Synthesis of optically active α-benzyl paraconic acids and their esters and assignment of their absolute configuration

Article abstract of DOI:10.1016/j.tetasy.2009.01.027

The cis- and trans-4-benzylparaconic acids and their ethyl esters were synthesized with high enantiomeric excess by hydrolysis of the corresponding diastereomeric lactonic esters using α-chymotrypsin. Thus, at low conversion values, cis- and trans-4-benzyl-5-oxo-3-tetrahydrofurancarboxylic acids were separately isolated with 99% ee and 92% ee, respectively. Both ethyl ester diastereomers were also obtained in enantiopure form. The absolute configuration of the trans-lactonic acid was assigned by ¹H NMR analysis of its ester derivatives with both enantiomers of 1-(9-anthryl)-2,2,2-trifluoroethanol, while that of the cis-lactonic acid was assigned by means of X-ray analysis of a crystalline derivative. The circular dichroism curves of the products obtained are also reported.

Full text of DOI:10.1016/j.tetasy.2009.01.027

Tetrahedron: Asymmetry 20 (2009) 313–321
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Synthesis of optically active a-benzyl paraconic acids and their esters
and assignment of their absolute configuration
*
Federico Berti, Cristina Forzato , Giada Furlan, Patrizia Nitti, Giuliana Pitacco,
*
Ennio Valentin , Ennio Zangrando
Dipartimento di Scienze Chimiche, Università degli Studi di Trieste, via Licio Giorgieri 1, I-34127 Trieste, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
The cis- and trans-4-benzylparaconic acids and their ethyl esters were synthesized with high enantio-
Received 26 November 2008
Accepted 23 January 2009
Available online 11 March 2009
meric excess by hydrolysis of the corresponding diastereomeric lactonic esters using
a-chymotrypsin.
Thus, at low conversion values, cis- and trans-4-benzyl-5-oxo-3-tetrahydrofurancarboxylic acids were
separately isolated with 99% ee and 92% ee, respectively. Both ethyl ester diastereomers were also
obtained in enantiopure form. The absolute configuration of the trans-lactonic acid was assigned by 1H
NMR analysis of its ester derivatives with both enantiomers of 1-(9-anthryl)-2,2,2-trifluoroethanol, while
that of the cis-lactonic acid was assigned by means of X-ray analysis of a crystalline derivative. The cir-
cular dichroism curves of the products obtained are also reported.
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
onate and bromoacetate were reacted, using a slightly modified
literature procedure,6 generating the triester intermediate 1 which
Compounds containing the
c-lactone ring are constantly syn-
rearranged under strongly basic conditions to give compound 2.7
thesized because of their potential use as drugs in the pharmaceu-
Reaction with paraformaldehyde in the presence of trace amounts
tical industry.1 Some alkyl-substituted
c-butyrolactones, such as
of potassium hydrate at room temperature8 furnished the
a
-ben-
-lactone 3. Hydrolysis and decarbox-
ylation, under acidic conditions, gave 3:7 diastereomeric
a
-benzyl-
a
-methyl-
c
-butyrolactone, have been shown to have
zyl-b,b-diethoxydicarbonyl-c
both inhibitory and stimulatory effects on GABAA receptors.2 The
a
interest in the synthesis of enantiopure functionalized b-carboxyl-
mixture of the cis- and trans-lactonic acids 4a and 4b, which were
esterified9 to the target lactonic esters 5a and 5b, respectively.
The lactonic esters 5a and 5b were separated by column chro-
matography. The assignment of the cis/trans configuration was
based on the 1H NMR chemical shift values of H-3 and H-4. As
reported in the literature10 for a series of different analogues, in
the trans-lactone, H-3 resonates at higher field than H-4, while
the reverse is true for the cis-lactone (Fig. 1).
These assignments were then confirmed by DIFNOE experi-
ments carried out on the cis-diastereomer 5a. Irradiation of H-4
at 3.08 ppm clearly enhanced the signal of H-3 at 3.30 ppm,
although the signal of H-3 was partially overlapped by one of the
benzyl protons.
ated c-butyrolactones (generally called paraconic acid derivatives)
is increasing, in view of their potential biological activity.3 We
recently focused our attention on the synthesis of optically active
diastereomeric ethyl
matic resolution of their esters with
c
-benzylparaconates involving kinetic enzy-
-chymotrypsin.4 The
-benzyl-
a
absolute configurations of the enantiopure cis- and trans-
c
paraconic acids were determined by means of a comparison of 1H
NMR spectra of their esters with (+)- and (ꢀ)-1-(9-anthryl)-2,2,2-
trifluoroethanol.5 Herein, we report the synthesis of their regioiso-
meric ethyl a-benzylparaconates in enantiopure form with the aim
of verifying the effects of a change in the position of the benzyl
group on the efficiency of the same hydrolytic enzyme.
2. Results and discussion
2.1. Synthesis of substrates
2.2. Enzymatic hydrolyses
Enzymatic hydrolyses were performed on the lactonic esters 5a
and 5b using a series of commercially available enzymes, namely
Porcine pancreatic 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
Racemic ethyl a-benzylparaconates 5a,b were synthesized fol-
lowing the procedure as indicated in Scheme 1. Diethyl benzylmal-
* Corresponding authors. Tel.: +39 040 5583917; fax: +39 040 5583903 (E.V.).
E-mail address: evalentin@units.it (E. Valentin).
0957-4166/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2009.01.027

314
F. Berti et al. / Tetrahedron: Asymmetry 20 (2009) 313–321
COOEt
COOEt
KH (1.2 eq)
(CH2O)n,KOH
r.t., 40 h
Br
COOEt
Ph
COOEt
Ph
Ph
COOEt
COOEt
EtOOC COOEt
EtONa/EtOH
r.t., 12 h
DME, Δ, 30 min
COOEt
1
2
EtOOC
EtOOC
HOOC
ROOC
Ph
Ph
Ph
Me3SiCl, ROH
r.t.,12 h
HCl 6M
Δ, 52 h
3
4
O
O
O
O
O
O
5a;
trans: R=Et:
6a
R=Me:
3
4a
cis: R=Et:
R=Me:
5b;
cis:
4b
trans:
6b
Scheme 1. Synthesis of racemic substrates 5a and 5b.
with 92% ee. Also CCL, Lipase AY, MML and CAL (Table 2, entries
2–5,) were completely regioselective affording the corresponding
lactonic acid 4b, however, with low enantioselectivity. The other
enzymes checked did not hydrolyse the substrate.
3.12ppm
EtOOC
3.08ppm
3.30ppm
H
3.23ppm
H
H
H
EtOOC
Ph
O
Ph
O
3
4
Enzymatic hydrolyses carried out with acetone as a cosolvent,
which had been successful for the
proved to be ineffective.
c
-benzylparaconate analogues,4
O
5a
O
5b
The lactonic esters (+)-5a and (+)-5b were obtained in 94% ee
and 96% ee, respectively, by hydrolysis with -CT of the corre-
a
Figure 1. Chemical shifts of H-3 and H-4 for lactones 5a and 5b.
sponding lactonic esters recovered from the previous reactions
(see Section 4).
