The first synthesis of both enantiomers of 2-hydroxycyclobutanone acetals by enzymatic transesterification: Preparation of (R)-(+)-2- benzyloxycyclobutanone and its antipode

Article abstract of DOI:10.1016/j.tetasy.2004.04.016

A new practical enzymatic synthesis of (R)-(+)- and (S)-(-)-2- acetoxycyclobutanone acetals with 97-99.9% ee has been carried out via enzymatic transesterification of readily available racemic 2-hydroxycyclobutanone acetals. The absolute configuration has

Full text of DOI:10.1016/j.tetasy.2004.04.016

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 15 (2004) 1711–1718
The first synthesis of both enantiomers of 2-hydroxycyclobutanone
acetals by enzymatic transesterification: preparation of (R)-(+)-2-
benzyloxycyclobutanone and its antipodeq
Damien Hazelard,a Antoine Fadela,* and Georges Morgantb
aLaboratoire des Carbocycles (Associꢀe au CNRS), Institut de Chimie Molꢀeculaire et des Matꢀeriaux d’Orsay, B^at. 420,
Universitꢀe Paris-Sud, 91405 Orsay, France
bLaboratoire de Cristallochimie Bioinorganique, Facultꢀe de Pharmacie. Universitꢀe Paris-Sud, 92296 Ch^atenay-Malabry, France
Received 15 March 2004; accepted 13 April 2004
Abstract—A new practical enzymatic synthesis of (R)-(þ)- and (S)-(ꢀ)-2-acetoxycyclobutanone acetals with 97–99.9% ee has been
carried out via enzymatic transesterification of readily available racemic 2-hydroxycyclobutanone acetals. The absolute configu-
ration has been established by X-ray analysis of the corresponding (S)-naproxenyl derivative. The first preparation of enantio-
merically pure (R)-(þ)- and (S)-(ꢀ)-2-benzyloxycyclobutanones was accomplished by means of protection of the hydroxy group
followed by deacetalation reaction.
ꢀ 2004 Elsevier Ltd. All rights reserved.
1. Introduction
study the synthesis of optically active cyclobutanones by
an enzymatic reaction, following a well-known enzyme-
catalyzed transesterification.8
The synthesis of optically active a-substituted cyclobu-
tanones via asymmetric reaction has not received much
attention with only a few methods for the synthesis of
racemic a-substituted cyclobutanones1–3 being described
and rarely for the optically active compounds. Poor to
good enantiomeric excesses have been generally
obtained.4
Herein starting from readily available 2-hydroxycy-
clobutanone (ꢁ)-3 (acyloin) or the corresponding acetals
4, we report on the preparation of optically active 2-
hydroxycyclobutanone and derivatives 5, by enantio-
meric transesterification with various lipases in organic
solvents (Scheme 1).9
Over the course of our work on the asymmetric syn-
thesis of cyclic analogues of naturally occurring a-amino
acids,5 we have previously published the aminocyclo-
butane carboxylic acids 16 prepared from readily avail-
able racemic a-substituted cyclobutanones 2.6;7 We
decided in connection with our ongoing programme, to
OR'
OR'
OR'
OR'
OH
( )-4
OR'
OR'
OR2
lipase
+
OH
4a and b
5a and b
R'= Me, Et
COOH
NH2
O
O
R
Scheme 1.
*
*
OH
R
1
3
2
2. Results and discussion
q Part of this study was previously reported at the Organic Chemistry
Symposium at Villers-sur-Mer (GECO 44, September 2003), France.
* Corresponding author. Tel.: +33-1-6915-7252; fax: +33-1-6915-6278;
e-mail: antfadel@icmo.u-psud.fr
The racemic starting material 2-hydroxycyclobutanone
3 (acyloin) was easily prepared from the now commer-
cially available 1,2-bis(trimethylsilyloxy)cyclobutene 6,10
according to Conia’s procedure11a with water in acetone,
0957-4166/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2004.04.016

1712
D. Hazelard et al. / Tetrahedron: Asymmetry 15 (2004) 1711–1718
catalyzed by ferric chloride dispersed on silica gel.12
Acetals 4 (dimethyl or diethyl) were obtained by heating
compound 6, in MeOH or EtOH, respectively (Scheme
2).11b
prove either the enantiomeric excess or the yield. The
acceptable enantioselectivity (61% ee) that was obtained
with ethyl acetate after 24 h, decreased drastically to 8%
ee over 7 days, presumably due to racemisation of ester
7a in such a medium (Table 1, entries 5–8). However, the
use of a nonpolar solvent such as cyclohexane or hex-
ane, improved the enantiomeric excess to 83% or 89%,
respectively (compare entry 3, to entries 9 and 10). In
addition, we found that the enzymatic transesterification
of 3 with lipase from Pseudomonas cepacia immobilized
on Hyflo Super Cell (PSL/HSC)14 or with lipase from P.
fluorescens on Hyflo Super Cell (AKL/HSC), gave ace-
tate (þ)-7a with 62% ee or 50% ee, respectively. The
absolute configuration of acetate (þ)-7a was determined
from X-ray structure of derivative as shown below.
O
H2O, acetone
FeCl3-silica gel
OH
OSiMe3
OSiMe3
cat.
3
O-R'
R'-OH
reflux
O-R'
OH
4a : R'= Me
4b : R'= Et
6
Scheme 2.
The encouraging results obtained in the preparation of
acetate (þ)-7a, in hexane solvent (89% ee, Table 1, entry
10), prompted us to investigate the CALB-catalyzed
transesterification from the readily available 2-hydroxy
acetals 4a and 4b. Furthermore these acetals, more stable
than their corresponding cyclobutanones 3, should pre-
vent racemisation under enzymatic reaction conditions.
First, the resolution of 2-hydroxycyclobutanone (ꢁ)-3
was carried out by different lipase-catalyzed enantiose-
lective acylations (Table 1). Treatment of alcohol 3 in a
mixture of anhydrous t-butyl methyl ether (TBME) at
room temperature with 2 equiv of vinyl acetate in the
presence of immobilized Candida antarctica lipase B
(Novozymꢁ 435, CALB - 80 mg/mmol of substrate),
gave the corresponding acetate (þ)-7a in good yields.
However the enantiomeric excesses were moderate
(Table 1, entries 1–3). Remaining starting material 3,
was recovered (25–45%) without any optical activity,
due to rapid racemisation by comparison to the reported
homologue hydroxycyclopentanone,13 which showed an
optical rotation under similar conditions.
