Chemoenzymatic synthesis of diastereomeric ethyl γ-benzyl paraconates and determination of the absolute configurations of their acids

Article abstract of DOI:10.1016/j.tetasy.2006.08.013

Enantiopure (99% ee) cis- and trans-γ-benzylparaconic acids and their ethyl esters were synthesized by a procedure involving kinetic enzymatic resolution of the corresponding lactonic esters with α-chymotrypsin (α-CT) with acetone added as a cosolvent. Th

Full text of DOI:10.1016/j.tetasy.2006.08.013

Tetrahedron: Asymmetry 17 (2006) 2344–2353
Chemoenzymatic synthesis of diastereomeric ethyl
c-benzyl paraconates and determination of the absolute
configurations of their acids
Federico Berti, Fulvia Felluga, Cristina Forzato,* Giada Furlan, Patrizia Nitti,
Giuliana Pitacco and Ennio Valentin*
`
Dipartimento di Scienze Chimiche, Universita di Trieste, via Licio Giorgieri 1, I-34127 Trieste, Italy
Received 25 July 2006; accepted 21 August 2006
Available online 26 September 2006
Abstract—Enantiopure (99% ee) cis- and trans-c-benzylparaconic acids and their ethyl esters were synthesized by a procedure involving
kinetic enzymatic resolution of the corresponding lactonic esters with a-chymotrypsin (a-CT) with acetone added as a cosolvent. Their
1
absolute configurations were determined by H NMR analysis of their 1-(9-anthryl)-2,2,2-trifluoroethyl esters.
ꢀ 2006 Elsevier Ltd. All rights reserved.
1. Introduction
strated by molecular mechanics calculations.10 Therefore
taking advantage of these observations, we took into con-
sideration c-benzylparaconic acid derivatives, to verify
whether the benzyl group on a lactone ring, although
located in a different position with respect to the lactam
ring, could also interact with the enzyme favourably.
Herein, we report the results obtained in the chemoen-
zymatic syntheses of so far unknown optically active
c-benzylparaconic acids, 1 and 2 (Fig. 1) and in the deter-
mination of their absolute configurations.
Interest in the c-lactone ring relies on the fact that it is part
of many enantiopure natural products1 showing biological
activity as antimicrobials, antitumourals, immunomodula-
tors, antifungal, plant growth inhibitors,2 and as key
flavours of aged alcoholic beverages.3 It can also be found
in ubiquitous products present in a variety of fruits and
flowers,4 in insect pheromones,5 as well as in lignans, a
wide class of natural compounds present in plants and in
their mammalian metabolites.6 Paraconic acids constitute
a small class of variously functionalized c-lactones exhibit-
ing antibiotic and antitumoural properties and character-
ized by the presence of a carboxylic group at the
b-position.7 In the frame of our work aimed at the chemo-
enzymatic synthesis of some of these systems,8 we recently
investigated the enantiopure synthesis of paraconic acid
itself (5-oxo-3-tetrahydrofurancarboxylic acid) and those
of its c-methyl and c,c-dimethyl derivatives in enantiome-
rically pure forms.9 A few aza-paraconic acid derivatives
(5-oxo-3-pyrrolidinecarboxylic acid) have also been stud-
ied, among which the N-benzyl c-lactamic ester proved
particularly suitable for kinetic resolution with a-chymo-
trypsin (a-CT), owing to favourable interactions between
the enzyme and the benzyl group at nitrogen, as demon-
HO2C
Ph
HO2C
Ph
O
O
O
O
1
2
Figure 1. Targeted molecules.
2. Results and discussion
2.1. Synthesis of substrates
Diastereomeric racemic lactonic esters 7 and 8 (Scheme 1)
were synthesized from ethyl 3-oxo-4-phenylbutanoate 311
and ethyl bromoacetate under basic conditions. The
resulting diethyl phenylacetylsuccinate 4 was reduced
with sodium borohydride to give the corresponding
*
Corresponding authors. Tel.: +39 040 558 3917; fax: +39 040 558 3903
(E.V.); e-mail: valentin@dsch.units.it
0957-4166/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2006.08.013

F. Berti et al. / Tetrahedron: Asymmetry 17 (2006) 2344–2353
2345
2.2. Enzymatic hydrolyses
COOEt
COOEt
Br
COOEt
Bn
COOEt
Bn
Enzymatic hydrolyses were performed using a series of
commercially available enzymes, namely Porcine pancre-
atic lipase (PPL), lipase from Pseudomonas species (PS),
lipase from Pseudomonas fluorescens (AK), Candida
cylindracea lipase (CCL), Aspergillus niger (AP12), lipase
from Candida rugosa (AY), Mucor miehei lipase (MML),
Candida antarctica lipase (CAL), porcine liver acetone
powder (PLAP), horse liver acetone powder (HLAP), a-
chymotrypsin (a-CT) and protease from Bacillus subtilis
(SUB). The reactions were monitored with a pH-stat
instrument by continuous addition of 1 M NaOH. The
main results are summarized in Tables 1 and 2.
O
EtONa/EtOH
O
4
3
NaBH4
EtOH
EtO2C
Bn
COOEt
COOEt
PTSA
3
2
Bn
O
toluene
reflux
O
OH
cis:
trans:
7
8
5,6
Scheme 1. Synthesis of substrates 7 and 8.
For cis lactone 7 (Table 1), the best results were obtained
using a-chymotrypsin, which hydrolyzed the ethoxy-
carbonyl group exclusively, furnishing the corresponding
lactonic acid (+)-1 with fairly good enantiomeric excess
(86%, E = 16) (entry 1). The enantioselectivity of the reac-
tion was greatly improved (E ꢀ 2400) by adding acetone as
a cosolvent, whose amount was optimized to 5% v/v. Un-
der these conditions (entry 2), acid (+)-1 was obtained with
>99% ee at 17% conversion. Increasing the amount of ace-
tone decreases the enzyme activity as its essential bound
water is stripped out from the enzyme’s surface.13
hydroxydiesters 5 and 6, which were not isolated, in an
admixture with the desired lactones 7 and 8. Complete lact-
onization was accomplished by heating the reaction mix-
ture in toluene, in the presence of PTSA as a catalyst.
The diastereomeric lactonic esters cis-7 and trans-8, formed
in about a 1:1 ratio, were then separated on column chro-
matography and subjected to enzymatic hydrolyses sepa-
rately. Since their 13C NMR spectra were practically
superimposable, their geometries were determined by the
fact that lactone 7 converted into its stereoisomer 8 almost
quantitatively (1:9), as well as by NOE difference measure-
ments. In particular, irradiation of the signal relative to
H-3 in compound 7 at 3.46 ppm caused enhancement of
the H-2 (6%) signal and that of H-4 at 2.65 ppm (10%).
In the trans derivative 8, irradiation of the H-2 signal at
4.87 ppm caused enhancement of the H-4 signal cis to the
ethoxycarbonyl group at 2.82 ppm (2%), while irradiation
of the H-4 signal trans to the ethoxycarbonyl group at
2.53 ppm enhanced the H-3 signal at 3.09 ppm (5%). There-
fore, since H-2 is cis to H-4 at 2.82 ppm and H-3 is cis to
H-4 at 2.53 ppm, H-2 and H-3 must be trans to each other.
Other enzymes, such as HLAP, MML and PLAP (Table 1,
entries 5–7) furnished less satisfactory results, showing an
exclusive preference for ring fission in the former two
cases, while with PLAP, the ratio between the hydrolysis
product from the ester group and that from the lactone
group was 3:7. In all cases however, the enantioselectivity
was poor.