(HLAP), a-chymotrypsin (a-CT) and proteases from Bacillus subtilis
2.3. Determination of the absolute configuration of the
products
(SUB). Hydrolyses were monitored by a pH-STAT instrument with
the continuousaddition of 1 M NaOH. Since the molecules presented
two possible sites of attack by the enzyme, namely the ethoxycar-
bonyl group and the lactone group, attention was paid to the regio-
selective enzymes, which were effective in hydrolysing the
ethoxycarbonyl group exclusively. Tables 1 and 2 list only the results
obtained with those enzymes which proved to be regioselective.
2.3.1. NMR analysis of derivatives 7 and 8
In our previous work, we assigned the absolute configuration of
c
-benzylparaconic acids,4 using a slightly modified method pro-
posed by Riguera13 for linear carboxylic acids. In accordance with
this method, the acid is transformed into a pair of diastereomeric
esters by reaction with the two enantiomers of 1-(9-anthryl)-
2,2,2-trifluoroethanol. The shielding due to the anthryl diamag-
netic anisotropy on the protons of the molecule is then evaluated
by 1H NMR. The absolute configuration of the molecule is deduced
The cis-diastereomer 5a was a good substrate for both
a-chy-
motrypsin ( -CT) and PPL, whose enantiomeric ratios E’s were
a
higher than 200 (Table 1, entries 1 and 2). As a consequence, the
resulting cis-lactonic acid (ꢀ)-(3S,4R)-4a was isolated in enantio-
pure form. In spite of its very low E-value, PLAP is interesting
because it proved to be enantiocomplementary with respect to
from the difference in chemical shift (Dd
R,S) between the two dia-
stereomers of the protons contained in the substituents L1 and L2,
linked to the stereocentre (Fig. 2).
a
-CT and PPL. Of the other enzymes checked, HLAP was not regio-
selective, leading to the ester (+)-(3R,4S)-5a with 83% ee, formed by
ring fission and ring closure reactions, together with the lactonic
acid (ꢀ)-(3S,4R)-4a with 55% ee. The same behaviour, albeit with
lower enantioselectivity, was observed for Lipase PS, while the
other enzymes proved to be uneffective.
In the original Riguera’s model, the minimum energy conforma-
tion of the esters was assumed to be that shown in Figure 2, that is,
with the protons of the two stereocentres in an anti-conformation.
To make sure that the methodology was also applicable to our
systems, a conformational study was performed on the two
diastereomers 7 and 8, which are obtained by esterification of
On the contrary, for the trans-diastereomer 5b, the hydrolysis
had fairly high enantioselectivity only with
a-chymotrypsin,
the trans-
a
-benzylparaconic acid (ꢀ)-4b with (+)- and (ꢀ)-1-(9-an-
whose enantiomeric ratio E, however, was not so high as for its dia-
stereomer 5a. The trans-lactonic acid 4b was therefore isolated
thryl)-2,2,2-trifluoroethanol (Scheme 2).
Table 1
Enzymatic hydrolysesa of compound 5a
Entry
Enzyme
Eb
Conv.c
Time (h)
Lactonic acid 4a
Unreacted ester 5a
Sign of
a
eed (%)
Abs Config.
Sign of
a
eee (%)
Abs Config.
1
2
3
a
PPL
PLAP
-CT
>200
>200
3
12
7
31
5.7
33
5.2
(ꢀ)
(ꢀ)
(+)
>99
>99
41
(3S,4R)
(3S,4R)
(3R,4S)
(+)
(+)
(ꢀ)
13
7
18
(3R,4S)
(3R,4S)
(3S,4R)
a
Reaction conditions: phosphate buffer, pH 7.4, rt.
!
½e:e: ð1ꢀe:e: Þꢁ
P
S
S
S
S
ln
ln
e:e: þe:e:
b
P
E-values E ¼
Calculated.12
were calculated from the formula containing the enantiomeric excesses of both the substrate and the product.11
½e:e: ð1þe:e: Þꢁ
P
e:e: þe:e:
P
c
d
e
Determined by chiral HRGC on the methyl ester derivative 6a.
Determined by chiral HRGC.

F. Berti et al. / Tetrahedron: Asymmetry 20 (2009) 313–321
315
Table 2
Enzymatic hydrolysesa of compound 5b
Entry
Enzyme
Eb
Conv.c
Time (h)
Lactonic acid 4b
Unreacted ester 5b
Sign of
a
eed (%)
Abs Config.
Sign of
a
eee (%)
Abs Config.
1
2
3
4
5
a
CCL
Lipase AY
MML
CAL
-CT
29
2
2
5
9
18
31
27
17
17
0.9
1.3
8.7
1.2
2.6
(ꢀ)
(ꢀ)
(ꢀ)
(ꢀ)
(ꢀ)
92
33
24
60
77
(3S,4S)
(3S,4S)
(3S,4S)
(3S,4S)
(3S,4S)
(+)
(+)
(+)
(+)
(+)
20
15
9
12
16
(3R,4R)
(3R,4R)
(3R,4R)
(3R,4R)
(3R,4R)
a
Reaction conditions: phosphate buffer, pH 7.4, rt.
!
½e:e: ð1ꢀe:e: Þꢁ
P
S
S
S
S
ln
ln
e:e: þe:e:
b
P
E-values E ¼
Calculated.12
were calculated from the formula containing the enantiomeric excesses of both the substrate and the product.11
½e:e: ð1þe:e: Þꢁ
P
e:e: þe:e:
P
c
d
e
Determined by chiral HRGC on the methyl ester derivative 6b.
Determined by chiral HRGC.
The ground state conformations of ester 8 correspond to those
supposed by the Riguera’s model; however, the ground state con-
formation of ester 7 is very different, since oxygen 3 and hydrogen
3 are found in an anti-conformation. For this reason, the shielding
effect of the anthryl system is predicted to operate on the same
side of the molecule (namely on C4 and C7) in both esters. This
can be clearly seen from the superimposition reported in Figure
3: in both esters, the C4-benzyl region of the molecules lies in
the cone of diamagnetic anisotropy (hemiangle 45° from the centre
of the anthryl system), while the protons at C2 are not influenced
by this effect.
(R) or (S)
H
Ar
O
L2
L1
ΔδR,S
F3C
H
O
Figure 2. Riguera’s model.
The two diastereomeric esters 7 and 8 have been submitted to
an extensive conformational search, which is carried out with a
Monte Carlo algorithm operating on PM3 geometry optimiza-
tions.14 We have found four and five different energy minima for
esters 7 and 8, respectively, and their structural parameters are re-
ported in Table 3, together with their enthalpy data.
The chemical shifts of the protons on C-2 and C-4 of the lactone
ring, as well as those of the benzylic protons in diastereomers 7
and 8, are reported in Table 4. The stereocentre of the alcoholic
component is indicated as 10.
Ar
H
CF3
H
O
(R)
O
(S)
F3C
Ar
HOOC
O
Ph
Ph
O
Ph
3
4
i) EDC, Et3N, DMAP
ii) (R)-alcohol
i) EDC, Et3N, DMAP
ii) (S)-alcohol
2
O
O
O
O
O
O
7
(–)-4b
8
Scheme 2. Synthesis of compounds 7 and 8 from (ꢀ)-4b.
