Chemoenzymatic synthesis of enantiopure hydroxy sulfoxides derived from substituted arenes

Article abstract of DOI:10.1039/c5ob02411k

Enantiopure β-hydroxy sulfoxides and catechol sulfoxides were obtained, by chemoenzymatic synthesis, involving dioxygenase-catalysed benzylic hydroxylation or arene cis-dihydroxylation and cis-diol dehydrogenase-catalysed dehydrogenation. Absolute configurations of chiral hydroxy sulfoxides were determined by X-ray crystallography, ECD spectroscopy and stereochemical correlation. The application of a new range of β-hydroxy sulfoxides as chiral ligands was examined.

Full text of DOI:10.1039/c5ob02411k

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Chemoenzymatic synthesis of enantiopure hydroxy
sulfoxides derived from substituted arenes†
Cite this: DOI: 10.1039/c5ob02411k
Derek R. Boyd,*a Narain D. Sharma,a John F. Malone,a Vera Ljubez,a
Deirdre Murphy,a Steven D. Shepherda and Christopher C. R. Allenb
Enantiopure β-hydroxy sulfoxides and catechol sulfoxides were obtained, by chemoenzymatic synthesis,
involving dioxygenase-catalysed benzylic hydroxylation or arene cis-dihydroxylation and cis-diol
dehydrogenase-catalysed dehydrogenation. Absolute configurations of chiral hydroxy sulfoxides were
determined by X-ray crystallography, ECD spectroscopy and stereochemical correlation. The application
of a new range of β-hydroxy sulfoxides as chiral ligands was examined.
Received 23rd November 2015,
Accepted 22nd January 2016
DOI: 10.1039/c5ob02411k
www.rsc.org/obc
→ 3,4-dihydroxy-3,4-dihydrochrysene → chrysene bis cis-di-
hydrodiol (f).5b The addition of these less common types of
1 Introduction
Ring hydroxylating arene dioxygenase enzymes, e.g. toluene enantiopure hydroxylated arene metabolites, into the chiral
dioxygenase (TDO), naphthalene dioxygenase (NDO), and pool, has presented further opportunities for chemoenzymatic
biphenyl dioxygenase (BPDO), are best known for their ability, synthesis, including their application as chiral reagents,
to catalyse the cis-1,2-dihydroxylation of monocyclic and poly- ligands or auxiliaries.
cyclic arenes and heteroarenes, in a regio- and stereo-selective
In our earlier studies,3b,c a series of 2-substituted indane
manner. Enantiopure cis-dihydrodiol metabolites, obtained by substrates were used with P. putida UV4 whole cells; it resulted,
TDO-catalysed oxidation of monocyclic arenes, have been initially, in TDO enzyme-catalysed benzylic monohydroxylation
widely used as precursors in the chemoenzymatic synthesis of to give the corresponding enantiopure cis isomers as the main
chiral natural and unnatural products of value in medicinal metabolites. Major objectives of the current study were to: (i)
chemistry.1a–e Enantiopure cis-diol metabolites (a) and (b), re-examine the stereochemistry and mechanism of the benzylic
derived from bromobenzene2a and 2-chloroquinoline2b hydroxylation of 2-chloroindane, using P. putida UV4, where
respectively, were also found to be useful precursors of chiral both mono- and di-hydroxylation at benzylic positions was
ligands (Scheme 1).1b
observed earlier, (ii) utilize mono- and di-hydroxylated 2-chloro-
While arene cis dihydroxylation, to yield cis-dihydrodiols, indane metabolites as synthetic precursors of enantiopure
has been the most widely studied of reactions catalysed by β-hydroxy sulfoxides, (iii) synthesise and aromatize diastereo-
arene dioxygenases, much less attention has been directed to meric monosubstituted benzene cis-diol sulfoxides and obtain
the ability of this enzyme system to catalyse other types of chiral hydroxy sulfoxides via chiral transfer and (iv) evaluate
hydroxylation. These include: (i) benzylic monohydroxylation the potential of hydroxy sulfoxides as chiral ligands.
of alcohols to give diols,3a–c e.g. 2-hydroxyindane → cis-1,2-
dihydroxyindane (c),3c (ii) sequential benzylic-1,3-dihydroxyla-
tion of benzocycloalkanes,3b,c e.g. indane → 1-hydroxyindane →
2 Results and discussion
(i) TDO-catalysed synthesis and stereochemical assignment
trans-1,3-dihydroxyindane (d),3c (iii) sequential benzylic
monohydroxylation and cis-dihydroxylation (trihydroxylation)
of monocyclic arenes, e.g. ethylbenzene → 1-phenylethanol →
cis-dihydrodiol (e)4a,b and (iv) sequential bis cis-dihydroxyla-
tion (tetrahydroxylation) of polycyclic arenes,5a,b e.g. chrysene
of hydroxylated 2-chloroindanes.
The regiochemistry and stereochemistry of TDO-catalysed
benzylic hydroxylation of 2-chloroindane 1 was investigated
using whole cells of P. putida UV4.3c An initial biotransform-
ation of substrate 1 (3.0 g) yielded only the trans-dihydroxy-
lated product 31S,3S (38% yield), which in principle could be
formed from either of the undetected intermediates, cis-21S,2R
or trans- 41S,2S chlorohydrins (Scheme 2).
aSchool of Chemistry and Chemical Engineering, Queen’s University, Belfast BT9
5AG, UK. E-mail: dr.boyd@qub.ac.uk; Fax: +44 (0)-28-9097-4687
bSchool of Biological Sciences, Queen’s University of Belfast, Belfast, BT9 5AG, UK
†Electronic supplementary information (ESI) available. CCDC 1413402, 1413403,
1413404 and 1413405. For ESI and crystallographic data in CIF or other elec-
tronic format see DOI: 10.1039/c5ob02411k
When this experiment was repeated using a shorter bio-
transformation on a smaller scale (0.25 g), only monohydroxy-
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Scheme 1 Selected examples of dioxygenase-catalysed enantioselective hydroxylations including, monocyclic arene cis-dihydroxylation (a), poly-
cyclic heteroarene cis-dihydroxylation (b), benzylic monohydroxylation (c), benzylic dihydroxylation (d), monocyclic arene trihydroxylation (e) and
polycyclic arene tetrahydroxylation (f). Reagents: (i) TDO/O2; (ii) NDO/O2; (iii) BPDO/O2.
Scheme 2 Biotransformation of 2-chloroindane (1) to yield monohydroxylated (21S,2R and 41S,2S) and dihydroxylated (31S,3S) metabolites using
P. putida UV4 as a source of TDO. Reagents: (i) TDO/O2; (ii) NaOMe/Et2O.
lation products were obtained.3c The main metabolites, cis- [α]D and the formation of MTPA ester derivatives. 1H-NMR ana-
chlorohydrin 21S,2R or 21R,2S (90% relative yield) and trans- lysis of the MTPA esters, formed using both MTPA chloride
chlorohydrin 41S,2S or 41R,2R (10% relative yield), having very enantiomers, indicated that (+) trans-chlorohydrin (41S,2S or
similar Rf values, were difficult to separate by chromatography. 41R,2R) was enantiopure (>98% ee).3c Based on the earlier use
A pure sample of the main chlorohydrin 2, obtained by frac- of NMR analysis of diMTPA ester derivatives of benzocyclo-
tional crystallization of the mixture, was assigned a (1S,2R) alkane cis-diols, in the determination of absolute configura-
configuration. This more abundant isomer, cis-21S,2R, isolated tions,3d the (1R,2R) configuration had been tentatively
during this study, was assumed to be the precursor of the assigned to metabolite 4. It was, however, noted that this con-
earlier isolated metabolite 31S,3S, formed via the metabolic figuration was unexpected, since the benzylic (S) hydroxylation
sequence 1 → 21S,2R → 31S,3S (Scheme 2). After the removal of was preferred in the initial TDO-catalysed step, 2-chloroindane
most cis-chlorohydrin 21S,2R, by repeated fractional crystalliza- 1 → cis-chlorohydrin 21S,2R. A similar (S) benzylic hydroxylation
tion, a small sample (ca. 20 mg) of the pure trans-chlorohydrin, of trans-chlorohydrin 41R,2R would thus yield compound 31R,3R
3c
41S,2S or 41R,2R, was separated from the residual mixture by not the isolated metabolite 31S,3S
reverse phase PLC (80% MeOH/H2O).
.
In view of the previous reservations expressed about the
Characterization of this metabolite was accomplished, by a reliability of the (1R,2R) absolute configuration, tentatively
combination of MS, IR, NMR spectroscopy, measurement of assigned to trans-chlorohydrin 4,3c and the requirement to
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produce further quantities of metabolites 21S,2R and 31S,3S, for indane (HR and HS respectively, in accordance with Sequence
potential applications in chemoenzymatic synthesis, a larger Rule priority). A mechanism, involving benzylic radical for-
scale biotransformation of 2-chloroindane 1 (5.0 g) was carried mation and stereospecific addition of a hydroxyl group, to
out. The resulting crude mixture of mono- and di-hydroxylated form a chiral benzyl alcohol with retention of configuration,
bioproducts was partially separated by column chromato- was assumed to occur, during the TDO-catalysed benzylic
graphy. A pure sample of more polar trans-diol 31S,3S (28% iso- hydroxylation of both chromane and 2-chloroindane 1, to yield
lated yield) was obtained and the less polar cis- and trans- (R)-chroman-4-ol and chlorohydrins 21S,2R and 41S,2S respectively.
chlorohydrins were collected as an inseparable mixture (8 : 1).
