Combined ruthenium(II) and lipase catalysis for efficient dynamic kinetic resolution of secondary alcohols. Insight into the racemization mechanism

Article abstract of DOI:10.1021/ja051576x

Pentaphenylcyclopentadienyl ruthenium complexes (3) are excellent catalysts for the racemization of secondary alcohols at ambient temperature. The combination of this process with enzymatic resolution of the alcohols results in a highly efficient synthesis of enantiomerically pure acetates at room temperature with short reaction times for most substrates. This new reaction was applied to a wide range of functionalized alcohols including heteroaromatic alcohols, and for many of the latter, enantiopure acetates were efficiently prepared for the first time via dynamic kinetic resolution (DKR). Different substituted cyclopentadienyl ruthenium complexes were prepared and studied as catalysts for racemization of alcohols. Pentaaryl-substituted cyclopentadienyl complexes were found to be highly efficient catalysts for the racemization. Substitution of one of the aryl groups by an alkyl group considerably slows down the racemization process. A study of the racemization of (S)-1-phenylethanol catalyzed by ruthenium hydride η⁵-Ph₅CpRu(CO) ₂H (8) indicates that the racemization takes place within the coordination sphere of the ruthenium catalyst. This conclusion was supported by the lack of ketone exchange in the racemization of (S)-1-phenylethanol performed in the presence of p-tolyl methyl ketone (1 equiv), which gave <1% of 1-(p-tolyl)ethanol. The structures of ruthenium chloride and iodide complexes 3a and 3c and of ruthenium hydride complex 8 were confirmed by X-ray analysis.

Full text of DOI:10.1021/ja051576x

Published on Web 05/27/2005
Combined Ruthenium(II) and Lipase Catalysis for Efficient
Dynamic Kinetic Resolution of Secondary Alcohols. Insight
into the Racemization Mechanism
Bele´n Mart´ın-Matute,† Michaela Edin,† Krisztia´n Boga´r,† F. Betu¨l Kaynak,‡ and
Jan-E. Ba¨ckvall*,†
Contribution from the Department of Organic Chemistry and Department of Structural
Chemistry, Arrhenius Laboratory, Stockholm UniVersity, SE-106 91 Stockholm, Sweden
Received March 11, 2005; E-mail: jeb@organ.su.se
Abstract: Pentaphenylcyclopentadienyl ruthenium complexes (3) are excellent catalysts for the racemization
of secondary alcohols at ambient temperature. The combination of this process with enzymatic resolution
of the alcohols results in a highly efficient synthesis of enantiomerically pure acetates at room temperature
with short reaction times for most substrates. This new reaction was applied to a wide range of functionalized
alcohols including heteroaromatic alcohols, and for many of the latter, enantiopure acetates were efficiently
prepared for the first time via dynamic kinetic resolution (DKR). Different substituted cyclopentadienyl
ruthenium complexes were prepared and studied as catalysts for racemization of alcohols. Pentaaryl-
substituted cyclopentadienyl complexes were found to be highly efficient catalysts for the racemization.
Substitution of one of the aryl groups by an alkyl group considerably slows down the racemization process.
A study of the racemization of (S)-1-phenylethanol catalyzed by ruthenium hydride η5-Ph5CpRu(CO)2H (8)
indicates that the racemization takes place within the coordination sphere of the ruthenium catalyst. This
conclusion was supported by the lack of ketone exchange in the racemization of (S)-1-phenylethanol
performed in the presence of p-tolyl methyl ketone (1 equiv), which gave <1% of 1-(p-tolyl)ethanol. The
structures of ruthenium chloride and iodide complexes 3a and 3c and of ruthenium hydride complex 8
were confirmed by X-ray analysis.
Introduction
from being limited to a maximum theoretical yield of 50%.
Strategies to increase the yield are therefore of great importance.
Due to the chiral nature of all living organisms, there is an
ever increasing demand for enantiomerically pure compounds,
primarily for use as pharmaceuticals, but also for use as flavor
and aroma chemicals, agricultural chemicals and specialty
materials. Great achievements in catalytic asymmetric synthetic
transformations using transition metals, enzymes and organo-
catalysts have been reported in recent years.1 However, despite
the fact that in nine of the top ten drugs produced, the active
ingredients are chiral,2 resolution of racemic mixtures is still
the most common way to prepare enantiomerically pure
compounds on an industrial scale.3 Immobilized lipases are
robust biocatalysts for kinetic resolution (KR) of esters in water
and of alcohols in organic solvents.4 Enzymatic KRs are often
very efficient in terms of selectivity, but suffer, as all resolutions,
In situ racemization of the slow-reacting enantiomer leads to
deracemization by dynamic kinetic resolution (DKR) and makes
possible a 100% yield. Secondary alcohols can be racemized
via transition metal-catalyzed hydrogen transfer reactions.5 In
recent years chemoenzymatic DKR of secondary alcohols
(Scheme 1) has been a rapidly evolving field of research.6,7,8
Various rhodium, iridium and ruthenium complexes are
known to catalyze rapid racemization of alcohols,5a,c,9,10 but only
few have proved compatible with an enzymatic reaction. The
(4) (a) Bornscheuer, U. T.; Kazlauskas, R. J. Hydrolases in Organic Synthesis;
Wiley-VCH: Weinheim, 1999. (b) Reetz, M. T. Curr. Opin. Chem. Biol.
2002, 6, 145-150. (c) Schmid, R. D.; Verger, R. Angew. Chem., Int. Ed.
1998, 37, 1608-1633.
(5) (a) Huerta, F. F.; Minidis, A. B. E.; Ba¨ckvall, J.-E. Chem. Soc. ReV. 2001,
30, 321-331. (b) Ito, M.; Osaku, A.; Kitahara, S.; Hirakawa, M.; Ikariya,
T. Tetrahedron Lett. 2003, 44, 7521-7523. (c) Pa`mies, O.; Ba¨ckvall, J.-E.
Chem. Eur. J. 2001, 7, 5052-5058.
† Department of Organic Chemistry.
‡ Department of Structural Chemistry.
(1) (a) Halpern, J.; Trost, B. M. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 5347.
(b) Catalytic Asymmetric Synthesis, 2nd ed.; Ojima, I., Ed.; Wiley-VCH:
New York, 2000. (c) ComprehensiVe Asymmetric Catalysis; Jacobsen, E.
N., Pfaltz, A., Yamamoto, H., Eds.; Springer: Berlin, 1999. (d) Noyori,
R. Asymmetric Catalysis in Organic Synthesis; John Wiley & Sons: New
York, 1994. (e) Enzyme Catalysis in Organic Synthesis: A ComprehensiVe
Handbook, 2nd ed.; Drauz, K., Waldmann, H., Eds.; Wiley-VCH: Wein-
heim, 2002; Vols. I-III. (f) Faber, K. Biotransformations in Organic
Chemistry, 4th ed.; Springer: Berlin, 2000. (g) Dalko, P. I.; Moisan, L.
