Photoactivated racemization catalyst for dynamic kinetic resolution of secondary alcohols

Article abstract of DOI:10.1021/jo1009036

Household fluorescent light activates a diruthenium complex to generate catalytic species highly active for the racemization of secondary alcohols under ambient conditions. This catalyst system is applicable for the chemoenzymatic dynamic kinetic resolution of racemic alcohols to give optically pure acetates under mild conditions.

Full text of DOI:10.1021/jo1009036

pubs.acs.org/joc
DKR of secondary alcohols since the Shvo complex (1)
Photoactivated Racemization Catalyst for Dynamic
Kinetic Resolution of Secondary Alcohols
4
was successfully employed by B €a ckvall and co-workers.
The DKR using 1 requires a special acyl donor such as p-
chlorophenyl acetate, ketone additive, and a thermostable
lipase at high temperature under anaerobic conditions. The
use of a monomeric ruthenium complex 2 or 3, which is
highly active at room temperature, has remarkably improved
the efficiency of chemoenzymatic DKR. Advantageous acyl
donors such as isopropenyl acetate and thermally labile enzy-
mes such as subtilisin can be used with them for the DKR at
6
room temperature. The success of 2 led to the development
of its analogues 3-5 displaying good racemization activities
at ambient temperature. It is noticeable that the DKR with 4
or 5 can be carried out at room temperature without caution
when exposed to air. However, the activation step using a
strong base such as potassium t-butoxide is required to gene-
Youngshil Do, In-Chul Hwang, Mahn-Joo Kim,* and
Jaiwook Park*
Department of Chemistry Pohang University of Science and
Technology (POSTECH), San 31 Hyojadong, Pohang,
Kyeongbuk 790-784, Republic of Korea
5
mjkim@postech.ac.kr; pjw@postech.ac.kr
Received May 8, 2010
7
5
,6a
8
rate active species from 2
The racemization using 4 and 5 also requires inorganic
and 3.
bases such as potassium carbonate and potassium pho-
7
sphate. Here we describe an interesting finding of a highly
active catalyst system for the racemization of secondary alco-
hols in the absence of base. In addition, this catalyst system is
the first case that provides catalytic species active for the
racemization of alcohols using light: (S)-1-phenylethanol
was racemized within 10 min using 2.0 mol % of 6a simply
by illuminating household 30 W fluorescent light under ambi-
ent conditions. Delightfully, the catalytic racemization was
also applicable for the chemoenzymatic DKR of secondary
alcohols (Schemes 1 and 2).
Household fluorescent light activates a diruthenium
complex to generate catalytic species highly active for
the racemization of secondary alcohols under ambient
conditions. This catalyst system is applicable for the
chemoenzymatic dynamic kinetic resolution of racemic
alcohols to give optically pure acetates under mild
conditions.
The diruthenium complex 6a was synthesized through a
9
procedure similar to that for a N-phenyl analogue (6b). Re-
crystallization of 6a from a solution of dichloromethane and
hexane provided crystals suitable for X-ray diffraction ana-
1
0
lysis. The molecular structure of 6a is almost same as that
of 6b, which has a Ru-Ru bond, two bridged CO, and trans-
located cyclopentadienyl rings.
Enzymatic kinetic resolution is still an important and eco-
nomical tool for producing optically active compounds, al-
though it has an intrinsic drawback of yielding a maximum
1
1
The photoinduced activity of 6a was examined for the
racemization of (S)-1-phenylethanol and compared with
those of related ruthenium and iron complexes (Table 1).
Benzene and tetrahydrofuran (THF) were better solvents
than toluene and acetone (entries 1-4). Under solventless
conditions, complete racemization was achieved using 0.1 mol %
1
of 50% of the desired enantiomer. Methods of racemizing
the recovered and undesired enantiomers can improve the ef-
ficiency of kinetic resolution. It is more desirable that the
racemization can be achieved in situ during the kinetic re-
solution. That is, dynamic kinetic resolution (DKR) pro-
vides single enantiomers from a racemic mixture with yields
2
(5) (a) Choi, J. H.; Kim, Y. H.; Nam, S. H.; Shin, S. T.; K., M.-J.; Park, J.
Angew. Chem., Int. Ed. 2002, 41, 2373. (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.
approaching 100%. Thus, many researchers have focused
on developing efficient chemoenzyamtic DKR, which re-
quires racemization catalysts compatible with the conditions
3
(6) (a) Kim, M.-J.; Chung, Y. I.; Choi, Y. K.; Lee, H. K.; Kim, D.; Park, J.
for enzymatic resolution.
