Ruthenium- and enzyme-catalyzed dynamic kinetic resolution of secondary alcohols

Article abstract of DOI:10.1021/ja983819+

Enzymatic resolution of secondary alcohols under substrate racemizing conditions was studied using an immobilized lipase from Candida antarctica in the presence of a ruthenium catalyst. A specifically designed acyl donor, 4- chlorophenyl acetate, was found to be compatible with both catalysts and resulted in an efficient dynamic kinetic resolution. Studies of the reaction in different solvents showed that nonpolar solvents gave the best results. With this process, a variety of racemic secondary alcohols were transformed to the corresponding enantiomerically pure acetates, making efficient use of all starting material. In most cases, the reaction proceeded with >99% ee and in good yield.

Full text of DOI:10.1021/ja983819+

J. Am. Chem. Soc. 1999, 121, 1645-1650
1645
Ruthenium- and Enzyme-Catalyzed Dynamic Kinetic Resolution of
Secondary Alcohols
B. Anders Persson,† Anna L. E. Larsson,† Mikae1l Le Ray,‡ and Jan-E. Ba1ckvall*,‡
Contribution from the Departments of Organic Chemistry, Uppsala UniVersity,
Box 531, S-751 21 Uppsala, Sweden, and Stockholm UniVersity, Arrhenius Laboratory,
SE-106 91 Stockholm, Sweden
ReceiVed NoVember 2, 1998
Abstract: Enzymatic resolution of secondary alcohols under substrate racemizing conditions was studied using
an immobilized lipase from Candida antarctica in the presence of a ruthenium catalyst. A specifically designed
acyl donor, 4-chlorophenyl acetate, was found to be compatible with both catalysts and resulted in an efficient
dynamic kinetic resolution. Studies of the reaction in different solvents showed that nonpolar solvents gave
the best results. With this process, a variety of racemic secondary alcohols were transformed to the corresponding
enantiomerically pure acetates, making efficient use of all starting material. In most cases, the reaction proceeded
with >99% ee and in good yield.
Introduction
During the last two decades, the synthesis of enantiomerically
pure, or enriched, compounds has emerged into one of the most
important fields of organic synthesis.1 In particular, catalytic
asymmetric synthesis, including both metal- and enzyme-
catalyzed reactions, has been a highly active area of research.
In enzyme-catalyzed transformations, the development of reac-
tions in nonaqueous media constitutes a major breakthrough
which has increased their use by nonspecialists.2 Today, kinetic
resolution of racemic substrates by enzyme catalysis has become
a standard reaction in organic synthesis.3 In particular, a variety
of efficient processes for lipase-catalyzed hydrolysis of esters
and acylation of alcohols are available.3,4
Figure 1. Enzymatic resolution of a secondary alcohol.
Scheme 1
resolution is that the maximum theoretical yield is limited to
50%. There are several ways to overcome this problem: (1)
the use of meso compounds or prochiral substrates;3f (2)
stereoinversion of the remaining enantiomer6f (e.g., Mitsunobu
reaction of remaining alcohol in Figure 1); and (3) dynamic
kinetic resolution (DKR).6,7 In DKR, the substrate is continu-
ously isomerized during the resolution process, and this leads
to efficient use of all starting material (Scheme 1). In such a
process, one can theoretically obtain 100% yield of one
enantiomer. Furthermore, provided that the rate of the equilibra-
tion of the substrate enantiomers is about the same as or higher
than the rate of removal of one enantiomer from the system
(krac g kR or kS), DKR will lead to higher enantiomeric ratios
of the product.7 Several examples of efficient dynamic enzy-
A kinetic resolution is generally defined as a process where
the two enantiomers of a racemic mixture are transformed to
products at different rates. Thus, in an efficient enzymatic
resolution, one of the enantiomers of the racemate is selectively
transformed to product, whereas the other is left behind (Figure
1).5 One obvious limitation with this type of enzymatic
† Uppsala University.
‡ Stockholm University.
(1) (a) Noyori, R. Asymmetric Catalysis in Organic Synthesis; John Wiley
& Sons: New York, 1994. (b) Koskinen, A. Asymmetric Synthesis of Natural
Products; John Wiley & Sons Ltd.: New York, 1993.
(2) (a) Cambou, B.; Klibanov, A. M. Biotechnol. Bioeng. 1984, 26, 1449.
(b) Kirchner, G.; Scollar, M. P.; Klibanov, A. M. J. Am. Chem. Soc. 1985,
107, 7072. (c) Klibanov, A. M. Acc. Chem. Res. 1990, 23, 114. (d) Parida,
S.; Dordich, J. S. J. Am. Chem. Soc. 1991, 113, 2253.
(3) (a) Ohno, M.; Otsaka, M. Org. React. 1990, 37, 1. (b) Faber, K.
Biotransformations in Organic Chemistry, Springer-Verlag: Heidelberg,
1992. (c) Wong, C. H.; Whitesides, G. M. Enzymes in Synthetic Organic
Chemistry; Elsevier Science Ltd.: Amsterdam, 1994. (d) Enzyme Catalysis
in Organic SynthesissA ComprehensiVe Handbook; Drauz, K., Waldmann,
H., Eds.; VCH: Weinheim, 1995. (e) Santaniello, E.; Ferraboschi, P.;
Grisenti, P.; Manzocchi, A. Chem. ReV. 1992, 92, 1071. (f) Schoffers, E.;
Golebiowski, A.; Johnson, C. R. Tetrahedron 1996, 52, 3769.
(4) Reviews on the use of lipases in organic synthesis: (a) Sih, C. J.;
Wu, S. H. Topics Stereochem. 1989, 19, 63. (b) Chen, C.-S.; Sih, C. J.
