A combined experimental and computational strategy in the assignment of absolute configurations of 4-methyl-5-oxo-tetrahydrofuran-3-carboxylic acids and their esters

Article abstract of DOI:10.1016/j.tetasy.2005.08.018

Enantiopure cis- and trans-4-methylparaconic acids and their alkyl esters were synthesized by a procedure involving the kinetic enzymatic resolution of diastereomeric lactonic esters. Thus, ethyl cis- and trans-4-methyl-5-oxo- tetrahydrofuran-3-carboxylates were isolated, at high conversion values, with 99% ee from the hydrolyses with HLAP and α-CT, respectively. The corresponding enantiopure cis- and trans-lactonic acids were also obtained. The absolute configurations of the products were assigned by chemical correlation, by analysis of their circular dichroism spectra and by electronic structure calculations. All three methodologies lead to the same assignment for the species considered, another example of successful interplay between experiment and theory.

Full text of DOI:10.1016/j.tetasy.2005.08.018

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 16 (2005) 3011–3023
A combined experimental and computational strategy in
the assignment of absolute configurations of
4-methyl-5-oxo-tetrahydrofuran-3-carboxylic acids and their esters
Cristina Forzato,* Giada Furlan, Patrizia Nitti, Giuliana Pitacco, Domenico Marchesan,
Sonia Coriani and Ennio Valentin*
`
Dipartimento di Scienze Chimiche, Universita di Trieste, via Licio Giorgieri 1, I-34127Trieste, Italy
Received 14 June 2005; revised 10 August 2005; accepted 11 August 2005
Abstract—Enantiopure cis- and trans-4-methylparaconic acids and their alkyl esters were synthesized by a procedure involving the
kinetic enzymatic resolution of diastereomeric lactonic esters. Thus, ethyl cis- and trans-4-methyl-5-oxo-tetrahydrofuran-3-carboxy-
lates were isolated, at high conversion values, with 99% ee from the hydrolyses with HLAP and a-CT, respectively. The correspond-
ing enantiopure cis- and trans-lactonic acids were also obtained. The absolute configurations of the products were assigned by
chemical correlation, by analysis of their circular dichroism spectra and by electronic structure calculations. All three methodologies
lead to the same assignment for the species considered, another example of successful interplay between experiment and theory.
ꢀ 2005 Published by Elsevier Ltd.
1. Introduction
4,11 respectively, of already known absolute configura-
tion (Fig. 1).
The 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,
immunomodulators, antifungal, plant growth inhibi-
tors,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 their mammalian metabolites.6
Paraconic acids constitute a small class of variously
functionalized c-lactones exhibiting antibiotic and anti-
tumoural properties and characterized by the presence
of a carboxylic group at the b-position.7 In the context
of our work aimed at the chemoenzymatic synthesis of
some of these systems, we recently investigated the syn-
thesis of paraconic acid (5-oxo-3-furancarboxylic acid)
itself and of its c-methyl and c,c-dimethyl derivatives
in enantiomerically pure forms.8 Herein, we report the
chemoenzymatic syntheses and absolute configuration
assignment of optically active a-methyl paraconic acids,
19 and 2,9 which can be chemically correlated with two
molecules, botryodiplodin 310 and epi-botryodiplodin
O
O
HO2C
HO2C
R
S S
S
O
O
OH
OH
O
O
O
O
( )-1
( )-2
(—)-3
(—)-4
Figure 1. a-Methyl-paraconic acids 1 and 2, botryodiplodin 3 and epi-
botryodiplodin 4.
2. Results and discussion
2.1. Synthesis of substrates
Chiral racemic lactones 1 and 2 were synthesized accord-
ing to a literature procedure12 from methyl 2-bromopro-
pionate 5 and diethyl malonate (Scheme 1). The
resulting intermediate 6 was treated with paraformalde-
hyde to afford the corresponding lactone 7, from which
a mixture of diastereomeric cis- and trans-lactonic acids
1 and 2 was obtained by prolonged heating in acidic
solution. Their esterification with methanol or ethanol
in the presence of trimethylsilyl chloride13 gave the
corresponding mixtures of cis- and trans-lactonic esters
*
Corresponding authors. Tel.: +39 040 5583917; fax: +39 040
5583903; e-mail: valentin@dsch.units.it
0957-4166/$ - see front matter ꢀ 2005 Published by Elsevier Ltd.
doi:10.1016/j.tetasy.2005.08.018

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C. Forzato et al. / Tetrahedron: Asymmetry 16 (2005) 3011–3023
EtO2C
EtO2C
(i) EtONa/EtOH
(ii) (CH2O)n
EtO2C
Br
EtO2C
CO2Et
CO2Me
NaH, DMF, r.t., 40 h EtO2C
CO2Me
50°C, 6 h
O
O
5
7
6
20% HCl
90°C, 52 h
RO2C
HO2C
MeOH (EtOH)
Me3SiCl
O
O
O
r.t., 14 h
O
R = Me: cis-8, trans-9
R = Et: cis-10, trans-11
1, 2
Scheme 1. Synthesis of substrates 8–11.
8, 912 and 10, 119 respectively. The overall yield was
around 90% in both cases. The diastereomeric lactonic
ester mixtures were separated on column chromatogra-
phy, with each isomer characterized spectroscopically
and then subjected to enzymatic resolution.
horse liver acetone powder (HLAP), a-chymotrypsin
(a-CT) and proteasis from Bacillus subtilis. The hydro-
lytic reactions were monitored by a pH-STAT instru-
ment with the addition of 1 M NaOH. The main
results are summarized in Table 1.
2.2. Enzymatic hydrolyses
Unfortunately, the hydrolyses proved only regioselective
in a few cases, while in general both alkoxycarbonyl and
lactone groups were hydrolyzed simultaneously, leading
to mixtures of products (Scheme 2). A further complica-
tion was the cyclization of the hydroxy half ester, result-
ing from the hydrolytic opening of the heterocycle,
occurring during the acidic work-up, with the sub-
sequent formation of the optically active parent molecule.
Therefore, in order to have a thorough understanding of
the outcome of the reaction, an accurate work-up had to
The enzymatic hydrolyses were performed on the lac-
tonic esters 8–11 using a series of commercially available
enzymes, namely porcine pancreatic lipase (PPL), lipase
from Pseudomonas species (PS), lipase from Pseudomo-
nas 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),
Table 1. Selected data for the enzymatic hydrolyses
Substrate
Enzyme Ea Conv.b Time
Acid
Abs.
(%) config. yield
Ester from ring fission
ee Abs. Rel.
(%) config. yield
Unreacted ester
(min)
ee
Rel.
ee
Abs.
(%) config.
cis
8
HLAP
—
16 32
10 72
20
6
24
437
(+)-1 51c
3R,4S
—
—
24
—
—
(+)-8
(+)-10 84
(+)-10 38
85
3R,4S
3R,4S
3R,4S
76
100
100
(ꢀ)-8
24
3S,4R
3S,4R
3S,4R
10 HLAP
10 HLAP
—
—
—
—
(ꢀ)-10 40
(ꢀ)-10 99
trans
9
9
a-CT
PPL
10 21
20
30
27
(ꢀ)-2 78c
(ꢀ)-2 73c
(ꢀ)-2 91d
(ꢀ)-2 53d
3S,4S
3S,4S
3S,4S
3S,4S
100
100
100
92
—
—
—
—
—
—
—
—
—
3R,4R
—
—
—
8
(+)-9
(+)-9
(+)-11 28
(+)-11 99
21
27
3R,4R
3R,4R
3R,4R
3R,4R
8
27
27 24
65
11 a-CT
11 a-CT
—
480
(+)-11 67
a The E values are given only for those enzymes that reacted regioselectively.
b Calculated.14
c Determined by chiral HRGC on the ethyl ester derivative.
d Determined by chiral HRGC on the methyl ester derivative.
RO2C
HO2C
RO2C
(+) or (—)
+
enzyme
and/or
CO2H
half-ester
O
O
unreacted
O
O
HO
lactonic ester
( )
parent
(+)- or (—)-
lactonic acid
not isolated
lactonic ester
(+)- or (—)-
lactonic ester
from ring fission
Scheme 2. Enzymatic resolution of lactonic esters.