Thus, hydroxy acetal 4a, was cleanly converted into
acetates (þ)-5a and (þ)-4a with lipase CALB in hexane
in the presence of vinyl acetate with excellent enantio-
meric excesses and yields (Table 2, entries 2 and 3,
compared to entries 1 and 4). Silica gel column chro-
matographic separation of the above mixture gave (S)-
(þ)-hydroxycyclobutanone methyl acetal (þ)-4a in
39.5% yield (ee ¼ 99:9%) and (R)-(þ)-2-acetoxycyclo-
butanone methyl acetal (þ)-5a in 42% yield
(ee P 97.6%), always with a very high enantiomeric
ratio E.15 However with lipase PSL/HSC, the reaction
Changing the acyl donor, to isopropenyl acetate, methyl
isobutyrate or ethyl acetate, did not significantly im-
Table 1. Enzymatic acylation of acyloin 3 with various lipases
O
O
O
lipase
O
+
O
(+)-7
a : X= Me
b : X= i-Pr
OH
OH
( )-3
X
3
Entry Lipase
Acyl donor
Solvent
Time
Conv.
(%)a
Yield
(%)b
Alcohol 3
Y (%)
Ester (R)f
7
Y (%)
Ee (%)c
½aꢂ
D
1
CALB
CALB
CALB
CALB
CALB
CALB
CALB
CALB
CALB
CALB
PSL/HSC
AKL/HSC
Vinyl acetate
Vinyl acetate
Vinyl acetate
Vinyl acetated
Isopropenyl acetated
Methyl isobutyrated
EtOAc
TBME
TBME
TBME
TBME
TBME
TBMEe
EtOAce
EtOAce
c-Hexane
Hexane
TBMEe
TBME
5.5 h
3.5 h
70
53
71
86
83
90
83
67
84
69
76
57
86
69
25
45
30
47
41
58
58
47
49
35.8
74
35
7a
7a
7a
7a
7a
7b
7a
7a
7a
7a
7a
7a
46
41
27
41
42
38.3
30.5
12
61
8
þ23:3
þ35
þ36
þ33
þ26
þ4:4
þ52
––
2
3
3.25 h
3.75 h
4 h
59
53
53
43
4
5
49
48
21
6
7 days
24 h
<30
30
7
26
22
8
EtOAc
7 days
3.34 h
2.15 h
11 days
6 h
35
39
9
Vinyl acetate
Vinyl acetate
Vinyl acetate
Vinyl acetate
27
83
89
62
50
þ70
þ76:5
þ53:4
þ43
10
11
12
40
21.5
11.8
34
<30
43
a Conversions were measured from 1H NMR spectra.
b Global yields were calculated from isolated yields of alcohols 3 and ester 7.
c Enantiomeric excesses were measured by GC analysis using chiral column (b-cyclodextrine DM).
d With 1.2 equiv of acyl donor.
e The reaction mixture was heated at 50 ꢂC.
f The absolute configuration was determined by X-ray analysis.

D. Hazelard et al. / Tetrahedron: Asymmetry 15 (2004) 1711–1718
1713
Table 2. Transesterification with lipase in the presence of vinyl acetatef
O R'
O R'
OH
(+)-4a and b
O R'
O R'
O R'
lipase
O R'
+
O-Ac
(+)-5a and b
OH
( )-4
a: R'= Me, b: R'= Et
Entry
4
Lipase
Solvent
Time
Conv. Yield
(%)a
Hydroxy acetal (S)c
Y (%) Ee (%) ½aꢂ
Acetate (R)c
E
(%)b
4
5
Y (%) Ee (%) ½aꢂ
D
D
1
2
3
4
5
6
4a
4a
4a
4a
4a
4b
CALB
CALB
CALB
CALB
Hexane
Hexane
Hexane
TBME
22 h
47 h
78 h
48d
47
68
79
(þ)-4a 35
(þ)-4a 40
(þ)-4a 39.5
(þ)-4a 36.4
87
91
þ11
(þ)-5a 33
98.6
99.3
97.6
––
þ12:7 405
þ14:2 910
þ13:9 810
þ11:7 (þ)-5a 39
þ12:7 (þ)-5a 42
51
82
––
99.9
3
7 days ––
6 days ––
4 days 40
––
––
––
––
––
––
––
––
PSL/HSC Hexane
CALB Hexane
––
91.5
3
30e
––
64.5
––
98
––
þ2:3
––
190
(þ)-4b 56
þ14:5 (þ)-5b 35.5
a Conversions were measured from 1H NMR spectra.
b Global yields were calculated from isolated yields of hydroxy acetal 4 and acetate 5.
c Enantiomeric excesses were measured by GC analysis using chiral column (b-cyclodextrine DM), and absolute configuration was determined by
X-ray analysis.
d Small scale.
e Formation of acyloin 3 by deacetalation.
f Transesterifications were carried out in the presence of 2 equiv of vinyl acetate.
was very slow and only gave the corresponding deace-
talation product 3 in 30% yield (Table 2, entry 5).
2-hydroxy acetal (ꢀ)-4a without racemisation. Treat-
ment of the latter with benzyl bromide/NaH followed by
deacetalation as above, furnished, via acetal (ꢀ)-8a,
antipode 2-benzyloxycyclobutanone (R)-(þ)-9 without
any change in enantiomeric excess (Scheme 3).
On the other hand, hydroxy ethyl acetal 4b, was slowly
converted into the corresponding acetate (þ)-5b with
excellent enantiomeric excess. However the remaining
hydroxy acetal (þ)-4b was only recovered with 64% ee
(Table 2, entry 6).
During these studies we also noticed that (þ)-4a upon
treatment with HOAc/DCC and DMAP (cat.) afforded
2-acetoxy acetal (ꢀ)-5a with retention of configuration.
While under Mitsunobu conditions (PPh3, DEAD,
HOAc),19 acetal (þ)-4a did not give the desired (þ)-5a
with inversion of configuration. This well-known
method20 has previously been used to increase the 50%
limit for the chemical yield of one enantiomer in con-
ventional resolution, by direct treatment of the enzy-
matic reaction mixture before chromatographic
separation.
The 2-hydroxy acetals (S)-(þ)-4a and 4b, on reaction
with benzyl bromide in the presence of NaH gave the
corresponding benzyloxy acetals (þ)-8a and 8b without
racemisation as indicated by GC analysis on a chiral
column. The deprotection of acetal (þ)-8a with a cata-
lytic amount of concentrated H2SO4 on silica gel (3/
100)16 in CH2Cl2, furnished for the first time optically
active 2-benzyloxycyclobutanone (S)-(ꢀ)-9 in excellent
yield (ee > 99%). However, using much more acidic
medium (concd H2SO4/silica gel, 20/100), resulted in
partial racemisation of the expected cyclobutanone (ꢀ)-
9 (ee ¼ 56%).17
Moreover, to assign for the first time the absolute con-
figuration of the carbon bearing the hydroxy group in 4a
and 5a, many derivatives were prepared. Only the (S)-5-
chloro-naproxenyl derivative 10, prepared from the (S)-
50-chloro-Naproxen 1121–23 and hydroxy acetal (þ)-4a,
gave suitable crystals (Scheme 4).
