Enantioselective Lewis acid catalyzed Michael reactions of alkylidene malonates. Catalysis by C2-symmetric bis(oxazoline) copper(II) complexes in the synthesis of chiral, differentiated glutarate esters

Article abstract of DOI:10.1021/ja002246+

C₂-symmetric bis(oxazoline)-Cu(II) complexes 1 catalyze the Mukaiyama Michael reaction of alkylidene malonates and enolsilanes. The use of hexafluoro-2-propanol is essential to induce catalyst turnover. High enantioselectivities are exhibited b

Full text of DOI:10.1021/ja002246+

9134
J. Am. Chem. Soc. 2000, 122, 9134-9142
Enantioselective Lewis Acid Catalyzed Michael Reactions of
Alkylidene Malonates. Catalysis by C2-Symmetric Bis(oxazoline)
Copper(II) Complexes in the Synthesis of Chiral, Differentiated
Glutarate Esters
David A. Evans,* Tomislav Rovis, Marisa C. Kozlowski, C. Wade Downey, and
Jason S. Tedrow
Contribution from the Department of Chemistry & Chemical Biology, HarVard UniVersity,
Cambridge, Massachusetts 02138
ReceiVed June 22, 2000
Abstract: C2-symmetric bis(oxazoline)-Cu(II) complexes 1 catalyze the Mukaiyama Michael reaction of
alkylidene malonates and enolsilanes. The use of hexafluoro-2-propanol is essential to induce catalyst turnover.
High enantioselectivities are exhibited by bulky alkylidene malonate â-substituents using catalyst 1a. The
glutarate ester products are readily decarboxylated to provide chiral 1,5-dicarbonyl synthons. Crystallographic
characterization of substrate-catalyst complexes provides insight into the binding event with these catalysts
and affords a rationale for the observed facial selectivities.
Introduction
have been reported for controlling this process in an absolute
sense.9 This report provides a full account of the development
of the addition reactions of enolsilanes to alkylidene malonates
catalyzed by the chiral copper complex 1a (eq 1).
The increasing demand for efficient methods to control
stereochemical relationships has mandated the development of
catalytic asymmetric bond-forming reactions. Lewis acids have
been documented to accelerate numerous bond-forming events,
and hence efforts have been directed at developing chiral
versions to control the overall process in an absolute sense.
Recent reports from this laboratory and others have focused on
the development of cationic bis(oxazoline)-Cu(II) complexes
as chiral Lewis acids1 in a variety of organic transformations
including Diels-Alder,2 hetero-Diels-Alder,3 aldol,4 Michael,5
ene,6 and enol amination7 reactions. The Mukaiyama Michael
reaction,8 the addition of an enolsilane to an R,â-unsaturated
carbonyl induced by a Lewis acid, is a particularly attractive
target for development. Despite its importance, few methods
(1) (a) Johnson, J. S.; Evans, D. A. Acc. Chem. Res. 2000, 33, 325-
335. (b) Evans, D. A.; Rovis, T.; Johnson, J. S. Pure Appl. Chem. 1999,
71, 1407-1415.
At the outset of this work, we speculated that the preorga-
nization afforded by bis(oxazoline)-Cu(II) complexes 1 in
(2) (a) Evans, D. A.; Miller, S. J.; Lectka, T. J. Am. Chem. Soc. 1993,
115, 6460. (b) Evans, D. A.; Murry, J. A.; von Matt, P.; Norcross, R. D.;
Miller, S. J. Angew. Chem., Int. Ed. 1995, 34, 798. (c) Evans, D. A.; Miller,
S. J.; Lectka, T.; von Matt, P. J. Am. Chem. Soc. 1999, 121, 7559. (d)
Evans, D. A.; Barnes, D. M.; Johnson, J. S.; Lectka, T.; von Matt, P.; Miller,
S. J.; Murry, J. A.; Norcross, R. D.; Shaughnessy, E. A.; Campos, K. R. J.
Am. Chem. Soc. 1999, 121, 7582. (e) Evans, D. A.; Johnson, J. S. J. Org.
Chem. 1997, 62, 786. (f) Evans, D. A.; Barnes, D. M. Tetrahedron Lett.
1997, 38, 57. (g) Evans, D. A.; Shaughnessy, E. A.; Barnes, D. M.
Tetrahedron Lett. 1997, 38, 3193. (h) Evans, D. A.; Kozlowski, M. C.;
Tedrow, J. S. Tetrahedron Lett. 1996, 37, 7481. (i) Evans, D. A.; Lectka,
T.; Miller, S. J. Tetrahedron Lett. 1993, 34, 7027. (j) Davies, I. W.;
Senanayake, C. H.; Larsen, R. D.; Verhoeven, T. R.; Reider, P. J.
Tetrahedron Lett. 1996, 37, 1725. (k) Davies, I. W.; Gerena, L.; Castonguay,
L.; Senanayake, C. H.; Larsen, R. D.; Verhoeven, T. R.; Reider, P. J. Chem.
Commun. 1996, 1753. (l) Davies, I. W.; Deeth, R. J.; Larsen, R. D.; Reider,
P. J. Tetrahedron Lett. 1999, 40, 1233. (m) Ghosh, A. K.; Mathivanan, P.;
Cappiello, J. Tetrahedron Lett. 1996, 37, 3815. (n) Ghosh, A. K.; Cho, H.;
Cappiello, J. Tetrahedron: Asymmetry 1998, 9, 3687. (o) Aggarwal, V.
K.; Anderson, E. S.; Jones, D. E.; Obierey, K. B.; Giles, R. Chem. Commun.
