Combined lipase-catalyzed resolution/Mitsunobu esterification for the production of enantiomerically enriched arylalkyl carbinols

Article abstract of DOI:10.1016/j.tetasy.2006.02.016

Several arylalkyl carbinols [1-indanol, 1-tetralol, 1-phenylethanol, 1-(1-naphthyl)ethanol, 1-(2-naphthyl)ethanol, 1-(4-methoxyphenyl)ethanol, 1-acenaphthenol] were deracemized through sequential combinations of lipase-catalyzed resolution and Mitsunobu inversion. The corresponding (R)-acetates were obtained in 72-83% yield and 89-99% ee.

Full text of DOI:10.1016/j.tetasy.2006.02.016

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Tetrahedron: Asymmetry 17 (2006) 797–800
Combined lipase-catalyzed resolution/Mitsunobu esterification
for the production of enantiomerically enriched arylalkyl carbinols
Nassima Bouzemi,a Louisa Aribi-Zouiouechea,* and Jean-Claude Fiaudb,*
a
`
´
´
Groupe de Synthese Asymetrique et Biocatalyse, Universite de Annaba, 23000 Annaba, Algeria
bLaboratoire de Catalyse Mole´culaire, ICMMO, Universite´ de Paris-sud, F-91405 Orsay cedex, France
Received 16 January 2006; accepted 21 February 2006
Available online 24 March 2006
Abstract—Several arylalkyl carbinols [1-indanol, 1-tetralol, 1-phenylethanol, 1-(1-naphthyl)ethanol, 1-(2-naphthyl)ethanol, 1-(4-meth-
oxyphenyl)ethanol, 1-acenaphthenol] were deracemized through sequential combinations of lipase-catalyzed resolution and Mitsunobu
inversion. The corresponding (R)-acetates were obtained in 72–83% yield and 89–99% ee.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
bination of biochemical and chemical reactions.3 Methods
based on a dynamic kinetic resolution processes combine a
lipase-catalyzed kinetic resolution and a transition-metal-
catalyzed racemization of the slowly reacting enantiomer.4
Another method has been described that allows the one-
pot conversion of the racemic alcohol 1 into a nearly quan-
titative yield of one enantiomerically enriched acetate (R)-2
[or (S)-2], without the need for separation. It involves an
efficient enzyme-catalyzed resolution of the racemic alcohol
through lipase-catalyzed acylation followed by a stereo-
selective substitution of the hydroxyl group (after conver-
sion into a good leaving group) of the unreacted alcohol
with an oxygen nucleophile.5 Alternatively, the substitution
of the hydroxyl group may be achieved through a Mitsunobu
reaction by a carboxylate.4f,5a,6 Moreover, the use of acetic
acid as the pronucleophile in this latter process will afford
the acetate (R)-2.
Optically active secondary alcohols are useful intermediates
in the preparation of bioactive compounds. Lipase-cata-
lyzed kinetic resolution of racemic alcohols has proved to
be a good method to obtain enantiomerically enriched
materials.1 One of the most popular methods is to acylate
the racemic alcohol with enol acetates (vinyl or isopropenyl
acetate) to give the acetylated alcohol. Even in the case
where the enantioselectivity factor is high (E >200), this
method may have drawbacks. Indeed, at 50% conversion,
the unreacted alcohol (S)-1 [or (R)-1] and the produced ace-
tate (R)-2 [or (S)-2] show the same high ee. Since they show
close physical properties, these compounds are usually sep-
arated through silica gel chromatography. A way to avoid
this separation is to use a cyclic anhydride as an acylating
agent.2 Under these conditions, the acidic hemisuccinate
formed and the neutral unreacted alcohol can be readily
separated by base aqueous extraction. However, no more
than 50% of the desired enantiomer is obtained (Scheme 1).
2. Results and discussion
A strategy for obtaining more than 50% of one enantiomer
is to carry out an enantioconvergent process, using a com-
In the course of our studies on the enzymatic resolution of
alkyl–aryl secondary alcohols,2g,7 we applied the aforemen-
(enzyme)cat
acylating agent
c = 0.5; E > 200
PPh3, DEAD
ROH
SOH
ROAc + SOH
ROAc
+
AcOH
(R)-1
(S)-1
(R)-2
(S)-1
(R)-2
Scheme 1. Deracemization of an alcohol through a selective kinetic resolution/substitution sequence.
*
Corresponding authors. Fax: +33 1 69154680; e-mail addresses: lzouioueche@yahoo.fr; fiaud@icmo.u-psud.fr
0957-4166/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2006.02.016

