) Myers, A. G.; Kephart, S. E.; Chen, H. J. Am.
Chem. Soc. 1992, 114, 7922-7923. (b) Denmark, S. E.; Griedel, B. D.;
Coe, D. M.; Schnute, M. E. J. Am. Chem. Soc. 1994, 116, 7026-7043.
(25) Gung, B. W.; Zhu, Z.; Fouch, R. A. J. Org. Chem. 1995, 60, 2860-
2864. See also ref 22b.
(26) (a) Evans, D. A.; McGee, L. R. Tetrahedron Lett. 1980, 21, 3975-
3978. (b) Nakamura, E.; Kuwajima, I. Tetrahedron Lett. 1983, 24, 3343-
3346. (c) Evans, D. A.; Nelson, J. V.; Taber, T. R. Top. Stereochem. 1982,
13, 1-115. (d) Hoffmann, R. W.; Ditrich, K.; Froech, S. Tetrahedron 1985,
41, 5517-5524. (e) Bernardi, A.; Capelli, A. M.; Comotti, A.; Gennari,
C.; Gardner, M.; Goodman, J. M.; Paterson, I. Tetrahedron 1991, 47, 3471-
3484. (f) Li, Y.; Paddon-Row, M. N.; Houk, K. N. J. Org. Chem. 1990,
55, 481-493.
(21) For previous studies on the diastereoselective addition of simple
chiral methyl ketone enols to aldehydes, see: (a) Seebach, D.; Ehrig, V.;
Teschner, M. Liebigs Ann. Chem. 1976, 1357-1369. (b) Evans, D. A.;
Nelson, J. V.; Vogel, E.; Taber, T. R. J. Am. Chem. Soc. 1981, 103, 3099-
3111. (c) Heathcock, C. H.; Pirrung, M. C.; Lampe, J.; Buse, C. T.; Young,
S. D. J. Org. Chem. 1981, 46, 2290-2300. (d) Lagu, B. R.; Crane, H. M.;
Liotta, D. C. J. Org. Chem. 1993, 58, 4191-4193. (e) Paterson, I.;
Goodman, J. M.; Isaka, M. Tetrahedron Lett. 1989, 30, 7121-7124. (f)
Trost, B. M.; Urabe, H. J. Org. Chem. 1990, 55, 3982-3983. (g) Gustin,
D. J.; VanNieuwenhze, M. S.; Roush, W. R. Tetrahedron Lett. 1995, 36,
3447-3450.
(22) For a definition of these terms see: Denmark, S. E.; Almstead, N.
G. In Modern Carbonyl Chemistry; Otera, J., Ed.; Wiley-VCH: Weinheim,
2000; Chapter 10.

8844 J. Am. Chem. Soc., Vol. 122, No. 37, 2000
Denmark and StaVenger
Scheme 9
Scheme 10
group that can provide information about the relative topicity
of bond formation. Thus, little direct speculation can be made
about the nature of the transition structure. However given the
ample precedent for boatlike structures in related systems it
seems reasonable to consider such assemblies in these additions
as well.
model, then addition of the enolate to the sterically more
accessible face would provide the observed anti-diastereomer,
Scheme 9.28
It seems that the stereoelectronic preferences of the oxygen
atom on the acceptor dominates the stereochemistry-determining
event, as both silyloxy and benzyloxy substrates provided similar
results, despite their vastly different steric profiles and coordi-
nating abilities.29 This result is in line with Heathcock’s analysis
for nonchelation controlled additions wherein electronic, rather
than steric, interactions dominate the reactive conformation of
simple R-oxygenated aldehydes.15e
Chiral methyl ketone enolates 9-11 were only weakly
diastereoselective in uncatalyzed reactions. Note that in these
additions the nature of the oxygen substituent did appear to play
a small role in stereoselection, with OTBS being unselective,
while OPiv and OBn were slightly anti-selective (Table 9). Such
modest changes in selectivity should be interpreted with extreme
caution. One simple explanation for this trend invokes a
conformation wherein the oxygenated substituent eclipses the
enol double bond to minimize dipoles.30 In this conformation,
the anti-diastereomer would be formed by attack of the less
hindered face of the enolate on the aldehyde through a boatlike
All of the achiral enolates reacted cleanly with a wide
selection of aldehydes, though the reaction rate was retarded
with increasing branching of the aldehyde partner. In addition,
conjugated aldehydes (aromatic and olefinic) were generally
more reactive than aliphatic aldehydes, presumably due both
to their smaller size and higher Lewis basicity.27 The 2-hexa-
none-derived enolate 2 also added cleanly to the R-oxygenated
aldehydes (S)-35 and (S)-37 in uncatalyzed reactions, though
the stereoselectivity of the process was low, favoring the anti-
isomer. In addition, it was found that the aldol additions
proceeded cleanly and without retardation when performed with
enolates formed in situ from the corresponding TMS enol ether
via the mercury-catalyzed trans-silylation reaction. Apparently
the presence of the mercury(II) species has little if any effect
on the uncatalyzed aldolization.
