The determination of sulfoxide configuration in five-membered rings using NMR spectroscopy and DFT calculations

Article abstract of DOI:10.1016/j.tetasy.2011.10.010

Cyclic five-membered ring sulfoxides and sulfones were prepared by a stepwise in situ oxidation of the corresponding sulfides with meta-chloroperbenzoic acid in an NMR tube. The oxidation was followed by NMR and both ¹H and ¹³C NMR data were collected. The geometries of all of the compounds were optimized using the DFT B3LYP/6-31G method and the ¹³C and ¹H chemical shifts were calculated for geometry-optimized structures with the DFT B3LYP/6-31++G method. The calculated ¹³C chemical shifts induced by oxidation (Δδ values) were in very good agreement with the experimental data and could be used to determine the oxidation state of the sulfur atom (-S-, -SO-, -SO₂-). The characteristic differences of the induced oxidation chemical shifts of the carbon atoms in the α-position and β-position to sulfur were successfully used to distinguish between the diastereoisomeric sulfoxides and allowed configuration determination.

Full text of DOI:10.1016/j.tetasy.2011.10.010

Tetrahedron: Asymmetry 22 (2011) 1797–1808
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
The determination of sulfoxide configuration in five-membered rings using
NMR spectroscopy and DFT calculations
⇑
M. Dra cˇ ínsk y´ , R. Pohl, L. Slav eˇ tínská, H. H rˇ ebabeck y´ , M. Bud eˇ šínsk y´
Institute of Organic Chemistry and Biochemistry, v.v.i., Academy of Sciences of the Czech Republic, Flemingovo nám. 2, CZ-166 10 Prague 6, Czech Republic
a r t i c l e i n f o
a b s t r a c t
Article history:
Cyclic five-membered ring sulfoxides and sulfones were prepared by a stepwise in situ oxidation of the
Received 3 October 2011
Accepted 20 October 2011
Available online 17 November 2011
corresponding sulfides with meta-chloroperbenzoic acid in an NMR tube. The oxidation was followed by
1
13
NMR and both H and C NMR data were collected. The geometries of all of the compounds were opti-
⁄⁄
13
1
mized using the DFT B3LYP/6-31G method and the C and H chemical shifts were calculated for geom-
⁄
⁄
13
etry-optimized structures with the DFT B3LYP/6-31++G method. The calculated C chemical shifts
induced by oxidation ( d values) were in very good agreement with the experimental data and could
D
be used to determine the oxidation state of the sulfur atom (–S–, –SO–, –SO
ences of the induced oxidation chemical shifts of the carbon atoms in the
2
–). The characteristic differ-
-position and b-position to
a
sulfur were successfully used to distinguish between the diastereoisomeric sulfoxides and allowed con-
figuration determination.
Ó 2011 Elsevier Ltd. All rights reserved.
1
. Introduction
The interest in determining the absolute stereochemistry of chi-
configuration of these functional groups can be elucidated by
NMR spectroscopy only indirectly [e.g., by aromatic solvent-in-
duced shift (ASIS) or by interaction with shift reagents].
ral compounds stems from the widely recognized fact that stereo-
chemistry often determines important chemical and physical
properties, biological activities and thus the pharmaceutical use
Such types of compounds are chiral sulfoxides. In the NMR
spectra, it is impossible to observe the coupling constants with
oxygen, which would be necessary to deduce the torsion angles
O–S–C–H or O–S–C–C and thus determine the configuration of
the sulfoxide group. The NOE contacts of the sulfoxide oxygen
are also inaccessible. There have been various attempts to deter-
mine the configuration of the sulfoxide group by NMR spectros-
copy. Some relations between the chemical shifts of the
neighboring hydrogens and the configuration of the sulfoxide
1
,2
of these compounds.
There are several instrumental methods for the determination of
the absolute configuration. The most widely used are X-ray crystal-
lography, chiroptical methods (CD, ORD), and NMR spectroscopy.
The use of X-ray diffraction is limited to compounds for which
well-defined monocrystals can be prepared. The chiroptical meth-
ods, whose instrumentation is not as common as that of the NMR
spectrometer or X-ray diffractometer, have some limitations con-
cerning the presence of certain chromophores and/or the availabil-
ity of structurally similar model compounds with known chirality.
Therefore, the method of choice is often NMR spectroscopy.
3
–5
group were observed,
but they are not generally applicable.
These chemical-shift relations can be only used for the particular
type of compounds where they were observed. An acetylene-like
5
–10
anisotropy of the sulfoxide group was proposed
(the protons
situated near a plane perpendicular to the S?O bond and passing
through its center are deshielded while protons situated near the
sulfur atom and more or less in line with the direction of the
S?O bond show a shielding effect, as compared with the same pro-
tons in the parent sulfide). However, this concept of acetylene-like
anisotropy was criticized as being oversimplified and inadvis-
The NMR parameters that are most often used to determine the
configuration at the asymmetric center are the NOE contacts be-
tween spatially close hydrogen atoms or certain spin–spin coupling
constants, which are known to be related to the stereochemistry
(
the most frequently applied are the Karplus-type relations of
1
1
vicinal coupling constants to the dihedral angle of coupled nuclei).
For some types of chiral functional groups, these NMR parameters
able. Other procedures for determining a sulfoxide-group config-
1
1–13
13–15
uration have used solvent-induced shifts,
and chiral NMR reagents.
shift reagents
1
6–20
(
NOE and proper coupling constants) are unavailable and the
Quantum chemical calculations can be used to estimate the en-
ergy-optimized geometry of medium-sized molecules as well as to
predict theoretically the NMR parameters (shielding constants and
⇑
Corresponding author.
E-mail address: budesinsky@uochb.cas.cz (M. Bud eˇ šínsk y´ ).
0
957-4166/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2011.10.010

