Direct catalytic asymmetric Michael reaction of hydroxyketones: Asymmetric Zn catalysis with a Et2Zn/ linked-BINOL complex

Article abstract of DOI:10.1021/ja028928+

Full details of our direct Michael addition of unmodified ketones using new asymmetric zinc catalysis are described. Et₂Zn/(S,S)-linked-BINOL complexes were successfully applied to direct 1,4-addition reactions of hydroxyketones. The first generation Et₂Zn/(S,S)-linked-BINOL 1 = 2/1 system was effective for 1,4-addition of 2-hydroxy-2′-methoxyacetophenone (3). Using 1 mol % of (S,S)-linked-BINOL 1 and 2 mol % of Et₂Zn, we found that a 1,4-addition reaction of β-unsubstituted enone proceeded smoothly at 4 °C to afford products in high yield (up to 90%) and enantiomeric excess (up to 95%). In the case of β-substituted enones, however, the first generation Et₂Zn/(S,S)-linked-BINOL 1 = 2/1 system was not at all effective. The second generation Et₂Zn/(S,S)-linked-BINOL 1 = 4/1 with MS 3A system was developed and was effective for various β-substituted enones to afford products in good dr, yield (up to 99%), and high enantiomeric excess (up to 99% ee). With the Et₂Zn/1 = 4/1 systems, catalyst loading for β-unsubstituted enone was reduced to as little as 0.01 mol % (substrate/chiral ligand = 10 000). The new system was also effective for 1,4-addition reactions of 2-hydroxy-2′-methoxypropiophenone (9) to afford chiral tert-alcohol in high enantiomeric excess (up to 96% ee). Mechanistic investigations as well as transformations of the Michael adducts into synthetically versatile intermediates are also described.

Full text of DOI:10.1021/ja028928+

Published on Web 02/04/2003
Direct Catalytic Asymmetric Michael Reaction of
Hydroxyketones: Asymmetric Zn Catalysis with a Et2Zn/
Linked-BINOL Complex
Shinji Harada, Naoya Kumagai, Tomofumi Kinoshita, Shigeki Matsunaga, and
Masakatsu Shibasaki*
Contribution from the Graduate School of Pharmaceutical Sciences, The UniVersity of Tokyo,
Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
Received October 14, 2002 ; E-mail: mshibasa@mol.f.u-tokyo.ac.jp
Abstract: Full details of our direct Michael addition of unmodified ketones using new asymmetric zinc
catalysis are described. Et2Zn/(S,S)-linked-BINOL complexes were successfully applied to direct 1,4-addition
reactions of hydroxyketones. The first generation Et2Zn/(S,S)-linked-BINOL 1 ) 2/1 system was effective
for 1,4-addition of 2-hydroxy-2′-methoxyacetophenone (3). Using 1 mol % of (S,S)-linked-BINOL 1 and 2
mol % of Et2Zn, we found that a 1,4-addition reaction of â-unsubstituted enone proceeded smoothly at 4
°C to afford products in high yield (up to 90%) and enantiomeric excess (up to 95%). In the case of
â-substituted enones, however, the first generation Et2Zn/(S,S)-linked-BINOL 1 ) 2/1 system was not at
all effective. The second generation Et2Zn/(S,S)-linked-BINOL 1 ) 4/1 with MS 3A system was developed
and was effective for various â-substituted enones to afford products in good dr, yield (up to 99%), and
high enantiomeric excess (up to 99% ee). With the Et2Zn/1 ) 4/1 systems, catalyst loading for
â-unsubstituted enone was reduced to as little as 0.01 mol % (substrate/chiral ligand ) 10 000). The new
system was also effective for 1,4-addition reactions of 2-hydroxy-2′-methoxypropiophenone (9) to afford
chiral tert-alcohol in high enantiomeric excess (up to 96% ee). Mechanistic investigations as well as
transformations of the Michael adducts into synthetically versatile intermediates are also described.
Introduction
reactions and Mannich reactions, direct catalytic asymmetric
1,4-addition reactions of unmodified ketones are very rare
The catalytic asymmetric carbon-carbon bond formation is
a major focus of modern synthetic organic chemistry.1 The
increasing demand for efficient and environmentally benign
processes requires the development of atom-economic asym-
metric catalysis2 in which enantiomerically enriched compounds
are produced using unmodified substrates. Toward this end, we
and others successfully demonstrated direct catalytic asymmetric
aldol reactions3-5and direct catalytic asymmetric Mannich
reactions6,7 that utilize unmodified ketones and/or aldehydes as
donors. In contrast to these promising results8 with aldol
despite their importance in synthetic organic chemistry for
providing 1,5-dicarbonyl chiral building blocks.9 Many excellent
catalytic asymmetric 1,4-addition reactions have been developed
over the past decade. Almost all of them utilize either active
methylene compounds, such as malonates10 and â-ketoesters,11
or reactive nucleophiles prepared by using no less than
(5) Unmodified ketones as donors: (a) List, B.; Lerner, R. A.; Barbas, C. F.,
III. J. Am. Chem. Soc. 2000, 122, 2395. (b) Trost, B. M.; Ito, H. J. Am.
Chem. Soc. 2000, 122, 12003. (c) List, B.; Pojarliev, P.; Castello, C. Org.
Lett. 2001, 3, 573. (d) Sakthivel, K.; Notz, W.; Bui, T.; Barbas, C. F., III.
J. Am. Chem. Soc. 2001, 123, 5260. (e) Trost, B. M.; Silcoff, E. R.; Ito, H.
Org. Lett. 2001, 3, 2497. (f) Saito, S.; Nakadai, M.; Yamamoto, H. Synlett
2001, 1245. (g) Mahrwald, R.; Ziemer, B. Tetrahedron Lett. 2002, 43, 4459.
For a partially successful attempt, see: (h) Nakagawa, M.; Nakao, H.;
Watanabe, K.-I. Chem. Lett. 1985, 391. Unmodified R-hydroxyketones as
donors: (i) Notz, W.; List, B. J. Am. Chem. Soc. 2000, 122, 7386. (j) Trost,
B. M.; Ito, H.; Silcoff, E. R. J. Am. Chem. Soc. 2001, 123, 3367. See also
ref 4d. Unmodified aldehydes as donors: (k) Co´rdova, A.; Notz, W.; Barbas,
C. F., III. J. Org. Chem. 2002, 67, 301. (l) Northrup, A. B.; MacMillan, D.
W. C. J. Am. Chem. Soc. 2002, 124, 6798. (m) Bøgevig, A.; Kumaragu-
rubaran, N.; Jørgensen, K. A. Chem. Commun. 2002, 620. For highly
selective direct aldol reaction using chiral auxiliary: (n) Evans, D. A.;
Tedrow, J. S.; Shaw, J. T.; Downey, C. W. J. Am. Chem. Soc. 2002, 124,
392.