On the other hand, the base induced hydrolysis of (R)-
(þ)-5a (>99% ee), with K2CO3/MeOH18 at 20 ꢂC, gave
H2SO4/silica gel
O
O R
O R
NaH, THF
then Br-Bn
O R
(3:100)
O R
CH2Cl2
90 %
90 %
OH
O-Bn
(S)-(-)-9
O-Bn
(+)-8a (99% ee)
(+)-4a (99% ee)
R= Me
R= Et
(+)-4b (65% ee)
(+)-8b (64% ee)
99% ee
H2SO4/silica gel
(3:100)
O R
O
O
K2CO3
MeOH
92 %
NaH
O R
O-Ac
O
(-)-4a
BnBr
CH2Cl2
91 %
O-Bn
(-)-8a
> 99% ee
O-Bn
(R)-(+)-9
> 99% ee
(+)-5a (>99% ee)
(+)-5b (98% ee)
(-)-4b
Scheme 3. Synthesis of 2-benzyloxycyclobutanone (ꢀ)-9 and its antipodes (þ)-9.

1714
D. Hazelard et al. / Tetrahedron: Asymmetry 15 (2004) 1711–1718
Cl
Cl
O
O
O
O
(+)-4a, DCC
O
O
CH2Cl2, 84 %
HO
(S)
O
(S)
(S)-11
(+)-10
Scheme 4.
The X-ray crystallographic analysis24 showed, as de-
picted in Figure 1, an (S)-configuration at the C2 centre.
Consequently the absolute configuration at C2 of the
(þ)-8a and cyclobutanone (ꢀ)-9 must be (S), while for
its antipode (ꢀ)-8a, cyclobutanone (þ)-9 and acetate
(þ)-5a, it must be (R). On the other hand, deprotection
of acetal (R)-(þ)-5a under acidic conditions (cat. H2SO4,
silica gel) gave the same acetoxycyclobutanone (þ)-7a,
obtained above by enzymatic reaction. Consequently its
absolute configuration must also be (R).
lipase from C. antarctica SP435 (CALB, immobilized on
a macroporous acrylic resin, Novo Nordisk, Denmark),
lipase from P. cepacia (PSL, Amano) was immobilized
on Hyflo Super Cell (PSL/HSC) according to Ref. 14.
Lipase from P. fluorescens (AKL, Amano).
4.1. ( )-2-Hydroxycylobutanone, 3
Prepared following the previously reported procedure11a
to a solution of 11.5 g (50 mmol) of 1,2-bis(trimethylsi-
lyloxy)cyclobutene 610 in 30 mL of acetone was added
successively 1.8 g of water (100 mmol) and a catalytic
amount (50 mg) of FeCl3/SiO2 (6/100).12 After stirring at
room temperature for 1 h and elimination of solvent, the
residue was filtered through a 2-cm pad of SiO2 eluted
with ether (80 mL). After concentration we obtained
4.25 g (94% yield) as viscous oil of pure acyloin 3, which
was used in further steps without additional purification.
Rf ¼ 0:13 (EtOAc/pentane, 3:7); IR (neat): m 3394 cmꢀ1
1
(OH), 1785 (C@O), 1400, 1275, 1140, 1075, 1037; H
NMR (CDCl3): d 1.72–1.95 (m, 1H–C3), 2.35–2.55 (m,
1H–C3), 2.60–3.00 (m, 2H–C4), 3.10 (br s, OH), 4.94
(ddt, J ¼ 8:4 Hz, J ¼ 10:5 Hz, J ¼ 2:0 Hz, 1H–C2); 13C
NMR (CDCl3): d 21.1 (C3), 38.4 (C4), 81.4 (C2), 209.3
(C1). All spectral data are identical with those previously
reported.11a
Figure 1. X-ray stereostructure of (2S,20S)-(þ)-10. Spheres are of
fixed, arbitrary radii. Some hydrogen atoms are omitted for clarity.
These results are in agreement with the usual enantio-
selectivity for the (R)-isomer generally reported for
transesterifications with C. antarctica lipase.25;26
4.2. ( )-2-Hydroxycylobutanone dimethyl acetal, 4a
3. Conclusion
Following the previously reported procedure,11b a solu-
tion of 11.5 g (50 mmol) of 1,2-bis(trimethylsilyl-
We have developed an efficient and practical chemoen-
zymatic synthesis of enantiopure (S)-(þ)-2-hydroxycy-
clobutanone acetal (þ)-4a with 35–40% yield and
87–99.9% ee, and (R)-(þ)-acetoxycyclobutanone acetal
(þ)-5a with 33–42% yield and 97.6–99.3% ee, and their
antipodes (ꢀ)-4a and (ꢀ)-5a, respectively. Application
in the preparation of (R)-(þ)-2-benzyloxycyclobutanone
(þ)-9 and its antipode (S)-(ꢀ)-9 was also accomplished
without racemisation, by means of protection and de-
acetalation with good yields. This approach should
constitute an efficient method for preparing starting
materials used in the synthesis of optically active
aminocyclobutanecarboxylic acids,6 which is currently
in progress in our laboratory.
