Enantioselective 1,4-addition of unmodified ketone catalyzed by a bimetallic Zn-Zn-linked-binol complex

Article abstract of DOI:10.1021/ol016981h

(Matrix Presented) 1,4-Addition (Michael addition) of 2-hydroxy-2′-methoxyacetophenone (2) to various αβ-unsaturated ketones was efficiently promoted by a bimetallic Zn-Zn-linked-BINOL complex 3 with good yield (up to 90%) and excellent enantiomeric excess (up to 99% ee). The resulting 2-hydroxy-1,5-diketones were successfully converted to synthetically more versatile esters and amides.

Full text of DOI:10.1021/ol016981h

ORGANIC
LETTERS
2001
Vol. 3, No. 26
4251-4254
Enantioselective 1,4-Addition of
Unmodified Ketone Catalyzed by a
Bimetallic Zn−Zn-Linked−BINOL
Complex
Naoya Kumagai, Shigeki Matsunaga, and Masakatsu Shibasaki*
Graduate School of Pharmaceutical Sciences, The UniVersity of Tokyo,
Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
mshibasa@mol.f.u-tokyo.ac.jp
Received October 31, 2001
ABSTRACT
1,4-Addition (Michael addition) of 2-hydroxy-2′-methoxyacetophenone (2) to various r,â-unsaturated ketones was efficiently promoted by a
bimetallic Zn−Zn-linked−BINOL complex 3 with good yield (up to 90%) and excellent enantiomeric excess (up to 99% ee). The resulting
2-hydroxy-1,5-diketones were successfully converted to synthetically more versatile esters and amides.
The catalytic asymmetric carbon-carbon bond formation is
a major focus of modern synthetic organic chemistry.1
Moreover, the increasing demand for efficient and environ-
mentally benign processes requires the development of atom
economic2 asymmetric catalysis in which enantiomerically
enriched compounds are produced using unmodified sub-
strates. Toward this end, we3 and others4,5 successfully
demonstrated direct catalytic asymmetric aldol reactions that
utilize unmodified ketones as donors. In contrast to these
promising results6 with aldol reactions, however, direct
catalytic asymmetric 1,4-addition reactions of unmodified
ketones are very rare7 despite their importance in synthetic
organic chemistry in providing 1,5-dicarbonyl chiral building
blocks.8,9 Thus, development of the direct catalytic asym-
(4) 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. For a partially successful attempt, see: (g) Nakagawa,
M.; Nakao, H.; Watanabe, K.-I. Chem. Lett. 1985, 391. Unmodified
R-hydroxyketones as donors: (h) The use of R-hydroxyketones with
chemical catalysts has been pioneered by List et al.: Notz, W.; List, B. J.
Am. Chem. Soc. 2000, 122, 7386. (i) Trost, B. M.; Ito, H.; Silcoff, E. R. J.
Am. Chem. Soc. 2001, 123, 3367. See, also ref 4d.
(5) Review for biological and chemical methods: (a) Machajewski, T.
D.; Wong, C.-H. Angew. Chem., Int. Ed. 2000, 39, 1352. For the use of
catalytic antibodies, see: (b) Turner, J. M.; Bui, T.; Lerner, R. A.; Barbas,
C. F., III; List, B. Chem Eur. J. 2000, 6, 2772 and references therein.
(6) For other promising atom economic asymmetric catalysis, see:
Anand, N. K.; Carreira, E. M. J. Am. Chem. Soc. 2001, 123, 9687.
(1) (a) ComprehensiVe Asymmetric Catalysis; Jacobsen, E. N.; Pfaltz,
A.; Yamamoto, H., Eds.; Springer, Berlin, 1999. (b) Catalytic Asymmetric
Synthesis, 2nd ed.; Ojima, I., 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) 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.
10.1021/ol016981h CCC: $20.00 © 2001 American Chemical Society
Published on Web 12/05/2001

