Catalytic Asymmetric Michael Reaction of β-Keto Esters: Effects of the Linker Heteroatom in Linked-BINOL

Article abstract of DOI:10.1021/ja037635t

We describe the development of a general catalytic asymmetric Michael reaction of acyclic β-keto esters to cyclic enones, in which asymmetric induction occurs at the β-position of the acceptors. Among the various asymmetric catalyst systems examined, the newly developed La-NR-linked-BINOL complexes (R = H or Me) afforded the best results in terms of reactivity and selectivity. In general, the NMe ligand 2 was suitable for the combination of small enones and small β-keto esters, and the NH ligand 1 was suitable for bulkier substrates (steric tuning of the catalyst). Using the La-NMe-linked-BINOL complex, the Michael reaction of methyl acetoacetate (8a) to 2-cyclohexen-1-one (7b) gave the corresponding Michael adduct 9ba in 82% yield and 92% ee. The linker heteroatom in linked-BINOL is crucial for achieving high reactivity and selectivity in the Michael reaction of β-keto esters. The amine moiety in the NR-linked-BINOL can also tune the Lewis acidity of the central metal (electronic tuning of the catalyst), which was supported by density functional studies and experimental results. Another advantage of the NR-linked-BINOL ligand as compared with O-linked-BINOL is the ease of modifying a substituent on the amine moiety, making it possible to synthesize a variety of NR-linked-BINOL ligands for further improvement or development of new asymmetric catalyses by introducing additional functionality on the linker with the amine moiety. The efficiency of the present asymmetric catalysis was demonstrated by the synthesis of the key intermediate of (-)-tubifolidine and (-)-19,20-dihydroakuammicine in only five steps compared to the nine steps required by the original process from the Michael product of malonate. This strategy is much more atom economical. On the basis of the results of mechanistic studies, we propose that a β-keto ester serves as a ligand as well as a substrate and at least one β-keto ester should be included in the active catalyst complex. Further improvement of the reaction by maintaining an appropriate ratio of the La-NMe-linked-BINOL complex and β-keto esters is also described.

Full text of DOI:10.1021/ja037635t

Published on Web 11/25/2003
Catalytic Asymmetric Michael Reaction of â-Keto Esters:
Effects of the Linker Heteroatom in Linked-BINOL
Keisuke Majima, Ryo Takita, Akihiro Okada, Takashi Ohshima, and
Masakatsu Shibasaki*
Contribution from the Graduate School of Pharmaceutical Sciences, The UniVersity of Tokyo,
Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
Received July 30, 2003; E-mail: mshibasa@mol.f.u-tokyo.ac.jp
Abstract: We describe the development of a general catalytic asymmetric Michael reaction of acyclic â-keto
esters to cyclic enones, in which asymmetric induction occurs at the â-position of the acceptors. Among
the various asymmetric catalyst systems examined, the newly developed La-NR-linked-BINOL complexes
(R ) H or Me) afforded the best results in terms of reactivity and selectivity. In general, the NMe ligand 2
was suitable for the combination of small enones and small â-keto esters, and the NH ligand 1 was suitable
for bulkier substrates (steric tuning of the catalyst). Using the La-NMe-linked-BINOL complex, the Michael
reaction of methyl acetoacetate (8a) to 2-cyclohexen-1-one (7b) gave the corresponding Michael adduct
9ba in 82% yield and 92% ee. The linker heteroatom in linked-BINOL is crucial for achieving high reactivity
and selectivity in the Michael reaction of â-keto esters. The amine moiety in the NR-linked-BINOL can also
tune the Lewis acidity of the central metal (electronic tuning of the catalyst), which was supported by density
functional studies and experimental results. Another advantage of the NR-linked-BINOL ligand as compared
with O-linked-BINOL is the ease of modifying a substituent on the amine moiety, making it possible to
synthesize a variety of NR-linked-BINOL ligands for further improvement or development of new asymmetric
catalyses by introducing additional functionality on the linker with the amine moiety. The efficiency of the
present asymmetric catalysis was demonstrated by the synthesis of the key intermediate of (-)-tubifolidine
and (-)-19,20-dihydroakuammicine in only five steps compared to the nine steps required by the original
process from the Michael product of malonate. This strategy is much more atom economical. On the basis
of the results of mechanistic studies, we propose that a â-keto ester serves as a ligand as well as a substrate
and at least one â-keto ester should be included in the active catalyst complex. Further improvement of
the reaction by maintaining an appropriate ratio of the La-NMe-linked-BINOL complex and â-keto esters
is also described.
Introduction
catalytic asymmetric Michael reaction of malonates to enones,
in which asymmetric induction occurs at the â-position of the
The catalytic asymmetric Michael reaction of enolates to R,â-
unsaturated carbonyl compounds is one of the most important
carbon-carbon bond forming reactions due to the ready
availability of both substrates, usefulness of enantiomerically
enriched Michael products, and high atom economy.1 Thus, the
development of catalytic asymmetric Michael reactions has been
extensively studied with several great successes, such as the
Lewis acid-promoted addition of enol silyl ethers to R,â-
unsaturated carbonyl compounds (Mukaiyama-Michael reac-
tion),2 which use stoichiometric amounts of silyl reagents and
bases for the preparation of substrates. The atom-economically
more desirable direct catalytic asymmetric Michael reaction was
recently developed by several groups.1,3 Among them, the
(2) For recent examples using a metal and chiral ligand complex, see: (a)
Kobayashi, S.; Suda, S.; Yamada, M.; Mukaiyama, T. Chem. Lett. 1994,
97. (b) Benardi, A.; Colombo, G.; Scolastico, C. Tetrahedron Lett. 1996,
37, 8921. (c) Evans, D. A.; Rovis, T.; Kozlowski, M. C.; Downey, W.;
Tedrow, J. J. Am. Chem. Soc. 2000, 122, 9134. (d) Evans, D. A.; Scheidt,
K. A.; Johnston, N.; Willis, M. J. Am. Chem. Soc. 2001, 123, 4480. For
recent examples using a chiral organocatalyst, see: (e) Zhang, F-. Y.; Corey,
E. J. Org. Lett. 2001, 3, 639. (f) Brown, S. P.; Goodwin, N. C.; MacMillan,
D. W. C. J. Am Chem Soc. 2003, 125, 1192. (g) Ooi, T.; Doda, K.; Maruoka,
K. J. Am. Chem. Soc. 2003, 125, 5139.
(3) Recently, a direct catalytic asymmetric Michael reaction of unmodified
ketones and aldehydes was reported, although Michael donors and/or
Michael acceptors were rather limited. For examples using unmodified
ketones as donors, see: (a) Zhang, F.-Y.; Corey, E. J. Org. Lett. 2000, 2,
1097. (b) Betancort, J. M.; Sakthivel, K.; Thayumanavan, R.; Barbas, C.
