Synthesis and conformational and configurational studies of diastereoisomeric O-protected 4-(arylsulfonimidoyl)butane-1,2,3-triols

Article abstract of DOI:10.1016/j.tet.2007.10.017

Chiral sulfoximines have applications as transition-state mimicking enzyme inhibitors, as peptide isosteres and as chiral auxiliaries in synthesis. To access the required O-protected 4-(arylsulfonimidoyl)butane-1,2,3-triols, 4S,5S-di(hydroxymethyl)-2,2-dimethyl-1,3-dioxolane (prepared from diethyl R,R-tartrate) was converted into its monobenzyl ether. Mitsunobu-like coupling with thiophenols gave 4S,5R-4-(benzyloxymethyl)-2,2-dimethyl-5-(arylthiomethyl)-1,3-dioxolanes. Sulfoxidation and S-imination (trifluoroacetamide, iodosobenzene diacetate, rhodium acetate) proceeded without stereoselectivity, giving inseparable diastereomeric mixtures of 4S,5R,S(±)-4-(benzyloxymethyl)-2,2-dimethyl-5-(N-(trifluoroacetyl)arylsulfonimidoylmethyl)-1,3-dioxolanes. Removal of the trifluoroacetyl protection allowed chromatographic separation of the diastereomeric 4S,5R,S(±)-4-(benzyloxymethyl)-2,2-dimethyl-5-(arylsulfonimidoylmethyl)-1,3-dioxolanes. The configurations at sulfur were determined by X-ray crystallography and some analysis of the solution and solid-state conformations was carried out. The resulting O-protected 4-(arylsulfonimidoyl)butane-1,2,3-triols are of use in developing enzyme inhibitors.

Full text of DOI:10.1016/j.tet.2007.10.017

Tetrahedron 63 (2007) 12601–12607
Synthesis and conformational and configurational
studies of diastereoisomeric O-protected
4
-(arylsulfonimidoyl)butane-1,2,3-triols
a
Joey S. W. Kwong, Mary F. Mahon, Matthew D. Lloyd and Michael D. Threadgill
b
a
a,*
a
Department of Pharmacy and Pharmacology, University of Bath, Claverton Down, Bath BA2 7AY, UK
X-ray Crystallographic Unit, Department of Chemistry, University of Bath, Claverton Down, Bath BA2 7AY, UK
b
Received 18 July 2007; revised 14 September 2007; accepted 4 October 2007
Available online 6 October 2007
Abstract—Chiral sulfoximines have applications as transition-state mimicking enzyme inhibitors, as peptide isosteres and as chiral auxilia-
ries in synthesis. To access the required O-protected 4-(arylsulfonimidoyl)butane-1,2,3-triols, 4S,5S-di(hydroxymethyl)-2,2-dimethyl-1,3-
dioxolane (prepared from diethyl R,R-tartrate) was converted into its monobenzyl ether. Mitsunobu-like coupling with thiophenols gave
4
S,5R-4-(benzyloxymethyl)-2,2-dimethyl-5-(arylthiomethyl)-1,3-dioxolanes. Sulfoxidation and S-imination (trifluoroacetamide, iodoso-
benzene diacetate, rhodium acetate) proceeded without stereoselectivity, giving inseparable diastereomeric mixtures of 4S,5R,S(ꢀ)-4-
benzyloxymethyl)-2,2-dimethyl-5-(N-(trifluoroacetyl)arylsulfonimidoylmethyl)-1,3-dioxolanes. Removal of the trifluoroacetyl protection
allowed chromatographic separation of the diastereomeric 4S,5R,S(ꢀ)-4-(benzyloxymethyl)-2,2-dimethyl-5-(arylsulfonimidoylmethyl)-
,3-dioxolanes. The configurations at sulfur were determined by X-ray crystallography and some analysis of the solution and solid-state con-
(
1
formations was carried out. The resulting O-protected 4-(arylsulfonimidoyl)butane-1,2,3-triols are of use in developing enzyme inhibitors.
Ó 2007 Elsevier Ltd. All rights reserved.
1
. Introduction
more potent and selective inhibitor of g-glutamylcysteine
synthetase. In 1 and 2, the tetrahedral sulfoximine unit is
acting as a mimic of the transition-state or intermediate of
4
,5
Sulfoximines have attracted chemical and biological atten-
tions since the discovery of aS,S(S)-methionine sulfoximine
(Fig. 1) as the toxic agent in agenised flour in the 1950s.
This compound inhibits glutamine synthetase, the enzyme
responsible for the formation of Gln from Glu and ammonia,
and g-glutamylcysteine synthetase, which catalyses the first
step in the biosynthesis of glutathione. Later studies showed
that the homologue aS,S(S)-buthionine sulfoximine 2 is a
2
–4
the enzyme-catalysed process. Sulfoximines are configura-
tionally stable. More recently, sulfoximines have been used in
asymmetric synthesis as chiral ligands or chiral auxiliaries,
1
1
2
6–8
9
,10
as peptidomimetics (e.g., 3, Fig. 1)
and as transition-state
3
11
mimics in the design of other enzyme inhibitors. As part of
our programme of design and synthesis of selective enzyme
inhibitors, we required the individual diastereoisomers
of O-protected 2S,3R-4-(arylsulfonimidoyl)butane-1,2,3-
1
2–14
triols with different configurations at sulfur.
O
R
HN
S
2. Synthesis
+
-
H N
CO
3
2
The synthetic approach to the target O-protected sulfoxi-
mine triols is shown in Scheme 1. We proposed that the
four-carbon unit bearing the two carbon chiral centres could
be introduced from a precursor available from the chiral
pool. The sulfoximine chiral centre could be created by dia-
stereoselective sulfoxidation of the intermediate aryl sulfide,
followed by imination or, less efficiently, by generation of
a mixture of diastereoisomeric sulfides and selective imina-
tion of one diastereoisomer.
1
: R = Me
: R = Bu
2
N
NHpeptide
peptide
S
R
O
O
O
3
Figure 1. Structures of aS,S(S)-methionine sulfoximine 1, aS,S(S)-buthio-
nine sulfoximine 2 and a peptidomimetic 3 containing a sulfoximine.
Keywords: Sulfoximine; Butanetriol; X-ray crystallography; Conformation;
Diastereoisomer.
Diethyl R,R-tartrate 4 contains the required secondary
alcohols in the configurations corresponding to those in
the synthetic targets 12 and 13. These were protected as
*
Corresponding author. Tel.: +44 1225 386840; fax: +44 1225 386114;
e-mail: m.d.threadgill@bath.ac.uk
0
040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.10.017

12602
J. S. W. Kwong et al. / Tetrahedron 63 (2007) 12601–12607
EtO2C
HO
CO2Et
OH
HO
OH
BnO
OBn
BnO
OH
i,ii
iii
O
O
O
O
+
O
O
O
5
9% overall
6: 6%
: 71%
4
5
6
7
7
vi: 9a: 44%
9
iv
9%
b: 69%
6
R
R
R
BnO
S
O
BnO
S
O
BnO
vii
10a: 96%
10b: 68%
S
BnO
Br
NCOCF3
v
O
O
O
O
O
O
X
O
viii
1
1
10
9
8
1
1a: 75%
1
1
1
1
2aS: 34%
2aR: 30%
2bS: 32%
2bR: 29%
11b: 83%
ix
R
R
R
x
3aR: 100%
3bR: 100%
BnO
O
S
O
BnO
S
O
BnO
S
O
NH
NH
NH
O
+
O
O
HO
OH
13R
a: R = H
b: R = Br
1
1
2S
12R
1
Scheme 1. Synthesis of the diastereoisomers of sulfoximines 13. Reagents and conditions: (i) (MeO)
ꢁ
2
CMe
SH, Bu
, H O, MeOH; (x) HCl, H
2
2
, TsOH, CH
2
Cl
2
, D; (ii) LiAlH
P, 1,1 -(azodicarbonyl)dipiperidine, THF, ))));
O, MeOH.
