Design of a new axially chiral molecule by conformational fixation: 2,6-dithiaspiro[3.3]heptane 2,6-dioxide and its heavier analogues

Article abstract of DOI:10.1016/j.tetasy.2013.05.020

We have designed a new axially chiral bis(sulfoxide) molecule with conformational rigidity: 2,6-dithiaspiro[3.3]heptane 2,6-dioxide 2a. This molecule has axial asymmetry due to two puckered thietane ring systems. The lone pairs on the sulfur show a strong s-character, which was expected to result in a high barrier to racemization, that is, inversion at the sulfur. We confirmed this prediction by calculations and experimentation. The lone pairs of the sulfur in 2a are sp^1.00 and the enthalpy of activation (ΔH ^?) for inversion is 47.5 kcal/mol (B3LYP/6-31G(d)). The ¹H NMR spectra of 2a showed two doublets and two doubled doublet peaks, which resulted from the rigidity of the four-membered ring frameworks without flipping. We separated the enantiomers of 2a by HPLC with a chiral stationary phase column to observe a set of complementary peaks. We also calculated the diselena- and ditellura congeners and confirmed that they also show axial chirality.

Full text of DOI:10.1016/j.tetasy.2013.05.020

Tetrahedron: Asymmetry 24 (2013) 781–784
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Design of a new axially chiral molecule by conformational fixation:
2,6-dithiaspiro[3.3]heptane 2,6-dioxide and its heavier analogues
⇑
Yuji Naruse , Yousuke Hasegawa, Motoya Araki
Department of Chemistry, Gifu University, 1-1 Yanagido, Gifu 501-1193, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
We have designed a new axially chiral bis(sulfoxide) molecule with conformational rigidity: 2,6-dithia-
spiro[3.3]heptane 2,6-dioxide 2a. This molecule has axial asymmetry due to two puckered thietane ring
systems. The lone pairs on the sulfur show a strong s-character, which was expected to result in a high
barrier to racemization, that is, inversion at the sulfur. We confirmed this prediction by calculations and
Received 3 April 2013
Revised 20 May 2013
Accepted 16 May 2013
1
.00
à
experimentation. The lone pairs of the sulfur in 2a are sp
and the enthalpy of activation (DH ) for
inversion is 47.5 kcal/mol (B3LYP/6-31G(d)). The 1H NMR spectra of 2a showed two doublets and two
doubled doublet peaks, which resulted from the rigidity of the four-membered ring frameworks without
flipping. We separated the enantiomers of 2a by HPLC with a chiral stationary phase column to observe a
set of complementary peaks. We also calculated the diselena- and ditellura congeners and confirmed that
they also show axial chirality.
Ó 2013 Elsevier Ltd. All rights reserved.
1
. Introduction
RY
YR
RY
YR
After our studies of ring strain in small ring systems1 and the
–4
barrier to inversion of amides,5 we showed6 that 2,6-diphospha-
and 2,6-diarsaspiro[3.3]heptane, 1b (Y = P; R = H) and 1c (Y = As;
R
R
R = H) existed as enantiomers at ambient temperature, while
R
R
diazaspiro[3.3]heptane 1a (Y = N; R = H)7,8 is a racemic mixture.
Y
Y
The 2,6-diazaspiro[3.3]heptane 1a and its amides were errone-
ously reported to have a planar azetidine framework.7 However,
they actually have a puckered conformation. Thus, the diaza mole-
cule 1a has an axial asymmetry (Fig. 1). However, the s-character
of the lone pair in 1a is low, which makes it prone to racemization,
although the high s-character of the lone pairs in 1b and 1c
increases their inversion barriers. Thus, 1b and 1c can exist as
enantiomers at ambient temperature without racemization (see
Y
Y
(
axS)-
(axR)-
enantiomers
1a Y = N; R = H
1
1
2
b Y = P; R = H
c Y = As; R = H
a Y = S; R = O
6
Scheme 1).
We further considered that if we could make the lone pairs in
2b Y = Se; R = O
2
c Y = Te; R = O
2
,6-diheterosubstituted spiro[3.3]heptanes have a strong s-charac-
ter such as in 1b and 1c, the molecules could exist as enantiomers.
We designed isolobal 2,6-dithiaspiro[3.3]heptane 2,6-dioxide 2a
Figure 1. Enantiomers of 2,6-disubstituted spiro[3.3]heptane.
(
Y = S; R = O) as a good candidate. It is also suitable for chiral metal
9
NaIO4
complex polymers and oligomers. Bis(sulfoxide) 2a was calcu-
S
S
O
S
S
O
lated to have a structure with C2 symmetry, which led to splitting
ionization potentials.10 However, 2,6-dithiaspiro[3.3]heptane 3
60%
3
2a
4
also should have a C2 symmetry due to the thietane ring puckering.
The conformational stabilities of these class of compounds are not
discussed. Some sulfoxide complexes are known to be coordinated
mCPBA
O S
2
SO2
7
3%
⇑
Corresponding author. Tel.: +81 58 293 2615; fax: +81 58 293 2794.
E-mail address: naruse@gifu-u.ac.jp (Y. Naruse).
Scheme 1. Preparation of 2a and 4.
0
957-4166/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetasy.2013.05.020