2. Stereoselection. In the uncatalyzed additions of achiral
enolates to chiral, R-oxygenated aldehydes, a definitive analysis
of the stereoselection process is difficult due to the small energy
differences involved (∆∆G‡(298 K) ) 0.5 kcal for 2.4-2.7/1,
anti/syn). However, if boatlike transition structures are consid-
ered and if the aldehyde is assumed to exist in a conformation
such that the oxygen is anti to the incoming nucleophile, as
suggested by the Heathcock modification15e of the Felkin-Ahn
(28) A referee has suggested that chair-like structures should be
considered as well. Although we cannot a priori exclude such structures
because of the absence of a stereochemical marker, our previous studies
on uncatalyzed reactions with E-configured enolates (ref 4) reveal an
overwhelming (albeit not exclusive) preference for reaction via boatlike
structures. Insofar as overriding steric interactions are unlikely to differentiate
unsubstituted from E-enolates we feel confident in this assumption.
(29) For a thorough discussion of the effects of R-heteroatom substituents
on the stereochemical course of addition to aldehydes see: (a) Reetz, M.
T. Angew. Chem., Int. Ed. Engl. 1984, 23, 556-569. (b) Reetz, M. T. Acc.
Chem Res. 1993, 26, 462-468. (c) Reetz, M. T. Chem. ReV. 1999, 99,
1121-1162.
(27) Based on the enthalpy of formation of aldehyde-BF3 complexes,
see: Maria, P.-C.; Gal, J.-F. J. Phys. Chem. 1985, 89, 1296-1304.
(30) Cowden, C. J.; Paterson, I. Org. React. 1997, 51, 1-200.

The Chemistry of Trichlorosilyl Enolates
J. Am. Chem. Soc., Vol. 122, No. 37, 2000 8845
Scheme 11
transition structure, Scheme 10. By changing the nature of the
oxygen substituent (size, hyperconjugative ability, chelating
potential (see below)) the energetic cost of placing it in an
eclipsing position may become higher, thus allowing an
electronically less favorable reactive conformation, with the
methyl group eclipsed, to compete, lowering the facial selectivity
of attack on the enolate.
merically enriched, stoichiometric enolization of the aldehyde
can be ruled out. A more likely scenario is that enolization does
take place and the resulting mixture inhibits the reaction either
through catalyst destruction or by interfering with catalyst
turnover.32
The successful catalyzed aldolization with cyclohexane-
carboxaldehyde and the less than satisfactory results with chiral
aldehydes (in addition to the wholly unsuccessful catalytic
additions to hydrocinnamaldehyde) highlight the dramatic
substrate dependence on the proposed enolization. This apparent
inconsistency may be rationalized by proposing that enolization
intercedes as a shunt from a structurally similar transition
structure. We suggest that enolization, like aldolization, requires
dual activation of the enolate and the aldehyde and that
enolization can only occur via a closed, eight-membered
transition structure, Scheme 11. Such a reactive conformation
is unfavorable if purely σ-complexation (φ ) 0°) of the aldehyde
(i.e. antiperiplanar to the aldehyde residue) to the silicon is
assumed. However, if the complexation is allowed to be looser
and the silicon slips to an anticlinal orientation relative to the
aldehyde residue (φ > 0°, e.g., 20-30°), such an eight-
membered-ring transition structure is feasible and perhaps
favorable. It hardly seems unreasonable that subtle differences
in the structure of the aldehyde or enolate could lead to small
changes in the conformation of the aldehyde/enolate complex
such that the relative energy barriers for enolization or aldoliza-
tion are altered.32b
2. Stereoselection. 2.1. Achiral Enolates and Achiral
Aldehydes. The catalyzed reactions involving achiral substrates
proceeded with moderate to high enantioselectivity when the
stilbenediamine-derived phosphoramide (S,S)-27 was used.
