The synthesis of chiral β-ketosulfoxides by enantioselective oxidation and their stereocontrolled reduction to β-hydroxysulfoxides

Article abstract of DOI:10.1016/j.tetasy.2005.12.004

Various chiral non-racemic β-ketosulfoxides, a class of compounds frequently used in asymmetric synthesis, were prepared in good yields by tert-butyl hydroperoxide oxidation of the corresponding sulfides in the presence of a complex between titanium and (

Full text of DOI:10.1016/j.tetasy.2005.12.004

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 17 (2006) 223–229
The synthesis of chiral b-ketosulfoxides by
enantioselective oxidation and their stereocontrolled reduction to
b-hydroxysulfoxides
Cosimo Cardellicchio,a,* Omar Hassan Omar,a Francesco Naso,a
Maria Annunziata M. Capozzi,b Francesco Capitellic and Valerio Bertolasid
aConsiglio Nazionale delle Ricerche, Istituto di Chimica dei Composti Organometallici (ICCOM), Dipartimento di Chimica,
`
Universita di Bari, via Orabona 4, 70126 Bari, Italy
b
`
Dipartimento di Scienze Agro-ambientali, Chimica e Difesa Vegetale (DISACD), Universita degli Studi di Foggia, via Napoli 25,
71100 Foggia, Italy
cConsiglio Nazionale delle Ricerche, Istituto di Cristallografia (IC), via Amendola 122/o, 70126 Bari, Italy
d
`
Dipartimento di Chimica and Centro di Strutturistica Diffrattometrica, Universita degli Studi di Ferrara, via Borsari 46,
44100 Ferrara, Italy
Received 8 November 2005; accepted 1 December 2005
Abstract—Various chiral non-racemic b-ketosulfoxides, a class of compounds frequently used in asymmetric synthesis, were pre-
pared in good yields by tert-butyl hydroperoxide oxidation of the corresponding sulfides in the presence of a complex between tita-
nium and (S,S)-hydrobenzoin. The ee values of almost all of the purified products were >98%. As ascertained by X-ray analysis and/
or by NMR spectroscopy, the use of the (S,S)-form of the ligand led to aryl b-ketosulfoxides with (RS)-configuration and to methyl
phenacyl sulfoxide with the (SS)-configuration. Some of the aryl ketosulfoxides were subjected to reduction with DIBAL-H/ZnCl2
and the corresponding b-sulfinylalcohols with an (R,RS)-configuration produced.
ꢀ 2005 Elsevier Ltd. All rights reserved.
1. Introduction
tion1,7,8 of (S)- or (R)-methyl p-tolyl sulfoxide which, in
turn, is obtained by the Andersen procedure.2,9
Enantiopure b-ketosulfoxides are of special interest in
enantioselective synthetic strategies, since they are pre-
cursors of b-sulfinylalcohols. In turn, these compounds
are useful building blocks in the synthesis of natural
and biologically active compounds presenting a variety
of structures.1–3 An additional recent use of the same sul-
finylalcohols is represented by the enantioselective pro-
tonation of lithium enolates of 2-arylcyclohexanones.4
In principle, in order to enlarge the number of possible
structures available, chiral non-racemic b-ketosulfoxides
could be produced by an enantioselective oxidation of
the corresponding sulfides.10 Various efforts have been
made toward this end.11–14 1-(Phenylsulfinyl)-propan-
2-one has been obtained by tert-butyl hydroperoxide
(TBHP) oxidation in the presence of a complex between
titanium and (+)-diethyl tartrate at ꢀ20 ꢁC (60% ee).11
The same compound has also been produced in up to
84% ee by dichlorocamphorsulfonyloxaziridine oxida-
tion.12 Phenyl phenacyl sulfoxide has been synthesized
in 57% ee by an oxidation with hydrogen peroxide in
the presence of chiral vanadium complexes.13 Some
b-ketosulfoxides have been obtained by oxidation with
cumene-, tert-butyl- or furyl hydroperoxide, in the pres-
ence of a titanium/diethyl tartrate complex at ꢀ25 ꢁC.
The sulfoxides were formed with ee values between
51% and 97%, but the isolated yields were in the range
The stereoselective reduction of b-ketosulfoxides repre-
sents the most convenient route to b-hydroxysulfoxides,
while the alternative procedure, consisting of oxidation
of the corresponding b-hydroxysulfides, is less fre-
quently used.5,6 In spite of their synthetic potential,
the types of b-ketosulfoxides readily available are rather
limited, since they are commonly prepared by the acyla-
*
Corresponding author. Tel.: +39 0805442077; fax: +39
0805442924; e-mail: cardellicchio@ba.iccom.cnr.it
0957-4166/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2005.12.004

224
C. Cardellicchio et al. / Tetrahedron: Asymmetry 17 (2006) 223–229
52–66%, because relatively large amounts (30–38%) of
the corresponding sulfone were produced.14
starting materials22–24 for our investigation on the oxi-
dation reaction. As outlined in our project, this process
was performed with TBHP at room temperature, in the
presence of a complex between titanium and (S,S)-
hydrobenzoin and led to the formation of the corre-
sponding b-ketosulfoxides25–29 1b–7b (Table 1).