Various ruthenium complexes (2-5) have been reported
as effective racemization catalysts for the chemoenzyamtic
J. Am. Chem. Soc. 2003, 125, 11494. (b) Bor ꢁe n, L.; Martı
Y.; C oꢁ rdova, A.; B €a ckvall, J.-E. Chem.;Eur. J. 2006, 12, 225.
7) (a) Kim, N.; Ko, S.-B.; Kwon, M. S.; Kim, M.-J.; Park, J. Org. Lett.
005, 7, 4523. (b) Kim, M.-J.; Choi, Y. K.; Kim, S.; Kim, D.; Han, K.; Ko,
´
n-Matute, B.; Xu,
(
2
S.-B.; Park, J. Org. Lett. 2008, 10, 1295.
(8) (a) Csjernyik, G.; Bog ꢁa r, K.; B €a ckvall, J. E. Tetrahedron Lett. 2004,
45, 6799. (b) Martı
´
n-Matute, B.; Edin, M.; Bog ꢁa r, K.; B €a ckvall, J.-E. Angew.
Chem., Int. Ed. 2004, 43, 6535.
(9) Casey, C. P.; Vos, T. E.; Singer, S. W.; Guzei, I. A. Organometallics
2002, 21, 5038.
(10) See Supporting Information.
(
1) Breuer, M.; Ditrich, K.; Habicher, T.; Hauer, B.; Kesseler, M.;
St u€ rmer, R.; Zelinski, T. Angew. Chem., Int. Ed. 2004, 43, 788.
(
(
2) Pellissier, H. Tetrahedron 2008, 64, 1563.
3) (a) P ꢀa mies, O.; B €a ckvall, J. E. Chem. Rev. 2003, 103, 3247. (b) Martı
´
n-
Matute, B.; B €a ckvall, J. E. Curr. Opin. Chem. Biol. 2007, 11, 226. (c) Lee,
J. H.; Han, K.; Kim, M.-J.; Park, J. Eur. J. Org. Chem. 2010, 999.
(
4) (a) Larsson, A. L. E.; Persson, B. A.; B €a ckvall, J.-E. Angew. Chem.,
Int. Ed. Engl. 1997, 36, 1211. (b) Persson, B. A.; Larsson, A. L. E.; Le Ray,
M.; B €a ckvall, J.-E. J. Am. Chem. Soc. 1999, 121, 1645.
(11) CCDC 764257 contains the supplementary crystallographic data for
4a. These data can be obtained free of charge from The Cambridge Crystal-
lographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
5
740 J. Org. Chem. 2010, 75, 5740–5742
Published on Web 07/16/2010
DOI: 10.1021/jo1009036
r 2010 American Chemical Society

Do et al.
JOCNote
a
SCHEME 1. Racemization Catalyst
TABLE 2. Racemization of Secondary Alcohols
SCHEME 2. Synthesis of 6a and DKR of 1-Phenylethanol
a
A solution of (S)-alcohol (>99% ee, 0.25 mmol) and 6a (2.0 mol %)
in benzene (0.80 mL) was illuminated with fluorescent light (30 W) at
b
3
0 °C. Measured by HPLC equipped with a chiral column (Chiral OD,
c
d
Daicel). Measured by GC equipped with a TR-WAX column. Deter-
mined by GC after conversion to 2-octyl acetate.
a
TABLE 3. Dynamic Kinetic Resolution of Secondary Alcohols
a
TABLE 1. Racemization of (S)-1-Phenylethanol
b
yield (%0
c
ee (%)
entry
alcohol
t (h)
d,e
1
2
3
4
5
6
a
1-phenylethanol
1-phenylethanol
1-phenylethanol
24
24
24
24
36
24
59
56
>99
>99
>99
>99
>99
97
d, f
96
90
97
84
b
ee (%)
c
yield (%)
entry
catalyst
solvent
t (min)
1-(4-methoxyphenyl)ethanol
1-(4-chlorophenyl)ethanol
2-octanol
1
2
3
4
5
6
7
8
9
6a
6a
6a
6a
6a
6a
6a
6b
6b
benzene
THF
toluene
acetone
none
benzene
benzene
benzene
THF
benzene
benzene
benzene
10
10
10
10
360
1200
1200
10
10
20
0.8
3.0
97.0
96.8
95.6
95.7
97.0
99.9
97.7
96.0
96.9
94.7
89.7
97.8
21.2
47.2
Sodium carbonate (1 equiv) and CALB (4 mg/mmol) were added
into a solution of alcohol (1.00 mmol), isopropenyl acetate (1.5 equiv),
and 6a (2 mol %) in degassed benzene (3.2 mL) under argon, and the
resulting mixture was illuminated with fluorescent light (30 W) at 30 °C.
d
3.9
99.9
e
f
b
c
89.8
Isolated yield. Determined by GC equipped with a chiral column (β-
d
DEX-TM). The reaction was performed in 0.25 mmol scale, and the
89.3
2.4
1.7
62.5
98.0
e
f
2 3
yield was measured by GC. Without Na CO . The reaction was
10
11
12
a
[Cp*Ru(CO)
[CpRu(CO)
[CpFe(CO)
2
]
2
performed exposed to air without caution.