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N. Bouzemi et al. / Tetrahedron: Asymmetry 17 (2006) 797–800
OH
OH
OH
OH
MeO
OH
1
2
3
OH
4
OH
OH
OMe
8
7
6
5
tioned Mitsunobu band procedure to obtain enantiomeri-
cally enriched acetates of arylalkyl carbinols 1–8 (1-aryleth-
anols 3, 4, 5, 7, 8, indanol 1, tetralol 2 and acenaphthenol
6), which are useful substrates for palladium-catalyzed cou-
pling reactions with stabilized carbanions.8
It can be seen that for alcohols 5 and 6, both conversions
and enantioselectivities go up as the catalyst amount
increases. Conversely, for substrate 1, the enantioselectivity
increases by decreasing the amount of catalyst for the same
conversion. Such studies allow us to choose the amount of
catalyst used and the reaction time for a satisfactory
enantioselectivity at ca. 50% substrate conversion (moni-
tored by chromatography). At ca. 50% conversion, the
reaction mixture was filtered (Celite) then the ee’s of the
ester produced and the unreacted alcohol measured (chiral
chromatography). To the filtrate was added PPh3
(2.4 mmol) and AcOH (2.4 mmol). The addition of diiso-
propylazodicarboxylate (DIAD) (2.4 mmol) was carried
out at 0 °C to convert the unreacted (S)-alcohol into
the (S)-acetate (room temperature, 24 h). The results are
collected in Table 4.
Racemic alcohols 1–8 (2 mmol) were treated with isopro-
penyl acetate (4 mmol) in diethyl ether (10 mL) in the pres-
ence of Candida antarctica lipase B (CAL B),9 for an
appropriate time.
A short study was undertaken for substrates 1, 5, and 6 in
order to investigate the effect of the catalyst amount with
regards to the conversion and enantioselectivity after 24–
30 h of reaction. The results are collected in Tables 1–3.
Table 1. CAL B catalyzed resolution of 1
a
a
At 50% conversion, both the produced acetate and the
unreacted alcohol showed ee >99%, except for 8, (91%
ee at 52% conversion). The acetate isolated after
Mitsunobu reaction showed either an excellent (>99%
from 1, 2, 4 substrates) or good (89–91% from 3, 5, 6, 7
substrates) enantiomeric excess. No residual alcohol was
detected.
CAL B (mg)
Conversion
eealcohol
eeacetate
Eb
150
30
12
6
0.54
0.51
0.50
0.47
0.99
0.99
0.99
0.88
0.85
0.91
0.99
0.99
60
110
>500
>500
Effect of the amount of catalyst used on the conversion and ee’s after 24–
30 h reaction: 2 mmol substrate, 10 mL diethyl ether, room temperature.
a Measured by HPLC using Chiralcel OD-H column.
b Calculated from eealcohol or eeacetate and conversion.10
Since the unreacted alcohols showed an ee >99% after the
enzymatic acylation process, the loss of enantiomeric pur-
ity of the acetate produced by the substitution step should
arise from a less than fully stereoselective substitution dur-
ing the Mitsunobu process. Such non-stereoselectivity has
yet been reported.11 The loss of stereoselectivity may arise
from a competitive unimolecular substitution process
proceeding via a benzylic carbocation. It is surprising to
see that 4 afforded a stereoselective reaction, although the
corresponding intermediate benzylic carbocation would
have been stabilized. The proper conditions to suppress
the racemization-induced process could not be found uptil
now.
Table 2. CAL B catalyzed resolution of 5
Eb
a
a
CAL B (mg)
Conversion
eealcohol
eeacetate
150
60
30
6
0.50
0.50
0.39
0.17
0.99
0.99
0.64
0.20
0.99
0.99
0.99
0.99
>500
>500
380
240
Effect of the amount of catalyst used on the conversion and ee’s after 24–
30 h reaction: 2 mmol substrate, 10 mL diethyl ether, room temperature.
a Measured by HPLC using Chiralcel OD-H column.
b Calculated from eealcohol or eeacetate and conversion.10
Table 3. CAL B catalyzed resolution of 6
Eb
a
a
CAL B (mg)
Conversion
eealcohol
eeacetate
3. Conclusion
60
30
6
0.50
0.30
0.07
0.99
0.42
0.07
0.99
0.99
0.99
>500
300
200
In conclusion, a single enantiomer of acetate of each alco-
hol 1–8 was obtained in 89–99% ee and in 70–83% yield
from the corresponding racemates, through a combined
lipase-catalyzed kinetic resolution followed by an in situ
inversion of the unreacted alcohol by a Mitsunobu
reaction.
Effect of the amount of catalyst used on the conversion and ee’s after 24–
30 h reaction: 2 mmol substrate, 10 mL diethyl ether, room temperature.
a Measured by HPLC using Chiralcel OD-H column.
b Calculated from eealcohol or eeacetate and conversion.10

