Enantioselective Monoreduction of 2-Alkyl-1,3-diketones Mediated by Chiral Ruthenium Catalysts. Dynamic Kinetic Resolution

Article abstract of DOI:10.1021/ol025527q

(Matrix Presented) The reduction of 2-alkyl-1,3-diketones using (R,R)- or (S,S)-RuCl[N-(tosyl)-1,2-diphenylethylenediamine](p-cymene) in the presence of formic acid and triethylamine affords syn-2-alkyl-3-hydroxy ketones as the major products with high en

Full text of DOI:10.1021/ol025527q

ORGANIC
LETTERS
2002
Vol. 4, No. 8
1263-1265
Enantioselective Monoreduction of
2-Alkyl-1,3-diketones Mediated by Chiral
Ruthenium Catalysts. Dynamic Kinetic
Resolution
Florence Eustache, Peter I. Dalko, and Janine Cossy*
Laboratoire de Chimie Organique associe´ au CNRS, ESPCI, 10 rue Vauquelin,
75231 Paris Cedex 05, France
janine.cossy@espci.fr
Received January 8, 2002
ABSTRACT
The reduction of 2-alkyl-1,3-diketones using (R,R)- or (S,S)-RuCl[N-(tosyl)-1,2-diphenylethylenediamine](p-cymene) in the presence of formic
acid and triethylamine affords syn-2-alkyl-3-hydroxy ketones as the major products with high enantioselectivity.
Asymmetric transformation of compounds containing con-
figurationally labile groups is an elegant way to create
simultaneously two or more stereogenic centers in a single
chemical operation.1 Despite the interest in such transforma-
tions, only a few enantiocatalytic methods have been
developed in the past few years.1-3 One of them, pioneered
by Noyori et al., allows the formation of optically active
2-alkyl-3-hydroxy esters through the use of ruthenium-
mediated asymmetric reduction of â-keto esters.3 As an
extension of our studies on the enantiocatalytic reduction of
â-dicarbonyl compounds,4 2-alkyl-1,3-diketones of type A
were investigated.
formic acid and triethylamine affords selectively 2-methyl-
3-hydroxy ketones of type B in high diastereo- and enanti-
oselectivity (Scheme 1).
Scheme 1. Dynamic Kinetic Resolution of 1,3-Diketones
We wish to report that the dynamic kinetic resolution of
such compounds using (R,R)- or (S,S)-RuCl[N-(tosyl)-1,2-
diphenylethylenediamine](p-cymene) in the presence of
(1) (a) Caddick, S.; Jenkins, K. Chem. Soc. ReV. 1996, 25, 447-456.
(b) Noyori, R.; Tokunaga, M.; Kitamura, M. Bull. Soc. Chem. Jpn. 1995,
68, 36-56. (c) Ward, R. S. Tetrahedron: Asymmetry 1995, 6, 1475-1490.
(d) Faber, K. Chem. Eur. J. 2001, 7, 5005-5010.
(2) For enzymatic dynamic kinetic resolution, see: Pesti, J. A.; Yin, J.;
Zhang, L-h.; Anzalone, L. J. Am. Chem. Soc. 2001, 123, 11075-11076.
(3) Kitamura, M.; Tokunaga, M.; Noyori, R. J. Am. Chem. Soc. 1993,
115, 144-152. For a recent review, see: Noyori, R.; Ohkuma, T. Angew.
Chem., Int. Ed. 2001, 40, 40-73.
(4) Cossy, J.; Eustache, F.; Dalko, P. I. Tetrahedron Lett. 2001, 42,
5005-5007.
The reduction of 2-methyl-1,3-diketone 1 in the presence
of (R,R)-RuCl[N-(tosyl)-1,2-diphenylethylenediamine](p-
cymene) [(R,R)-RuLn*] I (1%), triethylamine (2 equiv), and
formic acid (5 equiv) in dichloromethane at room temperature
10.1021/ol025527q CCC: $22.00 © 2002 American Chemical Society
Published on Web 03/26/2002

