Chiraloptical properties of adducts derived from cyclic nitrones and 2(5H)-furanones. Combined experimental and theoretical studies

Article abstract of DOI:10.1016/j.tetasy.2009.06.017

The validity of the Bucourt-Legrand empirical rule, which relates the configuration at the α-carbon atom in the lactone unit with the sign of the lactone n→π^* transition observed in the electronic circular dichroism (ECD) spectrum of 5-5-5 and

Full text of DOI:10.1016/j.tetasy.2009.06.017

Tetrahedron: Asymmetry 20 (2009) 1778–1790
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Chiraloptical properties of adducts derived from cyclic nitrones
and 2(5H)-furanones. Combined experimental and theoretical studies
*
Sebastian Stecko, Jadwiga Frelek, Marek Chmielewski
Institute of Organic Chemistry, Polish Academy of Sciences, Kasprzaka 44/52, 01-224 Warsaw, Poland
a r t i c l e i n f o
a b s t r a c t
Article history:
The validity of the Bucourt–Legrand empirical rule, which relates the configuration at the a-carbon atom
in the lactone unit with the sign of the lactone n?p
* transition observed in the electronic circular dichro-
Received 21 May 2009
Accepted 25 June 2009
Available online 17 July 2009
ism (ECD) spectrum of 5-5-5 and 5-5-6 fused heterocyclic systems, was investigated. For this purpose, a
combination of ECD spectroscopy, time-dependent density functional theory (TD-DFT) and molecular
modelling calculations supported additionally by X-ray diffraction analysis, was applied. Model com-
pounds were obtained via the 1,3-dipolar cycloaddition of 2(5H)-furanones and five- and six-membered
cyclic nitrones. In addition, cycloadducts either with or without an additional interfering chromophore
were selected. A comparison of the recorded ECD spectra with those simulated by the TD-DFT calcula-
tions gave a reasonable interpretation of the excitations observed in the 210–230 nm spectroscopic
range. Generally, calculations confirmed the validity of the Bucourt–Legrand rule and demonstrated that
ECD may be used as a highly sensitive probe for the three-dimensional molecular structure of the systems
studied herein. Notable behaviour, however, was observed in the case of some 5-5-6 fused systems
substituted with BnO group. In these cases, the conformational liability and coupling of molecular lactone
excitation with other chromophores cause a change of orientation of the transition dipole moments
resulting in a breakdown of the rule.
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
dard NMR techniques often do not provide unequivocal results
because of the overlap of diagnostic resonances with others. More-
The 1,3-dipolar cycloaddition (1,3-DC) reactions represent a
powerful tool for the construction of both heterocyclic and carbo-
cyclic rings.1 The best-known processes of this kind are reactions
between nitrones and alkenes leading to the formation of isoxazol-
idine rings.1 The efficient formation of functionalized isoxazoli-
dines and, after subsequent hydrogenolysis of N-O bond, also of
the b-amino alcohols enables the facile syntheses of various nitro-
gen-containing compounds.2–7 The utility of 1,3-DC involving nit-
rones in the synthesis of iminosugars has been demonstrated by
numerous research groups,8–11 including our own.12
Recently, we have demonstrated a general approach to imino-
sugars via the cycloaddition reaction between cyclic nitrones 1–2
and five- or six-membered unsaturated lactones 3–6 as a key step
in the synthesis (Chart 1). 12 These efforts were preceded by the de-
tailed studies on the asymmetric induction observed during reac-
tions between cyclic nitrones (e.g., 1 and 2) and both types of
lactones (e.g., 3–6)13,14 supported by DFT and molecular modelling
calculations.15
over, adducts frequently do not form crystals suitable for X-ray
analysis. These difficulties prompted us to undertake the investiga-
tion of electronic circular dichroism spectroscopy to find the rela-
tionship between the stereostructure of a cycloadduct and its
respective CD data.
In 1967, Legrand and Bucourt16 established a general rule for
five-, six- and seven-membered lactones, which correlates the sign
of the n?p
* Cotton effect (CE) with the sign of the O–C(@O)–C –Cb
a
dihedral angle, called the ‘ring-chirality rule’. According to this rule,
a negative n?p* CE is expected for a positive dihedral angle and a
positive CE is expected for a negative angle. This rule, however, is
only valid for the planar lactone chromophoric system.
Previously, we have shown that circular dichroism spectroscopy
is a useful tool for the determination of the absolute configuration
at the newly formed stereogenic centres of cycloadducts obtained
via 1,3-DC reactions between cyclic nitrones and d-lactones.13a,b
These studies pointed out that the ring-chirality rule can be suc-
cessfully applied in the stereochemical analysis of cycloadducts de-
rived from six-membered lactones, for example, 4 and 5, and cyclic
nitrones 1 and 2. These studies revealed that a negative sign of the
n?p* CE at around 220–230 nm corresponds to an (R)-absolute
A direct assignment of the absolute configuration of type A and
type B cycloadducts (Scheme 1) is not straightforward. The stan-
configuration at the
at that atom corresponds to an opposite sign of this transition.
a-carbon atom whereas the (S)-configurations
* Corresponding author. Tel./fax: +48 22 632 66 81.
E-mail address: chmiel@icho.edu.pl (M. Chmielewski).
0957-4166/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2009.06.017

S. Stecko et al. / Tetrahedron: Asymmetry 20 (2009) 1778–1790
trans
1779
cis
O
O
(
)
m
H
H
H
H
RO
O
O
O
O
OR
OR
+
+
N
O
m: 1,2
N
N
(
)
m
(
)
m
H
O
H
O
exo adduct
endo adduct
A
B
Scheme 1.
steric repulsion in the transition state.15 The formation of endo
adducts by furanones 3 and 6 enables us to examine their chiralop-
tical properties for the first time.
Ot-Bu
t-BuO
Ot-Bu
O
O
O
O
HO
In addition, we intend to support the experimental studies with
the quantum-mechanic simulations of CD properties of the ana-
lyzed cycloadducts. For this purpose, we decided to use DFT func-
tional methods,17 which are the most suitable for the analysis of
electronic properties of organic compounds. These studies were
preceded by a conformational analysis conducted applying molec-
ular modelling methods. Furthermore, we decided to study the
influence of additional chromophores (e.g., phenyl) present in the
molecule on the electronic transitions of the lactone chromophoric
system.
N
O
N
O
1
2
3
4
AcO
AcO
OBn
O
O
O
O
N
O
5
6
7
Chart 1.
2. Results and discussion
2.1. Chiraloptical properties of exo adducts derived from 2(5H)-
Moreover, it was demonstrated that both the substitution of the
lactone ring and its conformation influence the shape of the CD
spectra.
furanone 6
The CD data of exo adducts 8–21 (Chart 2) are collected in
Table 1 (for exo definition see Scheme 1). The UV spectra of most
adducts, except 8, 14 and 17, do not exhibit any characteristic
absorption within the measurement range. As can be seen from
Table 1, the CD spectra of 8–21 exhibit two CD bands between
211–220 nm and 189–199 nm. Based on the long-wavelength CD
band sign, the compounds investigated can be divided into two
groups. In the first group, represented by adducts 8–11, 13–15
and 21, the sign of this CE is negative, whereas in the second group
(16–20) the sign of the CE is positive. These results correspond
nicely to the trend observed previously for analogous adducts con-
taining the six-membered lactone ring.13 According to the respec-
tive NMR and X-ray18 data for adducts 9, 10, 15, 16 and 17, the
absolute configuration of compounds in the first group is (4aR),
while the configuration of compounds in the second group is
(4aS). A detailed investigation of the X-ray geometries of these cyc-
loadducts revealed the planarity of lactone chromophoric system
with the average value of dihedral angle O@C4–O3–C2 close to
177°. On this basis, we concluded that the ring-chirality rule is
applicable to this class of 5-5-5 fused cycloadducts.
Herein, we report our extended studies in this area concerning
the chiraloptical properties of cycloadducts derived from the five-
membered nitrones (e.g., 1 and 2) and 2(5H)-furanones 3 and 6.
The main goal of this work is to assess the possibility of an exten-
sion of the rule to cover these 5-5-5 fused adducts also. Consider-
ing the increased rigidity of the structures analyzed, a smaller
conformational effect should be expected in comparison to the ear-
lier studied 6-5-5 fused systems derived from the six-membered
lactones. On the other hand, the increased strain in 5-5-5 fused
systems may affect the lactone ring conformation and cause a
non-planarity of the chromophore. For these reasons, a detailed
analysis of X-ray geometries of several cycloadducts was con-
ducted. Furthermore, the influence of substituents on the shape
of CD spectra was investigated. In the latter case, the effect of
the substituent at the lactone ring and the presence of additional
groups on the pyrrolidine ring were considered.
As we demonstrated recently,14 the 1,3-DC reactions involving
c-lactones 3 and 6 display a lower diastereoselectivity in compar-
ison to related reactions of their d-analogues. In addition, we re-
ported that in addition to the exo adducts, the endo adducts were
also formed (for exo/endo definition see Scheme 1). In the latter
case, the endo approach is strongly disfavoured because of the
Further studies revealed that the rule is also applicable to ad-
ducts derived from the 5-substituted lactone 3. Comparison of CD
data of adducts 8 and 12 (Table 1, entry 1 and entry 14, Fig. 1)
R3
O
O
N
O
N
O
N
O
N
O
O
O
O
O
2
1a
H
H
H
H
H
H
H
H
H
H
H
H
H
4a
4b
H
H
O
O
O
O
R1
R1
R1
O
R1
N
5
6
O
R2
R2
R2
O
R2
R1: H
R2: H
R3: H
R3: H
R2: t-BuO R3: H
R1: t-BuO R2: H
8
9
10
13
16 R1: t-BuO R2: H
R1: t-BuO R2: H
14 R1: H
R2: t-BuO
15 R1: t-BuO R2: t-BuO
R1: H
R2: t-BuO
19 R1: H R2: t-BuO
20 R1: t-BuO R2: t-BuO
17
21
18 R1: t-BuO R2: t-BuO
R1: H
11 R1: t-BuO R2: t-BuO R3: H
12 R1: H
R2: H
R3: CH2OH
Chart 2.