(6) (a) Yamasaki, S.; Iida, T.; Shibasaki, M. Tetrahedron Lett. 1999, 40, 307.
(b) Yamasaki, S.; Iida, T.; Shibasaki, M. Tetrahedron 1999, 55, 8857.
(7) (a) List, B. J. Am. Chem. Soc. 2000, 122, 9336. (b) Notz, W.; Sakthivel,
K.; Bui, T.; Zhong, G.; Barbas, C. F., III. Tetrahedron Lett. 2001, 42, 199.
(c) Juhl, K.; Gathergood, N.; Jørgensen, K. A. Angew. Chem., Int. Ed. 2001,
40, 2995. (d) List, B.; Pojarliev, P.; Biller, W. T.; Martin, H. J. J. Am.
Chem. Soc. 2002, 124, 827. (e) Co´rdova, A.; Notz, W.; Zhong, G.;
Betancort, J. M.; Barbas, C. F., III. J. Am. Chem. Soc. 2002, 124, 1842. (f)
Co´rdova, A.; Watanabe, S.; Tanaka, F.; Notz, W.; Zhong, G.; Betancort,
J. M.; Barbas, C. F., III. J. Am. Chem. Soc. 2002, 124, 1866.
(1) (a) ComprehensiVe Asymmetric Catalysis; Jacobsen, E. N., Pfaltz, A.,
Yamamoto, H., Eds.; Springer: Berlin, 1999. (b) Catalytic Asymmetric
Synthesis, 2nd ed.; Ojima, I., Ed.; Wiley: New York, 2000.
(2) (a) Trost, B. M. Science 1991, 254, 1471. (b) Trost, B. M. Angew. Chem.,
Int. Ed. Engl. 1995, 34, 259.
(3) Reviews: (a) Palomo, C.; Oiarbide, M.; Garc´ıa, J. M. Chem.-Eur. J. 2002,
8, 37. (b) Alcaide, B.; Almendros, P. Eur. J. Org. Chem. 2002, 1595. (c)
List, B. Tetrahedron 2002, 58, 5573. (d) Shibasaki, M.; Yoshikawa, N.
Chem. ReV. 2002, 102, 2187 and references therein.
(4) Unmodified ketones as donors: (a) Yamada, Y. M. A.; Yoshikawa, N.;
Sasai, H.; Shibasaki, M. Angew. Chem., Int. Ed. Engl. 1997, 36, 1871. (b)
Yoshikawa, N.; Yamada, Y. M. A.; Das, J.; Sasai, H.; Shibasaki, M. J.
Am. Chem. Soc. 1999, 121, 4168. (c) Yamada, Y. M. A.; Shibasaki, M.
Tetrahedron Lett. 1998, 39, 5561. (d) Yoshikawa, N.; Shibasaki, M.
Tetrahedron 2001, 57, 2569. (e) Suzuki, T.; Yamagiwa, N.; Matsuo, Y.;
Sakamoto, S.; Yamaguchi, K.; Shibasaki, M.; Noyori, R. Tetrahedron Lett.
2001, 42, 4669. Unmodified R-hydroxyketones as donors: (f) Yoshikawa,
N.; Kumagai, N.; Matsunaga, S.; Moll, G.; Ohshima, T.; Suzuki, T.;
Shibasaki, M. J. Am. Chem. Soc. 2001, 123, 2466. (g) Kumagai, N.;
Matsunaga, S.; Yoshikawa, N.; Ohshima, T.; Shibasaki, M. Org. Lett. 2001,
3, 1539. (h) Yoshikawa, N.; Suzuki, T.; Shibasaki, M. J. Org. Chem. 2002,
67, 2556.
9
2582
J. AM. CHEM. SOC. 2003, 125, 2582-2590
10.1021/ja028928+ CCC: $25.00 © 2003 American Chemical Society

Direct Catalytic Michael Reaction of Hydroxyketones
A R T I C L E S
stoichiometric amounts of reagents, such as enol silyl ethers
and organometallic reagents.12Quite recently direct catalytic
asymmetric Michael reactions of unmodified ketones and
aldehydes were realized by using a phase transfer catalyst,13
proline,14 and chiral diamine.14 There remains room for im-
provement, however, in terms of substrate scope, catalyst
loading, enantioselectivity, and chemical yield. Thus, the
development of direct catalytic asymmetric 1,4-addition of
unmodified ketones, which have high reactivity and selectivity,
is in high demand. We recently communicated an efficient direct
catalytic asymmetric 1,4-addition of a hydroxyketone, which
afforded 1,4-adducts in good yield and high enantiomeric
excess.15 The reaction proceeded with a catalytic amount of base
(Et2Zn, 2 mol %) and chiral ligand (linked-BINOL 1, 1 mol %,
Figure 1).16,17 The system was applicable to only â-unsubstituted
enones (vinyl ketones) and indenones, however, leaving room
for improvement in terms of substrate scope. Herein we report
the full details of our asymmetric zinc catalysis in direct catalytic
asymmetric 1,4-addition reactions of hydroxyketones: (1) The
first generation Et2Zn/(S,S)-linked-BINOL 1 ) 2/1 complex was
applied to a 1,4-addition of â-unsubstituted enones and inde-
Figure 1. (S,S)-Linked-BINOL 1.
Figure 2. Concept for direct catalytic asymmetric Michael reaction using
hydroxyketone 3.
nones with 2-hydroxy-2′-methoxyacetophenone (3). (2) The
second generation Et2Zn/(S,S)-linked-BINOL 1 ) 4/1 with MS
3A system was then developed to widen the substrate scope
and was effective for various â-substituted enones to afford
products in high yield (up to 99%) and high enantiomeric excess
(up to 99%). With the Et2Zn/1 ) 4/1 system, catalyst loading
for â-unsubstituted enone was reduced to as little as 0.01 mol
% (substrate/chiral ligand ) 10 000). (3) A 1,4-addition of
2-hydroxy-2′-methoxypropiophenone (9) was examined. (4)
Finally, mechanistic investigations and transformations of 1,4-
adducts are also discussed.
(8) For other promising atom economic asymmetric catalysis for carbon-carbon
bond-forming reaction, see alkynylation: (a) Anand, N. K.; Carreira, E.
M. J. Am. Chem. Soc. 2001, 123, 9687. For other selected examples of
atom economic asymmetric catalysis, see â-lactam synthesis: (b) Taggi,
A. E.; Hafez, A. M.; Wack, H.; Young, B.; Drury, W. J., III; Lectka, T. J.
Am. Chem. Soc. 2000, 122, 7831. (c) Hodous, B. L.; Fu, G. C. J. Am.