Scheme 2. Reduction of 2-Methyl-1,3-diketone 1
Table 1. Influence of the Catalyst/Substrate Ratio and Temperature on the Dynamic Kinetic Resolution of 4
entry
T (°C)
cat. (%)
time
yield (%)
convn (%)
5/65a,b
5 ee6a (%)
5 conf
6 ee6a (%)
6 conf
1
2
3
4
50
20
50
20
5.0
5.0
0.5
0.5
0 h 45 min
3 h 0 min
1 h 15 min
30 h 0 min
96
95
89
53
100
100
100
54
72/28
77/23
78/22
72/28
88
92
93
92
2S,3S
2S,3S
2S,3S
2S,3S
37
48
48
48
afforded â-hydroxy ketones 2 and 2′ in a ratio of 68/325a
(yield 89%) (Scheme 2). The two isomers were separated,
and the major syn compound 2 was obtained with an
enantiomeric excess of 93%.6a The relative stereochemistry
Additional examples of this dynamic kinetic resolution are
reported in Table 2. The monoreduction of the 2-methyl-
benzoyl ketones 7a (R ) Me) and 7b (R ) homoallyl)
proceeded chemo- and stereoselectively (Table 2, entries
1-2, syn/anti g 91/9,5b eesyn g 96%). The relative stereo-
1
of 2 was determined by H NMR coupling constants,7 and
the absolute configuration of the newly formed stereogenic
centers was assigned by using Trost’s mandelic ester
method.8 According to this analysis, the reduction of 1, using
(R,R)-RuLn* I, afforded 2 as the major product. Furthermore,
the absolute configuration of 2 was ascertained by chemical
correlation. Accordingly, the hydroxy ketone 2 was trans-
formed to the corresponding acid 3 by a Baeyer-Villiger
oxidation9 followed by saponification. The optical rotation
of the obtained acid 3 was compared to the [R]D of the
enantiomer described in the literature.10
Table 2. Influence of R Groups on the Reduction of
2-Methyl-1,3-diketones
The influence of the catalyst/substrate ratio and the
influence of the temperature on the stereoselectivity of the
dynamic kinetic resolution were studied on compound 4
(Table 1). The reduction of 4 by using the (S,S)-RuLn*
catalyst II led to an inseparable mixture of two diastereo-
isomers, 5 and 6,5a,b favoring the (2S,3S)-isomer 5.8 Con-
siderable rate acceleration was observed in the formation 5
and 6 by performing the reaction at 50 °C compared to room
temperature (Table 1, entries 1, 2 and 3, 4). The diastereo-
and enantioselectivity of the transformation was only mar-
ginally influenced by the temperature and by the catalyst/
substrate ratio. However, the reaction time was increased at
lower catalyst/substrate loading (entry 4).
yield
(%) convn
8 ee
8
9 ee
9
entry 7
R
8 + 9 (%)
8/9
(%) conf (%) conf
1
2
3
4
a
-CH3
84
96 92/85b 966b 2S,3R
89 91/95b 986d 2S,3R
100 83/175b 896c 2S,3S 846c
100 97/35b 976c 2S,3R 806c
b -(CH2)2CHdCH2 87
c
-CH2NHCBz
81
88
d -(CH2)2NHBoc
chemistry of the hydroxy and methyl groups was determined
by 1H NMR analysis, and the absolute configurations of the
newly formed stereogenic centers were determined by the
mandelic ester method.8 Likewise, the reduction of com-
pounds having heteroatom-containing side chains such as
1264
Org. Lett., Vol. 4, No. 8, 2002

