Dioxygenase-catalysed sulfoxidation of bicyclic alkylaryl sulfides and chemoenzymatic synthesis of acyclic disulfoxides

Article abstract of DOI:10.1016/j.tet.2003.10.107

Toluene- and naphthalene-dioxygenase-catalysed oxidation of six bicyclic disulfide substrates, using whole cells of Pseudomonas putida, gave the corresponding monosulfoxides with high ee values and enantiocomplementarity, in most cases. Two alcohol-sulfox

Full text of DOI:10.1016/j.tet.2003.10.107

Tetrahedron 60 (2004) 549–559
Dioxygenase-catalysed sulfoxidation of bicyclic alkylaryl sulfides
and chemoenzymatic synthesis of acyclic disulfoxides
a
a
a
Derek R. Boyd,a Narain D. Sharma, Simon A. Haughey, Martina A. Kennedy,
,
*
John F. Malone,a Steven D. Shepherd,a Christopher C. R. Allenb and Howard Daltonc
aSchool of Chemistry, The Queen’s University of Belfast, David Keir Building, Belfast BT9 5AG, UK
bQUESTOR Centre, The Queen’s University of Belfast, Belfast BT9 5AG, UK
cDepartment of Biological Sciences, The University of Warwick, Coventry CV4, UK
Received 8 August 2003; revised 28 August 2003; accepted 17 October 2003
Abstract—Toluene- and naphthalene-dioxygenase-catalysed oxidation of six bicyclic disulfide substrates, using whole cells of
Pseudomonas putida, gave the corresponding monosulfoxides with high ee values and enantiocomplementarity, in most cases. Two
alcohol-sulfoxide diastereoisomers, formed from the reaction of the (R)-1,3-benzodithiole-1-oxide metabolite with n-butyllithium and
benzaldehyde, were separated and stereochemically assigned. Treatment, of enantiopure (1R,3R)-benzo-1,3-dithiole-1,3-dioxide, obtained
by chemoenzymatic synthesis, with alkyllithium reagents, resulted in a novel ring-opening reaction which proceeded with inversion of
configuration to yield a series of acyclic disulfoxides.
q 2003 Elsevier Ltd. All rights reserved.
1. Introduction
article, provide a further demonstration of the value of
enantiocomplementary dioxygenase enzymes for the pro-
duction of enantiopure cyclic monosulfoxides from 1,3-,
1,4- and 1,5-disulfides. The enantiopure monosulfoxide
metabolite 1B, from benzo-1,3-dithiole 1A, and the derived
disulfoxide 1C, have, in turn, been used to investigate their
reactions with alkyllithium reagents.
The potential of microbial enzymes in the biocatalytic
oxidation of sulfides, to yield enantiopure sulfoxides, has
been recognised for many years. t-Butyl p-tolyl sulfoxide,
the first reported enantiopure example of a sulfoxide
produced by enzyme-catalysed oxidation of an achiral
sulphide,1 was obtained using the fungus Aspergillus niger
(foetidus), a source of monooxygenase enzymes. More
recent biotransformation studies, from these2–7 and other
laboratories,8,9 have shown that the ring hydroxylating
dioxygenase enzymes (Rieske non-heme iron oxygenases),
present in the soil bacterium Pseudomonas putida, are
among the most stereoselective biocatalysts, currently
available, for the production of enantiopure acyclic
sulfoxides. Wild-type and mutant P. putida strains,2–8 and
E. coli recombinant strains,3,5,8,9 containing toluene dioxy-
genase (TDO) and naphthalene-dioxygenase (NDO), have
thus, to date, yielded .30 sulfoxides with high (.90%)
enantiomeric excess (ee) values.2–9 Routes to enantiopure
sulfoxides are required for asymmetric synthesis studies
(e.g. as chiral auxiliaries and ligands) and for the production
of pharmaceuticals including anti-ulcer drugs containing a
chiral sulfoxide group (e.g. the proton pump inhibitors
omeprazole, and lanzaprazole). The results, presented in this
2. Results and discussion
2.1. Dioxygenase-catalysed monosulfoxidation of sulfides
1A–8A to yield the corresponding sulfoxides 1B–8B
The initial phase of the study involved biotransformations of
bicyclic disulfide substrates 1A–6A using: (i) P. putida
UV4 (a constitutive mutant strain containing TDO), (ii)
P. putida NCIMB 8859 (a wild-type strain containing NDO)
and, to a lesser extent, (iii), P. putida 9816/11 (an inducible
mutant strain containing NDO). These whole-cell systems
provide sources of the required dioxygenase biocatalysts,
under biotransformation conditions similar to those reported
for earlier sulfoxidation studies.2–9 The isolated yields,
enantiopurity values, and absolute configurations of mono-
sulfoxides 1B–6B are shown in Table 1. Sulfoxides 1B,10
2Bcis,10 2B
,
10 3Bcis,10 3B 10 and 6B11 had earlier been
trans trans
Keywords: Dioxygenase-catalysed sulfoxidation; Enantiopure bicyclic
sulfoxides; Alkylithium; Acyclic disulfoxides.
reported as single enantiomers, while sulfoxides 4B and 5B
were obtained for the first time as single enantiomers, during
the present study.
*
Corresponding author. Tel.: þ44-2890274421; fax: þ44-2890382117;
e-mail address: dr.boyd@qub.ac.uk
0040–4020/$ - see front matter q 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2003.10.107

550
D. R. Boyd et al. / Tetrahedron 60 (2004) 549–559
Table 1. Isolated yields (%Yld.), ee values (% ee) and absolute
configurations (Ab.Con.) of sulfoxides 1B–8B obtained from the
corresponding sulfides 1A–8A using TDO (P. putida UV4) and NDO (P.
putida 8859) in whole-cell systems
alkenylphenyl sulfides (RSPh, R¼Me, Et, CH2vCH2, etc.),
using P. putida UV4 (TDO), showed that an (R)
configuration was observed in all cases.5 This empirical
method, of configuration assignment, was thus based on the
assumption that the cyclic alkylaryl and alkenylaryl sulfides
4A–6A would bind in a similar manner, at the active site of
TDO, and would also show a preference for (1R)
configurations for sulfoxide metabolites 4B–6B (Scheme 1).
Compound
TDO enzyme
NDO enzyme
% ee
%Yld. % ee Ab.Con. %Yld.
Ab.Con.
1B
2Bcis
20
40, 26
5
33
S
74, 72
49
7
—
—
78
26
60
21
2
.98
82
38
—
R
1R,2S
1R,2R
—
—
Sa
S
S
S
R
.98 1S,2R
.98 1S,2S
.98 1S,2R
2B
trans
3Bcis
3B
26
5
1, 3
18
.98
1R,2R
R
—
trans
4B
5B
6B
7B
8B
.98
80 (93)c
.98
38
b
b
b
23
5
10
.98
26
.98
R
R
R
Scheme 1.
43
Conversely, a strong preference for the opposite (S)
sulfoxide configuration was observed earlier, using NDO
with some alkylphenyl and alkenylphenyl sulfides (RSPh,
R¼Me, Et, CH2vCH2, etc.).5 X-ray crystallographic
evidence, of the substrate binding and catalytic sites of
NDO, that can account for the absolute stereochemistry of
the cis-diol metabolites of bicyclic alkenes (e.g. indene) and
arenes (e.g. naphthalene), has recently been reported.12 In
view of the similarity in shape between naphthalene and the
bicyclic sulfide substrates 4A and 6A it is probable that
substrate binding and catalysis, using NDO (Scheme 2), will
yield bioproducts of similar configuration (but opposite to
that obtained using TDO). Thus, absolute configurations of
sulfoxide metabolites 4B–6B were tentatively assigned by
comparison with earlier results, using the TDO and NDO
enzyme systems and acyclic alkylphenyl sulfides as
substrates.
a
Predicted absolute configuration.
No sulfoxide isolated; using P. putida 9816/11 as a source of NDO
biocatalyst.
Recrystallisation of bioproduct from P. putida 9816/11 gave an ee value
of .98%.
b
c
The circular dichroism (CD) spectra, of sulfoxide
metabolites 1B, 2Bcis, 2Btrans, 3Bcis, and 3Btrans, were
found to have a strong absorption around 220 nm due to
an n–pp transition associated with the sulfoxide group.10
This trend, of a positive CD absorption in the 220 nm
region, was consistently associated with the rigorously
established (R) configuration in sulfoxides 1B, 2Bcis, 2B
,
trans
3Bcis, and 3Btrans. The absolute configurations of sulfoxide
enantiomers 4B–6B have not been reported in the literature;
no consistent CD spectral trend was evident that would
allow reliable assignment of their absolute configurations.
Hence, alternative approaches, to the configuration assign-
ments for sulfoxide metabolites 4B–6B were examined.
Earlier studies, of the biotransformation of alkyl- and
Recrystallization of the bioproduct, (2)-1,2,3,4-tetrahydro-
1l4,5-benzodithiepin-1-oxide 5B (80–93% ee) obtained by
NDO-catalysed sulfoxidation, provided an enantiopure

D. R. Boyd et al. / Tetrahedron 60 (2004) 549–559
551
observed for TDO- and NDO-catalysed oxidation of some
acyclic alkylaryl sulfides5 (Scheme 1), were even more
common during the sulfoxidation of cyclic alkylaryl sulfides
to yield sulfoxide metabolites, 1B, 2Bcis, 2Btrans, 4B, 6B and
7B. The most striking examples of enantiocomplementarity
were found when TDO or NDO biocatalysts were used to
produce enantiopure sulfoxides 4B and 6B of opposite
configuration.
