Reductive desymmetrization of 2-alkyl-1,3-diketones catalyzed by optically active β-ketoiminato cobalt complexes

Article abstract of DOI:10.1021/ol016204h

(Equation presented) The reductive desymmetrization of acyclic 1,3-diketones was achieved for the first time by catalytic borohydride reduction in the presence of optically active β-ketoiminato cobalt(II) complex catalysts. In this reaction, various 2-sub

Full text of DOI:10.1021/ol016204h

ORGANIC
LETTERS
2001
Vol. 3, No. 16
2543-2546
Reductive Desymmetrization of
2-Alkyl-1,3-diketones Catalyzed by
Optically Active â-Ketoiminato Cobalt
Complexes
Yuhki Ohtsuka, Kiichirou Koyasu, Taketo Ikeno, and Tohru Yamada*
Department of Chemistry, Faculty of Science and Technology, Keio UniVersity,
Hiyoshi, Kohoku-ku, Yokohama 223-8522, Japan
yamada@chem.keio.ac.jp
Received May 31, 2001
ABSTRACT
The reductive desymmetrization of acyclic 1,3-diketones was achieved for the first time by catalytic borohydride reduction in the presence of
optically active â-ketoiminato cobalt(II) complex catalysts. In this reaction, various 2-substituted-1,3-diaryl-1,3-propanediones were converted
into the corresponding optically active 2-substituted-1,3-diaryl-3-hydroxypropanone in good-to-high yields with excellent diastereo- and
enantioselectivities and high catalytic efficiencies.
The strategy of enantioselective desymmetrization is often
used for the preparation of optically active compounds
because two or more stereocenters can be generated in one
reaction step.1 For example, the optically active 2-substituted-
3-hydroxyketones can be obtained by the enantioselective
reduction of the corresponding symmetrical 2-substituted-
1,3-diketones, which are readily prepared by Claisen con-
densation,2 etc. Whereas various reductive desymmetrizations
of symmetrical diketones have already been reported in
enzymatic reactions,3 the applications of the asymmetric
reduction catalyzed by metal complexes were limited to a
few cyclic symmetrical imides,4 diamides,5 and diketones.6
For the synthesis of the optically active 2-substituted-3-
hydroxyketone units that often appear in various natural
products,7 many studies have been conducted to develop the
most efficient methods. An aldol reaction is one of the most
reliable methods for this purpose, and its enantioselective
and catalytic versions have been examined using various
optically active transition metal complexes.8 In almost all
(4) (a) Matsuki, K.; Inoue, H.; Ishida, A.; Takeda, M.; Nakagawa, M.;
Hino, T. Chem. Pharm. Bull. 1994, 42, 9. (b) Ostendorf, M.; Romagnoli,
R.; Pereiro, I. C.; Roos, E. C.; Moolenaar, M. J.; Speckamp, W. N.;
Hiemstra, H. Tetrahedron: Asymmetry 1997, 8, 1773. (c) Kang, J.; Lee, J.
W.; Kim, J. I.; Pyun, C. Tetrahedron Lett. 1995, 36, 4265. (d) Shimizu,
M.; Nishigaki, Y.; Wakabayashi, A. Tetrahedron Lett. 1999, 40, 8873.
(5) Spivey, A. C.; Andrews, B. I.; Brown, A. D.; Frampton, C. S. Chem.
Commun. 1999, 2523.
(6) Shimizu, M.; Yamada, S.; Fujita, Y.; Kobayashi, F. Tetrahedron:
Asymmetry 2000, 11, 3883.
(1) (a) Willis, M. C. J. Chem. Soc., Perkin Trans. 1 1999, 1765. (b)
Schoffers, E.; Golebiowski, A.; Johnson, C. R. Tetrahedron 1996, 52, 3769.
(2) Magnani, A.; McElvain, S. M. Organic Syntheses; Wiley: New York,
1955; Collect. Vol. III, p 251.
(3) (a) Servi, S. Synthesis 1990, 1. (b) Csuk, R.; Gla¨nzer, B. I. Chem.
ReV. 1991, 91, 49. (c) Itsuno, S. Org. React. 1998, 52, 395.
(7) For recent examples of 2-substituted-3-hydroxyketone units in total
synthesis of natural products, see: (a) Loh, T.-P.; Feng. L.-C. Tetrahedron
Lett. 2001, 42, 3223. (b) Panek, J. S.; Jain, N. F. J. Org. Chem. 2001, 66,
2747. (c) Sawada, D.; Kanai, M.; Shibasaki, M. J. Am, Chem. Soc. 2000,
122, 10521. (d) Paterson, I.; Chen, D. Y.-K.; Acen˜a, J. L.; Franklin, A. S.
Org. Lett. 2000, 2, 1513.
10.1021/ol016204h CCC: $20.00 © 2001 American Chemical Society
Published on Web 07/17/2001