metric 1,4-addition reaction of unmodified ketones, which
has high reactivity and selectivity, is in high demand. Herein,
we report the enantioselective 1,4-addition of unmodified
hydroxyketone 2 catalyzed by a bimetallic Zn-Zn-linked-
BINOL complex 3 (Scheme 1).3f,3g,10,11 The reaction provides
droxy-2′-methoxyacetophenone (2),12 affording a practical
method to provide syn-1,2-dihydroxyketones through the
aldol reaction of 2 with various aldehydes. Thus, we
investigated the catalytic asymmetric 1,4-addition reaction
using 3 as a catalyst and 2 as a donor. As shown in Table 1,
Scheme 1. 1,4-Addition of Unmodified Hydroxyketone 2 to
Enones Catalyzed by (S,S)-Zn-Zn-linked-BINOL Complex 1
Table 1. 1,4-Addition of 2′-Hydroxy-2-methoxyacetophenone
(2) to p-Methoxyphenyl Vinyl Ketone (1a)
ketone 2
catalyst
(mol %)
temp.
(°C)
time
(h)
yielda
(%)
eeb
entry
(equiv)
(%)
1
2
3
4
5
6
7
8
2
1.1
2
2
2
2
2
2
5
5
5
5
5
3
1
1
-20
-20
-30
4
8
14
14
3
90
72
87
87
86
90
84
83
94
97
98
91
91
96
97
95
direct access to optically active 2-hydroxy-1,5-diketones in
a highly enantioselective manner (91-99% ee). The useful-
ness of the products was further exemplified by facile
transformations into synthetically versatile esters and amides
by regioselective rearrangements.
In our continuing investigations of the direct catalytic
asymmetric aldol reaction, the dinuclear Zn-Zn-linked-
BINOL complex 3 was determined to be very effective for
shielding one enantioface of enolate generated from 2-hy-
rt
1
-20
-20
4
14
30
8
a Isolated yield. Determined by chiral HPLC analysis.
b
5 mol % of 3 efficiently promoted the 1,4-addition of 2 to
p-methoxyphenyl vinyl ketone 1a 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 2 from 2.0 equiv to 1.1 equiv (entry 2), the reaction
rate and chemical yield decreased somewhat (14 h, 72%
yield), while high enantiomeric excess was maintained (97%
ee). Reaction temperature greatly affected the reaction rate.
By decreasing the reaction temperature to -30 °C (entry
3), higher enantiomeric excess was obtained (98% ee), but
a prolonged reaction time was necessary. At a higher
temperature (entry 4: 4 °C and entry 5: rt), a drastic
improvement in the reaction rate was observed. The reaction
reached completion after 3 h (entry 4) and 1 h (entry 5),
respectively, while maintaining a high enantiomeric excess
(91% ee). Good yield and excellent enantiomeric excess were
obtained even when the catalyst loading was decreased from
5 mol % to either 3 or 1 mol % (entries 6 and 7, respectively)
The reaction rate dropped significantly, however, at -20 °C.
Finally, as shown in entry 8, the reaction was completed
within 8 h to afford 4a in 83% yield and 95% ee with as
little as 1 mol % catalyst at 4 °C.
(7) (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. Unmodified aldehyde as a donor: (d) Betancort, J. M.;
Barbas, C. F., III. Org. Lett. 2001, 3, 3737.
(8) For recent reviews on the catalytic asymmetric 1,4-addition reactions,
see: (a) Krause, N.; Hoffmann-Ro¨der, A. Synthesis. 2001, 171. (b)
ComprehensiVe Asymmetric Catalysis; Jacobsen, E. N.; Pfaltz, A.; Yama-
moto, H., Eds.; Springer: Berlin, 1999; chapter 31.
(9) 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 mal-
onates: (f) Yamaguchi, M.; Shiraishi, T.; Hirama, M. J. Org. Chem. 1996,
61, 3520. â-Keto esters: (g) Ji, J.; Barnes, D. M.; Zhang, J.; King, S. A.;
Wittenberger, S. J.; Morton, H. E. J. Am. Chem. Soc. 1999, 121, 10215.
R-Cyano esters: (h) Sawamura, M.; Hamashima, H.; Ito, Y. Tetrahedron
1994, 50, 4439. Zn reagents: (i) Feringa, B. L. Acc. Chem. Res. 2000, 33,
346. B reagents: (j) Hayashi, T. Synlett 2001, 879. See also, ref 8, 10b and
references therein.
(10) For catalytic asymmetric syntheses using linked-BINOL as a chiral
ligand, 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) Kim, Y. S.; Matsunaga, S.; Das, J.; Sekine, A.; Ohshima, T.;
Shibasaki, M. J. Am. Chem. Soc. 2000, 122, 6506. (c) Matsunaga, S.;
Ohshima, T.; Shibasaki, M. Tetrahedron Lett. 2000, 41, 8473. (d) Matsu-
naga, S.; Ohshima, T.; Shibasaki, M. AdV. Synth. Catal., in press, and
references therein. See also refs 3f and 3g.
(12) 2 was prepared from commercially available 2′-methoxyaceto-
phenone via R-hydroxylation with C6H5I(OAc)2 and NaOH in CH3OH. (a)
Moriarty, R. M.; Hu, H.; Gupta, S. C. Tetrahedron Lett. 1981, 22, 1283.
(b) Togo, H.; Abe, S.; Nogami, G.; Yokoyama, M. Bull. Chem. Soc. Jpn.
1999, 72, 2351.
(11) For other chiral bimetallic Zn catalysts, see refs 4b, 4e, 4i and
references therein.
4252
Org. Lett., Vol. 3, No. 26, 2001

