New insights into the reduction of β,δ-diketo-sulfoxides

Article abstract of DOI:10.1016/S0957-4166(03)00125-3

New developments in the reduction of β,δ-diketo-sulfoxides, a reaction that affords important key intermediates for total synthesis, are described. We showed without ambiguity using NMR experiments, that the β-carbonyl group is totally enolised. This result is inconsistent with the previous hypothesis, which supposed the other tautomer (enolisation at the δ-position) as the major one. We propose a rationale to explain the side reactions occurring during the reduction of unprotected β,δ-diketo-sulfoxides and showed that judicious protection of the δ-carbonyl group gave all diastereoisomers of β-hydroxy-δ-ketosulfoxides.

Full text of DOI:10.1016/S0957-4166(03)00125-3

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 14 (2003) 1291–1301
New insights into the reduction of b,d-diketo-sulfoxides
Gilles Hanquet,* Xavier J. Salom-Roig, Laurence Gressot-Kempf, Steve Lanners and Guy Solladie´*
Laboratoire de Ste´re´ochimie associe´ au CNRS, ECPM, Universite´ Louis Pasteur, 25 rue Becquerel, 67087 Strasbourg, France
Received 21 January 2003; accepted 30 January 2003
Abstract—New developments in the reduction of b,d-diketo-sulfoxides, a reaction that affords important key intermediates for
total synthesis, are described. We showed without ambiguity using NMR experiments, that the b-carbonyl group is totally
enolised. This result is inconsistent with the previous hypothesis, which supposed the other tautomer (enolisation at the d-position)
as the major one. We propose a rationale to explain the side reactions occurring during the reduction of unprotected
b,d-diketo-sulfoxides and showed that judicious protection of the d-carbonyl group gave all diastereoisomers of b-hydroxy-d-keto-
sulfoxides. © 2003 Elsevier Science Ltd. All rights reserved.
1. Introduction
that chelated species and intramolecular hydride trans-
fer are important factors for the control of the
diastereoselectivity.3,4
In 1977 we published1 the first asymmetric aldol-type
condensation of a-sulfinyl ester enolates giving b-
hydroxy esters with high enantioselectivity (ee >85%).
Since that time the use of chiral sulfoxides in asymmet-
ric synthesis has increased greatly.2
b,d-Diketosulfoxides, which are easily prepared5 from
the corresponding b-ketoesters or b-diketones, are
excellent intermediates for the enantio- and diastereo-
selective synthesis of syn- and anti-1,3-diols.6 It was
shown that the b-carbonyl group could be reduced as in
any b-ketosulfoxide with high stereoselectivity and that
the resulting b-hydroxy-d-ketosulfoxide could also be
reduced to the corresponding syn- or anti-1,3-diols
following literature procedures (Scheme 2).
One of the most useful results we obtained later was the
stereoselective reduction of b-ketosulfoxides.3 Their
reduction with DIBAL-H and ZnCl2/DIBAL-H
occurred with the opposite diastereoselectivity (>95%)
(Scheme 1). Most of the experimental results showed
Scheme 1.
* Corresponding authors. Tel.: 33-3/90242746; fax: 33-3/90242742; e-mail: ghanquet@chimie.u-strasbg.fr
0957-4166/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0957-4166(03)00125-3

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G. Hanquet et al. / Tetrahedron: Asymmetry 14 (2003) 1291–1301
Scheme 2.
Despite several applications to the total synthesis of
natural products,6 this methodology is limited by the
poor yields obtained for the first reduction when the
d-carbonyl group is not protected. Furthermore, the
ZnX2-mediated reduction leading to the opposite
configuration of the b-hydroxy group was not efficient
in the case of b,d-diketosulfoxides as it only gave
degradation products. No studies on the reduction of
d-protected b,d-diketosulfoxides using ZnX2/DIBAL-H
system have been described so far.
forms are possible. So far, the tautomer II, with the
d-carbonyl enolised, has been supposed to be the major
one in solution (Scheme 2). The enol form of the
b-carbonyl group in tautomer I would impede its reduc-
tion to the alcohol.
In this regard, we now report the results we obtained in
the reduction of d-protected b,d-diketosulfoxides to b-
hydroxy-d-ketosulfoxides in both absolute configura-
tions. Accordingly, to gain a better understanding of
the factors that govern the diastereoselective reduction
of unprotected b,d-diketosulfoxides we undertook a
study of this reduction and the keto-enol tautomerism
of different b,d-diketosulfoxides.
Figure 1.
This hypothesis is in agreement with previous results
observed in the reduction of 4-sulfinyl-3-oxobutyric
esters 6.10 In such substrates, the enol tautomer was
present in a range of 20–30% depending on the nature
of the solvent and the substrate itself, but attributed
without any ambiguity at the b-position by NOESY
correlation experiments. As the reduction of butyrates 6
using 1.2 equiv. of DIBAL-H in THF provided 20–30%
of starting material, it was supposed that the enol
tautomer led to unreactive aluminium enolates as inter-
mediates (Scheme 4).
2. Results and discussion
The b,d-diketosulfoxides 1a–h (Table 1) were prepared
in high yields either from b-diketone 2a, b,d-diketo-
esters 2e,f and menthyl-p-tolylsulfinate 3, b-ketoester 2b
and methyl-p-tolylsulfoxide 4 or from esters 2c,d,g,h
and 1-(p-tolylsulfinyl)propan-2-one 5 (Scheme 3). It
should be noted that chromatographic purification of
b,d-diketosulfoxides must be carried out on silica gel
free of metallic impurities.9
We tried to reduce the b-carbonyl group in the b,d-
diketosulfoxides 1a–h with DIBAL-H using the previ-
ously described conditions. Table 1 summarises the
results obtained. Several notable features are evident: (i)
2 equiv. of DIBALl-H were necessary, probably due to
an acid–base reaction between the hydride and the
enolic proton; (ii) Only one diastereomer of the result-
ing b-hydroxy-d-ketosulfoxide 7a–h was detected by
The 1H NMR spectra of b,d-diketosulfoxides 1a–g
showed clearly that one of the two carbonyl groups is
totally enolised (a singlet corresponding to one vinylic
proton, 85% for 1h). These spectra also show one AB
pattern corresponding to the methylenic protons a to
the sulfoxide group (Fig. 1). Thus, two tautomeric
1
1
200 MHz H NMR of the crude product; (iii) The H
NMR of the crude product showed that all the starting
material had reacted. However, the yield of the isolated
Table 1. Reduction of b,d-diketosulfoxides 1a–h to the corresponding b-hydroxy-d-ketosulfoxides 7a–h by Dibal-H in THF
R
Sulfoxide configuration
7 (Isolated yields); configuration
1a
1b
1c
1d
1e
1f
CH3
(+)-(R)
(−)-(S)
(+)-(R)
(+)-(R)
(+)-(R)
(+)-(R)
(+)-(R)
(−)-(S)
35; RS,2S
33; SS,2R
35; RS,2S
33; RS,2S
45; RS,2S
44; RS,2S
52; RS,2S
33; RS,2S
CH3CH2CH2
TBSO(CH2)4
EtO2C(CH2)3
EtO2CCH2
MeO2CCH2
BnOCH2
1g
1h
tBuO2CCH(Me)CO(CH2)2

G. Hanquet et al. / Tetrahedron: Asymmetry 14 (2003) 1291–1301
1293
Scheme 3.
b-hydroxy-d-ketosulfoxide 7a–h, after purification by
column chromatography using demetallated silica gel,
was only 33–52%. Thus, we observed hydrogenolysis of
the CꢀS bond leading to the corresponding b-diketones
2a–h in 40–50% yield and the p-tolyldisulfide 8; (iv)
Even more intriguing was the improvement in the yield
of the isolated b-hydroxy d-ketosulfoxides 7e–g from
1e–g bearing electron-withdrawing groups in the h
position.
