On the use of succinic anhydride as acylating agent for practical resolution of aryl-alkyl alcohols through lipase-catalyzed acylation

Article abstract of DOI:10.1016/j.tetlet.2003.10.208

A comparison is carried out of the E-values recorded in the lipase-catalyzed resolution of a series of secondary aryl-alkyl alcohols with enol esters versus succinic anhydride. Whereas all the substrates could be resolved by a proper choice of the lipase/enol ester couple with moderate (E=50) to good (E>100) enantioselectivities, only some of them showed satisfactory enantioselectivity (E>50) with the use of succinic acid as acylating agent. Notably, indanol and 1-quinolin-3-yl-ethanol were resolved in a practical way, with E>100 and E>80, respectively.

Full text of DOI:10.1016/j.tetlet.2003.10.208

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 627–630
On the use of succinic anhydride as acylating agent for practical
resolution of aryl–alkyl alcohols through lipase-catalyzed acylation
a
Nassima Bouzemi, Hanane Debbeche, Louisa Aribi-Zouioueche
a
a,
*
b,
*
and Jean-Claude Fiaud
a
Groupe de Synth ꢀe se Asym eꢁ trique et Biocatalyse, Universit eꢁ d’Annaba, 23000, Algeria
b
Laboratoire de Catalyse mol eꢁ culaire, Universit eꢁ de Paris-Sud, 91405 Orsay cedex, France
Received 27 August 2003; accepted 17 October 2003
Abstract—A comparison is carried out of the E-values recorded in the lipase-catalyzed resolution of a series of secondary aryl–alkyl
alcohols with enol esters versus succinic anhydride. Whereas all the substrates could be resolved by a proper choice of the lipase/enol
ester couple with moderate (E ¼ 50) to good (E > 100) enantioselectivities, only some of them showed satisfactory enantioselectivity
(
E > 50) with the use of succinic acid as acylating agent. Notably, indanol and 1-quinolin-3-yl-ethanol were resolved in a practical
way, with E > 100 and E > 80, respectively.
Ó 2003 Elsevier Ltd. All rights reserved.
Enzymatic reactions have proved to be a convenient
method for obtaining optically enriched compounds
the unreacted alcohol by a simple aqueous base–organic
solvent liquid–liquid extraction. Moreover, since the
separation of these compounds is easy even for very
different amounts of product and unreacted substrate,
alcohols of high enantiomeric purity may be obtained
from a racemic substrate even in the cases of low E
values, provided the acylation is carried out to high
conversion.
1
from their racemic form by kinetic resolution. Notably,
alcohols can be resolved through lipase-catalyzed
transesterification (acylation) with enol esters in a––
2
generally––irreversible reaction. However, to be of
preparative interest such a process requires (i) a high
enantioselectivity factor E, (ii) easy separation of the
unreacted substrate (alcohol) from the product (ester).
The latter point is fulfilled in lipase-catalyzed hydrolysis
of esters, for which the unreacted ester and the acid
produced may be separated by a very convenient oper-
ation, that is a liquid–liquid extraction. This is not the
case for transesterification or acylation processes, since
alcohols and esters are both neutral compounds.
We have described the use of succinic anhydride as an
acylating agent for the resolution of substituted cyclo-
4
butylidenethanols. An industrial application of such a
5
process has been reported by Gutman.
Since the structure of the intermediate acyl enzyme
obtained by reaction of an enzyme with an acylating
6
The use of a cyclic anhydride as an acylating agent may
3
agent depends on the latter, we were interested by the
offer a convenient solution to this requirement. Indeed,
the acid–ester produced may be readily separated from
comparison of activity and enantioselectivity in the
acylation of various substrates with ÔstandardÕ acylating
agents such as vinyl or isopropenyl acetates on the one
hand, and succinic anhydride on the other.
We thus investigated the lipase-catalyzed acylation of
secondary benzylic alcohols 1–9 since these compounds
Keywords: Alkyl–aryl secondary alcohols; Acylation; Candida antarc-
tica lipase B (CAL B); Pseudomonas fluorescens lipase (PFL); Succinic
anhydride.
7
may lead to biologically active compounds or to
8
a-arylpropionic acids. Moreover, some are useful chiral
synthons and substrates for palladium-catalyzed sub-
*
Corresponding authors. Tel.: +33-1-69-15-78-19; fax: +33-1-69-15-
6-80; e-mail: fiaud@icmo.u-psud.fr
9
4
stitution reactions.
0
040-4039/$ - see front matter Ó 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.10.208