Angew. Chem., Int. Ed. Engl. 1989, 28, 695. (c) Boland, W.; Fro¨ssl, C.;
Lorentz, M. Synthesis 1991, 1049. (d) Faber, K.; Riva, S. Synthesis 1992,
895. (e) Theil, F. Chem. ReV. 1995, 95, 2203. (f) Schmid, R. D.; Verger,
R. Angew. Chem., Int. Ed. 1998, 37, 1608.
(5) (a) Chen, C.-S.; Fujimoto, Y.; Girdaukas, G.; Sih, C. J. J. Am. Chem.
Soc. 1982, 104, 7294. (b) Chen, C.-S.; Wu, S.-H.; Girdaukas, G.; Sih, C. J.
J. Am. Chem. Soc. 1987, 109, 2812.
(6) Reviews: (a) Yokozeki, K.; Nakamori, S.; Eguchi, C.; Ymada, K.;
Mitsugi, K. Agric. Biol. Chem. 1987, 109, 2845. (b) Ward, R. S.
Tetrahedron: Asymmetry 1995, 6, 1475. (c) Noyori, R.; Tokunaga, M.;
Kitamura, M. Bull. Chem. Soc. Jpn. 1995, 68, 36. (d) Caddick, S.; Jenkins,
K. Chem. Soc. ReV. 1996, 447. (e) Stu¨rmer, R. Angew. Chem., Int. Ed.
Engl. 1997, 36, 1173. (f) Stecher, H.; Faber, K. Synthesis 1997, 1.
(7) For a mathematical treatment of the kinetics in DKR, see: (a)
Kitamura, M.; Tokunaga, M.; Noyori, R. J. Am. Chem. Soc. 1993, 115,
144. (b) Kitamura, M.; Tokunaga, M.; Noyori, R. Tetrahedron 1993, 49,
1853.
10.1021/ja983819+ CCC: $18.00 © 1999 American Chemical Society
Published on Web 02/13/1999

1646 J. Am. Chem. Soc., Vol. 121, No. 8, 1999
Persson et al.
Scheme 2. Ruthenium-Catalyzed Racemization of
(+)-(R)-3a
Scheme 3
The ruthenium-catalyzed racemization of (+)-(R)-3 was then
combined with an enzyme-catalyzed transesterification using
Candida antarctica component B lipase16 supported on acrylic
resin (commercially available under the trade name Novozym
435). This enzyme has been successfully employed in esteri-
fications,17 transesterifications,18 and hydrolysis,19 perhydroly-
sis,20 and aminolysis21 of esters. It has been shown to possess
a very high thermostability, tolerating temperatures as high as
70-80 °C,17 which makes this enzyme most suitable for our
purposes. The use of catalyst 1 in combination with the enzyme
and different acyl donors gave poor results with decreased
activity of the enzyme, and furthermore, the rapid racemization
with this catalyst could not be reproduced in the presence of
the enzyme. On the other hand, combination of catalyst 2 with
the enzyme and the acyl donor worked better. Using vinyl
acetate as the acyl donor,22 a complete conversion of the alcohol
was achieved within 17 h. However, only 50% yield of the
acetate was obtained, and the rest was oxidized starting material
(Scheme 3 and Table 1, entry 1). The use of isopropenyl acetate,
from which acetone is formed in the acylation step, showed
the same phenomenon but to a lower extent than for vinyl
acetate. In this case, 72% of the substrate was converted to (R)-
1-phenylethyl acetate ((R)-4), and the remaining 28% was
oxidized (Table 1, entry 2).
a Reaction conditions: 2 mol % 1, 10 mol % NaOH, 4 h, or 2 mol
% 2, 24 h.
matic resolution have been reported,6-8 and recently the use of
transition metals for substrate racemization has attracted some
interest.6e,9
We have been involved in the combination of enzyme and
transition metal catalysis,9c,10 and in a preliminary communica-
tion we recently reported on an efficient enzymatic resolution
of 1-phenylethanol and 1-indanol coupled with ruthenium-
catalyzed racemization of the substrate.9c One problem with the
latter procedure was that 1 equiv of the corresponding ketone
(acetophenone and indanone, respectively) was required for a
good result. We have now overcome this problem, and here
we give a full account of our new results and discuss the scope
and limitations of the reaction.
Results and Discussion
During our studies on ruthenium-catalyzed hydrogen-transfer
reactions employing catalyst 1 and 2,11-13 we had observed that
alcohols undergo fast isomerization at the R-carbon leading to
racemization or epimerization.14 With the aim of developing a
DKR of alcohols, we studied the isomerization of (+)-(R)-3
with catalysts 1 and 2 (Scheme 2). Both of the catalysts were
able to catalyze the complete racemization of (+)-(R)-3, 1 with
a higher rate than 2.15 Although 1 is faster than 2, it requires
the presence of NaOH, which may interfere with the enzyme.
To avoid the problem with the oxidation associated with
alkenyl acetates as acyl donors, we turned our attention to other
(15) A highly efficient ruthenium catalyst for the racemization of
secondary alcohols was reported recently: Koh, J. H.; Jeong, H. M.; Park,
J. Tetrahedron Lett. 1998, 39, 5545. For a review on racemization of
optically active compounds, see: Ebbers, E. J.; Ariaans, G. J. A.; Houbiers,
J. P. M.; Bruggink, A.; Zwanenburg, B. Tetrahedron 1997, 53, 9417.
(16) X-ray structures of this enzyme have been solved recently: (a)
Uppenberg, J.; Hansen, M. T.; Patkar, S.; Jones, T. A. Structure 1994, 2,
293. (b) Uppenberg, J.; O¨ hrner, N.; Norin, M.; Hult, K.; Kleywegt, G. J.;
Patkar, S.; Waagen, V.; Anthonsen, T.; Jones, T. A. Biochemistry 1995,
34, 16838.