7
82
Y. Naruse et al. / Tetrahedron: Asymmetry 24 (2013) 781–784
at S.10 Although the selena congeners of 2,6-dithiaspiro[3.3]hep-
tane 3 were used as a twisting rod in order to prepare metal com-
plex polymers and oligomers, they are racemates or racemic
mixtures. However, the use of an enantiomer of disulfoxide 2a
would result in chirality-defined complexes, and thus unique prop-
erties due to this chirality should be expected.7
Table 1
Hybrids of the lone pair sp (RHF/6-31G(d)//B3LYP/6-31G(d))a
n
2a
2b
2c
1
1
spn
1.00
(0.87)
(0.60)
(0.51)b
a
By BMA; the results of the NBO analysis are shown in parentheses.
RHF/LANL2DZ//B3LYP/LANL2DZ.
b
2
. Results and discussion
We calculated12 the structure of 2a (Fig. 2) and analyzed its
Table 2
13
à
à
electronic structure by bond model analysis (BMA) and NBO
Calculated inversion barriers at the chalcogeno atom (
B3LYP/6-31G(d), ZPE corrected; values at B3LYP/6-311+G(d,p)//B3LYP/6-31G(d) are in
parentheses and those at BMK/6-311+G(d,p)//B3LYP/6-31G(d) are in brackets.)
D
H
and
D
G
in kcal/mol,
1
4
1.0
analysis. As expected, the hybridization of the lone pair is sp
0
.87
by BMA and sp
by NBO (Table 1). Furthermore, the calculated
inversion barrier at sulfur is 47.5 kcal/mol (B3LYP/6-31G(d),
2a
2b
2c
3
4
1
5,16
à
a
Table 2).
More precise calculations at B3LYP/6-311+G(d,p)//
D
D
H
47.5
(46.1)
53.2
51.1
0.46
0.62
17
[54.9]b
B3LYP/6-31G(d) and BMK /6-311+G(d,p)//B3LYP/6-31G(d) show
almost identical results. This inversion barrier is much higher than
that of 1,1 -hydroxy-2,2 -binaphthyl (2,2 -binaphthol, ca. 38 kcal/
mol). Thus, bis(sulfoxide) 2a should not racemize at ambient
temperature. In contrast, 2,6-dithiaspiro[3.3]heptane 3 has two
lone pairs of sp
(53.3)
[54.6]
(53.3)
[54.6]
(0.49)
[1.1]
(1.1)
[1.9]
(0.38)
[0.94]
(0.35)
[0.51]
[
48.3]
(46.1)
48.3]
à
[54.9]b
G
0
0
0
[
1
8
a
B3LYP/LANL2DZ.
BMK/LANL2DZ//B3LYP/LANL2DZ.
b
1
.09
0.40
and pure p orbitals (sp
and pure p orbitals
by NBO). 2,6-Dithiaspiro[3.3]heptane 2,2,6,6-tetraoxide 4 has no
7
.2
lone pairs, and the hybrids on S of the S–O bonds are sp and
6
.9
2.58
2.50
sp (sp
and sp
by NBO). Thus, we can expect that bis(sul-
The conformers of 2a with the mono- and diflipped thietane
fide) 3 and bis(sulfone) 4 should have low inversion barriers at
the thietane rings. In fact, the calculated inversion barriers of 3
and 4 are 0.46 and 0.62 kcal/mol, respectively. We expected that
these low barriers of 3 and 4 would lead to so facile inversion that
their H NMR signals should be fully averaged at ambient temper-
ature; only one singlet should be observed for the methylene
groups.
rings are only 1.7 and 3.4 kcal/mol higher in energy. The flipping
barriers at the thietane ring are 2.1 and 2.4 kcal/mol, respectively
(Fig. 3). However, its chirality is retained with facile flipping of
the thietane ring. This behavior is in a sharp contrast to 1b or 1c,
in which the inversion of the four-membered ring does not occur
without inversion at P and As. The heavier chalcogeno analogues
2b (Y = Se; R = O) and 2c (Y = Te; R = O) also have lone pairs with
1
dih(S6-C7-C4-C5)
-25.6°
dih(Se6-C7-C4-C5)
= -26.9°
C3
=
1
.505 Å
C3
1.887 Å
C3
C7 C4
66.0°
7
0.0°
C7
74.4°
S2
1.659 Å
C5
C4
Se2
Te2
.211 Å
C7
S6
C5
C4
2
Se6
Te6
(
sp0.51
dih(Te6-C7-C4-C5)
)
C5
C1
.878 Å
C1 2.028 Å
1
C1
sp1.00 (sp0.86
)
=
27.7°
(
sp0.80
)
1.703 Å 142.9°
148.1°
138.4°
76.2°
1.939 Å
70.0°
1.545 Å
8
3.6°
dih(S6-C7-C4-C5)
0.4°
dih(Se6-C7-C4-C5)
-18.8°
dih(Te6-C7-C4-C5)
= 18.5°
=
=
1
1
.510 Å
10.7°
101.2°
7.9°
1.885 Å
6
105.2°
72.1°
1.663 Å
7
5.5°
dih(Se6-C7-C4-C5)
= 3.0°
dih(Te6-C7-C4-C5)
= 1.3°
dih(S6-C7-C4-C5)
4.8°
=
Figure 2. Calculated structures with some selected parameters (B3LYP/6-31G(d); B3LYP/LANL2DZ for 2c).

