Lipase-catalyzed kinetic resolution of α-hydroxymethylcycloalkanones with a quaternary carbon center. Chemoenzymatic synthesis of chiral pseudoiridolactones

Article abstract of DOI:10.1016/j.tetasy.2010.04.043

The resolution of α-alkyl-α-hydroxymethylcyclopentanones 1 and cyclohexanones 3 has been efficiently achieved by using lipase-catalyzed transesterification reactions with vinyl acetate as the acylating agent. The enantiomeric selectivities were dependent

Full text of DOI:10.1016/j.tetasy.2010.04.043

Tetrahedron: Asymmetry 21 (2010) 1752–1757
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Lipase-catalyzed kinetic resolution of -hydroxymethylcycloalkanones
a
with a quaternary carbon center. Chemoenzymatic synthesis of chiral
pseudoiridolactones
Zineb Guerrab a,b, Stefan Schweiger a, Boujemâa Daou b, Mohammed Ahmar a, Bernard Cazes a,
*
a Université Lyon 1, CNRS UMR 5246-ICBMS, Laboratoire COSMO, Bât. Curien, 43 Bd du 11 Novembre 1918, F-69622 Villeurbanne, France
b Université Mohammed V-Agdal, LCPSOB, Av. Ibn Battouta, BP 1014, Rabat, Morocco
a r t i c l e i n f o
a b s t r a c t
Article history:
The resolution of a-alkyl-a-hydroxymethylcyclopentanones 1 and cyclohexanones 3 has been efficiently
achieved by using lipase-catalyzed transesterification reactions with vinyl acetate as the acylating agent.
The enantiomeric selectivities were dependent on both the ring size of the cycloalkanone and the bulk of
the carbon group located at the stereogenic quaternary center. The resolved a-alkyl-a-hydroxymethylcy-
Received 6 April 2010
Accepted 19 April 2010
Available online 24 May 2010
clopentanones 1 were used as enantiopure (or enantioenriched) precursors for the synthesis of the opti-
cally active pseudoiridolactones 6–7.
Dedicated to Henri Kagan on the occasion of
his 80th birthday
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
this field, lipases are the most frequently used catalysts, the advan-
tage of which lies on their high stability, activity in organic sol-
We recently described a new class of bicyclic d-lactones III—re-
ferred to as pseudoiridolactones—which contain a carbon group at
the bicyclic junction C-7a.1 Thus, these iridoid-like d-lactones III
feature a chiral full-carbon quaternary carbon atom and were syn-
thesized from racemic
I via an intramolecular Horner–Wadsworth–Emmons reaction
vents, and on their wide range of substrate specificities.7 Thus,
several lipase-catalyzed resolutions of primary alcohols containing
chiral quaternary carbon centers have been investigated.8–14 These
examples concern the resolutions of 2-hydroxy-2-phenylalkanols,8
a
-alkyl-
a
-hydroxymethyl-cyclopentanones
2-cyano-2-phenylhexanol,9
a 4-hydroxymethyl-4-methylcycloh-
exenic taxol intermediate,10 or tetronic acid derivatives11 and the
desymmetrization of prochiral 2,2-disubstituted 1,3-propanedi-
(HWE) as the key step (Scheme 1).
ols.12 The resolution of hydroxymethyl cyclohexenone13 and
a-tet-
ralones or a
-indanones14 was also successfully achieved.
O
P(OEt)2
Thus, in order to obtain these pseudoiridolactones III in an opti-
cally active form, we recently focused our attention to the lipase-
catalyzed resolution of the above-mentioned a-alkyl-a-hydroxym-
O
O
R'
O
R'
O
R'
7a
OH
O
n
O
R
HWE
R
ethylcyclopentanones I. To the best of our knowledge, only few of
them have been obtained in an enantiomerically pure form
through the chemical separation of racemic diastereomers,15 the
asymmetric Carroll rearrangement,16 the ozonolysis of chiral
exomethylenecyclopentanes,17 the lipase-mediated resolution of
racemic diols,18 or the catalytic asymmetric hydroxymethylation
of silicon enolates.19
Our research reported herein was extended to the homologous
cyclohexane-derived b-ketoalcohols IV (n = 2) which are also syn-
thetically useful highly functionalized chiral synthons.19
R
(n = 1)
(n = 2)
I
IV
II
III
Scheme 1. Synthesis of pseudoiridolactones.
Numerous biologically important natural products contain such
full-carbon quaternary carbon centers.2 Among them, the terpe-
noids family has many representative examples.3 Consequently,
methodologies for creating these quaternary stereocenters have
been a challenging area of research,4 and enantioselective synthe-
ses have been recently reviewed.5 Chemoenzymatic strategies
have been studied as well. Indeed, transformations based on enzy-
matic catalysis in organic solvents provide useful methods for the
synthesis of chiral molecules with high enantiomeric purity.6 In
2. Enzymatic resolution of b-ketoalcohols 1 and 3
2.1. Enzymatic resolution
We investigated the efficiency of some commercially available
* Corresponding author. Tel.: +33 4 78 08 00 20.
lipases to catalyze the transesterification of the last chiral b-ketoal-
E-mail address: bernard.cazes@univ-lyon1.fr (B. Cazes).