oxy)cyclobutene
6
(easily prepared by acyloin
condensation)10 in 15 mL of MeOH was heated at reflux
for 2 h. The solvent was removed under vacuum (pres-
sure > 90 mbar, to prevent loss of volatile acetal) and the
residue purified by flash chromatography (eluent, Et2O/
pentane, 2/8 fi 5/5), to yield 5.55 g (84%) of pure a-hy-
droxy acetal 4a as a colourless oil. Rf ¼ 0:16 (EtOAc/
pentane, 2:8), tR ¼ 11:03 min for (ꢀ)-4a/11.45 min for
(þ)-4a (b-cyclodextrine DM, 110 ꢂC, 0.8 bar); IR (neat):
m 3463 cmꢀ1 (OH), 2951, 1457, 1123, 1067, 1040; 1H
NMR (CDCl3): d 1.34–1.54 (m, 1H–C3), 1.54–1.70 (m,
1H–C3), 2.00–2.20 (m, 2H–C4), 2.65 (br s, OH), 3.25 (s,
3H), 3.50 (s, 3H), 4.17 (t, J ¼ 7:6 Hz, 1H–C2); 13C NMR
(CDCl3): d 24.0 (C3), 24.6 (C4), 48.3 (CH3), 49.4 (CH3),
71.8 (C2), 103.7 (C1); MS (IC) m=z (%): 150 [MþNH4]þ
(20), 118 (100), 103 (12). All spectral data are identical
with those previously reported.11b
4. Experimental section
The general experimental procedures and the analytical
instruments employed herein have been described in
detail in a previous paper.5a Enantiomeric excesses were
also performed on a GC chiral column Cydex B,
25 m · 0.25 mm, or b-cyclodextrine DM, 40 m ·
0.25 mm, 120 ꢂC, 1 bar). Tested lipases were as follows:
4.3. ( )-2-Hydroxycylobutanone diethyl acetal, 4b
Following the same procedure11b noted above, from
11.5 g (50 mmol) of 1,2-bis(trimethylsilyloxy)cyclobut-

D. Hazelard et al. / Tetrahedron: Asymmetry 15 (2004) 1711–1718
1715
ene 6 in 18 mL of EtOH. After heating at reflux for 2 h
usual workup and flash chromatography (eluent, Et2O/
pentane, 15:85 fi 30:70), 6.80 g (85%) of the diethyl
acetal 4a was obtained as a colourless oil. Rf ¼ 0:2
(Et2O/pentane, 3:7), tR ¼ 9:90 min for (ꢀ)-4b/10.47 min
for (þ)-4b, (b-cyclodextrine DM, 120 ꢂC, 0.8 bar); IR
(neat): m 3569, 3450 cmꢀ1 (OH), 2976, 1171, 1123, 1052;
1H NMR (CDCl3): d 1.18 (t, J ¼ 7:1 Hz, 3H), 1.24 (t,
J ¼ 7:1 Hz, 3H), 1.32–1.54 (m, 1H–C3), 1.54–1.79 (m,
1H–C3), 1.90–2.20 (m, 2H–C4), 2.79 (d, J ¼ 11:1 Hz,
OH), 3.54 (br q, J ¼ 7:1 Hz, 2H), 3.65 (br q, J ¼ 7:1 Hz,
2H), 4.03–4.22 (m, 1H–C2); 13C NMR (CDCl3): d 14.9
(CH3), 15.0 (CH3), 24.6 (C3), 24.7 (C4), 56.2 (O–CH2),
57.1 (O–CH2), 72.0 (C2), 103.0 (C1); ESþMS: m=z: 183.1
[MþNa]þ; HR ES+ MS: m=z: calcd mass for
C8H16NaO3: 183.0997. Found: 183.0992.
After stirring for 7 days at 50 ꢂC (conversion <30%) and
purification by FC (eluent: ether/pentane, 1/9 fi 2/8), we
obtained 33 mg (21%) as a colourless oil of isobutyrate
(þ)-7b (12% ee) and 50 mg (58% yield) of starting acyl-
oin 3.
4.4.2.1. Data for isobutyrate (R)-(+)-7b. ½aꢂ ¼ þ4:4
D
(c 1, CHCl3); ee ¼ 12%; Rf ¼ 0:55 (EtOAc/pentane, 3:7),
tR ¼ 8:98 min for (R)-(þ)-7b/9.16 min for (ꢀ)-7b (b-cy-
1
clodextrine DM, 130 ꢂC, 1 bar); H NMR (CDCl3): d
1.19 (d, J ¼ 6:8 Hz, 3H), 1.20 (d, J ¼ 6:8 Hz, 3H), 2.00–
2.20 (m, 1H–C3), 2.40–2.70 (m, 2H, H–C3 and Hisopropyl),
2.95 (dd, J ¼ 8:0 Hz, J ¼ 9:4 Hz, 2H–C4), 5.63 (dd,
J ¼ 6:4 Hz, J ¼ 7:6 Hz, 1H–C2); 13C NMR (CDCl3): d
0
18.7 (2CH3), 19.5 (C3), 34.4 (C2 ), 40.3 (C4), 80.3 (C2),
175.6 (COO), 203.0 (C@O); HRMS m=z: calcd mass for
C8H12O3: 156.0786. Found: 156.0781.
4.4. Enzymatic transesterification: general procedure B
4.4.3. (R)-(+)-2-Acetoxycylobutanone dimethyl acetal,
(R)-(+)-5a. According to procedure B: From 5.28 g
(40 mmol) of acetal (ꢁ)-4a, and vinyl acetate (6.88 g,
80 mmol) in the presence of lipase (CALB) (2.75 g) in
hexane (65 mL). After stirring at room temperature for
78 h (conversion 51%), and purification by FC (eluent:
ether/pentane, 1:9) we isolated 2.925 g (42 %) as a col-
ourless oil of acetate (R)-(þ)-5a (97.6% ee) and 2.085 g
(39.5% yield, 99.9% ee) of hydroxy acetal (S)-(þ)-4a
To 5 mmol of substituted cyclobutanol in dry 20 mL of
t-butylmethyl ether (TBME) was added enzyme (w/w of
substrate) and vinyl acetate or other acyl donors
(10 mmol). TLC monitored the reaction mixture stirred
at room temperature under argon. When the reaction
conversion was at about 50%, the solvent was filtered off
and the cake washed with ether. The concentration of
solvent and flash chromatography (FC) gave the ex-
pected products with good yields and high enantiomeric
excesses. The recovered enzyme was recycled.
{½aꢂ ¼ þ12:7 (c 1, CHCl3)}.
D
4.4.3.1. Data for acetate, (R)-(+)-5a. ½aꢂ ¼ þ13:9 (c
D
4.4.1.
(R)-(+)-2-Acetoxycyclobutanone,
(R)-(+)-7a.
1, CHCl3); ee ¼ 97:6%; Rf ¼ 0:36 (EtOAc/pentane, 2:8),
According to procedure B: From 258 mg (3 mmol) of
acyloin 3 and vinyl acetate (516 mg, 6 mmol) in the
presence of C. antarctica lipase B (Novozymꢁ 435,
CALB) (240 mg) in hexane (15 mL). After stirring for
135 min at rt, (conversion 40%) and purification by FC
(eluent: ether/pentane, 3/7 fi 1/1), we isolated 83 mg
(21.5 %) of acetate (þ)-7a as a colourless oil (89% ee)
and 92 mg (35.8% yield) of starting acyloin 3.
tR ¼ 69:86 min for (þ)-5a/68.95 min for (ꢀ)-5a, (b-cy-
clodextrine DM, 75 ꢂC, 0.75 bar); IR (neat): m 2957 cmꢀ1
,
1
1741 (C@O), 1241, 1058, 1040; H NMR (CDCl3): d
1.68–1.87 (m, 2H), 2.13 (s, CH3 acetate), 2.10–2.30 (m,
2H), 3.23 (s, CH3), 3.30 (s, CH3), 5.02–5.15 (m, 1H–C2);
13C NMR (CDCl3): d 21.1 (CH3 ester), 21.4 (C4), 26.1
(C3), 49.1 (CH3), 49.6 (CH3), 72.5 (C2), 103.9 (C1), 170.1
(COO); MS (CI) m=z (%): 193 [Mþ1þNH4]þ (20), 192
[MþNH4]þ (100), 175 [Mþ1]þ (6), 145 (92), 144 (99),
128 (99), 104 (54); ESþ MS m=z: 197.0 [MþNa]þ; HR
ESþ MS m=z: calcd mass for C8H14NaO4: 197.0790.