Using a-CT and the same conditions as above and leaving
the reaction to proceed to high conversion values (60%),
Table 1. Enzymatic hydrolysesa of racemic cis-lactone 7 at low conversion values
(+)-7
from HLAP, PLAP
CO2H
H3O+
Bn
EtO2C
Bn
HO2C
Bn
EtO2C
Bn
enzyme
+
+
O
O
O
CO2Et
O
O
O
OH
( )-
7
(+)-
1
(–)-7
H3O+
from MML
Entry
Enzyme
Acetone
(%, v/v)
E
Conv.b
Time
Lactonic acid 1
Unreacted ester 7
Ester 7 (from ring fission)
Sign
ee (%)c
Abs.
Sign
ee (%)d
Abs.
Sign
ee (%)d
Abs.
of a
config.
of a
config.
of a
config.
1
2
3
4
5
6
7
a-CT
0
5
10
20
0
16
2431
9
13
3
3
15
17
21
9
25
14
nd
7.75 h
6.5 h
(+)
(+)
(+)
(+)
—
86
>99
77
85
—
2R,3R
2R,3R
2R,3R
2R,3R
—
(ꢁ)
(ꢁ)
(ꢁ)
(ꢁ)
(ꢁ)
(ꢁ)
(ꢁ)
15
20
21
8
16
7
2S,3S
2S,3S
2S,3S
2S,3S
2S,3S
2S,3S
2S,3S
—
—
—
—
(+)
(ꢁ)
(+)
—
—
—
—
48
43
63
—
—
—
—
2R,3R
2S,3S
2R,3R
22.5 h
6.75 h
45 min
3 min
1.5 h
HLAP
MML
PLAP
0
0
—
—
—
—
nd
(
)
0
4
a Conditions: phosphate buffer, pH 7.4, rt.
b Calculated.12
c Determined by chiral HRGC on the methyl ester derivative.
d Determined by chiral HRGC.

2346
F. Berti et al. / Tetrahedron: Asymmetry 17 (2006) 2344–2353
Table 2. Enzymatic hydrolysesa of racemic trans-lactone 8 at low conversion values
Entry
Enzyme
Acetone
(%, v/v)
E
Conv.b
Time (h)
Lactonic acid 2
Unreacted ester 8
Sign of a
ee (%)c
Abs. config.
Sign of a
ee (%)d
Abs. config.
1
2
3
4
5
6
7
8
9
a-CT
0
5
10
20
0
20
0
20
0
2.3
12
15
230
3
3
3
5
4
35
26
30
13
24
25
24
11
31
19
46
35
2.75
1
0.5
2
6.4
7
1
5
2
4
8
(ꢁ)
(ꢁ)
(ꢁ)
(ꢁ)
(ꢁ)
(ꢁ)
(+)
(+)
(+)
(+)
(ꢁ)
(ꢁ)
32
81
83
99
56
62
44
66
49
43
50
66
2S,3R
2S,3R
2S,3R
2S,3R
2S,3R
2S,3R
2R,3S
2R,3S
2R,3S
2R,3S
2S,3R
2S,3R
(+)
(+)
(+)
(+)
(+)
(+)
(ꢁ)
(ꢁ)
(ꢁ)
(ꢁ)
(+)
(+)
16
29
36
15
21
21
14
8
22
10
43
36
2R,3S
2R,3S
2R,3S
2R,3S
2R,3S
2R,3S
2S,3R
2S,3R
2S,3R
2S,3R
2R,3S
2R,3S
PPL
CCL
AY
10
11
12
20
0
20
3
5
7
CAL
7.25
a Conditions: phosphate buffer, pH 7.4, rt.
b Calculated.12
c Determined by chiral HRGC on the methyl ester derivative.
d Determined by chiral HRGC.
the unreacted lactonic ester (2S,3S)-(ꢁ)-7 was obtained
namely with the ester carbonyl group eclipsed with the
hydrogen atom of the known alcohol stereocentre and anti-
periplanar (ap) with the hydrogen atom of the stereocentre
whose configuration has to be determined (conformers a
and c, Fig. 2). Owing to the fact that the aromatic ring is
coplanar with the proton at C10, this particular arrange-
ment would cause a shielding of the protons belonging to
the group lying on the same side as the aromatic group,
namely (L1 for conformer a and L2 for conformer c). A
conformer can be envisaged in each case in which the car-
bonyl group is synperiplanar (sp) with the hydrogen atom
of the stereocentre to be determined (conformers b and d,
Fig. 2), but conformers a and c prevail over the corre-
sponding b and d, as demonstrated by Riguera with several
conformational analyses carried out with molecular
mechanics and with the semiempirical Hamiltonians
AM1 and PM3.15 The absolute configuration of the stereo-
centre bearing L1 and L2 can thus be determined from the
differences in chemical shift of the corresponding protons
observed for the two diastereomers (DdR,S).
with >99% ee.
Conversely, hydrolyses of the trans lactonic ester 8 were
completely regioselective with all the enzymes used, leading
to lactonic acid 2 as the only product (Table 2). Again the
best results were obtained with a-CT and again using ace-
tone as a cosolvent, but in this case in an amount of 20%
v/v. In this manner, lactonic acid (ꢁ)-2 with >99% ee
was isolated (entry 4). The presence of the cosolvent was
also useful for the other enzymes listed in Table 2, as a
slight but visible improvement in the enantiomeric excess
of the product was observed.
The enzymes PPL and CAL showed the same enantio-
preference as a-CT, leading to the laevorotatory enantio-
mer of lactonic acid (ꢁ)-2, while CCL and AY showed
an opposite enantiopreference leading to acid (+)-2.
Enzymes HLAP, PLAP, SUB, Lipase PS, Lipase AK and
MML were also checked but all gave the product with very
low ee’s or as racemates.
H
O
F3C
R
L2
L1
O
Using a-CT and leaving the reaction to proceed to high
conversion values (61%), the unreacted ester (2R,3S)-(+)-
8 was obtained with >99% ee.
H
H
O
S
L2
L1
O
F3C
H
2.3. Determination of the absolute configurations of the
products
conformer a (ap)
conformer c (ap)
L1 shielded
L2 shielded
Of the several methods proposed in the literature to assign
the absolute configuration to optically active carboxylic
acids,14 we considered the method recently proposed by
Riguera et al., which looked attractive for its easiness
and generality.15 In this work, the absolute configuration
of the a-carbon of a carboxylic acid is assigned from the
H
O
H
O
R
S
F3C
Ar
Ar
H
H
O
O
F3C
L1
L1
L2
L2
1
conformer b (sp)
L2 shielded
conformer d (sp)
L1 shielded
values of the shielding effects observed in the H NMR
spectra of its esters with (R)-(ꢁ)- and (S)-(+)-(1-(9-an-
thryl)-2,2,2-trifluoro)ethanol.
Figure 2. Riguera’s models.
The core assumption of the method is that the ground state
conformation of such esters is that shown in Figure 2,
For the protons on L1, a negative value of DdR,S is
obtained, while the protons on L2 show a positive DdR,S
.

F. Berti et al. / Tetrahedron: Asymmetry 17 (2006) 2344–2353
2347
This method was validated by Riguera on a set of more
than 20 linear acids. However, the energy difference be-
tween the conformers found by Riguera’s calculations
was always small, in the order of 1 kcal/mol.
The optically active lactonic acids (+)-1, (ꢁ)-2, (ꢁ)-13 and
(ꢁ)-14 were thus reacted with commercially available (R)-
(ꢁ)- and (S)-(+)-(1-(9-anthryl)-2,2,2-trifluoro)ethanol.
The eight stereoisomers thus obtained, namely (+)-9, (+)-
10, (+)-11, (ꢁ)-12, (ꢁ)-15, (ꢁ)-16, (ꢁ)-17 and (ꢁ)-18
1
1
Moreover, a preliminary conformation analysis carried out
on the Riguera esters of our lactonic acids lead to the iden-
tification of at least four different conformers for each lac-
tone, and in several conformations, the orientation of the
anthryl group does not seem to be relevant as to a shielding
effect on the L1 and L2 groups. For these reasons we have
decided to synthesize the Riguera esters of lactones 1 and 2,
as well as of reference lactones 13 and 14 (Scheme 2),
whose absolute configurations are known to be (2S,3S)
and (2S,3R), respectively,9 and to submit all the molecules
to a more careful conformational analysis.