0957-4166/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2010.04.043

Z. Guerrab et al. / Tetrahedron: Asymmetry 21 (2010) 1752–1757
-alkyl-a-hydroxymethylcycloalkanones 1 and 3
1753
Table 1
Lipase-catalyzed transesterification of
a
O
O
O
R'
R'
R'
Lipase
OAc
20-25°C
+
OAc
OH
OH
n
n
n
R
R
R
(n = 1)
(n = 2)
(n = 1)
(n = 2)
(n = 1)
(n = 2)
2
4
1
3
1
3
Lipasea
Solvent
Time
(h)
Conversionc
(%)
Isolated
yieldd (%)
ee (%)
Eg
½
a 2D0
ꢀ
(R or S)
2 (4)
e
Entry
Substrate 1, 3
1 (3) 2 (4) 1 (3)
1 (3) 2 (4) f
O
ꢁ79.1
(S)
1
2
1a
1b
Amano PS Pentane
Amano PS Pentane
1
3
50
48
50
49
46
+58.7 (R) >99
>99
>99
1050
510
OH
O
O
ꢁ50.4
(S)
45.3
+87.8 (R) 82
OH
OH
Pentane, CH2Cl2, THF,
O(iPr)2
3
4
5
1c
1c
1c
Amano PS
120
72
0
—
Ph
O
OH
OH
Amano PS Benzene
48
50
50
47
46
49
+34.0
+81.4
ꢁ10.0
ꢁ17.0
72
78
6
Ph
O
Amano
Benzene
AK
48
>99
>99
1057
Ph
O
6
7
1d
1d
OH
OH
OH
Amano PS Pentane
96
16
0
O
O
Amano
Benzene
AK
49.7
47
48
49
49
+38.0 (R) ꢁ19.0 (S) 98
>99
98
922
525
Amano
Benzene
AK
8
1e
17
50.2
+11.0
ꢁ12.5
>99
nBu
O
O
O
9
3a
3a
Amano PS Benzene
120
72
0
—
OH
Amano
Benzene
AK
ꢁ18.0
(R)
10
46
49
44
+67.0 (S)
82
98
254
OH
OH
11
12
13
3b
3b
3b
Amano PS Benzene
120
120
11
0
—
Ph
O
Amano
Benzene
AK
OH
OH
0
—
Ph
O
Amano
Benzeneb
AK
50
45
47
+41.0 (R) ꢁ19.0 (S) 98
98
458
Ph
a
b
c
d
e
f
Reaction conditions: rac-1 (1 mmol), vinyl acetate (3 mmol), and lipase (0.5–1 weight/weight of 1 or 3) in the solvent (10 mL) were stirred at 20–25 °C.
The transesterification was carried out at 65 °C.
Conversion was calculated from the enantiomeric excess of the substrate 1(3) (ees) and of the product 2(4) (eep).20
Yield of isolated product after flash chromatography.
½
a 2D0
ꢀ
were obtained in CHCl3.
The ee of acetates 2(4) were obtained via their 1H NMR spectra in the presence of the chiral shift reagent (+)-Eu(hfc)3.
g
The enantiomeric ratio E was determined from the following equation: E = ln[1 ꢁ c(1 + eep)]/ln[1 ꢁ c(1 ꢁ eep)], where eep = product ee, ees = substrate ee; c = ees/
(ees + eep)%.20

1754
Z. Guerrab et al. / Tetrahedron: Asymmetry 21 (2010) 1752–1757
cohols ( )-1 and ( )-3. The kinetic resolutions were carried out
with vinyl acetate as an acyl donor to give the acetates 2 and 4,
along with the unreacted alcohols 1 and 3 as shown in Table 1.
The effects of the lipase, the solvent, and the temperature on the
reactivity and selectivity of the reaction were evaluated.
The ee of b-ketoalcohol (ꢁ)-1a was determined via its 1H NMR
spectrum in the presence of 50% of the chiral shift reagent (+)-
Eu(hfc)3.21 Indeed, the methyl groups located at the quaternary
carbon center of both enantiomers were well resolved (Table 1, en-
try 1). However, this procedure could not be extended to the other
b-ketoalcohols 1b–e. The ee (82%) of b-ketoalcohol (ꢁ)-1b was ob-
tained by gas chromatography on a chiral column ‘b-cyclodextrine’
(Table 1, entry 2). The ee (>99%) of b-ketoalcohol (+)-1d was deter-
mined by using 31P NMR after reaction of this b-ketoalcohol with
the derivatizing Anderson-Shapiro reagent [(+)-2-chloro-
4(R),5(R)-dimethyl-2-oxo-1,3,2-dioxaphospholane] (Table 1, entry
7).22 For the other b-ketoalcohols 1c,e and 3a,b, the ee determina-
tion was obtained after their transformation into their acetates
(2c,e and 4a,b, respectively, which were prepared by a DMAP,
catalyzed acetylation in dichloromethane). For these acetates, the
1H NMR spectra in the presence of 40–50% of the chiral shift re-
agent Eu(hfc)3 gave an easy separation of the acetate methyl groups
Table 1, entries 5, 8, 10, 13. This last NMR procedure was also used
for the ee determination of all the acetates 2 and 3 obtained directly
from the lipase-catalyzed transesterification reactions.