Angew. Chem., Int. Ed. 2004, 43, 5138-5175.
(6) (a) Pa`mies, O.; Ba¨ckvall, J.-E. Trends Biotechnol. 2004, 22, 130-135.
(b) Pa`mies, O.; Ba¨ckvall, J.-E. Chem. ReV. 2003, 103, 3247-3261.
(c) Pa`mies, O.; Ba¨ckvall, J.-E. Curr. Opin. Biotechnol. 2003, 14, 407-
413. (d) Kim, M.-J.; Anh, Y.; Park, J. Curr. Opin. Biotechnol. 2002, 13,
578-587, and erratum 2003, 14, 131. (e) See ref 5a.
(7) For a DKR employing acid zeolites for racemization of benzylic alcohols,
see: Wuyts, S.; De Temmerman, K.; De Vos, D. E.; Jacobs, P. A. Chem.
Eur. J. 2005, 11, 386-397.
(8) For a related DKR of amines see: Reetz, M. T.; Schimossek, K. Chimia
1996, 50, 668-669.
(2) Rouhi, A. M. Chem. Eng. News 2004, 82, 47-62.
(9) Dinh, P. M.; Howarth, J. A.; Hudnott, A. R.; Williams, J. M. J.; Harris,
W. Tetrahedron Lett. 1996, 37, 7623-7626.
(3) Breuer, M.; Ditrich, K.; Habicher, T.; Hauer, B.; Kesseler, M.; Stu¨rmer,
R.; Zelinski, T. Angew. Chem., Int. Ed. 2004, 43, 788-824.
(10) Koh, J. H.; Jeong, H. M.; Park, J. Tetrahedron Lett. 1998, 39, 5545-5548.
9
10.1021/ja051576x CCC: $30.25 © 2005 American Chemical Society
J. AM. CHEM. SOC. 2005, 127, 8817-8825
8817

A R T I C L E S
Mart´ın-Matute et al.
Scheme 1. Chemoenzymatic DKR of Secondary Alcohols
Recently, we communicated a highly efficient metal- and
enzyme-catalyzed DKR of alcohols at room temperature.22 This
is the fastest DKR of alcohols hitherto obtained by the
combination of metal and enzyme catalysts. Racemization was
effected by a new class of very potent hydrogen transfer catalysts
(3a-b). Evidence for the intermediacy of a ruthenium alkoxide
complex was also provided. Various mechanisms have been
proposed for Ru-catalyzed hydrogen transfer involving alcohols
and ketones,23 a transformation involved in the Ru-catalyzed
racemization of secondary alcohols. In some of those mech-
anisms the substrate is coordinated to the Ru center prior to
hydrogen transfer,5c,24 whereas in other mechanisms the substrate
is hydrogenated/dehydrogenated outside the coordination sphere
of the Ru.25,26 In some instances, it is difficult to determine
whether hydrogen transfer occurs inside or outside the coordina-
tion sphere of the metal.27,28
In this full account on mild and efficient DKR, a broad
substrate scope is demonstrated. Various heterocyclic alcohols
have successfully been deracemized for the first time by the
use of ruthenium catalyst 3a and an enzyme. Some examples
of potential applications are also given. A new and efficient
method for the preparation of ruthenium halide complexes 3a-
c, 5 and 6 has been developed. We have also prepared a
ruthenium hydride complex and studied its possible intermediacy
in the racemization mechanism. Furthermore, evidence is
presented that supports a mechanism in which the racemization
of the alcohol takes place within the coordination sphere of the
Ru atom. X-ray characterizations of the ruthenium precatalysts
3a, 3c and of ruthenium hydride 8 are provided.
first example was reported by Williams who combined a
rhodium catalyst and a lipase to obtain a DKR of secondary
alcohols with moderate efficiency.9 In 1997 we reported11 an
efficient DKR for the synthesis of enantiopure secondary
alcohols by use of ruthenium catalyst 112 in combination with
an immobilized lipase. This method has also been applied to
the DKR of different functionalized alcohols13-18 that are useful
building blocks in enantioselective synthesis. Kim and Park have
also employed catalyst 1 in the DKR of secondary alcohols19
and in the asymmetric transformation of ketones and enol
acetates to chiral acetates.20 In general, good yields and
enantioselectivities were obtained. A drawback with precatalyst
1 is that it needs activation at slightly elevated temperature;
hence, only thermostable enzymes can be used in the process.
Also, the addition of an appropriate hydrogen source is often
needed to prevent ketone formation, and p-chlorophenyl acetate
is required as a specifically designed acyl donor for good yields.
Results and Discussion
Synthesis of the Ruthenium Complexes. In our preliminary
work ruthenium complexes 3a and 3b were prepared by reaction
of C5Ph5X (X ) Cl, Br29) with [Ru3(CO)12] in toluene under
reflux.22 However, with this procedure the iodide complex (3c)
was not accessible since C5Ph5I could not be successfully
prepared. Therefore, we decided to develop a new method for
the synthesis of ruthenium halide complexes 3 (Scheme 2).
Recently, Kim and Park reported that ruthenium precatalyst
2 racemizes alcohols within 30 min at room temperature.21
However, when combined with an enzyme (lipase) in DKR at
room temperature very long reaction times (1.3 to 7 days) were
required, although the enzymatic KR takes only a few hours.
(22) Mart´ın-Matute, B.; Edin, M.; Boga´r, K.; Ba¨ckvall, J.-E. Angew. Chem.,
Int. Ed. 2004, 43, 6535-6539.
(11) (a) Larsson, A. L. E.; Persson, B. A.; Ba¨ckvall, J.-E. Angew. Chem., Int.
Ed. Engl. 1997, 36, 1211-1212. (b) Persson, B. A.; Larsson, A. L. E.; Le
Ray, M.; Ba¨ckvall, J.-E. J. Am. Chem. Soc. 1999, 121, 1645-1650.
(12) Menasche, N.; Shvo, Y. Organometallics 1991, 10, 3885-3891.
(13) Hydroxyacid derivatives: (a) Huerta, F. F.; Ba¨ckvall, J.-E. Org. Lett. 2001,
3, 1209-1212. (b) Runmo, A.-B. L.; Pa`mies, O.; Faber, K.; Ba¨ckvall, J.-
E. Tetrahedron Lett. 2002, 43, 2983-2986. (c) Huerta, F. F.; Laxmi, Y.
R. S.; Ba¨ckvall, J.-E. Org. Lett. 2000, 2, 1037-1040. (d) Pa`mies, O.;
Ba¨ckvall, J.-E. J. Org. Chem. 2002, 67, 1261-1265.
(23) For some reviews on the mechanism, see: (a) H2-hydrogenation and transfer
hydrogenation catalyzed by Ru-complexes: Clapham, S. E.; Hadzovic, A.;
Morris, R. H. Coord. Chem. ReV. 2004, 248, 2201-2237. (b) Gladiali, S.;
Alberico, E. Transition Metals for Organic Synthesis, 2nd ed.; Beller, M.,
Bolm, C., Eds.; Wiley-VCH: Weinheim, 2004; Vol. 2, pp 145-166.
