Synthesis and hydrolysis of optically active naphthyl-phenyl-bis(acyloxy) spiro-λ4-sulfane: Absolute configurations of spiro-λ4-sulfanes, related sulfonium salts and naphthyl phenyl sulfoxides determined by CD spectroscopy using exci

Article abstract of DOI:10.1016/j.tetasy.2003.09.011

(S)-(+)- and (R)-(-)-enantiomers of naphthyl-phenyl-bis(acyloxy)spiro- λ⁴-sulfane 2 were prepared from the precursors (R)-(-)- and (S)-(+)-naphthyl phenyl sulfoxide dicarboxylic acid 2a with acetic anhydride. The hydrolysis of spiro-λ⁴

Full text of DOI:10.1016/j.tetasy.2003.09.011

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 14 (2003) 3745–3753
Synthesis and hydrolysis of optically active
naphthyl-phenyl-bis(acyloxy)spiro-l4-sulfane: absolute
configurations of spiro-l4-sulfanes, related sulfonium salts and
naphthyl phenyl sulfoxides determined by CD spectroscopy using
exciton chirality and empirical rules
´
Jeno
3
Varga, Jo´zsef Ra´bai, Ferenc Ruff,* Arpa´d Kucsman, Eleme´r Vass, Miklo´s Hollo´si and
De´nes Szabo´*
Department of Organic Chemistry, Eo¨tvo¨s Lora´nd University, H-1518 Budapest 112, PO Box 32, Hungary
Received 28 July 2003; accepted 9 September 2003
Abstract—(S)-(+)- and (R)-(−)-enantiomers of naphthyl-phenyl-bis(acyloxy)spiro-l4-sulfane 2 were prepared from the precursors
(R)-(−)- and (S)-(+)-naphthyl phenyl sulfoxide dicarboxylic acid 2a with acetic anhydride. The hydrolysis of spiro-l4-sulfane
(R)-(−)-2 in acidic and basic solutions gave as major products sulfoxide (S)-(+)-2a and (R)-(−)-2a, respectively. The selectivity of
the reactions was interpreted with the different reactivities of the ortho and peri neighboring carboxylic groups of the sulfoxide
2a, and with the different ability of the five and six-membered rings to be cleaved in spiro-l4-sulfane 2. The absolute
configurations of the enantiomeric spiro-l4-sulfanes 2 and sulfoxides 2a were determined by CD spectroscopy. Exciton coupling
1
1
was observed in the spectrum of spiro-l4-sulfane 2 between the benzene La1and naphthalene Bb transitions, which results in a
negative couplet for (R)-(−)-2. Exciton coupling can be expected only for the Bb transitions of the S-phenyl and S-naphthyl rings
of the sulfoxides, which define a positive couplet for (S)-(+)-2a. Empirical rules were found to be valid for the determination of
configuration of spiro-l4-sulfanes and related sulfonium compound derivatives with a trigonal bipyramidal structure, and for that
of naphthyl-phenyl-sulfoxides. Both spiro-l4-sulfanes and sulfoxides should be viewed from the side of the lone pair; the axial
substituents in the former case and the downwards oriented SꢀO bond in the latter case are placed in a vertical plane. Rings and
substituents in the upper-right and lower-left sectors define positive exciton couplets, while the opposite case is characterized by
negative exciton-coupled circular dichroism (EC-CD).
© 2003 Elsevier Ltd. All rights reserved.
and sulfoxide carboxylic acid methyl esters 1c,
respectively3,5,6 without loss of the optical activity. X-
Ray crystallographic investigations proved that spiro-
l4-sulfanes (1) and their sulfonium salt derivatives 1b
possess trigonal bipyramidal structure,7–14 and the
geometry of the sulfonium salts is stabilized by an S···O
close contact. Methods for syntheses of diaryl spiro-l4-
sulfanes 1, sulfonium salts 1b and sulfoxide carboxylic
acid methyl esters 1c from sulfoxide carboxylic acids 1a
are shown in Scheme 1 (Z–Y=CH2–O, CO–NMe or
CO–O; Ar=phenyl or naphthyl ring).
1. Introduction
Enantiomers of optically active diaryl(acyloxy)(alkoxy)-
and diaryl(acylamino)(acyloxy)-spiro-l4-sulfanes
1
bearing S-phenyl and S-naphthyl rings were prepared
either from optically active precursor diaryl sulfoxides
1a1–3 by dehydration or from spiro-l4-sulfane racemates
by using the method of chromatographic resolution.4
The stereospecificity of sulfoxide dehydration (1a“1)
could be related to the different reactivities of the
carboxyl, hydroxymethyl and N-methylcarbamoyl sub-
stituents of the aryl groups, lying in the neighborhood
of the central sulfur atom. In other experiments opti-
cally active spiro-l4-sulfanes 1 and sulfoxide carboxylic
acids 1a were methylated to obtain sulfonium salts 1b
The hydrolysis of optically active diaryl(alkoxy)-
(acyloxy)- and diaryl(acylamino)(acyloxy)spiro-l4-sul-
fanes with S-phenyl and S-naphthyl rings 1 leading to
optically active sulfoxides 1a and 1a* as shown in
Scheme 2 were also investigated earlier in detail.3,5 Due
to the different reactivities of the axial groups, the
* Corresponding authors. Tel.: 36-1209-0555; fax: 36-1-372-2620; e-
mail: ruff@szerves.chem.elte.hu; szabod@szerves.chem.elte.hu
0957-4166/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2003.09.011

3746
J. Varga et al. / Tetrahedron: Asymmetry 44 (2003) 3745–3753
Scheme 1.
found to be valid for predicting the absolute configura-
tions of both trigonal bipyramidal diaryl-spiro-l4-sul-
fanes and diaryl-sulfonium salts with S···O close contact
and for that of substituted naphthyl phenyl sulfoxides.