4
, THF, D; (iii) NaH,
0
BnBr, DMF, 0 C; (iv) Ph
(vii) 3-ClPhCO
3
P, CBr
4
, THF; (v) PhSH, various bases, various conditions; (vi) PhSH/3-BrC
6
H
4
3
ꢁ
3
H, CH
2
Cl
2
, ꢂ78 C; (viii) CF
3
CONH , MgO, Rh
2
2
(OAc)
4
, PhI(OAc)
2
, CH
Cl
2 2
; (ix) NH
3
2
1
7
the acetonide by ketal exchange with 2,2-dimethoxypro-
pane; the esters (mixed methyl and ethyl esters) were then
reduced with lithium aluminium hydride to give the C -sym-
metric S,S-diol 5. Desymmetrisation by monobenzylation
with sodium hydride and benzyl bromide in DMF afforded
N-trifluoroacetyl sulfoximines. Application of this method
to the mixture of diastereoisomeric Ph-unsubstituted sulf-
oxides 10a gave a mixture of diastereoisomers of the
N-trifluoroacetyl sulfoximines 11a; the ratio of the diaste-
reoisomers shifted from 1:1 in 10a to 3:2 in 11a, indicating
that one diastereoisomer had reacted slightly more effi-
ciently, but the isomers again could not be separated. In par-
allel, the bromophenylsulfoxides 10b were converted into
the inseparable N-trifluoroacetyl sulfoximines 11b with no
change in the 1:1 ratio of diastereoisomers.
2
7
in 71% yield, which could be readily separated from the
small quantity of dibenzyl ether 6 produced. The next step
involved displacement of the primary OH with (substituted)-
thiophenols, for which it would be necessary to convert it
into a good leaving group. Treatment of 7 with tetrabromo-
methane and triphenylphosphine efficiently converted it into
the bromo compound 8. Interestingly, this primary alkyl ha-
lide could not be displaced with phenylthiolate anions under
a variety of forcing conditions; study of the required angle of
The trifluoroacetyl groups were rapidly cleaved from 11a
and 11b with ammonia, giving the free sulfoximines 12a
and 12b, respectively. Now, the individual diastereoisomers
contained H-bond donors and thus the diastereoisomers
could be separated chromatographically, giving good yields
of stereochemically pure 12aR, 12aS, 12bR and 12bS. The
acetal protection was removed by acid-catalysed hydrolysis
from 12aR and 12bR to give the homochiral diols 13aR and
13bR, respectively, to demonstrate that the secondary alco-
hols could be revealed without loss of stereochemical integ-
approach of the nucleophile to the electrophilic CH in 8 in
2
an S 2 process indicated that steric crowding between the
N
dioxolane and the incoming aromatic ring may preclude
reaction. In contrast, displacement of the primary OH with
the arylthio nucleophiles was achieved directly from 6 under
0
Mitsunobu conditions (arylthiol, tributylphosphine, 1,1 -
(azodicarbonyl)dipiperidine) to give the sulfides 9a and 9b
in good yields.
1
13
rity. However, simple examination of the 1-D H and
C
NMR spectra did not allow assignment of the configurations
at sulfur of the dioxolanylmethyl sulfoximines 12 or of the
diols 13.
At this point, it had been anticipated that the chirality of the
sulfides 9 could be exploited to drive the sulfoxidation in
a diastereoselective manner. However, no conditions could
be found to achieve this diastereoselection, so 9a was treated
with 3-chloroperoxybenzoic acid to give a high yield of the
sulfoxides 10a as an inseparable 1:1 mixture of diastereoiso-
mers. Similar reaction of the bromophenylsulfide 9b gave
the corresponding sulfoxides 10b, also as an inseparable
equimolar mixture. A variety of reagents and conditions
have been used to generate sulfoximines from sulfoxides,
3. X-ray crystallography and solution
conformation studies
For each pair of diastereoisomeric sulfoximines 12a and
12b, one diastereoisomer was an oil but the other formed
crystals (from ethanol/hexane) of quality suitable for
X-ray crystallographic structure determination. The crystal
structures (Fig. 2) confirmed that both crystalline diastereo-
isomers were of S configuration at sulfur, i.e., that they were
12aS and 12bS.
1
5
including sodium azide/hot concd sulfuric acid and O-
(
1
6
2,4,6-trimethylbenzenesulfonyl)hydroxylamine but many
are incompatible with the protecting groups used here.
Okamura and Bolm have developed a very mild sulfoxi-
mination in which PhI]NCOCF3 is generated in situ
from iodosobenzene diacetate and trifluoroacetamide and
Rh-catalysed transimination converts sulfoxides into
The conformations of 12aS in solution in chloroform and in
the crystal were compared with each other and with the

J. S. W. Kwong et al. / Tetrahedron 63 (2007) 12601–12607
12603
fused ring structures, MM2 energy-minimised structures
were calculated for 12aR and 12aS with and without the
constraints of these intramolecular H-bonds (Fig. 3). The
predicted conformations of the two diastereoisomers with-
out the intramolecular H-bonds are very similar to each
other. In contrast, the predicted intramolecularly H-bonded
conformation of 12aR is very crowded, with the six- and
five-membered rings almost orthogonal, whereas that of
12aS is more open. In the predicted intramolecularly
H-bonded conformation of 12aR, the dihedral angle be-
ꢁ
tween 4-H and 5-H of the dioxolane is ca. 90 ; the observed
J¼8.2 Hz coupling is inconsistent with such an angle. Thus
3
12aR is likely to adopt a conformation without an intra-
molecular H-bond in solution in chloroform, where this
dihedral angle is ca. 165 . The predicted conformation of
ꢁ
the diastereoisomer 12aS in the intramolecularly H-bonded
structure has the five-membered dioxolane ring in a half-
chair and the six-membered ring in a twist-boat; this gives
ꢁ
the dihedral angle between 4-H and 5-H as ca. 140 , whereas
the corresponding angle in the non-H-bonded conformer
ꢁ
3
is ca. 165 . The observed coupling J¼7.9 Hz between these
protons is consistent with both conformers. The NOESY
spectrum of 12aS also did not distinguish between the
possible conformers in chloroform but allowed assignment
of the signals from the geminal dimethyl unit. There were
cross-peaks between the 4-H signal and the upfield methyl
signal at d 1.21 and between the 5-H signal and the downfield
methyl peak at d 1.29, showing that the former singlet is due
Figure 2. X-ray crystal structures of 12aS and 12bS with crystallographic
numbering.
solution conformation of the diastereoisomer 12aR. Similar
comparisons were made for the Ar-bromo analogues 12bS
and 12bR. Since it may be postulated that the N–H of the
sulfoximine may form an intramolecular H-bond with the
adjacent dioxolane oxygen, forming five/six-membered
to the methyl cis to the 4-CH OBn and the latter is due to the
2
methyl trans to this substituent. The NMR spectra of the
Ar-bromo analogues 12bR and 12bS were very similar,
showing that the remote bromine had little effect on the
Figure 3. MM2 energy-minimised model structures of 12aR and 12aS without and with constraining intramolecular H-bond from sulfoximine N–H to O-1 of
the dioxolane ring. Red, O; white, H; grey, C; blue, N; yellow, S.

