COMMUNICATIONS
reflections with I > s(I) were used in the refinement of 302 parameters. The
procedure was the same as for 5a.
Mechanistic Insights into Cu-Catalyzed
Asymmetric Aldol Reactions: Chemical and
Spectroscopic Evidence for a Metalloenolate
Intermediate**
Crystallographic data (excluding structure factors) for the structures
reported in this paper have been deposited with the Cambridge Crystallo-
graphic Data Centre as supplementary publication no. CCDC-102362 and
CCDC-102363. Copies of the data can be obtained free of charge on
application to CCDC, 12 Union Road, Cambridge CB21EZ, UK (fax:
(44)1223-336-033; e-mail: deposit@ccdc.cam.ac.uk).
Brian L. Pagenkopf, Jochen Krüger, Aleksandar
Stojanovic, and Erick M. Carreira*
Received: July 21, 1998 [Z12188IE]
German version: Angew. Chem. 1998, 110, 3318 ± 3321
The aldol reaction ranks among the premier methods for
carbon ± carbon bond formation in chemical synthesis. Ad-
vances in both diastereoselective and enantioselective proc-
esses have produced remarkable achievements in the syn-
thesis of stereochemically complex structures.[1] In contrast to
the wealth of empirical and theoretical data available for
diastereoselective aldol additions of metalloenolates to alde-
hydes,[2] mechanistic understanding of catalytic asymmetric
processes with enol silanes is less advanced. Insight into the
latter would be of considerable assistance in the design of
newer, more efficient methods for asymmetric synthesis.[3]
We recently reported a catalytic aldol addition of the silyl
dienolate 1 to a range of aldehydes in the presence of a
bisphosphanyl-CuII fluoride complex which is generated in
situ from (S)-Tol-BINAP,[4] Cu(OTf)2, and (Bu4N)Ph3SiF2
(Scheme 1).[5] Aromatic, heteroaromatic, and a,b-unsaturated
Keywords: asymmetric catalysis ´ copper ´ cycloadditions ´
Lewis acids ´ synthetic methods
[1] See for example: a) D. L. Boger, S. M. Weinreb, Hetero Diels ± Alder
Methodology in Organic Synthesis; Academic Press, New York, 1987,
chap. 2, 9; b) L. F. Tietze, G. Kettschau, Stereoselective Heterocyclic
Synthesis I, Vol. 189 (Ed.: P. Metz), Springer, Berlin, 1997, p. 1; c) H.
Waldmann, Synthesis 1994, 535; d) Organic Synthesis Highlights II
(Ed.: H. Waldmann), VCH, Weinheim, 1995, p. 37; e) S. M. Weinreb
in Comprehensive Organic Synthesis, Vol. 5 (Eds.: B. M. Trost, I.
Flemming, M. F. Semmelhack), Pergamon, Oxford, 1991, p. 401.
[2] See for example: a) K. Maruoka, T. Itoh, T. Shirasaka, H. Yamamoto,
J. Am. Chem. Soc. 1988, 110, 310; b) G. Keck, X.-Y. Li, D.
Krishnamurthy, J. Org. Chem. 1995, 60, 5998; c) Q. Gao, K. Ishihara,
T. Maruyama, M. Mouri, H. Yamamoto, Tetrahedron, 1994, 50, 979;
d) Q. Gao, T. Maruyama, M. Mouri, H. Yamamoto, J. Org. Chem.
1992, 57, 1951; e) M. Bednarski, S. Danishefsky, J. Am. Chem. Soc.
Ê
1986, 108, 7060, and references therein; f) S. E. Schaus, J. Branalt,
E. N. Jacobsen, J. Org. Chem. 1998, 63, 403; g) M. Johannsen, K. A.
Jùrgensen, J. Org. Chem. 1995, 60, 5757; h) A. Graven, M. Johannsen,
K. A. Jùrgensen, Chem. Commun. 1996, 2372.
2 mol %
[CuF2{(S)-tol-binap}]
THF, –78 °C
Me
O
Me
O
Me
O
Me
O
HO
+
[3] For reactions with a normal electron demand: a) M. Johannsen, S.
Yao, K. A. Jùrgensen, Chem. Commun. 1997, 2169; b) S. Yao, M.
Johannsen, H. Audrain, R. G. Hazell, K. A. Jùrgensen, J. Am. Chem.
Soc. 1998, 120, 8599. For reactions with an inverse electron demand:
a) D. A. Evans, J. S. Johnson, J. Am. Chem. Soc. 1998, 120, 4895; b) J.
Thorhauge, M. Johannsen, K. A. Jùrgensen, Angew. Chem. 1998, 110,
2543; Angew. Chem. Int. Ed. 1998, 37, 2404.