For spiro-l4-sulfanes the Martin–Balthazor conven-
tion,18 for sulfonium salts and sulfoxides the Cahn–
Ingold–Prelog convention were used to designate the
absolute configurations.
Scheme 2.
2. Results and discussion
2.1. Resolution of precursor sulfoxide 2a
hydrolysis reaction proved to be stereospecific. Never-
theless, the configuration of the sulfoxide products was
found to depend on the pH of the media pointing to
reaction pathways which differ in the order of the
opening of the spiro rings. Kinetic measurements
showed that the rate of the hydrolysis of spiro-l4-sul-
fanes is influenced by the structure of the nucleophile
(H2O or OH−), the leaving group ability of the axial
groups and the size of the spiro rings.15,16 The key steps
in the hydrolysis mechanism of the spiro-l4-sulfanes are
the equilibrium opening of the first spiro ring and the
nucleophilic attack on the resulted monocyclic sulfo-
nium centre. Sulfonium salt intermediates with a six-
membered ring were found to react much more slowly
than those with a five-membered ring.16
The resolution of racemic 2-(8-carboxy-1-naphthylsulfi-
nyl)benzoic acid 2a8 was carried out by an improved
salting out selective extraction procedure published ear-
lier.19 To the aqueous solution of two equivalents of the
dipotassium salt of sulfoxide were added one equivalent
of (−)-quinine sulfate and chloroform, and the mixture
was shaken until the partition equilibrium was reached.
The partially resolved sulfoxide was isolated from both
phases. (+)-2a and (−)-2a were found in 45 and 43%
enantiomeric excess in the organic and the aqueous
phases, respectively. The enantiomerically pure enan-
tiomers were obtained by utilizing the different solubili-
ties of the enantiomeric and racemic forms of 2a. The
enantiomers dissolve in dioxane, whereas the insoluble
racemic form can be filtered off. Thus both (S)-(+)-2a
and (R)-(−)-2a diaryl sulfoxide dicarboxylic acids were
obtained in enantiomerically pure form from the diox-
ane solutions. (For the designation of configurations
see Section 2.5.) The enantiomeric excess was deter-
mined by 1H NMR spectroscopy using the complex
formed from the corresponding dimethyl ester of (+)-2a
and (−)-2a and the chiral shift reagent Eu(tfc)3.
The absolute configurations of the optically active com-
pounds were investigated by CD spectroscopy,1,2,5,6,17
stereospecific syntheses1,3,5 and in a few cases by X-ray
analysis.1,2 In CD studies molecules of known absolute
configurations were used as references.
Herein we report the synthesis of the enantiomers of an
optically active naphthyl-phenyl-bis(acyloxy)spiro-l4-
sulfane, starting from optically active sulfoxide dicar-
boxylic acid enantiomers. The selectivity of the
dehydration reactions is associated with the different
reactivities of the carboxylic groups, linked to the ortho
and peri positions of the S-phenyl and S-naphthyl rings
in the precursor sulfoxide. The reverse reaction yielding
optically active sulfoxide dicarboxylic acids was also
studied in order to clear up the role of the acyloxy spiro
rings with different ring size. The absolute configura-
tions of the model compounds were investigated by CD
spectroscopy, considering the coupling of the electric
transition dipole moments. Empirical rules14 were
2.2. Formation of spiro-l4-sulfane (R)-(−)-2 and (S)-
(+)-2
When (S)-(+)- and (R)-(−)-2a sulfoxide dicarboxylic
acids were treated at room temperature with acetic
anhydride in dichloromethane, (R)-(−)- and (S)-(+)-
3H-2,1-benzoxathiole-1-spiro-1%-(3H-naphtho[1,8-d,e]-
2,1-oxathiine)-3,3%-dione, i.e. (R)-(−)-2 and (S)-(+)-2,
respectively, were obtained. (For the designation of
configurations see Section 2.4.) The mechanism of the
conversion of sulfoxide (S)-(+)-2a into spiro-l4-sulfane
(R)-(−)-2 is shown in Scheme 3.

J. Varga et al. / Tetrahedron: Asymmetry 44 (2003) 3745–3753
3747
Scheme 3.
In an earlier paper1 we described the stereospecific
synthesis of diaryl(acyloxy)(alkoxy)spiro-l4-sulfane
enantiomers starting from optically active diaryl sulfox-
ides having carboxyl and hydroxymethyl substituents
on the aryl rings. As dehydrating agent acetyl chloride
was used. The stereospecific ring closure was explained
by the formation of an isolated unstable mixed anhy-
dride intermediate which transforms stereospecifically
into the given spiro-l4-sulfane enantiomer. In the same
way we may suppose that the peri-carboxyl group in
the naphthalene ring is acetylated selectively when one
of the enantiomers of 2a is treated with acetic anhy-
dride, which leads to the reactive mixed anhydride
intermediate 2d. In the following step the sulfinyl-oxy-
gen attacks the carbon atom of the acetylated carboxyl
group and one of the spiro ring is formed (2d“2e).