C. Forzato et al. / Tetrahedron: Asymmetry 16 (2005) 3011–3023
3013
be followed. Initially, the crude hydrolysis mixture was
extracted at pH 7.4 to isolate the unreacted lactonic
ester from the organic phase. Acidification of the aque-
ous phase to pH 2 and extraction allowed the isolation
of the lactonic ester, derived from the hydrolytic ring
fission, in an admixture with the lactonic acid. This
latter compound was esterified with an alcohol different
from that originally present, so as to distinguish the two
esters by gas-chromatographic analysis.
pounds is a problem that can be solved either by chem-
ical correlation, circular dichroism empirical rules
application, circular dichroism comparison with known
1
compounds or by H NMR in some cases. An alterna-
tive, or complementary, way to assign the absolute con-
figuration is represented by theoretical calculations of
the specific rotation and comparison with sign and mag-
nitude of the corresponding experimental values.
2.3.1. Determination of the absolute configurations of the
products by chemical correlation. The absolute configu-
rations of the trans-products were assigned by the con-
version of acid (ꢀ)-2 into the already known epi-
botryodiplodin (ꢀ)-4.11 The acid (ꢀ)-2 with 91% ee
was converted into the corresponding unstable acyl
chloride 13, and immediately transformed into the
corresponding 4-acetyl derivative (ꢀ)-15 (numbering is
reversed, owing to a different priority) using a literature
procedure (Scheme 3).15 Protection of the carbonyl
group with 1,2-ethanedithiol to give (ꢀ)-17 and reduc-
tion of the lactone carbonyl group with DIBAL-H fur-
nished the protected lactol (ꢀ)-18 as a diastereomeric
mixture, owing to the double configuration of the acetal
carbon atom. Deprotection of the carbonyl function
with silver nitrite and iodine in aqueous THF16 afforded
epi-botryodiplodin (ꢀ)-4, whose absolute configuration
is (3S,4S). As a consequence, the configuration of (ꢀ)-
2 is also (3S,4S) and those of its methyl and ethyl esters
(+)-9 and (+)-11, respectively, are (3R,4R).
For the cis-lactonic esters 8 and 10 the enzyme HLAP
proved more effective, while for the trans-diastereomers
9 and 11 a-CT gave the best results, although both with
low enantiomeric ratios. Interestingly, the methyl deriv-
ative 8 underwent hydrolytic ring fission preferentially
over the hydrolysis of the methoxycarbonyl group
(3:1), whereas the ethyl ester 10 was hydrolyzed at the
ring only. At low conversion values, the esters (+)-8
and (+)-10 were obtained with 85% and 84% ee, respec-
tively, while at high conversion value the unreacted ester
(ꢀ)-10 could be separated with 99% ee. In that manner,
although the lactonic acid 1 could not be obtained di-
rectly in either satisfactory yield or enantiopurity, both
enantiomers of its ethyl ester with good enantiomeric
excesses could be separated.
Conversely, at low conversion values the trans-diaste-
reomers 9 and 11 were hydrolyzed by a-CT at the alk-
oxycarbonyl group exclusively, thus affording the
corresponding acids (ꢀ)-2 with 78% and 91% ee, respec-
tively. At high conversion values, only ethyl ester (+)-11
could be obtained in 99% ee. In that case, however, a
partial hydrolysis of the lactone ring was observed.
Finally, trans-isomer 9 was hydrolyzed successfully by
PPL with the same enantiopreference as a-CT but in a
slightly lower enantiomeric ratio. In fact, the resulting
acid (ꢀ)-2 was obtained with 73% ee.
The absolute configuration of the cis-diastereomers was
determined starting from ethyl ester (ꢀ)-10 with 99% ee.
Chemical hydrolysis under acidic conditions afforded
the corresponding acid 1 with 99% ee in an admixture
with 20% of (ꢀ)-2 with 70% ee (indicating an inversion
at the a-carbon atom), to which the same procedure
used above for (ꢀ)-2 was applied, with the aim of arriv-
ing at the natural molecule (3R,4S)-(ꢀ)-botryodiplodin
3.17 However, after having obtained the unstable acyl
chloride 12, the subsequent reaction with methyl magne-
sium iodide afforded the corresponding 4-acetyl lactone
(ꢀ)-14, in an admixture with 30% of its trans-diastereo-
mer (+)-15 with 48% ee. Compound (ꢀ)-14 with 91% ee
2.3. Determination of the absolute configurations of
the products
From an experimental point of view, the assignment of
the absolute configuration to new enantiopure com-
O
O
MeMgI
HO2C
Cl
(COCl)2
LiBr, CuBr
3
4
4 3
THF
CH2Cl2,
1% DMF
O
O
O
O
O
O
(3S,4R)-12
(3S,4S)-13
(3R,4S)-(—)-14
(3S,4S)-(—)-15
cis-(3S,4R)-1
trans-(3S,4S)-(—)-2
HS(CH2)2SH
Zn(OTf)2
CH2Cl2, 5h, r.t.
S
O
S
S
S
DIBAL-H
toluene,
–78°C
AgNO2/I2
aq. THF
S S
4
3
OH
OH
O
O
O
O
(3R,4S)-(—)-16
(3S,4S)-(—)-17
(3S,4S)-(—)-4
(3S,4S)-(—)-18
Scheme 3. Synthesis of epi-botriodiplodin 4.

3014
C. Forzato et al. / Tetrahedron: Asymmetry 16 (2005) 3011–3023
was purified by flash-chromatography and characterized
spectroscopically, while the trans-diastereomer 15 was
identified by chiral HRGC as the enantiomer of the al-
ready known (ꢀ)-15. Since in the conversion of 118 into
(+)-15, an inversion of configuration occurred at the b-
carbon atom, the absolute configuration of C-a is the
same in both lactones, that is, R. As a consequence,
the absolute configurations of 1 and (ꢀ)-10 are
(3S,4R). From the cis-lactone (ꢀ)-14, the protected
compound (ꢀ)-16 with 90% ee was obtained. However,
the remaining steps applied so successfully to the trans-
isomer with the eventual obtainment of (ꢀ)-epi-botryo-
diplodin 4 proved completely unsuccessful when applied
to the cis-isomer with the aim of preparing (ꢀ)-botryo-
diplodin 3. Different reaction conditions, different pro-
tecting groups and deprotecting strategies were also
attempted, although with no result.
7000
5000
(–)-2
(+)-11
(–)-15
[Θ]
0
-5000
200
250
300
350
λ (nm)
Figure 3. CD spectra of the trans-lactones (ꢀ)-2, (+)-11 and (ꢀ)-15 in
methanol.
2.3.2. Determination of the absolute configurations of the
products by circular dichroism. Circular dichroism is
considered a reliable method for establishing the abso-
lute configuration of c-lactones by the application of
empirical rules. Among the several rules present in the
literature,19 the Okuda rule20 originally stated for a-hy-
droxy-c-lactones also proved valid for a-methyl-c-lac-
tones.21 In accordance with this rule, the sign of the
Cotton effect associated to the n ! p* transition was
determined by the absolute configuration of C-a and
hence by the orientation of the a-substituent with
respect to the ring average plane. The signs of the Cotton
effects found for the above mentioned lactones support
the assignments made for their absolute configurations.
Thus, from the cis-diastereomers, compounds (ꢀ)-10
and (ꢀ)-14, which exhibit a negative Cotton effect
(Fig. 2), possess their a-carbon atom in an (R)-configu-
ration. Therefore, the configurations of (ꢀ)-10 and (ꢀ)-
14 are (3S,4R) and (3R,4S), respectively. Application of
the rule to the trans-lactones (Fig. 3) indicates that the
configuration of the a-carbon atom of compounds
(ꢀ)-2 and (ꢀ)-15 is S, since their CD curves show a
positive Cotton effect, while that of (+)-11, exhibiting
a negative Cotton effect, is R. Therefore, the configura-
tions of (ꢀ)-2, (+)-11 and (ꢀ)-15 are (3S,4S), (3R,4R)
and (3S,4S), respectively.
The protected lactones (ꢀ)-16 and (ꢀ)-17 exhibit CD
curves complicated by the n ! r* transition bands of
the sulfur atoms, which overlap the n ! p* transition
bands of the lactone function. In fact, in the protected
c-lactol (ꢀ)-18 in which the lactone function is not pres-
ent, the UV spectrum exhibits two bands at 214 and
242 nm.
In Table 2 are listed the most significant UV and CD
spectroscopic data for compounds (ꢀ)-2, (ꢀ)-10, (+)-
11, (ꢀ)-14, (ꢀ)-15, (ꢀ)-16 and (ꢀ)-17, in two different
solvents, together with their specific rotation values.
2.4. Theoretical calculations
Advances in the fields of time dependent-density func-
tional theory (TD-DFT)22 and solvated environment
models23 have provided the organic chemists with a
quick and reliable tool for determining the absolute con-
figuration of relatively large chiral molecules (see also
Ref. 24 for a review). Calculated values of specific rota-
tion can be directly related to experimental data, and the
correct absolute configuration is obtained by simply
comparing both the sign and magnitudes of the two val-
ues.24 The amount of theoretical studies that have been
published in the recent years elucidates the requirements
to get accurate specific rotation values (within an error
of ꢁ30 units of specific rotation): optimize the molecular
geometry using DFT, along with the B3LYP functional
and a basis set of at least 6-31G** quality; calculate the
specific rotation value on this geometry using TD-DFT
with the B3LYP functional and a diffused basis set (of
aug-cc-pVDZ quality).25 Using this recipe, the absolute
configuration of a large number of (rigid) molecules
has been assigned in a reliable way.26
1000
0
[Θ]
(–)-10
-1000
(–)-14
-2000
For the molecules considered herein, further complica-
tions arise in comparison to most of the molecules that
are being considered nowadays. First, our lactones
have more than one stable conformation, so that the
optimization and the specific rotation calculation have
to be iterated for each conformer. The total specific
rotation is then obtained by adding together the values
of specific rotation for the various conformers, each of
them weighted by the population fraction of the given
-3000
-4000
250
300
350
200
λ
(nm)
Figure 2. CD spectra of the cis-lactones (ꢀ)-10 and (ꢀ)-14 in
methanol.

