Enantioselective synthesis of 1,4-dihydrobenzoxathiins via sulfoxide-directed borane reduction

Article abstract of DOI:10.1055/s-2006-950243

A novel sulfoxide-directed borane reduction was shown to give a variety of 2-substituted 1,4-dihydrobenzoxathiins. For all substrates evaluated, the reaction is completely stereospecific. Application of this methodology to the chiral synthesis of an artif

Full text of DOI:10.1055/s-2006-950243

PAPER
3389
Enantioselective Synthesis of 1,4-Dihydrobenzoxathiins via Sulfoxide-Directed
Borane Reduction
Sulfoxide-Directed
Bo
a
rane
R
educ
r
tion to 1
j
,4-dihy
o
drobenzoxath
r
iins ie S. Waters,* Ekama Onofiok, David M. Tellers, Jennifer R. Chilenski, Zhiguo Jake Song
Department of Process Research, Merck Research Laboratories, P.O. Box 2000, Rahway, NJ 07065, USA
Fax +1(732)5941499; E-mail: marjorie_waters@merck.com
Received 12 May 2006; revised 5 June 2006
generated centers are independently controlled by the
Abstract: A novel sulfoxide-directed borane reduction was shown
to give a variety of 2-substituted 1,4-dihydrobenzoxathiins. For all
substrates evaluated, the reaction is completely stereospecific. Ap-
plication of this methodology to the chiral synthesis of an artificial
sweetener was demonstrated.
chiral sulfoxide.7 From these results and additional kinetic
data, we proposed the mechanism shown in Scheme 1 in
which the sulfoxide directs the borane to deliver the two
hydrogens from the same face of the molecule as the oxy-
gen.8 In further studies, the reaction rates of 1 with BH3-
THF and BD3-THF were measured and the isotope effect
kH/kD was determined to be 1.4. This low value is consis-
tent with hydride transfer not being the rate-determining
step.9 A plausible scenario is that transfer of the borane
from THF to the sulfoxide is rate-determining.9e
Key words: asymmetric synthesis, sulfoxide, dihydrobenzoxathi-
in, reduction
The dihydrobenzoxathiin ring structure is present in a va-
riety of compounds of biological interest, including anti-
hypertensive agents, antioxidants, estrogen receptor
modulators, adrenoreceptor antagonists and artificial
sweeteners.1 Previous methods for the preparation of the
dihydrobenzoxathiin core structure include intramolecu-
lar alkoxide displacement,1a ring-closing Michael addi-
tion of a phenol to an a,b-unsaturated ester,2 Diels–Alder
reactions of o-thioquinones with substituted styrenes,3
and acid-catalyzed reductive ring closure of phenol ke-
tones.4 Although extension of these methodologies would
be expected to allow for absolute stereochemical control
of the C-2 and C-3 dihydrobenzoxathiin centers, examples
of such stereocontrol have been conspicuously absent
from the literature.
H
H
B
H
O
S
O
S
Ar
Ar
BH3-THF
Ar
Ar
rate-determining
step
O
O
H
B
O
H
H
S
Ar
Ar
S
Ar
O
O
Ar
H
H
During the development of a practical synthesis of a selec-
tive estrogen receptor modulator (SERM),5 we discovered
a novel sulfoxide directed borane reduction of vinyl sul-
foxide 1 which gave dihydrobenzoxathiin 2 with complete
stereospecificity (Equation 1). This unusual and efficient
reaction was unprecedented in the literature.6
Scheme 1 Proposed mechanism for borane reduction
The generality of this novel oxidation–reduction sequence
for the enantioselective synthesis of dihydrobenzoxathiins
has not previously been demonstrated. Herein we wish to
report the enantioselective synthesis of a variety of 2-sub-
stituted-1,4-benzoxathiins. We further demonstrate the
value of this novel methodology by completing the first
enantioselective synthesis of isovanillin sweetener 14.
In our initial study, we demonstrated through labeling ex-
periments with BD3 that the reduction of 1 occurs with
both hydrogens originating from the borane species. We
also observed that the stereoconfigurations of the newly
O
BnO
S
BnO
S
OBn
I
OBn
I
BH3-THF
O
O
(S)-1, 99% ee
(S,R)-2, 99% ee
Equation 1
SYNTHESIS 2006, No. 20, pp 3389–3396
1
7.
1
0
.
2
0
0
6
Advanced online publication: 10.10.2006
DOI: 10.1055/s-2006-950243; Art ID: M03106SS
© Georg Thieme Verlag Stuttgart · New York

3390
M. S. Waters et al.
PAPER
Previously the precursor 1,4-benzoxathiins have been pre- Uemura and co-workers have shown that BINOL is an ef-
pared in modest yield by intramolecular ring closure of fective ligand for catalytic titanium-mediated oxidation of
alkynylselenonium salts10 and, more recently, via sodium alkyl aryl sulfides.14a In contrast to the tartrate system, the
hydride-induced ring opening and closing of 5-aryloxy- Uemura system requires at least a full equivalent of water
1,2,3-thiadiazoles.11 Dehydrative cyclization of phenol relative to the sulfide, and nonpolar solvents to obtain
ketones would provide a facile entry into the benzoxathiin high yields and enantioselectivities, CCl4 being optimal.
core and we have found that phenylphosphonic dichloride Oxidation of 5f with cumene hydroperoxide using a sto-
is an effective dehydrating agent for this purpose.5 Thus, ichiometric amount of the catalyst mixture 2:1:20 Ti(Oi-
a series of dihydroquinones 4 were prepared in good yield Pr)4/(R)-BINOL/H2O gave the sulfoxide 6f in 54% ee
by alkylation of 2-mercapto-1,4-dihydroquinone 3 with (Table 2, entry 1). Several solvent systems were evaluated
commercially available a-haloketones. When the crude as an alternative to using CCl4. Slightly reduced enanti-
dihydroquinones 4 were treated with two equivalents of oselectivity was seen with toluene (entry 2) and using
phenylphosphonic dichloride in acetonitrile, the desired DME gave racemic product (entry 3). Interestingly, when
benzoxathiins 5a–e were isolated in 40–88% yield from 3 the oxidation was run in ester solvents, good conversion
(Table 1).
was seen with enantioselectivity comparable to the CCl4
system. Ethyl, isopropyl, and butyl acetate all gave rea-
sonable enantioselectivity (entries 4–6) for the sulfoxide.