(17) (a) Arroyo, M.; Sinisterra, J. V. J. Org. Chem. 1994, 59, 4410. (b)
Bjo¨rkling, F.; Godtfredsen, S. E.; Kirk, O. J. Chem. Soc., Chem. Commun.
1989, 934.
(8) (a) Chen, S. T.; Huang, W.-H.; Wang, K.-T. J. Org. Chem. 1994,
59, 7580. (b) Um, P.-J.; Drueckhammer, D. G. J. Am. Chem. Soc. 1998,
120, 5605. (c) van der Deen, H.; Cuiper, A. D.; Hof, R. P.; van Oeveren,
A.; Feringa, B. L.; Kellog, R. M. J. Am. Chem. Soc. 1996, 118, 3801.
(9) (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) Larsson, A. L. E.; Persson, B.
A.; Ba¨ckvall, J. E. Angew. Chem., Int. Ed. Engl. 1997, 36, 1211. (d) Reetz,
M. T.; Schimossek, K. Chimia 1996, 50, 668.
(10) (a) Schink, H. E.; Ba¨ckvall, J. E. J. Org. Chem. 1992, 57, 1588; J.
Org. Chem. 1992, 57, 6082 (correction). (b) Ba¨ckvall, J. E.; Gatti, R.;
Schink, H. E. Synthesis 1993, 343. (c) Gatti, R. P. G.; Larsson, A. L. E.;
Ba¨ckvall, J. E. J. Chem. Soc., Perkin Trans. 1 1997, 4, 577. (d) Yoshisaki,
H.; Ba¨ckvall, J. E. J. Org. Chem. 1998, 63, 9339.
(11) (a) Chowdhury, R. L.; Ba¨ckvall, J. E. J. Chem. Soc., Chem. Commun.
1991, 1063. (b) Ba¨ckvall, J. E.; Andreasson, U. Tetrahedron Lett. 1993,
34, 5459. (c) Ba¨ckvall, J. E.; Chowdhury, R. L.; Karlsson, U.; Wang, G.-
Z. In PerspectiVes in Coordination Chemistry; Williams, A. F., Floriani,
C., Merbach, A. E., Eds.; Verlag: Basel, 1992; p 463.
(12) (a) Wang, G.-Z.; Ba¨ckvall, J. E. J. Chem. Soc., Chem. Commun.
1992, 337. (b) Wang, G.-Z.; Andreasson, U.; Ba¨ckvall, J. E. J. Chem. Soc.,
Chem. Commun. 1994 1037. (c) Almeida, M. L. S.; Kocˇovsky´, P.; Ba¨ckvall,
J. E. J. Org. Chem. 1996, 61, 6587. (d) Almeida, M. L. S.; Beller, M.;
Wang, G.-Z.; Ba¨ckvall, J. E. Chem. Eur. J. 1996, 2, 1533.
(18) (a) Anthonsen, H. W.; Hoff, B. H.; Anthonsen, T. Tetrahedron:
Asymmetry 1995, 6, 3015. (b) Hoff, B. H.; Anthonsen, H. W.; Anthonsen,
T. Tetrahedron: Asymmetry 1996, 7, 3187. (c) Sundram, H.; Golebiowski,
A.; Johnson, C. R. Tetrahedron Lett. 1994, 35, 6975. (d) Orrenius, C.;
Mattson, A.; Norin, T.; O¨ hrner, N.; Hult, K. Tetrahedron: Asymmetry 1994,
5, 1363. (e) Orrenius, C.; O¨ hrner, N.; Rotticci, D.; Mattson, A.; Hult, K.;
Norin, T. Tetrahedron: Asymmetry 1995, 6, 1217. (f) Orrenius, C.; Norin,
T.; Hult, K.; Carrea, G. Tetrahedron: Asymmetry 1995, 6, 3023. (g) Mattson,
A.; Orrenius, C.; O¨ hrner, N.; Unelius, C. R.; Hult, K.; Norin, T. Acta Chem.
Scand. 1996, 50, 918. (h) O¨ hrner, N.; Martinelle, M.; Mattson, A.; Norin,
T.; Hult, K. Biocatalysis 1994, 9, 105. (i) Tanaka, K.; Osuga, H.; Suzuki,
H.; Shogase, Y.; Kitahara, Y. J. Chem. Soc., Perkin Trans. 1 1998, 935. (j)
Uenishi, J.; Hiraoka, T.; Hata, S.; Nishiwaki, K.; Yonemitsu, O.; Nakamura,
K.; Tsukube, H. J. Org. Chem. 1998, 63, 2481. (k) Danieli, B.; Lesma, G.;
Luisetti, M. Tetrahedron 1997, 53, 5855. (l) Mattson, A.; O¨ hrner, N.; Hult,
K.; Norin, T. Tetrahedron: Asymmetry 1993, 4, 925.
(19) (a) Johnson, C. R.; Bis, S. J. Tetrahedron Lett. 1992, 33, 7287. (b)
Partali, V.; Waagen, V.; Alvik, T.; Anthonsen, T. Tetrahedron: Asymmetry
1993, 4, 961. (c) Waagen, V.; Hollingsæter, I.; Partali, V.; Thorstad, O.;
Anthonsen, T. Tetrahedron: Asymmetry 1993, 4, 2265. (d) Chapman, D.