C. Forzato et al. / Tetrahedron: Asymmetry 16 (2005) 3011–3023
3015
Table 2. Specific rotations, UV and CD data for compounds (ꢀ)-2, (ꢀ)-10, (+)-11, (ꢀ)-14, (ꢀ)-15, (ꢀ)-16 and (ꢀ)-17
25
D
Compound
Abs. config.
ee (%)
½aŠ (c, g/100 mL)
UV data
kmax (emax
CD data
[H] (k)
Solvent
)
(ꢀ)-2
(3S,4S)
91
ꢀ66.2 (0.63)
ꢀ70.7 (0.28)
213 (112)
223a (86)
+3439 (219)
+3697 (220)
MeOH
MeCN
(ꢀ)-2
(3S,4S)
91
199 (78)
214 (106)
223a (85)
(ꢀ)-10
(ꢀ)-10
(+)-11
(+)-11
(ꢀ)-14
(3S,4R)
(3S,4R)
(3R,4R)
(3R,4R)
(3R,4S)
>99
>99
>99
>99
99
ꢀ18.5 (0.33)
ꢀ15.7 (0.68)
+68.5 (0.87)
+63.0 (0.57)
ꢀ8.8 (0.17)
213 (335)
ꢀ3021 (213)
ꢀ3616 (215)
ꢀ5119 (218)
ꢀ4613 (220)
MeOH
MeCN
MeOH
MeCN
MeOH
222a (261)
209 (310)
213a (288)
213 (308)
223a (216)
195 (426)
209a (320)
213 (705)
244a (333)
279 (153)
ꢀ3678 (216)
+271 (296)
(ꢀ)-14
(ꢀ)-15
(ꢀ)-15
(ꢀ)-16
(ꢀ)-16
(3R,4S)
(3S,4S)
(3S,4S)
(3R,4S)
(3R,4S)
99
90
90
95
95
ꢀ6.7 (0.18)
ꢀ72.1 (0.58)
ꢀ70.1 (0.60)
ꢀ10.0 (0.18)
ꢀ14.7 (0.36)
198 (1387)
242 (479)
278 (183)
ꢀ4096 (217)
MeCN
MeOH
MeCN
MeOH
MeCN
+287 (295)
213 (130)
225a (90)
272 (23)
+6073 (214)
ꢀ479 (281)
208 (149)
245a (43)
286 (30)
+6438 (216)
ꢀ563 (286)
213 (962)
242 (320)
+5776 (200)
ꢀ1427 (223)
ꢀ1506 (241)
+5874 (197)
ꢀ2115 (224)
ꢀ1939 (239)
211 (398)
213 (855)
242 (315)
(ꢀ)-17
(ꢀ)-17
(3S,4S)
(3S,4S)
90
90
ꢀ51.7 (0.70)
ꢀ54.4 (0.32)
212 (824)
244 (189)
ꢀ5013 (206)
MeOH
MeCN
ꢀ2285 (246)
196 (3836)
203a (3226)
243 (204)
ꢀ4600 (206)
ꢀ2517 (245)
a Shoulder.
conformer calculated according to Boltzmannꢀs statis-
tics based on the relative conformational (free) ener-
gies.27 A second complication that can arise for both
rigid and flexible molecules is the solute–solvent inter-
action. The experimental specific rotation is in most
cases recorded in solution, and the effect of the solvent
molecules on the solute can be very large28 and can
even change the sign of the specific rotation, which
would result in a wrong absolute configuration assign-
ment if not taken into account.29 A very ꢁpopularꢀ
method to treat the solute–solvent interaction in spe-
cific rotation is the polarizable continuum model23
(PCM): the solvent is modelled as a polarizable contin-
uum surrounding the molecule, the latter being placed
in a molecule-shaped cavity formed by compenetrating
spheres, each one of them centred on the position of a
heavy atom.30
The absolute configuration of paraconic acid, the pre-
cursor of the molecules considered here, and those of
the diastereomeric cis- and trans-c-methyl paraconic
acids and their esters have been successfully assigned
using this methodology,29,31 showing the possibility of
employing the same approach for the molecules under
investigation here.
2.4.1. Computational procedure. The specific rotation
of molecule 2 could be measured directly in methanol
solution, where specific rotation calculations on this
molecule were therefore performed. Calculated and
experimental values of the specific rotation of the ethyl
ester 11 (from which 2 derives) were considered as an
alternative source of information for the absolute con-
figuration assignment of molecule 2. Due to an isomer-
ization process that takes place during the hydrolysis of

3016
C. Forzato et al. / Tetrahedron: Asymmetry 16 (2005) 3011–3023
10 that yields molecule 1 in an admixture with 2, it was
not possible to isolate the sole molecule of 1 and mea-
sure its specific rotation. Therefore, in order to assign
the absolute configuration of 1, specific rotation calcula-
tions and measurements were performed on molecule
10, from which the absolute configuration of 1 is directly
derived.
opment version of the DALTON program.33 Moreover,
for molecule (3S,4R)-10, calculations of specific rotation
at 578, 546 and 436 nm were also performed for reasons
that will be explained later. The specific rotation calcu-
lations on species (3S,4R)-10 and (3S,4S)-11 were car-
ried out only for those conformers with population
fraction larger than 3%—that is, conformers I–IX in
the case of (3S,4S)-11, conformers IV–VI, X, XI, XV–
XVIII for (3S,4R)-10 in vacuum and conformers IV–
VI, X, XI, XIII, XV–XVIII for (3S,4R)-10 in methanol
solution (Fig. 4).
To assign the absolute configuration by electronic struc-
ture calculations, we considered the three lactones
(3S,4S)-2, (3S,4R)-10 and (3S,4S)-11. Geometry optimi-
zations at the B3LYP/6-31G** level were carried out
both in vacuum and in methanol solution (as modelled
by the PCM) for lactones (3S,4S)-2 and (3S,4R)-10,
whereas the geometry of species (3S,4S)-11 was only
optimized in vacuum. All geometry optimizations were
performed with the GAUSSIAN 03 program.32 For the
trans-a-methyl paraconic acid 2, we found a total of
six conformational forms (labelled I, IV, VII, X, XIII
and XVI in Fig. 4), derived from the carboxylic group
torsional motion (three positions) and the five-member
ring puckering (two positions). For molecules 10 and
11, the number of optimized conformers reached the
14 and 18 forms, respectively, due to the addition of
the ethyl group torsion. For all three lactones, specific
rotation calculations were carried out at the sodium D
line (589 nm), all of which were carried out with a devel-
For consistency, the specific rotation calculations on the
vacuum optimized structures were carried out in vac-
uum, whereas those for the solvent relaxed conformers
were performed in solvent. London orbitals have been
used to ensure gauge-origin independence of the results.
2.4.2. Discussion and results. We report in Figure 4 the
population fractions of the various conformers of all
three molecules, both for the vacuum and PCM solvated
cases where available. According to the nomenclature
introduced in our previous paper29 on paraconic acid,
conformers labelled I–IX represent the so called ꢁbot-
tom-of-planeꢀ forms, whereas those labelled X–XVIII
are the ꢁtop-of-planeꢀ ones (see also Fig. 5 for an exam-
ple of bottom–top conformers). In Figure 6, the
weighted specific rotations of the same molecules are gi-
ven while Figure 7 shows the trend of the calculated spe-
cific rotation values of molecule (3S,4R)-10 at different
wavelengths both in vacuum and in methanol, together
with the experimental measures (in methanol).
Population fractions
XVIII
100%
XVII
XVI
XV
80%
60%
40%
20%
0%
XIV
XIII
XII
XI
X
IX
VIII
VII
VI
V
IV
III
II
I
In our previous studies on the specific rotation and
absolute configuration of other members of the para-
conic acid family,29,31 we found that the main contribu-
tion of the solute–solvent interaction to the final specific
rotation came from geometry relaxation effects, that is,
it was due to changes in the relative stability of the dif-
ferent conformers in solution, in particular a stabiliza-
tion of the ꢁtop-of-planeꢀ forms with respect to the
ꢁbottom-of-planeꢀ ones.
2-Vacuum
2-Methanol
11-Vacuum
10-Vacuum
10-Methanol
Figure 4. The population fraction of molecules 2, 10 and 11. In the
case of molecule 2, only the conformers I, IV, VII, X, XIII and XVI
exist. For molecules 2 and 10, both the vacuum and solvated cases are
reported.
For molecule (3S,4S)-2 (see the first and second columns
in Fig. 4), the stabilization due to solvation is very small:
the methyl group in trans apparently destabilizes all
Figure 5. Two conformational forms of the trans-a-methylparaconic acid molecule 2. On the left, the ꢁbottom-of-planeꢀ, and on the right the ꢁtop-of-
planeꢀ (as reported in the text).

C. Forzato et al. / Tetrahedron: Asymmetry 16 (2005) 3011–3023
3017
configuration. The third column of Figure 6 shows that
almost all the weighted specific rotation are negative in
sign, and the total specific rotation is ꢀ51, in good
agreement with the experimental value of ꢀ68, confirm-
ing the assignment (3S,4S)-(ꢀ) and (3R,4R)-(+)
obtained from the corresponding acid case.
Specific Rotation
60
40
20
0
-20
-40
-60
-80
-100
Molecule (3S,4R)-10 is a far more complicated case than
the two previous ones. The fourth column of Figure 4
clearly shows that there is no predominance of the ꢁbot-
tom-of-planeꢀ forms on the ꢁtop-of-planeꢀ ones, and as a
consequence the solvent effect is expected to be strong,
as also seen from the modification of the conformational
space in methanol shown in the fifth column of Figure 4.
The ꢁtop-of-planeꢀ forms account for 46% of the confor-
mational space in the vacuum case, and more than 80%
in the solvated one. We can therefore conclude that spe-
cific rotation results from vacuum calculations alone
cannot be considered a reliable source of data to com-
pare with the experimental data and assign the absolute
configuration.
2-Vacuum
2-Methanol
11-Vacuum
10-Vacuum
10-Methanol
Figure 6. The calculated weighted specific rotation for the conformers
of molecules (3S,4S)-2, (3S,4R)-10 and (3S,4S)-11, the colours
referring to the same conformers of Figure 4. The two lines represent:
) the total specific rotation value, ( ) the experimental value. For
compound 11 the specific rotation of (3R,4R)-(+)-11 was measured
{[a]D = +68.5 (c 0.87, methanol) ee >99%}.
(
Total Specific Rotation
60
40
20
0
-20
-40
-60
-80
-100
As it can be seen in column four of Figure 6, the calcu-
lated total specific rotation in vacuum is +21, whereas
the experimental result is ꢀ19 in methanol solution.
As the calculated value of +21 was obtained for the
(3S,4R)-enantiomer, it would appear that the absolute
configuration should be (3R,4S)-(ꢀ) and (3S,4R)-(+)
(with a very small deviation from experiment of 2 units)
if the results obtained in vacuum are used to assign the
absolute configuration. However, as previously stated,
the solvent effect is in this case expected to be fairly
large: the last column in Figure 6 shows that the total
specific rotation changes sign going from vacuum to a
methanol solution, with a value of ꢀ43 and supporting
a (3S,4R)-(ꢀ) and (3R,4S)-(+) absolute configurationꢀs
assignment. Also in our previous studies on variously
substituted paraconic acids and esters, we found that
the inclusion of solvent effects was mandatory for mole-
cules having a conformational space similar to that of
molecule 10, and in all these cases that the specific rota-
tion signs predicted including the solvent effect were
always in agreement with experimental data.29,31
Vacuum
Methanol
Exp
598nm
578nm
546nm
436nm
Wavelength
Figure 7. The total optical rotation calculated at different wavelengths
for the molecule (3S,4R)-10, both in vacuum and for a methanol
solution. The experimental values, also obtained in methanol, are
reported for comparison.
ꢁtop-of-planeꢀ forms, and the solute–solvent interaction
is not strong enough to stabilize them. With the confor-
mational space being almost identical in the two cases
(vacuum and methanol solution), the solvent effect on
the total specific rotation of molecule (3S,4S)-2 is
expected to be very small. This is confirmed by the results
shown in Figure 6: the only changes that can be seen are
a reduction in the value of the weighted specific rotation
of conformer I and a change in sign in the specific rota-
tion of conformers IV and VII. Despite these variations,
the total specific rotation is ꢀ63 units in vacuum and
ꢀ65 units in methanol solution; both values are in
very good agreement with the experimental value of
ꢀ66 units. Our assignment of the absolute configu-
ration of molecule (3S,4S)-2 is thus (3S,4S)-(ꢀ) and
(3R,4R)-(+).
To put the above conclusion on a more firm footing, the
total specific rotation of molecule (3S,4R)-10 was calcu-
lated and measured at four different wavelengths, as
reported in Figure 7. The (3S,4R)-(ꢀ) and (3R,4S)-(+)
hypothesis drawn from the results obtained in solution
is the only one capable of reproducing the experimental
specific rotation trend over the entire range of wave-
lengths, opposite to what was observed for the vacuum
calculation.34
Another piece of evidence in favour of the assignment
based on the results of the solvent calculations is the
positive experimental specific rotation value of ca. +4 units
measured in cyclohexane solution. Assuming that the
calculations in vacuum can be considered as reliable
descriptors of this kind of apolar solution (as done for
instance by Lattanzi et al.35 for CCl4 solutions), the
comparison between calculated specific rotation in vac-
uum and measured specific rotation in cyclohexane solu-
A similar situation was observed for molecule (3S,4S)-
11. The sterical hindrance of the methyl group in trans
leads again to a conformational space dominated by
the ꢁbottom-of-planeꢀ forms (accounting for more than
97% of the population, as shown in the third column
of Fig. 4). Also in this case, the solvent effect was
expected to be negligible, and the results of the calculation
in vacuum can be trusted in order to assign the absolute