Finally the second spiro ring is closed by the attack of
the free ortho-carboxyl group on the positive sulfur
atom as shown in Scheme 3.
and 41% e.e., respectively. On the basis of the present
experimental data and earlier findings3,5,15,16 obtained
for the hydrolysis of spiro-l4-sulfanes with different
axial substituents, we propose two ways of mechanism
(path A and path B) to explain the formation of
sulfoxide enantiomers in the hydrolysis of spiro-l4-sul-
fane (R)-(−)-2 (Scheme 4).
Path A (basic medium). By an equilibrium splitting of
the hypervalent bonds in compound (R)-(−)-2, one of
the spiro rings can be opened, resulting in the forma-
tion of monocyclic acyloxysulfonium–carboxylate zwit-
terion intermediates 3 and 7 (path A and path B). It
seems very likely that the equilibria may be shifted
toward 3 (with the conservation of the six-membered
ring), because in compound 2 the SꢁO hypervalent
,
bond in the five-membered ring is longer (1.869 A) and
8
,
weaker than in the six-membered one (1.839 A).
Although the sulfonium centre built in a six-membered
ring (as in 3) is known to be less reactive16 than its
five-membered analogue (as in 7), the hydroxide ions in
basic medium are strong enough nucleophiles to attack
effectively the less reactive sulfonium centre in 3 which
can be present in greater concentration than 7. The
reaction of 3 leads to a monocyclic (hydroxy)(acyloxy)-
l4-sulfane 4 from which (R)-(−)-2a is formed by ring-
opening associated with proton-transfer.
The selective acetylation of the peri-carboxyl group can
be attributed to the conformation of the precursor
sulfoxide 2a. It is known that phenyl sulfoxides with
ortho-carboxyl group are stabilized by an effective S···O
close contact of 1,5 type.20 On the other hand, the
peri-carboxyl group could participate only in a less
effective S···O interaction of 1,6 type, so its acetylation
is presumably more favorable. Conclusions about the
enantiomeric purity of spiro-l4-sulfane 2 enantiomers
were drawn from hydrolysis experiments (see Section
2.3).
Path B (neutral and acidic media). In neutral and acidic
media water molecule as a poor nucleophile can not
cleave the six-membered hetero ring in cyclic
acyloxysulfonium-carboxylate 3, but can react with the
more reactive sulfonium centre in the analogous inter-
mediates 7 or 5 having five-membered hetero ring.
2.3. Hydrolysis of spiro-l4-sulfane (R)-(−)-2
Previous experiments showed that the hydrolysis of
Path A and path B describe two different stereospecific
ways of enantiomeric sulfoxide formation. Because the
reactivity of the two acyloxysulfonium-carboxylate 3
and 7, formed as key intermediates from the starting
spiro-l4-sulfane (R)-(−)-2, are not extremely different,
the two ways of reaction take place parallel, and so the
complex reaction cannot be regarded stereospecific.
Nevertheless, path A dominates in basic conditions
while path B in neutral and acidic conditions. Unfortu-
nately, from these results we cannot determine exactly
the enantiomeric excess of the starting spiro-l4-sulfane
2 enantiomers, and can only assert that it may be not
less than 66%.
racemic diaryl-bis(acyloxy)spiro-l4-sulfane
2
takes
place very rapidly,15 even in a solvent containing only a
few percent of water. Both the opening of the spiro ring
and the hydrolysis of the monocyclic acyloxysulfonium
salt21 are fast reactions. We investigated now an opti-
cally active starting material, spiro-l4-sulfane (R)-(−)-2,
and found that the enantiomeric distribution of the
sulfoxide product depends on the pH of the medium,
similar to the case of diaryl(alkoxy)(acyloxy)- and
diaryl-(acylamino)(acyloxy)spiro-l4-sulfanes.3,5 In basic
medium sulfoxide (R)-(−)-2a was formed in 66% e.e.,
whereas in neutral and acidic solvents (S)-(+)-2a in 61

3748
J. Varga et al. / Tetrahedron: Asymmetry 44 (2003) 3745–3753
Scheme 4.
2.4. Configuration of diaryl-spiro-l4-sulfanes and related
band may be smaller (compounds 10, 11 and 15) or it
may even be missing (compounds 12 and 13) from the
CD spectra. The sign of the exciton couplet is charac-
teristic for the absolute configuration of the compounds
and it can be determined17 from the orientation of the
coupled electric transition dipole moments of the two
aromatic rings. The sign of the couplet comes from that
of the long wavelength band of the exciton couplet,
found at about 240 nm (Table 1). The similarity
between the CD spectra of spiro-l4-sulfanes and their
sulfonium salt derivatives is the consequence of their
analogous trigonal bipyramidal arrangement about the
central sulfur atom.
sulfonium salts
The absolute configurations of spiro-l4-sulfanes 8 and
13 were determined by X-ray crystallography,1 while
that of the other spiro-l4-sulfanes 9–12 and 14–16 and
sulfonium salts 8b, 11b and 13b–16b, were obtained by
comparative analysis of the CD spectra6,17 (see Table 1
and Figure 1).
The bands in the UV and CD spectra were assigned to
1
1
1
the Bb, La, and Lb transitions of the aromatic rings.
