Dynamic kinetic resolution of benzoins by lipase-metal combo catalysis

Article abstract of DOI:10.1021/jo061060b

(Chemical Equation Presented) The synthesis of some noncommercial racemic 1,2-diaryl-2-hydroxyethanones (benzoins) is described, optimizing the previously reported methodologies. In a further step, the kinetic resolution of these substrates is reported, obtaining conversions of around 50% and ee_p higher than 99% in very short reaction times. As enzymatic catalyst, after screening of several enzymes, the lipase TL (from Pseudomonas stutzeri) was the most efficient, working in an organic solvent with a very low log P value, such as THF. Finally, the dynamic-kinetic resolution of different benzoins using a lipase-ruthenium-catalyzed transesterification in organic solvents is described for the first time, obtaining conversions up to 90% maintaining the excellent enantioselectivity in all cases.

Full text of DOI:10.1021/jo061060b

Dynamic Kinetic Resolution of Benzoins by Lipase-Metal Combo
Catalysis
Pilar Hoyos,† Mar´ıa Ferna´ndez,† Jose´ Vicente Sinisterra,†,‡ and Andre´s R. Alca´ntara*,†,‡
Grupo de Biotransformaciones, Dpto Qu´ımica Orga´nica y Farmace´utica, Facultad Farmacia, UniVersidad
Complutense, Plaza Ramo´n y Cajal s/n, E-28040 Madrid, Spain, and SerVicio de Biotransformaciones
Industriales, Parque Cient´ıfico de Madrid, Pol´ıgono Industrial Zona Oeste, Complejo BP Solar,
E-28760 Tres Cantos, Madrid, Spain
andalcan@farm.ucm.es
ReceiVed May 24, 2006
The synthesis of some noncommercial racemic 1,2-diaryl-2-hydroxyethanones (benzoins) is described,
optimizing the previously reported methodologies. In a further step, the kinetic resolution of these substrates
is reported, obtaining conversions of around 50% and eep higher than 99% in very short reaction times.
As enzymatic catalyst, after screening of several enzymes, the lipase TL (from Pseudomonas stutzeri)
was the most efficient, working in an organic solvent with a very low log P value, such as THF. Finally,
the dynamic-kinetic resolution of different benzoins using a lipase-ruthenium-catalyzed transesterification
in organic solvents is described for the first time, obtaining conversions up to 90% maintaining the excellent
enantioselectivity in all cases.
Introduction
the synthesis of different heterocycles.6 These compounds are
generally obtained through benzoin condensation, one of the
most traditional C-C bond-forming reactions in organic chem-
istry, which uses a nonchiral catalyst such as cyanide,7 thiamine,8
or other chiral thiazolium and triazolium salts in a biomimetic
manner.9 Chiral benzoins can also be obtained enzymatically
by the enantioselective benzoin or acyloin condensation cata-
lyzed by thiamine diphosphate dependent enzymes:10 pyruvate
decarboxylase (PDC), benzoylformate decarboxylase (BFD), and
Optically pure R-hydroxy ketones are important structural
units for many drugs and natural products, such as the
antidepressant bupropion and its metabolites,1 a component of
indinavir (inhibitor of HIV protease2), some antitumoral anti-
biotics such as olivomycin A and chromomycin A3,3 or some
inhibitors of amyloid-â protein production, useful in the
treatment of Alzheimer’s disease.4
Benzoins (1,2-diaryl-2-hydroxyethanone structures) are par-
ticularly useful as urease inhibitors5 or as building blocks for
(5) Tanaka, T.; Kawase, M.; Tani, S. Bioorg. Med. Chem. 2004, 12, 501-
505.
* To whom correspondence should be addressed. Phone: +34-91-3941820.
Fax: +34-91-3941822. Web page: www.biotransformaciones.com.
† Universidad Complutense.
(6) (a) Pei, W. W.; Li, S. H.; Nie, X. P.; Li, Y. W.; Pei, J.; Chen, B. Z.;
Wu, J.; Ye, X. L. SynthesissStuttgart 1998, 1298-1304. (b) Abdou, W.
M.; El-Khoshnieh, Y. O.; Kamel, A. A. Heteroatom Chem. 1999, 10, 481-
487. (c) Mohan, J.; Khatter, D. Ind. J. Heterocycl. Chem. 2002, 12, 45-
48. (d) Wildemann, H.; Dunkelmann, P.; Muller, M.; Schmidt, B. J. Org.
Chem. 2003, 68, 799-804. (e) Singh, M. S.; Singh, A. K. Synthesiss
Stuttgart 2004, 6, 837-839.
