Highly chemo-, diastereo-, and enantioselective reduction of 1,2-dialkyl-3-aryl-1,3-diketones for preparation of aldol-type compounds

Article abstract of DOI:10.1021/ol016676w

Equation presented Highly chemo-, diastereo-, and enantioselective borohydride reduction of 2-substituted-1,3-diketones was achieved in the presence of the optically active β-ketoiminato cobalt complex catalysts to afford the optically active 2-substituted-3-hydroxyketones. The present catalytic and enantioselective reduction could provide an alternative potential for preparation of optically active anti-aldol-type compounds.

Full text of DOI:10.1021/ol016676w

ORGANIC
LETTERS
2001
Vol. 3, No. 21
3421-3424
Highly Chemo-, Diastereo-, and
Enantioselective Reduction of
1,2-Dialkyl-3-aryl-1,3-diketones for
Preparation of Aldol-Type Compounds
Yuhki Ohtsuka, Kiichirou Koyasu, Daichi Miyazaki, 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 August 31, 2001
ABSTRACT
Highly chemo-, diastereo-, and enantioselective borohydride reduction of 2-substituted-1,3-diketones was achieved in the presence of the
optically active â-ketoiminato cobalt complex catalysts to afford the optically active 2-substituted-3-hydroxyketones. The present catalytic and
enantioselective reduction could provide an alternative potential for preparation of optically active anti-aldol-type compounds.
The aldol reaction is one of the most useful and reliable
methods in organic synthesis for preparation of 2-substituted-
3-hydroxycarbonyl units accompanied with new carbon-
carbon bond formation.1 Optically active 2-substituted-3-
hydroxycarbonyl units are often observed in natural products,
and their hydroxy or carbonyl groups could be stereoselec-
tively2 or stereospecifically3 converted into various func-
tionalities. Therefore, highly diastereoselective and/or enan-
tioselective versions of the aldol reaction are indispensable
for the total synthesis of complicated natural products. A
wide variety of enantioselective aldol reactions, especially
catalytic versions by optically active transition-metal com-
plexes, have been dynamically studied for a decade.4 For
multigram preparation in laboratories, however, some dif-
ficulties can be found in almost all of catalytic aldol
reactions; the preparation of silyl or metal enolates is required
beforehand or a relatively large loading of optically active
catalysts is needed in order to achieve high diastereo- and
enantioselectivities, etc. Alternatively, optically active 2-sub-
stituted-3-hydroxyketones could be also prepared from the
corresponding 2-substituted-1,3-diketones with catalytic and
enantioselective reductions. Very recently, we reported that
symmetrical 2-substituted-1,3-diaryl-1,3-diketones could be
(1) (a) Heathcock, C. H. ComprehensiVe Organic Synthesis; Heathcock,
C. H., Ed.; Pergamon Press: Oxford, 1991; Vol. 2, p 133. (b) Mukaiyama,
T. Org. React. 1982, 28, 203.
(2) For recent examples of the total synthesis of natural products, see:
(a) Wakabayashi, T.; Mori, K.; Kobayashi, S. J. Am. Chem. Soc. 2001,
123, 1372. (b) Evans, D. A.; Fitch, D. M.; Smith, T. E.; Cee, V. J. J. Am.
Chem. Soc. 2000, 122, 10033. (c) Ma, D.; Sun, H. Tetrahedron Lett. 2000,
41, 1947.
(3) For recent examples of the total synthesis of natural products, see:
(a) Paterson, I.; Davies, R. D. M.; Marquez, R. Angew. Chem., Int. Ed.
2001, 40, 603. (b) Shing, T. K. M.; Jiang, Q. J. Org. Chem. 2000, 65,
7059. (c) Davenport, R. J.; Regan, A. C. Tetrahedron Lett. 2000, 41, 7622.
(4) (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.
10.1021/ol016676w CCC: $20.00 © 2001 American Chemical Society
Published on Web 09/22/2001