Table 1 Preparation of 1,4-Benzoxathiins
R
O
Table 2 Optimization of the Oxidation Sulfide 5f to Sulfoxide 6f
BnO
SH
OH
BnO
S
Et3N
O
X
+
O
R
CH2Cl2
OH
BnO
S
3
4
BnO
S
PhC(CH3)2OOH
O
BnO
S
Ti(Oi-Pr)4,
(R)-BINOL, H2O
PhPOCl2
O
5f
6f
MeCN, 80 °C
O
R
5
Entry
Solvent
ee (%)
54
1
2
3
4
5
6
CCl4
Entry
Product
5a
R
Yield (%)
toluene
38
1
2
3
4
5
4-CH3C6H4
4- CH3OC6H4
4-BrC6H4
CH3
69
40
88
55
71
dimethoxyethane
EtOAc
0
5b
52
5c
i-PrOAc
n-BuOAc
54
5d
55
5e
t-Bu
A variety of aryl and alkyl 1,4-benzoxathiins were oxi-
dized with cumene hydroperoxide using a 15 mol% cata-
lyst mixture of 2:1:20 (R)-BINOL/Ti(Oi-Pr)4/H2O in
isopropyl acetate at room temperature. The observed
enantioselectivity varied greatly for the substrates. Aryl
substrates bearing electron-donating and electron-neutral
substituents gave modest selectivity (48 and 52%,
Table 3, entries 1, 2). For aryl substrates with an electron-
withdrawing substituent (Table 3, entry 3), significantly
decreased enantioselectivity was obtained. For the alkyl
substrates, the methyl compound gave only modest 52%
ee (entry 4), while the more bulky tert-butyl substrate
gave excellent selectivity (entry 5), giving the sulfoxide in
96% ee.
With the benzoxathiin substrates in hand, we turned our
attention to the development of an efficient asymmetric
oxidation of the sulfide.12 The Kagan system which em-
ploys Ti(Oi-Pr)4/diethyl tartrate/water as the catalyst sys-
tem has been shown to be particularly effective in
achieving high selectivity for alkyl aryl sulfides.13 Modi-
fications of the original procedure have been reported al-
lowing the use of catalytic amounts of the titanium
reagent and using alternate ligands that provide enhanced
selectivity for specific substrates.14 Previously, we report-
ed that the oxidation to give 1 in 90–91% ee was best per-
formed using a modified Kagan-type oxidation.15 When
the 2-phenyl-1,4-benzoxathiin 5f was subjected to the
same oxidation conditions, the sulfoxide 6f was obtained
in only 7% ee.16 Using the original Kagan system at room
temperature,17 the sulfoxide 6f was obtained with only
slightly better enantioselectivity (33% ee). A variety of al-
ternate ligands was evaluated under the same conditions;
none gave significantly improved enantioselectivity.
Upon completion of the oxidation reaction, the crude re-
action mixtures were passed through silica gel, diluted
with toluene and treated with 1.2 equivalents of borane-
THF to effect olefin reduction. In every instance, the sulf-
oxide-directed reduction occurred with complete ste-
reospecificity and generally good yields to provide the
Synthesis 2006, No. 20, 3389–3396 © Thieme Stuttgart · New York

PAPER
Sulfoxide-Directed Borane Reduction to 1,4-Dihydrobenzoxathiins
3391
Table 3 Enantioselective Preparation of 1,4-Dihydrobenzoxathiins
O
BnO
S
BnO
S
CHP
BH3-THF
toluene
BnO
S
catalysta
i-PrOAc
O
R
O
R
O
R
5
6
7b
Entry
Product
R
6 ee (%)
59
7 ee (%)
60
Yield (%)
1
2
3
4
5
7a
7b
7c
7d
7e
p-Tol
64
70
68
63
86
4-MeOC6H4
4-BrC6H4
Me
48
48
26
26
52
51
t-Bu
96
97
a The catalyst was 15 mol% of 2:1:20 (R)-BINOL/Ti(Oi-Pr)4/H2O.
b The S-configuration was assigned based on X-ray data of 7e (see below).
enantiomerically enriched dihydrobenzoxathiin. The The absolute configuration of product 7e was unambigu-
enantiomeric excess of the reduced products were identi- ously determined as the (S)-dihydrobenzoxathiin by X-
cal to that of the sulfoxide intermediates. This is consis- ray crystallography on a single crystal (Figure 1).18 Thus
tent with our previous observations and the proposed the corresponding chiral sulfoxide 6e is believed to be the
mechanism in Scheme 2.
S-isomer based on the known correlation between the
sulfoxide 1 and the dihydrobenzoxathiin 2.19
O
O
OH
1) DDQ, dioxane
1) PhMe3N+Br3
–
2) PhCOCl (a) or
4-ClC6H4COCl (b)
MeMgCl
85%
2) 3, Et3N
MeO
MeO
OH
MeO
76%
67%
OR
OH
9a R = benzoate
9b R = p-chlorobenzoate
8
BnO
S
O
BnO
S
NaOH
PhPOCl2
O
MeOH
96%
MeCN, reflux
82%
OH
OMe
OMe
OR
11a,b
OR
10a,b
BnO
S
BnO
S
1) PhC(CH3)2OOH
Ti-BINOL, i-PrOAc
O
O
2) BH3-THF, toluene
60%
OMe
OMe
12
OH
13
78% ee
OH
HO
S
H2, Pd(OH)2/C
O
MeOH
40%
OMe
OH
14
Scheme 2
Synthesis 2006, No. 20, 3389–3396 © Thieme Stuttgart · New York

3392
M. S. Waters et al.
PAPER
Determination of Kinetic Isotope Effect
A slurry of 1 in CH2Cl2 (59.5 mg/mL) was cooled and maintained
at –12 °C. A solution of borane (10–30 mol%) was added and the
reaction progress monitored by React-IR. Kinetic data was collect-
ed and analyzed from 5% to 90% completion to determine the rate
constants. The reaction has previously been shown to be first order
in both borane and substrate. The experimental rate constants from
two separate runs are shown below in Table 4.
Table 4 Kinetics of Borane Reduction of 1
Figure 1 ORTEP diagram of 7e
Borane
Conversion
(mol%)
kobs (s–1)
kobs Borane
(average)
This oxidation-reduction sequence allows for the prepara-
tion of a class of compounds which were previously avail-
able only in racemic form. We applied this reduction
methodology to the preparation of potential food additives
such as 14, a compound reported to be 500 times sweeter
than sucrose.1e The synthesis starting from isovanillin is
shown in Scheme 2. Grignard addition to the aldehyde20
followed by oxidation with DDQ21 furnished the ketone
intermediate.22 Since previous experiments have shown
that the dehydrative cyclization is more effective when the
aromatic ring contains electron-withdrawing substituents
(Table 1, entries 1–3), the phenol was protected as an es-
ter. Using the benzoate ester, the dehydrative cyclization
gave the desired product 11a in only 60% yield. To de-
crease the aromatic ring electron-density, the p-chlo-
robenzoate 9b was prepared. After bromination and
alkylation with 3 to give the hydroxyketone 10b, the de-
hydrative cyclization cleanly furnished the desired benz-
oxathiin 11b in 82% isolated yield.