1780
S. Stecko et al. / Tetrahedron: Asymmetry 20 (2009) 1778–1790
Table 1
substituents on the pyrrolidine ring have only a minor influence on
the shape of CD curve and changes are observed in the range below
205 nm only.
UV and CD data of compounds 8–21 derived from lactone 6 recorded in acetonitrile
Entry
Compd
C4a
CD De (k)
To exclude the possible solute-solvent interactions, which could
have an effect on the CD spectra, the CD measurement for adducts
10, 15, 16 and 17 were also performed in solid state (nujol mull). In
all cases, the solid-state data were in an excellent agreement with
the respective data recorded in solution (Fig. 3). Accordingly, it can
be concluded that the same molecular species are present both in
solution and in the solid state and only one conformer is present, or
predominates strongly, in solution. Such a good agreement of CD
data obtained by different measurement techniques indicates that
the determination of absolute configuration of adducts 8–21, as
well as of those derived from lactone 3, can be performed on the
basis of the chiraloptical data measured in solution.
1
2
3
4
5
6
7
8
8a,b
12
9
(R)
(R)
(R)
(R)
(R)
(R)
(R)
(R)
(R)
(S)
(S)
(S)
(S)
(S)
ꢀ1.0 (217)
ꢀ1.0 (217)
ꢀ1.8 (211)
ꢀ1.5 (217)
ꢀ2.3 (219)
ꢀ2.3 (212)
ꢀ2.5 (217)
ꢀ2.7 (220)
ꢀ2.2 (211)
+2.0 (216)
+2.5 (220)
+2.2 (212)
+2.8 (216)
+2.4 (216)
+0.3 (189)
+0.1 (190)
ꢀ1.9 (193)
ꢀ2.1 (199)
+0.9 (191)
ꢀ4.8 (191)
(185)e
ꢀ0.1 (192)
+2.3 (193)
+2.1 (198)
+4.8 (191)
ꢀ1.2 (191)
13
14c
10
11
15
21
16
17d
19
18
20
ꢀ1.8 (204)
ꢀ2.3 (202)
9
10
11
12
13
14
+2.0 (204)
CD values are given as
e
(k/nm) and De (k/nm), respectively.
a
(1aS,4aR,4bR)-enantiomer.
b
c
UV
UV
UV
e
e
e
(k) = 960 (195).
(k) = 1290 (193).
(k)= 560 (200).
d
e
Negative inflexion point.
Figure 3. The CD spectra of cycloadduct 16 recorded in acetonitrile solution and
nujol mull.
2.2. Chiraloptical properties of endo adducts derived from
2(5H)-furanone 6
The CD and UV data for endo adducts 22–29 (Chart 3, for endo
definition see Scheme 1) are collected in Table 2. Generally, the
CD spectra exhibit two CD bands at around 204 nm and 190 nm
(Fig. 4). An exception with respect to the position of the long-
wavelength CD band is found for compound 29. In this single case,
the band is shifted to 235 nm (Fig. 4).
The inspection of data collected in Table 2 demonstrated that
the sign of long-wavelength band depends on the configuration
at the C-4a carbon atom. Analogously to the exo adducts, the endo
adducts can be divided into two groups. In the first group, com-
pounds 22–26 and 29, the sign of this band is negative whereas
Figure 1. The CD spectra of compounds 8 and 12 recorded in acetonitrile.
showed that the introduction of a hydroxymethyl group on the lac-
tone moiety does not affect the shape of the CD curve. This observa-
tion indicates a lack of the electronic influence and the steric
hindrance of this substituent on the lactone chromophoric system.
This is a general trend observed for all adducts derived from lactone
3. As can be seen from the data collected in Table 1 and Figure 2, the
Figure 2. The CD spectra of adducts 8, 11, 13–15 and 21 taken in acetonitrile.

S. Stecko et al. / Tetrahedron: Asymmetry 20 (2009) 1778–1790
1781
O
O
N
O
N
R3
O
O
O
HO
H
H
H
H
H
H
H
H
H
O
O
R1
Ot-Bu
O
R1
N
R2
R2
Ot-Bu
R1: t-BuO R2: H
R3: H
R2: t-BuO R3: H
R2: H R3: CH2OH
R3: CH2OH
R2: t-BuO R3: CH2OH
R1: t-BuO R2: H
27
29
22
23 R1: H
28 R1: H
R2: t-BuO
R1: H
24
25 R1: t-BuO R2: H
26 R1: H
30
R1,R2,R3: H
Chart 3.
Table 2
Table 3
UV and CD data of endo adducts 22–29 derived from lactones 3 and 6 recorded in
Basis-set saturation effect on calculated n?p* transition of a lactone chromophore for
acetonitrile
8
Entry
Compd
C4a
UV
e
(k)
CD
D
e
(k)
Basis set
Transition n?p*
Rvel
ꢀ3.3
a,b
1
2
3
4
5
6
7
8
22
23
24
25
26
29
27
28
(R)
(R)
(R)
(R)
(R)
(R)
(S)
(S)
2750 (195)
ꢀ3.5 (205)
ꢀ4.3 (203)sh
ꢀ1.9 (204)
ꢀ3.5 (204)
ꢀ3.5 (205)
ꢀ0.7 (235)
+3.1 (204)
+4.3 (203)
k (nm)
f
%
2100 (195)
ꢀ4.0 (187)
6-31G(d)
225
225
225
225
225
226
226
225
226
226
0.0006
0.0005
0.0006
0.0006
0.0007
0.0005
0.0005
0.0007
0.0005
0.0007
66(6)
65(6)
67(6)
67(6)
68(5)
68(6)
67(5)
68(5)
68(6)
66(6)
a
6-31+G(d,p)
6-31++G(d,p)
6-31++G(2d,p)
6-311G(d,p)
6-311+G(d,p)
6-311++G(d,p)
6-311G(2d,p)
6-311+G(2d,p)
6-311++G(2d,p)
ꢀ3.1
ꢀ7.8
ꢀ8.3
ꢀ6.1
ꢀ6.7
ꢀ7.1
ꢀ7.3
ꢀ6.3
ꢀ10.5
a
ꢀ4.9 (192)
(190)b
+0.4 (197)
3030 (196)
800 (193)
a
a
UV and CD values are given as
e (k/nm) and De (k/nm), respectively.
sh: Shoulder.
a
No characteristic absorption in measurement range.
Positive inflexion point.
b
a
A
content of the n?p* transition of lactone chromophore in simulated
transition.
In parentheses content of the
simulated transition.
p?
p* transition of the lactone chromophore in
b
in the second group, adducts 27 and 28, the sign is positive. Consid-
ering the NMR and X-ray data for adducts 22 and 25,19 it can be as-
sumed that the negative sign of the ca. 204 nm CD band corresponds
to the (4aR)-absolute configuration. Therefore, for the second group
displaying a positive sign of the same band, the (4aS)-absolute con-
figuration should be expected (see Table 2).
O@C4–O3–C2 equal to 177° was found. On this basis, it can be con-
cluded that the ring-chirality rule should be applicable to the endo
adducts also.
In comparison to the CD spectra of exo adducts discussed ear-
lier, the long-wavelength CD band is blue-shifted by about
10 nm. It seemed possible that in the endo adducts the close prox-
imity of lactone and pyrrolidine rings would cause a slight defor-
mation of the 5-5-5 fused system to minimize the repulsion
between both rings. Therefore, a distortion of the lactone rings
leading to some non-planarity of the chromophore could be ex-
pected. Detailed analysis of the X-ray geometries of 22 and 25,
however, showed that for both compounds the dihedral angle
The X-ray data for compound 25 provide additional evidence
supporting the configurational assignment. The ORTEP representa-
tion shown in Figure 5 clearly demonstrates the (4aR)-absolute
configuration in accordance to our prediction made on the basis
on the CD data. Due to the excellent agreement between CD curves
for 25 recorded in solution and in nujol mull (Fig. 6) we can assume
that the same molecular species are present in both states. There-
fore, adduct 25 can be considered as a model compound in the
determination of the absolute configuration for remaining com-
pounds reported in Table 2.
Figure 5. ORTEP representation of compound 25 (for clarity some hydrogen atoms
Figure 4. The CD spectra of compounds 22, 23 and 29 recorded in acetonitrile.
are omitted).