1998, 1985. (p) Brimble, M. A.; McEwan, J. F. Tetrahedron: Asymmetry
1997, 8, 4069. (q) Takacs, J. M.; Lawson, E. C.; Reno, M. J.; Youngman,
M. A.; Quincy, D. A. Tetrahedron: Asymmetry 1997, 8, 3073. (r) Takacs,
J. M.; Quincy, D. A.; Shay, W.; Jones, B. E.; Ross, C. R., II Tetrahedron:
Asymmetry 1997, 8, 3079. (s) Chow, H.-F.; Mak, C. C. J. Org. Chem. 1997,
62, 5116.
(3) (a) Evans, D. A.; Johnson, J. S. J. Am. Chem. Soc. 1998, 120, 4895.
(b) Evans, D. A.; Olhava. E. J.; Johnson, J. S.; Janey, J. M. Angew. Chem.,
Int. Ed. 1999, 37, 3372. (c) Evans, D. A.; Johnson, J. S.; Olhava, E. J. J.
Am. Chem. Soc. 2000, 122, 1635. (d) Thorhauge, J.; Johannsen, M.;
Jørgensen, K. A. Angew. Chem., Int. Ed. 1999, 37, 2404. (e) Yao, S.;
Johannsen, M.; Audrain, H.; Hazell, R.; Jørgensen, K. A. J. Am. Chem.
Soc. 1998, 120, 8599. (f) Johannsen, M.; Yao, S.; Jørgensen, K. A. Chem.
Commun. 1997, 2169. (g) Ghosh, A. K.; Mathivanan, P.; Cappielo, J.;
Krishnan, K. Tetrahedron: Asymmetry 1996, 7, 2165. (h) Johannsen, M.;
Jørgensen, K. A. J. Org. Chem. 1995, 60, 5757. (i) Johannsen, M.;
Jørgensen, K. A. J. Chem. Soc., Perkin Trans. 2 1997, 1183. (j) Johannsen,
M.; Jørgensen, K. A. Tetrahedron 1996, 52, 7321. (k) Yao, S.; Johannsen,
M.; Hazell, R. G.; Jørgensen, K. A. Angew. Chem., Int. Ed. 1998, 37, 3121.
(l) Jnoff, E.; Ghosez, L. J. Am. Chem. Soc. 1999, 121, 2617. (m) Motorina,
I. A.; Grierson, D. S. Tetrahedron Lett. 1999, 40, 7215.
(4) (a) Evans, D. A.; Murry, J. A.; Kozlowski, M. C. J. Am. Chem. Soc.
1996, 118, 5814. (b) Evans, D. A.; Kozlowski, M. C.; Burgey, C. S.;
MacMillan, D. W. C. J. Am. Chem. Soc. 1997, 119, 7893. (c) Evans, D.
A.; Kozlowski, M. C.; Murry, J. A.; Burgey, C. S.; Campos, K. R.; Connell,
B. T.; Staples, R. J. J. Am. Chem. Soc. 1999, 121, 669. (d) Evans, D. A.;
Burgey, C. S.; Kozlowski, M. C.; Tregay, S. W. J. Am. Chem. Soc. 1999,
121, 686. (e) Kobayashi, S.; Nagayama, S.; Busujima, T. Chem. Lett. 1999,
71. (f) Kobayashi, S.; Nagayama, S.; Busujima, T. Tetrahedron 1999, 55,
8739. (g) Reichel, F.; Fang, X.; Yao, S.; Ricci, M.; Jørgensen, K. A. Chem.
Commun. 1999, 1505.
10.1021/ja002246+ CCC: $19.00 © 2000 American Chemical Society
Published on Web 09/13/2000

Michael Reactions of Alkylidene Malonates
J. Am. Chem. Soc., Vol. 122, No. 38, 2000 9135
Reaction Development. Initial addition reactions with the
phenyl-substituted alkylidene malonates and enolsilane 2 in the
presence of [Cu(S,S)-t-Bu-box](SbF6)2 revealed that the sto-
ichiometric process provides the Michael adduct in 91% ee (90%
conversion) (eq 4); however, under catalytic conditions, no
turnover is observed. Upon warming the reaction mixture to
-20 °C, the adduct is formed (40% conversion) with a
significant decrease in selectivity (40% ee). A number of
literature reports have appeared documenting the dramatic
impact of alcoholic additives on catalyst turnover13 and work
within our group had shown that these Cu(II) catalysts retain
their activity in the presence of such addends.14 Accordingly,
we evaluated a number of alcohols in an attempt to promote
reaction turnover (Table 1). As the data indicate, enantioselec-
tivities increase significantly in the presence of alcoholic
additives, suggesting that turnover in their absence was due to
the intervention of a second, less selective pathway.
Figure 1. Binding motifs of 1,2 and 1,3 dicarbonyl substrates with
bis(oxazoline)-Cu(II) complexes.
controlling π-facial discrimination in the Diels-Alder process
(eq 2a) via substrate-catalyst complex 5 should be transferable
to Michael reactions of enolsilanes (eq 2b). While this analogy
has stimulated the development of these valuable addition
processes,5a we have also explored the even more reactive
alkylidene malonate Michael acceptors using this family of
catalyst complexes.
It was felt that the enhanced reactivity of substituted
alkylidene malonates might accommodate the inclusion of a
wider range of â-substituents into the Michael acceptor.
However, the analogies for asymmetric induction in this process
are not well developed. While the unsaturated imide and R-keto
ester-Cu(II) complexes 5 and 6 place the ligand chirality close
to the prochiral centers in the bound reactants, the putative
catalyst-substrate complex 7 positions the ligand some distance
from the resident prochiral center in the Michael acceptor.