(ii) Chemoenzymatic synthesis of enantiopure β-hydroxy
cis-Chlorohydrin 21S,2R was isolated in pure form by fractional
sulfoxides, derived from metabolites 21S,2R and 31S,3S
.
crystallization (29% yield) and the residual mixture (4 : 1;
100 mg) of cis- and trans-chlorohydrins was stirred with Enantiopure β-hydroxy sulfoxides have been used as chiral
NaOMe in Et2O solution. It yielded (21 mg) of enantiopure auxiliaries,8a protonating agents8b ligands,8c and synthetic pre-
epoxide 51S,2R, [α]D +55 (CHCl3) of established (1S,2R) absolute cursors. Earlier approaches to the synthesis of β-hydroxy sulfoxide
configuration,6 after PLC separation from the unreacted cis- enantiomers have included asymmetric sulfoxidations of
isomer 21S,2R. This result showed that the (1R,2R) configura- β-keto sulfides using chemical oxidants, e.g. t-butyl hydro-
tional assignment, originally assumed for the minor trans- peroxide, diethyl tartrate, Ti(i-PrO)4 8d and enzymatic oxidants,
chlorohydrin precursor 4, was incorrect.3c It should have been e.g. cyclohexanone monooxygenase.8e In this study, chemical
(1S,2S), which is now consistent with trans-diol 31S,2S meta- and enzymatic methods were combined, to provide alternative
bolite being formed from both cis-21S,2R and trans-41S,2S chloro- chemoenzymatic synthesis pathways to enantiopure β-hydroxy
hydrin intermediates (Scheme 2).
sulfoxides, involving TDO-catalysed mono- and di-hydroxy-
Mechanistic studies of TDO-catalysed benzylic hydroxy- lations and chemical sulfoxidations.
lation, using specifically deuterated chromane enantiomers as
Treatment of the cis-chlorohydrin 21S,2R with thiophenol
substrates, with P. putida UV4 whole cells or purified TDO, and a base (K2CO3) in acetonitrile solution, resulted in a
demonstrated an exclusive formation of the (R) enantiomer nucleophilic substitution of the Cl atom, to give β-hydroxy
(>98% ee) with retention of configuration (Scheme 3).7
A
sulfide 61S,2S in 80% yield. The reaction is assumed to
similar stereopreference was observed, during abstraction of proceed, via an SN2 mechanism, with inversion of configur-
prochiral benzylic hydrogen atoms in chromane and 2-chloro- ation at C-2 (Scheme 4). Similar treatment of the residual
Scheme 3 Stereoselectivity of TDO-catalysed benzylic hydroxylation of chromane and 2-chloroindane using P. putida UV4. Reagents: (i) TDO/O2.
Scheme 4 Synthesis of β-hydroxy sulfides 61S,2S, 91S,2R. and β-hydroxy sulfoxides 71S,2S,R’, 81S,2S,S’, 101S,2R,S’, 111S,2R,R’. Reagents: (i) PhSH, K2CO3,
MeCN; (ii) DMD/Me2CO.
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inseparable mixture (7 : 3) of chlorohydrins 21S,2R and 41S,2S
,
configurations and conversely strong negative absorptions for
present in the mother liquors, yielded a mixture of the (S) sulfoxides.9a The ECD spectrum of trans β-hydroxy sulfoxide
β-hydroxy sulfides 61S,2S (76% yield) and 91S,2R (71% yield), 71S,2S,R′ (λ 241 nm, Δε +9.15), was therefore consistent with an
which was separated by column chromatography.
(R) sulfoxide configuration and trans β-hydroxy sulfoxide
When the hydroxy sulfide isomers 61S,2S and 91S,2R were 81S,2S,S′ (λ 245 nm, Δε −7.51) had the opposite (S) configuration
separately treated with a solution of dimethyl dioxirane (DMD) at the chiral sulfoxide centre.
in acetone, β-hydroxy sulfoxide diastereoisomeric pairs
Similarly, ECD spectroscopy of β-hydroxy sulfoxides
71S,2S,R′/81S,2S,S′ and 101S,2R,S′/111S,2R,R′ respectively were pro- 101S,2R,S′ (λ 243 nm, Δε −8.15) and 111S,2R,R′ (λ 246 nm, Δε
duced (83–88% yield). Pure samples of individual diastereoi- +6.53) was employed, to assign them the (S) and (R) sulfoxides
somers were obtained using multiple elution PLC. Change of configurations respectively. Unequivocal evidence of the val-
configuration was assumed at C-2 (inversion), during the syn- idity of the NMR coupling constant method, for assignment of
thesis of β-hydroxy sulfides 61S,2S and 91S,2R. As an exocyclic cis or trans relative configurations in five membered rings, and
stereogenic centre was introduced during sulfoxidation, rigor- reliability of the ECD method for determination of absolute
ous methods were required for assignment of absolute con- configurations of sulfoxides, was provided by X-ray crystal
figurations to β-hydroxy sulfoxide diastereoisomers 71S,2S,R′
81S,2S,S′, 101S,2R,S′ and 111S,2R,R′
,
structure analysis of β-hydroxy sulfoxide 111S,2R,R′, using the
anomalous dispersion method (Fig. 1). This confirmed the cis
relationship, and absence of intramolecular H-bonding,
between OH and SvO groups and the (1S,2R,R′) absolute
configuration.
.
(iii) Stereochemical assignment of β-hydroxy sulfoxides
71S,2S,R′, 81S,2S,S′, 101S,2R,S′ and 111S,2R,R′
.
Treatment of trans-1,3-diol metabolite 31S,3S, in a similar
manner to chlorohydrins 21S,2R and 41S,2S (PhSH, K2CO3,
MeCN), yielded a mixture of two products, which were separ-
ated by column chromatography (Scheme 5). Nucleophilic sub-
stitution at C-2 yielded the expected trans-diol sulfide 121S,3S
as the major product (34% yield). The unexpected minor
Since absolute configurations had already been established for
the cis- and trans-chlorohydrins, 21S,2R and 41S,2S, a combi-
nation of spectroscopy (NMR, ECD), stereochemical correlation
and X-ray crystallography was used to confirm the relative and
absolute configurations at each of the three chiral centres in
the derived β-hydroxy sulfoxides 71S,2S,R′, 81S,2S,S′, 101S,2R,S′ and
111S,2R,R′
.
Although it is generally more difficult to assign vicinal cis
or trans configurations in five-membered rings relative to six-
membered rings, using NMR spectroscopy, it had earlier been
established3c that disubstituted cis-1,2-indanes exhibited
smaller vicinal coupling constants (J1,2, Hz) than their trans
isomers. On this basis the J1,2 values for cis/trans disubstituted
1,2-indanes were presumed to be: 21S,2R (5.0)/41S,2S (5.8), 91S,2R
(4.9)/61S,2S (5.7), 101S,2R,S′ (6.8)/71S,2S,R′ (7.3) and 111S,2R,R′ (5.6)/
81S,2S,S′ (6.4).
The electronic circular dichroism (ECD) spectra of alkylaryl
sulfoxide enantiomers were reported to show strong posi-
tive absorptions (Cotton effects) at ca. 235–255 nm for (R) Fig. 1 X-ray crystal structure of sulfoxide 111S,2R,R’
.
Scheme 5 Synthesis of β-hydroxy sulfides 121S,3S and 161S,2R,3R and the derived β-hydroxy sulfoxides 131S,3S,R’, 141S,3S,S’ and 171S,2R,3R,R’. Reagents:
(i) PhSH, K2CO3, MeCN; (ii) DMD/Me2CO.
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product was identified as the more polar isomeric trans-1,2-
diol sulfide 161S,2R,3R (15% yield).
A
possible mechanism for the formation of sulfide
161S,2R,3R would involve: (i) base-catalysed cyclization of trans-
1,3-diol 31S,3S to give the undetected epoxide intermediate
151S,2R,3S and (ii) nucleophilic attack of thiophenoxide, at the
preferred benzylic position of epoxide 151S,2R,3S, to yield trans-
diol sulfide 161S,2R,3R. It was surprising that under similar reac-
tion conditions trans-chlorohydrin 41S,2S did not yield epoxide
51S,2R (Scheme 2), which could also have been attacked by thio-
phenoxide. It is possible that, due to steric interactions, a
change in preferred conformation between the trans OH group
and Cl atom in chlorohydrin 31S,3S, relative to chlorohydrin
41S,2S, would facilitate cyclization and yield the epoxide inter-
Fig. 3 X-ray structure of 171S,2R,3R,R’
.
In the crystal of sulfoxide 171S,2R,3R,R′ the five-membered
ring has a substantial envelope conformation, with C-2 nearly
0.4 Å out of the plane of the other four atoms. With the OH
group on C-2 almost fully axial, the sulfur atom and the other
OH group are thus pseudo-axial. By contrast, in hydroxy sulfox-
ides 111S,2R,R′ and 141S,3S,S′ the ring has a more shallow envel-
ope conformation and thus the substituents on C-2, although
tending slightly towards the axial, cannot be described as truly
axial.
mediate 151S,2R,3S
.
Sulfoxidation of trans-1,3-sulfide 121S,3S, using DMD as
oxidant, gave a mixture of β-hydroxy sulfoxide diastereoisomers
131S,3S,R′ (45% yield) and 141S,3S,S′ (37% yield), which was sep-
arated by PLC. The absolute configurations of the sulfoxide
chiral centres in diastereoisomers 141S,3S,S′ (λ 244 nm, Δε
−5.28) and 131S,3S,R′ (λ 248 nm, Δε +4.40) were assigned as (S)
and (R) respectively, based on their ECD spectra. X-ray crystal
structure analysis of diastereoisomer, β-hydroxy sulfoxide
141S,3S,S′, using the anomalous dispersion method, confirmed
its absolute configuration as (1S,3S,S′) (Fig. 2). H-bonding with
allylic OH groups led to a directing effect of DMD during
stereoselective epoxidations.10 A similar rationalization could
account for the formation of both diastereoisomers 131S,3S,R′
and 141S,3S,S′, with DMD directed by a benzylic OH group
toward either lone pair on the sulfur atom of trans-1,3-sulfide
(iv) Chemoenzymatic synthesis of cis-diol sulfoxides 19b1S,2S,S′
,
and 20b1S,2S,R′
.