Other phosphoramide structures were markedly less selective,
as was also true in the related reactions of trichlorosilyl enolates
of cyclic ketones where both diastereo- and enantioselectivity
were low.4 The opposite absolute configuration of adducts
provided by cyclohexanediamine catalyst (R,R)-29 was expected
B. Catalyzed Reactions. 1. Reactivity Trends. The mech-
anism of the phosphoramide-catalyzed aldol additions of trichlo-
rosilyl enolates is the subject of an extensive, ongoing inves-
tigation. For the purposes of the immediate discussion, we
assume that the reaction pathway for the methyl ketones
described herein is the same as for the substituted enolates that
are the subject of the mechanistic studies.1a,3d,4,5 At the current
level of understanding, the dominant catalyzed pathway involves
the intermediacy of a cationic, diphosphoramide silyl enolate
complex, which, upon binding an aldehyde, reacts through a
chairlike transition structure organized around a hexacoordinate
silicon species. Furthermore, a second pathway, which is
typically less facially selective, involves a cationic monophos-
phoramide species wherein the transition structure resembles a
boat, organized around a cationic, pentacoordinate silicon center.
This second pathway can contribute significantly in reactions
catalyzed by bulky phosphoramides and/or at low catalyst
loading. A more detailed analysis of the mechanism of this
reaction (specifically with regard to cyclic ketone enolates)
including the relative stability of chair- and boatlike transition
structures for both tbp and octahedral siliconate arrangements
will be the subject of an upcoming report.31
Although the selectivities of the reactions with chiral alde-
hydes were often high, the yields of the processes were low.
This was the case regardless of the protecting group used and
did not change over a range of reaction conditions. A control
experiment with the TBS-protected, quaternary aldehyde 42
demonstrated that neither oxygenation nor silyl-protection in
the R-position of the aldehyde acceptor was harmful to the
overall efficiency of the catalyzed pathway, though the selectiv-
ity obtained was rather low. Because of this, and the previous
problems with enolizable aldehydes,4 it is reasonable to conclude
that at least some of the problem is due to enolization and
trichlorosilyl-group transfer. However, as the aldehyde that was
recovered from one of the catalytic reactions was still enantio-
(32) (a) We have recently noticed that both aldehydes and ketones are
converted to trichlorosilyl enolates in the presence of SiCl4 and phosphor-
amides without the need for added base. This implies that the generation
of HCl is thermodynamically favorable. If this also occurs with the chiral
aldehydes, trichlorosilyl enolates, and phosphoramides at a rate competitive
with aldolization, then only a small amount of HCl needs to be generated
to inhibit the catalyst. (b) Preliminary experiments suggest that SiCl4 can
form adducts of aliphatic aldehydes in the presence of phosphoramides.
This might also constitute a explanation for the failure of these substrates
to react. T. Wynn, unpublished observations from these laboratories.
(31) Denmark, S. E.; Su, X.; Wong, K.-T.; Nishigaichi, Y.; Stavenger,
R. A.; Pham, S. M. Manuscript in preparation.

8846 J. Am. Chem. Soc., Vol. 122, No. 37, 2000
Denmark and StaVenger
as this catalyst is enantiomorphic to both phosphoramides (R)-
30 and (S,S)-27.
in the present case. As catalyst loading drops the rate of the
di-phosphoramide pathway (chairlike) decreases as the square
of the concentration, while the mono-phosphoramide pathway
(boatlike) drops linearly. With methyl ketone enolates, these
two pathways retain the same topicity at the enol faces, but
change the face of the aldehyde being attacked. From the results
in Table 5 it can be concluded that at loadings from 1 to 5 mol
%, both mono- and di-phosphoramide pathways are operative,
while at loadings above 5 mol %, only the di-phosphoramide
pathway is operative and the constant er from 5 to 20 mol %
represents the energy difference between competing hexacoor-
dinate, chairlike transition structures.
Unfortunately, it is difficult to draw useful transition structures
to explain the absolute stereoselection process for these catalyzed
aldol additions. In addition to the obvious difficulties of drawing
conclusions on the basis of a single stereochemical observable
(enantioselectivity), the sheer size and complexity of the system
makes a fundamental analysis challenging. Issues that must be
addressed before proposing reasonable transition structures
include (but are not limited to) the following: multiple
configurations around a (chiral) octahedral silicon center; order
and timing of Lewis base (phosphoramide and aldehyde)
complexation to silicon; conformational freedom of rotation
about the presumed phosphoryl oxygen-silicon bonds; and
timing of C-C bond formation (i.e., determining the stereo-
chemistry determining step). These considerations must be
resolved before embarking on an analysis of the traditional aldol
problems involving sets of boatlike and chairlike transition
structures leading to the observed products. While we have made
preliminary attempts to tackle these questions computationally,
we quickly realized that the magnitude of the problem surpassed
our current capabilities. Indeed, analysis of simple molecular
models reveals the vast number of potential configurations and
conformations of the proposed quaternary molecular assembly
and the task becomes clear and daunting.