F., III. Tetrahedron Lett. 2001, 42, 4441. (c) List, B.; Pojarliev, P.; Martin,
H. J. Org. Lett. 2001, 3, 2423. (d) Kumagai, N.; Matsunaga, S.; Shibasaki,
M. Org. Lett. 2001, 3, 4251. (e) Enders, D.; Seki, A. Synlett 2002, 26. (f)
Harada, S.; Kumagai, N.; Kinoshita, T.; Matsunaga, S.; Shibasaki, M. J.
Am. Chem. Soc. 2003, 125, 2582. (g) Andrey, O.; Alexakis, A.; Bernar-
dinelli, G. Org. Lett. 2003, 5, 2559. For examples using unmodified
aldehydes as donors, see: (h) Betancort, J. M.; Barbas, C. F., III. Org.
Lett. 2001, 3, 3737. (i) Alexakis, A.; Andrey, O. Org. Lett. 2002, 4, 3611.
(j) Melchiorre, P.; Jørgensen, K. A. J. Org. Chem. 2003, 68, 4151. For
examples using R-cyano esters as donors, see: (k) Sawamura, M.;
Hamashima, H.; Ito, Y. J. Am. Chem. Soc. 1992, 114, 8295. (l) Sawamura,
M.; Hamashima, H.; Ito, Y. Tetrahedron 1994, 50, 4439. (m) Taylor, M.
S.; Jacobsen, E. N. J. Am. Chem. Soc. 2003, 125, 11204.
(1) For recent reviews of catalytic asymmetric Michael reactions, see: (a)
Kanai, M.; Shibasaki, M. In Catalytic Asymmetric Synthesis, 2nd ed.; Ojima,
I., Ed.; Wiley: New York, 2000; pp 569-592. (b) Tomioka, K.; Nagaoka,
Y. In ComprehensiVe Asymmetric Catalysis; Jacobsen, E. N., Pfaltz, A.,
Yamamoto, H., Eds.; Springer: Berlin, 1999; Vol. 3, Chapter 31.1. (c)
Sibi, M.; Manyem, S. Tetrahedron 2000, 56, 8033. (d) Krause, N.;
Hoffmann-Ro¨der, A. Synthesis 2001, 171. (e) Alexakis, A.; Benhaim, C.
Eur. J. Org. Chem. 2002, 3221. (f) Christoffers, J.; Baro, A. Angew. Chem.,
Int. Ed. 2003, 42, 1688.
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J. AM. CHEM. SOC. 2003, 125, 15837-15845
15837

A R T I C L E S
Majima et al.
enones, has been widely examined, and several excellent
catalysts were developed (eq 1).4,5 This methodology was
successfully applied to the syntheses of several natural products6
such as Strychnos alkaloids.6b-d Structurally related â-keto esters
have also been studied as Michael donors because of the higher
potential of the corresponding Michael products to be useful in
further transformations (eq 2).7 In this case, appropriate sub-
stituents can be introduced into the ketone unit (R2) prior to
the Michael reaction, while one of the ester units in the Michael
product of malonate is often removed by decarboxylation during
the synthetic process (vide infra).6a-d,8 Moreover, the charac-
teristic reactivity of â-keto esters allows for additional substit-
uents (R4) to be more efficiently introduced at the R-position
of â-keto esters to construct quaternary carbon stereocenters in
the presence of a ketone moiety other than malonate (vide infra).
Despite the usefulness of the above-mentioned reactions
(shown in eq 2), the catalytic asymmetric Michael reaction of
R-substituted â-keto esters, especially indan-1-one-2-carboxy-
late, to methyl vinyl ketone was mainly studied; thus, the chiral
center was constructed at the R-position of the â-keto esters
(eq 3).9,10 In contrast to the successful asymmetric induction at
the R-position of â-keto esters (eq 3), only a few asymmetric
Michael reactions of â-keto esters to â-substituted enones, such
as cyclic enones, achieved asymmetric induction at the â-posi-
tion of the acceptor (eq 2).11-13 This was probably due to the
preferential coordination of Michael donors (malonates or â-keto
esters) to a chiral complex in a bidentate chelating manner rather
than to Michael acceptors (enones),9,10 resulting in difficulty in
controlling the facial selectivity of the Michael acceptors.
Barnes, Ji, and co-workers reported a Michael reaction of â-keto
esters to nitrostyrenes using the chiral bisoxazoline-Mg
complex and amine base.11 Jørgensen and co-workers recently
employed the chiral bisoxazoline-Cu complex to promote a
Michael reaction of several cyclic â-keto esters such as
4-hydroxycoumarins to â,γ-unsaturated R-keto esters.12 Ikariya
and co-workers recently reported the catalytic asymmetric
Michael reaction of methyl acetoacetate to an enone, cyclopen-
tenone, using a chiral Ru complex.13 While the level of
enantioselection for these reactions is encouraging, there remains
room for improvement in terms of substrate generality. Herein,
(8) The intermediate of strychnine synthesis (ref 6d) can be synthesized from
the Michael product of â-keto ester in one step, a shorter process than that
reported using the Michael product of malonate. For preliminary results,
see the Supporting Information.
(9) (a) Hermann, K.; Wynberg, H. J. Org. Chem. 1979, 44, 2238. (b) Cram,
D. J.; Sogah, G. D. Y. J. Chem. Soc., Chem. Commun. 1981, 625. (c)
Brunner, H.; Hammer, B. Angew. Chem., Int. Ed. Engl. 1984, 23, 312. (d)
Desimoni, G.; Dusi, G.; Faita, G.; Quadrelli, P.; Righetti, P. Tetrahedron
1995, 51, 4131. (e) Sasai, H.; Emori, E.; Arai, T.; Shibasaki, M. Tetrahedron
Lett. 1996, 37, 5561. (f) Christoffers, J.; Ro¨ssler, U.; Werner, T. Eur. J.
Org. Chem. 2000, 701. (g) Nakajima, M.; Yamaguchi, Y.; Hashimoto, S.
Chem. Commun. 2001, 1596. (h) Suzuki, T.; Torii, T. Tetrahedron:
Asymmetry 2001, 12, 1077.
(10) For high substrate generality using chiral palladium complexes, see: (a)
Hamashima, Y.; Hotta, D.; Sodeoka, M. J. Am. Chem. Soc. 2002, 124,
11240. (b) Hamashima, Y.; Takano, H.; Hotta, D.; Sodeoka, M. Org. Lett.
2003, 5, 3225.