T.; Crout, D. H. G.; Mahmoudian, M.; Scopes, D. I. C.; Smith, P. W. Chem.
Commun. 1996, 2415.
(20) Ru¨sch gen Klaas, M.; Warwel, S. Synth. Commun. 1998, 251.
(21) (a) Conde, S.; Lo´pez-Serrano, P.; Fierros, M.; Biezma, M. I.;
Mart´ınez, A.; Rodr´ıguez-Franco, M. I. Tetrahedron 1997, 53, 11745. (b)
de Castro, M. S.; Gago, J. V. S. Tetrahedron 1998, 54, 2877.
(22) (a) Castaing-Degueil, M.; de Jeso, B.; Drouillard, S.; Maillard, B.
Tetrahedron Lett. 1987, 28, 953. (b) Wang, Y. F.; Lalonde, J. J.;
Momongam, M.; Bergbreiter, D. E.; Wong, C. H. J. Am. Chem. Soc. 1988,
110, 7200.
(13) This catalyst is readily prepared from Ru3(CO)12 and tetraphenyl
cyclopentadienone: Shvo, Y.; Menashe, N. Organometallics 1991, 10, 3885.
(14) (a) Chowdhury, R. L. Unpublished results from these laboratories.
(b) Andreasson, U.; Ba¨ckvall, J. E.; Chowdhury, R. L.; Wang, G. Z. Conf.
Abstr. OMCOS 7, Kobe, Japan, 1993; p 68. See also: Geneˆt, J. P.;
Ratovelomanana-Vidal V.; Pinel, C. Synlett 1993, 478.

Ru- and Enzyme-Catalyzed DKR of Secondary Alcohols
J. Am. Chem. Soc., Vol. 121, No. 8, 1999 1647
Table 1. Enzymatic Resolution of 1-Phenylethanol (rac-3)
Coupled with Ruthenium-Catalyzed Racemization Employing
Catalyst 2a
Table 2. Enzymatic Resolution of 1-Phenylethanol (rac-3)
Coupled with Ruthenium-Catalyzed Racemization Employing
Catalyst 2 in Various Solventsa
entry
1
solvent
time (h) convb (%) (R)-4:5b ee of (R)-4c (%)
t-BuOH
20
40
20
40
20
40
20
40
20
20
97
>99
99
>99
>99
>99
>99
>99
98
61:39
67:33
83:17
87:13
81:19
86:14
82:18
86:14
65:35
72:28
>99
>99
>99
2
3
4
n-hexane
toluene
n-Bu2O
>99
>99
>99
5
6
THF
1,4-dioxane
99
a The reactions were performed on a 2 mmol scale with 2 mol % of
complex 2, 1 equiv of acetophenone, 50 mg of Novozym 435, and the
acyl donor (ROAc) in 5 mL of t-BuOH at 70 °C under argon
atmosphere. b The conversion and ratio of products were determined
by 1H NMR and GC. The relative amount of formed acetophenone (5)
has been corrected for the amount of added acetophenone. c The ee
was determined on (R)-4 using chiral HPLC on a Chiralcel OD-H
column using 5% i-PrOH in hexane, 0.5 mL/min. d The ee was
determined on the alcohol corresponding to (R)-4 (i.e., (+)-(R)-3) by
chiral HPLC using the same conditions as for the acetate. e The reaction
was run on half the scale as above (1 mmol).
a The reactions were performed on a 1 mmol scale with 2 mol % of
complex 2, 30 mg of Novozym 435, 1.0 equiv of benzophenone, and
3.0 equiv of acyl donor (4-Cl-PhOAc) in 2.5 mL of solvent at 70 °C
under argon atmosphere. b The conversion and ratio of products were
determined by 1H NMR and GC. c The ee was determined on the
alcohol corresponding to (R)-4 (i.e., (+)-(R)-3) by chiral HPLC on a
Chiralcel OD-H column using 5% i-PrOH in hexane, 0.5 mL/min.
enzyme and would finally redeliver its hydrogens back to the
substrate ketone. This worked to some extent,24 but as the results
without ketone were similar, we decided to omit any ketone
when turning to other substrates.
types of activated esters. Activated esters, such as trichloroethyl
esters2b and trifluoroethyl esters,23 have been used in trans-
esterifications, and they shift the equilibrium of the enzyme-
catalyzed acyl transfer toward acylated product. For our
purposes, however, esters with protons in the R-position to the
oxygen are not suitable since the alcohol released will interfere
with the ruthenium catalyst (vide infra). Aryl esters were
therefore considered as acyl donors, and these esters should also
be more reactive than alkyl esters and therefore favor acylation
to an aliphatic alcohol. An additional advantage with these
esters, e.g., aryl acetates, is that the reactivity can be tuned with
electron-withdrawing (or electron-donating) substituents. At-
tempts to use phenyl acetate as the acyl donor showed that this
ester was not active enough in the transesterification. Electron-
withdrawing groups on the aryl ring increased the reactivity,
and 4-chlorophenyl acetate was found to be an excellent acyl
donor in the ruthenium- and enzyme-catalyzed DKR of rac-3
using enzyme Novozym 435 (N-435) and catalyst 2 (Table 1,
entry 3). It is interesting to note that the selectivity of the enzyme
is excellent irrespective of which acyl donor was used, and the
ee was >99% for all three acyl donors employed.