However, conformational effects within the complex were not
discounted as a potential element in the transmission of ligand
chirality to the reaction.10
Concurrent with this investigation, Bernardi and Scolastico
had shown that R-alkylidene keto esters undergo Michael
addition with enolsilanes mediated by bis(oxazoline)-Cu(II)
complexes.11 This reaction is stoichiometric in Cu(II) complex,
with one exception (eq 3). In another relevant investigation,
Tietze has demonstrated that Lewis acid-mediated intramolecular
allylsilane additions to alkylidene malonates are effectively
controlled by an oxazolidinone auxiliary.12
Hexafluoro-2-propanol (HFIP) proved to be the most efficient
alcohol in promoting turnover in this reaction. However,
considerable starting alkylidene malonate still remained. We
speculated that the enolsilane was being competitively hydro-
lyzed during the course of the reaction. To test this hypothesis,
the reaction of enolsilane 2 and HFIP in CH2Cl2 (-78 °C) was
monitored by in situ IR spectroscopy (eq 6a). No change was
observed over the course of 1 h. Upon addition of complex 1a
to this solution, the immediate appearance of the carbonyl stretch
of tert-butylthioacetate (1675 cm-1) was noted and complete
hydrolysis of the enolsilane was observed within 40 min at -78
°C. This suggests that coordination of HFIP to the Lewis acid
is required to produce a species acidic enough to decompose
the enolsilane.15 This hypothesis was validated by the observa-
tion that 2-propanol leads to faster hydrolysis (and lower
conversion to product) than the more acidic HFIP, despite the
significant difference in the pKa’s of these two alcohols (30.3
vs 17.9 in DMSO,16 respectively). We suggest that, in the
presence of complex 1a, the pKa of 2-propanol is effectively
lower because of the higher equilibrium constant between bound
alcohol (1a‚ROH) and free alcohol (eq 6b).
(5) (a) Evans, D. A.; Willis, M. C.; Johnston, J. N. Org. Lett. 1999, 1,
865. (b) Kitajima, H.; Katsuki, T. Synlett 1997, 568. (c) Kitajima, H.; Ito,
K.; Katsuki, T. Tetrahedron 1997, 53, 17015.
(6) (a) Evans, D. A.; Burgey, C. S.; Paras, N. A.; Vojkovsky, T.; Tregay,
S. W. J. Am. Chem. Soc. 1998, 120, 5824. (b) Gao, Y.; Lane-Bell, P.;
Vederas, J. C. J. Org. Chem. 1998, 63, 2133. (c) See refs 3h and 3j.
(7) Evans, D. A.; Johnson, D. S. Org. Lett. 1999, 1, 595.
(8) For a seminal reference, see: Narasaki, K.; Soai, K.; Mukaiyama,
T. Chem. Lett. 1974, 1223.
(9) (a) Oare, D. A.; Heathcock, C. H. Top. Stereochem. 1991, 20, 124.
(b) Oare, D. A.; Heathcock, C. H. Top. Stereochem. 1989, 19, 227. (c)
Yura, T.; Iwasawa, N.; Narasaka, K.; Mukaiyama, T. Chem. Lett. 1988,
1025. (d) Kobayashi, S.; Suda, S.; Yamada, M.; Mukaiyama, T. Chem. Lett.
1994, 97. (e) Kitajima, H.; Katsuki, T. Synlett 1997, 568.
(10) Part of this work has already been communicated: Evans, D. A.;
Rovis, T.; Kozlowski, M. C.; Tedrow, J. S. J. Am. Chem. Soc. 1999, 121,
1994.
(11) Bernardi, A.; Colombo, G.; Scolastico, C. Tetrahedron Lett. 1996,
37, 8921. These workers have also investigated Ti-TADDOL as a
stoichiometric promoter of this reaction: Bernardi, A.; Karamfilova, K.;
Boschin, G.; Scolastico, C. Tetrahedron Lett. 1995, 36, 1363.
(12) Tietze, L. F.; Schu¨nke, C. Eur. J. Org. Chem. 1998, 2089.
(13) (a) Kawara, A.; Taguchi, T. Tetrahedron Lett. 1994, 35, 8805. (b)
See ref 9e.
(14) See refs 3c and 5a.
(15) (a) Ishihara, K.; Nakamura, S.; Kaneeda, M.; Yamamoto, H. J. Am.
Chem. Soc. 1996, 118, 12854. (b) Ishihara, K.; Kurihara, H.; Matsumoto,
M.; Yamamoto, H. J. Am. Chem. Soc. 1998, 120, 6920.
(16) Bordwell, F. G. Acc. Chem. Res. 1988, 21, 456.

9136 J. Am. Chem. Soc., Vol. 122, No. 38, 2000
EVans et al.
Table 2. Slow Addition of Nucleophile Increases Turnovera
Table 1. Effect of Additives on the Michael Reaction of 2 and
Benzylidene Malonate 3a
a Enolsilane added to a solution of substrate, catalyst, and additive.
b Addition time for delivery of enolsilane 2 to reaction flask via syringe
pump. c Conversion determined by 1H NMR. d Enantiomeric excess
determined by HPLC using a Chiralcel AD column. (1a): [Cu(S,S)-
t-Bu-box](SbF6)2.
a Enolsilane (2 equiv) added to a solution of substrate, catalyst and
additive (1.5 equiv). b Determined by 1H NMR. c Enantiomeric excess
determined by HPLC on Chiralcel AD column. (1a): [Cu(S,S)-t-Bu-
box](SbF6)2.
Figure 2. PM3 model of [Cu(S,S)-t-Bu-box]‚3 (X)2 illustrating a
In an attempt to minimize enolsilane decomposition, we
investigated the use of a slow addition procedure. Syringe pump
addition of the enolsilane to a catalyst-malonate mixture over
the course of 10 h at -20 °C resulted in complete conversion
to product (entry 2 in Table 2) affording the Michael adduct in
89% ee. This reaction was also conducted at a lower temperature
with the aim of improving selectivities. Unfortunately, this
strategy proved untenable as slow addition over 18 h was
insufficient to achieve complete conversion.17
predicted gearing of the ester group by the ligand substituent.