1782
S. Stecko et al. / Tetrahedron: Asymmetry 20 (2009) 1778–1790
Figure 8. The lowest-energy conformer of adduct 29 (two projections are shown).
the rule assumes the planarity of lactone chromophore and the
lack of electronic influence of other components of the molecule
on the lactone chromophore. The difficulties arise when an addi-
tional strong chromophore is present in the molecule. These ques-
tions prompted us to undertake an investigation of the origin of the
ring-chirality rule applying quantum-mechanic calculation. Sev-
eral of the earlier discussed cycloadducts were chosen as a calcula-
tion model. The presence of heteroatoms makes these molecules
particularly attractive for such a purpose. Moreover, a comparison
of the influence of different substituents on the net CD is possible
by simple modification of the hydroxy group protection.
Taking into consideration the fact that the electronic properties
of organic compounds are determined by their electronic structure,
a density functional theory has been chosen as the most adequate
calculation method for this purpose. Initially, the simplest adduct 8
was chosen as a model for theoretical studies.
Figure 6. The CD data of adduct 25 recorded in acetonitrile solution and in solid
state (nujol mull).
The observed difference in position of the n?p
* bands between
exo adducts and endo adducts may be caused by the specific arrange-
ment of the lactone and the pyrrolidine rings. Conformational anal-
ysis of model adduct 30, without any substituents attached to the 5-
5-5 ring fused system,15b as well as of adduct 22, revealed that the
isoxazolidine ring adopts an envelope conformation with the co-pla-
nar arrangement of C-1a, C-4a, C-4b and N-8 atoms. The O-1 atom is
localized between both five-membered rings (Fig. 7). Such an
arrangement minimizes the steric repulsion between the lactone
and pyrrolidine rings. A detailed analysis of the lowest-energy con-
formers of 30 and 22 suggests a possible interaction between the
carbonyl group and hydrogen atom at C-5, which may affect the
electronic transitions of this chromophore group (Fig. 7). In addition,
for compound 22, there is also indication of some steric repulsion
involving protons of the tert-butyl group (Fig. 7).
The experimental CD spectrum of adduct 8 in acetonitrile is
shown in Fig. 9. The observed broadening of CD band may indicate
The red-shift (approx. 30 nm) of the n?p* CE observed for ad-
duct 29 can be caused by the perpendicular arrangement of the
pyrrolidine and lactone rings, according to the molecular model-
ling calculations. The electronic repulsion of 6-Ot-Bu and the car-
bonyl group causes a distortion of the lactone ring as can be seen
in Figure 8. Thus, the dihedral angle, usually falling within 174–
177° range, here is found to be 167° only. For this reason, the
ring-chirality rule is not applicable to this molecule.
2.3. Theoretical investigation of the Legrand–Bucourt empirical
rule
The effectiveness of the Legrand–Bucourt empirical rule in the
determination of the chiraloptical properties of various lactones
has been demonstrated repeatedly.13a,b,20 As mentioned before,
Figure 9. Experimental and theoretical CD spectra of compound 8.
Figure 7. The lowest-energy conformer of adduct 22 (three projections are shown). For clarity, some hydrogen atoms are omitted.

S. Stecko et al. / Tetrahedron: Asymmetry 20 (2009) 1778–1790
1783
Figure 10. Conformers of compound 8 (for clarity some hydrogen atoms are omitted). Total energies, relative energies and Boltzmann statistic (in parentheses) are given.
the presence of several (at least two) electronic transitions differ-
ing only slightly in energy. For certain lactone chromophores, the
n?p* transition overlaps the respective
p?
p* transition because
of their similar energy.21 Therefore, the poorly resolved CD bands
are observed in the spectrum. To provide evidence for this state-
ment the MO theoretical calculations were performed.
Before simulation of the CD spectrum of 8, the conformational
aspects were evaluated by applying the combination of molecular
mechanics and DFT calculations. The conformational search was
carried out using MM+ force field.22 The low conformational labil-
ity of five-membered fused ring system makes it rather rigid, and
only a few conformers within the range of 10 kcal/mol were found.
The resulting conformers were further re-optimized by the DFT
calculations at B3LYP/6-31+G(d) level of theory (in vacuo), result-
ing in the structures shown in Figure 10 as the lowest-energy min-
ima.15b These conformers can be divided into three types with
respect to the isoxazolidine ring. The co-planar arrangement of
C-1a, C-4a, C-4b and O-1 atoms in type I conformer ensures the
planarity of lactone moiety (Fig. 10). On the other hand, for type
II conformers, the oxygen atom O-1 is out-of-plane formed by C-
1a, C-4a, C-4b and N-8 and therefore the lactone ring is not pla-
nar.15b Type II conformers differ mostly in the conformation of
the pyrrolidine ring. Structures IIA and IIB have higher energies
(Fig. 10) with respect to the conformer I and are negligible in the
Boltzmann population at room temperature. The low conforma-
tional lability of the 5-5-5 fused system also prevents free inver-
ΔE
-0.77eV (LUMO)
-5.92eV (HOMO)
∗
ΔE = 7.2eV (n→π )
-7.98eV (HOMO-1)
∗
ΔE = 7.9eV (π→π )
-8.69eV (HOMO-2)
Figure 12. Experimental and theoretical CD spectra of (a) adduct 16; b) adduct 10
and c) adduct 22. In all cases a rotatory strength Rvel was included.
Figure 11. Molecular orbitals involved in transitions of compound 8.