The Kagan modified Sharpless reagent, (Ti (i-PrO)4/DET/
t-BuOOH), had earlier11 been used to obtain sulfoxide 6B,
as a single enantiomer (8% yield), after separation from a
product mixture containing three other sulfoxidation
products (92% yield). Biocatalysis now provides a comple-
mentary synthesis (asymmetric oxidation) of sulfoxide 6B
where either enantiomer is available in higher yield and
state of purity. While the stereoselectivity values, found
during sulfoxidations using TDO or NDO, were similar, the
isolated yields were generally better, using the NDO system.
Scheme 2.
sample whose absolute configuration was unequivocally
established, as (1S) by X-ray crystallography, using the
anomalous dispersion method (Fig. 1). The tetrahydro-
dithiepine ring adopts the chair conformation, with an
equatorial oxygen atom. This result lends additional support
to the tentative assignments of (1R) and (1S) configurations
for alkylaryl sulfoxides 4B–6B formed with TDO and NDO
biocatalysts, respectively.
Results from earlier biotransformation studies, using both
acyclic sulfides, and the corresponding racemic sulfoxides
as substrates, for purified dioxygenases (TDO and NDO), or
whole cell bacterial strains, containing TDO and NDO,5,8
suggested that the enantiopure sulfoxide products were
exclusively (or mainly) formed by asymmetric sulfoxida-
tion. During the present study, the cyclic racemic sulfoxides
1B–8B were also tested as substrates for the UV4 and 8859
strains of P. putida. With the exception of recovered
sulfoxide 8B (1S, 74% ee, 8859 strain), the other
biotransformations showed only poor enantioenrichment
of residual sulfoxides. On this basis, it would again appear
that the high ee values, observed for the sulfoxide
metabolites of cyclic sulfides, using TDO and NDO, were
mainly the products of asymmetric sulfoxidation rather than
kinetic resolution. However, during the course of these
biotransformation studies of racemic sulfoxides with P.
putida UV4, tentative evidence was found of other reactions
occurring (,5% yield of bioproducts). This included
evidence of a reductase-catalysed deoxygenation of
sulfoxides which will be presented elsewhere.
Figure 1. X-ray structure of 5B.
As an extension to the dioxygenase-catalysed sulfoxidation
study, the monosulfide isosteres 7A and 8A, of the parent
disulfide substrate 1A, were also examined. Thus, the
corresponding enantioenriched sulfoxides, 7B and 8B, of
known absolute configuration, were obtained with TDO and
NDO as biocatalysts (Table 1). While sulfoxides 7B,
obtained using TDO and NDO, were of opposite absolute
configuration, surprisingly, identical (1R) configurations
were found for the sulfoxide metabolites 8B using either
enzyme. Sulfoxide 7B was the most polar of the five chiral
metabolites isolated with P. putida UV4 and 2,3-dihydro-
benzo[b]thiophene 7A as substrate. The structure and
stereochemistry (absolute configurations and ee values) of
the other metabolites, resulting from benzylic hydroxy-
lation, desaturation and dihydroxylation of the heterocyclic
and carbocyclic rings, will be discussed elsewhere.
2.2. Reaction of (R)-benzo-1,3-dithiole-1-oxide 1B with
n-butyllithium and benzaldehyde
Small quantities, of enantiopure (þ)- and (2)-sulfoxide 1B,
had earlier been obtained by chromatographic resolution of
the racemate, using semi-preparative chiral stationary phase
HPLC (CSPHPLC).10 Treatment, of the sulfoxide
enantiomers 1B with strong base, potassium bis(trimethy-
silyl) acetamide, yielded a carbanion at C-2 that was used in
the nucleophilic substitution of alkyl halides, to provide
twelve enantiopure 2-substituted benzo-1,3-dithiole sulf-
10
oxides, including compounds 2Bcis, 2Btrans, 3Bcis, 3B
.
trans
Absolute configuration determination, of the derived
(1S,2S,20S)-2-(20-methylbutyl)-1,3-benzodithiole 1-oxide,
by X-ray crystallography, allowed the configurations of
the other 2-substituted benzo-1,3-dithiole sulfoxides 1B,
2Bcis, 2Btrans, 3Bcis, 3Btrans to be unequivocally assigned by
stereochemical correlation and CD spectral comparison.
The results, shown in Table 1, indicate that the cyclic
sulfoxides were isolated in variable yields (1–78%) and that
all but the sulfoxides 3Btrans and 7B could be obtained with
high ee values (.90%), using either TDO or NDO as
biocatalyst. The contrasting stereopreferences, previously
A major disadvantage of the CSPHPLC resolution pro-
cedure was that only small quantities, of each sulfoxide

552
D. R. Boyd et al. / Tetrahedron 60 (2004) 549–559
Scheme 3.
enantiomer 1B (ca: 40 mg), were obtained for reactivity
studies.10 With the availability of larger samples of the
enantiopure benzo-1,3-dithiole sulfoxide 1B, from the
NDO-catalysed biotransformation route, it was possible to
re-examine the reactivity of this compound and its
derivatives. Thus, the second phase of the study involved
the reactions of enantiopure monosulfoxide 1B and
disulfoxide 1Ctrans with alkyllithium reagents.
dithiole 11 ([a]D¼212, 49% yield) was obtained. Similar
treatment (72 h), of the more hindered cis sulfoxide 10,
yielded the (þ)-enantiomer of 2-substituted benzo-1,3-
dithiole 11 ([a]D¼þ12, 44% yield). Since the absolute
configuration, of the exocyclic chiral centre of sulfoxide 10,
was established as (10S) by X-ray crystallography, sulfoxide
9 must have the (1R,2R,10R) configuration. The formation,
of either the (10R) or (10S) enantiomer of alcohol 11,
provides a good example, of the transfer of chirality from a
(1R) cyclic sulfoxide stereogenic centre in metabolite 1B, to
a new exocyclic chiral centre in alcohol 11. The converse
process, i.e. chiral relay from the chiral alcohol centres in an
arene cis-dihydrodiol metabolite, to a new chiral sulfoxide
centre of either configuration (catechol sulfoxides), has
recently been reported from these laboratories.7
(R)-Monosulfoxide metabolite 1B ([a]D¼þ505) was
treated with 1 equiv. of n-butyllithium in dry THF
(278 8C) followed by the addition of benzaldehyde to the
C-2 carbanion intermediate, to yield a diastereoisomeric
mixture of 2-substituted benzo-1,3-dithiole sulfoxides 9/10
(Scheme 3). Separation, by PLC, gave cis isomer 10 as a
crystalline solid (Rf 0.31, [a]D¼þ344, 31% yield) and trans
isomer 9 as a viscous oil (Rf 0.19, [a]D¼þ116, 23% yield).
X-ray crystallographic analysis (Fig. 2) confirmed the cis
geometry of sulfoxide 10 and, using the anomalous
dispersion method, allowed assignment of absolute con-
figuration, (1R,2S,10S), of the three chiral centres. The
heterocyclic ring adopts an envelope conformation, with
pseudoaxial oxygen and pseudoequatorial side chain at C(2).
The marked degree of diastereoselectivity, found during
substitution at the C-2 position for the (R) enantiomer of
monosulfoxide 1B, was0 noteworthy; thus0, only two
diastereoisomers, (1R,2S,1 S)-10 and (1R,2R,1 R)-9, of the
possible four were detected. Examination of molecular
models suggests that this could be due to the preferential
attractive interactions between the sulfoxide oxygen atom
and the 0 lithium alkoxide, f0avouring chelate formations
(1R,2R,1 R)-9p and (1R,2S,1 S)-10p (Scheme 4). Similar
types of chelate interactions have been suggested, to
account for the diastereoselectivity associated with carba-
nion reactions of trans-1,3-dithiane 1,3-dioxide with
benzaldehyde.14
Figure 2. X-ray structure of 10.
The X-ray crystallographic analysis, of the minor dia-
stereoisomer 9, was precluded, since it could not be
obtained in crystalline form. Its absolute configuration
was, however, assigned by a mild rhenium-catalysed
deoxygenation process.13 Thus, using the trans mono-
sulfoxide 9 and a catalytic amount of ReOCl3(PPh3)2 in the
presence of triphenyl phosphine (ambient temperature,
1.5 h), the (2)-enantiomer of 2-substituted benzo-1,3-
Scheme 4.
2.3. Ring-opening reactions of (1R,3R)-disulfoxide 1C
and monosulfoxides 7B and 8B
trans
Chemical oxidation of (þ)-(R)-benzo-1,3-dithiole 1-oxide

D. R. Boyd et al. / Tetrahedron 60 (2004) 549–559
553
1B ([a]D¼þ505), using NaIO4 as oxidant, yielded enantio-
Table 2. Reactions of bicyclic sulfoxides 1Ctrans, 7B and 8B with
alkyllithium reagents to yield the acyclic disulfoxides 13–17 and
monosulfoxides 18 and 19
pure (þ)-(1R,3R)-disulfoxide 1C
([a]D¼þ646, 75%
trans
yield, Scheme 3) as a major product. Compound 1Ctrans was
readily separated from achiral (1R,3S) isomer 1Ccis (19%
yield) by flash chromatography. It was anticipated that
Reactant sulfoxide
Structure Ab.Con.