Table 3. Effect of Ester Substituent on the Michael Reaction of 2
and Benzylidene Malonates
Ester Gearing. At the outset of this study, it was not evident
how the bis(oxazoline)-Cu(II) complex 7 might impart π-facial
selectivity to the alkylidene malonate acceptors. Examination
of models (PM3) of alkylidene malonate-copper complexes
provided little insight into the potential origins of π-facial
selectivity (Figure 1). In one possible option, it was speculated
that the ligand substituents might influence the conformation
of the ester substituents thereby relaying the influence of the
chiral ligand closer to the reaction center, Figure 2. As such,
an increase in the size of this substituent might lead to an
increase in reaction enantioselectivity. Correspondingly, a
smaller ester should lead to lower selectivity if this “gearing
premise” is valid.
To test this gearing hypothesis, a number of benzylidene
malonates with varying ester substituents were synthesized.
When these substrates were subjected to the catalyzed reaction
at ambient temperature, the Michael adduct was formed in good
yield (Table 3). Enantioselectivity increases as a function of
increasing ester size. Isopropyl esters reverse this trend while
the bulky tert-butyl esters proved to be unreactive under these
conditions. Upon cooling this reaction to -20 °C, however, we
a Enantiomeric excesses were determined by chiral HPLC using a
Chiralcel AD column. b Enolsilane added to substrate, catalyst, and
alcohol over the course of 1-15 s. c Enolsilane added to substrate,
catalyst, and alcohol over the course of 10 h. d Enolsilane added to
substrate, catalyst, and alcohol over 16 h. (1a): [Cu(S,S)-t-Bu-
box](SbF6)2.
noted that the ethyl and isobutyl esters provide the Michael
adduct in identical enantioselectivity, despite the significant
difference observed between these two substrates at ambient
temperature. Furthermore, the bulkier isobutyl ester provides
the Michael adduct in lower conversion even with slow addition
of enolsilane. Accordingly, it was concluded that enantioselec-
tivities in these reactions were governed by factors other than
ester size and that the gearing hypothesis could not account for
the observed selectivities at lower temperatures. As such, we
wondered whether the methyl ester could provide the conjugate
adduct in equivalent selectivities as the larger esters at a lower
temperature. This was particularly attractive because conversion
using the smaller ester was invariably higher under identical
conditions. Indeed, at -78 °C, the methyl ester affords the
(17) Addition times varied between 8 and 16 h. Changing the substrate
required reoptimization of addition times. Alkylidene malonate 10i proved
resilient to this protocol, affording only 55% conversion under the optimized
addition time of 16 h. We suggest that the bulk of this substrate is
responsible. From this and other data, we concluded that slow addition would
prove insufficient as a general solution.

Michael Reactions of Alkylidene Malonates
J. Am. Chem. Soc., Vol. 122, No. 38, 2000 9137
Table 6. Temperature Profilea
Table 4. Effect of Solvent and Concentration on the Michael
Reaction of 2 and Benzylidene Malonatesa
a Enolsilane added to a solution of substrate, catalyst, and additive.
b Determined by 1H NMR. c Enantiomeric excess determined by HPLC.
(1a): [Cu(S,S)-t-Bu-box](SbF6)2.
a Enolsilane added to a solution of substrate, catalyst, and additive.
b In substrate. c Determined by 1H NMR. d Enantiomeric excess deter-
mined by HPLC. (1a): [Cu(S,S)-t-Bu-box](SbF6)2.
Table 7. Scope of the Catalyzed Michael Reaction between 2 and
10: Aryl Substituents (Eq 12)a
Table 5. Catalyst Surveya
a Enolsilane added to a solution of substrate, catalyst, and additive.
b In substrate. c Determined by 1H NMR. d Enantiomeric excess deter-
mined by HPLC. Absolute configuration determined by X-ray crystal-
lography. (1a): [Cu(S,S)-t-Bu-box](SbF6)2.
a Reaction conducted with 2.2 equiv of 2 and 2 equiv of hexafluoro-
2-propanol (HFIP) relative to 10 in PhMe/CH2Cl2 (3:1). b Isolated yield.
c Determined by chiral HPLC (see Supporting Information). Absolute
configuration as indicated. d 20 mol % catalyst used and 2.5 equiv of
2 added. (1a): [Cu(S,S)-t-Bu-box](SbF6)2.
Michael adduct in 91% ee and quantitative conversion. Under
identical conditions, the ethyl and isobutyl esters exhibited little
reaction.
The temperature profile of this reaction reveals descending
selectivity with ascending temperature. However, conversion
does not respond linearly to temperature (Table 6). At temper-
atures above -30 °C, the reaction does not proceed to
completion. We believe this supports our assertion of the
importance of alcohol solubility to the success of this process.
Electrophile Scope. A variety of alkylidene malonates were
evaluated as substrates. The reaction affords high enantiose-
lectivities for aryl (phenyl ) 93% ee, 2-methoxyphenyl ) 99%
ee, 2-naphthyl ) 93% ee) and heteroaryl (2-furyl ) 94% ee,
3-indolyl ) 86% ee) alkylidene malonates, Table 7. 1-Naphthyl
alkylidene malonate proved to be nonselective (0-5% ee) under
these conditions for reasons that remain unclear (entry 3). To
evaluate relative reactivity of this substrate with the related
2-naphthyl alkylidene malonate, 1 equiv of enolsilane and a 1:1
mixture of these two alkylidene malonates (10c and 10d) were
subjected to 10 mol % catalyst under the standard reaction
conditions in a competition experiment (eq 13). 2-Naphthyl
alkylidene malonate provides the Michael adduct in 77%
conversion with 94% ee, while 1-naphthyl alkylidene malonate
affords only 12% conversion and 6% ee product.