(11) For Michael reaction of â-keto esters to nitrostyrene derivatives (six
examples), see: (a) Ji, J.; Barnes, D. M.; Zhang, J.; King, S. A.;
Wittenberger, S. J.; Morton, H. E. J. Am. Chem. Soc. 1999, 121, 10215.
(b) Barnes, D. M.; Ji, J.; Fickes, M. G.; Fitzgerald, M. A.; King, S. A.;
Morton, H. E.; Plagge, F. A.; Preskill, M.; Wagaw, S. H.; Wittenberger, S.
J.; Zhang, J. J. Am. Chem. Soc. 2002, 124, 13097.
(4) For catalytic asymmetric Michael reactions of malonates reported by our
group, see: (a) Sasai, H.; Arai, T.; Shibasaki, M. J. Am. Chem. Soc. 1994,
116, 1571. (b) Sasai, H.; Arai, T.; Satow, Y.; Houk, K. N.; Shibasaki, M.
J. Am. Chem. Soc. 1995, 117, 6194. (c) Arai, T.; Sasai, H.; Aoe, K.;
Okamura, K.; Date, T.; Shibasaki, M. Angew. Chem., Int. Ed. Engl. 1996,
35, 104. (d) Kim, Y. S.; Matsunaga, S.; Das, J.; Sekine, A.; Ohshima, T.;
Shibasaki, M. J. Am. Chem. Soc. 2000, 122, 6506. (e) Xu, Y.; Ohori, K.;
Ohshima, T.; Shibasaki, M. Tetrahedron 2002, 58, 2585. (f) Takita, R.;
Ohshima, T.; Shibasaki, M. Tetrahedron Lett. 2002, 43, 4661. For reviews,
see: (g) Shibasaki, M.; Sasai, H.; Arai, T. Angew. Chem., Int. Ed. Engl.
1997, 36, 1236. (h) Shibasaki, M.; Yoshikawa, N. Chem. ReV. 2002, 102,
2187. For a review of O-linked-BINOL, see: (i) Matsunaga, S.; Ohshima,
T.; Shibasaki, M. AdV. Synth. Catal. 2002, 343, 1.
(5) For other examples of catalytic asymmetric Michael reactions of malonates,
see: (a) Yamaguchi, M.; Shiraishi, T.; Hirama, M. J. Org. Chem. 1996,
61, 3520. (b) Perrard, T.; Plaquevent, J.-C.; Desmurs, J.-R.; Hebrault, D.
Org. Lett. 2000, 2, 2959. (c) Halland, N.; Aburel, P. S.; Jørgensen, K. A.
Angew. Chem., Int. Ed. 2003, 42, 661. (d) Annamalai, V.; DiMauro, E. F.;
Carroll, P. J.; Kozlowski, M. C. J. Org. Chem. 2003, 68, 1973. See also
ref 1b.
(6) (a) Yamada, K.-i.; Arai, T.; Sasai, H.; Shibasaki, M. J. Org. Chem. 1998,
63, 3666. (b) Shimizu, S.; Ohori, K.; Arai, T.; Sasai, H.; Shibasaki, M. J.
Org. Chem. 1998, 63, 7547. (c) Ohori, K.; Shimizu, S.; Ohshima, T.;
Shibasaki, M. Chirality 2000, 12, 400. (d) Ohshima, T.; Xu, Y.; Takita,
R.; Shimizu, S.; Zhong, D.; Shibasaki, M. J. Am. Chem. Soc. 2002, 124,
14546 (Additions and Corrections 2003, 125, 2014). (e) Nara, S.; Toshima,
H.; Ichihara, A. Tetrahedron Lett. 1996, 37, 6745. (f) Nara, S.; Toshima,
H.; Ichihara, A. Tetrahedron 1997, 53, 9509.
(7) For a general review of â-keto esters describing the ubiquitous importance
of â-keto esters in organic chemistry, see: Benetti, S.; Romagnoli, R.; Risi,
C. D.; Spalluto, G.; Zanirato, V. Chem. ReV. 1995, 95, 1065.
(12) For Michael reaction of several cyclic â-keto esters such as 4-hydroxy-
coumarins to â,γ-unsaturated R-keto esters (several examples), see: (a)
Halland, N.; Velgaard, T.; Jørgensen, K. A. J. Org. Chem. 2003, 5067. (b)
Halland, N.; Hansen, T.; Jørgensen, K. A. Angew. Chem., Int. Ed. 2003,
42, 4955.
(13) For Michael reaction of â-keto ester to enone (one example), see: Watanabe,
M.; Murata, K.; Ikariya, T. J. Am. Chem. Soc. 2003, 125, 7508. The authors
proposed that the reactions might proceed through a transition state similar
to that postulated for transfer hydrogenation, in which enone might be fixed
in the chiral catalyst complex through a hydrogen bond between the
carbonyl oxygen of enone and the amine proton of a chiral ligand.
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15838 J. AM. CHEM. SOC. VOL. 125, NO. 51, 2003

Catalytic Michael Reaction of â-Keto Esters
A R T I C L E S
excess (entry 3). Other more Lewis acidic lanthanide metals
gave unsatisfactory results (entries 4 and 5). These findings
suggested that the use of â-keto esters as ligands would prevent
dissociation of the product from the complex or form undesired
complexes with more Lewis acidic Ln catalysts.14 Thus, a less
Lewis acidic metal was expected to be more suitable for the
reaction of â-keto esters. Because La is the weakest Lewis acid
of the lanthanide metals, we expected that a linker heteroatom
on linked-BINOL would electronically tune the properties of
the La catalyst. We examined S-linked-BINOL 615 (entry 6)
and NR-linked-BINOLs 1 (R ) H) and 2 (R ) Me) (entries 7
and 8) and found that nitrogen on the linker accelerates the
reaction with high selectivity (up to 92% ee). Coordination of
the electron-rich amine moiety to the central metal might
decrease the Lewis acidity of the central metal. Although on
the basis of the oxophilicity of hard lanthanide metals, an oxygen
linker would be expected to decrease the Lewis acidity more
than a nitrogen linker; in this case, the high electron-donating
ability of the amine moiety, which is spatially fixed in the
vicinity of the central metal by two BINOL units, might
effectively influence the Lewis acidity of the central metal. The
electronic effects of the NR moiety were demonstrated by
comparing the NEt ligand 3 with the NCH2CF3 ligand 4 (entries
9 and 10). The size of the trifluoroethyl group is regarded to be
the same as that of the ethyl group, but the electronic properties
of the trifluoroethyl group are quite different from those of the
ethyl group because of the electron-withdrawing nature of the
fluorine atom. As we presumed, NCH2CF3 ligand 4 had much
lower reactivity and selectivity (11% yield, 24% ee, entry 10)
than the NEt ligand 3 (60% yield, 88% ee, entry 9). These results
directly support our hypothesis that the amine moiety of NR-
linked-BINOL can tune the Lewis acidity of the central metal.