Alkyl lithium Di- and mono-sulfoxide products
a
Number Yield [a]D Ab.Con.
treatment of (þ)-disulfoxide 1C
in a manner similar to
trans
(þ) sulfoxide 1B, i.e. reaction with n-butyllithum in dry
THF (278 8C), followed by addition of benzaldehyde,
would give the two diastereoisomers of alcohol sulfoxide 12
(Scheme 3). In an earlier study,14 on the synthesis and
1C
trans
1C
1R,3R
1R,3R
1R,3R
1R,3R
1R,3R
R
BuLi
PhLi
MeLi
HexylLi
t-BuLi
BuLi
13
14
15
16
17
18
19
49
32
59
65
30
28
34
2180 1R,3S
b b
trans
1C
trans
1C
2234 1R,3S
2247 1R,3S
þ75 1R,3S
trans
1C
trans
reaction of (^)-disulfoxide 1C
with n-butyllithum and
trans
7B
8B
213c
þ74d
R
R
pivalaldehyde, alcohol disulfoxide diastereoisomers of
similar structure to compound 12 (Ph replaced by t-Bu)
were reported. However, spectral analysis and PLC
purification indicated that only one product was formed
from the reaction of n-butyllithum/benzaldehyde (278 8C)
with the (1R,3R) enantiomer of cyclic disulfoxide 1Ctrans; it
was identified as the acyclic disulfoxide 13 ([a]D¼2180,
49% yield, Scheme 5). When this reaction was repeated
under identical conditions, but without addition of benzal-
dehyde, the acyclic (2)-disulfoxide 13 was again formed
(Scheme 5).
S
BuLi
a
CHCl3 solvent.
Achiral compound.
Formed from 7B of 90% ee.
Formed from 8B of 73% ee.
b
c
d
(R/S or S/R) (mp 136 8C) isomeric forms,15,16 confirmed that
it was, indeed, the meso compound.
1
The characteristic H NMR spectral data, reported for the
racemic (1R,3R/1S,3S) and (1R,3S/1S,3R) diastereoisomeric
pairs of sulfoxide 15,15 suggested that the ring-opening
product 15 ([a]D¼2234, 59% yield) was either (1R,3S) or
(1S,3R) diastereoisomer. Unfortunately an [a]D value for
either enantiomer of compound 15 has not been reported.
The (1R,3S) configuration for (2)-sulfoxide 15 was
confirmed by partial deoxygenation, using the rhenium
complex-catalysed procedure (Scheme 6).13 As expected
from earlier studies,13 the dialkyl sulfoxide group was
deoxygenated more slowly compared with the alkylaryl
sulfoxide group, leading to a 2:1 ratio of dialkyl sulfoxide
20 and alkylaryl sulfoxide 21. Partial racemisation, of
monosulfoxides 20 ([a]D¼227, 24% ee) and 21
([a]D¼2110, 87% ee), occurring to different degrees
during the deoxygenation process, was also observed.
Despite the partial racemisation, it was possible to assign
(S) and (R) configurations, respectively, to monosulfoxides
(2)-20 and (2)-21, by comparison of the [a]D values with
authentic samples;18 thus, a (1R,3S) configuration was
assigned to disulfoxide 15. The CD spectra of single
diastereoisomers 13, 15–17, obtained by the ring-opening
reaction of disulfoxide 1C
(Scheme 5), displayed a
Scheme 5.
trans
similar pattern, i.e. a strong positive absorption at 218–
220 nm and a strong negative absorption at 246–256 nm.
The similarity in CD spectra of compounds 13, 15–17 and
unequivocal assignment of absolute configuration to
disulfoxide 15 led us to the conclusion that in the ring-
opening reactions inversion of configuration had occurred.
This premise was supported by two reports in the
literature,19,20 where enantiopure acyclic alkylaryl mono-
sulfoxides were found to react with alkyllithium reagents, to
yield dialkyl sulfoxides via an SN2 exchange process
occurring with inversion of configuration. As found for
acyclic alkylaryl sulfoxides,19,20 the aryl–SO bond in the
Since only a few methods are available for the synthesis of
enantiopure acyclic disulfoxides, using either chemical or
enzymatic approaches,15–18 the unusual ring-opening reac-
tion of (1R,3R)-disulfoxide 1C
trans
(Scheme 5). Reactions of 1C
was examined further
with other alkyllithium
trans
reagents (RLi, R¼Ph, Me, (CH2)5Me, t-Bu) were conducted
under identical conditions. 1H NMR analysis, of the
resulting acyclic disulfoxide products 13–17 indicated
that in all cases single diastereoisomers were formed, albeit
in relatively modest yields (28–65%, Table 2). Compound
14 was the only disulfoxide obtained without either a
measurable optical rotation or CD absorption. This
observation was consistent with total inversion of configur-
ation, occurring during the ring opening process, to yield
achiral meso isomer 14. Comparison of the melting points
and 1H NMR data for disulfoxide 14 (mp 124–125 8C,
[a]D¼0), isolated during the present study, with that
reported for the meso (mp 123 8C, [a]D¼0) and racemic
Scheme 6.

554
D. R. Boyd et al. / Tetrahedron 60 (2004) 549–559
cyclic disulfoxide 1C
alkyl–SO bond.
was cleaved in preference to the
absolute configurations, using either TDO or NDO as
trans
biocatalyst. The monosulfoxide 1B was found to undergo an
a-hydrogen atom abstraction process with butyllithium
followed by reaction, at low temperatures, with benzal-
dehyde in a diastereoselective manner, to form alcohols 9
and 10. Under these conditions, disulfoxide 1Ctrans was
found to undergo a ring-opening reaction to yield the acyclic
disulfoxides. A new chemoenzymatic route to enantiopure/
enantioenriched disulfoxides (13, 15–17) and mono-
sulfoxides (18 and 19) was revealed, by the reactions of
sulfoxides 1C, 7B and 8B, with alkyllithium reagents.
It was reported earlier20 that alternative reactions of acyclic
monosulfoxides with alkyl lithium reagents result in (a)
abstraction of an a-hydrogen atom to give an a-lithio-
sulfoxide (carbanion formation), and (b) replacement of an
aryl sulfoxide group with the alkyllithium group (group
exchange). The relative proportion of either reaction was
found to depend on the structure of sulfoxide (number and
acidity of a-hydrogen atoms, substituent size and leaving
group ability) and the type of alkyllithium reagent (size and
basicity). Our observation of ring-opening reactions (group
exchange), of disulfoxide 1Ctrans with alkyllithium reagents
(278 8C), suggests that the temperature may also be an
important factor. The reported14 substitution reaction of a
racemic sample of compound 1Ctrans, using n-butyllithium
and pivalaldehyde to form t-butyl analogues of compounds
(1R,3R,10S)-12 and (1R,3R,10R)-12 (Scheme 3), was carried
4. Experimental
4.1. General
1H NMR spectra were recorded at 300 MHz (Bruker
Avance DPX-300) and 500 MHz (Bruker Avance DRX-
500) in CDCl3 solvent, unless stated otherwise. Chemical
shifts (d) are reported in ppm relative to SiMe4; coupling
constants (J) are given in Hz. Mass spectra were recorded at
70 eV on a VG Autospec Mass Spectrometer, using a heated
inlet system. Accurate molecular weights were determined
by the peak matching method with perfluorokerosene as
standard. Elemental microanalyses were obtained on a
Perkin–Elmer 2400 CHN microanalyser. HPLC analyses
were carried out using a Perkin–Elmer Series 3B liquid
chromatograph coupled to a Perkin–Elmer LC1-100
computing integrator. Analytical TLC was performed on
Merck Kieselgel 60254 plastic sheets and preparative TLC
(PLC) on glass plates (20 cm£20 cm) coated with Merck
Kieselgel PF254þ366. Optical rotation ([a]D) measurements
were carried out with a Perkin–Elmer 214 polarimeter at
ambient temperature (ca. 20 8C) at a concentration of
1
out at higher temperatures (0 to 245 8C). Furthermore, H
NMR spectral analysis of the crude product mixture,
obtained from the reaction of compound 1C
n-butyllithium and benzaldehyde at a relatively higher
temperature (245 08C) indicated the formation of
compounds (1R,3R,1 S)-12 and (1R,3R,10R)-12.
with
trans
When the enantiopure monosulfoxide metabolites 4B–6B
containing six and seven-membered rings, were converted
to the corresponding disulfoxides, and subsequently treated
with alkyllithium reagents, no evidence of comparable ring-
opening reactions was observed. However, under the
standard reaction conditions monosulfoxide metabolites
7B and 8B, containing a five-membered ring, were also
found to undergo a similar ring opening reaction to give the
corresponding acyclic dialkyl monosulfoxides 18 and 19 in
low yields (28 and 34%, Scheme 5, Table 2). Since only
limited amounts of enantioenriched/enantiopure sulfoxides
7B and 8B were available from the small-scale bio-
transformations, additional samples of enantioenriched
sulfoxides (2)-(R)-7B (90% ee) and (2)-(S)-8B (73% ee)
were synthesised by chemical asymmetric sulfoxidation using
the Kagan modified Sharpless reagent (Ti(i-PrO)4/DET/
t-BuOOH).11
,0.01 g cm23 and are given in units of 1021 deg cm2 g21
.