BH3
BH3
BD3
BD3
28.9
11.9
13.8
15.0
5.1 × 10–4
6.9 × 10–4
3.9 × 10–4
4.6 × 10–4
6.0 × 10 –4
4.3 × 10 –4
Benzoxathiins 5; General Procedure
Benzyloxythiophenol 3 (2.32 g, 10 mmol) and haloketone (10.2
mmol) were dissolved in CH2Cl2 (20 mL). Et3N (1.5 mL, 10.5
mmol) was added and the mixture stirred for 30–60 min. The mix-
ture was poured into aq 2 N HCl (20 mL) and the product extracted
with CH2Cl2 (20 mL). The combined organics were washed with aq
2 N HCl (20 mL), dried (MgSO4), filtered and concentrated to dry-
ness. The crude intermediate 4 was combined with MeCN (50 mL)
and refluxed with a slight N2 purge. PhPOCl2 (20 mmol) was added
dropwise over 1–2 min. After 1–4 h at reflux, the reaction was
cooled to r.t. and poured into aq 0.5 M Na2CO3 (100 mL). The prod-
uct was worked up individually as follows:
2-(4-Methylphenyl)-6-(phenylmethoxy)-1,4-benzoxathiin (5a)
The product was isolated directly by filtration. The product was fur-
ther purified by stirring in MeOH (25 mL) at 60 °C for 15 min fol-
lowed by cooling to r.t. Filtration gave a pale yellow solid (2.38 g)
in 69% yield; mp 143–144 °C.
1H NMR (400 MHz, CDCl3): d = 7.51–7.41 (m, 7 H), 7.19 (d,
J = 8.1 Hz, 2H), 6.90 (d, J = 8.8 Hz, 1 H), 6.73 (dd, J = 8.8, 2.9 Hz,
1 H), 6.67 (d, J = 2.8 Hz, 1 H), 5.74 (s, 1 H), 5.02 (s, 2 H), 2.39 (s,
3 H).
Although electron-poor substrates are more effective in
the cyclization, the resulting benzoxathiins give lower se-
lectivity in the subsequent oxidation (Table 3, entries 1–
3). Compound 11 was oxidized using the typical proce-
dure, giving the sulfoxide in only 40% ee. When the ester
group was hydrolyzed to give the free phenol, oxidation of
compound 12 gave the corresponding sulfoxide in 78%
ee. Borane reduction of the crude product furnished the
desired dihydrobenzoxathiin 13 in 78% ee and 60% yield.
Debenzylation via hydrogenolysis using Pearlman’s cata-
lyst provided the target compound 14 in 40% yield, com-
pleting the first asymmetric synthesis of this compound.
13C NMR (100 MHz, CDCl3): d = 155.8, 150.7, 146.0, 138.6, 136.8,
130.8, 129.2, 128.7, 128.1, 127.5, 124.3, 120.7, 118.1, 114.0, 112.8,
92.4, 70.7, 21.3.
Anal. Calcd for C22H18O2S: C, 76.27; H, 5.24. Found: C, 75.51; H,
5.13.
In summary, we have developed a practical and catalytic
asymmetric synthesis of 1,4-dihydrobenzoxathiins, which
was successfully applied to the asymmetric synthesis of a
sweetener. This novel sulfoxide-directed reduction meth-
odology should find its applications in the synthesis of
similar compounds.
2-(4-Methoxyphenyl)-6-(phenylmethoxy)-1,4-benzoxathiin (5b)
The product was isolated directly by filtration. The product was fur-
ther purified by stirring in MeCN (25 mL) at 60 °C for 15 min fol-
lowed by cooling to r.t. Filtration gave a pale yellow solid (1.43 g)
in 40% yield; mp 159–161 °C.
1H NMR (400 MHz, CDCl3): d = 7.53 (d, J = 8.9 Hz, 2 H), 7.46–
7.31 (m, 5 H), 6.90 (d, J = 8.8 Hz, 1 H), 6.89 (d, J = 8.6 Hz, 2 H),
6.72 (dd, J = 8.8, 2.9 Hz, 1 H), 6.66 (d, J = 2.9 Hz, 1 H), 5.64 (s, 1
H), 5.01 (s, 2 H), 3.84 (s, 3 H).
13C NMR (100 MHz, CDCl3): d = 160.0, 155.8, 150.6, 146.0, 136.8,
128.7, 128.1, 127.5, 126.3, 125.8, 120.9, 118.1, 114.0, 113.9, 112.8,
91.1, 70.7, 55.4.
All solvents and reagents were obtained from commercial sources
and used without further purification. BD3-THF was purchased
from Alfa Aesar. Reactions were run under N2 and monitored by
HPLC on an HP1100. Flash chromatography was performed on sil-
ica gel (230–400 mesh). NMR data were obtained on a Bruker 400
MHz instrument. Racemic sulfoxides were prepared by oxidation
with MCPBA for use as reference compounds for ee determination.
Melting points are uncorrected.
Anal. Calcd for C22H18O3S: C, 72.90; H, 5.01. Found: C, 71.64; H,
4.73.
Synthesis 2006, No. 20, 3389–3396 © Thieme Stuttgart · New York

PAPER
Sulfoxide-Directed Borane Reduction to 1,4-Dihydrobenzoxathiins
3393
2-(4-Bromophenyl)-6-(phenylmethoxy)-1,4-benzoxathiin (5c)
The product was isolated directly by filtration. The product was fur-
ther purified by stirring in MeOH (25 mL) at 60 °C for 15 min fol-
lowed by cooling to r.t. Filtration gave a bright yellow solid (3.60
g) in 88% yield; mp 134–136 °C.
1H NMR (400 MHz, CDCl3): d = 7.42 (m, 9 H), 6.87 (d, 8.8 Hz, 1
H), 6.71 (dd, J = 8.8, 2.9 Hz, 1 H), 6.64 (d, J = 2.8 Hz, 1 H), 5.79 (s,
1 H), 5.01 (s, 2 H).
layers were concentrated in vacuo and purified by chromatography
(5% MTBE in hexanes).
Vinyl Sulfoxide 6a
A 59% ee was determined by SFC with a (S,S)-Whelko column, 4%
MeOH/CO2 for 4 min to 40% MeOH/CO2 over 18 min, then hold
for 3 min, 1.5 mL/min, 200 bar, 35 °C, UV at 215 nm; tR (major)
14.4 min, tR (minor) 11.3 min.
13C NMR (100 MHz, CDCl3): d = 155.8, 149.2, 145.5, 136.6, 132.2,
131.6, 128.6, 128.1, 127.4, 125.7, 122.5, 120.0, 118.0, 114.0, 112.7,
94.1, 70.6.