(Scheme 2), were analyzed by H NMR spectroscopy. H
NMR spectra of all compounds were analyzed thoroughly
by means of 2D experiments and spin–spin decoupling
experiments in order to have
assignment.
a complete proton
Table 3 lists the chemical shift of the protons involved in
the shielding effect by the diamagnetic anisotropy of the
anthrylic group, while Figure 3 shows the assigned config-
urations for the cis diastereomers, for a better comprehen-
sion. From the chemical shifts of H-3 in their respective
diastereomeric pairs 9/10, 11/12, 15/16 and 17/18, it is
evident that its orientation remains fixed and it does not
depend on the configuration of the chiral auxiliary, thus
supporting the conformations proposed. The same can be
said for the anthryl substituent, whose carbon resonances
remain practically identical for all compounds. Compari-
H
R
H
S
HO2C
R
F3C
Ar
Ar
F3C
OH
OH
O
O
cis-(+)-1: R = Bn
1
trans-(–)-2: R = Bn
cis-(–)-13: R = Me
trans-(–)-14: R = Me
son of the H NMR spectra of esters 15 and 16 (entries 5
and 6), derived from the reference lactone (2S,3S)-13,
yields a negative value of DdR,S for both the methine pro-
ton at C2 and the methyl group on the same carbon, while
a positive DdR,S is observed for the methylene protons at
C4. On the contrary, esters 17 and 18, derived from lactone
(2S,3R)-14, show a positive DdR,S for both the C2 proton
and methyl, and a negative DdR,S for the C4 methylene (en-
tries 7 and 8). The opposite shielding effects thus indicate a
different configuration at C3 for the two pairs of reference
esters, while the application of Riguera rules lead to the
correct assignment of (S)-absolute configuration at C3 for
15 and 16, and (R)- for 17 and 18. The four diastereomeric
esters have been submitted to an extensive conformational
H
R
H
S
F3C
Ar
Ar
F3C
O
O
O
R
O
O
R
O
O
O
cis-(+)-9: R = Bn
cis-(+)-10: R = Bn
trans-(+)-11: R = Bn
cis-(–)-15: R = Me
trans-(–)-17: R = Me
trans-(–)-12: R = Bn
cis-(–)-16: R = Me
trans-(–)-18: R = Me
Ar: 9-anthryl
Scheme 2. Riguera’s esters from lactones (+)-1, (ꢁ)-2, (ꢁ)-13 and (ꢁ)-14.
Table 3. Chemical shifts and DdR,S for the protons affected by the diamagnetic anisotropy of the aromatic ring
Entry
Compd
H-3
H-2
d (ppm)
H-4
CH2Ph
CH3
d, ppm
d (ppm)
DdR,S
H-4 cis
DdR,S
H-4 trans
DdR,S
d, ppm
DdR,S
DdR,S
to COOR
to COOR
1
2
3
4
5
6
7
8
(10R,2R,3R)-9
(10S,2R,3R)-10
(10R,2S,3R)-11
(10S,2S,3R)-12
(10R,2S,3S)-15
(10S,2S,3S)-16
(10R,2S,3R)-17
(10S,2S,3R)-18
3.64
3.73
3.26
3.28
3.63
3.59
3.19
3.20
4.92
4.78
4.88
4.73
4.76
4.96
4.69
4.53
+0.14
+0.15
ꢁ0.20
+0.16
2.76
2.88
2.70
2.84
2.90
2.87
2.79
2.96
ꢁ0.12
ꢁ0.14
+0.03
ꢁ0.17
2.68
2.74
2.52
2.60
2.70
2.61
2.77
2.89
ꢁ0.06
ꢁ0.08
+0.09
ꢁ0.12
2.77a
2.39a
3.14a
2.98a
+0.38
+0.16
0.83
1.36
1.60
1.41
ꢁ0.53
+0.19
a Average chemical shift of the two geminal protons.
2.52,2.26
Ph
2.88
2.87,2.67
2.90
0.83
2.87 1.36
Ph
2.70
4.92
4.78
2.61
O
H 4
H
H
2.76
O
O
O
O
Me
Me
H
O
H 4
H
H
4
H
H
O
2R
H
H
O
2R
O
1'R
1'S
1'R
4
1'S
F3C
Ar
H
Ar
F3C
F3C
Ar
O
Ar
F3C
O
O
2S
2S
O
O
3S
O
O
3S
3R
2.68
H
3R
H
2.74
H
H
4.76
4.96
H
3.63
(–)-15
H
3.59
H
3.64
H
3.73
(+)-10
(–)-16
(+)-9
Figure 3. Stereochemistry and 1H NMR data of interest for Riguera’s derivatives (+)-9, (+)-10, (ꢁ)-15 and (ꢁ)-16.

2348
F. Berti et al. / Tetrahedron: Asymmetry 17 (2006) 2344–2353
search, carried out with a Monte Carlo algorithm operating
on PM3 geometry optimizations.16
3), thus suggesting that both the cis and trans derivatives
have the same configuration at C3. According to the Rigu-
era rules, the absolute configuration at this centre should
be R. The conformational analysis confirms this prediction,
although the picture here is much more complicated than
in the simple Riguera explanation. The analysis was car-
ried out on the model structures of the (3R) lactone esters.
Also due to the presence of the benzyl group at the 2-posi-
tion of the lactone rings, multiple minima have been
obtained.
We have found two energy minima for each compound,
and the absolute minimum was always that identified by
Riguera (Table 4), the other being very close in energy.
Nevertheless, after obtaining and considering the popula-
tion of each conformation by Boltzmann statistics at room
temperature (Table 4), a qualitative analysis of the shield-
ing effects on each conformer leads to the correct
predictions.