Before turning to other substrates, studies were undertaken
to improve the process and make it more general. The addition
of 1 equiv of the corresponding ketone to the alcohol was an
obvious drawback and would put severe limitations on the
procedure, especially when performing the reaction on more
sophisticated substrates. However, by gradually decreasing the
amount of ketone, the yield of (R)-4 went down and the amount
of oxidized starting material increased, suggesting that there
was a hydrogen-consuming process taking place, possibly
involving the enzyme. The addition of 1 equiv of ketone would
prevent this side reaction by keeping a constant and high
concentration of the corresponding ketone in the reaction
mixture. Since the substrate structure requirement for the enzyme
is limited to a relatively small group next to the alcohol function,
we thought that benzophenone could work as a hydrogen
acceptor in the catalytic cycle. This would provide a general
ketone to be used with any substrate, since the intermediate
benzhydrol formed would be too sterically demanding for the
The resolution of 3 catalyzed by 2 (2 mol %) and Novozym
435 using 3 equiv of 4-chlorophenyl acetate was then examined
using a variety of solvents.25 As shown in Table 2, full
conversion was obtained within 20 h for all of the solvents
tested, where nonpolar solvents such as toluene and hexane gave
the best results; t-BuOH was the slowest among the solvents
tested. The selectivity of the enzyme, however, did not vary
significantly in any of the solvents. Significant amounts of
acetophenone 5 were formed as a byproduct in all cases, again
t-BuOH being the poorest solvent. Toluene was finally chosen
as the solvent for further studies.
To study the scope of the reaction, a variety of substrates
were resolved using the same reaction conditions as in Table 1
but employing toluene as the solvent and without added ketone.
The results are summarized in Table 3. The phenylethanol (3)
gave the acetate 4 in 80% yield with >99% ee. The fused ring
systems, indanol and dehydronaphthol (6 and 8, entries 2 and
3), afforded the acetates in high selectivities and in good yields.
The 4-bromo-substituted derivative 10 did not significantly
change the rate or selectivity of the reaction and gave enantio-
merically pure 11 in 78% yield. However, a methoxy substituent
in the 4-position (12, entry 5) had a negative effect on the
efficiency of the process, and the corresponding acetate (13)
was obtained in only 60% yield and 91% ee. In this reaction,
large amounts of oxidized ketone were formed, which is a result
of the high reduction potential of benzylic alcohols with
electron-donating groups in the 4-position.26,27 Slightly longer
reaction times were required for the 1-naphthyl derivative 14
(24) Using 1 equiv of benzophenone gave a high initial formation of
acetophenone which dropped during the course of the reaction, indicating
that benzophenone indeed worked as a hydrogen mediator. After 24 h, the
product composition was acetate/acetophenone 87:13, and that without added
ketone was 85:15. Adding hydrogen gas (5 mL) and closing the system
had no effect.
(25) For other solvent studies using Novozym 435, see refs 17a, 18f,
and 18i.
(26) This electronic effect has been seen by others in ruthenium-catalyzed
asymmetric transfer hydrogenation reactions: (a) Hashiguchi, S.; Fujii, A.;
Takehara, J.; Ikariya, T.; Noyori, R. J. Am. Chem. Soc. 1995, 117, 7562.
(b) Jiang, Y.; Jiang, Q.; Zhu, G.; Zhang, X. Tetrahedron Lett. 1997, 38,
215.
(23) Hennen, W. J.; Sweers, H. M.; Wang, Y.-F.; Wong, C.-H. J. Org.
Chem. 1988, 53, 4939.
(27) Adkins, H.; Elofson, R. M.; Robinson, A. G. J. Am. Chem. Soc.
1949, 71, 3622.

1648 J. Am. Chem. Soc., Vol. 121, No. 8, 1999
Persson et al.
Table 3. Enzymatic Resolution of Secondary Alcohols Coupled
with Ruthenium-Catalyzed Racemization Employing Catalyst 2a
that of 1-phenylethanol (3), both in terms of reaction time and
yield (entry 7).28 The result from alcohol 18 demonstrates that
going from methyl to ethyl carbinol makes no significant change
in either yield or selectivity, giving acetate 19 in 80% yield
and 98% ee.29 The best substrate in terms of yield was
phenoxypropanol (20), which afforded acetate 21 in 88%
isolated yield (entry 9). High selectiVities and good yields were
also obtained with the aliphatic substrates 22, 24, and 26
(entries 10-12). It is interesting to note that these alcohol
derivatives are difficult to obtain in high ee from asymmetric
reduction of the corresponding ketone. For example, the highest
reported enantioselectivity in the reduction of 2-octanone is 79%
ee.30 DKR of two chiral centers in the same molecule is
exemplified by diol 26, which gave diacetate 27 with >99% ee
(entry 12). This compound is an important synthetic building
block for the transformation into enantiomerically pure 2,5-
dimethylpyrrolidine via a two-step procedure.31 The introduction
of small functional groups next to the alcohol is tolerated, as
demonstrated by the R-chloro-substituted alcohol 28 (entry 13).32
This would allow further functionalization of the products and
increase the synthetic utility of the process. Acetate 29, for
example, can easily be converted into the corresponding amino
alcohol by a two-step procedure.33 The initial experiment using
the conditions of entry 11 gave acetate 29 in 71% yield but
only 58% ee, indicating that the racemization was too slow
compared to acylation. Increasing the amount of catalyst 2 and
at the same time decreasing the amount of enzyme gave acetate
29 in 68% yield and 79% ee.
b
The separation of product from unreacted acyl donor,
4-chlorophenyl acetate, was in some cases difficult. This
problem was solved to some extent by performing a selective
hydrolysis of 4-chlorophenyl acetate in the presence of the
product acetate. This was accomplished by treating the mixture
with a saturated solution of NaHCO3 in methanol and carefully
monitoring the reaction by GC. Kinetic experiments showed
that the rate of hydrolysis of 4-chlorophenyl acetate was nearly
200 times faster than that of acetate 4, which was used as the
model substrate, allowing a more than 95% recovery of the
product.