Table 3
PM3 conformation analysis of esters 7 and 8: structures, energies and predicted shielding effects
2
O3
H1'
CF3
3
H3
O
6
1'
O4
4
O
2' 3'
7
8
9
0
0
0
0
0
0
0
Compound Conf. C3 C2 C1 H1
H1 C1 O4C6 C1 O4C6O3 O3C6C3C2 C3C4C7C8 C4C7C8C9
DHf rel (absolute) Population (%) Shielding on C2 Shielding on C4–C7
(Kcal/mol)
7
0
1
2
3
181.8
176.5
185.8
177.5
0.4
198.0
205.6
199.0
357.6
19.6
15.2
19.5
254.2
243.1
55.7
72.3
71.3
160.4
162.6
277.7
256.3
100.0
109.9
0 (ꢀ224.22)
7.69
99.99
—
—
No
Yes
No
Yes
No
Yes
No
7.75
8.80
240.3
—
Yes
8
0
1
2
3
4
182.7
182.3
181.0
180.6
211.8
5.5
4.9
5.2
4.8
181.5
356.7
358.6
4.4
182.9
350.4
64.0
252.8
69.4
75.6
239.2
73.1
72.9
172.0
169.0
74.3
77.8
76.9
109.5
289.3
256.3
0 (ꢀ224.30)
0.51
61.7
26
10
1.9
0.4
No
Yes
No
No
No
Yes
No
Yes
No
1.08
2.06
7.22
Yes

316
F. Berti et al. / Tetrahedron: Asymmetry 20 (2009) 313–321
For this reason, shielding on the C4 side of the molecules is less
significant in compound 8. This allows us to predict the values of
dR,S in qualitative accordance with the experimental data, and
D
thus determines the absolute configuration of compound (ꢀ)-4b
to be (3S,4S).
It was not possible to apply the same method to the cis-a-ben-
zylparaconic acid (ꢀ)-4a because it did not react with either
enantiomer of 1-(9-anthryl)-2,2,2-trifluoroethanol, although
many attempts have been made also by changing the reaction
conditions.
2.3.2. X-ray analysis of (ꢀ)-9
The assignment of the (3S,4R) absolute configuration to the cis-
isomer (ꢀ)-4a was accomplished by means of X-ray analysis of the
ester (ꢀ)-9, which is obtained from the reaction of (ꢀ)-4a with
2,40-dibromoacetophenone under basic conditions (Scheme 3).
Single crystal structural analysis reveals in the unit cell the
presence of two independent molecules having a different confor-
mation about the O–C ester bond (C(9)–O(2)–C(8)–C(7) torsion an-
gle of 134.6(5)°, see Fig. 5, and of 77.7(5)° in the other molecule).
The lactone ring presents an ‘envelope’ conformation with carbon
C(10) slightly displaced by 0.53(1) Å (0.55(1) Å in the other spe-
cies) from the coplanar O(4)/C(11)/C(12)/C(13) atoms. The two
independent molecules in the crystal packing interact through
Figure 3. Overlay of the ground state conformations of esters 7 (blue) and 8
(green).
weak
rings 3.860(4) Å).
p–p stacking Br–phenyl rings (distance between centroid
Table 4
2.3.3. CD analysis
Selected chemical shift values for compounds 7 and 8
Since both lactonic acids (ꢀ)-4a and (ꢀ)-4b were substituted at
H-2
D
dR,S
H-4
D
dR,S
CH2Ph
D
dR,S
+0.16
the a-position, we analyzed their circular dichroism spectra in or-
der to verify whether the empirical rules15 formulated for the
assignment of the absolute configuration to -lactones were valid.
Among these rules, the Okuda rule16 found its applicability to
substituted -lactones. The Okuda rule was originally assessed
for -hydroxy-
-alkyl-
(10R,3S,4S)-7
(10S,3S,4S)-8
4.11a
4.25a
ꢀ0.14
3.21
3.17
+0.04
3.14a
2.98a
c
a-
a
Average chemical shift of the two geminal protons (see Section 4).
c
a
c-lactones, but its validity was further extended to
a
c
-lactones.17 In accordance with this rule, the sign of the
*
p transition of the lactone
The observed difference in chemical shifts can be explained on
the basis of the very different population of the other conformation
available for the two compounds. In ester 7, the ground state con-
formation is also the only one to be populated at room tempera-
ture, while the conformations of ester 8 are very close in energy,
and over 25% of the molecules populate conformation 1, where
the shielding operates on C2 (Fig. 4).
Cotton effect associated with the n?
group is strictly dependent on the absolute configuration of C-a.
Since the CD curves of the lactones (ꢀ)-4a and (ꢀ)-4b are opposite
(Fig. 6), the two lactones must have opposite absolute configura-
tions at C-
a. The corresponding esters (+)-5a and (+)-5b also have
opposite Cotton effect, and hence they have opposite configuration
Figure 4. Conformations 0 (left) and 1 (right) of ester 8.

F. Berti et al. / Tetrahedron: Asymmetry 20 (2009) 313–321
317
Br
O
Br
HOOC
Ph
DBU, toluene
O
+
r.t., 12h
O
Ph
O
O
O
Br
O
O
(–)-4a
(–)-9
Scheme 3. Synthesis of the ester (ꢀ)-9.
6
4
2
Δε
0
-2
-3
200
210
220
230
240
250
Figure 5. ORTEP diagram of one of the two independent molecules of 9.
λ/nm
Figure 7. CD spectra of lactones (+)-5a (red) and (+)-5b.
(Fig. 7). As a consequence, the validity of the Okuda rule is
confirmed.
odologies is sometimes necessary to arrive at the correct
assignment of the absolute configuration.
3. Conclusions
4. Experimental
4.1. General
The cis- and trans
fully resolved by -Chymotrypsin (
ven to be particularly suitable for kinetic resolution of N-benzyl
-lactamic esters18 and cis- and trans- -benzylparaconates,4 thus
a
-benzylparaconates 5a and 5b were success-
a
a-CT), which has already pro-
c
c
IR spectra were recorded on a Jasco FT/IR 200 spectrophotome-
ter. 1H NMR and 13C NMR spectra were run on a Jeol EX-400 spec-
trometer (400 MHz for proton, 100 MHz for carbon) and on a Jeol
EX-270 spectrometer (270 MHz for proton, 68 MHz for carbon)
using deuteriochloroform as a solvent and tetramethylsilane as
the internal standard. Coupling constants are given in Hertz. Opti-
cal rotations were determined on a Perkin Elmer Model 241 polar-
suggesting that the presence of a benzyl group on either a lactone
ring or a lactam ring is important for a favourable interaction with
the enzyme, independent of the position of the group. Further-
more, this work demonstrates that the joint use of different meth-
1
0
imeter; ½a D
obtained on a Jasco J-710 spectropolarimeter (0.1 cm cell);
values are given in cm2 mmolꢀ1. UV spectra were recorded on a
ꢁ
values are given in 10ꢀ1 deg cm2 gꢀ1. CD spectra were
D
e
UNICAM HekIOS b spectrophotometer;
e values are given in
dm3 molꢀ1 cmꢀ1. Capillary gas chromatographic measurements
were performed on a Carlo Erba GC 8000 instrument and on a Shi-
madzu GC-14B instrument, equipped with a flame ionization
detector, the capillary columns being OV 1701 (25 m ꢂ 0.32 mm)
-1
Δε
TM
-2
-3
-4
(carrier gas He, 40 KPa, split 1:50) and a Chiraldex type G-TA, tri-
fluoroacetyl
c
-cyclodextrin (40 m ꢂ 0.25 mm) (carrier gas He, 180
KPa, split 1:100) or DiMePe b-cyclodextrin (25 m ꢂ 0.25 mm)
(carrier gas He, 110 KPa, split 1:50). Enzymatic hydrolyses were
performed using a pH-stat Controller PHM290 Radiometer Copen-
hagen. Mass spectra were recorded on an ion trap instrument Fin-
ningan GCQ (70 eV). HRMS spectra were performed on a Finnigan
MAT95XP spectrometer. TLCs were performed on PolygramÒ Sil
G/UV254 silica gel pre-coated plastic sheets (eluant: light petro-
leum–ethyl acetate). Flash chromatography was run on silica gel
200
210
220
230
240
250
λ/nm
Figure 6. CD spectra of lactones (ꢀ)-4a (red) and (ꢀ)-4b.