The optimized reaction conditions were applicable to
various vinyl ketones 1,13 which usually tend to polymerize
under harsh reaction conditions (Table 2). Because of the
Table 3. 1,4-Addition of 2-Hydroxy-2′-methoxyacetophenone
(2) to Indenones 5a
Table 2. 1,4-Addition of 2-Hydroxy-2′-methoxyacetophenone
(2) to Various Vinyl Ketones 1a
prod- catalyst temp time yieldb
entry X1 X2 enone uct (mol %) (°C) (h)
(%)
eed
drc (%)
1
2
3
4
5
6
H
H
H
H
H
H
5a
5a
5a
5b
5b
6a
6a
6a
6b
6b
6c
1
1
3
1
1
1
4
-20
-20
4
1.5
4
68 95/5 97
74 98/2 99
80 98/2 99
76 86/14 99
74 98/2 99
65 97/3 97
vinyl
time yieldb
eec
H
entry
R1
ketone product
(h)
(%)
(%)
H
3
Br
Br
H
2
1
2
3
4
5
6
p-MeOC6H4
C6H5
o-MeOC6H4
p-ClC6H4
CH3
1a
1b
1c
1d
1e
1f
4a
4b
4c
4d
4e
4f
8
4
83
86d
95
93
94
92
93
91
-20
-20
4
MeO 5c
4
12
12
4
90
84d
86
a Reactions were run on 1 mmol scale (entry 1-3, 6) or on 0.5 mmol
scale (entry 4, 5) at 0.25 M (entry 2, 3, 4, 6) or at 0.4 M (entry 1, 4) in 5.
bIsolated yield. cDetermined by 1H NMR analysis of crude mixture.
dDetermined by chiral HPLC analysis.
CH3CH2
4
82
a Reactions were run on 1.0 mmol scale at 0.4 M in 1. Isolated yield
unless otherwise noted. cDetermined by chiral HPLC analysis. dDetermined
by 1H NMR analysis with hexamethyldisiloxane as an internal standard.
b
The relative and absolute configurations of the 1,4-
adducts17 can be explained in a similar manner as those of
the previous direct aldol reaction with 3.3f,3g The bimetallic
Zn complex 3 functions as Brønsted base to generate a Zn-
enolate from 2-hydroxy-2′-methoxyacetophenone (2). The
formation of a chelate complex between the (S,S)-catalyst 3
and the enolate, including the participation of the 2′-methoxy
group in a chelate formation (Figure 1),18 would result in an
mild basicity of Zn-Zn-linked-BINOL complex 3, 1,4-
addition of 2 proceeded smoothly with only a small amount
of polymerization. Aryl vinyl ketones with and without
substituents on the aromatic ring were successfully converted
to corresponding 1,4-adducts in good chemical yield (83-
90%) and enantiomeric excess14 (92-95% ee) (entries 2-4).
Alkyl vinyl ketones 1e and 1f also afforded the desired 1,4-
adducts in good yield and enantiomeric excess (entries 5,
6).
With indenone 5a,15 good diastereomeric ratio (dr) and
excellent enantiomeric excess were observed at 4 °C (Table
3, entry 1: 98% ee, dr ) 95/5), although the chemical yield
was modest due to polymerization. An excellent diastereo-
meric ratio was achieved, when the reaction was run at -20
°C (entry 2: dr 98/2, 99% ee). With 3 mol % catalyst
loading, the chemical yield was slightly improved (entry 3:
80% yield). The relative configuration of 6a was determined
by X-ray crystallography.16 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).
(13) Beracierta, A. P.; Whiting, D. A. J. C. S. Perkin Trans. 1 1978,
1257.
(14) General procedure: To a stirred solution of (S,S)-linked-BINOL
(0.01 mmol) in THF (0.3 mL) at -78 °C was added Et2Zn (20 µL, 0.02
mmol, 1.0 M in hexanes). The resulting mixture was stirred for 30 min at
-20 °C, and a solution of 2 (2.0 mmol) in THF (2.0 mL) was added. After
the mixture was warmed to 4 °C, 1a (1.0 mmol) was added and the reaction
mixture was stirred for 8 h at 4 °C, followed by addition of saturated aqueous
NH4Cl. The mixture was extracted with ethyl acetate (× 3), and the
combined organic layers were washed with brine and dried over Na2SO4.
The solvent was removed under reduced pressure, and the residue was
purified by flash silica gel column chromatography (hexane/acetone 6/1)
to afford 4a (272.5 mg, 0.829 mmol, 83%).
Figure 1. Working model for transition state.
efficient shielding of the Si-face of the enolate. Considering
the steric repulsion between the enolate and enones, the
enones 1 and 5 seem to coordinate to the other Zn metal as
(15) Hauser, F. M.; Zhou, M.; Sun, Y. Synth. Commun. 2001, 31, 77.
(16) See Supporting Information.
Org. Lett., Vol. 3, No. 26, 2001
4253