3018
C. Forzato et al. / Tetrahedron: Asymmetry 16 (2005) 3011–3023
tion again confirms the (3S,4R)-(ꢀ) and (3R,4S)-(+)
assignment obtained before. Thus, the solvent treatment
allowed by the PCM theory improved the calculated val-
ues of the specific rotation calculation, leading to the
correct absolute configuration determination even for
this quite difficult molecule.
4. Experimental
4.1. General
IR spectra were recorded on a Jasco FT/IR 200 spectro-
photometer. H NMR and 13C NMR spectra were run
1
on a Jeol EX-400 spectrometer (400 MHz for proton,
100 MHz for carbon), and on a Jeol EX-270 spectro-
meter (270 MHz for proton, 68 MHz for carbon) using
deuteriochloroform as a solvent and tetramethylsilane
as the internal standard. Chemical shifts are expressed
in parts per million (d). Coupling constants are given in
Hertz. Optical rotations were determined on a Perkin
Elmer Model 241 polarimeter. CD spectra were obtained
on a Jasco J-700A spectropolarimeter (0.1 cm cell). GLC
analyses were run on a Carlo Erba GC 8000 instrument
and on a Shimadzu 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-cyclodextrin (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).
Enzymatic hydrolyses were performed using a pH-stat
Controller PHM290 Radiometer Copenhagen. Mass
spectra were recorded on a VG 7070 (70 eV) spectro-
meter and on a ion trap instrument Finnigan GCQ
(70 eV). TLCꢀs were performed on Polygramꢁ Sil G/
UV254 silica gel pre-coated plastic sheets (eluant: light
petroleum/ethyl acetate). Flash chromatography was
run on silica gel for flash-chromatography (BDH). Light
petroleum refers to the fraction with bp 40–70 ꢂC and
ether to diethyl ether. Diethyl malonate and methyl
2-bromopropionate 5 were purchased from Sigma–
Aldrich.
3. Conclusions
Apart from the obvious consideration that kinetic enzy-
matic resolution is an important tool for the obtainment
of enantiopure molecules, we have also demonstrated
that, although chemical correlation is one of the most
reliable methods in assigning the absolute configuration,
provided either a natural or a synthetic molecule with
known absolute configuration is available in the litera-
ture, also a careful application of empirical methods
in the circular dichroism spectroscopy can be a satisfac-
tory methodology. Thus, for example, the absolute con-
figuration of the trans-a-methylparaconic acid (ꢀ)-2
was assigned as (3S,4S), being correlated with the al-
ready known epi-botryodiplodin (ꢀ)-4 by chemical steps
of known stereochemistry. Its CD curve shows a posi-
tive Cotton effect which is consistent with the (S)-config-
uration of its a-carbon atom, in accordance with the
Okuda rule. As to the cis-a-methylparaconic acid 1, its
absolute configuration was established as being
(3S,4R), by an inversion of configuration occurring at
the b-carbon atom of its 4-acetyl lactone derivative
(ꢀ)-14, which furnished the trans-diastereomer (+)-15
of known absolute configuration. This assignment was
confirmed by the finding that the CD spectrum of the
ethyl ester of the cis-a-methylparaconic acid (ꢀ)-10
exhibited a negative Cotton effect, which can be related
with the (R)-configuration of its a-carbon atom, in
accordance with the Okuda rule. Finally, theoretical
calculations at the DFT/B3LYP level of the optical
rotatory power on the trans-a-methylparaconic acid
(3S,4S)-2, the ethyl ester of the trans-a-methylparaconic
acid (3S,4S)-11 and that of the ethyl ester of the cis-a-
methylparaconic acid (3S,4R)-10 supported the correct-
ness of the experimental assignments (3S,4S)-(ꢀ)-2,
(3S,4S)-(ꢀ)-11 and (3S,4R)-(ꢀ)-10—and thus from the
latter the (3S,4R)-1 one for the cis-a-methylparaconic
acid. Due to the high flexibility of the three molecules
considered, a thorough investigation of their conforma-
tional space was required. The molecular structures of
all energetically relevant conformers were optimized
and the total specific rotatory power was obtained from
a Boltzmann average of the specific rotation of each
conformer. For the ethyl ester of the cis-a-methylpara-
conic acid (3S,4R)-10, in particular, inclusion of the sol-
vent effect during both the optimization process and the
specific rotation calculation via the PCM model and, at
the same time, an analysis of the specific rotation disper-
sion curve over a range of frequencies proved to be the
key factors in the correct assignment of its absolute con-
figuration. Thus, despite the floppiness of the molecules
investigated the computational procedure adopted
proved to be a promising and reliable method in pre-
dicting the absolute configuration of this class of
compounds.
4.2. Synthesis of substrates
4.2.1. 1,1-Diethyl, 2-methyl 1,1,2-propanetricarboxylate
6.36 To a solution of 6.44 g (40 mmol) of diethyl mal-
onate in 50 mL of anhydrous DMF, 1.60 g of 60% NaH
was cautiously added at rt, under an argon atmosphere.
A solution of 6.68 g (40 mmol) of methyl 2-bromopropi-
onate 5 in 5.0 mL of DMF was then added and the mix-
ture stirred at 0 ꢂC for 30 min and at rt for 40 h. At the
end of the reaction, the mixture was poured into water
and extracted with ether. The organic phase was washed
with water and dried over anhydrous Na2SO4. Evapora-
tion of the solvent gave 8.95 g (91% yield) of 6. 1H NMR
and 13C NMR data are in accordance with those re-
ported in the literature.36
4.2.2. Diethyl 4-methyl-5-oxo-tetrahydrofuran-3,3-dicar-
boxylic acid 7.37 To a solution of 6 (8.15 g, 33.1 mmol)
in 20 mL of anhydrous ethanol, polymeric aldehyde
(2.00 g, 66.2 mmol) was added, under stirring and in
an argon atmosphere at rt. The mixture was heated to
50 ꢂC and sodium ethoxide (prepared from 20 mg of
sodium and 3.0 mL of anhydrous ethanol) added. The
mixture was stirred at 50 ꢂC for 6 h. At the end of the
reaction, the mixture was poured into cold water, neu-
tralized with concd H2SO4 and extracted with ether.
The organic phase was washed with water and dried
over anhydrous Na2SO4. After evaporation of the