The (10R)-ester 9 of cis lactone 1 shows four conformations
close in energy, while the ground conformation 0 (Table 4)
only represents 47% of the lactone population at room tem-
perature. A shielding effect on the protons at C2 can be
predicted for this conformation, as well as for conforma-
tion 2. Thus, C2 is shielded in about 73% of the population
of this compound, while the shielding effects operate on C4
in the remaining 27%. The (10S) ester 10 of the same lac-
tone shows a very different conformational space, and
although four minima are also found for this compound,
The anthryl group is approximately coplanar with H10
(Table 4, C30C20C10H10 dihedral angle). This orientation
assures that the cone of diamagnetic anisotropy (hemiangle
45ꢁ) affects only the protons lying on the same side as the
aromatic moiety and located 4 or 5 bonds away from the
C10 stereocentre.15a,c
The esters of the cis- and trans-lactones 9–12 of unknown
configuration at C3, show the same shielding effect (Table
Table 4. PM3 conformation analysis of esters 9–12 and 15–18: structures, energies and predicted shielding effects
O
O
6
H1' CF3
1'
O
2'
3'
O6'
3
H3
2
R
0
0
0
0
0
0
0
Compd
Conf. C3 C2 C1 H1
H1 C1 O6 C6 O6C6C3H3 PM3
Population Shielding Shielding Predicted Predicted
(ꢁ)
(ꢁ)
(ꢁ)
DHf,rel (absolute) (%)
on C2
on C4
DdR,S
DdR,S
(kcal/mol)
on C2
on C4
(10R,2R,3R)-9
0
1
2
3
0
1
2
3
183.9
182.5
186.7
187.7
158.1
171.2
176.2
156.4
23.3
358.1
158.9
351.5
135.4
156.1
5.0
0 (ꢁ221.86)
47.1
27.0
25.0
0.9
Y
N
Y
N
Y
N
N
Y
N
Y
N
Y
N
Y
Y
N
11.8
30.6
32.9
337.6
1.8
0.33
0.38
2.3
>0
<0
(10S,2R,3R)-10
(10R,2S,3R)-11
0 (ꢁ224.04)
99.87
0.12
4.0
6.0
7.1
2.4
343.5
0.1
146.7
1 · 10ꢁ3
6 · 10ꢁ4
0
1
2
3
4
5
0
1
2
3
4
5
202.0
201.4
200.7
199.6
199.7
187.4
162.8
164.9
172.5
171.3
165.7
165.6
357.4
358.6
14.6
16.1
16.5
159.4
162.3
174.1
4.4
1.3
3.6
170.0
2.0
149.0
193.8
355.7
356.3
0 (ꢁ227.90)
85.8
10.7
1.4
1.3
0.5
N
N
N
Y
Y
Y
Y
N
Y
Y
N
N
N
N
Y
N
N
N
N
Y
N
N
Y
Y
1.2
2.5
2.5
3
3.4
28.5
0.3
>0
<0
(10S,2S,3R)-12
326.9
335.6
330.6
3.0
323.9
329.7
0 (ꢁ226.74)
63.0
16.0
8.4
7.3
3.1
0.8
1.2
1.3
1.8
2.0
2.1
(10R,2S,3S)-15
(10S,2S,3S)-16
0
1
0
1
181.2
183.9
185.2
184.3
10.4
8.7
13.2
4.7
178.4
5.3
175.8
2.1
0 (ꢁ251.47)
2.4
98.2
1.8
89.8
10.2
Y
N
N
Y
N
Y
Y
N
<0
>0
>0
<0
0 (ꢁ251.80)
1.2
(10R,2S,3R)-17
(10S,2S,3R)-18
0
1
0
1
172.4
186.8
184.2
187.6
22.5
22.1
3.8
183.1
5.7
185.7
3.3
0 (ꢁ254.33)
0.5
72.0
28.0
90.0
10.0
N
Y
Y
N
Y
N
N
Y
0 (ꢁ253.82)
9.2
1.3

F. Berti et al. / Tetrahedron: Asymmetry 17 (2006) 2344–2353
2349
its ground conformation 0 is almost the only one populated
at room temperature (Table 4). This conformation corre-
sponds to that predicted by Riguera, and the shielding ef-
fect of the anthryl group operates on C2. If we compare
the populations of conformers shielding on C2 and C4 in
the (10R) and (10S) esters, we can then predict a positive
DdR,S on C2 and a negative DdR,S on C4. These predictions
are in agreement with the experimental values of DdR,S
reported in Table 3, and for this reason the absolute
configuration (R)- is assigned to carbon 3. Due to the
cis relationship between the substituents at C3 and C2, it
follows that C2 also has an (R)-configuration.
Benzoyl chloride and Meldrum’s acid were purchased from
Sigma–Aldrich.
Compound 3 was prepared by acylation of Meldrum’s
acid, followed by hydrolysis, in accordance with the
literature.17
The ketodiester 4 was prepared from compound 3, in
accordance with the literature procedure used for the
dimethyl analogue.18
3.1.1. Diethyl phenylacetylsuccinate 4. Colourless oil, bp
175–177 ꢁC (1 mmHg); IR (neat): 1732, 1502, 1412, 1259,
1
The (10R)-ester 11 of the trans lactone 2 shows six energy
minima, and in the first two conformations 0 and 1 (more
than 96% of the total population at room temperature), the
anthryl group is arranged in such a way that there is no
shielding effect on any proton of the molecule (Table 4).
The (10S) ester 12 of the same lactone shows also six min-
ima, but this time the ground conformation (63% of the
population) obeys Riguera’s prediction and is shielded at
C2. The same shielding effect was also observed for the
third conformation of this compound (8%). Thus, by com-
paring the irrelevant shielding effects on the (10R) ester with
the effects on the (10S) derivative, we can predict a positive
DdR,S at C2, and a negative DdR,S at C4 also for the trans
pair. Again the predictions are in agreement with the exper-
imental data reported in Table 3, and thus we assigned the
(R)-configuration to C3 also for the trans lactones, whose
configuration at C2 must be (S).
1184, 698; H NMR, d: 7.35–7.20 (5H, m, Ph), 4.25–4.05
(5H, 2q + m, 2OCH2CH3, CH), 4.01, 3.95 (2H, AB system,
CH2Ph), 2.90 (2H, part AB of an ABX system,
JAB = 17.5 Hz, CH2COO), 1.26, 1.23 (6H, 2t, 2OCH2CH3);
13C NMR, d: 201.3 (s, C@O), 170.9 (s, COO), 168.9 (s,
COO), 133.1 (s, Ph), 129.5 (2d, Ph), 128.3 (2d, Ph), 126.9
(d, Ph), 61.5 (t, OCH2), 60.6 (t, OCH2), 53.0 (d, CH),
49.2 (t, CH2COO), 32.3 (t, CH2Ph), 13.8 (q, CH3), 13.7
(q, CH3); MS, m/z: 293 (100, M+Å), 275 (2), 259 (3), 246
(43), 231 (7), 219 (27), 218 (24), 201 (23), 173 (77), 155
(5), 145 (45), 127 (27), 118 (28), 99 (17), 91 (42), 65 (13),
55 (5); HRMS (EI) calcd for C16H20O5 (M+), 292.1311,
found 292.1302.
3.2. Reduction of the ketodiester 4 with NaBH4
A mixture of 1.07 g (3.65 mmol) of 4 and 92 mg of NaBH4
in 3.5 mL of ethanol was kept under stirring for 4 h at
room temperature. After the usual workup, a mixture of
the corresponding hydroxyesters 5 and 6 and lactones 7
and 8 was obtained. Conversion of the hydroxyesters into
the corresponding lactones was accomplished by refluxing
in toluene and p-toluenesulfonic acid for 2 h. Compounds
7 and 8 were obtained in the ratio of 53:47, respectively,
determined by 1H NMR analysis. Equilibration of the mix-
ture with DBU changed the ratio to 1:9, respectively. The
diastereoisomers were then separated by flash-chromato-
graphy (eluent: light petroleum–ethyl acetate 9:1).
3. Experimental
3.1. General
IR spectra were recorded on a Jasco FT/IR 200 spectro-
photometer. 1H NMR and 13C NMR spectra were run
on a Jeol EX-400 spectrometer (400 MHz for proton,
100 MHz for carbon), and on a Jeol EX-270 spectrometer
(270 MHz for proton, 68 MHz for carbon) using deuterio-
chloroform as a solvent and tetramethylsilane as the inter-
nal standard. Coupling constants are given in Hz. Optical
rotations were determined on a Perkin Elmer Model 241
polarimeter. CD spectra were obtained on a Jasco J-
700 A spectropolarimeter (0.1 cm cell). GC analyses were
run on a Carlo Erba GC 8000 instrument and on a Shima-
dzu GC-14B instrument, the capillary columns being OV
1701 (25 m · 0.32 mm) (carrier gas He, 40 kPa, split 1:50)
and a ChiraldexTM type G-TA, trifluoroacetyl c-cyclo-
dextrin (40 m · 0.25 mm) (carrier gas He, 180 kPa, split
1:100) or DiMePe b-cyclodextrin (25 m · 0.25 mm) (carrier
gas He, 110 kPa, split 1:50). Enzymic hydrolyses were per-
formed using a pH-stat Controller PHM290 Radiometer
Copenhagen. Mass spectra were recorded on a VG 7070
(70 eV) spectrometer. HRMS spectra were performed on
a Finnigan MAT95XP spectrometer. TLC’s were per-
formed on Polygramꢂ Sil G/UV254 silica gel pre-coated
plastic sheets (eluant: light petroleum–ethyl acetate). Flash
chromatography was run on silica gel 230–400 mesh
ASTM (Kieselgel 60, Merck). Light petroleum refers to
the fraction with bp 40–70 ꢁC and ether to diethyl ether.