Figure 2. HMBC (1H–13C NMR) of b,d-diketosulfoxide 1b
and corresponding correlations observed.
Additionally, we prepared the d-enol-methyl ether 10a
and 10b11 of the corresponding sulfoxides 1a and 1b in
73 and 65% yields by addition of 2 equiv. of the (R)- or
(S)-p-tolylmethylsulfoxide lithium anion to a THF
solution of 9a and 9b, respectively12 at −78°C. Reduc-
tion of 10a and 10b, in which the enolised carbonyl is
fixed in the d-position, afforded the b-hydroxysulfox-
ides 11a–b and 12a–b (80% conversion) as 6/4 (2S,RS)/
(2R,RS) and 7/3 (2R,SS)/(2S,SS) diastereomeric
mixtures respectively using DIBAL-H. Pure (2S,RS)-
12a and (2R,SS)-12b in 81 and 63% yields was isolated
using ZnI2/DIBAL-H system. Assignment of the
Additionally, the reduction of the b,d-diketosulfoxides
1a–h using the system ZnX2/DIBAL-H, in order to
obtain the opposite absolute configuration of the
stereogenic b-hydroxylic centre, led only to degradation
products and/or a mixture of diastereoisomers in low
yields.
We first carefully examined the enolate structure in the
starting b,d-diketosulfoxides 1a,b,f,g using NMR exper-
iments. Thus, the HMBC spectrum (1H–13C coupling)
of compound 1b for example in CDCl3 showed a
correlation between C-2 and the AB-system of H-1 but
not of H-5. Besides, a correlation of C-4 with C-5 and
C-6 is also observed. No correlation between C-4 and
H-1 can be distinguished. These observations would
point to consider the tautomer I as the major form in
the I–II equilibrium (Fig. 2). The same correlations are
observed when the HMBC spectra are recorded in
THF-d8 or toluene-d6.
1
configuration at C-2 based on the H NMR spectra13
was confirmed by chemical correlation with the known
d-keto-b-hydroxy-sulfoxides 7a,b and 16a,b prepared by
acidic treatment of compounds 11a,b and 12a,b. Dike-
tone 2a-b and p-tolyldisulfide 8 coming from the
hydrogenolysis of CꢀS bond usually observed during
1
the reduction of 1a–g, were not present in H NMR of
the crude reaction mixture (Scheme 5).
Scheme 4.

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G. Hanquet et al. / Tetrahedron: Asymmetry 14 (2003) 1291–1301
This last experiment suggested that the presence of the
two side products 2 and 8 in the reduction of b,d-dike-
tosulfoxides 1a–h was dependent on the position of the
enol function.
ment in the yield of the b-hydroxy-d-ketosulfoxide 7e–
g.
In protecting the d-carbonyl group one can avoid the
formation of any enol tautomer. During our work on
the asymmetric synthesis of Pamamycin-607,15 we have
used a dioxolane as protecting group for the d-carbonyl
as previously mentioned in literature.16
In fact, we propose that under the reaction conditions
(THF, −78°C) even if the tautomer I is the major one,14
the minor II is also present. The initially formed ratio
could however be altered by addition of DIBAL-H to
the mixture which could thus induce an irreversible
reaction predominantly with the minor but more reac-
tive tautomer II. In both cases, addition of the first
equivalent of DIBAL-H would lead, after acid–base
reaction, to the aluminium–enolates A and B. While in
the case of A, addition of a second equivalent of
DIBAL-H led to the b-hydroxy-d-ketosulfoxide, in the
case of B, the b-carbonyl was not available and after
chelation of aluminium to the basic oxygen of the
sulfoxide, an intramolecular hydride transfer took place
with a CꢀS bond cleavage and the formation of the
b-diketone 2 and p-tolylsulfenic acid which dimerised
to p-tolyldisulfide 8 (Scheme 6).
Thus, by treatment of the b-keto-d-dioxolanesulfoxide
13 prepared as previously described15 with 2.5 equiv. of
DIBAL-H in THF at −78°C, we obtained the corre-
sponding b-hydroxy-d-dioxolanesulfoxide 14 with a de
higher than 95%.17 The S configuration of 14 was
assigned according to the expected stereochemical
course for DIBAL-H reduction of b-ketosulfoxides.13
No degradation products were observed in this step.
Hydrolysis of the ketal group was accomplished with-
out prior isolation18 of 14 yielding enantiomerically
pure b-hydroxy-d-ketosulfoxide 7b in 80% yield from 13
(Scheme 7).
The (SS,2S)-diastereomer 16b was prepared in 77%
yield by reduction of 13 with ZnI2/DIBAL-H and sub-
sequent hydrolysis of the ketal group.
According to this hypothesis, the presence of elec-
tronegative groups in 1e–g would displace the keto-enol
equilibrium to the tautomer II leading to an improve-
Scheme 5. Reaction conditions: (a) K2CO3, DMSO, Me2SO4; (b) (+)-(R) or (−) (S)-methyl-p-tolyl-sulfoxide (2 equiv.), LDA (2
equiv.), THF, −78°C; (c) Dibal-H 2.5 equiv., 90% (conversion), THF, −78°C; (d) ZnI2, Dibal-H 2.5 equiv., THF, −78°C.

G. Hanquet et al. / Tetrahedron: Asymmetry 14 (2003) 1291–1301
1295
Scheme 6.
Scheme 7.

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G. Hanquet et al. / Tetrahedron: Asymmetry 14 (2003) 1291–1301
We would also like to point out that the absence of
degradation products allowed the purification of 14 and
15 simply by washing the crude products with ether
instead of the usual laborious purification by column
chromatography on metal-free silica gel.
propylamine (0.48 ml; 3.5 mmol; 3.2 equiv.) and n-BuLi
(2.2 ml of a 1.6 M solution in hexane, 3.56 mmol, 3.3
equiv.)] in THF (25 ml) at −78°C, was added dropwise
a solution of (−)-(S)-methyl-p-tolylsulfoxide (0.183 g;
1.19 mmol; 1.1 equiv.) in THF (3 ml). After stirring for
1 h at −78°C, ethyl butyrylacetate (0.17 g; 1.08; 1
equiv.) was added and the resulting solution was stirred
at rt for 4 h. The reaction mixture was then hydrolysed
with saturated NH4Cl (50 ml) and acidified to pH 3–4
with aqueous 10% HCl. The phases were separated and
the aqueous layer was extracted with AcOEt (3×50 ml).