1784
S. Stecko et al. / Tetrahedron: Asymmetry 20 (2009) 1778–1790
Table 4
UV and CD data of compounds 31–34 derived from nitrone 7 recorded in acetonitrilea
Entry
Compound
C4a
UV
e
(k)
CD De (k)
1
2
3
4
31
32
33
34
(S)
(R)
(S)
(R)
9900 (207)
11,000 (205)
9010 (205)
1800 (206)
ꢀ3.9 (182)
+1.4 (191)
ꢀ1.1 (184)
+0.8 (190)
+8.3 (193)
ꢀ0.6 (198)
+6.8 (192)
+0.1 (198)
+2.7 (212)sh
+0.7 (213)
+1.1 (213)sh
+0.2 (212)
ꢀ0.5 (228)
+0.6 (223)
ꢀ0.8 (225)
+0.2 (223)sh
UV and CD values are given as
e (k/nm) and De (k/nm), respectively.
sh: shoulder.
a
An additional low-intensity band corresponding to 1Lb transition of the phenyl group was observed at around 257 nm.
This result suggests that Legrand and Bucourt’s assumption
about the lack of a significant influence of other atoms on the
chiraloptical properties of the lactone cannot be true since the
observed transitions constitute a mixture of several transitions
stemming from various molecular components. Of course, it should
be taken into account that their relative contributions depend on
their distance to the lactone chromophoric system.
O
N
O
O
H
H
O
H
H
H
toluene, rt
50h, 73%
H
OBn
7 + 6
OBn
O
O
N
31
(exo-anti)
32
(exo-syn)
In continuation of the theoretical studies, adducts bearing addi-
tional substituents were investigated. As it was pointed out earlier,
the presence of an additional hydroxymethyl substituent near the
lactone moiety does not affect the chiraloptical properties of the
studied adducts. For this reason, only compounds with an RO-sub-
stituent at the pyrrolidine ring were taken into consideration and
compounds 10, 16 and 22 were chosen as models. For all of them,
the DFT optimization was carried out using X-ray geometries as an
input. In all cases, the computationally optimized geometry and
the structure obtained by the X-ray were similar.
ratio 92:8
O
O
O
H
O
H
HO
HO
H
H
toluene, rt
48h, 72%
H
H
OBn
OBn
7 + 3
O
N
O
N
33
(exo-anti)
34
(exo-syn)
ratio 93:7
Based on the conformational search for adduct 16, five minima
were found, but only the global minimum was considered for fur-
ther studies (the difference in energy of other structures exceeds
2 kcal/mol, so they do not have a significant thermal population
at room temperature).15 Figure 12a shows simulated and experi-
mental spectra of compound 16, with both curves being in a good
agreement.
The transposition of the substituent from C-5 in 16 to C-6 in 10
changed the shape of the CD curve (Fig. 12b). The adduct 10 shows
two negative poorly resolved bands, in contrast to the CD curve of
16 showing only one broadened band. For the lowest-energy con-
former of 10, the simulated curve is in very good agreement with
the experimental spectrum, as can be seen in Figure 12b.
As was discussed earlier, the endo adducts feature a characteris-
tic increase in energy of the n?p* transition that is manifested in
the presence of appropriate CE in spectral range of 203–205 nm.
As can be seen in Table 2 and Figure 12c, the CD curve of adduct
22 contains one broadened negative band at 205 nm. The simulated
curve shown in Figure 12c is in excellent agreement with the
experimental one.
Scheme 2.
sion at the nitrogen atom. Thus, the cis arrangement of the nitrogen
lone pair and the H-4b atom is observed which was corroborated
by both X-ray analysis18 and the conformational search for numer-
ous cycloadducts. The conformer with the trans arrangement of the
nitrogen lone pair and the H-4b proton (Fig. 10, III) is substantially
higher in energy (ca. 8.3 kcal/mol) with respect to all other con-
formers15b and therefore has no significance for the chiraloptical
properties. Such a result is in accordance with previous NMR stud-
ies carried out by Font and de March.23
For the lowest-energy conformer of 8 (conformer I), the absorp-
tion and CD spectra have been calculated applying the time-depen-
dent DFT (TD-DFT)24 method using B3LYP functional and different
basis sets (Table 3). For the treatment of the solvent effect, the
polarized continuum model (PCM)25 method was used with aceto-
nitrile as the solvent. The calculations were carried out using the
GAUSSIAN 03 suite of quantum chemical programs.26
The analysis of the basis-set saturation effect gave similar re-
sults (Table 3) showing only small basis-set dependence on the cal-
culated transitions. According to the results obtained, for further
CD curve simulations a B3LYP/6-311+G(d,p) level of theory has
been chosen. The simulated and experimental CD spectra of 8 (con-
former I) are shown in Figure 9. Both experimental and theoretical
curves are in a good agreement. Detailed analysis of the lowest-en-
ergy transitions in the spectral range from 209 to 225 nm confirms
their complex character. However, the most important electronic
transition (HOMO-1?LUMO) was found to have mostly the n?p*
character. For example, its content at 225 nm is 68% and at
The agreement above between simulated and experimental CD
spectra confirms the accuracy of Legrand and Bucourt rule by both
experiment and theory.
2.4. Chiraloptical properties of adducts derived from 2(5H)-
furanones and six-membered nitrone 7
Next, the experimental and theoretical studies of systems con-
taining an additional strong chromophore were carried out. For
this purpose, four adducts shown in Scheme 2 were selected.
219 nm it is 22%. As an additional component, the p?p
* transition
was found, however, its contribution is lesser. Figure 11 presents
molecular orbitals involved in the transitions of compound 8. As
shown in Figure 11, the molecular orbitals participating in the
transition of the chromophore group have a complex character
with a large contribution of the carbonyl group orbitals. The energy
The reaction of chiral nitrone 7 with achiral lactone 6 afforded a mixture of two
exo products 31 and 32 in a ratio of 92:8 (HPLC) and 73% yield (Scheme 2). The
absolute configuration of products was assigned analyzing the NMR spectra.
Additionally, the configurational assignment of 31 is supported by the X-ray analysis
(Fig. 13). The replacement of achiral lactone 6 by its chiral analogue 3 did not
significantly change the outcome of reaction and again two products 33 and 34 were
obtained (ratio 93:7, yield 72%; Scheme 2). As in the previous experiment, the major
product was identified as an exo-anti adduct and the minor one as an exo-syn isomer.
for the n?p* and
p?
p* transitions equals 7.2 and 7.9 eV, respec-
tively. The energy difference is only 0.7 eV thus confirming the pre-
vious prediction.

S. Stecko et al. / Tetrahedron: Asymmetry 20 (2009) 1778–1790
1785
In Table 4, a summary of the relevant UV and CD data of adducts
31–34 is given. Apparently, the presence of a hydroxymethyl group
at the lactone moiety had no significant influence on the dichroic
spectra of the investigated molecules.
According to data recorded in Table 4, the CD curves of adducts
31–34 are characterized by four CEs at around 186, 195, 213 and
225 nm. Such a complex character of the CD curves may indicate
that the MOs of the lactone chromophore mix strongly with the
MOs localized at the benzyloxy chromophore. This observation is
in an agreement with our theoretical calculation of molecular orbi-
tals for 31 (vide infra).
As indicated in previous paragraphs, the base transition of the
lactone unit (n?p
*) is observed at around 215 nm. On this basis,
it was assumed that for adduct 31 the CE at 212 nm corresponds
to this transition. Moreover, the positive sign of this band, corre-
sponding to the (4aS)-absolute configuration corroborated our pre-
vious conclusion, based on the X-ray geometry (Fig. 13), that
compound 31 obeys the Bucourt–Legrand rule. The CD band at
Figure 15. The CD data of 31 recorded in solution and in solid state.
around 228 nm originates most probably from the
of benzyloxy group.
p?p
* transition
conclusion contradicts the experimental data available for 31.
The similarity of the CD curves of 31 recorded in acetonitrile solu-
tion and nujol mull (Fig. 15) allowed us to conclude that in both
states, the same molecular system is present. Moreover, the tem-
perature-dependent CD measurements suggest strongly the pre-
dominance of one conformer in solution.
The re-calculation of energy for type I and type III conformers of
31 with the higher basis set increased the relative energy differ-
ence from 0.9 to 1.0 kcal/mol which indicates the decrease of con-
former III content from 20% to 15% only.
Figure 16a and b show the simulated CD curves for both con-
formers 31-I and 31-III, respectively. Due to the planarity of lac-
tone chromophore in 31-III, this conformer was considered in
the simulation of weight-average CD curve with respect to the
Boltzmann distribution of conformers (85:15). Both experimental
and average theoretical curves are in a satisfactory agreement
(Fig. 16c).
A detailed analysis of the calculated transitions in the spectral
range from 210 to 240 nm confirms their complex character and
the strong interference of the phenyl chromophore with the lac-
tone moiety. The molecular orbitals involved in the most impor-
tant transitions of both chromophores for compound 31 are
shown in Figure 17. As in the previous examples (Fig. 11), the lac-
Figure 13. The ORTEP representation of compound 31.
The conformational analysis of compound 31 revealed three
low-energy conformers (Fig. 14). Type I conformer has a planar lac-
tone ring and the chair conformation of piperidine ring with an
equatorial BnO substituent. The planarity of lactone chromophore
was also observed for the type II conformer. The axial arrangement
of the BnO group increased, however, its energy with respect to the
conformer I by 2.5 kcal/mol. Therefore, conformer II was omitted
from further discussion owing to its presumed negligible contribu-
tion to the Boltzmann population at room temperature.
The type III conformer, with the trans arrangement of H-4b and
nitrogen’s lone pair, is only slightly more energetic when com-
pared to the conformer I (DE 0.9 kcal/mol). According to the theo-
retical calculations, approximately 20% content of III in the
conformational equilibrium should be expected. However, this
tone orbitals (p, n and p
*) are an admixture with a large contribu-
tion of orbitals from other components of the molecule. The
calculation proves that the transition at around 230 nm corre-
sponds to the p?p
* electronic transition of the phenyl group. This
transition is an admixture of energetically close transitions (from
HOMO, HOMO-1, HOMO-2 to LUMO, LUMO+1, LUMO+2). The lac-
tone n?p* transition can be found at around 213 nm which con-
firms the previous assumption based on the correlation of
experimental data of 31 with 5-5-5 fused series of compounds
8–21. However, these molecular excitations are not localized but
couple with both phenyl p? p?
p* and lactone p* transitions.
Figure 14. Conformers of compound 31 (for clarity some hydrogen atoms are omitted). Total energies, relative energies and Boltzmann statistic (in parentheses) are given.