The n“s* band due to the excitation of the electron in
the sulfur lone pair cannot be found in the UV spec-
trum as it is blue shifted because of the high positive
charge of the sulfur atom.17 An exciton coupling
For the definition of a new empirical rule we concluded
from the structure of spiro-l4-sulfanes and related sul-
fonium salts of known absolute configuration that if the
molecule of trigonal bipyramidal geometry is viewed
from the side of the equatorial lone pair, ‘apical axis’ is
vertical and the hetero rings fused with the aromatic
rings or the substituents involved in the S···O close
contact are in the upper-right and the lower-left sector,
1
between the La transition of the benzene rings or that
of the 1La and 1Bb transitions of the benzene and
naphthalene rings, respectively, was observed in the CD
spectra of these compounds. It must be mentioned,
however, that in some cases the couplet is rather
unsymmetric, the intensity of the short wavelength

J. Varga et al. / Tetrahedron: Asymmetry 44 (2003) 3745–3753
3749
Table 1. Wavelength and Dm values (dm3 mol−1 cm−1, in acetonitrile) of the long wavelength bond of the exciton couplet for
spiro-l4-sulfanes and sulfonium salts of trigonal bipyramidal geometry. Formulas are given in Figure 1.
Compound
Formula
U–V–S
Z–Y
u/nm
Dm
Ref.
a
(R)-(−)-2
(S)-(+)-2
(S)-(−)-8
(R)-(+)-8
(S)-(−)-8b
(S)-(+)-9
(S)-(+)-10
(S)-(+)-11
(R)-(+)-11b
(S)-(+)-12
(R)-(+)-13
(S)-(−)-13
(S)-(+)-13b
(R)-(−)-13b
(R)-(+)-14
(S)-(+)-14b
(S)-(+)-15
(R)-(−)-15b
(S)-(+)-16
(R)-(+)-16b
D
C
CO–O–S
CO–O–S
CO–O–S
CO–O
CO–O
CH2–O
CH2–O
CH2–O
CO–O
236
236
234.5
234.5
243
236
242
238.5
239
243
237.5
237.5
242
242
236
237.5
237.5
227
235
235.5
−61.8
86.6
52.3
−52.3
−22.8
53.5
83.9
42.4
42.1
27.2
75.4
−75.4
29.9
−29.9
71.0
89.9
125
a
17
A, X=H
B
B
A, X=H
A, X=Cl
A, X=H
A, X=H
1,6,17
5,6
17
CO–O–S
C(OCH3)ꢀO···S+
CO–O–S
17
CO–O–S
CO–O
6,17
6
CO–O–S
CO–NMe
CO–NMe
CO–NMe
CH2–O
CH2–O
CH2–O
CH2–O
CO–NMe
CO–NMe
CH2–O
CH2–O
CO–NMe
CO–NMe
C(OCH3)ꢀO···S+
CO–O–S
17
A, X=Cl
1,6,17
17
C
D
C
D
C
C
E
E
E
E
CO–O–S
CO–O–S
6
C(OCH3)ꢀO···S+
C(OCH3)ꢀO···S+
CO–O–S
5
6
6
C(OCH3)ꢀO···S+
CO–O–S
1,6,17
5,6
6
C(OCH3)ꢀO···S+
CO–O–S
60.5
80.4
103
6
C(OCH3)ꢀO···S+
a This work.
then the sign of the exciton couplet is positive (Formu-
las A, C and E in Fig. 1 and Table 1). On the other
hand, the sign of the couplet is negative if the hetero
rings or the given substituents are in the upper-left and
lower-right sectors (Formulas B and D in Fig. 1, Table
1). The sign of the sectors is opposite to that used for
the octant rule of ketones.22 The rule was found to be
valid for the sign of the Cotton effect of the band near
to 240 nm even in those cases when the short wave-
length band of the couplet was missing from the CD
spectrum (e.g. in the case of compounds 12 and 13,
Table 1). The sign of the couplet is related to the
configuration of the molecules and does not have any
connection with the stereochemical descriptors (R) and
(S), which are based on a priority convention and do
not express any stereochemical analogy. It is remark-
able that spiro-l4-sulfanes and their sulfonium salt
derivatives, with different chemical bonds but with the
same spatial arrangement, give rise to couplets with the
same sign. Besides, the first eluted enantiomer of spiro-
l4-sulfanes on an HPLC column with the chiral sorbent
Kromasil CHI DMB shows
a
positive exciton
couplet4,6,17 and therefore a structure analogous to
those given in formulas A, C or E in Figure 1.
Figure 1. Schematic representation of the empirical rule for prediction of the sign of the exciton couplet for spiro-l4-sulfanes and
related sulfonium salts of trigonal bypyramidal structure. The molecules are viewed from the side of the equatorial lone pair (not
shown in the Figure as being in overlap with the central sulfur atom); Z–Y and U–V–S symbols are explained in Table 1.

3750
J. Varga et al. / Tetrahedron: Asymmetry 44 (2003) 3745–3753
Data obtained from the CD and UV spectra of naphthyl-
phenyl-bis(acyloxy)spiro-l4-sulfanes enantiomers 2 are
given in Table 2.
1
1
The La and Lb transitions of the naphthalene and the
1Lb transition of the benzene ring show Cotton effects
of small intensity between 260 and 330 nm. One can find,
however, a high intensity negative exciton couplet at 236
and 216 nm in the CD spectrum of the (−)-2 (Fig. 2) and
a positive one for the (+) enantiomer (Table 2). This
couplet can be assigned to the coupled electrical transition
dipoles of the 1Bb transition of the naphthalene (long-axis
1
polarization) and the La transition of the benzene ring
(polarization direction along the aromatic para-carbon
and the carbonyl-carbon atoms). As shown in Figure 3
the given transition dipole moments define a negative
projection angle for the (R)-enantiomer, so this configu-
Figure 2. CD (—) and U
acetonitrile).