Vinyl Sulfoxide 6b
A 48% ee was determined by SFC with a (S,S)-Whelko column, 4%
MeOH/CO2 for 4 min to 40% MeOH/CO2 over 18 min, then hold
for 3 min, 1.5 mL/min, 200 bar, 35 °C, UV at 215 nm; tR (major)
15.2 min, tR (minor) 12.1 min.
Anal. Calcd for C21H15BrO2S: C, 61.32; H, 3.68. Found: C, 61.15;
H, 3.40.
Vinyl Sulfoxide 6c
2-Methyl-6-(phenylmethoxy)-1,4-benzoxathiin (5d)
The product was extracted with EtOAc (2 × 50 mL). The combined
organics were dried (MgSO4), filtered, and concentrated to an oil.
The product was purified by silica gel chromatography (5% MTBE
in hexanes) to give 1.48 g (55%) of a colorless oil that solidified on
standing.
1H NMR (400 MHz, CDCl3): d = 7.38 (m, 5 H), 6.68 (d, J = 8.8 Hz,
1 H), 6.64 (dd, J = 8.8, 2.8 Hz, 1 H), 6.57 (d, J = 2.8 Hz, 1 H), 4.99
(s, 2 H), 4.90 (dd, J = 2.0, 1.0 Hz, 1 H), 1.89 (d, J = 1.0 Hz, 3 H).
A 26% ee was determined by SFC with a (S,S)-Whelko column, 4%
MeOH/CO2 for 4 min to 40% MeOH/CO2 over 18 min, then hold
for 3 min, 1.5 mL/min, 200 bar, 35 °C, UV at 215 nm; tR (major)
13.6 min, tR (minor) 11.4 min.
Vinyl Sulfoxide 6d
A 52% ee was determined by SFC with a (S,S)-Whelko column, 4%
MeOH/CO2 for 4 min to 40% MeOH/CO2 over 18 min, then hold
for 3 min, 1.5 mL/min, 200 bar, 35 °C, UV at 215 nm; tR (major) 9.6
min, tR (minor) 9.0 min.
13C NMR (100 MHz, CDCl3): d = 155.5, 149.4, 145.5, 136.8, 128.6,
128.1, 127.5, 119.7, 117.8, 113.8, 112.8, 89.8, 70.6, 20.0.
Vinyl Sulfoxide 6e
Anal. Calcd for C16H14O2S: C, 71.08; H, 5.22. Found: C, 70.73; H,
5.03.
A 96% ee was determined by SFC with a Chiralpak AS column, 4%
MeOH/CO2 for 4 min to 40% MeOH/CO2 over 18 min, then hold
for 3 min, 1.5 mL/min, 200 bar, 35 °C, UV at 215 nm, tR (major)
14.4 min, tR (minor) 18.1 min.
2-(1,1-Dimethylethyl)-6-(phenylmethoxy)-1,4-benzoxathiin (5e)
The product was extracted with EtOAc (2 × 50 mL). The combined
organics were dried (MgSO4), filtered, and concentrated. The prod-
uct was purified by silica gel chromatography (30 g, 5% MTBE in
hexanes) to give 2.19 g (71%) of a white crystalline solid; mp 93–
94 °C.
1H NMR (400 MHz, CDCl3): d = 7.38 (m, 5 H), 6.78 (d, J = 8.7 Hz,
1 H), 6.69 (dd, J = 8.8, 2.8 Hz, 1 H), 6.65 (d, J = 2.8 Hz, 1 H), 5.14
(s, 1 H), 5.00 (s, 2 H), 1.18 (s, 9 H).
2-(4-Methylphenyl)-6-(phenylmethoxy)-2,3-dihydro-1,4-ben-
zoxathiin (7a)
The combined fractions were slurried in MeOH and the product was
isolated by filtration; yield: 0.67 g (64%); white solid; mp 115–
117 °C.
A 60% ee was determined by HPLC with Chiralcel OD-H column,
2% i-PrOH–hexanes to 15% i-PrOH–hexanes over 30 min, 0.8 mL/
min, 25 °C, 220 nm, tR (major) 12.3 min, tR (minor) 14.2 min.
1H NMR (400 MHz, CDCl3): d = 7.46–7.24 (m, 9 H), 6.88 (d,
J = 8.9 Hz, 1 H), 6.77 (d, J = 2.9 Hz, 1 H), 6.69 (dd, J = 2.9, 8.9 Hz,
1 H), 5.10 (dd, J = 1.5, 9.6 Hz, 1 H), 5.02 (s, 2 H), 3.30 (dd, J = 9.6,
13.0 Hz, 1 H), 3.07 (dd, J = 1.8, 13.0 Hz, 1 H), 2.41 (s, 3 H).
13C NMR (100 MHz, CDCl3): d = 153.4, 147.0, 138.3, 137.5, 137.2,
129.5, 128.6, 128.0, 127.6, 126.1, 119.5, 118.0, 113.2, 112.6, 70.7,
32.0, 21.3.
13C NMR (100 MHz, CDCl3): d = 161.6, 155.6, 146.9, 136.9, 128.6,
128.1, 127.5, 121.9, 117.6, 113.9, 112.6, 89.8, 70.7, 36.4, 27.6.
Anal. Calcd for C19H20O2S: C, 73.04; H, 6.45. Found: C, 72.94; H,
6.32.
Ti-BINOL Catalyst Stock Solution
(R)-BINOL (2.15 g, 7.5 mmol) was dissolved in i-PrOAc (75 mL).
The solution was degassed and Ti(Oi-Pr)4 (1.06 g, 3.8 mmol) was
added on the subsurface giving a dark red solution. H2O (1.35 mL,
75 mmol) was added to the mixture on the subsurface over 2 min
giving an orange slurry. The catalyst solution should be used within
one day.
Anal. Calcd for C22H20O2S: C, 75.83; H, 5.79. Found: C, 75.85; H,
5.67.
2-(4-Methoxyphenyl)-6-(phenylmethoxy)-2,3-dihydro-1,4-ben-
zoxathiin (7b)
The combined fractions were slurried in MeOH and the product was
isolated by filtration; yield: 0.77 g (70%); white solid; mp 112–
115 °C.
