Asymmetric transformations of acyloxyphenyl ketones by enzyme-metal multicatalysis

Article abstract of DOI:10.1021/jo026122m

A multipathway process comprising several enzyme- and metal-catalyzed reactions has been explored for the asymmetric transformations of acyloxyphenyl ketones to optically active hydroxyphenyl alcohols in the ester forms. The process comprises nine component reactions in three pathways, all of which take place by the catalytic actions of only two catalysts, a lipase and a ruthenium complex. The synthetic reactions were carried out on 0.2-0.6 mmol scales for eight different substrates under an atmosphere of hydrogen (1 atm) in toluene at 70°C for 3 days. In most cases, the yields were high (92-96%) and the optical purities were excellent (96-98% ee), This work thus has demonstrated that enzyme-metal multicatalysis has great potential as a new methodology for asymmetric transformations.

Full text of DOI:10.1021/jo026122m

SCHEME 1. P la u sible Rea ction P a th w a y for th e
Asym m etr ic Tr a n sfor m a tion of
3′-Acetoxya cetop h en on e (1a )
Asym m etr ic Tr a n sfor m a tion s of
Acyloxyp h en yl Keton es by En zym e-Meta l
Mu ltica ta lysis
Mahn-J oo Kim,* Min Young Choi, Min Young Han,
Yoon Kyung Choi, J ae Kwan Lee, and J aiwook Park*,1
National Research Laboratory of Chirotechnology,
Department of Chemistry, Division of Molecular and
Life Sciences, Pohang University of Science and Technology,
San 31 Hyojadong, Pohang, Kyongbuk 790-784, Korea
mjkim@postech.ac.kr
Received J une 29, 2002
Abstr a ct: A multipathway process comprising several
enzyme- and metal-catalyzed reactions has been explored
for the asymmetric transformations of acyloxyphenyl ketones
to optically active hydroxyphenyl alcohols in the ester forms.
The process comprises nine component reactions in three
pathways, all of which take place by the catalytic actions of
only two catalysts, a lipase and a ruthenium complex. The
synthetic reactions were carried out on 0.2-0.6 mmol scales
for eight different substrates under an atmosphere of
hydrogen (1 atm) in toluene at 70 °C for 3 days. In most
cases, the yields were high (92-96%) and the optical purities
were excellent (96-98% ee), This work thus has demon-
strated that enzyme-metal multicatalysis has great poten-
tial as a new methodology for asymmetric transformations.
Development of methods for the catalytic asymmetric
transformations of prochiral molecules is one of the
intensive research areas in synthetic organic chemistry.2
Most of the procedures reported so far are based on
transformations employing either a metal complex or an
enzyme as the catalyst. Recently, we became interested
in new approaches using an enzyme and a metal complex
together for the enantioselective catalytic reactions. It
has been demonstrated that the enzyme-metal combina-
tions such as lipase/ruthenium or lipase/palladium are
useful as the catalytic systems for the dynamic kinetic
resolution (DKR) of secondary alcohols,3 allylic acetates,4
and amines5 as well as for the asymmetric transforma-
tions of simple ketones,6 enol acetates,6 and ketoximes.7
(1) Email: pjw@postech.ac.kr.
We now wish to report the use of the enzyme-metal
combination as the catalyst system for a multipathway
process, in which prochiral substrates are converted by
the cooperative catalytic actions of an enzyme and a
metal complex via several pathways to optically active
chiral products.
A lipase/ruthenium-catalyzed multipathway process
proposed for the asymmetric conversion of 3′-acetoxyac-
etophenone (1a ) to (R)-1-(3-hydroxyphenyl)ethyl acetate
(6a ) is described in Scheme 1. In this scheme, the
prochiral substrate is converted to the chiral product via
three pathways. In the first pathway (1a f 2a f 3a f
6a ), the starting material is reduced through Ru-
(2) (a) Comprehensive Asymmetric Catalysis I-III; J acobsen, E. N.;
Pfaltz, A.; Yamamoto, H. Eds.; Springer-Verlag: Berlin, 1999. (b)
Noyori, R. Asymmetric Catalysis in Organic Synthesis; Wiley: New
York, 1994.