(c) Ba¨ckvall, J.-E. J. Organomet. Chem. 2002, 105-111. (d) Sa´nchez-
Delgado, R. A.; Rosales, M. Coord. Chem. ReV. 2000, 196, 249-280.
(e) Zassinovich, G.; Mestroni, G.; Gladiali, S. Chem. ReV. 1992, 92, 1051-
1069.
(14) Hydroxynitriles: (a) Pa`mies, O.; Ba¨ckvall, J.-E. AdV. Synth. Catal. 2001,
343, 726-731. (b) Pa`mies, O.; Ba¨ckvall, J.-E. AdV. Synth. Catal. 2002,
344, 947-952.
(24) (a) Gladiali, S.; Mestroni, G. Transition Metals for Organic Synthesis;
Beller, M., Bolm, C., Eds.; Wiley-VCH: Weinheim, 1998, Vol. 2, pp 97-
119. (b) Aranyos, A.; Csjernyik, G.; Szabo´, K. J.; Ba¨ckvall, J.-E. Chem.
Commun. 1999, 351-352. (c) Mizushima, E.; Yamaguchi, M.; Yamagishi,
T. J. Mol. Catal. A. Chem. 1999, 148, 69-75. (d) Standfest-Hauser, C.;
Slugovc, C.; Mereiter, K.; Schmid, R.; Kirchner, K.; Xiao, L.; Weissen-
steiner, W. J. Chem. Soc., Dalton Trans. 2001, 2989-2995.
(25) (a) Noyori, R.; Hashiguchi, S. Acc. Chem. Res. 1997, 30, 97-102.
(b) Alonso, D. A.; Brandt, P.; Nordin, S. J. M.; Andersson, P. G. J. Am.
Chem. Soc. 1999, 121, 9580-9588. (c) Yamakawa, M.; Ito, H.; Noyori,
R. J. Am. Chem. Soc. 2000, 122, 1466-1478. (d) Petra, D. G. I.; Reek, J.
N. H.; Handgraaf, J.-W.; Meijer, E. J.; Dierkes, P.; Kamer, P. C. J.; Brussee,
J.; Schoemaker, H. E.; van Leeuwen, P. W. N. M. Chem. Eur. J. 2000, 6,
2818-2829.
(15) Azido alcohols: Pa`mies, O.; Ba¨ckvall, J.-E. J. Org. Chem. 2001, 66, 4022-
4025.
(16) Halo alcohols: Pa`mies, O.; Ba¨ckvall, J.-E. J. Org. Chem. 2002, 67, 9006-
9010.
(17) Hydroxyphosphonates: Pa`mies, O.; Ba¨ckvall, J.-E. J. Org. Chem. 2003,
68, 4815-4818.
(18) Diols: (a) Persson, B. A.; Huerta, F. F.; Ba¨ckvall, J.-E. J. Org. Chem.
1999, 64, 5237-5240. (b) Edin, M.; Steinreiber, J.; Ba¨ckvall, J.-E. Proc.
Natl. Acad. Sci. U.S.A. 2004, 101, 5761-5766. (c) Mart´ın-Matute, B.;
Ba¨ckvall, J.-E. J. Org. Chem. 2004, 69, 9191-9195.
(19) Kim, M.-J.; Choi, Y. K.; Choi, M. Y.; Kim, M. J.; Park, J. J. Org. Chem.
2001, 66, 4736-4738.
(26) Casey, C. P.; Singer, S. W.; Powell, D. R.; Hayashi, R. K.; Kavana, M. J.
Am. Chem. Soc. 2001, 123, 1090-1100.
(20) (a) Jung, H. M.; Koh, J. H.; Kim, M.-J.; Park, J. Org. Lett. 2000, 2, 409-
411. (b) Jung, H. M.; Koh, J. H.; Kim, M.-J.; Park, J. Org. Lett. 2000, 2,
2487-2490.
(27) (a) Casey, C. P.; Vos, T. E.; Bikzhanova, G. A. Organometallics 2003,
22, 901-903. (b) Johnson, J. B.; Ba¨ckvall, J.-E. J. Org. Chem. 2003, 68,
7681-7684.
(21) (a) Choi, J. H.; Kim, Y. H.; Nam, S. H.; Shin, S. T.; Kim, M.-J.; Park, J.
Angew. Chem., Int. Ed. 2002, 41, 2373-2376. (b) Choi, J. H.; Choi, Y.
K.; Kim, Y. H.; Park, E. S.; Kim, E. J.; Kim, M.-J.; Park, J. J. Org. Chem.
2004, 69, 1972-1977.
(28) Daley, C. J. A.; Bergens, S. H. J. Am. Chem. Soc. 2002, 124, 3680-3691.
(29) Connelly, N. G.; Manners, I. J. Chem. Soc., Dalton Trans. 1989, 283-
288.
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Dynamic Kinetic Resolution of Secondary Alcohols
A R T I C L E S
Scheme 2. Synthesis of Ruthenium Complexes
Figure 1. (a) X-ray crystal Structure of 3a:32 Thermal ellipsoids are drawn at 50% probability. Selected bond lengths (Å): Ru(B)-C(1B) 1.878(5),
Ru(B)-C(2B) 1.888(5), Ru(B)-Cl(B) 2.3982(11). Selected angles (deg): C(1B)-Ru(B)-C(2B) 88.9(2), C(1B)-Ru(B)-Cl(B) 89.59(14), C(2B)-R(B)-
Cl(B) 87.71 (17). (b) X-ray crystal Structure of 3c: Thermal ellipsoids are drawn at 50% probability. Selected bond lengths (Å): Ru(1)-C(1) 1.866(4),
Ru(1)-C(2) 1.879(4), Ru(1)-I(1) 2.7230(4). Selected angles (deg): C(1)-Ru-C(2) 90.61(18), C(1)-Ru-I(1) 84.23(12), C(2)-Ru-I(1) 85.55 (13).
Reaction of R′MgBr (R′ ) Ph, p-Tol) with substituted cyclo-
pentadienones followed by in situ reduction of the magnesium
alkoxide with LiAlH4 afforded tetrasubstituted cyclopentadienes
4 in high yields.30 Oxidative addition of 4 to Ru(0) afforded,
after treatment with excess of haloform, Ru-complexes 3a-c,
5 and 6 in good to excellent yields. In the case of complex 5,
a significant amount of a new complex was obtained (45%).
