Highly enantioselective dynamic kinetic resolution of 1,2-diarylethanols by a lipase-ruthenium couple

Article abstract of DOI:10.1021/ol800163z

A practical procedure has been developed for the dynamic kinetic resolution of 1,2-diarylethanols. This procedure employs a highly enantioselective lipase from Pseudomonas stutzeri (trade name, lipase TL) as the resolution catalyst and a ruthenium complex as the racemization catalyst. Sixteen 1,2-diarylethanols have been efficiently resolved to provide their acetyl derivatives with good yields (95-97%) and high enantiomeric excesses (96-99%).

Full text of DOI:10.1021/ol800163z

ORGANIC
LETTERS
2008
Vol. 10, No. 6
1295-1298
Highly Enantioselective Dynamic Kinetic
Resolution of 1,2 Diarylethanols by a
Lipase Ruthenium Couple
−
−
Mahn-Joo Kim,* Yoon Kyung Choi, Sol Kim, Daeho Kim, Kiwon Han,
Soo-Byung Ko, and Jaiwook Park*
Department of Chemistry, Pohang UniVersity of Science and Technology (POSTECH),
San-31 Hyojadong, Pohang 790-784, Korea
mjkim@postech.ac.kr; pjw@postech.ac.kr
Received January 23, 2008
ABSTRACT
A practical procedure has been developed for the dynamic kinetic resolution of 1,2-diarylethanols. This procedure employs a highly
enantioselective lipase from Pseudomonas stutzeri (trade name, lipase TL) as the resolution catalyst and a ruthenium complex as the racemization
catalyst. Sixteen 1,2-diarylethanols have been efficiently resolved to provide their acetyl derivatives with good yields (95
enantiomeric excesses (96 99%).
−97%) and high
−
Optically pure 1,2-diarylethanols are pharmaceutically in-
teresting as a result of the great potential of combretastatin
(1) and analogs as anti-cancer agents.1 We herein wish to
report a novel procedure for their enantioselective synthesis,
in which their racemic forms are converted to desirable single
enantiomers via enzyme/metal-catalyzed dynamic kinetic
resolution.
Dynamic kinetic resolution (DKR) provides a practical
method for the conversion of racemic substrates to single
enantiomeric products. In the past decade, we and others have
developed a new approach using two different types of
catalyst systems, enzyme and metal, in combination for
efficient DKR.2 For example, the DKR of racemic secondary
alcohols can be accomplished with lipase-Ru combina-
tions.3,4 Here, lipase acts as an enantioselective resolution
catalyst and Ru complex as a racemization catalyst for the
(1) (a) Petit, G. R.; Cragg, G. M.; Herald, D. L.; Schmidt, J. M.;
Lohavanijaya, P. Can. J. Chem. 1982, 60, 1374-1376. (b) Petit, G. R.;
Singh, S. B.; Cragg, G. M. J. Org. Chem. 1985, 50, 3404-3406. (c)
Ramacciotti, A.; Fiaschi, R.; Napolitano, E. Tetrahedron: Asymmetry 1996,
7, 1101-1104. (d) Cirla, A.; Mann, J. Nat. Prod. Rep. 2003, 20, 558-564.
(2) For reviews, see: (a) Kim, M.-J.; Ahn, Y.; Park, J. Curr. Opin.
Biotechnol. 2002, 13, 578-587. (b) Pamies, O.; Ba¨ckvall, J.-E. Chem. ReV.
2003, 103, 3247-3262. (c) Kim, M.-J.; Ahn, Y.; Park, J. Bull. Kor. Chem.
Soc. 2005, 26, 515-522. (d) Kim, M.-J.; Park, J.; Ahn, Y. In Biocatalysis
in the Pharmaceutical and Biotechnology Industries; Patel, R. N., Ed.; CRC
Press: Boca Raton, FL, 2007; pp 249-272. (e) Mart´ın-Matute, B.; Ba¨ckvall,
J.-E. Curr. Opin. Chem. Biol. 2007, 11, 226-232.
Figure 1. Structure of combretastatin.
10.1021/ol800163z CCC: $40.75
© 2008 American Chemical Society
Published on Web 02/28/2008