Circular dichroism spectra were recorded on a JASCO J-720
instrument, using spectroscopic grade acetonitrile as
solvent. Enantiopurity of sulfoxides was determined by
CSPHPLC analysis, using Chiralcel OB, OD and OJ
columns and hexane/2-propanol (9/1) as eluent. The
NCIMB 8859 strain of P. putida was acquired from the
National Cultures of Industrial and marine Bacteria,
Aberdeen. The 9816/11 strain of P. putida originated from
thelaboratoriesofProfessor D. T. Gibson(University ofIowa)
and the UV4 strain of P. putida was originally provided by
Zeneca (now Avecia Lifescience Molecules, Billingham).
It was assumed that inversion of configuration had occurred,
again, during the ring-opening reaction of compound (2)-
(R)-7B to yield monosulfoxide 18 ([a]D¼213, 28% yield)
and of compound (2)-(S)-8B to give the hemiacetal
derivative 19 ([a]D¼þ74, 34% yield). Chiral stationary
phase HPLC (CSPHPLC) analysis of the sulfoxide 19 (49%
ee), obtained from sulfoxide 8B (73% ee), showed that
partial racemization had occurred. The ee value for
sulfoxide 18 could not be obtained using the latter
CSPHPLC method.
4.2. Synthesis and characterization of compounds
1A–8A
The di- and mono-sulfide substrates 1A–3A,10 4A,21 5A,22
6A,23 7A,24 8A25 were synthesised using the reported
methods.
4.2.1. 1,3-Benzodithiole 1A. Colourless oil; bp 113–
114 8C/3.5 mmHg; lit.10 105 8C/3 mmHg; dH (500 MHz,
CDCl3) 4.48 (2H, s, CH2), 7.00–7.02 (2H, dd, J¼5.7,
3.3 Hz, 2£Ar-H), 7.19–7.22 (2H, dd, J¼5.7, 3.3 Hz,
2£Ar-H).
3. Conclusions
The dioxygenase enzyme system has been shown to catalyse
the enantioselective heteroatom oxidation of bicyclic
sulfides (7A, 8A) and disulfides (1A–6A). In many cases,
the corresponding enantiopure monosulfoxides (e.g. 1B,
2Bcis, 2Btrans, 3Bcis, 4B–6B) were obtained with opposite
4.2.2. 2-Methyl-1,3-benzodithiole 2A. Colourless oil; bp
98 8C/0.05 mmHg; lit.10 62–64 8C/0.02 mmHg; dH

D. R. Boyd et al. / Tetrahedron 60 (2004) 549–559
555
1
(500 MHz, CDCl3) 1.70 (3H, d, JMe,H¼6.8 Hz, Me), 4.98
(1H, q, JH,Me¼6.8 Hz, CHMe), 7.01–7.03 (2H, dd, J¼5.8,
3.2 Hz, 2£Ar-H), 7.21–7.23 (2H, dd, J¼5.8, 3.2 Hz,
2£Ar-H).
medium using ethyl acetate.2,5 Yields, chiroptical and H
NMR spectral data, obtained for each biotransformation, are
summarised below.
4.3.1. 1,3-Benzodithiole 1A. (i) TDO product: (S)-1,3-
benzodithiole-1-oxide 1B; white crystalline solid, 22 mg,
20% yield; [a]D¼2170 (c 1.0, CHCl3); lit.10 [a]D¼2505
(EtOH); 33% ee (CSPHPLC, Chiralcel OB, a¼1.4); dH
(500 MHz, CDCl3) 4.18 (1H, d, JA,B¼13.0 Hz, CHAHB),
4.33 (1H, d, JB,A¼13.0 Hz, CHAHB), 7.30–7.33 (1H, m, Ar-
H), 7.48–7.54 (2H, m, 2£Ar-H), 7.89–7.90 (1H, m, Ar-H).
4.2.3. 2-Ethyl-1,3-benzodithiole 3A. Colourless oil; bp
70 8C/0.02 mmHg; lit.10 72–76 8C/0.01 mmHg; dH
(300 MHz, CDCl3) 1.02 (3H, t, JMe,CH ¼7.0 Hz, CH2Me),
2
1.90–1.97 (2H, m, CH2Me), 4.76 (1H, t, J
H), 6.98–7.03 (2H, m, Ar-H), 7.18–7.22 (2H, m, Ar-H).
¼7.0 Hz, 2-
CH2;Me
4.2.4. 2,3-Dihydro-1,4-benzo[d]dithiine 4A. Yellow oil;
(Rf 0.4, hexane); lit.21 82.5–85 8C/0.18 mmHg; dH
(500 MHz, CDCl3) 3.26 (4H, s, 2£CH2S), 6.97–7.00 (2H,
dd, J¼5.9, 3.4 Hz, 2£Ar-H), 7.13–7.17 (2H, dd, J¼5.9,
3.4 Hz, 2£Ar-H).
(ii) NDO (8859) product: (R)-1,3-benzodithiole-1-oxide 1B;
400 mg, 74% yield; [a]D¼þ504 (c 1.9, CHCl3); .98% ee
(CSPHPLC). A 10 litre fermenter (15 g substrate) gave
sulfoxide 1B, 12 g, 72% yield; [a]D¼þ498 (c 1.9, CHCl3)
.98% ee (CSPHPLC).
4.2.5. 3,4-Dihydro-2H-1l4,5-benzodithiepin 5A. White
solid; mp 60–61 8C (from CHCl3); lit.22 59–60 8C; dH
(500 MHz; CDCl3) 2.30 (2H, m, CH2CH2CH2), 2.86 (4H,
m, CH2CH2CH2), 7.15–7.18 (2H, dd, J¼5.7, 3.5 Hz, 2£Ar-
H), 7.62–7.64 (2H, dd, J¼5.6, 3.5 Hz, 2£Ar-H).
(iii) NDO (9816/11) product: (R)-1,3-benzodithiole-1-oxide
1B; 60 mg, 54% yield; [a]D¼þ401 (c 1.3, CHCl3); 81% ee
(CSPHPLC).
4.3.2. 2-Methyl-1,3-benzodithiole 2A. (i) TDO products:
(1S,2R)-2-methyl-1,3-benzodithiole-1-oxide 2Bcis; white
crystalline solid, 2.21 g, 40% yield; [a]D¼2319 (c 0.7
CHCl3); .98% ee (CSPHPLC, Chiralcel OD, a¼1.33);
lit.10 [a]D¼268 (EtOH) for 25% ee; dH (500 MHz, CDCl3)
1.83 (3H, d, JMe,H¼6.9 Hz, Me), 4.44 (1H, q, JH,Me¼6.9 Hz,
CHMe), 7.26–7.30 (1H, ddd, J5,4¼7.8 Hz, J5,6¼7.0 Hz,
J5,7¼1.0 Hz, 5-H), 7.43–7.46 (2H, m, 4-H and 6-H), 7.84–
7.86 (1H, dd, J7,6¼7.2 Hz, J7,5¼1.0 Hz, 7-H) and (1S,2S)-2-
4.2.6. 1,4-Benzo[d]dithiine 6A. Light pink coloured oil; bp
58–60 8C/0.03 mmHg; lit.23 67–70 8C/0.1 mmHg; dH
(500 MHz, CDCl3) 6.52 (2H, s, 2£CHS), 7.19–7.23 (2H,
dd, J¼5.8, 3.4 Hz, 2£Ar-H), 7.26–7.29 (2H, dd, J¼5.8,
3.4 Hz, 2£Ar-H).
4.2.7. 2,3-Dihydrobenzo[b]thiophene 7A. Colourless oil;
bp 44–46 8C/0.15 mmHg; lit.24 67–69 8C/2 mmHg; dH
(500 MHz, CDCl3) 3.23–3.27 (2H, m, SCH2), 3.30–3.34
(2H, m, CH2Ar), 6.90–6.93 (1H, ddd, J5,4¼J5,6¼7.4 Hz,
J5,7¼1.0 Hz, 5-H), 7.00–7.04 (1H, ddd, J6,5¼J6,7¼7.4 Hz,
methyl-1,3-benzodithiole-1-oxide 2B
; 290 mg, 5%
trans
yield; [a]D¼257 (c 0.5, CHCl3); .98% ee (CSPHPLC,
Chiralcel OD, a¼1.14); lit.10 [a]D¼229 (EtOH) for 25%
ee; dH (500 MHz, CDCl3) 1.60 (3H, d, JMe,H¼7.4 Hz, Me),
4.59 (1H, q, JH,Me¼7.4 Hz, CHMe), 7.28–7.33 (1H, m,
5-H), 7.47–7.48 (2H, m, 4-H and 6-H), 7.83–7.85 (1H, dd,
J7,6¼7.7 Hz, J7,5¼0.7 Hz, 7-H). When repeated on a 10 litre
fermenter-scale (10.0 g of substrate 2A), 1S,2R)-2-methyl-
1,3- benzodithiole-1-oxide 2Bcis; 2.9 g, 26% yield;
[a]D¼2316 (c 0.7 CHCl3); .98% ee (CSPHPLC) and
(1S,2S)-2-methyl-1,3-benzodithiole-1-oxide 2Btrans; 66 mg,
1% yield; [a]D¼260 (c 0.7, CHCl3); .98% ee (CSPHPLC)
were obtained.
J6,4¼0.6 Hz, 6-H), 7.08–7.10 (1H, ddd, J4,5¼7.4 Hz, J4,6
¼
0.6 Hz, 4-H), 7.12–7.13 (1H, dd, J7,6¼7.4 Hz, J7,5¼1.0 Hz,
7-H).