Another way around this problem would be to design other
types of acyl donors that could be more easily separated from
the products. We therefore prepared some substituted aryl
acetates, 4-NO2, 2-CO2H, and 4-CO2H, and tested them under
the conditions of entry 1, Table 3. The carboxylic derivatives
gave very poor results, which undoubtedly could be ascribed
to the acid functionality. The 4-NO2 derivative gave a 60% yield
of acetate, which should be compared with 76% using 4-chlo-
rophenyl acetate.
We were also interested in whether the number of halogens
attached to the phenyl acetate would influence the rate of the
acylation step. This would give the possibility to match the rate
of the enzyme-catalyzed acylation with the racemization of a
given alcohol. A variety of mono-, di-, and trichloro-substituted
phenyl acetates was prepared and compared using 1-phenyl-
a The reactions were performed on a 2 mmol scale with 2 mol % of
complex 2, 60 mg of Novozym 435, and 3 equiv of acyl donor (4-Cl-
PhOAc) in 5 mL of toluene at 70 °C under argon atmosphere. b Isolated
yield. c Unless otherwise noted, the ee was determined on the alcohol
corresponding to the acetate formed, by using chiral HPLC on a
Chiralcel OD-H column. d Products were contaminated with 4-Cl-
1
PhOAc after flash chromatography. Yields were calculated from H
NMR spectrum. e The ee was determined on the 2-chlorobenzoic acid
ester of the alcohol corresponding to the acetate formed, by using chiral
HPLC on a Chiralcel OD-H column. f The reaction was run with half
the amount of solvent. Under the general conditions, the reaction time
was 68 h. g The ee was determined on the alcohol corresponding to
the acetate formed, by using chiral GC on a CP-Chirasil Dex CB. h The
reaction was performed on a 1 mmol scale with 4 mol % of complex
2, 60 mg of Novozym 435, and 3 equiv of acyl donor (4-Cl-PhOAc)
in 3 mL of toluene at 70 °C under argon atmosphere. i R,R/meso 86:
14. j Half the amount of enzyme (30 mg) and double the amount (4
mol %) of complex 2 were used (see text). k The ee was determined
on the acetate by using chiral HPLC on a Chiralcel OD-H column.
(28) A big difference in rate between 1-naphthylethanol (14) and
2-naphthylethanol (16) has been observed in ruthenium-catalyzed asym-
metric transfer hydrogenation reactions. See ref 26a.
(29) Substrates with larger groups (e.g., isopropyl) next to the alcohol
function are too sterically demanding for this particular enzyme; see ref
18e.
(30) Almquist, F.; Torstensson, L.; Gudmundsson, A.; Frejd, T. Angew.
Chem., Int. Ed. Engl. 1997, 36, 376.
(31) Short, R. P.; Kennedy, R. M.; Masamune, S. J. Org. Chem. 1989,
54, 1755.
(32) Closely related substrates gave low E values when using Candida
antarctica in hydrolysis of the corresponding butanoic esters; see ref 19b.
(33) Ader, U.; Schneider, M. P. Tetrahedron: Asymmetry 1992, 3, 205.
(entry 6). Only 73% conversion was obtained after 48 h, finally
giving the product in 69% yield after 72 h. About 20% was
oxidized byproduct (16% isolated). The other naphthyl deriva-
tive, (2-naphthyl)-1-ethanol (16), showed behavior similar to

Ru- and Enzyme-Catalyzed DKR of Secondary Alcohols
J. Am. Chem. Soc., Vol. 121, No. 8, 1999 1649
analysis. By using an activated aryl acetate, this problem was
completely avoided. The reason for this is that the phenol
released contains neither R-protons nor keto functionality;
hydrogens cannot be abstracted or added to it, and therefore it
does not interfere with the ruthenium catalyst.
The somewhat long reaction times (>40 h) are mainly a result
of the rate-determining racemization. This could, according to
Scheme 1, lead to partial acylation of the wrong isomer, giving
ee values below the reported >99%. However, the high
preference (E value often >200)18 for C. antarctica to acylate
only the R-isomer compensates for this. The case of 2-octanol
(entry 11) also shows that the reaction times can be shortened
from 68 to 24 h simply by concentrating the reactions from 0.4
to 0.8 M (in substrate). Since most examples in Table 3 were
run at 0.4 M, the reaction times can be brought down by carrying
out the reactions at a higher concentration.
Figure 2. Novozym 435-catalyzed acylation of 1-phenylethanol (3),
in toluene at 30 °C, using chloro-substituted phenyl acetates (PA) as
acyl donors: (2) 2,4-dichloro-PA; (9) 4-chloro-PA; ([) PA; (b) 2,4,6-
trichloro-PA; (×) 2,4,5- trichloro-PA.
Scheme 4
Conclusion
We have demonstrated that it is possible to combine transition
metal and enzyme catalysis to obtain dynamic kinetic resolution
of alcohols. In situ isomerization of the substrate alcohol by a
ruthenium catalyst and enzymatic acylation with a specifically
designed acyl donor resulted in full transformation of the
racemic alcohol to enantiomerically pure acetate. The yields
and selectivities were consistently high, and in most cases ee’s
were >99%.
ethanol (3) and N-435 in toluene at 30 °C. The results are
summarized in Figure 2. The mono- and disubstituted derivatives
were comparable in rate, with the latter being somewhat faster.