Earlier tandem biotransformations of alkylaryl sulfides, using
P. putida UV4 whole cells as a TDO source, in some cases,
resulted in heteroatom oxidation to yield enantiopure sulf-
oxides, and further metabolism, to yield the corresponding cis-
dihydrodiol sulfoxides. Thus, cis-dihydrodiol sulfoxides
19a1S,2S,R′ and 19b1S,2S,S′, were isolated as single diastereo-
isomers, via TDO-catalysed (P. putida UV4) oxidation of the
alkylaryl sulfide 18a and the diaryl sulfide 18b respectively.11a,b
Since no evidence of the alternative diastereoisomers 19a1S,2S,S′
and 19b1S,2S,R′ was found, using P. putida UV4, a chemoenzy-
matic approach to synthesise both cis-diol sulfoxide diastereo-
isomers, was adopted (Scheme 6).
121S,3S
.
Only one β-hydroxy sulfoxide isomer was obtained upon
treatment of β-hydroxy sulfide 161S,2R,3R with DMD. The struc-
ture and absolute configuration (1S,2R,3R,R′) of β-hydroxy sulf-
oxide 171S,2R,3R,R′ was assigned by a combination of NMR
spectroscopy and X-ray crystallography, using the anomalous
dispersion method (Fig. 3). The formation of
a single
cis-Diol sulfides 23a1S,2S and 23b1S,2S were obtained from
the hydroxylated metabolite 22 (X = I) derived from iodo-
benzene 21 (X = I), via a palladium-catalysed cross coupling
process, using tributyltin reagents (R = Me or Ph, Scheme 6).11c
Treatment of sulfides 23b1S,2S and 23a1S,2S with DMD, gave
diastereoisomer, 171S,2R,3R,R′, was again assumed to be due to
H-bonding of DMD with a benzylic hydroxyl group. This
directed the oxidant preferentially toward one of the lone pairs
on the sulfur atom in hydroxy sulfide 161S,2R,3R, thus reducing
steric interactions between the bulky phenyl group and the
mixtures of cis-diol sulfoxide diastereoisomers 19b1S,2S,S′
/
other aryl ring and yielding compound 171S,2R,3R,R′
.
20b1S,2S,R and 19a1S,2S,S′/20a1S,2S,R′. Diastereoisomers 19b1S,2S,S′
and 20b1S,2S,R′ were separated by multi elution PLC, but dia-
stereoisomers 19a1S,2S,S′/20a1S,2S,R′ could not be separated.
(v) Stereochemical assignment of sulfoxide cis-diol 20b1S,2S,R′
.
Since the metabolites 19a1S,2S,R′ and 19b1S,2S,S′, obtained
directly from tandem biotransformations of sulfides 18a and
18b, were obtained as gums, their absolute configurations
were assigned using ECD spectroscopy.11a With a crystalline
sample of (+)-sulfoxide cis-diol 20b1S,2S,R′ available, its absolute
configuration was confirmed by X-ray crystallography (Fig. 4).
It is noteworthy that the X-ray crystal structure of compound
20b1S,2S,R′ contained equal proportions of two crystallographically
Fig. 2 X-ray crystal structure of 141S,3S,S’
.
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C-2. In common with other cis-dihydrodiol metabolites 22
[X = F, Br, CH2(SO)Me, CH(CF3)OH] reported earlier,11d–f the
crystal structure of 20b1S,2S,R′ showed the presence of only
intermolecular H-bonding between OH groups and also
between OH groups and sulfoxide oxygen atoms. The cis-di-
hydrodiols 22 [X = F, Br, CH(CF3)OH] and β-cis-diol sulfoxide
22 [X = 1,3-dithienyl sulfoxide] all crystallized out exclusively as
the M conformers, with only crystalline cis-diol sulfoxide 22
[X = CH2(SO)Me] having a P conformation.11e Sulfoxide 20b1S,2S,R′
was thus exceptional by having both M and P conformations
present in the same crystal.
The M or P diene conformations of cis-dihydrodiol enantio-
mers 22 (X = F, Br, Me, CF3, CN), in solution, were studied
earlier by both calculated and experimental ECD spectro-
scopy.11d The preferred equilibrium ratio of the M and P
conformers was dependent on several factors, including
intramolecular OH–OH, OH–π and OH–F hydrogen bonds. The
M conformation, observed exclusively in the crystalline state,
was found to be favoured in solutions of cis-dihydrodiols 22
(X = F, Br, CF3, CN) with only cis-dihydrodiol 22 (X = Me) prefer-
ring the P conformation. It is probable that, in addition to
intramolecular OH–OH, OH–π and OH–F hydrogen bonding
interactions, the hydroxyl and sulfoxide groups present in sulf-
oxide 20b1S,2S,R′ are also involved in similar interactions in
solution. This will determine the M : P conformational
equilibrium.
Scheme 6 TDO-catalysed oxidation of the sulfides 18a and 18b to
yield cis-diol sulfoxides 19a1S,2S,R’ and 19b1S,2S,S’ and chemoenzymatic
synthesis of cis-diol sulfoxides 19b1S,2S,S’, and 20b1S,2S,R’ from the cis-
dihydrodiol metabolite 22 (X = I) of iodobenzene 21. Reagents and con-
ditions: (i) P. putida UV4, (ii) n-Bu3SnSR, (iii) DMD, acetone.
(vi) Chemical aromatization of enantiopure cis-diol
sulfoxide 20b1S,2S,R′
.
Since arene cis-dihydrodiol enantiomers were known to aroma-
tise under acidic or basic conditions12a–d and elevated temp-
eratures, it was assumed that these characteristics would
reduce their potential as chiral auxiliaries or ligands. In this
context, the possibility of forming more stable phenolic sulf-
oxide enantiomers from the corresponding arene cis-diol sulf-
oxide diastereoisomers, via chirality transfer, was examined
(Scheme 7).
Results from an earlier kinetic study of the aromatization of
seventeen different monocyclic cis-dihydrodiol metabolites,
under acid conditions (aq HClO4, 25 °C), indicated that ortho-
phenol sulfoxides were generally formed in preference to the
meta isomers.12a Thus, GC-MS analysis showed that the major
ortho-phenol sulfoxide 24bR (X = H, 78%) and minor meta
isomer 25bR (X = H, 22%) were formed from a diastereo-
isomeric mixture of cis-dihydrodiol sulfoxides 19b1S,2S,S′/20b1S,2S,R′
but their % ee values were not determined (Schemes 6 and 7).
The acid-catalysed aromatization of cis-diol sulfoxide dia-
stereoisomer 20b1S,2S,R′ was repeated using aq. HCl. The
Fig. 4 X-ray crystal structures of cis-diol sulfoxide conformers 20b1S,2S,R’
(M) and 20b1S,2S,R’ (P) viewed along the diene central bond.
independent molecules, in the unit cell with identical 1S,2S,R′ phenol sulfoxides 24bR and 25bR (X = H) were methylated
absolute configurations, but with different M and P diene (CH2N2) to yield the corresponding ethers 24bR and 25bR (X =
conformations. In the crystalline state, the M conformer, Me), which were used directly for chiral stationary phase HPLC
with torsion angle −13° along the diene unit, had a pseudo- (CSP HPLC) analysis. It was found that a significant degree of
axial OH group at C-2 and a pseudo-equatorial OH group at racemization had occurred in both ortho isomer 24bR (>98
C-1. Conversely, the other independent molecule adopted a → 68% ee) and meta isomer 25bR (>98 → 67% ee). As acid-cata-
P conformation, with torsion +16° along the diene unit, leading lysed racemization of other types of chiral sulfoxides using
to a pseudo-axial OH at C-1 and a pseudo-equatorial OH at HCl had been observed earlier,9b no further aromatization
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Scheme 8 Dimethyl sulfoxide reductase-catalysed stereoselective
deoxygenation of racemic phenol sulfoxide 24aR/24aS. Reagents and
conditions: (i) C. braakii DMSO 11.
the potentially more useful ortho-phenol sulfoxides 28aR and
28bR. Formation of an intramolecular H-bond between the
sulfoxide group and the proximate OH group in catechols 28aR
and 28bR may render the other OH group more susceptible to
methylation. A similar result was observed during methylation
of a chiral catechol metabolite derived from cis-dihydrodiol 22
[X = CH(CF3)OH], where ortho OH group was preferentially
methylated due to intramolecular H-bonding.13
Kinetic resolution of racemic ortho-phenol sulfoxide sub-
strate 24aR/24aS, to yield the residual (S)-enantiomer 24aS
(>98% ee) and the corresponding ortho-phenol sulfide 30, was
achieved by enantioselective deoxygenation (Scheme 8). This
involved the use of whole cells of Citrobacter braakii DMSO11
expressing dimethyl sulfoxide reductase.11b ortho-Phenol sulf-
oxide 24bR (X = H) could not be obtained in enantiopure form,
from the corresponding cis-diol sulfoxide 20b1S,2S,R′ by this
method (Scheme 7). As alkyl ortho-phenol sulfoxides have
Scheme 7 Chemoenzymatic synthesis of enantioenriched phenol sulf-
oxides 24bR/24bS, 25bR/25bS (X = H) and enantiopure alkylaryl sulf-
oxides 27aR, 29aR and diaryl sulfoxide 29bR. Reagents and conditions:
(i) aq·HCl; (ii) E. coli narB; (iii) CH2N2, Et2O.
study of sulfoxide cis-diol diastereoisomers was undertaken.
