Lipase-catalyzed kinetic resolution of P-chiral phosphorus compounds: Enantiopreference of Pseudomonas lipase and Candida antarctica lipase

Article abstract of DOI:10.1016/S0040-4039(01)01349-1

Optically active 1-hydroxymethylalkylphenylphosphine oxides 1a-c were prepared by Pseudomonas fluorescens lipase (lipase AK) and Candida antarctica lipase (CAL)-catalyzed optical resolution. Lipase AK-catalyzed resolution of tert-butyl derivative 1c showed R-selectivity, whereas CAL preferred the S-enantiomer.

Full text of DOI:10.1016/S0040-4039(01)01349-1

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 6569–6571
Lipase-catalyzed kinetic resolution of P-chiral phosphorus
compounds: enantiopreference of Pseudomonas lipase and
Candida antarctica lipase
Kosei Shioji,* Yuichiro Ueno, Yoshimitsu Kurauchi and Kentaro Okuma
Department of Chemistry, Faculty of Science, Fukuoka University, Jonan-ku, Fukuoka 814-0180, Japan
Received 18 June 2001; accepted 19 July 2001
Abstract—Optically active 1-hydroxymethylalkylphenylphosphine oxides 1a–c were prepared by Pseudomonas fluorescens lipase
(lipase AK) and Candida antarctica lipase (CAL)-catalyzed optical resolution. Lipase AK-catalyzed resolution of tert-butyl
derivative 1c showed R-selectivity, whereas CAL preferred the S-enantiomer. © 2001 Elsevier Science Ltd. All rights reserved.
Optically active phosphines possessing a chiral center at
the phosphorus are precursors of P-chiral bisphosphine
ligands which are widely used as catalysts for asymmet-
ric synthesis.1 The synthesis of these enantiomerically
pure phosphines requires chiral auxiliaries such as men-
thol, (−)-sparteine, (−)-ephedrine, a camphor derivative,
or (S)-(−)-a-methylbenzylamine.2 Since most of them
were derived from natural products, it is difficult to
obtain both enantiomers.
Racemic 1-hydroxymethylalkylphenylphosphine oxides
1a,c were prepared by a one-pot alkylation of ethyl
phenylphosphinate with alkyllithium and gaseous form-
aldehyde in 75 and 90% yields, respectively.5 1-Hydrox-
ymethyl cyclohexylphenylphosphine oxide (1b) was
prepared from dichlorophenylphosphine and cyclo-
hexylmagnesium bromide in 34% overall yield.6 Lipase-
catalyzed acylation of 1 with an acyl donor in
diisopropyl ether (IPE) afforded the corresponding
acylated phosphine oxides 2 (Scheme 1). The chiral
recognition of primary alcohols was generally difficult
due to the lower bulkiness around the hydroxyl group
compared to secondary alcohols. Only lipases from
pseudomonas and porcine pancreas are known to
resolve primary alcohols efficiently. Using lipase AK
and PS, the acylation with vinyl acetate proceeded
stereoselectively. These results are summarized in Table
1. Enol esters such as vinyl acetate are useful acyl
donors.7 The enantioselectivity in the lipase AK-cata-
lyzed acylation increased with increasing bulkiness of
the acyl moiety (entries 1–3, 7–9, and 13–15). When
Recently, much attention is being paid to enzymatic
optical resolution of hetero-organic compounds the
stereogenic centers of which are located on the het-
eroatom such as sulfur, phosphorus, silicon, and ger-
mane.3 Kielbasinski and co-workers have reported
enzyme-promoted kinetic resolution of racemic, P-chi-
ral phosphonyl and phosphorylacetates, P-chiral
hydroxymethylphosphonate and phosphinates, and P-
chiral phosphinyl acetate.4 In this communication, we
report lipase-catalyzed kinetic resolution of P-chiral
phosphine oxide containing a 1-hydroxymethyl group.
O
P
R
O
O
Lipase AK or PS
+
OH
P
OCOR'
P
R
OH
R
Ph
Ph
OCOR'
Ph
2a-c*
1a-c*
1a-c
a : R = Bun
b : R = c-C6H11
c : R = But
R' = CH3, CH3CH2,
CH3CH2CH2
Scheme 1.
* Corresponding author. E-mail: shioji@fukuoka-u.ac.jp
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01349-1