In recent years, work performed in these laboratories
has opened a new route leading to chiral non-racemic
sulfoxides by an innovative procedure involving stereo-
controlled displacements of a carbanionic leaving group
from a suitable sulfinyl compound.15–21 The starting
materials required for our method were often produced
by different types of enantioselective hydroperoxide oxi-
dation of the corresponding sulfide in the presence of
chiral titanium complexes.15,16,18–21 For example, di-
alkyl (arylsulfinyl)- or (alkylsulfinyl)methylphosphonates
were synthesized in high ee values (91–>98%) by using
catalytic amounts of a titanium complex with (R)- or
(S)-1,10-bi-2-naphthol (BINOL).19,20 On the other hand,
enantiopure (R)-benzyl p-bromophenyl sulfoxide, a gen-
eral precursor of dialkyl sulfoxides, was obtained by
using (S,S)-hydrobenzoin (HB) as a ligand in the tita-
nium complex.16 These procedures are simple and
cheap, work at room temperature, use commercially
available compounds, afford the sulfoxides in high yields
and in high enantiomeric purity and can be easily scaled
up to a multigram scale. Among the procedures we have
reported, the oxidation with TBHP in the presence of
catalytic amounts of a complex between titanium and
(S,S)-hydrobenzoin16 appeared particularly convenient
for the oxidation of b-ketosulfides, in order to obtain
useful chiral b-ketosulfoxides. We report herein the
results concerning this oxidation process, followed by a
study concerning the reduction of the carbonyl function.
2-Naphthyl phenacyl sulfide 1a was oxidized to sulfox-
ide 1b in n-hexane. The titanium complex was prepared
with, or without, added water (Table 1, entries 1 and
2). Enantiopure (+)-1b was obtained, regardless of
the presence of added water during the formation of
the titanium active species, in similar isolated yields
(57–60%). An improvement of the isolated yields (86–
90%) of the same enantiopure 1b was observed when
the reaction was performed in CCl4 (Table 1, entries
3 and 4). The enantioselective oxidation of compounds
2a–7a was performed in CCl4, without adding water.
High enantiomeric purities (92–>98% ee) were also
obtained in the oxidation of 4-bromophenyl phenacyl
sulfide 2a, 2-bromophenyl phenacyl sulfide 3a and
p-tolyl phenacyl sulfide 4a (Table 1, entries 5–7). In
particular, sulfoxide (+)-2b was obtained directly in an
enantiopure form, whereas (+)-3b and (+)-4b increased
their ee values from 92% and 96%, respectively, to
>98% by crystallization. A lower enantiomeric purity
(76% ee) was obtained in the case of methyl phenacyl
sulfoxide (+)-5b (Table 1, entry 8). On the other
hand, 1-arylthio-propan-2-ones 6a and 7a were oxi-
dized in good yields (82–86%) to give (+)-6b and (+)-
7b in enantiomerically pure forms (Table 1, entries 9
and 10).
2. Results and discussion
2.2. Determination of the sulfur configuration of the
b-ketosulfoxides 1b–7b
2.1. Enantioselective oxidation of sulfides 1a–7a
(R)-(+)-Benzyl p-bromophenyl sulfoxide was obtained
by using the (S,S)-hydrobenzoin as a chiral ligand for
the titanium atom in the TBHP oxidation of the corre-
Aryl phenacyl sulfides 1a–4a, methyl phenacyl sulfide 5a
and 1-arylthio-propan-2-ones 6a and 7a were chosen as
Table 1. Enantioselective oxidation of b-ketosulfides
O
S
O
O
TBHP, rt
S
R'
R"
R'
R"
Ti(O-
i
Pr)4/HB
1a -7a
1b - 7b
HB = (S,
S
)-Hydrobenzoin
Entry
Substrate
R0
R00
Solvent
Watera
Time (h)
72
Product
Yieldb (%)
eec
1
2
3
4
5
6
7
8
9
1a
1a
1a
1a
2a
3a
4a
5a
6a
7a
2-Naphthyl
2-Naphthyl
2-Naphthyl
2-Naphthyl
4-Br-C6H4
2-Br-C6H4
p-Tolyl
Methyl
2-Naphthyl
p-Tolyl
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Me
Me
Hexane
Hexane
CCl4
CCl4
CCl4
CCl4
CCl4
CCl4
CCl4
0.5
0
0.5
0
0
0
0
0
0
0
(R)-1b
(R)-1b
(R)-1b
(R)-1b
(R)-2b
(R)-3b
(R)-4b
(S)-5b
(R)-6b
(R)-7b
60
57
86
90
75
81
74
69
86
82
>98
>98
>98
>98
>98
92 (>98d)
96 (>98d)
76
48
48
48
48
72
48
24
24
48
>98
>98
10
CCl4
a Water/sulfide molar ratio.
b Yields refer to pure isolated products.
c Determined by HPLC.
d After crystallization.

C. Cardellicchio et al. / Tetrahedron: Asymmetry 17 (2006) 223–229
225
sponding sulfide.16 Herein, the production of (+)-sul-
2.3. Reduction of b-ketosulfoxides 1b, 2b, 6b and 7b
foxides 1b–7b was observed. Compounds (R)-(+)-4b8 and
(S)-(+)-5b27 had previously been reported in the litera-
ture. The other configurations were attributed using
NMR techniques, by adding (R)-(methoxy)phenylacetic
acid16,17,30 to an enantioenriched mixture of (+)-aryl
sulfoxides 1b–4b and 6b–7b. Since the methylene signals
of the more abundant enantiomers showed upfield
shifts, the (R)-configuration was attributed to sulfoxides
1b–4b and 6b–7b according to a proposed model.30 Fur-
thermore, we were able to obtain suitable crystals of (+)-
3b for an X-ray analysis. It was found that (+)-3b had
an (R)-configuration (Fig. 1).