The first lipase tested, Amano PS (Pseudomonas cepacia), was
very efficient to resolve the
a-methyl-substituted b-ketoalcohols
1a and 1b in pentane at room temperature (entries 1 and 2). On
the contrary, it turned out to be inefficient to acylate 1c, whatever
the solvent used (pentane, CH2Cl2, THF, or diisopropylether) (entry
3). The transesterification was very slow and poorly enantioselec-
tive in benzene (entry 4). Then, another lipase, Amano AK (Pseudo-
monas fluorescens), was tested. The transesterification was also
slow to achieve a 50% conversion, but was efficient after 48 h (en-
try 5). Similar results were obtained with the b-ketoalcohol 1d. The
lipase Amano PS was unreactive with 1d (entry 6), while the reac-
tion with lipase Amano AK gave a good resolution in benzene after
16 h (entry 7). The b-ketoalcohol 1e was similarly resolved by the
lipase Amano AK in benzene (entry 8). Thus, the efficiency of reso-
lution of the chiral b-ketoalcohols 1 strongly depends on the bulk
of the substituent of the quaternary carbon atom.
The configurations of the unreacted b-ketoalcohol 1(3) and of
the acetates 2(4) given in Table 1 were established by comparison
with the known enantiomeric forms of several b-ketoalcohols 1(3):
(ꢁ)-(S)-1a,15 (+)-(R)-1b,19a (+)-(R)-1d,16 (ꢁ)-(R)-3a,13b and (ꢁ)-(S)-
3b.19 The enantioenriched b-ketoalcohol (+)-1c is known,19b but its
configuration is uncertain.
The resolution of the homologous a-hydroxymethylcyclohexa-
nones 3a–b was then studied with the same lipases. Unlike ketoalco-
hols 1a and 1c, the b-ketoalcohols 3a and 3b were unreactive with
the lipase Amano PS (compare entries 1/9 and 4/11), which demon-
strates that the efficiency of the resolution depends on the ring size
of the cycloalkanone. The b-ketoalcohol 3a was resolved by the li-
pase Amano AK in benzene (entry 10). Moreover, the b-ketoalcohol
3b was unreactive in benzene at room temperature (entry 12), but
heating the reaction mixture at 65 °C allowed the transesterification
reaction to be achieved with a good enantioselectivity (entry 13).
3. Synthesis of the chiral pseudoiridolactones 6 and 7
With the optically active a-alkyl-a-hydroxymethyl-cyclopenta-
nones 1 in hands (with ee = 82–99%), we could synthesize the chiral
pseudoiridolactones 6 and 7 through the methodology already de-
scribed (Table 2).1 The esterification of b-ketoalcohols 1 to phospho-
noacetates 5 was performed by reaction with phosphonoacetic acid
in the presence of dicyclohexylcarbodiimide DCC (74–92% yield).
The Horner–Wadsworth–Emmons reaction was achieved under
2.2. Determination of the enantiomeric excess
Several means were used to determine the enantiomeric excess
(ee) of the b-ketoalcohols 1(3) and the acetates 2(4).
Table 2
Synthesis of pseudoiridolactones 6-7 from the
a
-alkyl-
a
-hydroxymethylcyclopentanones 1
O
H
P(OEt)2
O
PO(OEt)2
CO2H
O
O
O
R'
R'
LiBr
R'
R'
R'
R'
4
H2
R'
R'
4a
O
NEt3
OH
O
O
O
cat Pd/C
0-20°C
DCC
R
R
R
R
DMAP
0-20°C
1
5
6
7
a 2D0
ꢀ
½
a 2D0
ꢀ
½ ꢀ
a 2D0
b
b
b
Entry
1
1
ee (%) (R or S)
b-Ketoalcohol 1
5 Yielda (%)
6 Yielda (%)
7 Yielda (%)
½
O
(ꢁ)-1a
(ꢁ)-1b
>99 (S)
92
ꢁ38.5
ꢁ32.4
86
+208.9
+184.4
97
+82.0
+28.6
OH
O
2
3
82 (S)
74
90
80
81
96
94
OH
O
OH
(+)-1c
(+)-1d
(+)-1e
99
+30.1
+28.5
ꢁ16.0
+52.4
+83.4
ꢁ34.0
ꢁ27.0
+26.4
Ph
O
93c
97
OH
4
5
98 (R)
78
76
84
80
O
OH
99
+101.0
nBu
a
b
c
Yield of isolated product after flash chromatography.
were obtained in CHCl3 (c ꢂ1).
The fully saturated lactone 7f is obtained in place of lactone 7d.
½ ꢀ
a 2D0

Z. Guerrab et al. / Tetrahedron: Asymmetry 21 (2010) 1752–1757
1755
mild conditions (LiBr, NEt3 at 0–20 °C) to give the unsaturated bicy-
clic-d-lactones 6 (80–86% yield). Finally, catalytic hydrogenation of
the C-4/C-4a double bond gave the pseudoiridolactones 7 (93–97%
yield). Of course, in the case of the d-lactone 6d, the catalytic hydro-
genation gave directly the fully saturated pseudoiridolactone 7f in
place of pseudoiridolactone 7d (Table 2, entry 4). As these transfor-
mations do not involve the quaternary carbon atom, the configura-
tion of this carbon was retained within molecules 5–7.