Due to the extremely low solubility of this new complex, the
structure could not be confirmed by NMR, but two strong bands
at 1960 and 1767 cm-1 in the IR spectrum clearly indicate the
presence of nonbridging and bridging CO ligands. It was
Figure 2. X-ray crystal Structure of 8. Thermal ellipsoids are drawn at
assigned as dimer 7.31 The structures of complexes 3a and 3c
50% probability. Selected bond lengths (Å): Ru(1)-C(1) 1.795(5),
were confirmed by X-ray diffraction analysis (Figure 1).32
Ruthenium hydride η5-Ph5CpRu(CO)2H (8) was prepared in
82% yield by oxidative addition of 4 (R ) R′ ) Ph) to Ru(0)
Ru(1)-C(2) 1.811(5), Ru(1)-Cp carbons: Ru(1)-C(3) 2.270(3), Ru(1)-
C(4) 2.268(3), Ru(1)-C(5) 2.267(3), Ru(1)-C(6) 2.251(3), Ru(1)-C(7)
2.286(3). Selected angles (deg): C(1)-Ru(1)-C(2) 89.3(2).
(Scheme 2). Thus, in a sealed tube a mixture of cyclopentadiene
4 (R ) R′ ) Ph) and [Ru3(CO)12] was stirred in decane/toluene
(2:1) for 2.5 days at 160 °C. While cooling the tube, a precipitate
fell out, which was collected by filtration. The 1H NMR of this
complex showed a hydride resonance at -9.4 in toluene-d8
suggesting structure 8. The structure was confirmed by X-ray
diffraction analysis (Figure 2) and elemental analysis. The five
Ru-Cp carbons bond lengths are very similar, providing
evidence for η5-coordination of the cyclopentadienyl ligand. The
(30) A slightly modified method was employed for the synthesis of 4 (R ) Ph,
R′ ) Me). See Supporting Information for details.
(31) In the case of Cp and Cp* complete transformation to the corresponding
ruthenium dimers occurs after only 3 h. See for example: (a) Nelson, G.
O.; Sumner, C. E. Organometallics 1986, 5, 1983-1990. (b) Blackmore,
T.; Bruce, M. I.; Stone, F. G. A. J. Chem. Soc. A 1968, 2458-2162.
(c) Doherty, N. M.; Knox, S. A. R.; Morris, M. J. Inorg. Synth. 1990, 28,
189-191.
(32) Complete details of the X-ray analysis are given in the crystal structure
analysis report in the Supporting Information.
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J. AM. CHEM. SOC. VOL. 127, NO. 24, 2005 8819

A R T I C L E S
Mart´ın-Matute et al.
Scheme 4. DKR of 1-Phenylethanol Catalyzed by Candida
antarctica Lipase B and a Ruthenium Catalyst
Table 1. Dynamic Kinetic Resolution of 1-Phenylethanola
entry
Ru-catalyst
time (h)
%yieldb
% eeb
1
2
3
4
5d
6
7
3a
3b
3c
3c
3c
5
3
3
3
7.5
3
95 (92)c
98
>99
>99
93
93
35
60
66
86
58
Figure 3. Racemization of (S)-9 (0.5 M in toluene) catalyzed by: 3a (2),
3b (b), 3c (×), 5 ([), 6 (9), after treatment with t-BuOK. Catalyst
concentration: 0.0025 M.
3
18
99
99
5
75
a Unless otherwise noted, Ru-catalyst (5 mol %), CALB (6 mg), Na2CO3
(1 mmol) and t-BuOK (5 mol %) were stirred in toluene (2 mL) for 6 min
before adding 9 (1 mmol). After 4 min, isopropenyl acetate (1.5 mmol)
was added and the mixture was stirred under an argon atmosphere.
b Determined by chiral GC. c Isolated yield. d 6 mol % of t-BuOK.
Scheme 3. Racemization of (S)-1-Phenylethanol
two Ru-CO bond lengths (1.795, 1.811 Å) are slightly shorter
than those in ruthenium chloride 3a (1.878, 1.888 Å) and in
ruthenium iodide 3c (1.866, 1.879 Å).
Racemization of (S)-1-Phenylethanol. With five catalysts
in hand we studied the racemization of (S)-1-phenylethanol
((S)-9) at room temperature (Scheme 3). In our previous
communication we reported the efficient activation of Ru-halide
complexes by t-BuOK, and we identified the formation of Ru-
alkoxide complex 10 as the key intermediate.22
Figure 4. GC chromatogram of DKR of 1-phenylethanol (9) catalyzed by
ruthenium complex 3b: (a) 42% conversion, (b) 91% conversion.
encountered is that the base used to activate the metal catalyst
can catalyze direct chemical esterification of the alcohol by the
acyl donor, and this pathway leads to racemic product. We tested
complexes 3a-c and 5 in the DKR of 1-phenylethanol (rac-9)
as a model substrate (Scheme 4, Table 1). For the kinetic
resolution we have employed Candida antarctica lipase B
(CALB)34,35 as the enzyme and isopropenyl acetate as the acyl
donor. The reactions were run at ambient temperature.
Complexes 3a,b both gave excellent results and afforded
enantiopure acetate 11 in high yields within 3 h (Table 1, entries
1 and 2). The combination of catalysts 3a,b with the enzyme is
so efficient that the starting alcohol 9 stays racemic throughout
the reaction (Figure 4). Surprisingly, iodide complex 3c gave
after 3 h only 60% of acetate 11 and in only 93% ee (Table 1,
entry 3). A plausible explanation is that due to the higher
solubility of KI compared to KBr and KCl, the generation of
the ruthenium tert-butoxide complex 10 becomes reversible.
This leads to the presence of ruthenium iodide complex 3c and
t-BuOK, and the latter can catalyze chemical acylation of the
alcohol, resulting in a lower enantiopurity of acetate 11. The
yield does not increase with time, and after 7.5 h only 66%
(93% ee) of acetate product was obtained (entry 4). Increasing
the added amount of t-BuOK to 6 mol % resulted in an increase
of chemically acylated product (entry 5). As expected from
To compare the catalytic activity of ruthenium complexes
3a-c, 5 and 6, the corresponding ruthenium alkoxides were
generated by treatment of the catalyst (0.5 mol %) with t-BuOK
(1 mol %) in toluene, and after 6 min (S)-9 was added. The
results are presented in Figure 3. The racemization rate is
affected by the substituents on the Cp ring. In general, pentaaryl-
substituted catalysts rapidly racemized (S)-9.33 The substitution
of only one of the phenyl groups by a methyl group slowed
considerable the rate of racemization. The racemization is not
significantly affected by the nature of the halide atom, indicating
that the active intermediate formed from complexes 3a-c in
the catalytic cycle might be the same.
Dynamic Kinetic Resolution of Secondary Alcohols. Al-
though several metal complexes are known to catalyze fast
racemization of alcohols, their combination with an enzyme-
catalyzed kinetic resolution is not always straightforward. For
example, the metal catalyst may interfere with the enzyme to
give poor resolution or the enzyme may slow or inhibit
racemization by the metal catalyst. Another problem often
(33) The racemization is even faster when only 1 mL of toluene is employed:
Csjernyik, G.; Boga´r, K.; Ba¨ckvall, J.-E. Tetrahedron Lett. 2004, 45, 6799-
6802.
(34) Immobilized and commercially available as Novozym-435.