12604
J. S. W. Kwong et al. / Tetrahedron 63 (2007) 12601–12607
conformations of the diastereoisomers in solution. Overlap
of some signals and poor resolution of some multiplets in
the H NMR spectra of the deprotected derivatives 13aR
and 13bR precluded any detailed analysis of their conforma-
tions in solution.
recorded either on a Jeol EX270, Varian Mercury 400 or Var-
ian United Inova 600 spectrometers of samples in CDCl3,
unless otherwise stated. Mass spectra were obtained by elec-
trospray (ES), electron impact (EI) or fast atom bombard-
ment (FAB) ionisation. Melting points were measured with
a Thermo Galen Kofler block (uncorrected). Optical
rotations were measured in a 1.0 dm cell on an Optical
Activity Ltd. polarimeter and concentrations are expressed
in g/100 mL. The chromatographic stationary phase was
silica gel. THF refers to tetrahydrofuran and DMF refers
to dimethylformamide. THF was dried with Na. Solutions
1
The crystal structures of 12aS and 12bS (Fig. 2) are remark-
ably similar and show extended conformations, with
intermolecular H-bonding. In the structure of 12aS, the dihe-
dral angle between the 4-CH OBn and the 5-CH SO(NH)Ph
2
2
ꢁ
groups is 104 , corresponding to a half-chair conformation
for the five-membered ring. The former bulky substituent
almost eclipses the 5-H and that the latter large group is close
in organic solvents were dried with MgSO . Solvents were
4
evaporated under reduced pressure. Experiments were con-
ducted at ambient temperature, unless otherwise stated.
to eclipsing the 4-H. The methyl cis to the 5-CH SO(NH)Ph
2
group is in the pseudo-axial position. The crowded 5-C–
CH S bond is in a staggered conformation, with the sulfoxi-
5.2. 4S,5S-Di(hydroxymethyl)-2,2-dimethyl-1,3-
dioxolane (5)
2
mine antiperiplanar to 4-C and gauche to the ring-oxygen.
Interestingly, the bond from the CH to the sulfoximine is
2
also staggered but with the apparently bulky groups (Ph
and dioxolane) almost gauche to each other (dihedral angle
Diethyl (R,R)-2,3-dihydroxybutanedioate
4
(15.0 g,
70 mmol), 2,2-dimethoxypropane (32 g, 320 mmol) and
ꢁ
8
angle between the 4-CH OBn and the 5-CH SO(NH)Ph
1 ). The structure of 12bS shows a slightly smaller dihedral
TsOH$H O (198 mg, 1.0 mmol) in CH Cl (200 mL) were
2
2
2
boiled under reflux in a Soxhlet apparatus for 7 days through
˚
activated 4 A molecular sieves (33 g). Dry Na CO (83 mg,
1.0 mmol) was added. Filtration, drying, evaporation and
chromatography (EtOAc/hexane, 2:3) afforded a mixture
of diethyl, monoethyl-monomethyl and dimethyl esters of
(4R,5R)-2,2-dimethyl-1,3-dioxolane-4,5-dicarboxylic acid
2
2
ꢁ
groups (97 ) and the half-chair conformation of the dioxo-
lane ring is distorted. The eclipsing of the 4-H and 5-H by
their vicinal substituents is correspondingly diminished.
2
3
The methyl cis to the 5-CH SO(NH)Ph group is again in
2
the pseudo-axial position. The conformational arrangements
of the two major side-chains are very similar to those in
(12 g, ca. 67%) as a pale buff oil. LiAlH (2.0 M in THF,
4
1
2aS. As expected, the sulfoximine-sulfur atoms were
approximately tetrahedral. The O]S]N bond angles in
51.5 mL, 103 mmol) was added during 1.5 h to this material
in dry THF (80 mL) and the mixture was boiled under reflux
for 5 h, then cooled to 0 C. Water (10 mL), aq NaOH (4 M,
ꢁ
S]N bond lengths of 1.52 A and S]O bond lengths of
ꢁ
1
2aS and 12bS were both 122 . Both compounds had
˚
10 mL) and water (30 mL) were added cautiously in turn.
The suspension was filtered and the solids were extracted
with boiling 1,4-dioxane (3ꢃ100 mL). The solvents were
evaporated from the combined extracts to give 5 (6.7 g,
85%) as a pale yellow oil with spectroscopic data identical
˚
.46 A.
1
4. Conclusions
1
4,18
to those reported in the literature.
In this paper, we have reported the synthesis of two series of
diastereoisomeric O-protected 4-(arylsulfonimidoyl)butane-
5.3. 4S,5S-Di(benzyloxymethyl)-2,2-dimethyl-1,3-
dioxolane (6) and 4S,5S-4-benzyloxymethyl-5-
hydroxymethyl-2,2-dimethyl-1,3-dioxolane (7)
1
,2,3-triols, deriving the configuration of the two secondary
alcohols from diethyl R,R-tartrate. A Mitsunobu reaction in-
troduced the arylthio substituents. Peroxyacid sulfoxidation
proceeded without diastereocontrol and Rh-catalysed oxida-
tive imination gave the corresponding N-trifluoroacetyl
sulfoximines as inseparable mixtures of diastereoisomers
at sulfur. Removal of the TFA protection afforded the
free NH sulfoximines, which were readily separated chro-
matographically. The configurations of the crystalline S(S)
dioxolanes 12aS and 12bS were established by X-ray
crystallography, for both the S-Ph and S-(3-BrAr) series.
However, both corresponding S–R stereoisomers 12aR and
NaH (60% in mineral oil, 1.9 g, 46 mmol, pre-washed with
dry pentane) was stirred in dry DMF (20 mL) at 0 C under
ꢁ
N for 30 min. Compound 5 (6.7 g, 42 mmol) in dry DMF
2
(20 mL) was then added dropwise and the mixture was
stirred for 30 min before benzyl bromide (7.35 g,
43 mmol) was added. The mixture was stirred for 1.5 h
and was poured into ice-water (250 mL) and extracted thrice
with Et O. The combined extracts were washed with water
2
and brine. Drying, evaporation and chromatography (hex-
ane/Et O, 1:1] gave 6 (500 mg, 6%) as a pale yellow oil
1
2bS were oils. Removal of the acetonide protection
2
exposed the secondary alcohols in 13aR and 13bR. The
homochiral O-protected 4-(arylsulfonimidoyl)butane-1,2,3-
triols are of potential use in developing enzyme inhibitors.
with spectroscopic data identical to those reported in the
literature. Further elution gave 7 (3.6 g, 71%) as a pale
1
4
yellow oil with spectroscopic data identical to those reported
in the literature.