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N. Bouzemi et al. / Tetrahedron: Asymmetry 17 (2006) 797–800
Table 4. Deracemization of alcohols 1–8 through a resolution/inversion process
799
Substratea
CAL B catalyzed resolutionb
Mitsunobu inversion
(R)-Acetate (% ee)c Yielde (%)
CAL B (mg)
Reaction time (h)
(S)-Alcohol (% ee)c
(R)-Acetate (% ee)c
Ed
1
12
100
50
24
24
24
24
30
30
64
24
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
91
>500
>500
>500
>500
>500
>500
>500
110
>99
>99
91
>99
89
89
90
82
82
79
76
74
72
83
81
70
2
3
4
40
5
120
120
40
6
7
8d
40
a 2 mmol substrate, 10 mL diethyl ether, room temperature.
b Conversion = 0.50.
c Ee determined by HPLC using CHIRALCEL OD-H or OB-H column.
d Calculated from eealcohol and eeacetate and conversion c = 0.510 (except for 8, where c = 0.53).
e Isolated yield.
4. Experimental
1: (S)-(+)-Indan-1-ol: HPLC (ChiralcelÒ OD-H), t(S)
=
21.3; t(R) = 24.4; (hexane/i-PrOH 98:2, flow: 0.8 mL/
4.1. General
min).12
2: (S)-(+)-1,2,3,4-Tetrahydro-1-naphthalenol: HPLC (Chi-
ralcelÒ OB-H), t(S) = 27.3; t(R) = 48.0; (hexane/i-PrOH
99:1, flow: 0.8 mL/min).12
Bruker AM 250 spectrometer, operating at 250 MHz for
1H, and at 62.5 MHz for 13C, was used for the NMR spec-
tra, which are referenced to the solvent as the internal stan-
dard. Optical rotations were determined using a Perkin–
Elmer 241 Polarimeter at room temperature using a cell
of 1 dm length and k = 589 nm.
3: (S)-(À)-1-(2-Naphthyl)ethanol: HPLC (ChiralcelÒ OD-
H), t(S) = 35.0; t(R) = 36.9 (hexane/i-PrOH 95:5, flow:
0.5 mL/min).13
4: (S)-(À)-1-(6-Methoxy-2-naphthyl)ethanol: HPLC (Chi-
ralcelÒ OD-H), t(S) = 15.0; t(R) = 18.2 (hexane/i-PrOH
90:10, flow: 1 mL/min).12
The enantiomeric excesses were measured by a chiral sta-
tionary phase HPLC on ChiralcelÒ OD-H column or a
ChiralcelÒ OB-H column. Retention times are reported in
minutes.
5: (S)-(À)-1-(1-Naphthyl)ethanol: HPLC (ChiralcelÒ OD-
H), t(S) = 9.6; t(R) = 15.0 (hexane/i-PrOH 90:10, flow:
1 mL/min).14
6: (S)-(+)-1-Acenaphthenol: HPLC (ChiralcelÒ OD-H),
t(S) = 33.2; t(R) = 36.3 (hexane/i-PrOH 97:3, flow:
1 mL/min).14
4.2. Typical procedure for synthesis of enantiomerically pure
acetates (R)-1a–8a
7: (S)-(À)-1-Phenylethanol: HPLC (ChiralcelÒ OB-H),
t(S) = 7.75; t(R) = 11.3 (hexane/i-PrOH 94:6, flow:
1 mL/min).12
Racemic alcohols 1–8 (2 mmol) were added to isopropenyl
acetate (4 mmol) in 10 mL of diethyl ether in the presence
of an adjusted amount of immobilized lipase from C. ant-
arctica B. The mixture was stirred at room temperature
for an appropriate time (see Tables 1–3) until the conver-
sion reached ca. 50% (chiral chromatography). The reac-
tion was stopped by filtering off the solid enzyme on