318
F. Berti et al. / Tetrahedron: Asymmetry 20 (2009) 313–321
230–400 mesh ASTM (Kieselgel 60, Merck). Light petroleum refers
to the fraction with bp 40–70 °C, and ether to diethyl ether.
Commercial grade solvents were used without further purification.
Diethyl benzylmalonate, ethyl bromoacetate, (+) and (ꢀ)-1-(9-an-
thryl)-2,2,2-trifluoroethanol were commercial products.
CDCl3) d 175.0 (s, C-5), 168.0 (s, COOEt), 167.2 (s, COOEt), 137.6 (s,
Ph), 129.0 (2 ꢂ d, Ph), 128.2 (2 ꢂ d, Ph), 126.6 (d, Ph), 69.3 (t, C-2),
62.4 (t, OCH2CH3), 62.2 (t, OCH2CH3), 59.8 (s, C-3), 46.4 (d, C-4),
32.3 (t, CH2Ph), 13.6 (q, CH3CH2O), 13.5 (q, CH3CH2O).
4.2.4. Ethyl 4-benzyl-5-oxo-3-tetrahydrofurancarboxylate 5a,b19
Compound 3 (8.0 g, 25 mmol) in 150 mL of 20% HCl was re-
fluxed for 52 h. After evaporation of the solvent, a mixture of dia-
stereomeric acids 4a,b, in the ratio of 28:72 (1H NMR), was
obtained as a white solid (5.24 g, 95%). Their esterification was car-
ried out in 120 mL of anhydrous ethanol, with 6.6 mL (52.4 mmol)
of trimethylsilyl chloride added9 under an Ar atmosphere and stir-
red for 12 h. Evaporation of the solvent left a 28:72 mixture of 5a
and 5b, respectively (5.38 g, 91%).
4.2. Synthesis of racemic substrates
4.2.1. 3-Phenyl-1,2,2-propanetricarboxylic acid 1,2,2-triethyl
ester 17
To a solution of 150 mmol of EtONa in EtOH (3.45 g of Na in
85 mL of absolute ethanol), 23.3 mL (100 mmol) of diethyl benzyl-
malonate and 13.3 mL (120 mmol) of ethyl bromoacetate were
added. The mixture was stirred for 12 h under an argon atmo-
sphere. After evaporation of the solvent, 3 N H2SO4 was added,
and the mixture was extracted with ether and the organic phase
dried on anhydrous Na2SO4. After evaporation of the solvent, com-
Separation of the crude reaction mixture by flash chromatogra-
phy (petroleum ether and ethyl acetate in 4:1 ratio) furnished 5a
(0.75 g, 13%) and 5b (2.17 g, 37%) as oils. 5a:
m
max(film)/cmꢀ1
pound 1 was obtained as a colourless oil (33.0 g, 98%).
m
max(film)/
1776 (O–C@O), 1732 (COO), 744–698; 1H NMR (400 MHz; CDCl3)
d 7.33–7.20 (5H, m, Ph), 4.38 (1H, dd, J1 2.9, J2 9.5, H-2), 4.28
(1H, dd, J1 6.2, J2 9.5, H-2), 4.18 (1H, q, J 7.1, OCH2CH3), 4.13 (1H,
q, J 7.1, OCH2CH3), 3.30 (1H, m, H-3), 3.29 (1H, dd, J1 4.5, J2 14.5,
CHPh), 3.08 (1H, ddd, J1 4.5, J2 8.3, J3 10.0, H-4), 2.83 (1H, dd, J1
10.0, J2 14.5, CHPh), 1.24 (3H, t, J 7.1, CH3CH2O); 13C NMR
(100 MHz; CDCl3) d 176.1 (s, C-5), 170.6 (s, COOEt), 138.0 (s, Ph),
128.7 (2 ꢂ d, Ph), 128.6 (2 ꢂ d, Ph), 126.8 (d, Ph), 67.7 (t, C-2),
61.4 (t, OCH2CH3), 44.0 (d, C-3), 44.0 (d, C-4), 32.2 (t, CH2Ph),
14.0 (q, CH3); m/z (EI, 70 eV): 248 (M+Å, 20), 220 (18), 191 (13),
190 (100), 175 (23), 157 (6), 148 (33), 147 (48), 144 (14), 131
(31), 129 (18), 117 (10), 116 (6), 115 (15), 104 (7), 103 (7), 92
(7), 91 (74), 65 (13), 29 (7); HRMS (EI, 70 eV): calculated for
C14H16O4 (M+Å) 248.1049, experimental 248.1049; HRGC (b-CDX):
tR = 238.7 min for the (+)-(3R,4S) enantiomer and tR = 250.2 min
cmꢀ1 1736 (COO), 1171 (C–O–C); 1H NMR (400 MHz; CDCl3) d
7.25 (3H, m, Ph), 7.09 (2H, m, Ph), 4.22 (2H, q, J 7.1, OCH2CH3),
4.21 (2H, q, J 7.1, OCH2CH3), 4.16 (2H, q, J 7.1, OCH2CH3), 3.39
(2H, s, CH2Ph), 2.85 (2H, s, CH2COOEt), 1.27 (3H, t, J 7.1, CH3CH2O),
1.26 (6H, t, J 7.1, CH3CH2O); 13C NMR (100 MHz; CDCl3) d 171.1 (s,
COOEt), 170.0 (s, COOEt), 169.9 (s, COOEt), 135.8 (s, Ph), 130.1
(2 ꢂ d, Ph), 128.4 (2 ꢂ d, Ph), 127.2 (d, Ph), 61.8 (t, OCH2CH3),
61.7 (t, OCH2CH3), 60.8 (t, OCH2CH3), 55.9 (s, C(COOEt)2), 38.6 (t,
CH2Ph), 36.8 (t, CH2COOEt), 14.1 (q, CH3CH2O), 14.0 (q, CH3CH2O),
13.9 (q, CH3CH2O).
4.2.2. 3-Phenyl-1,1,2-propanetricarboxylic acid 1,1,2-triethyl
ester 27
To a suspension of 18.0 g of KH (30% KH in mineral oil washed
with petroleum ether), 150 mL of 1,2-dimethoxyethane was added.