Chem. Soc. 2002, 124, 1578. R-amination: (d) Kumaragurubaran, N.; Juhl,
K.; Zhuang, W.; Bøgevig, A.; Jørgensen, K. A. J. Am. Chem. Soc. 2002,
124, 6254 and references therein. (e) List, B. J. Am. Chem. Soc. 2002,
124, 5656.
(9) For recent reviews on the catalytic asymmetric 1,4-addition reactions, see:
(a) Krause, N.; Hoffmann-Ro¨der, A. Synthesis 2001, 171. (b) Comprehen-
siVe Asymmetric Catalysis; Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.;
Springer: Berlin, 1999; Chapter 31.
(10) For recent leading references, see: Yamaguchi, M.; Shiraishi, T.; Hirama,
M. J. Org. Chem. 1996, 61, 3520. See also ref 17a.
Results and Discussion
(11) For recent leading references, 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) Hamashima, Y.; Hotta, D.; Sodeoka, M. J. Am. Chem.
Soc. 2002, 124, 11240 and references therein. See also: (c) Sawamura,
M.; Hamashima, H.; Ito, Y. Tetrahedron 1994, 50, 4439 for R-cyano esters.
(12) Excellent catalytic asymmetric 1,4-addition reactions with latent enolates,
such as enol silyl ether, are established (>90% ee), although those reactions
require stoichiometric amounts of reagents to prepare latent enolates. For
recent representative examples, see: (a) Kobayashi, S.; Suda, S.; Yamada,
M.; Mukaiyama, T. Chem Lett. 1994, 97. (b) Kitajima, H.; Ito, K.; Katsuki,
T. Tetrahedron 1997, 53, 17015. (c) Evans, D. A.; Rovis, T.; Kozlowski,
M. C.; Downey, W.; Tedrow, J. S. J. Am. Chem. Soc. 2000, 122, 9134. (d)
Zhang, F.-Y.; Corey, E. J. Org. Lett. 2001, 3, 639. (e) Evans, D. A.; Scheidt,
K. A.; Johnston, J. N.; Willis, M. C. J. Am. Chem. Soc. 2001, 123, 4480
and references therein. For leading references on catalytic asymmetric 1,4-
addition reactions of other carbon nucleophiles, see Zn reagents: (f) Feringa,
B. L. Acc. Chem. Res. 2000, 33, 346. B reagents: (g) Hayashi, T. Synlett
2001, 879. Ti reagents: (h) Hayashi, T.; Tokunaga, N.; Yoshida, K.; Han,
J.-W. J. Am. Chem. Soc. 2002, 124, 12102.
(A) First Generation Et2Zn/(S,S)-Linked-BINOL 1 ) 2/1
System. In our continuing investigation of direct catalytic
asymmetric aldol reactions, a Et2Zn/(S,S)-linked-BINOL 1
complex was determined to be very effective for shielding one
enantioface of an enolate generated from 2-hydroxy-2′-meth-
oxyacetophenone (3), affording a practical method to provide
syn-1,2-dihydroxyketones through the aldol reaction of 3 with
various aldehydes.18 We anticipated that the efficient enantioface
selection would also be applicable to asymmetric 1,4-addition
reactions to afford optically active 2-hydroxy-1,5-dicarbonyl
compounds 4 as shown in Figure 2. Thus, we investigated the
catalytic asymmetric 1,4-addition reaction using vinyl ketone
2a as a substrate. As shown in Table 1, 5 mol % of 1 and 10
mol % of Et2Zn efficiently promoted the 1,4-addition of 3 to
2a at -20 °C to afford 4a in 90% yield and 94% ee after 8 h
(Table 1, entry 1). These promising results led us to further
examine the effects of catalyst loading, changes in the reaction
temperature, and various ketone equivalents (Table 1). By
reducing the amount of ketone 3 from 2.0 to 1.1 equiv (entry
2), we found that the reaction rate and chemical yield decreased
(14 h, 72% yield), while high enantiomeric excess was
maintained (97% ee). The reaction temperature greatly affected
the reaction rate. By decreasing the reaction temperature to -30
°C (entry 3), we obtained a higher enantiomeric excess (98%
(13) Zhang, F.-Y.; Corey, E. J. Org. Lett. 2000, 2, 1097.
(14) (a) Betancort, J. M.; Sakthivel, K.; Thayumanavan, R.; Barbas, C. F., III.
Tetrahedron Lett. 2001, 42, 4441. (b) List, B.; Pojarliev, P.; Martin, H. J.
Org. Lett. 2001, 3, 2423. Unmodified aldehydes as donors: (c) Betancort,
J. M.; Barbas, C. F., III. Org. Lett. 2001, 3, 3737. (d) Enders, D.; Seki, A.
Synlett 2002, 26. (e) Alexakis, A.; Andrey, O. Org. Lett. 2002, 4, 3611.
(15) Kumagai, N.; Matsunaga, S.; Shibasaki, M. Org. Lett. 2001, 3, 4251.
(16) For the synthesis and application of linked-BINOL, see: (a) Matsunaga,
S.; Das, J.; Roels, J.; Vogl, E. M.; Yamamoto, N.; Iida, T.; Yamaguchi,
K.; Shibasaki, M. J. Am. Chem. Soc. 2000, 122, 2252. (b) Matsunaga, S.;
Ohshima, T.; Shibasaki, M. AdV. Synth. Catal. 2002, 344, 4. Linked-BINOL
is also commercially available from Wako Pure Chemical Industries, Ltd.
Catalog No. 152-02431 for (S,S)-ligand, No. 155-02421 for (R,R)-ligand.
Fax +1-804-271-7791 (USA), +81-6-6201-5964 (Japan), +81-3-5201-6590
(Japan).
(17) For other examples of catalytic asymmetric syntheses using linked-BINOL
as a chiral ligand, see: (a) Kim, Y. S.; Matsunaga, S.; Das, J.; Sekine, A.;
Ohshima, T.; Shibasaki, M. J. Am. Chem. Soc. 2000, 122, 6506. (b)
Matsunaga, S.; Ohshima, T.; Shibasaki, M. Tetrahedron Lett. 2000, 41,
8473. (c) Takita, R.; Ohshima, T.; Shibasaki, M. Tetrahedron Lett. 2002,
43, 4661. See also refs 4f and 4g. For related compounds: (d) Vogl, E.
M.; Matsunaga, S.; Kanai, M.; Iida, T.; Shibasaki, M. Tetrahedron Lett.
1998, 39, 7917. (e) Ishitani, H.; Kitazawa, T.; Kobayashi, S. Tetrahedron
Lett. 1999, 40, 2161 and references therein.