1
4
5. Experimental
5.4. 4S,5R-4-(Benzyloxymethyl)-5-(bromomethyl)-
,2-dimethyl-1,3-dioxolane (8)
2
5
.1. General
Ph P (353 mg, 1.3 mmol) in dry THF (1.0 mL) was added
3
IR spectra were obtained on a Perkin–Elmer 782 spectrom-
eter as KBr discs or as liquid films. NMR spectra were
dropwise to 7 (280 mg, 1.1 mmol) and CBr (409 mg,
4
1.2 mmol) in dry THF (2.0 mL) at 0 C under N and the
2
ꢁ

J. S. W. Kwong et al. / Tetrahedron 63 (2007) 12601–12607
12605
mixture was stirred for 3 h. Evaporation and chromato-
graphy (hexane/Et O, 1:1) gave 8 (240 mg, 69%) as a
A)), 3.04 (0.5H, dd, J¼13.2, 4.2 Hz, SCH (isomer B)), 3.06
(0.5H, dd, J¼13.2, 2.2 Hz, SCH (isomer A)), 3.22 (0.5H, dd,
J¼13.2, 7.2 Hz, SCH (isomer B)), 3.51 (0.5H, dd, J¼10.1,
5.7 Hz, BnOCH (isomer B)), 3.55 (0.5H, dd, J¼9.8, 5.7 Hz,
BnOCH (isomer A)), 3.62 (0.5H, dd, J¼9.8, 4.9 Hz, BnOCH
(isomer B)), 3.68 (0.5H, dd, J¼9.5, 5.3 Hz, BnOCH (isomer
A)), 3.91 (0.5H, dt, J¼5.3, 8.3 Hz, 4-H (isomer A)), 3.97
(0.5H, m, 5-H (isomer B)), 4.15 (0.5H, dt, J¼5.3, 8.3 Hz,
4-H (isomer B)), 4.41 (0.5H, ddd, J¼9.8, 8.3, 2.3 Hz, 5-H
(isomer A)), 4.50 (0.5H, d, J¼12.1 Hz, PhCH), 4.52 (0.5H,
2
1
colourless oil: H NMR d 1.43 (3H, s, Me), 1.45 (3H, s,
Me), 3.46–3.54 (2H, m, BrCH ), 3.62–3.69 (2H, m,
2
BnOCH ), 4.04–4.12 (2H, m, 4,5-H ), 4.59 (2H, s, PhCH ),
2
2
2
1
3
7
(
.30–7.38 (5H, m, Ph-H5); C NMR d 27.1 (Me), 27.2
Me), 32.6 (BrCH ), 70.4 (BnOCH ), 73.6 (PhCH ), 77.2
2
2
2
(
5-C), 78.8 (4-C), 110.0 (CMe ), 127.7 (Ph 3,5-C ), 127.8
2 2
(
3
3
Ph 2,6-C ), 128.4 (Ph 4-C), 137.7 (Ph 1-C); MS (FAB) m/z
2
8
1
17.0563 (M+H) (C H O Br requires 317.0575),
14 20 3
8
1
16.0503 (M) (C H O Br requires 316.0497), 235
1
d, J¼12.1 Hz, PhCH), 4.55 (1H, s, PhCH ), 7.23–7.35 (5H,
4
19
3
2
2
0
(
MꢂBr), 220 (MꢂCH Br); [a] +3.6 (c 1.7, CHCl3).
m, Ph-H ), 7.50–7.53 (3H, m, S-Ph 3,4,5-H ), 7.65–7.67
5
2
D
3
1
3
(2H, m, S-Ph 2,6-H2); C NMR d 26.8 (Me), 26.9 (Me),
27.0 (Me), 27.2 (Me), 60.2 (SCH (isomer B)), 62.2 (SCH
5
(
.5. 4S,5R-4-(Benzyloxymethyl)-2,2-dimethyl-5-
phenylthiomethyl)-1,3-dioxolane (9a)
2
2
(isomer A)), 69.6 (BnOCH (isomer B)), 70.0 (BnOCH (iso-
2 2
mer A)), 73.2 (5-C (isomer A)), 73.5 (PhCH (isomer B)),
2
PhSH (327 mg, 3.0 mmol) was added to Bu P (601 mg,
3
73.7 (PhCH (isomer A)), 73.9 (5-C (isomer B)), 78.6 (4-C
2
(isomer B)), 79.0 (4-C (isomer A)), 110.0 (CMe ), 110.2
2
(CMe ), 123.8 (CH), 124.3 (CH), 127.6 (CH), 127.7 (CH),
2
0
.97 mmol) in dry THF (7.0 mL) under Ar at 0 C and the
3
2
.0 mmol) and 1,1 -(azodicarbonyl)dipiperidine (749 mg,
ꢁ
mixture was sonicated for 30 min. During this sonication,
7 (500 mg, 2.0 mmol) in dry THF (3.0 mL) was added.
The mixture was stirred at 20 C for 16 h. Filtration, evapo-
127.8 (CH), 128.4 (CH), 129.2 (CH), 129.3 (CH), 131.2
(S-Ph 4-CH), 131.3 (S-Ph 4-CH), 137.6 (C-Ph 1-C), 137.7
(C-Ph 1-C), 143.5 (S-Ph 1-C (isomer B)), 144.5 (S-Ph 1-C
(isomer A)); MS (FAB) m/z 361 (M+H), 303 (M+Hꢂ
ꢁ
ration and chromatography (hexane/Et O, 5:1) gave 9a
2
1
20
D
(
300 mg, 44%) as a pale yellow oil: H NMR d 1.40 (3H,
Me CO); [a] +4.4 (c 2.0, CHCl ).
2
3
s, Me), 1.44 (3H, s, Me), 3.19 (1H, d, J¼4.3 Hz, SCH),
3
.20 (1H, d, J¼4.3 Hz, SCH), 3.63 (2H, d, J¼4.7 Hz,
5.8. 4S,5R,S(±)-4-(Benzyloxymethyl)-2,2-dimethyl-5-
(3-bromophenylsulfinylmethyl)-1,3-dioxolane (10b)
BnOCH ), 4.04–4.09 (2H, m, 4,5-H ), 4.54 (1H, d, J¼
2
2
1
7
4.9 Hz, PhCH), 4.57 (1H, d, J¼14.9 Hz, PhCH), 7.16–
5
1
3
.36 (10H, m, 2ꢃPh-H ); C NMR d 27.1 (Me), 27.2
Compound 9b was treated with 3-chloroperoxybenzoic acid,
as for the synthesis of 10a, to give 10b (68%) as a 3:2 mix-
ture of diastereoisomers as a yellow oil: H NMR d 1.16
(
(
Me), 36.7 (SCH ), 70.7 (BnOCH ), 73.5 (PhCH ), 77.0
2 2 2
5-C), 79.4 (4-C), 109.7 (CMe ), 126.2 (Ph-C ), 127.8 (Ph-
2
1
2
C ), 128.4 (Ph-C ), 128.9 (Ph-C ), 129.2 (2ꢃPh 4-C),
(1.8H, Me), 1.21 (1.2H, Me), 1.25 (1.8H, Me), 1.26 (1.2H,
Me), 3.42 (dd, J¼9.6, 6.8 Hz) and 3.43 (dd, J¼9.7,
6.8 Hz) (BnOCHH), 3.65 (dd, J¼10.7, 4.7 Hz) and 3.66
(dd, J¼10.2, 4.7 Hz) (BnOCHH), 3.79 (dd, J¼14.1, 8.6 Hz)
and 3.81 (dd, J¼14.4, 9.7 Hz) (SCHH), 3.86–3.92 (1H, m,
4-H), 3.99 (dd, J¼11.2, 2.3 Hz) and 4.03 (dd, J¼11.2,
2.2 Hz) (SCHH), 4.14–4.19 (1H, m, 5-H), 4.49 (2H, s,
PhCH ), 7.23–7.37 (5H, m, Ph-H ), 7.54–7.60 (2H, m,
2
2
2
0
1
35.8 (Ph 1-C), 137.8 (Ph 1-C); MS (FAB) m/z 345.1522
(
1
M+H) (C H O S requires 345.1519), 329 (MꢂCH ),
2
0
24
3
3
2
0
09 (PhSH), 91 (Bn); [a] +4.4 (c 2.0, CHCl ).