Found: 197.0781.
4.4.1.1. Data for acetate (R)-(+)-7a. ½aꢂ ¼ þ77 (c 1,
D
CHCl3); ee ¼ 89%; Rf ¼ 0:4 (EtOAc/pentane, 3:7),
tR ¼ 10:11 min for (þ)-7a/11.62 min for (ꢀ)-7a (b-cy-
clodextrine DM, 120 ꢂC, 0.8 bar); IR (neat): m 2967 cmꢀ1
,
1
4.4.4. (R)-(+)-2-Acetoxycylobutanone diethyl acetal, (R)-
(+)-5b. According to procedure B: From 480 mg
(3 mmol) of ethyl acetal (ꢁ)-4b, and vinyl acetate
(516 mg, 6 mmol) in the presence of lipase (CALB)
(250 mg) in hexane (15 mL). After stirring at 20 ꢂC for 4
days, (conversion 40%) and purification by FC (eluent:
ether/pentane, 1:9) we obtained 215 mg of acetate (R)-
(þ)-5b (35.5%) as a colourless oil (98% ee) and 270 mg
(56% yield; 64.5% ee) of hydroxy acetal (S)-(þ)-4b,
1797 (C@O), 1748 (COO), 1374, 1227, 1083; H NMR
(CDCl3): d 1.93–2.23 (m, 1H–C3), 2.11 (s, 3H), 2.39–2.60
(m, 1H–C3), 2.91 (dd, J ¼ 8:0 Hz, J ¼ 10:0 Hz, 2H-C4),
5.63 (dd, J ¼ 9:0 Hz, J ¼ 9:0 Hz, 1H–C2); 13C NMR
(CDCl3): d 19.4 (C3), 20.3 (CH3), 40.3 (C4), 80.2 (C2),
169.4 (COO), 202.8 (C@O).
All spectral data are identical with those previously re-
ported.11
½aꢂ ¼ þ14:5 (c 1, CHCl3); tR ¼ 10:47 min (b-cyclodex-
D
trine DM, 120 ꢂC, 0.8 bar).
4.4.2. (R)-(+)-2-Isobutyroxycyclobutanone, (R)-(+)-7b.
According to procedure B: From 86 mg (1 mmol) of
acyloin 3 and methyl isobutyrate (122 mg, 1.2 mmol) in
the presence of lipase (CALB) (86 mg) in TBME (4 mL).
4.4.4.1. Data for acetate, (R)-(+)-5b. ½aꢂ ¼ þ2:3
D
½aꢂ ¼ þ12:5 (c 1, CHCl3); ee ¼ 98%; Rf ¼ 0:33 (Et2O/
365
pentane, 3:7), tR ¼ 170:65 min for (þ)-5b/172.43 min for

1716
D. Hazelard et al. / Tetrahedron: Asymmetry 15 (2004) 1711–1718
(ꢀ)-5b (b-cyclodextrine DM, 60 ꢂC, 1 bar); IR (neat):m
2977 cmꢀ1, 1742 (C@O), 1374, 1239, 1084, 1052; 1H
NMR (CDCl3): d 1.17 (t, J ¼ 7:1 Hz, 3H), 1.22 (t,
J ¼ 7:1 Hz, 3H), 1.65–1.88 (m, 2H), 2.08 (s, CH3 acetate),
2.10–2.23 (m, 2H), 3.37–4.62 (m, 4H), 4.97–5.10 (m, 1H–
C2); 13C NMR (CDCl3): d 15.1 (CH3), 15.4 (CH3), 21.0
(CH3 acetate), 21.5 (C4), 27.2 (C3), 57.4 (2C, O–CH2), 73.3
(C2), 103.3 (C1), 170.1 (COO); ESþ MS m=z: 225.1
[MþNa]þ; HR ESþ MS m=z: calcd mass for
C10H18NaO4: 225.1103. Found: 225.1104.
(%): 240 [M+NH4]þ (12), 208 (18), 191 (34), 176 (100),
107 (13); HR ESþ MS m=z: calcd mass for C13H18NaO3:
245.1154. Found: 245.1150.
4.6.2. (R)-())-2-Benzyloxycylobutanone dimethyl acetal,
(R)-())-8a. Following the procedure noted above: From
NaH (2.2 mmol), THF (20 mL), hydroxy methyl acetal
(R)-(ꢀ)-4a (264 mg, 2 mmol, ee ¼ 99%), BnBr (3 mmol,
360 lL), stirred at room temperature for 10 h, we ob-
tained after flash chromatography (eluent, ether/pen-
tane, 1/9 fi 3/7), 400 mg (90%) of pure benzyloxy acetal
4.5. Deprotection of acetate: general procedure C
(R)-(ꢀ)-8a as colourless oil, ½aꢂ ¼ ꢀ28 (c 1, CHCl3),
D
ee ¼ 99%. All spectral data are identical with those for
4.5.1. (R)-())-2-Hydroxycyclobutanone dimethyl acetal,
(R)-())-4a. Acetate (R)-(þ)-5a (2.090 mg, 12 mmol,
99.6% ee) was added to a suspension of K2CO138 (2.7 g,
2 equiv) in 20 mL of MeOH. The reaction mixture was
stirred at room temperature for 4 h, then filtered over
Celite and the cake washed with ether (50 mL). The
organic layer was dried over MgSO4, filtered and then
concentrated. Flash chromatography (eluent, ether/
pentane, 1:9 fi 3/7) furnished 1.460 g (92 %) of hydroxy
antipode (þ)-8a.
4.6.3. (S)-(+)-2-Benzyloxycylobutanone diethyl acetal,
(S)-(+)-8b. Following the procedure used for (S)-(þ)-
8a: From NaH (2.2 mmol), THF (20 mL), hydroxy ethyl
acetal (S)-(þ)-4b (320 mg, 2 mmol, ee ¼ 64:5%), BnBr
(3 mmol, 360 lL), stirred at room temperature for 9 h,
we obtained after flash chromatography (eluent, ether/
pentane, 1/9 fi 3/7), 450 mg (90%) of pure benzyloxy
acetal (R)-(ꢀ)-4a. ½aꢂ ¼ ꢀ12:5 (c 1, CHCl3);
D
ee ¼ 99:6% (b-cyclodextrine DM, 110 ꢂC, 0.8 bar). All
acetal (S)-(þ)-8b as colourless oil. ½aꢂ ¼ þ11:6 (c 1,
D
spectral data are identical with those noted above.