C. Forzato et al. / Tetrahedron: Asymmetry 16 (2005) 3011–3023
3019
solvent, 7 was obtained in 89% yield (7.18 g). Colourless
82 (27), 71 (28), 69 (79), 59 (42), 56 (16), 55 (100), 54
(18); HRGC (c-CDX): Rt 39.18 min for enantiomer
(3S,4R) and Rt 42.82 for enantiomer (3R,4S) (100 ꢂC
10 min, 3 ꢂC/min, 150 ꢂC). Compound 9: Pale yellow
1
oil; IR (neat), cmꢀ1: 1789, 1735; H NMR d 4.73 (d,
J = 9.9, 1H, H-2), 4.33 (d, J = 9.9, 1H, H-2), 4.28 (q,
J = 7.2, 2H, OCH2CH3), 4.27 (q, J = 7.2, 2H,
OCH2CH3), 3.26 (q, J = 7.4, 1H, CHCH3), 1.31 (t,
J = 7.2, 3H, CH3CH2O), 1.31 (d, J = 7.4, 3H, CH3CH),
1.30 (t, J = 7.2, 3H, CH3CH2O); 13C NMR d 176.1 (s,
C-5), 168.1 (s, COOEt), 167.7 (s, COOEt), 69.0 (t,
C-2), 62.5 (t, OCH2CH3), 62.4 (t, OCH2CH3), 60.2 (s,
C(COOEt)2), 39.9 (d, CHCH3), 14.0 (q, CH3CH2O),
13.9 (q, CH3CH2O), 11.2 (q, CH3CH); MS, m/z: 244
(M+Å, 8), 199 (37), 173 (66), 171 (100), 143 (66), 141
(62), 127 (40), 126 (46), 100 (50), 99 (88).
1
oil, IR (neat), cmꢀ1: 1776, 1732; H NMR d 4.49 (dd,
J1 = 8.8, J2 = 9.2, 1H, H-2), 4.27 (dd, J1 = 9.2, J2 =
9.5, 1H, H-2), 3.78 (s, 3H, OCH3), 3.12 (m, 1H,
CHCOOMe), 2.88 (dq, J1 = 7.1, J2 = 10.6, 1H,
CHCH3), 1.36 (d, J = 7.1, 3H, CH3CH); 13C NMR d
177.4 (s, C-5), 170.9 (s, COOMe), 66.5 (t, C-2), 52.4
(q, CH3O), 47.6 (d, CHCOOMe), 37.7 (d, CHCH3),
14.4 (q, CH3CH); MS, m/z 158 (M+Å, 1), 127 (21), 144
(18), 101 (12), 99 (29), 83 (30), 82 (18), 71 (29), 69 (67),
59 (44), 56 (15), 55 (100), 54 (15); HRGC (c-CDX): Rt
29.72 min for enantiomer (3S,4S) and Rt 30.23 for enan-
tiomer (3R,4R) (100 ꢂC 10 min, 3 ꢂC/min, 150 ꢂC).
4.2.3. cis- and trans-4-Methyl-5-oxo-tetrahydrofuran-3-
carboxylic acids 1 and 2.9,38 Lactone 7 (4.40 g,
18 mmol) was added to 125 mL of 20% HCl and
refluxed for 52 h. After evaporation of the solvent, a
mixture of 1 and 2, in the ratio of 23:77, respectively,
was obtained (2.54 g, 98% yield). White solid, mp 58–
70 ꢂC (of the mixture); IR (Nujol) cmꢀ1: 3130, 1731.
For the sake of clarity, the NMR spectra are given sep-
arately for the two isomers.
4.2.5. cis- and trans-Ethyl 4-methyl-5-oxo-tetrahydrofu-
ran-3-carboxylates 10 and 11.9,39 To a solution of
2.16 g of the 23:77 mixture of 1 and 2 in 75 mL of anhy-
drous ethanol, 4.2 mL (33 mmol) of trimethyl silyl chlo-
ride was added and stirred in argon atmosphere at rt
overnight. After evaporation of the solvent, a 23:77 mix-
ture of 10 and 11, respectively, was obtained in 95%
yield. Separation by flash-chromatography (eluant:
petroleum ether/ethyl acetate 85:15) afforded 0.42 g of
Compound 1: 1H NMR d (D2O) 4.54 (dd, J1 = 6.8,
J2 = 9.8, 1H, H-2), 4.30 (dd, J1 = 6.8, J2 = 9.8, 1H, H-
2), 3.41 (m, 1H, CHCOOH), 3.05 (dq, J1 = 7.3,
J2 = 8.8, 1H, CHCH3), 1.06 (d, J = 7.3, 3H, CH3CH);
13C NMR d (D2O) 181.7 (s, COOH), 175.2 (s, C-5),
68.7 (t, C-2), 45.0 (d, CHCOOH), 36.6 (d, CHCH3),
1
10 and 1.17 g of 11. IR, H NMR and MS data are in
accordance with those reported in the literature.39 Com-
pound 10: 13C NMR d 177.6 (s, C-5), 170.4 (s, COOEt),
67.1 (t, C-2), 61.3 (t, OCH2CH3), 44.8 (d, CHCOOEt),
36.5 (d, CHCH3), 14.1 (q, CH3CH2O), 11.2 (q, CH3CH);
HRGC (c-CDX): Rt 41.47 min for enantiomer (3S,4R)
and Rt 45.90 for enantiomer (3R,4S) (100 ꢂC 10 min,
3 ꢂC/min, 150 ꢂC); compound 11: 13C NMR d 177.5 (s,
C-5), 170.4 (s, COOEt), 66.6 (t, C-2), 61.5 (t, OCH2CH3),
47.8 (d, CHCOOEt), 37.7 (d, CHCH3), 14.4 (q,CH3CH),
14.0 (q, CH3CH2O); HRGC (c-CDX): Rt 31.15 min for
enantiomer (3S,4S) and Rt 31.48 for enantiomer
(3R,4R) (100 ꢂC 10 min, 3 ꢂC/min, 150 ꢂC).
1
10.0 (q, CH3CH). H NMR d (CDCl3) 9.99 (br s, 1H,
OH), 4.56 (dd, J1 = 4.2, J2 = 6.5, 1H, CH2O), 4.38
(dd, J1 = 6.5, J2 = 9.3, 1H, CH2O), 3.51 (ddd,
J1 = 4.2, J2 = 7.0, J3 = 9.3, 1H, CHCOOH), 2.99 (dq,
J1 = 7.3, J2 = 9.2, 1H, CHCH3), 1.33 (d, J = 7.7, 3H,
1
CH3CH). Compound 2: H NMR d (D2O) 4.46 (dd,
J1 = 8.8, J2 = 9.2, 1H, H-2), 4.25 (dd, J1 = 6.8,
J2 = 9.8, 1H, H-2), 3.16 (q, J = 9.2, 1H, CHCOOH),
2.88 (dq, J1 = 7.2, J2 = 9.9, 1H, CHCH3), 1.17 (d,
J = 7.2, 3H, CH3CH); 13C NMR d (D2O) 181.8 (s,
COOH), 174.5 (s, C-5), 68.0 (t, C-2), 47.1 (d,
CHCOOH), 37.9 (d, CHCH3), 13.5 (q, CH3CH).
4.3. Chemical hydrolysis
Lactones 10 and 11 were hydrolyzed separately under
acidic conditions (6 M HCl, reflux) to give the corre-
sponding lactonic acids 1 (in admixture with 20% of 2)
and 2 (as a pure compound) in quantitative yield.
4.2.4. cis- and trans-Methyl 4-methyl-5-oxo-tetrahydro-
furan-3-carboxylates 8 and 9.12 To a solution of 3.60 g
(24.9 mmol) of the 23:77 mixture of 1 and 2 in 150 mL of
anhydrous methanol, 7.5 mL (56.2 mmol) of trimethyl
silyl chloride was added and stirred overnight under
argon atmosphere at rt. After evaporation of the solvent
a 23:77 mixture of 8 and 9, respectively, was obtained in
97% yield. Separation by flash-chromatography (petro-
leum ether/ethyl acetate 85:15) afforded 0.83 g of 8
and 2.27 g of 9 as pure compounds.
Compound ( )-2: white solid, mp 92–98 ꢂC; MS, m/z
145 (MH+, 35), 100 (16), 99 (18), 85 (100), 82 (57), 71
(79), 69 (41), 68 (39).
4.4. Enzymatic hydrolyses
To the appropriate lactones 8–11 (1 mmol) in 0.1 M
phosphate buffer (14 mL), at pH 7.4, were added the fol-
lowing amounts of enzymes: 0.150 g of porcine pancre-
atic lipase (PPL), 0.140 g of lipase from Pseudomonas
species (Amano PS, 30,000 U/g), 0.052 g of lipase from
C. cylindracea (CCL, 943 U/mg), 0.160 g of lipase from
A. niger (Amano AP 12, 120,000 U/g), 0.400 g of lipase
from M. miehei (MML, Lipozyme), 0.180 g of lipase
from C. antarctica (Novozyme 435ꢁ, 7000 U/g),
0.230 g of porcine liver acetone powder (PLAP),
Compound 8: Pale yellow oil, IR (neat), cmꢀ1: 1792,
1732; H NMR d 4.52 (dd, J1 = 4.2, J2 = 9.5, 1H, H-2),
1
4.35 (dd, J1 = 7.0, J2 = 9.5, 1H, H-2), 3.76 (s, 3H,
OCH3), 3.48 (ddd, J1 = 4.2, J2 = 7.0, J3 = 9.1, 1H,
CHCOOMe), 2.93 (dq, J1 = 7.5, J2 = 9.1, 1H, CHCH3),
1.23 (d, J = 7.5, 3H, CH3CH); 13C NMR d 177.5 (s, C-5),
171.0 (s, COOMe), 67.1 (t, C-2), 52.1 (q, CH3O), 44.8 (d,
CHCOOMe), 36.5 (d, CHCH3), 11.2 (q, CH3CH); MS,
m/z 158 (M+Å, 2), 127 (18), 144 (23), 99 (35), 83 (36),