3.2.1. Ethyl cis-2-benzyltetrahydro-5-oxo-3-furancarboxyl-
ate 7. Colourless solid, mp 70–74 ꢁC; IR (nujol): 1776,
1
1732; H NMR, d: 7.29–7.19 (5H, m, Ph), 4.87 (1H, part
X of an ABX system, J2,3 = 7.3 Hz, JAX = 5.0 Hz, JBX
=
7.9 Hz, H-2), 4.16, 4.15 (2H, 2q, J = 6.9 Hz, OCH2CH3),
3.47 (1H, part X of an ABX system, J2,3 = 7.3 Hz,
JAX = 5.4 Hz, JBX = 8.6 Hz, H-3), 2.94 (1H, part A of an
ABX system, JAB = 14.6 Hz, JAX = 5.0 Hz, CHPh), 2.92
(1H, part
B
of an ABX system, JAB = 14.6 Hz,
JBX = 7.9 Hz, CHPh), 2.85 (1H, part A of an ABX system,
JAB = 17.6 Hz, JAX = 5.4 Hz, H-4 cis to the ethoxy-
carbonyl group), 2.66 (1H, part B of an ABX system,
JAB = 17.6 Hz, JBX = 8.6 Hz, H-4 trans to the ethoxycar-
bonyl group), 1.25 (3H, t, J = 7.1 Hz, OCH2CH3); 13C
NMR, d: 174.2 (s, C-5), 170.8 (s, COOEt), 134.9 (s, Ph),
129.8 (d, Ph), 128.6 (2d, Ph), 127.2 (d, Ph), 81.5 (d, C-2),
61.7 (t, OCH2CH3), 44.4 (d, C-3), 40.3 (t, CH2Ph), 32.0
(t, C-4), 14.0 (q, OCH2CH3); MS, m/z: 249 (13, MH+),
230 (15), 203 (18), 202 (91), 185 (32), 184 (66), 174 (37),
173 (17), 158 (18), 157 (20), 156 (29), 130 (16), 129 (100),

2350
F. Berti et al. / Tetrahedron: Asymmetry 17 (2006) 2344–2353
128 (16), 101 (42), 91 (44), 83 (33), 65 (15), 55 (18);
HRMS (EI) calcd for C14H16O4 (M+), 248.1049, found
248.1048.
Enzymatic hydrolysis of the trans-lactonic ester 8 (300 mg,
1.2 mmol) with a-CT (14.4 mg) as the hydrolytic enzyme in
6.0 mL of acetone and 24.0 mL of phosphate buffer gave
after 30 min (13% conversion), (ꢁ)-2 with >99% ee.
3.2.2. Ethyl trans-2-benzyltetrahydro-5-oxo-3-furancarb-
1
oxylate 8. Yellow oil, IR (film): 1776, 1732; H NMR,
3.3.2. (2S,3R)-(ꢁ)-2-Benzyltetrahydro-5-oxo-3-furancarb-
oxylic acid 2. White solid, mp 159–160 ꢁC; IR (nujol):
1776, 1716; 1H NMR, d: 7.35–7.23 (5H, m, Ar), 4.91
d: 7.35–7.20 (5H, m, Ph), 4.87 (1H, part X of an ABX sys-
tem, J2,3 = 7.3 Hz, JAX = 5.1 Hz, JBX = 5.9 Hz, H-2), 4.13,
4.12 (2H, 2q, J = 6.9 Hz, OCH2CH3), 3.15 (1H, part A of
an ABX system, JAB = 14.3 Hz, JAX = 5.1 Hz, CHPh),
3.09 (1H, part X of an ABX system, J2,3 = 7.3 Hz,
JAX = 8.8 Hz, JBX = 9.5 Hz, H-3), 3.06 (1H, part B of an
ABX system, JAB = 14.3 Hz, JBX = 5.9 Hz, CHPh), 2.82
(1H, part
X
of an ABX system, J2,3 = 6.9 Hz,
JAX = 4.6 Hz, JBX = 6.1 Hz, H-2), 3.14 (1H, apparent dt,
J2,3 = 6.9 Hz, JAX = 8.1 Hz, JBX = 9.5 Hz, H-3), 3.18
(1H, part
A
of an ABX system, JAB = 14.5 Hz,
JAX = 4.6 Hz, CHPh), 3.03 (1H, part B of an ABX system,
JAB = 14.5 Hz, JBX = 6.1 Hz, CHPh), 2.83 (1H, part A of
an ABX system, JAB = 17.9 Hz, JAX = 8.1 Hz, H-4 cis to
the carboxy group), 2.53 (1H, part B of an ABX system,
JAB = 17.9 Hz, JBX = 9.5 Hz, H-4 trans to the carboxy
group); 13C NMR, d: 175.6 (s, COOH), 174.0 (s, C-5),
134.6 (s, Ph), 129.9 (d, Ph), 128.8 (2d, Ph), 127.4 (d, Ph),
81.2 (d, C-2), 43.8 (d, C-3), 40.2 (t, CH2Ph), 31.7 (t, C-4);
MS, m/z: 220 (4, M+Å), 202 (66), 184 (54), 176 (15), 174
(1H, part
JAX = 8.8 Hz, H-4 cis to the ethoxycarbonyl group), 2.53
(1H, part of an ABX system, JAB = 17.6 Hz,
A
of an ABX system, JAB = 17.9 Hz,
B
JBX = 9.5 Hz, H-4 trans to the ethoxycarbonyl group),
1.24 (3H, t, J = 7.1 Hz, OCH2CH3); 13C NMR, d: 174.3
(s, C-5), 170.9 (s, COOEt), 134.9 (s, Ar), 129.8 (d, Ar),
128.7 (2d, Ar), 127.2 (d, Ar), 81.6 (d, C-2), 61.8 (t,
CH3CH2O), 44.5 (d, C-3), 40.4 (t, CH2Ph), 32.1 (t, C-4),
14.1 (CH3CH2O); MS, m/z: 249 (60, MH+), 231 (14), 210
(15), 209 (100), 202 (20), 191 (29), 185 (18), 184 (30), 174
(13), 157 (13), 129 (63), 117 (12), 101 (29), 91 (43), 83
(22), 65 (12), 55 (17); HRMS (EI) calcd for C14H16O4
(M+), 248.1049, found 248.1048.
(30), 158 (12), 156 (13), 129 (17), 101 (38), 92 (62), 91
25
(100), 83 (51), 65 (18), 55 (20); ½aꢂD ¼ ꢁ49:0 (c 0.20,
CH3OH); HRMS (EI) calcd for C12H12O4 (M+),
220.0736, found 220.0735.
Enzymatic hydrolysis of the trans-lactonic ester 8 (1.24 g,
5.0 mmol) was carried out with a-CT (60 mg) as the hydro-
lytic enzyme in 16 mL of acetone and 64 mL of phosphate
3.3. Enzymatic hydrolyses
Enzymatic hydrolysis of cis-lactonic ester 7 (880 mg,
3.54 mmol) carried out with a-CT (42.5 mg) as the hydro-
lytic enzyme in 4.0 mL of acetone and 76.0 mL of phos-
phate buffer gave after 26 h (17% conversion) the lactonic
acid, (+)-1 with >99% ee.
buffer, gave after 1 h (61% conversion), (+)-8 with >99%
ee; ½aꢂD ¼ þ19:6 (c 0.24, CH3OH).