(18) J. Am. Chem. Soc. 2003, 125, 2169-2178 Direct Catalytic Asymmetric
Aldol Reaction of Hydroxyketones: Asymmetric Zinc Catalysis with a Et2-
Zn/linked-BINOL Complex (1) by Kumagai, N.; Matsunaga, S.; Kinoshita,
T.; Harada, S.; Okada, S.; Sakamoto, S.; Yamaguchi, K.; Shibasaki, M.,
See, also refs 4f and 4g.
9
J. AM. CHEM. SOC. VOL. 125, NO. 9, 2003 2583

A R T I C L E S
Harada et al.
Table 1. Optimization of 1,4-Addition Reaction of Vinyl Ketone 2a
with 3
Table 3. 1,4-Addition Reaction of Indenones 5a
catalyst temp time yieldb
ee
(%)
ketone 3
(equiv)
catalyst
(mol %)
temp
(°C)
time
(h)
ee
(%)
yielda
1
2
entry
X
X
enone product (mol %) (°C)
(h)
(%)
drc
entry
1
2
3
4
5
6
7
2
1.1
2
2
2
5
5
5
5
3
1
1
-20
-20
-30
4
-20
-20
4
8
14
14
3
14
30
8
90
72
87
87
90
84
83
94
97
98
91
96
97
95
1
2
3
4
5
6
H
H
H
Br
Br
H
H
5a
5a
5a
5b
5b
6a
6a
6a
6b
6b
6c
1
1
3
1
1
1
4
-20
-20
4
-20
-20
1.5
4
3
2
4
68 95/5
74 98/2
80 98/2
76 86/14 99
74 98/2
65 97/3
97
99
99
H
H
H
H
99
97
2
2
MeO 5c
4
a Reactions were run on a 1 mmol scale (entries 1-3, 6) or on a 0.5
mmol scale (entries 4, 5) at 0.25 M (entries 2, 3, 4, 6) or at 0.4 M (entries
1, 4) in 5. b Isolated yield. c Determined by 1H NMR analysis of crude
mixture.
a Isolated yield.
Table 2. 1,4-Addition Reaction of Various Vinyl Ketones 2a
Scheme 1. Unsuccessful Trials of 1,4-Addition Reactions with
â-Substituted Enones Using a Et2Zn/(S,S)-Linked-BINOL 1 ) 2/1
System
vinyl
ketone
time
(h)
yieldb
(%)
ee
(%)
1
entry
R
product
1
2
3
4
5
6
p-MeOC6H4
C6H5
o-MeOC6H4
p-ClC6H4
CH3
2a
2b
2c
2d
2e
2f
4a
4b
4c
4d
4e
4f
8
4
12
12
4
83
95
93
94
92
93
91
86c
90
84c
86
82
CH3CH2
4
a Reactions were run on a 1.0 mmol scale at 0.4 M in 2. b Isolated yield
unless otherwise noted. c Determined by 1H NMR analysis with hexa-
methyldisiloxane as an internal standard.
With indenone 5a, good diastereomeric ratio and excellent
enantiomeric excess were observed at 4 °C (Table 3, entry
1: 97% ee, dr ) 95/5), although the chemical yield was modest
due to polymerization. An excellent diastereomeric ratio was
achieved when the reaction was run at -20 °C (entry 2: dr
98/2, 99% ee). With 3 mol % ligand loading, the chemical yield
was slightly improved (entry 3: 80% yield). The relative
configuration of 6a was determined by X-ray crystallography.19
Indenones 5b and 5c also gave 1,4-adducts in excellent
stereoselectivity at -20 °C (entry 5, dr ) 98/2, 99% ee; entry
6, dr ) 97/3, 97% ee).
(B) Second Generation Et2Zn/(S,S)-Linked-BINOL 1 )
4/1 System. In contrast to the successful results with vinyl
ketones and indenones, 1,4-addition reactions with other Michael
acceptors, such as â-substituted enones, were a formidable task.
As shown in Scheme 1, using Et2Zn (5 mol %) and (S,S)-linked-
BINOL 1 (10 mol %), we found that 1,4-addition reactions with
acyclic (eq 1) and cyclic enones (eq 2) afforded products in
poor yield (8a, 27%; 8b, 27%; and 8c, 7%), although the
enantioselectivity was excellent (82-98% ee). The results
ee), but a prolonged reaction time was necessary. At a higher
temperature (entry 4: 4 °C), there was a drastic improvement
in the reaction rate. The reaction reached completion after 3 h
(entry 4) while maintaining a high enantiomeric excess (91%
ee). Good yield and excellent enantiomeric excess were obtained
even when the ligand loading was decreased from 5 to either 3
or 1 mol % (entries 5 and 6, respectively). The reaction rate
dropped significantly, however, at -20 °C. Finally, as shown
in entry 7, the reaction was completed within 8 h to afford 4a
in 83% yield and 95% ee with 1 mol % of (S,S)-linked-BINOL
1 and 2 mol % of Et2Zn at 4 °C.
The optimized reaction conditions were applicable to various
vinyl ketones 2, which usually tend to polymerize under harsh
reaction conditions (Table 2). The mild basicity of the Et2Zn/
(S,S)-linked-BINOL complex allowed for 1,4-addition of 3 to
proceed smoothly with only a small amount of polymerization.
Aryl vinyl ketones with and without substituents on the aromatic
ring were successfully converted to the corresponding 1,4-
adducts in good chemical yield (83-90%) and enantiomeric
excess (92-95% ee; entries 1-4). Alkyl vinyl ketones 2e and
2f also afforded the desired 1,4-adducts in good yield and
enantiomeric excess (entries 5 and 6).
(19) The relative configurations of 6a, 8g, and 8o were determined by X-ray
analysis, see Supporting Information. The absolute configurations of the
carbinolic stereocenters on 4c, 6a, and 8i were determined by Mosher’s
method. (a) Dale, J. A.; Mosher, H. S. J. Am. Chem. Soc. 1973, 95, 512.
9
2584 J. AM. CHEM. SOC. VOL. 125, NO. 9, 2003

Direct Catalytic Michael Reaction of Hydroxyketones
A R T I C L E S
Table 4. Optimization of 1,4-Addition Reaction of â-Substituted
Enone 7a
Scheme 2. 1,4-Addition Reaction of â-Substituted Cyclic Enones
7 and N-Benzylmaleimide 7q with the Second Generation Et2Zn/
(S,S)-Linked-BINOL 1 ) 4/1 with MS 3A System
additive
additive
Et2Zn ligand 1 (mg/mmol (mg/mmol time yielda
drb
(%) (syn/anti) (syn/anti)
ee (%)
entry (mol %) (mol %)
of 7a)
none
none
none
of 7a)
(h)
1
2
3
4
5
6
7
8
10
15
20
20
20
20
20
20
5
5
5
10
5
5
7
7
7
48
3
3
27
44
68
51
90
91
87
93
82/18
84/16
83/17
84/16
73/27
77/23
76/24
78/22
98/nd
98/nd
97/nd
98/nd
95/91
95/87
95/93
95/93
none
MS 13X
MS 5A
MS 4A
MS 3A
150
150
150
150
5
5
3
3
10-12) were also appropriate substrates even in the presence
of oxygen functional groups (entry 11, TBDPS-ether, and entry
12, BOM-ether). Dialkyl substituted enone 7n afforded product
8n in high enantiomeric excess (syn: 93% ee), although the
reactivity was low (yield 39% after 24 h).
