C2-symmetric copper(II) complexes as chiral Lewis acids. Catalytic enantioselective aldol additions of silylketene acetals to (benzyloxy)acetaldehyde

Full text of DOI:10.1021/ja960712i

5814
J. Am. Chem. Soc. 1996, 118, 5814-5815
Scheme 1
C2-Symmetric Copper(II) Complexes as Chiral
Lewis Acids. Catalytic Enantioselective Aldol
Additions of Silylketene Acetals to
(Benzyloxy)acetaldehyde
David A. Evans,* Jerry A. Murry, and Marisa C. Kozlowski
Department of Chemistry, HarVard UniVersity
Cambridge, Massachusetts 02138
ReceiVed March 5, 1996
The Lewis acid-catalyzed addition of enolsilanes to aldehydes,
commonly known as the Mukaiyama aldol reaction,1,2 is an
important variant of the general aldol process. This reaction
has become the focal point for the development of enantiose-
lective variants through catalysis by chiral Lewis acids.3 In this
communication we document the use of copper(II) complexes
as effective enantioselective catalysts for this process where the
catalyst activates specific aldehydes through bidentate coordina-
tion, an organizational feature not common to the chiral catalysts
previously reported for this process.3
Table 1. Catalyzed Enantioselective Aldol Reactions between
R-(Benzyloxy)acetaldehyde and Representative Enolsilanes
We have recently demonstrated that bidentate coordinating
bis(oxazolinyl) Cu(II) complexes 1 function as effective chiral
Lewis acids in the Diels-Alder reaction of acrylimide dieno-
philes4 and that tridentate bis(oxazolinyl)pyridine (pybox)5 Cu-
(II) complexes 2 catalyze the analogous reaction with aldehyde
dienophiles (Scheme 1).6 These catalysts have now been applied
to the aldol reaction of (benzyloxy)acetaldehyde with a range
of silylketene acetals. This aldehyde was chosen on the
assumption that effective catalyst-substrate organization might
be achieved through bidentate chelation to the aldehyde
substrate. In our initial survey, the addition of silylketene acetal
3a to (benzyloxy)acetaldehyde was catalyzed by Cu(II) com-
plexes 1a,b and 2a,b (eqs 1 and 2). Although both catalysts
proved to be highly enantioselective, the exceptional levels of
asymmetric induction exhibited by the phenyl-substituted pybox
complex 2b7 which afforded 4a in 99% ee and 100% yield (5
mol % 2b, -78 °C, CH2Cl2, 15 min) prompted us to select this
complex for further development. Upon optimization, 0.5 mol
% of catalyst 2b at 1 M concentration of aldehyde was found
to catalyze the reaction in 12 h without compromising the yield
or enantiomeric purity.
The reaction was found to be quite general with respect to
the silylketene acetal structure (Table 1).8 The enolsilanes
derived from tert-butyl thioacetate, ethyl thioacetate, and ethyl
acetate provided the respective â-hydroxy esters 4a-c in 98-
99% ee. In a related reaction, dioxolinone derivative 3d9
provided the corresponding adduct 4d in 92% ee and 94%
yield.10 Extension of the reaction to Chans diene11 afforded,
after reduction with Me4NBH(OAc)3,12 the anti diol 4e (15:1
anti:syn) in 97% ee. This synthetically valuable diol can be
purified by recrystallization to give the pure anti diolester as a
single enantiomer. Finally, substituted enolsilanes may also be
employed. For example, the (Z)-propionate derived silylketene
(1) (a) Mukaiyama, T.; Narasaka, K.; Banno, K. Chem. Lett. 1973, 1011-
4. (b) Mukaiyama, T.; Banno, K.; Narasaka, K. J. Am. Chem. Soc. 1974,
96, 7503-9.
(2) (a) Gennari, C. In ComprehensiVe Organic Synthesis; Trost, B. M.,
Fleming, I., Eds.; Pergamon Press: New York, 1991; Vol. 2, Chapter 2.4.
(b) Heathcock, C. H. In Asymmetric Synthesis; Morrison, J. D., Ed.;
Academic Press: San Diego, CA, 1984; Vol. 3, Chapter 2. (c) Evans, D.
A. Aldrichimica Acta 1982, 15, 23-32.
(3) (a) Carreira, E. M.; Singer, R. A.; Lee, W. J. Am. Chem. Soc. 1994,
116, 8837-8. (b) Keck, G. E.; Krishnamurthy, D. J. Am. Chem. Soc. 1995,
117, 2363-4. (c) Mikami, K.; Matsukawa, S. J. J. Am. Chem. Soc. 1994,
116, 4077-8. (d) Kobayashi, S.; Uchiro, H.; Shiina, I.; Mukaiyama, T.
Tetrahedron 1993, 49, 1761-72. (e) Corey, E. J.; Cywin, C. L.; Roper, T.