3020
C. Forzato et al. / Tetrahedron: Asymmetry 16 (2005) 3011–3023
0.900 g of Horse liver acetone powder (HLAP), 0.019 g
of a-chymotrypsin (a-CT, 51.8 U/mg) and 0.100 g of
subtilisin (39.1 U/mg). The course of the reaction was
monitored with a pH-STAT, with continuous addition
of 1.0 N NaOH. At about 20% conversion, the reaction
mixture was extracted with ether to separate the unre-
acted lactone. The mother liquors were acidified with
5% HCl to pH 2 and extracted with ether to obtain
the corresponding lactonic acids 1, 2 or the lactonic es-
ters (8–11) derived from the hydroxy halfester interme-
diates. The organic phases were dried over anhydrous
Na2SO4 and treated with diazomethane to esterify the
carboxylic group before chiral HRGC analysis.
the unstable compound 13 was obtained in quantitative
1
yield. Pale yellow oil. IR (neat), cmꢀ1: 1822, 1776; H
NMR d 4.60 (dd, J1 = 8.8, J2 = 9.2, 1H, H-2), 4.37
(dd, J1 = 9.2, J2 = 9.5, 1H, H-2), 3.56 (ddd, J1 = 8.8,
J2 = 9.2, J3 = 9.5, 1H, H-3), 3.00 (dq, J1 = 7.3,
J2 = 9.9, 1H, H-4), 1.45 (d, J = 7.3, 3H, CH3CH); 13C
NMR d (68 MHz) 175.9 (s, C-5), 171.7 (s, COCl), 65.6
(t, C-2), 58.2 (d, C-3), 37.7 (d, C-4), 14.6 (q, CH3CH).
4.4.6. (3R,4S)-(ꢀ)-4-Acetyl-3-methyl-2(3H)-dihydrofura-
none 14. To a stirred suspension of CuBr (0.81 g,
5.64 mmol) in anhydrous THF (7.4 mL), a solution of
anhydrous LiBr (0.98 g, 11.2 mmol) in anhydrous
THF (7.4 mL) was added. The mixture was stirred
under argon atmosphere for 5 min at rt. Then, a solu-
tion of 3 M MeMgI (1.87 mL, 5.61 mmol) in ether was
quickly added, followed by the addition of the optically
active compound 12 (0.76 g, 4.7 mmol), in anhydrous
THF (7 mL). The mixture was stirred for 1 h, the solu-
tion was quenched with a saturated aqueous solution
of NH4Cl and extracted with ethyl acetate. The organic
extracts were dried over anhydrous Na2SO4 and, after
evaporation of the solvent, (ꢀ)-14 was obtained [in an
admixture with 30% of the trans-isomer (+)-15] and
purified by flash-chromatography (petroleum ether/
ethyl acetate 85:15) (67% yield). Yellow oil; IR (neat),
cmꢀ1: 1761, 1716; 1H NMR d (270 MHz) 4.53 (dd,
J1 = 6.3, J2 = 9.6, 1H, H-5), 4.29 (dd, J1 = 6.9,
J2 = 9.6, 1H, H-5), 3.60 (ddd, J1 = 6.3, J2 = 6.9,
J3 = 8.9, 1H, H-4), 2.95 (dq, J1 = 7.5, J2 = 8.9, 1H, H-
3), 2.24 (s, 3H, CH3CO), 1.22 (d, J = 7.5, 3H, CH3CH);
13C NMR d (68 MHz) 205.3 (s, COCH3), 177.5 (s, C-2),
66.7 (t, C-5), 51.1 (d, C-4), 36.5 (d, C-3), 30.5 (q,
CH3CO), 11.3 (q, CH3CH); MS, m/z 143 (MH+, 100),
4.4.1. Ethyl (3S,4R)-(ꢀ)-4-methyl-5-oxo-tetrahydro-
furan-3-carboxylate 10. Lactone ( )-10 (0.43 g,
2.50 mmol) was hydrolyzed with HLAP (2.25 g) in
38 mL phosphate buffer following the general proce-
dure. After 7 h and 17 min (72% conversion), the unre-
acted lactone (ꢀ)-10 was recovered in 22% yield.
25
½aŠ ¼ ꢀ18:5 (c 0.33, MeOH); >99% ee (determined by
D
chiral HRGC on a c-CDX column).
4.4.2. Ethyl (3R,4R)-(+)-4-methyl-5-oxo-tetrahydro-
furan-3-carboxylate 11. Lactone ( )-11 (0.50 g,
2.90 mmol) was hydrolyzed with a-CT (37 mg) in phos-
phate buffer (45 mL) following the general procedure.
After 9 h and 10 min (65% conversion), the unreacted
lactone (+)-11 was recovered in 28% yield.
25
½aŠ ¼ þ68:5 (c 0.87, MeOH); >99% ee (determined by
D
chiral HRGC on a c-CDX column).
4.4.3.
(3S,4S)-(ꢀ)-4-Methyl-5-oxo-tetrahydrofuran-3-
carboxylic acid 2. Lactone ( )-11 (0.73 g, 4.27 mmol)
was hydrolyzed with a-CT (55.5 mg) in a phosphate buf-
fer (45 mL) following the general procedure. After
27 min (24% conversion), the lactonic acid (ꢀ)-2 was
125 (13), 100 (24), 98 (14), 87 (49), 85 (80), 71 (20), 69
25
(22); ½aŠ ¼ ꢀ8:8 (c 0.17, CH3OH); 99% ee. HRGC
D
(c-CDX): Rt 35.31 min for (3R,4S)-enantiomer and Rt
36.85 for (3S,4R)-enantiomer (150 ꢂC isotherm).
recovered in 14% yield. White solid, mp 98–100 ꢂC;
25
½aŠ ¼ ꢀ66:2 (c 0.63, MeOH); 91% ee (determined by
D
chiral HRGC on a c-CDX column of its methyl ester
4.4.7. (3S,4S)-(ꢀ)-4-Acetyl-3-methyl-2(3H)-dihydrofura-
none 15. To a stirred suspension of CuBr (1.00 g,
6.99 mmol) in anhydrous THF (10 mL), a solution of
anhydrous LiBr (1.22 g, 14.0 mmol) in anhydrous
THF (10 mL) was added. The mixture was stirred under
an argon atmosphere for 5 min at rt. Subsequently, a
solution of 3 M MeMgI (2.33 mL, 6.99 mmol) in ether
was quickly added followed by the addition of the opti-
cally active compound 13 (0.94 g, 5.82 mmol), in anhy-
drous THF (8 mL). The mixture was stirred for
35 min, quenched with a saturated aqueous solution of
NH4Cl and extracted with ethyl acetate. The organic
extracts were dried over anhydrous Na2SO4 and, after
evaporation of the solvent, (ꢀ)-15 was obtained and
purified by flash-chromatography (petroleum ether/
ethyl acetate 85:15) (61% yield). Yellow oil; IR (neat),
derivative).
4.4.4. cis-4-Methyl-5-oxo-tetrahydro-3-furanoyl chloride
12. To a solution of 0.60 g (4.2 mmol) of 1 [in an
admixture with 20% of (ꢀ)-2], dichloromethane
(11 mL) and 1% DMF (0.110 mL), a solution of oxalyl
chloride (0.4 mL) in dichloromethane (5 mL) was added.
The mixture was stirred for 2 h at rt. After evaporation
of the solvent, the unstable compound 12 was obtained
in quantitative yield. Yellow oil, IR (neat), cmꢀ1: 1776;
1H NMR d 4.58 (dd, J1 = 4.8, J2 = 9.9, 1H, H-2), 4.43
(dd, J1 = 7.0, J2 = 9.9, 1H, H-2), 3.96 (ddd, J1 = 4.8,
J2 = 7.0, J3 = 8.8, 1H, H-3), 3.07 (dq, J1 = 7.6,
J2 = 8.8, 1H, H-4), 1.40 (d, J = 7.3, 3H, CH3CH); 13C
NMR d (68 MHz) 166.3 (s, C-5), 164.1 (s, COCl), 66.2
(t, C-2), 55.6 (d, C-3), 36.8 (d, C-4), 11.0 (q, CH3).
1
cmꢀ1: 1776, 1716; H NMR d 4.48 (t, J = 8.8, 1H, H-
5), 4.20 (t, J = 9.3, 1H, H-5), 3.25 (q, J = 9.4, 1H, H-
4), 2.85 (dq, J1 = 7.1, J2 = 10.3, 1H, H-3), 2.27 (s, 3H,
CH3CO), 1.36 (d, J = 7.1, 3H, CH3CH); 13C NMR d
204.2 (s, COCH3), 177.6 (s, C-2), 66.2 (t, C-5), 55.5 (d,
C-4), 36.9 (d, C-3), 29.9 (q, CH3CO), 14.8 (q, CH3CH);
4.4.5. trans-4-Methyl-5-oxo-tetrahydro-3-furanoyl chlo-
ride 13. To a solution of 0.83 g (5.8 mmol) of (ꢀ)-2 in a
mixture of dichloromethane (16 mL) and 1% DMF
(0.160 mL), a solution of oxalyl chloride (0.5 mL) in
dichloromethane (6 mL) was added. The mixture was
stirred for 2 h at rt. After evaporation of the solvent,
MS, m/z 143 (MH+, 100), 125 (17), 100 (30), 87 (64), 85
25
(74), 71 (16), 69 (21); ½aŠ ¼ ꢀ72:1 (c 0.58, CH3OH);
D