The reduction of a b-ketosulfoxide to the corresponding
sulfinyl alcohol has represented the crucial step of vari-
ous procedures leading to several synthetic targets.1,31–34
The mechanism of these reactions has been thoroughly
investigated for different reagents and conditions. When
hydrides were used in the presence of zinc halides,32 the
(R)-p-tolylsulfinyl group induced an almost exclusive
formation of the sulfinyl alcohol with an (R)-configu-
ration at the carbon stereogenic center. Thus, the reduc-
tion step appeared of interest not only for the
production of the sulfinyl alcohols, but also because it
allowed us to ascertain whether the same stereochemical
course was also valid for groups different from the p-
tolyl group. The b-ketosulfoxides 1b, 2b, 6b and 7b were
chosen for this investigation (Table 2).
In summary, the TBHP oxidation in the presence of a
catalytic amount of the complex between titanium and
hydrobenzoin, yielded high ee values (92–>98% ee), spe-
cifically when aryl b-ketosulfides were oxidized. A lower
value was obtained in the case of the oxidation of methyl
derivative 5b (76% ee). However, this variation was not
sufficient enough to establish a safe correlation between
structure and ee value, since the mechanistic picture of
these oxidation reactions cannot be depicted with the
available data without resorting to speculation.
b-Ketosulfoxides 1b, 2b, 6b and 7b were reduced to the
corresponding sulfinylalcohols 1c,35 2c, 6c and 7c36 with
DIBAL-H in the presence of a solution of zinc chloride
in THF (Table 2). 2-Naphthyl phenacyl sulfoxide 1b was
reduced to 1c in 87% de, when the hydride was dissolved
in THF (Table 2, entry 1). On the other hand, complete
O2
Br1
C7
S1
C8
C14
C2
C9
C1
C13
C3
O1
C10
C6
C12
C4
C11
C5
Figure 1. Asymmetric unit with atomic numbering scheme for (R)-(+)-3b. Ellipsoids drawn at 30% probability level.
Table 2. Stereoselective reduction of b-ketosulfoxides
O
S
OH
R"
O
S
O
DIBAL-H
R'
R'
R"
ZnCl2/THF
H
1b, 2b, 6b, 7b
1c, 2c, 6c, 7c
Entry
Substrate
R0
R00
Solventa
Product
Yieldb
dec
87
>98
97
>98
86
87
1
2
3
4
5
6
(R)-1b
(R)-1b
(R)-2b
(R)-2b
(R)-6b
(R)-7b
2-Naphthyl
2-Naphthyl
4-Br-C6H4
4-Br-C6H4
2-Naphthyl
p-Tolyl
Ph
Ph
Ph
Ph
Me
Me
THF
Toluene
THF
Toluene
Toluene
Toluene
(R,RS)-1c
(R,RS)-1c
(R,RS)-2c
(R,RS)-2c
(R,RS)-6c
(R,RS)-7c
86
80
60
93
91
70
a Solvent for DIBAL-H (see text).
b Yields refer to pure isolated products.
c Determined by HPLC or NMR.

226
C. Cardellicchio et al. / Tetrahedron: Asymmetry 17 (2006) 223–229
O2
C11
C10
C9
C8
C7
C5
C6
C12
Br1
C13
S1
C4
C3
C1
C14
C2
O1
Figure 2. Asymmetric unit with atomic numbering scheme for (R,RS)-(+)-2c. Ellipsoids drawn at 30% probability level.
stereoselectivity (de > 98%) was obtained by using a
solution of DIBAL-H in toluene (Table 2, entry 2). In
the case of p-bromophenyl phenacyl sulfoxide 2b, a
97% de value was measured when a solution of DI-
BAL-H in THF was used (Table 2, entry 3), whereas
complete stereochemical control was detected when a
solution of DIBAL-H in toluene was employed (Table
2, entry 4). Thus, we decided to perform the reduction
of the other substrates 6b and 7b, in which the less hin-
dered methyl group is bound to the carbonyl moiety, by
using DIBAL-H in toluene. In these cases, lower stereo-
selectivity was observed (86–87% de, Table 2, entries 5
and 6).
1c, 2c and 6c, which have a structure different from that
of p-tolyl sulfoxides. Finally, we succeeded in obtaining
a suitable crystal of compound 2c, for the X-ray deter-
mination of configuration. The (R,RS)-configuration
was attributed to this compound by using this technique
(Fig. 2).
It is worth noting that this X-ray experiment gave a fur-
ther confirmation that the b-ketosulfoxide 2b, which is
the precursor of 2c, has the same (RS)-configuration.
3. Conclusion
2.4. Determination of the configuration of the sulfinyl
alcohols 1c, 2c, 6c and 7c
The enantioselective oxidation of b-ketosulfides by
TBHP in the presence of a titanium complex with
(S,S)-hydrobenzoin represents a convenient route to
the corresponding b-ketosulfoxides in terms of reaction
conditions, yields and enantioselectivities. This oxida-
tion offers a ready access to a variety of compounds
structurally different from those previously reported,
which are almost invariably characterized by the pres-
ence of the p-tolyl group. It is worth noting that in addi-
tion to the new aryl sulfoxides which were synthesized, a
high stereoselectivity in the reduction of the carbonyl
moiety was observed, thus forming synthetically useful
b-sulfinylalcohols in a simple and straightforward route.