V (- - -) spectra of (R)-(−)-2 (in
Table 2. Spectral data of naphthyl-phenyl-bis(acyloxy)spiro-
l4-sulfane 2, (8-carboxy-1-naphthylsulfinyl)benzoic acid
2a and (8-carboxy-1-naphthylsulfinyl)benzoic acid methyl
ester 2c. Solvent: acetonitrile; for 2c acetonitrile and ethanol
Compound
Spectrum
u/nm
(CD: Dm/dm3 mol−1 cm−1; UV:
m/103 dm3 mol−1 cm−1
)
(R)-(−)-2a
(S)-(+)-2b
CD
UV
CD
UV
CD
217 (43.3)h 236 (−61.8)h 274
(−1.4)i 312 (−2.3)i 330 (−1.9)i
200 (39.1)g 219 (38.0)h 313 (6.9)i
ꢀ333(4.3)i
216 (−61.3)h 236 (86.8)h 273 (2.7)i
311 (3.5)i 328 (3.3)i
200 (43.1)g 219 (42.1)h 313 (7.6)i
ꢀ327 (6.1)i
(R)-(−)-2ac
(S)-(+)-2ad
(S)-(+)-2ce
(S)-(+)-2cf
198 (48.0)g 230.5 (−47.0)h 257.5
(−43.6)h ꢀ278 (−7.6)i 301 (11.2)i
200 (37.0)g 227 (47.5)h 294 (8.1)i
198 (−48.8)g 232 (48.0)h 257.5
(45.2)h ꢀ281 (7.4)i 304 (−11.6)i
200 (36.8)g 227 (47.3)h 294 (7.9)i
198 (−48.8)g 232 (36.3)h 257
(36.5)h ꢀ283 (3.0)i 301 (−8.6)i
199 (39.4)g 227 (52.5)h 294 (8.8)i
198 (−61.1)g ꢀ223.5 (38.5)j 234
(47.9)h 257 (45.8)h ꢀ282 (6.5)i
302 (−9.1)i
UV
CD
1
1
Figure 3. Orientation of the benzene La and naphthalene Bb
transition dipole moments of (R)-(−)-2, which define negative
chirality.
UV
CD
UV
CD
ration can be assigned to (−)-2, exhibiting a negative
couplet in the CD spectrum.
UV
199 (41.7)g 227 (55.6)h 295 (9.4)i
The same result is obtained with the application of the
empirical rule. On the basis of the sign of the bands at
236 nm in the CD spectrum (Table 1) the structures D
and C (Fig. 1) and therefore configuration (R) and (S),
respectively, can be proposed for the (−)- and (+)
enantiomers of 2.
Structures:
a
Formula D, Fig. 1; U–V–S=CO–O–S, Z–Y=CO–O.
b Formula C, Fig. 1; U–V–S=CO–O–S, Z–Y=CO–O.
c Formula F, Fig. 7; X=Y=COOH.
d Formula G, Fig. 7; X=Y=COOH.
e Formula G, Fig. 7; X=Y=COOMe; solvent: acetonitrile.
f Formula G, Fig. 7; X=Y=COOMe; solvent: ethanol.
Assignments:
2.5. Configuration of naphthyl phenyl sulfoxides
g 1Bb transition of the benzene ring.
The CD spectra of dialkyl, alkyl phenyl and diphenyl
sulfoxides are widely discussed in the literature.23–25 Three
bands can be found in the UV spectra of naphthyl-phenyl-
sulfoxides substituted with two carboxyl groups (com-
pound 2a) at about 200, 230 and 295 nm. In the CD
h 1Bb transition of the naphthalene ring and 1La transition of the
benzene ring.
1
1
i 1La and Lb transitions of the naphthalene ring and Lb transition of
the benzene ring.
j n“s* transition of the sulfur lone pair.

J. Varga et al. / Tetrahedron: Asymmetry 44 (2003) 3745–3753
3751
Figure 4. CD (—) and UV (- - -) spectra of (S)-(+)-2a (in
acetonitrile).
1
Figure 6. Orientation of the Bb transition dipole moments of
benzene and naphthalene rings in (S)-(+)-2a, which define
positive chirality.
The CD spectrum of (+)-2c, the dimethyl ester of
sulfoxide-(+)-2a, (Fig. 5) recorded in acetonitrile is very
similar to that of sulfoxide dicarboxylic acid (+)-2a (Fig.
4). Intramolecularhydrogenbondsseemstohavenoeffect
on the electronic transitions of the sulfoxide 2a. Compar-
ing the curves of (+)-2c in acetonitrile and ethanol, a
shoulder can be seen at 223.5 nm in the latter solvent.
This can be assigned to the n“s* transition of the sulfur
atom, which is blue shifted in the protic solvent. The CD
spectra of the enantiomers of (+)-2a, (+)-2c and (−)-2a
are analogous to those of (S)-(+)-13a, (S)-(+)-15a
(configuration determined by X-ray diffraction1) and
(S)-(+)-16a6 andtothatof(R)-(−)-14a6 ofknownabsolute
configuration, respectively (Table 3). This suggests (S)
configuration for (+)-2a and (+)-2c, while (R) configura-
tion for (−)-2a.
Figure 5. CD spectra of (S)-(+)-2c in acetonitrile (—) and
ethanol (- - -).
spectrum (Fig. 4) two additional Cotton effects are
present in the vicinity of 260 and 280 nm. The CD bands
at 200 and 300 nm are of opposite sign as the others. These
1
1
1
bands can be assigned to the Bb, La and Lb electronic
transitions of the naphthalene and benzene rings as given
in Table 2.