in manner A and B, affording (R)-4 and (R,S)-6 respectively
(Figure 1).
Scheme 3. Transformation of 6a into Lactam 12aa
To demonstrate the utility of the 1,4-adducts as chiral
building blocks, several transformations were performed via
regioselective rearrangements. As shown in Scheme 2, the
Scheme 2. Transformation of 1,4-Adduct via Regioselective
Rearrangementa
a (i) O-Mesitylenesulfonylhydroxylamine, CH3CN, rt, 1 h. (ii)
AlCl3, CH2Cl2, rt, 30 min.
unusually stable and treatment of 11a either with basic
alumina or with silica gel resulted only in recovery of 11a
even at an elevated temperature. Rearrangement of 11a
proceeded smoothly in the presence of AlCl323 to give lactam
12a in 79% yield. The optically active lactam 12a should
be useful for synthesizing various biologically interesting
compounds.
In conclusion, we achieved a highly enantioselective 1,4-
addition reaction of unmodified hydroxyketone 2 to enones,
which leads to optically active 2-hydroxy-1,5-diketones. It
is noteworthy that the reaction was efficiently catalyzed by
as little as 1 mol % of Zn-Zn-linked-BINOL complex 3,
affording the 1,4-adducts in good yield (up to 90%), excellent
enantiomeric excess, and diastereomeric ratio (up to 99%
ee, dr ) 98/2). The 1,4-adducts were successfully converted
to the synthetically more versatile ester and amide. Further
investigation on the substrate scope, reaction mechanism, and
catalyst structure is currently in progress.
a (i) O-mesitylenesulfonylhydroxylamine, CH2Cl2, rt, 24 h.; (ii)
DIBAL, CH2Cl2, -78 °C to room temperature, 2 h; (iii) mCPBA,
NaH2PO4, ClCH2CH2Cl, 50 °C, 24 h.
Beckmann rearrangement of benzoate 7c19 with O-mesit-
ylenesulfonylhydroxylamine (MSH)20 gave 1,5-diamide 8c
in 80% yield. The subsequent DIBAL reduction of 8c
afforded 9c in 81% yield. The o-methoxyphenyl group in
9c acts as a protecting group for amine, which is removable
by oxidative cleavage.21 On the other hand, Baeyer-Villiger
oxidation of benzoate 7c with mCPBA regioselectively gave
1,5-diester 10c in 68% yield with the aid of electron-donating
groups on the aromatic rings. As shown in Scheme 3,
treatment of 6a with MSH gave oxime mesitylenesulfonate
11a in 92% yield as a 15/1 diastereomixture.22 11a was
(17) The absolute configurations of 4c and 6a were determined by
Mosher’s method. Those of others were temporarily determined by analogy.
(a) Dale, J. A.; Mosher, H. S. J. Am. Chem. Soc. 1973, 95, 512.
(18) The chelate complex formation through the coordination of 2′-
methoxy group was essential to achieve high ee in the direct aldol reaction
of 2 and aldehydes. See ref 3h.
Acknowledgment. We thank Prof. S. Kobayashi, Mr. R.
Akiyama, and Mr. H. Usuda at the University of Tokyo for
their generous support in X-ray crystallographic analysis of
6a. We thank RFTF for financial support.
(19) The benzoate 7c was prepared by treating 4c with benzoyl chloride.
See Supporting Information.
(20) Tamura, Y.; Fujiwara, H.; Sumoto, K.; Ikeda, M.; Kita, Y. Synthesis
1973, 215.
Supporting Information Available: Experimental pro-
cedures, characterization data for products 4, 6-10, 12 and
the CIF file for 6a. This material is available free of charge
via the Internet at http://pubs.acs.org.
(21) (a) Porter, J. R.; Traverse, J. F.; Hoveyda, A. H.; Snapper, M. C. J.
Am. Chem. Soc. 2001, 123, 10409. (b) Porter, J. R.; Traverse, J. F.; Hoveyda,
A. H.; Snapper, M. C. J. Am. Chem. Soc. 2001, 123, 984. (c) Ishitani, H.;
Ueno, M.; Kobayashi, S. J. Am. Chem. Soc. 2000, 122, 8180 and references
therein.
OL016981H
1
(22) Determined by H NMR analysis of isolated product.
(23) Tanga, M. J.; Reist, E. J. J. Heterocycl. Chem. 1986, 23, 747.
4254
Org. Lett., Vol. 3, No. 26, 2001