6570
K. Shioji et al. / Tetrahedron Letters 42 (2001) 6569–6571
vinyl butyrate was used as an acyl donor, the ee of the
recovered 1 was improved (entries 3, 9, 15).8 On the
other hand, there were no steric effects of the acyl
moiety on the lipase PS-catalyzed acylations.
configuration. Hence, the remaining enantiomer of 1c
in AK-catalyzed resolution has (S)-configuration.
Recently, Tuomi and Kazlauskas have shown that
Pseudomonas cepacia lipase (PCL) binds to primary
alcohols in a different mode from secondary ones.13
The enantioselectivity of lipase AK for primary alco-
hols 1 suggested that the phenyl group of 1 binds to an
alternative hydrophobic pocket in a narrow groove not
used by secondary alcohols.
The absolute configuration of the remaining alcohol 1c
by using lipase AK-catalyzed resolution was determined
as follows: Enantiomerically pure hydroxyalkyl phos-
phine oxide 1c was converted into O-tosyl derivative 3c
in 90% yield, which was reduced to phosphine oxide 4c
by tributyltin hydride in DME in 94% yield [h]2D5 −21.0
(c 1.96, C6H6) (Scheme 2).10,11 The sign of the optical
rotation of 4c was compared with the literature value.12
The enantiomeric excess of (S)-4c was determined by
HPLC (>98% ee). Since none of the conversion
involved the chiral center at the phosphorus, the whole
sequence did not cause any change in its absolute
The CAL-catalyzed optical resolution of racemic 1a–c
using vinyl esters as an acyl donor proceeded with poor
stereoselectivity (E<5). The E values were not influ-
enced by the lengthening in the alkyl chain of vinyl
esters. The higher enantioselectivity in the case of 1c
was observed by using isopropenyl acetate as an acyl
donor (Scheme 3). Interestingly, reversed enantioselec-
Table 1. Pseudomonas lipase-catalyzed kinetic resolution of racemic 1-hydroxymethylalkylphenylphosphine oxides 1a
Entry
1
Lipaseb
R%
Time (h)
Conv. (%)
Ee % of 1c
Ee % of 2c
Ed
[h]2D5 of 1e
1
2
3
4
5
6
7
8
a
a
a
a
a
a
b
b
b
b
b
b
c
c
c
c
c
c
AK
AK
AK
PS
PS
PS
AK
AK
AK
PS
PS
PS
AK
AK
AK
PS
PS
PS
CH3
0.75
1
2
0.5
0.7
1
0.75
0.75
1.5
1
1
1
3
4
7
3
3
6
50
56
53
52
58
55
52
48
49
37
45
37
42
58
59
50
47
70
83
\98
\98
81
84
76
94
85
90
51
67
51
32
69
\98
23
34
84
77
86
75
60
63
86
91
94
88
83
86
45
51
68
23
38
34
28
34
65
17
10
10
50
66
95
23
20
24
4
CH2CH3
(CH2)2CH3
CH3
CH2CH3
(CH2)2CH3
CH3
CH2CH3
(CH2)2CH3
CH3
CH2CH3
(CH2)2CH3
CH3
CH2CH3
(CH2)2CH3
CH3
CH2CH3
(CH2)2CH3
−28.1
9
−21.8
−44.0
10
11
12
13
14
15
16
17
18
6
27
2
3
4
78
a
,
Lipase (20 mg) was added to a mixture of ( )-1 (0.023 mmol), acyl donor (0.165 mmol), and molecular sieves 3 A (20 mg), in diisopropyl ether
(2.0 ml) at 36°C.
b AK, Pseudomonas fluorescens lipase (Amano); PS; Pseudomonas cepacia lipase.
c Enantiomeric excess (ee %) was determined by HPLC (CHIRALPAK AD, Daicel).
d E values were calculated by the method according to Ref. 9.
e Compounds 1a and 1c; (c 2.00, C6H6), >98% ee. 1b; (c 1.23, C6H6), >98% ee.
O
O
O
P
But
Bu3SnH, NaI
TsCl, Toluene
P
But
OH
P
But
OTs
Me
Ph
Ph
Ph
Et3N, Me3N•HCl,
DME, in reflux
(S)-4c
1c*
3c*
Scheme 2.
O
O
O
P
But
CAL
+
P
But
OCOCH3
P
OH
OH
But
Ph
Ph
OCOCH3
Ph
(R)-1c
(S)-2c
1c
E = 21
+44.1 (c 0.78, C6H6)
40% yield, >98% ee
Scheme 3.

