1,4-Asymmetric reduction of γ-keto sulfoxides bearing the 2,4,6-triisopropylphenyl group

Article abstract of DOI:10.1039/b004782L

Reduction of γ-keto sulfoxides bearing the 2,4,6-triisopropylphenyl group with DIBAL gives γ-hydroxy sulfoxides with high stereoselectivity in the ratio 95:5. In comparison with the lower stereoselectivities obtained in the reaction of γ-keto sulfoxides bearing p-tolyl or 2,4,6-trimethylphenyl groups, the sterically bulky (2,4,6-triisopropylphenyl)-sulfinyl group is extremely efficient in effecting high 1,4-remote asymmetric induction. The Royal Society of Chemistry 2000.

Full text of DOI:10.1039/b004782L

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1,4-Asymmetric reduction of ꢀ-keto sulfoxides bearing the
2,4,6-triisopropylphenyl group
Shuichi Nakamura, Masayuki Kuroyanagi, Yoshihiko Watanabe and Takeshi Toru
1
Department of Applied Chemistry, Nagoya Institute of Technology, Gokiso, Showa-ku,
Nagoya 466-8555, Japan
Received (in Cambridge, UK) 14th June 2000, Accepted 31st July 2000
Published on the Web 6th September 2000
Reduction of γ-keto sulfoxides bearing the 2,4,6-triisopropylphenyl group with DIBAL gives γ-hydroxy sulfoxides
with high stereoselectivity in the ratio 95:5. In comparison with the lower stereoselectivities obtained in the reaction
of γ-keto sulfoxides bearing p-tolyl or 2,4,6-trimethylphenyl groups, the sterically bulky (2,4,6-triisopropylphenyl)-
sulfinyl group is extremely efficient in effecting high 1,4-remote asymmetric induction.
Introduction
Asymmetric induction at a site remote from a chiral auxiliary or
a chiral center is one of the most challenging problems in syn-
thetic chemistry to be solved.1 The carbonyl-face-selective reac-
tions of β-keto sulfoxides have been intensively studied.2,3 In
particular, the reduction of β-keto sulfoxides with diisobutyl-
aluminium hydride (DIBAL) shows an interesting aspect,
giving β-hydroxy sulfoxides with high diastereoselectivity.2
The diastereoselective outcome in the reduction with DIBAL is
derived from intramolecular hydride transfer through a six-
membered cyclic transition state, whereas the DIBAL reduction
in the presence of a Lewis acid gives the product with reversed
stereochemistry, which is rationalized by a conformationally
rigid six-membered cyclic intermediate involving chelation of
a Lewis acid with the sulfinyl and carbonyl oxygens. It would
Scheme 1 Reagents and conditions: (a) 3-chloro-1-phenylpropan-1-
be interesting to establish the highly stereoselective asymmetric
one, DBU, benzene, rt; (b) MCPBA, CH2Cl2, Ϫ78 to Ϫ30 ЊC.
reduction of ketones remote by one more carbon from the
sulfinyl group, i.e. γ-keto sulfoxides,4,5 because the conform-
3-[(2,4,6-triisopropylphenyl)sulfinyl]-propiophenone
3a–c
ationally flexible and unstable seven-membered cyclic structure
would make it difficult to obtain high stereoselectivity. Indeed,
Solladié et al. have reported that the reduction of γ-keto
sulfoxides with DIBAL proceeds with moderate diastereo-
selectivity without Lewis acids and gives the product with the
reversed diastereoselectivity when carried out in the presence of
Yb(OTf)3.5 These results encouraged us to examine the stereo-
chemical effect of a sterically bulky substituent on the sulfur in
the reduction of γ-keto sulfoxides. Recently, we reported the
high efficiency of the bulky (2,4,6-triisopropylphenyl)sulfinyl
group as a chiral auxiliary in the radical β-addition to
2-sulfinylcyclopent-2-enones6,7 and in the Grignard reaction to
1-sulfinyl-2-naphthaldehydes.8 These reactions proceed with
high stereoselectivity by complete blocking of the side opposite
to the reaction site by the bulky 2,4,6-triisopropylphenyl group.