complete conversion of racemic alcohols to single enantio-
meric acyl derivatives (Scheme 1). To date, most studies have
2), this enzyme displayed a high enantioselectivity (E > 200)
toward 1,2-diphenylethanol 2a.8
Scheme 2. PSL-Catalyzed Transesterification of
Scheme 1. Dynamic Kinetic Resolution of Secondary
1,2-Diarylethanols
Alcohols
been done to find efficient racemization catalysts, while few
studies have been done to find highly enantioselective
enzymes for new applications. The enzyme most frequently
employed in the previous DKR processes is Candida
antarctica lipase B (CALB; trade name, Novozym-435),
which accepts a limited range of secondary alcohols carrying
one small (up to three carbon unit) and one significantly
larger substituent at the hydroxymethine center with high
enantioselectivity.5 Accordingly, the enzyme is inapplicable
to 1,2-diarylethanols with two bulky substituents at the
hydroxymethine center.
Through screening experiments, we found that Pseudo-
monas stutzeri lipase (PSL; trade name,6 lipase TL) is highly
enantioselective toward 1,2-diarylethanols.7 In the trans-
esterification reactions carried out in the presence of iso-
propenyl acetate in toluene at room temperature (Scheme
(3) (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) Kim, M.-J.;
Chung, Y. I.; Choi, Y. K.; Lee, H. K.; Kim, D.; Park, J. J. Am. Chem. Soc.
2003, 125, 11494-11495. (c) 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. (d) Akai, S.; Tanimoto, K.; Kita, Y. Angew. Chem., Int. Ed. 2004,
43, 1407-1410. (e) Mart´ın-Matute, B.; Edin, M.; Boga´r, K.; Ba¨ckvall, J.-
E. Angew. Chem., Int. Ed. 2004, 43, 6535-6539. (f) Kim, M.-J.; Kim, H.
M.; Kim, D. H.; Park, J. Green Chem. 2004, 6, 471-474. (g) Kim, N.; Ko,
S.-B.; Kwon, M. S.; Kim, M.-J.; Park, J. Org. Lett. 2005, 7, 4523-4526.
(h) Mart´ın-Matute, B.; Edin, M.; Boga´r, K.; Kaynak, F. B.; Ba¨ckvall, J.-E.
J. Am. Chem. Soc. 2005, 127, 8817-8825. (i) Ko, S.-B.; Baburaj, B.; Kim,
M.-J.; Park, J. J. Org. Chem. 2007, 72, 6860-6864. (j) Kim, M.-J.; Lee,
H. K.; Park, J. Bull. Kor. Chem. Soc. 2007, 28, 2096-2098. (k) Boga´r, K.;
Vidal, P. H.; Leo´n, A. R. A.; Ba¨ckvall, J.-E. Org. Lett. 2007, 9, 3401-
3404.
Such a high level of enantioselectivity was also observed
with its analogues 2b-o, in which one of two phenyl rings
is monosubstituted at the meta or para position (entries
2-15, Table 1). The ring substituent varies from a small (F,
Table 1. Enantioselectivity in PSL-Catalyzed
Transesterification
entry
alcohol
Ea
entry
alcohol
Ea
(4) For DKR of secondary alcohols with other enzyme-metal couples,