Attempts to obtain enantiopure phenols 24bR and 25bR (X = H)
by heating the cis-diol sulfoxide 20b1S,2S,R′ (120 °C, >1 h) were
also unsuccessful.
structural features similar to β-hydroxy sulfoxides 71S,2S,R′
81S,2S,S′, 101S,2R,S′ and 111S,2R,R′, phenol sulfoxide 24aS was also
included in a preliminary study of their value as chiral ligands.
,
(vii) Enzymatic aromatization of enantiopure cis-diol
sulfoxides 19a1S,2S,R′ and 20b1S,2S,R′
.
An enzymatic approach to aromatization of cis-diol sulfoxides,
under neutral conditions (pH 7.2), was also examined, as a
possible route to chiral hydroxy sulfoxides. Biotransformations
(viii) Evaluation of β-hydroxy sulfoxide enantiomers as chiral
ligands
of substituted benzene cis-diols using whole cells of an Different types of enantiopure metabolites, (e.g. a–e,
E. coli narB recombinant strain, expressing naphthalene cis- Scheme 1), obtained by TDO-catalysed hydroxylation of arenes,
diol dehydrogenase (NCDD), had resulted in dehydrogenation heteroarenes and benzocycloalkanes, have been used in the
to give a wide range of the corresponding catechols.11a,13 chemoenzymatic synthesis of chiral ligands and reagents
Under similar conditions, with sulfoxide cis-diols 19a1S,2S,R′
,
(Fig. 5).14a–c This approach was exemplified by the use of
and 20b1S,2S,R′ as substrates, the corresponding catechol sulf- bromobenzene cis-dihydrodiol (a, Scheme 1) in the synthesis
oxides 26aR and 26bR were obtained (Scheme 7). The crude of organophosphorus chiral ligands. Thus, the mixed phosphine–
catechol 26aR (60–80% yield) was identified by NMR and MS phosphine oxide enantiomer 31 was used in the asymmetric
analysis; purification by chromatography resulted in its allylation of aldehydes and asymmetric hydrogenation of alke-
decomposition. Catechol metabolite 26bR was found to be nes.14a Enantiopure 2,2′-bipyridines 32 and 33 and derived
more stable and a pure sample was obtained by recrystalliza- N-oxides, synthesised from a 2-chloroquinoline cis-dihydrodiol
tion. Methylation (CH2N2) of crude catechol 26aR, yielded the metabolite (b), also proved to be efficient chiral ligands; they
stable derivatives 27aR and 29aR. Similar treatment of crude were used for catalytic asymmetric allylic oxidation, cyclopropa-
catechol 26bR yielded only the dimethylated catechol 27bR. No nation of alkenes, aminolysis of epoxides and allylation of alde-
evidence was obtained of monomethylated catechol 29bR or hydes.14b,c The availability of enantiopure indene cis-diol (c) of
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Fig. 5 Chiral ligands 31–34 and 36.
either configuration by TDO- or NDO-catalysed benzylic hydroxy-
lation of 2-indanol, was used in the chemoenzymatic synthesis
of either cis-amino alcohol enantiomer 34 (Fig. 5).3c cis-Amino
indanol enantiomers 34 are widely used as ligands in asym-
metric synthesis, including aldol and cycloaddition reactions.
Relatively few reports have appeared on the potential of
β-hydroxy sulfoxide enantiomers as chiral auxiliaries or
ligands.8a,c Several acyclic β-hydroxy alkylaryl sulfoxides proved
to be very useful chiral auxiliaries in asymmetric biaryl Suzuki
reactions (>97% de).8a The enantioselective addition of diethyl-
zinc to aldehydes is among the most widely studied ligand-
accelerated reactions.15a A wide range of chiral ligands con-
tinue to be evaluated using this reaction,15b,c including
β-hydroxy alkylaryl sulfoxides.8c Both cyclic and acyclic
β-hydroxy sulfoxides were found to be chiral ligands, catalysing
the addition of diethyl zinc to benzaldehyde (Scheme 9).8c
When a trans-β-hydroxy sulfoxide moiety was part of a five-
membered ring, the resulting benzylic alcohols 35R/35S were
obtained with low ee values (2–11%); higher values (23–45%
ee) resulted from the use of six-membered cyclic cis-β-hydroxy
sulfoxide ligands.8c The latter study prompted this preliminary
Table 1 Enantiomeric excess values and absolute configurations of
1-phenyl propanol 35, obtained using ligands 71S,2S,R’, 101S,2R,S’, 111S,2R,R’
,
131S,3S,R’ and 24aS to catalyse the reaction of benzaldehyde with
diethylzinc
Ligand
configuration
1-Phenyl propanol
35 (% ee)
Ligand
Configuration
7
1S,2S,R′
1S,2R,S′
1S,2R,R′
1S,3S,R′
S
2
15
32
20
30
S
R
S
R
S
10
11
13
24a
(20%), where a cis-β-hydroxy sulfoxide group was present in
each case. The highest reported ee value (45%)8c of the
1-phenyl propanol product 35 from this reaction, with a
β-hydroxy sulfoxide ligands, was obtained using cis isomer 36.
The proximity of OH and SvO groups, in the cis ligands
101S,2R,S′, 111S,2R,R′ and 131S,3S,R′ relative to the trans ligand
71S,2S,R′, appears to be an important factor, during coordi-
nation to the zinc atom, in the preferred transition state, and
thus in the ee value of 1-phenyl propanol 35.
Application of ortho-phenol sulfoxide 24aS, as a chiral
ligand, resulted in a similar degree of stereoselectivity (30%
ee), but of opposite absolute configuration, relative to that
found using hydroxy sulfoxide 111S,2R,R′ (32% ee).
evaluation of the new hydroxy sulfoxide enantiomers 71S,2S,R′
101S,2R,S′ 111S,2R,R′ 131S,3S,R′ and 24aS as chiral ligands
(Scheme 9).
,
,
,
The trans-β-hydroxy sulfoxide 71S,2S,R′, was the first to be
used as a chiral ligand. The reaction was monitored by HPLC
and upon completion, 1-phenyl propanol 35 was isolated with
a very low ee value (2%, CSP HPLC analysis, Table 1). Improved
ee values were however obtained, using the five membered
ring ligands 101S,2R,S′ (15%), 111S,2R,R′ (32%) and 131S,3S,R′
The results presented in Table 1, allied to those obtained
earlier,8c with 45% being the maximum ee value for 1-phenyl
propanol 35, indicate that β-hydroxy sulfoxides are among the
less efficient ligands used for this type of reaction.15a–c Never-
theless, the earlier success of β-hydroxy sulfoxide enantiomers
as chiral auxiliaries,8a suggests that hydroxy sulfoxides 71S,2S,R′
,
101S,2R,S′, 111S,2R,R′, 131S,3S,R′ and 24aS could be of more value
in this context.
3 Conclusions
A
range of cyclic β-hydroxy sulfoxide enantiomers was
obtained, by chemoenzymatic synthesis, initiated by TDO-cata-
lysed benzylic mono- and di-hydroxylation of 2-chloroindane,
to yield both cis- and trans-chlorohydrins as single enantio-
mers. Nucleophilic substitution, using the thiophenolate
Scheme 9 Asymmetric synthesis of benzylic alcohol 35S/35R using
hydroxy sulfoxides 71S,2S,R’, 101S,2R,S’, 111S,2R,R’, 131S,3S,R’, and 24aS as
chiral ligands.
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anion, resulted in an inversion of configuration at C-2 and for- crude mixture of bioproducts obtained was purified by column
mation of cis- and trans-β-hydroxy sulfides. Sulfoxidation, chromatography (25% EtOAc in hexane), to yield a mixture of
using DMD, yielded separable mixtures of enantiopure indane (−)-(1S,2R)-2-chloro-2,3-dihydro-1H-inden-1-ol 21S,2R (1.62 g,
β-hydroxy sulfoxide isomers, whose absolute configurations 29%) and (+)-(1S,2S)-2-chloro-2,3-dihydro-1H-inden-1-ol 41S,2S
were determined by a combination of ECD spectroscopy and (0.210 g, 4%) and also the pure more polar (−)-(1S,3S)-1,3-di-
X-ray crystallography.
hydroxy-2-chloro-2,3-dihydro-1H-inden-1-ol 31S,3S (1.68 g, 28%).