1786
S. Stecko et al. / Tetrahedron: Asymmetry 20 (2009) 1778–1790
made for (4aR)-configuration. The discrepancy observed for the CD
data recorded in solution and in solid state indicates that a differ-
ent molecular species exists in both states. Such an extraordinary
behaviour of adduct 32 may be caused by the interaction of the
benzyloxy group and the lactone ring which is advantageously sit-
uated for the presumed orbital overlapping.
The above unexpected observations were confirmed by confor-
mational analysis. All three conformers which were found for ad-
duct 32 are depicted in Figure 19. Structures I and II are equal in
energy and represent the global minima, whereas the invertomer
III is higher in energy by about 3.3 kcal/mol, and can be omitted
because of a presumed lack of significant contribution to the Boltz-
mann distribution of conformers. An increased energy for III is a
function of the electronic repulsion between the lone pair of nitro-
gen and both lone pairs of oxygen atom within the BnO group. To
minimize this interaction, the piperidine ring adopts a twist-boat
conformation.
As mentioned before, both predicted conformers I and II are
energetically equal. In case of conformer I, the more favourable
conformation of the isoxazolidine ring results in the piperidine ring
adopting the 4C1 chair conformation with an unfavourable axial
arrangement of the BnO substituent. In the case of conformer II
with an equatorial BnO substituent and 4C1 conformation of the
piperidine ring the isoxazolidine ring adopts a less preferred con-
formation with the O-1 oxygen atom out of the envelope plane.
In both cases (I and II), the lactone chromophore system is planar.
Additionally, the proximity of the oxygen atom of the benzyloxy
group and the relatively acidic H-4a proton may indicate a possible
internal hydrogen-bonding type interaction which may stabilize
the adduct’s conformation. Very recently, we postulated an analo-
gous interaction for the structurally related adduct 9, which was
corroborated by the NMR and DFT studies.15b However, a detailed
comparison of conformers of 32 with those obtained for 9 suggests
that this extra stabilization is weaker in adduct 32 because of the
less effective overlapping of interacting orbitals.
Both the simulated and experimental CD spectra for conformers
I and II of adduct 32 are presented in Figure 20. Their comparison
revealed that the simulated CD curve of I corresponds better to the
solution data whereas the simulated CD curve of II has a shape that
is similar to that of the curve recorded in the solid state. Based on
this result, it can be concluded that conformer I predominates in
solution whilst conformer II, with an equatorial BnO substituent,
is present in the solid state. Unfortunately, we could not confirm
this conclusion by X-ray analysis because compound 32 does not
form suitable crystals.
Analogously to adduct 31, the computational investigation of
MOs of 32 confirmed the complex character of experimentally ob-
served electronic transitions by showing the strong interference of
the phenyl group localized MOs and base transitions of the lactone
chromophore system.
Figure 16. (a) Simulated CD curve for conformer I; (b) simulated CD curve for
conformer III and (c) experimental and simulated CD curves for adduct 31.
To conclude, adducts 31 and 33 obey the Bucourt–Legrand rule
whereas compounds 32 and 34 do not comply with the rule. This is
most likely because of the specific stereochemical arrangement of
the interacting chromophores, namely, the lactone unit and the
benzyloxy group.
The situation is more complex for the exo-syn adduct 32 (Table
4). As shown for earlier examples, for adduct with (4aR)-configura-
tion, a negative band in the spectroscopic range 210–220 nm
should be present. Unexpectedly, the CD curve of compound 32 re-
corded in acetonitrile has a positive CE in this range. This may sug-
gest that the ring-chirality rule is not applicable to compounds 32
and 34 (Fig. 18). However, the low intensity of the CD band at
213 nm may indicate that in the solution, a mixture of at least
two conformers is present. Indeed, when the CD measurements
were done in nujol mull or KCl pellet, the change of the sign of
the bands above 205 nm was observed (Fig. 18). The negative sign
of the band at around 208 nm nicely corresponds to the prediction
3. Conclusions
Herein, the relationship between the molecular structure and
the chiroptical properties of 5-5-5 and 5-5-6 fused heterocyclic
systems, derived from the five- and six-membered cyclic nitrones
and 2(5H)-furanones, was investigated by electronic circular
dichroism spectroscopy, time-dependent density functional the-
ory, molecular modelling calculations and the X-ray diffraction
analysis.

S. Stecko et al. / Tetrahedron: Asymmetry 20 (2009) 1778–1790
1787
Figure 17. Molecular orbitals involved in transitions of compound 31.
may serve as a useful indicator during the assignment of configu-
ration. A characteristic blue-shift of the CD band for endo adducts
was confirmed by theoretical calculation using DFT methods.
The computed O@C4–O3–C2 dihedral angle provides the corrob-
orating evidence for the planarity of the lactone chromophore. The
band at around 213 nm (or 204 nm for endo adducts) has mainly
the n?p
* transition character. Its positive or negative sign, contin-
gent upon the (4aS)- or (4aR)-absolute configuration, respectively,
is predicted by both the Bucourt–Legrand rule and the TD-DFT cal-
culations, in most cases. Generally, the agreement between the
simulated and the experimental ECD spectra was very satisfactory
and demonstrates that the rule can be successfully applied to the
assignment of the absolute configuration of the investigated 5-5-5
fused cycloadducts. However, the CD spectra of 5-5-6 fused ad-
ducts with an additional benzyloxy substituent are particularly
sensitive to the changes of the molecular conformation. The differ-
ent conformers of the same adduct can have a radically different
CD spectrum. In some cases, a difference between solution and so-
lid-state CD spectra was observed proving that the different
molecular species (conformers) are present in both states. More-
over, the presence of an additional chromophore group compli-
cates the CD spectra due to its interference with the lactone
chromophore. Therefore, to successfully apply the Bucourt–Le-
Figure 18. The CD data of 32 recorded in MeCN and in solid state (nujol mull and
KCl pellet).
The comparison of experimental data for the exo adducts and
endo adducts in 5-5-5 fused series of compound revealed signifi-
cant difference in the position of the long-wavelength band which
Figure 19. Conformers of adduct 32. Total energies, relative energies and Boltzmann statistic (in parentheses) are given.