X-Ray diffraction studies2 proved that the SꢀO bond and
the benzene ring are nearly in the same plane in the
1
1
Table 3. l/nm (Dm) values (in acetonitrile) of the Cotton effect of the Bb transition of the naphthalene ring and La
transition of the benzene ring in naphthyl phenyl sulfoxides. Formulas are given in Figure 7
Compound
Formula
Y
X
l/nm (Dm)
Ref.
b
(R)-(−)-2a
(S)-(+)-2a
(S)-(+)-2c
F
COOH
COOH
COOMe
CH2OH
CH2OH
CH2OH
CONHMe
CONHMe
COOH
COOMe
COOH
COOMe
–
COOH
COOH
COOMe
COOH
COOH
COOMe
COOH
COOMe
CH2OH
CH2OH
CONHMe
CONHMe
–
230.5 (−47.0) 257.5 (−43.5)
232 (48.0) 257.5 (45.2)
232 (36.3) 257 (36.5)
233 (−77.5)
233 (77.5)
234 (−48.2)
230 (−40.4), 254 (−43.4)
229 (−31.8), 253.5 (−51.6)
232 (65.3), 259 (15.2)
231 (46.6), 254 (10.8)
230 (49.9), 255.5 (23.7)
229.5 (78.4), 256 (35.6)
242 (−7.1)
b
G
G
F
G
F
b
6
(R)-(−)-13a
(S)-(+)-13a
(R)-(−)-13c
(R)-(−)-14a
(R)-(−)-14c
(S)-(+)-15a
(S)-(+)-15c
(S)-(+)-16a
(S)-(+)-16c
(S)-(+)-17a
1
6
6
F
F
6
1,6
6
G
G
G
G
–
6
6
24
a (2-Naphthyl) (4-tolyl) sulfoxide.
b This work.

3752
J. Varga et al. / Tetrahedron: Asymmetry 44 (2003) 3745–3753
3. Experimental
3.1. CD measurements
energetically most favored conformation of the naph-
thyl-phenyl-sulfoxides, and the naphthalene ring is by
about 110° twisted with respect to this plane (Fig. 6).
CD spectra of the samples were measured on a Jasco
J 810 Dichrograph. Circular dichroism is expressed as
Dm, in units of dm3 mol−1 cm−1. Measurements were
carried out at rt in 0.05 cm cells. Acetonitrile and
ethanol were used as solvents. The concentration of
the samples ranged between 3.5 and 3.8 mM.
The aromatic rings together with their C-substituents
are placed in the region opposite to the S“O bond
direction and there is a close contact between the
sulfur atom and the oxygen atom of the carbonyl
group bound to the benzene ring. It seems from the
CD spectra (+)-2a and (+)-2c that exciton coupling
1
occurs in these compounds between the Bb bands of
3.2. (R)-(−)- and (S)-(+)-2-(8-Carboxy-1-naphthylsulfi-
nyl)benzoic acid 2a
the benzene and naphthalene rings, as an EC-CD
spectrum can be observed (Table 2, Figs. 4 and 5).
1
Though the true directions of the two Bb transitions
To a solution of KHCO3 (6 g, 60 mmol) in water (100
mL) was added racemic sulfoxide 2a (6.8 g, 20 mmol)
and stirred to afford a clear solution. Then it was
transferred into a separatory funnel and mixed with
(−)-quinine sulfate dihydrate (7.82 g, 10 mmol) and
chloroform (250 mL). The mixture was shaken until
two clear liquid phases were formed at 25°C equi-
librium temperature (ꢀ300 shakings). The water layer
was separated and washed with chloroform (3×10 mL),
then acidified with 1N H2SO4 (ꢀ45 mL) at 5°C to yield
a solid precipitate. It was kept in ice-bath for 1 h, then
filtered off and washed free from H2SO4 with distilled
water to give sulfoxide (−)-2a monohydrate (3.59 g);
[h]578=−222 (c=0.5, DMF, 25°C); e.e.=43%. The
above sulfoxide monohydrate (2.52 g, 7.04 mmol of
[h]578=−222) was stirred with dioxane (50 mL) at rt for
1 h. The crystalline precipitate was filtered off and
washed with dioxane (3×5 mL) and dried to afford 1.82
g of the racemic sulfoxide 2a–dioxane 1:1 complex. The
dioxane solution was treated with charcoal at rt for 1 h,
then filtered and evaporated in vacuo at 35–40°C. The
resulting oil was dissolved in 0.5N KHCO3 (20 mL) and
about 5 mL of the solvent was removed in vacuo. The
dioxane-free solution obtained was acidified at 10°C by
1N H2SO4 (pH 2). The white crystalline product was
filtered off and washed with water and dried over KOH
in a vacuum desiccator to yield enantiomerically pure
sulfoxide (−)-2a monohydrate (1.01 g); [h]578=−508 (c
0.5, DMF, 25°C); e.e. >98%; mp 235–250°C (dec.); IR
wmax (KBr)/cm−1 3537s (OH, H2O), 3300–2200br (OH,
COOH), 1695vs (CꢀO), 989vs (SꢀO). 1H NMR (250
MHz, DMSO-d6) l 13.38 (br, 2H, COOH), 7.40–8.52
(m, ArH).
dipoles of the disubstituted aromatic rings are not
known, they seem to define positive chirality and a
positive couplet in the given conformation for com-
pounds (+)-2a with an (S)-configuration (Fig. 6).