The initial rate of the nonsubstituted phenyl acetate was similar
but reached equilibrium at ca. 30% conversion, where it stopped
even after prolonged reaction times. Interestingly, the initial rates
of the trisubstituted analogues were by far the slowest, although
50% conversion was reached after extended reaction times (not
shown in Figure 2). This difference in rate may be explained
by the size of these compounds and the steric restrictions of
the enzyme, which counterbalance the good activation of these
compounds.
Experimental Section
General. Solvents for extraction and chromatography were technical
grade and distilled: pentane, hexane, and ethyl acetate (EtOAc). GC
columns used were Rescom SE54 and Chrompack CP-Chiracil-Dex
CB.
All reactions were performed under dry nitrogen or argon atmosphere
in oven-dried (140 °C) glassware, except for those reactions utilizing
water as a solvent, which were run in air. Brine refers to a saturated
solution of NaCl. Novozym 435 (C. antarctica lipase B; 8200 units/g)
was a generous gift from Novo Nordisk A/S, Denmark. Substrates 3,
6, 8, 10, 12, 14, 16, 18, 22, and 24 were commercially available and
used without further purification. 2,5-Hexanediol (26) was prepared
by NaBH4 reduction of commercially available 2,5-hexanedione using
standard techniques. 1-Phenoxy-2-propanol37 (20) and 1-phenoxy-3-
chloro-2-propanol38 (28) were prepared according to literature proce-
dures.
[Ru2(CO)4(µ-H)(C4Ph4COHOCC4Ph4)] (2). A modified synthesis
of this catalyst was used.13,39 In step 1, Ru3(CO)12 (1.205 g, 1.885 mmol)
and tetraphenylcyclopentadienone (2.899 g, 7.54 mmol) in mesitylene
(18 mL) was heated to reflux under argon for 24 h. The mixture was
cooled to room temperature, flushed with argon several times, and
heated to reflux for an additional 6 h. The solvent was distilled off
under reduced pressure, and the crude, dark red mixture was separated
on silica (CH2Cl2) to yield Ru(CO)3(η4-Ph4C4CO) (2.018 g, 63%).
In step 2, the product from the first step was dissolved in acetone
(120 mL). Saturated Na2CO3 (aqueous, 60 mL) was added, and the
mixture was stirred under argon at ambient temperature for 1.5 h. The
brown-orange mixture changed to bright orange during the course of
the reaction. Saturated NH4Cl (aqueous, 150 mL) was added, and the
acetone was removed in vacuo. The aqueous solution was extracted
with CH2Cl2 (3 × 100 mL), and the combined organic phases were
dried (MgSO4). The solvent was evaporated, and the orange residue
was purified on a short silica column. Hexane was used until the red
fraction had moved about 2-3 cm on the column, and then hexane/
CH2Cl2 (gradient 50:50 to 0:100) was used to yield the title compound
(1.336 g, 69%).
Mechanistic Considerations
The mechanism of the ruthenium-catalyzed hydrogen-transfer
reaction has been studied in some detail.11-13,34,35 The reaction
proceeds through a base-mediated hydrogen abstraction from a
hydrogen donor, in our case the substrate itself, forming an
intermediate ruthenium alkoxy species. Abstraction of the
R-proton gives the intermediate ketone and a ruthenium hydride
complex. Subsequent readdition of the hydrogens to the ketone
completes the catalytic cycle to give the racemized substrate
(Scheme 4).
The problems with oxidized starting material when using
vinyl and isopropenyl acetates as acyl donors (Table 1) could
be explained by this mechanism. When the acyl part of these
acyl donors is transferred to the substrate, the remaining vinyl
alcohol is rapidly tautomerized into the corresponding carbonyl
compound, acetaldehyde and acetone, respectively. Both of these
can compete with the intermediate ketone of the substrate as
hydrogen acceptors in the catalytic cycle and thereby consume
the hydrides on ruthenium, resulting in an overall oxidation of
the starting material.36 The formation of 2-propanol when using
isopropenyl acetate as acyl donor was also confirmed by GC
(34) (a) Morton, D.; Cole-Hamilton, D. J. J. Chem. Soc., Chem. Commun.
1988, 1154. (b) Osakada, K.; Kim, Y. J.; Tanaka, M.; Ishiguro, S. I.;
Yamamoto, A. Organometallics 1991, 10, 197. (c) Sasson, Y.; Blum, J. J.
Org. Chem. 1975, 40, 1887. (d) Dobson, A.; Robinson, S. D. Inorg. Chem.
1977, 16, 137. (e) Shinoda, S.; Itagaki, H.; Saito, Y. J. Chem. Soc., Chem.
Commun. 1985, 860.
(35) (a) Shvo, Y.; Blum, Y. Isr. J. Chem. 1984, 24, 144. (b) Blum, Y.;
Czarkie, D.; Stein, Z.; Shvo, Y. Organometallics 1985, 4, 1459. (c) Shvo,
Y.; Czarkie, D.; Rahamin, Y. J. Am. Chem. Soc. 1986, 108, 7400. (d) Abed,
M.; Goldberg, I.; Stein, Z.; Shvo, Y. Organometallics 1988, 7, 2054.
(36) The ethanol or 2-propanol formed is then acylated by the enzyme,
and the process becomes irreversible.
(37) Waagen, V.; Partali, V.; Hollingsaeter, I.; Huang, M. S. S.;
Anthonsen, T. Acta Chem. Scand. 1994, 48, 506.
(38) Stephenson, O. J. Chem. Soc. 1954, 1571. See also ref 19b.
(39) Beller, M. Unpublished results from these laboratories.

1650 J. Am. Chem. Soc., Vol. 121, No. 8, 1999
Persson et al.