(3) (a) Persson, B. A.; Larsson, A. L. E.; Ray, M. L.; Ba¨ckvall, J .-E.
J . Am. Chem. Soc. 1999, 121, 1645. (b) Koh, J . H.; J ung, H. M.; Kim,
M.-J .; Park, J . Tetrahedron Lett. 1999, 40, 6281. (c) Huerta, F. F.;
Laxmi, Y. R. S.; Ba¨ckvall, J .-E. Org. Lett. 2000, 2. 1037. (d) Lee, D.;
Huh, E. A.; Kim, M.-J .; J ung, H. M.; Koh, J . H.; Park, J . W. Org. Lett.
2000, 2, 2377. (e) Kim, M.-J .; Choi, Y. K.; Choi, M. Y.; Kim, M. J .;
Park, J . J . Org. Chem. 2001, 66, 4736. (f) Pamies, O.; Ba¨ckvall, J .-E.
J . Org. Chem. 2001, 66, 4022. (g) Pamies, O.; Ba¨ckvall, J .-E. J . Org.
Chem. 2002, 67, 1261. (h) Choi, J . H.; Kim, Y. H.; Nam, S. H.; Shin, S.
T.; Kim, M.-J .; Park, J . Angew. Chem., Int. Ed. 2002, 41, 2373.
(4) (a) Allen, J . V.; Williams, J . M. J . Tetrahedron Lett. 1996, 37,
1859. (b) Choi, Y.-K.; Suh, J . H.; Lee, D.; Lim, I.; J ung, J . Y.; Kim,
M.-J . J . Org. Chem. 1999, 64, 8423.
(5) Reetz, M. T.; Schimossek, K. Chimia 1996, 50, 668.
(6) (a) J ung, H. M.; Koh, J . H.; Kim, M.-J .; Park, J . Org. Lett. 2000,
2, 409. (b) J ung, H. M.; Koh, J . H.; Kim, M.-J .; Park, J . Org. Lett. 2000,
2, 2487.
(7) Choi, Y. K.; Kim, M. J .; Ahn, Y.; Kim, M.-J . Org. Lett. 2001, 3,
4099.
10.1021/jo026122m CCC: $22.00 © 2002 American Chemical Society
Published on Web 11/26/2002
J . Org. Chem. 2002, 67, 9481-9483
9481

TABLE 1. Lip a se/Ru th en iu m -Ca ta lyzed Asym m etr ic
catalyzed hydrogenation to yield racemic alcohol 2a ,
which is then resolved dynamically by two coupled
reactions, Ru-catalyzed racemization and lipase-catalyzed
enantioselective acylation, to give optically active diac-
etate 3a . The lipase-catalyzed regioselective deacylation
of 3a affords monoacetate 6a as the final product. In the
second (1a f 4a f 5a f 6a ), the substrate is first
deacylated by lipase and then reduced by the ruthenium
catalyst to racemic alcohol 5a . The racemic 5a is then
resolved dynamically by two coupled reactions, Ru-
catalyzed racemization and lipase-catalyzed regio-/enan-
tioselective acylation, to give the final product 6a . In the
third (1a f 2a f 5a f 6a ), the monoacetate 2a in the
first pathway is converted by lipase-catalyzed deacylation
to 5a in the second pathway. Overall, the substrate is
converted to the product via nine catalytic steps: two Ru-
catalyzed reductions, two Ru-catalyzed racemizations,8
three lipase-catalyzed deacylations, and two lipase-
catalyzed acylations. It is noteworthy that the DKRs take
place at two stages for the conversions of racemic 2a and
5a to single enantiomers 3a and 6a , respectively. The
overall reaction corresponds to the asymmetric reductive
acyl migration, in which the acyl group moves from an
aryl OH to an OH group at the stereogenic center of the
reduced side chain.
