Highly compatible metal and enzyme catalysts for efficient dynamic kinetic resolution of alcohols at ambient temperature

Article abstract of DOI:10.1002/anie.200461416

(Chemical equation presented). The combination of highly compatible metal and enzyme catalysts allows the fastest dynamic kinetic resolution of alcohols ever reported. The use of ruthenium catalyst 1a (or 1b) and an immobilized lipase results in a highly

Full text of DOI:10.1002/anie.200461416

Angewandte
Chemie
Dynamic Kinetic Resolution
Highly Compatible Metal and Enzyme Catalysts
for Efficient Dynamic Kinetic Resolution of
Alcohols at Ambient Temperature**
BelØn Martín-Matute, Michaela Edin, Krisztiµn Bogµr,
and Jan-E. Bäckvall*
The demand for chiral compounds as single enantiomers has
increased dramatically in recent years, driven by the pharma-
ceutical industry and also by other applications, such as
[*] Dr. B. Martín-Matute, M. Edin, K. Bogµr, Prof. Dr. J.-E. Bäckvall
Department of Organic Chemistry, Arrhenius Laboratory
Stockholm University
10691 Stockholm (Sweden)
Fax: (+46)8-154-908
E-mail: jeb@organ.su.se
[**] We are grateful for financial support from the Swedish Research
Council, the Swedish Foundation for Strategic Research, and the
Ministerio de Educación y Ciencia of Spain.
Supporting information for this article (NMR data for 3a and 5g) is
available on the WWW under http://www.angewandte.org or from
the author.
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DOI: 10.1002/anie.200461416
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agrochemicals, flavors, fragrances, and materials. Dynamic
some fine-tuning and optimization, we were able to find
reaction conditions under which the DKR process has almost
the same rate as the kinetic resolution. Herein we report a
DKR process (Scheme 1) that is more than two orders of
kinetic resolution (DKR) is a powerful tool to transform a
racemic mixture into one enantiomer.[1] This strategy over-
comes the limitation of the maximum 50% yield in a kinetic
resolution (KR) by combining it with an in situ racemization
of the substrate. Recently the coupling of enzymes and
transition metals for the DKR of alcohols has attracted
considerable attention.[2,3] In these reactions, in situ racemi-
zation by a metal occurs during the enzymatic resolution. The
first example was reported by Williams and co-workers who
used a rhodium catalyst and a lipase to obtain a DKR of
secondary alcohols with moderate efficiency.[4] In 1997 our
group reported[5] an efficient DKR process for the synthesis of
enantiopure secondary alcohols by the use of ruthenium
catalyst 1[6] in combination with an immobilized lipase. This
Scheme 1. DKR of 1-phenylethanol.
magnitude faster than our previous procedures[2,5] and one
order of magnitude faster than the hitherto fastest procedure
reported.[17] We also provide evidence for the intermediacy of
a ruthenium alkoxide complex.
In one experiment a solution of 1-phenylethanol (4a) in
toluene (0.3m) was added to a mixture of KOtBu and
ruthenium complex 3b, under an argon atmosphere. After
stirring for 5 min, Na2CO3, Candida antarctica lipase B
(CALB[19]), and isopropenyl acetate were added. After 4 h,
only 55% yield of enantiopure (R)-1-phenylethanol acetate
(5a) was obtained (Table 1, entry 1).[20] Surprisingly, when the
Table 1: Dynamic kinetic resolution of 1-phenylethanol.[a]
method has also been applied to the DKR of different
functionalized alcohols, such as hydroxyacid derivatives,[7]
hydroxynitriles,[8] azidoalcohols,[9] haloalcohols,[10] hydroxy-
phosphonates,[11] and diols.[12] Kim, Park, and co-workers have
also employed catalyst 1 in the DKR of protected hydroxy-
acids, diols, and hydroxyaldehydes,[13] and in the asymmetric
transformation of ketones and enol acetates to chiral
acetates.[14] In general, good yields and enantioselectivities
were attained. However, complex 1 suffers from some
drawbacks: it is activated at high temperature and therefore
a thermally stable enzyme is required. Also, the addition of an
appropriate hydrogen source is needed in some cases to
prevent ketone formation.