The combined organic layers were washed with brine,
dried (MgSO4) and concentrated. The crude product
was purified by column chromatography on metal-free
silica gel (hexane:ethyl acetate, 4:1) to afford 1b as a
beige solid (0.190 g; 67%). Rf=0.59 (ethyl acetate/
dichloromethane, 1:1). [h]2D0=−131 (c 0.5, acetone).
3. Conclusions
In conclusion, we have demonstrated that b,d-diketo-
sulfoxides have the b-carbonyl enolised in solution.
This fact leads to the formation of side-products by
reaction with DIBAL-H or ZnX2/DIBAL-H. With the
d-carbonyl functionality appropriately protected (as the
enol ether or the dioxolane) side-reactions can be
avoided in the reduction of b,d-diketosulfoxides
improving yields, facilitating purification, and giving
for the first time a high yielding method to access the
1
Mp=44–46°C. H NMR (200 MHz; CDCl3): l=0.94
(2S,SS)- or (2R,RS)-b-hydroxy-d-ketosulfoxides.
A
(t, 3H, J=7.3 Hz), 1.64 (sext., 2H, J=7.3 Hz), 2.28 (t,
2H, J=7.3 Hz), 2.43 (s, 3H), 3.65 (AB system of the
enol form, 1.9H, JAB=12.8 Hz, Dw=30.3 Hz), 3.93 (AB
system of the keto form, 0.1H, JAB=13.5 Hz, Dw=30.8
Hz), 5.53 (s, 0.95H), 7.33 (B fragment of an (AB)2
system, 2H, JAB=8.4 Hz, Dw=41 Hz), 7.54 (A frag-
ment of an (AB)2 system, 2H, JAB=8.4 Hz, Dw=41
Hz), 14.20 (broad s, 0.95H, enol) ppm. 13C NMR (50
MHz, CDCl3): l=13.8, 19.0, 21.6, 40.6, 65.6, 101.9,
124.2, 130.1, 140.2, 142.2, 181.2, 196.5 ppm. IR (film):
w=3100–3000, 2980–2800, 1640–1580 cm−1. Anal. calcd
for C14H18O3S (266.35): C, 63.13; H, 6.81. Found: C,
63.00; H, 6.93%.
detailed study on the reduction of several functionalised
d-enol methyl ether b-ketosulfoxides is now under
investigation.
4. Experimental
4.1. General
All reactions were carried out under dry argon. Stan-
dard syringe and cannula techniques were employed for
transfer of dry solvents and air- or moisture-sensitive
reagents. Tetrahydrofuran (THF) was distilled under
argon from sodium/benzophenone, dichloromethane
from phosphorus pentoxide, diisopropylamine from
KOH. n-Butyllithium was purchased as a 1.6 M solu-
tion in hexane. Starting materials not mentioned below
were commercially available. Enantiopure menthyl-p-
tolylsulfinates 3 and methyl-p-tolylsulfoxides 4 in both
configurations were prepared according to previously
described methods.19 Reactions were monitored by thin
layer chromatography on silica gel plates (Merck
60F254) and stained by use of p-anisaldehyde. Merck
silica gel 60H was used for column chromatography
and demetallated following a known procedure20 when
required. NMR spectra were obtained at 200 MHz (1H)
or 50 MHz (13C) and 400 MHz (1H) or 10 MHz (13C)
on Bruker AC 200 and AC 400 instruments, with
deuterochloroform as solvent. Chemical shifts (l) are
given in ppm relative to tetramethylsilane (l=0 ppm)
or to residual protons in the solvent as internal stan-
dard. IR spectra were recorded with a Perkin–Elmer
Spectrum One, and absorption bands are given in cm−1.
The Microanalyses Service of the Strasbourg Faculty of
Chemistry performed microanalyses.
4.4. Methyl 5-(tert-butyldimethylsilyloxy)pentanoate, 2c
A solution of d-valerolactone (8 g; 79.9 mmol; 1 equiv.)
in MeOH (260 ml) was treated with 10 drops of concen-
trated H2SO4 and heated under reflux for 21 h. The
mixture was cooled to rt and imidazole (275 mg) was
added. After 15 min of stirring, methanol was evapo-
rated and the resulting oil was suspended in 50 ml of
DMF. Then imidazole (13.6 g; 0.2 mol; 1.5 equiv.) and
TBSCl (18.1 g; 0.12 mol; 1.5 equiv.) were added and the
mixture was stirred for 21 h at rt. The reaction mixture
was hydrolysed at 0°C with H2O (50 ml) and diluted
with ether (50 ml). The stirring was continued until a
clear phase-separation occurred. The aqueous layer was
extracted with ether (2×50 ml). The combined organic
phases were washed with saturated NH4Cl (3×50 ml)
and brine (2×50 ml), dried (MgSO4), and concentrated.
The resulting yellow oil was purified by column chro-
matography on silica gel (hexane/ethyl acetate, 9:1) to
afford methyl-5-(t-butyldimethylsilyloxy)pentanoate (10
g; 80%) as a yellow oil. Rf=0.52 (ethyl acetate/hexane,
4.2. (+)-(RS)-1-(p-Tolylsulfinyl)-2,4-pentanedione, 1a
1
1:9). H NMR (200 MHz; CDCl3): l=−0.05 (s, 6H),
0.8 (s, 9H), 1.37–1.70 (m, 4H), 2.24 (t, 2H, J=7 Hz),
3.53 (t, 2H, J=6 Hz), 3.56 (s, 3H). 13C NMR (50 MHz,
CDCl3): l=−5.4, 18.2, 21.4, 25.9, 32.1, 33.7, 51.3, 62.6,
173.9 ppm. IR (film): w=2960–2860, 1740–1720 cm−1.
Anal. calcd for C12H26O3Si (246.423): C, 58.49; H,
10.63. Found: C, 58.59; H, 10.74%.
The b,d-diketosulfoxyde 1a was prepared according to
literature methods5a
4.3. (−)-(SS)-1-(p-Tolylsulfinyl)-2,4-heptanedione, 1b
To a solution of LDA [prepared at −78°C from diiso-

G. Hanquet et al. / Tetrahedron: Asymmetry 14 (2003) 1291–1301
1297
L
-tartrate dihydrate (100 ml) was added. The stirring
4.5.
(+)-(RS)-1-(p-Tolylsulfinyl)-2,4-dioxo-8-(t-butyl-
was continued until a clear phase-separation occurred.