C. Forzato et al. / Tetrahedron: Asymmetry 16 (2005) 3011–3023
3021
90% ee. HRGC (c-CDX): Rt 20.00 min for enantiomer
(3S,4S) and Rt 21.64 for enantiomer (3R,4R) (150 ꢂC
isotherm).
ene (21 mL) at ꢀ78 ꢂC under argon atmosphere, DI-
BAL-H (1 M in THF) (1.8 mL) was added and the
mixture was stirred for 1 h. After the addition of a solu-
tion of 2 M 2-propanol in toluene (12 mL), the temper-
ature was allowed to rise to 0 ꢂC and water (1.2 mL) was
added. After addition of ethyl acetate (24 mL) the mix-
ture was vigorously stirred and added with Kieselgur
and anhydrous Na2SO4 (2.4 g). The solid was filtered
off and washed with a 4:1 mixture of toluene/ethyl ace-
tate. After evaporation of the solvent, the crude reaction
mixture was purified by flash-chromatography (petro-
leum ether/ethyl acetate 75:25); a mixture of the two iso-
mers of (ꢀ)-18 was obtained (60% isomer A, 40% isomer
B). Oil, IR (neat), cmꢀ1: 3408, 730; MS, m/z 222 (1), 221
(1), 220 (M+Å, 4), 219 (MꢀH+, 3), [calcd for C9H16O2S2
and C9H15O2S2+: 222 (0.3), 221 (0.7), 220 (M+Å, 4.3), 219
(MꢀH+, 3)], 205 (6), 204 (7), 203 (MꢀOH+, 53), [calcd
for C9H15OS2+: 205 (4.7), 204 (6.1), 203 (MꢀOH+,
4.4.8. (3R,4S)-(ꢀ)-3-Methyl-4-(2-methyl-1,3-dithiolan-2-
yl)-2(3H)-dihydrofuranone 16. To a solution of ethane-
dithiol (0.57 mL, 6.8 mmol) in anhydrous dichlorometh-
ane (7.0 mL), Zn(OTf)2 (1.38 g, 3.8 mmol) was added. A
solution of (ꢀ)-14 (0.30 g, 2.1 mmol) in anhydrous
dichloromethane (7.0 mL) was added under vigorous
stirring. After 5 h of stirring at rt water (16 mL) was
added. The mixture was extracted with a 1:1 mixture
of ether/n-hexane, the combined extracts were washed
with 3 M HCl and with a saturated aqueous solution
of NaHCO3. Evaporation of the solvent gave the prod-
uct (ꢀ)-16, which was purified by flash-chromatography
(62% yield). Pale yellow oil; IR (neat), cmꢀ1: 1776, 773;
1H NMR d 4.48 (dd, J1 = 7.0, J2 = 9.6, 1H, H-5), 4.43
(dd, J1 = 6.0, J2 = 9.6, 1H, H-5), 3.42–3.23 (m, 4H,
CH2S), 3.10 (dt, J1 = 6.4, J2 = 8.1, 1H, H-4), 2.80 (quin-
tet, J = 7.7, 1H, H-3), 1.78 (s, 3H, CH3C), 1.41 (d,
J = 7.3, 3H, CH3CH); 13C NMR d (68 MHz) 178.9 (s,
C-2), 70.4 (t, C-5), 66.6 (s, CCH3S), 51.2 (d, C-4), 40.1
(t, CH2S), 39.5 (t, CH2S), 38.4 (d, C-3), 31.5 (q,
CH3C), 12.0 (q, CH3CH); MS, m/z: 221 (2), 220 (4),
53)], 121 (17), 120 (13), 119 (100), [calcd for C4H7S+:
25
121 (8.9), 120 (6), 119 (100)]; ½aŠ ¼ ꢀ29:5 (c 0.38,
D
CH3OH).
1
Isomer A (60%): H NMR d 5.02 (dd, J1 = 0.7, J2 =
9.2, 1H, H-2), 4.21 (t, J = 9.1, 1H, H-5), 3.82 (t,
J = 9.1, 1H, H-5), 3.75 (d, J = 9.2, 1H, OH), 3.36
(m, 4H, CH2S), 2.39 (dt, J1 = 4.5, J2 = 8.6, 1H, H-4),
2.13 (m, 1H, H-3), 1.81 (s, 3H, CH3C), 1.19 (d,
J = 7.3, 3H, CH3CH); 13C NMR d 105.0 (d, C-2),
70.5 (t, C-5), 68.6 (s, CCH3S), 58.2 (d, C-4), 46.7 (d,
C-3), 40.2 (t, CH2S), 40.0 (t, CH2S), 34.2 (q, CH3C),
20.8 (q, CH3CH).
+
219 (MH+, 17), 218 (M+Å, 5), [calcd for C9H15O2S2
and C9H14O2S2: 221 (2), 220 (2.4), 219 (MH+, 17), 218
(M+Å, 5)], 145 (12), 121 (16), 120 (12), 119 (100) [calcd
for C4H7S+: 121 (8.9), 120 (6), 119 (100)];
25
D
½aŠ ¼ ꢀ10:0 (c 0.18, CH3OH); 95% ee. HRGC (b-
CDX): Rt 174.43 min for enantiomer (3S,4R) and Rt
177.16 for enantiomer (3R,4S) (150 ꢂC isotherm).
Isomer B (40%): 1H NMR d 5.39 (dd, J1 = 3.7, J2 = 4.8,
1H, H-2), 4.25 (dd, J1 = 2.6, J2 = 8.8, 1H, H-5), 3.83,
(dd, J1 = 5.9, J2 = 9.0, 1H, H-5), 3.36 (m, 4H, CH2S),
2.60 (dt, J1 = 6.0, J2 = 8.2, 1H, H-4), 2.50 (d, J = 3.4,
1H, OH), 2.14 (m, 1H, H-3), 1.79 (s, 3H, CH3C), 1.20
(d, J = 7.0, 3H, CH3CH); 13C NMR d 101.1 (d, C-2),
70.7 (C-5), 69.4 (s, CCH3S), 55.1 (d, C-4), 43.0 (d, C-
3), 39.7 (t, CH2S), 39.5 (t, CH2S), 32.2 (q, CH3C), 14.5
(q, CH3CH).
4.4.9. (3S,4S)-(ꢀ)-3-Methyl-4-(2-methyl-1,3-dithiolan-2-
yl)-2(3H)-dihydrofuranone 17. To a solution of ethane-
dithiol (0.700 mL, 8.3 mmol) in dichloromethane
(7.7 mL), Zn(OTf)2 (1.7 g, 4.7 mmol) was added. A solu-
tion of (ꢀ)-15 (0.37 g, 2.6 mmol) in dichloromethane
(7.7 mL) was added under vigorous stirring. After 5 h
of stirring at rt, water (30 mL) was added. The mixture
was extracted with a 1:1 mixture of ether/n-hexane, the
combined extracts were washed with 3 M HCl and a sat-
urated solution of NaHCO3. Evaporation of the solvent
gave the product (ꢀ)-17, which was purified by flash-
chromatography (80% yield). Pale yellow oil; IR (neat),
cmꢀ1: 1776, 714; 1H NMR d 4.46 (dd, J1 = 8.1, J2 = 9.5,
1H, H-5), 4.14 (dd, J1 = 7.5, J2 = 9.5, 1H, H-5), 3.38 (m,
2H, CH2S), 3.32 (m, 2H, CH2S), 2.70 (q, J = 7.7, 1H, H-
4), 2.63 (quintet, J = 7.2, 1H, H-3), 1.81 (s, 3H, CH3C),
1.42 (d, J = 7.0, 3H, CH3CH); 13C NMR d 179.5 (s, C-
2), 69.4 (t, C-5), 68.2 (s, CCH3S), 54.5 (d, C-4), 40.8 (d,
C-3), 39.9 (t, CH2S), 39.8 (t, CH2S), 33.0 (q, CH3C),
17.9 (q, CH3CH); MS, m/z 221 (3), 220 (4), 219
(MH+, 40), [calcd for C9H15O2S2+: 221 (3.6), 220
(4.6), 219 (MH+, 40)], 145 (8), 121 (9), 120 (6), 119
4.4.11. epi-Botryodiplodin (ꢀ)-4. To a suspension of
AgNO2 (28 mg, 0.18 mmol) and I2 (23 mg, 0.09 mmol)
in aqueous THF (1 mL), stirred for 30 min at rt, com-
pound (ꢀ)-18 (33 mg, 0.15 mmol) was added and the
mixture stirred for a further 5 h. An aqueous solution
of Na2S2O3Æ5H2O (3 mL) was added at 0 ꢂC and the
mixture was extracted with dichloromethane. The or-
ganic phase was washed with brine and dried over anhy-
drous Na2SO4. Evaporation of the solvent gave the
desired compound (ꢀ)-4, which was purified by flash-
chromatography (17% overall yield). IR, 1H NMR
and 13C NMR were in accordance with those reported
25
in the literature.11 ½aŠ ¼ ꢀ65:9 (c 0.22, CHCl3) {lit.
D
25
D
(100) [calcd for C4H7S+: 121 (8.9), 120 (6), 119 (100)];
½aŠ ¼ ꢀ83 (c 0.69, CHCl3)}.40
25
½aŠ ¼ ꢀ51:7 (c 0.70, CH3OH); 90% ee. HRGC (b-
D
CDX): Rt 129.06 min for (3R,4R)-enantiomer and Rt
134.40 for (3S,4S)-enantiomer (150 ꢂC isotherm).
Acknowledgements
4.4.10. (2R*,3S,4S)-(ꢀ)-2-Hydroxy-3-methyl-4-(2-methyl-
1,3-dithiolan-2-yl)-tetrahydrofuran 18. To a solution of
compound (ꢀ)-17 (0.26 g, 1.2 mmol) in anhydrous tolu-
Financial supports by PRIN 2003 and the University of
Trieste are gratefully acknowledged.