(80 mg, 0.31 mmol) in toluene (30 mL) was refluxed in a round-
bottomed flask equipped with a Dean–Stark system. After comple-
tion of the reaction, toluene was evaporated and Et2O (20 mL) was
added. The organic solution was washed twice with 5% aqueous
NaHCO3 (2 ꢃ 6 mL) and 5% aq NaCl (2 mL). The resulting aqueous
phases were extracted with ether (2 ꢃ 10 mL). The combined or-
ganic phases were dried over MgSO4. After evaporation of the sol-
vents, the crude oil was purified by flash chromatography (PE/EE
60:40) to give the b-ketal-ester as a colorless oil (1.42 g, 98%).
Rf = 0.50 (PE/EE 50:50). 1H NMR (300 MHz, CDCl3) d: 4.15 (q,
3J = 7.1 Hz, 2H, OCH2CH3), 3.90–3.98 (m, 4H, OCH2CH2O), 2.02–
2.10 (m, 1H, CqCHaHb), 1.85–1.89 (CqCHaHb), 1.50–172 (m, 4H,
2 ꢃ CH2), 1.35–1.46 (m, 2H, CH2), 1.26 (t, 3J = 7.1 Hz, 3H, OCH2CH3),
1.25 (s, 3H, CqCH3).
4. Conclusion
The kinetic resolution of various
a-alkyl-a-hydroxymethyl-
cyclopentanones 1 and cyclohexanones 3 was performed by a li-
pase-catalyzed transesterification with vinyl acetate as the acylat-
ing agent in organic solvents with an enantiomeric ratio E superior
to 250. The efficiency of the resolution was dependent on the ring
size of the substrate and on the bulkiness of the carbon group on
5.2.2. 2-Hydroxymethyl-2-methylcyclohexanone 3a25
Step 1: The above-mentioned ketal-ester (1.42 g, 6.22 mmol)
was slowly added to a stirred suspension of lithium aluminum hy-
dride (260 mg, 6.85 mmol) in ether (10 mL) stirred at 0 °C under a
nitrogen atmosphere. After 1 h, the hydrolysis of the reaction mix-
the quaternary
a
-carbon atom. The enantiopure (or enantioen-
riched) -alkyl-
a
a-hydroxymethylcyclopentanones 1 so obtained
were the precursors of the optically active pseudoiridolactones 6–7.
ture was performed by adding successively H2O (282
lL), a 5%
NaOH solution (282 L). The mixture
l
L), and then water (2 ꢃ 282
l
5. Experimental
was stirred for 0.5–1 h until a white precipitate appeared. This solid
was filtered on a sintered glass filter. The organic phase was evap-
orated under vacuum to give a crude b-ketal-alcohol as a yellow oil
(quantitative yield) which was used directly in the next step.
Step 2: 2 M HCl (1.8 mL) was added to a solution of the crude b-
ketal-alcohol in ether (10 mL) at room temperature. After stirring
for 2 h, the organic phase was successively washed with saturated
NaHCO3 (5 mL), then brine before drying over anhydrous Na2SO4.
After evaporation of the solvent, purification by flash chromatogra-
phy (PE/EE 60:40) afforded the already known25 2-hydromethyl-2-
methylcyclohexanone 3a (804 mg, 92%). Rf = 0.20 (PE/EE 50:50). IR
5.1. Methods and materials
Dichloromethane and ether were distilled from calcium hydride
and stored under nitrogen. Thin-layer chromatography (TLC) was
performed using precoated Kieselgel 60 F254 plates (Merck). Detec-
tion was done by UV (254 nm) followed by charring with 4% p-
anisaldehyde, 5% acetic acid, and 5% sulfuric acid in 86% ethanol.
Flash chromatography was performed on Silica Gel 60 (40–
63 l
m, Merck) and refers to the procedure of Still.24 IR spectra
were recorded on a Perkin–Elmer 298 spectrophotometer and ob-
tained from thin films on NaCl plates for oils. 1H and 13C NMR spec-
tra were respectively recorded at 300 MHz and 75 MHz on a Bruker
DRX 300. 1H and 13C NMR chemical shifts were obtained in CDCl3
and reported in ppm relative to CHCl3 (1H: d = 7.26) and CDCl3 (13C:
d = 77.16) as internal standards, respectively. Multiplicities are de-
scribed as s (singlet), d (doublet), t (triplet), q (quartet), m (multi-
plet); coupling constants (J) are reported in hertz. Optical rotation
was measured with a Perkin–Elmer 141 polarimeter. PE refers to
petroleum ether and EE to ethyl ether.
Lipases Amano PS (P. cepacia) and Amano AK (P. fluorescens)
were supplied by Amano Pharmaceutical Co. Ltd, Japan. The shift
reagent Europium tris[3-(heptafluoropropylhydroxymethylene)-
(+)-camphorate],21 (+)-Eu(hfc)3, and the derivatizing agent (+)-2-
chloro-4(R),5(R)-dimethyl-2-oxo-1,3,2-dioxaphospholane22 were
purchased from Aldrich and Fluka, respectively.
(neat): 3420, 2940, 1700, 1450, 1310, 1120, 1040, 900, 800 cmꢁ1
.
1H NMR (300 MHz, CDCl3) d: 3.56 (d, 2J = 11.4 Hz, 1H, CHaHbOH),
3.42 (d, 2J = 11.4 Hz, 1H, CHaHbOH), 2.63 (t, 3J = 7.1 Hz, 1H, CqCH2),
2.45 (dd, 2J = 14.3 Hz, 3J = 6.2 Hz, 1H, CHaHb–CO), 2.27 (dd,
2J = 14.3 Hz, 3J = 4.6 Hz, 1H, CHaHb–CO), 1.55–1.85 (m, 5H,
2 ꢃ CH2 and OH), 1.19 (s, 3H, CqCH3). 13C NMR (75.5 MHz, CDCl3)
d: 218.5 (C@O), 69.4 (CH2OH), 50.5 (Cq), 39.4 (CH2–CO), 35.9
(CqCH2), 27.7, 21.1 and 20.6 (3 ꢃ CH2).