1
798
M. Dra cˇ ínsk y´ et al. / Tetrahedron: Asymmetry 22 (2011) 1797–1808
Table 1
The experimental and calculated 13C chemical-shift changes induced by the oxidation of sulfides 1a and 2a to the corresponding sulfoxides and sulfones
Compd
Solv.
C-1
C-2
À7.73
C-3
C-4
C-5
C-6
1b–1a
1c–1a
1d–1a
2b–2a
SO (exo)
Exp.
Calcd
Exp.
Calcd
Exp.
Calcd
Calcd
Exp.
Calcd
Exp.
Calcd
Calcd
Exp.
Calcd
Exp.
Calcd
Calcd
Exp.
D
D
D
D
D
D
2
O
2
O
2
O
2
O
2
O
2
O
18.36
17.23
10.69
11.26
5.19
À3.59
À0.97
À0.18
À0.08
À1.15
À0.80
0.43
À0.88
À0.26
À0.88
À0.73
À1.29
À2.61
À1.77
À1.02
À1.73
À0.93
À1.02
À1.08
À3.80
À2.74
0.89
À0.32
À1.77
1.21
À0.70
À3.06
À3.78
À0.06
À0.27
0.00
24.57
23.85
19.76
21.13
15.70
16.21
26.76
27.96
27.39
27.72
27.87
18.24
18.70
17.60
18.52
18.06
17.17
17.83
18.62
À6.62
À11.06
À13.23
À7.20
À7.17
À4.07
À5.03
À3.66
À5.85
À3.98
À4.82
À4.34
À4.64
À6.19
À4.80
À5.62
À5.76
À5.99
SO (endo)
0.47
SO
2
À1.92
À0.78
À0.79
À0.90
À1.10
À1.62
À1.30
0.66
6.47
SO (exo)
Vacuum
CDCl
CDCl
19.08
20.37
19.14
19.38
19.53
8.94
9.31
7.90
8.71
8.09
3
3
D
D
2
O
O
1.26
0.17
2
2
2
c–2a
d–2a
SO (endo)
Vacuum
CDCl
CDCl
À2.75
À2.89
À2.75
À1.54
À2.71
À4.22
À2.73
À3.78
3
À0.07
3
0.55
D
D
2
O
O
À0.18
0.52
À1.04
À1.77
À1.35
2
SO
2
Vacuum
6.12
4.99
6.11
D
D
2
O
O
Calcd
2
Table 2
The experimental and calculated 1H chemical-shift changes induced by the oxidation of sulfides 1a and 2a to the corresponding sulfoxides and sulfones
Compd
Solv.
H-1
H-2
0.09
H-3
H-4
H-5
0.23
0.35
0.40
H-6en
H-6ex
1b–1a
1c–1a
1d–1a
S@O (exo)
Exp.
Calcd
Exp.
Calcd
Exp.
Calcd
Exp.
Calcd
Exp.
Calcd
Exp.
CDCl
CDCl
3
À0.35
À0.35
À0.10
À0.31
0.02
À0.01
0.02
0.16
0.13
0.17
0.27
0.09
0.07
0.17
0.13
0.22
0.19
À0.28
À0.13
À0.02
À0.08
0.19
0.21
0.08
0.11
0.90
0.82
1.05
0.86
0.05
À0.16
À0.20
À0.63
0.38
À0.56
À0.65
À0.29
À0.65
0.38
3
À0.41
0.28
À0.34
0.55
0.55
0.54
0.96
0.34
0.41
0.44
0.49
D
D
2
O
O
2
0.22
S@O (endo)
CDCl
CDCl
3
À0.23
À0.27
À0.10
0.02
3
À0.17
0.04
0.40
D
D
2
O
O
0.20
2
À0.09
À0.84
À0.98
À0.50
À0.95
À0.14
SO
2
CDCl
CDCl
3
À0.05
À0.01
0.11
3
0.08
0.07
À0.06
À0.08
0.45
À0.08
D
D
2
O
O
0.14
0.11
0.16
À0.01
0.42
Calcd
2
À0.06
2b–2a
2c–2a
2d–2a
S@O (exo)
Calcd
Exp.
Calcd
Exp.
Calcd
Calcd
Exp.
Calcd
Exp.
Vacuum
À0.65
À0.29
À0.60
À0.13
À0.55
À0.31
0.09
À0.06
0.05
À0.05
0.21
0.04
0.56
0.55
0.55
0.48
0.53
0.26
0.35
0.33
0.10
À0.05
0.18
0.02
0.21
0.29
0.12
0.22
0.09
0.20
0.27
0.25
0.34
0.13
0.02
0.09
0.03
0.09
0.17
0.25
0.23
0.29
0.25
0.08
0.24
0.20
0.28
0.14
0.24
0.23
0.23
À0.32
À0.25
À0.30
À0.11
À0.27
À0.07
0.17
0.77
0.95
0.91
1.03
0.98
À0.64
À0.56
À0.62
À0.40
À0.04
0.13
0.37
0.31
0.61
0.44
CDCl
CDCl
3
3
D
D
2
O
O
2
S@O (endo)
Vacuum
0.04
CDCl
CDCl
3
À0.10
À0.04
À0.04
À0.11
0.08
3
À0.17
D
D
2
O
O
0.22
Calcd
Calcd
Exp.
2
À0.07
À1.10
À0.53
À0.77
SO
2
Vacuum
À0.01
D
D
2
O
O
0.44
0.42
0.39
Calcd
2
0.06
0.24
coupling constants). High-level ab initio calculations with gauge-
independent atomic orbitals (GIAOs) have been shown to provide
Recently, we have demonstrated that a combination of the NMR
data with the ab initio calculations can be used to distinguish be-
tween the sulfoxides with a different configuration of the S@O
group in the cyclic sulfoxides forming six-membered rings.30
Herein we present a similar study of cyclic sulfoxides with
five-membered rings.
21,22
good agreement with experimental NMR data.
The combina-
tion of theoretical calculations and experimental NMR spectra
has already been used to solve various stereochemical prob-
2
3–28
lems.
In a previous paper,29 various methods of quantum chemical
1
13
calculations were tested to reproduce the observed H and
C
2
2
. Results and discussion
chemical shifts of the starting model sulfides and their oxidation
products (sulfoxides and sulfones). It has been shown that the
determination of the energy-minimized conformation is a very
important condition for obtaining realistic data in the subsequent
calculation of the NMR chemical shifts. The correlation between
the calculated and observed chemical shifts was good for carbon
atoms but somewhat less satisfactory for hydrogen atoms. The best
agreement between the calculated and experimental data was
found for chemical shifts induced by the oxidation of sulfides to
.1. Thiolevoglucosane and thiolevogalactosane
The first group of compounds studied were sulfoxides derived
from 1,6-anhydro-b-
the preparation and NMR data of 1,6-anhydro-1-thio-b-
anose (thiolevoglucosan) 1, 1,6-anhydro-1-thio-b- -galactopyra-
D-hexopyranoses. Recently, we have described
D
-glucopyr-
D
3
1
nose 2, and the corresponding sulfoxides and sulfones. The X-ray
structures of sulfoxides 1b and 1c and sulfone 1d have also been de-
3
1,32
sulfoxides and sulfones (the
Dd values).
scribed.
From the vicinal couplings J(H2,H3) and J(H3,H4), it was

M. Dra cˇ ínsk y´ et al. / Tetrahedron: Asymmetry 22 (2011) 1797–1808
1799
3
2
1
0
0
0
0
intercept = -0.0789
slope = 1.0077
corr.coef. = 0.9902
1.0
intercept = 0.1012
slope = 0.7498
corr. coeff. = 0.7456
0
0
.5
.0
2
b (CDCl3)
2b (D O)
2
2
2
2
2
2
1
1
b (CDCl3)
c (CDCl3)
2c (CDCl )
3
2
2
1
c (D O)
d (D O)
b (CDCl3)
2
2
b (D O)
2
c (D O)
2
-
-
0.5
1.0
1b (D O)
1c (CDCl3)
1c (D O)
1d (CDCl3)
1d (D O)
Plot 1 Regr
2
d (D O)
2
b (D O)
2
2
c (D O)
2
-
10
1d (D O)
Plot 1 Regr
2
2
-
10
0
10
20
30
-1.0
-0.5
0.0
0.5
1.0
calculated 13C chem. shifts induced by oxidation [ppm]
calculated 1H chem. shifts induced by oxidation [ppm]
Figure 1. The correlation of the calculated and observed 13C (left) and 1H (right) chemical shifts induced by the oxidation of compounds 1a and 2a to sulfoxides 1b, 1c, 2b, 2c,
and to sulfones 1d and 2d.
Figure 2. The observed (black) and calculated (red) induced 13C oxidation shifts (
D
d-values) illustrated on the example of thio-galacto derivatives 2. The hydrogen atoms
were omitted for the sake of clarity.
established that the chair-boat conformation equilibrium of the
pyranose ring depends on the solvent. A remarkable decrease of
optimized geometries of both forms and the final theoretical chem-
ical shifts were obtained by weighing the calculated shifts with the
chair/boat populations determined from experimental NMR data.
The values of J(H2,H3) for compounds 2a–2d showed a very
small population of the boat form and were slightly influenced
by solvent. Therefore, we have limited our calculations here to
the chair form and performed geometry optimization as well as
the following chemical shift calculation first in a vacuum and then
the chair conformation 1
C
was observed when going from CDCl
4
3
to D
2
O for sulfide 1a (95?60%) and endo-sulfoxide 1c (94?11%)
while smaller changes were shown by exo-sulfoxide 1b (85?88%)
and sulfone 1d (72?63%). Since the observed averaged chemical
shifts are strongly influenced by the geometry and population of
both of the conformers present, we started our calculation with
thegeometryoptimizationofthechairandboatforms ofcompounds
3 2
also in CDCl and D O (using the PCM model) to test the possibility
1
a–1d. Subsequently, the chemical shifts were calculated using
of reproducing the solvent effect.
X
X
X
X
OH
OH
O
O
H
H
H
OH
OH
a: X = S
O
H
O
H
H
b: X = SO (S) (exo-)
H
H
OH
c: X = SO (R) (endo-)
d: X = SO2
H
OH
HO
OH
OH
OH
OH
OH
H
2
(Gal)
chair 1C4
1
(Glc)
boat E3,O
1 (Glc)