2
]
2
720
1200
2
]
2
The racemization using 6a under fluorescent light was
tested for several (S)-alcohols (Table 2). A benzylic alcohol
having an electron-donating substituent on the phenyl ring
was racemized faster than that having an electron-withdrawing
one (entries 1 and 2). An aliphatic alcohol, 2-octanol, was
racemized a little faster than the latter (entry 3). The catalyst
system was tested for the DKR of secondary alcohols (Table 3).
Candida antarctica lipase B (CALB; trade name Novozym 435)
immobilized on acrylic resin was employed for the enzymatic
acylation of the alcohols. Although the DKR without base
A solution of (S)-1-phenylethanol (>99% ee, 0.25 mmol) and
catalyst (2.0 mol %) was illuminated with fluorescent light (30 W) at
b
3
0 °C. Measured by HPLC equipped with a chiral column (Chiral OD,
c
Daicel). The intensities of 1-phenylethanol and acetophenone were
d
measured by GC equipped with a TR-WAX column. (S)-1-Phenyletha-
nol (>99% ee, 0.60 mL, 5.0 mmol) without solvent was reacted with 6a
(
e
4.6 mg, 0.10 mol %). The reaction was carried out in the dark. The
f
reaction was carried out in the dark at 50 °C.
of 6a, although it took 6 h (entry 5). In the absence of light, 6a
was inactive at 30 °C (entry 6). Thermal activation of 6a was
negligible at 50 °C in the dark (entry 7). The racemization using
b was much slower than that using 6a in benzene due to its poor
solubility, while the former was comparable to the latter in THF
entries 8 and 9). Pentamethylcyclopentadienylruthenium dicar-
bonyl dimer ([Cp*Ru(CO) ] ) showed an activity less than a half
of that of 6a (entry 10). Cyclopentadienylruthenium dicarbonyl
dimer ([CpRu(CO) ] ) showed a poor activity (entry 11),
2
while its iron analogue ([CpFe(CO) ] ) was practically inactive
2
entry 12).
1
5
(
entry 1) or in the air (entry 2) was not successful, employing
sodium carbonate under anaerobic conditions gave good
results in the DKR of benzylic alcohols (entries 3-5) as well
as in that of 2-octanol (entry 6).
Although detailed studies are required for the mechanism,
a pathway for the catalytic racemization is proposed in
Scheme 3 on the basis of the chemistry for the ruthenium
complexes related to 6a and the factors that affect the race-
6
(
2
2
12
13
2
2
14
mization. The photochemistry of [CpRu(CO) ] has been ex-
2 2
(
16
tensively studied, and its photolysis at low energy (λ > 400
(
12) [Cp*Ru(CO)
King, R. B.; Iqbal, M. Z.; King, J. A. D. J. Organomet. Chem. 1979, 171, 53.
13) [CpRu(CO) was prepared according to the literature procedure:
Humphries, A. P.; Knox, S. A. R. J. Chem. Soc., Dalton Trans. 1975, 1710.
14) [CpFe(CO) was purchased from Strem Chemicals and used as
received.
2 2
] was prepared according to the literature procedure:
(15) It is known that acetic acid formed during DKR inhibits the
racemization: see ref 5b.
(16) (a) Bitterwolf, T. E. Coord. Chem. Rev. 2000, 419, 206–207.
(b) Bitterwolf, T. E.; Linehan, J. C.; Shade, J. E. Organometallics 2000, 19,
4915.
(
2 2
]
(
2 2
]
J. Org. Chem. Vol. 75, No. 16, 2010 5741

Do et al.
JOCNote
SCHEME 3. Proposed Pathway for the Photoinduced Racemiz-
ation of Secondary Alcohols
elimination and insertion reaction, and the racemization is
realized through the alkoxide exchange. Recently, B €a ckvall
and co-workers suggested an analogous ruthenium alkoxide
as the key intermediate for the racemization of alcohols using
2
0
3
that the illumination is not necessary after the generation of B
on the basis of density functional calculations. It is notable
2
1
orC. The rutheniumhydride 7 can also beformedduring the
racemization, producing ketone as the byproduct, but the
5
reverse reaction can possibly regenerate C.
b,22
In summary, we have found a simple and efficient catalyst
system for the racemization of secondary alcohols, which
consists of household fluorescent light and a diruthenium
complex stable under amibient conditions. Using this cata-
lyst system, we have demonstrated the chemoenzymatic DKR
of various secondary alcohols under mild conditions.