see: (a) Dinh, P. M.; Howarth, J. A.; Hudnott, A. R.; Williams, J. M. J.;
Harris, W. Tetrahedron Lett. 1996, 37, 7623-7626. (b) Wuyts, S.; De
Temmerman, K.; De Vos, D. E.; Jacobs, P. A. Chem. Eur. J. 2005, 11,
386-397. (c) Akai, S.; Tanimoto, K.; Kanao, Y.; Egi, M.; Yamamoto, T.;
Kita, Y. Angew. Chem., Int. Ed. 2006, 45, 2592-2595, (d) Berkessel, A.;
Sebastian-Ibarz, M. L.; Mu¨ller, T. N. Angew. Chem., Int. Ed. 2006, 45,
6567-6570. (e) Wuyts, S.; Wahlen, F. J.; Jacobs, P. A.; De Vos, D. E.
Green Chem. 2007, 9, 1104-1108.
1
2
3
4
5
6
7
8
9
2a
2b
2c
2d
2e
2f
2g
2h
2i
>200
>200
>200
>200
200
>200
>200
>200
164
10
11
12
13
14
15
16
17
18
2j
2k
2l
2m
2n
2o
2p
2q
2r
>200
>200
>200
>200
>200
>200
166
(5) Kazlauskas, R. J.; Weissfloch, A. N. E.; Rappaport, A. T.; Cuccia,
L. A. J. Org. Chem. 1991, 56, 2656-2665.
38
8
(6) Commercially available from Meito Sangyo, Japan (MW, 27000;
specific activity, ca. 650 U/g for p-nitrophenyl acetate).
a The E values indicating the enantioselectivity, the ratio in reactivity
between two enantiomers of alcohol, are obtained using the equation: E )
ln[1 - c(1 + eep)]/ln[1 - c(1 - eep)], where c ) ees/(ees + eep).10
(7) For recent studies on PSL-catalyzed resolution of secondary alcohols,
see: (a) Aoyagi, Y.; Agata, N.; Shibata, N.; Horiguchi, M.; Williams, R.
M. Tetrahedron Lett. 2000, 41, 10159-10162. (b) Aoyagi, Y.; Iijima, A.;
Williams, R. M. J. Org. Chem. 2001, 66, 8010-8014. (c) Aoyagi, Y.; Saitoh,
Y.; Ueno, T.; Horiguchi, M.; Takeya, K.; Williams, R. M. J. Org. Chem.
2003, 68, 6899-6904. (d) Demir, A. S.; Findik, H.; Ko¨se, E. Tetrahedron:
Asymmetry 2004, 15, 777-781. (e) Kato, K.; Gong, Y.; Saito, T.; Yokogawa,
Y. J. Mol. Catal. B: Enzym. 2004, 30, 61-68. (f) Moore, B. D.; Stevenson,
L.; Watt, A.; Flitsch, S.; Turner, N. J.; Cassidy, C.; Grahan, D. Nat.
Biotechnol. 2004, 22, 1133-1138. (g) Gill, I. I.; Das, J.; Patel, R. N.
Tetrahedron: Asymmetry 2007, 18, 1330-1337. (h) Mart´ınez, I.; Markovits,
A.; Chamy, R.; Markovits, A. Appl. Biochem. Biotechnol. 2004, 112, 55-
62. (i) Shoji, M.; Kishida, S.; Takeda, M.; Kakeya, H.; Osada, H.; Hayashi,
Y. Tetrahedron Lett. 2002, 43, 9155-9158.
Me, OMe, and iPr) to a significantly larger group (OPh).
Interestingly, the change in the size and position of the
(8) To the best of our knowledge, this is the highest enantioselectivity
of a lipase so far reported with 2a. A low enantioselectivity (E ) 6) toward
2a was previously reported for lipase PS. Ema, T.; Kageyama, M.; Korenaga,
T.; Sakai, T. Tetrahedron: Asymmetry 2003, 14, 3943-3947.
1296
Org. Lett., Vol. 10, No. 6, 2008