Tr a n sfor m a tion s of Acyloxyp h en yl Keton es (1a -h ).a
sub- prod-
%
%
sub- prod-
%
%
entry strate uct yield eeb entry strate uct yield eeb
1
2
3
4
1a
1b
1c
1d
6a
6b
6c
6d
95
96
94
93
98
98
93
96
5
6
7
8
1e
1f
1g
1h
6e
6f
6g
6h
88
88
92
89
89
98
96
98
a
Lipases employed: lipase PS-D (entries 1-6), lipase PS-TN13
b
(entries 7 and 8). On the basis of the analyses by HPLC using a
chiral column. The ee values of 6c-f were determined in the
deacylated forms, which were obtained by hydrolysis (K2CO3,
MeOH/H2O). Analytical conditions: Whelk-O1, hexane/2-propanol
) 90/10 (6a ,b,h ), 95/5 (6c-f,g), flow rate ) 1.0 (6a ,b,g,h ), 0.5 mL/
min (6c-f), UV 217 nm.
the reaction was complete, the catalysts were filtered off.
The filtrate was concentrated and then subjected to a
column chromatography to fractionate the desired prod-
ucts. The optical purities were determined by HPLC
using a chiral column. The results are given together with
those from the reaction of 1a in Table 1.
The reaction of the 3′-butanoyloxyacetophenone 1b
gave 6b in high yield (96%) and excellent ee (98%) (entry
2). The slightly reduced yields (93-94%) and ee values
(93-96%) were obtained from the transformation of
indanone derivatives 1c and 1d to 6c and 6d , respectively
(entries 3 and 4). The reactions of tetralone derivatives
1e and 1f afforded 6e and 6f in good yields (88%) but
substantially different optical purities, 89% and 98%,
respectively (entries 5 and 6). Two acyl derivatives of 4-(4-
hydroxyphenyl)-2-butanone, 1g and 1h , were trans-
formed to 6g and 6h , respectively, with the almost same
level of high enantioselectivity (96-98% ee) and good
yields (89-92%) (entries 7 and 8). In general, the
butanoylated substrates gave higher ee values compared
to the acetylated substrates. All of these results thus
prove that all the substrates examined were converted
successfully to the optically active products by lipase/
ruthenium multicatalysis.
In conclusion, this work has demonstrated for the first
time that a multipathway transformation takes place
efficiently by the cooperative action of only two distinct
catalysts, a lipase and a ruthenium complex, to produce
chiral products of high optical purity in good yield. It is
notable that the chiral products obtained are useful as
intermediates for the synthesis of chiral drugs such as
rivastigmine (trade name Exelon) and its analogues for
the treatment of Alzheimer’s disease.14 Now enzyme-
metal multicatalysis offers new opportunity for asym-
metric synthesis and its scope will expand with efforts
to find proper combinations between enzymes and metal
catalysts for new applications.
According to the scheme, the reactions of 1a 9 were
explored with a ruthenium complex 7 and an immobilized
lipase. A single reaction was carried out with a solution
containing 1a (0.56 mmol), 710 (4 mol %), and lipase PS-
D11 (0.25 mass equiv) in toluene (1.4 mL) under an
1
atmosphere of hydrogen (1 atm) at 70 °C. The H NMR
analysis12 of the reaction mixture at an early stage (3 h)
indicated that all the intermediates (2a , 16%; 3a , 24%;
4a , 17%; 5a , 8%) proposed in the scheme are present
together with substrate (18%) and product (17%). The
qualitative analysis by TLC (n-hexane:EtOAc ) 4:1) also
supported this observation clearly: Rf ) 0.06, 0.18, 0.25,
0.27, 0.43, 0.44 for 5a , 2a , 4a , 6a , 1a , and 3a , respec-
tively. After 24 h, all substrate was consumed and the
yield of product reached about 90% with negligible or
small amounts of intermediates (2a , < 1%; 3a , < 5%;
4a , < 1%; 5a , <5%). The further reaction for additional
48 h provided 6a almost exclusively (95% isolated yield)
with excellent optical purity (98% ee).