(35) To control the water activity, the enzyme was stored in a sealed container
with a saturated solution of LiCl for a minimum of 24 h.
9
8820 J. AM. CHEM. SOC. VOL. 127, NO. 24, 2005

Dynamic Kinetic Resolution of Secondary Alcohols
A R T I C L E S
Figure 3, catalyst 5 did not give good results under DKR
conditions (entries 6 and 7).
metal- and enzyme-catalyzed DKR procedure we have been able
to successfully obtain very high selectivity for a variety of
aliphatic substrates. Thus, cyclohexylmethylcarbinol (entry 15)
gave enantiopure acetate in quantitative yield. We were pleased
to find that 2-octanol afforded the corresponding acetate in
excellent yield and >98% ee (entry 16).39 DKR of 4-phenyl-
2-butanol afforded the acetate in high yield and good enantio-
selectivity (entry 17). Whereas CALB shows an excellent
selectivity (E > 200) and activity (only 0.5 mg of enzyme were
employed) for this substrate, the selectivity for 1-phenyl-2-
propanol is not so high (E ) 70). Furthermore, the kinetic
resolution is rather slow (only 30% conversion to acetate after
2.5 h using 15 mg of enzyme/mmol of alcohol). However, the
use of 40 mg of enzyme/mmol of alcohol under DKR conditions
afforded quantitative conversion to the acetate in 91% ee in
only 6 h (entry 18). The DKR of 1-phenoxypropan-2-ol is of
practical interest since this alcohol is a useful intermediate for
bactericides,40 and also for the synthesis of hemilabile bidentate
ligands. The racemization of this substrate is rather slow, but
the acetate was obtained in excellent yield in >92% ee (entry
19).
We have also now tested a series of heteroaromatic substrates.
Interestingly, excellent results were obtained with the piperidine
derivative (entry 20). Also, benzofuran, furan, thiophene, and
4-pyridine-substituted alcohols gave excellent yields and high
ee (96 to >99) (entries 21-24). 1-(2-Furyl)ethanol and its
derivatives are important building blocks for the synthesis of
carbohydrates, macrospelides H, G,41a and A, B,41b and phero-
mones and alkaloids.41c-d Also some functionalized alcohols
were subjected to DKR (entries 25-26).14,16 A great advantage
of these alcohols is that they can be further transformed into
more complex molecules. â-Chloro alcohols are important
building blocks for the synthesis of chiral epoxides and amino
alcohols. This kind of substrates can be also resolved to
enantiopure acetates at room temperature. Thus, 2-chloro-1-
phenylethyl acetate was obtained in high yield and excellent ee
(entry 25). â-Hydroxy nitriles are also versatile building blocks.
For example, they are useful precursors for γ-amino alcohols.
The DKR of 3-hydroxy-3-phenylpropanenitrile (entry 26) was
complete in only 6 h. High temperatures and larger amounts of
enzyme are needed due to the slow racemization and slow KR.
This DKR product can also easily be further manipulated into
Due to the more straightforward syntheses of complexes 3a,b
and their high efficiency as racemization catalysts, we decided
to investigate the combination of these catalysts with different
enzymes to study the scope and limitations of the metal- and
bio-catalyzed DKR of a variety of secondary alcohols. The
catalyst was activated by a catalytic amount of t-BuOK in the
presence of the enzyme and Na2CO3. The required amount of
the base depends on the amount of enzyme employed and on
the substrates. Therefore, it was optimized for each entry. The
enzymatic resolution of most substrates was efficiently catalyzed
by CALB. The amount of enzyme employed depends on each
substrate, too. For a successful DKR, the resolution rate should
not exceed the racemization rate too much, to avoid depletion
of the resolved enantiomer; this could result in an ee decrease
of the ester product. A great advantage of this system is that
isopropenyl acetate can be employed as the acyl donor, and
therefore the only byproduct is acetone, which can be easily
removed after the reaction. It is interesting to note that acetone
is not interfering with this catalyst, indicating that the intermedi-
ate ketone from dehydrogenation of the alcohol stays coordi-
nated to the metal (vide infra). The results from the DKR of
secondary alcohols are summarized in Table 2. In general,
secondary alcohols bearing an aromatic group are readily
transformed to enantiopure acetates in excellent yields and with
short reaction times. Similar to 1-phenylethanol (Table 2, entries
1 and 2), the 2-naphthyl derivative (entry 3) is transformed to
enantiopure acetate in only 3 h in excellent yield. The more
sterically hindered 1-naphthyl derivative required longer reaction
times (entry 4). Longer reaction times were also needed for
2-fluorenyl- and biphenyl-substituted alcohols (entries 5 and 6).
In these cases the need for longer reaction times is most probably
due to low solubility of the alcohols under the reaction
conditions. The kinetic resolution of the ethyl carbinol in entry
7, as shown in separate experiments, is very slow, but with the
use of 40 mg of enzyme per mmol of alcohol under DKR
conditions, the product was obtained in 92% yield and >99%
ee after 17 h. We also studied the effect on the DKR of the
variation in the electronic properties of the alcohols. Aromatic
alcohols bearing an electron-donating group on the ring were
successfully converted to the acetates (entries 8 and 9).
Substrates with electron-withdrawing groups on the phenyl ring
gave almost quantitative yields of enantiopure acetates in all
cases (entries 10-14); however, longer reaction times were
required. For substrates bearing a coordinating group (entries
11 and 12) a possible explanation is that coordination of these
N-containing groups to the ruthenium center slows down the
reaction rate. However, this explanation seems to be less likely
since electron-deficient substrates not bearing a coordinating
group also required longer reaction times (entries 13 and 14).
Therefore, the rates of some of the steps in the catalytic cycle
might be also slowed (vide infra).
(36) Review on metal-catalyzed hydrogenation of ketones: Noyori, R.; Ohkuma,
T. Angew. Chem., Int. Ed. 2001, 40, 40-73.
(37) Reviews on asymmetric transfer hydrogenation of ketones: (a) Palmer,
M. J.; Wills, M. Tetraherdron: Asymmetry 1999, 10, 2045-2061. (b) Wills,
M.; Palmer, M.; Smith, A.; Kenny, J.; Walsgrove, T. Molecules 2000, 5,
4-18.
(38) For reduction of 2-alkanones, see: Sarvary, I.; Almqvist, F.; Frejd, T. Chem.
Eur. J. 2001, 7, 2158-2166.
(39) Reduction of 2-hexanone using catalytic hydrogenation gives 96% yield
of the alcohol in 75% ee, and reduction of 2-nonanone gives the alcohol in
100% yield, 1% ee. See ref 36.
(40) Naoaki, T.; Kenji, K.; Yoshihiko, Y.; Kenji, I.; Junzo, H. Enzymatic
manufacture of (R)-2-hydroxy-1-phenoxypropanes from phenoxyacetones.
(Kanefaguchi Chemical Industry Co., Ltd., Japan). Jpn. Kokai Tokkyo Koho
5, 2000.