These successful asymmetric inductions rely on our newly
developed and efficient method for the preparation of the
optically active diacetone--glucosyl 2,4,6-triisopropylbenzene-
sulfinate, from which the chiral (2,4,6-triisopropylphenyl)
sulfoxides can be easily prepared.7,9 We now report highly
diastereoselective reduction of γ-keto sulfoxides having a steric-
ally bulky aryl group.
(Scheme 1). The sulfides 2a–c were prepared by treatment of the
corresponding thiols 1a–c with 3-chloro-1-phenylpropan-1-one
in the presence of 1,8-diazabicyclo[4.3.0]undec-7-ene (DBU)
at room temperature. The sulfides 2a–c were oxidized with
MCPBA to give the 3-(arylsulfinyl)propiophenones 3a–c in
high yields.
The carbonyl reduction of the 3-(arylsulfinyl)propio-
phenones 3a–c with various reducing reagents without or in the
presence of Lewis acids was next examined. The results are
summarized in Table 1.
The reduction of 3a (Ar = p-Tol) and 3b (Ar = 2,4,6-
trimethylphenyl) with DIBAL proceeded with moderate
diastereoselectivity at Ϫ78 ЊC in THF to afford the alcohols 4a
and 4b (entries 1 and 2). The DIBAL reduction of 3-[(2,4,6-
triisopropylphenyl)sulfinyl]propiophenone 3c proceeded with
high stereoselectivity to give the γ-hydroxy sulfoxide 4c in
the ratio 97:3 at Ϫ78 ЊC and 93:7 at Ϫ105 ЊC, favoring the
(SS*,S*)-isomer (entries 3 and 4). The reduction of 4c with
other reducing agents such as LiAlH4, -Selectride and NaBH4
gave the product 4c with lower stereoselectivity (entries 5–8).
The stereoselectivity in the DIBAL reduction of 3c in the
presence of ZnCl2 or Yb(OTf)3 in either THF or CH2Cl2 was
reduced, but not reversed (entries 9–12), although Solladié et al.
have shown that the reduction of the p-tolyl γ-keto sulfoxide
with Yb(OTf)3 affords the product having the opposite con-
figuration as a major product.5 The weak effect of Lewis acids
on the stereoselectivity in the reduction of 3c would be ascribed
Results and discussion
We first examined the selectivity in the reduction of racemic
3-(p-tolylsulfinyl)-, 3-[(2,4,6-trimethylphenyl)sulfinyl]- and
DOI: 10.1039/b004782l
J. Chem. Soc., Perkin Trans. 1, 2000, 3143–3148
This journal is © The Royal Society of Chemistry 2000
3143

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Table 1 Stereoselective reduction of 3-(arylsulfinyl)propiophenones 3a–ca
Yield of
product 4
(%)
Diastereomer
ratio (SS*,S*):
(SS*,R*)
Reducing
agent
Entry
Substrate 3
Solvent
Lewis acid
1
2
3
4
5
6
7
8
9
3a
3b
3c
3c
3c
3c
3c
3c
3c
3c
3c
3c
THF
THF
THF
THF
THF
THF
THF
EtOH
THF
THF
CH2Cl2
CH2Cl2
DIBAL
DIBAL
DIBAL
DIBALc
LiAlH4
98
99
90
31
88
89
52
80
30
31
96
90
86:14b
92:8
97:3
93:7
74:26
70:30
50:50
51:49
80:20
55:45
74:26
74:26
-Selectride
NaBH4
NaBH4
DIBAL
DIBAL
DIBAL
DIBAL
ZnCl2
Yb(OTf)3
d
10
11
12
Yb(OTf)3
a Reaction was carried out at Ϫ78 ЊC unless otherwise noted. b Reduction of 4-(p-tolyl)butan-2-one with DIBAL has been reported to give the butan-
2-ol product in the ratio 80:20.4c c Reaction was carried out at Ϫ105 ЊC. d Yb(OTf)3 (2.0 equiv.) was used.
to an incompletely chelated intermediate bearing the bulky
(2,4,6-triisopropylphenyl)sulfinyl group. Having established a
high diastereoselection in the reaction of 3c, we examined the
chiral sulfoxides. In order to prepare the chiral sulfoxides, we
first tried the Sharpless oxidation10 of the sulfide 2c, resulting
in low yield and low enantioselectivity. The chiral sulfoxides
were successfully prepared via the chiral sulfinates (Scheme 2).