Partially racemized ortho- and meta-phenol sulfoxides were A pure sample of (−)-(1S,2R)-2-chloro-2,3-dihydro-1H-inden-
formed, via chemoenzymatic synthesis and chiral transfer, 1-ol 21S,2R was isolated from the mixture by fractional crystalli-
involving TDO-catalysed cis-dihydroxylation of alkylaryl and zation (EtOAc/hexane). Spectra of compounds 21S,2R ([α]D −52,
diaryl sulfides, followed by acid-catalysed dehydration. De- CHCl3) and 31S,3S ([α]D −91 MeOH) were indistinguishable
hydrogenation of arene cis-dihydrodiol sulfoxides, catalysed by from authentic samples.3c
NCDD, also resulted in chiral transfer. The resulting enantio-
Synthesis of (+)-(1S,2R)-1a,6a-dihydro-6-H-indeno[1,2-b]-
pure catechol sulfoxides were stabilized as methyl ether deriva- oxirene-51S,2R from trans-chlorohydrin 41S,2S. A small portion
tives. A comparative study of the potential of four β-hydroxy (100 mg, 0.60 mmol) of the mixture (4 : 1) of (+)-chlorohydrin
sulfoxides and one alkyl ortho-phenol sulfoxide, as chiral 41S,2S and (−)-chlorohydrin 21S,2R, left after the separation of
ligands for the addition reaction of benzaldehyde with diethyl- majority chlorohydrin 21S,2R was dissolved in dry Et2O (10 mL)
zinc, was conducted.
and stirred overnight with excess of sodium methoxide (65 mg,
1.2 mmol). The sodium salts were filtered off, and the crude
product left after removal of Et2O was purified by PLC (25%
EtOAc in hexane), to give epoxide 51S,2R as an oil (21 mg, 33%);
[α]D +55 (c 0.5, CHCl3); lit.,6 [α]D −55 (CHCl3) for (1R,2S) enan-
tiomer; δH (500 MHz, CDCl3) 2.99 (1 H, dd, J3,2 2.9, J3,3′ 18.0,
3-H), 3.25 (1 H, d, J3′,3 18.0, 3′-H), 4.15 (1 H, t, J2,1 = J2,3 2.9,
2-H), 4.27 (1 H, d, J1,2 2.9, 1-H), 7.22–7.50 (4 H, m, Ar); m/z (EI)
132 (M+, 73%), 104 (100).
(+)-(1S,2S)-2-(Phenylthio)-2,3-dihydro-1H-inden-1-ol 61S,2S. A
solution of (−)-chlorohydrin 21S,2R (0.5 g, 3 mmol), in dry
acetonitrile (10 mL) containing thiophenol (1.65 g, 15 mmol)
and K2CO3 (0.5 g), was refluxed overnight. The cooled reaction
mixture was filtered, to remove the solid salts, the filtrate con-
centrated under reduced pressure, and the crude product was
purified by column chromatography (15% Et2O in hexane) to
give (+)-thiophenyl 61S,2S as a white crystals (0.574 g, 80%);
m. p. 111 °C (from hexane); [α]D +9.0 (c 1.1, MeOH); (Found:
4 Experimental
1H and 13C NMR spectra were recorded on Bruker Avance
DPX-300 and DPX-500 instruments. Mass spectra were run 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 the
standard. Elemental microanalyses were carried out on a
Perkin-Elmer 2400 CHN microanalyser and IR spectra were
recorded using a Perkin-Elmer Spectrum RX1 FT-IR spectro-
meter. ECD spectra were obtained using a Jasco J-720 instru-
ment. A Perkin-Elmer 341 polarimeter was used for optical
rotation ([α]D) measurements (ca. 20 °C, 10−1 deg cm2 −1).
g
Flash column chromatography and PLC were performed on
Merck Kieselgel type 60 (250–400 mesh) and PF254/366 respect-
ively. Merck Kieselgel type 60F254 analytical plates were used
for TLC. CSP HPLC analysis was carried out using a Shimadzu
LC-A liquid chromatograph connected to Hewlett Packard
diode array detector using Chiralpak AS or Chiralcel OB
C, 74.0; H, 5.8.
C15H14OS requires C, 74.4; H, 5.8%);
δH (500 MHz, CDCl3) 2.90 (1 H, dd, J3,2 7.3, J3,3′ 16.2, 3-H), 3.46
(1 H, dd, J3′,2 7.8, J3′,3 16.2, 3′-H), 3.80 (1 H, m, 2-H), 5.13 (1 H,
d, J1,2 5.7, 1-H), 7.20–7.47 (7 H, m, Ar), 7.49–7.51 (2 H, m, Ar);
δC (125 MHz, CDCl3) 37.52, 54.88, 81.13, 124.32, 124.67,
127.01, 127.28, 128.72, 129.10 (2C), 131.43 (2C), 134.85,
140.46, 142.80; m/z (EI) 242 (M+, 100%), 133 (92), 132 (87),
123 (75), 110 (57).
analytical columns. Metabolites 21S,2R, 31S,3S, 41S,2S, 19a1S,2S,R′
,
20a1S,2S,S′, 20b1S,2S,R′, 22 (X = I), 23a1S,2S and 23b1S,2S, were
available from earlier studies3c,11a–c and compounds 34 and 35
from commercial sources.
TDO-catalysed benzylic hydroxylations were conducted
using P. putida UV4 whole cells. This is a proprietary mutant
strain derived from a wild-type strain (P. putida NCIB 11767)
originally constructed at ICI using reported methods.1a,16a,b
We thank Dr R. Holt (robert.holt@npilpharma.co.uk) for
making this strain available to us. NCDD-catalysed dehydro-
genations were conducted using whole cells of the recombi-
nant strain E. coli DH5α(pUC129:narB) which was developed at
the Queen’s university of Belfast.16b
(−)-(1S,2R)-2-(Phenylthio)-2,3-dihydro-1H-inden-1-ol 91S,2R
.
Thiophenol (0.65 g, 5.9 mmol) and K2CO3 (0.5 g) were added
to a mixture (7 : 3) of (−)-chlorohydrin 21S,2R and (+)-chloro-
hydrin 41S,2S (0.170 g, 1 mmol), in dry acetonitrile (5 mL).
The reaction mixture was refluxed overnight, worked up in a
similar manner to the preceding synthesis. The resulting two
thiophenyl products 61S,2S (0.131 g, 76%, less polar) and 91S,2R
were separated by column chromatography (15% Et2O in
hexane). Thiophenyl compound 91S,2R was obtained as white
crystalline solid (52 mg, 71%); m. p. 92–93 °C (from hexane);
[α]D −51.1 (c 0.8, MeOH); (Found: C, 74.3; H, 5.7. C15H14OS
requires C, 74.4; H, 5.8%); δH (500 MHz, CDCl3) 3.10 (1 H, dd,
(i) Biotransformation of 2-chloro-2,3-dihydro-1H-indene 1 to
yield (1S,2R)-2-chloro-2,3-dihydro-1H-inden-1-ol 21S,2R
The earlier biotransformation of 2-chloro-2,3-dihydro-1H- J3,2 8.0, J3,3′ 15.9, 3-H), 3.30 (1 H, dd, J3′,2 7.6, J3′,3 15.9, 3′-H),
indene 13c (5 g), using P. putida UV4, was repeated and the 4.05 (1 H, m, 2-H), 4.7 (1 H, br, OH), 5.08 (1 H, d, J1,2 4.9, 1-H),
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7.21–7.32 (6 H, m, Ar), 7.48–7.50 (3 H, m, Ar); δC (125 MHz, J2,3 8.4, 2-H), 5.64 (1 H, d, J1,2 7.3, 1-H), 7.13 (1 H, m, Ar–H),
CDCl3) 36.96, 54.55, 74.77, 124.67, 125.37, 127.23, 127.30, 7.24 (2 H, m, Ar–H), 7.28 (1 H, m, Ar–H), 7.54 (3 H, m, Ar–H),
128.91, 129.16 (2C), 130.84 (2C), 134.88, 141.39, 142.87; m/z 7.68 (2 H, m, Ar–H); δC (125 MHz, CDCl3) 26.78, 72.83, 75.32,
(EI) 242 (M+, 98%), 132 (97), 133 (97), 123 (100), 110 (77).
124.07, 124.30 (2C), 124.86, 127.46, 128.88, 129.29 (2C),
(−)-(1S,3S)-2-(Phenylthio)-2,3-dihydro-1H-indene-1,3-diol 131.09, 139.12, 142.04, 142.20; νmax/cm−1 3290 (OH), 1028
121S,3S and (+)-(1S,2R,3R)-3-(phenylthio)-2,3-dihydro-1H- (SO); ECD (MeOH): λ/nm 241 (Δε +9.15), 218 (Δε −12.9).
indene-1,2-diol 161S,2R,3R. A mixture of (−)-(1S,3S)-1,3- (−)-(1S,2S)-2-[(S′)-Phenylsulfinyl]-2,3-dihydro-1H-inden-1-ol
dihydroxy-2-chloro-2,3-dihydro-1H-inden-1-ol 31S,3S (0.750 g, 81S,2S,S′. More polar white crystalline solid (56 mg, 43%);
4 mmol), thiophenol (2.2 g, 20.0 mmol) and K2CO3 (1.5 g) in m. p. 112–113 °C; [α]D −137 (c 1.1 MeOH); (Found: C, 69.3;
dry acetonitrile (15 mL) was refluxed overnight. Workup proce- H, 5.3. C15H14O2S requires C, 69.8; H, 5.4%); δH (500 MHz,
dure similar to that used for the synthesis of compounds 61S,2S CDCl3) 2.94 (1 H, dd, J3,2 8.8, J3,3 16.1, 3-H), 3.03 (1 H, dd,
and 91S,2R, followed by column chromatography (25% Et2O J3′,2 8.8, J3′,3 16.1, 3′-H), 3.54 (1 H, ddd, J2,1 6.4, J2,3′ = J2,3 8.8,
in hexane), gave two thiophenyl compounds 121S,3S and 2-H), 4.7 (1 H, br s, OH), 5.80 (1 H, d, J1,2 6.4, 1-H), 7.15 (1 H,
161S,2R,3R. (−)-Thiophenyl compound 121S,3S; semisolid from m, Ar–H), 7.25 (2 H, m, Ar–H), 7.40 (1 H, m, Ar–H), 7.57 (3 H,
less polar fraction (0.358 g, 34%); [α]D −76 (c 0.6, MeOH); m, Ar–H), 7.76 (2 H, m, Ar–H); δC (125 MHz, CDCl3) 30.90,
(Found: M+, 258.0718. C15H14O2S requires 258.0715); 72.77, 76.35, 124.41(2C), 124.45, 124.53, 127.66, 128.78, 129.55
δH (500 MHz, CDCl3) 3.77 (1 H, dd, J2,1 5.1, J2,3 7.3, 2-H), 4.63 (2C), 131.71, 138.31, 142.28, 142.89; νmax/cm−1 3326 (OH),
(2 H, br s, 2 × OH), 5.10 (1 H, d, J1,2 5.1, 1-H), 5.24 (1 H, d, 1011 (SO); ECD (MeOH): λ/nm 245 (Δε −7.51), 218 (Δε +11.7).