D 3
5
(
.6. 4S,5R-4-(Benzyloxymethyl)-2,2-dimethyl-5-
3-bromophenylthiomethyl)-1,3-dioxolane (9b)
2
5
Compound 7 was treated with 3-bromothiophenol, as for the
synthesis of 9a, to give 9b (69%) as a yellow oil: H NMR
S-Ph 3,5-H ), 7.70 (1H, t, J¼8 Hz, S-Ph 4-H), 7.94 (2H, d,
2
1
13
J¼8 Hz, S-Ph 2,6-H ); C NMR d 26.4 (Me), 26.6 (Me),
2
d 1.39 (3H, s, Me), 1.43 (3H, s, Me), 3.16–3.19 (2H, m,
SCH ), 3.59–3.66 (2H, m, BnOCH ), 4.03–4.05 (2H, m,
58.5 (SCH ), 59.3 (SCH ), 69.6 (BnOCH ), 69.7 (BnOCH ),
2
2
2
2
72.9 (5-C), 73.3 (5-C), 73.6 (PhCH ), 73.7 (PhCH ), 78.1 (4-
2 2
2
2
4
5
,5-H ), 4.57 (2H, s, PhCH ), 7.08 (1H, t, J¼8.0 Hz, Ar
C), 78.2 (4-C), 110.8 (CMe ), 127.7 (CH), 127.8 (CH), 127.9
2
2
2
-H), 7.22 (1H, ddd, J¼8.1, 1.8, 1.0 Hz, Ar 6-H), 7.42–7.46
(C-Ph 2,6-C ), 128.0 (CH), 128.2 (S-Ph 2,6-C ), 128.3 (CH),
2
2
1
3
(5H, m, Ph-H ), 7.48–7.51 (2H, m, Ar 2,4-H ); C NMR
d 27.0 (Me), 27.1 (Me), 36.3 (SCH ), 70.5 (BnOCH ), 73.6
128.47 (CH), 128.49 (CH), 128.53 (C-Ph 3,5-C ), 129.0
2
(CH), 129.5 (S-Ph 3,5-C ), 134.6 (S-Ph 4-C), 134.8 (S-Ph
2
5
2
2
2
(
C), 127.3 (CH), 127.8 (Ph 3,5-C ), 128.4 (Ph 2,6-C ), 129.0
PhCH ), 77.2 (5-C), 79.1 (4-C), 110.0 (CMe ), 122.8 (Ar 3-
4-C), 135.3 (S-Ph 1-C), 135.4 (S-Ph 1-C), 137.32 (C-Ph
1-C), 137.35 (C-Ph 1-C); F NMR d ꢂ76.0 (1.8F, s),
3
2
2
1
9
2
2
2
0
(
Ph 4-C), 130.2 (Ar-CH), 131.2 (Ar-CH), 132.3 (Ar-CH),
37.7 (Ph 1-C), 138.5 (Ar 1-C); [a]D +6.1 (c 2.5, CHCl3).
ꢂ75.9 (1.2F, s); [a]D +3.7 (c 2.0, CHCl ).
2
0
1
5.9. 4S,5R,S(±)-4-(Benzyloxymethyl)-2,2-dimethyl-5-
(N-(trifluoroacetyl)phenylsulfonimidoylmethyl)-1,3-
dioxolane (11a)
5
5
.7. 4S,5R,S(±)-4-(Benzyloxymethyl)-2,2-dimethyl-
-(phenylsulfinylmethyl)-1,3-dioxolane (10a)
Compound 9a (180 mg, 0.52 mmol) was stirred with 3-
chloroperoxybenzoic acid (111 mg, 0.52 mmol) in CH Cl
PhI(OAc) (242 mg, 0.75 mmol) was stirred vigorously with
2
10a (180 mg, 0.5 mmol), CF CONH (113 mg, 1.0 mmol),
2
2
2
3
ꢁ
NaHCO , water). Drying and evaporation gave 10a
(
15 mL) at ꢂ78 C for 5 h. The mixture was washed (aq
MgO (81 mg, 2.0 mmol) and Rh (OAc) (5.5 mg,
2 4
2.5 mol %) in CH Cl (10 mL) for 6 days. Filtration (Cel-
2
3
2
Ò
(
pale yellow oil: IR nmax 1265 cm
180 mg, 96%) as a 1:1 mixture of diastereoisomers as a
;
ite ), evaporation and chromatography (hexane/Et O, 1:1)
2
ꢂ1
1
H NMR d 1.37
afforded 11a (176 mg, 75%) as a 3:2 mixture of diastereoiso-
ꢂ1
(
(
1.5H, s, Me), 1.45 (1.5H, s, Me), 1.46 (1.5H, s, Me), 1.47
1.5H, s, Me), 2.84 (0.5H, dd, J¼13.2, 9.8 Hz, SCH (isomer
mers as a pale yellow oil: IR n
1422, 1265, 1173 cm
H NMR d 1.16 (1.8H, Me), 1.21 (1.2H, Me), 1.25 (1.8H,
;
max
1

12606
J. S. W. Kwong et al. / Tetrahedron 63 (2007) 12601–12607
Me), 1.26 (1.2H, Me), 3.42 (dd, J¼9.6, 6.8 Hz) and 3.43 (dd,
J¼9.7, 6.8 Hz) (BnOCHH), 3.65 (dd, J¼10.7, 4.7 Hz) and
J¼2.9, 8.7 Hz, 5-H), 4.51 (2H, s, PhCH ), 7.27–7.35 (5H,
2
m, Ph-H ), 7.50 (2H, m, S-Ph 3,5-H ), 7.59 (1H, m, S-Ph
5
2
1
3
3
1
3
.66 (dd, J¼10.2, 4.7 Hz) (BnOCHH), 3.79 (dd, J¼
4.1, 8.6 Hz) and 3.81 (dd, J¼14.4, 9.7 Hz) (SCHH),
.86–3.92 (1H, m, 4-H), 3.99 (0.5H, dd, J¼11.2, 2.3 Hz)
4-H), 8.00 (2H, m, S-Ph 2,6-H2); C NMR d 26.8 (Me),
26.9 (Me), 61.3 (SCH ), 70.0 (BnOCH ), 73.6 (PhCH ),
73.7 (5-C), 78.7 (4-C), 110.4 (CMe ), 127.6 (Ph 3,5-C ),
2
2
2
2
2
and 4.03 (0.5H, dd, J¼11.2, 2.2 Hz) (SCH), 4.14–4.19
127.7 (Ph 4-C), 128.4 (Ph 3,5-C ), 128.5 (Ph 2,6-C ),
2 2
129.0 (Ph 2,6-C ), 133.1 (Ph 4-C), 137.6 (Ph 1-C), 141.5
2
(
1H, m, 5-H), 4.49 (2H, s, PhCH ), 7.23–7.37 (5H, m, Ph-
2
H ), 7.54–7.60 (2H, m, S-Ph 3,5-H ), 7.70 (1H, t, J¼8 Hz,
(Ph 1-C); MS (FAB) m/z 376 (M+H); MS (ES) m/z 775
(2M+Na), 399 (M+Na), 375 (M); [a]D +8.4 (c 2.3,
5
2
1
3
20
S-Ph 4-H), 7.94 (2H, d, J¼8 Hz, S-Ph 2,6-H ); C NMR
2
d 26.4 (Me), 26.6 (Me), 58.5 (SCH ), 59.3 (SCH ), 69.6
2
CHCl ). Further elution gave 12aS (47 mg, 34%) as a white
2
3
ꢁ
ꢂ1
3332, 734 cm ; H NMR
max
1
(
(
(