An empirical rule can also be used for the determina-
tion of the configuration of naphthyl-phenyl-sulfox-
ides. The molecules of the given type should be
viewed from the direction of the lone pair with the
SꢀO bond placed downwards in a vertical plane (Fig.
7).
If the naphthalene ring is in the upper-right or lower-
left sector then the sign of the Cotton effect found
between 230 and 250 nm and assignable to the naph-
1
1
thalene Bb and benzene La transitions is positive. If
the naphthalene ring is situated in the upper-left or
lower-right sector then the Cotton effect is negative
(Fig. 7, Table 3). The signs of the sectors is the same
as those for spiro-l4-sulfanes and sulfonium salts. The
rule proved to be valid for determining the configura-
tion of (S)-(+)-(2-naphthyl) (4-tolyl) sulfoxide 1724
(Table 3) as well as (S)-alkyl-phenyl- and (S)-alkyl-
naphthyl-sulfoxides.25 For alkyl aryl sulfoxides the
position of the aromatic ring defines the sign of the
couplet.
To prepare the (+)-enantiomer of 2a the chloroform
phase was extracted with 1N Na2CO3 solution (3×50
mL) and acidified with 5N H2SO4 (30 mL) at 5°C. The
precipitate was collected by filtration, washed with
water and dried to yield compound (+)-2a monohydrate
(3.46 g); [h]578=+232 (c 0.5, DMF, 25°C); e.e.=45%.
To obtain the enantiomerically pure enantiomer of
(+)-2a a similar procedure was applied as described for
the purification of (−)-2a (1.0 g); [h]578=+510 (c 0.5,
DMF, 25°C); e.e.>98%.
Figure 7. Schematic representation of the empirical rule for
prediction of the sign of the exciton couplet for naphthyl
phenyl sulfoxides. The molecules are viewed from the direc-
tion of the lone pair (not shown in the Figure as being in
overlap with the central sulfur atom) with the SꢀO bond
placed downwards in a vertical plane; X and Y symbols are
explained in Table 3.
3.3. (R)-(−)- and (S)-(+)-3H-2,1-benzoxathiole-1-spiro-
1%-(3H-naphtho[1,8-d,e]-2,1-oxathiine-3,3%-dione 2
Sulfoxide (S)-(+)-2a (0.18 g, 0.50 mmol) was dried by
azeotropic distillation of dioxane in vacuo at 40°C

J. Varga et al. / Tetrahedron: Asymmetry 44 (2003) 3745–3753
3753
(3×10 mL). The residue was dissolved in dry pyridine (2
mL) and to this solution was added a mixture of 1:9
dichloromethane-acetic anhydride (0.5 mL). After stir-
ring for 10 min at rt diethyl ether (4 mL) was added
and the crystals precipitated was filtered off, washed
with diethyl ether (3x2 mL) and dried to afford (R)-(−)-
2 (0.12 g, 75%); [h]578=−416 (c 0.5, DMF, 25°C); mp
249–256°C (dec.); IR wmax (KBr)/cm−1 1724vs, 1695vs
5. Szabo´, D.; Varga, J.; Csa´mpai, A.; Kapovits, I. Tetra-
hedron: Asymmetry 2000, 11, 1303.
6. Varga, J.; Szabo´, D.; Hollo´si, M. Enantiomer 2000, 5,
513.
7. Kapovits, I.; Ka´lma´n, A. J. Chem. Soc., Chem. Commun.
1971, 649.
8. Kapovits, I.; Ra´bai, J.; Szabo´, D.; Czako´, K.; Kucsman,
´
A.; Argay, Gy.; Fu¨lo¨p, V.; Ka´lma´n, A.; Koritsa´nszky, T.;
1
(CꢀO); H NMR (250 MHz, CDCl3) l 7.56–8.76 (m,
ArH).
Pa´rka´nyi, L. J. Chem. Soc., Perkin Trans. 2 1993, 847.
´
9. Szabo´, D.; Kapovits, I.; Kucsman, A.; Huszthy, P.;
Argay, Gy.; Czugler, M.; Fu¨lo¨p, V.; Ka´lma´n, A.; Korit-
sa´nszky, T.; Pa´rka´nyi, L. J. Mol. Struct. 1993, 300, 23.
10. Szabo´, D.; Kapovits, I.; Argay, Gy.; Czugler, M.;
Ka´lma´n, A.; Koritsa´nszky, T. J. Chem. Soc., Perkin
Trans. 2 1997, 1045.
Spiro-l4-sulfane (S)-(+)-2 was prepared by a similar
procedure starting from sulfoxide (R)-(−)-2a. Yield:
0.13 g (80%); [h]578=+387 (c 0.5, DMF, 25°C).
3.4. Hydrolysis of spiro-l4-sulfane (R)-(−)-2
´
11. Szabo´, D.; Kapovits, I.; Kucsman, A.; Fu¨lo¨p, V.; Czu-
gler, M.; Ka´lma´n, A. Struct. Chem. 1990, 1, 305.
(A) The mixture of spiro-l4-sulfane (R)-(−)-2 (0.1 g,
0.31 mmol), acetone (2 mL) and aqueous Na2CO3 (1
M, 2 mL) was stirred at rt for 15 min then acidified
with HCl (2 M, 2 mL). Acetone was removed in vacuo,
the crystals were collected by filtration, washed with
water and dried. Yield: 0.087 g, (83%). (R)-(−)-2a;
[h]578=−342 (c 0.5, DMF, 25°C), e.e. 66%.