Celite and the solvent evaporated under reduced pressure.
8: (S)-(À)-1-(4-Methoxyphenyl)ethanol: HPLC (ChiralcelÒ
OB-H), t(S) = 31.6; t(R) = 42.35 (hexane/i-PrOH 96:4,
flow: 1 mL/min).12
The conditions for the analysis of acetates (R)-1a–8a are
reported below:
The crude mixture of the (R)-acetate and unreacted (S)-
alcohol was dissolved in 4 mL of diethyl ether. To this solu-
tion were added AcOH (0.144 g, 2.4 mmol) and PPh3
(0.628 g, 2.4 mmol). The reaction mixture was immediately
cooled to 0 °C and a solution of diisopropyl azodicarboxy-
late (DIAD) (0.48 g, 2.4 mmol) was added dropwise, under
vigorous stirring during 20 min. The mixture was allowed
to warm to room temperature and stirred for 24 h. Concen-
tration of reaction mixture in vacuo followed by silica gel
column chromatographic purification of the residue using
hexane and ethyl acetate (8:2) gave only the acetates (R)-
1a–8a in 70–83% yield.
1a: (R)-(+)-Indan-1-yl acetate: HPLC (ChiralcelÒ OD-H),
t(R) = 6.18; t(S) = 6.69; (hexane/i-PrOH 98:2, flow:
0.8 mL/min).12
2a: (R)-(+)-1,2,3,4-Tetrahydro-1-naphthalenol
acetate:
HPLC (ChiralcelÒ OB-H), t(R) = 15.6; t(S) = 17.5 (hex-
ane/i-PrOH 99:1, flow: 0.6 mL/min).12
3a: (R)-(+)-1-(2-Naphthyl)ethyl acetate: HPLC (Chiral-
celÒ OD-H), t(R) = 8.95; t(S) = 10.25 (hexane/i-PrOH
95:5, flow: 0.6 mL/min).13
4a: (R)-(+)-1-[2-(6-Methoxynaphthyl)]ethyl
acetate:
HPLC (ChiralcelÒ OD-H), t(R) = 9.87; t(S) = 10.8
(hexane/i-PrOH 90:10, flow: 0.6 mL/min).12
5a: (R)-(+)-1-(1-Naphthyl)ethyl acetate: HPLC (Chiral-
celÒ OD-H), t(R) = 8.15; t(S) = 10.2 (hexane/i-PrOH
90:10, flow: 0.6 mL/min).14
The conditions for the analysis of alcohols (R)-1–8 are
reported below:

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N. Bouzemi et al. / Tetrahedron: Asymmetry 17 (2006) 797–800
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6a: (R)-(+)-1-Acenaphthylenol-1,2-dihydro
acetate:
HPLC (ChiralcelÒ OD-H), t(R) = 11.3; t(S) = 12.8
(hexane/i-PrOH 99.3:0.7, flow: 1 mL/min).14
7a: (R)-(+)-1-Phenylethylacetate: HPLC (ChiralcelÒ OB-
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flow: 0.5 mL/min).12
8a: (R)-(+)-1-(4-Methoxyphenyl)ethyl acetate: HPLC
(ChiralcelÒ OB-H), t(S) = 31.5; t(R) = 34.7 (hexane/
i-PrOH 99.2:0.8, flow: 1 mL/min).12
Acknowledgments
´
Professor Olivier Riant (unite de chimie organique et
´
´
medicinale, universite catholique de Louvain-la-Neuve,
Belgium) is acknowledged for welcoming N. Bouzemi to
carry out HPLC measurements for ee’s determinations.
The authors are grateful to the Agence nationale pour la
´
Recherche en Sante (Algerian National research project
no. 05/05/01/00 03) for funding.
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