(7) (a) Correia, J. J. Org. Chem. 1983, 48, 3343-3344. (b) Breslow, R.
Acc. Chem. Res. 2004, 37, 471-478.
(8) Hanson, R. W. J. Chem. Educ. 1993, 70, 257-257.
(9) Enders, D.; Kallfass, U. Ang. Chem., Int. Ed. 2002, 41, 1743-1745.
‡ Pol´ıgono Industrial Zona Oeste.
(1) Fang, Q. K.; Han, Z.; Grover, P.; Kessler, D.; Senanayade, C. H.;
Wald, S. A. Tetrahedron: Asymmetry 2002, 11, 3659-3663.
(2) Kajiro, H.; Mitamura, S.; Mori, A.; Hiyama, T. Tetrahedron:
Asymmetry 1998, 9, 907-910.
(3) Roush, W. R.; Briner, K.; Kesler, B. S.; Murphy, M.; Gustin, D. J.
J. Org. Chem. 1996, 61, 6098-6099.
(4) Wallace, O. B.; Smith, D. W.; Deshpande, M. S.; Polson, C.;
Felsenstein, K. M. Bioorg. Med. Chem. Lett. 2003, 13, 1203-1206.
10.1021/jo061060b CCC: $33.50 © 2006 American Chemical Society
Published on Web 09/07/2006
7632
J. Org. Chem. 2006, 71, 7632-7637

Dynamic Kinetic Resolution of Benzoins
TABLE 1. Substrates of the Enzymatic Kinetic Resolution
substrates
products
1a
1b
Ar ) Ph
(R)-(-)-1a
(R)-(-)-1b
(S)-(+)-2a: Ar ) Ph; R ) -CH3
(S)-(+)-2b: Ar ) Ph; R ) -C3H7
Ar ) 2-furanyl
(S)-(+)-2c: Ar ) 2-furanyl; R ) -CH3
(S)-(+)-2d: Ar ) 2-furanyl; R ) -C3H7
(S)-(+)-2e: Ar ) 3-furanyl; R ) -CH3
(S)-(+)-2f: Ar ) 2-thienyl; R ) -CH3
(S)-(+)-2g: Ar ) 2-thienyl; R ) -C3H7
(S)-(+)-2h: Ar ) 3-thienyl; R ) -C3H7
(S)-(+)-2i: Ar ) 4-MeOC6H4-; R ) -C3H7
(S)-(+)-2j: Ar ) 4-EtOC6H4-; R ) -C3H7
1c
1d
Ar ) 3-furanyl
Ar ) 2-thienyl
(R)-(-)-1c
(R)-(-)-1d
1e
1f
1g
Ar ) 3-thienyl
Ar ) 4-MeOC6H4
Ar ) 4-EtOC6H4
(R)-(-)-1e
(R)-(-)-1f
(R)-(-)-1g
benzaldehyde lyase (BAL). Other biocatalytical methods for the
synthesis of enantiomerically pure benzoins are the enantiose-
lective reduction of R-diketones11 and the fungal deracemiza-
tion12 or lipase-catalyzed kinetic resolution of racemic benzoin.13
enantioselective acylation, as well as the combination of this
process with a ruthenium-catalyzed substrate racemization,
obtaining the homochiral acylated products in higher yields
through a DKR process.
Despite the progress in asymmetric synthesis, the dominant
production method to obtain a single enantiomer in industrial
synthesis is based on the kinetic resolution of racemates.14
However, an important drawback of kinetic resolutions (KR)
is the intrinsic limitation of the maximum theoretical yield at
50%. Under some circumstances, it is possible to obtain a yield
of 100% by carrying out substrate racemization under the
resolution conditions in a dynamic kinetic resolution (DKR)
process.15 For this purpose, one of the best methods to obtain
enantiomerically pure secondary alcohols is to combine an
enzymatic resolution with a transition-metal-mediated catalyzed
racemization via hydrogen transfer.16 Nevertheless, the first basic
requirement for an efficient DKR is to identify an effective KR.
Thus, in this work we report both a convenient enzymatic kinetic
resolution of racemic benzoins by means of a lipase-catalyzed
Results and Discussion
Some of the substrates employed in the enzymatic resolution
(shown in Table 1), such as benzoin (1a), 2-furoin (1b), and
4,4′-dimethoxybenzoin (1f), are commercially available. 3-Fu-
roin (1c) and 4,4′-diethoxybenzoin (1g) were synthesized
following the methodology previously described by our group.10e
2,2′-Thenoin (1d) and 3,3′-thenoin (1e) were also synthesized
following a classical benzoin condensation through a more
simple procedure than that described by Roberts-Bleming et
al.,17 reaching similar yields as those described but employing
a much easier workup protocol, as described in the Experimental
Section.