6
28
N. Bouzemi et al. / Tetrahedron Letters 45 (2004) 627–630
OH
silica-gel flash chromatography. The eeÕs of both com-
pounds could be measured before separation through
analysis using chiral HPLC (Scheme 1).
OH
OH
n
With succinic anhydride as acylating agent, the unre-
acted (S)-alcohol and the monosuccinate produced were
separated by aqueous base–organic solvent liquid–liquid
extraction. The aqueous phase was made alkaline with
sodium hydroxide and the resulting (R)-alcohol
extracted with an organic solvent (Scheme 2). Enantio-
meric excesses of the unreacted (S)-enriched-alcohol and
the (R)-enriched-alcohol produced were evaluated by
chiral HPLC.
R
R = OMe
R = H
3
4
5
n = 1
n = 2
1
2
OH
OH
OH
N
R
6
R = H
7
9
The results are collected in Tables 1 and 2 [acylations
with vinyl acetate (VA) or isopropenyl acetate (IA)] and
Tables 3 and 4 (acylations with succinic anhydride).
With the exception of 9, all the substrates could be
resolved by suitable choice of the lipase/acylating agent
couple, with moderate (E ¼ 40) to good (E > 100)
enantioselectivities. Generally, CAL B displayed better
selectivities than PFL. They were often different
R = OMe
8
Compounds 1, 4, 5 and 7 were commercially available,
whereas the other alcohols were obtained through
borohydride reduction of the corresponding methyl
ketone with the exception of 9, which required a differ-
6
according to the nature of the enol acetate, as expected.
10
ent synthetic procedure.
For the resolution of indanol 1, the amount of lipase
CAL B could be reduced from 300 to 25 mg and even
6 mg while keeping an enantioselectivity factor E > 100.
The catalyst CAL B could be recovered and re-used up
to seven times without a decrease in enantioselectivity
(E > 100).
Reactions were carried out using 2 mmol of racemic
substrate dissolved in diethyl ether (10 mL). Vinyl or
isopropenyl acetates (4 mmol, 2 equiv) or succinic
anhydride (2 mmol), were then added, followed by the
enzyme. Two commercially available lipases were used:
11
Pseudomonas fluorescens lipase (PFL) and Candida
12
antarctica lipase B (CAL B), an immobilized enzyme.
The resulting mixture was stirred at room temperature
for the appropriate time to reach approximately 50%
conversion.
Acylations of acenaphthenol 5 and 2-(2-naphthyl)etha-
nol 4 also showed high selectivities, provided PFL
(E > 130) was used for the former and CAL B (E > 140)
for the latter.
With enol esters as acylating agents, the unreacted
alcohol and the acetate produced were separated by
E values recorded using succinic anhydride as the acyl-
ating agent were generally different from those measured
[lipase]cat
rac-ROH
+
(S)-ROH + (R)-ROAc
+
AcO
R'
Et O
2
HO
R'
R' = H (vinyl acetate)
O
R' = CH (isopropenyl acetate)
3
H
R'
Scheme 1. Lipase-catalyzed acylation with enol acetates.
O
[lipase]cat
rac-ROH
+
(S)-ROH
+
(R)-RO-CO-CH2-CH2-CO2H
O
Et O
2
base aqueous extraction
O
unreacted (S)-ROH
in organic phase)
RO-CO-CH2-CH2-CO2H
(in aqueous phase)
(
saponification,
extraction
NaOH
(R)-ROH
Scheme 2. Lipase-catalyzed acylation with succinic anhydride.