Scheme 3 Reagents and conditions: (a) DIBAL, THF, Ϫ78 ЊC.
attached to the carbonyl group, showing very weak steric or
electronic effects of these substituents on the stereoselectivity.
1
The absolute configuration of 8c was determined by the H
NMR spectral behavior of the (R)-MTPA ester11 of the sulfone
10 prepared on treatment of the sulfoxide (SS,S)-8c with
MCPBA, followed by acylation (Scheme 4).
Scheme 2 Reagents and conditions: (a) (EtO)2CHCH2CH2MgBr, THF,
Ϫ78 ЊC, 1 h; (b) 50% TFA, CHCl3, 0 ЊC, 12 h; (c) RMgX, THF, Ϫ78 ЊC;
(d) PCC, CH2Cl2, rt.
Treatment of (RS)-diacetone--glucosyl 2,4,6-triisopropyl-
benzenesulfinate7,9
5
with 3,3-diethoxypropylmagnesium
bromide furnished the sulfinyl acetal 6, which was converted to
the aldehyde 7 on treatment with 50% TFA. Aldehyde 7 was
then allowed to react with PhMgBr, MeMgI and EtMgBr to
give the alcohols 8c–e, respectively, as a diastereomeric mixture.
Finally, 8c–e were oxidized by pyridinium chlorochromate
(PCC) to give ketones (S)-9c–e with 98% ees, completing the
synthesis of the substrates required for the stereoselective
reduction study.
Scheme 4 Reagents and conditions: (a) MCPBA, CH2Cl2, rt; (b) DCC,
(R)-MTPA, DMAP, CH2Cl2, rt.
The correlation between the configuration of the carbonyl-
oxy methine carbon and the upfield shift of the methylene
1
protons in the H NMR spectra of the MTPA esters has been
Reduction of (S)-9c–e with DIBAL at Ϫ78 ЊC in THF gave
the γ-hydroxy sulfoxides 8c–e in 92–96% yield with high stereo-
selectivity (Scheme 3).
High stereoselectivity was obtained in the reaction of all
γ-keto sulfoxides 9c–e irrespective of the substituent (R)
established. We, however, failed to assign the configuration of
our products owing to the complicated methylene proton sig-
nals of the minor isomer in the 1H NMR spectrum (CDCl3) of
11. Instead, we observed that the signal due to the methoxy
protons appeared at δ 3.48 in the major isomer and at δ 3.42 in
3144
J. Chem. Soc., Perkin Trans. 1, 2000, 3143–3148

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Fig. 1 1H NMR spectral behavior of the (R)-MTPA ester 11.
the minor isomer. According to the established configuration–
correlation model shown in Fig. 1, we assigned the configur-
ation of the minor isomer to be R due to the upfield shift of the
methoxy proton signal relative to the signal in the major isomer
caused by the anisotropic effect of the phenyl group.
The stereochemistry of 8c was further confirmed by its
conversion to the known homoallyl alcohol 1312 (Scheme 5).
Fig. 2 Assumed transition state in reduction of sulfinyl ketones (S)-9
with DIBAL.
cannula, and were introduced into the reaction vessels through
a rubber septum. Diethyl ether and THF were distilled from
sodium–benzophenone under a nitrogen atmosphere before use
(deep blue solution: ketyl from benzophenone and sodium).