K. Shioji et al. / Tetrahedron Letters 42 (2001) 6569–6571
6571
tivity in the resolution of 1c between CAL and pseu-
domonas lipase (AK and P) was observed.
afforded the phosphine oxide 1. Compound 1a; colorless
oil, 1H NMR (400 MHz, CDCl3): 0.83 (t, 3H, J=7.2 Hz),
1.31–1.62 (m, 4H), 1.85–1.96 (m, 1H), 2.12–2.25 (m, 1H),
4.05–4.14 (m, 2H), 7.27–7.74 (m, 5H). 13C NMR (100
MHz, CDCl3): 13.5, 32.6 (d, JPC=4.2 Hz), 24.0 (d,
Although the binding mode of CAL for 1c showing
opposite enantioselectivity is unclear, these results are
quite satisfactory for obtaining both enantiomers of 1c.
After the optical resolution of racemic 1c using lipase
AK, the partially resolved 2c (68% ee) was hydrolyzed
by H2SO4 in MeOH, followed by acylation by CAL to
give enantiomerically pure (S)-1c and (R)-1c in 41 and
39% yields, respectively.
J
PC=14.1 Hz), 26.0 (d, JPC=67.2 Hz), 60.9 (d, JPC=79.6
Hz), 128.1, 128.2, 129.4, 130.3, 130.4, 131.3, 131.52,
131.6. Compound 1c: colorless crystals, 1H NMR (400
MHz, CDCl3): 1.14 (d, 9H, JPH=14.0 Hz), 4.33 (dd, 2H,
J=68.0, 14.0 Hz), 7.42–7.72 (m, 5H). 13C NMR (100
MHz, CDCl3): 24.7, 32.6 (d, JPC=64.9 Hz), 57.3 (d,
JPC=70.7 Hz), 128.0, 128.1, 128.2, 128.8, 131.5, 131.55,
131.6, 131.62. Anal. calcd for C11H17O2P: C, 62.25; H,
8.07. Found: C, 62.10; H, 8.05.
References
6. Compound 1b: Colorless crystals, 1H NMR (400 MHz,
CDCl3): 1.14–2.07 (m, 11H), 4.16 (dd, 2H, J=68.0, 14.0
Hz), 7.44–7.73 (m, 5H). 13C NMR (100 MHz, CDCl3):
24.7, 24.9, 25.7, 26.1, 26.2, 36.0 (d, JPC=66.6 Hz), 59.0
(d, JPC=76.5 Hz), 128.3, 128.4, 128.5, 129.1, 130.0, 130.9,
131.0, 131.7. Anal. calcd for C11H17O2P: C, 65.53; H,
8.04. Found: C, 65.14; H, 7.91
7. Wang, Y. F.; Lalonde, J. J.; Momongan, M.; Bergbreiter,
D. E.; Wong, C.-H. J. Am. Chem. Soc. 1988, 110, 7200.
8. Lipase AK (2.0 g), IPE (200 ml) containing racemic
phosphine oxide 1 (0.5 g), vinyl lactate (3.0 ml), and
1. Pietrusiewicz, K. M.; Zablocka, M. Chem. Rev. 1994,
1375 and references cited therein.
2. (a) Lewis, R. A.; Mislow, K. J. Am. Chem. Soc. 1969, 91,
7009; (b) Yamanoi, Y.; Imamoto, T. J. Org. Chem. 1999,
64, 2988; (c) Juge, S.; Stephan, M.; Laffitte, J. A.; Genet,
J. P. Tetrahedron Lett. 1990, 31, 6357; (d) Corey, E. J.;
Chen, Z.; Tanoury, G. J. J. Am. Chem. Soc. 1993, 115,
11000; (e) Haynes, R. A.; Freeman, R. N.; Mitchell, C.
R.; Vonwiller, S. C. J. Org. Chem. 1994, 59, 2919.
3. (a) Fukai, T.; Kawamoto, T.; Tanaka, A. Tetrahedron:
Asymmetry 1994, 5, 73; (b) Tacke, R.; Wagner, S. A.;
Sperlich, J. Chem. Ber. 1994, 127, 639.
,
molecular sieves 3 A (2.0 g) were mixed in 500 ml flask
and shaken at 36°C. The mixture was filtered off to stop
the reaction at more than 50% conversion, and the filtrate
was concentrated. The ester and alcohol were isolated by
column chromatography on silica gel. Remaining alcohol
1: 41% yield, >98% ee, [h]2D5 −44.0 (c 2.00, C6H6). Acetate
2: 57% yield, 68% ee, [h]2D5 +9.0 (c 5.00, C6H6).
9. Chen, C. S.; Fujimoto, Y.; Girdauskas, G.; Sih, C. J. J.
Am. Chem. Soc. 1982, 104, 7294.
10. Yoshida, Y.; Sakakura, Y.; Aso, N.; Okada, S.; Tanabe,
Y. Tetrahedron 1999, 55, 2183.
11. Ueno, Y.; Tanaka, C.; Okawara, M. Chem. Lett. 1983,
795.
4. (a) Kielbasinski, P.; Zurawinski, R.; Pietrusiewicz, K. M.;
Zablocka, M.; Mikolajczyk, M. Polish J. Chem. 1998, 72,
564; (b) Kielbasinski, P.; Goralczyk, P.; Mikolajczyk, M.;
Wieczorek, M. W.; Majzner, W. R. Tetrahedron: Asym-
metry 1998, 9, 2641; (c) Kielbasinski, P.; Omelanczuk, J.;
Mikolajczyk, M. Tetrahedron: Asymmetry 1998, 9, 3283;
(d) Kielbasinski, P.; Zurawinski, R.; Pietrusiewicz, K. M.;
Zablocka, M.; Mikolajczyk, M. Tetrahedron Lett. 1994,
35, 7081; (e) Serreqi, A. N.; Kazulauskas, R. J. J. Org.
Chem. 1994, 59, 7609.
5. To a solution of ethyl phenylphosphinate 3.0 g (17.6
mmol) in THF was added alkyllithium (38.8 mmol) at
−78°C. After stirring for 1 h, to the reaction mixture was
added gaseous formaldehyde. After stirring for 6 h at this
temperature, the reaction mixture was warmed to room
temperature. Standard work-up and recrystallization
12. Evan, P. K. J. Am. Chem. Soc. 1976, 98, 4805. R-form;
[h]2D5 +21.7 (c 1.83, C6H6).
13. Tuomi, W. V.; Kazlauskas, R. J. J. Org. Chem. 1999, 64,
2638.