1
800
M. Dra cˇ ínsk y´ et al. / Tetrahedron: Asymmetry 22 (2011) 1797–1808
exo-series
endo-series
X
3
a: X
8
=
S
X
X
b: X = SO [exo]
c: X = SO [endo]
d: X = SO2
R1
R1
X
R2
R2
1
2
9 : R1 = R = H
2
4
5
6
7
: R = R = H
1
2
10 : R1 , R = O
2
: R , R = O
1
2
1
2
: R = OH; R = H
: R = H; R = OH
11 : R = OH; R = H
1
2
12 :R1 = H; R2 = OH
1
0syn
10syn
1
0anti
10anti
8ex
5
en
7
7
8
ex
3
en
6
5
ex
1
9ex
1
(SO-endo)
9ex
2
O
X
6
5ex
O(SO-exo)
8en
8en
5en
3ex
O
X
9
en
2
9en
(
SO-exo)
3en
3ex
O
(
SO-endo)
Figure 3. The norbornane derivatives studied with annealed tetrahydrothiophene rings 3–12 and numbering of the atoms used in this paper.
Table 3
The experimental 13C chemical shifts of norbornane derivatives 3–12 in CDCl
3
Compd
X
C-1
C-2
C-3
C-5
C-6
C-7
C-8
138.13
137.83
136.80
136.10
C-9
C-10
3
a
S
45.97
45.12
45.20
45.51
52.92
47.78
38.09
38.00
36.36
55.28
55.02
54.06
36.36
55.28
55.02
54.06
52.92
47.78
38.09
38.00
45.97
45.12
45.20
45.51
138.13
137.83
136.80
136.10
42.50
41.96
41.80
41.41
3
b
SO (exo)
SO (endo)
SO
3
3
c
d
2
4
4
4
4
a
b
c
S
40.89
40.17
40.12
40.68
53.45
48.16
42.16
41.93
38.75
57.15
56.14
58.13
38.75
57.15
56.14
58.13
53.45
48.16
42.16
41.93
40.89
40.17
40.12
40.68
28.05
27.93
27.87
28.36
28.05
27.93
27.87
28.36
32.23
31.82
31.90
32.32
SO (exo)
SO (endo)
SO
d
2
5
5
5
5
a
b
c
S
39.98
39.13
39.61
39.62
52.31
47.42
41.89
40.34
38.42
57.10
56.53
53.01
37.52
55.98
55.36
52.10
47.06
42.78
37.49
36.24
54.52
52.94
53.22
53.17
215.88
216.03
214.44
212.87
43.53
43.30
43.87
44.54
31.92
31.38
31.67
31.70
SO (exo)
SO (endo)
SO
d
2
6
6
6
6
a
b
c
S
39.92
39.14
39.23
39.61
52.73
47.51
41.17
40.82
38.33
56.51
55.59
52.86
38.03
56.78
55.90
52.74
48.79
43.87
37.54
37.07
49.46
48.41
48.33
48.71
73.58
73.25
72.94
72.92
41.00
40.70
40.71
41.14
28.89
28.50
28.50
28.93
SO (exo)
SO (endo)
SO
d
2
7
7
7
7
a
b
c
S
41.68
40.83
40.83
41.26
53.30
47.93
42.24
41.73
38.96
57.30
56.41
53.25
38.39
56.83
55.82
52.72
43.17
38.80
32.79
32.64
47.27
46.44
46.46
46.88
71.43
70.85
70.65
71.18
38.58
38.12
37.90
38.26
31.71
31.09
31.33
31.62
SO (exo)
SO (endo)
SO
d
2
8
8
8
8
a
b
c
S
45.62
45.20
46.15
45.05
54.11
48.08
39.35
39.42
34.54
54.66
54.43
52.95
34.54
54.66
54.43
52.95
54.11
48.08
39.35
39.42
45.62
45.20
46.15
45.05
137.09
136.60
137.25
136.75
137.09
136.60
137.25
136.75
55.15
54.56
52.52
49.44
SO (exo)
SO (endo)
SO
d
2
9
9
9
9
a
b
c
S
41.69
39.70
39.90
39.09
49.70
45.53
39.51
38.14
33.17
52.46
51.86
49.76
33.17
52.46
51.86
49.76
49.70
45.53
39.51
38.14
41.69
39.70
39.90
39.09
22.38
22.70
22.13
22.10
22.38
22.70
22.13
22.10
43.53
43.60
42.41
40.23
SO (exo)
SO (endo)
SO
d
2
10a
10b
10c
10d
S
39.74
37.50
38.04
37.86
46.99
45.13
38.92
37.11
33.50
51.60
52.16
49.83
33.86
52.70
53.28
51.09
50.54
45.88
39.15
37.20
56.26
53.69
54.55
53.33
215.72
215.80
ꢀ215.0
214.20
40.38
43.93
40.60
40.23
40.23
40.75
41.12
38.54
SO (exo)
SO (endo)
SO
2
1
1a
S
41.09
47.60
33.65
32.76
48.42
49.94
69.38
39.48
35.94