CHCl3); ee ¼ 64%; Rf ¼ 0.55 (Et2O/pentane, 3:7);
tR ¼ 253:54 min for (þ)-8b/251.48 min for (ꢀ)-8b (b-cy-
clodextrine DM, 110 ꢂC, 0.8 bar); IR (neat): m 2976 cmꢀ1
,
4.5.2. (R)-())-2-Hydroxycyclobutanone diethyl acetal,
(R)-())-4b. Following procedure C: From acetate (R)-
(þ)-5b (101 mg, 0.5 mmol, 98% ee), K2CO3 (100 mg), in
MeOH (3 mL) stirred at 20 ꢂC for 2 h, we obtained after
flash chromatography quantitatively the expected hy-
1454, 1231, 1176, 1125, 1099, 1053; 1H NMR (CDCl3): d
1.19 (t, J ¼ 7:2 Hz, 3H), 1.27 (t, J ¼ 7:2 Hz, 3H), 1.62–
1.84 (m, 2H–C3), 1.84–2.20 (m, 2H–C4), 3.41–3.75 (m, q,
J ¼ 7:2 Hz, 4H), 3.90–4.03 (m, like dt, 1H–C2), 4.58 (m,
like AB system, 2Hbenzyl), 7.26–7.47 (m, 5H); 13C NMR
(CDCl3): d 15.2 (CH3), 15.6 (CH3), 21.4 (C3), 26.2 (C4),
57.3 (O–CH2), 57.5 (O–CH2), 70.9 (CH2 benzyl), 78.8
(C2), 104.2 (C1), [6 arom. C: 127.5 (1C), 127.7 (2C),
128.2 (2C), 138.3 (1C)]; ESþ MS m=z: 273.1 [MþNa]þ;
HRMS m=z: calcd mass for [MꢀC2H4], C13H18O3:
222.1256. Found: 222.1248.
droxy (R)-(ꢀ)-4b ½aꢂ ¼ ꢀ22 (c 1, CHCl3); (ee ¼ 98%).
D
4.6. Benzyl protection: general procedure D
4.6.1. (S)-(+)-2-Benzyloxycylobutanone dimethyl acetal,
(S)-(+)-8a. To a suspension of 630 mg (15.7 mmol) of
NaH (w/w 60% in oil), washed with hexane (3 · 5 mL),
was added THF (50 mL). After cooling to 0 ꢂC, a solu-
tion of 1.24 g (9.4 mmol) of hydroxy acetal (S)-(þ)-4a
(99.6% ee) in THF (10 mL) was slowly added dropwise
then stirred at room temperature for 30 min. The mix-
ture was recooled to 0 ꢂC and 1.5 mL (12.5 mmol) of
benzyl bromide added and then stirred at rt for 9 h.
After hydrolysis with NH4Cl saturated solution (15 mL)
and extraction with Et2O (2 · 100 mL), the organic layer
was dried over MgSO4, filtered then concentrated.
Purification of the residue by FC (eluent, ether/pentane,
1:9 fi 3/7) afforded 1.88 g (90%) of the benzyloxy acetal
4.7. Deacetalation reaction into cyclobutanone:
procedure E
4.7.1. (R)-(+)-2-Benzyloxycyclobutanone, (R)-(+)-9. To a
stirred suspension of silica gel (3 g) and 90 lL of concd
H2SO4 in 5 mL of CH2Cl2, was added a solution of
16
dimethyl acetal (R)-(ꢀ)-8a (960 mg, 4.3 mmol,
ee ¼ 99:6%) in CH2Cl2 (1 mL). After stirring at room
temperature for 2 h (conversion 90%), the mixture was
filtered and the silica gel washed with CH2Cl2 (20 mL).
The organic layer was concentrated and then purified by
flash chromatography (eluent, CH2Cl2) to furnish 666
mg (88%) of pure 2-benzyloxycyclobutanone (R)-(þ)-9
(ee > 99%) and 95 mg (10%) of starting compound (R)-
(ꢀ)-8a.
(S)-(þ)-8a (ee ¼ 99:6%) as a colourless oil. ½aꢂ ¼ þ28:1
D
and ½aꢂ ¼ þ88 (c 1, CHCl3); ee ¼ 99:6%; Rf ¼ 0:56
365
(EtOAc/pentane, 2:8); tR ¼ 31:51 min/32.05 min, (b-cy-
clodextrine DM, 150 ꢂC, 1 bar); IR (neat): m 2949 cmꢀ1
,
1453, 1234, 1120, 1081, 1041; 1H NMR (CDCl3): d 1.53–
1.80 (m, 2H–C3), 1.87–2.22 (m, 2H–C4), 3.24 (s, 3H),
3.35 (s, 3H), 3.95 (m, like triplet, 1H–C2), 4.57 (m, like
AB system, 2Hbenzyl), 7.25–7.50 (m, 5H); 13C NMR
(CDCl3): d 21.2 (C3), 25.0 (C4), 49.1 (CH3), 49.3 (CH3),
70.8 (CH2 benzyl), 78.0 (C2), 104.5 (C1), [6 arom. C: 127.5
(1C), 127.7 (2C), 128.1 (2C), 137.9 (1C)]; MS (CI) m=z
4.7.1.1. Data for (R)-(+)-9. ½aꢂ ¼ þ81:2 (c 1, CHCl3);
D
ee ¼ 99:4%; Rf ¼ 0:27 (Et2O/pentane, 3:7), tR ¼
142:15 min for (þ)-9/143.11 min for (ꢀ)-9, (b-cyclodex-
trine DM, 110 ꢂC/1 bar); IR (neat): m 1786 cmꢀ1 (C@O),

D. Hazelard et al. / Tetrahedron: Asymmetry 15 (2004) 1711–1718
1717
1455, 1167; 1H NMR (CDCl3):
d
1.93 (dddd,
800, k ¼ 0:710693 A (Mo-Ka), l ¼ 0:227 mmꢀ1; 5599
reflections measured (0 6 h 6 10, 0 6 k 6 10, 0 6 l 6 48)
on a Nonius CAD4 diffractometer. The structure was
ꢁ
J ¼ 7:8 Hz, J ¼ 7:3 Hz, J ¼ 10:2 Hz, J ¼ 21:2 Hz, 1H–
C3), 2.29 (dddd, J ¼ 5:4 Hz, J ¼ 8:1 Hz, J ¼ 9:8 Hz,
J ¼ 21:2 Hz, 1H–C3), 2.60–2.91 (m, 2H–C4), 4.70 (m,
like AB system, 2Hbenzyl), 4.60–4.82 (m, 1H–C2), 7.25 (m,
5H); 13C NMR (CDCl3): d 19.5 (C3), 39.1 (C4), 71.9
(C2), 86.9 (Cbenzyl), [6 arom. C: 127.9,127.95 (2C), 128.3
(2C), 137.1], 206.5 (C1). All spectral data are identical
with those reported for the racemic compound.17
27
solved with SIR92 and refined with CRYSTALS.27
Hydrogen atom riding, refinement converged to RðgtÞ ¼
0:0540 for the 1697 reflections having I ¼ 2rðIÞ, and
wRðgtÞ ¼ 0:0565, Goodness-of-Fit S ¼ 1:1037, residual
3
ꢁ
electron density: ꢀ0.35 and 0.35 e A .