5.3. General procedure for the lipase-catalyzed asymmetric
transesterification of b-ketoalcohols 1 and 3
The racemic b-ketoalcohol 1 (or 3) (1 mmol) and vinyl acetate
(3 mmol) were dissolved in the appropriate organic solvent
(10 mL/mmol). The lipase (0.5–1 weight/weight of 1 or 3) was then
added. The reaction mixture was stirred at the defined conditions
and was monitored by TLC and gas chromatography. When the
maximum conversion was reached, the reaction was terminated
by filtration over Celite, eluting with ether. The acetate 2 (or 4)
and the recovered b-ketoalcohol 1 (or 3) were separated by flash
chromatography over silica (petroleum ether/diethyl ether 50:50).
The racemic 2-hydroxymethyl-2,4,4-trimethylcyclopentanone
1a,1b 2-hydroxymethyl-2-methylcyclopentanone 1b,1b 2-hydroxy-
methyl-2-benzylcyclopentanone 1c,1b 2-hydroxymethyl-2-allylcy-
clopentanone 1d,1b 2-hydroxymethyl-2-butylcyclopentanone 1e,1b
and 2-hydroxymethyl-2-benzylcyclohexanone 3b1b were synthe-
sized following literature procedures.
5.3.1. 2-Acetoxymethyl-2,4,4-trimethylcyclopentanone 2a
Following the general transesterification procedure, a mixture
of b-ketoalcohol 1a (200 mg, 1.28 mmol), vinyl acetate (330 mg,
3.84 mmol), and the crude enzyme Amano PS (128 mg) in pentane
(15 mL) was stirred at 25 °C for 1 h. Purification by flash chroma-
tography gave the acetate 2a (125 mg, 49%) and the recovered
alcohol 1a (96 mg, 48%).
5.2. Synthesis of 2-hydroxymethyl-2-methylcyclohexanone 3a
2-Hydroxymethyl-2-methylcyclohexanone 3a was prepared
through the reduction of the diethylketal of the known ethyl 1-
methyl-2-oxocyclohexanecarboxylate23 as follows.
5.2.1. Ethyl 1-methyl-(2,2-ethylenedioxy)cyclohexane-
carboxylate23
Acetate (+)-(R)-2a: Rf = 0.45 (PE/EE 50:50); ½a D20
¼ þ58:7 (c 1.05,
ꢀ
CHCl3); ee >99%. 1H NMR (300 MHz, CDCl3) d: 3.95 (d, 2J = 10.7 Hz,
1H, CHaHb–OAc), 3.90 (d, 2J = 10.7 Hz, 1H, CHaHb–OAc), 2.25 (d,
2J = 17.3 Hz, 1H, (C-5)HaHb), 2.17 (d, 2J = 17.3 Hz, 1H, (C-5)HaHb),
A solution of ethyl 1-methyl-2-oxocyclohexanecarboxylate23
(1.16 g, 6.3 mmol), ethyleneglycol (700 mg, 7.9 mmol), and PTSA

1756
Z. Guerrab et al. / Tetrahedron: Asymmetry 21 (2010) 1752–1757
2.02 (s, 3H, CO–CH3), 1.98 (d, 2J = 13.6 Hz, 1H, (C-3)HaHb), 1.68 (d,
2J = 13.6 Hz, 1H, (C-3)HaHb), 1.14 (s, 3H, gem-CH3), 1.12 (s, 3H,
gem-CH3), 1.11 (s, 3H, (C-2)CH3). 13C NMR(75 MHz, CDCl3) d:
224.0 (C-1, C@O), 171.3 (C@O, ester), 70.1 (CH2–OAc), 55.0 (C-5),
52.1 (C-2), 39.5 (C-3), 30.3 (gem-CH3), 30.2 (gem-CH3), 21.5 (CH3–
CO), 17.4 (C-4), 16,4 ((C-2)CH3).
Acetate (ꢁ)-2e: Rf = 0.40 (PE/EE 50:50); ½a D20
¼ ꢁ12:5 (c 1.0,
ꢀ
CHCl3); ee = 99%. 1H NMR(300) MHz, CDCl3) d: 4.20 (d,
2J = 10.7 Hz, 1H, CHaHb–OAc), 4.02 (d, 2J = 10.7 Hz, 1H, CHaHb–
OAc), 2.10 (s, 1H, CO–CH3), 2.0–2.03 (m, 1H, C(5)HH), 1.55–1.85
(m, 1H + 4H, C(5)HH and 2 ꢃ CH2), 1.32 (t, 3J = 7.1 Hz, 2H,
C(2)CH2), 1.18 (m, 4H, 2 ꢃ CH2), 0.90 (t, 3J = 6.6 Hz, 3H, CH3).
Ketolcohol (ꢁ)-(S)-1a: ½a D20
ꢀ
¼ ꢁ79:1 (c 1.00, CHCl3), ee >99%.