It should be noted that the apparent facial selectivities (er)
of the methyl ketone enolate additions are slightly lower than
the facial selectivities (er of the adduct arising from a di-
phosphoramide (chairlike) transition structure) of the reactions
of cyclic ketone enolates. This lower enantioselectivity observed
with some of the substrates (particularly acetophenone) was
somewhat surprising, especially given the excellent enantio-
selectivities obtained with the propiophenone-derived enolate.4
However, it is important to recognize that changes in the relative
diastereoselection processes (i.e. chairlike vs boatlike transition
structures) can manifest themselves in the enantioselectivity of
the reaction if the change in relative topicity is due to a change
at the face of the aldehyde.33 Although modest diastereoselect-
ivity was obtained with the propiophenone enolate, the dr was
highly dependent on catalyst loading. It is perhaps not surprising
that lower enantioselectivity was observed with the acetophe-
none-derived enolate 6, arising not from poor facial selectivity
in the competing chairlike transition structures but from lesser
differentiation of competing chair and boat structures. An
explanation for the low selectivity observed with the pinacolone-
derived enolate 5 is less clear and may be due either to a chair-
boat selection problem, as above, or to inherently lower facial
selectivity arising from the steric bulk of the enolate.
Not surprisingly, in view of the cationic nature of the reactive
silicon intermediates, the reaction medium had a dramatic effect
on the selectivity of the overall process. Dichloromethane and
propionitrile were the only solvents truly suited for the reaction.
The in situ formation and use of enolate 2 demonstrated that
the presence of a small amount of mercury salts had no effect
on the stereoselectivity of the aldolization catalyzed by (S,S)-
27 (compare Scheme 3 and Table 7, entry 2). In contrast, when
the reaction was performed without intermediate removal of the
SiCl4 and TMSCl (with enol ethers 32 and 33, Scheme 2) much
lower yields and attenuated enantioselectivities were observed.
Fortunately, the additional manipulation of reagent removal is
neither time-consuming nor challenging when nonvolatile
enolates are used.
2.2. Achiral Enolates and Chiral Aldehydes. The yields of
the catalyzed additions of enolate 2 to chiral aldehydes (S)-35
and (S)-37 were modest, though the selectivities obtained do
show considerable promise. The catalyzed reactions were all
(save that catalyzed by (S,S)-27) anti-selective. As previously
observed in the achiral enolate/achiral aldehyde systems,
solvents other than CH2Cl2 led to less selective reactions.
Although the phosphoramide (R,R)-27 proved to be the best
catalyst, the cyclohexanediamine-derived catalyst (R,R)-29 also
performed well, providing up to 10/1 diastereoselectivity. This
is in contrast to the very poor enantioselectivity observed in
the additions with acetone enolate 1 and benzaldehyde (Table
3, entry 2). When the benzyloxy aldehyde (S)-37 was used, less
substrate control was observed and the configuration of catalyst
27 played a larger role in the stereochemical course of the
reaction.
The stereochemical course of the catalyzed additions to chiral
aldehydes (S)-35 and (S)-37 was predictable on the basis of the
intrinsic facial selectivity of the aldehyde and the influence of
the catalyst (R,R)-27 on the external stereoselection process.
First, if one applies the Felkin-Heathcock analysis to the (S)-
configured aldehyde, approach to the Re face of the carbonyl
group is preferred which leads to the anti-diastereomer. Second,
if one assumes that the catalyst (R,R)-27 has the same facial
bias for the enolate 2 as it does for the cyclohexanone enolate
then with the additional assumption of a chairlike transition
structure, attack on the Re face of the aldehyde is again preferred
which further reinforces the formation of the anti-adduct,
Scheme 12. When (S,S)-27 was used, syn-selectivity was
obtained with aldehyde (S)-35; apparently the catalyst can
override the intrinsic facial selectivity of the aldehyde in this
mismatched case. Unfortunately, it is unclear at this time how
the enolate face is shielded by the complex involving chiral
phosphoramides. Given the unknown configuration around
silicon, the conformational degrees of freedom, and number of
third row elements, even computational modeling has little hope
of providing compelling answers.