Compound 7c had spectroscopic properties identical to
those of (R,RS)-7c sulfoxide reported in the literature.36
The absolute configuration of the new stereogenic center
of compounds 1c, 2c, and 6c can be inferred from the
NMR spectra of the products, according to a well-estab-
1
lished rule.32–34 The patterns of the H NMR signals of
the hydrogen atoms of the methylene group of b-sulfinyl
alcohol is peculiar. In fact, the distances between them
are greater (0.30–0.50 ppm) for the (R,SS)- and (S,RS)-
enantiomers than for the (R,RS)- and (S,SS)-couple
(0.17–0.27 ppm). Furthermore, a conformational analy-
sis,37 performed on b-sulfinyl alcohols using both NMR
and IR, assigned the configurations and described the
role of the hydrogen bonding. We found that the dis-
tances between the signals of the hydrogen atoms of
the methylene group of the prevailing or exclusive reac-
tion products 1c, 2c, 6c and 7c were in the region of
0.18–0.25 ppm. Furthermore, in the case of entries 1,
3, 5 and 6, it was possible to measure the distances
between the signals of the corresponding residual stereo-
isomers, which were in the interval 0.38–0.47 ppm.
Therefore, we can conclude that the main products of
our reactions should have the (R,RS)- or the (S,SS)-
configuration. Since the starting sulfoxides had an
(RS)-configuration, 1c, 2c, 6c and 7c must have the
(R,RS)-configuration. Thus, the reported rule that an
(RS)-sulfinyl group should induce the formation of an
(R)-stereogenic center on the carbon atom in the
hydride reduction performed in the presence of zinc
halides can also be considered valid for b-ketosulfoxides
4. Experimental
The purified reaction products were characterized by
1
their H and 13C NMR spectra, recorded in CDCl3 at
500 and 125 MHz, respectively. If possible, their mass
spectra were determined by GC/MS analysis (70 eV).
The ee values were measured by HPLC with the
(R,R)-Whelk-O1 column or Chiralcel OD-H column.
The X-ray data for the o-bromophenyl phenacyl sulfox-
ide 3b and 2-(p-bromophenylsulfinyl)-1-phenyl-ethanol
2c were collected on a single-crystal Nonius Kappa
CCD area detector diffractometer equipped with a fine
focus sealed graphite-monochromated Mo-Ka radiation
˚
(k = 0.71073 A). Crystallographic data have been depos-
ited with the Cambridge Crystallographic Data Centre
as supplementary publications no. CCDC 239452 3b
and CCDC 239453 2c. Copies of the data can be

C. Cardellicchio et al. / Tetrahedron: Asymmetry 17 (2006) 223–229
227
obtained, free of charge, on application to CCDC, 12
Union Road, Cambridge CB2 1EZ, UK (fax: +44-(0)
1223-336033 or E-mail: deposit@ccdc.cam.ac.uk).
chloride/ethyl acetate 9:1 for compounds 1b–5b, ethyl
acetate/petroleum ether 8:2 for compound 6b and ethyl
acetate/petroleum ether/methanol 6:4:1 for compound
7b). The sulfoxides were purified by crystallization.
4.1. Materials
4.2.1. (R)-2-Naphthyl phenacyl sulfoxide 1b. Mp 134–
1-(p-Tolylthio)-propan-2-one 7a is commercially avail-
able. Aryl or alkyl phenacyl sulfides 1a–5a were pro-
duced by reacting bromoacetophenone with the
appropriate sodium thiolate.
135 ꢁC (hexane/EtOH 6:1) (lit.25 racemic 1b mp
25
106 ꢁC). ½aꢁD ¼ þ204:5 (c 1.01, CHCl3). The ee value
was measured by HPLC (Column: (R,R)-Whelk-O1,
5 lm. Eluent: hexane/i-propanol 60:40).
4.1.1. 2-Naphthyl phenacyl sulfide 1a. Mp 98–100 ꢁC
(CH3OH) (lit.22 mp 96.5–97.5 ꢁC).
4.2.2. (R)-p-Bromophenyl phenacyl sulfoxide 2b.26 Mp
25
111–113 ꢁC (hexane/EtOH 10:1). ½aꢁD ¼ þ174:3 (c
1.00, CHCl3). The ee value was measured by HPLC
(Column: (R,R)-Whelk-O1, 5 lm. Eluent: hexane/i-pro-
panol 70:30).
4.1.2. p-Bromophenyl phenacyl sulfide 2a. Mp 85–86 ꢁC
(CH3OH) (lit.23 mp 77–78 ꢁC).
4.1.3. o-Bromophenyl phenacyl sulfide 3a. Mp 75–76 ꢁC
4.2.3. (R)-o-Bromophenyl phenacyl sulfoxide 3b. Mp
95–96 ꢁC, (hexane/EtOH 8:1). ½aꢁD ¼ þ390:4 (c 1.01,
25
(CH3OH). MS (70 eV): 308 (M+2, 2), 306 (M+, 2), 105
1
(100), 77 (33), 51 (20). H NMR (500 MHz, CDCl3).
