Practical ruthenium/lipase-catalyzed asymmetric transformations of ketones and enol acetates to chiral acetates.

Article abstract of DOI:10.1021/ol006169z

Ketones were asymmetrically transformed to chiral acetates by one-pot processes using a lipase and an achiral ruthenium complex under 1 atm of hydrogen gas in ethyl acetate. Molecular hydrogen was also effective for the transformation of enol acetates to chiral acetates without additional acyl donors with the same catalyst system.

Full text of DOI:10.1021/ol006169z

ORGANIC
LETTERS
2000
Vol. 2, No. 16
2487-2490
Practical Ruthenium/Lipase-Catalyzed
Asymmetric Transformations of Ketones
and Enol Acetates to Chiral Acetates
,†
Hyun M. Jung, Jeong H. Koh, Mahn-Joo Kim,* and Jaiwook Park*
Department of Chemistry, DiVision of Molecular & Life Science, Pohang UniVersity of
Science and Technology (POSTECH), San 31 Hyoja Dong, Pohang 790-784, Korea
pjw@postech.ac.kr
Received June 6, 2000
ABSTRACT
Ketones were asymmetrically transformed to chiral acetates by one-pot processes using a lipase and an achiral ruthenium complex under 1
atm of hydrogen gas in ethyl acetate. Molecular hydrogen was also effective for the transformation of enol acetates to chiral acetates without
additional acyl donors with the same catalyst system.
A combination of enzymatic resolution and achiral metal
catalysis has emerged as an attractive method for the
preparation of enantiomerically enriched compounds.1 A few
examples with lipases and transition-metal catalysts were
found by the dynamic kinetic resolution (DKR) of simple
alcohols,1b,d-g R-hydroxy acid esters,1i allyl alcohols,2 allyl
acetates,1a,h and an amine.1c As novel extensions of the DKR
of alcohols, we have demonstrated catalytic asymmetric
transformation of enol acetates as well as ketones into chiral
acetates by combining a lipase and a ruthenium complex.3
For the transformation of ketones, 2,6-dimethylheptan-4-ol
and 4-chlorophenyl acetate have been used as a hydrogen
donor and an acyl donor, respectively.4 Although the desired
chiral acetates were produced in high yields and in high
optical purities, practical applications of the processes were
frequently hindered by separation problems caused by 2,6-
dimethylheptan-4-one and unreacted 4-chlorophenyl acetate
in product mixtures.5 Herein we describe a significant
advance to solve the separation problems by using molecular
hydrogen or formic acid as a hydrogen donor and ethyl
acetate as an acyl donor.
We focused on the known catalytic activity of ruthenium
complex 4 for the reduction of ketones with formic acid or
molecular hydrogen (Scheme 1).6 Acetophenone was selected
Scheme 1. Transformation of Ketones to Chiral Acetates with
† E-mail: mjkim@postech.ac.kr.
H2 and Ethyl Acetates
(1) (a) Allen, J. V.; Williams, J. M. J. Tetrahedron Lett. 1996, 37, 1859.
(b) Dinh, P. M.; Howarth, J. A.; Hudnott, A. R.; Williams, J. M. J.; Harris,
W. Tetrahedron Lett. 1996, 37, 7623. (c) Reetz, M. T.; Schimossek, K.
Chimia 1996, 50, 668. (d) Larsson, A. L. E.; Persson, B. A.; Ba¨ckvall,
J.-E. Angew. Chem., Int. Ed. Engl. 1997, 36, 121. (e) Persson, B. A.; Larsson,
A. L. E.; Ray, M. L.; Ba¨ckvall, J.-E. J. Am. Chem. Soc. 1999, 121, 1645.
(f) Persson, B. A.; Huerta, F. F.; Ba¨ckvall, J.-E. J. Org. Chem. 1999, 64,
5237. (g) Koh, J. H.; Jung, H. M.; Kim, M.-J.; Park, J. Tetrahedron Lett.
1999, 40, 6281. (h) Choi, Y. K.; Suh, J. H.; Lee, D.; Lim, I. T.; Jung, J. Y.;
Kim, M.-J. J. Org. Chem. 1999, 64, 8323. (i) Huerta, F. F.; Laxmi, Y. R.
S.; Ba¨ckvall, J.-E. Org. Lett. 2000, 2, 1037.
(2) Lee, D.; Huh, E.; Kim, M.-J.; Jung, H. M.; Koh, J. H.; Park, J. Org.
Lett. In press.
(3) Jung, H. M.; Koh, J. H.; Kim, M.-J.; Park, J. Org. Lett. 2000, 2,
409.
as a standard substrate and was subjected to various reaction
conditions with using complex 4 and Novozym 435 (Table
10.1021/ol006169z CCC: $19.00 © 2000 American Chemical Society
Published on Web 07/20/2000