N. Bouzemi et al. / Tetrahedron Letters 45 (2004) 627–630
Table 1. CAL B-catalyzed acylation of alcohols 1–9 with enol esters
629
a
b
e
Substrate
Enol ester
Conversion
%)
Unreacted alcohol
Acetate produced
E
(
c
d
c
d
%
Yield
%Ee
s
%Yield
%Ee
s
1
1
2
2
3
3
4
4
5
5
6
6
7
7
9
IA
54
29
50
53
50
50
43
50
51
26
50
50
5
23
35
34
34
42
42
40
26
25
18
31
33
62
41
53
>99 (S)
40 (S)
29
21
32
40
42
43
18
28
25
18
31
33
3
85 (R)
>99 (R)
>99 (R)
89 (R)
60
300
VA
IA
>99 (S)
>99 (S)
>99 (S)
>99 (S)
73 (S)
>1000
90
VA
IA
>99 (R)
99 (R)
97 (R)
>1000
750
140
VA
IA
VA
IA
96 (S)
95 (S)
34 (S)
97 (R)
93 (R)
97 (R)
260
90
VA
IA
90
>99 (S)
>99 (S)
5 (S)
>99 (R)
>99 (R)
>99 (R)
>99 (R)
67 (+)
>1000
>1000
40
VA
IA
VA
f
IA
50
6
>99 (S)
5 ())
37
4
>1000
5
a
b
c
d
e
f
2
Determined from HPLC of the mixture on a Chiralcel OD-H capillary column.
mmol in 10 mL diethyl ether; 22–24 h reaction time, unless otherwise stated. CAL B (300 mg).
â
After silica gel chromatography, hexane/ethyl acetate 80:20 (except for 9 60:40).
â
Determined by HPLC with a Chiralcel OD-H capillary column, after acylation (Ac
13
2
3
O, DMAP, NEt ).
Calculated from E ¼ ln½ð1 ꢀ cÞð1 ꢀ ee
4 h reaction time.
s
Þꢁ= ln½ð1 ꢀ cÞð1 þ ee Þꢁ.
s
1
Table 2. PFL-catalyzed acylation of alcohols 1–9 with enol esters
a
b
e
Substrate
Enol ester
Conversion
%)
Unreacted alcohol
Acetate produced
E
(
c
d
c
d
%
Yield
%Ees
%Yield
%Ees
f
1
1
2
2
3
3
4
4
5
5
6
6
7
7
8
IA
VA
53
53
50
51
13
34
12
17
51
32
––
––
14
41
23
40
28
32
32
72
42
52
9
>99 (S)
>99 (S)
>99 (S)
>99 (S)
15 (S)
51 (S)
13 (S)
20 (S)
97 (S)
47 (S)
––
42
19
20
29
11
33
7
88 (R)
87 (R)
>99 (R)
95 (R)
>99 (R)
>99 (R)
96 (R)
>99 (R)
94 (R)
99 (R)
––
80
70
f
f
IA
VA
>1000
200
230
330
56
f
IA
VA
IA
VA
IA
46
21
26
240
130
310
21
26
VA
f
IA
VA
f
––
––
IA
VA
58
45
59
16 (S)
68 (S)
29 (S)
14
27
22
>99 (R)
>99 (R)
>99 (R)
130
190
260
g
IA
a
2
mmol in 10 mL diethyl ether; 22–24 h reaction time, unless otherwise stated; PFL (50 mg).
b;c;d;e
See footnotes, Table 1.
f
48 h reaction time.
g
72 h reaction time.
Table 3. CAL B-catalyzed acylation of alcohols 1–9 with succinic anhydride
a
b
e
Substrate
Conversion (%)
Unreacted alcohol
Alcohol from ester saponification
E
c
d
c
d
%Yield
%Ees
%Yield
%Eep
1
2
3
4
5
6
7
9
44
46
60
43
18
<5
19
48
47
38
46
60
79 (S)
79 (S)
69 (S)
81 (S)
15 (S)
––
25
30
13
38
12
––
16
31
>99 (R)
91 (R)
47 (R)
96 (R)
67 (R)
480
50
6
110
6
––
12
85
66
31
19 (S)
92 ())
81 (R)
92 (+)
f
50
a;b;c;d;e
See footnotes, Table 1.
4 h reaction time.
f
1