4.7.2.
(S)-())-2-Benzyloxycyclobutanone,
(S)-())-9.
Acknowledgements
According to procedure E: From 444 mg (2 mmol) of
dimethyl acetal (S)-(þ)-8a (ee ¼ 98%), we obtained after
FC 320 mg (91%) of benzyloxycyclobutanone (S)-(ꢀ)-9
ꢀ
D.H. and A.F. want to thank Mr. C. Merienne for
assistance with X-ray analysis.
(ee ¼ 98%) ½aꢂ ¼ ꢀ80 (c 1, CHCl3); tR ¼ 143:11 min,
D
(b-cyclodextrine DM, 110 ꢂC/1 bar), and 22 mg of
starting acetal (S)-(þ)-8a. All spectral data are identical
with those reported for the racemic compound.17
References and notes
1. Conia, J.-M.; Sandre, J.-P. Bull. Soc. Chim. Fr. 1963, 744.
2. (a) Vidal, J.; Huet, F. J. Org. Chem. 1988, 53, 611; (b)
Cohen, T.; Ouellette, D.; Senaratne, K. P. A.; Yu, L.-C.
Tetrahedron Lett. 1981, 22, 3377.
3. (a) Shevchuk, T. A.; Kulinkovich, O. G. Russ. J. Org.
Chem. 2000, 36, 491; (b) Wassermann, H. H.; Hearn, M.
J.; Cochoy, R. E. J. Org. Chem. 1980, 45, 2874.
4. For optically active cyclobutanones, see: (a) Fitjer, L.
Cyclobutanes. In Synthesis: by Ring Enlargement. Houben-
Weyl (Methods of Organic Chemistry); de Meijere, A.,
Ed.; Thieme: Stuttgart, 1997; Vol. E 17e, p 251; (b) Cho, S.
Y.; Cha, J. K. Org. Lett. 2000, 2, 1337; (c) Yoshida, M.;
Ismail, M. A. H.; Nemoto, H.; Ihara, M. J. Chem. Soc.,
Perkin Trans. 1 2000, 2629; (d) Nemoto, H.; Miyata, J.;
Hakamata, H.; Fukumoto, K. Tetrahedron Lett. 1995, 36,
1055; (e) Nemoto, H.; Miyata, J.; Hakamata, H.; Nag-
amochi, M.; Fukumoto, K.. Tetrahedron 1995, 51, 5511;
(f) Krief, A.; Ronvaux, A.; Arounarith, T. Tetrahedron
1998, 54, 6903; (g) Rouge, P. D.; Moglioni, A. G.;
4.8. (+)-(2S,20S)-2-[20-(500-Chloro-600-methoxynaphthalen-
200-yl)propionyloxy]cyclobutanone dimethyl acetal, (+)-10
To
a
solution of (S)-(þ)-5-chloro-Naproxen 1121
(120 mg, 0,45 mmol), (þ)-2-hydroxycyclobutanone me-
thyl acetal (þ)-4a (57 mg, 0.43 mmol), and DMAP (cat.
7 mg) in dry CH2Cl2 (4 mL) was added a solution of
dicyclohexylcarbodiimide (DCC), (100 mg, 048 mmol) in
dry CH2Cl2 (4 mL) at 0 ꢂC. The reaction mixture was
allowed to warm to room temperature with stirring for
14 h. The urea formed was filtered off, washed with
CH2Cl2 and the organic layer concentrated under vac-
uum. Silica gel column chromatography (eluent, EtOAc/
petrol ether, 5:95 fi 3/7) gave the corresponding ester
(þ)-10 (137 mg, 84% yield). Crystallisation from ether/
pentane furnished nice colourless crystals. The X-ray
analysis of these crystals showed an (2S,20S) configura-
~
Moltrasio, G. Y.; Ortuno, R. M.. Tetrahedron: Asymmetry
2003, 14, 193; (h) Ollivier, J.; Legros, J.-Y.; Fiaud, J.-C.;
€
de Meijere, A.; Salaun, J.. Tetrahedron Lett. 1990, 31,
4135.
tion.24 ½aꢂ ¼ þ5:4 (c 1, CHCl3); mp 77.9 ꢂC (from ether/
D
pentane); tR ¼ 213:95 min (Cydex B, 180 ꢂC/1.05 bar);
Rf ¼ 0:55 (EtOAc/pentane, 3:7); IR (neat): m 2941 cmꢀ1
,
1735 (C@O), 1630 and 1602 (Naphth), 1276, 1179, 1156,
5. (a) Fadel, A.; Khesrani, A. Tetrahedron: Asymmetry 1998,
9, 305; (b) Fadel, A.; Tesson, N. Eur. J. Org. Chem. 2000,
2153; (c) Tesson, N.; Dorigneux, B.; Fadel, A. Tetrahe-
dron: Asymmetry 2002, 13, 2267.
1
1073; H NMR (CDCl3): d 1.60 (d, J ¼ 7:2 Hz, 3H),
1.66–1.89 (m, 2H–C3), 2.00–2.30 (m, 2H–C4), 3.04 (s,
3H, OCH3 acetal), 3.07 (s, 3H, OCH3 acetal), 3.94 (q,
J ¼ 7:2 Hz, 1H, CHCH3), 4.04 (s, 3H, OCH3), 5.00–5.13
(m, 1H–C2), 7.01 (d, J ¼ 8:9 Hz, 1H), 7.57 (dd,
J ¼ 8:9 Hz, J ¼ 1:5 Hz, 1H), 7.68–7.79 (m, 2H), 8.16 (d,
J ¼ 8:9 Hz, 1H); 13C NMR (CDCl3): d 18.1 (CH3), 21.2
ꢀ
6. Truong, M.; Lecornue, F.; Fadel, A. Tetrahedron: Asym-
metry 2003, 14, 1063, and references cited therein.
€
7. Salaun, J.; Fadel, A.; Conia, J. M. Tetrahedron Lett. 1979,
1429.