Dihydrobenzoxathiins 7; General Procedure
The benzoxathiin 5 (3 mmol) was dissolved in the catalyst stock so-
lution (9 mL). Cumene hydroperoxide (87%, 550 mg, 3.1 mmol)
was added and the reaction was left aside overnight until complete
by HPLC. The crude mixture was assayed for ee of the vinyl sulfox-
ide 6. The mixture was concentrated onto silica gel (5 g) and puri-
fied by flash chromatography (25 g silica gel, 3 × 50 mL CH2Cl2,
3 × 50 mL EtOAc). The EtOAc eluents were combined, concentrat-
ed and slurried in toluene (9 mL). The mixture was cooled to 5–
10 °C and 1 M BH3-THF (3.6 mL) was added dropwise. The solu-
tion was allowed to warm to r.t. The mixture was washed with aq
10% tartaric acid solution (2 × 10 mL). The combined aqueous lay-
ers were back-extracted with CH2Cl2 (5 mL) The combined organic
A 48% ee was determined by HPLC with Chiralcel OD-H column,
2% i-PrOH–hexanes to 15% i-PrOH–hexanes over 30 min, 0.8 mL/
min, 25 °C, 220 nm, tR (major) 16.5 min, tR (minor) 18.7 min.
1H NMR (400 MHz, CDCl3): d = 7.47–7.34 (m, 9 H), 6.99–6.95 (m,
2 H), 6.87 (d, J = 8.9 Hz, 1 H), 6.77 (d, J = 2.9 Hz, 1 H), 6.69 (dd,
J = 8.9, 3.0 Hz, 1 H), 5.08 (dd, J = 9.6, 1.7 Hz, 1 H), 5.02 (s, 2 H),
3.85 (s, 3 H), 3.31 (dd, J = 13.1, 9.7 Hz, 1 H), 3.05 (dd, J = 13.1, 1.9
Hz, 1 H).
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PAPER
13C NMR (100 MHz, CDCl3): d = 159.8, 153.4, 147.0, 137.2, 132.7,
128.6, 128.0, 127.6, 127.4, 119.5, 118.0, 114.2, 113.2, 112.6, 76.3,
70.7, 55.4, 32.0.
funnel to the MeMgCl solution over 1 h. The reaction was warmed
to r.t. and allowed to stand overnight. The slurry was quenched into
5% H3PO4 (420 mL) and the product was extracted with EtOAc
(2 × 250 mL). The combined organics were washed with aq 10 wt%
K2HPO4 (200 mL). The organic layer was dried (MgSO4) and con-
centrated to a white solid. The product was recrystallized from 2:1
hexanes–MTBE to give 14.04 g (85%) of 8 as a white solid which
was identified by comparison with literature data.20
1H NMR (400 MHz, CDCl3): d = 6.96–6.81 (m, 3 H), 5.83 (br s, 1
H, OH), 4.80 (q, J = 6.4 Hz, 1 H), 3.88 (s, 3 H), 1.87 (br s, 1 H, OH),
1.46 (d, J = 6.4 Hz, 3 H).
Anal. Calcd for C22H20O3S: C, 72.50; H, 5.53. Found: C, 72.72; H,
5.65.
2-(4-Bromophenyl)-6-(phenylmethoxy)-2,3-dihydro-1,4-benz-
oxathiin (7c)
The combined fractions were slurried in MeOH and the product was
isolated by filtration; yield: 0.84 g (68%); white solid; mp 123–
124 °C.
A 26% ee was determined by treatment of a sample with excess Mg
in THF followed by hydrolysis with H2O to furnish 7f which was
analyzed by literature procedure.5
Anal. Calcd for C9H12O3: C, 64.27; H, 7.19. Found: C, 64.39; H,
7.27.
5-Acetyl-2-methoxyphenyl 4-Chlorobenzoate (9b)
1H NMR (400 MHz, CDCl3): d = 7.56–7.54 (m, 2 H), 7.45–7.27 (m,
7 H), 6.86 (d, J = 8.9 Hz, 1 H), 6.75 (d, J = 2.9 Hz, 1 H), 6.69 (dd,
J = 8.9, 3.0 Hz, 1 H), 5.10 (dd, J = 9.4, 1.8 Hz, 1 H), 5.01 (s, 2 H),
3.23 (dd, J = 13.0, 9.4 Hz, 1 H), 3.06 (dd, J = 13.0, 2.0 Hz, 1 H).
13C NMR (100 MHz, CDCl3): d = 153.4, 146.4, 139.3, 137.0, 131.9,
128.6, 128.0, 127.7, 127.5, 122.4, 119.4, 117.7, 113.2, 112.5, 75.8,
70.6, 31.9.
Alcohol 8 (14.45 g, 85.9 mmol) was dissolved in 1,4-dioxane (100
mL). DDQ (19.62 g, 86.4 mmol) was added portionwise under cool-
ing using a cold water bath. The reaction was allowed to stay for
1 h. The mixture was concentrated in vacuo, taken up in CH2Cl2
(100 mL) and filtered through Solkaflok to remove DDQH2. To the
filtrate, Et3N (14.4 mL, 103.3 mmol) was added followed by 4-chlo-
robenzoyl chloride (11.0 mL, 86.7 mmol) and was allowed to sit
overnight. The mixture was washed with aq 1 N HCl (2 × 100 mL).
The organic layer was slurried with DARCO G-60 (25 g) and fil-
tered through silica gel (100 g). The cake bed was washed with
CH2Cl2 (300 mL). The combined filtrates were concentrated to give
an orange solid. The product was recrystallized twice from EtOAc–
hexanes (1:1) to give 9b (19.88 g, 76%) as a white solid; mp 150–
152 °C.
Anal. Calcd for C21H17BrO2S: C, 61.02; H, 4.15. Found: C, 61.16;
H, 4.00.
2-Methyl-6-(phenylmethoxy)-2,3-dihydro-1,4-benzoxathiin
(7d)
Yield: 0.52 g (63%); white solid; mp 52–53 °C.
A 51% ee was determined by SFC with Chiralpak AD column, 4%
MeOH/CO2 for 4 min, then to 40% MeOH/CO2 over 18 min, hold-
ing at 40% MeOH for 3 min, 1.5 mL/min, 200 bar, 35 °C, UV at 215
nm, tR (major) 13.3 min, tR (minor) 12.7 min.
1H NMR (400 MHz, CDCl3): d = 8.14 (d, J = 8.6 Hz, 2 H), 7.90 (dd,
J = 8.7, 2.1 Hz, 1 H), 7.78 (d, J = 2.1 Hz, 1 H), 7.49 (d, J = 8.5 Hz,
2 H), 7.04 (d, J = 8.6 Hz, 1 H), 3.88 (s, 3 H), 2.56 (s, 3 H).
13C NMR (100 MHz, CDCl3): d = 195.8, 163.6, 155.2, 140.1, 139.5,
1H NMR (400 MHz, CDCl3): d = 7.45–7.34 (m, 5 H), 6.77 (d,
J = 8.9 Hz, 1 H), 6.71 (d, J = 2.9 Hz, 1 H), 6.66 (dd, J = 8.8, 2.9 Hz,
1 H), 5.00 (s, 2 H), 4.30–4.26 (m, 1 H), 2.99 (dd, J = 12.9, 7.8 Hz,
1 H), 2.94 (dd, J = 12.8, 2.8 Hz, 1 H), 1.47 (d, J = 6.3 Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 153.2, 146.2, 137.2, 128.6, 128.0,
127.5, 119.2, 117.9, 113.1, 112.6, 70.7, 70.6, 31.4, 21.2.