This hypothesis was also supported by B3LYP16 density
functional studies.17 One advantage of the NR-linked-BINOL
ligand is its versatility; the ligand can be readily synthesized
from the corresponding primary amine,18 making electronic as
well as steric fine-tuning of the catalyst possible. The ease of
handling the La-NR-linked-BINOL complexes is equivalent
to that of the La-O-linked-BINOL complex.4d,i It is easily
prepared as a pale-yellow powder by simply mixing La(O-i-
Figure 1. Structures of (S,S)-NR-linked-BINOLs 1-4, (S,S)-O-linked-
BINOL 5, and (S,S)-S-linked-BINOL 6.
Table 1. Catalyst Screening for Catalytic Asymmetric Michael
Reaction of â-Keto Estera
c
time
(h)
yieldb
(%)
ee
entry
catalyst
(S)-LSB
(%)
1
2
39
94
60
42
36
24
24
24
24
24
72
24
66
19
nrd
24
65
77
60
11
6
0
(S)-ALB
3
4
5
6
7
8
9
10
La-(S,S)-5 (O)
Pr-(S,S)-5 (O)
Sm-(S,S)-5 (O)
La-(S,S)-6 (S)
La-(S,S)-1 (NH)
La-(S,S)-2 (NMe)
La-(S,S)-3 (NEt)
La-(S,S)-4 (NCH2CF3)
74
51
nde
58
90
92
88
24
a The product was obtained as a 1:1 mixture of diastereomers. b Isolated
yield. c The enatiomeric excess was determined by GC analysis after
conversion to the appropriate derivatives; see the Supporting Information.
d No reaction. e Not determined.
we report a general catalytic asymmetric Michael reaction of
â-keto esters to cyclic enones using the newly developed
La-NR-linked-BINOL (R ) H (1) or Me (2), Figure 1)
complexes. An amine moiety in the NR-linked-BINOL can
electronically tune the Lewis acidity of the central metal and
sterically tune the chiral environment of the La-NR-linked-
BINOL complex. The selectivity of this reaction is highly
dependent on the bulkiness of the â-keto esters, and high
reactivity and selectivity were accomplished by an appropriate
choice of the substituent (R) in the NR-linked-BINOL ligand.
In addition, we demonstrated the usefulness of the corresponding
Michael product by synthesis of the key intermediate of (-)-
tubifolidine and (-)-19,20-dihydroakuammicine. Using the
Michael adduct of the â-keto ester, the key intermediate was
synthesized in fewer steps as compared with using the Michael
adduct of malonates (five steps vs nine steps). Finally, several
mechanistic investigations of the Michael reactions are discussed
to gain insight into the active catalyst species.
(14) Although, in general, there is a linear relation between pKa and log K
(stability constant of the chelating agent), acetylacetone has a greater
stability constant value (log K ) 17.4) than ethyl acetoacetate (log K )
14.2). See: (a) Calvin, M.; Wilson, K. W. J. Am. Chem. Soc. 1945, 67,
2003. This discrepancy would result from the interference of the strong
ester resonance of the ethyl acetate, which prevents the carbonyl group
from taking part fully in the resonance of the chelate ring like the chelation
of acetylacetone to metal. See also: (b) Martell, E.; Calvin, M. Chemistry
of the Metal Chelate Compounds; Prentice Hall: New York, 1952. In
addition, in the case of â-diketone complexes of lanthanide ions, more acidic
â-diketone complexes show higher stability. For example, tris(1,1,1,2,2,3,3-
heptafluoro-7,7-dimethyl-4,6-octanedionato)europium [Eu(fod)3] is more
stable than tris(dipivalomethanato)europium [Eu(dpm)3] against carboxylic
acids and phenols. See: (c) Liu, K.-T.; Hsu, M.-F.; Chen, J.-S. Tetrahedron
Lett. 1974, 25, 2179. A logical extension of these results is that the â-keto
ester would form more stable lanthanide complexes than malonates.
(15) Kumagai, N.; Matsunaga, S.; Kinoshita, T.; Harada, S.; Okada, S.;
Sakamoto, S.; Yamaguchi, K.; Shibasaki, M. J. Am. Chem. Soc. 2003, 125,
2169.
Results and Discussion
Catalyst Development for the Asymmetric Michael Reac-
tion of â-Keto Esters. In our preliminary studies, asymmetric
induction in the Michael reaction of â-keto ester 8a to 7b was
not observed even when using excellent catalysts for the Michael
reaction of malonates, such as LSB4b and ALB4c,e complexes
(Table 1, entries 1 and 2). Only the La-O-linked-BINOL
complex4d,f,i afforded 9ba in moderate yield and enantiomeric
(16) (a) Becke, A. D. J. Chem. Phys. 1993, 98, 5648. (b) Lee, C.; Yang, W.;
Parr, R. G. Phys. ReV. B 1988, 37, 785.
(17) Final geometry optimization and calculation of atomic charges (Mulliken
charges) of the La complexes were performed by means of the B3LYP
hybrid density functional method using a LanL2DZ basis set with Gaussian
98. Further examination of natural bond orbital analysis (Pop ) NPA) and
more desirable calculations using the MP2 method for the calculation of
atomic charges was not possible due to the existence of lanthanum atoms
in the molecule. For details, see the Supporting Information.
(18) For details, see the Supporting Information.
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A R T I C L E S
Majima et al.
Table 2. Effects of the Substituent (R) on the NR-Linked-BINOL
Table 3. Catalytic Asymmetric Michael Reaction of â-Keto Esters
to Enones Using the La-NR-Linked-BINOL Complexesa
Liganda
c
â-keto
ester
ligand
R
time
(h)
yieldb
(%)
ee
entry
enone
(%)
1
2
3
4
5
6
7
8
9
7a
7a
7b
7b
7b
7c
7c
7b
7b
8a
8a
8a
8a
8a
8a
8a
8g
8g
H (1)
Me (2)
H (1)
Me (2)
Et (3)
H (1)
Me (2)
H (1)
24
24
24
24
24
24
24
48
48
67
82
69
77
60
83
52
67
40
65
73
90
92
88
91
90
73
21
c
â-keto
ester
time
(h)
yieldb
(%)
ee
entry
enone
ligand
product
(%)
1d
2d
7a
7a
7a
8a
8c
8d
8e
8a
8b
8c
8d
8e
8f
8g
8a
8b
8c
8d
8e
8f
2
2
1
1
2
2
2
2
1
1
1
2
1
1
1
1
1
1
9aa
9ac
9ad
9ae
9ba
9bb
9bc
9bd
9be
9bf
9bg
9ca
9cb
9cc
9cd
9ce
9cf
24
24
24
48
24
42
24
36
48
48
48
42
24
24
24
48
48
48
94
85
75
84
82
71
71
81
73
65
67
83
88
91
87
83
74
66
73
80
75
72
92
88
91
87
80
73
73
92
89
90
88
83
77
69
Me (2)
3e
4e
7ah
7b
7b
7b
7b
7bh
7bh
7bh
7c
a Products were obtained as a 1:1 mixture of diastereomers. b Isolated
yield. c The enantiomeric excess was determined by GC analysis after
conversion to the appropriate derivatives. For the determination of the
absolute configuration, see the Supporting Information.