J3,2 7.3, 3-H), 7.26–7.57 (9 H, m, Ar); δC (125 MHz, CDCl3)
(−)-(1S,2R)-2-[(S′)-Phenylsulfinyl]-2,3-dihydro-1H-inden-1-ol
64.41, 72.44, 78.18, 124.13, 125.67, 127.48, 129.14 (2C), 129.34, 101S,2R,S′. Less polar colourless crystalline diastereoisomer
129.65, 131.16 (2C), 134.22, 141.02, 143.28; m/z (EI) 258 (14 mg, 25%); m. p. 106–107 °C (from EtOAc/hexane);
(M+, 53%), 148 (100), 131 (85), 120 (55).
[α]D −171 (c 0.81, MeOH); (Found: M+, 258.0717. C15H14O2S
(+)-Thiophenyl compound 161S,2R,3R
;
colourless crystals requires 258.0714); δH (500 MHz, CDCl3) 2.79 (1 H, dd, J3,2 8.6,
from more polar fraction (0.162 g, 15%); m. p. 97–99 °C J3,3 16.7, 3-H), 3.58 (1 H, ddd, J2,1 6.8, J2,3′ 7.8, J2,3 8.6, 2-H),
(from EtOAc/hexane); [α]D +7 (c 0.4, MeOH); (Found: C, 69.5; 3.72 (1 H, dd, J3′,2 7.8, J3′,3 16.7, 3′-H), 5.38 (1 H, d, J1,2 6.8,
H, 5.3. C15H14O2S requires C, 69.8; H, 5.4%); δH (500 MHz, 1-H), 7.25–7.28 (3 H, m, Ar), 7.51–7.55 (4 H, m, Ar), 7.71–7.31
CDCl3), 4.23 (1 H, m, 2-H), 4.38 (1 H, d, J1,2 6.8, 1-H), 5.02 (2 H, m, Ar); δC (125 MHz, CDCl3) 27.97, 67.60, 76.28, 124.46
(1 H, m, 3-H), 7.25–7.49 (9 H, m, Ar); δC (125 MHz, CDCl3) (2C), 124.94, 125.10, 127.56, 129.23 (2C), 129.57, 130.92,
60.40, 79.60, 86.73, 124.25, 125.26, 125.86, 127.45, 128.77, 140.98, 142.72, 142.89; νmax/cm−1 3400 (OH) 1034 (SO); ECD
129.14, 129.19 (2C), 131.64 (2C), 141.01, 142.82; m/z (EI) (MeOH): λ/nm 243 (Δε −8.15), 216 (Δε +15.1).
258 (M+, 12%), 240 (16), 109 (32), 57 (100).
(+)-(1S,2R)-2-[(R′)-Phenylsulfinyl]-2,3-dihydro-1H-inden-1-ol
111S,2R,R′. More polar colourless crystalline diastereoisomer
(32 mg, 57%); m. p. 149–150 °C (from EtOAc); [α]D +100 (c 0.8,
MeOH) (Found: C, 69.7; H, 5.1. C15H14O2S requires C, 69.8; H,
(ii) General procedure for sulfoxidation of phenyl sulfides
using dimethyldioxirane
Dimethyldioxirane (DMD) was prepared as a solution in 5.4%); δH (500 MHz, CDCl3) 2.59 (1 H, dd, J3,2 8.2, J3,3 16.0,
acetone by the addition of potassium peroxymonosulfate 3-H), 3.21 (1 H, dd, J3′,2 8.8, J3′,3 16.0, 3′-H), 3.62 (1 H, ddd,
(Oxone) to a mixture of water, acetone and sodium bicarbonate J2,1 5.6, J2,3′ 8.8, J2,3 8.2, 2-H), 4.72 (1 H, br s, OH), 5.59 (1 H, d,
in accordance with the literature procedure.17 A solution of J1,2 5.6, 1-H), 7.20–7.26 (4 H, m, Ar–H), 7.56–7.58 (3 H, m,
dimethyldioxirane (DMD) (ca. 0.08 M) was added dropwise, to Ar–H) 7.80–7.82 (2 H, m, Ar–H); δC (125 MHz, CDCl3) 31.35,
a stirring solution of the phenyl sulfide maintained at 0 °C in 60.41, 65.86, 75.70, 124.79, 125.20 (2C), 125.30, 127.71, 129.43
acetone solution. The progress of the reaction was constantly (2C), 131.75, 140.55, 142.59, 142.72; νmax/cm−1 3353 (OH),
monitored by TLC. When the starting compound was just con- 1013 (SO); ECD (MeOH): λ/nm 246 (Δε +6.53), 216 (Δε −12.3).
sumed, the reaction was terminated by removal of the solvent
Crystal data for compound 111S,2R,R′. C15H14O2S, M = 258.3,
in vacuo and the mixture of sulfoxide diastereoisomers was monoclinic, a = 8.6093(11), b = 6.0390(7), c = 11.4715(14) Å, U =
separated by PLC (40–100% EtOAc in hexane). Phenyl sulf- 596.3(2) Å3, T = 153(2) K, space group P21 (no. 4), Mo-Kα radi-
oxides 71S,2S,R′ and 81S,2S,S′ (from sulfide 61S,2S), 101S,2R,S′ and ation, λ = 0.71073 Å, Z = 2, F(000) = 272, Dx = 1.439 g cm−3, μ =
111S,2R,R′ (from sulfide 91S,2R), 131S,3S,R′ and 141S,3S,S′ (from 0.261 mm−1, Bruker SMART CCD diffractometer, ϕ/ω scans,
sulfide 121S,3S), 171S,2R,3R,R′ (from sulfide 161S,2R,3R), 20b1S,2S,R′ 3.6° < 2θ < 56.8°, measured/independent reflections: 6656/
and 19b1S,2S,S′ (from sulfide 23b1S,2S) were synthesised by the 2573, Rint = 0.042, direct methods solution, full-matrix least
2
procedure.
squares refinement on Fo , anisotropic displacement para-
(+)-(1S,2S)-2-[(R′)-Phenylsulfinyl]-2,3-dihydro-1H-inden-1-ol meters for non-hydrogen atoms; all hydrogen atoms located in
71S,2S,R′. Less polar crystalline white solid (58 mg, 45%); a difference Fourier synthesis but included at positions calcu-
m. p. 128–129 °C; [α]D +217 (c 0.9, MeOH); (Found: C, 69.5; lated from the geometry of the molecules using the riding
H, 5.3. C15H14O2S requires C, 69.8; H, 5.4%); δH (500 MHz, model, with isotropic vibration parameters. R1 = 0.040 for 2392
CDCl3) 2.57 (1 H, dd, J3,2 8.4, J3,3 16.1, 3-H), 3.27 (1 H, dd, data with Fo > 4σ(Fo), 164 parameters, ωR2 = 0.095 (all data),
J3′,2 9.0, J3′,3 16.1, 3′-H), 3.46 (1 H, ddd, J2,1 7.3 = J2,3′ 9.0, GoF = 1.02, Δρmin,max = −0.24/0.32 e Å−3. CCDC1413402.
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The absolute configuration is confirmed as (1S,2R,R′) from the Dx = 1.447 g cm−3, μ = 0.258 mm−1, Bruker SMART CCD
anomalous scattering arising from the sulfur atom; Flack para- diffractometer, ϕ/ω scans, 4.4° < 2θ < 57.3°, measured/independent
meter x = −0.05(8).
reflections: 13 537/2915, Rint = 0.089, direct methods solution,
2
(+)-(1S,3S)-2-[(R′)-Phenylsulfinyl]-2,3-dihydro-1H-inden-1-ol full-matrix least squares refinement on Fo , anisotropic dis-
131S,3S,R′. More polar diasteroisomer, a viscous oil (47 mg, placement parameters for non-hydrogen atoms; all hydrogen
45%); [α]D +99.0 (c 0.9, MeOH); (Found: M+ 274.0669 atoms located in a difference Fourier synthesis but included at
C15H14SO3 requires 274.0664); δH (500 MHz, CDCl3) 2.43 (1 H, positions calculated from the geometry of the molecules using
br s, OH), 3.25 (1 H, dd, J2,1 5.5, J2,3 7.1, 2-H), 4.72 (1 H, br s, the riding model, with isotropic vibration parameters. R1
OH), 5.49 (1 H, d, J1,2 5.5, 1-H), 5.65 (1 H, d, J3,2 7.1, 3-H), 7.34 0.061 for 2303 data with Fo > 4σ(Fo), 174 parameters, ωR2
=
=
.
(4 H, m, Ar–H), 7.59 (3 H, m, Ar–H), 7.85 (2 H, m, Ar–H); 0.157 (all data), GoF = 0.98, Δρmin,max = −0.64/0.74 e Å−3
δC (125 MHz, CDCl3) 73.31, 74.45, 75.47, 124.31, 124.93, 125.17 CCDC 1413404. The absolute configuration is confirmed as
(2C), 129.36, 129.66 (2C), 129.86, 131.93, 141.16, 141.63, (1S,2R,3R,R′) from the anomalous scattering arising from the
143.27; m/z (LSIMS) 297 [(M + Na)+, 47%], 275 [(M + H)+, sulfur atom; Flack parameter x = 0.10(14).