A solution of 33.0 g (98.1 mmol) of compound 1 in 150 mL of 1,2-
dimethoxyethane was added dropwise to the mixture, and the
resulting mixture was refluxed for 30 min. At the end of the reac-
tion, 20 mL of cool water was added and 4 M HCl until neutraliza-
tion. The mixture was extracted with ether, and the organic phase
was washed with NaHCO3 saturated solution, water and brine, and
dried over anhydrous Na2SO4. Evaporation of the solvent gave
for the (ꢀ)-(3S,4R) enantiomer (150 °C isotherm); HRGC (
tR = 222.6 min for the (ꢀ)-(3S,4R) enantiomer and tR = 231.7 min
for the (+)-(3R,4S) enantiomer (150 °C isotherm). 5b: max(film)/
c-CDX):
m
cmꢀ1 1776 (O–C@O), 1732 (COO), 758–698; 1H NMR (400 MHz;
CDCl3) d 7.32–7.19 (5H, m, Ph), 4.28 (1H, t, J 8.8, H-2), 4.21 (1H,
dd, J1 8.8, J2 9.1, H-2), 4.04 (1H, q, J 7.1, OCH2CH3), 4.01 (1H, q, J
7.1, OCH2CH3), 3.24 (1H, dd, J1 6.4, J2 9.7, CHPh), 3.23 (1H, m, H-
4), 3.12 (1H, dt, J1 8.8, J2 9.1, H-3), 3.03 (1H, dd, J1 6.4, J2 13.7, CHPh),
1.18 (3H, t, J 7.1, CH3CH2O); 13C NMR (100 MHz; CDCl3) d 176.4 (s,
C-5), 170.7 (s, COOEt), 136.7 (s, Ph), 129.4 (2 ꢂ d, Ph), 128.6 (2 ꢂ d,
Ph), 127.0 (d, Ph), 67.2 (t, C-2), 61.6 (t, OCH2CH3), 44.6 (d, C-3), 44.4
(d, C-4), 34.7 (t, CH2Ph), 13.9 (q, CH3); m/z (EI, 70 eV): 248 (M+Å, 35),
220 (10), 203 (16), 191 (12), 190 (91), 176 (12), 175 (100), 157 (10),
148 (39), 147 (63), 144 (11), 131 (26), 129 (26), 117 (10), 115 (16),
104 (6), 92 (10), 91 (98), 65 (15), 29 (9); HRMS (EI, 70 eV): calcu-
lated for C14H16O4 (M+Å) 248.1049, experimental 248.1046; HRGC
(b-CDX): tR = 138.7 min for the (+)-(3R,4R) enantiomer and
compound 2 as an oil (30.7 g, 93%); m
max(film)/cmꢀ1 1736 (COO),
1171 (C–O–C); 1H NMR (400 MHz; CDCl3) d 7.40–7.00 (5H, m,
Ph), 4.18 (4H, q, J 7.1, 2 OCH2CH3), 4.05 (2H, q, J 7.1, OCH2CH3),
3.70 (1H, d, J 9.2, CH(COOEt)2), 3.40 (1H, dt, J2,3 7.3, J1,2 9.2,
CHCH2Ph), 2.93 (2H, d, J 7.3, CH2Ph), 1.28 (3H, t, J 7.1, CH3CH2O),
1.24 (3H, t, J 7.1, CH3CH2O), 1.08 (3H, t, J 7.1, CH3CH2O); 13C NMR
(100 MHz; CDCl3) d 172.6 (s, COOEt), 167.8 (s, COOEt), 167.5 (s,
COOEt), 137.6 (s, Ph), 129.0 (2 ꢂ d, Ph), 128.4 (2 ꢂ d, Ph), 126.6
(d, Ph), 61.6 (t, OCH2CH3), 61.5 (t, OCH2CH3), 60.6 (t, OCH2CH3),
53.4 (d, CH(COOEt)2), 46.4 (d, CHCOOEt), 36.0 (t, CH2Ph), 13.9 (q,
CH3CH2O), 13.8 (q, CH3CH2O), 13.7 (q, CH3CH2O).
tR = 140.5 min for the (ꢀ)-(3S,4S) (150 °C isotherm); HRGC (
c-
CDX): tR = 116.0 min for the (ꢀ)-(3S,4S) enantiomer and
tR = 123.6 min for the (+)-(3R,4R) enantiomer (150 °C isotherm).
4.2.3. Diethyl 4-benzyl-5-oxo-3,3-tetrahydrofurandicarboxylate 3
At first, 3.50 g (2.5 equiv) of paraformaldehyde (polyoxymethyl-
ene) and 72 mg (1.3 mmol) of KOH were added to compound 2
(15.74 g, 46.8 mmol).8 The mixture was stirred for 40 h at rt. At
the end of the reaction, the mixture was filtered and washed with
CHCl3. Evaporation of the solvent gave compound 3 as a colourless
4.2.5. cis-4-Benzyl-5-oxo-3-tetrahydrofurancarboxylic acid 4a
Compound 5a (60 mg, 0.24 mmol) was hydrolyzed in 5 mL of
6 M HCl at reflux for 2 h. White solid, mp 125–127 °C; mmax(film)/
cmꢀ1 3000, 1761, 1685, 744–698; 1H NMR (400 MHz; CDCl3) d
7.30–7.20 (5H, m, Ph), 4.44 (1H, dd, J1 2.6, J2 9.5, H-2), 4.31 (1H,
dd, J1 4.8, J2 9.5, H-2), 3.35 (1H, dd, J1 8.0, J2 14.3, CHPh), 3.35
(1H, m, H-3), 3.10 (1H, ddd, J1 4.6, J2 8.0, J3 9.6, H-4), 2.92 (1H,
dd, J1 9.6, J2 14.3, CHPh); dY (400 MHz; D2O) 7.25–7.14 (5H, m,
Ph), 4.35 (1H, dd, J1 2.2, J2 9.8, H-2), 4.28 (1H, dd, J1 6.0, J2 9.8, H-
2), 3.36 (1H, ddd, J1 5.7, J2 8.2, J3 9.8, H-4), 3.21 (1H, ddd, J1 2.2,
J2 6.0, J3 8.2, H-3), 3.08 (1H, dd, J1 5.7, J2 14.6, CHPh), 2.66 (1H,
dd, J1 9.8, J2 14.6, CHPh); 13C NMR (100 MHz; CDCl3) d 176.6 (s,
C-5), 175.7 (s, COOH), 137.7 (s, Ph), 129.4 (2 ꢂ d, Ph), 128.6
oil (14.92 g, 99%); m H
max(film)/cmꢀ1 1789 (O–C@O), 1735 (COO); 1
NMR (270 MHz; CDCl3) d 7.31–7.20 (5H, m, Ph), 4.62 (1H, d, J 9.9,
H-2), 4.38 (1H, d, J 9.9, H-2), 4.23 (1H, q, J 7.2, OCH2CH3), 4.20
(1H, q, J 7.2, OCH2CH3), 4.08 (1H, q, J 7.2, OCH2CH3), 4.04 (1H, q, J
7.2, OCH2CH3), 3.49 (1H, t, X part of an ABX system, JAX 6.9, JBX
6.3, H-4), 3.08 (1H, A part of an ABX system, JAB 14.2, JAX 6.9, CHPh),
3.04 (1H, B part of an ABX system, JAB 14.2, JBX 6.3, CHPh), 1.26 (3H,
t, J 7.2, CH3CH2O), 1.23 (3H, t, J 7.2, CH3CH2O); 13C NMR (68 MHz;

F. Berti et al. / Tetrahedron: Asymmetry 20 (2009) 313–321
319
(2 ꢂ d, Ph), 126.8 (d, Ph), 67.7 (t, C-2), 44.0 (d, C-4), 43.7 (d, C-3),
31.9 (t, CH2Ph); dC (68 MHz; D2O) 180.8 (s, C-5), 175.8 (s, COOH),
138.3 (s, Ph), 129.2 (2 ꢂ d, Ph), 129.1 (2 ꢂ d, Ph), 127.3 (d, Ph),
69.6 (t, C-2), 44.6 (d, C-4), 43.7 (d, C-3), 31.9 (t, CH2Ph); m/z (EI,
70 eV) 220 (M+Å, 22), 192 (20), 175 (9), 162 (19), 148 (50), 147
(60), 131 (26), 130 (11), 129 (14), 117 (4), 115 (14), 104 (11),
103 (9), 92 (17), 91 (100), 77 (8), 69 (13), 65 (18), 51 (8), 39 (8);
HRMS (EI, 70 eV) calculated for C12H12O4 (M+Å) 220.0736, experi-
mental 220.0738.