4-Chlorophenyl Acetate. Acetyl chloride (2.4 mL, 33 mmol) was
added dropwise to a solution of 4-chlorophenol (3.86 g, 30.0 mmol),
Et3N (9.11 g, 90 mmol), and DMAP (73 mg, 0.6 mmol) in CH2Cl2 (60
mL). The reaction mixture was stirred at room temperature for 16 h.
The solution was washed with 1 M HCl (3 × 50 mL), and the combined
aqueous phases were extracted with ether (3 × 50 mL). The combined
organic phases were washed with saturated Na2CO3 (aqueous, 30 mL)
and brine (20 mL) and dried over MgSO4. The solvent was evaporated,
and the crude mixture was purified on silica using MPLC (EtOAc/
Compounds 11, 23, and 27 are known in the literature, but no NMR
spectra were given. We therefore provide their NMR spectra as
Supporting Information.
Selective Hydrolysis of 4-Chlorophenyl Acetate. The following
procedure is representative: 0.648 g of a mixture of 1,2,3,4-tetrahydro-
1-naphthyl acetate (9) and 4-chlorophenyl acetate in 15 mL of a 4:1
mixture of methanol and saturated NaHCO3 (aqueous) was stirred at
room temperature. The reaction was followed by GC. After 2.5 h, the
methanol was evaporated and the aqueous phase extracted with Et2O
(3 × 30 mL). The combined organic phases were washed with 2 M
NaOH and brine and finally dried over Na2SO4. The solvent was
removed in vacuo and the residue chromatographed through a short
plug of SiO2 (pentane/Et2O 9:1) to give 0.246 g of pure 1,2,3,4-
tetrahydro-1-naphthyl acetate (8) (65% yield overall from racemic 8).
This was then hydrolyzed according to the general procedure before
ee determination.
1
pentane gradient) to yield 4-chlorophenyl acetate (4.423 g, 86%). H
NMR: δ 2.35 (3 H, s, CH3), 7.04 (2 H, dm, J ) 7.9 Hz, ArH) 7.36 (2
H, dm, J ) 7.9 Hz, ArH). 13C NMR: δ 21.0, 122.9, 129.4, 131.2,
149.1, 169.2.
General Procedure for the Ruthenium- and Enzyme-Coupled
Resolution of Secondary Alcohols. Catalyst [Ru2(CO)4(µ-H)(C4Ph4-
COHOCC4Ph4] (2) (43 mg, 0.04 mmol) and Novozym 435 (60 mg)
were placed in a two-necked flask with a condenser, and the atmosphere
was changed to argon. Argon was bubbled through a solution of racemic
1-phenylethanol (3, 244 mg, 2 mmol) and 4-chlorophenyl acetate (1.02
g, 6 mmol) in toluene (5 mL), followed by transfer to the ruthenium
catalyst and enzyme. The reaction was stirred under argon for 46 h at
70 °C. The reaction mixture was filtered and separated on silica (ether/
pentane 2:98) to yield (R)-1-phenylethyl acetate (4, 135 mg, 80%).40
The acetate was hydrolyzed by treatment with K2CO3 (276 mg, 2 mmol)
in methanol/water (4:1), 16 h at room temperature. The methanol was
evaporated, and the aqueous phase was extracted with Et2O (3 × 50
mL). The combined organic phases were washed with brine, dried over
Na2SO4, and reduced in vacuo. The residue was purified on a short
silica column (Et2O/pentane 10:90). The ee of the alcohol was
determined with chiral HPLC on a Chiralcel OD-H column, using 5%
2-propanol in hexane, 0.5 mL/min: ee > 99.5% racemic 1-phenyl-
ethanol (3) used as reference.
Acknowledgment. Financial support from the Swedish
Natural Science Research Council, the Swedish Research
Council for Engineering Sciences, and the Swedish Foundation
for Strategic Research is gratefully acknowledged.
Supporting Information Available: Additional experimen-
tal procedures and NMR data for 11, 23, and 27 (PDF). This
material is available free of charge via the Internet at
http://pubs.acs.org.
JA983819+
(41) NMR data can be found in the following references. 4: Bianchi,
D.; Cesti, P.; Battistel, E. J. Org. Chem. 1988, 53, 5531. 7: Pincock, J. A.;
Wedge, P. J. J. Org. Chem. 1995, 60, 4067. 9: Boyd, D. R.; Sharma, N.
D.; Kerley, N. A.; McMordie, R. A. S.; Sheldrake, G. N.; Williams, P.;
Dalton, H. J. Chem. Soc, Perkin Trans. 1 1996, 1, 67. 13: Brown, S. M.;
Davies, S. G.; de Sousa, J. A. A. Tetrahedron: Asymmetry 1993, 4, 813.
15: Pirkle, W. H.; Hauske, J. R. J. Org. Chem. 1976, 41, 801. 17: Legros,
J. Y.; Toffano, M.; Fiaud, J. C. Tetrahedron 1995, 51, 3235. 19: Rao, B.
R.; Nambudiry, M. E. N. Synth. Commun. 1991, 21, 1721. 21: Funahashi,
K. Bull. Chem. Soc. Jpn. 1979, 52, 1488. 25: See ref 22b. 29: Iqbal, J.;
Srivastava, R. R. Tetrahedron 1991, 47, 3155.
The 1H NMR and 13C NMR spectra of each compound were in good
agreement with the data previously reported in the literature.41
(40) The separation of 1-phenylethyl acetate (4) and 4-chlorophenyl
acetate is difficult, and in most cases only unreacted 1-phenylethanol (3)
was separated in this purification. The hydrolysis was performed on the
mixture of (R)-1-phenylethyl acetate and 4-chlorophenyl acetate, and the
(R)-1-phenylethanol was isolated in the purification after the hydrolysis step.