(41) (a) Kobayashi, Y.; Wang, Y.-G. Tetrahedron Lett. 2002, 43, 4381-4384.
(b) Kobayashi, Y.; Kumar, G. B.; Kurachi, T.; Acharya, H. P.; Yamazaki,
T.; Kitazume, T. J. Org. Chem. 2001, 66, 2011-2018. (c) Samojski, A.;
Grynkiewicz, G. Total Synthesis of Natural Products; ApSimon, J., Ed.;
Wiley: New York, 1984; Vol. 6, pp 141-235. (d) See also: Stampfer,
W.; Edegger, K.; Kosjek, B.; Faber, K.; Kroutil, W. AdV. Synth. Catal.
2004, 346, 57-62.
(42) Kamal, A.; Khanna, G. B. R.; Ramu, R. Tetrahedron: Asymmetry 2002,
13, 2039-2051.
(43) DKR of allylic alcohols at room temperature has been previously reported,
but longer reaction times (48 h) were needed: Lee, D.; Huh, E. A.; Kim,
M.-J.; Jung, H. M.; Koh, J. H.; Park, J. Org. Lett. 2000, 2, 2377-2379.
The results obtained for aliphatic substrates should be of
importance since these alcohols are not readily accessible via
asymmetric reduction. Synthesis of enantiomerically pure
aromatic alcohols has been successfully accomplished via
stereoselective hydrogenation of ketones and through transfer
hydrogenation reactions but the corresponding aliphatic sub-
strates proceed with lower selectivity.36-38 However, with our
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J. AM. CHEM. SOC. VOL. 127, NO. 24, 2005 8821

A R T I C L E S
Mart´ın-Matute et al.
Table 2. Dynamic Kinetic Resolution Various Alcoholsa
a Unless otherwise noted, Ru-catalyst 3a (5 mol %), CALB (6 mg), Na2CO3 (1 mmol) and t-BuOK were stirred in toluene (2 mL) for 6 min before adding
the alcohol (1 mmol). After 4 min, isopropenyl acetate (1.5 mmol) was added and the mixture was stirred under an argon atmosphere at ambient temperature.
b Unless otherwise noted, determined by chiral GC. c Isolated yield in parentheses. d 3b: 4 mol %. e 3 mL of toluene. f CALB: 12 mg, 5 mL of toluene and
40 °C. g Determined by chiral HPLC. h CALB: 40 mg. i Yield determined by 1H NMR spectroscopy. j CALB: 2 mg. k CALB: 0.5 mg. l CALB: 1 mg,
40 °C. m The THF from the t-BuOK solution was not evaporated. n 50 °C. o The THF from the t-BuOK solution was not evaporated; enzyme: PS-C
“Amano II”, 100 mg. p CALB: 100 mg, 100 °C. q 9% of cinnamonitrile was also produced. r 11% of 4-phenyl-2-butanone was also formed. s 35 °C. t CALB:
1 mg. u 3 equiv of isopropenyl acetate.
important antidepressants, such as fluoxetine, tomoexetine and
norfluoxetine.42 Allylic alcohols are also important building
blocks that can be transformed to a wide range of more complex
molecules. The enantiopure acetate was obtained in 89% yield
(>99% ee) (entry 27).43 Another potential application is shown
in entry 28. The starting amino alcohol can be easily obtained
from dibenzylamine. Deprotection after DKR can provide
(R)-1-amino-2-propanol efficiently and economically (Acros).
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8822 J. AM. CHEM. SOC. VOL. 127, NO. 24, 2005

Dynamic Kinetic Resolution of Secondary Alcohols
A R T I C L E S
Scheme 5. Alkoxide Exchange Reaction
Scheme 6. Mechanism of Racemization
Sulcatol acetate (entry 29) can also be easily obtained via DKR.
Sulcatol is a male-produced pheromone with important biologi-
cal activity, such as insect pest control.44 Besides, it can be
readily transformed to pityol, an important pest attractant.45
Finally, diols can also be transformed to enantiopure diacetates
in excellent yield, enantioselectivity, and diastereoselectivity
(entry 30).
Mechanism of the Ruthenium-Catalyzed Racemization.
The first step in the catalytic cycle is the activation of the
ruthenium halide complex. In our previous communication22 we
reported the formation of a ruthenium tert-alkoxide (10)46 by
reaction of ruthenium chloride 3a with t-BuOK. We observed
the formation of complex 10 by mixing complex 3a with a slight
excess of t-BuOK in deuterated toluene. The NMR resonances
of 10 differ from those of 3a, t-BuOK, and t-BuOH in deuterated
toluene. The formation of this intermediate was also supported
by a strong color change of the reaction mixture from yellow
to red. Furthermore, when (S)-9 was added to the NMR tube
containing alkoxide 10, racemization immediately occurred.47
It was suggested that in the next step, complex 10 reacts with
(S)-9 in a ligand exchange reaction to give a new alkoxide. We
decided to investigate this alkoxide ligand exchange reaction
in more detail. Since a secondary alcohol undergoes rapid R-CH
bond cleavage (leading to racemization), a tertiary alcohol must
be used in the exchange studies. Therefore, to study the alkoxide
exchange, tert-alkoxide complex 10 was allowed to react with
another tertiary alcohol, tert-amyl alcohol. Complex 3a was
mixed with t-BuOK in an NMR tube in toluene-d8 at room
temperature. Once complex 10 had been formed, the NMR tube
was cooled in a liquid nitrogen bath. Then, tert-amyl alcohol
(3 equiv) was added. After less than 10 min at -40 °C the
formation of a new complex (12) was observed by 13C NMR
spectroscopy (about 20%).48 When only 1 equiv of tert-amyl
alcohol was employed, the equilibrium was established also very
fast (within minutes) at 10 °C (Scheme 5). The 13C resonances
in deuterated toluene of the new tert-amyl alkoxide complex
are very similar but clearly distinguishable from those of
complex 10.49 The mechanism of the alkoxide exchange reaction
remains unclear. There are two principal mechanisms for ligand
substitution reactions, one dissociative and the other associative.
A dissociative pathway would lead to the formation of free
alkoxide, which in the presence of isopropenyl acetate is
expected to result in classical chemical acylation in the DKR.
However, under DKR reaction conditions enantiopure acetates
are obtained, indicating that free alkoxide is not produced. An
associative pathway would require a η5 to η3 ring slippage.50
Further studies to establish the detailed mechanism of this
alkoxide exchange are required and are currently underway in
our laboratory.
Reaction of (S)-9 with alkoxide 10 would give the enantiopure
Ru-complex 13 via a ligand exchange process (step ii in Scheme
6). Complex 13 can undergo â-hydride elimination and form a
ruthenium hydride complex (8) and the oxidized product,
acetophenone.