5d
6d
7d
8d
9e
Pr)3 and NR-linked-BINOL, and removing the solvent.18
Moreover, the complex can be stored under air (>6 weeks).18
Effects of the Substituent (R) on the NR-Linked-BINOL
Ligand. Before optimization of the reaction conditions, we
further examined the effects of the substituent (R) on the NR-
linked-BINOL ligand using combinations of selected substrates
(Table 2). When the smallest â-keto ester, methyl acetoacetate
(8a), was used for the Michael reactions to cyclic enones 7a-c
(five- to seven-membered ring), the NMe ligand 2 gave the
highest selectivity (entries 1-7). In the case of 2-cyclohepten-
1-one (7c), however, there was a considerable decrease in
reactivity using the NMe ligand 2 (24 h, 52% yield, entry 7) as
compared with the reaction using the smaller NH ligand 1 (24
h, 83% yield, entry 6). When a bulkier â-keto ester 8g was
used, there was a great difference in enantioselectivity between
the reaction of the NH ligand 1 (73% ee, entry 8) and NMe
ligand 2 (21% ee, entry 9). In general, the NMe ligand 2 was
suitable for the combination of small enones and small â-keto
esters, and the NH ligand 1 was suitable for bulkier substrates,
suggesting that substituents of the linker nitrogen can sterically
tune the chiral environment of the catalyst. This tendency was
also observed with other combinations of substrates (see Table
3). An NEt ligand 3, electronically more suitable than NMe
ligand 2 or NH ligand 1, was expected to give better results;
however, there was slightly lower reactivity and selectivity
(entry 5). In this case, the strict steric effects of amine
substituents might exceed the electronic effects.
10f
11e
12d
13g
14g
15g
16f
17e
18e
7c
7c
7c
7ch
7ch
7ch
8g
9cg
a Products were obtained as a 1:1 mixture of diastereomers. b Isolated
yield. c The enantiomeric excess was determined by GC analysis after
conversion to the appropriate derivatives. For the determination of the
absolute configuration, see the Supporting Information. d Solvent composi-
tion, THF/DME (9:1). e THF. f THF/HFIP (19:1). g THF/HFIP (19:1), 2.0
M. h A 1.2 equiv sample of enone was used.
while maintaining selectivity. For example, the yield of 9ba
was improved from 77% (entry 4, Table 2) to 82% (entry 3,
Table 5) by the addition of DME. As shown in Table 3, the
Michael reaction of a variety of acyclic â-keto esters, 8a-g, to
cyclic enones 7a-c was promoted by the La-NR-linked-
BINOL complex to afford Michael adducts with moderate to
good enantiomeric excess. To the best of our knowledge, this
is the first example of a general catalytic asymmetric Michael
reaction of acyclic â-keto esters to cyclic enones in which
asymmetric induction occurs at the â-position of the enones
(eq 2).
Synthetic Application of the Michael Product of â-Keto
Ester. The usefulness of the Michael product of â-keto esters
was demonstrated (Scheme 1). Indole 12 is the key intermediate
of (-)-tubifolidine6b and (-)-19,20-dihydroakuammicine,6c
which were synthesized from the Michael product of malonate
(R)-13 through a C-C bond cleavage (decarboxylation) and
formation (aldol reaction). Using (R)-9ba as a starting material,
which was prepared using the (R,R)-NMe ligand 2 (82%, 92%
ee), the key intermediate 12 was synthesized more efficiently
in terms of atom economy. The chemoselective reduction of
the â-ketone by the Ru catalyst20 and dehydration by DCC-
CuCl21 provided 10 in good yield (84% and 81%, respectively),
which was further converted to indole product by Fisher’s indole
Scope and Limitations of the Catalytic Asymmetric
Michael Reaction of â-Keto Esters Using La-NR-Linked-
BINOL Complexes. We then investigated the scope and
limitations of several substrates after optimizing the reaction
conditions, e.g., solvent composition and concentration. For the
reaction using the NMe ligand 2, the addition of DME (THF:
DME ) 9:1) often improved the reactivity with the same
enantioselectivity. On the other hand, when the NH ligand 1
was used, the addition of 1,1,1,3,3,3-hexafluoro-2-propanol
(HFIP)4f sometimes had positive effects in terms of reactivity
9
15840 J. AM. CHEM. SOC. VOL. 125, NO. 51, 2003

Catalytic Michael Reaction of â-Keto Esters
A R T I C L E S
Scheme 1. Synthesis of the Key Intermediate of (-)-Tubifolidine and (-)-19,20-Dihydroakuammicinea
a Key: (a) catalytic RuCl3, catalytic DPPB, MeOH, H2 (30 atm), 50 °C, 84%; (b) CuCl, DCC, benzene, reflux, 81%; (c) PhNHNH2‚HCl, AcOH, reflux;
(d) DIBAL-H, toluene, -78 °C, 72% (two steps); (e) Ms2O, i-Pr2NEt, CH2Cl2, -20 °C, then H2NCH2CH(OMe)2, 4 °C, 60%.