CH2Cl2 was distilled from calcium hydride. All reactions
were monitored by TLC carried out on 0.25 mm Merck silica
gel plates (60f-254). The TLC plates were visualized with UV
light and 7% phosphomolybdic acid or p-anisaldehyde in
ethanol, followed by heating. Column chromatography was
carried out on a column packed with Fuji Silysia silica gel
BW-200. 1H NMR (200 MHz) and 13C NMR (50.3 MHz)
spectra for solutions in CDCl3 were recorded on a Varian
Gemini-200. Chemical shifts (δ) are expressed in ppm down-
field from internal tetramethylsilane or CHCl3, and J-values
are given in Hz. IR spectra were recorded on a JASCO A-102
or a JASCO FT/IR-200 spectrometer. Mass spectra (eV) were
recorded on a Hitachi M-2000 spectrometer. Microanalyses
were performed with a Perkin-Elmer 240. Optical rotations
were measured on a JASCO DIP-4 polarimeter operating at
λ = 589 nm corresponding to the sodium -line, in the indicated
solvent and concentration in grams of solute per 100 mL.
Scheme
5
Reagents and conditions: (a) i, LDA, THF, Ϫ78 ЊC;
ii, ICH2Si(CH3)3, Ϫ78 ЊC to rt; (b) TBAF, THF, rt.
Treatment of a diastereomeric mixture of 8c with LDA (2.2
equiv.) and (iodomethyl)trimethylsilane gave the β-silyl sulf-
oxide 12.13 The sulfoxide 12 was allowed to react with a THF
solution of tetrabutylammonium fluoride (TBAF) to afford a
91% yield of the homoallyl alcohol 13, the (S)-configuration and
the optical purity (92% ee) of which were determined by com-
parison of the [α]D-value with that reported in the literature.14
The high stereoselectivity, which is not much affected by the
substituents attached to the carbonyl group, in the reduction of
the γ-keto sulfoxide (S)-9 with DIBAL, would be ascribed to a
cyclic transition state as depicted in Fig. 2.
Since a chair-like 7-membered transition state, giving the
(R)-isomer, would be less stable than a twisted-chair transi-
tion state, we assumed the presence of a twisted-chair transition
state involving a trigonal bipyramidal structure.15 The bulky
triisopropylphenyl group is placed at the pseudoequatorial
position and it may fix the cyclic transition state more effi-
ciently than the p-tolyl and mesityl groups. The reduction
would preferably occur from the re face of the carbonyl.
In summary, the bulky (2,4,6-triisopropylphenyl)sulfinyl
group has been demonstrated to be a powerful chiral inducer in
the stereoselective reduction of γ-keto sulfoxides. This efficient
1,4-remote asymmetric reduction is based on the availability of
the chiral γ-keto sulfoxides.
[α]D-Values are given in units of 10Ϫ1 deg cm2
g
Ϫ1. HPLC
analyses were performed on a JASCO TRI ROTOR IV using
4.6 × 250 mm COSMOSIL, CHIRALCEL OD-H and
CHIRALPAC AD packed columns.
Preparation of 3-(arylsulfinyl)propiophenones
1-Phenyl-3-(p-tolylsulfanyl)propan-1-one 2a. To a solution of
toluene-p-thiol 1a (203.5 mg, 1.64 mmol) in benzene (5.0 mL)
was added DBU (0.27 mL, 1.80 mmol) at room temperature
and the mixture was stirred for 10 min. A solution of 3-chloro-
1-phenylpropan-1-one (304 mg, 1.80 mmol) in benzene
(1.8 mL) was then added. After stirring for 5 h, the reaction
mixture was concentrated under reduced pressure to give the
crude product. Since product 2a could not be separated
from 3-chloro-1-phenylpropan-1-one by column chromato-
graphy (silica gel 10 g; hexane–ethyl acetate 90:10), the crude
product was used without further purification for the next
oxidation.
Experimental
General
All reactions were performed in oven- and flame-dried glass-
ware under a positive pressure of argon. Air- and moisture-
sensitive reagents and solvents were transferred via syringe or
J. Chem. Soc., Perkin Trans. 1, 2000, 3143–3148
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1-Phenyl-3-[(2,4,6-trimethylphenyl)sulfanylpropan-1-one 2b.