Branched alkyl substrates also give Michael adducts in high
enantioselectivity (cyclohexyl ) 95% ee, isopropyl ) 93% ee,
tert-butyl ) 90% ee, Table 8). This reaction proceeds with equal
facility at lower catalyst loading (5 mol %, entry 2) and on a
1-g scale (entry 3), affording adducts in 95% ee and quantitative
yield. Unbranched alkyl substrates are far less effective as
substrates in this reaction. Ethylidene malonate gives the
Michael adduct in only 43% ee. In an attempt to delineate the
limits of acceptable substitution patterns, alkyl substituents
Solvent Polarity. During the course of these investigations,
it was noted that hexafluoro-2-propanol is sparingly soluble in
CH2Cl2 at low temperatures. Since the success of the slow
addition procedure was presumably due to a reduction in the
rate of the destructive enolsilane hydrolysis by maintaining a
low local concentration of one of the reactants, we wondered
whether we could take advantage of the solubility properties of
HFIP to lower its concentration in solution relative to the other
reagents, thus favoring the productive Michael pathway (Table
4). A decrease in the amount of solvent used and, hence, an
increase in the concentrations of electrophile, nucleophile, and
catalyst resulted in a significant increase in conversion to 87%
(0.5 M vs 0.2 M in substrate). The use of a less polar reaction
medium (CH2Cl2/PhMe mixtures, entries 3 and 4 in Table 4)
resulted in complete conversion to product at 0.2 M concentra-
tion. Reactions in toluene afford no discernible benefits.
Therefore, given that the active catalyst must be made in CH2-
Cl2, the mixed solvent system was chosen for further develop-
ment. With the optimized reaction conditions in hand, the effect
of ligand architecture on the reaction of enolsilane 2 and
benzylidene malonate 10 (Table 5) was investigated. tert-Butyl
bis(oxazoline) proved to be the optimal ligand for copper(II) in
this reaction. It is interesting that the copper complex derived
from phenyl bis(oxazoline) provides the Michael adduct of
opposite configuration. This effect had previously been observed
in several other reactions.3a-c,h,6a Although various rationales
have been advanced to account for this reversal (vide infra), it
remains an unresolved issue in the field. As will be discussed
below, some insight into this effect has been gained from
crystallographic studies of catalyst-substrate complexes.

9138 J. Am. Chem. Soc., Vol. 122, No. 38, 2000
EVans et al.
Table 9. Variation of the Nucleophile in the Catalyzed Michael
intermediate in size between methyl and isopropyl were
screened. Each substrate examined afforded lower enantiose-
lectivities than methyl itself (ethyl ) 22% ee, n-propyl ) 27%
Reaction between 17 and 10 (Eq 16)a
a Reaction conducted with 2.2 equiv of 17 and 2 equiv of hexafluoro-
2-propanol (HFIP) relative to 10a in CH2Cl2. b Determined by 1H NMR
of the unpurified reaction mixture. c Determined by chiral HPLC on a
Chiralcel AD column. Configuration assigned by analogy. d Reaction
conducted at -50 °C with slow addition of nucleophile (16 h). (1a):
[Cu(S,S)-t-Bu-box](SbF6)2.
Table 10. Diastereoselectivity in the Michael Reaction of
Propionate Enolsilane and Alkylidene Malonates (Eq 17)a
ee, isobutyl ) 33% ee). We speculated that the absolute
stereochemistry of the Michael adduct derived from benzylidene
Table 8. Scope of the Catalyzed Michael Reaction between 2 and
10: Alkyl Substituents (Eq 14)
a Reaction conducted with 2.2 equiv of 19 and 2 equiv of hexafluoro-
2-propanol (HFIP) relative to 10 in CH2Cl2. b Ratio of enolsilane
geometry. c Determined by 1H NMR of the unpurified reaction mixture.
d Determined by chiral HPLC on Chiralcel OJ and AD columns.
Absolute configuration not assigned. (1a): [Cu(S,S)-t-Bu-box](SbF6)2.
1,4- and 1,6-addition pathways. The tiglic aldehyde-derived
alkylidene malonate 10n affords high yields of the Michael
adduct. The regioselectivity of the addition was found to be
90:10 in favor of the 1,4 product which was formed in 94% ee
and good yield (eq 15).
a Reaction conducted with 2.2 equiv of 2 and 2 equiv of hexafluoro-
2-propanol (HFIP) relative to 10 in PhMe/CH2Cl2 (3:1). b Isolated yield.
c Determined by chiral HPLC (see Supporting Information). Configu-
ration provided in parantheses, where assigned. d 5 mol % catalyst used.
e 5 mol % catalyst used on a 5-mmol scale. f Conversion (as determined
Nucleophile Scope. In an effort to expand the scope of
acceptable nucleophiles, we examined the reaction of a number
of unsubstituted ketone-derived enolsilanes. Within this series,
pinacolone- and acetophenone-derived enolsilanes were less
reactive18 and considerably less selective. S-Phenyl thioester
derived enolsilane was also less selective than the S-tert-butyl
thioacetate analogue illustrating the importance of steric hin-
drance at that position. We briefly examined the effect of the
silyl moiety (entry 4) and found that TES enolsilane derived
from S-tert-butyl thioacetate, while very selective at a slightly
higher temperature,was not amenable to catalyst turnover.
Diastereoselective Michael reactions were examined using
propionate-derived enolsilanes. Selectivities were found to
depend significantly on enolsilane geometry. Benzylidene
malonate 10a afforded anti-Michael adduct with either the (E)
or (Z) enolsilane, but only the latter was selective (92:8 vs 55:
45). Enantioselectivity in this reaction is moderate, providing
the anti diastereomer in 80% ee. The results with ethylidene
malonate were complementary: (E) enolsilane affords a highly
anti-selective Michael adduct (95:5) while the (Z) enolsilane
leads to poor syn selectivity (71:29).