Scheme 1. Chemoselective Borohydride Reduction of Aromatic vs. Aliphatic Ketones
converted into the corresponding optically active 2-substituted-
aromatic alcohol was 67% ee. When only 0.25 equiv of the
premodified borohydride was used, high enantioselectivity
was realized with high chemo- and diastereoselectivity.
These observations suggested that the excess hydride in
the catalytic system caused noncatalytic reduction, resulting
in low selectivities. To maintain the initial reaction condi-
tions, therefore, five portions of the 0.1 equiv of the
premodified borohydride were successively added at 1 h
intervals to the reaction to obtain the 3-aryl-3-hydroxyketones
in 43% yield with 97% chemoselectivity, 99% anti-selectiv-
ity, and 94% enantiomeric excess (Scheme 2). The enantio-
meric excesses of the 2-methyl-1,3-diketone remaining after
the kinetic resolution were determined by HPLC. Since
racemization of 2-substituted-1,3-diketones gradually pro-
ceeded at room temperature, the reaction mixture was directly
injected into an HPLC chiral column (Daicel chiralpak AD,
5% 2-propanol in n-hexane) to determine the ee of 2,4-
dimethyl-1-phenyl-1,3-pentanedione to be 99% ee. These
observations indicated that the cobalt complex catalyzed
reduction selectively afforded one isomer among the possible
eight isomers and that the kinetic resolution was excellent.
After the detailed optimization,7 the present kinetic resolu-
tion system was successfully applied to enantioselective
reduction of various 2-substituted-1-alkyl-3-aryl-1,3-dike-
tones to optically active 2-substituted-3-hydroxyketones
(Table 1). The 1,3-diketones having 2-methyl, 2-ethyl, and
2-allyl groups were converted into the corresponding 3-aryl-
3-hydroxyketones with high chemo-, diastereo-, and enan-
tioselectivities (entries 1-3). Kinetic resolution in the
enantioselective reduction of the substrate containing a tert-
butyl ketone (entry 4) showed that the corresponding reduced
product was obtained in 48% yield and indicated 99%
chemoselectivity, 99% anti-selectivity, and 97% ee. The
present highly selective kinetic resolution could also be
applied to substrates having primary alkyl ketones, such as
n-nonyl ketone, isobutyl ketone, and benzyl ketone, to obtain
the corresponding anti-hydroxyketones with high selectivities
(entries 5-7).
3-hydroxyketones with excellent diastereoselectivity and
enantiomeric excess with high catalytic efficiency catalyzed
by the optically active â-ketoiminato cobalt complexes.5 In
this Letter, we would like to describe that a highly chemo-,
diastereo-, and enantioselective borohydride reduction of
unsymmetrical 2-substituted-1,3-diketones was achieved in
the presence of the optically active â-ketoiminato cobalt
complexes to afford optically active anti-2-substituted-3-
hydroxyketones.
A preliminary examination of the borohydride reduction
using a catalytic amount of the cobalt complexes revealed
that aromatic ketones were preferentially reduced in the
presence of aliphatic ketones. As shown in Scheme 1, to the
methanol solution of 0.5 mmol of 2-undecanone and 0.5
mmol of 2-acetonaphthone was added 0.1 mmol of sodium
borohydride. After 8 h, 2-undecanone, an alkyl ketone, was
reduced to the corresponding alcohol in 25% yield and
2-acetonaphthone, an aromatic ketone, in 11% yield, respec-
tively. The chemoselectivity for the reduction of the aliphatic
ketone was about 70%. In contrast, in the presence of 0.05
mmol of â-ketoiminato cobalt complex 1, the chemoselec-
tivity was completely reversed. By treatment of the pre-
modified borohydride,6 an aromatic ketone, 2-acetonaphtho-
ne, was selectively reduced to 1-(2-naphthyl)-1-ethanol in
45% yield while the aliphatic ketone was reduced in only
5% yield. The chemoselectivity of the aromatic ketone was
90%. These observations encouraged us to apply the cobalt-
catalyzed reduction to 1-alkyl-3-aryl-1,3-diketones to prepare
the corresponding 1-alkyl-3-aryl-3-hydroxyketones.
As the unsymmetrical 2-substituted-1,3-diketone model for
chemo-, diastereo-, and enantioselective reduction, 2,4-
dimethyl-1-phenyl-1,3-pentanedione was adopted. Since
kinetic resolution must be considered for the model substrate,
0.5 equiv of the premodified borohydride was employed in
the presence of 5 mol % of the optically active â-ketoiminato
cobalt complex catalyst 2. After 24 h, the reaction was
quenched to afford the corresponding hydroxyketones in 44%
yield with 88% aromatic vs 12% aliphatic alcohol. Though
the diastereoselectivity in the aromatic alcohol was deter-
mined to be 93% anti, the enantioselectivity of the anti-
The excellent stereoselectivity in the present catalytic
reduction system can be explained as follows: In the
presence of (R,R)-cobalt catalyst, the enantioselective reduc-
(5) Ohtsuka, Y.; Koyasu, K.; Ikeno,; T. Yamada, T. Org. Lett. 2001, 3,
2543.
(6) Sugi, K. D.; Nagata, T.; Yamada, T.; Mukaiyama, T. Chem. Lett.
1996, 1081.
(7) To reduce the excess hydride in the catalytic system and avoid
noncatalytic reduction further, four portions of the 0.1 equiv of the
premodified borohydride were successively added at 2 h intervals to the
reaction mixture.
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Org. Lett., Vol. 3, No. 21, 2001