CHCl3). The ee value was measured by HPLC (Column:
(R,R)-Whelk-O1, 5 lm. Eluent: hexane/i-propanol
70:30). 1H NMR (500 MHz, CDCl3) 7.96–7.92 (m,
2H), 7.88 (dd, J = 1.6, J = 7.8 Hz, 1H), 7.62–7.58 (m,
2H), 7.55 (ddd, J = 1.2, J = 7.4, J = 7.8 Hz, 1H), 7.49–
7.45 (m, 2H), 7.39 (ddd, J = 1.6, J = 7.4, J = 7.9 Hz,
1H), 4.64 (d, J = 14.2 Hz, 1H), 4.33 (d, J = 14.2 Hz,
1H). 13C NMR (125 MHz, CDCl3) 190.9, 142.6, 136.2,
134.1, 133.0, 132.7, 128.9, 128.7, 128.6, 126.8, 118.6,
62.4. Anal. Calcd for C14H11BrO2S: C, 52.03; H, 3.43.
Found: C, 52.00; H, 3.70. X-ray determination of config-
uration: A colorless prismatic sample of 0.26 · 0.22 ·
0.17 mm was subjected to a single-crystal X-ray analysis.
The crystal is orthorhombic, space group P212121
(Z = 4), with the following unit cell dimensions:
7.99–7.94 (m, 2H), 7.61–7.57 (m, 1H), 7.55 (ddd,
J = 0.3, J = 1.4, J = 7.9 Hz, 1H), 7.50–7.45 (m, 2H),
7.38 (ddd, J = 0.3, J = 1.6, J = 7.9 Hz, 1H), 7.24 (ddd,
J = 1.4, J = 7.4, J = 7.9 Hz, 1H), 7.07 (ddd, J = 1.6,
J = 7.4, J = 7.9 Hz, 1H), 4.33 (s, 2H). 13C NMR
(125 MHz, CDCl3) 193.6, 136.0, 135.3, 133.6, 133.1,
130.3, 128.7, 128.6, 127.9, 127.8, 124.7, 40.0. Anal.
Calcd for C14H11BrOS: C, 54.74; H, 3.61. Found: C,
54.55; H, 3.99.
4.1.4. p-Tolyl phenacyl sulfide 4a. Mp 36–37 ꢁC
(CH3OH) (lit.23 mp 36–37 ꢁC).
4.1.5. Methyl phenacyl sulfide 5a. Kugelrohr oven temp
100–105 ꢁC, p = 0.01 Torr (lit.24 bp 80 ꢁC, p = 0.05
Torr).
˚
˚
˚
a = 4.7728(1) A, b = 9.2710(2) A, c = 30.2029(7) A, cell
3
˚
volume = 1336.44(5) A , calculated density = 1.606
g cmꢀ3, F(000) = 648. A total of 12,777 reflections were
collected at 293(2) K in the h range of 4.03–27.99ꢁ, and
then corrected for Lorentz and polarization effects, and
for absorption effects (l = 32.22 cmꢀ1).38 The number
of independent reflections was 3218, with Rint = 0.0612,
and omission of intensities with I 6 2r(I) gave 2380 ob-
served reflections employed for the structure solution
by Direct Methods application (SIR97).39 Afterwards,
the structure was refined by a full matrix least squares
technique (SHELXL-97):40 all non-hydrogen atoms were
refined anisotropically, while the hydrogen atoms were
localized by difference Fourier map application, with
the exception of H(4) and H(10) atoms, which were
4.1.6. 1-(2-Naphthylthio)-propan-2-one 6a. Mp 50–
51 ꢁC (CH3OH) (lit.22 mp 46–46.2 ꢁC) was obtained by
treating chloroacetone with sodium 2-naphthalene-
thiolate.
Racemic sulfoxides 1b–7b were prepared by peracetic
acid oxidation of the sulfides.
4.2. Enantioselective oxidation of sulfides 1a–7a with
tert-butyl hydroperoxide in the presence of a titanium/
hydrobenzoin catalyst
A solution of Ti(O-i-Pr)4 (51 mg, 0.18 mmol) in 5 mL of
the specified solvent was added to a solution of (S,S)-
hydrobenzoin (77 mg, 0.36 mmol) in 10 mL of the sol-
vent under a nitrogen atmosphere. When necessary
(Table 1, entries 1 and 3), water (3.6 mmol) was added at
this stage. The mixture was stirred for 1 h at rt. A solu-
tion of sulfide (7.2 mmol) in 45 mL of the solvent was
then added and the mixture was stirred for 30 min. After
this time, 7.9 mmol of a commercial 80% solution of
tert-butyl hydroperoxide (in di-tert-butylperoxide/water
3:2) was added and the stirring was continued for the
time specified in Table 1. The solvent was then removed
in vacuo and the evaporated mixture was subjected to
column chromatography on silica gel (eluent methylene
placed in idealized positions and had assigned a common
˚
isotropic thermal parameter (C–H = 0.93 A, Uiso
-
(H) = 1.2Uiso(C)). Final residuals were R = 0.0445 and
wR = 0.0963, using the weighting scheme w ¼ ½r2ðF o2Þþ
2
ð0:0446PÞ þ 0:3902Pꢁꢀ1 (where P ¼ ðF o2 þ 2F c2Þ=3) and
refining 199 parameters. In the final difference Fourier
map, the highest residual peak has density of 0.448
e Aꢀ3. The (R)-configuration was attributed to the sulfur
˚
stereogenic center as determined by the Flack parame-
ter = 0.016(13),41 calculated after the least-squares
refinement.