BnOCH ), 69.7 (BnOCH ), 72.9 (4-C), 73.3 (4-C), 73.6
2
solid: mp 86–88 C; IR n
2
PhCH ), 73.7 (PhCH ), 78.1 (5-C), 78.2 (5-C), 110.8
2
d 1.21 (3H, s, Me trans to CH OBn), 1.29 (3H, s, Me cis
2
2
CMe ), 127.7 (Ph-CH), 127.8 (Ph-CH), 127.9 (C-Ph 2,6-
2
to CH OBn), 3.39 (1H, dd, J¼14.2, 8.2 Hz, SCH), 3.50–
2
C ), 128.0 (Ph-CH), 128.2 (S-Ph 2,6-C ), 128.3 (Ph-CH),
2
3.54 (2H, m, SCH+BnOCH), 3.64 (1H, dd, J¼9.7, 5.3 Hz,
2
1
1
28.47 (Ph-CH), 128.49 (Ph-CH), 128.53 (C-Ph 3,5-C2),
29.0 (Ph-CH), 129.5 (S-Ph 3,5-C ), 134.8 (Ph 1-C), 135.3
BnOCH), 3.93 (1H, dt, J¼7.6, 5.3 Hz, 4-H), 4.31 (1H, dt,
J¼3.4, 8.2 Hz, 5-H), 4.51 (2H, s, PhCH ), 7.26–7.35 (5H,
2
2
1
9
(
Ph 1-C), 135.4 (Ph 1-C), 138.0 (Ph 1-C); F NMR
d ꢂ76.0 (1.8F, s), ꢂ75.9 (1.2F, s); MS (FAB) m/z
72.1382 (M+H) (C H NO F S requires 472.1406), 472
m, Ph-H ), 7.48 (2H, m, S-Ph 3,5-H ), 7.58 (1H, m, S-Ph
5
2
1
3
4-H), 7.96 (2H, m, S-Ph 2,6-H2); C NMR d 26.7 (Me),
26.8 (Me), 61.0 (SCH ), 69.9 (BnOCH ), 73.5 (5-C), 73.6
4
2
2
25
5
3
2
2
2
0
(
M+HꢂO), 414 (M+HꢂMe CO); [a] +5.1 (c 2.6, CHCl3).
(PhCH ), 78.6 (4-C), 110.1 (CMe ), 127.6 (Ph 3,5-C ),
2 2 2
2
D
1
27.7 (Ph 4-C), 128.4 (Ph 3,5-C ), 128.5 (Ph 2,6-C ),
2 2
5
5
.10. 4S,5R,S(±)-4-(Benzyloxymethyl)-2,2-dimethyl-
-(N-trifluoroacetyl-3-bromophenylsulfonimidoyl-
methyl)-1,3-dioxolane (11b)
128.8 (Ph 2,6-C ), 133.0 (Ph 4-C), 137.6 (Ph 1-C), 141.5
2
(Ph 1-C); MS (FAB) m/z 376 (M+H); [a]D +7.8 (c 2.3,
CHCl3).
2
0
Compounds 10b were treated with trifluoroacetamide,
PhI(OAc) and Rh (OAc) , as for the synthesis of 11a, to
give 11b (83%) as a 1:1 mixture of diastereoisomers as a
pale yellow oil: IR nmax 1746, 1216, 1176 cm ; H NMR
d 1.15 (1.5H, s, Me), 1.21 (1.5H, s, Me), 1.26 (1.5H, s,
Me), 1.28 (1.5H, s, Me), 3.49 (1H, m, BnOCH), 3.66
5.12. 4S,5R,S(R)-4-(Benzyloxymethyl)-2,2-dimethyl-5-
(3-bromophenylsulfonimidoylmethyl)-1,3-dioxolane
(12bR) and 4S,5R,S(S)-4-(benzyloxymethyl)-2,2-
dimethyl-5-(3-bromophenylsulfonimidoylmethyl)-
1,3-dioxolane (12bS)
2
2
4
ꢂ1
1
(
4
0.5H, dd, J¼8.2, 4.8 Hz, BnOCH), 3.68 (0.5H, dd, J¼8.2,
Compounds 11b were treated with NH , as for the synthesis
3
.8 Hz, BnOCH), 3.70–3.75 (0.5H, m, SCH), 3.76 (0.5H,
of 12aR and 12aS except that the chromatographic eluant
was EtOAc/hexane (7:3), to give 12bR (29%) as a pale yel-
low oil: H NMR d 1.22 (3H, s, Me), 1.32 (3H, s, Me), 3.34
dd, J¼14.6, 9.8 Hz, SCH), 3.87 (1H, m, 4-H), 4.05 (0.5H,
1
dd, J¼10.0, 2.2 Hz, SCH), 4.09 (0.5H, dd, J¼9.9 Hz,
2
.3 Hz, SCH), 4.14–4.22 (1H, m, 5-H), 4.51 (2H, s,
(1H, dd, J¼14.5, 9.0 Hz, SCH), 3.46 (1H, dd, J¼14.5,
2.7 Hz, SCH), 3.52 (1H, dd, J¼9.8, 6.3 Hz, BnOCH), 3.69
(1H, dd, J¼9.8, 5.1 Hz, BnOCH), 3.86 (1H, ddd, J¼7.8,
6.3, 4.7 Hz, 4-H), 4.31 (1H, ddd, J¼8.6, 7.8, 2.7 Hz, 5-H),
4.53 (2H, s, PhCH ), 7.29–7.37 (5H, m, Ph-H ), 7.38 (1H,
PhCH ), 7.27–7.40 (5H, m, Ph-H ), 7.43 (1H, dt, J¼1.9,
2
5
8
(
.0 Hz, Ar 5-H), 7.72–7.85 (2H, m, Ar 4,6-H ), 8.08
2
0.5H, t, J¼1.6 Hz, Ar 2-H), 8.11 (0.5H, t, J¼1.9 Hz, Ar
1
3
2
(
-H); C NMR d 26.4 (Me), 26.5 (Me), 26.6 (Me), 58.6
SCH ), 59.4 (SCH ), 69.5 (BnOCH ), 69.6 (BnOCH ),
2
5
t, J¼7.8 Hz, Ar 5-H), 7.75 (1H, ddd, J¼7.8, 2.0, 0.8 Hz,
2
2
2
2
7
(
1
5
1
1
2.9 (5-C), 73.4 (5-C), 73.8 (PhCH ), 77.97 (4-C), 78.02
2
Ar 4-H or Ar 6-H), 7.82 (1H, ddd, J¼7.8, 2.0, 0.8 Hz, Ar
1
3
4-C), 110.8 (CMe ), 110.9 (CMe ), 123.3 (Ar 3-C),
2
6-H or Ar 4-H), 8.08 (1H, t, J¼1.9 Hz, Ar 2-H); C NMR
2
26.7, 126.8, 127.8, 128.0, 128.1, 128.5, 128.6, 130.83 (Ar
-C), 130.85 (Ar 5-C), 131.3 (Ar 2-CH), 131.4 (Ar 2-C),
37.2 (Ph 1-C), 137.3 (Ph 1-C), 137.4 (Ar 1-C), 137.5 (Ar
d 26.7 (Me), 26.8 (Me), 59.7 (SCH ), 69.9 (BnOCH ),
2
2
73.6 (5-CH), 73.7 (PhCH ), 78.4 (4-C), 110.3 (CMe ),
2
2
122.8 (Ar 3-C), 126.9, 127.7, 127.9, 128.5, 130.4, 131.6,
136.7, 137.5 (Ph 1-C), 141.6 (Ar 1-C); MS (ES) m/z
1
9
-C), 137.7, 137.8; F NMR d ꢂ76.0 (1.5F, s, CF ),
3
2
0
81
ꢂ75.9 (1.5F, s, CF ); [a] +4.3 (c 1.4, CHCl ).
