tion step.10 Allylic alcohols have a C-C double bond that
can be functionalized via different chemical transformations,
such as epoxidation, cyclopropanation, hydrogenation, aziri-
dination, or it can simply be cleaved under oxidative
conditions, providing synthetically useful acyloins.11
antarctica lipase B (CALB), Pseudomonas cepacia lipase I
(PS-C “Amano” I) and Pseudomonas cepacia lipase II (PS-C
“Amano” II), Pseudomonas stutzeri lipase, Candida rugosa
lipase, Candida cylindracea lipase in toluene at room
temperature. The results are summarized in Table 1. All of
Acyloins are R-hydroxy ketones, and they are convenient
building blocks in the asymmetric synthesis of biological
active compounds.12 Recently, several methods have been
developed for their enantioselective preparation. For example,
lipase-catalyzed kinetic resolution13 and chemoenzymatic
dynamic kinetic resolution14 have been reported as attractive
routes. The use of R-hydroxy ketones as substrates in
combined metal- and enzyme-catalyzed DKR is not feasible
because of the formation of an intermediate diketone, which
would lead to rearrangement of the starting material.
Furthermore, enzymatic resolution of R-hydroxy ketones is
associated with either long reaction times or moderate
enantioselectivity (moderate E values). Herein, we report on
a highly efficient approach toward R-hydroxy ketones via
chemoenzymatic dynamic kinetic resolution of allylic alcohols
(using catalyst 1, Figure 1) and subsequent oxidation of the
Table 1. Enzymatic Kinetic Resolution of
(rac)-3,4-Diphenyl-3-buten-2-ol (2)a
time
%
% ee % ee
entry
enzyme
(h) convn.b of 3b of 2b
E
1
2
3
4c
5
6
CALB
24
24
24
24
24
17
30
18
2
1
<1
>99
>99
>99
>99
>99
20 >240
43 >240
23 >240
3
1
PS-C Amano I
PS-C Amano II
P. stutzeri lipase
C. rugosa lipase
-
-
-
C. cylindracea lipase 24
>99 <2
a Conditions: (rac)-2 (0.2 mmol), isopropenyl acetate (0.3 mmol), CALB
(6 mg)/PS-C Amano I (20 mg)/PS-C Amano II (20 mg)/Pseudomonas
stutzeri lipase (5 mg)/Candida rugosa lipase (20 mg)/Candida cylindracea
lipase (20 mg) in toluene (1 mL) at rt under argon. b Determined by HPLC
equipped with a chiral column (Chiralcel OD-H, 0.46 cm Ø*25 cm). c THF
(1 mL) was used as the solvent.
the tested enzymes catalyzed the desired transesterification
reaction with excellent enantioselectivity. Three of the six
enzymes employed, CALB, PS-C “Amano” I, and PS-C
“Amano” II showed reasonably good activity, and the
calculated E values were high (entries 1-3, Table 1). When
the reaction was run with CALB and PS-C “Amano” II, 17
and 18% of enantiopure acetate (R)-3 was obtained after 24
h, respectively. With PS-C “Amano” I, 30% of (R)-2 was
produced under the same reaction conditions. However, we
chose to use CALB in the DKR since it is less expensive
than the Amano enzymes.
Next, the effect of the temperature on the CALB-catalyzed
kinetic resolution of (rac)-2 was studied. The reaction was
carried out at rt, 50 °C, and 80 °C, and the reaction was
monitored by analytical HPLC (Table 2). The enzymatic
resolution was complete after 24 h at 80 °C (entry 3).
Figure 1. Racemization catalyst 1.
enantiopure (R)-allylic acetates to give optically pure R-
acetoxy ketones as protected acyloins.
First, we studied enzymatic kinetic resolution of (rac)-
3,4-diphenyl-3-buten-2-ol, (rac)-2, as model substrate using
different commercially available lipases such as Candida
(9) (a) Stu¨rmer, R. Angew. Chem., Int. Ed. Engl. 1997, 36, 1173. (b)
Kim, M.-J.; Ahn, Y.; Park, J. Curr. Opin. Biotechnol. 2002, 13, 578.
Erratum: Kim, M.-J.; Anh, Y.; Park, J. Curr. Opin. Biotechnol. 2003, 14,
131. (c) Pellissier, H. Tetrahedron 2003, 59, 8291. (d) Pamie`s; Ba¨ckvall,
J.-E. Chem. ReV. 2003, 103, 3247. (e) Pamie`s, O.; Ba¨ckvall, J.-E. Trends
in Biotechnol. 2004, 3, 130. (f) Turner, N. J. Curr. Opin. Chem. Biol. 2004,
8, 114. (g) Mart´ın-Matute, B.; Ba¨ckvall, J.-E. Curr. Opin. Chem. Biol. 2007,
11, 226. (h) Mart´ın-Matute, B.; Edin, M.; Ba¨ckvall, J. E. Chem.-Eur. J.
2006, 12, 6053.
(10) (a) Lee, D.; Huh, E. A.; Kim, M.-J.; Jung, H. M.; Koh, J. H.; Park,
J. Org. Lett. 2000, 2, 2377. (b) Akai, S.; Tanimoto, K.; Kita, Y. Angew.
Chem., Int. Ed. 2004, 43, 1407. (c) Mart´ın-Matute, B.; Edin, M.; Boga´r,
K.; Kaynak, F. B.; Ba¨ckvall, J.-E. J. Am. Chem. Soc. 2005, 127, 8817. (d)
Akai, S.; Tanimoto, K.; Kanao, Y.; Egi, M.; Yamamoto, T.; Kita, Y. Angew.
Chem., Int. Ed. 2006, 45, 2592.
Table 2. CALB-Catalyzed Enzymatic KR of
(rac)-3,4-Diphenyl-3-buten-2-ol (2) at Different Temperaturesa
(11) Jacobsen, E. N.; Pfaltz, A.; Yamamoto, H. ComprehensiVe Asym-
metric Catalysis; Springer: Berlin, 1999.
entry
temp
time (h) % convn.b % ee of 3b % ee of 2b
(12) (a) Whitesell, j. K.; Buchanan, C. M. J. Org. Chem. 1986, 51, 5443.
(b) Chandhary, A. G.; Kingston, D. G. I. Tetrahedron Lett. 1993, 34, 4921.
(c) Gala, D.; DiBenedetto, D. J.; Clark, J. E.; Murphy, B. L.; Schumacher,
D. P.; Steinman, M. Tetrahedron Lett. 1996, 37, 611.
(13) (a) Adam, W.; Dia`z, M. T.; Fell, R. T.; Saha-Mo¨ller, C. R.
Tetrahedron: Asymmetry 1996, 7, 2207. (b) Kamal, A.; Sandbohr, M.;
Shaik, A. A.; Sravanthi, W. Tetrahedron: Asymmetry 2003, 14, 2839.
(14) (a) O¨ dman, P.; Wessjohan, L. A.; Bornscheuer, U. T. J. Org. Chem.
2005, 70, 9551. (b) Hoyos, P.; Ferna´ndez, M.; Sinisterra, J. V.; Alca´ntara,
A. R. J. Org. Chem. 2006, 71, 7632.
1
2
3
rt
50 °C
80 °C
24
24
24
17
42
50
>99
>99
>99
20
74
>99
a Conditions: (rac)-2 (0.2 mmol), isopropenyl acetate (0.3 mmol), CALB
(6 mg) in toluene (1 mL) under argon. b It was determined by HPLC
equipped with chiral column (Chiralcel OD-H, 0.46 cm Ø*25 cm).
3402
Org. Lett., Vol. 9, No. 17, 2007