Ketoalcohol (+)-1e: ½a D20
¼ þ11 (c 1.0, CHCl3); ee = 99%.
ꢀ
5.3.6. 2-Acetoxymethyl-2-methylcyclohexanone 4a27
Following the general transesterification procedure, a mixture
of b-ketoalcohol 3a (100 mg, 0.7 mmol), vinyl acetate (181 mg,
2.1 mmol), and lipase P. fluorescens AK (70 mg) in benzene (5 mL)
was stirred at 20 °C for 72 h. Purification by flash chromatography
gave the acetate 4a (56 mg, 44%) and the recovered alcohol 3a
(49 mg, 49%).
5.3.2. 2-Acetoxymethyl-2-methylcyclopentanone 2b
Following the general transesterification procedure, a mixture
of b-ketoalcohol 1b (657 mg, 5.13 mmol), vinyl acetate (1.32 g,
15.4 mmol), and the crude enzyme Amano PS (400 mg) in pentane
(40 mL) was stirred at 25 °C for 3 h. Purification by flash chroma-
tography gave the acetate 2b (402 mg, 46%) and the recovered
alcohol 1b (328 mg, 50%).
Acetate (+)-(R)-2b: Rf = 0.38 (PE/EE 50:50); ½a D20
¼ þ87:8 (c
ꢀ
Acetate (ꢁ)-(R)-4a: Rf = 0.44 (PE/EE 50:50); ½a D20
¼ ꢁ18 (c 1.09,
ꢀ
1.02, CHCl3), ee >99%. 1H NMR (300 MHz, CDCl3) d: 4.05 (d,
2J = 10.8 Hz, 1H, CHaHb–OAc), 3.45 (d, 2J = 10.8 Hz, 1H, CHaHb–
OAc), 2.2–2.4 (m, 2H, 5-H), 2.01 (s, 3H, CO–CH3), 1.7–1.8 (m, 4H,
4H, 3-H and 4-H), 1.01 (s, 3H, (C-2)CH3). 13C NMR(75 MHz, CDCl3)
d: 220.9 (C-1, C@O), 171.2 (C@O, ester), 68.2 (CH2–OAc), 48.6 (C-2),
38.3 (C-5), 33.7 (C-3), 21.2 (CH3–CO), 20.0 (CH3), 19.1 (C-4).
CHCl3); ee = 98%. 1H NMR (300 MHz, CDCl3) d: 4.20 (d, 2J = 11.1 Hz,
1H, CHaHb–OAc), 4.14 (d, 2J = 11.1 Hz, 1H, CHaHb–OAc), 2.42–2.45
(m, 1H, (C-6)HH), 2.06 (s, 3H, CO–CH3), 1.75–1.93 (m, 7H, (C-
6)HH and 3 ꢃ CH2), 1.17 (s, 3H, (C-2)CH3).
Ketoalcohol (+)-(S)-3a: ½a D20
¼ þ67 (c 1.01, CHCl3); ee = 82%.
ꢀ
Ketoalcohol (ꢁ)-(S)-1b: ½a D20
¼ ꢁ50:4 (c 1.0, CHCl3), ee = 82%
ꢀ
5.3.7. 2-Acetoxymethyl-2-benzylcyclohexanone 4b
Following the general transesterification procedure, a mixture
of b-ketoalcohol 3b (109 mg, 0.5 mmol), vinyl acetate (129 mg,
1.5 mmol), and lipase P. fluorescens AK (50 mg) in benzene (5 mL)
was stirred at 65 °C for 18 h. Purification by flash chromatography
gave the acetate 4b (59 mg, 45%) and the recovered alcohol 3b
(51 mg, 47%).
determined by gas chromatography using a Shimadzu GC-14A
chromatograph equipped with a chiral capillary column Cyclodex
btm (60 m ꢃ 0.25 mm ID ꢃ 0.25
l
film): N2 carrier gas
(ꢂ1 cm3 minꢁ1); temperature program from 40 °C to 200 °C at
5 °C minꢁ1; tR((+)-1b) = 30.5 min, and tR((ꢁ)-1b) = 31.2 min.
5.3.3. 2-Acetoxymethyl-2-benzylcyclopentanone 2c26
Following the general transesterification procedure, a mixture
of b-ketoalcohol 1c (120 mg, 0.59 mmol), vinyl acetate (152.2 mg,
1.77 mmol), and the enzyme P. fluorescens AK (59 mg) in benzene
(8 mL) was stirred at 25 °C for 48 h. Purification by flash chroma-
tography gave the acetate 2c (68 mg, 47%) and the recovered alco-
hol 1c (49 mg, 49%).
Acetate (ꢁ)-(S)-4b: Rf = 0.50 (PE/EE 50:50); ½a D20
¼ ꢁ19 (c 1.05,
ꢀ
CHCl3); ee = 98%. 1H NMR (300 MHz, CDCl3) d: 7.22–7.26 (m, 5H,
H
arom), 4.78 (d, 2J = 11.5 Hz, 1H, CHaHb–OAc), 4.51 (d, 2J = 11.5 Hz,
1H, CHaHb–OAc), 3.38 (d, 2J = 13.7 Hz, 1H, CHaHb–Ph), 3.10 (d,
2J = 13.7 Hz, 1H, CHaHb–Ph), 2.77 (t, 3J = 6.6 Hz, 2H, CH2–CO), 2.39
(s, 3H, CO–CH3), 1.90–1.96 (m, 6H, 3 ꢃ CH2).