Table 1. Various Catalystsa for Enantioselective Desymmetrization
entry
catalyst
yield (%)b
anti-selectivity (%)c
ee (anti, %)d
recovery (%)b
3
diols yield (%)b
1
2
3
4
5
6
7e
1
2
65
58
65
55
71
75
93
93
99
94
98
96
95
99
33
45
89
81
87
92
99
27
39
11
41
28
15
7
3a
3b
3c
3d
3d
24
1
1
10
a Procedure A: to a solution of the modified borohydride was added a solution of the cobalt catalyst and the substrate; 0.5 mmol of substrate, 0.025 mmol
(5 mol %) of cobalt catalyst, 0.5 mmol of NaBH4, 1.5 mmol of EtOH, 7 mmol of tetrahydrofurfuryl alcohol (THFA) in CHCl3 (total 28 mL) at 0 °C, 10 h.
b Isolated yield. c Determined by 1H NMR analysis. d Determined by HPLC analysis. e Procedure B: to a solution of the cobalt catalyst and the substrate was
added a solution of the modified borohydride; 0.25 mmol of substrate, 0.0125 mmol (5 mol %) of cobalt catalyst 3d, 0.25 mmol of NaBH4, 0.25 mmol of
EtOH, 3.5 mmol of THFA in CHCl3 (total 14 mL) at -20 °C, 10 h.
catalytic enantioselective aldol reactions, however, prepara-
tions of silyl or metal enolates8,9 are required in advance
along with a relatively large amount of loading of the catalyst
for high enantio- and/or diastereoselectivity. These disad-
vantages have made the enantioselective and catalytic aldol
reactions difficult to use on a multigram scale in laboratory
and manufacturing processes. The diastereo- and enantio-
selective reductions of the corresponding 2-substituted-1,3-
diketones conventionally prepared by the Claisen condensa-
tion should be an alternative solution for synthesis of aldol-
type compounds.
Recently, we developed optically active â-ketoiminato
cobalt complex catalysts10 for the highly enantioselective
borohydride reduction of ketones11 and imines12 to afford
the corresponding secondary alcohol and amines with high
catalytic efficiencies13 and reported that the 1,3-diaryl-1,3-
diketones were converted by the catalytic system into the
corresponding 1,3-diols with high enantioselectivity.14 In this
communication, we would like to describe the first successful
reaction for the reductive desymmetrization of acyclic
symmetrical diketones with high stereoselectivities and high
catalytic efficiencies and to propose a new method for the
preparation of optically active aldol-type compounds with
high enantioselectivity.
The desymmetrization of 1,3-diphenyl-2-methyl-1,3-pro-
panedione into optically active 1,3-diphenyl-3-hydroxy-2-
methylpropanone was adopted as a model reaction for
screening the various optically active â-ketoiminato cobalt
complexes for the catalytic borohydride reduction (Table 1).
Each ligand of the cobalt catalyst was prepared from the
corresponding optically active 1,2-disubstituted-1,2-ethyl-
enediamine and 1,3-dicarbonyl compound.13 Although the
anti-selectivity of the resulting â-hydroxyketones was excel-
lent in each case, the enantiomeric excesses of the anti
products varied widely, being sensitive to the structure of
the cobalt complex catalysts (entries 1-6). The catalyst 1
or 2 afforded a low or moderate ee of the anti product (entries
1 and 2), whereas the enantioselectivity was remarkably
improved when employing the series 3 catalysts derived from
the optically active 1,3-bis(2,4,6-trimethylphenyl)ethylene-
diamine (entries 3-6). Among the series 3 catalysts, it was
found that catalyst 3d, having acetyl groups on both side
chains, was the most efficient catalyst for the reductive
desymmetrization of the 1,3-diphenyl-2-methyl-1,3-pro-
panedione (entry 6). After optimization of the reaction
conditions, 99% ee of the anti product was isolated in 93%
yield with 99% diastereoselection (entry 7).
(8) (a) Carreira, E. M. ComprehensiVe Asymmetric Catalysis; Jacobsen,
E. N., Pfaltz, A., Yamamoto, H., Eds.: Springer: Heidelberg, 1999; Vol.
3, p 998. (b) Machajewski, T. D.; Wong, C.-H. Angew. Chem., Int. Ed.
2000, 39, 1352.
(9) Mukaiyama, T. Org. React. 1982, 28, 203.
(10) Nagata, T.; Yorozu, K.; Yamada, T.; Mukaiyama, T. Angew. Chem.,
Int. Ed. Engl. 1995, 34, 2145.
(11) (a) Sugi, K. D.; Nagata, T.; Yamada, T.; Mukaiyama, T. Chem.
Lett. 1996, 737. (b) Sugi, K. D.; Nagata, T.; Yamada, T.; Mukaiyama, T.
Chem. Lett. 1996, 1081. (c) Nagata, T.; Sugi, K. D.; Yamada, T.;
Mukaiyama, T. Synlett 1996, 1076.
(12) Sugi, K. D.; Nagata, T.; Yamada, T.; Mukaiyama, T. Chem. Lett.
1997, 493.
(13) Nagata, T.; Sugi, K. D.; Yorozu, K.; Yamada, T.; Mukaiyama, T.
Catal. SurV. Jpn. 1998, 2, 47.
(14) Ohtsuka, Y.; Kubota, T.; Ikeno, T.; Nagata, T.; Yamada, T. Synlett
2000, 535.
The catalytic and enantioselective desymmetrization was
successfully applied to the preparation of various optically
active 2-substituted-1,3-diaryl-3-hydroxypropanones from the
corresponding 1,3-diketones (Table 2). Various 2-methyl-
2544
Org. Lett., Vol. 3, No. 16, 2001