RCHO
OSiMe3
R
O
acidic workup
1
2
72-98% yield
65-94% ee
Scheme 1. Catalytic aldol addition of 1 to aldehydes.
[4] a) K. Hattori, H. Yamamoto, J. Org. Chem. 1992, 57, 3264; b) K.
Hattori, H. Yamamoto, Tetrahedron 1993, 49, 1749; c) K. Ishihara, M.
Miyata, K. Hattori, H. Yamamoto, J. Am. Chem. Soc. 1994, 116,
10520.
[5] a) H. Ishitani, S. Kobayashi, Tetrahedron Lett. 1996, 37, 7357; b) S.
Kobayashi, S. Komiyama, H. Ishitani, Angew. Chem. 1998, 110, 1026;
Angew. Chem. Int. Ed. 1998, 37, 979.
aldehydes furnished aldol adducts with up to 95% ee and in
98% yield. Importantly, we postulated a metalloenolate as a
key intermediate in the catalytic cycle.[6, 7] This role for a late
transition metal catalyst contrasts the more conventional
function of such metals as Lewis acids in related processes
(AgI,[8] CuII,[9] PdII,[6a±c] and NiII[10]). Here we report chemical
and spectroscopic data that support the postulated catalytic
cycle and the involvement of metalloenolate and metal
aldolate intermediates.
In mechanistic studies of the Cu-mediated reaction we
observed that 5 mol% of the corresponding CuIF complex
(prepared in situ from (S)-Tol-BINAP, [CuOTf ´ C6H6], and
(Bu4N)Ph3SiF2) served equally well in the catalytic aldol
reaction of 1 and benzaldehyde (7; 94% ee and 97% yield).
Â
Â
Â
[6] See for example: a) P. Herczegh, I. Kovacs, L. Szilagyi, M. Zsely, F.
Sztaricskai, A. Berecibar, A. Olesker, G. Lukacs, Tetrahedron Lett.
1992, 33, 3133; b) R. Lock, H. Waldmann, Tetrahedron Lett. 1996, 37,
2753; c) P. N. Devine, M. Reilly, T. Oh, Tetrahedron Lett. 1993, 34,
5827; d) H. Waldmann, M. Braun, M. Dräger, Angew. Chem. 1990,
102, 1445; e) M. M. Midland, R. Koops, J. Org. Chem. 1992, 57, 1158;
f) A. K. McFarlane, G. Thomas, A. Whiting, J. Chem. Soc. Perkin
Trans. 1 1995, 2803.
[7] a) D. Ferraris, B. Young, T. Dudding, T. Lectka J. Am. Chem. Soc.
1998, 120, 4548; b) H. Nakamura, K. Nakamura, Y. Yamamoto, J. Am.
Chem. Soc. 1998, 120, 4242; c) E. Hagiwara, A. Fujii, M. Sodeoka, J.
Am. Chem. Soc. 1998, 120, 2474.
[8] SMART, SAINT, and XPREP: Area Detector Control and Integra-
tion Software. Siemens Analytical X-ray Instruments Inc. Madison,
WI (USA), 1995.
[9] G. Cascarano, A. Altomare, C. Giacovazzo, A. Guagliardi, A. G. G.
Moliterni, D. Siliqi, M. C. Burla, G. Polidori, M. Camalli, Acta
Crystallogr. Sect. A 1996, 52, C50.
[10] a) W. T. Busing, K. O. Martin, H. A. Levy, ORFLS, Report ORNL-
TM-305. Oak Ridge National Laboratory, TN (USA), 1962; b) A.
Hazell, KRYSTAL, An integrated system of crystallographic pro-
grams, Aarhus University (Denmark), 1995.
[*] Prof. Dr. E. M. Carreira, Dr. B. L. Pagenkopf, Dr. J. Krüger,
Dr. A. Stojanovic
Arnold and Mabel Beckman Laboratory for Chemical Synthesis,
California Institute of Technology
Pasadena, CA 91125 (USA)
Fax: (1)626-564-9297
[**] B.L.P. thanks the National Institutes of Health (NIH), J.K. thanks the
Deutsche Forschungsgemeinschaft, and A.S. is grateful to the
Schweizerischer Nationalfonds for postdoctoral fellowships. Financial
support was provided by the Packard Foundation, National Science
Foundation (USA), NIH (USA), and generous funds from Eli Lilly,
Merck, Novartis, Pfizer, Upjohn, and Zeneca.
[11] D. Rogers, Acta Crystallogr. Sect. A 1981, 37, 734.
[12] M. N. Burnett, C. K. Johnson, ORTEP-III, Report ORNL-6895. Oak
Ridge National Laboratory, TN (USA), 1996.
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