(150 °C isotherm); HRGC (
enantiomer and tR = 102.3 min for the (3R,4R) enantiomer (150 °C
isotherm).
c
-CDX): tR = 97.4 min for the (3S,4S)
4.3. Enzymatic hydrolyses
To the lactones 5a and 5b (1 mmol) in 0.1 M phosphate buffer
(14 mL), at pH 7.4, the following amounts of enzymes were added:
0.150 g of Porcine Pancreatic Lipase (PPL, 46,000 U/g), 0.970 g of li-
pase from Pseudomonas species (Amano PS, 30,000 U/g), 0.033 g of
lipase from P. fluorescens (Amano AK, 30,000 U/g), 0.160 g of lipase
from C. Cylindracea (CCL, 943,000 U/g), 0.019 g of lipase from A. ni-
ger (Amano AP 12, 120,000 U/g), 0.330 g of lipase from C. rugosa
(Amano AY, 30,000 U/g), 0.400 g of lipase from M. miehei (MML,
Lipozyme), 0.180 g of lipase from C. antarctica (Novozyme 435Ò
CAL, 7000 U/g), 0.230 g of Porcine liver acetone powder (PLAP),
4.2.6. trans-4-Benzyl-5-oxo-3-tetrahydrofurancarboxylic acid 4b
Compound 5b (420 mg, 1.70 mmol) was hydrolyzed in 14 mL of
6 M HCl at reflux for 2 h. White solid, mp 100–101 °C; mmax(film)/
cmꢀ1 3000, 1748, 1727, 758–683; 1H NMR (400 MHz; CDCl3) d
7.61 (1H, br s, OH), 7.32–7.22 (5H, m, Ph), 4.26 (2H, d, J 8.4, H-2),
3.26 (1H, dt, J1 5.8, J2 9.5, H-4), 3.19 (1H, t, J 8.4, H-3), 3.16 (2H,
d, J 5.8, CH2Ph); 1H NMR (400 MHz; D2O) d 7.24–7.15 (5H, m,
Ph), 4.30 (1H, dd, J1=8.4, J2=9.2, H-2), 4.18 (1H, dd, J1 8.1, J2 9.2,
H-2), 3.28 (1H, ddd, J1 5.7, J2 7.7, J3 9.0, H-4), 3.19 (1H, app. t, J
8.4, H-3), 3.06 (1H, dd, J1 5.7, J2 14.0, CHPh), 2.84 (1H, dd, J1 7.7,
J2 14.0, CHPh); 13C NMR (100 MHz; CDCl3) d 176.9 (s, C-5), 175.5
(s, COOH), 136.2 (s, Ph), 129.4 (2 ꢂ d, Ph), 128.6 (2 ꢂ d, Ph), 127.0
(d, Ph), 66.9 (t, C-2), 44.1 (d, C-4), 43.5 (d, C-3), 34.1 (t, CH2Ph);
m/z (EI, 70 eV): 220 (M+Å, 32), 175 (24), 162 (12), 148 (60), 147
(77), 131 (25), 129 (20), 115 (19), 104 (7), 103 (7), 92 (13), 91
(100), 77 (12), 69 (15), 65 (24), 51 (12), 41 (13), 39 (14), 32 (10),
28 (27); HRMS (EI, 70 eV): calculated for C12H12O4 (M+Å)
220.0736, experimental 220.0736.
0.900 g of Horse liver acetone powder (HLAP), 0.013 g of
a-chymo-
trypsin ( -CT, 79,000 U/g) and 0.086 g of Subtilisin (11,600 U/g).
a
The course of the reaction was monitored with a pH-STAT, with
continuous addition of 1.0 M NaOH. At about 20% conversion, the
reaction mixture was extracted with ether to separate the unre-
acted lactone. The mother liquors were acidified with 3.0 N HCl
to pH 2 and extracted with ether to obtain the corresponding lac-
tonic acid 1 and/or the lactonic ester 3 derived from the hydroxy
halfester intermediate. The organic phases were dried over anhy-
drous Na2SO4 and treated with diazomethane to esterify the car-
boxylic group before chiral HRGC analysis.
4.3.1. cis-(ꢀ)-(3S,4R)-4-Benzyl-5-oxo-3-tetrahydrofurancarboxylic
acid 4a
4.2.7. Methyl cis-4-benzyl-5-oxo-3-tetrahydrofurancarboxylate
6a
Enzymatic hydrolysis of cis-lactonic ester 5a (0.13 g, 0.5 mmol)
Esterification of acid 4a with diazomethane furnished 6a as an
m
was carried out with a-CT (9.0 mg) in 10 mL of phosphate buffer to
oil.
max(film)/cmꢀ1 1776, 1732, 698; 1H NMR (400 MHz; CDCl3)
give, after 6 h (21% conversion), the lactonic acid (ꢀ)-4a with >99%
d 7.33–7.13 (5H, m, Ph), 4.38 (1H, dd, J1 3.3, J2 9.5, H-2), 4.29
(1H, dd, J1 6.3, J2 9.5, H-2), 3.69 (3H, s, OCH3), 3.34 (1H, ddd, J1
3.3, J2 6.3, J3 8.3, H-3), 3.30 (1H, dd, J1 4.4, J2 14.7, CHPh), 3.10
(1H, ddd, J1 4.4, J2 8.3, J3 10.0, H-4), 2.80 (1H, dd, J1 10.0, J2 14.7,
CHPh); 13C NMR (100 MHz; CDCl3) d 176.1 (s, C-5), 171.0 (s,
COOMe), 137.9 (s, Ph), 128.7 (2 ꢂ d, Ph), 128.6 (2 ꢂ d, Ph), 126.9
(d, Ph), 67.6 (t, C-2), 52.2 (q, OCH3), 44.0 (d, C-3), 43.9 (d, C-4),
32.4 (t, CH2Ph); m/z (EI, 70 eV): 234 (M+Å, 18), 206 (15), 176 (64),
175 (16), 148 (30), 147 (48), 144 (10), 131 (24), 129 (23), 117
(11), 116 (10), 115 (29), 103 (9), 92 (10), 91 (100), 77 (10), 65
(21), 55 (11), 51 (10), 39 (13); HRMS (EI, 70 eV): calculated for
C13H14O4 (M+Å) 234.0892, experimental 234.0891. HRGC (b-CDX):
tR = 188.6 min for the (3R,4S) enantiomer and tR = 203.1 min for
ee (19 mg, 17% yield), white solid, mp 108–109 °C; ½a D25
¼ ꢀ103:0
ꢁ
(c 0.93, MeOH); >99% ee (by chiral HRGC analysis on a b-CDX col-
umn of its methyl ester 6a); kmax(MeOH)/nm 211 (5335), 257
(197); CD (MeOH):
(+)-5a was recovered with 27% ee (97 mg, 75% yield).