M. Dra cˇ ínsk y´ et al. / Tetrahedron: Asymmetry 22 (2011) 1797–1808
1801
Table 3 (continued)
Compd
X
C-1
C-2
C-3
C-5
C-6
C-7
C-8
69.10
69.00
68.36
C-9
39.73
39.04
36.66
C-10
11b
11c
11d
SO (exo)
SO (endo)
SO
39.13
40.27
38.59
44.12
39.59
37.08
52.96
51.49
49.90
51.63
52.46
48.76
43.34
39.52
36.31
47.24
47.33
46.46
35.83
35.54
35.00
2
12a
12b
12c
12d
S
41.91
39.87
40.82
39.99
50.76
46.45
51.60
38.62
33.84
51.24
53.56
49.48
34.38
52.14
52.40
50.43
48.80
45.32
48.02
37.30
46.43
44.04
46.48
43.50
74.60
75.12
73.90
74.74
31.50
31.41
30.47
31.36
40.93
43.91
42.11
39.14
SO (exo)
SO (endo)
SO
2
Table 4
The experimental 1H chemical shifts of norbornane derivatives 3–12 in CDCl
3
Compd
X
1
2
3en
3ex
5ex
5en
6
7
8en
8ex
9en
9ex
10anti
10syn
3
3
3
3
a
b
c
S
2.54
2.70
2.78
2.76
2.52
3.04
1.93
2.32
2.46
2.22
2.45
2.56
2.86
3.30
3.68
3.32
2.46
2.22
2.45
2.56
2.86
3.30
3.68
3.32
2.52
3.04
1.93
2.32
2.54
2.70
2.78
2.76
6.15
6.22
6.14
6.15
6.15
6.22
6.14
6.15
1.53
1.67
1.56
1.56
1.69
1.39
1.75
1.46
SO (exo)
SO (endo)
SO
d
2
4
4
4
4
a
b
c
S
2.06
2.19
2.18
2.14
2.21
2.82
1.98
2.45
2.37
2.09
2.46
2.57
3.01
3.44
3.62
3.18
2.37
2.09
2.46
2.57
3.01
3.44
3.62
3.18
2.21
2.82
1.98
2.45
2.06
2.19
2.18
2.14
1.11
1.26
1.13
1.30
1.50
1.61
1.60
1.64
1.11
1.26
1.13
1.30
1.50
1.61
1.60
1.64
0.98
1.15
1.24
1.31
1.32
1.15
1.73
1.50
SO (exo)
SO (endo)
SO
d
2
5
5
5
5
a
b
c
S
2.53
2.66
2.65
2.64
2.58
3.17
2.35
2.72
2.54
2.26
2.61
2.71
3.12
3.51
3.70
3.37
2.53
2.23
2.57
2.68
3.08
3.46
3.65
3.33
2.59
3.20
2.41
2.76
2.48
2.57
2.57
2.57
—
—
—
—
—
—
—
—
1.87
2.20
1.88
2.03
2.10
2.22
2.22
2.28
1.63
1.79
1.82
1.90
1.84
1.62
2.27
1.86
SO (exo)
SO (endo)
SO
d
2
6
6
6
6
a
b
c
S
2.12
2.24
2.24
2.22
2.15
2.74
1.88
2.32
2.38
2.15
2.46
2.56
2.98
3.41
3.62
3.18
2.42
2.10
2.43
2.60
3.02
3.38
3.60
3.23
2.14
2.74
1.88
2.24
2.00
2.14
2.14
2.11
3.79
3.93
3.78
3.90
—
—
—
—
1.67
1.80
1.64
1.80
1.32
1.44
1.44
1.48
1.46
1.64
1.70
1.75
1.33
1.16
1.16
1.44
SO (exo)
SO (endo)
SO
d
2
7
7
7
7
a
b
c
S
2.04
2.14
2.14
2.11
2.36
2.95
2.13
2.59
2.38
2.11
2.48
2.59
3.06
3.45
3.64
3.23
2.44
2.16
2.51
2.63
3.06
3.47
3.64
3.25
2.95
3.57
2.81
3.26
2.15
2.28
2.25
2.22
—
—
—
—
4.23
4.30
4.32
4.34
0.85
1.00
0.85
1.03
2.02
2.09
2.07
2.11
1.12
1.18
1.35
1.42
1.39
1.27
1.79
1.55
SO (exo)
SO (endo)
SO
d
2
8
8
8
8
a
b
c
S
2.77
2.94
3.02
3.04
3.22
3.58
2.57
2.93
2.70
2.11
2.19
2.28
2.40
3.10
3.55
3.16
2.70
2.11
2.19
2.28
2.40
3.10
3.55
3.16
3.22
3.58
2.57
2.93
2.77
2.94
3.02
3.04
6.20
6.25
6.34
6.26
6.20
6.25
6.34
6.26
1.80
1.86
1.76
1.75
1.74
1.77
1.48
1.48
SO (exo)
SO (endo)
SO
d
2
9
9
9
9
a
b
c
S
2.16
2.27
2.30
2.37
2.74
3.25
2.41
2.72
2.81
2.88
2.72
2.85
2.69
2.96
3.37
3.01
2.81
2.88
2.72
2.85
2.69
2.96
3.37
3.01
2.74
3.25
2.41
2.72
2.16
2.27
2.30
2.37
1.74
1.49
1.66
1.49
1.32
1.33
1.50
1.41
1.74
1.49
1.66
1.49
1.32
1.33
1.50
1.41
1.45
1.64
1.65
1.61
1.56
1.78
1.59
1.61
SO (exo)
SO (endo)
SO
d
2
1
1
1
1
0a
0b
0c
0d
S
2.68
2.78
2.78
2.87
3.03
3.71
2.76
3.06
2.92
2.46
2.61
2.76
2.67
3.16
3.50
3.20
2.86
2.25
2.38
2.53
2.69
3.13
3.48
3.17
3.08
3.72
2.82
3.07
2.56
2.74
2.74
2.82
—
—
—
—
—
—
—
—
2.59
2.20
2.44
2.22
1.97
2.24
1.98
2.14
1.79
2.24
2.06
2.06
1.76
2.10
1.92
1.92
SO (exo)
SO (endo)
SO
2
1
1
1
1
1a
1b
1c
1d
S
2.24
2.32
2.49
2.42
2.68
3.19
2.36
2.70
2.84
2.78
2.65
2.74
2.64
2.88
3.28
3.04
2.84
2.86
2.58
2.82
2.77
2.86
3.30
3.02
2.82
3.27
2.56
2.78
2.22
2.27
2.30
2.38
4.30
3.93
4.24
4.02
—
—
—
—
1.79
1.98
2.02
1.99
1.42
1.66
1.49
1.47
2.41
1.89
2.26
1.97
1.21
1.37
1.40
1.40
SO (exo)
SO (endo)
SO
2
1
1
1
1
2a
2b
2c
2d
S
2.25
2.32
2.32
2.42
3.04
3.50
3.25
2.88
3.22
2.88
3.18
3.05
2.95
3.08
3.18
3.10
3.01
3.98
3.96
4.35
2.78
3.03
3.04
3.03
2.92
3.43
3.17
2.81
2.30
2.42
2.49
2.51
—
—
—
—
4.16
4.51
4.38
4.47
1.54
1.27
1.79
1.35
2.02
2.03
2.10
2.02
1.50
1.82
1.69
1.61
1.43
1.74
1.61
1.50
SO (exo)
SO (endo)
SO
2
X
H
H
H
-
92º
H
H
H
X
H
-
26º
-151º
32º
9
4º
1
54º
H
H
X
2
8º
H
H
-29º
H
X
EX-exo
EX-endo
EX-exo
EX-endo
3a - 7d
8a - 12d
Figure 4. Two possible conformations EX-endo and EX-exo of the tetrahydrothiophene ring in exo-derivatives 3a–7d and endo-derivatives 8a–12d.

1
802
M. Dra cˇ ínsk y´ et al. / Tetrahedron: Asymmetry 22 (2011) 1797–1808
-
-
0.41
0.58
-0.33
-0.13
+0.09
+0.16
-
0.72
-0.77
-0.21
-0.53
-
1.84
+0.24
-
0.12
-0.18
+0.31
+0.57
+
0.09
+0.11
O
O
S
S
S
+
+
18.40
18.18
+17.39
+14.38
+14.98
-
-
5.29
5.39
-11.29 +18.17
-11.53
-
-
11.52
10.90
O
O
4
b (SO-exo)
4c (SO-endo)
4d (SO2)
+
0.07
-3.30
-5.39
-3.30
-5.39
+
0.03
-
1.99
-1.79
1.17
-2.60
-0.44
+
0.32
-0.17
-0.15
+
-0.28
+
0.56
+0.19
+0.47
-
-
4.17
5.19
O
-10.19
-12.72
-11.56
-12.91
O
S
S
S
+
+
19.29
19.59
+18.69
+21.10
+16.59
+18.67
d (SO2)
O
O
9c (SO-endo)
9
9
b (SO-exo)
Figure 5. The observed (black) and calculated (red) oxidation-induced chemical shifts of carbon atoms in sulfoxides 4b, 4c, 9b, 9c, and in the corresponding sulfones 4d, 9d.
The hydrogen atoms are omitted for the sake of clarity.
Table 5
The experimental and calculated 13C chemical-shift changes induced by the oxidation of norbornane sulfides 3a–12a to sulfoxides 3b–12b, 3c–12c, and sulfones 3d–12d
Comp.
X
C-1
C-2
C-3
C-5
C-6
C-7
C-8
C-9
C-10
3b–3a
3c–3a
3d–3a
SO (exo)
Exp.
Calcd
Exp.
Calcd
Exp.
Calcd
À0.85
À1.23
À0.77
0.25
À5.14
18.92
18.77
18.66
19.82
17.70
18.54
18.92
18.77
18.66
19.82
17.70
18.54
À5.14
À0.85
À1.23
À0.77
0.25
À0.30
À0.27
À1.33
À0.86
À2.03
À1.83
À0.30
À0.27
À1.33
À0.86
À2.03
À1.83
À0.54
À0.89
À0.70
À0.57
À1.09
À1.11
À5.35
À14.83
À15.27
À14.92
À14.33
À5.35
À14.83
À15.27
À14.92
À14.33
SO (endo)
SO
2
À0.46
À0.46
À0.34
À0.34
4b–4a
4c–4a
4d–4a
SO (exo)
Exp.
Calcd
Exp.
Calcd
Exp.
Calcd
À0.72
À1.84
À0.77
0.24
À5.29
À5.39
18.40
18.18
17.39
18.17
14.38
14.98
18.40
18.18
17.39
18.17
14.38
14.98
À5.29
À5.39
À0.72
À1.84
À0.77
0.24
À0.12
À0.12
À0.41
À0.58
À0.33
À0.13
0.09
0.09
0.09
SO (endo)
À11.29
À11.53
À11.52
À10.90
À11.29
À11.53
À11.52
À10.90
À0.18
0.11
0.31
À0.18
0.11
0.31
SO
2
À0.21
À0.21
À0.53
À0.53
0.57
0.57
0.16
5b–5a
5c–5a
5d–5a
SO (exo)
Exp.
Calcd
Exp.
Calcd
Exp.
Calcd
À0.85
À0.57
À0.37
À0.43
À0.36
À0.39
À4.89
À5.35
18.68
18.39
18.11
18.34
14.59
15.34
18.46
17.97
17.84
17.89
14.58
15.01
À4.28
À4.62
À1.58
À1.46
À1.30
À1.10
À1.35
À1.37
0.15
À0.76
À1.44
À0.90
À3.01
À1.92
À0.23
À0.24
0.34
0.61
1.01
À0.54
À0.37
À0.25
À0.30
À0.22
À0.64
SO (endo)
À10.42
À11.74
À11.97
À11.75
À9.57
À10.65
À10.82
À10.46
SO
2
1.09
6b–6a
6c–6a
6d–6a
SO (exo)
Exp.
Calcd
Exp.
Calcd
Exp.
Calcd
À0.78
À0.68
À0.69
À0.25
À0.31
À0.56
À5.22
À5.54
18.18
18.20
17.26
18.21
14.53
15.18
18.75
18.24
17.87
18.04
14.71
15.28
À4.92
À5.02
À1.05
À2.22
À1.13
À0.47
À0.75
À0.86
À0.33
À0.30
0.15
À0.39
À0.29
À0.39
À0.21
0.04
0.13
SO (endo)
À11.56
À12.01
À11.91
À11.30
À11.25
À11.48
À11.72
À11.06
À0.64
À0.45
À0.66
À0.25
À0.29
0.14
SO
2
0.14
0.48
0.21
7b–7a
7c–7a
7d–7a
SO (exo)
Exp.
Calcd
Exp.
Calcd
Exp.
Calcd
À0.85
À1.27
À0.85
À0.82
À0.42
À0.63
À5.37
À4.80
18.34
18.15
17.45
17.94
14.29
14.99
18.44
18.28
17.43
17.90
14.33
14.83
À4.37
À3.95
À0.83
À2.27
À0.81
À0.44
À0.39
À2.30
À0.58
À0.46
À0.21
À0.68
À0.05
À0.32
0.00
À0.62
À0.11
À0.38
À0.17
À0.09
0.15
0.14
SO (endo)
À11.06
À11.05
À11.57
À10.56
À10.38
À10.75
À10.53
À9.63
À0.78
À0.52
À0.25
0.43
SO
2
8b–8a
8c–8a
8d–8a
SO (exo)
Exp.
Calcd
Exp.
Calcd
Exp.
Calcd
À0.42
À0.44
0.53
À6.03
À6.26
20.12
19.36
19.89
20.23
18.41
18.59
20.12
19.36
19.89
20.23
18.41
18.59
À6.03
À6.26
À0.42
À0.44
0.53
À0.49
À1.20
0.16
À0.49
À1.20
0.16
À0.59
À0.23
À2.63
À2.83
À5.71
À5.64
SO (endo)
À14.76
À14.61
À14.69
À14.04
À14.76
À14.61
À14.69
À14.04
1.07
1.07
0.09
0.09
SO
2
À0.57
À0.57
À0.34
À0.34
À0.49
À0.49
0.47
0.47
9b–9a
9c–9a
9d–9a
SO (exo)
Exp.
Calcd
Exp.
Calcd
Exp.
Calcd
À1.99
À0.17
À1.79
1.17
À4.17
À5.19
19.29
19.59
18.69
21.10
16.59
18.67
19.29
19.59
18.69
21.10
16.59
18.67
À4.17
À5.19
À1.99
À0.17
À1.79
1.17
0.32
0.66
0.32
0.66
0.07
0.03
À1.12
À3.29
À3.30
À5.39
SO (endo)
À10.19
À12.72
À11.56
À12.91
À10.19
À12.72
À11.56
À12.91
À0.15
À0.15
0.19
0.19
SO
2
À2.60
À2.60
À0.28
0.47
À0.28
0.47
À0.44
À0.44