D. Tetrahedron Lett. 1992, 33, 6907-10. (f) Parmee, E. R.; Hong, Y.;
Tempkin, O.; Masamune, S. Tetrahedron Lett. 1992, 33, 1729-32. (g)
Kiyooka, S.; Kaneko, Y.; Kume, K. Tetrahedron Lett. 1992, 33, 4927-30.
(h) Furuta, K.; Maruyama, T.; Yamamoto, H. J. Am. Chem Soc. 1991, 113,
1041-2. (i) Permee, E. R.; Tempkin, O.; Masamune, S.; Abiko, A. J. Am.
Chem. Soc. 1991, 113, 9365-6.
(8) Catalyst 2b was prepared by mixing phenyl pybox (1.0 equiv) CuCl2
(1.0 equiv) and AgSbF6 (2.0 equiv) in CH2Cl2 at room temperature for 4 h
followed by filtration through a cotton plug. The resulting solution is stable
to air and moisture and may be stored for up to 1 week without any special
precautions. (Benzyloxy)acetaldehyde (0.50 mmol) and silylketene acetal
(0.60 mmol) were added sequentially to a 12.5 mM solution of 2b at -78
°C. After the reaction was complete (e12 h), the mixture was filtered
through silica and the silyl ether was hydrolyzed with 1 N HCl in THF to
yield the hydroxy ester.
(4) Evans, D. A.; Miller, S. J.; Lectka, T. J. Am. Chem. Soc. 1993, 115,
6460-1.
(9) Sato, M.; Sunami, S.; Sugita, Y.; Kaneko, C. Chem. Pharm. Bull.
1994, 42, 839-45.
(5) Nishiyama, H.; Kondo, M.; Nakamura, T.; Itoh, K. Organometallics
1991, 10, 500-8.
(10) The addition of this nucleophile to aldehydes has recently been
reported. See: Singer, R. A.; Carriera, E. M. J. Am. Chem. Soc. 1995, 117,
12360-12361.
(6) Evans, D. A.; Murry, J. A.; von Matt, P.; Norcross, R. D.; Miller, S.
J. Angew. Chem., Int. Ed. Engl. 1995, 34, 798-800.
(11) Brownbridge, P.; Chan, T. H.; Brook, M. A.; Kang, G. J. Can. J.
Chem. 1983, 61, 688-93.
(7) Other substituted pybox complexes gave lower enantioselectivity:
tert-butyl pybox (9% ee), isopropyl pybox (85% ee), benzyl pybox (67%
ee).
(12) Evans, D. A.; Chapman, K. T.; Carreira, E. M. J. Am. Chem. Soc.
1988, 110, 3560-78.
S0002-7863(96)00712-3 CCC: $12.00 © 1996 American Chemical Society

Communications to the Editor
J. Am. Chem. Soc., Vol. 118, No. 24, 1996 5815
Scheme 2
Scheme 3
pyramidal coordination where substrate (Me) and ligand (Ph)
substituents mask opposite RCHO enantiofaces. On the other
hand, 6 underwent rapid reaction providing a 98.5:1.5 mixture
of diastereomers favoring the chelation-controlled product 7.
In the square pyramidal complex B (R ) Me), the methyl
substituent in 6 reinforces the facial bias imposed by the catalyst.
A corollary to this experiment is that 5 is predicted to be a
catalyst inhibitor. This has also been shown to be the case.
While these results are consistent with the square pyramidal
model B (R ) Me), a trigonal bipyramidal model A (R ) Me)
would predict the opposite matched and mismatched relation-
ships.
The silyl transfer component of the reaction has also been
investigated. Silicon transfer from the initially formed catalyst-
Nu-RCHO complex may proceed via intramolecular or inter-
molecular processes. It has been reported that intermolecular
silyl transfer results in a catalytically competent silicon inter-
mediate which affords an avenue for a competing achiral
catalytic process that may compete with the enantioselective
variant.17 We have investigated this possibility in the present
system by employing a mixture of two different silylketene
acetals which should exhibit similar reactivities (Scheme 3).
Treatment of 0.6 equiv each of silylketene acetals 3a and 3h
with 1.0 equiv of (benzyloxy)acetaldehyde and 10 mol % of
catalyst 2b afforded significant quantities of the four possible
products as detected by GLC analysis.18 Deprotection of the
silyl ethers and chiral HPLC analysis of the derived alcohols
indicated that both aldol adducts 4a and 4b were enantiomeri-
cally pure (99% ee). Accordingly, we conclude that although
there is a large intermolecular silyl transfer component in the
reaction, the transient silyl species which we speculate might
be R3SiSbF619 does not compete effectively at -78 °C with the
copper catalyst in this aldol reaction.
acetal 3f provided the syn aldol adduct 4f in high diastereo-
and enantioselectivity (97:3 syn:anti, syn 97% ee). On the other
hand, the corresponding (E)-propionate silylketene acetal 3f
proved to be a much poorer substrate, giving lower conversion
and selectivity (86:14 syn:anti, syn 85% ee). The geometric
requirement for disposing the alkyl and OTMS moieties in an
anti orientation for optimal enantioselectivity is also evident in
the analogous reaction of the silylketene acetal 3g which also
affords a highly selective aldol reaction with good control at
both stereogenic centers.