The good results from the asymmetric transformation
of 1a encouraged us to examine additional compounds
1b-h as the substrates for lipase-ruthenium multica-
talysis. Each of their reactions was carried out on a
smaller scale with a substrate (0.2 mmol), a lipase (0.1-
0.25 mass equiv), and 7 (2-4 mol %) in toluene (0.5 mL)
at 70 °C under hydrogen gas (1 atm) for 3 days. After
(8) The Ru-catalyzed racemization takes place via oxiation-reduc-
tion by hydrogen transfer. For detailed a mechanism, see: Laxmi, Y.
R. S.; Ba¨ckvall, J .-E. Chem. Commun. 2000, 611; also ref 3a.
(9) The substrates were prepared readily by the reaction of phenolic
ketones with Ac2O in the presence of DMAP and Et3N in CH2Cl2.
(10) For the synthesis of 7, see: (a) Menashe, N.; Shvo, Y. Organo-
metallics 1991, 10, 3885. (b) Casey, C. P.; Singer, S. W.; Powell, D. R.;
Hayashi, R. K.; Kavana, M. J . Am. Chem. Soc. 2001, 123, 1090..
(11) Lipase PS-D is a trade name for Pseudomonas cepacia lipase
immobilized on earth, which is available from Amano, J apan.
(12) Some characteristic 1H NMR peaks for 1a -6a are as follows:
1a , singlet at 2.60 ppm, CH3COPhOAc; 2a , multiplet at 4.90 ppm,
CH3CH(OH)PhOAc; 3a , quartet at 2.07 ppm, CH3CH(OAc)PhOAc; 4a ,
singlet at 2.57 ppm, CH3COPhOH.; 5a , multiplet at 4.84 ppm,
CH3CH(OH)PhOH.; 6a , quartet at 5.81 ppm, CH3CH(OAc)PhOH.
Exp er im en ta l Section
Gen er a l P r oced u r e. The procedure for the synthesis of 6a
is described as representative. Substrate (1a , 100 mg, 0.56
mmol), 7 (24 mg, 0.022 mmol), and lipase PS-D (25 mg) were
(13) Pseudomonas cepacia lipase immobilized on Toyonite. For its
preparation, see: Kamori, M.; Hori, T.; Yamashita, Y.; Horose, Y.;
Naoshima, Y. J . Mol. Catal. B: Enzym. 2000, 9, 269.
(14) (a) Chen, C.-P.; Prasad, K.; Repic, O. Tetrahedron Lett. 1991,
32, 7175. (b) Bar-On, P.; Millard, C. B.; Harel, M.; Dvir, H.; Enz, A.;
Sussman, J . L.; Silman, I. Biochemistry 2002, 41, 3555.
9482 J . Org. Chem., Vol. 67, No. 26, 2002

added to a flask equipped with a grease-free high-vacuum
stopcock. The flask was then degassed under vacuum and
charged with argon, followed by the addition of toluene (1.4 mL).
The reaction flask was subject to degassing under vacuum for
the removal of argon, charged with hydrogen, and then heated
at 70 °C for 3 days. The reaction mixture was cooled to room
temperature, and the catalysts were filtered off. The resulting
filtrate was concentrated and then subjected to flash column
chromatography (silica gel, ethyl acetate/n-hexane ) 1/ 6) to
obtain 6a (96 mg, 0.53 mmol, 95% yield, 98%ee). The optical
purity was determined by HPLC using a chiral column (Whelk-
O1) under the following conditions: hexane/2-propanol ) 90/
10, flow rate 1.0 mL/min, UV 217 nm.