The aqueous layer was acidified to pH 5–6 with a 10%
solution of H2SO4 and extracted with AcOEt (3×100
ml). The combined organic layers were washed with
brine, dried (MgSO4), and concentrated. The crude
product was purified by column chromatography on
metal-free silica gel (gradient hexane/dichloromethane,
4:1 to dichloromethane 100% for apolar products and
dichloromethane/ethyl acetate, 4:1 to ethyl acetate
100% for the polar ones) to afford 7a as a beige solid
dimethylsilyloxy)octane, 1c
To a solution of LDA [prepared at −15°C from diiso-
propylamine (3.8 ml; 27 mmol; 4.4 equiv.) and n-BuLi
(17 ml of a 1.55 M solution in hexane; 26.4 mmol; 4.3
equiv.) in THF (30 ml)] was added (+)-(R)-1-(p-tolyl-
sulfinyl)-2-propanone 55a (2.5 g; 12.9 mmol; 2.1 equiv.)
in THF (20 ml) at −15°C via cannula. After stirring for
2 h at 0°C, the resulting orange solution was added
dropwise to a solution of methyl-5-(t-butyldimethylsilyl-
oxy)pentanoate 2c (1.51 g; 6.1 mmol; 1 equiv.) in THF
(20 ml) at −78°C. The reaction mixture was stirred for
1.5 h at −78°C and hydrolysed with saturated NH4Cl
(140 ml) and acidified to pH 3 with 10% HCl. After
extraction with ethyl acetate (3×100 ml), the organic
phase was dried (MgSO4) and the solvent evaporated.
Finally the crude product was purified by column chro-
matography on metal free silica gel (ethyl acetate/
dichloromethane, 9:1) to afford 1c as a beige solid (2 g,
80%). Rf=0.37 (ethyl acetate/dichloromethane, 9:1).
(177.5
mg,
35%).
Rf=0.18
(ethyl
acetate/
dichloromethane, 1:1). [h]2D0=+240 (c 2, acetone). Mp=
94–95°C. 1H NMR (200 MHz; CDCl3): l=2.12 (s, 3H),
2.37 (s, 3H), 2.65 (AB fragment of an ABX system
degenerated in A2, 2H), 2.85 (AB fragment of an ABX
system, 2H, JAX=9.5 Hz, JBX=3 Hz, JAB=13 Hz,
Dw=42 Hz), 4.46 (s large, 1H), 4.60 (m, X of an ABX
system, 1H), 7.39 ((AB)2 system, 4H, JAB=8 Hz, Dw=
38 Hz) ppm. 13C NMR (50 MHz, CDCl3): l=21.3,
30.7, 49.4, 62.2, 62.9, 129.9, 123.9, 141.6, 139.7, 207.5
ppm. Anal. calcd for C12H16O3S (240.32): C, 59.97; H,
6.71. Found: C, 59.51; H, 6.82%.
[h]2D0=+167 (c 1, CHCl3). H NMR (200 MHz; CDCl3):
l=0.04 (s, 6H), 0.89 (s, 9H), 1.44–1.72 (m, 4H), 2.32 (t,
2H, J=7 Hz), 2.42 (s, 3H), 3.63 (AB system, 2H,
1
4.8. (+)-(RS,2S)-1-(p-Tolylsulfinyl)-8-(t-butyldimethyl-
silyloxy)-2-hydroxy-4-pentanone, 7c
JAB=12.5 Hz, Dw=29 Hz), 3.61 (t, 2H, J=6 Hz), 5.53
(s, 1H), 7.43 ((AB)2 system, 4H, JAB=8 Hz, Dw=41 Hz)
ppm. 13C NMR (50 MHz, CDCl3): l=−5.4, 18.2, 21.4,
21.8, 25.9, 32.1, 38.3, 62.6, 65.5, 101.8, 124, 130, 139.8,
142.2, 181, 196.2 ppm. IR (film): w=3040–2840, 1600,
1090 cm−1. Anal. calcd for C21H34O4SSi (410.645): C,
61.42; H, 8.35. Found: C, 61.38; H, 8.37%.
Compound 7c (275 mg; 35%) was isolated as a beige
solid from the starting material 1c (0.783 g; 1.9 mmol;
1 equiv.), by the method described for 7a. Rf=0.13
(ethyl acetate/dichloromethane, 1:4). Mp=64–65°C.).
[h]2D0=+87 (c 1.14, chloroform). H NMR (200 MHz;
1
CDCl3): l=0.005 (s, 6H), 0.85 (s, 9H), 1.41–1.65 (m,
4H), 2.39 (s, 3H), 2.41 (t, 2H, J=7 Hz), 2.63 (AB
fragment of an ABX system degenerated in A2, 2H),
2.87 (AB fragment of an ABX system, 2H, JAX=9.5
Hz, JBX=2.5 Hz, JAB=13 Hz, Dw=49 Hz), 3.56 (t, 2H,
J=6 Hz), 4.28 (s large, 1H), 4.60 (m, X of an ABX
system, 1H), 7.41 ((AB)2 system, 4H, JAB=8 Hz, Dw=
37 Hz) ppm. 13C NMR (50 MHz, CDCl3): l=−5.5, 18,
19.7, 21.2, 25.7, 31.9, 43.1, 48.4, 62.5, 62.8, 129.8, 133.7,
141.3, 139.8, 209.4 ppm. IR (film): w=3580–3260, 1705,
1100 cm−1. Anal. calcd for C21H36O4SSi (412.66): C,
61.12; H, 8.79. Found: C, 60.94; H, 8.92%.
4.6. Ethyl (RS)-5,7-dioxo-8-(p-tolylsulfinyl)octanoate, 1d
Compound 1d (0.450 g; 45%) was isolated as an orange
oil from the starting materials (+)-(R)-1-(p-tolylsulfi-
nyl)-2-propanone 55a (1.16 g; 5.9 mmol; 2 equiv.) and
ethyl glutarate 2d (0.54 ml; 2.95 mmol; 1 equiv.), by the
method described for 1c. Rf=0.56 (ethyl acetate/
1
dichloromethane, 1:1). H NMR (200 MHz; CDCl3):
l=1.20 (t, 3H, J=7 Hz), 1.84 (m, 2H), 2.27 (t, 2H,
J=7 Hz), 2.30 (t, 2H, J=7 Hz), 2.36 (s, 3H), 3.59 (AB
system, 2H, JAB=13 Hz, Dw=24 Hz), 4.07 (q, 2H, J=7
Hz), 5.47 (s, 1H), 7.37 ((AB)2 system, 4H, JAB=8 Hz,
Dw=40 Hz), 14.20 (broad s, 1H) ppm. 13C NMR (50
MHz, CDCl3): l=14, 20.2, 21.2, 33, 37.5, 60.2, 65,
101.8, 129.8, 123.9, 142, 139.6, 172.6, 180.4, 195.3 ppm.
4.9. (+)-(RS,5S)-Ethyl-5-oxo-7-hydroxy-8-(p-tolylsulfi-
nyl)-octanoate, 7d
Compound 7d (65 mg; 33%) was isolated as a yellow oil
from the starting material 1d (0.196 g; 0.58 mmol; 1
equiv.), by the method described for 7a. Rf=0.28 (ethyl
acetate/dichloromethane, 1:1). 1H NMR (200 MHz;
CDCl3): l=1.23 (t, 3H, J=7 Hz), 1.85 (q, 2H, J=7
Hz), 2.28 (t, 2H, J=7 Hz), 2.40 (s, 3H), 2.48 (t, 2H,
J=7 Hz), 2.70 (AB fragment of an ABX system degen-
erated in A2, 2H), 2.87 (AB fragment of an ABX
system, 2H, JAX=9.5 Hz, JBX=3 Hz, JAB=13.5 Hz,
Dw=56 Hz), 4.09 (q, 2H, J=7 Hz), 4.23 (d, 1H, J=3.5
Hz), 4.61 (m, X of an ABX system, 1H), 7.42 ((AB)2
system, 4H, JAB=8 Hz, Dw=36 Hz) ppm. 13C NMR
(50 MHz, CDCl3):14.2, 19.2, 21.1, 34.2, 42.35, 48.97,
51.89, 62.04, 69.88, 129.1, 132.9, 134.8, 142.2, 173.88,
207.3 ppm.