Various ruthenium, rhodium, and iridium complexes are
known to catalyze fast racemization of alcohols.[2c,4,5,15,16]
Unfortunately, almost all of these catalysts do not work in
the DKR of alcohols when combined with the enzyme.
Recently, Kim, Park, and co-workers reported that ruthenium
catalyst 2 racemizes alcohols within 30 min at room temper-
ature.[17] However, when combined with an enzyme (lipase) in
DKR at room temperature, very long reaction times (1.3–
7 days) were required, in spite of the fact that the enzymatic
reaction (in KR) takes only a few hours.
Very recently we found that complexes 3a–c catalyze the
racemization of chiral alcohols highly efficiently at room
temperature after being activated by KOtBu.[18] For example,
3a (0.5 mol%) racemized (S)-1-phenylethanol within 10 min
and resulted in 50% racemization after less than 2 min.
Initial attempts to combine catalyst 3a (or 3b) with an
enzymatic resolution were unsuccessful and gave either no
DKR or led to very long reaction times for the DKR (several
days). This was frustrating, as the isolated reactions (race-
mization and enzymatic resolution) are very fast. Finally, after
Entry
Ru catalyst
t [h]
Yield [%][b]
ee [%][b]
1[c]
2[d]
3
3b
3b
3b
3a
3b
4
4
3
3
15
55
>99
>99
>99
>99
>99
99 (97)[e]
98
4
95 (92)[e]
60
5[f]
[a] Unless otherwise noted, Ru catalyst (4 mol%) and KOtBu (5 mol%)
were stirred in toluene (2 mL) for 6 min before adding 4a (1 mmol). After
4 min CALB (6 mg), Na2CO3 (1 mmol), and isopropenyl acetate
(1.5 mmol) were added and the mixture was stirred under an argon
atmosphere. [b] Determined by chiral GC. [c] A solution of 4a in toluene
(3.3 mL) was added to a mixture of Ru catalyst and KOtBu. [d] Toluene:
3.3 mL. [e] Yield of isolated product. [f] Under an air atmosphere.
mixture of KOtBu and complex 3b was stirred for 6 min in
toluene before adding the alcohol 4a, acetate 5a was obtained
in 99% yield with > 99% ee in 4 h (Table 1, entry 2). When
the concentration of 4a was increased to 0.5m, 5a was
obtained after only 3 h in 98% yield (> 99% ee) (Table 1,
entry 3). Similar results were obtained with catalyst 3a under
the same reaction conditions (Table 1, entry 4). It was
observed that the system is very sensitive to molecular
oxygen; thus when the reaction was run under an air
atmosphere, only 60% yield was attained after 15 h
(Table 1, entry 5).
To study the scope of the reaction, a variety of substrates
were tested with the reaction conditions used in Table 1,
entry 4.[21] For most substrates we obtained the best results
when employing 5 mol% of 3a. The amount of KOtBu
needed depends on the substrate and on the amount of CALB
employed;[22] therefore it was optimized for each entry. The
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results are summarized in Table 2. Similarly to 5a (Table 2,
entries 1 and 2), the naphthyl derivative 5b was obtained in
93% yield after 3 h (Table 2, entry 3). The ethyl carbinol 4c
reacts slower with the enzyme and required the use of 40 mg
coordination to the ruthenium center. Excellent selectivity
and yield were also obtained with the aliphatic substrate 4h
(Table 2, entry 9). DKR of diol 6 is also possible when using
5 mol% of catalyst 3a at room temperature, although 72 h
were needed to attain 93% yield.
However, at 508C enantiopure
Table 2: DKR of various alcohols.[a]
diacetate
7 was obtained after
Entry
Alcohol
KOtBu
t [h]
Product
Yield [%][b,c] ee [%][b]
10 h in 94% yield (Table 2,
entry 10).