Experimental Section
Racemization of (S)-1-Phenylethanol: To a solution of 6a
4.6 mg, 2.0 mol %) in dry benzene (0.8 mL) in a 4 mL vial
(
was added (S)-1-phenylethanol (>99% ee, 0.25 mmol). The
reaction mixture was placed about 10 cm from a 30 W fluores-
cent lamp and illuminated with stirring at 30 °C. The ee value
was measured by HPLC equipped with a chiral column (Chiral
OD, Daicel).
Dynamic Kinetic Resolution of 1-Phenylethanol: To a 50 mL
flask equipped with a grease-free high-vacuum stopcock were
added 6a (18.4 mg, 0.020 mmol) and degassed benzene (3.2 mL,
0
.30 M). The flask was filled with argon and stirred for 10 min.
Then, Novozym 435 (4.0 mg), Na CO (104 mg, 1.00 mmol),
-phenylethanol (120 μL, 1.00 mmol), and isopropenyl acetate
168 μL, 1.5 mmol) were added sequentially. The resulting red-
nm) results in the homolysis of the Ru-Ru bond through the
opening of the bridged form to the trans terminal form, as in
2
3
1
(
1
6a
intermediate A. In order to check the possibility of radical
1
7
intermediates, we tested the racemization of (S)-1-phenyl-
ethanol in the presence of radical scavengers such as 2,2,6,6-
tetramethylpiperinyloxy radical (TEMPO) and 2,6-di-tert-
butyl-4-methylphenol (BHT). In the case using TEMPO (1.0
equiv), the racemization was somewhat slower (6.7% ee after
brown suspension was placed about 10 cm from a 30 W fluore-
scent lamp and illuminated with stirring at 30 °C for 24 h. The
reaction mixture was concentrated and purified by chromato-
graphy on a silica gel column (ethyl acetate/hexane =1/8) to give
(
R)-1-phenylethylacetate (156 mg, 95% yield, >99% ee).
3
0 min) than that without it, forming acetophenone in 30%
yield. However, no effect was observed in the case using BHT
1.0%eeafter 10 min). Meanwhile, the presence of CO (1 atm)
stopped the racemization (92% ee after 10 min; 92% ee after
Acknowledgment. We are grateful for the financial sup-
port from Korea Science and Engineering Foundation (No.
0090087801), and the Korean Ministry of Education thro-
ugh the BK21 project for our graduate program.
(
2
1
6a
3
0 min). Thus, before the homolysis of the Ru-Ru bond,
intermediate A would react with an alcohol with the dissocia-
tion of the CO ligand to give intermediate B. Then, the real
catalytic species C and ruthenium hydride 7 are formed from
B. In fact, ruthenium hydride 7 was observed in the reaction
Supporting Information Available: Experimental details.
Preparation and characterization of compounds 6a, [Cp*Ru-
(
2 2 2 2
CO) ] , and [CpRu(CO) ] . X-ray analysis of complex 6a. This
material is available free of charge via the Internet at http://
pubs.acs.org.
1
8,19
mixture duringthe racemization.
Theinterconversion bet-
ween (R)-C and (S)-C can occur through reversible β-hydride
(
20) Nyhl ꢁe n, J.; Privalov, T.; B €a ckvall, J.-E. Chem.;Eur. J. 2009, 15,
5220.
(21) The racemization continued in the dark after generating active
species with fluorescent light. The racemization was almost completed
after 30 min (1.0% ee) when the illunination was discontinued after 5 min
(48.7% ee).
(17) Photoredox catalysis with visible light attracts much attention of
organic chemists due to its efficiency and practical advantages: Zeitler, K.
Angew. Chem., Int. Ed. 2009, 48, 9785–9789. and references therein.
(
18) The characteristic hydride peak for 5 was observed at -9.6 ppm in
1
the reaction mixture (C
19) The corresponding ruthenium chloride complex was recovered in
1% yield by the reaction with CHCl after the racemization.
6 6
D ) by H NMR.
(
(22) Martı
´
n-Matute, B.; Edin, M.; Bog ꢁa r, K.; Kaynak, F. B.; B €a ckvall,
8
3
J.-E. J. Am. Chem. Soc. 2005, 127, 8817–8825.
5
742 J. Org. Chem. Vol. 75, No. 16, 2010