The racemic acylated products were also chemically synthe-
sized in order to identify the kinetic resolution products by
comparison with their HPLC retention times and UV spectra,
except those esters of 3-furoin (1c), as their extreme lability, as
described,10e avoids the preparation of the standards.
Various commercial lipase preparations, either immobilized
or crude enzyme powder, were tested for the transesterification
process, using racemic benzoin 1a as the standard substrate.
The lipases were tested using different solvents and tempera-
tures, and vinyl acetate as acyl donor, following the methodology
described by Aoyagi et al.13b Because of the low solubility of
1a in the low polarity organic solvents usually employed in
lipase-catalyzed transesterifications, some different lipase prepa-
rations (immobilized lipases from Candida antarctica B, Ther-
momyces laenuginosus, and Rhizomucor miehei, lipase from
Pseudomonas cepacia, and Lipase TL from Pseudomonas
stutzeri) were tested in tBuOMe, chloroform, and THF, solvents
with a low value of log P (lower than 2), which are generally
considered harmful for the lipase catalysis.18
(10) (a) Demir, A. S.; Du¨nwald, T.; Iding, H.; Pohl, M.; Mu¨ller, M.
Tetrahedron: Asymmetry 1999, 10, 4769-4774. (b) Demir, A. S.; Pohl,
M.; Janzen, E.; Mu¨ller, M. J. Chem. Soc., Perkin Trans. 1 2001, 633-635.
(c) Demir, A. S.; Sesenoglu, O¨ .; Eren, E.; Hosrik, B.; Pohl, M.; Janzen, E.;
Kolter, D.; Feldmann, R.; Du¨nkelmann, P.; Mu¨ller, M. AdV. Synth. Catal.
2002, 344, 96-103. (d) Dunkelmann, P.; Kolter-Jung, D.; Nitsche, A.;
Demir, A. S.; Siegert, P.; Lingen, B.; Baumann, M. J. Am. Chem. Soc.
2002, 124, 12084-12085. (e) Hischer, T.; Gocke, D.; Ferna´ndez, M.; Hoyos,
P.; Alca´ntara, A. R.; Sinisterra, J. V.; Hartmeier, W.; Ansorge-Schumacher,
M. B. Tetrahedron 2005, 61, 7378-7383. (f) Dom´ınguez de Mar´ıa, P.;
Stillger, T.; Pohl, M.; Wallert, S.; Drauz, K.; Gro¨ger, H.; Trauthwein, H.;
Liese, A. J. Mol. Catal. B: Enzym. 2006, 38, 43-47.
(11) (a) Buisson, D.; Baba, S. E.; Azerad, R. Tetrahedron Lett. 1986,
27, 4453-4454. (b) Maruyama, R.; Nishizawa, M.; Itoi, Y.; Ito, S.; Inoue,
M. J. Biotechnol. 2002, 94, 157-169. (c) Saito, T.; Maruyama, R.; Ono,
S.; Yasukawa, N.; Kodaira, K.; Nishizawa, M.; Ito, S.; Inoue, M. Appl.
Biochem. Biotechnol. 2003, 111, 185-190. (d) Mahmoodi, N. O.; Moham-
madi, H. G.. Monatsh. Chem. 2003, 134, 1283-1288. (e) Demir, A. S.;
Hamamci, H.; Ayhan, P.; Duygu, A. N.; Igdir, A. C.; Capanoglu, D.
Tetrahedron: Asymmetry 2004, 15, 2579-2582.
(12) Demir, A. S.; Hamamci, H.; Sesenoglu, O.; Neslihanoglu, R.;
Asikoglu, B.; Capanoglu, D. Tetrahedron Lett. 2002, 43, 6447-6449.
(13) (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.
(14) . Ghanem, A.; Aboul-Enein, H. Y. Chirality 2005, 17, 1-15 and
references therein.
(15) (a) Stecher, H.; Faber, K. Synthesis 1997, 1-17. (b) El Gihani, M.
T.; Williams, J. M. J. Curr. Opin. Biotechnol. 1999, 3, 11-15. (c) Faber,
K. Chem. Eur. J. 2001, 7, 5004-5010. (d) Pa´mies, O.; Ba¨ckvall, J. E. Trends
Biotechnol. 2004, 22, 130-135.