1
by H NMR). (1a): [Cu(S,S)-t-Bu-box](SbF6)2.
and ethylidene malonate corresponded to opposite facial attack
by the nucleophile. As such, substituents larger than methyl
would, in principle, provide selectivities intermediate between
phenyl (+93) and methyl (-43). Indeed, this proved to be the
case (vide infra).
One dienic ester was also evaluated (eq 15). With such
Stereochemical Models. The departure from previously
exploited binding motifs (5 and 6 in Figure 1) necessitated the
substrates, the reaction is potentially complicated by competing
(18) Mayr, H.; Patz, M. Angew. Chem., Int. Ed. 1994, 33, 938.

Michael Reactions of Alkylidene Malonates
J. Am. Chem. Soc., Vol. 122, No. 38, 2000 9139
Figure 3. PM3 model and X-ray structure of [Cu(S,S)-t-Bu-box](SbF6)2 complex 1a with alkylidene malonate 10a (counterions omitted for clarity).
Table 11. Correlation of Ligand Substituents with Selectivity (Eq 18)a
development of a new model to explain the observed product
stereochemistry. PM3-level calculations predicted a complex
devoid of obvious steric impediment to incoming nucleophiles
from either face of the coordinated alkylidene malonate complex
(Figure 3).19 Fortuitously, attempts to induce the formation of
X-ray-quality crystals of substrate-catalyst complexes were
successful. The crystal structure provided considerable impetus
for the development of a stereochemical model.
The crystal structure of {Cu[(S,S)-t-Bu-box](10a)}(SbF6)2
(1a‚10a) depicted in Figure 3 is the first crystallographically
characterized bis(oxazoline)-Cu(II) complex containing a bound
substrate. It provides evidence in support of our hypothesis1
that substrates bind to this complex in a distorted square-planar
geometry analogous to the coordination geometry observed in
a Reaction conducted with 2.2 equiv of 2 and 2 equiv of hexafluoro-
the aquo complex {Cu[(S,S)-t-Bu-box](OH2)2}(SbF6)2.20 The
magnitudes of the O-Cu-N-C dihedral angle distortions are
different for the alkylidene malonate complex than that observed
in the dihydrate crystal structure (13.6 and 17.4° vs 29.3 and
30.4°, respectively). In contrast to the PM3 model, the crystal
structure depicts the alkylidene malonate as being significantly
distorted from planarity in the metal-substrate complex. The
six-membered ring formed by the dicarbonyl, alkene carbon,
and copper atom is in a boat conformation with the alkene
carbon and metal at the apexes.21 The ligand sits preferentially
on one face of the olefin, positioning the â-phenyl substituent
in the substrate away from the proximal tert-butyl substituent
on the ligand. A small pyramidalization of the R-carbon of the
olefin (3°) is noted in this structure. A similar pyramidalization
has been used to rationalize facial selectivity in an auxiliary-
controlled alkylidene malonate Diels-Alder reaction.22 Pyra-
2-propanol (HFIP) relative to 10 in PhMe/CH2Cl2 (3:1). b Enantiose-
lectivity afforded by ligand-Cu complex. Determined by chiral HPLC
(see Supporting Information).
midalization has also been invoked to explain diastereoselec-
tivity in chiral dioxolenone functionalization.23 While it is
hazardous to extrapolate from solid state to solution structures,
it should be noted that the sterically more accessible face of
the prochiral carbon in 1a‚10a (Figure 3) correlates with the
stereochemical outcome of the Michael adducts themselves. In
an attempt to optimize Michael additions to n-alkyl-substituted
alkylidene malonates, we examined their reactions with enol-
silane 2 in the presence of varying bis(oxazoline) copper(II)
catalysts. A comparison of benzylidene malonate and several
alkylidene malonates (Me, n-Pr, i-Bu) in the presence of t-Bu,
Ph, i-Pr, and Bn bis(oxazoline)-Cu(II) catalysts is illustrated
in Table 11. The results varied as illustrated above: t-Bu-box
was optimal for benzylidene malonate (93% ee), i-Pr-box for
ethylidene malonate (50% ee), and Ph-box was best for
malonates 10l and 10m (43% and 72% ee), respectively. It is
significant that facial selectivities exhibited by i-Pr- and Bn-
box are always identical, similar to t-Bu-box with 10a and 10l
and with Ph-box for 10j and 10m. Ph-box and t-Bu-box always
display opposite facial selectivity.
(19) Geometry optimizations were performed at the PM3(tm) level using
the Spartan Semiempirical Program 5.0 (Wavefunction Inc., Irvine, CA
92612) on a Silicon Graphics Impact 10000 (195 MHz, 128 M RAM)
running IRIX 6.2. Calculations were performed without counterions or
solvent using the following parameters: optcycle ) 5000, maxcycle )
10000, charge ) 2, multiplicity ) 2. Calculations converged (energy
difference between cycles <0.0005 kcal/mol) in e4 h CPU time.
(20) Evans, D. A.; Peterson, G. S.; Johnson, J. S.; Barnes, D. M.; Campos,
K. R.; Woerpel, K. A. J. Org. Chem. 1998, 63, 4541.
(21) This is not suprising considering that this ring needs to accommodate
five 120° angles (C-C-O, C-C-C, and C-O-Cu), one 90° angle (square
planar Cu), and two long bonds (2.0 Å, Cu-O). Indeed, a molecular
mechanics geometry optimization of this ring alone predicts an identical
conformation despite the failure of PM3 to do likewise.