Scheme 2. Highly Chemo-, Diastereo-, and Enantioselective Borohydride Reduction of 2-Methyl-1,3-diketone
Table 1. Highly Chemo-, Diastereo-, and Enantioselective Reduction of Various 2-Alkyl-1,3-diketonesa
Org. Lett., Vol. 3, No. 21, 2001
3423

tion of aromatic ketone proceeds by Si-face selectivity.8 In
addition to the enantioselective sense, the reduction of the
aromatic ketone in 2-alkyl-1,3-diketone should be dominant
according to the Felkin-Anh model. Since racemization on
the activated methyne of 2-alkyl-1,3-diketone was not
observed during the present reaction conditions (-20 °C),
the Si-face of carbonyl in the aromatic ketone should be
attacked by a hydride equivalent on condition that the
reduction proceeded according to the Felkin-Anh model.5
Therefore, the anti-2-substituted-3-(R)-hydroxyketones should
be afforded predominantly. The absolute configurations of
the resulting 2-substituted-3-hydroxyketones were deter-
mined. The anti-1-hydroxy-2,4,4-trimethyl-1-phenyl-3-pen-
tanone (entry 4 in Table 1) was conventionally transformed
into the corresponding p-bromobenzoate. As a result of the
X-ray analysis, it was revealed that the (1R,2S)-form was
obtained, corresponding to the (R,R)-cobalt complex catalyst
2 (Figure 1). The enantioselective sense in the present cobalt-
catalyzed reduction of 1,2-dialkyl-3-aryl-l,3-diketone was in
perfect accord with the previous results of enantioselective
reduction of various carbonyl compounds9 and also supported
the proposed mechanism for the high diastereo- and enan-
tioselectivity.5
Figure 1. The absolute configuration of p-bromobenzoate of anti-
1-hydroxy-2,4,4-trimethyl-1-phenyl-3-pentanone corresponding to
the (R,R)-cobalt catalyst was determined by X-ray analysis.
to the preparation of optically active 2-substituted-3-aryl-3-
hydroxyketones. It was expected that the present catalytic
reaction could provide an alternative potential for preparation
of optically active anti-aldol-type compounds. Further studies
on the enantioselective catalytic reduction of other types of
dicarbonyl compounds are currently underway.
It is noted that the highly chemo-, diastereo-, and enan-
tioselective borohydride reduction catalyzed by the optically
active â-ketoiminato cobalt complex was successfully applied
Supporting Information Available: Experimental pro-
cedures and X-ray analysis data. This information is available
free of charge via the Internet at http://pubs.acs.org.
(8) Nagata, T.; Sugi, K. D.; Yamada, T.; Mukaiyama, T. Synlett 1996,
1076.
(9) Nagata, T.; Sugi, K. D.; Yorozu, K.; Yamada, T.; Mukaiyama, T.
Catal. SurV. Jpn. 1998, 2, 47.
OL016676W
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Org. Lett., Vol. 3, No. 21, 2001