1).7,8 Formic acid in toluene acted as a hydrogen donor
compatible with 4-chlorophenyl acetate. However, 30% of
than 90% of the acetophenone was consumed within 24 h,
and 1-phenylethanol was accumulated under 1 atm of H2 at
70 °C (Figure 1). Another feature of the reaction profile in
Table 1. Transformation of Acetophenone to 1-Phenylethyl
Acetatea
time yield
%
entry
1
H donor
HCO2H
acyl donor
(h) (%)b eec
4-chlorophenyl acetated 34
70
0e
96
(1.0 equiv)
HCO2H
2
3
4-chlorophenyl acetated 34
(1.2 equiv)
HCO2H‚NEt3 4-chlorophenyl acetated 44
94
99
(1.0 equiv)
H2 (1 atm)
HCO2H‚NEt3 ethyl acetateg
4
5
4-chlorophenyl acetatef
44
96
95
63
99
97
(1.0 equiv)
6
7h
8h
H2 (1 atm)
H2 (1 atm)
H2(1 atm)
ethyl acetateg
96
96
96
89
96
ethyl acetateg
95 >99
75 82
methyl propionateg
Figure 1. Reaction profile of acetophenone under a hydrogen
atmosphere in ethyl acetate.
a The reactions were carried out on a 0.25 mmol scale with 2 mol % of
1
4 and 7 mg of Novozym-435 at 70 °C. b The yield was determined by H
NMR. c The % ee was determined by HPLC using a chiral column ((R,R)
Whelk-01, Merck). d 3.0 equiv. e 1-Phenylethanol was formed in 81%. f 1.1
equiv. g Novozym-435 (21 mg) was used in 0.8 mL of the acyl donor. h The
reaction mixture was concentrated to one-third in volume every 24 h and
the fresh acyl donor was added.
Figure 1 is that the transformation appears to stop at about
90% production of 3a after 96 h. Noticeably, an apparent
increase in the yield as well as in the optical purity of 3a
was achieved by periodic removal of ethanol and addition
of fresh ethyl acetate during the transformation (entry 7).
However, replacement of ethyl acetate with methyl propi-
onate led to a rather poor result in both the yield and the
optical purity of 3a.9
Various ketones, 1a-i, were subjected to the reaction
conditions of entry 6 in Table 1 to investigate the scope of
this process for the preparation of chiral acetates 3a-i (Table
2): In all cases, ketones 1 were consumed completely, and
acetates 3 were easily isolated in good to high yields. In
addition, the enantioselectivities for (R)-3 were generally high
and comparable to those given by the process using 2,6-
heptan-4-ol and 4-chlorophenyl acetate in toluene.10 How-
ever, 4-phenylbutan-2-one (1h) and 1-phenylacetone (1i)
were exceptional substrates that transformed to acetates 3h
and 3i with low optical purities, although the yields were
comparable to others.
Enol acetates 5 were prepared from the corresponding
ketones 111 and were transformed to chiral acetates 3 under
1 atm of H2 in toluene (Table 3). In comparison with the
results from the previous processes using 2,6-dimethylheptan-
4-ol as a hydrogen donor, the isolated yields of acetates 3
were higher, and their optical purities were nearly the same
in most cases. However, enol acetates 5g-i were transformed
to the corresponding acetates 3g-i with distinctly low
enantioselectivities. Decreasing the amount of the lipase
the acetophenone remained after the reaction with 1 equiv
of formic acid, while the use of more than 1 equiv made the
lipase inactive. A significant improvement was achieved by
employing triethylamine (entry 3): Only 6% of the ac-
etophenone remained and optically pure 1-phenylethyl acetate
(3a) was produced in a 94% yield in the reaction with 1
equiv of the 1:1 mixture of triethylamine and formic acid.
Ethyl acetate also acted as an acyl donor, although more
lipase and longer reaction times were needed for results
comparable to those with 4-chlorophenyl acetate. As a
hydrogen donor, molecular hydrogen showed apparent
advantages over formic acid: Only 1 equiv of 4-chlorophenyl
acetate is enough for a satisfactory result (entry 4), and the
combination with ethyl acetate produces 3a in much higher
yield than that of formic acid and ethyl acetate (entry 6).
Furthermore, in contrast to previous conditions for the
reduction of ketones,6a 1 atm of H2 was enough to provide
1-phenylethanol for the enzymatic resolution. In fact, more
(4) Ba¨ckball and co-workers have selected 4-chlorophenyl acetate from
a series of known acyl donors for enzymatic kinetic resolution of alcohols.1d,e
(5) Selective hydrolysis of unreacted 4-chlorophenyl acetate was needed
before chromatographic separation of product acetates, and the separation
of 2,6-dimethylheptan-4-one was difficult in the purification of aliphatic
acetates.
(6) (a) Blum, Y.; Czarkie, D.; Rahamim, Y.; Shvo, Y. Organometallics
1985, 4, 1459. (b) Menashe, N.; Salant, E.; Shvo, Y. J. Organomet. Chem.
1996, 514, 97.
(7) The ruthenium complex is readily prepared from Ru3(CO)12 and
tetraphenylcyclopentadienone: Shvo, Y.; Menashe, N. Organometallics
1991, 10, 3885.
(8) The lipase from Candida antarctica is immobilized on acrylic resin
(trade name: Novozym 435, Nordisk Korea).
(9) The inhibition of methanol liberated from dimethyl malonate has been
noted in an enzymatic kinetic resolution: Fehr, C.; Galindo, J. Angew.
Chem., Int. Ed. 2000, 39, 569.
(10) The absolute configuration of the acetates was determined by
comparing their optical rotations with known data. See: (a) Naemura, K.;
Murata, M.; Tanaka, R.; Yano, M.; Hirose, K.; Tobe, Y. Tetrahedron:
Asymmetry 1996, 7, 3285. (b) Laumen, K.; Schneider, M. P. J. Chem. Soc.,
Chem. Commun. 1988, 598.
(11) For the synthesis of enol acetates, see: Larock, R. C. ComprehensiVe
Organic Transformations; VCH: New York, 1989.
2488
Org. Lett., Vol. 2, No. 16, 2000