4.2.4. (R)-p-Tolyl phenacyl sulfoxide 4b. Mp 90–91 ꢁC
25
(hexane) (lit.8 mp 82–83.5 ꢁC). ½aꢁD ¼ þ178:0 (c 0.99,

228
C. Cardellicchio et al. / Tetrahedron: Asymmetry 17 (2006) 223–229
CHCl3) {lit.8 [a]D = +180.9 (c 1, CHCl3)}. The ee value
was measured by HPLC (Column: (R,R)-Whelk-O1,
5 lm. Eluent: hexane/i-propanol 60:40).
CDCl3) 7.69–7.65 (m, 2H), 7.55–7.51 (m, 2H), 7.40–
7.27 (m, 5 H), 5.35 (dd, J = 2.7, J = 9.8 Hz, 1H), 4.12–
3.87 (m, 1H), 3.21 (dd, J = 9.8, J = 13.1 Hz, 1H), 2.96
(dd, J = 2.7, J = 13.1 Hz, 1H). 13C NMR (125 MHz,
CDCl3) 142.7, 141.7, 132.6, 128.7, 128.3, 125.9, 125.7,
125.5, 70.8, 64.3. Anal. Calcd for C14H13BrO2S: C,
51.70; H, 4.03. Found: C, 51.84; H, 4.36. X-ray determi-
nation of configuration: A colorless prismatic sample of
0.50 · 0.28 · 0.14 mm was subjected to a single-crystal
X-ray analysis. The crystal is orthorhombic, space
group P212121 (Z = 4), with the following unit cell
4.2.5. (S)-Methyl phenacyl sulfoxide 5b. Mp 84–85 ꢁC
(ethyl acetate/hexane), (lit.24 racemic 5b mp 84 ꢁC).
25
½aꢁD ¼ þ52:0 for a 76% ee (c 1.40, EtOH) {lit.27
[a]D = +63 (EtOH)}. The ee value was measured by
HPLC (Column: Chiralcel OD-H. Eluent: hexane/i-pro-
panol 70:30).
˚ ˚
dimensions: a = 5.7750(1) A, b = 10.8140(2) A, c =
4.2.6. (R)-1-(2-Naphthylsulfinyl)-propan-2-one 6b. Mp
25
3
˚
˚
105–107 ꢁC (hexane/EtOH 4:1) ½aꢁD ¼ þ231:2 (c 0.99,
22.0340(4) A, cell volume = 1376.04(4) A , calculated
density = 1.570 g cmꢀ3, F(000) = 656. A total of 17,026
reflections was collected at 293(2) K in the h range of
2.10–30.06ꢁ, and they were corrected for Lorentz and
polarization effects, and for absorption effect (l =
31.30 cmꢀ1).38 The number of independent reflections
was 4011, with Rint = 0.0482, and omission of intensities
with I 6 2r(I) gave 3488 observed reflections employed
for the structure solution by Direct Methods applica-
tion.39 Afterwards, the structure was refined by a full
matrix least squares technique. All non-hydrogen atoms
were refined anisotropically, while the hydrogen atoms
were localized by difference Fourier map application.
CHCl3). The ee value was measured by HPLC (Column:
(R,R)-Whelk-O1, 5 lm. Eluent: hexane/i-propanol
60:40). 1H NMR (500 MHz, CDCl3) 7.89–7.87 (m,
1H), 7.65 (d, J = 8.5 Hz, 1H), 7.61–7.55 (m, 2H), 7.29–
7.23 (m, 3H), 3.61 (d, J = 13.8 Hz, 1H), 3.55 (d,
J = 13.8 Hz, 1H), 1.91 (s, 3H). 13C NMR (125 MHz,
CDCl3) 199.4, 139.8, 134.6, 132.8, 129.7, 128.5,
128.0, 127.4, 124.8, 119.5, 68.4, 32.0. Anal. Calcd for
C13H12O2S: C, 67.21; H, 5.21. Found C, 67.22; H, 5.32.
4.2.7. (R)-1-(p-Tolylsulfinyl)-propan-2-one 7b. Mp 37–
25
38 ꢁC (hexane), (lit.28 mp 38 ꢁC). ½aꢁD ¼ þ233:8 (c
1.15, CHCl3) {lit.29 [a]D = +216.7 (c 2, CHCl3)}. The
ee value was measured by HPLC (Column: (R,R)-
Whelk-O1, 5 lm. Eluent: hexane/i-propanol 70:30).
Final residuals were R = 0.0359 and wR = 0.0865,
2
using the weighting scheme w ¼ ½r2ðF o2Þþð0:0421PÞ þ
0:4116Pꢁꢀ1 (where P ¼ ðF o2 þ2F 2cÞ=3) and refining 215
parameters. In the final difference Fourier map, the
highest residual peak has density of 0.521 e Aꢀ3. The
˚
4.3. Stereoselective reduction of b-ketosulfoxides
(R)-configuration was attributed to both the sulfur and
the carbon stereocenter, as Flack parameter =
ꢀ0.004(9),41 calculated after least-squares refinement.