(mol%)
1[d]
2
4a
4a
5
5
3
3
5a 98
5a 95 (92)
>99
>99
The necessity for premixing
complex 3a (or 3b) with KOtBu
in toluene suggests that a new
ruthenium complexis formed and
this is supported by a color change
from yellow to dark red within a
few minutes. This intermediate is
most likely ruthenium alkoxide 8,
which is crucial for initiating the
racemization under DKR condi-
tions. The formation of intermedi-
ate 8 is inhibited or slowed down
when the substrate alcohol is pres-
ent in the reaction mixture. A
ligand-exchange reaction of 8 with
the substrate gives alkoxide 9,
which undergoes b-hydride elimi-
nation and forms ruthenium hy-
dride 10 and the oxidized product
11. Insertion of the ketone into the
3
4b 6.25
3
5b 93
>99
>99
4[e]
4c
8
17
5c 92 (90)
5
6
7
4d 7.5
6
6
5d 96 (94)
5e 93 (91)
>99
>99
>99
4e
4 f
5
5
20
5 f
99 (97)
8
9
4g
4h
5
7
20
17
5g 98 (95)
5h 98[f]
>99
>99
À
Ru H bond produces the racemic
alkoxide complex 12. Alkoxide
exchange with S alcohol releases
rac alcohol and regenerates inter-
mediate 9 (Scheme 2).
Alcohol complexes of tungsten,
rhenium, and molybdenum have
>99
(99:1 d.r.)
10[g]
6
6
10
7
94 (90)
previously
been
prepared.[23]
Recently, Casey et al. observed a
Ru–alcohol complexby NMR
[a] Unless otherwise noted, Ru catalyst 3a (5 mol%), CALB (6 mg), Na2CO3 (1 mmol), and KOtBu were
stirred in toluene (2 mL) at room temperature for 6 min before adding the alcohol (1 mmol). After
4 min, isopropenyl acetate (1.5 mmol) was added and the mixture was stirred at room temperature
under an argon atmosphere. [b] Determined by chiral GC. [c] Yield of isolated product in parenthesis.
spectroscopy.[24]
Unfortunately,
attempts to prepare the alkoxide
complexby deprotonation with a
base were unsuccessful.[24] The
postulated ruthenium alkoxide
complex 8 in Scheme 2, would be
1
[d] 3b: 4 mol%. [e] CALB: 40 mg. [f] Yield determined by H NMR spectroscopy. [g] 508C.
of CALB and 8 mol% of KOtBu. Although a longer reaction
time is needed (17 h), 5c was obtained in high yield and
enantioselectivity (92%, > 99% ee) (Table 2, entry 4). Elec-
tron-rich alcohol 4d did not significantly change the rate or
selectivity of the reaction and gave enantiomerically pure 5d
in 96% yield after 6 h (Table 2, entry 5). Similarly, electron-
withdrawing groups on the phenyl ring gave enantiopure
acetates in excellent yields. Thus, 5e was obtained in 93%
yield in 6 h (Table 2, entry 6). Despite the prolonged reaction
times needed for alcohols 4 f and 4g, this is the first time that
acetates 5 f and 5g are obtained through DKR (Table 2,
entries 7 and 8). A plausible explanation that accounts for the
need for longer reaction times is that the nitrogen-containing
substituents on the substrates slow down the reaction rate by
easy to observe as it cannot undergo b-hydride elimination.
When complex 3a and KOtBu were mixed in [D8]toluene in
an NMR tube and shaken vigorously, a fine new precipitate of
KCl was formed that was allowed to settle. The quantitative
formation of a new ruthenium complexwas observed by
13C NMR spectroscopy. The resonance of the five equivalent
quaternary carbons of the cyclopentadienyl ring of 8 is shifted
to higher frequency (d = 108.8 ppm) than that of 3a (d =
107.1 ppm) in [D8]toluene. Similar changes are observed for
the resonance of the CO ligands (d = 202.8 ppm in 8 and
198.0 ppm in 3a). The resonances of the tert-butoxide ligand
are also observed (d = 34.3 and 73.1 ppm), and differ from
those of tBuOH (d = 31.3 and 68.2 ppm) and of KOtBu (d =
37.6 and 66.5 ppm) in [D8]toluene. Furthermore, when an
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filtered and concentrated. Purification by column chromatography
(SiO2; pentane/Et2O 98:2) afforded (R)-1-phenylethanol acetate (5a)
as a colorless oil (151 mg, 92% yield, > 99% ee).