To find out if ruthenium hydride 8 is an active catalytic
intermediate, the racemization of (S)-9 catalyzed by 5 mol %
of ruthenium hydride 8 was studied.51 Since 8 needs to transfer
the hydride to a ketone, 5 mol % of acetophenone was added
to the reaction mixture. The racemization was followed by chiral
(44) (a) Byrne, K. J.; Swigar, A. A.; Silverstein, R. M.; Borden, J. H.; Stokkink,
E. J. Insect Physiol. 1974, 20, 1895-1900. (b) For a recent synthesis of
(R)-sulcatol and (2S,5R)-pityol see: Chen, S.-L.; Hu, Q.-Y.; Loh, T.-P.
Org. Lett. 2004, 6, 3365-3367.
(45) See for example: Trudel, R.; Guertin, C.; de Groot, P. J. Appl. Entomol.
2004, 128, 403-406.
(50) The possible pathways for alkoxide exchange include: (i) ring slippage,
(ii) alkoxide loss, (iii) CO loss, (iv) alkoxide attack at CO followed by
alkoxide loss.
(46) Ru-alkoxide complexes: (a) ref 28 (b) Loren, S. D.; Campion, B. K.; Heyn,
R. H.; Tilley, T. D.; Bursten, B. E.; Luth, K. W. J. Am. Chem. Soc. 1989,
111, 4712-4718. (b) Re-alkoxide complex: Saura-Llamas, I.; Gladysz, J.
A. J. Am. Chem. Soc. 1992, 114, 2136-2144. (c) Ru-alcohol complex:
See ref 27a. (d) W-alcohol and Mo-alcohol complexes: Bullock, R. M.
Chem. Eur. J. 2004, 10, 2366-2374 and references therein.
(47) The mixture was analyzed by chiral GC.
(51) As shown in Figure 3, the racemization of (S)-9 catalyzed by complexes
3a-c can be performed by the use of only 0.5 mol % of catalyst with
short reaction times. In sharp contrast, the racemization of (S)-9 catalyzed
by 1 mol % of ruthenium hydride 8 (in the presence of 1 mol %
acetophenone) required very long reaction times (1.5 days). Only when
5 mol % of ruthenium hydride 8 was used (in the presence of 5 mol % of
acetophenone) could shorter reaction times be realized but still with an
induction period of 2.5 h (Figure 5).
(48) See 13C NMR spectra in Supporting Information.
(49) See Experimental Section for details.
9
J. AM. CHEM. SOC. VOL. 127, NO. 24, 2005 8823

A R T I C L E S
Mart´ın-Matute et al.
Scheme 7. Crossover Experiment: Racemization of
(S)-1-Phenylethanol in the Presence of 1 Equiv of p-Tolyl Methyl
Ketone (16)
In the ketohydride complex 14 with σ-bonded oxygen there
is free rotation around the ruthenium oxygen bond, and the
hydride addition (i.e. insertion) can take place from either face
of the prochiral ketone. The readdition of the hydride
(14 f 15) most likely occurs via slippage to π-coordinated
ketone (not shown) followed by insertion.55 Insertion of the
ketone into the Ru-H bond produces the racemic alkoxide
complex 15 (step iV). Alkoxide exchange with (S)-9 releases
racemic alcohol (rac-9) and regenerates intermediate 13.
To obtain further insight into the mechanism of the race-
mization, the racemization of (S)-9 was carried out in the
presence of 1 equiv of tolyl methyl ketone (16) (Scheme 7).
The reaction was carried out at room temperature in toluene
with 1 mol % of catalyst 3a, which was activated by 2 mol %
of t-BuOK. After 5 min complete racemization of (S)-9 to rac-9
had occurred, but only 1% of the added ketone had been
converted to alcohol (1-(p-tolyl)ethanol) (about 1% of aceto-
phenone was also observed). These results show that, at room
temperature, the ketone obtained from the alcohol stays in the
coordination sphere of the Ru atom during racemization and
does not exchange with free ketone. This observation is best
explained by the intermediacy of a η3-ruthenium hydride ketone
complex after â-hydride elimination.56
In conclusion, we have studied the scope and limitation of
the DKR catalyzed by ruthenium complexes 3 in combination
with different lipases. A wide range of secondary alcohols,
including aliphatic and heteroaromatic alcohols, have been
deracemized to give the corresponding acetates in excellent
yields and enantioselectivities via DKR. The DKR of important
intermediates in the synthesis of some products of biological
interest has been accomplished, showing the applicability of
this process. Also, a new convenient method for the preparation
of (η5-R5Cp)Ru(CO)2X (R ) Ph, Me, p-Tol, X ) Cl, Br, I)
complexes in good yields was developed. We have studied the
mechanism of the racemization of secondary alcohols catalyzed
by Ru complexes and proven the intermediacy of Ru alkoxides.
The most likely pathway for racemization involves â-elimination
from an alkoxide complex to give a hydride ketone complex
that undergoes reversible insertion. Interestingly, the ketone stays
coordinated during the racemization and does not leave the
coordination sphere. Study of the racemization catalyzed by
η5-Ph5C5 ruthenium hydride 8 indicates that the latter complex
is not an abundant catalytic species in the racemization.
Figure 5. Racemization of (S)-1-phenylethanol catalyzed by η5-ruthenium
hydride 8.
GC. As shown in Figure 5, ruthenium hydride complex 8 can
catalyze the racemization of secondary alcohols, but with a long
induction period of 2.5 h. After this induction period the
racemization takes off and is complete after an additional
30 min. This result indicates that the reaction of the ruthenium
hydride with acetophenone is rather slow.52 However, once a
small amount of the active species (the alkoxide) is formed,
the racemization of (S)-9 proceeds very fast. During the first
2 h the reaction mixture remains yellowish (Ru hydride 8 is a
light brown powder), and then it turns orange and finally dark
red. The red color is a clear indication of formation of Ru-
alkoxides (ruthenium tert-butoxide complex 10 in toluene is a
red solution).
Our results imply that, although ruthenium hydride inter-
mediates are most likely involved in the racemization of
secondary alcohols, the ruthenium η5-hydride 8 is not an
abundant species in the catalytic process. A proposed mechanism
for the catalytic cycle is shown in Scheme 6. The first step is
the formation of tert-alkoxide 10 by reaction of the ruthenium
halide with t-BuOK (Scheme 6, step i). A very fast ligand-
exchange reaction of 10 with the substrate would give enan-
tiopure alkoxide complex 13 (step ii), which undergoes â-hy-
dride elimination via a η5 f η3 ring slippage (step iii) to give
hydride ketone complex 14. Thus we propose that the ketone
stays coordinated to the ruthenium center (14). This explains
why there is no interference between the acetone (produced from
isopropenyl acetate) and the ruthenium hydride intermediate.
To keep an 18-electron system, we propose that a η5 f η3 ring
slippage is required in the â-elimination, i.e. transformation
13 f 14. Another possibility involves CO dissociation instead
of ring slippage, but this seems less likely since high temper-
atures are usually required to dissociate CO from the coordina-
tion sphere of the ruthenium center.53,54
(52) In accordance, related 18-electron hydride [2,5-Me2-3,4-Ph2(η5-C4CNHPh)]-
Ru(CO)2H reacts very slowly with benzaldehyde: Casey, C. P.; Vos, T.