4.8 mL of a 0.5 M solution of ZnCl2 in THF was added
to a solution of 2 mmol of b-ketosulfoxide in 5 mL of
THF at room temperature. After 30 min, the tempera-
ture was lowered to ꢀ100 ꢁC and 4 mL of a solution
of DIBAL-H 1 M in the specified solvent (Table 2)
was added. The temperature was kept below ꢀ80 ꢁC
and the mixture allowed to react for 1 h. The reaction
mixture was quenched with methanol and the solvent re-
moved in vacuo. The residue was treated first with water
and then with a solution of NaOH 2.5 M. The mixture
was extracted three times with methylene chloride and
the extracts then dried and evaporated in vacuo. The
crude mixture was separated with column chromatogra-
phy on silica gel, eluent methylene chloride/ethyl acetate
7:3 for compounds 1c and 2c and only ethyl acetate for
compounds 6c and 7c. The stereoisomeric composition
4.3.3. (R,RS)-1-(2-Naphthylsulfinyl)-propan-2-ol 6c. Mp
25
108–110 ꢁC, (hexane/EtOH 15:1). ½aꢁD ¼ þ239 (c 1.00,
CHCl3) for an 86% de. The diastereoisomeric composi-
tion of the (R,RS)/(S,RS)-mixture was determined by
HPLC (Column: (R,R)-Whelk-O1, 5 lm. Eluent: hex-
ane/i-propanol 85:15). 1H NMR (500 MHz, CDCl3)
8.21–8.19 (m, 1H), 8.00 (d, J = 8.7 Hz, 1H), 7.96–7.90
(m, 2H), 7.65–7.59 (m, 3H), 4.58–4.51 (m, 1H), 3.92–
3.39 (m, 1H), 3.05 (dd, J = 9.1, J=13.2 Hz, 1H), 2.87
(dd, J = 2.5, J=13.2 Hz, 1H), 1.33 (d, J = 6.4 Hz, 3 H).
13C NMR (125 MHz, CDCl3) 140.7, 134.5, 132.8,
129.8, 128.5, 128.1, 128.0, 127.5, 124.5, 119.5, 65.2,
63.4, 23.3. Anal Calcd. for C13H14O2S: C, 66.64; H,
6.02. Found: C, 66.85; H, 6.34.
1
was measured by H NMR or by HPLC. In particular,
(R,R)-Whelk-O1 column was able to separate the four
stereoisomers.
4.3.4. (R,RS)-1-(p-Tolylsulfinyl)-propan-2-ol (7c). Col-
25
orless oil. ½aꢁD ¼ þ241:0 (c 1.00, CHCl3) for a 87% de
4.3.1. (R,RS)-1-Phenyl-2-(2-naphthylsulfinyl)-ethanol 1c.
Mp 128–129 ꢁC, (hexane/EtOH 16:1). (lit.35 racemic
{lit.36 [a]D = +273 for a > 90% de (c 1.1, CHCl3)}. The
diastereoisomeric composition of the (R,RS)/(S,RS)-
mixture was determined by HPLC (Column: (R,R)-
Whelk-O1, 5 lm. Eluent: hexane/i-propanol 80:20).
25
1c mp 124–126 ꢁC). ½aꢁD ¼ þ55:2 (c 0.98, CHCl3). The
diastereoisomeric composition was determined by
HPLC (Column: (R,R)-Whelk-O1, 5 lm. Eluent: hex-
ane/i-propanol 70:30).
Acknowledgements
4.3.2. (R,RS)-1-Phenyl-2-(p-bromophenylsulfinyl)-ethanol
25
2c. Mp 129–131 ꢁC, (hexane/EtOH 10:1). ½aꢁD ¼ þ72:6
This work was financially supported in part by the
MIUR Rome (National Project ÔStereoselezione in Sin-
tesi Organica. Metodologie e ApplicazioniÕ), by the
FIRB project (ÔProgettazione, preparazione e valutazi-
(c 0.99, CHCl3). The diastereoisomeric composition was
determined by HPLC (Column: (R,R)-Whelk-O1, 5 lm.
Eluent: hexane/i-propanol 70:30). H NMR (500 MHz,
1

C. Cardellicchio et al. / Tetrahedron: Asymmetry 17 (2006) 223–229
229
20. Capozzi, M. A. M.; Cardellicchio, C.; Naso, F. Tetra-
hedron: Asymmetry 2004, 15, 1471–1476.
21. Cardellicchio, C.; Fracchiolla, G.; Naso, F.; Tortorella, P.
Tetrahedron 1999, 55, 525–532.
one biologica e farmacologica di nuove molecole
organiche quali potenziali farmaci innovativiÕ) and by
the University of Bari.
22. Banfield, J. E.; Davies, W.; Gamble, N. W.; Middleton, S.
J. Chem. Soc. 1956, 4791–4799.
References
23. Ratts, K. W. J. Org. Chem. 1972, 37, 848–851.
24. Wagner, P. J.; Lindstrom, M. J. J. Am. Chem. Soc. 1987,
109, 3062–3067.
25. Miocque, M.; Moskowitz, H.; Blanc-Guenee, J.; Saint-
Marc, A. M.; Raynaud, G.; Thomas, J.; Gouret, C.;
Pourrias, B. Chim. Ther. 1972, 283–286; Chem. Abstr. 77,
164281.
´
1. Solladie, G. Optically Active b-Ketosulfoxides in Asym-
metric Synthesis. In Advanced Asymmetric Synthesis;
Stephenson, G. R., Ed.; Chapman and Hall: London,
1996; pp 60–92.