Scheme 2. Chemoselective Allylation at the R-Position of the
â-Keto Ester
to characterize the active species and there are no reports of
detailed mechanistic investigations except for a few examples
of the reactions catalyzed by the lanthanide-containing chiral
heterobimetallic complex (LSB),4b the aluminum-containing
chiral heterobimetallic complex (ALB),4c and chiral transition-
metal complexes.10a,13,24 Although, as mentioned, we developed
an efficient asymmetric Michael reaction of malonate catalyzed
by the La-O-linked-BINOL complex,4d,f,i the details of the
reaction are not yet clear due to the difficulty in determining
the catalyst structure of alkali-metal-free lanthanide complexes.25
In contrast to the successful structural determination of hetero-
bimetallic complexes containing a lanthanide metal, alkali
metals, and BINOL,4b,g,h there had been only a little information
on the structure of alkali-metal-free Ln-BINOL complexes
available before we elucidated the structure of the La-BINOL-
Ph3AsdO complex,25a which promoted the catalytic asymmetric
epoxidation of a variety of R,â-unsaturated carbonyl com-
pounds.25a,26 In the absence of Ph3AsdO, the La-BINOL
complex should exist as a mixture of oligomeric species on the
basis of the results of laser desorption/ionization time-of-flight
mass spectrometry, the obscure 13C NMR spectrum, and
asymmetric amplification in the epoxidation, making it diffi-
cult to determine the structure of the La-BINOL complex.25a
Ph3AsdO is an effective additive to realize high reactivity and
selectivity, and the role of Ph3AsdO was elucidated to promote
the formation of the monomeric species by the coordination of
Ph3AsdO to the lanthanum metal, leading to the structural
determination (including X-ray analysis).25a On the basis of the
high stability of La-1,3-diketone complexes such as Ln(acac)3
synthesis. After a 1,2-reduction of the R,â-unsaturated ester,
the resulting alcohol was displaced by aminoacetaldehyde
dimethyl acetal through methanesulfonyl ester to provide the
key intermediate 12.22 Compared with the previous synthesis
using the Michael adduct of malonate as a starting material (13
to 12), the present synthesis requires fewer steps (five steps vs
nine steps) and all the carbon atoms of the Michael donor were
efficiently utilized for the construction of the carbon skeleton
of 12 without C-C bond cleavage.
Using the characteristic reactivity of â-keto ester, an ad-
ditional substituent can be chemoselectively introduced at the
R-position of â-keto esters in the presence of another ketone in
the molecule, making it possible to construct a quaternary carbon
stereocenter. Although high levels of diastereoselectivity have
not yet been achieved (2:1), the allyl substituent was successfully
introduced at the R-position of the â-keto ester in 99% yield to
afford 17 (Scheme 2),23 which can be utilized for further
transformations to synthesize complex compounds.
Mechanistic Studies. Although many asymmetric catalysts
for the Michael reaction have been developed, it is still difficult
(19) Although it is possible that the role of the amine is to enolize the â-keto
ester, it might not be very feasible on the basis of the results of the
corresponding La-O-linked-BINOL, which promoted the reaction in a way
similar to that of La-NR-linked-BINOL. See the Mechanistic Studies.
(20) For the first example of catalytic asymmetric hydrogenation of 1,3-
dicarbonyl compounds using an Ru catalyst, see: (a) Noyori, R.; Ohkuma,
T.; Kitamura, M.; Takaya, H.; Sayo, N.; Kumobayashi, H.; Akutagawa, S.
J. Am. Chem. Soc. 1987, 109, 5856. For review, see: (b) Ager, D. J.;
Laneman, S. Tetrahedron: Asymmetry 1997, 8, 3327 and references therein.
For in situ generation of Ru-diphosphine catalysts from anhydrous RuCl3,
see: (c) Madec, J.; Pfister, X.; Phansavath, P.; Vidal, V. R.; Geneˆt, J.-P.
Tetrahedron 2001, 57, 2563.
(21) (a) Alexandre, C.; Rouessac, F. Bull. Soc. Chim. Fr. 1971, 1837. For an
example of synthetic application, see: (b) Knight, S. D.; Overman, L. E.;
Pairaudeau, G. J. Am. Chem. Soc. 1995, 117, 5776. See also ref 6d.
(22) Spectroscopic data were identical to the reported data (ref 6b).
(23) Tsuji, J.; Shimizu, I.; Minami, I.; Ohashi, Y.; Sugiura, T.; Takahashi, K. J.
Org. Chem. 1985, 50, 1523.
(24) For an example of mechanistic investigation and improvement based on
the mechanism of Rh-catalyzed asymmetric Michael-type reaction, see:
Hayashi, T.; Takahashi, M.; Takaya, Y.; Ogasawara, M. J. Am. Chem. Soc.
2002, 124, 5052.
(25) (a) Nemoto, T.; Ohshima, T.; Yamaguchi, K.; Shibasaki, M. J. Am. Chem.
Soc. 2001, 123, 2725. Kobayashi et al. reported the structural information
on Yb- and Sc-BINOL complexes prepared from Yb(OTf)3 or Sc(OTf)3,
BINOL, and a tertiary amine, see: (b) Kobayashi, S.; Ishitani, H.; Hachiya,
I.; Araki, M. Tetrahedron 1994, 40, 11623 and references therein.
(26) (a) Nemoto, T.; Ohshima, T.; Shibasaki, M. J. Synth. Org. Chem. Jpn.
2002, 60. 94. (b) Nemoto, T.; Ohshima, T.; Shibasaki, M. J. Am. Chem.
Soc. 2001, 123, 9474. (c) Nemoto, T.; Tosaki, S.-y.; Ohshima, T.; Shibasaki,
M. Chirality 2003, 15, 306. (d) Nemoto, T.; Kakei, H.; Gnanadesikan, V.;
Tosaki, S.-y.; Ohshima, T.; Shibasaki, M. J. Am. Chem. Soc. 2002, 124,
14544. (e) Tosaki, S.-y.; Nemoto, T.; Ohshima, T.; Shibasaki, M. Org.
Lett. 2003, 5, 495. (f) Ohshima, T.; Gnanadesikan, V.; Shibuguchi, T.;
Fukuta, Y.; Nemoto, T.; Shibasaki, M. J. Am. Chem. Soc. 2003, 125, 11206.
9
J. AM. CHEM. SOC. VOL. 125, NO. 51, 2003 15841

A R T I C L E S
Majima et al.
Figure 2. ESI-MS (positive mode) spectra of solutions of La-NMe-linked-BINOL with or without â-keto ester 8a.
complexes, â-keto ester should have a high affinity for lan-
thanide metals.14 Thus, we expected that the â-keto ester could
stabilize the monomeric species in a way similar to that of
Ph3AsdO. Despite numerous attempts to obtain a crystal for
X-ray analysis or an informational NMR spectrum with or
without â-keto ester, only unsatisfactory results were obtained,
suggesting that even in the presence of the â-keto ester, the
La-NR-linked-BINOL complexes exist as a mixture of several
species in solution.
ionization mass spectrometry (ESI-MS) analysis. The ESI-MS
spectrum of the solution generated from the La(O-i-Pr)3 and
NMe-linked-BINOL 2 in a ratio of 1:1 is shown in Figure 2a.