D
e
217 = ꢀ3.7,
D
e
263 = ꢀ0.1. The unreacted ester
4.3.2. Ethyl cis-(+)-(3R,4S)-4-benzyl-5-oxo-3-tetrahydrofuran-
carboxylate 5a
Enzymatic hydrolysis of cis-lactonic ester (+)-5a with 27% ee
(0.60 g, 0.24 mmol) was carried out with
a-CT (5.0 mg) in 10 mL
of phosphate buffer to give, after 15.5 h (36% conversion), the unre-
acted lactonic ester (+)-5a with 94% ee (41 mg, 68% yield), oil,
½
a 2D5
ꢁ
¼ þ124:8 (c 1.4, MeOH); ee 94% (by chiral HRGC on a b-CDX
column). kmax(MeOH)/nm 217 (2745), 254 (533); CD (MeOH):
217 = +5.0,
the (3S,4R)-enantiomer (150 °C isotherm); HRGC
(c-CDX):
tR = 186.5 min (3S,4R) enantiomer and tR = 203.6 min (3R,4S)-enan-
tiomer (150 °C isotherm).
D
e
D
e
262 = +0.1. The lactonic acid (ꢀ)-4a was recovered
with 88% ee (20 mg, 38% yield).
4.2.8. Methyl trans-4-benzyl-5-oxo-3-tetrahydrofurancarboxylate
6b
4.3.3. trans-(ꢀ)-(3S,4S)-4-Benzyl-5-oxo-3-tetrahydrofurancarb-
oxylic acid 4b
Esterification of the acid 4b with diazomethane furnished 6b as
Enzymatic hydrolysis of trans-lactonic ester 5b (248 mg,
1 mmol) was carried out with a-CT (15 mg) in 14 mL of phosphate
an oil.
m
max(film)/cmꢀ1 1776, 1732, 758–698; 1H NMR (400 MHz;
CDCl3) d 7.33–7.17 (5H, m, Ph), 4.28 (1H, dd, J1 8.4, J2 9.2, H-2),
4.21 (1H, dd, J1 8.8, J2 9.2, H-2), 3.58 (3H, s, OCH3), 3.28–3.14
(3H, m, CHPh + H-4 + H-3), 3.04 (1H, dd, J1 6.4, J2 13.7, CHPh); 13C
NMR (100 MHz; CDCl3) d 176.3 (s, C-5), 171.3 (s, COOMe), 136.6
(s, Ph), 129.5 (2 ꢂ d, Ph), 128.7 (2 ꢂ d, Ph), 127.1 (d, Ph), 67.2 (t,
C-2), 52.5 (q, OCH3), 44.5 (d, C-3), 44.5 (d, C-4), 34.7 (t, CH2Ph);
m/z (EI, 70 eV): 234 (M+Å, 44), 206 (14), 203 (10), 177 (8), 176
(74), 175 (68), 157 (6), 148 (47), 147 (63), 144 (9), 131 (24), 129
(19), 117 (8), 115 (15), 104 (8), 103 (7), 92 (10), 91 (100), 65
(14); HRMS (EI, 70 eV) calculated for C13H14O4 (M+Å) 234.0892,
experimental 234.0892; HRGC (b-CDX): tR = 110.4 min for the
(3R,4R) enantiomer and tR = 113.4 min for the (3S,4S) enantiomer
buffer to give, after 56 min (18% conversion), the lactonic acid (ꢀ)-
4b with 92% ee (29 mg, 13% yield), white solid, mp 130–132 °C;
½
a 2D5
ꢁ
¼ ꢀ29:2 (c 0.24, MeOH); 92% ee (determined by chiral HRGC
on a b-CDX column of its methyl ester 6b); kmax(MeOH)/nm 218
(1311), 258 (172); CD (MeOH): 221 = +0.8, 263 = +0.03. The
D
e
De
unreacted ester (+)-5b was recovered with 20% ee (20.4 mg, 82%
yield).
4.3.4. Ethyl trans-(+)-(3R,4R)-4-benzyl-5-oxo-3-tetrahydrofuran-
carboxylate 5b
Enzymatic hydrolysis of trans-(+)-lactonic ester 5b having 17%
ee (0.18 g, 0.74 mmol), carried out with
a-CT (12.0 mg) in 11 mL

320
F. Berti et al. / Tetrahedron: Asymmetry 20 (2009) 313–321
of phosphate buffer, gave after 8.5 h (70% conversion) the unre-
CH2O), 4.64 (1H, dd, J1 2.3, J2 9.6, H-2), 4.35 (1H, dd, J1 6.3, J2 9.6,
H-2), 3.48 (1H, m) 3.34 (1H, dd, J1 3.7, J2 13.9,), 3.4–3.0 (2H, m);
13C NMR (100 MHz; CDCl3) d 190.2 (s), 175.9 (s), 170.2 (s), 138.3
(s), 132.5 (s), 132.3 (2 ꢂ d), 129.5 (s), 129.2 (2 ꢂ d), 128.7 (4 ꢂ d),
126.8 (d), 67.7 (t), 66.1 (t), 44.3 (d), 44.0 (d), 32.0 (t); m/z (EI,
70 eV): 419 (M+H+, 4), 417 (M+H+, 4), 360 (7), 358 (7), 219 (6),
200 (100), 198 (97), 185 (59), 183 (56), 144 (83), 91 (17).
acted lactonic ester (+)-5b with 96% ee (73 mg, yield 40%), oil,
½
a 2D5
ꢁ
¼ þ34:6 (c 0.24, MeOH); 96% ee (by chiral HRGC on a b-CDX
column). kmax(MeOH)/nm 215 (925), 258 (3573); CD (MeOH):
D
e
221 = ꢀ2.6,
D
e
263 = ꢀ0.1. The lactonic acid (ꢀ)-4b was recovered
with 51% ee (52 mg, 32% yield).
4.4. General procedure for the synthesis of esters 7 and 8
4.6. Conformational analysis
To a solution of 0.13 mmol of the carboxylic acid (ꢀ)-4b in
1.5 mL of CH2Cl2, 40 mg of (R) or (S)-1-(9-anthryl)-2,2,2-trifluoro-
ethanol was added. EDC (83 mg), Et3N (0.04 mL) and DMAP
(24 mg) were then added. The mixture was kept under stirring
for 24 h. At the end of the reaction, CH2Cl2 was added, and the or-
ganic phase was washed with 5% KHSO4, water, 5% NaHCO3, water,
and dried over anhydrous Na2SO4. Although the derivatives 7 and 8
obtained were purified by flash chromatography, they were always
about 20% of the unreacted 1-(9-anthryl)-2,2,2-trifluoroethanol in
an admixture.