The reaction was carried out as described above except using
2,4,6-trimethylbenzenethiol 1b (1.15 g, 7.54 mmol), DBU (1.25
mL, 8.34 mmol) and 3-chloro-1-phenylpropan-1-one (1.41 g,
8.34 mmol). Usual work-up gave the crude product, which was
purified by column chromatography (silica gel 30 g; hexane–
ethyl acetate 90:10) to afford 2b (1.74 g, 82%) (Found: C,
76.01; H, 7.09. C18H20OS requires C, 76.22; H, 6.99%); Rf 0.24
(hexane–ethyl acetate 90:10); νmax(neat) 2980, 1710, 1070, 950
cmϪ1; δH 2.26 (s, 3H, ArCH3), 2.51 (s, 6H, ArCH3), 3.02 (ddd,
2H, J 6.3, 6.5 and 9.5, SCH2), 3.17 (ddd, 2H, J 6.3, 6.5 and 9.5,
COCH2), 6.93 (s, 2H, ArH), 7.40–7.60 (m, 3H, ArH) 7.85–7.95
(m, 2H, ArH); m/z (EI) 284 (Mϩ, 100%), 207 (60), 179 (40),
133 (52).
C24H32O2S requires C, 74.82; H, 8.53%); Rf 0.35 (hexane–ethyl
acetate 70:30); νmax(neat) 2970, 2920, 1685, 1460, 1360, 1050
cmϪ1; δH 1.25 [d, 18H, J 6.9, CH(CH3)2], 2.90 [hep, 1H, J 6.9,
CH(CH3)2], 3.20–3.30 (m, 1H, SCH), 3.50–3.75 (m, 3H, SCH
and COCH2), 3.80–4.10 [br, 2H, CH(CH3)2], 7.10 (s, 2H, ArH),
7.40–7.65 (m, 3H, ArH), 7.95–8.05 (m, 2H, ArH); δC 23.8, 24.3,
24.7, 28.1, 33.1, 34.3, 48.3, 123.1, 128.1, 128.7, 133.6, 134.0,
136.2, 152.2, 196.9; m/z (EI) 384 (Mϩ, 1%), 252 (90), 149 (80),
105 (100%).
Stereoselective reduction of 3-(arylsulfinyl)propiophenones 3a–c
For the detailed experimental procedures, see the stereoselective
reduction of 9c–e described below.
Preparation of chiral ꢀ-keto sulfoxides
1-Phenyl-3-[(2,4,6-triisopropylphenyl)sulfanyl]propan-1-one
2c. The reaction was carried out as described above except
using 2,4,6-triisopropylbenzenethiol 1c (1.10 g, 4.65 mmol),
DBU (0.70 mL, 4.65 mmol) and 3-chloro-1-phenylpropan-1-
one (713 mg, 4.22 mmol). Usual work-up gave the crude
product, which was purified by column chromatography (silica
gel 50 g; hexane–ethyl acetate 97:3) to afford 2c (1.40 g, 90%)
(Found: C, 78.21; H, 8.75. C24H32OS requires C, 78.07; H,
8.89%); Rf 0.45 (hexane–ethyl acetate 90:10); νmax(neat) 2970,
1710, 1300, 1070, 940 cmϪ1; δH 1.25 [d, 18H, J 6.9, CH(CH3)2],
2.90 [hep, 1H, J 6.9, CH(CH3)2], 3.00 (t, 2H, J 7.1, SCH2), 3.20
(t, 2H, J 7.1, COCH2), 3.90 [hep, 2H, J 6.9, CH(CH3)2], 7.10
(s, 2H, ArH), 7.40–7.65 (m, 3H, ArH), 7.85–7.95 (m, 2H, ArH);
m/z (EI) 368 (Mϩ, 42%), 236 (54), 203 (100).