(22) Katagiri, N.; Watanabe, N.; Sakaki, J.-i.; Kawai, T.; Kaneko, C.
Tetrahedron Lett. 1990, 31, 4633.
(23) Seebach, D.; Zimmermann, J.; Gysel, U.; Ziegler, R.; Ha, T.-K. J.
Am. Chem. Soc. 1988, 110, 4763.

9140 J. Am. Chem. Soc., Vol. 122, No. 38, 2000
EVans et al.
Figure 4. Two views of the X-ray crystal structure of the [Cu(S,S)-Ph-box](SbF6)2 complex of malonate 10a (counterions omitted in the left view
for clarity).
Figure 5. Comparison of the X-ray crystal structures of [Cu(S,S)-t-Bu-box](SbF6)2 and [Cu(S,S)-Ph-box](SbF6)2 complexes of malonate 10a.
As mentioned previously, the reversal of facial selectivity
exhibited by t-Bu-box and Ph-box Cu(II) complexes is an
unsolved problem in this field and has been observed in the
ene3h,6c and hetero-Diels-Alder3c reactions. The primary ratio-
nale that has been posited to account for this observation
involves a change in geometry of the catalyst-substrate complex
from distorted square planar to tetrahedral.24 This proposal is
unsatisfying in the face of structural and circumstantial evidence
against this metal geometry.25 We speculated that there could
be a structural difference in the solid-state geometries of cat-
alyst-substrate complexes of t-Bu-box and Ph-box, which may
provide some insight into π-facial discrimination in these reac-
tions. Suitable X-ray-quality crystals of malonate bound to [Cu-
(S,S)-Ph-box](SbF6)2 complex were obtained from pentane/di-
chloromethane solution; the structure is illustrated in Figure 4.
The crystal structure of [Cu(S,S)-Ph-box(10a)](SbF6)2 (1d‚
10a) reveals a distorted octahedral geometry at the copper center
with each SbF6 counterion in a weak bonding interaction (2.35
and 2.65 Å). The metal geometry and counterion contact
distances correlate well with the crystal structure of the
corresponding dihydrate, suggesting that this may be a general
phenomenon for these complexes.14a The dicarbonyl is bound
in the equatorial plane with a small distortion (1.4 and 2.3°)
from the N-Cu-N plane. The â-phenyl substituent is bent
toward the phenyl group on the ligand backbone, thereby
exposing the convex re face toward nucleophilic attack. This
corresponds to facial selectivity complementary to that exhibited
by the crystal structure of {Cu[(S,S)-t-Bu-box](10a)](SbF6)2
complex (vide supra). The source of this turnover is unclear. It
is tempting to invoke an edge-face interaction between the
alkylidene malonate phenyl group and the ligand substituent,
validated by a reasonable ortho hydrogen-arene centroid
distance of ∼3.1 Å and a centroid-centroid distance of 5.4 Å.26
However, turnover between the Ph-box and t-Bu-box catalysts
is observed with both aryl and alkyl alkylidene malonates
(24) (a) Johannsen, M.; Yao, S.; Graven, A.; Jørgensen, K. A. Pure Appl.
Chem. 1998, 70, 1117. (b) References 3f and 3h.
(25) (a) Evans, D. A.; Johnson, J. S.; Burgey, C. S.; Campos, K. R.
Tetrahedron Lett. 1999, 40, 2879. (b) See also refs 3c and 2l.
(26) Centroid distances in documented edge-face complexes span a range
from 4.5 to 7 Å; see: Quan, R. W.; Li, Z.; Jacobsen, E. N. J. Am. Chem.
Soc. 1996, 118, 8156 and references therein.

Michael Reactions of Alkylidene Malonates
J. Am. Chem. Soc., Vol. 122, No. 38, 2000 9141
Scheme 1
Figure 6. X-ray crystal structure of [Cu(S,S)-t-Bu-box](SbF6)2 complex
1a with alkylidene malonate 10j.
curvature in the six-membered ring formed by the dicarbonyl
and copper atom is not as pronounced in this structure as in the
benzylidene malonate-Cu(II) complex and presents the opposite
face toward nucleophilic attack, corresponding to the observed
absolute stereochemistry of the major enantiomer.
Mechanistic Considerations. A coherent mechanistic ex-
planation of this reaction begins to emerge from consideration
of the results described above. Two-point binding of the
alkylidene malonate to the bis(oxazoline)-copper complex is
presumed since this affords the most reactive of the possible
catalyst-substrate complexes. This assumption is reinforced by
crystallographic characterization of these substrate-catalyst
complexes. A possible rationale for the poor results afforded
by the extremely bulky 1-naphthyl alkylidene malonate is that
it does not react by the two-point binding motif but rather by
single-point coordination, accounting for its lower reactivity and
complete lack of selectivity.
The broad outline of a catalytic cycle is provided in Scheme
1. Addition of the enolsilane to the alkylidene malonate may
proceed by an open transition state. The intermediate silyloxy-
carbenium/malonyl enolate zwitterion may either exist as ion
pair 21a or close reversibly to form the cyclobutane 21b.27
Hexafluoro-2-propanol serves as the proton source and ultimate
silicon acceptor. The order of these two events remains
undetermined. Dissociation of the neutral product from the
suggesting edge-face interaction may not be the exclusive factor
influencing π-facial selectivity.