(16) (a) Kim, M. J.; Ahn, Y.; Park, J. Curre. Opin. Biotechnol. 2002,
13, 578-587. (b) Kim, M. J.; Chung, Y.; Choi, Y. K.; Lee, H. K.; Kim,
D.; Park, J. J. Am. Chem. Soc. 2003, 125, 11494-11495. (c) Pa´mies, O.;
Ba¨ckvall, J. E. Curr. Opin. Biotechnol. 2003, 14, 407-413. (d) Mart´ın-
Matute, B.; Edin, M.; Boga´r, K.; Ba¨ckvall, J. E. Angew. Chem., Int. Ed.
2004, 43, 6535-6539. (e) Mart´ın-Matute, B.; Edin, M.; Boga´r, K.; Kaynak,
F. B.; Ba¨ckvall, J. E. J. Am. Chem. Soc. 2005, 127, 8817-8825.
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Org. Chem. 2003, 68, 7115-7118.
J. Org. Chem, Vol. 71, No. 20, 2006 7633

Hoyos et al.
TABLE 2. Ps. stutzeri Lipase-Catalyzed Kinetic Resolution of
1,2-diphenylethyl butyrate, Table 1, 2b) was much easier to
purify from the reaction mixture by column chromatography.
These findings suggest that vinyl butyrate is the most convenient
acyl donor.
Different Benzoinsa
In a second step, the effect of temperature on the KR of 1a
was studied. The results in Table 2 (entries 3-5) show that the
conversion rate increased when the reaction temperature was
raised, maintaining in all cases the excellent enantioselectivity
observed. The most favorable temperature for this substrate was
50 °C because of the highest yield and eep values obtained at a
really short reaction time (4 h). This optimal temperature value
agrees with the one provided by the supplier,23 although when
the enzyme stability at 50 °C was tested by incubation in the
reaction medium a moderate decrease in the lipase activity was
observed after 4 h (data not shown).
The KR of some other racemic benzoins (1b-1g, Table 1)
was carried out in a similar way, and different acylating agents
and temperatures were tested in each case. The results in Table
2 (entries 6-17) show excellent conversions and enantioselec-
tivity, except for the kinetic resolution of 3,3′-furoin (1c), which
once again showed a remarkable tendency toward racemization.10e
In fact, it is well-known that benzoins are prone to suffer from
auto-oxidation process leading to the corresponding dicarbonyl
compounds.24 This process is favored by the presence of bases
because the enediolate intermediate is more sensitive to oxida-
tion.25 On the other hand, this side reaction is even more severe
for substrates possessing electron-rich aromatic rings,26 which
are very easily oxidized, particularly at high temperatures. In
some cases, e.g., for 1b and 1c, although the enzyme activity
is higher at 50 °C, this temperature should not be used as a
greater percentage of substrate is oxidized. Nevertheless, in most
cases, the exceptional catalytic behavior of Lipase TL at high
temperature made possible the kinetic resolution at a reaction
rate which is higher than that of the collateral oxidation, so that
excellent conversions and enantioselectivities were reached in
a very short reaction time (4-6 h).
b
T
convb reaction eep
entry substrate
acyl donor
(°C) (%) time (h) (%)
E
1
2
3
4
5
6
7
8
9
11
12
13
14
15
16
17
18
1a
1a
1a
1a
1a
1b
1b
1b
1c
1d
1d
1d
1e
1e
1f
vinyl acetate
rt
50
45
49
49
50
45
48
49
43
27
29
43
42
49
49
49
35
30
24
24
4
>99 >200
>99 >200
>99 >200
>99 >200
>99 >200
95
95
95
51
84
94
>99 >200
94 66
>99 >200
>99 >200
>99 >200
>99 >200
vinyl butyrate rt
vinyl butyrate 37
vinyl acetate
vinyl butyrate 50
vinyl acetate rt
50
4
24
24
24
24
24
24
6
24
6
6
92
113
125
4
15
47
vinyl butyrate rt
vinyl butyrate 37
vinyl acetate
vinyl acetate
rt
rt
vinyl butyrate 37
vinyl butyrate 50
vinyl butyrate rt
vinyl butyrate 50
vinyl butyrate 50
vinyl butyrate 50
1g
1a
6
24
trifluoroethyl
butyrate
50
a Reaction conditions: 0.47 mmol of 1 was dissolved in 5 mL of THF,
and Lipase TL (20 mg/mL) and the acyl donor (6 equiv) were added under
inert atmosphere. b Determined by HPLC analysis using Chiralcel OD
column.
Only Lipase TL showed activity in this process, as was
described by Aoyagi et al.,13b and no conversion was detected
for the other enzymatic preparations. Lipase from Pseudomonas
stutzeri has been frequently included in previous screenings for
searching the best catalyst in the resolution of different
compounds,19 but very few papers describe this uncommon
enzyme as the best for transesterification processes.13a,b,20 The
kinetic resolution of 1a catalyzed by Lipase TL in THF was
carried out under different experimental conditions, as shown
in Table 2 (entries 1-5).