131.6, 130.4, 128.9, 128.1, 127.4, 123.2, 111.6, 56.1, 26.2.
Anal. Calcd for C16H13ClO4: C, 63.06; H, 4.30. Found: C, 63.01; H,
4.21.
5-(2-{[2-Hydroxy-5-(benzyloxy)phenyl]thio}acetyl)-2-methoxy-
phenyl 4-Chlorobenzoate (10b)
Anal. Calcd for C16H16O2S: C, 70.56; H, 5.92. Found: C, 70.57; H,
5.77.
Ketone 9b (13.72 g, 45.0 mmol) was slurried in 1:1 dimethoxy-
ethane–CH2Cl2 (100 mL) and heated to 40-45 °C to dissolve. Phen-
yltrimethylammonium tribromide (17.71 g, 47.1 mmol) was added
and the mixture was kept for 1 hour at 40–45 °C. The reaction was
partitioned between EtOAc (240 mL) and H2O (160 mL). The lay-
ers were separated and the organic layer washed with brine (160
mL). The organic layer was dried (MgSO4) and filtered. Directly to
the crude solution, was added benzyloxythiophenol 3 (10.50 g, 45.2
mmol) followed by Et3N (6.5 mL, 46.6 mmol). The reaction was
kept for 1.5 h at r.t. The mixture was concentrated in vacuo and the
solvent was changed to MeOH (200 mL). The slurry was cooled to
10 °C and the solid was isolated by filtration to give 10b (18.43 g,
76%) as a white solid; mp 134–136 °C.
1H NMR (400 MHz, CDCl3): d = 8.13 (d, J = 8.6 Hz, 2 H), 7.88–
7.85 (m, 1 H), 7.75 (dd, J = 0.5, 2.0 Hz, 1 H), 7.51–7.32 (m, 7 H),
7.11 (d, J = 2.6 Hz, 1 H), 7.03 (d, J = 8.6 Hz, 1 H), 6.92 (m, 2 H),
4.97 (s, 2 H), 4.17 (s, 2 H), 3.89 (s, 3 H).
13C NMR (100 MHz, CDCl3): d = 192.8, 163.5, 156.0, 152.4, 152.2,
140.3, 139.6, 136.9, 131.6, 128.9, 128.54, 128.46, 128.2, 127.9,
127.4, 127.2, 123.5, 121.8, 119.4, 118.3, 116.6, 111.8, 70.8, 56.1,
44.1.
2-(1,1-Dimethylethyl)-6-(phenylmethoxy)-2,3-dihydro-1,4-
benzoxathiin (7e)
Yield: 0.82 g (86%); white solid; mp 95–98 °C.
A 97% ee was determined by SFC with Chiralpak AD column, 4%
MeOH/CO2 for 4 min, then to 40% MeOH/CO2 over 18 min, hold-
ing at 40% MeOH for 3 min, 1.5 mL/min, 200 bar, 35 °C, UV at 215
nm, tR (major) 9.9 min, tR (minor) 11.2 min.
1H NMR (400 MHz, CDCl3): d = 7.45–7.32 (m, 5 H), 6.78 (d,
J = 8.9 Hz, 1 H), 6.71 (d, J = 2.9 Hz, 1 H), 6.65 (dd, J = 8.9, 2.9 Hz,
1 H), 5.00 (s, 2 H), 3.72 (dd, J = 9.9, 1.7 Hz, 1 H), 3.05 (dd, J = 12.6,
9.9 Hz, 1 H), 2.95 (dd, J = 12.7, 1.8 Hz, 1 H), 1.06 (s, 9 H).
13C NMR (100 MHz, CDCl3): d = 153.0, 147.3, 137.2, 128.5, 127.9,
127.5, 118.9, 118.3, 112.8, 112.3, 82.3, 70.6, 34.8, 26.0, 25.7.
Anal. Calcd. for C19H22O2S: C, 72.57; H, 7.05. Found: C, 72.72; H,
7.05.
3-(a-Hydroxyethyl)-6-methoxyphenol (8)
A 3 M solution of MeMgCl in THF (80 mL, 240 mmol) was diluted
with THF (400 mL) and cooled to 5 °C. Isovanillin (14.92 g, 98.1
mmol) was dissolved in THF (100 mL) and added via an addition
Anal. Calcd for C29H23ClO6S: C, 65.10; H, 4.33. Found: C, 64.76;
H, 4.10.
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PAPER
Sulfoxide-Directed Borane Reduction to 1,4-Dihydrobenzoxathiins
3395
5-[6-(Benzyloxy)-1,4-benzoxathiin-2-yl]-2-methoxyphenyl 4-
Chlorobenzoate (11b)
1H NMR (400 MHz, CDCl3): d = 7.44–7.31 (m, 5 H), 7.00–6.66 (m,
6 H), 5.66 (br s, 1 H, OH), 5.03 (dd, J = 9.7, 1.5 Hz, 1 H), 5.01 (s, 2
H), 3.92 (s, 3 H), 3.27 (dd, J = 13.0, 9.7 Hz, 1 H), 3.04 (dd, J = 13.0,
1.7 Hz, 1 H).
13C NMR (100 MHz, CDCl3): d = 153.2, 146.7, 146.5, 145.8, 137.0,
133.6, 128.5, 127.9, 127.4, 119.3, 117.8, 113.0, 12.3, 110.6, 76.1,
70.5, 56.0, 31.8.
Phenol ketone 10b (16.04 g, 30.0 mol) was slurried in MeCN (150
mL) and heated to reflux. With slight N2 purge to a reflux condens-
er, PhPOCl2 (8.5 mL, 60.0 mmol) was added. The reaction was kept
for 2.5 h until complete by HPLC. The reaction was cooled to r.t.
and the solid was isolated by filtration. The vinyl sulfide 11b was
obtained as a white solid (12.76 g, 82%); mp 193–196 °C.
1H NMR (400 MHz, CDCl3): d = 8.17 (d, J = 8.6 Hz, 2 H), 7.51–
7.37 (m, 9 H), 7.00 (d, J = 8.7 Hz, 1 H), 6.87 (d, J = 8.8 Hz, 1 H),
6.70 (dd, J = 8.8, 2.9 Hz, 1 H), 6.64 (d, J = 2.9 Hz, 1 H), 5.68 (s, 1
H), 5.00 (s, 2 H), 3.84 (s, 3 H).