4.2.8. 1,3-Benzoxathiole 8A. Colourless liquid; bp 36 8C/
0.05 mmHg; lit.25 93–95 8C/5 mmHg; dH (500 MHz,
CDCl3) 5.66 (2H, s, CH2), 6.81–6.83 (1H, ddd,
J7,6¼8.0 Hz, J7,5¼1.2 Hz, J7,4¼0.4 Hz, 7-H), 6.85–6.89
(1H, ddd, J6,7¼8.0 Hz, J6,5¼7.0 Hz, J6,4¼1.2 Hz, 6-H),
6.97–7.00 (1H, ddd, J5,4¼7.7 Hz, J5,6¼7.6 Hz, J5,7
¼
1.2 Hz, 5-H), 7.15–7.17 (1H, ddd, J4,5¼7.7 Hz,
J4,6¼1.2 Hz, J4,7¼0.4 Hz, 4-H).
(ii) NDO (8859) products: (1R,2S)-2-methyl-1,3-benzo-
dithiole-1-oxide 2Bcis; 2.21 g, 40% yield; [a]D¼þ256 (c
1.8, CHCl3); 82% ee (CSPHPLC) and (1R,2R)-2-methyl-
1,3-benzodithiole-1-oxide 2Btrans; 390 mg, 7% yield;
[a]D¼þ21 (c 0.7, CHCl3); .38% ee (CSPHPLC).
10
10
Sulfoxides 1B,10 2Bcis,10 2B
,
3Bcis,10 3B
,
trans
6B,11
trans
7B,26,27 and 8B,25 synthesised by the literature methods,
were found to be spectrally identical to the metabolites
isolated during the study.
4.3.3. 2-Ethyl-1,3-benzodithiole 3A. (i) TDO products:
(1S,2R)-2-ethyl-1,3- benzodithiole-1-oxide 3Bcis; white
crystalline solid, 165 mg, 55% yield; [a]D¼2189 (c 0.5,
CHCl3); .98% ee (CSPHPLC, Chiralcel OD, a¼1.36); dH
4.3. Biotransformation of substrates 1A–8A using
P. putida UV4, P. putida 8859 and P. putida 9816/11 to
yield sulfoxides 1B–8B
(300 MHz, CDCl3) 1.30 (3H, t, JMe,CH ¼7.4 Hz, CH2Me),
2
Biotransformations of the bicyclic substrates 1A–8A were
carried out with whole cell preparations of P. putida UV4
(TDO) and P. putida 8859 (NDO) and P. putida 9816/11
(NDO), using both small-scale (,10 g) shake-flask and 10 l
fermenter (.10 g) conditions reported earlier for the
sulfoxidation of both acyclic5 and cyclic sulfides.2 The
workup procedure involved extraction of the culture
2.05–2.16 (1H, m, CH2Me), 2.33–2.44 (1H, m, CH2Me),
4.26 (1H, dd, JH,CH2¼7.6 Hz, 2-H), 7.25–7.28 (1H, m, Ar-
H), 7.45–7.46 (2H, m, Ar-H), 7.84–7.86 (1H, d, J¼7.7 Hz,
Ar-H) and (1R,2R)-2-ethyl-1,3-benzodithiole-1-oxide
3Btrans;white crystalline solid, 15 mg, 5% yield;
[a]D¼þ24 (c 0.4, CHCl3); 18% ee (CSPHPLC, Chiralcel
OD, a¼1.11); dH (300 MHz, CDCl3) 1.18 (3H, t,

556
D. R. Boyd et al. / Tetrahedron 60 (2004) 549–559
JMe,CH ¼7.4 Hz, CH2Me), 1.65 (1H, m, CH2Me), 2.00 (1H,
ometer, vscan, 10,2u,1108, measured/independent reflec-
tions: 5093/1195, direct methods solution, full matrix least
squares refinement on F02; anisotropic displacement par-
ameters for non-hydrogen atoms, hydrogens located in
difference Fourier but included at positions calculated from
the geometry of the molecule using the riding model,
R1¼0.044 for 1115 data with F0 . 4sðF0Þ; 111 parameters,
wR2¼0.113 (all data), GoF¼1.07, Flack absolute structure
parameter x¼20.09(4) establishes the absolute configur-
2
0
0
m, CH2Me), 4.48 (1H, dd, J2,1 A¼8.7 Hz, J2,1 B¼6.2 Hz,
H-2), 7.26–7.32 (1H, m, Ar-H), 7.47 (2H, m, Ar-H), 7.87
(1H, d, J¼7.7 Hz, Ar-H).
4.3.4. 2,3-Dihydro-1,4-benzo[d]dithiine 4A. (i) TDO
product: (R)-2,3-dihydrobenzo[d]dithiin-1-oxide 4B; white
solid, 14 mg, 13% yield; mp 104–105 8C (from CHCl3);
[a]D¼þ37 (c 1.3, CHCl3); HRMS found: Mþ, 184.0016,
C8H8OS2 requires 184.0017; dH (500 MHz, CDCl3) 3.05
(1H, ddd, J3A,3B¼13.4 Hz, J3A,2A¼6.6 Hz, J3A,2B¼3.8 Hz,
SCHAHB), 3.13 (1H, ddd, J3B,3A¼13.4 Hz, J3B,2A¼10.8 Hz,
J3B,2B¼3.6 Hz, SCHAHB), 3.40 (1H, ddd, J2A,2B¼13.4 Hz,
J2A,3A¼6.6 Hz, J2A,3B¼3.6 Hz, SOCHAHB), 3.76 (1H,
ddd, J2B,2A¼13.4 Hz, J2B,3A¼10.8 Hz, J2B,3B¼3.4 Hz,
ation as (1S), Drmin,max¼20.30/0.23 e A23. CCDC refer-
˚
ence number 212386, Crystallographic data (excluding
structure factors) for the structures in this paper have been
deposited with the Cambridge Crystallographic Data
Centre. Copies of the data can be obtained, free of
charge, on application to CCDC, 12 Union Road,
Cambridge, CB2 1EZ, UK [fax:þ44(0)-1223-336033 or
e-mail: deposit@ccdc.cam.ac.uk].
SOCHAHB), 7.25–7.28 (1H, ddd, J6,5¼8.2 Hz, J6,7
7.5 Hz, J6,8¼1.2 Hz, 6-H), 7.31–7.32 (1H, dd, J5,6
8.2 Hz, J5,7¼1.2 Hz, 5-H), 7.37–7.40 (1H, ddd, J7,8
¼
¼
¼
7.8 Hz, J7,6¼7.5 Hz, J7,5¼1.2 Hz, 7-H), 7.73–7.75 (1H,
dd, J8,7¼7.8 Hz, J8,6¼1.2 Hz, 8-H); .98% ee (CSPHPLC,
Chiralcel OB, a¼1.4).
4.3.7. 1,4-Benzo[d]dithiine 6A. (i) TDO product: (S)-1,4-
benzo[d]dithiin-1-oxide 6B; white solid, 25 mg, 23% yield;
[a]D¼2376 (c 0.5, CHCl3); lit.11 [a]D¼2383 (CHCl3);
.98% ee (CSPHPLC, Chiralcel OB, a¼1.17); dH
(500 MHz, CDCl3) 7.05 (1H, d, J3,2¼9.4 Hz, SCH), 7.31
(ii) NDO (8859) product: (S)-2,3-dihydrobenzo[d]dithiin-1-
oxide 4B; 85 mg, 78% yield; [a]D¼235 (c 1.1, CHCl3);
.98% ee (CSPHPLC).
(1H, d, J2,3¼9.4 Hz, S(O)CH), 7.51–7.54 (1H, ddd, J6,5
¼
J6,7¼7.6 Hz, J6,8¼1.4 Hz, 6-H), 7.56–7.60 (1H, ddd,
J7,6¼J7,8¼7.6 Hz, J7,5¼1.3 Hz, 7-H), 7.60–7.62 (1H, dd,
(iii) NDO (9816/11) product: (S)-2,3-dihydrobenzo[d]-
dithiin-1-oxide 4B; 67 mg, 62% yield; [a]D¼237 (c 1.3,
CHCl3); .98% ee (CSPHPLC); CD (l, nm) 313 (D1
20.375), 271 (D1 0.240), 256 (D1 22.27), 242 (D1 0.561),
229 (D1 22.815), 213 (D1 25.865), 194.2 (D1 2.100).
J5,6¼7.6 Hz, J5,7¼1.3 Hz, 5-H), 7.94–7.96 (1H, dd, J8,7¼
7.6 Hz, J8,6¼1.4 Hz, 8-H); CD (l, nm) 311 (D1 0.522), 272
(D1 20.444), 255 (D1 3.357), 243 (D1 20.675), 229
(D1þ3.657), 213 (D1 7.470).
(ii) NDO (8859) product: (R)-benzo[d]dithiin-1-oxide 6B;
66 mg, 60% yield; [a]D¼þ373 (c 1.0, CHCl3); .98% ee
(CSPHPLC).