Table 2. Catalytic Desymmetrization of Various
2-Alkyl-1,3-diaryl-1,3-propanedionesa
Figure 1. Diastereo- and enantioselectivity in the catalytic reduc-
tion system.
one of the products, the presentation in Figure 1 is fully
supported by experimental results.
The absolute configuration of the resulting R-substituted-
â-hydroxyketones was confirmed. The stereoselectively
obtained product, the anti-1,3-di(p-bromophenyl)-3-hydroxy-
2-methyl-1-propanone, was conventionally converted into the
corresponding (R)-R-methoxyphenylacetate. As a result of
the X-ray analysis, it was revealed that (2S,3R)-1,3-di(p-
bromophenyl)-3-hydroxy-2-methyl-1-propanone was ob-
tained, corresponding to the (R,R)-cobalt complex catalyst
(Figure 2). The enantioselective sense in the present reduction
of 1,3-diaryl-2-substituted-1,3-propanedione was in perfect
accord with various examples of cobalt complex catalyzed
a Procedure B (see Table 1). b Isolated yield. c Determined by 1H NMR.
d Values for ee’s of anti products were determined by HPLC analysis.
1,3-diaryl-1,3-diketones, having p-methylphenyl-, 2-naph-
thyl-, p-bromophenyl-, or p-methoxyphenyl- as the aryl
group, were converted into the corresponding anti-2-methyl-
3-hydroxyketones in good-to-high yields with excellent anti-
selectivity and excellent enantioselectivity (entries 2-5). For
the catalytic and enantioselective desymmetrization of vari-
ous 2-substituted-1,3-diketones, such as 2-ethyl-, 2-allyl-,
2-benzyl-, and 2-isopropyl-, the corresponding anti-2-alkyl-
3-hydroxyketones were obtained with excellent anti-selectiv-
ity and excellent enantioselectivity (entries 6-9).
The excellent stereoselectivity in the present catalytic
reduction system can be explained as follows (Figure 1). The
hydride equivalent nucleophile should attack one of the
carbonyl groups in the 1,3-diaryl-1,3-propanedione according
to the Felkin-Anh model to afford the corresponding anti
product with high selectivity. Concerning the excellent
enantioselectivity, the optically active â-ketoiminato cobalt
complex could distinctly recognize the re/si face of the
carbonyl group similar to the cobalt-catalyzed borohydride
reduction of the aryl ketones.11c Since the reaction takes place
with high enantioselectivity and the operation of path A
appears as a consequence of the absolute configuration of
Figure 2. X-ray analysis of (R)-R-methoxyphenylacetate of anti-
1,3-di(p-bromophenyl)-3-hydroxy-2-methyl-1-propanone corre-
sponding to the (R,R)-cobalt catalyst.
Org. Lett., Vol. 3, No. 16, 2001
2545

reductions of carbonyl compounds reported by our research
group.13 Also, this observation would support the above-
mentioned mechanism for the highly diastereo- and enantio-
selection.
In summary, the successful reaction of the catalytic
desymmetrization of acyclic symmetrical diketones was first
achieved for the enantioselective reduction catalyzed by the
optically active â-ketoiminato cobalt complexes. In the
presence of a 5 mol % or less amount of the cobalt complex
catalysts, various 2-substituted-1,3-diaryl-1,3-propanediones
were transformed into the corresponding optically active
2-substituted-1,3-diaryl-3-hydroxypropanones with high di-
astereo- and enantioselectivities. These results indicated that
enantioselective borohydride reduction catalyzed by cobalt
complexes would provide a new method for preparing
optically active aldol-type compounds. Further applications
to other types of dicarbonyl compounds are currently
underway.
Supporting Information Available: Experimental pro-
cedures, spectral data for new compounds, and X-ray analysis
data. This material is available free of charge via the Internet
at http://pubs.acs.org.
OL016204H
2546
Org. Lett., Vol. 3, No. 16, 2001