1788
S. Stecko et al. / Tetrahedron: Asymmetry 20 (2009) 1778–1790
Nitrone 7 was prepared following the literature procedure.27
Compounds 8–29 were prepared following our previously pub-
lished procedures.14
Cycloadduct 13 was obtained following the reported proce-
dure23 starting from nitrone 6 and lactone 11. The enantioenriched
sample of 13 (0.5 mg, ee 90%) was obtained by HPLC using Chiral-
celÒ OD-H (Daicel) column (eluent: hexane/i-propanol 60:40 v/v,
flow 1 mL/min, UV detection at 195 nm). Retention times:
7.3 min for (1aR,4aS,4bS)-ent-13 and 8.2 min for (1aS,4aR,4bR)-13.
4.2. Cycloaddition of nitrone 7 to lactones 3 and 6. General
method
To a solution of the lactone (0.36 mmol) in toluene (3 mL, anhy-
drous) a solution of nitrone 7 (0.47 mmol) in toluene (2 mL) was
added and the mixture was stirred under argon. The progress of
reaction was monitored by TLC. After complete consumption of
the lactone, the reaction mixture was concentrated and the residue
was chromatographed on a silica gel using hexane/ethyl acetate
mixture (1:1 v/v, for lactone 6 or 1:2 v/v, for lactone 3) as an eluent.
The cycloadducts’ ratio was assigned by the HPLC. The assignments
of NMR peaks were performed by using COSY experiments.à
4.2.1. (1aR,4aS,4bS,5R)-5-Benzyloxy-octahydrofuro[3,4-d]pyri-
din[1,2-b]isoxazol-4(3H)-one 31
Colourless crystals, mp 77–79 °C (benzene); [a]D = +57.3 (c 1.85,
CH2Cl2); 1H NMR (500 MHz, toluene-d8, 70 °C, hydrogen atoms of
Ph group omitted) d: 4.43 (1H, d, J 12.0 Hz, OCHHPh), 4.13 (1H, d,
J 12.0 Hz, OCHHPh), 4.02 (1H, dd, J 10.5, 3.1 Hz, H2), 3.86 (1H, dd,
0
J 7.1, 6.0, 3.1 Hz, H1a), 3.61 (1H, dd, J 10.5, 6.0 Hz, H2 ), 3.46 (1H,
m, H4b), 3.15–3.02 (2H, H5, H8), 2.99 (1H,m, H4a), 2.44 (1H, m,
0
0
0
H8 ), 1.76 (1H, m, H6), 1.56 (1H, m, H7), 1.05–0.85 (2H, H6 , H7 );
13C NMR (125 MHz, toluene-d8, carbon atoms of Ph group omit-
ted): 175.3, 75.9, 74.5, 73.7, 70.7, 69.5, 51.9, 50.2, 20.9; IR (film)
Figure 20. Experimental and simulated CD curves for adduct 32; (a) CD data
recorded in MeCN and simulated CD curve for conformer I; (b) CD data recorded in
nujol and simulated CD curve for conformer II.
m
: 1770 cmꢀ1; HR MS (ESI): m/z Calcd for [M+Na+] C16H19NO4Na:
312.1206. Found: 312.1200; Anal. Calcd for C16H19NO4: C, 66.42;
H, 6.62; N, 4.84. Found: C, 66.39; H, 6.60, N, 4.83; HPLC: LiChro-
spher Si60Ò, eluent: hexane/i-propanol 95:5, retention time
6.7 min.
grand rule for the unequivocal configurational assignment, the
TD-DFT calculations are strongly recommended to support the
conclusions are strongly recommended.
4.2.2. (1aS,4aR,4bS,5R)-5-Benzyloxy-octahydrofuro[3,4-d]pyri-
din[1,2-b]isoxazol-4(3H)-one 32
Colourless oil, ½a D25
ꢂ
¼ þ11:3 (c 0.6, CH2Cl2); 1H NMR (500 MHz,
4. Experimental
toluene-d8, hydrogen atoms of Ph group omitted) d: 4.45 (1H, d, J
12.0 Hz, OCHHPh), 4.26 (1H, d, J 12.0 Hz, OCHHPh), 4.05 (1H,
ddd, J 7.7, 6.2, 2.1 Hz, H1a), 3.98 (1H, dd, J 10.3, 2.1 Hz, H2), 3.74
4.1. General methods
0
(1H, dd, J 10.3, 6.2 Hz, H2 ), 3.17 (1H, dd, J 10.3, 4.1 Hz, H5), 3.10
Melting points were determined using Köfler hot-stage appara-
tus with microscope and are uncorrected. Proton and carbon NMR
spectra were recorded on a Bruker DRX 500 Avance Spectrometer
at 500 MHz and 125 MHz, respectively, using deuterated solvents
and TMS as an internal standard. Chemical shifts are reported as
d values in parts per million and coupling constants are in Hertz.
Infrared spectra were recorded on an FT-IR-1600 Perkin–Elmer
spectrophotometer. The optical rotations were measured with a
JASCO J-2000 digital polarimeter. High resolution mass spectra
were recorded on ESI-TOF Mariner spectrometer (Perspective Bio-
system). The HPLC analysis was carried out on Hitachi chromato-
graph with L-2130 pump and L-2450 DAD detector equipped
with a LiChrospherÒ Si60 analytical column.
Thin layer chromatography (TLC) was performed on aluminium
sheets Silica Gel 60 F254 (20 ꢁ 20 ꢁ 0.2) from Merck. Column chro-
matography was carried out using Merck silica gel 230–400 mesh.
The TLC spots were visualized in UV (254 nm) and by treatment
with alcoholic solution of ninhydrine, aqueous solution of KMnO4
or with ceric sulfate/phosphomolybdenic acid solution.
0
(1H, m, H8), 3.00 (1H, dd, J 7.7, 1.7 Hz, H4a), 2.52 (1H, m, H8 ),
2.12 (1H, dd, J 10.3, 1.7 Hz, H4b), 1.83 (1H, m, H6), 1.58 (1H, m,
H7), 1.18 (1H, m, H7 ), 1.04 (1H, m, H6 ); 13C NMR (125 MHz, tolu-
0
0
ene-d8, carbon atoms of Ph group omitted): 174.2, 76.2, 75.2,
74.8, 73.9, 72.4, 54.8, 49.3, 30.7, 22.0; IR (film) m
: 1767 cmꢀ1; HR
MS (ESI): m/z Calcd for [M+Na+] C16H19NO4Na: 312.1206. Found:
312.1192; Anal. Calcd for C16H19NO4: C, 66.42; H, 6.62; N, 4.84.
Found: C, 66.38; H, 6.59; N, 4.84. HPLC: LiChrospher Si60Ò, eluent:
hexane/i-propanol 95:5, retention time 11.8 min.
As we already demonstrated recently,14b the cycloaddition reactions between
à
c
-lactones and five-membered nitrones are reversible and their stereochemical
outcome depends on the reaction conditions. Such behavior has never been observed
for the reactions involving d-lactones regardless of the type of nitrone.13
reversibility of the reaction is also observed for the 1,3-DC of -lactones (3, 6) with
6-membered nitrone 7. The reflux of toluene solution of exo-anti adduct 31 gave, after
4 days, the equilibrium mixture of compounds 31 and 32 in the ratio 2:1.
A
c