4.3.5. 3,4-Dihydro-2H-1l4,5-benzodithiepin 5A. (i) NDO
(8859)
product:
(S)-1,2,3,4-tetrahydro-1l4,5-benzo-
dithiepin-1-oxide 5B; colourless crystalline solid, 30 mg,
26% yield; mp 120–121 8C (from CHCl3/hexane);
[a]D¼271 (c 1.4, CHCl3); Found: C, 54.7; H, 5.0;
C9H10OS2 requires C, 54.5; H, 5.1%; dH (500 MHz,
CDCl3) 2.41–2.49 (2H, m, 4-H), 2.61–2.63 (1H, m,
3-HA), 2.87–2.88 (1H, m, 3-HB), 2.97–3.00 (1H, m,
2-HA), 3.25–3.27 (1H, m, 2-HB), 7.38–7.41 (1H, td,
J7,6¼J7,8¼7.5 Hz, J7,9¼1.4 Hz, 7-H), 7.58–7.59 (2H, m,
6-H and 8-H), 7.87–7.89 (1H, dd, J9,8¼7.7 Hz, J9,7¼1.4 Hz,
9-H); 80% ee (CSPHPLC, Chiralcel OB, a¼1.25).
(ii) NDO (9816/11) product: (S)-1,2,3,4-tetrahydro-1l4,5-
benzodithiepin-1-oxide 5B; 20 mg, 10% yield; [a]D¼282
(c 0.8, CHCl3); 93% ee (CSHPLC, Chiralcel OB, a¼1.25);
CD (l, nm) 265 (D1 22.162), 250 (D1 0.439), 236 (D1
21.243), 228 (D1 0.448), 220 (D1 21.423), 215 (D1
20.589), 198 (D1 27.96).
(iii) NDO (9816/11) product: (R)-benzo[d]dithiin-1-oxide
6B; 47 mg, 43% yield; [a]D¼þ373 (c 1.0, CHCl3); .98%
ee (CSPHPLC).
4.3.8. 2,3-Dihydrobenzo[b]thiophene 7A. (i) TDO pro-
duct: (R)-2,3-dihydrobenzo[b]thiophene-1-oxide 7B; white
solid, 40 mg, 5% yield; [a]D¼259 (c 1.0, CHCl3); lit.27
[a]D¼2285 (Me2CO); 26% ee (CSPHPLC, Chiralcel OB,
a¼1.7); dH (500 MHz, CDCl3) 3.23–3.26 (1H, m, 3-HA),
3.28–3.34 (1H, m, 3-HB), 3.39–3.40 (1H, m, 2-HB), 3.83–
3.91 (1H, m, 2-HA), 7.41–7.44 (1H, ddd, J5,4¼J5,6¼7.4 Hz,
J5,7¼0.5 Hz, 5-H), 7.46–7.47 (1H, dd, J4,5¼7.4 Hz, J4,6
1.2 Hz, 4-H), 7.50–7.53 (1H, ddd, J6,5¼J6,7¼7.4 Hz, J6,4
¼
¼
1.2 Hz, 6-H), 7.83–7.85 (1H, dd, J7,6¼7.4 Hz, J7,5 0.5, 7-H).
(ii) NDO (8859) product: (S)-2,3-dihydrobenzo[b]thio-
phene-1-oxide 7B; 48 mg, 21% yield; [a]D¼þ95 (c 1.1,
CHCl3); 38% ee (CSPHPLC); CD (l, nm) 263 (D1 0.882),
231 (D1 0.733), 217 (D1 22.586), 198 (D1 5.447).
4.3.6. X-ray crystal structure analysis of (S)-1,2,3,4-
tetrahydro-1l4,5-benzodithiepin-1-oxide 5B. Recrystal-
lization of compound 5B (93% ee) gave a sample whose
X-ray crystal structure analysis showed it to be of .98% ee
and of the (S) configuration.
(iii) NDO (9816/11) product: (S)-2,3-dihydrobenzo[b]thio-
phene-1-oxide 7B; 19 mg, 17% yield; [a]D¼þ27 (c 1.0,
CHCl3), 11% ee (CSPHPLC).
Crystal data for 5B: C9H10OS2, Mr¼198.3, orthorhombic,
3
˚
˚
a¼8.106(4), b¼9.043(3), c¼13.042(6) A, V¼956.0(7) A ,
4.3.9. 1,3-Benzoxathiole 8A. (i) TDO product: (R)-
benzo[1,3]oxathiol-3-oxide 8B; white solid, 11 mg, 11%
yield; [a]D¼þ194 (c 1.0, CHCl3); .98% ee (CSPHPLC,
Chiralcel OB, a¼1.3); dH (500 MHz, CDCl3) 4.98 (1H, d,
˚
T¼293 K, Cu Ka radiation, l¼1.54178 A, space group
P212121, Z¼4, Dx¼1.378 g cm23, 0.50£0.40£0.34 mm3,
m¼4.63 mm21, F(000)¼416, Siemens P3/V2000 diffract-

D. R. Boyd et al. / Tetrahedron 60 (2004) 549–559
557
23
˚
JA,B¼11.0 Hz, CHAHB), 5.49 (1H, d, JB,A¼11.0 Hz,
CHAHB), 7.18–7.20 (1H, ddd, J4,5¼7.6 Hz, J4,6¼1.2 Hz,
J4,7¼0.5 Hz, 4-H), 7.22–7.24 (1H, ddd, J5,4¼7.6 Hz,
J5,6¼7.2 Hz, J5,7¼1.2 Hz, 5-H), 7.56–7.59 (1H, ddd,
J6,7¼7.7 Hz, J6,5¼7.2 Hz, J6,4¼1.2 Hz, 6-H), 7.88–7.90
(1H, ddd, J7,6¼7.7 Hz, J7,5¼1.2 Hz, J7,4¼0.5 Hz, 7-H); CD
(l, nm) 285 (D1 22.831), 215 (D1 6.55), 208 (D1 5.259),
199 (D1 15.600).
Drmin,max¼20.47/0.54e A
.
CCDC reference number
212387.
4.4.3. (1R,2R,10R)-2-(10-Phenylmethanol)-benzo-1,3-
dithiole-1-oxide 9. White solid, 108 mg, 23% yield; Rf
0.19 (1% MeOH in CHCl3); [a]D¼þ116 (c 1.2, CHCl3);
HRMS found: Mþ276.0291, C14H12O2S2 requires
0
276.0278; dH (300 MHz; CDCl3) 4.68 (1H, d, J2,1
¼
10.0 Hz, 2-H), 0 4.93 (1H, br s, OH), 5.32 (1H, d,
0
(ii) NDO (8859) product: (R)-benzo[1,3]oxathiol-3-oxide
8B; 50 mg, 2% yield; [a]D¼þ87 (c 0.5, CHCl3); 43% ee
(CSPHPLC)
J1 ,2¼10.0 Hz, 1 -H), 7.22–7.44 (6H, m, Ar-H), 7.49–7.52
(2H, m, Ar-H), 7.83 (1H, d, J¼7.8 Hz, Ar-H); m/z 276 (Mþ,
4%), 259 (11), 229 (28) and 153 (100).
(iii) NDO (9816/11) product: (R/S)-benzo[1,3]oxathiol-3-
oxide 8B; 200 mg, 70% yield; [a]D¼0 (c 0.5, CHCl3);
racemic (CSPHPLC).
4.4.4. Deoxygenation of (1R,2S,10S)-2-(10-phenylmetha-
nol)-benzo-1,3-dithiole-1-oxide (10) and (1R,2R,10R)-2-
(10-phenylmethanol)-benzo-1,3-dithiole-1-oxide 9. To
each sample of monosulfoxides 10 and 9 (20 mg,
0.72 mmol), dissolved separately in CH2Cl2 (3 ml), was
added triphenyl phosphine (25 mg, 0.1 mmol) and a
catalytic amount of trichlorooxobis(triphenyl phosphine)-
rhenium. The two reaction mixtures were allowed to stir at
room temperature (sulfoxide 9 for 2 h and sulfoxide 10 for
72 h). The products were pur0ified by PLC to give the
corresponding sulfides (þ)-(1 S)-11; 8 mg, 44% yield;
[a]D¼þ12 (c 0.75, Me2CO) from 1R,2S,10S-10 and (2)-
(10R)-11; 9 mg, 49% yield; [a]D¼212 (c 0.9, Me2CO) from
1R,2R,10R-9); HRMS found: Mþ260.0342, C14H12OS2
requires 260.0330; dH (300 MHz, CDCl3) 4.66 (1H, d,
J¼8.2 Hz, 2-H), 4.89 (1H, d, J¼8.2 Hz, 10-H), 7.03–7.06
(2H, m, Ar-H), 7.18–7.25 (3H, m, Ar-H), 7.32–7.40 (5H,
m, Ar-H); m/z 260 (Mþ, 9%) and 153 (100).
4.4. Reaction of (1)-(R)-benzo-1,3-dithiole-1-oxide 1B
with n-butyllithium and benzaldehyde
n-Butyllithium solution in hexane (1.6 M, 1.6 ml) was
added to a stirring solution of (þ)-(R)-benzo-1,3-dithiole-1-
oxide 1B (300 mg, 1.7 mmol in 10 ml of dry THF) kept
under nitrogen at 278 8C. After 0.5 h, benzaldehyde
(186 mg, 1.7 mmol) was added to the reaction mixture; it
was allowed to warm to room temperature and stirred for
another 0.5 h. The reaction mixture was then carefully
poured into water (50 ml), the products extracted with ether
(3£25 ml), the extract washed with water (30 ml) and dried
(MgSO4). Removal of the solvent yielded the crude product
mixture which on separation by PLC (1% MeOH in CHCl3)
afforded pure samples of cis-(1R,2S,10S)-2-(10-phenyl-
methanol)-benzo-1,3-dithiole-1-oxide 10 and the more
polar trans-(1R,2R,10R)-2-(10-phenylmethanol)-benzo-1,3-
dithiole-1-oxide 9.