3022
C. Forzato et al. / Tetrahedron: Asymmetry 16 (2005) 3011–3023
17. Nouguier, R.; Gastaldi, S.; Stien, D.; Bertrand, M.; Villar,
References
F.; Andrey, O.; Renaud, P. Tetrahedron: Asymmetry 2003,
14, 3005–3018.
18. Maurit, M. E.; Shternberg, A. M.; Pakhomov, G. I.;
Bazilevskaya, G. I.; Smirnova, G. V.; Preobrazhenskii, N.
A. Zh. Obshch. Khim. 1960, 30, 2256–2259 (CAN 55:64702
AN 1961:64702).
19. (a) Snatzke, G.; Ripperger, H.; Horstmann, C.; Schreiber,
K. Tetrahedron 1966, 22, 3103–3116; (b) Jennings, J. P.;
Klyne, W.; Scopees, P. M. J. Chem. Soc. 1965, 7211–
7229.
20. Okuda, T.; Harigaya, S.; Kiyomoto, A. Chem. Pharm.
Bull. 1964, 12, 504–506.
1. Koch, S. C. C.; Chamberlin, A. R. In Enantiomerically
Pure c-Butyrolactones in Natural Products Synthesis; Atta-
ur-Rahman, Ed.; Elsevier: Amsterdam, 1995.
2. (a) Das, B.; Venkataiah, B.; Kaschinatam, A. Tetrahedron
1999, 55, 6585–6594; (b) Ghotak, A.; Sarkar, S.; Ghosh, S.
Tetrahedron 1997, 53, 17335–17342; (c) Rodriguez, A. D.;
Pina, I. C.; Barnes, C. L. J. Org. Chem. 1995, 60, 8096–
˜
8100; (d) Chen, Y.-L.; Wang, T.-C.; Chang, N.-C.; Chang,
Y.-L.; Teng, C.-M.; Tseng, C.-C. Chem. Pharm. Bull.
1988, 46, 962–965; (e) Hoffmann, H. M. R.; Rabe, J.
Angew. Chem. Int., Ed. Engl. 1985, 24, 94–110; (f) Lee,
K.-H.; Hall, I. H.; Mar, E.-C.; Starnes, C. O.; El Gebali, S.
A.; Waddell, T. G.; Hadgraft, R. I.; Ruffner, C. G.;
Weidner, I. Science 1977, 196, 533–536; (g) Kupchan, S.
M.; Thomas, A. M.; Eakin, M. A. J. Med. Chem. 1971, 14,
1147–1152.
21. Forzato, C.; Nitti, P.; Pitacco, G. Tetrahedron: Asymmetry
1997, 8, 4101–4110.
22. (a) Gross, E. K. U.; Kohn, W. Adv. Quantum Chem. 1990,
21, 255–291; (b) Gross, E. K. U.; Dobson, J. F.; Petersilka,
M. Top. Curr. Chem. 1996, 181, 81–172; (c) Dobson, J. F.
In Electronic Density Functional Theory. Recent Progress
and New Directions; Dobson, J. F., Vignale, G., Das, M.
P., Eds.; Plenum: New York, 1998; pp 43–53; (d)
Autschbach, J.; Patchkovskii, S.; Ziegler, T.; van Gisber-
gen, S. J. A.; Baerends, E. J. J. Chem. Phys. 2002, 117,
581–592; (e) Grimme, S. Chem. Phys. Lett. 2001, 339, 380–
388; (f) Ruud, K.; Helgaker, T. Chem. Phys. Lett 2002,
352, 533–539.
23. (a) Miertus, S.; Scrocco, E.; Tomasi, J. Chem. Phys. 1981,
55, 117–129; (b) Cammi, R.; Tomasi, J. J. Comput. Chem.
1995, 16, 1449–1458; (c) Cances, E.; Mennucci, B.;
Tomasi, J. J. Chem. Phys. 1997, 107, 3032–3041; (d)
Mennucci, B.; Cances, E.; Tomasi, J. J. Phys. Chem. B
1997, 101, 10506–10517.
3. (a) Benedetti, F.; Forzato, C.; Nitti, P.; Pitacco, G.;
Valentin, E.; Vicario, M. Tetrahedron: Asymmetry 2001,
12, 505–511; (b) Pollnitz, A. P.; Jones, G. P.; Sefton, M. A.
J. Chromatogr. A 1999, 857, 239–246; (c) Otsuka, K.;
Zenibayashi, Y.; Itoh, M.; Totsuka, A. Agric. Biol. Chem.
1974, 38, 485–490; (d) Kepner, R. E.; Webb, A. D.;
Muller, C. J. Am. J. Enol. Vitic. 1972, 23, 103–105.
4. Fronza, G.; Fuganti, G.; Grasselli, P.; Servi, S. Chimia
1993, 47, 43–45, and references cited therein.
5. (a) Mori, K. In Techniques in Pheromone Research;
Hummel, H. H., Miller, T., Eds.; Springer: New York,
1989; (b) Silverstein, R. M. In Semiochemistry Flavors and
Pheromones; Acree, T., Ed.; Proceedings ACS Sympo-
sium; Walter de Gruyter: Berlin, 1985.
24. Polavarapu, P. L. Chirality 2002, 14, 768–781.
25. (a) Stephens, P. J.; Devlin, F. J.; Cheeseman, J. R.; Frish,
M. J. J. Phys. Chem. A 2001, 105, 5356–5371; (b)
Cheeseman, J. R.; Frish, M. J.; Devlin, F. J.; Stephens,
P. J. J. Phys. Chem. A 2000, 104, 1039–1046.
26. (a) Crassou, J.; Jiang, Z.; Schurig, V.; Polavarapu, P. L.
Tetrahedron: Asymmetry 2004, 15, 1995–2001; (b) Ste-
phens, P. J.; Devlin, F. J.; Cheeseman, J. R.; Frish, M. J.;
Bortolini, O.; Besse, P. Chirality 2003, 15, S57–S64.
27. (a) Stephens, P. J.; Devlin, F. J.; Cheeseman, J. R.; Frish,
M. J.; Rosini, C. Org. Lett. 2002, 4(26), 4595–4598; (b)
Pecul, M.; Ruud, K.; Rizzo, A.; Helgaker, T. J. Phys.
Chem. A 2004, 108, 4269–4276.
28. (a) Stephens, P. J.; Devlin, F. J.; Cheeseman, J. R.; Frish,
M. J.; Mennucci, B.; Tomasi, J. Tetrahedron: Asymmetry
2000, 11, 2443–2448; (b) Mennucci, B.; Tomasi, J.;
Cammi, R.; Cheeseman, J. R.; Frisch, M. J.; Devlin, F.
J.; Gabriel, S.; Stephens, P. J. J. Phys. Chem. A 2002, 106,
6102–6113.
6. (a) Murphy, P. A.; Hendrich, S. Ad. Food Nutr. Res. 2002,
44, 195–246; (b) Ward, R. S. Nat. Prod. Rep. 1999, 16, 75–
96; (c) Ayres, D. C.; Loicke, J. D. Lignans; Cambridge
University Press, 1990.
7. (a) Bo¨hm, C.; Reiser, O. Org. Lett. 2001, 3, 1315–
1318, and references cited therein; (b) Forzato, C.;
Nitti, P.; Pitacco, G.; Valentin, E. In Targets in Hetero-
cyclic Systems, Chemistry and Properties; Attanasi, O.,
Spinelli, D., Eds.; S.C.I.: Roma, 1999; Vol. 3, pp 93–115.
8. Comini, A.; Forzato, C.; Nitti, P.; Pitacco, G.; Valentin,
E. Tetrahedron: Asymmetry 2004, 15, 617–625.
9. Preobrazhenskii, N. A.; Maurit, M. E.; Bazilevskaya, G.
I.; Smirnova, G. V.; Elꢀmanovich, M. M.; Valakhanovich,
A. I.; Persiyanova, E. Zh. Obshch. Khim. 1960, 30, 2250–
2256 (CAN 55:48614 AN 1961:48614).
10. (a) Fuska, J.; Proksa, B.; Uhrin, D. Folia Microbiol.
(Prague, Czech Republic) 1988, 33, 238–240; (b) Moreau,
S.; Lablache-Combier, A.; Biguet, J.; Foulou, C.; Delf-
osse, M. J. Org. Chem. 1982, 47, 2358–2359; (c) Fuska, J.;
Kuhr, I.; Nemec, P.; Fuskova, A. J. Antibiot. 1974, 27,
123–127; (d) Arsenault, G. P.; Althaus, J. R.; Divekar, P.
V. J. Chem. Soc. D, Chem. Commun. 1969, 1414–1415; (e)
Gupta, R. S.; Chandran, R. R.; Divekar, P. V. Ind. J. Exp.
Biol. 1966, 4, 152–153.
11. Fujimoto, Y.; Kamiya, M.; Tsunoda, H.; Ohtsubo, K.;
Tatsuno, T. Chem. Pharm. Bull. 1980, 28, 1062–
1066.
12. Ishida, A.; Saijo, S.; Noguchi, K.; Wada, M.; Takaiti, O.;
Himizu, J.-I. Chem. Pharm. Bull. 1979, 27, 625–632.
13. Brook, M. A.; Chan, T. H. Synthesis 1983, 3, 201–
203.
14. Rakels, J. L. L.; Straathof, A. J. J.; Heijnen, J. J. Enzyme
Microb. Technol. 1993, 15, 1051–1056.
15. Babudri, F.; Fiandanese, V.; Marchese, G.; Punzi, A.
Tetrahedron 1999, 55, 2431–2440.
29. Marchesan, D.; Coriani, S.; Forzato, C.; Nitti, P.; Pitacco,
G.; Ruud, K. J. Phys. Chem. A 2005, 109, 1449–1453.
30. Barone, V.; Cossi, M.; Tomasi, J. J. Chem. Phys. 1997,
107, 3210–3221.
31. Coriani, S.; Forzato, C.; Marchesan, D.; Nitti, P.; Pitacco,
G., in preparation.
32. GAUSSIAN 03, revision A.1; Gaussian: Pittsburgh, PA,
2003.
33. DALTON,
A molecular electronic structure program,
release 2.0, 2005, see http://www.kjemi.uio.no/software/
dalton/.
34. Giorgio, E.; Viglione, R. G.; Zanasi, R.; Rosini, C. J. Am.
Chem. Soc. 2004, 126, 12968–12976.
35. Lattanzi, A.; Viglione, R. G.; Scettri, A.; Zanasi, R. J.
Phys. Chem. A 2004, 108, 10749–10753.
36. Pierik, A. J.; Ciceri, D.; Bro¨ker, G.; Edwards, C. H.;
McFarlane, W.; Winter, J.; Buckel, W.; Golding, B. T. J.
Am. Chem. Soc. 2002, 124, 14039–14048.
16. Nishide, K.; Yokota, K.; Nakamura, D.; Sumiya, T.;
Node, M. Tetrahedron Lett. 1993, 34, 3425–3428.

C. Forzato et al. / Tetrahedron: Asymmetry 16 (2005) 3011–3023
3023
37. Piskov, V. B. Zh. Obshch. Khim. 1962, 32, 2046–2050
(CAN 58:26798, AN 1963:26798).
38. Dowd, P.; Shapiro, M.; Kang, J. Tetrahedron 1984, 40,
3069–3086.
39. Shimada, S.; Hashimoto, Y.; Nagashima, T.; Hasegawa,
M.; Saigo, K. Tetrahedron 1993, 49, 1589–1604.
40. Rehnberg, N.; Magnusson, G. Acta Chem. Scand. 1990,
44, 377–383.