1
a Isolated yield. b Determined by H NMR analysis of crude mixture.
suggested that the catalyst turnover step would be problematic
using the Et2Zn/(S,S)-linked-BINOL 1 ) 2/1 complex.
The results with cyclic enones and related compounds are
shown in Scheme 2. In case of cyclic enones (eq 3), 1,4-addition
reactions proceeded with excellent diastereoselectivity to give
8c, 8o, and 8p as single diastereomers. Diastereoisomer was
not observed in any case (dr > 98/2). Good to high ee was also
achieved (8c, 85% ee; 8o, 99% ee; 8p, 98% ee), although the
chemical yield remained moderate (8c, 81%; 8o, 61%; 8p, 45%).
In the case of N-benzylmaleimide (7q, eq 4), the reactivity was
much higher than that of cyclic enones, and the reaction
proceeded smoothly with 1 mol % of 1 and 4 mol % of Et2Zn
to afford 8q in 84% yield, >99% ee, and in high dr (94/6). The
relative configuration of 8o was determined by X-ray crystal-
lography.19
The successful results obtained using the Et2Zn/1 ) 4/1 with
MS 3A system in less reactive â-substituted enones 7 led us to
apply the new system to vinyl ketone 2e to compare the
effectiveness of the new system with the prior Et2Zn/1 ) 2/1
system. Reaction profiles using four different conditions, (A) 2
mol % of Et2Zn in the absence of (S,S)-linked-BINOL 1, (B) 2
mol % of Et2Zn, 1 mol % of (S,S)-1, (C) 2 mol % of Et2Zn, 0.5
mol % of (S,S)-1, and (D) 2 mol % of Et2Zn, 0.5 mol % of
(S,S)-1 with MS 3A, are summarized in Figure 3. The 1,4-
addition reactions were performed using 2 mol equiv of ketone
3 at 0 °C. Ligand acceleration was observed in (B) and (C) as
compared to (A). With conditions (C), in which only one-half
the amount of chiral ligand was used as compared to conditions
(B), the reaction proceeded at a rate similar to (B). Because the
enantiomeric excesses in conditions (B) and (C) were similarly
high (B, 93% ee; C, 93% ee), the results suggest that no racemic
pathway with ligand-free Et2Zn was involved and that a small
excess of Et2Zn interacts with Zn/1/ketone 3 complex and
accelerates the reaction rate.20 It is noteworthy that a similar
reaction rate and ee were achieved with only one-half the amount
On the basis of our investigations of the structure of the Et2-
Zn/(S,S)-linked-BINOL 1 complex with and without hydroxy-
ketone 3, a small excess amount of Et2Zn with respect to (S,S)-
linked-BINOL 1 was expected to be effective for efficient
catalyst turnover.18 As summarized in Table 4, entries 1-3, the
chemical yield increased significantly by changing the ratio of
Et2Zn/(S,S)-linked-BINOL 1, and the best chemical yield was
obtained with an Et2Zn/1 ) 4/1 ratio (entry 1, 27%; entry 2,
44%; entry 3, 68%). Enantiomeric excess was similar when the
ratio of Et2Zn/1 ) 2/1, 3/1, or 4/1 (98, 98, and 97%,
respectively). With 20 mol % of Et2Zn, less chiral ligand
afforded better chemical yield (entry 3, 5 mol % of 1, 68%;
entry 4, 10 mol % of 1, 51%), indicating the effectiveness of
the new Et2Zn/1 ) 4/1 ratio. Examination of various achiral
additives indicated that activated molecular sieves were effective
for further improving reactivity. Among various types of
molecular sieves (MS; entries 5-8), the best reactivity (yield
93%), diastereoselectivity (syn/anti ) 78/22), and enantio-
selectivity (95% ee for syn, 93% ee for anti) were achieved
with MS 3A (entry 8). Molecular sieves were used after
activation at 160 °C under reduced pressure (ca. 0.7 kPa) for 3
h prior to use.
With the optimized Et2Zn/ 1 ) 4/1 with MS 3A system at
-20 °C, 1,4-addition reactions of various â-substituted enones
with ketone 3 were examined. The results with acyclic enones
are summarized in Table 5. 7a and its derivatives 7d-7g, with
either electron-donating or -withdrawing substituents on the
aromatic ring, afforded products syn-selectively in good yield
(entries 1-5, 93-99%) and high enantiomeric excess (entries
1-5, syn: 95-97% ee). The relative configuration of 8g was
determined by X-ray crystallography.19 R-Enolizable enones
such as 7b (entry 6) and 7h (entry 7) were also suitable
substrates, and products were obtained in good dr (entry 6,
86/14; entry 7, 86/14) and ee (entry 6, syn 99% ee; entry 7,
syn 87% ee). With sterically hindered enone 7i, the dr was high
(syn/anti ) 93/7), but the chemical yield and ee were modest
(yield 58%, syn: 74% ee). â-Alkyl-substituted enones (entries
(20) For the beneficial effects of additional achiral base to enhance the reaction
rate of bifunctional asymmetric catalysis: (a) Arai, T.; Yamada, Y. M. A.;
Yamamoto, N.; Sasai, H.; Shibasaki, M. Chem.-Eur. J. 1996, 2, 1368. (b)
Tian, J.; Yamagiwa, N.; Matsunaga, S.; Shibasaki, M. Angew. Chem., Int.
Ed. 2002, 41, 3636.
9
J. AM. CHEM. SOC. VOL. 125, NO. 9, 2003 2585

A R T I C L E S
Harada et al.