E.; Singer, S. W.; Guzei, I. A. Organometallics 2002, 21, 5038-5046.
(53) (a) Guari, Y.; Sabo-Etienne, S.; Chaudret, B. J. Am. Chem. Soc. 1998, 120,
4228-4229. (b) Guari, Y.; Sabo-Etienne, S.; Chaudret, B. Eur J. Inorg.
Chem. 1999, 1047-1055.
(54) Other conceivable mechanisms are hydride migration to the cyclopentadienyl
ring and hydride migration to CO to give a formyl intermediate. We are
currently investigating the mechanism of this remarkable C-H bond
cleavage in our laboratories.
(55) If the ketone from â-elimination were only π-bonded no racemization could
take place, since the hydride would readd to the same enantioface from
which it was eliminated.
(56) An interesting question is why the ring slippage readily occurs for the
alkoxide in â-elimination and not for the hydride in its reaction with a
ketone. This is probably due to that the ketone is not nucleophilic enough
to induce a ring slip. In the alkoxide the C-H can interact with ruthenium
and induce a push of electrons to favor the ring slip.
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Dynamic Kinetic Resolution of Secondary Alcohols
A R T I C L E S
NMR (toluene-d8, 75 MHz, -15 °C) (selected peaks) δ 202.78, 108.51,
74.53, 39.11, 32.33, 10.20. The resonances of the tert-pentoxide ligand
differ from those of tert-pentanol in toluene-d8 (70.10, 36.59, 28.81,
8.64). The resonances of the five equivalent carbons of the cyclo-
pentadienyl ring and of the CO ligand are also clearly distinguishable
from those of tert-butoxide complex 10 under the same conditions
[(toluene-d8, 75 MHz; -15 °C) δ 202.86, 108.20].48
Racemization of (S)-1-Phenylethanol (9) Catalyzed by Ph5CpRu-
(CO)2H (8) in the Presence of Acetophenone. A solution of (S)-9
(122 mg, 1 mmol) and acetophenone (6 mg, 0.05 mmol) in toluene
(2 mL) was added to a flame-dried flask containing ruthenium hydride
complex 8 (30 mg, 0.05 mmol) under an argon atmosphere. The mixture
was stirred at room temperature. Aliquots were analyzed by chiral GC.
The results are presented in Figure 5.
Experimental Section
General Procedure for Racemization of (S)-1-Phenylethanol ((S)-
9) Catalyzed by Ruthenium Halide Complexes. To a Schlenk type
flask containing Ru complex 3a (3.2 mg, 0.005 mmol) in toluene
(2 mL) was added a solution of t-BuOK (0.5 M in THF; 20 µL,
0.01 mmol) under an argon atmosphere. After 6 min, (S)-1-phenyle-
thanol (120 µL, 1 mmol) was added. Samples of the reaction mixture
were collected under a rigorous argon atmosphere and analyzed by
chiral GC. After 30 min, chiral GC analysis showed complete
racemization of 1-phenylethanol.
General Procedure for DKR of Secondary Alcohols. Dynamic
kinetic resolution of 1-phenylethanol: A solution of t-BuOK (0.5 M
in THF; 100 µL, 0.05 mmol) was added to a 10 mL Schlenk flask.
The THF was carefully removed under vacuum and the flask filled
with argon. CALB (6 mg), Na2CO3 (106 mg, 1 mmol) and Ru-catalyst
3a (25 mg, 0.04 mmol) were quickly added. The Schlenk flask was
evacuated and filled with argon. Toluene (2 mL) was added, and the
mixture was stirred for 6 min. Then 1-phenylethanol (120 µL, 1 mmol)
was added, and after 4 min, isopropenyl acetate (165 µL, 1.5 mmol)
was added. After being stirred for 3 h at ambient temperature, the
reaction mixture was filtered and concentrated. Purification by column
chromatography (SiO2; pentane/diethyl ether 98:2) afforded (R)-1-
phenylethanol acetate as a colorless oil (151 mg, 92% yield,
>99% ee).
Racemization of (S)-1-Phenylethanol (9) in the Presence of 1
Equiv of p-Tolyl Methyl Ketone (16). Potassium tert-butoxide
(0.5 M in THF, 0.02 mmol, 40 µL) was added at room temperature to
a solution of catalyst 3a (0.01 mmol, 6.4 mg) in toluene (2 mL), and
the flask was flushed with argon. After stirring for 6 min, p-methyl-
acetophenone (1.0 mmol, 0.135 mL) and (S)-1-phenylethanol
(1.0 mmol, 0.120 mL) were added successively. Aliquots were analyzed
by chiral GC. After 5 min, complete racemization of (S)-9 to rac-9
had occurred and only 1% of the added ketone had been converted to
alcohol (1-(p-tolyl)ethanol) (about 1% of acetophenone was also
observed).
Formation of (η5-Ph5Cp)Ru(CO)2(OtBu) (10) and Reaction with
tert-Amyl Alcohol: (η5-Ph5Cp)Ru(CO)2(tPentoxide) (12). A solution
of t-BuOK in THF (82 µL, 0.04 mmol; 0.5M) was added to an NMR
tube. The THF was evaporated under reduced pressure. Then
(η5-Ph5Cp)Ru(CO)2Cl (3a) (20 mg, 0.03 mmol) was placed in the NMR
tube. The tube was evacuated and filled with argon before adding
toluene-d8 (0.5 mL). The tube was shaken vigorously, and a fine new
precipitate of KCl was formed and allowed to settle. The quantitative
formation of complex 10 was observed by 13C NMR spectroscopy:
13C NMR (toluene-d8, 75 MHz, ambient temperature) δ 202.80, 132.72,
131.24, 128.06, 127.81, 108.75, 73.11, 34.28. The NMR tube was
cooled in a liquid nitrogen bath. Then tert-amyl alcohol (100 µL,
0.092 mmol; 0.914 M in toluene-d8) was added. At -40 °C the
formation of complex 12 was observed by 13C NMR in less than 10
min (about 20%). When only 1 equiv of tert-amyl alcohol was
employed, the equilibrium was very fast established at 10 °C. 12: 13C
Acknowledgment. We thank Dr. L. Eriksson for fruitful
discussions concerning the structures of 3a, 3b and 8. We are
grateful for financial support from the Swedish Research
Council, the Swedish Foundation for Strategic Research, the
Ministerio de Educacio´n y Ciencia of Spain (B.M.-M.) and the
Scientific and Technical Research Council of Turkey (F.B.K).
Supporting Information Available: Experimental details and
analysis of new secondary alcohols and acetates. Preparation
and characterization of compounds 3-8 and 12. X-ray analysis
of complexes 3a, 3c and 8. This material is available free of
charge via the Internet at http://pubs.acs.org.
JA051576X
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J. AM. CHEM. SOC. VOL. 127, NO. 24, 2005 8825