456.0642 (M+H) (C H
455.0585 (M) (C H
454.0669 (M+H) (C H
BrNO S requires 456.0668),
4
3
D
3
20 25
8
1
BrNO S requires 456.0590),
4
2
0
24
7
25 4
9
5
(
.11. 4S,5R,S(R)-4-(Benzyloxymethyl)-2,2-dimethyl-5-
phenylsulfonimidoylmethyl)-1,3-dioxolane (12aR)
and 4S,5R,S(S)-4-(benzyloxymethyl)-2,2-dimethyl-5-
phenylsulfonimidoylmethyl)-1,3-dioxolane (12aS)
BrNO S requires 454.0682),
BrNO S requires 453.0610); [a]D
24 4
2
0
7
9
20
453.0604 (M) (C H
2
0
+3.2 (c 1.5, CHCl ). Further elution gave 12bS (32%) as a
3
ꢁ
1
(
white solid: mp 75–77 C; H NMR d 1.20 (3H, s, Me),
1
.31 (3H, s, Me), 2.32 (1H, br s, NH), 3.38 (1H, dd, J¼
Compounds 11a (176 mg, 0.37 mmol) were stirred with
NH (35% in water, 2.0 mL) in MeOH (5.0 mL) for 16 h.
Evaporation and chromatography (EtOAc/hexane, 2:3)
yielded 12aR (42 mg, 30%) as a pale yellow oil: IR n
14.3, 8.7 Hz, SCH), 3.52 (1H, dd, J¼9.5, 6.3 Hz, BnOCH),
3.54 (1H, dd, J¼14.3, 3.0 Hz, SCH), 3.66 (1H, dd, J¼9.5,
5.1 Hz, BnOCH), 3.89 (1H, ddd, J¼8.0, 6.3, 5.1 Hz, 4-H),
4.33 (1H, ddd, J¼8.5, 8.0, 2.9 Hz, 5-H), 4.53 (2H, s,
PhCH ), 7.27–7.39 (5H, m, Ph-H ), 7.36 (1H, t, J¼8.0 Hz,
3
max
ꢂ1
1
3
332, 733 cm ; H NMR d 1.33 (3H, s, Me), 1.37 (3H, s,
2
5
Me), 3.10 (1H, br s, NH), 3.30 (1H, dd, J¼13.6, 8.7 Hz,
SCH), 3.45 (1H, dd, J¼13.6, 2.9 Hz, SCH), 3.53 (1H, dd,
J¼9.8, 5.8 Hz, BnOCH), 3.67 (1H, dd, J¼9.8, 5.3 Hz,
BnOCH), 3.90 (1H, dt, J¼7.7, 5.3 Hz, 4-H), 4.45 (1H, dt,
Ar 5-H), 7.70 (1H, ddd, J¼8.0, 2.1, 1.0 Hz, Ar 4-H or Ar
6-H), 7.90 (1H, ddd, J¼8.0, 2.1, 1.0 Hz, Ar 6-H or Ar
1
3
4-H), 8.14 (1H, t, J¼1.9 Hz, Ar 2-H); C NMR d 26.7
(Me), 26.8 (Me), 61.0 (SCH ), 69.9 (BnOCH ), 73.7
2
2

J. S. W. Kwong et al. / Tetrahedron 63 (2007) 12601–12607
12607
(
PhCH +5-C), 78.4 (4-C), 110.3 (CMe ), 122.7 (Ar 3-C),
2
5.16. Crystal data for 12bS
2
1
27.2, 127.7 (Ph 3,5-C ), 127.9, 128.5 (Ph 2,6-C ), 130.3
2 2
(
1
Ar 5-C), 131.8 (Ar 2-C), 136.0, 137.5 (Ph 1-C), 144.3 (Ar
-C). Anal. Calcd for C H BrNO S: C, 52.87; H, 5.32;
N, 3.08. Found: C, 52.82; H, 5.22; N, 3.06; [a]D +2.6 (c
Crystals of quality suitable for X-ray crystallography were
grown from EtOH/hexane. C H NO SBr, M¼454.37,
2
0
24
4
20 24
4
2
0
˚
monoclinic, a¼12.3520(2), b¼5.5440(1), c¼15.7540(3) A,
ꢁ
˚
3
1
.5, CHCl3).
b¼103.459(1) , U¼1049.20(3) A , T¼150(2) K, space
ꢂ1
group¼P2 , Z¼2, m(Mo Ka)¼2.083 mm , 5447 reflec-
1
5.13. 2S,3R,S(R)-1-(Benzyloxy)-4-(phenyl-
sulfonimidoyl)butane-2,3-diol (13aR)
tions (R ¼0.0506), R1¼0.0347 and wR2¼0.0731 based
int
2
19
on 4752 F with F ꢄ4s(F ). Software used: SHELXS,
o
o
2
0
21
SHELXL-97 and ORTEX. H1 located and refined at
˚
0.89 A from N1. CCDC 654428.
Compound 12aR (38 mg, 0.1 mmol) was stirred with aq HCl
(9 M, 1.0 mL) in MeOH (5.0 mL) for 4 h. Evaporation and
chromatography (EtOAc/MeOH, 7:3) afforded 13aR
ꢂ1
(
37 mg, 100%) as a pale yellow oil: IR nmax 3305 cm
;
Acknowledgements
1
H NMR d 2.68 (1H, br, OH), 3.13 (1H, dd, J¼13.8,
1
.7 Hz, SCH), 3.45 (1H, dd, J¼13.8, 10.1 Hz, SCH), 3.59–
We thank Dr. Timothy J. Woodman (University of Bath) for
the NMR spectra, Dr. James Amato (University of Bath) and
the EPSRC Mass Spectrometry Centre (Swansea) for the MS
spectra and the University of London School of Pharmacy
Microanalysis Service for the microanalytical data. We are
grateful to the University of Bath for a studentship (to
J.S.W.K.).