M. Dra cˇ ínsk y´ et al. / Tetrahedron: Asymmetry 22 (2011) 1797–1808
1803
Table 5 (continued)
Comp.
X
C-1
C-2
C-3
C-5
C-6
C-7
C-8
0.08
1.12
À0.72
À0.72
À1.52
À0.44
C-9
3.55
0.67
0.22
C-10
0.52
10b–10a
10c–10a
10d–10a
SO (exo)
SO (endo)
Exp.
Calcd
Exp.
Calcd
Exp.
Calcd
À2.24
À0.65
À1.70
0.52
À1.86
18.10
19.47
18.66
20.91
16.33
18.83
18.84
19.19
19.42
20.10
17.23
18.11
À4.66
À2.57
À0.42
À1.71
0.67
À5.20
À8.07
À4.40
À11.39
À12.33
À13.34
À12.71
À1.32
0.89
À12.37
À9.88
0.50
À3.15
À1.69
À4.96
SO
2
À1.88
À2.93
À0.15
À1.38
À12.54
À0.87
0.08
11b–11a
11c–11a
11d–11a
SO (exo)
Exp.
Calcd
Exp.
Calcd
Exp.
Calcd
À1.96
À0.26
À0.82
0.65
À3.48
À5.32
19.31
19.44
17.84
21.31
16.25
19.08
18.87
19.21
19.70
21.52
16.00
18.83
À5.08
À5.82
À2.70
À0.31
À2.61
À0.56
À3.48
À0.69
À0.28
0.25
0.60
À0.11
À0.28
À0.40
À3.55
À0.94
À5.39
0.61
SO (endo)
À8.01
À8.90
À0.38
0.02
À0.44
À12.26
À10.52
À12.63
À13.11
À12.11
À13.29
0.25
SO
2
À2.50
À1.02
À2.82
0.58
À0.75
À0.12
12b–12a
12c–12a
12d–12a
SO (exo)
Exp.
Calcd
Exp.
Calcd
Exp.
Calcd
À2.04
À1.76
À1.09
0.20
À4.31
À6.03
0.84
À13.16
À12.14
À12.96
17.40
19.64
19.72
20.69
15.64
18.93
17.76
19.44
18.02
20.15
16.05
18.53
À3.48
À5.67
À2.39
À0.76
0.05
0.52
À0.21
À0.70
À0.43
0.14
À0.09
0.44
2.98
À0.14
1.18
À3.48
À1.79
À5.27
SO (endo)
À0.78
À1.03
À13.07
À11.50
À13.31
0.50
0.64
SO
2
À1.92
À2.93
À0.14
À0.08
À2.68
À1.93
À0.46
those of endo-sulfoxide 2c with somewhat smaller downfield shifts
of the - and larger upfield shifts of the b-carbon atoms.
intercept = -0.0146
slope = 1.0424
corr.coeff. = 0.9711
2
1
0
a
2
.2. Norbornane derivatives with an annealed tetrahydrothio-
phene ring
0
0
The second group of compounds used in our study was a series
of norbornane derivatives with either exo- and/or endo-annealed
tetrahydrothiophene rings 3–12 (see Fig. 3).
The synthesis of sulfides 3a–12a will be described in a separate
publication. The corresponding sulfoxides 3b–12b, 3c–12c, and
sulfones 3d–12d were prepared by the in situ oxidation of sulfides
3
b, 3c, 3d
4b, 4c, 4d
5
6
7
8
9
1
1
1
b, 5c, 5d
b, 6c, 6d
b, 7c, 7d
3
3
a–12a in CDCl with meta-chloroperbenzoic acid (MCPBA) di-
b, 8c, 8d
1
3
1
b, 9c, 9d
rectly in the NMR tube. The observed C and H chemical shifts
of compounds 3a–12d are presented in Tables 3 and 4. While the
NMR spectra of the starting sulfides and sulfones (as the end-prod-
uct oxidation) can be obtained in a pure form and the structure
assignment of the signals is straightforward, the spectra of the dia-
stereomeric sulfoxides always had to be analyzed as the mixtures
of both and are usually still in the presence of either the starting
sulfide or sulfone. In all cases, the preferred formation of one sulf-
oxide was observed. After the structural assignment of signals to
both sulfoxides, we had to determine the configuration at the sul-
fur atom in both. The results of the theoretical calculations of the
chemical shifts proved helpful.
-
-
10
20
0b, 10c, 10d
1b, 11c, 11d
2b, 12c, 12d
Plot 1 Regr
-
20
-10
0
10
20
observed 13C chemical shifts induced by oxidation [ppm]
Figure 6. The correlation of the observed and calculated oxidation-induced
chemical shifts of carbon atoms in the whole series of norbornane derivatives 3–12.
As we showed in a previous paper,30 the configuration of the
sulfoxides is clearly reflected by chemical-shift changes induced
by the oxidation of sulfides to sulfoxides. The calculated and ob-
served chemical shifts induced by the oxidation of sulfides 1a
and 2a are summarized in Tables 1 and 2. Their correlation is gen-
The annellation to the rigid bicyclic norbornane significantly
limits the possible conformations of the five-membered tetrahy-
drothiophene ring to two boat forms EX-endo and EX-exo, as shown
schematically in Figure 4. They differ by the torsion angles of the
hydrogens in positions 2, 3 and 5, 6 and should be distinguishable
by their corresponding J(H,H) coupling constants. Protons H-2 and
H-6 should have large coupling constants with both H-3 and H-5 in
the EX-exo conformers of 3a–12d (torsion angles around 150° and
30°) while in the EX-endo conformers one large J and a second J close
to zero (torsion angles around 30° and 90°) should be observed.
erally very good for C but less satisfactory for the 1H-oxidation-
13
induced shifts (see Fig. 1). The use of PCM for the calculations of
the chemical shifts of compounds 2a–2d in CDCl and D O did
3 2
not show better agreement with the observed data than the results
obtained in vacuum, which are in agreement with our previous re-
sults.3
3,34
Therefore, the solvent effect was also neglected in our
However, the character of the H NMR spectra (overlap of signals,
1
calculations of other groups of compounds.
2nd order) does not allow the extraction of the corresponding J-
values for all of the compounds studied.
The use of the calculation induced 13C oxidation shifts (
Dd-
values) is illustrated by the example of the thio-galacto derivatives
in Figure 2. The characteristic differences in the d-values for the
carbon atoms at the -position and the good agreement between
Therefore, the geometry of each molecule 3a–12d in both con-
formations EX-endo and EX-exo was optimized using the DFT method
2
D
at the B3LYP/6-31G level of theory and the C and 1H chemical
⁄
⁄
13
a
the observed and calculated data make it possible to distinguish
between the diastereomeric sulfoxides and assign the configura-
shifts were calculated for the optimized structures using B3LYP/
6-31++G . The calculated data were very close to the experimental
⁄⁄
tion of the SO group. The
D
d-values for sulfone 2d are similar to
chemical shifts for compounds 3–12 in the EX-exo conformation.