S. Stecko et al. / Tetrahedron: Asymmetry 20 (2009) 1778–1790
1789
4.2.3. (1aR,2R,4aS,4bS,5R)-5-Benzyloxy-2-hydroxymethyl-octa-
hydrofuro[3,4-d]pyridino[1,2-b]isoxazol-4(3H)-one 33
Colourless oil; [
D = +2.2 (c 2.24, CH2Cl2); 1H NMR (500 MHz,
toluene-d8, 90 °C, hydrogen atoms of Ph group omitted) d: 4.41
(1H, d, J 12.0 Hz, OCHHPh), 4.20 (1H, d, J 12.0 Hz, OCHHPh), 4.05
(1H, m, H1), 3.99 (1H, m, H2), 3.77–3.69 (2H, CH2OH), 3.26 (1H,
dd, J 12.0, 2.8 Hz, H4b), 3.14–2.96 (3H, H4a, H5, H8), 2.40 (1H, m,
Acknowledgement
a
]
We are most indebted to Mr. Grzegorz Lipner (IOC PAS, War-
saw) for providing us with computer capabilities.
References
0
0
0
H8 ), 1.80 (1H, m, H6), 1.52 (1H, m, H7), 1.11–0.92 (2H, H6 , H7 );
13C NMR (125 MHz, toluene-d8, carbon atoms of Ph group omit-
ted): 174.5, 82.8, 79.6, 76.3, 74.1, 72.0, 70.6, 63.3, 53.0, 49.7,
1. (a) Padwa, A.. 1,3-Dipolar Cycloaddition Chemistry; Wiley: New York, 1984; (b)
Gothelf, K. V.; Jörgensen, K. A. Chem. Rev. 1998, 98, 863–909; (c) Karlsson, S.;
Högberg, H.-E. Org. Prep. Proced. Int. 2001, 33, 103–172; (d) Kobayashi, S.;
Jörgensen, K. A. Cycloaddition Reactions in Organic Synthesis; Wiley-VCH:
Weinheim, 2002; (e) Pellissier, H. Tetrahedron 2007, 63, 3235–3285; (f)
Padwa, A. In Synthetic Applications of 1,3-Dipolar Cycloaddition Chemistry
Toward Heterocycles and Natural Products; Padwa, A., Pearson, W. H., Eds.;
Wiley & Sons: Hoboken, NJ, 2003; (g) Merino, P.. In Science of Synthesis; Padwa,
A., Ed.; George Thieme: New York, NY, 2004; Vol. 27, p 511.
19.8; IR (film)
m
: 3433, 1769 cmꢀ1; HR MS (ESI): m/z Calcd for
[M+Na+] C17H21NO5Na: 342.1312. Found: 342.1308; Anal. Calcd
for C17H21NO5: C, 63.94; H, 6.63; N, 4.39. Found: C, 63.95; H,
6.60; N, 4.36. HPLC: LiChrospher Si60Ò, eluent: hexane/i-propanol
90:10, retention time 9.3 min.
2. (a) Gallos, J. K.; Koumbis, A. E. Curr. Org. Chem. 2003, 7, 397–426; (b) Gallos, J.
K.; Koumbis, A. E. Curr. Org. Chem. 2003, 7, 771–797; (c) Koumbis, A. E.; Gallos,
J. K. Curr. Org. Chem. 2003, 7, 585–628.
3. (a) Frederickson, M. Tetrahedron 1997, 53, 403–425; (b) Nair, V.; Suja, T. D.
Tetrahedron 2007, 63, 12247–12275; (c) Broggini, G.; Zecchi, G. Synthesis 1999,
905–917.
4.2.4. (1aS,2R,4aR,4bS,5R)-5-Benzyloxy-2-hydroxymethyl-octa-
hydrofuro[3,4-d]pyridin[1,2-b]isoxazol-4(3H)-one (34)
Colourless oil; [a]
D = +100.3 (c 0.75, CH2Cl2); 1H NMR (500 MHz,
toluene-d8, hydrogen atoms of Ph group omitted) d: 4.75 (1H, d, J
11.0 Hz, OCHHPh), 4.54 (1H, d, J 11.0 Hz, OCHHPh), 4.34 (1H, dd,
J 7.5, 1.6 Hz, H1a), 4.25 (1H, ddd, J 2.9, 2.7, 1.6 Hz, H2), 3.70 (1H,
m, H5), 3.35 (1H, dd, J 7.5, 6.1 Hz, H4a), 3.29 (1H, dd, J 12.1,
2.9 Hz, CHHOH), 3.21 (1H, m, H8), 3.10 (1H, dd, J 12.1, 2.7 Hz,
4. (a) Merino, P.; Tejero, T. Molecules 1999, 4, 169–179; (b) Revuelta, J.; Cicchi, S.;
Goti, A.; Brandi, A. Synthesis 2007, 485–504.
5. Ashry, E. S.; Nemr, A. Synthesis of Naturally Occurring Nitrogen Heterocycles from
Carbohydrates; Blackwell Publishing: Oxford, 2005.
6. Hudlicky´, T.; Reed, J. W. The Way of Synthesis; Wiley-VCH: Weinheim, 2007.
7. Lopez, M. D.; Cobo, J.; Nogueras, M. Curr. Org. Chem. 2008, 12, 718–750.
8. (a) Cicchi, S.; Goti, A.; Brandi, A. J. Org. Chem. 1995, 60, 4743–4748; (b) Goti, A.;
Cicchi, S.; Cacciarini, M.; Cardona, F.; Fedi, V.; Brandi, A. Eur. J. Org. Chem. 2000,
3633–3645; (c) Cordero, F.; Pisaneschi, F.; Gensini, M.; Goti, A.; Brandi, A. Eur. J.
Org. Chem. 2002, 1941–1951; (d) Pisaneschi, F.; Cordero, F.; Brandi, A. Eur. J.
Org. Chem. 2003, 4373–7375; (e) Cardona, F.; Moreno, G.; Guarana, F.; Vogel, P.;
Schetz, C.; Merino, P.; Goti, A. J. Org. Chem. 2005, 70, 6552–6555; (f) Pisaneschi,
F.; Piacenti, M.; Cordero, F.; Brandi, A. Tetrahedron: Asymmetry 2006, 17, 292–
296.
9. (a) Carmona, A. T.; Whigtman, R. H.; Robina, I.; Vogel, P. Helv. Chim. Acta 2003,
86, 3066–3073; (b) McCraig, A.; Meldrum, K. P.; Whigtman, R. H. Tetrahedron
1998, 54, 9429–9446; (c) Hull, A.; Meldrum, K. P.; Therand, P. R.; Whigtman, R.
H. Synlett 1997, 123–125; (d) McCraig, A.; Wightman, R. H. Tetrahedron Lett.
1993, 34, 3939–3941.
0
CHHOH), 2.20 (1H, dd, J 9.6, 6.1 Hz, H4b), 2.12 (1H, m, H8 ), 1.80
(1H, m, H6), 1.43–1.15 (2H, H7), 0.90 (1H, m, H6 ); 13C NMR
0
(125 MHz, toluene-d8, carbon atoms of Ph group omitted): 174.3,
86.6, 78.1, 74.9, 73.3, 71.9, 62.8, 54.4, 50.8, 30.3, 21.6; IR (film) m:
3436, 1767 cmꢀ1; HR MS (ESI): m/z Calcd for [M+Na+] C17H21NO5
Na: 342.1312. Found: 342.1305; Anal. Calcd for C17H21NO5: C,
63.94; H, 6.63; N, 4.39. Found: C, 63.92; H, 6.62; N, 4.37. HPLC:
LiChrospher Si60Ò, eluent: hexane/i-propanol 90:10, retention
time 18.1 min.
10. Kuban, J.; Kolarovic, A.; Fisera, L.; Jager, V.; Humpa, O.; Pronayova, N. Synlett
2001, 1866–1868.
4.3. The UV and CD measurements
11. Tufariello, J. J. J. Am. Chem. Soc. 1980, 102, 373–376.
12. (a) Socha, D.; Jurczak, M.; Chmielewski, M. Carbohydr. Res. 2001, 336, 315–318;
(b) Rabiczko, J.; Urban´ czyk-Lipkowska, Z.; Chmielewski, M. Tetrahedron 2002,
The UV spectra were measured in acetonitrile on Varian Cary
100 spectrophotometer. The CD spectra were recorded between
180 and 360 nm at room temperature with a JASCO J-820 spectro-
polarimeter using acetonitrile solution. The solutions with concen-
tration in the range of 0.5–1.0 ꢁ 10ꢀ4 mol/dm3 were examined in
cells with a path length of 0.1, 0.5 or 1 cm. For the solid-state CD
measurements a sample of crystalline compound (1–3 mg) was
ground with Nujol to form a homogenous Nujol mull, which was
rotated around the optical axis during entire measurement using
original JASCO equipment for this purpose. The low-temperature
spectra were recorded in EPA (diethyl ether/iso-pentane/ethanol
5:5:2 v/v) solution with a concentration of 0.956 mmol/dm3 in
range of 210–350 nm in the 0.1- and 1-cm cells.
´
58, 1433–1441; (c) Socha, D.; Pasniczek, K.; Jurczak, M.; Solecka, J.;
Chmielewski, M. Carbohydr. Res. 2006, 341, 2005–2011; (d) Pas´niczek, K.;
Socha, D.; Solecka, J.; Jurczak, M.; Chmielewski, M. Can. J. Chem. 2006, 84, 534–
539; (e) Panfil, I.; Solecka, J.; Chmielewski, M. J. Carbohydr. Chem. 2006, 25,
673–684; (f) Pas´niczek, K.; Solecka, J.; Chmielewski, M. J. Carbohydr. Chem.
´
2007, 26, 195–211; (g) Stecko, S.; Jurczak, M.; Urbanczyk-Lipkowska, Z.;
Solecka, J.; Chmielewski, M. Carbohydr. Res. 2008, 343, 2215–2220; (h) Stecko,
S.; Solecka, J.; Chmielewski, M. Carbohydr. Res. 2009, 344, 167–176; (i) Stecko,
S.; Pas´niczek, K.; Jurczak, M.; Solecka, J.; Chmielewski, M. Polish J. Chem. 2009,
83, 237–243.
´
´
´
13. (a) Pasniczek, K.; Socha, D.; Jurczak, M.; Frelek, J.; Suszczynska, A.; Urbanczyk-
Lipkowska, Z.; Chmielewski, M. J. Carbohydr. Chem. 2003, 22, 613–629; (b)
´
Socha, D.; Jurczak, M.; Frelek, J.; Klimek, A.; Rabiczko, J.; Urbanczyk-Lipkowska,
Z.; Suwin´ ska, K.; Chmielewski, M.; Cardona, F.; Goti, A.; Brandi, A. Tetrahedron:
Asymmetry 2001, 12, 3163–3172; (c) Jurczak, M.; Rabiczko, J.; Socha, D.;
Chmielewski, M.; Cardona, F.; Goti, A.; Brandi, A. Tetrahedron: Asymmetry 2000,
11, 2015–2022.
4.4. The computational methods
´
´
14. (a) Stecko, S.; Pasniczek, K.; Jurczak, M.; Urbanczyk-Lipkowska, Z.;
Chmielewski, M. Tetrahedron: Asymmetry 2006, 17, 68–78; (b) Stecko, S.;
Pas´niczek, K.; Jurczak, M.; Urban´ czyk-Lipkowska, Z.; Chmielewski, M.
Tetrahedron: Asymmetry 2007, 18, 1085–1093.
The quantum-mechanic calculations were carried out using
GAUSSIAN 03 suite.26 The geometry optimization of cycloadducts
was carried out using DFT methods17 at the B3LYP/6-31+G(d) level
of theory.28 The stationary points were characterized by the fre-
quency calculations in order to verify that the obtained minima
have zero imaginary frequency. The optimizations were carried
out using Berny analytical gradient optimization method.29
The UV and CD spectra were simulated using time-dependent
DFT (TD-DFT)24 methods at the B3LYP/6-311+G(d,p) theory level.
For the treatment of solvent effect, the polarized continuum model
(PCM)25 method was used with acetonitrile as the solvent.
The conformational search was carried out using HYPERCHEM v.7.5
suite program. For all molecular modelling calculations the MM+
force field method was used.22
15. (a) Stecko, S.; Pas´niczek, K.; Michel, C.; Milet, A.; Perez, S.; Chmielewski, M.
´
Tetrahedron: Asymmetry 2008, 19, 1660–1669; (b) Stecko, S.; Pasniczek, K.;
Michel, C.; Milet, A.; Perez, S.; Chmielewski, M. Tetrahedron: Asymmetry 2008,
19, 2140–2148.
16. Legrand, M.; Bucourt, R. Bull. Soc. Chim. Fr. 1967, 2241–2242.
17. Dreizler, R.; Gross, E. Density Functional Theory; Plenum Press: New York, 1995.
18. Crystallographic data for the structures 9, 10, 16–17 was reported before (see
Ref. 14a,b) and are available from the Cambridge Crystallographic Data Center,
Cambridge, UK, as a supplementary publications: 9 (CCDC No. 634391), 10
(CCDC No. 282893), 16 (CCDC No. 282892) and 17 (CCDC No. 282896). The
crystallographic data for compound 15 were deposited in CCDC and are
available as supplementary data (CCDC No. 722668).
19. Crystallographic data for the structures 22 and 25 was reported earlier (see Ref.
14a,b) and is available from the Cambridge Crystallographic Data Center,
Cambridge, UK, as a Supplementary publications: 22 (CCDC No. 634282), 25
(CCDC No. 282895).