Although the resolution in entry 1 is much better than that
published by Aoyagi et al.13b (only a 40% yield after 42 h, no
eep data reported), it is necessary to further improve the
efficiency of the KR in order to have an optimal starting point
for an ulterior DKR. As it has been shown that the structure of
the acyl donor influences the catalytic efficiency of the
lipase,21,22 vinyl butyrate was tested as acyl donor, and this gave
an excellent behavior at a slightly lower reaction time (24 h,
Table 2, entry 2). Furthermore, the reaction product ((S)-2-oxo-
After reaching the maximum conversion for each case, the
optically pure products 2a-c,g-j were purified by silica gel
column chromatography, and the optical rotations were mea-
sured. The absolute configurations of the acylated product of
1a (2a and 2b), 1b (2c), 1d (2g), and 1f (2i) were assigned to
be S, according to a correlation of the positive optical rotations
values of the benzoins with data from the literature10c,27 and to
HPLC data of the standards. Consequently, the absolute
configuration of 2h and 2j was assigned assuming a uniform
reaction mechanism.
For this substrate, according to Kazlauskas’ rule,28 which
predicts the enantiomer that will be preferentially converted by
(21) (a) Armesto, N.; Ferrero, M.; Ferna´ndez, S.; Gotor, V. J. Org. Chem.
2002, 67, 4978. (b) Ardhaoui, M.; Falcimaigne, A.; Ognier, S.; Engasser,
J. M.; Moussou, P.; Pauly, G.; Ghoul, M. Biotechnol. 2004, 110, 265. (c)
Kroutil, W.; Hagmann, L.; Schuez, T. C.; Jungmann, V.; Pachlatko, J. P.
J. Mol. Catal. B: Enzymol. 2005, 32, 247.
(22) Faber, K. Biotransformations in Organic Chemistry, 5th ed.;
Springer: Berlin, 2004.
(18) (a) Carrea, G.; Riva, S., Angew. Chem., Int. Ed. 2000, 39, 2226-
2254. (b) Hari Krishna, S.; Divakar, S.; Prapulla, S. G.; Karanth, N. G. J.
Biotechnol. 2001, 87, 193-201. (c) Sonwalkar, R. D.; Chen, C. C.; Ju, L.
K. Bioresour. Technol. 2003, 87, 69-73. (d) Suan, C. L.; Sarmidi, M. R.,
J. Mol. Catal. B: Enzym. 2004, 28, 111-119.
(19) (a) Demir, A. S.; Findik, H.; Ko¨se, E. Tetrahedron: Asymmetry
2004, 15, 777-781. (b) Kato, K.; Gong, Y.; Saito, T.; Yokogawa, Y. J.
Mol. Catal. B: Enzymol. 2004, 30, 61. (c) Zhang, J.; Wu, J.; Yang, L. J.
Mol. Catal. B: Enzymol. 2004, 31, 67. (d) Moore, B. D.; Stevenson, L.;
Watt, A.; Flitsch, S.; Turner, N. J.; Cassidy, C.; Graham, D. Nat. Biotechnol.
2004, 22, 1133-1138.
(20) (a) Shoji, M.; Kishida, S.; Takeda, M.; Kakeya, H.; Osada, H.;
Hayashi, Y. Tetrahedron Lett. 2002, 43, 9155-9158. (b) Aoyagi, Y.; Saitoh,
Y.; Ueno, T.; Horiguchi, M.; Takeya, K. J. Org. Chem. 2003, 68, 6899-
6904. (c) Mart´ınez, I.; Markovits, A.; Chamy, R.; Markovits, A. Appl.
Biochem. Biotechnol. 2004, 112, 55-62.
(23) http://www5.mediagalaxy.co.jp/meito/kaseihin/index_e.html.
(24) (a) Belkov, I. A.; Freidin, B. G. Kinet. Catal. 1988, 29, 893-897.
(b) Belkov, I. A.; Freidin, B. G. Kinet. Catal. 1991, 32, 17-21. (c)
Allohedan, H. A. J. Chem. Res., Synop. 1991, 342-342.
(25) Duhamel, L.; Launay, J.-C. Tetrahedron Lett. 1983, 24, 4209-4212.
(26) Corrie, J. E. Tetrahedron 1998, 54, 5407-5416.
(27) (a) Kenyon, J.; Patel, R. L. J. Chem. Soc. 1965, 435-438. (b) Enders,
D.; Breuer, K.; Teles, J. H. HelV. Chim. Acta 1996, 79, 1217-1221.