25
3.4. General procedure for the synthesis of the carboxylic
acid derivatives (+)-9, (+)-10, (+)-11, (ꢁ)-12 and (ꢁ)-15,
(ꢁ)-16, (ꢁ)-17, (ꢁ)-18
3.3.1. (2R,3R)-(+)-2-Benzyltetrahydro-5-oxo-3-furancarb-
oxylic acid 1. White solid, mp 147–149 ꢁC; IR (nujol):
To a solution of 0.13 mmol of the carboxylic acid (+)-1,
(ꢁ)-2, (ꢁ)-13 or (ꢁ)-14 in 1.5 mL of CH2Cl2, 40 mg
(0.14 mmol) of (R)-(ꢁ)- or (S)-(+)-1-(9-anthryl)-2,2,2-tri-
fluoroethanol was added. EDCÆHCl (83 mg, 0.43 mmol),
Et3N (0.04 mL, 0.28 mmol) and DMAP (24 mg,
0.20 mmol) were then added. The mixture was kept under
stirring for 24 h. At the end of the reaction, CH2Cl2 was
added and the organic phase was washed with a 5% solu-
tion of KHSO4, water, 5% solution of NaHCO3, water
and dried over anhydrous Na2SO4. The ester was purified
by flash chromatography (eluent: light petroleum–ethyl
acetate 9:1).
1776, 1716; 1H NMR, d: 7.35–7.20 (5H, m, Ar), 4.89
3
(1H, part
X
of an ABX system, J2,3 = 7.2 Hz,
JAX = 3.8 Hz, JBX = 9.3 Hz, H-2), 3.53 (1H, apparent dt,
3J2,3 = 7.2 Hz, JAX = 5.2 Hz, JBX = 8.4 Hz, H-3), 3.05
(1H, part
A
of an ABX system, JAB = 14.6 Hz,
JAX = 8.6 Hz, CHPh), 3.01 (1H, part B of an ABX system,
JAB = 14.6 Hz, JBX = 9.3 Hz, CHPh), 2.87 (1H, part A of
an ABX system, JAB = 17.9 Hz, JAX = 5.2 Hz, H-4 cis to
the carboxy group), 2.72 (1H, part B of an ABX system,
JAB = 17.9 Hz, JBX = 8.4 Hz, H-4 trans to the carboxy
group); 13C NMR, d: 175.1 (s, COOH), 174.3 (s, C-5),
135.8 (s, Ph), 129.2 (2d, Ph), 128.7 (2d, Ph), 127.2 (d,
Ph), 80.5 (d, C-2), 44.0 (d, C-3), 37.5 (t, CH2Ph), 32.0 (t,
C-4); MS, m/z: 220 (4, M+Å), 202 (69), 184 (77), 174 (41),
158 (22), 156 (36), 130 (23), 129 (44), 117 (16), 115 (15),
3.4.1. (10R,2R,3R)-(+)-1-(9-Anthryl)-2,2,2-trifluoroethyl 2-
benzyltetrahydro-5-oxo-3-furancarboxylate 9. IR (CHCl3):
1786, 1766 cmꢁ1; 1H NMR, d: 8.62 (1H, s, Ar), 8.58 (1H, d,
J = 9.5 Hz, Ar), 8.36 (1H, d, J = 8.8 Hz, Ar), 8.08 (1H, d,
J = 4.0 Hz, Ar), 8.06 (1H, d, J = 3.7 Hz, Ar), 7.90 (1H,
q, J = 8.1 Hz, CHCF3), 7.69 (1H, m, Ar), 7.62 (1H, m,
Ar), 7.54 (2H, m, Ar), 7.18 (3H, m, Ph), 6.99 (2H, m,
Ph), 4.92 (1H, ddd, J2,3 = 7.3 Hz, JAX = 3.5 Hz,
JBX = 9.6 Hz, H-2, part X of an ABX system), 3.64 (1H,
ddd, J2,3 = 7.3 Hz, JAX = 5.3 Hz, JBX = 8.9 Hz, H-3, part
X of an ABX system), 2.87 (1H, part A of an ABX system,
JAX = 3.5 Hz, JAB = 14.6 Hz, CHPh), 2.76 (1H, part A of
an ABX system, JAB = 17.9 Hz, JAX = 5.3 Hz, H-4 cis to
101 (29), 92 (51), 91 (100), 83 (41), 65 (19), 55 (25);
25
½aꢂD ¼ þ125:6 (c 0.16, CH3OH); HRMS (EI) calcd for
C12H12O4 (M+), 220.0736, found 220.0731.
Enzymatic hydrolysis of cis-lactonic ester 7 (720 mg,
2.90 mmol), carried out in 66.5 mL of phosphate buffer
with 3.5 mL of acetone added, using a-CT (34.8 mg) as
the hydrolytic enzyme gave, after 4 days (60% conversion)
25
the unreacted lactone (ꢁ)-7 with 99% ee; ½aꢂD ¼ ꢁ79:4 (c
0.34, CH3OH).

F. Berti et al. / Tetrahedron: Asymmetry 17 (2006) 2344–2353
2351
the alkoxycarbonyl group), 2.68 (1H, part B of an ABX sys-
tem, JAB = 17.9 Hz, JBX = 8.9 Hz, H-4 trans to the alkoxy-
carbonyl group), 2.67 (1H, dd, part B of an ABX system,
JAB = 14.6 Hz, JBX = 9.6 Hz, CHPh); 13C NMR, d: 173.8
(s, C-5), 168.6 (s, COO), 135.7 (s, Ph), 132.0 (d, Ar),
131.8 (s, Ar), 131.6 (s, Ar), 131.1 (s, Ar), 130.7 (s, Ar),
129.8 (d, Ar), 129.5 (d, Ar), 129.2 (2d, Ph), 128.6 (2d,
Ph), 128.2 (d, Ar), 127.1 (d, Ar), 127.0 (d, Ph), 125.9 (d,
126.8 (d, Ar), 125.5 (d, Ar), 125.2 (d, Ar), 125.1 (d, Ar),
1
124.0 (q, JCF = 290 Hz, CF3), 122.1 (d, Ar), 119.9 (s, Ar),
2
81.0 (d, C-2), 69.9 (q, JCF = 33 Hz, CHCF3), 43.8 (d, C-
3), 40.2 (t, CH2Ph), 31.5 (t, C-4); MS, m/z: 479 (30, M+1),
478 (100, M+Å), 291 (27), 259 (91), 239 (25), 207 (91), 191
25
(12); ½aꢂD ¼ þ7:7 (c 0.13, CHCl3).
3.4.4. (10S,2S,3R)-(ꢁ)-1-(9-Anthryl)-2,2,2-trifluoroethyl 2-
benzyltetrahydro-5-oxo-3-furancarboxylate 12. IR (CHCl3):
1786, 1766 cmꢁ1; 1H NMR, d: 8.60 (1H, s, Ar), 8.56 (1H, d,
J = 8.9 Hz, Ar), 8.28 (1H, d, J = 8.9 Hz, Ar), 8.06 (2H, 2d,
J = 8.4 Hz, Ar), 7.79 (1H, q, J = 7.9 Hz, CHCF3), 7.65 (1H,
t, J = 7.7 Hz, Ar), 7.52 (3H, m, Ar), 7.09 (3H, m, Ph), 7.02
(2H, m, Ph), 4.73 (1H, ddd, J2,3 = 7.0 Hz, JAX = 6.1 Hz,
JBX = 4.7 Hz, H-2, part X of an ABX system), 3.28 (1H,
1
Ar), 125.3 (2d, Ar), 124.1 (q, JCF = 282 Hz, CF3), 122.2
2
(d, Ar), 120.0 (s, Ar), 80.5 (d, C-2), 69.8 (q, JCF = 31 Hz,
CHCF3), 44.3 (d, C-3), 37.4 (t, CH2Ph), 31.9 (t, C-4); MS,
m/z: 479 (20, M+1), 478 (65, M+Å), 291 (10), 260 (30), 259
25
(100), 239 (23), 207 (36), 191 (24); ½aꢂD ¼ þ86:7 (c 0.15,
CHCl3).