´
12. Szabo´, D.; Kapovits, I.; Kucsman, A.; Czugler, M.;
Fu¨lo¨p, V.; Ka´lma´n, A. Struct. Chem. 1991, 2, 529.
´
13. Szabo´, D.; Kapovits, I.; Kucsman, A.; Nagy, P.; Argay,
Gy.; Ka´lma´n, A. J. Mol. Struct. 1999, 476, 157.
´
14. Szabo´, D.; Ruff, F.; Kucsman, A. Targets in Heterocyclic
Systems 2001, 5, 199 and references cited therein.
15. Vass, E.; Ruff, F.; Kapovits, I.; Ra´bai, J.; Szabo´, D. J.
Chem. Soc., Perkin Trans. 2 1993, 855.
(B) The mixture of spiro-l4-sulfane (R)-(−)-2 (0.1 g,
0.31 mmol), acetone (2 mL) and water (2 mL) was
stirred at rt for 15 min. Acetone was removed in vacuo,
the crystals were collected by filtration, washed with
water and dried. Yield: 0.086 g, (82%). (S)-(+)-2a;
[h]578=+316 (c 0.5, DMF, 25°C), e.e. 61%.
16. (a) Vass, E.; Ruff, F.; Kapovits, I.; Szabo´, D.; Kucsman,
´
´
A. J. Chem. Soc., Perkin Trans. 2 1997, 2061; (b) Ada´m,
´
T.; Ruff, F.; Kapovits, I.; Szabo´, D.; Kucsman, A. J.
Chem. Soc., Perkin Trans. 2 1998, 1269; (c) Nagy, P.;
Csa´mpai, T.; Szabo´, D.; Varga, J.; Harmat, V.; Ruff, F.;
´
Kucsman, A. J. Chem. Soc., Perkin Trans. 2 2001, 339.
17. Szendeffy, Sz.; Szarvas, Sz.; Szabo´, D.; Kapovits, I.;
(C) The mixture of spiro-l4-sulfane (R)-(−)-2 (0.1 g,
0.31 mmol), acetone (2 mL) and aqueous HCl (1 M, 1
mL) was stirred at rt for 15 min. Acetone was removed
in vacuo, the crystals were collected by filtration,
washed with water and dried. Yield: 0.089 g, (85%).
(S)-(+)-2a; [h]578=+212 (c 0.5, DMF, 25°C), e.e. 41%.
Hollo´si, M. Enantiomer 1998, 3, 323.
18. Martin, J. C.; Balthazor, T. M. J. Am. Chem. Soc. 1977,
99, 152.
19. Ra´bai, J. Angew. Chem., Int. Ed. Engl. 1992, 31, 1631.
´
20. Kucsman, A.; Kapovits, I. In Organic Sulfur Chemistry:
Theoretical and Experimental Advances; Bernardi, F.;
Csizmadia, I. G.; Mangini, A., Eds. Nonbonded Sulfur-
Oxygen Interaction in Organic Sulfur Compounds;
Elsevier: Amsterdam, 1985; p. 185.
Acknowledgements
21. Oae, S.; Numata, T.; Yoshimura, T. In The Chemistry of
the Sulphonium Group; Stirling, C. J. M., Ed. Heterosul-
phonium Salts; Wiley: New York, 1981; p. 571.
22. Lambert, J. B.; Shurvell, H. F.; Lightner, D. A.; Cokks,
R. G. Organic Structural Spectroscopy; Prentice Hall:
Upper Sadle River, NJ, 1998; pp. 312–318.
This work was supported by the Hungarian Scientific
Research Foundation (OTKA, Nos. T 029799, T
034866 and T 043639).
23. (a) Mislow, K.; Green, M. M.; Laur, P.; Melillo, J. T.;
Simmons, T.; Ternay, A. L., Jr. J. Am. Chem. Soc. 1965,
87, 1958; (b) Moretti, I.; Torre, G.; Gottarelli, G. Tetra-
hedron Lett. 1976, 17, 711; (c) Moriyama, M.;
Yoshimura, T.; Furukawa, N.; Numata, T.; Oae, S.
Tetrahedron 1976, 32, 3003; (d) Sztaricskai, F.; Dinya, Z.;
Batta, Gy.; Mocsa´ri, A.; Hollo´si, M.; Majer, Zs.;
Masuma, R.; Omura, S. J. Antibiot. 1997, 50, 866 and
references cited therein.
References
´
1. Szabo´, D.; Szendeffy, Sz.; Kapovits, I.; Kucsman, A.;
Czugler, M.; Ka´lma´n, A.; Nagy, P. Tetrahedron: Asym-
metry 1997, 8, 2411.
2. Szabo´, D.; Szendeffy, Sz.; Kapovits, I.; Kucsman, A.;
´
Argay, Gy.; Ka´lma´n, A.; Pa´rka´nyi, L. Tetrahedron:
Asymmetry 1997, 8, 2403.
24. Saeva, F. D.; Rayner, D. R.; Mislow, K. J. Am. Chem.
Soc. 1968, 90, 4177.
25. Rosini, C.; Donnoli, M. I.; Superchi, S. Chem. Eur. J.
3. Varga, J.; Szabo´, D.; Sa´r, C. P.; Kapovits, I. Tetrahedron
Asymmetry 2001, 12, 745.
4. Szo´ka´n, Gy.; Szarvas, Sz.; Majer, Zz.; Hollo´si, M.;
2001, 7, 72.
Szabo´, D.; Kapovits, I. J. Liq. Chromatogr. 1999, 22, 993.