(28) (a) Kazlauskas, R. J.; Weissfloch, A. N. E.; Rappaport, A. T.; Cuccia,
L. A. J. Org. Chem. 1991, 56, 2656-2665. (b) Weissfloch, A. N. E.;
Kazlauskas, R. J. J. Org. Chem. 1995, 60, 6959-6969.
7634 J. Org. Chem., Vol. 71, No. 20, 2006

Dynamic Kinetic Resolution of Benzoins
FIGURE 1. (A) DKR of 1a adding fresh enzyme after 48 h; (B) sequential DKR of 1a.
TABLE 3. One-Pot Dynamic Kinetic Resolution of Different
Benzoinsa
SCHEME 1. (a) Preferred Enantiomer According to
Kazlauskas’ Rule.28 (b) S-(+) Enantiomer of Acylated
Benzoins
Shvo’s
catalyst
b
lipase
T
convb reaction eep
entry substrate amt (mg) (equiv) (°C)
(%)
time (h) (%)
most of lipases depending on the relative size of substituents
(m ) medium, L ) large) around the stereocenter, as depicted
in Scheme 1, the R-enantiomer was expected to be preferentially
recognized by the lipase. In this case, special enzymatic substrate
recognition was observed, and unexpectedly the S-enantiomer
was acylated by the lipase. As had been previously pointed out
by Mart´ın-Matute and Ba¨ckvall29 for lipase B from C. antarc-
tica, the keto group of benzoin could bond to the enzyme in
the active site, and in this way it will behave like a small group
instead as a large group.
To carry out the DKR, the lipase-metal combo catalysis16
was followed. In this methodology, the DKR is obtained in a
one-pot methodology by coupling the enzymatic KR with an
in situ ruthenium-based racemization process. Thus, the DKR
of benzoin was carried out using Shvo’s catalyst30 (1-hydroxy-
tetraphenylcyclopentadienyl (tetraphenyl-2,4-cyclopentadien-1-
one)-µ-hydrotetracarbonyldiruthenium) at 50 °C. The use of
vinyl esters as acyl donors in the lipase-catalyzed KR results
in the formation of acetaldehyde, which can interfere with the
hydrogen transfer catalyst employed in the DKR.16c Thus, an
activated ester (trifluoroethyl butyrate) was chosen as the
acylating agent because, according to literature data,16a,b the
isolation of products is easier when using this kind of activated
esters compared to aryl esters, also decribed for DKR. In a
previous experiment, benzoin KR was carried out with this acyl
donor (Table 2, entry 18), resulting in a lower reaction rate than
that obtained using vinyl butyrate. In any case, different
1
2
3
4
5
6
7
8
1a
1a
1a
1a
1a
1a
1b
1e
25
50
75
100
50
50
0.05
0.05
0.05
0.05
0.1
0.05
0.05
0.05
50
50
50
50
50
40
50
50
68
71
84
40
52
87
78
76
48
48
48
48
48
55
72
72
>99
>99
>99
>99
>99
>99
>99
>99
50
50
a Reaction conditions: 0.011 mmol of Shvo’s catalyst, Lipase TL (20
mg/mL), 0.235 mmol of 1 in 2.5 mL of THF, trifluoroethyl butyrate (1.32
mmol), at 50°C under inert atmosphere. b Determined by HPLC analysis
using Chiralcell OD column.
experimental conditions (relative amounts of enzyme and metal
catalyst) were tested in order to optimize the DKR with this
acyl donor. The results are summarized in Table 3 (entries 1-5).
As can be seen, conversions as high as 84%, with excellent
enantioselectivity, are described for the first time in the acylation
of benzoin. However, due to the lower enzymatic activity with
trifluoroethyl butyrate, longer reaction time (48 h) is required
for the process, so that the side oxidation to the dicarbonyl
compound is increased. The conversion was slightly improved
by lowering the reaction temperature to 40 °C and leaving the
reaction time up to 55 h (entry 6).
Two other substrates were tested, 1b and 1e, which gave
similar conversion values (around 80%), not detecting any trace
of the other enantiomer of the corresponding esters. Thus, the
excellent enzymatic enantioselectivity is not altered by the metal
catalyst.
(29) Mart´ın-Matute, B.; Ba¨ckvall, J. E. J. Org. Chem. 2004, 69, 9191-
9195.
(30) (a) Persson, B. A.; Larsson, A. L. E.; Le Ray, M.; Ba¨ckvall, J. E.
J. Am. Chem. Soc. 1999, 121, 1645-1650. (b) Karvembu, R.; Prabhakaran,
R.; Natarajan, K. Coord. Chem. ReV. 2005, 249, 911-918.