The turnover in facial selectivity exhibited by the catalyst
[Cu(S,S)-t-Bu-box](SbF6)2 (1a) in the Mukaiyama Michael
reaction of ethylidene malonate 10j as compared to bulky
alkylidene malonates was also an aspect of this reaction that
required further analysis. We hoped that the elucidation of the
solid state structure of its complex with the catalyst would
provide some insight into the significantly lower selectivities
exhibited by unbranched alkyl substituents. X-ray-quality
crystals of {Cu[(S,S)-t-Bu-box](10j)}(SbF6)2 were obtained from
pentane/dichloromethane and the solved structure is shown in
Figure 6. This structure has the closest SbF6-Cu contact
distance observed to date in the t-Bu-box series (2.73 Å vs 3.30
Å for {Cu[(S,S)-t-Bu-box](OH2)2}(SbF6)2 and 4.60 Å for {Cu-
[(S,S)-t-Bu-box](10a)}(SbF6)2). The dicarbonyl binds to the
metal in a distorted square-planar geometry similar to the
benzylidene malonate Cu(II) complex (15.1 and 16.5°). The
Scheme 2
a Br2, MeOH, CH2Cl2. b Rh/Al2O3, H2, MeOH. c RuCl3‚H2O, NaIO4, MeCN/CCl4/H2O; then CH2N2. d Br2, THF/H2O. e BH3‚DMS, THF. f NaCl,
wet DMSO, 130 °C. g TFA, CH2Cl2. h (R)-a-Naphthylmethylbenzylamine, EDCI, DMAP, CH2Cl2.

9142 J. Am. Chem. Soc., Vol. 122, No. 38, 2000
EVans et al.
copper complex allows for catalyst turnover. The competing
hydrolysis must proceed by alcohol coordination to copper. The
strong Lewis acid activation of HFIP by Cu(II) significantly
changes the acidity of this proton.28
DMSO at 130 °C in the presence of NaCl. Higher temperatures
consistently led to lower yields, presumably due to competing
thioester hydrolysis. Selective hydrolyis or alcoholysis of the
thioester is possible using documented procedures.32
Stereochemical Proof. Absolute stereochemistry was unam-
biguously assigned for compounds 15a, 15f, 15g, 15h, and 15j
by the procedures illustrated in Scheme 2. An X-ray crystal
structure of 15a allowed the assignment of the stereochemistry
of this adduct as depicted. Chemical correlation of adducts 15f
and 15g to this structure was accomplished. Correlation of 15h
to the known lactone 2629 confirmed that the absolute stereo-
chemistry of this adduct was as assigned. The absolute stere-
ochemistry of the methyl substrate 15j was assigned by chemical
correlation with glutarate amide 28,30 formed from the Michael
adduct (44% ee) as a 73:27 ratio of 1,5-anti to 1,5-syn
diastereomers (46% de). The stereochemical assignment for the
aryl and branched alkyl Michael adducts conforms to a
conserved π-facial selectivity for the corresponding alkylidene
malonate substrates. As expected, absolute stereochemistry of
the methyl-substituted Michael adduct corresponds to a reversal
in π-facial selectivity.
Conclusion. The Mukaiyama Michael reaction of alkylidene
malonates and enolsilanes is efficiently catalyzed by bis-
(oxazoline)-Cu(II) complexes. Catalyst turnover in this reaction
is not observed in the absence of protic additives and high
conversion is achieved in the presence of hexafluoro-2-propanol.
A competing enolsilane decomposition pathway is effectively
minimized in low-polarity solvents relying on the poor solubility
of the fluorinated alcohol at low temperature. Large â-substit-
uents afforded highest enantioselectivities in this reaction,
typically >90% ee. Crystallographic characterization of substrate-
catalyst complexes has provided considerable insight into how
these complexes may behave in solution and into the source of
enantioselectivity. The Michael adducts are formed in high
yields and may be readily decarboxylated to afford chiral,
differentiated glutarate esters.
Product Elaboration. The Michael adducts undergo facile
monodecarbomethoxylation under Krapcho conditions31 to af-
ford chiral differentiated glutarate esters. Optimal decarboxyl-
ation conditions involved heating the malonate ester in wet
(27) Electron-deficient alkylidene malonates form cyclobutanes upon
reaction with electron-rich olefins, see: Evans, S. B.; Abdelkader, M.;
Padias, A. B.; Hall, H. K., Jr. J. Org. Chem. 1989, 54, 2848.
Acknowledgment. Support for this research was provided
by the NSF and the NIH (GM-33328). Postdoctoral fellowships
from NSERC (T.R.) and NSF (M.C.K) are gratefully acknowl-
edged. The amino alcohols and acids utilized in the preparation
of the box ligands were generously provided by NSC Technolo-
gies.
2+
(28) The pKa of Cu(H2O)6 has been determined to be 7.53 (cf.:
Kobayashi, S.; Nagayama, S.; Busujima, T. J. Am. Chem. Soc. 1998, 120,
8287). The pKa of hexafluoro-2-propanol in water is 10.6 (Ballinger, P.;
Long, F. A. J. Am. Chem. Soc. 1959, 81, 1050). If we assume that the
metal center increases the Lewis acidity of HFIP by a factor of 5-8 pKa
units, this places the acidity of the copper-bound alcohol in the range of
∼2.6-5.
(29) Paquette, L. A.; Dahnke, K.; Doyon, J.; He, W.; Wyant, K.;
Friedrich, D. J. Org. Chem. 1991, 56, 6199.
Supporting Information Available: Complete experimental
procedures, crystallographic data, and characterization of new
compounds (PDF). This material is available free of charge via
the Internet at http://pubs.acs.org.
(30) (a) Hoye, T. R.; Koltun, D. O. J. Am. Chem. Soc. 1998, 120, 4638.
(b) Konoike, T.; Araki, Y. J. Org. Chem. 1994, 59, 7849
(31) Krapcho, A. P. Synthesis 1982, 805.
(32) (a) Minato, H.; Kodama, H.; Miura, T.; Kobayashi, M. Chem. Lett.
1977, 413. (b) Minato, H.; Takeda, K.; Miura, T.; Kobayashi, M. Chem.
Lett. 1977, 1095.
JA002246+