The preparation of 1e,6b 1f,6b 1g6c and 1h6a has been
described elsewhere.
4.7. (+)-(RS,2R)-1-(p-Tolylsulfinyl)-2-hydroxy-4-penta-
none, 7a
To a solution of b,d-diketosulfoxide 1a (0.503 g; 2.11
mmol; 1 equiv.) in THF (30 ml) a solution of DIBAL-
H (4.3 ml of a solution 1 M in toluene; 4.22 mmol; 2
equiv.) was added dropwise at −78°C. Stirring was
continued for 20 min at −78°C before adding MeOH
(15 ml) and then the solution was stirred for 30 min at
rt. The solvent was evaporated and the residue was
dissolved in AcOEt (100 ml), and saturated disodium

1298
G. Hanquet et al. / Tetrahedron: Asymmetry 14 (2003) 1291–1301
The preparation of 7e,6b 7f,6b 7g14 and 7h6a has been
l=2.29 (s, 3H), 2.51 (s, 3H), 3.67 (s, 3H), 3.72 (B
fragment of an AB system, 1H, JAB=21 Hz, Dk=55
Hz), 3.92 (A fragment of an AB system, 1H, JAB=21
Hz, Dk=55 Hz), 5.51 (s, 1H), 7.28 (B fragment of an
(AB)2 system, 2H, JAB=8 Hz, Dk=68 Hz), 7.51 (A
fragment of an (AB)2 system, 2H, JAB=8 Hz, Dk=68
Hz) ppm. 13C NMR (100 MHz, CDCl3): l=20.66,
21.81, 34.9, 56.29, 70.82, 99.74, 124.6, 130.3, 140.6,
142.4, 176.3, 188.81 ppm. IR (film): w=1660–1640,
1620–1580 cm−1.
described elsewhere.
4.10. (E)-Ethyl 3-methoxy-2-butenoate, 9a
To a solution of ethyl-acetoacetate (2 g; 0.016 mol; 1
equiv.) in DMSO (50 ml) was added K2CO3 (3.17 g;
0.023 mol; 1.5 equiv.). After stirring for 1 h at rt,
Me2SO4 (1.30 ml; 0.021 mol, 1.3 equiv.) was added. The
reaction was stirred 48 h and hydrolysed with water (50
ml) and diluted with ethyl acetate (50 ml). The aqueous
layer was extracted with ethyl acetate (3×50 ml) and the
combined organic layers were washed with brine (100
ml), dried (MgSO4) and concentrated. The crude oil
was purified by column chromatography on silica gel
(with hexane/ethyl acetate, 9:1 as eluent) to afford a
colourless oil 9a (1.63 g, 71%). Rf=0.74 (ethyl acetate/
4.13. (−)-(E,RS)-1-(p-Tolylsulfinyl)-4-methoxy-3-hexene-
2-one, 10b
Compound 10b (0.478 g; 55%) was isolated as a yellow
oil from the starting materials (−)-(S)-methyl-p-tolyl-
sulfoxide (0.99 g; 6.48 mmol; 2.1 equiv.) and 9b (0.53 g;
3.09 mmol; 1 equiv.), by the method described for 1b.
Rf=0.43 (ethyl acetate/dichloromethane, 1:1). [h]2D0=
1
hexane, 1:1). H NMR (400 MHz; CDCl3): l=1.27 (t,
3H, J=7 Hz), 2.22 (s, 3H), 3.63 (s, 3H), 4.16 (q, 2H,
J=7 Hz), 5.01 (s, 1H) ppm. 13C NMR (100 MHz,
CDCl3): l=14.8, 19.22, 55.72, 59.68, 91.25, 168.2,
173.4 ppm. IR (film): w=1700–1650, 1640–1600 cm−1.
230 mg of (Z)-isomer were also isolated. Rf=0.44
(ethyl acetate/hexane, 1:1). 1H NMR (400 MHz;
CDCl3): l=1.24 (t, 3H, J=7 Hz), 2.02 (s, 3H), 3.84 (s,
3H), 4.15 (q, 2H, J=7 Hz), 4.82 (s, 1H) ppm. 13C
NMR (100 MHz, CDCl3): l=14.5, 18.22, 55.4, 56.61,
97.4, 168.4, 169.46 ppm. IR (film): w=1700–1650, 1640–
1600 cm−1.
1
−216 (c 1.14, CHCl3). H NMR (200 MHz; CDCl3):
l=0.89 (t, 3H, J=7.3 Hz), 1.50 (sext, 2H, J=7.3 Hz),
2.65 (m, 2H), 2.41 (s, 3H), 3.61 (s, 3H), 3.69 (B frag-
ment of an AB system, 1H, JAB=19 Hz, Dk=54 Hz),
3.88 (A fragment of an AB system, 1H, JAB=19 Hz,
Dw=54 Hz), 5.91 (s, 1H), 7.30 (B fragment of an (AB)2
system, 2H, JAB=8 Hz, Dk=68 Hz), 7.53 (A fragment
of an (AB)2 system, 2H, JAB=8 Hz, Dk=68 Hz) ppm.
13C NMR (50 MHz, CDCl3): l=13.9, 20.6, 21.5, 34.9,
55.9, 70.6, 98.9, 124.3, 130.0, 140.2, 141.9, 179.7, 188.1
ppm. IR (film): w=1660–1640, 1620–1580 cm−1.
4.11. (E)-Ethyl 3-methoxy-2-hexenoate, 9b
4.14. (E,2S,RS)-1-(p-Tolylsulfinyl)-4-methoxy-3-butene-
2-ol, 11a
To a solution of ethylbutyrylacetate (2 g; 0.013 mol; 1
equiv.) in DMSO (50 ml) was added K2CO3 (2.62 g;
0.019 mol; 1.5 equiv.). After stirring for 1 h at rt,
Me2SO4 (1.20 ml; 0.017 mol, 1.3 equiv.) was added. The
reaction was stirred 48 h and hydrolysed with water (50
ml) and diluted with ethyl acetate (50 ml). The aqueous
layer was extracted with ethyl acetate (3×50 ml) and the
combined organic layers were washed with brine (100
ml), dried (MgSO4) and concentrated. The crude oil
was purified by column chromatography on silica gel
(with hexane/ethyl acetate, 9:1 as eluent) to afford a
colourless oil 9b (1.31 g, 60%). Rf=0.64 (ethyl acetate/
Using the method described for 7a, reduction of 10a led
to a 6/4 mixture of 11a and 12a with 20% of recovered
starting material. A sample of compound 11b could be
separated from 12a after flash chromatography, but
contaminated by the corresponding enone 17a resulting
from its degradation on silica gel. Rf=0.31 (ethyl ace-
tate/dichloromethane, 1:1). 1H NMR (200 MHz;
CDCl3): l=2.12 (s, 3H), 2.42 (s, 3H), 2.88 (AB frag-
ment of an ABX system, 2H, JAX=11.2 Hz, JBX=2 Hz,
J
AB=13.6 Hz, Dk=118 Hz), 3.39 (s broad, 1H), 3.47 (s,
3H), 4.49 (d, 1H, J=12 Hz), 4.78–4.94 (m, X fragment
of an ABX system, 1H), 7.39 (B fragment of an (AB)2
system, 2H, JAB=8 Hz, Dkw=44 Hz), 7.58 (A fragment
of an (AB)2 system, 2H, JAB=8 Hz, Dk=44 Hz) ppm.