substituent did not affect the enantioselectivity seriously. For
example, compare 2b-d with 2i-k (entries 2-4 and 9-11)
and 2e-h with 2l-o (entries 5-8 and 12-15). All of them
except 2i were accepted with the same level of high
enantioselectivity (E > 200). A slightly lower but still high
level of enantioselectivity was observed for 2i (E ) 164).
The replacement of a phenyl ring by another aromatic ring
in 2a was acceptable for high enantioselectivity as observed
for 2p (E ) 166, entry 16).
M), PSL (24 mg, 120 mg/mmol of substrate), 5 (0.016
mmol), isopropenyl acetate (0.3 mmol), K2CO3 (0.2 mmol),
toluene (0.65 mL), room temperature, 3 days. The results
are given in Table 2. In all cases, almost quantitative yields
Table 2. DKR of 1,2-Diarylethanols with PSL and 5a
On the contrary, the enzymatic enantioselectivity was
dramatically reduced toward 1,3-diphenyl-1-propanol 2q (E
) 38) and further reduced toward 1,4-diphenyl-2-butanol 2r
(E ) 8) (entries 17 and 18). These results indicate that proper
positioning of each aromatic ring around the hydroxymethine
center is essential for high enantioselectivity. Overall, all of
the observations clearly indicate that PSL could serve as the
efficient resolution catalyst for the DKR of 1,2-diaryl-
ethanols.9
As the racemization catalyst for DKR, we initially tested
air-stable 4, which had previously showed a good perfor-
mance in the DKR with Novozym-435,3g but later we found
its new analogue 5 was similarly good in both activity and
air stability but more practical to synthesize. The synthesis
of 5 was achieved by two different methods. The first method
is the reaction of 6 with benzoyl chloride in toluene at 80
°C, which was completed in 6 h with 95% yield.10 The
second is the reaction of 7 with benzoyl chloride in toluene
at room temperature, which reached completion within only
2 h to afford 92% yield.11 In contrast to these methods, the
synthesis of 4 required a long reaction time (5 days) even at
high reaction temperature (110 °C) for a moderate yield
(65%).3g
entry
alcohol
isolated yield (%)
optical purity (% ee)b
1
2
3
4
5
6
7
8
2a
2b
2c
2d
2e
2f
2g
2h
2i
2j
2k
2l
2m
2n
2o
2p
98
96
97
99
98
97
96
95
95
96
99
96
98
95
97
97
98
98
97
96
97
97
99
99
98
98
99
98
98
96
99
98
9
10
11
12
13
14
15
16
a Reaction conditions: alcohol (0.2 mmol, 0.3 M), enzyme (24 mg, 120
mg/mmol of substrate), 5 (0.016 mmol), isopropenyl acetate (0.3 mmol),
K2CO3 (0.2 mmol), toluene (0.65 mL), room temperature, 3 days. b Optical
purities were determined by HPLC using a chiral column ((R,R) Whelk-
O1).
(95-99%) were obtained with excellent enantiomeric ex-
cesses (96-99% ee). The patterns of HPLC chromatograms
taken for measuring the ee values of the products suggested
that all of the products should have the same absolute
configuration. We have assigned it as R by comparing the
optical rotation of an acetylated product 3a with the literature
value.12 These results thus indicate that all the DKR reactions
proceeded efficiently to give desirable single enantiomeric
products.
Figure 2. Ru complexes.
The conversion of the acetylated products to the corre-
sponding optically active alcohols can be readily achieved
by basic hydrolysis. As a representative example, 3a (98%
ee) was deacetylated with K2CO3 in MeOH-H2O to give
(R)-2a quantitatively without loss in enantiomeric excess.13
In summary, we have demonstrated for the first time that
1,2-diarylethanols are efficiently resolved by PSL in kinetic
and dynamic kinetic resolutions. Their DKR reactions by
the combination of PSL and 5 are straightforward and
The DKR reactions with PSL and 5 were carried out under
the conditions optimized for 2a: substrate (0.2 mmol, 0.3
(9) Lately, a group from Spain reported the use of PSL (lipase TL) in
the DKR of benzoins. (a) Hoyos, P.; Ferna´ndez, M.; Sinisterra, J. V.;
Alca´ntara, A. J. Org. Chem. 2006, 71, 7632-7637. (b) Hoyos, P.; Buthe,
A.; Ansorge-Schumacher, M. B.; Sinisterra, J. V.; Alca´ntara, A. R. J. Mol.
Catal. B: Enzym. 2007, in press (doi:10.1016/j.molcatb.2007.10.009).
(10) Chen, C.-S.; Fujimoto, Y.; Girdaukas, G.; Sih, C. J. J. Am. Chem.
Soc. 1982, 104, 7294-7299.
(11) Ruthenium complexes 6 and 7 were prepared according to the known
procedures. (a) Mays, M. J.; Morris, M. J.; Raithby, P. R.; Shvo, Y.; Czarkie,
D. Organometallics 1989, 8, 1162-1167. (b) Blum, Y.; Czarkle, D.;
Rahamlm, Y.; Shvo, Y. Organometallics 1985, 4, 1459-1461. (c) Kim,
N. Studies on Recyclable Racemization Catalysts for Dynamic Kinetic
Resolution of Secondary Alcohols, Ph.D. Thesis, Pohang University of
Science and Technology, Pohang, 2005.
(12) [R]25 ) +21.8 (c 1.0, CHCl3, 98% ee), (lit.8 [R]15 ) +14.0 (c
D
D
0.5, CHCl3, 66% ee).
(13) (R)-2a (white solid, 98% yield, 98% ee): mp 69-70 °C (lit.14 66-
70 °C); [R]25D ) -53.8 (c 1.0, EtOH) (lit.14 [R]23D ) -52.9 (c 1.0, EtOH,
>98% ee).
(14) David, C.; Paul, H.; Julian, P. H.; Ian, C. L.; Graham, M.; Paul,
M.; Christopher, J. P.; James, A. R.; Simon, W.; Antonio, Z.-G. Org. Proc.
Res. DeV. 2003, 7, 89-94.
Org. Lett., Vol. 10, No. 6, 2008
1297

provide high yields and excellent optical purities, both
approaching 100%. The procedure thus can serve as a
protocol for the synthesis of a wide range of enantiopure
1,2-diarylethanols. Further studies for the application of this
protocol to 1 and close analogues are in progress.
2006-000-10696-0) and by the Korean Ministry of Education
and Human Resources through KRF (BK21 program and
KRF-2006-311-C00089).
Supporting Information Available: Experimental pro-
cedures for kinetic and dynamic kinetic resolution and
analytical data of products. This material is available free
of charge via the Internet at http://pubs.acs.org.
Acknowledgment. This work was supported by the
Korean Ministry and Science and Technology through
KOSEF (Center for Integrated Molecular System and R01-
OL800163Z
1298
Org. Lett., Vol. 10, No. 6, 2008