1
804
M. Dra cˇ ínsk y´ et al. / Tetrahedron: Asymmetry 22 (2011) 1797–1808
O
O
O
O
O
β
X
H
H
N
H
N
H
N
CH3
CH3
H
H
N
N
H
N
H
N
H
α
N
γ
X
α
X
X
CH3
δ
CH3
β
H
O
O
O
CH3
1
3 cis- (LL)
15 cis- (LL)
16 trans- (LD)
17
18
1
4 trans- (LD)
β(cis)
O
H
β(trans)
H
O
O
H
H
a: X = S
γ(trans)
γ(cis)
H
X
b: X = SO (R)
c: X = SO (S)
d: X = SO2
X
N
N
H
H
H
H
δ(trans)
O
H
δ(trans)
δ(cis)
δ(cis)
O
H
O
O
O
O
O
O
H
H
N
H
S
S
O
S
O
S
N
N
N
O
O
O
SO (R)
SO (S)
SO (S)
SO (R)
Figure 7. Cyclodipeptides 13–18. The symbols used to distinguish the methylene protons of the thia-proline ring and the orientation of the sulfoxide group in the isomer with
an (R) or (S) configuration are shown below.
Table 6
The experimental 13C chemical shifts (in ppm) of cyclodipeptides 13–18 in CDCl
3
Compd
X
(X)-Pro
2nd residue
C@O
Ca
Cb
C
c
Cd
C@O
C
a
Cb
NMe
1
1
3a
3c
Sa
SO (S)
162.56
159.70
60.23
85.54
—
—
28.95
51.66
47.10
42.66
163.86
162.68
63.54
63.03
36.90
36.49
32.96
33.08
14a
14b
14c
14d
Sb
SO (R)
SO (S)
163.98
n.d.
n.d.
61.03
79.08
84.32
69.72
—
—
—
—
27.64
46.80
49.63
46.72
47.88
44.53
42.74
37.35
163.04
n.d.
n.d.
65.17
64.76
64.62
64.05
37.00
37.11
37.35
36.93
32.50
32.66
32.53
32.44
SO
2
n.d.
n.d.
15a
15b
15d
Sc
SO (R)
SO
163.48
n.d.
n.d.
61.15
57.46
56.60
33.20
55.11
53.47
—
—
—
45.65
70.75
64.15
163.41
n.d.
n.d.
63.58
63.49
63.18
36.59
36.56
36.54
32.68
32.93
33.16
2
16a
16b
16c
16d
Sd
SO (R)
SO (S)
164.11
n.d.
n.d.
59.86
56.56
56.02
54.82
33.71
54.49
55.55
53.09
—
—
—
—
47.51
69.96
67.30
63.67
165.29
n.d.
n.d.
65.34
65.53
65.06
64.20
36.95
37.10
37.06
36.95
32.28
32.66
32.91
32.94
SO
2
n.d.
n.d.
17a
17b
17c
17d
S
167.60
n.d.
n.d.
61.42
58.24
58.15
56.31
33.09
53.17
53.17
51.56
—
—
—
—
48.52
69.43
67.77
63.06
165.69
n.d.
n.d.
51.38
51.67
51.17
50.57
16.80
16.21
15.98
16.45
—
—
—
—
SO (R)
SO (S)
SO
2
n.d.
n.d.
18a
18b
18c
18d
S
166.96
167.79
167.03
165.17
60.45
57.00
56.84
55.62
33.98
54.52
55.07
52.80
—
—
—
—
48.25
70.46
68.03
63.64
164.98
164.66
166.48
164.57
62.97
63.14
62.82
61.96
33.43
33.52
33.41
33.54
16.93; 18.81
17.13; 18.79
17.55; 18.88
17.10; 18.73
SO (R)
SO (S)
SO
2
n.d. = not determined.
Aromatic carbons:
a
1
1
1
1
34.41 (i-), 129.90 (o-), 128.74 (m-); 127.57 (p-).
34.20 (i-), 129.76 (o-), 128.75 (m-); 128.02 (p-).
34.13 (i-), 129.78 (o-), 128.99 (m-); 127.74 (p-).
34.34 (i-), 129.67 (o-), 128.84 (m-),128.04 (p-).
b
c
d
One exception to this rule was compound 12, where the intramo-
lecular H-bond between the OH group and sulfoxide oxygen could
stabilize the EX-endo conformation of compounds 12b and 12d.
These values were then used to determine the chemical shifts
shown for the pairs of diastereomeric sulfoxides 4b, 4c and 9b,
9c, and the corresponding sulfones 4d, 9d in Figure 5.
The characteristic differences of the
at the - and particularly in the b-position were successfully used
to distinguish diastereoisomeric sulfoxides and determine their
configuration. Sulfones showed upfield d values for the carbon
at the b-position similar to the corresponding endo-sulfoxides
Dd values of carbon atoms
a
induced by the oxidation (
ides 3b–12b, 3c–12c, and sulfones 3d–12d. A comparison of the
experimental and calculated d values of the carbon atoms is
Dd values) of sulfides 3a–12a to sulfox-
D
D