4.4.5. Sodium periodate oxidation of (1)-(R)-1,3-benzo-
dithiole-1-oxide 1B. (þ)-(R)-1,3-Benzodithiole-1-oxide 1B
(260 mg, 1.52 mmol) in methanol (15 ml) was oxidized
using a solution of sodium periodate (360 mg, 1.68 mmol)
in water (10 ml) at 50 8C for 24 h. PLC (5% MeOH in
CHCl3), of the reaction mixture, afforded pure samples of
(1R,3R)-1,3-benzodithiole-1,3-dioxide 1Ctrans and the more
polar cis-1,3-benzodithiole-1-oxide 1Ccis.
4.4.1. (1R,2S,10S)-2-(10-Phenylmethanol)-benzo-1,3-
dithiole-1-oxide 10. Colourless crystals, 147 mg, 31%
yield; Rf 0.31 (1% MeOH in CHCl3); mp 163–164 8C
(from CHCl3/hexane); [a]D¼þ344 (c 0.49, CHCl3); HRMS
found: Mþ276.0278, C14H12O2S2 requires 276.0278; dH
0
(300 MHz, CDCl3) 4.23 (1H, d, JOH,1 1.7, OH), 4.65 (1H, d,
(1R,3R)-1,3-Benzodithiole-1,3-dioxide 1Ctrans. White crys-
talline solid, 156 mg, 75% yield; Rf 0.33 (5% MeOH in
CHCl3); mp 123–126 8C (from CHCl3/hexane);
[a]D¼þ646 (c 1.5, CHCl3); HRMS found: Mþ185.9810,
C7H6O2S2 requires 185.9809; dH (300 MHz; CDCl3) 4.46
(2H, s, CH2), 7.82–7.85 (2H, m, Ar-H), 7.99–8.02 (2H, m,
Ar-H); m/z 186 (Mþ, 32%) and 156 (100). Benzo-1,3-
dithiole-1,3-dioxide 1Ccis. 40 mg, 19% yield; Rf 0.22 (5%
MeOH in CHCl3); mp 179–180 8C; HRMS found:
Mþ185.9814, C7H6O2S2 requires 185.9809; dH (300 MHz,
CDCl3) 4.24 (1H, d, JA,B¼13.2 Hz, CHAHB), 5.03 (1H, d,
JB,A¼13.2 Hz, CHAHB), 7.85–7.88 (2H, m, Ar-H), 8.08–
8.11 (2H, m, Ar-H); m/z 186 (Mþ, 33%) and 156 (100).
0
0
J2,1¼4.8 Hz, 2-H), 5.77 (1H, d, J2,1 ¼4.8 Hz, 1 -H), 7.25–
7.28 (1H, m, Ar-H), 7.36–7.46 (5H, m, Ar-H), 7.54 (2H, d,
J¼7.1 Hz, Ar-H), 7.77 (1H, d, J¼7.6 Hz, Ar-H); m/z 276
(Mþ, 7%), 259 (13), 229 (30) and 153 (100).
4.4.2. X-ray crystal structure analysis of (1R,2S,10S)-2-
(10-phenylmethanol)-benzo-1,3-dithiole-1-oxide 10. Crystal
data for 10: C14H12O2S2, Mr¼276.4, orthorhombic,
3
˚
˚
a¼5.531(1), b¼10.410(3), c¼21.931(7) A, V¼1262.8(6) A ,
˚
T¼293 K, Cu Ka radiation, l¼1.54178 A, space group
P212121, Z¼4, Dx¼1.45 g cm23
,
0.56£0.49£0.43 mm3,
m¼3.74 mm21, Siemens P3/V2000 diffractometer, vscan,
8 , 2u , 1508; measured/independent reflections: 2748/
2303, direct methods solution, full matrix least squares
refinement on F02; anisotropic displacement parameters for
non-hydrogen atoms, hydrogens located in difference Fourier
but included at positions calculated from the geometry of the
molecule using the ridingmodel, R1¼0.071 for2181datawith
F0 . 4sðF0Þ; 165 parameters, wR2¼0.188 (all data),
GoF¼1.05, Flack absolute structure parameter x¼0.00(4)
establishes the absolute configuration as (1R,2S,10S),
4.5. Ring opening reactions of bicyclic disulfoxide 1C
and monosulfoxides 7B and 8B with alkyl and aryl-
lithium reagents
trans
4.5.1. Reaction of (1R,3R)-1,3-benzodithiole-1,3-dioxide
1C
with n-butyllithium and benzaldehyde. n-Butyl-
lithium solution in hexane (1.6 M, 0.53 ml) was added to
trans
stirred solution (1R,3R)-1,3-benzodithiole-1,3-dioxide

558
D. R. Boyd et al. / Tetrahedron 60 (2004) 549–559
1C
(100 mg, 0.54 mmol, [a]D¼þ646) in dry THF at
by PLC on silca gel (5% MeOH in CHCl3); (2)-(S)-
(phenylsulfanylmethyl)methyl sulfoxide 20; 8 mg, 40%
yield; [a]D¼227 (c 0.81, CHCl3); 24% ee (Chiralcel OJ)
and (2)-(R)-(methylsulfanylmethyl)phenyl sulfoxide 21;
5 mg, 22% yield; [a]D¼2110 (c 0.45, CHCl3); 87% ee
(Chiralcel OD). Spectral data for sulfoxides 20 and 21 were
in agreement with the literature values.6
trans
278 8C. After 0.5 h, benzaldehyde (0.06 ml, 0.6 mmol) was
added to the reaction mixture; it was allowed to warm to
room temperature, stirred overnight, and worked up as
described earlier. Purification by PLC (5% MeOH in
CHCl3) afforded a pure sample of (2)-(butane-1-sulfinyl-
methanesulfinyl)-benzene 13; white solid, 64 mg, 49%
yield; Rf 0.43 (5% MeOH in CHCl3); mp 82–84 8C (from
CH2Cl2/hexane); [a]D¼2180 (c 1.69, CHCl3); HRMS
found: Mþ244.0582, C11H16O2S2 requires 244.0592; dH
(500 MHz, CDCl3) 0.93 (3H, t, J¼7.5 Hz, (CH2)3Me),
1.46–1.53 (2H, m, (CH2)2CH2CH3), 1.75–1.82 (2H, m,
CH2CH2CH2CH3), 3.03–3.09 (1H, m, CHAHB-
(CH2)2CH3), 3.18–3.24 (1H, m, CHAHB(CH2)2CH3), 3.91
(1H, d, J¼13.3 Hz, SO–CHAHB–SO), 4.15 (1H, d,
J¼13.3 Hz, SO–CHAHB–SO), 7.55–7.59 (3H, m, Ar-H),
7.68–7.71 (2H, m, Ar-H); m/z 244 (Mþ, 2%) and 126 (100);
CD (l, nm) 251 (D1 211.18), 220 (D1 16.67).
4.5.5. Reaction of (1)-(1R,3R)-benzo-1,3-dithiole-1,3-
dioxide 1C
with n-hexyllithium. (1R,3R)-Benzo-1,3-
1C
trans
dithiole-1,3-dioxide
(40 mg,
0.22 mmol,
trans
[a]D¼þ646) and n-hexyllithium solution in hexane
(2.0 M, 0.15 ml) yielded (2)-(1R)-[(3S)-n-hexylsulfinyl]-
methylphenyl sulfoxide 16; white solid, 38 mg, 65% yield;
mp 128–130 8C (from benzene); Rf 0.2 (CHCl3);
[a]D¼2247 (c 1.7, CHCl3); HRMS found: Mþ272.0902,
C13H20O2S2 requires 272.0905; dH (500 MHz, CDCl3) 0.89
(3H, t, JMe,CH ¼7.1 Hz, Me), 1.30–1.34 (4H, m, (CH2)3-
2
(CH2)2Me), 1.45–1.47 (2H, m, (CH2)2CH2(CH2)2Me),
1.77–1.82 (2H, m, CH2CH2(CH2)3Me), 3.04–3.08 (1H,
m, CHAHB–(CH2)4Me), 3.16–3.21 (1H, m, CHAHB–
4.5.2. Reaction of (1)-(1R,3R)-benzo-1,3-dithiole-1,3-
dioxide with phenyllithium. General procedure. The
lithium reagent (1.1 molar equiv.) was added to a stirring
solution (278 8C, under nitrogen) of the disulfoxide
(1Ctrans) or mono-sulfoxide (7B, 8B) (1.0 mmol in
,20 ml of dry THF). The reaction mixture was allowed
to warm up to room temperature, stirred overnight, and
then quenched with water; it was extracted with ethyl
acetate, the extract dried (MgSO4), concentrated under
reduced pressure, and the crude product purified by
PLC.
0
0
0
0
(CH2)4Me), 3.90 (1H, d, JA B ¼13.2 Hz, SO–CHA HB –
0
0
0
0
SO), 4.13 (1H, d, JB A ¼13.2 Hz, SO–CHA HB –SO),
7.55–7.60 (3H, m, Ar-H), 7.68–7.71 (2H, m, Ar-H); m/z
272 (Mþ, 1%), 210 (5), 126 (81) and 43 (100); CD (l, nm)
256 (D1 221.39), 221 (D1 23.55).