(R)-5-Acetoxy-5,6,7,8-tetr a h yd r o-1-n a p h th ol (6e): [R]20
D
) +123.2° (c ) 2.0, CHCl3, 89% ee); 1H NMR (300 MHz, CDCl3,
ppm) 7.21-7.01 (m, 1H), 6.87 (d, J ) 7.7 Hz, 1H), 6.73 (d, J )
7.8 Hz 1H), 5.98 (q, J ) 3.8 Hz, 1H), 2.87-2.61 (m, 1H), 2.65-
2.41 (m, 1H), 2.09 (s, 3H), 2.01-1.84 (m, 2H), 1.84-1.58 (m, 2H);
13C NMR (300 MHz, CDCl3, ppm) 171.7, 154.0, 136.7, 127.3,
125.2, 122.4, 115.0, 70.7, 29.2, 23.1, 22.2, 18.6; HRMS (EI+)
C12H14O3 calcd 206.0943, found 206.0942.
(R)-5-Bu t a n oyloxy-5,6,7,8-t et r a h yd r o-1-n a p h t h ol (6f):
1
[R]20 ) +103.7° (c ) 2.0, CHCl3, 98% ee); H NMR (300 MHz,
D
CDCl3, ppm) 7.08 (t, J ) 7.8 Hz, 1H), 6.88 (d, J ) 7.7 Hz, 1H),
6.75 (d, J ) 7.9 Hz 1H), 6.02-5.99 (m, 1H), 2.84-2.75 (m, 1H),
2.61-2.51 (m, 1H), 2.33 (t, J ) 7.4 Hz, 2H), 1.98-1.87 (m, 4H),
1.75-1.68 (m, 2H), 0.96 (t, J ) 7.4 Hz, 3H); 13C NMR (300 MHz,
CDCl3, ppm) 174.4, 154.0, 136.8, 127.2, 125.3, 122.2, 114.9, 70.5,
37.4, 29.3, 23.2, 19.3, 18.7, 14.3; HRMS (EI+) C14H18O3 calcd
234.1256, found 234.1252.
(R)-1-Acetoxy-1-(3-h yd r oxyp h en yl)eth a n e (6a ): [R]20
)
D
+108.2° (c ) 1.0, MeOH, 98% ee); 1H NMR (300 MHz, CDCl3,
ppm) 7.20 (t, J ) 7.8 Hz, 1H), 6.89 (d, J ) 7.7 Hz, 1H), 6.82 (s,
1H), 6.72 (dd, J 1 ) 7.9 Hz, J 2 ) 2.5 Hz, 1H), 5.81(q, J ) 6.5 Hz,
1H), 2.07 (s, 3H), 1.50 (d, J ) 6.6 Hz, 3H); 13C NMR (300 MHz,
CDCl3, ppm) 170.8, 155.5, 142.8, 129.3, 117.6, 114.5, 112.7, 72.1,
21.7, 21.0; HRMS (EI+) C10H12O3 calcd 180.0786, found 180.0784.
(R)-2-Acetoxy-4-(4-h yd r oxyp h en yl)bu ta n e (6 g): [R]20
)
D
+6.13° (c ) 2.0, CHCl3, 96% ee); 1H NMR (300 MHz, CDCl3,
ppm) 7.03 (d, J ) 8.4 Hz, 2H), 6.75 (d, J ) 8.5 Hz, 2H), 4.95-
4.89 (m, 1H), 2.61-2.49 (m, 2H), 2.04 (s, 3H), 1.97-1.82 (m, 1H),
1.81-1.73 (m, 1H) 1.24 (d, J ) 6.2 Hz, 3H); 13C NMR (300 MHz,
CDCl3, ppm) 171.9, 154.7, 134.0, 130.0, 116.0, 71.5, 38.4, 31.5,
22.0, 20.7; HRMS (EI+) C12H16O3 calcd 208.1099, found 208.1098.