M. Dra cˇ ínsk y´ et al. / Tetrahedron: Asymmetry 22 (2011) 1797–1808
1805
Table 7
The experimental 1H chemical shifts of cyclodipeptides 13–18 in CDCl
3
Compd
X
(X)Pro
2nd residue
a
b (cis)
b (trans)
c
(cis)
c
(trans)
d (cis)
d (trans)
a
b1
b2
c
NMe
1
1
3a
3c
Sa
SO (S)
5.15
4.51
—
—
—
—
2.34
1.68
2.77
2.51
4.66
4.71
2.97
3.43
4.34
4.38
3.39
3.28
3.23
3.19
—
—
3.13
3.26
14a
14b
14c
14d
Sb
SO (R)
SO (S)
3.61
3.23
2.99
3.12
—
—
—
—
—
—
—
—
2.89
3.11
2.88
3.16
2.82
2.62
2.82
3.16
4.36
4.58
4.74
4.58
3.21
3.65
3.46
3.16
4.29
4.38
4.36
4.34
3.25
n.d.
n.d.
n.d.
3.16
n.d.
n.d.
n.d.
—
—
—
—
3.08
3.17
3.12
3.16
SO
2
15a
15b
15d
Sc
SO (R)
SO
3.98
4.65
4.56
0.83
0.28
1.01
2.82
2.96
3.07
—
—
—
—
—
—
5.11
5.68
5.09
4.06
3.66
3.96
4.35
4.40
4.44
3.44
3.35
3.41
3.15
3.16
3.22
—
—
—
3.16
3.20
3.20
2
16a
16b
16c
16d
Sd
SO (R)
SO (S)
2.59
3.41
2.71
2.80
2.92
2.67
3.16
3.30
3.11
3.40
3.56
3.38
—
—
—
—
—
—
—
—
4.79
5.07
5.44
4.86
4.20
4.09
3.52
3.99
4.28
4.30
4.40
4.34
3.28
3.28
3.30
3.28
3.16
3.20
3.23
3.22
—
—
—
—
3.06
3.06
3.10
3.12
SO
2
17a
17b
17c
17d
S
4.39
5.22
4.66
4.88
3.33
3.03
3.30
3.70
3.40
3.72
4.10
3.70
—
—
—
—
—
—
—
—
4.86
4.89
3.90
4.44
4.48
4.60
5.55
4.85
4.20
4.33
4.33
4.25
1.51
1.56
1.58
1.57
—
—
—
—
—
—
—
—
—
—
—
—
SO (R)
SO (S)
SO
2
18a
18b
18c
18d
S
4.39
5.13
4.58
4.87
3.17
2.88
3.40
3.58
3.45
3.72
3.90
3.71
—
—
—
—
—
—
—
—
4.99
5.20
5.70
5.03
4.46
4.40
3.82
4.33
3.90
3.93
3.99
3.97
2.32
2.32
2.32
2.32
—
—
—
—
0.99; 1.08
1.04; 1.10
1.06; 1.11
1.01; 1.09
—
—
—
—
SO (R)
SO (S)
SO
2
n.d. = not determined.
Aromatic protons:
a
7
7
7
7
.07 (o-), 7.27 (m-), 7.25 (p-).
.08 (o-), 7.31 (m-), 7.29 (p-).
.04 (o-), 7.31 (m-), 7.27 (p-).
.09 (o-), ꢀ7.32 (m-, p-).
b
c
d
Table 8
The experimental and calculated 13C chemical-shift changes induced by the oxidation of cyclodipeptide sulfides 13a–18a to the corresponding sulfoxides 13b–18b, 13c–18c and
sulfones 13d–18d
Compd
X
(X)Pro
2nd residue
C
a
Cb
C
c
Cd
C
a
Cb
C
c
NMe
0.12
1
3c–13a
S@O (S)
Exp.
25.31
29.76
—
—
22.71
22.62
À4.44
À0.51
À0.30
À0.41
À0.56
—
—
Calcd
À3.67
0.12
1
1
1
1
4b–14a
4c–14a
4d–14a
5b–15a
SO (R)
SO (S)
Exp.
Calcd
Exp.
Calcd
Exp.
Calcd
Exp.
18.05
18.19
23.29
23.62
8.69
11.88
À3.69
À3.79
—
—
—
—
—
—
21.91
21.21
19.16
18.93
21.99
22.16
19.08
22.90
—
À3.35
À3.11
À5.14
À5.30
À10.53
À11.26
25.10
À0.41
0.11
0.24
0.35
À0.09
À0.07
0.79
—
—
—
—
—
—
—
—
0.16
À0.02
0.03
0.23
À0.55
À0.43
À1.12
À0.12
À0.09
À0.36
0.83
SO
SO (R)
SO
2
À0.06
1.36
À0.03
0.25
0.18
Calcd
—
26.97
À0.90
1
5d–15a
2
Exp.
Calcd
À4.55
À4.75
20.27
20.29
—
—
18.50
20.33
À0.40
À0.40
À0.05
À0.39
—
—
0.48
0.44
16b–16a
16c–16a
16d–16a
SO (R)
SO (S)
Exp.
Calcd
Exp.
Calcd
Exp.
Calcd
À3.30
À3.13
À3.84
À5.86
À5.04
À4.97
20.78
21.21
21.84
19.04
19.38
20.30
—
—
—
—
—
—
22.45
23.25
19.79
18.75
16.16
18.94
0.19
À0.10
À0.28
À0.22
À1.14
À1.15
0.15
0.06
0.11
—
—
—
—
—
—
0.38
À0.03
0.63
0.04
0.66
À0.50
SO
2
0.00
À0.04
0.26
17b–17a
17c–17a
17d–17a
SO (R)
SO (S)
Exp.
Calcd
Exp.
Calcd
Exp.
Calcd
À3.18
À4.01
À3.27
À6.96
À5.11
À5.47
20.08
20.01
20.08
18.16
18.47
19.00
—
—
—
—
—
—
20.91
20.61
19.25
15.88
14.54
15.48
0.29
À0.04
À0.21
À0.67
À0.81
À0.92
À0.59
À0.19
À0.82
À0.73
À0.35
À0.43
—
—
—
—
—
—
—
—
—
—
—
—
SO
2
18b–18a
18c–18a
18d–18a
SO (R)
SO (S)
Exp.
Calcd
Exp.
Calcd
Exp.
Calcd
À3.45
À3.97
À3.61
À4.05
À4.83
À5.48
20.54
20.31
21.09
21.78
18.82
21.31
—
—
—
—
—
—
22.21
21.78
19.78
17.51
15.39
17.86
0.17
À0.09
À0.15
1.54
0.09
À0.16
À0.02
4.04
0.11
0.98
0.20; À0.02
0.08; À0.13
0.62; 0.07
0.10; À0.18
0.17; À0.08
À0.48; À0.82
—
—
—
—
—
—
SO
2
À1.01
À0.52