(S)-1,1-Diethoxy-3-[(2,4,6-triisopropylphenyl)sulfinyl]propane
6. A THF (5 mL) solution of 3,3-diethoxypropylmagnesium
bromide, prepared from 3-bromo-1,1-diethoxypropane (1.04 g,
4.93 mmol) and magnesium (144 mg, 5.92 mg-atom), was
slowly added to a THF (20 mL) solution of (R)-(Ϫ)-diacetone-
-glucosyl 2,4,6-triisopropylbenzenesulfinate6,8 5 (2.09 g, 4.09
mmol) at Ϫ78 ЊC, and the mixture was stirred for 1 h, quenched
with saturated aq. NH4Cl (10 mL), and extracted with CH2Cl2.
The combined organic extracts were washed with brine, dried
over Na2SO4, and concentrated under reduced pressure to leave
an oil, which was purified by column chromatography (silica gel
50 g; hexane–ethyl acetate 85:15) to afford 6 (1.42 g, 91%, 98%
ee) (Found: C, 69.06; H, 10.01. C22H38O3S requires C, 69.01; H,
10.10%); [α]D19 Ϫ80.4 (c 0.60, CHCl3); HPLC (CHIRALPAC AD,
hexane–PriOH 97:3, flow rate 0.5 mL minϪ1) tR 36.0 (S) and
47.8 min (R); Rf 0.37 (hexane–ethyl acetate 70:30); νmax(neat)
2950, 1460, 1360, 1250, 1020 cmϪ1; δH 1.25 [d, 18H, J 6.9,
CH(CH3)2], 1.27 (t, 6H, J 7.0, CH2CH3), 1.90–2.30 (m, 4H,
CH2), 2.80–3.00 [m, 2H, CH(CH3)2 and SOCH], 3.35–3.70 (m,
3H, OCH2 and SOCH), 3.70–4.10 [br, 2H, CH(CH3)2], 4.66 (t,
1H, J 5.3, OCH), 7.07 (s, 2H, ArH); δC 15.3, 23.7, 24.3, 24.6,
28.0, 28.6, 34.3, 49.5, 61.7, 61.9, 101.3, 134.2, 152.2; m/z (EI)
382 (Mϩ, 12%), 234 (100).
1-Phenyl-3-(p-tolylsulfinyl)propan-1-one 3a. To a solution of
the contaminated 2a (419 mg) in CH2Cl2 (8.2 mL) was added
MCPBA (421 mg, 2.44 mmol) at Ϫ78 ЊC. The mixture was
warmed to Ϫ30 ЊC and stirred for 4 h. Saturated aq. Na2SO3
(10 mL) was added and the mixture was extracted with CH2Cl2.
The combined organic extracts were washed successively with
saturated aq. Na2CO3 and brine, dried over Na2SO4, and con-
centrated under reduced pressure to leave a solid, which was
purified by column chromatography (silica gel 20 g; hexane–
ethyl acetate 60:40) to afford 3a (346 mg, 84% on the basis of
toluene-p-thiol) (Found: C, 70.56; H, 5.92. C16H16O2S requires
C, 70.54; H, 5.91%); mp 102–103 ЊC; Rf 0.28 (hexane–ethyl
acetate 50:50); νmax(KBr) 3050, 2930, 1680, 1590, 1410, 1350,
1050, 970, 740 cmϪ1; δH 2.42 (s, 3H, ArCH3), 3.00–3.60 (m, 4H,
SCH2 and COCH2), 7.30–7.60 (m, 7H, ArH), 7.90–7.95 (m, 2H,
ArH); δC 21.3, 30.3, 50.7, 123.9, 128.0, 128.6, 129.9, 133.5,
136.1, 140.0, 141.5, 196.9; m/z (EI) 272 (Mϩ, 0.2%), 132 (50),
105 (100).