Table 5. 1,4-Addition Reaction of â-Substituted Acyclic Enones with the Second Generation Et2Zn/(S,S)-Linked-BINOL 1 ) 4/1 with MS 3A
System
1
a Isolated yield. b Determined by H NMR analysis of crude mixture.
of chiral ligand 1. In the presence of MS 3A (D), the reaction
rate increased dramatically, strongly supporting the effectiveness
of the optimized conditions for â-substituted enones.
mol % (entry 6) and 0.02 mol % (entry 7), the reaction rate
and chemical yield decreased at 4 °C. At room temperature,
the reaction proceeded smoothly even with 0.02 mol % of (S,S)-
linked-BINOL 1 (substrate/chiral ligand ) 5000) to afford 4e
in good yield (entry 8: 90%) after 13 h, maintaining high
enantiomeric excess (entry 8: 91% ee). With 0.01 mol %
loading (substrate/chiral ligand ) 10 000), 4e was obtained in
moderate yield (78%) and good ee (89%). It is noteworthy that
the substrate/chiral ligand ratio improved by 2 orders of
magnitude from substrate/chiral ligand ) 100 with the prior
Zn/1 ) 2/1 ratio system to 5000-10 000 with the new Zn/1 )
4/1 ratio and MS 3A system even with reduced amounts of
ketone 3. The results in entries 8 and 9 indicate that the new
system is exceptionally efficient in terms of catalyst loading
among reported catalytic asymmetric carbon-carbon bond-
forming reactions. Using as little as 1.5 mg of (S,S)-linked-
BINOL 1 and 10 µL of commercially available Et2Zn solution
As shown in Table 6, in the case of the first Et2Zn/1 ) 2/1
without MS 3A system, addition of 2 mol equiv of ketone 3
was essential to achieve satisfactory chemical yield (entry 1,
86% with 2 equiv of 3; entry 2, 53% with 1.1 equiv of 3),
probably due to problems in the catalyst turnover step. With
the new Et2Zn/1 ) 4/1 with MS 3A system, however, there
was no difficulty in catalyst turnover with only 1.1 equiv of
ketone 3. With 0.5 mol % of (S,S)-linked-BINOL 1, 2 mol %
of Et2Zn, and 1.1 equiv of 3, the reaction reached completion
within 3 h to give product 4e in better yield and ee (entry 3:
yield 90%, 96% ee). With reduced catalyst loading (entry 4,
0.25 mol %; entry 5, 0.1 mol %), the reaction proceeded
efficiently to afford 4e in good yield and high ee after 5 h (entry
5, yield 86%, 96% ee; entry 6, yield 83%, 96% ee). With 0.05
9
2586 J. AM. CHEM. SOC. VOL. 125, NO. 9, 2003

Direct Catalytic Michael Reaction of Hydroxyketones
A R T I C L E S
Table 7. Optimization of 1,4-Addition Reaction of Vinyl Ketone 2e
with rac-2-Hydroxy-2′-methoxypropiophenone (rac-9)
ee (%)
10e
93
96 22
96 35
96 33
Et2Zn
entry (mol %)
ligand 1
(mol %)
ketone 9
(equiv)
time
(h)
yielda
(%)
additive
9
1
2
3
4
10
10
20
20
5
5
5
5
2.2
2.2
2.2
5
none
16
16
16
16
15
35
51
88
8
MS 3A
MS 3A
MS 3A
a Isolated yield.
Table 8. 1,4-Addition Reaction of Various Vinyl Ketones 2 with
Racemic Ketone 9
Figure 3. Reaction profiles of 1,4-addition reaction using Et2Zn alone,
Et2Zn/(S,S)-linked-BINOL 1 ) 2/1, 4/1 without MS 3A, and 4/1 with MS
3A systems.
Table 6. Optimization of 1,4-Addition Reaction of Vinyl Ketone 2e
with the Second Generation Et2Zn/(S,S)-Linked-BINOL 1 ) 4/1
with MS 3A System
vinyl
ketone
time
(h)
yielda
(%)
ee
(%)
1
entry
R
product
1
2
3
4
5
6
p-MeOC6H4
C6H6
o-MeOC6H4
p-BrC6H4
CH3
2a
2b
2c
2g
2e
2f
10a
10b
10c
10g
10e
10f
12
24
24
24
16
24
95
82
78
82
88
86
90
93
91
93
96
90
CH3CH2
yielda
(%)
ee
(%)
a Isolated yield.
ketone
(equiv)
ligand
(mol %)
Et2Zn
(mol %)
temp
(°C)
time
(h)
entry
1b
2b
3
4
5
6
7
8
9
2
1
1
2
2
2
1
0.4
0.2
0.08
0.08
0.04
4
4
4
4
4
4
4
rt
rt
4
4
3
5
5
16
30
13
28
86
53
90
86
83
72
74
90
78
93
97
96
96
96
95
88
91
89
ratio of Et2Zn/(S,S)-linked-BINOL 1 and the addition of MS
3A were again important to achieve high yield. With 2.2 mol
equiv of racemic ketone 9 and the Et2Zn/(S,S)-linked-BINOL
1 ) 2/1 complex, 10e was obtained in 15% yield in the absence
of MS 3A (entry 1) and 35% yield in the presence of MS 3A
(entry 2). With a 4/1 ratio, chemical yield improved to 51%,
maintaining high ee (96% ee, entry 3). By increasing the amount
of rac-9, chemical yield was improved to 88% (entry 4, 96%
ee). Interestingly, the recovered ketone 9 was optically active
in all cases (entries 1-4).
Under the optimized conditions, the 1,4-addition reaction of
ketone 9 to various vinyl ketones proceeded smoothly as shown
in Table 8 (entries 1-6). The present reaction provides a new
methodology of synthesizing optically active chiral tert-alcohol
in a catalytic asymmetric manner. Good yield (78-95%) and
high ee (90%-96%) were achieved with vinyl ketones; however,
the reaction did not proceed with other acceptors such as 7a,
probably due to steric hindrance.
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
0.5
0.25
0.1
0.05
0.02
0.02
0.01
a Isolated yield. b In the absence of MS 3A.
in hexanes (1.0 M, 0.01 mmol), we obtained 4.63 g of product
4e (entry 9).
(C) Construction of Chiral Tetrasubstituted Carbon
Stereocenter. Catalytic asymmetric construction of a chiral
tetrasubstituted carbon stereocenter,21 which is not accessible
via asymmetric hydrogenation reactions,22 is one of the most
important topics in recent synthetic organic chemistry. We
envisioned that the present asymmetric zinc catalysis would also
differentiate the enantioface of tetrasubstituted enolate derived
from 2-hydroxy-2′-methoxypropiophenone (9). The 1,4-adduct
would then be chiral tert-alcohol. As shown in Table 7, the
(D) Transformation of 1,4-Adducts. The usefulness of the
Michael adduct becomes much higher by assuming that the
2-methoxyphenyl moiety is a placeholder for further conver-
sions. To demonstrate the utility of the 1,4-adducts as chiral
building blocks, several transformations were performed via
regioselective rearrangements. As shown in Scheme 3, the
Beckmann rearrangement of benzoate 11c with O-mesitylene-
(21) Review: Corey, E. J.; Guzman-Perez, A. Angew. Chem., Int. Ed. 1998,
37, 388.