Scheme 3. Reduction of an Aliphatic 1,3-Diketone
7c-7d (entries 3-4) afforded the syn isomers as the major
product with an enantiomeric excess greater than 89%.
When bulky groups (phenyl or isopropyl) were present
such as in compounds 10a (R ) phenyl) and 10b (R )
isopropyl), the reaction proceeded at a lower rate than that
for compounds 1, 4, and 7a-d (Table 3). The increase of
the syn isomer 14 (Scheme 3). While the relative stereo-
1
chemistry was established by H NMR analysis,7 the (S,S)
absolute configuration of 14 was ascertained by comparing
the optical rotation of the product with the literature value.11
Also, the absolute configurations of the newly formed
stereogenic centers were ascertained by using Trost’s man-
delic ester method.8
In summary, a short entry to 2-alkyl 3-hydroxy ketones
by using configurationally labile R-substituted dicarbonyl
compounds was developed. The dynamic kinetic resolution
of these compounds, by using a RuCl[N-(tosyl)-1,2-diphe-
nylethylenediamine](p-cymene)-mediated reduction in the
presence of formic acid and triethylamine, afforded the major
syn compounds for a variety of linear substrates with high
enantioselectivity (ee in the range of 88-98%). This method
complements the recently developed â-ketoiminato cobalt
complex mediated enantioselective reduction of Yamada et
al. which produces the anti isomer as the major product.12
These reactions offer an alternative for the preparation of
aldol type intermediates by a non aldol pathway under easily
scalable conditions.13 The application of this reaction to the
synthesis of natural products is currently underway.
Table 3. Influence of Sterically Hindered R Groups on the
Reduction of 2-Alkyl-1,3-diketones
reaction yield convn
time (%) (%)
11 ee 11 12 ee 12
11/ 12 (%) conf (%) conf
entry 10
R
1
2
a
b
Ph 24 h 38
i-Pr 3 days 36
57 67/335a,b 256d 2S,3S 256d
39 66/345a 916e 2S,3S 186e
steric hindrance around the ketone decreased both the
diastereo- and enantioselectivity of the reduction. For the
reduction of compound 10a (R ) Ph) (Table 3, entry 1), the
dynamic kinetic resolution afforded a 67/335a,b mixture of
an inseparable mixture of syn/anti diastereomers 11a and
12a in 38% combined yield with 25% ee6d for each
diastereomer (57% conversion). The absolute configurations
of the newly formed stereocenters were deduced from X-ray
crystal structure analysis of the fully reduced product issued
from 10a.4 Likewise, in the case of diketone 10b having an
isopropyl group, a mixture of two inseparable diastereomers
in a ratio 66/34 was obtained5a and the major syn isomer
11b was formed with 91% ee.6e
Acknowledgment. One of us, F.E., thanks Rhodia and
the CNRS for a grant.
Supporting Information Available: Experimental pro-
cedures for the transfer hydrogenation reaction and charac-
terization of the products. This material is available free of
charge via the Internet at http://pubs.acs.org.
OL025527Q
(8) The absolute configurations of the alcohols were determined via the
(R)- and (S)-O-methylmandelic esters, according to Trost B. M.; Belletire,
J. L.; Godelski, S.; McDougal, P. G.; Balkovec, J. M. J. Org. Chem. 1986,
51, 2370-2374.
An aryl activating group was not necessary for the reaction.
The reduction of diketone 13 afforded a 72/285a mixture of
â-keto alcools 14 and 15 in 92% yield and with 94% ee for
(9) Yoshikawa, N.; Yamada, Y. M. A.; Das, J.; Sasai, H.; Shibashaki,
M. J. Am. Chem. Soc. 1999, 121, 4168-4178.
(10) (a) Ghosh, A. K.; Kim, J.-H. Tetrahedron Lett. 2001, 42, 1227-
1231. (b) Ghosh, A. K.; Fidanze, S.; Onishi, M. Hussain, K. A. Tetrahedron
Lett. 1997, 41, 7171-7174.
(5) The diastereoselectivity was determined (a) by 1H NMR analysis.
(b) By HPLC analysis.
(11) Evans, D. A.; Kozlowski, M. C.; Murry, J. A.; Burgey, C. S.;
Campos, K. R.; Connell, B. T.; Staples, R. J. J. Am. Chem. Soc. 1999, 121,
669-685.
(6) The enantiomeric purity was determined by chiral HPLC. Condi-
tions: (a) Daicel Chiracel OD-H column; eluent hexane/2-propanol: 98/2.
(b) Daicel Chiracel OD-H column; eluent hexane/2-propanol: 99/1. (c)
Daicel Chiracel OJ-H column; eluent hexane/2-propanol: 95/5. (d) Daicel
Chiracel OD-H column; eluent cyclohexane/2-propanol: 95/5. (e) Daicel
Chiracel OJ-H column; eluent hexane/2-propanol: 98/2.
(7) For discussion of the stereostructural assignment of aldol-type
products by using 1H NMR, see: Heathcock, C. H. In Asymmetric Synthesis;
Morrison, J. D., Ed.; Academic Press: London, 1984; Vol. 3, pp 111-
212.
(12) Ohtsuka, Y.; Koyasu, K.; Ikeno, T.; Yamada, T. Org. Lett. 2001,
3, 2543-2546.
(13) For a comprehensive review of catalytic enantioselective aldol
reaction, see: Nelson, S. G. Tetrahedron: Asymmetry 1998, 9, 357-389.
For related reactions affording â-hydroxy ketones by non aldol pathway,
see: (a) Krauss, I. J.; Wang, C. C.-Y.; Leighton, J. L. J. Am. Chem. Soc.
2001, 123, 11514-11515. (b) Langer, P. Angew. Chem., Int. Ed. 2000, 39,
3049-3052 and references cited.
Org. Lett., Vol. 4, No. 8, 2002
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