´
2. Solladie, G. Synthesis 1981, 185–196.
3. Carreno, M. C. Chem. Rev. 1995, 95, 1717–1760.
˜
4. Asensio, G.; Cuenca, A.; Rodriguez, N.; Medio-Simon,
M. Tetrahedron: Asymmetry 2003, 14, 3851–3855.
5. Breitschuh, R.; Seebach, D. Synthesis 1992, 1170–1178.
6. Singh, S.; Kumar, S.; Chimni, S. S. Tetrahedron: Asym-
metry 2001, 12, 2457–2462.
26. Nishio, M. Chem. Pharm. Bull. 1969, 17, 262–273.
27. El Ouazzani, H.; Khiar, N.; Fernandez, I.; Alcudia, F. J.
Org. Chem. 1997, 62, 287–291.
`
28. Solladie, G.; Ghiatou, N. Tetrahedron: Asymmetry 1992,
1, 33–38.
7. Kunieda, N.; Suzuki, A.; Kinoshita, M. Bull. Chem. Soc.
Jpn. 1981, 54, 1143–1150.
8. Annunziata, R.; Cinquini, M.; Cozzi, F. J. Chem. Soc.,
Perkin Trans. 1 1979, 1687–1690.
29. Iwata, C.; Maezaki, N.; Hattori, K.; Fujita, M.; Moritani,
Y. Chem. Pharm. Bull. 1993, 41, 339–345.
30. Buist, P. H.; Marecak, D.; Holland, H. L.; Brown, F. M.
Tetrahedron: Asymmetry 1995, 6, 7–11.
9. Andersen, K. K. Stereochemistry, Conformation, and
Chiroptical Properties of Sulfoxides. In The Chemistry of
Sulphones and Sulphoxides; Patai, S., Rappoport, Z.,
Stirling, C., Eds.; John Wiley and Sons: New York,
1988; pp 55–94.
´
´
31. Solladie, G.; Greck, C.; Demailly, G.; Solladie-Cavallo, A.
Tetrahedron Lett. 1982, 23, 5047–5050.
´
´
32. Solladie, G.; Frechou, C.; Demailly, G.; Greck, C. J. Org.
Chem. 1986, 51, 1912–1914.
´
33. Solladie, G.; Maestro, M. C.; Rubio, A.; Pedregal, C.;
10. Bolm, C.; Muniz, K.; Hildebrand, J. P. Oxidations of
˜
Carreno, M. C.; Garcia Ruano, J. L. J. Org. Chem. 1991,
˜
Sulfides. In Comprehensive Asymmetric Catalysis; Jacob-
sen, E. N., Pfalz, A., Yamamoto, H., Eds.; Springer:
Berlin, 1999; pp 697–710.
56, 2317–2322.
´
34. Solladie, G.; Demailly, G.; Greck, C. J. Org. Chem. 1985,
50, 1552–1554.
11. Dunach, E.; Kagan, H. B. Nouv. J. Chim. 1985, 9, 1–3.
12. Davis, F. A.; ThimmaReddy, R.; Weismiller, M. C. J. Am.
Chem. Soc. 1989, 111, 5964–5965.
13. Bolm, C. Coord. Chem. Rev. 2003, 237, 245–256.
14. Lattanzi, A.; Bonadies, F.; Schiavo, A.; Scettri, A.
Tetrahedron: Asymmetry 1998, 9, 2619–2625.
15. Capozzi, M. A. M.; Cardellicchio, C.; Naso, F. Eur. J.
Org. Chem. 2004, 1855–1863.
16. Capozzi, M. A. M.; Cardellicchio, C.; Naso, F.; Rosito, V.
J. Org. Chem. 2002, 67, 7289–7294.
17. Capozzi, M. A. M.; Cardellicchio, C.; Naso, F.; Spina, G.;
Tortorella, P. J. Org. Chem. 2001, 66, 5933–5936.
18. Capozzi, M. A. M.; Cardellicchio, C.; Naso, F.; Torto-
rella, P. J. Org. Chem. 2000, 65, 2843–2846.
19. Capozzi, M. A. M.; Cardellicchio, C.; Fracchiolla, G.; Naso,
F.; Tortorella, P. J. Am. Chem. Soc. 1999, 121, 4708–4709.
35. Oswald, A. A. J. Org. Chem. 1961, 26, 842–846.
36. Asensio, G.; Gavina, P.; Cuenca, A.; Ramirez de Arellano,
˜
M. C.; Domingo, L. R.; Medio-Simon, M. Tetrahedron:
Asymmetry 2000, 11, 3481–3493.
37. Brunet, E.; Garcia Ruano, J. L.; Hoyos, M. A.; Rodri-
guez, J.; Prados, P.; Alcudia, F. Org. Magn. Res. 1983, 21,
643–648.
38. Blessing, R. H. Acta Crystallogr. A 1995, 51, 33–38.
39. Altomare, A.; Burla, M. C.; Camalli, M.; Cascarano, G.
L.; Giacovazzo, C.; Guagliardi, A.; Moliterni, A. G. G.;
Polidori, G.; Spagna, R. J. Appl. Crystallogr. 1999, 32,
115–119.
40. Sheldrick, G. M. SHELXL-97. Program for the Refine-
ment of Crystal Structures. University of Go¨ttingen,
Germany, 1997.
41. Flack, H. D. Acta Cryst. A 1983, 39, 876–881.