Received: July 23, 2004
Keywords: enantioselectivity · enzyme catalysis · kinetic
.
resolution · reaction mechanisms · ruthenium
[1] For examples, see: a) K. Faber, Chem. Eur. J. 2001, 7, 5005 –
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[2] For chemoenzymatic DKR, see: a) O. Pàmies, J.-E. Bäckvall,
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Bäckvall, Chem. Rev. 2003, 103, 3247 – 3262; c) F. F. Huerta,
A. B. E. Minidis, J.-E. Bäckvall, Chem. Soc. Rev. 2001, 30, 321 –
331; d) M.-J. Kim, Y. Ahn, J. Park, Curr. Opin. Chem. Biol. 2002,
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109, 1221 – 1222; Angew. Chem. Int. Ed. Engl. 1997, 36, 1173 –
1174.
[3] For a related DKR of amines, see: M. T. Reetz, K. Schimossek,
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[4] P. M. Dinh, J. A. Howarth, A. R. Hudnott, J. M. J. Williams,
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[6] N. Menasche, Y. Shvo, Organometallics 1991, 10, 3885 – 3891.
[7] a) F. F. Huerta, J.-E. Bäckvall, Org. Lett. 2001, 3, 1209 – 1212;
b) A.-B. Runmo, O. Pàmies, K. Faber, J.-E. Bäckvall, Tetrahe-
dron Lett. 2002, 43, 2983 – 2986; c) F. F. Huerta, Y. R. S. Laxmi,
J.-E. Bäckvall, Org. Lett. 2000, 2, 1037 – 1040; d) O. Pàmies, J.-E.
Bäckvall, J. Org. Chem. 2002, 67, 1261 – 1265.
Scheme 2. Proposed mechanism for the racemization.
excess of 1-phenylethanol (4a) was added to the NMR tube,
the formation of acetophenone (11) was immediately
observed.
[8] a) O. Pàmies, J.-E. Bäckvall, Adv. Synth. Catal. 2001, 343, 726 –
731; b) O. Pàmies, J.-E. Bäckvall, Adv. Synth. Catal. 2002, 344,
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[9] O. Pàmies, J.-E. Bäckvall, J. Org. Chem. 2001, 66, 4022 – 4025.
[10] O. Pàmies, J.-E. Bäckvall, J. Org. Chem. 2002, 67, 9006 – 9010.
[11] O. Pàmies, J.-E. Bäckvall, J. Org. Chem. 2003, 68, 4815 – 4818.
[12] a) B. A. Persson, F. F. Huerta, J.-E. Bäckvall, J. Org. Chem. 1999,
64, 5237 – 5240; b) M. Edin, J. Steinreiber, J.-E. Bäckvall, Proc.
Natl. Acad. Sci. USA 2004, 101, 5761 – 5766; c) B. Martín-
Matute, J.-E. Bäckvall, J. Org. Chem., in press.
In summary, we have developed a highly efficient DKR of
secondary alcohols at room temperature that for the first time
provides enantiopure products in high yields in very short
reaction times. Furthermore, isopropenyl acetate can be
employed as the acyl donor, which makes the purification of
the products very easy. We have also proven the intermediacy
of Ru alkoxides in this process. This mild procedure makes it
possible to use sensitive and/or less-thermostable enzymes in
future applications.
[13] M.-J. Kim, Y. K. Choi, M. Y. Choi, M. J. Kim, J. Park, J. Org.
Chem. 2001, 66, 4736 – 4738.
[14] a) H. M. Jung, J. H. Koh, M.-J. Kim, J. Park, Org. Lett. 2000, 2,
409 – 411; b) H. M. Jung, J. H. Koh, M.-J. Kim, J. Park, Org. Lett.
2000, 2, 2487 – 2490.