The observation that the product er decreases with decreasing
catalyst loading is consistent with a change in relative rates of
the two reaction pathways, and is not ascribable to intervention
of an uncatalyzed, racemic pathway.34 In the case of the
cyclohexanone enolate, lowering catalyst loading decreases the
diastereoselectivity, but not the enantiomeric composition of the
diastereomers. The implication is clear; with less catalyst the
same process that impacts the relative stereoselection process
for the cyclohexanone enolate (chairlike versus boatlike transi-
tion structures) also causes the erosion of the enantioselectivity
(33) The minor diastereomers in the aldol additions of substituted
trichlorosilyl enolates are nearly racemic indicating that a topicity change
at either enolate or aldehyde is equally feasible.
(34) The methyl ketone enolates are less reactive than the substituted
enolates. In addition, control experiments showed that only 4% of the aldol
product is formed in the absence of catalyst under the conditions of the
catalyzed reactions.

The Chemistry of Trichlorosilyl Enolates
J. Am. Chem. Soc., Vol. 122, No. 37, 2000 8847
Scheme 12
2.3. Chiral Enolates and Achiral Aldehydes. This series
of additions also served to illustrate the utility of in situ
generation and reaction of trichlorosilyl enolates. In a number
of examples, both catalyzed and uncatalyzed additions were
performed cleanly and selectively with the in situ protocol
developed previously. In addition to the convenience the in situ
procedure provides, these studies with chiral methyl ketones
demonstrated the compatibility of the trichlorosilyl enolate/
phosphoramide technology with several common protecting
groups.
suggests that a pathway involving chelation of the silicon cation
may become possible with smaller and more basic oxygen
functions.35
Conclusion
A mild, general method for the synthesis of methyl ketone-
derived trichlorosilyl enolates has been developed. This mer-
cury(II)-catalyzed trimethylsilyl to trichlorosilyl metathesis was
shown to be compatible with a variety of oxygen functions on
the starting ketone, in addition to being amenable to in situ
formation and use of the trichlorosilyl enolates, with no change
in the selectivity of the ensuing reactions. It was shown that
trichlorosilyl enolates of methyl ketones are unselective in
uncatalyzed reactions when either donor or acceptor centered
substrate control is possible. However, high diastereoselectivity
could be obtained by the combination of either chiral enolates
or chiral aldehydes with the appropriate chiral phosphoramide
catalyst. In addition, the same chiral catalysts provide good to
high absolute control (enantioselectivity) in the addition of
achiral enolates to achiral (including one enolizable) aldehydes.
Extension of these studies to include chiral ethyl ketones bearing
oxygen substituents in the R′- and â′-positions along with further
exploration of catalyst dependencies are currently under inves-
tigation. Kinetic analysis of the reactions of methyl ketone
enolates is also of importance in substantiating the existence of
the dual reaction pathways and will be reported in due course.
The additions of both pivaloyloxy- and silyloxy-enolates to
benzaldehyde catalyzed by (R,R)-27 demonstrated that this
process can be extremely syn-diastereoselective. When the
catalyst (S,S)-27 was used in an overall mismatched case only
low selectivity was observed, still favoring the syn-isomer. Thus,
the internal selectivity of the chiral enolate (established from
the weak syn selectivity observed with achiral catalyst 31a)
dominated the stereochemical course of addition. Apparently,
in catalyzed aldol additions of trichlorosilyl enolates, the facial
bias provided by stereogenic centers on the enolate is higher
than the bias provided by stereogenic centers on the aldehyde
portion.
The reactions catalyzed by (R,R)-27 were highly syn-
diastereoselective and correlated well with the size of the
protecting group, The overall syn-selectivity can be rationalized
by assuming an eclipsed conformation of the oxygen substituent
to minimize dipoles,30 similar to that described above for the
uncatalyzed additions, Scheme 13. The observation that dia-
stereoselectivity decreases in the order OTBS > OPiv > OBn
Experimental Section
See Supporting Information.
Acknowledgment. We thank the National Science Founda-
tion for continued financial support (CHE 9500397 and 9803124).
R.A.S. thanks the University of Illinois and the Eastman
Chemical Co. for graduate fellowships. We thank S. M. Pham
for carrying out a key control experiment with 31a.
Scheme 13
Supporting Information Available: Full experimental
procedures for aldol addition reactions and full characterization
data for all aldol adducts and derivatives are described (PDF).
This material is available free of charge via the Internet at
http://pubs.acs.org.
JA001023G
(35) The possibility of chelation of the silicon by the R-oxygen substituent
becomes more plausible in the catalyzed reactions wherein the silicon is a
more electrophilic cationic center. The intriguing possibility that the sense
of internal diastereoselection might be tunable by the use of catalysts which
prefer the mono- versus the diphosphoramide pathway is currently under
investigation.