ꢂ
8. For specialized books see: (a) Poppe, L.; Novak, L.
Selective Biocatalysis: a Synthetic approach; VCH: Wein-
0
(C3), 26.2 (C4), 44.9 (C2 ), 49.0 (CH3 acetal), 49.3
(CH3 acetal), 56.7 (CH3–O–Ar), 73.1 (C2), 103.6 (C1), [10
Naphth. C:113.7 (d), 116.5 (s), 123.6 (d), 126.1 (d), 127.4
(d), 127.6 (d), 129.3(s)þ, 130.8 (s), 136.0 (s), 152.3 (s,
€
heim, 1992; For reviews see: (b) Boland, W.; Forossl, C.;
Lorenz, M. Synthesis 1991, 1049; (c) Banfi, L.; Guanti, G..
Synthesis 1993, 1029; (d) Azerad, R.. Bull. Soc. Chim. Fr.
1995, 132, 17; (e) Schoffers, E.; Golebiowski, A.; Johnson,
C. R.. Tetrahedron 1996, 52, 3769, and references cited
therein.
C6 )], 178.3 (s, C1 ); ES MS m=z: 401.2 [MþNa]þ; HR
ESþ MS m=z: calcd mass for C20H23ClNaO5: 401.1132.
Found: 401.1135.
00
0
9. Therisod, M.; Klibanov, A. M. J. Am. Chem. Soc. 1986,
108, 5638, and references cited therein.
€
10. (a) Ruhlmann, K. Synthesis 1971, 236, and references cited
4.8.1. X-ray structure analysis of (+)-10.24 Crystal data
for (þ)-(2S,20S)-10: white crystal of 0.20 · 0.25 ·
0.30 mm. C20H23Cl1O5, M ¼ 378:85: orthorhombic sys-
tem, space group P 21, 21, 21 (No. 19), Z ¼ 4, with a ¼
therein; (b) Bloomfield, J. J.; Nelke, J. M. Org. Synth.
1977, 57, 1.
11. (a) Conia, J. M.; Barnier, J. P. Terahedron Lett. 1971,
€
4981; (b) Barnier, J. P.; Denis, J. M.; Salaun, J.; Conia, J.
M. Tetrahedron 1974, 30, 1405.
ꢁ
7:434 (3), b ¼ 7:500 (3), c ¼ 34:260 (4) A, a ¼ b ¼ c ¼
3
90ꢂ, V ¼ 1910:1 (11) A , d ¼ 1:304 g cmꢀ3, F ð000Þ ¼
ꢁ
€
12. Fadel, A.; Yefsah, R.; Salaun, J. Synthesis 1987, 37.

1718
D. Hazelard et al. / Tetrahedron: Asymmetry 15 (2004) 1711–1718
13. Easwar, S.; Desai, S. B.; Argade, N. P.; Ganesh, K. N.
Tetrahedron: Asymmetry 2002, 13, 1367.
14. Bovara, R.; Carrera, G.; Ferrara, L.; Riva, S. Tetrahedron:
Asymmetry 1991, 2, 931.
24. Crystallographic data for compound (þ)-10 has been
deposited with the Cambridge Crystallographic Data
Centre as supplementary publication number CCDC
232786. Copies of the data can be obtained, free of
charge, on application to CCDC, 12 Union Road,
Cambridge CB2 1EZ, UK. Fax: +44-1233-336033, e-mail:
deposit@ccdc.cam.ac.uk.
15. Chen, C.-S.; Fujimoto, Y.; Girdaukas, G.; Sih, C. J. J.
Am. Chem. Soc. 1982, 104, 7294, With E ¼ ln½ð1 ꢀ eesÞ
ðeep=ðees þ eepÞꢂ=ln½ð1 þ eesÞðeep=ðees þ eepÞÞꢂ and c ¼
ees=ðees þ eepÞ.
25. For recent reports of the enantioselectivity of Candida
antarctica lipase for the (R)-isomer: see (a) Forro’, E.;
16. Huet, F.; Lechevallier, A.; Pellet, M.; Conia, J. M.
Synthesis 1978, 63.
€ €
Kanerva, L. T.; Fulop, F. Tetrahedron: Asymmetry 1998,
17. For racemic compound, see: Bisel, Ph.; Breiting, E.;
Frahm, A. W. Eur. J. Org. Chem. 1998, 729.
18. (a) Green, F. R. III; Olyslager, R. J. E. Eur. Patent Appl.
EP 280.232, 1988; Chem. Abstr. 1989, 110, 37813h; (b)
Fadel, A.; Arzel, Ph. Tetrahedron: Asymmetry 1997, 8, 283.
19. Mitsunobu, O. Synthesis 1981, 1.
9, 513; (b) Conti, P.; Dallanoce, C.; De Amici, M.; De
Micheli, C.; Carrea, G.; Zambianci, F. Tetrahedron:
Asymmetry 1998, 9, 657; (c) Ziegler, T.; Bien, F.; Jurisch,
C. Tetrahedron: Asymmetry 1998, 9, 765; (d) Conde, S.;
Fierros, M.; Rodriguez-Franco, M. I.; Puig, C. Tetrahe-
dron: Asymmetry 1998, 9, 2229; (e) Bit, C.; Mitrochkine,
€
ꢀ
A. A.; Gil, G.; Pierrot, M.; Reglier, M. Tetrahedron:
Asymmetry 1998, 9, 3263.
20. (a) Vanttinen, E.; Kanerva, L. T. Tetrahedron: Asymmetry
1995, 6, 1779; (b) Virsu, P.; Liljeblad, A.; Kanerva, A.;
Kanerva, L. T. Tetrahedron: Asymmetry 2001, 12, 2447.
21. The (S)-50-chloro-Naproxen22 was readily prepared by a
26. For crystallographic data of lipase B from Candida
antarctica, which reveal a stereoscopic pocket for second-
monochlorination of (S)-Naproxenꢁ with SO2Cl2 in
ary alcohols: see Uppenberg, J.; Ohrner, N.; Norin, M.;
23
€
good yield.
Hult, K.; Kleywegt, G. J.; Patkar, S.; Waagen, V.;
Anthonsen, T.; Jones, T. A. Biochemistry 1995, 35,
16838.
22. (a) Piccolo, O.; Valoti, E.; Visentin, G. (Zambon group)
EP 0163338 A1 19851204, CAN 105: 60435, AN 1986:
460435; (b) Piccolo, O.; Spreafico, F.; Visentin, G. J. Org.
Chem. 1987, 52, 10.
23. (a) Yu, G.; Mason, H. J.; Galdi, K.; Wu, X.; Cornelius, L.;
Zhao, N.; Witkus, M.; Ewing, W. R.; Macor, J. E.
Synthesis 2003, 403; (b) Watson, W. D. J. Org. Chem.
1985, 50, 2145.
27. SIR92, A program for crystal structure solution: (a)
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