There were several peaks assigned to the complexes of La:2 )
1:1 to 4:5, supporting our assumption that the La-2 complex
itself exists as a mixture of oligomeric species. When â-keto
ester 8a (1 equiv with respect to the La-2 complex) was added
to a solution of the La-2 (1:1) complex (Figure 2b), the relative
intensities of the peaks of higher order oligomers (La:2 ) 2:2
to 4:5) decreased and several peaks derived from the â-keto
ester-containing species (La:2:8a ) 1:1:1 to 3:2:2) appeared.27
To gain insight into the structure of La-NR-linked-BINOL
complexes in solution directly, we performed electrospray
9
15842 J. AM. CHEM. SOC. VOL. 125, NO. 51, 2003

Catalytic Michael Reaction of â-Keto Esters
A R T I C L E S
Figure 3. Effects of nonenantiopure ligands (nonlinear effects) (b, ee of the product; 2, yield).
Further addition of â-keto ester (2-10 equiv with respect to
the La-2 complex, Figure 2c,d) made the peaks in the high
molecular weight region (MW > 1500) almost disappear.18
When 4 or 10 equiv of â-keto ester was added, five main peaks
were detected; two were derived from the complexes of La:2
) 1:1 or 1:2, and the other three peaks were derived from the
species that contain â-keto ester(s) and only one molecule of
NMe ligand 2 (La:2:8a ) 1:1:1, 2:1:1, and 2:1:2). Although
the complex did not converge to one species, even after the
addition of excess â-keto ester, these results support our
expectation that several relatively stable monomeric species are
formed by the coordination of â-keto ester to the lanthanum
metal.28 Using malonate [dibenzyl malonate (18)] instead of
â-keto ester, however, only obscure ESI-MS spectra were
obtained.29
was a clear linear relation between the enantiomeric excess of
NMe ligand 2 and that of the Michael adduct 9ba. When the
La-O-linked-BINOL complex was used for the reaction of
â-keto ester, a linear relation was observed again (Figure 3b).
On the other hand, in the reaction of malonate 18, both La-
NMe-linked-BINOL and La-O-linked-BINOL complexes dis-
played positive nonlinear effects30 (Figure 3c,d). These findings
indicate that the structures of the active species of both the La-
NMe-linked-BINOL complex and the La-O-linked-BINOL
complex are similar. Thus, the differences between La-NMe-
linked-BINOL and La-O-linked-BINOL complexes in the
asymmetric Michael reaction would be caused mainly by the
electronic property of the linker heteroatom (vide supra).
Moreover, the results of ESI-MS analysis as well as the clear
linear relation between the enantiomeric excess of the NMe
ligand 2 and that of Michael adduct 9ba suggested that the active
species in the Michael reaction of â-keto ester promoted by
La-NMe-linked-BINOL complex is a monomeric species.
Examinations of the nonlinear effects shown in Figure 3 and
ESI-MS analysis led us to suppose that the active species in
the Michael reaction of â-keto ester would be different from
that of malonate; the former would be a monomeric species,
and the latter would be an oligomeric species. In addition, it is
reasonable to assume that the active species includes at least
one â-keto ester other than the substrate. â-Keto ester can
function as a ligand to promote the fragmentation of the
To obtain further information about the active species, we
next examined the Michael reaction using the nonenantiopure
La-NMe-linked-BINOL complex. As shown in Figure 3a, there
(27) Because lanthanum has essentially only one stable isotope, it is difficult to
confirm the assignment by the ion distribution pattern of the observed peaks.
Thus, we performed ESI-MS analysis using ethyl acetoacetate (8b) instead
of methyl acetoacetate (8a). In this case, peaks corresponding to the
complexes of La:2:8b ) 1:1:1 to 3:2:2 were detected.
(28) The existence of large peaks assigned to the La:2 ) 1:1 and 1:2 complexes,
even in the presence of excess â-keto ester, might be caused by
fragmentation through ionization on ESI(+)-MS analysis, although other
possibilities cannot be excluded.
(29) This might be due to the lower coordination ability of malonate to the
lanthanum metal. See ref 14. In addition, when O-linked-BINOL 5 or NH-
linked-BINOL 1 was used as a chiral ligand instead of NMe-linked-BINOL
2, only obscure spectra were obtained. Furthermore, the addition of enone
had no effect on the ESI-MS spectrum in the presence of â-keto ester.
(30) (a) Girard, C.; Kagan, H. B. Angew. Chem., Int. Ed. 1998, 37, 2922. (b)
Kagan, H. B. Synlett 2001, 888.
9
J. AM. CHEM. SOC. VOL. 125, NO. 51, 2003 15843

A R T I C L E S
Majima et al.
Table 4. Effects of the Catalyst Loadinga
plex, 2.0 equiv of â-keto ester 8a gave a much higher yield
and better enantiomeric excess (entry 6) than 1.0 equiv of 8a
(entry 5), while 2.0 equiv of enone 7b increased only the
reactivity (entry 7). From these results, more than 2 equiv of
â-keto ester with respect to the La-NMe-linked-BINOL
complex is necessary to realize high reactivity and selectivity.
On the other hand, in the Michael reaction of malonate 18,
higher catalyst loading increased the reactivity with only a slight
loss of selectivity (entries 8 and 9). The same tendency was
observed using O-linked-BINOL 5 instead of NMe-linked-
BINOL 2 (entries 10-13). An additional 1 equiv of â-keto ester
seems to tune the structure of the chiral La-ligand complex,
affording high reactivity and selectivity.
c
X
La−2:8a
ratio
yieldb
(%)
ee
entry
ligand
product
(mol %)
(%)
The effects of the ratio of the La-NMe-linked-BINOL
complex and â-keto ester as well as enone were further
investigated using 10 mol % La-NMe-linked-BINOL complex
(Table 5). As with using stoichiometric amounts of the La-
NMe-linked-BINOL complex (entry 7, Table 4), an excess
amount of enone had positive effects only on the reactivity
(entries 1 and 2, Table 5). In contrast, although the results shown
in Table 4 suggested that more â-keto ester gave better results,
in this case, only amounts slightly larger than 1.0 equiv of â-keto
ester gave a lower yield and enantiomeric excess (entries 4-7,
Table 5). While the reason for this is not yet clear, it is possible
that excess â-keto ester leads to the production of undesired
complexes or the prevention of the coordination of enone. On
the basis of the results shown in Tables 4 and 5, the appropriate
ratio between the La-NMe-linked-BINOL complex and
â-keto ester to generate the desired active species effectively is
1:2 to 1:10. The tendency for the effects of â-keto ester in the
Michael reaction is very similar to that of Ph3AsdO in
epoxidation, in which the addition of 1 equiv of Ph3AsdO
afforded the best results in terms of reactivity and selectiv-
ity.25a Therefore, we propose that â-keto ester has a role not
only as a substrate but also as a ligand to promote the generation
of an active monomeric species in a way similar to that of
Ph3AsdO.