(22) For excellent achievements in catalytic asymmetric hydrogenation of
ketones, see review: Noyori, R.; Ohkuma, T. Angew. Chem., Int. Ed. 2001,
40, 40 and references therein.
9
J. AM. CHEM. SOC. VOL. 125, NO. 9, 2003 2587

A R T I C L E S
Harada et al.
Scheme 3. Transformation of Michael Adduct via Regioselective
Rearrangement Reaction 1a
Figure 4. Protected ketone 17 and 18.
Reactions using protected ketones such as 17 and 18 (Figure
4) gave either no 1,4-adduct (17) or only trace amounts of 1,4-
adduct (18: 6% at 4 °C after 12 h) in low enantiomeric excess
(<9% ee) using 5 mol % of 1 and 20 mol % of Et2Zn with MS
3A, suggesting the importance of the OH-group in ketones to
promote the reaction. The tendency was the same as that
observed in the direct catalytic asymmetric aldol reaction with
the Zn/1 system.18
a (i) O-Mesitylenesulfonylhydroxylamine, CH2Cl2, room temperature, 24
h; (ii) DIBAL, CH2Cl2, -78 °C to room temperature, 2 h; (iii) mCPBA,
NaH2PO4, ClCH2CH2Cl, 50 °C, 24 h.
Scheme 4. Transformation of Michael Adduct via Regioselective
The fact that recovered ketone 9 was optically active with
the (R)-configuration (8-35% ee; Table 7) provided a clue to
the mechanism of the present asymmetric zinc catalysis. To
obtain more precise results, reaction profiles using optically
active (S)-9 (>99% ee, 2.5 equiv)26 with (a) Et2Zn/(S,S)-linked-
BINOL 1 and (b) Et2Zn/(R,R)-linked-BINOL were examined.
The results are shown in Figure 5. With (b) (R,R)-linked-
BINOL, only a trace amount of 10e was obtained (yield < 2%
determined by 1H NMR), and the ee of recovered ketone 9 was
still 99% ee, suggesting that trace, if any, enolization occurred
under the reaction conditions. On the other hand, with (a) (S,S)-
linked-BINOL 1, the reaction proceeded smoothly to afford
product 10e in 97% ee, and the ee of the recovered ketone was
lower (97% ee) than that of starting ketone 9 (>99% ee). These
results indicate that the Et2Zn/linked-BINOL complex recog-
nizes the absolute configuration of R-hydroxyketone very well.
In addition, the 1,4-addition reaction proceeded smoothly even
when the racemic-9 was used, and the ee of the product was
similarly high as summarized in Table 8 (10e, 96% ee, Table
8, entry 5). Thus, it seemed that one enantiomer, (S)-9, was
involved in the reaction pathway using (S,S)-linked-BINOL 1,
while the other enantiomer, (R)-9, would not interact with the
Zn/(S,S)-linked-BINOL complex at all. The (R)-9 enantiomer
had no adverse effects on the reaction with (S,S)-linked-BINOL
1. The results are also consistent with the exceptionally low
catalyst loading for the 1,4-addition reaction of 2e with ketone
3 (Table 6, 0.01 mol %, substrate/chiral ligand ) up to 10 000).
The absolute configuration of the 1,4-adduct 4e was R, which
should not interact well with the Zn/(S,S)-linked-BINOL/ketone
3 complex. Thus, product inhibition was not problematic in the
case of the present 1,4-addition reaction, unlike many other
common asymmetric catalyses by chiral Lewis acids.27
Rearrangement Reaction 2a
a
(i) O-Mesitylenesulfonylhydroxylamine, CH3CN, room temperature,
1 h; (ii) AlCl3, CH2Cl2, room temperature, 30 min.
sulfonylhydroxylamine (MSH)23 gave 1,5-diamide 12c in 80%
yield. The subsequent DIBAL reduction of 12c afforded 13c in
81% yield. The o-methoxyphenyl group in 13c acts as a
protecting group for amine, which is removable by oxidative
cleavage.24 On the other hand, Baeyer-Villiger oxidation of
benzoate 11c with mCPBA regioselectively gave 1,5-diester 14c
in 68% yield with the aid of electron-donating groups on the
aromatic rings. As shown in Scheme 4, treatment of 6a with
MSH gave oxime mesitylenesulfonate 15a in 92% yield as a
15/1 diastereomixture. 15a was unusually stable, and treatment
of 15a either with basic alumina or with silica gel resulted only
in recovery of 15a even at an elevated temperature. Rearrange-
25
ment of 15a proceeded smoothly in the presence of AlCl3 to
give lactam 16a in 79% yield. The optically active lactam 16a
should be useful for synthesizing various biologically interesting
compounds.
(E) Mechanistic Studies and Discussion. Because the
chirality in the 1,4-adducts from vinyl ketones 2 is induced in
the hydroxyketone part (Tables 2, 6, and 8), it is clear that the
catalyst system differentiates the enantioface of enolate derived
from hydroxyketones. In all cases with â-unsubstituted and
â-substituted enones, the absolute configurations of the 1,4-
adducts were the same as those of the R-position in aldol adducts
(2R).18 We believe that the active species for the present Michael
reaction would be the same as that for the direct catalytic
asymmetric aldol reaction with the Zn/(S,S)-linked-BINOL 1
system.18 To clarify the mechanism and catalytic cycle of the
present reaction, several mechanistic studies were performed.
To gain more insight into the catalytic cycle, initial rate
kinetics were investigated using enone 2e and ketone 3. Under
(26) Optically active ketone 9 (99% ee) was prepared as shown in the scheme
below. Starting from the racemic ketone 9, the aldol reaction with (R,R)-
linked-BINOL was repeated by using recovered ketone 9 each time. After
four direct aldol reaction and recovery processes, ketone 9 was recovered
in high ee (>99% ee).
(23) Tamura, Y.; Fujiwara, H.; Sumoto, K.; Ikeda, M.; Kita, Y. Synthesis 1973,
215.
(24) (a) Porter, J. R.; Traverse, J. F.; Hoveyda, A. H.; Snapper, M. C. J. Am.
Chem. Soc. 2001, 123, 10409. (b) Ishitani, H.; Ueno, M.; Kobayashi, S. J.
Am. Chem. Soc. 2000, 122, 8180 and references therein.
(25) Tanga, M. J.; Reist, E. J. J. Heterocycl. Chem. 1986, 23, 747.
(27) In the direct aldol reaction of 3 with Zn/linked-BINOL complex, the
maximum substrate/chiral ligand ratio was 1000, probably due to the product
(dihydroxyketone) inhibition.