Y. Naruse et al. / Tetrahedron: Asymmetry 24 (2013) 781–784
783
endo,endo-2a
exo,endo
exo,exo
Figure 3. Reaction co-ordinates for inversion at the sulfur atom and flipping of the thietane ring in 2a (B3LYP/6-31G(d)).
11.817
1
2.987
δ/ppm
4.0
3.5
Figure 4. 1H NMR spectra of 2a (CDCl
, 400 MHz).
3
Figure 6. HPLC analysis of 2a.
peaks at d 64.19, 62.85 and 26.62 ppm; bis(sulfone) 4 showed
two peaks at d 74.81 and 35.47 ppm. These results led us to con-
clude that all of the hydrogen atoms in 3 and 4 are fully averaged
at ambient temperature, while those in 2a are not. While the two
thietane rings in 3 and 4 flip very easily, those in 2a are fixed. Thus,
pair peaks of diastereomers
2
a does not racemize at ambient temperature and could be sepa-
rated into enantiomers.
1
We initially attempted H NMR analysis with the chiral
δ/ppm
4.0
3.5
solvating shift reagent N-((R)-phenethyl)-3,5-dinitrobenzamide21
(
Fig. 5). While two sets of isointensity peaks were observed, they
Figure 5. 1H NMR spectra of 2a with the solvating chiral shift reagent N-((R)-
22
were not fully separated.
phenethyl)-3,5-dinitrobenzamide (CDCl , 400 MHz).
3
We then subjected 2a to HPLC analysis with a chiral stationary
phase column. We observed a set of peaks of enantiomers using
Daicel CHIRALCEL-OD (Fig. 6). The observed peaks had almost the
same area. Screening revealed that Daicel CHIRALPAK-IF gave
superior results, and these two peaks had opposite optical
rotations.
high s-character and high inversion barriers (Tables 1 and 2). The
most stable conformers of 2a and 2b were exo,exo, while that of
2
c was endo,endo (Fig. 2). We assume that preference of the
exo,exo-conformer in 2a and 2b results from the steric repulsion
between the other ring and the S–O or Se–O group; with the longer
C–Te bonds, the antiperiplanar interaction between C–H bonds and
Te–O in 2c stabilizes the endo,endo-conformer.
3. Conclusion
To examine our predictions, we prepared compounds 2a and 4.
8,19
2
,6-Dithiaspiro[3.3]heptane 31
was oxidized with NaIO
4
to give
In conclusion, we have designed new, conformationally fixed
chiral 2,6-dichalcogenospiro[3.3]heptane 2,6-dioxides. The axial
chirality is due to high inversion barriers at the chalcogeno atom,
the lone pairs of which have high s-character.
10,19,20
colorless crystals of 2a (60%).
oxidized with mCPBA to afford bis(sulfone) 4 (73%).
The resulting 2a was further
19,20
1
The H NMR spectrum of 3 showed only one singlet at d
.30 ppm. However, a set of doubled doublets at d 3.82 and 3.76
3
and a set of doublets at d 3.42 and 3.32 ppm were observed for
a (Fig. 4). Bis(sulfone) 4 with no lone pairs showed only one sin-
glet at d 4.42 ppm. For the C NMR, bis(sulfide) 3 showed two
peaks at d 39.78 and 34.38 ppm; bis(sulfoxide) 2a showed three
Acknowledgment
2
13
We gratefully acknowledge the assistance provided by Daicel
Co. in screening the chiral stationary phase columns.