Ketoalcohol (+)-(R)-3b: ½a D20
¼ þ40 (c 1.03, CHCl3); ee >99%.
ꢀ
Acetate (ꢁ)-2c: Rf = 0.40 (PE/EE 50:50); ½a D20
¼ ꢁ17 (c 1.1,
ꢀ
CHCl3); ee >99%. 1H NMR (300 MHz, CDCl3) d: 7.1–7.40 (m, 5H, Har-
om), 4.09 (s, 2H, CH2–OAc), 2.88 (d, 2J = 13.4 Hz, 1H, CHaHb–Ph),
2.69 (d, 2J = 13.4 Hz, 1H, CHaHb–Ph), 2.06 (s, 3H, CO–CH3), 1.50–
2.20 (m, 6H, 3 ꢃ CH2).
6. Synthesis of the pseudoiridolactones 6–7
The synthesis of the optically active pseudoiridolactones 6–7
was achieved as previously described for the racemic form of these
same pseudoiridolactones.1b The yields and the optical rotations
Ketoalcohol (+)-1c: ½a D20
¼ þ81:4 (c 1.00, CHCl3), ee >99%.
ꢀ
½
a 2D0
ꢀ
(ꢂ1, CHCl3) are given in Table 2. Their spectroscopic data
5.3.4. 2-Acetoxymethyl-2-allylcyclopentanone 2d
are all given in Ref. 1b.
Following the general transesterification procedure, a mixture
of b-ketoalcohol 1d (100 mg, 0.65 mmol), vinyl acetate
(167.7 mg, 1.95 mmol), and P. fluorescens AK (65 mg) in benzene
(6 mL) was stirred at 25 °C for 16 h. Purification by flash chroma-
tography gave the acetate 2d (60 mg, 47%) and the recovered alco-
hol 1d (49 mg, 49%).
Acknowledgments
We thank Université Claude Bernard-LYON and CNRS for finan-
cial support. One of us (Z. Guerrab) gratefully thanks the Région
Rhône-Alpes for a Ph.D. Fellowship (MIRA program). S. Schweiger
also thanks the European Erasmus program for a fellowship.
Acetate (ꢁ)-(S)-2d: Rf = 0.42 (PE/EE 50:50); ½a D20
¼ ꢁ19 (c 1.01,
ꢀ
CHCl3); ee = 99%. 1H NMR (300 MHz, CDCl3) d: 5.70 (ddt,
3
3Jtrans = 17.3 Hz, Jcis = 9.6 Hz, 1H, 3J = 7.5 Hz, CH@CH2), 5.13 (d,
3
4
3Jtrans = 17.3 Hz, 1H, C@CHH), 5.09 (dt, Jcis = 9.6 Hz, Jallyl = 1.0 Hz,
1H, C@CHH), 4.09 (d, 2J = 10.9 Hz, 1H, CHaHb–OAc), 4.03 (d, 2J =
10.9 Hz, 1H, CHaHb–OAc), 2.22–2.30 (m, 4H, CH2–CO and CH2–
CH@CH2), 2.10–2.20 (m, 4H, 2 ꢃ CH2), 2.03 (s, 3H, CO–CH3).
References
1. (a) Guerrab, Z.; Daou, B.; Fkih-Tetouani, S.; Ahmar, M.; Cazes, B. Tetrahedron
Lett. 2003, 44, 5727–5730; (b) Guerrab, Z.; Daou, B.; Fkih-Tetouani, S.; Ahmar,
M.; Cazes, B. Tetrahedron 2007, 63, 3367–3379.
Ketoalcohol (+)-(R)-1d: ½a D20
¼ þ38 (c 1.05, CHCl3); ee = 98%.
ꢀ
2. For recent examples in the literature, see: (a) Overman, L. E. Pure Appl. Chem.
1994, 66, 1423–1430; (b) Gotchev, D. B.; Copmins, D. L. J. Org. Chem. 2006, 71,
9393–9402; (c) Acherar, S.; Audran, G.; Cecchin, F.; Monti, H. Tetrahedron 2004,
60, 5907–5912; (d) Nicolau, K. C.; Gray, D. L. F. J. Am. Chem. Soc. 2004, 126, 607–
612; (e) Campbell, E. L.; Zuhl, A. M.; Liu, C. M.; Boger, D. L. J. Am. Chem. Soc.
2010, 132, 3009–3012; (f) Tonder, J. E.; Hosseini, M.; Ahrenst, A. B.; Tanner, D.
Org. Biomol. Chem. 2004, 2, 1447–1455; (g) Chandra, H.; Pigza, J. A.; Han, J.-S.;
Mutnick, D.; Johnston, J. N. J. Am. Chem. Soc. 2009, 131, 3470–3471.
5.3.5. 2-Acetoxymethyl-2-butylcyclopentanone 2e
Following the general transesterification procedure, a mixture
of b-ketoalcohol 1e (900 mg, 5.3 mmol), vinyl acetate (1.38 g,
15.9 mmol), and lipase Amano AK (530 mg) in benzene (50 mL)
was stirred at 25 °C for 17 h. Purification by flash chromatography
gave the acetate 2e (548 mg, 49%) and the recovered alcohol 1e
(433 mg, 48%).