9
2588 J. AM. CHEM. SOC. VOL. 125, NO. 9, 2003

Direct Catalytic Michael Reaction of Hydroxyketones
A R T I C L E S
Scheme 5. Working Catalytic Cycle of Direct Catalytic
Asymmetric Michael Reaction
Scheme 6. Postulated Transition State Models for Acyclic Enones
(eq 5) and Cyclic Enones (eq 6)
Figure 5. Reaction profiles of 1,4-addition reaction with optically active
ketone (S)-9 (99% ee) catalyzed by (a) Et2Zn/(R,R)-linked-BINOL and (b)
Et2Zn/(S,S)-linked-BINOL.
conditions (1) first generation Zn/(S,S)-linked-BINOL 1 ) 2/1
without MS 3A, the reaction was around 0.8-order on enone
2e, 0.7-order on Zn/1 complex, and 0.8-order on ketone 3,28
suggesting that the 1,4-addition step and product dissociation
step would be equally slow. In contrast, under (2) the Et2Zn/
(S,S)-linked-BINOL 1 ) 4/1 with MS 3A system, the reaction
was first-order on enone 2e, first-order on Zn/1 complex, and
zero-order on ketone 3.28 These results clearly indicate that the
rate-determining step in the catalytic cycle is the 1,4-addition
step. Thus, the effectiveness of the Zn/1 ) 4/1 with MS 3A
system on acceleration of the catalyst dissociation step was
clear.29 The rate-determining step was completely different from
the case of the direct aldol reaction, where kinetics suggested
that 1,2-addition was fast and the rate-determining step would
be the catalyst turnover step.30 The difference can be rationalized
by considering the above-mentioned results in Figure 5 with
optically active ketone 9. Interaction of (2R)-1,4-adducts with
Zn/1 should be weaker than that of aldol adducts (dihydroxy-
ketones). Thus, the rates for the product dissociation step would
be different from each other.
via a bifunctional mechanism utilizing two or more zinc centers
seems reasonable on the basis of related examples of achiral
zinc catalysis.31 Zn-binaphthoxide (Ar*O-Zn, Zn-1 in Scheme
5) would function as a Brønsted base to deprotonate the R-proton
in 3 to form (II). Enones come from the Re-face of the enolate
selectively to be activated by the Lewis acidic zinc center. Initial
rate kinetics suggested that the 1,4-addition to form (IV) is the
rate-limiting step. Protonation with phenolic proton of 1
(Ar*OH) followed by ligand exchange with 3 would regenerate
(I). The product dissociation step via exchange with ketone 3
(IV) proceeded smoothly with the Et2Zn/(S,S)-linked-BINOL
1 ) 4/1 and MS 3A system. Considering the relative configura-
tions of 1,4-adducts from acyclic and cyclic enones, we proposed
the working transition state models for acyclic enones (Scheme
6, eq 5) and cyclic enones (Scheme 6, eq 6). In the case of
The postulated catalytic cycle is shown in Scheme 5. We
believe that the same Zn/ligand 1/ketone 3 oligomeric complex
(I) as involved in direct aldol reaction would be the putative
actual active species.18 Although the exact structure of actual
active oligomeric species has not yet been clarified, the reaction
(31) Bifunctional mechanism was proposed for the reaction by achiral dinuclear
Zn complexes as zinc metalloenzyme models. For selected recent examples,
see: (a) Chapman, W. H., Jr.; Breslow, R. J. Am. Chem. Soc. 1995, 117,
5462. (b) Yashiro, M.; Ishikubo, A.; Komiyama, M. J. Chem. Soc., Chem.
Commun. 1995, 1793. (c) Koike, T.; Inoue, M.; Kimura, E.; Shiro, M. J.
Am. Chem. Soc. 1996, 118, 3091. (d) Molenveld, P.; Kapsabeils, S.;
Engbersen, J. F. J.; Reinhoudt, D. N. J. Am. Chem. Soc. 1997, 119, 2948.
(e) Kaminskaia, N. V.; Spingler, B.; Lippard, S. J. J. Am. Chem. Soc. 2000,
122, 6411. (f) Abe, K.; Izumi, J.; Ohba, M.; Yokoyama, T.; Okawa, H.
Bull. Chem. Soc. Jpn. 2001, 74, 85 and references therein.
(28) See Supporting Information for detailed results, including numerical data.
(29) For precedent examples where activated molecular sieves had a key role
to accelerate the product dissociation step in the catalytic cycle, see: Iida,
T.; Yamamoto, N.; Sasai, H.; Shibasaki, M. J. Am. Chem. Soc. 1997, 119,
4783 and references therein.
(30) In the case of the direct aldol reaction, the reaction was first-order on ketone
3, first-order on Zn/1 complex, and zero-order on aldehyde 3.18
9
J. AM. CHEM. SOC. VOL. 125, NO. 9, 2003 2589

A R T I C L E S
Harada et al.
acyclic enones, the reaction would proceed through the s-cis
conformation, and relatively lower diastereoselectivity (Table
5, 61/39-93/7) as compared to that of cyclic enones was
attributed to the conformational flexibility between s-cis and
s-trans forms. The conformation of cyclic enone is fixed to
s-trans, thus leading to high diastereoselectivity (86/14-98/2,
Table 3, and single diastereomer, Scheme 2).
optically active ketone 9 afforded a clue to the reason for the
exceptionally low catalyst loading for â-unsubstituted enone.
Kinetic studies revealed that the rate-determining step is the
1,4-addition step, which is different from the direct aldol
reaction. Application of the present efficient asymmetric zinc
catalysis to other asymmetric reactions such as direct aldol and
Michael reactions of unmodified esters is currently underway
in our group.
Summary
We successfully developed new highly enantioselective 1,4-
addition reactions of hydroxyketones. The first generation Et2-
Zn/linked-BINOL ) 2/1 complex was effective for 1,4-addition
of â-unsubstituted enones and indenones with 2-hydroxy-2′-
methoxyacetophenone. The second generation Et2Zn/(S,S)-
linked-BINOL 1 ) 4/1 with MS 3A system was developed to
widen the substrate scope and was effective for various
â-substituted enones to afford products in up to 99% yield and
up to 99% ee. With the new 4/1 system, ligand loading for the
â-unsubstituted enone was reduced to as little as 0.01 mol %
(substrate/chiral ligand ) 10 000). Mechanistic studies using
Acknowledgment. We thank financial support by RFTF and
Grant-in-Aid for Encouragements for Young Scientists (B) (for
S.M.). We thank Prof. S. Kobayashi and Mr. T. Hamada at the
University of Tokyo for generous support in X-ray analysis.
Supporting Information Available: Experimental procedures,
characterization of the products, X-ray data (CIF), and detailed
data for kinetic studies (PDF). This material is available free
of charge via the Internet at http://pubs.acs.org.
JA028928+
9
2590 J. AM. CHEM. SOC. VOL. 125, NO. 9, 2003