1790
S. Stecko et al. / Tetrahedron: Asymmetry 20 (2009) 1778–1790
20. (a) Forzatto, C.; Nitti, P.; Pitacco, G.. Tetrahedron: Asymmetry 1997, 8, 4101–
4110; (b) Forzatto, C.; Nitti, P.; Pitacco, G.; Valentin, E. Tetrahedron: Asymmetry
1999, 10, 1243–1254; (c) Castronovo, F.; Clericuzio, M.; Toma, L.; Vidari, G.
Tetrahedron 2001, 57, 2791–2798.
21. Snatzke, G.; Snatzke, R. In Analytiker-Taschenbuch Band 1; Kienitz, H., Bock, R.,
Fresenius, W., Huber, W., Tölg, G., Eds.; Springer: Berlin, Heildelberg, New
York,, 1980; pp 218–244.
22. (a) Allinger, N. L. J. Am. Chem. Soc. 1977, 99, 8127–8135; (b) N.L. Allinger, Y.H.
Yuh, Quantum Chemistry Program Exchange, Bloomington, Indiana, Program
No. 395, in: U. Burkert, N.L. Allinger (Eds.), Molecular Mechanics, ACS
Monograph 177, American Chemical Society, Washington, D.C., 1982.; (c) Lii,
J.; Gallion, S.; Bender, C.; Wikstrom, H.; Allinger, N. L.; Flurchick, K. M.; Teeter,
M. M. J. Comput. Chem. 1989, 10, 503–512.
23. (a) Cid, P.; de March, P.; Figueredo, M.; Font, J.; Milan, S. Tetrahedron Lett. 1992,
33, 667–670; (b) Cid, P.; de March, P.; Figueredo, M.; Font, J.; Milan, S.; Soria, A.;
Virgilli, A. Tetrahedron 1993, 49, 3857–3870; (c) Alonso-Perarnau, D.; de March,
P.; Figueredo, M.; Font, J.; Soria, A. Tetrahedron 1993, 49, 4267–4274.
24. Autschbach, J.; Ziegler, T. J. Chem. Phys. 2002, 116, 891–896.
Millam, J. M.; Iyengar, S. S.; Tomasi, J.; Barone, V.; Mennucci, B.; Cossi, M.;
Scalmani, G.; Rega, N.; Petersson, G. A.; Nakatsuji, H.; Hada, M.; Ehara, M.;
Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda, Y.;
Kitao, O.; Nakai, H.; Klene, M.; Li, X.; Knox, J. E.; Hratchian, H. P.; Cross, J. B.;
Bakken, V.; Adamo, C.; Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev,
O.; Austin, A. J.; Cammi, R.; Pomelli, C.; Ochterski, J. W.; Ayala, P. Y.;
Morokuma, K.; Voth, G. A.; Salvador, P.; Dannenberg, J. J.; Zakrzewski, V. G.;
Dapprich, S.; Daniels, A. D.; Strain, M. C.; Farkas, O.; Malick, D. K.; Rabuck, A.
D.; Raghavachari, K.; Foresman, J. B.; Ortiz, J. V.; Cui, Q.; Baboul, A. G.;
Clifford, S.; Cioslowski, J.; Stefanov, B. B.; Liu, G.; Liashenko, A.; Piskorz, P.;
Komaromi, I.; Martin, R. L.; Fox, D. J. ; Keith, T.; Al-Laham, M. A.; Peng, C. Y.;
Nanayakkara, A.; Challacombe, M.; Gill, P. M. W.; Johnson, B.; Chen, W.;
Wong, M. W.; Gonzalez, C.; Pople, J. A. GAUSSIAN 03, Revision B.04; Gaussian,
Inc.: Pittsburgh PA, 2003.
27. Ashoorzadeh, A.; Caprio, V. Synlett 2005, 346–348.
28. (a) Becke, A. D. J. Chem. Phys. 1993, 98, 5648–5652; (b) Becke, A. D. Phys. Rev. A
1988, 38, 3098–3100; (c) Lee, C.; Yang, W.; Parr, R. G. Phys. Rev. B 1988, 37,
785–789.
25. (a) Miertus, S.; Scrocco, E.; Tomasi, J. J. Chem. Phys. 1981, 55, 117–129; (b)
Mennucci, B.; Tomasi, J. J. Chem. Phys. 1997, 106, 5151–5158.
26. Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.;
Cheeseman, J. R.; Montgomery, Jr., J. A.; Vreven, T.; Kudin, K. N.; Burant, J. C.;
29. Schlegel, H. B. Geometry Optimization on Potential Energy Surface. In Modern
Electronic Structure Theory;; Yarkony, D. R., Ed.; World Scientific Publishing:
Singapore, 1994.