3.4.2. (10S,2R,3R)-(+)-1-(9-Anthryl)-2,2,2-trifluoroethyl 2-
benzyltetrahydro-5-oxo-3-furancarboxylate 10. IR (CHCl3):
1786, 1766 cmꢁ1; 1H NMR, d: 8.64 (1H, d, J = 8.0 Hz, Ar),
8.60 (1H, s, Ar), 8.37 (1H, d, J = 8.8 Hz, Ar), 8.06 (2H, d,
J = 8.0 Hz, Ar), 7.96 (1H, q, J = 7.9 Hz, CHCF3), 7.66
(2H, m, Ar), 7.55 (1H, d, J = 6.6 Hz, Ar), 7.53 (1H, d,
J = 8.4 Hz, Ar), 7.05 (3H, m, Ph), 6.64 (2H, m, Ph), 4.78
(1H, ddd, J2,3 = 7.3 Hz, JAX = 9.7 Hz, JBX = 3.7 Hz, H-2,
part X of an ABX system), 3.73 (1H, dt, J2,3 = 7.3 Hz,
JAX = 6.8 Hz, JBX = 8.9 Hz, H-3, part X of an ABX sys-
tem), 2.88 (1H, part A of an ABX system, JAB = 17.6 Hz,
JAX = 6.8 Hz, H-4 cis to the alkoxycarbonyl group), 2.74
part X of an ABX system, J2,3 = 7.0, JAX = 9.5, JBX
4.7, H-3), 3.03 (1H, part A of an ABX system, JAB
14.3 Hz, JBX = 4.7 Hz, CHPh), 2.94 (1H, part B of an
ABX system, JAB = 14.3 Hz, JAX = 6.1 Hz, CHPh), 2.84
=
=
(1H, part A of an ABX system, JAB = 17.9 Hz, JAX
=
8.4 Hz, H-4 cis to the alkoxycarbonyl group), 2.60 (1H, part
B of an ABX system, J = 17.9 Hz, JBX = 9.5 Hz, H-4 trans
to the alkoxycarbonyl group); 13C NMR, d: 173.5 (s, C-5),
169.4 (s, COO), 134.4 (s, Ph), 131.9 (d + s, Ar), 131.6 (s,
Ar), 131.2 (s, Ar), 130.6 (s, Ar), 129.8 (d, Ar), 129.7 (2d,
Ph), 128.7 (2d, Ph), 128.2 (d, Ar), 127.3 (d, Ph), 127.0 (d,
1
Ar), 125.8 (d, Ar), 125.3 (2d, Ar), 124.1 (q, JCF = 292 Hz,
(1H, part B of an ABX system, JAB = 17.6 Hz, JBX
=
CF3), 122.2 (d, Ar), 120.1 (s, Ar), 81.0 (d, C-2), 69.9 (q,
2JCF = 35 Hz, CHCF3), 44.2 (d, C-3), 40.4 (t, CH2Ph),
31.9 (t, C-4); MS, m/z: 479 (10, M+1), 478 (36, M+Å), 291
8.9 Hz, H-4 trans to the alkoxycarbonyl group), 2.52 (1H,
part A of an ABX system, JAB = 14.3 Hz, JAX = 9.7 Hz,
CHPh), 2.26 (1H, part B of an ABX system, JAB = 14.3 Hz,
JBX = 3.7 Hz, CHPh); 13C NMR, d: 173.8 (s, C-5), 168.4 (s,
COO), 135.2 (s, Ph), 132.0 (d, Ar), 131.8 (s, Ar), 131.6
(s, Ar), 131.1 (s, Ar), 130.7 (s, Ar), 129.8 (d, Ar), 129.7 (d,
Ar), 129.0 (2d, Ph), 128.4 (2d, Ph), 128.3 (d, Ar), 127.2
(d, Ar), 126.9 (d, Ph), 125.9 (d, Ar), 125.3 (d, Ar), 125.2
(9), 260 (18), 259 (100), 239 (27), 208 (32), 207 (87), 193
25
(10), 191 (10), 179 (14); ½aꢂD ¼ ꢁ22:5 (c 0.40, CHCl3).
3.4.5. (10R,2S,3S)-(ꢁ)-1-(9-Anthryl)-2,2,2-trifluoroethyl 2-
methyltetrahydro-5-oxo-3-furancarboxylate 15. IR (CHCl3):
1
1786, 1766 cmꢁ1; H NMR, d: 8.60 (1H, d, J = 8.9 Hz, Ar),
2
(d, Ar), 124.1 (q, JCF = 278 Hz, CF3), 122.3 (d, Ar), 120.0
8.59 (1H, s, Ar), 8.34 (1H, d, J = 8.9 Hz, Ar), 8.05 (1H, d,
J = 8.4 Hz, Ar), 8.03 (1H, d, J = 8.0 Hz, Ar), 7.90 (1H, q,
J = 8.0 Hz, CHCF3), 7.64 (2H, m, Ar), 7.52 (1H, t, J =
8.4 Hz, Ar), 7.50 (1H, t, J = 8.4 Hz, Ar), 4.76 (1H, quintet,
2
(s, Ar), 80.2 (d, C-2), 69.5 (q, JCF = 31 Hz, CHCF3), 44.3
(d, C-3), 37.0 (t, CH2Ph), 31.6 (t, C-4); MS, m/z: 479 (23,
M+1), 478 (61, M+Å), 291 (32), 260 (27), 259 (100), 239
25
(23), 207 (28), 191 (19); ½aꢂD ¼ þ95:6 (c 0.25, CHCl3).
J = 6.6 Hz, H-2), 3.63 (1H, ddd, J2,3 = 6.6 Hz, JAX =
9.1 Hz, JBX = 7.1 Hz, H-3, part X of an ABX system),
2.90 (1H, part A of an ABX system, JAB = 17.6 Hz,
JAX = 9.1 Hz, H-4 cis to the alkoxycarbonyl group), 2.70
(1H, part B of an ABX system, JAB = 17.6 Hz, JBX = 7.1 Hz,
H-4 trans to the alkoxycarbonyl group), 0.83 (3H, d,
J = 6.6 Hz, CH3); 13C NMR, d: 174.2 (s, C-5), 168.5 (s,
COO), 131.9 (d, Ar), 131.7 (s, Ar), 131.6 (s, Ar), 131.1 (s,
Ar), 130.6 (s, Ar), 129.7 (d, Ar), 129.6 (d, Ar), 128.2 (d,
Ar), 127.0 (d, Ar), 125.9 (d, Ar), 125.3 (2d, Ar), 124.2 (q,
1JCF = 271, CF3), 122.3 (d, Ar), 120.1 (s, Ar), 76.0 (d, C-
3.4.3. (10R,2S,3R)-(+)-1-(9-Anthryl)-2,2,2-trifluoroethyl 2-
benzyltetrahydro-5-oxo-3-furancarboxylate 11. IR (CHCl3):
1786, 1766 cmꢁ1; 1H NMR, d: 8.58 (1H, s, Ar), 8.47 (1H, d,
J = 8.9 Hz, Ar), 8.28 (1H, d, J = 8.9 Hz, Ar), 8.05 (1H, d,
J = 8.0 Hz, Ar), 8.04 (1H, d, J = 8.0 Hz, Ar), 7.75 (1H,
q, J = 7.9 Hz, CHCF3), 7.65 (1H, t, J = 7.7 Hz, Ar), 7.51
(3H, m, Ar), 7.33–7.21 (5H, m, Ph), 4.88 (1H, ddd,
J2,3 = 7.1 Hz, JAX = 5.3 Hz, JBX = 5.7 Hz, H-2, part X of
an ABX system), 3.26 (1H, ddd, J2,3 = 7.1 Hz, JAX
=
2
8.6 Hz, JBX = 9.7 Hz, H-3, part X of an ABX system),
3.18 (1H, part A of an ABX system, JAB = 14.6 Hz,
JAX = 5.3 Hz, CHPh), 3.09 (1H, part B of an ABX system,
JAB = 14.6 Hz, JBX = 5.7 Hz, CHPh), 2.70 (1H, part A of an
ABX system, JAB = 17.9 Hz, JAX = 8.6 Hz, H-4 cis to the
alkoxycarbonyl group), 2.52 (1H, part B of an ABX system,
JAB = 17.6 Hz, JBX = 9.7 Hz, H-4 trans to the alkoxycar-
bonyl group); 13C NMR, d: 173.4 (s, C-5), 169.1 (s, COO),
134.4 (s, Ph), 131.8 (d, Ar), 131.7 (s, Ar), 131.6 (s, Ar),
131.1 (s, Ar), 130.4 (s, Ar), 129.8 (2d, Ph), 129.7 (s, Ar),
129.6 (s, Ar), 128.8 (2d, Ph), 128.1 (d, Ar), 127.4 (d, Ph),
2), 69.5 (q, JCF = 35 Hz, CHCF3), 44.8 (d, C-3), 31.2 (t,
C-4), 16.2 (q, CH3); MS, m/z: 403 (19, M+1), 402 (77,
M+Å), 333 (4, MꢁCF3), 259 (53), 239 (17), 207 (100), 179
25
(12); ½aꢂD ¼ ꢁ72:6 (c 0.72, CHCl3).