Table 2. Transformation of Ketones to Chral Acetatesa
Table 3. Transformation of Enol Acetates to Chral Acetatesa
increased the optical purities of 3g-i with extended reaction
times, although 3i was obtained only in 47% ee despite
decreasing the amount to one-third of the standard condition.
Ruthenium complex 4 is a versatile redox catalyst that can
be reduced not only by alcohols but also by formic acids or
molecular hydrogen.6 The reduced species is known to revert
slowly to 4 with evolving molecular hydrogen.6a This
unproductive consumption of reductants would be respon-
sible for the incomplete reduction of acetophenone with 1
equiv of formic acid.12 Interestingly, triethylamine appeared
to prevent the unproductive reversion to 4, and a significant
improvement was achieved by the use of HCO2H‚NEt3 salt
in combination with 4-chlorophenyl acetate. However, the
salt was not suitable to ethyl acetate because of hydrolysis
to produce acetic acid and ethanol, which can interfere in
the acetylation step. The hydrolysis was not observed in the
reaction with molecular hydrogen in ethyl acetate. Thus, only
alcohols 2 were formed as side products in the transformation
of ketones 1 under a hydrogen atmosphere in ethyl acetate.
A disadvantage in the use of ethyl acetate is a slow acyl-
transfer rate, which was supplemented by using three times
more lipase for the results as compared to those with
4-chlorophenyl acetate. Another drawback is the generation
of ethanol, which would interfere with the substrate alcohols
in the catalytic reactions. However, fortunately, the effect
was not serious under the conditions in Table 2. Furthermore,
the interference can be readily minimized by periodic change
of the reaction medium with fresh ethyl acetate. Meanwhile,
the reduction of ketones 1 in ethyl acetate is fast enough to
provide intermediate alcohols 2 even under 1 atm of H2. In
contrast to the previous reduction with 2,4-dimethylheptan-
4-ol, the reduction with H2 accompanies a decrease in the
concentration of hydrogen mediators, making the racemiza-
tion of intermediate alcohols 2 slow. This effect would
deteriorate the enantioselectivity seriously when the acety-
lation proceeds with low specificity. Such a situation resulted
in the distinctively low optical purities of 3h and 3i, which
was observed again in the transformation of enol acetates 5i
with H2. Generally, enol acetates 5 in toluene were trans-
formed with faster rates than those of ketones 1 in ethyl
(12) There is a suggestion that a hydrogen-consuming process involving
the employed enzyme is possible in the dynamic kinetic resolution of
secondary alcohols.1e
Org. Lett., Vol. 2, No. 16, 2000
2489

acetate, possibly due to the difference in acylation rates. It
is also notable that enol acetates 5 were intact under the same
conditions as used in Table 3 but without the lipase while
the hydrogenation of simple alkenes is much faster than that
of ketones by the same catalyst (4) under 500 psi of H2 at
145 °C.6a In comparison with 2,6-dimethylheptan-4-ol and
formic acid, H2 proved to be a better hydrogen donor in many
aspects, including directly usable purity, cheaper price, and
easier separation of product acetates 3 from the reaction
mixtures.
catalytic activities of a ruthenium complex and a lipase. In
particular, the transformations under 1 atm of H2 demon-
strated the widely applicable activity of the readily available
ruthenium catalyst. The developed processes were suitable
for the preparation of various chiral acetates except those
for which the specificities of the lipase are low.
Acknowledgment. We thank the financial support of the
POSTECH/BSRI(1999) and the Korea Research Foundation
through the Polymer Research Institute in 1999.
In summary, we have developed highly practical one-pot
processes for asymmetric transformations of ketones and enol
acetates to chiral acetates. We found the conditions for
employing ethyl acetate and molecular hydrogen as an acyl
donor and a hydrogen donor, respectively, by combining
Supporting Information Available: Typical experimen-
tal procedures. This material is available free of charge via
the Internet at http://pubs.acs.org
OL006169Z
2490
Org. Lett., Vol. 2, No. 16, 2000