1
hexane, 1:1). H NMR (200 MHz; CDCl3): l=0.94 (t,
3H, J=7.3 Hz), 1.28 (t, 3H, J=7.3 Hz), 1.58 (sext, 2H,
J=7.3 Hz), 2.71 (m, 2H), 3.63 (s, 3H), 4.14 (q, 2H,
J=7.3 Hz), 4.99 (s, 1H) ppm. 13C NMR (50 MHz,
CDCl3): l=13.8, 14.4, 20.9, 33.8, 55.3, 59.3, 90.5,
167.7, 176.7 ppm. IR (film): w=1700–1650, 1640–1600
cm−1.
4.15. (E)-S(R)]-1-(p-Tolylsulfinyl)-4-oxo-2-butene, 17a
Enone 17a resulting from chromatography of 11a was
isolated as colourless oil. Rf: 0.3 (dichloromethane/ethyl
1
acetate: 3/2). H NMR (400 MHz; CDCl3): l=2.22 (s,
3H), 2.46 (s, 3H), 3.69 (AB fragment of an ABX
system, 2H, JAX=JBX=8 Hz, JAB=13 Hz, Dk=38 Hz),
6.09 (d, 1H, Jtrans=16 Hz), 6.58 (dt, X fragment of an
ABX system, 1H, JBX=8 Hz, Jtrans=16 Hz), 7.37 (B
fragment of an (AB)2 system, 2H, JAB=8 Hz, Dkw=44
Hz), 7.56 (A fragment of an (AB)2 system, 2H, JAB=8
Hz, Dk=44 Hz) ppm. 13C NMR (100 MHz, CDCl3):
l=1.4, 21.9, 27.65, 59.53, 124.51, 124.6, 130.4, 133.52,
137.6, 139.42, 142.56, 197.4 ppm. [h]2D0=+57 (c 0.15,
CHCl3).
4.12. (+)-(E,RS)-1-(p-Tolylsulfinyl)-4-methoxy-3-butene-
2-one, 10a
Compound 10a (0.478 g; 55%) was isolated as a yellow
oil from the starting materials (+)-(R)-methyl-p-tolyl-
sulfoxide (1.2 g; 7.8 mmol; 2.1 equiv.) and 9a (0.51 g;
3.1 mmol; 1 equiv.), by the method described for 1a.
Rf=0.53 (ethyl acetate/dichloromethane, 1:1). [h]2D0=
+262 (c 0.8 CHCl3). 1H NMR (400 MHz; CDCl3):

G. Hanquet et al. / Tetrahedron: Asymmetry 14 (2003) 1291–1301
1299
4.16. (E,2R,SS)-1-(p-Tolylsulfinyl)-4-methoxy-3-hexene-
mol; 2.2 equiv.) and TMSCl (14.1 ml; 0.11 mol; 4.4
equiv.) in CH2Cl2 (120 ml) was heated at reflux under
argon for 5 days. The mixture was cooled to rt and
treated with saturated NaHCO3 (200 ml). The aqueous
layer was extracted with CH2Cl2 and the combined
organic layers were dried (MgSO4) and evaporated. The
yellow oil obtained was purified by distillation to afford
ethyl 3-(1,3-dioxolane)-hexanoate (4.44 g; 86%). Rf=
0.27 (ethyl acetate/hexane, 1:1). bp=107–110°C. 1H
NMR (200 MHz; CDCl3): l=0.92 (t, 3H, J=7.3 Hz),
1.26 (t, 3H, J=7.3 Hz), 1.31–1.50 (m, 2H), 1.73–1.81
(m, 2H), 2.62 (s, 2H), 3.93–4.00 (m, 4H), 4.14 (q, 2H,
J=7.3 Hz) ppm. 13C NMR (50 MHz, CDCl3): l=13.5,
16.8, 39.9, 42.6, 60.4, 65.0, 109.4, 169.6 ppm. IR (film):
w=1720 cm−1. Anal. calcd for C10H8O4 (202.25): C,
59.39; H, 8.97. Found: C, 59.41; H, 8.91%.
2-ol, 11b
Using the method described for 7a, reduction of 10b led
to a 7/3 mixture of 11b and 12b. A sample of com-
pound 11b could be separated from 12b after flash
chromatography but contaminated traces of the corre-
sponding enone 17b resulting from its degradation on
silica gel. Rf=0.34 (ethyl acetate/dichloromethane, 1:1).
1H NMR (200 MHz; CDCl3): l=0.72 (t, 2H, J=7.3
Hz), 1.12–1.50 (m, 2H), 1.79–1.96 (m, 2H), 2.41 (s, 3H),
2.75 (AB fragment of an ABX system, 2H, JAX=10.4
Hz, JBX=2 Hz, JAB=13.2 Hz, Dw=124 Hz), 3.46 (s,
3H), 3.65 (s broad, 1H), 4.45 (d, 1H, J=11 Hz),
4.70–4.90 (m, X fragment of an ABX system, 1H), 7.33
(B fragment of an (AB)2 system, 2H, JAB=8 Hz, Dk=
44 Hz), 7.53 (A fragment of an (AB)2 system, 2H,
J
AB=8 Hz, Dk=44 Hz) ppm.
4.20. (−)-(SS)-1-(p-Tolylsulfinyl)-4-(1,3-dioxolane)-2-
oxo-heptane, 13
4.17. (E,2R,RS)-1-(p-Tolylsulfinyl)-4-methoxy-3-butene-
2-ol, 12a
Compound 13 (3.13 g; 68%) was isolated as a yellow oil
from the starting materials (+)-(S)-methyl-p-tolylsulfox-
ide (5.04 g; 32.7 mmol; 2.2 equiv.) and ethyl 3-(1,3-
dioxolane)-hexanoate (3 g; 14.8 mmol; 1 equiv.), by the
method described for 1b. Rf=0.56 (ethyl acetate/
Compound 12a (0.072 g; 81%) was isolated as a pale
yellow oil from the starting material 10a (0.084 g, 0.34
mmol), by the method described for 16b. Purification
was achieved by flash chromatography (ethyl acetate/
hexane, 3/7). Rf=0.27 (ethyl acetate/dichloromethane,
1:1). H NMR (200 MHz; CDCl3): l =1.90 (s, 3H),
2.41 (s, 3H), 2.97 (AB fragment of an ABX system, 2H,
dichloromethane, 1:1). [h]2D0=−167 (c 1, acetone). H
1
NMR (200 MHz; CDCl3): l=0.86 (t, 3H, J=7 Hz),
1.22–1.42 (m, 2H), 1.49–1.59 (m, 2H), 2.40 (s, 3H), 2.72
(B fragment of an AB system, 1H, JAB=13.52 Hz,
Dk=18.6 Hz), 2.85 (A fragment of an AB system, 1H,
1
J
AX=9 Hz, JBX=4.1 Hz, JAB=13 Hz, Dw=82 Hz), 3.36
(d, 1H, J=2 Hz), 3.5 (s, 3H), 4.51 (d, 1H, J=11 Hz),
4.89–4.98 (m, X of an ABX system, 1H), 7.33 (B
fragment of an (AB)2 system, 2H, JAB=8 Hz, Dk=44
Hz), 7.5 (A fragment of an (AB)2 system, 2H, JAB=8
Hz, Dk=44 Hz) ppm. 13C NMR (100 MHz, CDCl3):
l=17.24, 21.82, 54.78, 66.8, 98.77, 124.3, 130.4, 141.2,
142.3, 158.02 ppm. [h]2D0=+188 (c 0.9, CHCl3).