3.4.6. (10S,2S,3S)-(ꢁ)-1-(9-Anthryl)-2,2,2-trifluoroethyl 2-
methyltetrahydro-5-oxo-3-furancarboxylate 16. IR (CHCl3):
1
1786, 1766 cmꢁ1; H NMR, d: 8.60 (1H, d, J = 7.7 Hz, Ar),
8.59 (1H, s, Ar), 8.34 (1H, d, J = 9.1 Hz, Ar), 8.05 (1H, d,
J = 8.0 Hz, Ar), 8.04 (1H, d, J = 7.3 Hz, Ar), 7.87 (1H, q,
J = 8.0 Hz, CHCF3), 7.66 (1H, t, J = 7.8 Hz, Ar), 7.60

2352
F. Berti et al. / Tetrahedron: Asymmetry 17 (2006) 2344–2353
(1H, t, J = 7.3 Hz, Ar), 7.53 (1H, t, J = 6.2 Hz, Ar), 7.51
(1H, t, J = 7.1 Hz, Ar), 4.96 (1H, quintet, J = 6.6 Hz, H-
2), 3.59 (1H, ddd, J2,3 = 6.6 Hz, JAX = 7.0 Hz, JBX = 9.4 Hz,
H-3, part X of an ABX system, H-3), 2.87 (1H, part A of an
ABX system, JAB = 17.6 Hz, JAX = 9.4 Hz, H-4 cis to the
alkoxycarbonyl group), 2.61 (1H, part B of an ABX system,
JAB = 17.6 Hz, JBX = 7.0 Hz, H-4 trans to the alkoxycar-
bonyl group), 1.36 (3H, d, J = 6.6 Hz, CH3); 13C NMR,
d: 174.2 (s, C-5), 168.6 (s, COO), 131.9 (d, Ar), 131.8
(s, Ar), 131.5 (s, Ar), 131.1 (s, Ar), 130.7 (s, Ar), 129.8 (d,
Ar), 129.6 (d, Ar), 128.2 (d, Ar), 127.0 (d, Ar), 125.9
(q, CH3). MS, m/z: 403 (21, M+1), 402 (86, M+Å), 333 (5,
MꢁCF3), 259 (53), 239 (18), 208 (31), 207 (100), 179 (14);
25
½aꢂD ¼ ꢁ1:9 (c 0.26, CHCl3).
3.5. Conformational analysis
A set of optimized conformations for all the analyzed com-
pounds was obtained by a simple Monte Carlo search.
Each rotatable bond was allowed to rotate in order to gen-
erate the starting set of geometries. Each bond was twisted
by 10ꢁ torsional increments randomly and the initial set
was thus obtained. The geometries were optimized first
using molecular mechanics calculations with the Cornell
version of the Amber forcefield;19 the optimizations were
carried out with the Polak–Ribiere conjugate gradient
1
(d, Ar), 125.3 (2d, Ar), 124.2 (q, JCF = 278 Hz, CF3),
122.2 (d, Ar), 120.2 (s, Ar), 76.0 (d, C-2), 69.7 (q,
2JCF = 35 Hz, CHCF3), 44.4 (d, C-3), 31.1 (t, C-4), 16.7 (q,
CH3); MS, m/z: 403 (13, M+1), 402 (53, M+Å), 333 (2,
25
MꢁCF3), 259 (39), 239 (11), 207 (100), 179 (13); ½aꢂD
¼
˚
algorithm to a gradient of 0.001 kcal/A mol. The first 10
ꢁ36:3 (c 0.60, CHCl3).
conformations obtained at this first step were then submit-
ted to a further refinement, and their geometries were reop-
timized with a semiempirical calculation using the AM1
Hamiltonian16 as implemented in Sybyl6.820 (Sybyl6.8, Tri-
pos Inc., 1699 South Hanley Road, St. Louis, MO 63144,
USA). The SCF convergence limit for the UHF calculation
was set to full accuracy, while the GNORM keyword was
set to 0.001. All the calculations were carried out on a
Silicon Graphic Octane workstation.
3.4.7.
(10R,2S,3R)-(ꢁ)-1-(9-Anthryl)-2,2,2-trifluoroethyl
2-methyltetrahydro-5-oxo-3-furancarboxylate
17. IR
1
(CHCl3): 1786, 1766 cmꢁ1; H NMR, d: 8.60 (1H, s, Ar),
8.58 (1H, d, J = 8.9 Hz, Ar), 8.32 (1H, d, J = 8.9 Hz,
Ar), 8.05 (1H, d, J = 8.4 Hz, Ar), 8.04 (1H, d, J =
8.4 Hz, Ar), 7.83 (1H, q, J = 7.9 Hz, CHCF3), 7.67 (1H,
t, J = 7.7 Hz, Ar), 7.59 (1H, t, J = 7.7 Hz, Ar), 7.52 (2H,
m, Ar), 4.69 (1H, dq, J2,3 = 8.0 Hz, J2,Me = 6.2 Hz, H-2),
3.19 (1H, dt, J2,3 = 8.0 Hz, JAX = 9.5 Hz, JBX = 9.5 Hz,
H-3, part X of an ABX system, H-3), 2.79 (1H, part A of
an ABX system, JAB = 17.9 Hz, JAX = 9.5 Hz, H-4 cis to
the alkoxycarbonyl group), 2.77 (1H, part B of an ABX
system, JAB = 17.9 Hz, JBX = 9.5 Hz, H-4 trans to the alk-
oxycarbonyl group), 1.60 (3H, d, J = 6.2 Hz, CH3); 13C
NMR, d: 173.5 (s, C-5), 169.0 (s, COO), 131.9 (d,
Ar), 131.8 (s, Ar), 131.5 (s, Ar), 131.1 (s, Ar), 130.6
(s, Ar), 129.8 (d, Ar), 129.7 (d, Ar), 128.2 (d, Ar), 127.0 (d,
Ar), 125.6 (d, Ar), 125.3 (2d, Ar), 124.1 (q, 1JCF = 284 Hz,
CF3), 122.2 (d, Ar), 120.0 (s, Ar), 77.6 (d, C-2), 70.1 (q,
2JCF = 35 Hz, CHCF3), 47.3 (d, C-3), 32.2 (t, C-4), 20.8
(q, CH3); MS, m/z: 403 (21, M+1), 402 (99, M+Å), 333 (5,
Acknowledgement
MUR (PRIN 2004, 2005) and the University of Trieste are
gratefully acknowledged for financial support.
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7.3 Hz, JAX = 8.3 Hz, JBX = 9.0 Hz, H-3, part X of an
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