7
84
Y. Naruse et al. / Tetrahedron: Asymmetry 24 (2013) 781–784
S. Bull. Chem. Soc. Jpn. 1996, 69, 2781; Inagaki, S.; Ohashi, S.; Yamamoto, T.
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a
solution of
3 (0.80 g,
6
7
.
.
6.0 mmol) in MeOH (20 mL) was added NaIO
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(2.9 g, 13 mmol) at 0 °C.
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solvent was removed in vacuo. The resulting white cake was extracted with
8
9
.
.
Its mono-Boc amide is commercially available.
CHCl
give a crude product, which was recrystallized from hexane–CH
to give colorless crystals (0.59 g, 3.6 mmol, 60%). Mp 146.0–146.6 °C (lit.
3
(30 mL ꢀ 3), and the extracts were filtered and concentrated in vacuo to
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Cl five times
2
19
1
1
5
6
2
46 °C). H NMR (CDCl ) d 3.82 (dd, J = 11.2, 5.1 Hz, 2H), 3.76 (dd, J = 11.2,
.1 Hz, 2H), 3.42 (d, J = 11.2 Hz, 2H), 3.32 (d, J = 11.2 Hz, 2H); C NMR (CDCl ) d
3
4.19, 62.85, 26.62.
3
2
012, 41, 850.
13
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,6-Dithiaspiro[3.3]heptane 2,2,6,6-tetraoxide 4. To a suspension of mCPBA
(
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CH Cl (10 mL) was added 2a (0.10 g, 0.76 mmol) at 0 °C. After the mixture was
2
2
2. Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.;
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stirred for 10 h (with gradual warming to rt), the resulting slurry was filtered
and the filtrate was concentrated in vacuo. The crude white powder was
suspended with powdered Na S O and K CO (1 g each) in CH Cl (10 mL) to
2 2 3 2 3 2 2
remove contamination from mCPBA and 3-chlorobenzoic acid. Filtration and
concentration in vacuo afforded a crude product, which was recrystallized
from hexane–CH Cl to give colorless crystals (0.11 g, 0.56 mmol, 73%). Mp
2 2
1
9
1
1
3
2
41.5–242.0 °C (lit. 244.5 °C). H NMR (CDCl
d 74.81, 35.47.
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) d 4.42 (s, 8H); C NMR (CDCl )
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2
2
2. A solution of disulfoxide 2a (6.9 mg, 0.050 mmol) and N-((R)-phenethyl)-3,5-
(0.70 mL) was subjected to 1
H
dinitrobenzamide (0.10 g, 0.32 mmol) in CDCl
NMR analysis.
3
1
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