(R)-1-Bu tan oyloxy-1-(3-h ydr oxyph en yl)eth an e (6b): [R]20
D
1
) +90.7° (c ) 2.0, CHCl3, 98% ee); H NMR (300 MHz, CDCl3,
ppm) 7.20 (t, J ) 7.9 Hz, 1H), 6.91 (d, J ) 7.6 Hz, 1H), 6.82 (s,
1H), 6.76 (dd, J 1 ) 1.7 Hz, J 2 ) 5.5 Hz, 1H), 5.83 (q, J ) 6.6 Hz,
1H), 2.32 (t, J ) 7.4 Hz, 2H), 1.70-1.62 (m, 2H), 1.51 (d, J )
6.6 Hz, 3H), 0.94 (q, J ) 7.3 Hz, 3H); 13C NMR (300 MHz, CDCl3,
ppm) 174.1, 156.5, 144.2, 130.5, 118.8, 115.5, 113.8, 72.7, 37.3,
22.9, 19.1, 14.3; HRMS (EI+) C12H16O3 calcd 208.1099, found
208.1101.
(R)-2-Bu t a n oyloxy-4-(4-h yd r oxyp h en yl)b u t a n e
D
(6h ):
[R]20 ) +2.40° (c ) 2.0, CHCl3, 98% ee); 1H NMR (300 MHz,
CDCl3, ppm) 7.02 (d, J ) 8.4 Hz, 1H), 6.74 (d, J ) 8.4 Hz, 1H),
4.99-4.88 (m, 1H), 2.65-2.50 (m, 2H), 2.28 (t, J ) 7.4 Hz, 3H),
1.97-1.82 (m, 1H), 1.81-1.66 (m, 1H), 1.73-1.60 (m, 2H), 1.24
(d, J ) 6.2, 3H), 0.96 (t, J ) 7.4 Hz, 3H); 13C NMR (300 MHz,
CDCl3, ppm) 174.2, 154.5, 134.3, 130.1, 115.9, 70.9, 38.6, 37.3,
31.6, 20.8, 19.3, 14.4; HRMS (EI+) C14H20O3 calcd 236.1412,
found 236.1413.
(R)-1-Acetoxy-4-h yd r oxyin d a n e (6c): [R]20D ) +92.7° (c )
1
1.0, MeOH, 93% ee); H NMR (300 MHz, CDCl3, ppm) 7.13 (t,
J ) 6.7 Hz, 1H), 7.00 (d, J ) 6.6 Hz, 1H), 6.76 (d, J ) 6.7 Hz,
1H), 6.20 (q, J ) 3.3 Hz, 1H), 3.20-3.00 (m, 1H), 3.00-2.71 (m,
1H), 2.52-2.35 (m, 1H), 2.22-2.01 (m, 1H), 2.08 (s, 3H); 13C
NMR (300 MHz, CDCl3, ppm) 172.2, 152.7, 143.5, 131.0, 128.9,
118.1, 115.7, 78.6, 32.5, 26.9, 21.8; HRMS (EI+) C11H12O3 calcd
192.0786, found 192.0789.
Ack n ow led gm en t. This work was supported by the
Korean Ministry of Science and Technology through the
NRL program and Samsung Fine Chemical Co. We
thank the Korean Ministry of Education for financial
support to our graduate program through the BK21
program.
(R)-1-Bu ta n oyloxy-4-h yd r oxyin d a n e (6d ): [R]20D ) +79.8°
(c ) 2.0, CHCl3, 96% ee); 1H NMR (300 MHz, CDCl3, ppm) 7.12
(t, J ) 7.7 Hz, 1H), 6.98 (d, J ) 7.5 Hz, 1H), 6.76 (d, J ) 7.9 Hz,
1H), 6.22 (q, J ) 3.2 Hz, 1H), 3.09-2.99 (m, 1H), 2.88-2.79 (m,
1H), 2.60-2.47 (m, 1H), 2.30 (t, J ) 7.4 Hz, 2H), 2.15-2.05 (m,
1H), 1.72-1.60 (m, 2H), 0.94 (t, J ) 7.4 Hz, 3H); 13C NMR (300
MHz, CDCl3, ppm) 174.8, 152.9, 144.0, 130.8, 129.1, 118.3, 115.8,
79.1, 37.1, 32.8, 27.1, 19.2, 14.3; HRMS (EI+) C13H16O3 calcd
220.1099, found 220.1102.
J O026122M
J . Org. Chem, Vol. 67, No. 26, 2002 9483