A set of optimized conformations for all the analyzed com-
pounds was obtained by a simple Monte Carlo search. Each rotat-
able bond was allowed to rotate in order to generate the starting
set of geometries. Each bond was twisted by 10° torsional incre-
ments randomly, and the initial set was thus obtained. The geom-
etries were optimized first using molecular mechanics calculations
with the Cornell version of the Amber forcefield;20 the optimiza-
tions were carried out with the Polak-Ribiere conjugate gradient
algorithm to a gradient of 0.001 kcal/Å mol. The first 10 conforma-
tions obtained at this first step were then submitted to a further
refinement, and their geometries were reoptimized with a semi-
empirical calculation using the AM1 Hamiltonian14 as imple-
mented in Sybyl6.8.21 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.
4.4.1. (10R,3S,4S)-1-(9-Anthryl)-2,2,2-trifluoroethyl-4-benzyl-5-
oxo-3-tetrahydrofurancarboxylate 7
1H NMR (400 MHz; CDCl3) d 8.58 (1H, s, Ar), 8.45 (1H, d, J 8.8,
Ar), 8.25 (1H, d, J 9.1, Ar), 8.05 (1H, d, J 8.4, Ar), 8.03 (1H, d, J 8.4,
Ar), 7.68 (1H, q, J 7.7, CHCF3), 7.65 (1H, t, J 7.7, Ar), 7.50 (3H, m,
Ar), 7.22 (3H, m, Ph), 7.15 (2H, m, Ph), 4.19 (1H, t, J 9.0, H-2),
4.03 (1H, t, J 9.0, H-2), 3.31 (1H, ddd, J1 9.9, J2 8.8, 8.4, H-3), 3.21
(1H, ddd, J1 9.9, J2 5.4, J3 8.4, H-4), 3.14 (2H, AB part of an ABX sys-
tem, CH2Ph); 13C NMR (100 MHz; CDCl3) d 175.9 (s, C-5), 169.0 (s,
COO), 136.2 (s, Ph), 131.8 (d, Ar), 131.6 (s, Ar), 131.2 (s, Ar), 130.9
(s, Ar), 130.8 (d, Ar), 130.5 (s, Ar), 129.7 (d, Ar), 129.5 (2 ꢂ d, Ph),
128.9 (2 ꢂ d, Ph), 128.2 (d, Ar), 127.3 (d, Ph), 126.9 (d, Ar), 125.6
(d, Ar), 125.3 (d, Ar), 125.2 (d, Ar), 123.9 (q, J 231, CF3), 122.2 (d,
Ar), 120.1 (s, Ar), 70.0 (q, J 35, CHCF3), 66.6 (t, C-2), 44.4 (d), 44.0
(d), 34.5 (t, CH2Ph).
4.7. X-ray crystallography for compound 9
Diffraction data were collected at room temperature on a Non-
ius DIP-1030H system with Mo K
a radiation (k = 0.71073 Å). Cell
refinement, indexing and scaling of the data sets were carried
out using Denzo and Scalepack.22 The structure was solved by di-
rect methods and Fourier analyses,23 and was refined by the full-
matrix least-squares method based on F2.23 All the calculations
were performed using the WinGX System, Ver 1.70.01.24
4.4.2. (10S,3S,4S)-1-(9-Anthryl)-2,2,2-trifluoroethyl-4-benzyl-5-
oxo-3-tetrahydrofurancarboxylate 8
Crystal data: C20H17BrO5, M = 417.25, monoclinic, space group
P21, a = 9.045(3), b = 23.144(4), c = 9.077(3) Å, b = 103.64(3)°, V =
1H NMR (400 MHz; CDCl3) d 8.63 (1H, s, Ar), 8.56 (1H, d, J 8.8,
Ar), 8.26 (1H, d, J 9.1, Ar), 8.08 (1H, d, J 8.4, Ar), 7.73 (1H, q, J 7.9,
CHCF3), 7.66 (1H, t, J 7.9, Ar), 7.54 (3H, m, Ar), 6.94 (2H, m, Ph),
6.85 (3H, m, Ph), 4.31 (1H, t, J 8.4, H-2), 4.19 (1H, t, J 8.4, H-2),
3.29 (1H, dt, J1 9.7, J2 8.4, H-3), 3.17 (1H, ddd, J1 9.7, J2 5.4, J3 6.5,
H-4), 3.03 (1H, dd, J1 5.4, J2 14.3, CHPh), 2.92 (1H, dd, J1 6.5, J2
14.3, CHPh); 13C NMR (100 MHz; CDCl3) d 175.9 (s, C-5), 169.1 (s,
COO), 135.8 (s, Ph), 131.7 (d, Ar), 131.4 (s, Ar), 131.1 (s, Ar),
130.8 (s, Ar), 130.6 (s, Ar), 129.6 (d, Ar), 129.5 (d, Ar), 129.1
(2 ꢂ d, Ph), 128.5 (2 ꢂ d, Ph), 128.0 (d, Ar), 126.8 (d, Ph), 126.7
(d, Ar), 125.7 (d, Ar), 125.1 (2d, Ar), 124.0 (q, J 284, CF3), 122.1
(d, Ar), 120.0 (s, Ar), 69.71 (q, J 35, CHCF3), 66.6 (t, C-2), 44.1 (2d,
C-3+C-4), 34.4 (t, CH2Ph).
1846.6(9) Å3, Z = 4,
q l(Mo–Ka ,
calcd = 1.501 g/cm3, ) =2.253 mmꢀ1
F(000) = 848. Final R = 0.0389, wR2 = 0.0812, S = 0.870 for 469
parameters and 19,765 reflections, 6306 unique [R(int) = 0.0460],
of which 3599 with I > 2r(I), max positive and negative peaks in
D
F
map 0.277, ꢀ0.316 e Åꢀ3
. Absolute structure parameter
0.026(8).25
Crystallographic data (excluding structure factors) for 9 have
been deposited with the Cambridge Crystallographic Data Centre
as supplementary publication numbers CCDC 709657. Copies of
the data can be obtained, free of charge, on application to CCDC,
12 Union Road, Cambridge, CB2 1EZ, UK [fax: +44(0)-1223-
336033 or e-mail: deposit@ccdc.cam.ac.uk.]
Acknowledgements
4.5. Synthesis of ester 9
MIUR (PRIN 2005) and the University of Trieste are gratefully
acknowledged for financial support.
4-Bromophenacylcis-(ꢀ)-(3S,4R)-4-benzyl-5-oxo-3-tetrahyd-
rofurancarboxylate 9: To 18 mg (0.08 mmol) of (ꢀ)-4a with >99%
ee, 2 mL of toluene, 12
lL (0.08 mmol) of 1,8-diazabicy-
clo[5.4.0]undec-7-ene (DBU) and 22.3 mg (0.08 mmol) of 2,40-
dibromoacetophenone were added. After stirring overnight, water
and ether were added, and the organic phase was separated and
dried over anhydrous Na2SO4. Evaporation of the solvent gave
25 mg (0.06 mmol, 75% yield) of (ꢀ)-9. Crystals of good quality
were obtained from a CDCl3/EtOH mixture. White solid, mp 111–
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