4.5.6. Reaction of (1)-(1R,3R)-benzo-1,3-dithiole-1,3-
dioxide 1C
with t-butyllithium. (1R,3R)-Benzo-1,3-
trans
dithiole-1,3-dioxide 1Ctrans (60 mg, 0.32 mmol) and t-butyl-
lithium solution in pentane (1.7 M, 0.3 ml) yielded (þ)-
(1R)-[(3S)-t-butylsulfinyl]methylphenyl sulfoxide 17 as a
light yellow coloured oil, 20 mg, 30% yield; Rf 0.2 (CHCl3);
[a]D¼þ75 (c 1.0, CHCl3); HRMS found: MþþH 245.0666,
C11H16S2O2þH requires 245.0670; dH (500 MHz; CDCl3)
1.21 (9H, s, But), 3.91 (1H, d, JAB¼12.4 Hz, CHAHB), 3.95
(1H, d, JBA¼12.4 Hz, CHAHB), 7.58 (3H, m, Ar-H), 7.79
(2H, m, Ar-H); m/z (CI) 245 (MþþH, 7%), 189 (15), 126
(96) and 57 (100); CD (l, nm) 250 (D1 214.66), 218 (D1
26.49).
(1R,3R)-Benzo-1,3-dithiole-1,3-dioxide 1Ctrans. (50 mg,
0.27 mmol, [a]D¼þ646) and phenyllithium solution in
cyclohexane (1.8 M, 0.25 ml) yielded meso bis-(phenyl-
sulfinyl) methane 14; white solid, 23 mg, 32% yield; mp
124–125 8C (from CHCl3); lit.14 123 8C; Rf 0.25 (CHCl3);
dH (500 MHz; CDCl3) 4.10 (1H, d, JA,B¼12.7 Hz,–SO–
CHAHB–SO–), 4.20 (1H, d, JB,A¼12.7 Hz,–SO–CHAHB–
SO–), 7.51–7.59 (6H, m, Ar-H), 7.68–7.74 (4H, m, Ar-H).
4.5.3. Reaction of (1)-(1R,3R)-benzo-1,3-dithiole-1,3-
dioxide 1C
with methyllithium. (1R,3R)-Benzo-1,3-
4.5.7. Reaction of (2)-(R)-2,3-dihydrobenzothiophene-1-
oxide 7B with n-butyllithium. n-Butyllithium solution in
hexane (1.6 M, 0.53 ml) and (2)-(R)-2,3-dihydro-
benzo[b]thiophene-1-oxide 7B (90% ee) (118 mg,
0.78 mmol) yielded (2)-(R)-n-butylphenethyl sulfoxide 18
as a colourless oil, 45 mg, 28% yield; Rf 0.51 (5% MeOH in
CHCl3); [a]D¼213.3 (c 1.98, CHCl3); HRMS found:
Mþ210.1072, C12H18OS requires 210.1078; dH (500 MHz;
CDCl3) 0.95 (3H, t, J1,2¼7.4 Hz, Me), 1.39–1.55 (2H, m,
CH2Me), 1.71–1.78 (2H, m, CHEHFCH2Me), 2.60–2.66
(1H, ddd, JC,D¼13.0 Hz, JC,A¼9.0 Hz, JC,B¼8.5 Hz,
PhCH2–HCHD), 2.70–2.76 (1H, ddd, JD,C¼13.0 Hz,
JD,A¼7.8 Hz, JD,B¼5.9 Hz, PhCH2–HCHD), 2.86–2.93
(1H, ddd, JE,F¼12.8 Hz, JE,G¼10.0 Hz, JE,H¼7.2 Hz,
trans
dithiole-1,3-dioxide 1C
(45 mg, 0.24 mmol, [a]D¼
trans
þ646) and methyllithium solution in hexane (1.6 M,
0.25 ml) yielded (2)-(1R)-[(3S)-methylsulfinyl] methylphe-
nyl sulfoxide 15; white solid, 38 mg, 59% yield; mp 135 8C
(from CHCl3); Rf 0.22 (CHCl3); [a]D¼2234 (c 0.8,
CHCl3); HRMS found: Mþ202.0118, C8H10O2S2 requires
202.0122; dH (500 MHz, CDCl3) 2.98 (3H, s, Me), 3.91
(1H, d, JA,B¼13.1 Hz, CHAHB), 4.13 (1H, d, JB,A¼13.1 Hz,
CHAHB), 7.55–7.60 (3H, m, Ar-H), 7.67–7.70 (2H, m,
Ar-H); m/z: 202 (Mþ1%),139 (26), 125 (53), 109 (72), 91
(100); CD (l, nm) 251 (D1 218.15), 220 (D1 20.42).
4.5.4. Deoxygenation of disulfoxide 15. To a solution of
(2)-(1R)-[(3S)-methylsulfinyl] methylphenyl sulfoxide 15
(22 mg, 0.11 mmol, [a]D¼2234) in CH2Cl2 (3 ml) was
added triphenylphosphine (25 mg, 0.1 mmol) along with a
catalytic amount of trichlorooxobis(triphenylphosphine)-
rhenium; the reaction mixture was stirred (2 h) at room
temperature. Triphenylphosphine oxide was removed from
the reaction mixture by reverse phase PLC (70% MeOH in
H2O). The product was further separated into two sulfoxides
SOCHEHF), 2.93–2.98 (1H, ddd, JF,E¼12.8 Hz, JF,G
¼
9.3 Hz, JF,H¼5.6 Hz, SOCHEHF), 3.04–3.10 (1H, ddd,
JA,B¼14.0 Hz, JA,C¼9.0 Hz, JA,D¼7.8 Hz, Ph–CHAHB),
3.11–3.17 (1H, ddd, JB,A¼14.0 Hz, JB,C¼8.5 Hz,
JB,D¼5.9 Hz, Ph–CHAHB), 7.23–7.26 (3H, m, Ar-H),
7.31–7.34 (2H, m, Ar-H); m/z (EI) 210 (Mþ, 13%), 194
(24), 193 (32), 154 (7), 135 (8), 105 (100), 91 (69), 77 (57),
57 (92), 41 (47), 29 (55).

D. R. Boyd et al. / Tetrahedron 60 (2004) 549–559
559
King, A.; McMurray, B. T.; Holt, R.; Dalton, H. J. Chem. Soc.,
Perkin Trans. 1 2001, 3288–3296.
4.5.8. Reaction of (2)-(S)-1,3-benzoxathiole 8B with
n-butyllithium. n-Butyllithium solution in hexane (1.6 M,
0.16 ml) and (2)-(S)-1,3-benzoxathiole-1-oxide 8B (73%
ee) (35 mg, 0.23 mmol) yielded (þ)-(R)-n-butylphenoxy-
methyl sulfoxide 19 as an oil; 16 mg, 34% yield; Rf 0.52
(5% MeOH in CHCl3); [a]D¼þ74 (c 0.6, CHCl3); HRMS
found: Mþ, 212.0866, C11H16O2S requires 212.0871; m/z
212 (Mþ, 70%), 108 (97), 107 (88), 94 (96), 79 (95), 77 (87),
65 (92), 57 (66), 55 (99), 51 (94), 41 (97), 39 (95), 29 (100),
7. Boyd, D. R.; Sharma, N. D.; Ljubez, V.; Byrne, B. E.;
Shepherd, S. D.; Allen, C. C. R.; Kulakov, L. A.; Larkin, M. J.;
Dalton, H. Chem. Commun. 2002, 1914–1915.
8. Lee, K.; Brand, J. M.; Gibson, D. T. Biochem. Biophys. Res.
Commun. 1995, 212, 9–15.
9. Kerridge, A.; Willetts, A.; Holland, H. L. J. J. Mol. Catal. B:
Enzyme 1999, 6, 59–65.
10. Boyd, D. R.; Sharma, N. D.; Dorman, J. H.; Dunlop, R.;
Malone, J. F.; McMordie, R. A. S.; Drake, A. J. Chem. Soc.,
Perkin Trans. 1 1992, 1105–1110.
27 (95); dH (500 MHz; CDCl3) 0.98 (3H, t, J
CH2;Me
Me), 1.44–1.59 (2H, m, CH2Me), 1.78–1.85 (2H, m,
CH2CH2Me), 2.80–2.91 (2H, m, CH2CH2CH2Me), 4.92
¼7.3 Hz,
11. Cecchet, E.; Di Furia, F.; Licini, G.; Modena, G. Tetrahedron:
Asymmetry 1996, 7, 369–372.
(1H, d, JA,B¼10.2 Hz, OCHAHB), 5.02 (1H, d, JB,A
¼
10.2 Hz, OCHAHB), 7.02–7.08 (3H, m, Ar-H), 7.31–7.33
(2H, m, Ar-H); 49% ee (CSP-HPLC, Chiralcel OD Column
a¼1.1).
12. Karlsson, A.; Parales, J. V.; Parales, R. E.; Gibson, D. T.;
Eklund, H.; Ramaswamy, S. Science 2003, 299, 1039–1042.
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Acknowledgements
We thank the BBSRC, DTI, Avecia Lifesciences Molecules,
Astra Zeneca and Oxford Asymmetry for financial support
under the LINK Scheme (N. D. S.), DENI (S. H., S. S.) and
the Queen’s University of Belfast (M. K.) for postgraduate
studentship.
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