(S)-3-[(2,4,6-Triisopropylphenyl)sulfinyl]propanal 7. To
a
solution of 6 (140 mg, 0.366 mmol) in CHCl3 (0.5 mL) was
added 50% trifluoroacetic acid (0.5 mL) at 0 ЊC. The mixture
was stirred for 12 h. Saturated aq. Na2CO3 was added and the
mixture was extracted with CH2Cl2. The combined organic
extracts were washed with brine, dried over Na2SO4, and con-
centrated under reduced pressure to leave an oil, which was
purified by column chromatography (silica gel 5 g, hexane–ethyl
acetate 70:30) to afford 7 (98 mg, 87%) (Found: C, 70.09; H,
9.15. C18H28O2S requires C, 70.10; H, 9.10%); [α]D20 Ϫ122.6 (c
0.70, CHCl3); Rf 0.16 (hexane–ethyl acetate 70:30); νmax(KBr)
2950, 1650, 1080, 990 cmϪ1; δH 1.25 [d, 18H, J 6.9, CH(CH3)2],
2.90 [hep, 1H, J 6.9, CH(CH3)2], 3.00–3.20 (m, 3H, CH(CH3)2
and SOCH), 3.50–3.60 (m, 1H, SOCH), 3.80–4.10 [br, 2H,
CH(CH3)2], 7.10 (s, 2H, ArH), 9.90 (s, 1H, CHO); δC 23.7, 24.1,
24.2, 24.5, 28.0, 34.2, 38.2, 46.2, 123.1, 133.6, 152.6, 198.4; m/z
(EI) 308 (Mϩ, 0.2%), 235 (100), 151 (50).
1-Phenyl-3-[(2,4,6-trimethylphenyl)sulfinyl]propan-1-one 3b.
The reaction was carried out as described above except using 2b
(735 mg, 2.59 mmol) and MCPBA (672 mg, 3.88 mmol). Usual
work-up gave a solid, which was purified by column chrom-
atography (silica gel 30 g; hexane–ethyl acetate 60:40) to afford
3b (729 mg, 99%) (Found: C, 71.97; H, 6.71. C18H20O2S requires
C, 71.91; H, 6.76%); Rf 0.32 (hexane–ethyl acetate 50:50);
νmax(KBr) 2930, 1680, 1450, 1380, 1230, 1060, 970, 850, 770
cmϪ1; δH 2.29 (s, 3H, ArCH3), 2.58 (s, 6H, ArCH3), 3.20–3.40 (m
1H, SCH), 3.50–3.65 (m, 3H, SCH and COCH2), 6.87 (s, 2H,
ArH), 7.40–7.60 (m, 3H, ArH), 7.95–8.00 (m, 2H, ArH);
δC 19.1, 21.0, 32.6, 46.5, 127.8, 128.1, 128.8, 131.0, 133.6,
136.2, 138.2, 141.2, 197.0; m/z (EI) 300 (Mϩ, 10%), 168 (70),
105 (100).
(SS,S)- and (SS,R)-1-Phenyl-3-[(2,4,6-triisopropylphenyl)-
sulfinyl]propan-1-ols 8c. To a solution of 7 (293 mg, 0.950
mmol) in THF (3.0 mL) was added PhMgBr (1.48 mol LϪ1
solution in THF, 1.0 mL, 1.48 mmol) at Ϫ78 ЊC. The reaction
mixture was then slowly warmed to Ϫ20 ЊC over a period of 1 h.
Usual work-up gave the crude product, which was purified by
column chromatography (silica gel 30 g; hexane–ethyl acetate
60:40) to give 8c (304 mg, 83%). The (SS*,S*):(SS*,R*) dia-
stereomer ratio was determined to be 57:43 by HPLC analysis.
1-Phenyl-3-[(2,4,6-triisopropylphenyl)sulfinyl]propan-1-one
3c. The reaction was carried out as described above except using
2c (156 mg, 0.423 mmol) and MCPBA (116 mg, 0.635 mmol).
Usual work-up gave the crude product, which was purified by
column chromatography (silica gel 10 g; hexane–ethyl acetate
80:20) to afford 3c (161.5 mg, 99%) (Found: C, 74.96; H, 8.39.
(S)-4-[(2,4,6-Triisopropylphenyl)sulfinyl]butan-2-ol 8d. The
reaction was carried out as described above except using 7 (104
3146
J. Chem. Soc., Perkin Trans. 1, 2000, 3143–3148

View Article Online
mg, 0.336 mmol) and MeMgI (0.96 mol LϪ1 solution in Et2O;
0.55 mL, 0.528 mmol). Usual work-up gave the crude product,
which was purified by column chromatography (hexane–ethyl
acetate 50:50) to afford 8d (73 mg, 67%). The (SS*,S*):
(SS*,R*) diastereomer ratio was determined to be 80:20 by
HPLC analysis.