3. For examples in the terpenoid area, see: (a) Drege, E.; Tominiaux, C.; Morgant,
G.; Desmaële, D. Eur. J. Org. 2006, 4825–4840; (b) Trost, B. M.; Dong, L.;
Schroeder, C. M. J. Am. Chem. Soc. 2005, 127, 10259–10268; (c) Yoda, H.;

Z. Guerrab et al. / Tetrahedron: Asymmetry 21 (2010) 1752–1757
1757
Maruyama, K.; Takabe, K. Tetrahedron Lett. 2003, 44, 1775–1777; (d) Barriault,
L.; Denissova, I. Org. Lett. 2002, 4, 1371–1374.
4. (a) Martin, S. F. Tetrahedron 1980, 36, 419–460; (b) Fuji, K. Chem. Rev. 1993, 93,
2037–2066.
5. (a) Cozzi, P. G.; Hilgraf, R.; Zimmermann, N. Eur. J. Org. 2007, 5969–5994; (b)
Bella, M.; Gasperi, T. Synthesis 2009, 1583–1614.
13. (a) Yamada, Y.; Nagaoka, H.; Inoue, T.; Sagawa, S.; Miyaoka, H. Chem. Pharm.
Bull. 2002, 42, 405–407; (b) Yamada, Y.; Suma, A.; Hara, A.; Kajiwara, Y.;
Miyaoka, H. Tetrahedron: Asymmetry 1999, 10, 3189–3196.
14. Mahapatra, T.; Nanda, N. J. Tetrahedron: Asymmetry 2008, 19, 1224–1232.
15. Kunisch, F.; Hobert, K.; Welzel, P. Tetrahedron Lett. 1985, 26, 5433–5436.
16. Enders, D.; Knopp, M. Tetrahedron 1996, 52, 5805–5818.
6. (a) Klibanov, A. M. Acc. Chem. Res. 1990, 23, 114–120; (b) Santaniello, E.;
Ferraboschi, P.; Grisenti, P.; Manzocchi, A. Chem. Rev. 1992, 92, 1071–1140; (c)
Wong, C.-H.; Whitesides, G. M. Enzymes in Organic Chemistry; Pergamon:
Oxford, 1994; (d) Faber, K. Pure Appl. Chem. 1997, 69, 1613–1632; (e) Faber, K.
Biotransformations in Organic Chemistry, 4th ed.; Springer: Berlin, 2000.
7. Chen, C.-S.; Sih, C. J. Angew. Chem., Int. Ed. 1989, 28, 695–707.
8. Kellogg, R. M.; Hof, R. P. Tetrahedron: Asymmetry 1994, 5, 565–568.
9. Cheong, C. S.; Kim, I. O. Biotechnol. Lett. 1996, 18, 1419–1422.
10. Johnson, C. R.; Xu, Y.; Nicolau, K. C.; Yang, Z.; Guy, R. K. Tetrahedron Lett. 1995,
36, 3291–3294.
17. Cho, S. Y.; Shibasaki, M. Tetrahedron: Asymmetry 1998, 9, 3751–3754.
18. Tanaka, H.; Kozuki, Y.; Ogasawara, K. Tetrahedron Lett. 2002, 43, 4175–4178.
19. (a) Ishikawa, S.; Hamada, T.; Manabe, K.; Kobayashi, S. J. Am. Chem. Soc. 2004,
126, 12236–12237; (b) Kobayashi, S.; Ogino, T.; Shimizu, H.; Ishikawa, S.;
Hamada, T.; Manabe, K. Org. Lett. 2005, 7, 4729–4731.
20. Chen, C. S.; Fujimoto, Y.; Girdaukas, G.; Sih, C. S. J. Am. Chem. Soc. 1982, 104,
7294–7299.
21. Fraser, R. R.. In Asymmetric Synthesis; Morrison, J. D., Ed.; Academic Press: New
York, 1983; Vol. 1, pp 173–196.
22. Anderson, R. C.; Shapiro, M. J. J. Org. Chem. 1984, 49, 1304–1305.
23. Winfield, C.; Al-Mahrizy, Z.; Gravestock, M.; Bugg, T. D. H. J. Chem. Soc., Perkin
Trans. 1 2000, 3277–3289.
11. Tauchi, T.; Sakuma, H.; Ohno, T.; Mase, N.; Yoda, H.; Takabe, K. Tetrahedron:
Asymmetry 2006, 17, 2195–2198.
12. (a) Akai, S.; Naka, T.; Takebe, Y.; Kita, Y. Tetrahedron Lett. 1997, 38, 4243–4246;
(b) Akai, S.; Naka, T.; Fujita, T.; Takebe, Y.; Tsujino, T.; Kita, Y. J. Org. Chem. 2002,
67, 411–419; (c) Chênevert, R.; Duguay, D.; Touraille, F.; Caron, D. Tetrahedron:
Asymmetry 2004, 15, 863–866.
24. Still, W. C.; Khan, M.; Mitra, A. J. Org. Chem. 1978, 43, 2923–2925.
25. Heinz, U.; Adams, E.; Klintz, R.; Welzel, P. Tetrahedron 1990, 46, 4217–4230.
26. Hirano, F.; Wakabayashi, S. Bull. Chem. Soc. Jpn. 1975, 48, 2579–2583.
27. Brindaban, R.; Dutta, P.; Sarkar, A. J. Chem. Soc., Perkin Trans. 1 2000, 2223–2225.