Nevertheless, to improve the results, we tried a different
sequential strategy: as mentioned before, the enzyme suffers
from a moderate deactivation when incubated at 50 °C, so an
extra amount of enzyme was added to the reaction media after
J. Org. Chem, Vol. 71, No. 20, 2006 7635

Hoyos et al.
FIGURE 2. Sequential DKR of different benzoins: (A) DKR of 1b; (B) DKR of 1d; (C) DKR of 1e; (D) DKR of 1f; (E) DKR of 1g.
48 h in order to compensate the decrease of enzymatic activity.
The results are shown in Figure 1A. As can be seen, the
conversion was increased up to 93% with an eep value higher
than 99%, although the reaction time had to be extended up to
168 h.
To the best of our knowledge, these are the best results
described for the DKR of benzoin, but a large increase in the
reaction time was demanded as a consequence of the slow
acylation capability of the lipase with trifluoroethyl butyrate,
so that another strategy was followed: thus, in a first step, vinyl
butyrate (much better acyl donor, but unsuited for DKR16c) and
a small amount of lipase was used for a quick KR; after
evaporating the remnant acyl donor, Shvo’s catalyst, trifluoro-
ethyl butyrate, and a new amount of fresh lipase were added
(second step). Finally, to compensate the previously mentioned
enzymatic deactivation, in a third step, a new portion of enzyme
7636 J. Org. Chem., Vol. 71, No. 20, 2006

Dynamic Kinetic Resolution of Benzoins
General Procedure for the Synthesis of the Racemic Acylated
Products (2a-j): Synthesis of 2-Oxo-1,2-diphenylethyl Butyrate
(2b). Compound 1a (212.25 mg, 1 mmol) was dissolved in
dichloromethane (3 mL), and triethylamine (1.1 mmol) and butyryl
chloride (1.5 mmol) were added. The mixture was stirred at room
temperature for 15 h. Purification by column chromatography (SiO2,
n-hexane/ethyl acetate, 5:1) yielded 2b as a colorless oil. 1H NMR
(250 MHz, CDCl3): δ 7.97 (2H, dd, J ) 8.3, 2.0 Hz), 7.96 (2H,
dd, J ) 8.3, 1.5 Hz), 7.57 (1H, t, J ) 1.3 Hz), 7.54 (1H, t, J ) 2.4
Hz), 7.51 (1H, m), 7.48 (1H, d, J ) 1.9 Hz), 7.45 (1H, dd, J )
1.4, 2.0 Hz), 7.42 (1H, m), 7.39 (1H, dd, J ) 1.9, 2.0 Hz), 7.37
(1H, d, J ) 1.9 Hz), 6.89 (1H, s), 2.54 (1H, c, J ) 7.6 Hz), 2.42
(1H, c, J ) 7.6 Hz), 1.74 (2H, sex, J ) 7.4 Hz), 1.0 (3H, t, J ) 7.4
Hz). 13C NMR (63 MHz, CDCl3): δ 194.3, 173.6, 135.1, 134.1,
133.8, 129.6, 129.5, 129.5, 112.8, 76.9, 36.2, 18.8, 14.0.
General Procedure for the Kinetic Resolution of Benzoins.
Compound 1a (100 mg, 0.47 mmol) was dissolved in 5 mL of THF,
and lipase from Ps. stutzeri (20 mg/mL) and vinyl butyrate (358
µL, 2.82 mmol) were added. The mixture was stirred at 50 °C under
argon for 4 h. Conversion (50%) and enantiomeric excess (>99%)
were determined by HPLC analysis (n-hexane/2-propanol, 90:10).
The product (S)-2b was purified by column chromatography (SiO2,
n-hexane/EtOAc, 5:1). NMR data of (S)-2b are similar to those of
rac-2b. [R]20D: +117.8 (c 3.5 CHCl3).
was added. The results obtained are depicted in Figure 1B,
yielding 92% of conversion of enantiopure (S)-(+)-2b at a much
shorter reaction time (only 48 h vs 168 h in Figure 1A).
These conditions were adopted for testing the lipase capability
in the DKR of some other benzoins, as shown in Figure 2. As
can be seen, the DKRs applying this sequential methodology
lead to good conversion values (between 50 and 90%) for the
different substrates tested, maintaining for all cases the excellent
optical purity of the products at reduced reaction times (48-72
h).