100%]; νmax/cm−1 3350 (OH), 1015 (SO); ECD (MeOH): λ/nm
248 (Δε +4.40), 216 (Δε −8.20).
(+)-(1S,2S)-1,2-Dihydroxy-3-(S′)-phenylsulfinyl-cyclohexa-3,5-
diene 19b1S,2S,S′. Light yellow coloured gum (102 mg, 18%);
(−)-(1S,3S)-2-[(S′)-Phenylsulfinyl]-2,3-dihydro-1H-inden-1-ol Rf 0.56 (6% MeOH/CHCl3); [α]D +263 (c 0.6, MeOH); (Found:
141S,3S,S′. Less polar colourless crystalline diastereoisomer M+, 236.0510. C12H12O3S requires 236.0507); δH (500 MHz,
(39 mg, 37%); m. p. 155 °C; [α]D −144 (c 1.0, MeOH); (Found: CDCl3) 3.05 (1 H, d, JOH,1 7.7, OH), 3.21 (1 H, d, JOH,2 7.4, OH),
C, 65.4; H, 5.0. C15H14O3S requires C, 65.7; H, 5.1%); 4.20 (2 H, m, 1-H, 2-H), 6.11 (1 H, ddd, J6,5 9.5, J6,1 3.6, J6,4 1.0,
δH (500 MHz, CDCl3) 2.21 and 2.87 (1 H each, br s, OH), 3.39 6-H), 6.16 (1 H, ddd, J5,6 9.5, J5,4 5.4, J5,1 1.0, 5-H), 6.72 (1 H,
(1 H, dd, J2,1 6.3, J2,3 6.6, 2-H), 5.10 (1 H, d, J1,2 6.3, 1-H), 6.06 dd, J4,5 5.4, J4,6 0.8, 4-H), 7.48–7.52 (3 H, m, Ar–H), 7.72–7.74
(1 H, d, J3,2 6.6, 3-H), 7.34 (2 H, m, Ar–H), 7.43 (2 H, m, Ar–H), (2 H, m, Ar–H); δC (125 MHz, CDCl3) 66.00, 67.70, 123.30,
7.60 (3 H, m, Ar–H), 7.88 (2 H, m, Ar–H); δC (125 MHz, CDCl3) 124.98, 125.43, 129.45 (2C), 131.51 (2C), 132.99, 142.53, 144.7;
73.91, 74.76, 77.51, 124.39 (2C), 124.69, 126.04, 129.38, ECD (MeOH): λ/nm 273 (Δε +4.64), 217 (Δε −9.77).
129.51 (2C), 130.40, 131.50, 138.67, 140.68, 143.27; νmax/cm−1
3308 (OH), 1010 (SO); ECD (MeOH): λ/nm 244 (Δε −5.28), diene 20b1S,2S,R′
(+)-(1S,2S)-1,2-Dihydroxy-3-(R′)-phenylsulfinyl-cyclohexa-3,5-
11c
.
White crystalline solid (0.153 g, 27%),
216 (Δε +9.67).
m. p. 110–112 °C (from EtOAc/hexane); Rf 0.46 (6% MeOH/
Crystal data for compound 141S,3S,S′. C15H14O3S, M = 274.3, CHCl3); [α]D +297 (c 1.0, MeOH); (Found: M+, 236.0519.
orthorhombic, a = 5.4884(5), b = 11.4294(9), c = 19.5736(16) Å, C12H12O3S requires 236.0507); δH (500 MHz, CDCl3) 2.98 (1 H,
U = 1227.8(2) Å3, T = 153(2) K, space group P212121 (no. 19), d, JOH,1 8.9, OH), 3.44 (1 H, d, JOH,2 3.1, OH), 4.19 (1 H, dd, J2,
Mo-Kα radiation, λ = 0.71073 Å, Z = 4, F(000) = 576, Dx
=
8.4, J2,1 6.4, 2-H), 4.30 (1 H, dd, J1,2 6.1, J1,6 2.7, 1-H), 6.09
OH
1.484 g cm−3, μ = 0.264 mm−1, Bruker SMART CCD diffract- (2 H, m, 5-H, 6-H), 6.75 (1 H, m, 4-H), 7.50–7.55 (3 H, m,
ometer, ϕ/ω scans, 4.1° < 2θ < 56.9°, measured/independent Ar–H), 7.63–7.65 (2 H, m, Ar–H); δC (75 MHz, CDCl3) 64.41,
reflections: 13 801/2821, Rint = 0.065, direct methods solution, 69.27, 121.73, 124.66, 129.42, 129.53 (2C), 131.22 (2C), 137.06,
2
full-matrix least squares refinement on Fo , anisotropic dis- 141.90, 142.27; ECD (MeOH): λ/nm 228 (Δε +10.13), 228
placement parameters for non-hydrogen atoms; all hydrogen (Δε −9.52).
atoms located in a difference Fourier synthesis but included at
Crystal data for compound 20b1S,2S,R′′. C12H12O3S, M =
positions calculated from the geometry of the molecules using 236.3, orthorhombic, a = 8.108(3), b = 11.284(4), c = 24.513(8)
the riding model, with isotropic vibration parameters. R1
0.039 for 2504 data with Fo > 4σ(Fo), 174 parameters, ωR2
=
=
Å, U = 2242.7(14) Å3, T = 293(2) K, space group P212121 (no. 19),
Mo-Kα radiation, λ = 0.71073 Å, Z = 8, F(000) = 992, Dx
=
0.91 (all data), GoF = 1.01, Δρmin,max = −0.27/0.40 e Å−3. CCDC 1.400 g cm−3, μ = 0.276 mm−1, Siemens P3 diffractometer,
1413403. The absolute configuration is confirmed as (1S,3S,S′) ω scans, 3.3° < 2θ < 65.1°, measured/independent reflections:
from the anomalous scattering arising from the sulfur atom; 4569/4569, direct methods solution, full-matrix least squares
2
Flack parameter x = −0.05(8).
(+)-(1S,2R,3R)-3-[(R′)-Phenylsulfinyl]-indan-1,2-diol 171S,2R,3R,R′
refinement on Fo , anisotropic displacement parameters for
non-hydrogen atoms; all hydrogen atoms located in a differ-
.
Colourless crystalline solid compound 171S,2R,3R,R′ (53 mg, ence Fourier synthesis but included at positions calculated
62%); m. p. 180–81 °C; [α]D +50 (c 0.51, CHCl3); (Found: from the geometry of the molecules using the riding model,
C, 65.5; H, 4.9. C15H14O3S requires C, 65.7; H, 5.1%); with isotropic vibration parameters. R1 = 0.049 for 3069 data
δH (500 MHz, CDCl3) 2.95 and 3.21 (1 H each, br s, OH), 4.57 with Fo > 4σ(Fo), 294 parameters, ωR2 = 0.120 (all data), GoF =
(1 H, m, 1-H), 4.66 (1 H, m, 2-H), 4.90 (1 H, m, 3-H), 7.17–7.88 1.03, Δρmin,max = −0.25/0.33 e Å−3. CCDC 1413405. The struc-
(9 H, m, Ar–H); m/z (LSIMS) 297 [(M + Na) +, 100%], 275 ture comprises two crystallographically-independent mole-
[(M + H)+, 23%).
cules. The absolute configuration in both is confirmed as
Crystal data for compound 171S,2R,3R,R′. C15H14O3S, M = (1S,2S,R′) from the anomalous scattering arising from the
274.3, orthorhombic, a = 7.292(2), b = 11.750(3), c = 14.698(4) sulfur atom; Flack parameter x = 0.00(9).
Å, U = 1259.4(6) Å3, T = 153(2) K, space group P212121 (no. 19),
Biotransformation of (1S,2S)-1,2,3-(R′-methylsulfinyl)cyclo-
Mo-Kα radiation, λ = 0.71073 Å, Z = 4, F(000) = 576, hexa-3,5-diene-1,2-diol 19a1S,2S,R′ to yield 3-(R)-methylsulfinyl-
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1,2-dihydroxybenzene 26aR. cis-Diol sulfoxide diastereoisomer δH (500 MHz, CDCl3) 2.83 (3 H, s, –SOMe), 3.93 (3 H, s, –OMe),
11a
19a1S,2S,R′
was used as substrate with whole cells of E. coli 7.13 (1 H, dd, J6,5 7.9, J6,4 1.6, 6-H), 7.19 (1 H, dd, J5,4 = J5,6 7.9,
narB11a,13 (19 h), to yield catechol 26aR. Ethyl acetate extraction 5-H), 7.33 (1 H, dd, J4,5 7.9, J4,6 1.6, 4-H); δC (125 MHz, CDCl3)
of the centrifuged medium, containing the biotransformed 41.98, 61.35, 115.04, 119.81, 125.55, 137.89, 142.71, 149.44;
products, yielded a crude sample of 3-methylsulfinyl-1,2-dihy- m/z (EI) 186 (M+, 40%), 183 (36), 169 (100), 141 (93), 111 (63),
droxybenzene 26aR, which was found to decompose during 51 (48).
attempted chromatographic purification. A crude sample of
(+)-1,2-Dimethoxy-3-[(R)-methylsulfinyl]benzene 27aR. Light
catechol 26aR was characterized by NMR and MS spectra ana- yellow oil (57 mg, 50%); Rf 0.17 (50% EtOAc/hexane); [α]D +220
lyses before methylation. Catechol 26aR was obtained as a (c 0.47, CHCl3); (Found: M+, 200.0500. C9H12O3S requires
light brown gum (0.57 g, 72% crude yield); Rf 0.18 (60% EtOAc/ 200.0507); δH (500 MHz, CDCl3) 2.78 (3 H, s, –SOMe), 3.91
hexane); (Found: M+, 172.0192. C7H8O3S requires 172.0194); (3 H, s, –OMe), 3.92 (3 H, s, –OMe), 7.05 (1 H, dd, J6,5 8.0, J6,4
δH (500 MHz, CDCl3) 2.97 (3 H, s, Me), 6.59 (1 H, dd, J6,5 7.9, 1.5, 6-H), 7.28 (1 H, dd, J5,4 = J5,6 8.0, 5-H), 7.42 (1 H, dd, J4,5
J6,4 1.5, 6-H), 6.84 (1 H, t, J5,4 = J5,6 7.9, 5-H), 7.03 (1 H, dd, 8.0, J4,6 1.5, H-4); δC (125 MHz, CDCl3) 42.16, 56.07, 61.05,
J4,5 7.9, J4,6 1.5, 4-H), 10.71 (1 H, br s, OH); m/z (EI) 172 114.90, 115.66, 125.07, 139.15, 144.02, 152.05; m/z (EI) 200
(M+, 98%), 157 (52), 111 (100), 97 (49), 83 (58), 57 (60), 55 (54).