Anal. Calcd for C22H20O4S: C, 69.45; H, 5.30. Found: C, 69.13; H,
5.12.
(2S)-2-(3-Hydroxy-4-methoxyphenyl)-2,3-dihydro-1,4-benz-
oxathiin-6-ol (14) Dihydrobenzoxathiin 13 (700 mg, 1.84 mmol)
was dissolved in MeOH (5.5 mL) and AcOH (0.6 mL) and hydro-
genated using 20% Pd(OH)2/C (1.5 g) as catalyst at 100 psi and
35 °C for 8 h. The catalyst was removed by filtration through Solka-
flok and the filtrate concentrated to a solid. The solid was purified
by chromatography on silica gel using 25% MTBE–hexanes as the
eluent. The isolated solid was recrystallized from 1:2 MTBE–hex-
anes giving the desired product 14 as a white solid (216 mg, 40%),
which was identified by comparison with literature data;1e mp
144 °C (Lit.1e mp 136 °C).
1H NMR (400 MHz, CDCl3): d = 7.00 (d, J = 1.8 Hz, 1 H), 6.93–
6.87 (m, 2 H), 6.80 (d, J = 8.8 Hz, 1 H), 6.60 (d, J = 2.9 Hz, 1 H),
6.51 (dd, J = 8.7, 2.9 Hz, 1 H), 5.67 (br s, 1 H, OH), 5.01 (dd,
J = 9.6, 1.7 Hz, 1 H)), 4.47 (br s, 1 H, OH), 3.92 (s, 3 H), 3.26 (dd,
J = 13.0, 9.6 Hz, 1 H), 3.03 (dd, J = 13.1, 1.9 Hz, 1 H).
13C NMR (100 MHz, CDCl3): d = 163.7, 155.6, 151.4, 149.3, 145.6,
140.0, 139.6, 136.6, 131.6, 128.8, 128.5, 128.0, 127.6, 127.3, 126.6,
123.0, 119.0, 117.9, 113.8, 112.6, 112.1, 92.1, 70.5, 56.0.
Anal. Calcd for C29H21ClO5S: C, 67.37; H, 4.09. Found: C, 67.22;
H, 3.92.
5-[6-(Benzyloxy)-1,4-benzoxathiin-2-yl]-2-methoxyphenol (12)
Vinyl sulfide 11b (6.45 g, 12.5 mol) was slurried in EtOH (50 mL
EtOH). Aq 10 N NaOH (4 mL, 40 mmol) was added and the mixture
was heated to 65–70 °C for 2 h. The mixture was cooled to r.t. re-
sulting in a thick slurry formation. H2O (100 mL) was added. With
vigorous stirring, AcOH (1.5 mL) was added to adjust the pH to ~9.
The resulting solid was isolated by filtration and the cake washed
with H2O (50 mL), 5% AcOH (2 × 50 mL), and MeOH (50 mL).
The product 12 was obtained as an off white solid (4.54 g, 96%); mp
144–147 °C. NOTE: The product decomposed upon chromatogra-
phy on silica gel.
1H NMR (400 MHz, DMSO-d6): d = 7.43–7.31 (m, 5 H), 7.09–7.07
(m, 1 H), 6.98–6.95 (m, 1 H), 6.91 (d, J = 8.8 Hz, 1 H), 6.81–6.78
(m, 1 H), 6.07 (s, 1 H), 5.04 (s, 2 H), 3.77 (s, 3 H).
13C NMR (100 MHz, DMSO-d6): d = 155.7, 149.9, 148.8, 146.9,
145.4, 137.2, 128.8, 128.2, 128.0, 126.1, 121.0, 118.4, 115.7, 114.5,
112.8, 112.3, 111.8, 92.0, 70.1, 56.0.
13C NMR (100 MHz, CDCl3): d = 149.6, 146.6, 146.5, 145.7, 133.6,
119.4, 118.1, 117.7, 112.9, 112.8, 112.3, 110.6, 76.0, 56.0, 31.7.
Anal. Calcd for C15H14O4S: C, 62.05; H, 4.86. Found: C, 62.13; H,
4.58.
Acknowledgment
We are grateful to Mirlinda Biba for analytical support and
Matthew Bio for helpful suggestions and discussions.
Anal. Calcd for C22H18O4S: C, 69.82; H, 4.79. Found: C, 69.52; H,
4.46.
References
(1) (a) Tegeler, J. J.; Ong, H. H.; Profitt, J. A. J. Heterocycl.
Chem. 1983, 20, 867. (b) Capozzi, G.; Lo Nostro, P.;
Menichetti, S.; Nativi, C.; Sarri, P. Chem. Commun. 2001,
551. (c) Kim, S.; Wu, J. Y.; Birzin, E. T.; Frisch, K.; Chan,
W.; Lee-Yuh, P.; Yang, Y. T.; Mosley, R. T.; Fitzgerald, P.
M. D.; Sharma, N.; Dahllund, J.; Thorsell, A.; DiNinno, F.;
Rohrer, S. P.; Schaeffer, J. M.; Hammond, M. L. J. Med.
Chem. 2004, 47, 2171. (d) Melchiorre, C.; Brasili, L.;
Giardina, D.; Pigini, M.; Strappaghetti, G. J. Med. Chem.
1984, 27, 1535. (e) Arnoldi, A.; Bassoli, A.; Merlini, L.;
Ragg, E. J. Chem. Soc., Perkin Trans. 1 1993, 1359.
(2) Cabiddu, S.; Floris, C.; Melis, S.; Sotgiu, F.; Cerioni, G. J.
Heterocycl. Chem. 1986, 23, 1815.
5-[(2S)-6-(Benzyloxy)-2,3-dihydro-1,4-benzoxathiin-2-yl]-2-
methoxyphenol (13)
Vinyl sulfide 12 (2.26 g, 6.0 mmol) was slurried in i-PrOAc (18
mL). The catalyst stock solution (see general procedures, 18 mL)
was added followed by cumene hydroperoxide (87%, 1.1 mL, 6.3
mmol). The orange slurry was stirred at r.t. overnight giving a yel-
low slurry. SFC assay showed the intermediate sulfoxide with 78%
ee. The resulting solid was isolated by filtration and washed with i-
PrOAc (10 mL). The solid was hot slurried in toluene (50 mL),
cooled to r.t. and isolated by filtration. The crude orange solid was
slurried in toluene (18 mL) and cooled to 10 °C. A 1 M borane-THF
solution (8 mL, 8.0 mmol) was added dropwise. The reaction was
warmed to r.t. and kept for 1 h giving complete dissolution. SFC
analysis of the crude reaction gave 78% ee of the product. Aq 10%
tartaric acid solution (20 mL) was added and the mixture was fil-
tered through Solkaflok to remove solids. The filtrates were separat-
ed and the organic layer washed with aq 10% tartaric acid (20 mL).