We next investigated the scope of the reaction with respect
to the aldehyde component. Reactions with benzaldehyde and
dihydrocinnamaldehyde were nonselective. Apparently the
requirement for a chelating substituent on the aldehyde partner
is critical to catalyst selectivity, as R-(tert-butyldimethylsiloxy)-
acetaldehyde gave diminished enantioselectivity (56% ee).
Interestingly, â-(benzyloxy)propionaldehyde provided racemic
product, indicating a strict requirement for a five-membered
catalyst-aldehyde chelate.
Stereochemical models of the catalyst-RCHO complex in
the two probable penta-coordination geometries (square pyra-
midal or trigonal bipyramidal) are illustrated below.13 In the
symmetric trigonal bypyramidal model A (R ) H), the si
aldehyde enantioface is masked by the ligand phenyl group
exposing the re enantioface to nucleophilic attack. In the
alternate square pyramidal complex B (R ) H) the re aldehyde
enantioface is shielded.14 Since enantioselective formation of
(S)-â-hydroxy esters is observed in all cases (si facial attack),
the absolute stereochemistry of the products is consistent with
the proposed square pyramidal coordination model. Additional
support for this proposed RCHO-catalyst geometry has been
obtained from ESR spectroscopy which indicates that the copper
geometry is unequivocally square pyramidal.15
Double stereodifferentiating experiments with (R)- and (S)-
R-(benzyloxy)propional (5) and (6) have been carried out to
provide further support for the catalyst-RCHO model (Scheme
2). It has been well established that bidentate chelation between
the dO and OBn moieties will reverse the inherent Felkin
aldehyde diastereoface selectivity with this substrate.16 In the
mismatched experiment, 5 afforded a poorly selective, slow
reaction. This result is consistent with catalyst-RCHO square
In conclusion, we have documented an efficient, catalytic,
enantioselective addition of silylketene acetal nucleophiles to
(benzyloxy)acetaldehyde utilizing the C2-symmetric bis(oxa-
zolinyl)pyridine Cu(II) complex 2b. Further studies to address
the scope of these reactions and the coordination chemistry of
related complexes will be forthcoming.
Acknowledgment. Financial support was provided by the National
Science Foundation and the National Institutes of Health. Fellowships
from the National Institutes of Health (J.A.M.) and the National Science
Foundation (M.C.K.) are gratefully acknowledged. We would like to
thank Professor William Tolman (University of Minnesota) for helpful
discussions concerning the ESR experiments. The NIH BRS Shared
Instrumentation Grant Program 1-S10-RR04870 and the NSF (CHE
88-14019) are acknowledged for providing NMR facilities.
Supporting Information Available: Experimental procedures and
spectral data, including ESR spectra, for all compounds (6 pages).
Ordering information is given on any current masthead page.
(13) Five-coordinate Cu(II) complexes exhibit a strong tendency toward
either square pyramidal or trigonal bipyramidal geometries, see: Hathaway,
B. J. In ComprehensiVe Coordination Chemistry; Wilkinson, G., Ed.;
Pergamon Press: New York, 1987; Vol. 5, Chapter 53.
JA960712I
(14) In the square pyramidal geometry, the strong coordinating site resides
in the ligand plane with a weaker coordination site in the axial position.
For maximal RCHO activation, we presume that carbonyl coordination
occurs in the ligand plane.
(15) The ESR data were obtained at 132 K and 9.4 GHz. The Hamiltonian
spin parameters are: g ) 2.09, g| ) 2.28, and A| ) 180.2 G. The ratio of
g|/A| is indicative of distortion away from square pyramidalization: a value
of 126 × 104 is consistent with negligible amounts of distortion. See: (a)
ref 13, page 662. (b) Batra, G.; Mathur, P. Transition Met. Chem. 1995,
20, 26-9.
(16) Gennari has shown that the SnCl4-mediated addition of 3a to
R-(benzyloxy)propionaldehyde provides the chelation-controlled anti adduct
(98:2 anti:syn). Gennari, C.; Cozzi, P. G. Tetrahedron 1988, 44, 5965-74.
(17) (a) Hollis, T. K.; Bosnich, B. J. Am. Chem. Soc. 1995, 117, 4570-
81. (b) Carreira, E. M.; Singer, R. A. Tetrahedron Lett. 1994, 35, 4323-6.
(18) The appropriate control experiments were performed ruling out
catalyst-promoted silicon scrambling of the silylketene acetals or of the
product silyl ethers.
(19) Olah, G. A.; Heiliger, L.; Li, X.-Ya; Prakash, G. K. S. J. Am. Chem.
Soc. 1990, 112, 5991-5995.