(M+, 93%), 185 (89), 184 (94), 168 (86), 127 (82), 109 (100), 77
Biotransformation of (1S,2S)-1,2,3-(R′- and S′-phenylsulfinyl)- (94); ECD (MeOH): λ/nm 287 (Δε +3.152), 241 (Δε +38.08), 226
cyclohexa-3,5-diene-1,2-diol 20b1S,2S,R′ and 19b1S,2S,S′ to yield (Δε +27.11), 210 (Δε −35.14), 200 (Δε +3.305), 195 (Δε −3.717),
3-phenylsulfinyl-1,2-dihydroxybenzene enantiomers 26bR and 192 (Δε +1.308).
26bS. cis-Diol sulfoxides 1,2-diol 20b1S,2S,R′ (150 mg,
(+)-3-[(S)-Phenylsulfinyl]-1,2-dimethoxybenzene 27bS. Light
0.64 mmol) and 19b1S,2S,S′ (0.5 g, 2.12 mmol) were meta- yellow oil (32 mg, 90%); Rf 0.80 (3% MeOH/CHCl3); [α]D +161
bolized, separately, using E. coli narB (18 h). Ethyl acetate (c 0.32, CHCl3); (Found: M+, 262.0662. C14H14O3S requires
extraction of the centrifuged culture media yielded the corres- 262.0664); δH (500 MHz, CDCl3) 3.80 (3 H, s, OMe), 3.85 (3 H,
ponding catechol sulfoxides, 3-[(R)-phenylsulfinyl]benzene-1,2- s, OMe), 7.00 (1 H, dd, J6,5 8.1, J6,4 1.4, 6-H), 7.23 (1 H, t, J5,4
=
diol 26bR (90 mg, 60% crude yield) and 3-[(S)phenylsulfinyl]- J5,6 8.1, 5-H), 7.41 (3 H, m, Ar–H), 7.47 (1 H, dd, J4,5 8.1, J4,6
benzene-1,2-diol 26bS (0.4 g, 81% crude yield). Small portions 1.4, 4-H), 7.73 (2 H, m, Ar–H); δC (125 MHz, CDCl3) 56.00,
of catechol sulfoxide enantiomers 26bR and 26bS were purified 60.73, 114.98, 115.84, 124.88, 125.31, 129.09 (2C), 130.90 (2C),
by recrystallization for characterization. The remaining crude 139.22, 145.09, 145.90, 152.32; m/z (EI) 262 (M+, 8%), 247 (7),
samples were methylated with diazomethane.
246 (22), 245 (100), 91 (23), 77 (21), 51 (25); νmax (KBr)/cm−1
Catechol 26bS was obtained as white solid; m. p. 153– 3156, 3064, 2962, 2941, 2838, 1590, 1480, 1272, 1035 (SvO),
154 °C; [α]D +298 (c 0.36, MeOH); (Found: M+, 234.0340. 782, 690.
C12H10O3S requires 234.0351); δH (500 MHz, CDCl3) 5.86 (1 H,
br s, OH), 6.76 (1 H, dd, J6,5 7.9, J6,4 1.5, 6-H), 6.83 (1 H, t, J5,4
J5,6 7.9, 5-H), 7.00 (1 H, dd, J4,5 7.9, J4,6 1.5, 4-H). 7.51 (3 H, m,
(−)-3-[(R)-Phenylsulfinyl]-1,2-dimethoxybenzene 27bR. (19 mg,
74%); [α]D −159 (c 0.43, CHCl3).
Aromatization of sulfoxide cis-diol 20b1S,2S,R′. A small
=
Ar–H), 7.69–7.70 (2 H, m, Ar–H), 10.72 (1 H, br s, OH); sample (ca. 10 mg) of enantiopure sulfoxide cis-diol 20b1S,2S,R′
δC (125 MHz, CDCl3) 116.71, 117.92, 120.33, 122.77, 124.84, was treated with aq. HCl (0.5 M, 5 mL). The reaction mixture
129.57 (2C), 131.63 (2C), 143.40, 146.22, 146.31; m/z (EI) 234 was left overnight at room temperature, extracted with EtOAc,
(M+, 15%), 186 (5), 91 (38), 85 (91), 83 (100), 47 (22); ECD the extract concentrated, and the residue treated at 0 °C with
(MeOH): λ/nm 237.2 (Δε −3.642), 220.2 (Δε +2.171), 208.4 ether solution of diazomethane. The mixtures of methyl
(Δε −6.918), 194.8 (Δε +10.840).
ethers, 24bR/24bS and 25bR/25bS (X = Me) of phenols 24bR/
Catechol 26bR; [α]D −303 (c 0.59, MeOH); ECD (MeCN): 24bS and 25bR/25bS (X = H), obtained were analysed by
λ/nm 238.0 (Δε +4.992), 220.0 (Δε −2.358), 208.0 (Δε +9.994), CSPHPLC (Chiralpak AS column, 0.5 mL min−1, 20% IPA/
194.6 (Δε −16.400).
hexane). The elution profiles of enantiomers 24bR (52.9 min,
64%), 24bS (71.2 min, 12%), 25bS (58.8 min, 4%), 25bR
(62.0 min, 20%), and their relative ratios provided unequivocal
(iii) Methylation using diazomethane
A sample of catechol (e.g. 26aR; 100 mg) in methanol solution evidence of racemization.
(5 mL) was treated at 0 °C with excess of freshly prepared solu-
Asymmetric alkylation of benzaldehyde to form alcohol
tion of diazomethane in ether. After leaving the mixture in an 35. Diethyl zinc solution in hexane (0.1 mL, 1 M) was added to
ice bath (1 h), the solvents were removed and the crude a stirred solution of benzaldehyde (100 mg, 1 mmol) and
mixture of methylated product/s separated by PLC (50% EtOAc hydroxy sulfoxide ligand (Table 1, 0.02 mmol) in dry toluene
in hexane). Methylated catechols 29aR and 27aR (from 26aR), (3 mL) under a nitrogen atmosphere. When the reaction was
27bS (from 26bS) and 27bR (from 26bR) were synthesised by complete (monitored by TLC), saturated solution of NH4Cl
the same procedure.
(5 mL) was added and the stirring continued for 10 min. The
(+)-2-Methoxy-3-[(R)-methylsulfinyl]phenol 29aR. White crys- product was extracted with EtOAc (2 × 5 mL), the extract dried
talline solid (40 mg, 37%); Rf 0.1 (50% EtOAc/hexane); (Na2SO4) and concentrated under reduced pressure. The
m. p. 135–38 °C (from EtOAc); [α]D +229 (c 0.36, CHCl3); residue was purified by PLC (25% Et2O in hexane) to give
(Found: M+, 186.0359. C8H10O3S requires 186.0351); 1-phenylpropanol 35. The absolute configuration of the
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product was determined by comparison of its [α]D value with
that reported in the literature. Enantiomeric purity values
(S isomer 10.7 min, R isomer 12.5 min) were confirmed by CSP
HPLC analysis (Chiralcel OB column, 10% IPA in hexane).
8 (a) P.-E. Broutin and F. Colobert, Org. Lett., 2003, 5, 3281;
(b) H. Kosugi, M. Abe, R. Hatsuda, H. Uda and M. Kato,
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Acknowledgements
We thank Dr B. E. Byrne for preliminary synthesis studies of
arene cis-diol sulfoxides and Dr O. Ichihara for preliminary
results from the use of hydroxysulfoxides as chiral ligands. We
gratefully acknowledge the financial support received from
BBSRC/DTI/Zeneca/Oxford Asymmetry under the LINK
Scheme (NDS), DENI/Avecia for a CAST award (DM), DENI 10 W. Adam and A. K. Smerz, J. Org. Chem., 1996, 61,
(SDS) and Queen’s University Belfast (VL) for postgraduate
3506.
studentships.
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S. D. Shepherd, C. C. R. Allen, L. A. Kulakov, M. J. Larkin
and H. Dalton, Chem. Commun., 2002, 1914;
(b) D. R. Boyd, N. D. Sharma, A. W. T. King,
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M. Kwit, D. R. Boyd, N. D. Sharma, J. F. Malone and
A. F. Drake, J. Am. Chem. Soc., 2005, 127, 4308;
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A. W. T. King, B. T. McMurray, A. Alves-Areias,
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N. D. Sharma, H. Dalton, D. J. Gray and G. N. Sheldrake,
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D. A. Clarke, T. Howard and H. Dalton, Tetrahedron: Asym-
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