630
N. Bouzemi et al. / Tetrahedron Letters 45 (2004) 627–630
Table 4. PFL-catalyzed acylation of alcohols 1–8 with succinic anhydride
a
b
c
Substrate
Conversion (%)
Unreacted alcohol
Alcohol from ester saponification
E
d
e
d
e
%Yield
%Ees
%Yield
%Ee
p
f
1
2
3
4
5
6
7
8
30
67
30
50
58
32
43 (S)
78 (S)
62 (S)
13 (S)
97 (S)
––
22
37
14
11
27
>99 (R)
86 (R)
75 (R)
73 (R)
93 (R)
300
30
13
7
48
45
15
51
110
––
15
27
g
<5
15
––
58
16 (S)
47 (S)
12
85 (R)
86 (R)
h
35
a;b;c;d;e
See footnotes, Table 1.
8 h reaction time.
f
4
g
96 h reaction time.
h
72 h reaction time.
with enol esters, either much lower (as for 3) or higher
for 1). Satisfactory enantioselectivities were recorded
2. Wang, Y. F.; Lalonde, J. J.; Momongan, M.; Bergbreiter,
D. E.; Wong, C.-H. J. Am. Chem. Soc. 1988, 110, 7200–
(
7
. Terao, Y.; Tsuji, K.; Murata, M.; Achiwa, K.; Nishio, T.;
205.
only for 1, 2, 4 and 5. Under these conditions, enanti-
omers of R configuration were more reactive, and could
be isolated from saponification of the succinic mono-
ester collected in the alkaline aqueous phase. To our
delight the system succinic anhydride/CAL B resolved
3
Watanabe, N.; Seto, K. Chem. Pharm. Bull. 1989, 37,
653–1655.
1
4
. Fiaud, J.-C.; Gil, R.; Legros, J.-Y.; Aribi-Zouioueche, L.;
Konig, W. A. Tetrahedron Lett. 1992, 33, 6967–6970.
. Gutman, A. L.; Brenner, D.; Boltanski, A. Tetrahedron:
Asymmetry 1993, 4, 839–844.
1
-(3-quinolyl)ethanol 9 with higher activity and selec-
5
tivity (E ¼ 85) than IA/CAL B (E ¼ 5 in a very slow
reaction), and still better than the result we obtained
previously (E ¼ 17) using rabbit gastric lipase (RGL) as
6. (a) Ema, T.; Maeno, S.; Takaya, Y.; Sakai, T.; Utaka, M.
Tetrahedron: Asymmetry 1996, 7, 625–628; (b) Hoff, B. H.;
Anthonsen, H. W.; Anthonsen, T. Tetrahedron: Asymme-
try 1996, 7, 3187–3192; (c) Anthonsen, Y.; Hoff, B. H.
Chem. Phys. Lipids 1998, 93, 199–207; (d) Kawasaki, M.;
Goto, M.; Kawabata, S.; Kometani, T. Tetrahedron:
Asymmetry 2001, 12, 585–596.
14
the catalyst.
In conclusion, it has been shown that succinic anhydride
can be used as an acylating agent in lipase-catalyzed
kinetic resolution of benzylic-type alcohols. This pro-
cedure brings an improvement in the separation of the
product from the unreacted substrate. This has been
exemplified by a practical resolution of indanol and
hitherto now unsatisfactory resolution of 1-quinolin-3-
yl-ethanol.
7
. Nishikawa, T.; Yoshita, M.; Obi, K.; Isobe, M. Tetrahe-
dron Lett. 1994, 35, 7997–8000.
8
. Effenberger, F.; J €a ger, J. Chem. Eur. J. 1997, 3, 1370–
1374.
9. (a) Legros, J.-Y.; Toffano, M.; Fiaud, J.-C. Tetrahedron
1995, 55, 3235–3246; (b) Legros, J.-Y.; Toffano, M.;
Fiaud, J.-C. Tetrahedron: Asymmetry 1995, 6, 1899–1902;
(
c) Boutros, A.; Legros, J.-Y.; Fiaud, J.-C. Tetrahedron
Lett. 1999, 40, 7329–7332; (d) Boutros, A.; Legros, J.-Y.;
Fiaud, J.-C. Tetrahedron 2000, 56, 2239–2246; (e) Legros,
J.-Y.; Primault, G.; Toffano, M.; Rivi ꢀe re, M.-A.; Fiaud,
J.-C. Org. Lett. 2000, 2, 433–436; (f) Legros, J.-Y.;
Primault, G.; Fiaud, J.-C. Tetrahedron 2001, 57, 2507–
Acknowledgements
Financial support by the ÔAgence nationale pour la
Recherche en Sant ꢁe Õ (project no. 05/05/01/00 003) is
gratefully acknowledged. The authors are grateful to
Abdelkrim Boukhelouf and Amor Dehane for technical
assistance.
2514; (g) Legros, J.-Y.; Boutros, A.; Fiaud, J.-C.; Toffano,
M. J. Mol. Catal. A. Chem. 2003, 196, 21–25.
1
1
0. Taylor, R. J. Chem. Soc. B 1971, 36, 2382–2387.
1. PFL [E.C.3.1.1.3], lipase from Pseudomonas fluorescens
was obtained from Fluka. The specific activity was 31.5 U/
mg. The purified form (AS: 3500 U/mg) showed in our
hands both a reduced activity and enantioselectivity.
â
1
2. CAL B (Chirazyme , L-2, c.-F,C2, Lyo) from Candida
antarctica, B fraction, was purchased from Boehringer
Mannheim. The specific activity was 4500 U/g.
3. Kagan, H.; Fiaud, J.-C. Kinetic resolution. In Topics in
Stereochemistry; Eliel, E, Wilen, S. H., Eds.; Interscience,
1988. p 249.
References and Notes
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. Wong, C.-H.; Whitesides, G. M. Enzymes in Synthetic
Organic Chemistry; Pergamon: Oxford, 1994; Faber, K.
Biotransformations in Organic Chemistry; Springer: Berlin,
14. Legros, J.-Y.; Toffano, M.; Drayton, S. K.; Rivard, M.;
Fiaud, J.-C. Tetrahedron Lett. 1997, 38, 1915–1918.
1995.