The combined aqueous layers were back-extracted with CH2Cl2 (20
mL). The combined organics were dried (MgSO4) and concentrated
to dryness. The product was purified by column chromatography on
silica gel using 50% MTBE–hexanes as eluent. The product was
further purified by stirring in MeOH (20 mL) at 60 °C for 15 min
followed by cooling to r.t., and isolation by filtration to give 13 as a
white solid (1.36 g, 60%); mp 132–134 °C.
(3) Capozzi, G.; Falciani, C.; Menichetti, S.; Nativi, C. J. Org.
Chem. 1997, 62, 2611.
(4) Kim, S.; Wu, J. Y.; Chen, H. Y.; DiNinno, F. Org. Lett.
2003, 5, 685.
(5) Song, Z. J.; King, A. O.; Waters, M. S.; Lang, F.; Zewge, D.;
Bio, M.; Leazer, J. L.; Javadi, G.; Kassim, A.; Tschaen, D.
M.; Reamer, R. A.; Rosner, T.; Chilenski, J. R.; Mathre, D.
J.; Volante, R. P.; Tillyer, R. Proc. Natl. Acad. Sci. U.S.A.
2004, 101, 5776.
(6) The reduction of sulfoxides to sulfides with borane reagents
has been reported, see: Cha, J. S.; Kim, J. E.; Kim, J. D.
Tetrahedron Lett. 1985, 26, 6453; and references cited
therein.
An 84% ee was determined by SFC with Chiralpak AD-H, 30%
MeOH/CO2 for 90 min, 1.5 mL/min, 200 bar, 35 °C, UV at 215 nm,
tR (major) 48.5 min, tR (minor) 59.6 min.
Synthesis 2006, No. 20, 3389–3396 © Thieme Stuttgart · New York

3396
M. S. Waters et al.
PAPER
(7) For reviews on sulfoxide directed reactions, see:
(a) Hoveyda, A. H.; Evans, D. A.; Fu, G. C. Chem. Rev.
1993, 93, 1307. (b) Fernandez, I.; Khiar, N. Chem. Rev.
2003, 103, 3651. (c) Solladie, G. Synthesis 1981, 185.
(8) (a) This mechanism differs from the hydroboration-type
reaction observed on enamino sulfoxides, see: Ogura, K.;
Tomori, H.; Fujita, M. Chem. Lett. 1991, 1407.
(15) Ti(Oi-Pr)4 (0.15 mol%), diisopropylethylamine (0.3 mol%),
diisopropyl tartrate (0.3 mol%), and H2O (0.15 mol%) as the
catalyst and cumene hydroperoxide (CHP, 1.2 equiv) as the
oxidant. See ref 5.
(16) Compounds 5f and 6f were prepared previously, see
reference 5 for experimental details.
(17) The catalyst was 2:1:1 molar ratio of Ti(Oi-Pr)4/D-diethyl
tartrate/H2O in CH2Cl2. The substrate was added to the
catalyst solution followed by cumene hydroperoxide (CHP).
(18) Crystal data for compound 7e: C19H22O2S, M = 314.44,
orthorhombic, P212121, a = 9.5087(11) Å, b = 9.5799(11)
Å, c = 18.842(2) Å, a = 90, b = 90, g = 90, V = 1716.4(3)
Å3, T = 298(2) K, Z = 4, rcalcd = 1.217 Mg/m3, m = 0.193
mm–1, F(000) 672, 3456 independent reflections
(Rint = 0.0421), 18173 reflections collected; refinement
method, full-matrix least squares refinement on F2;
Goodness-of-fit on F2 = 1.024; Final R indices [I > 2s(I)]
R1 = 0.0412, wR2 = 0.0958.
(b) Additional details and discussion of the proposed
mechanism can be found in reference 5.
(9) For examples of measured kinetic isotope effects for borane
reductions, see: (a) Hawthorne, F. M.; Lewis, E. S. J. Am.
Chem. Soc. 1958, 80, 4296. (b) Lewis, E. S.; Grinstein, R.
H. J. Am. Chem. Soc. 1962, 84, 1158. (c) White, S. S. Jr.;
Kelly, H. C. J. Am. Chem. Soc. 1970, 92, 4203. (d) Corey,
E. J.; Link, J. O.; Bakshi, R. K. Tetrahedron Lett. 1992, 33,
7107. (e) Linney, L. P.; Self, C. R.; Williams, I. H. J. Chem.
Soc., Chem. Commun. 1994, 1651.
(10) Watanabe, S.; Mori, E.; Nagai, H.; Iwamura, T.; Iwama, T.;
Kataoka, T. J. Org. Chem. 2000, 65, 8893.
(19) A tentative assignment of the S-configuration for 6a–e and
7a–d can be made based on the mechanism and analogy to
7e. This is consistent with the facial selectivity previously
reported by us (see ref. 5).
(20) Suetsugu, M.; Fujiwara, R. Japanese Patent JP11029515,
1999; Chem. Abstr. 1999, 130, 200767.
(11) Katritzky, A. R.; Nikonov, G. N.; Tymoshenko, D. O.;
Moyano, E. L.; Steel, P. J. Heterocycles 2002, 57, 483.
(12) For a review on enantioselective preparation of sulfoxides,
see: Kagan, H. B. In Asymmetric Oxidation of Sulfides in
Catalytic Asymmetric Synthesis; Ojima, I., Ed.; Wiley-VCH:
New York, 2000, 2nd ed., 327–356.
(21) Becker, H. D.; Bjoerk, A.; Adler, E. J. Org. Chem. 1980, 45,
(13) Pitchen, P.; Dunach, E.; Deshmukh, M. N.; Kagan, H. B. J.
Am. Chem. Soc. 1984, 106, 8188.
1596.
(22) Initially, this sequence was done on commercially available
3-benzyloxy-4-methoxy benzaldehyde; however, the
dehydrative cyclization failed to give the desired product.
(14) (a) Komatsu, N.; Hashizume, M.; Sugita, T.; Uemura, S. J.
Org. Chem. 1993, 58, 4529. (b) Brunel, J. M.; Kagan, H. B.
Synlett 1996, 404. (c) Donnoli, M. I.; Superchi, S.; Rosini,
C. J. Org. Chem. 1998, 63, 9392. (d) Matsugi, M.; Fukuda,
N.; Muguruma, Y.; Yamaguchi, T.; Minamikawa, J.;
Otsuka, S. Tetrahedron 2001, 57, 2739. (e) Hogan, P. J.;
Hopes, P. A.; Moss, W. O.; Robinson, G. E.; Patel, I. Org.
Process Res. Dev. 2002, 6, 225.
Synthesis 2006, No. 20, 3389–3396 © Thieme Stuttgart · New York