1
806
M. Dra cˇ ínsk y´ et al. / Tetrahedron: Asymmetry 22 (2011) 1797–1808
The orientation of the phenyl ring of the (N-Me)Phe residue
folded over the diketopiperazine ring in sulfides 13a–16a was
found in the crystal and confirmed as a highly preferred conforma-
3
2
1
0
0
0
0
intercept = -0.0231
slope = 1.0233
corr.coeff.= 0.9851
tion in solution by the small values of J(Ha,Hb1) and J(Ha,Hb2) =
3
.0–4.5 Hz, corresponding to the gauche position of the coupled
protons. We have observed that this conformation can influence
the formation of the oxidation products because of steric hin-
drance. All of the possible oxidation products (two sulfoxides and
sulfone) were obtained from both trans-cyclodipeptides 14a and
16a, where the phenyl ring is sufficiently far away from the sulfur
atom. However, in the case of sulfide 13a, the only product of oxi-
dation was sulfoxide 13c with a pseudoequatorial S@O group.
Interesting results were observed for the oxidation of sulfide 15a.
Again, there was only one sulfoxide 15c with a pseudoequatorial
S@O group formed, but it was further oxidized to sulfone 15d.
Similar differences in the formation of oxidation products were
1
1
1
1
1
1
1
1
1
3c
4b
4c
4d
5b
5d
6b
6c
6d
17b
1
1
1
1
7c
7d
8b
8c
30
observed for cyclodipeptides with thia-pipecolic acid. The folded
-
10
18d
Plot 1 Regr
rotamer of the phenyl ring of the Phe residue also stays as a pre-
ferred conformation in sulfoxides and sulfones as evidenced by
-
10
0
10
20
30
the small values of the vicinal coupling constants J(H
a
,Hb) = 3.2–
1
3
1
observed 13C chem.shifts induced by oxidation [ppm]
4.5 Hz of the Phe residue. The
C and H chemical shifts of com-
pounds 13–18 are summarized in Tables 6 and 7.
Figure 8. The correlation of the calculated and observed 13C chemical shifts
induced by the oxidation of cyclodipeptides 13a–18a.
A conformation analysis of the five-membered ring was per-
1
formed with the assistance of the observed H vicinal coupling
constants considering the pseudorotation cycle. All compounds of
but somewhat smaller downfield
position.
D
d values for the carbon at the
a
-
this series, except for 14a and 14c, preferred a single conformation:
d
E for 14a, 14d, a
N
T for 13a–13d,
b
T
N
for 15a–15d, 17a–17d, 18a–
a
A comparison of the experimental and calculated
D
d values for
18d and
imately a 51:49 mixture of
14c was about a 74:26 mixture of
b
T for 16a–16d. Compound 14a was found to be approx-
d
the whole series of norbornane derivatives 3–12 is shown in Ta-
ble 5 and graphically in Figure 6. The remarkably deviated points
belong to compound 12 discussed above.
b N
E and T conformers while compound
a
d
b
E and T .
The geometry of all of the starting sulfides and their oxidation
products was again optimized using the DFT method at the
⁄
⁄
13
1
2
.3. Cyclodipeptides containing thiaproline
B3LYP/6-31G level of theory. The C and H chemical shifts were
then calculated for the individual preferred conformations using
⁄⁄
Another model used for the precursors of the in situ oxidation
the DFT B3LYP 6-31++G method. In the case of the equilibrium
population of two conformers, the final calculated chemical shifts
were weighed by conformer populations. The calculated data ob-
tained in this way were used for the calculation of the chemical
was a series of cis- and trans-cyclodipeptides with proline contain-
ing a sulfur atom at the b- or -position as one residue and N-
methylated phenylalanine, alanine, or valine as the second residue
see Fig. 7, compounds 13a–18a). Recently, we have collected the
c
(
shifts induced by oxidation (
Dd values). A comparison of the calcu-
X-ray structure data for these compounds, which will be published
in a separate paper. These sulfides can, in principle, be oxidized
with meta-chloroperbenzoic acid (MCPBA) firstly to two sulfoxides
lated and experimental d values of the carbon atoms is given in
D
Table 8 and their correlation is shown in Figure 8.
The use of the calculated induced 13C oxidation shifts (
Dd-
[
with an (R)- and (S)- configuration] and finally to the sulfones. The
values) is illustrated using the example of cyclodipeptide 17 in
Figure 9. The characteristic differences in the d-values for the car-
bon atoms at the -position and b-position and the good agree-
in situ oxidation of sulfides by the stepwise addition of MCPBA to a
D
1
solution of sulfide in CDCl
3
in an NMR tube was followed by H and
a
1
3
C NMR spectroscopy. The proton and carbon signals of the sulfox-
ment between the observed and calculated data make it possible
ides and sulfones were assigned using 2D-homonuclear (2D-H,H-
COSY) and heteronuclear (2D-H,C-HSQC and 2D-HMBC) correlated
NMR experiments. The annellation of the five-membered ring of
thia-proline to the nearly planar dioxopiperazine (DKP) ring re-
duces the conformational space of the thia-proline significantly.
to distinguish between the diastereomeric sulfoxides 17b and
17c and assign the configuration of the SO group. The
Dd-values
for sulfone 17d are similar to those of endo-sulfoxide 17c with
somewhat smaller downfield shifts of the
a- and larger upfield
shifts of the b-carbon atoms.
Figure 9. The observed (black) and calculated (red) induced 13C oxidation shifts (
Dd-values) illustrated on the example of thia-cyclodipeptide derivatives 17.

M. Dra cˇ ínsk y´ et al. / Tetrahedron: Asymmetry 22 (2011) 1797–1808
1807
3
. Conclusion
N-methylated phenylalanine, alanine or valine as the second one
was kindly supplied by Professor F. Borremans (Univ Gent, Bel-
gium). Recently, we have collected the X-ray crystallographic data
for compounds 13a–16a, which will be published, together with
their preparation, in a separate paper.
The chemical shifts of sulfides, sulfoxides, and sulfones with
a sulfur atom in a five-membered ring were calculated using the
⁄⁄
GIAO DFT B3LYP 6-31++G method. An important condition for
obtaining reasonable values of calculated chemical shifts is the ba-
sic knowledge of the conformation of the five-membered ring and
its geometry optimization (we used the DFT B3LYP 6-31 G meth-
od). A better agreement between the calculated and experimental
chemical shifts was obtained for the carbon atoms. To determine
the configuration of diastereomeric sulfoxides, we suggest the
use of the C chemical shifts induced by oxidation (
The characteristic differences of the calculated d values and their
good agreement with the experimental values for carbon atoms at
the -position and particularly at the b-position allowed successful
configuration assignment of sulfoxides derived from thiolevog-
lucosane 1 and thiolevogalactosane 2, from the series of substi-
tuted norbornane derivatives with an annealed tetrahydrothio-
phene ring 3–12 and from cyclodipeptides containing thia-proline
4.2. Preparation of sulfoxides and sulfones
⁄
⁄
The preparation of sulfoxides 1b, 1c, 2b, 2c, and sulfones 1d, 2d
3
1
has been described in previous papers. All other sulfoxides and
sulfones herein were prepared by in situ stepwise oxidation of
the corresponding sulfides with a meta-chloroperbenzoic acid
1
3
Dd values).
D
3
(MCPBA) in an NMR tube in a CDCl solution. The oxidation reac-
1
13
tions were monitored by the H and C NMR spectra as shown
1
3
a
for the in situ oxidation on the C NMR spectra of norbornane
derivative 6a in Figure 10. The addition of MCPBA was finished
when the sulfide was completely oxidized to the corresponding
sulfone and a small amount of unreacted MCPBA appeared in the
spectrum (the final molar ratio of the MCPBA added to the sulfone
was approximately 2.1:1). The structures of the products were
determined from the NMR spectra, and the presence of the corre-
sponding sulfoxides and sulfones was confirmed by mass spec-
1
3–18. We believe that the computation/experimental method de-
scribed can be generally applied for other compounds containing
five-membered sulfoxide rings.
trometry directly in the CDCl
.3. NMR experiments
The NMR spectra were measured on a Bruker AVANCE 600
3
solutions.
4
4
. Experimental
4
.1. Starting compounds (sulfides)
1
13
instrument (with the H at 600.13 MHz and the C at 150.9 MHz
frequency using a 5 mm TXI cryo-probe) or Bruker AVANCE 500
The preparation and NMR data of 1,6-anhydro-1-thio-b-
D
-glu-
copyranose (thiolevoglucosan) 1a and 1,6-anhydro-1-thio-b-
D-
1
13
galactopyranose 2a are already published.31 The X-ray structures
instrument (with the H at 500.13 MHz and the C at 125.8 MHz
frequency). About 5–10 mg of the sample in 0.6 ml of CDCl3 was
3
1,32
of sulfoxides 1b, 1c, and sulfone 1d have also been described.
1
used. The chemical shifts are given in d-scale (with the H shifts
The synthesis of norbornane derivatives with the annealed tetra-
hydrothiophene rings 3a–12a will be described in a separate paper.
A series of cis- and trans-cyclodipeptides 13a–18a with proline
1
3
referenced to TMS and the C shifts referenced to CDCl
d(CDCl ) 77.00 ppm). The typical experimental conditions for the
H NMR spectra were sixteen scans, with a spectral width of
3
using
3
1
containing a sulfur atom at the b- or
c
-position as one residue and
3
5
9
10
(C)
10
2
1
6
10
5
3
5
7
8
9
9
3
(B)
2
1
7
6
8
1
0
9
1
7
2
6
8
3
5
(A)
6
8
2
7
1
7
0
65
60
55
50
45
40
35
30 ppm
Figure 10. The in situ stepwise oxidation of norbornane derivative 6a monitored by the 13C NMR spectra: (A) starting sulfide 6a in CDCl
3
; (B) mixture of sulfoxides 6b and 6c
in the ratio of approximately 2.5:1 after the first addition of MCPBA; (C) the final product sulfone 6d after the second addition of MCPBA. The assignment of the carbon signals
is shown in the circles. The colors are used to distinguish between compounds 6a (black), 6b (red), 6c (blue), and 6d (green).

1
808
M. Dra cˇ ínsk y´ et al. / Tetrahedron: Asymmetry 22 (2011) 1797–1808
6
kHz and an acquisition time of 5 s, yielding 60 K data points. The
FIDs were zero-filled to 128 K data points. The 2D-homonuclear
H,H-COSY and H,H-ROESY) and 2D-heteronuclear (H,C-HSQC and
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