JAB=13.52 Hz, Dk=18.6 Hz), 3.91 (s, 4H), 3.97 (s, 2H),
7.32 (B fragment of an (AB)2 system, 2H, JAB=8.02
Hz, Dk=42.3 Hz), 7.53 (A fragment of an (AB)2 sys-
tem, 2H, JAB=8.02 Hz, Dk=42.3 Hz) ppm. 13C NMR
(50 MHz, CDCl3): l=13.4, 16.0, 20.8, 39.5, 51.1, 64.2,
68.4, 108.8, 123.5, 129.4, 139.2, 141.4, 198.8 ppm. Anal.
calcd for C16H22O4S (310.41): C, 61.91; H, 7.14. Found:
C, 61.76; H, 6.97%.
4.18. (E,2S,SS)-1-(p-Tolylsulfinyl)-4-methoxy-3-hexene-
2-ol, 12b
4.21. (−)-(2R,SS)-1-(p-Tolylsulfinyl)-4-heptanone-2-ol, 7b
Compound 12b (0.042 mg; 63%) was isolated as a white
solid from the starting material 10b (0.058 g, 0.23
mmol), by the method described for 16b. Purification
was achieved by washing the crude product with ether.
Rf=0.30 (ethyl acetate/dichloromethane, 1:1). 1H NMR
(200 MHz; CDCl3): l=0.88 (t, 2H, J=7.3 Hz), 1.50
(m, 2H), 2.16 (t, 2H, J=7.3 Hz), 2.41 (s, 3H), 2.95 (AB
To a solution of 13 (2.03 g; 6.55 mmol; 1 equiv.) in
THF (100 ml) was added dropwise under argon and at
−78°C a solution of DIBAL-H (10.9 ml of a 1 M
solution in toluene; 16.0 mmol; 2.5 equiv.). Stirring was
continued for 1.5 h at −78°C before adding MeOH (20
ml). Then the solvent was evaporated and the residue
was dissolved in AcOEt (40 ml) and saturated disodium
fragment of an ABX system, 2H, JAX=8.5 Hz, JBX
=
L-tartrate dihydrate (80 ml) was added. The stirring was
3.7 Hz, JAB=13 Hz, Dk=84 Hz), 3.30 (d, 1H, J=2
Hz), 3.48 (s, 3H), 4.47 (d, 1H, J=11 Hz), 4.85–4.99 (m,
X of an ABX system, 1H), 7.34 (B fragment of an
(AB)2 system, 2H, JAB=8 Hz, Dk=44 Hz), 7.57 (A
fragment of an (AB)2 system, 2H, JAB=8 Hz, Dk=44
Hz) ppm. 13C NMR (50 MHz, CDCl3): l=13.9, 21.2,
21.6, 33.0, 54.5, 64.0, 66.2, 98.4, 124.1, 130.2, 140.8,
142.1, 161.2 ppm. Anal. calcd for C15H22O3S (282.39):
C, 63.80; H, 7.85. Found: C, 63.85; H, 8.02%.
continued until a clear phase separation occurred. The
aqueous layer was extracted with AcOEt (3×100 ml).
The combined organic layers were washed with brine,
dried (MgSO4), and concentrated. The yellow oil
obtained (14) was suspended in a mixture of THF (20
ml) and water (15 ml) and oxalic acid (0.06 g; 0.6
mmol; 0.1 equiv.) was added. The mixture was refluxed
for 2 h and treated with saturated NaHCO3. The
aqueous phase was extracted with ethyl acetate and the
combined organic layers were washed with brine, dried
(MgSO4), and concentrated. The crude product was
washed with ether to afford 7b (1.40 g; 80%) as a white
solid. Compound 7b could be also obtained from (−)-
(SS)-1-(p-tolylsulfinyl)-2,4-heptanedione 1b (33%) by
4.19. Ethyl 3-(1,3-dioxolane)hexanoate15
A solution of ethyl butyrylacetate (4 g; 0.025 mol; 1
equiv.), freshly distilled ethylene glycol (3.1 ml; 0.05

1300
G. Hanquet et al. / Tetrahedron: Asymmetry 14 (2003) 1291–1301
1
the method described for 7a. Rf=0.42 (ethyl acetate/
dichloromethane, 1:1). [h]2D0=−222 (c 1, acetone). Mp=
1.02, acetone). H NMR (200 MHz; CDCl3): l=0.90
(t, 3H, J=7.3 Hz), 1.58 (sext, 2H, 7.3 Hz), 2.40 (t, 2H,
J=7.3 Hz), 2.41 (s, 3H), 2.78 (AB fragment of an ABX
system, 2H, JAX=7.3 Hz, JBX=4.9 Hz, JAB=17.5 Hz,
Dk=37.7 Hz), 2.93 (AB fragment of an ABX system,
2H, JAX=7.5 Hz, JBX=4.4 Hz, JAB=12.9 Hz, Dk=24
Hz), 3.98 (d, 1H, J=2.7 Hz), 4.50–4.55 (m, X of an
ABX system, 1H), 7.32 (B fragment of an (AB)2 system,
2H, JAB=8.22 Hz, Dk=41.5 Hz), 7.53 (A fragment of
an (AB)2 system, 2H, JAB=8.22 Hz, Dk=41.5 Hz) ppm.
13C NMR (50 MHz, CDCl3): l=13.7, 17.1, 21.5, 45.6,
48.4, 62.1, 64.8, 124.2, 130.2, 140.3, 142.0, 210.5 ppm.
Anal. calcd for C14H20O3S (268.39): C, 62.66; H, 7.51.
Found: C, 62.60; H, 7.46%.