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[16] J. H. Koh, H. M. Jung, J. Park, Tetrahedron Lett. 1998, 39, 5545 –
5548.
[17] a) J. H. Choi, Y.-H. Kim, S. H. Nam, S. T. Shin, M.-J. Kim, J.
Park, Angew. Chem. 2002, 114, 2479 – 2482; Angew. Chem. Int.
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E. S. Park, E. J. Kim, M. J. Kim, J. Park, J. Org. Chem. 2004, 69,
1972 – 1977.
Experimental Section
Complexes 3a and 3b were prepared as described in the litera-
ture.[18,25] Toluene was dried over CaH2 overnight, distilled under
argon, and stored over 4-Š molecular sieves. Isopropenyl acetate was
washed with saturated K2CO3, dried with CaCl2, and distilled under
argon. 1H NMR and 13C NMR spectra of acetates were in good
agreement with the data previously reported in the literature.[26]
Dynamic kinetic resolution of 1-phenylethanol (4a): A solution
of KOtBu (0.5m in THF; 100 mL, 0.05 mmol) was added to a 10-mL
Schlenk flask. The THF was carefully removed under vacuum, and
the flask was filled with argon. CALB[19] (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.[27] 1-
Phenylethanol (4a) (120 mL, 1 mmol) was then added, and after 4 min
isopropenyl acetate (165 mL, 1.5 mmol) was added. After being
stirred for 3 h at ambient temperature, the reaction mixture was
[18] G. Csjernyik, K. Bogꢀr, J.-E. Bäckvall, Tetrahedron Lett. 2004,
45, 6799 – 6802.
[19] Immobilized and commercially available as Novozym-435.
[20] Under the same reaction conditions, (2-naphthyl)-1-ethanol
gave (2-naphthyl)-1-ethanol acetate in 100% yield but 0% ee.
[21] To avoid opening of the reaction vessel, the order of addition of
reagents was changed slightly: Toluene was added to a mixture
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of KOtBu, Ru complex, CALB, and Na2CO3. After 6 min the
alcohol was added and the mixture was stirred for 4 min. Finally,
isopropenyl acetate was added.
[25] N. G. Connelly, I. Manners, J. Chem. Soc. Dalton Trans. 1989,
283 – 288.
[26] NMR data can be found in the following references: 5a: D.
Bianchi, P. Cesti, E. Battistel, J. Org. Chem. 1988, 53, 5531 –
5535; 5b: J. Y. Legros, M. Toffano, J.-C. Fiaud, Tetrahedron 1995,
51, 3235 – 3246; 5c: B. R. Rao, M. E. N. Nambudiry, Synth.
Commun. 1991, 21, 1721 – 1727; 5d: S. M. Brown, S. G. Davies,
J. A. A. de Sousa, Tetrahedron: Asymmetry 1993, 4, 813 – 822;
5e: Y. Kita, Y. Takebe, K. Murata, T. Naka, S. Akai, J. Org.
Chem. 2000, 65, 83 – 88; 5 f: A. Kamal, M. Sandbhor, K. V.
Ramana, Tetrahedron: Asymmetry 2002, 13, 815 – 820; 5h:
reference [5b]; 7: J. S. Wallace, B. W. Baldwin, C. J. Morrow, J.
Org. Chem. 1992, 57, 5231 – 5239.
[22] 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. An excess of KOtBu is needed to consume the water in the
reaction mixture. To test this hypothesis, DKR of 4a was carried
out under the same reaction conditions as in Table 1, entry 4, but
employing 40 mg of CALB instead of 6 mg. Acetate 5a was
obtained in only 57% yield after 3 h.
[23] a) R. M. Bulloc, Chem. Eur. J. 2004, 10, 2366 – 2374, and
references therein; b) V.-I. Bakhmutov, E. V. Vorontsov, D. Y.
Antonov, Inorg. Chim. Acta 1998, 278, 122 – 126.
[24] C. P. Casey, T. E. Vos, G. A. Bikzhanova, Organometallics 2003,
22, 901 – 903.
[27] Stirring for 10 min gave essentially the same result but stirring
for 1.5 h gave less-reproducible results.
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