Through this DKR, it would be possible to obtain the
S-enantiomer of benzoins in very good yield and enantiopurity
by a further mild basic hydrolysis of S-esters as described,13b
while by using BAL-mediated condensation10 the enantiomer
obtained is the antipode R-benzoin, so that the significance of
this lipase-metal combo catalysis is even higher. This is another
example on the use of different enzymes to obtain complemen-
tary enantiomers,31 which can be particularly useful in the
synthesis of chiral building blocks. Further experiments are
being conducted in our laboratory (use of second-generation
ruthenium catalysts) to improve the DKR methodology and to
apply it to new benzoins.
General Procedure for “One-Pot” Dynamic Kinetic Resolu-
tion of Benzoin Compounds. Shvo’s catalyst (12 mg, 0.011 mmol)
and lipase from Ps. stutzeri (50 mg) were added to a 5 mL flask.
rac-1a (50 mg, 0.235 mmol), anhydrous THF (2.5 mL), and
trifluoroethyl butyrate (200 µL, 1.32 mmol) were added, and the
mixture was stirred at 50 °C under argon. Conversion and
enantiomeric excess were determined by HPLC analysis (n-hexane/
2-propanol, 90:10).
General Procedure for “Sequential” Dynamic Kinetic Reso-
lution of Benzoin Compounds. First Step (Quick KR). Com-
pound 1a (50 mg, 0.235 mmol) was dissolved in 2.5 mL of
anhydrous THF, and lipase from Ps. stutzeri (25 mg) and vinyl
butyrate (300 µL, 2.36 mmol) were added. The mixture was stirred
at 50 °C under argon until 30% conversion was reached (2.75 h).
Second Step (DKR). The mixture was filtered, and THF and the
remnant acyl donor were evaporated. The solid was resolved in
2.5 mL of THF, and Shvo’s catalyst (6 mg, 0.0055 mmol) and
trifluoroethyl butyrate (200 µL, 1.32 mmol) were added. The new
reaction mixture was stirred at 50 °C under argon. Third Step.
After 17 h, 25 mg of fresh enzyme was added, and the mixture
was stirred at 50 °C under argon until no remnant substrate was
detected by HPLC analysis (n-hexane/2-propanol, 90:10).
Conclusions
In this paper, the first case of dynamic kinetic resolution of
benzoin-type substrates is described by employing a kinetic
resolution of racemic substrates (lipase-catalyzed enantioselec-
tive acylation) combined with an in situ ruthenium-catalyzed
substrate racemization, proficiently obtaining the homochiral
S-acylated products (yields up to 90%, with enantiomeric excess
values higher than 99%). In all cases, the particular stereobias
of the lipase toward the racemic substrates allows the production
of the opposite enantiomer of that one described through a
different enzymatic methodology.
Experimental Section
General Procedure for the Synthesis of Thenoins: 2-Thenoin
(1d). Thiamine hydrochloride (1.686 g, 5 mmol) was dissolved in
absolute ethanol (30 mL), and triethylamine (4.2 mL, 30 mmol)
and 2-thiophenecarboxaldehyde (8.9 mL, 100 mmol) were added.
The mixture was stirred at room temperature under argon. After
24 h, the product started to precipitate. It was filtered, and the white
solid collected (1d) (10.75 g, 48 mmol) was washed with cold
Acknowledgment. We gratefully acknowledge Novozymes
and Meito & Sangyo for their generous gift of enzymes, the
Biotechnology Group of the University of Aachen (RWTH) for
their help in the development of this work, and the Complutense
University of Madrid for the concession of a Ph.D. grant.
1
ethanol (48% yield). H NMR (250 MHz, CDCl3): δ 7.79 (1H,
dd, J ) 3.8, 1.0 Hz), 7.75 (1H, dd, J ) 4.9, 1.1 Hz), 7.34 (1H, dd,
J ) 5.9, 1.1 Hz), 7.15 (1H, dd, J ) 4.9 Hz), 7.13 (1H, dddd, J )
3.5, 1.2, 0.6 Hz), 7.01 (1H, dd, J ) 5.1, 3.5 Hz), 6.07 (1H, s), 4.41
(1H, 2d, J ) 1.4, 0.8 Hz). 13C NMR (63 MHz, CDCl3): δ 190.3,
142.4, 139.6, 135.8, 134.7, 128.8, 127.6, 127.3, 127.2, 71.3.
Supporting Information Available: General experimental
procedure, full spectroscopic data for all new compounds, and
chromatograms. This material is available free of charge via the
Internet at http://pubs.acs.org.
(31) Bore´n, L.; Mart´ın-Matute, B.; Xu, Y.; Co´rdova, A.; Ba¨ckvall, J. E.
Chem. Eur. J. 2006, 12, 225-232.
JO061060B
J. Org. Chem, Vol. 71, No. 20, 2006 7637