1
80–83°C. H NMR (200 MHz; CDCl3): l=0.89 (t, 3H,
J=7.3 Hz), 1.57 (sext, 2H, 7,3 Hz), 2.39 (t, 2H, J=7.3
Hz), 2.43 (s, 3H), 2.64 (A2 system, d, 2H, J=6.2 Hz)
2.86 (AB fragment of an ABX system, 2H, JAX=9.5
Hz, JBX=2.6 Hz, JAB=13.5 Hz, Dk=55 Hz), 4.10 (s
broad, 1H), 4.57–4.69 (m, X of an ABX system, 1H),
7.35 (B fragment of an (AB)2 system, 2H, JAB=8.02
Hz, Dk=36 Hz), 7.53 (A fragment of an (AB)2 system,
2H, JAB=8.02 Hz, Dk=36 Hz) ppm. 13C NMR (50
MHz, CDCl3): l=13.7, 17.1, 21.5, 45.6, 48.5, 61.5,
63.7, 124.1, 130.2, 139.8, 141.8, 210.3 ppm. IR (film):
w=3380, 2950, 1700, 1080 cm−1 Anal. calcd for
C14H20O3S (268.39): C, 62.66; H, 7.51. Found: C, 62.75;
H, 7.67%.
4.24. (−)-(2S,SS)-1-(p-Tolylsulfinyl)-4-(1,3-dioxolane)-
heptane-2-ol, 15
4.22. (−)-(2R,SS)-1-(p-Tolylsulfinyl)-4-(1,3-dioxolane)-
An analytical sample of 15 could be obtained by crys-
tallisation in ether as a white solid. Rf=0.42 (ethyl
acetate/dichloromethane, 1:1). [h]2D0=−44 (c 0.5, ace-
tone). Mp=70–73°C. 1H NMR (200 MHz; CDCl3):
l=0.90 (t, 3H, J=7.2 Hz), 1.20–1.48 (m, 2H), 1.55–
1.67 (m, 2H), 1.91 (B fragment of an ABX system, 1H,
heptane-2-ol, 14
An analytical sample of 14 could be obtained by purifi-
cation by column chromatography on silica gel (hex-
ane/ethyl acetate 10:1) as a yellow oil. Rf=0.43 (ethyl
acetate/dichloromethane, 1:1). [h]2D0=−236 (c 1.22, ace-
1
J
BX=3.38 Hz, JAB=14.7 Hz, Dk=29 Hz), 2.04 (A
tone). H NMR (200 MHz; CDCl3): l=0.86 (t, 3H,
fragment of an ABX system, 1H, JAX=8.56 Hz, JAB
=
J=7.2 Hz), 1.20–1.42 (m, 2H), 1.49–1.61 (m, 2H), 1.81
14.7 Hz, Dk=29 Hz), 2.41 (s, 3H), 2.85 (B fragment of
an ABX system, 1H, JBX=4.46 Hz, JAB=13.1 Hz,
Dk=44.3 Hz), 3.05 (A fragment of an ABX system, 1H,
(AB fragment of a degenerated ABX system, 2H, JAX
=
1.94 Hz), 2.38 (s, 3H), 2.81 (m, 2H), 3.90 (s, 4H), 4.09
(s broad, 1H), 4.39–4.51 (m, 1H), 7.30 (B fragment of
an (AB)2 system, 2H, JAB=8.14 Hz, Dk=42.5 Hz), 7.51
(A fragment of an (AB)2 system, 2H, JAB=8.14 Hz,
Dk=42.5 Hz) ppm. 13C NMR (50 MHz, CDCl3): l=
14.3, 17.1, 21.5, 39.6, 42.6, 63.1, 64.5, 64.7, 64.9, 111.4,
124.0, 130.0, 140.9, 141.4 ppm. IR (film): w=3520–
3480, 2980–2800 cm−1. Anal. calcd for C16H24O4S
(312.42): C, 61.51; H, 7.74. Found: C, 61.64; H, 7.83%.
J
AX=7.08 Hz, JAB=13.1 Hz, Dk=44.3 Hz), 3.95 (s,
4H), 4.02 (s broad, 1H), 4.19–4.31 (X fragment of a
ABX system, m, 1H), 7.33 (B fragment of an (AB)2
system, 2H, JAB=8.14 Hz, Dk=42.5 Hz), 7.57 (A frag-
ment of an (AB)2 system, 2H, JAB=8.14 Hz, Dk=42.5
Hz) ppm. 13C NMR (50 MHz, CDCl3): l=14.3, 17.2,
21.5, 39.6, 42.3, 64.1, 64.2, 64.7, 64.9, 111.6, 124.3,
130.1, 140.8, 141.7 ppm. IR (film): w=3520–3480, 2980–
2800 cm−1. Anal. calcd for C16H24O4S (312.42): C,
61.51; H, 7.74. Found: C, 61.39; H, 7.74%.
4.23. (−)-(2S,SS)-1-(p-Tolylsulfinyl)-4-heptanone-2-ol,
16
To anhydrous ZnI2 (173 mg, 0.54 mmol; 1.1 equiv.), a
solution of ketosulfoxide 13 (153 mg, 0.49 mmol; 1
equiv.) was added. After stirring for 30 min at rt, the
solution was cooled to −78°C and (0.82 ml, 1.23 mmol;
2.5 equiv.) of a 1.5 M solution of DIBAL-H in toluene
was added dropwise and stirred for 1 h. The reaction
mixture was quenched with 10 ml of MeOH. The
solvent was then evaporated and a saturated disodium
References
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L
-tartrate dihydrate solution (30 ml) and 30 ml of ethyl
acetate were added. The stirring was continued until a
clear phase-separation occurred. The aqueous layer was
extracted with ethyl acetate and the combined organic
layers were dried (MgSO4) and evaporated. The yellow
oil obtained (15) was suspended in a mixture of THF
(20 ml) and water (15 ml) and oxalic acid (45 mg; 0.5
mmol; 0.1 equiv.) was added. The mixture was refluxed
for 2 h and treated with a saturated solution of
NaHCO3. The aqueous phase was extracted with ethyl
acetate and the combined organic layers were washed
with brine, dried (MgSO4) and concentrated. The crude
product was washed with ether to afford 16b. Rf=0.22
(ethyl acetate/dichloromethane, 1:1). [h]2D0=−184 (c

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14. A hydrogen bond between the enolic H and the basic
oxygen of the sulfoxide group could provide an expla-
nation for this fact.
8. Evans, D. A.; Chapman, K. T.; Carreira, E. M. J. Am.
15. (a) Hanquet, G.; Solladie´, G.; Salom-Roig, X. J. Tetra-
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17. We have observed that by using commercially available
1 M DIBAL-H solution in toluene instead of hexane
the de was higher.
18. We purified only an analytical sample of 14 and 15 for
identification purposes.
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11. Attempts to prepare the corresponding silyl-enol ether
failed as the condensation of methylsulfoxide anion on
the silylated analogue of 9b provided only starting
material (Salom-Roig, X.; Pederson, B., unpublished
results).
12. E configuration of 9a and 9b has been assessed by
NOE. difference experiments. Less than 10% of Z iso-
mer is observed and separated from the crude mixture
by chromatography.
19. Solladie´, G.; Hutt, J.; Girardin, A. Synthesis 1987, 173–
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20. Hubbard, J. S.; Harris, T. M. J. Org. Chem. 1981, 46,
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13. Carren˜o, M. C.; Garc´ıa Ruano, J. L.; Mart´ın, A. M.;