1
2
3
4
5
2
2
2
2
2
2
2
2
2
5
5
5
5
9ba
9ba
9ba
9ba
9ba
9ba
9ba
19
10
25
50
1:10
1:4
1:2
1:1.3
1:1
1:2
42
52
49
39
32
68
53
61
91
7
89
89
85
79
79
87
80
96
91
68
44
88
93
75
100
100
100
10
100
10
100
10
100
6d
7e
8
1:1
9
19
10
11
12
13
9ba
9ba
19
1:10
1:1
22
39
80
19
a Products were obtained as a 1:1 mixture of diastereomers. b Isolated
yield. c The enantiomeric excess was determined by GC analysis after
conversion to the appropriate derivatives. For the determination of the
absolute configuration, see the Supporting Information. d A 2.0 equiv sample
of 8a was used. e A 2.0 equiv sample of 7b was used.
Table 5. Effects of the Equivalence of Enone or â-Keto Estera
c
X
Y
La−2:8a
yieldb
(%)
ee
entry
(mol %)
(mol %)
ratio
(%)
Improvement of the Catalytic Asymmetric Michael Reac-
tion of â-Keto Ester Based on the Reaction Mechanism. The
above-mentioned finding prompted us to determine how to
maintain the appropriate ratio of the La-NMe-linked-BINOL
complex and â-keto ester in the course of the reaction to realize
higher catalyst activity. When the catalyst amount was reduced
to 5 mol % La-NMe-linked-BINOL complex (the initial ratio
of La-2 and â-keto ester was 1:20), the Michael adduct 9ba
was obtained in 62% yield and 87% ee even after 48 h (Table
6, entry 2). To maintain the appropriate ratio and decrease the
catalyst loading, the substrates were added in several portions.
When the substrates were added in two portions, even 5 mol %
La-2 complex gave results (77% yield, 92% ee, entry 3)
comparable to those of the standard reaction conditions (10 mol
% La-2 complex, one portion, entry 1). This procedure made
it possible to achieve a high turnover number (TON; around
50) using only 1.25 mol % La-2 complex (entry 5). Because
an excess amount of enone increased the reactivity without a
loss of selectivity, enone 7b was added in one portion with a
two-portion addition of â-keto ester 8a, resulting in an improve-
ment of yield from 77% (entry 3) to 81% (entry 6). Slow
addition of â-keto ester was also examined, but only a slight
improvement was observed as compared with multiportion
1
2
3
4
5
6
7
10
2.5
1
1
1
1
1
1
1.1
1.2
1.3
1.4
1:10
1:10
1:10
1:11
1:12
1:13
1:14
quant
quant
77
69
63
91
91
92
91
89
88
87
1
1
59
56
a Products were obtained as a 1:1 mixture of diastereomers. b Isolated
yield. c The enantiomeric excess was determined by GC analysis after
conversion to the appropriate derivatives. For the determination of the
absolute configuration, see the Supporting Information.
oligomeric species into a monomeric species. The role of â-keto
ester as a ligand was elucidated by the following experiments.
The effects of catalyst loading of the Michael reaction of â-keto
ester 8a or malonate 18 to enone 7b were investigated using
the NMe-linked-BINOL 2 or O-linked-BINOL 5 ligand. When
â-keto ester 8a was used as a Michael donor, higher catalyst
loading (g50 mol % La-NMe-linked-BINOL complex) de-
creased the reactivity and selectivity (entries 3-5, Table 4).31
In the presence of 100 mol % La-NMe-linked-BINOL com-
(31) Because of low solubility of the catalyst in high loading, the concentration
of the substrate was set to 0.2 M. This condition afforded a lower yield
and enantiomeric excess (0.2 M, 42%, 89% ee, entry 1, Table 4) than
optimized reaction conditions (1.0 M, 82%, 92% ee, entry 5, Table 3).
9
15844 J. AM. CHEM. SOC. VOL. 125, NO. 51, 2003

Catalytic Michael Reaction of â-Keto Esters
A R T I C L E S
Table 6. Low Catalyst Loading Maintaining the Appropriate Ratio
of La-2 and 8aa
acceptor, using novel La-NR-linked-BINOL (R ) H (1) or
Me (2)) complexes (up to 92% ee). In addition, we demonstrated
that a linker heteroatom in linked-BINOL can tune the catalyst
profile electronically and sterically. In general, the NMe ligand
2 was suitable for the combination of both small enones and
â-keto esters, and the NH ligand 1 was suitable for bulkier
substrates. The usefulness of the Michael product was demon-
strated by the synthesis of the key intermediate 12 of (-)-
tubifolidine and (-)-19,20-dihydroakuammicine. Compared with
previous syntheses using the Michael adduct of malonate as a
starting material (13 to 12), the synthesis from the Michael
adduct of â-keto esters (9ba to 12) is a shorter process (five
steps vs nine steps) and all the carbon atoms of the Michael
donor were efficiently utilized for the construction of the carbon
skeleton of 12 without C-C bond cleavage. Several mechanistic
studies revealed that at least one â-keto ester served as a ligand
to promote the generation of an active monomeric species in a
way similar to that of Ph3AsdO in a La-BINOL-promoted
epoxidation. To generate the desired active species effectively,
maintaining the ratio of the La-NMe-linked-BINOL complex
and â-keto ester at 1:2 to 1:10 was very important. On the basis
of this finding, we succeeded in reducing the catalyst amount
by multiportion addition of â-keto ester. Further studies are
currently under investigation in our group.
initial
La−2:8a
ratio
c
X
time
(h)
yieldb
(%)
ee
entry
(mol %)
n
(%)
TON
1
2
3
4
1:10
1:20
1:10
1:10
1:10
1:10
10
5
5
2.5
1.25
5
0
0
1
2
3
1
24
48
48
72
96
48
79
62
77
62
61
81
92
87
92
89
87
92
8
12
15
25
49
16
5
6d
a Products were obtained as a 1:1 mixtures of diastereomers. b Isolated
yield. c The enantiomeric excess was determined by GC analysis after
conversion to the appropriate derivatives. For the determination of the
absolute configuration, see the Supporting Information. d 7b was added in
one portion at first.
Acknowledgment. This work was supported by RFTF and a
Grant-in-Aid for Encouragements for Young Scientists (A) from
the Japan Society for the Promotion of Science (JSPS).
addition. While this method has not been fully optimized, it
will enable the practical use of this reaction.
Supporting Information Available: Experimental procedures
and characterization of the products and other detailed results
and discussion (PDF). This material is available free of charge
via the Internet at http://pubs.acs.org.
Conclusion
We successfully developed a general catalytic asymmetric
Michael reaction of acyclic â-keto esters to cyclic enones, in
which asymmetric induction occurs at the â-position of the
JA037635T
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J. AM. CHEM. SOC. VOL. 125, NO. 51, 2003 15845