3
m, PhCH +4-H), 7.27–7.35 (5H, m, Ph-H ), 7.56 (2H, m,
S-Ph 3,5-H ), 7.64 (1H, m, S-Ph 4-H), 7.98 (2H, m, S-Ph
2
2
7
4
2
.63 (2H, m, BnOCH ), 3.69 (1H, m, 3-H), 4.54–4.56 (3H,
2
2
5
1
3
,6-H2); C NMR d 59.8 (SCH ), 66.4 (4-C), 71.0 (1-C),
2
2.4 (3-C), 73.5 (PhCH ), 127.7 (Ph 3,5-C ), 127.8 (Ph
2
2
-C), 128.1 (Ph 3,5-C ), 128.5 (Ph 2,6-C ), 129.4 (Ph
2
2
,6-C ), 133.5 (Ph 4-C), 137.7 (Ph 1-C), 142.6 (Ph 1-C);
2
+
MS (FAB) m/z 336 (M+H); MS (ES ) m/z 693 (2M+Na),
6
3
3
71 (2M+H), 336.1264 (M+H) (C H NO S requires
7
References and notes
1
23
4
ꢂ
36.1264); MS (ES ) m/z 372/370 (M+Cl); MS (EI) m/z
36 (M+H), 244 (MꢂBn), 214 (MꢂBnOCH ), 91 (Bn);
1. Bentley, H. R.; McDermott, E. E.; Whitehead, J. K. Nature
1950, 165, 735.
2
2
0
[
a] +5.5 (c 1.3, CHCl ).
D 3
2
. Rowe, W. B.; Ronzio, R. A.; Meister, A. Biochemistry 1969, 8,
2674.
5.14. 2S,3R,S(R)-1-(Benzyloxy)-4-(3-bromophenyl-
sulfonimidoyl)butane-2,3-diol (13bR)
3. Richman, P. G.; Orlowski, M.; Meister, A. J. Biol. Chem. 1973,
48, 6684.
2
Compound 12bR was treated with aq HCl, as for the synthe-
sis of 13aR, to give 13bR (100%) as a pale yellow solid: mp
4. Griffith, O. W.; Meister, A. J. Biol. Chem. 1979, 254, 7558.
5. Fruehauf, J. P.; Zonis, S.; Al-Bassam, M.; Kyshtoobayeva, A.;
Dasgupta, C.; Milovanovic, T.; Parker, R. J.; Buzaid, A. C.
Chem.-Biol. Interact. 1998, 112, 277.
6. Remy, P.; Langner, M.; Bolm, C. Org. Lett. 2006, 8, 1209.
7. Reggelin, M.; Zur, C. Synthesis 2000, 1.
8. Okamura, H.; Bolm, C. Chem. Lett. 2004, 33, 482.
9. Bolm, C.; Moll, G.; Kahmann, J. D. Chem.—Eur. J. 2001, 7,
1118.
10. Bolm, C.; M €u ller, D.; Dahloff, C.; Hackenberger, C. P. R.;
Weinhold, E. Bioorg. Med. Chem. Lett. 2003, 13, 3207.
11. Mock, W. L.; Zhang, J. Z. J. Biol. Chem. 1991, 266, 6393.
12. Goodyer, C. L. M.; Chinje, E. C.; Jaffar, M.; Stratford, I. J.;
Threadgill, M. D. Bioorg. Med. Chem. 2003, 11, 4189.
13. McDonald, M. C.; Mota-Filipe, H.; Wright, J. A.;
Abdelrahman, M.; Threadgill, M. D.; Thompson, A. S.;
Thiemermann, C. Br. J. Pharmacol. 2000, 130, 843.
14. El-Hamamsy, M. H. R. I.; Smith, A. W.; Thompson, A. S.;
Threadgill, M. D. Bioorg. Med. Chem. 2007, 15, 4552.
15. Johnson, C. R.; Schroeck, C. W. J. Am. Chem. Soc. 1973, 95,
7418.
ꢁ
ꢂ1
3425 cm ; H NMR d 3.00 (2H, br,
max
1
7
2
1
3–76 C; IR n
ꢃOH), 3.13 (1H, d, J¼14 Hz, SCH), 3.45 (1H, dd, J¼
3.9, 10.1 Hz, SCH), 3.59–3.64 (2H, m, BnOCH ), 3.70
2
(
1H, m, 2-H), 4.52 (1H, d, J¼11.7 Hz, PhCH), 4.54 (1H,
d, J¼11.7 Hz, PhCH), 4.55 (1H, br d, J¼10 Hz, 3-H),
7
7
(
.27–7.36 (5H, m, Ph-H ), 7.43 (1H, t, J¼7.9 Hz, Ar 5-H),
5
.75 (1H, ddd, J¼8.0, 1.9, 0.8 Hz, Ar 4-H or Ar 6-H), 7.91
1H, ddd, J¼8.0, 1.9, 0.8 Hz, Ar 6-H or Ar 4-H), 8.12 (1H,
1
3
t, J¼1.8 Hz, Ar 2-H); C NMR d 59.9 (SCH ), 66.5
2
(
3-C), 71.0 (1-C), 72.3 (2-C), 73.6 (PhCH ), 123.4 (Ar
2
3
-C), 126.7, 127.9 (Ph 3,5-C ), 128.0, 128.6 (Ph 2,6-C ),
2 2
1
30.9, 131.1, 136.7, 137.6 (Ph 1-C), 141.0 (Ar 1-C). Anal.
Calcd for C H BrNO S: C, 49.28; H, 4.87; N, 3.38. Found:
1
7
20
4
2
0
C, 49.48; H, 4.61; N, 2.95; [a]D +2.5 (c 1.7, CHCl3).
5
.15. Crystal data for 12aS
Crystals of quality suitable for X-ray crystallography were
grown from EtOH/hexane. C H NO S, M¼375.47, ortho-
2
0
25
4
˚
rhombic, a¼5.5540(1), b¼18.4970(3), c¼19.2410(4) A,
16. Tamura, Y.; Minamikawa, J.; Sumoto, K.; Fujii, S.; Ikeda, M.
J. Org. Chem. 1973, 38, 1239.
17. Okamura, H.; Bolm, C. Org. Lett. 2004, 6, 1305.
18. Feit, P. W. J. Med. Chem. 1964, 7, 14.
19. Sheldrick, G. M. Acta Crystallogr. 1990, A46, 467.
20. Sheldrick, G. M. SHELXL-97, A Computer Program for Crystal
Structure Refinement; University of G €o ttingen: G €o ttingen, 1997.
21. McArdle, P. J. Appl. Crystallogr. 1995, 28, 65.
˚
3
U¼1976.67(6) A , T¼150(2) K, space group¼P2 2 2 ,
1
1 1
ꢂ1
Z¼4, m(Mo Ka)¼0.188 mm , 4490 reflections (R ¼
int
2
0
.04977), R1¼0.03581 and wR2¼0.0772 based on 3837 F
1
9
with F ꢄ4s(F ). Software used: SHELXS, SHELXL-
o o
2
0
21
9
with C14A–C20A, respectively. H1 located and refined at
7
and ORTEX. Atoms C14–C20 disordered in 1:1 ratio
˚
.89 A from N1. CCDC 654427.
0