0.049 mmol) at Ϫ78 ЊC. After stirring of the mixture for 1 h,
MeOH (1.0 mL) was added. Usual work-up gave the crude
product which was purified by column chromatography (silica
gel 1 g; hexane–ethyl acetate 70:30) to afford 8c (12 mg, 93%).
The (SS,S):(SS,R) diastereomer ratio was determined to be
95:5 by HPLC analysis (Found: C, 74.57; H, 8.86. C24H34O2S
requires C, 74.47; H, 8.96%); HPLC (COSMOSIL, hexane–
iPrOH 93:7, flow rate 1.0 mL minϪ1) tR 15.1 (SS,S) and 18.7
min (SS,R); Rf 0.13 (hexane–ethyl acetate 70:30); νmax(neat)
3450, 3000, 1680, 1080 cmϪ1; δH 1.25 [d, 18H, J 6.9, CH(CH3)2],
2.20–2.50 (m, 2H, CH2), 2.80 [hep, 1H, J 6.9, CH(CH3)2],
2.70–3.00 (m, 1H, SCH), 3.06 (s, 1H, OH), 3.40–3.60 (m, 1H,
SCH), 3.70–4.00 [br, 2H, CH(CH3)2], 4.90–5.00 (m 1H,
CHOH), 7.06 (s, 2H, ArH), 7.20–7.40 (m, 5H, ArH); δC 23.7,
24.2, 24.6, 28.0, 34.3, 50.8, 72.9, 122.9, 123.3, 125.8, 127.8,
128.6, 133.8, 143.6, 152.4; m/z (EI) 386 (Mϩ, 45%), 351 (50), 279
(100), 233 (55).
(S)-1-[(2,4,6-Triisopropylphenyl)sulfinyl]pentan-3-ol 8e. The
reaction was carried out as described above except using 7 (98
mg, 0.318 mmol) and EtMgBr (0.88 mol LϪ1 solution in Et2O,
0.60 mL, 0.528 mmol). Usual work-up gave the crude product,
which was purified by column chromatography (hexane–ethyl
acetate 70:30) to afford 8e (85 mg, 79%). The (SS*,S*):
(SS*,R*) diastereomer ratio was determined to be 66:34 by
HPLC analysis.
(S)-1-Phenyl-3-[(2,4,6-triisopropylphenyl)sulfinyl]propan-1-
one 9c. To a CH2Cl2 (1.0 mL) solution of PCC (254 mg, 1.18
mmol) was added a solution of 8c (304 mg, 0.787 mmol)
in CH2Cl2 (1.0 mL) at room temperature. After stirring of
the mixture for 2 h, Et2O was added and the supernatant
decanted from the black gum. The insoluble residue was
washed thoroughly with Et2O. The ethereal solution was con-
centrated under reduced pressure to leave a residue, which was
purified by column chromatography (silica gel 30 g; hexane–
ethyl acetate 80:20) to afford 9c (200 mg, 66%, 98% ee). HPLC
(CHIRALPAC AD hexane–iPrOH 95:5, flow rate 0.5 mL
minϪ1) tR 30.9 (R) and 33.3 min (S); [α]D20 Ϫ107.4 (c 0.486,
CHCl3).
(S)-4-[(2,4,6-Triisopropylphenyl)sulfinyl]butan-2-ol 8d. The
reaction was carried out as described above except using 9d (36
mg, 0.112 mmol) and DIBAL (0.95 mol LϪ1 solution in hexane,
0.18 mL, 0.17 mmol). Usual work-up gave the crude product,
which was purified by column chromatography (hexane–ethyl
acetate 60:40) to afford 8d (35 mg, 96%). The (SS*,S*):
(SS*,R*) diastereomer ratio was determined to be 98:2 by
HPLC analysis (Found: C, 70.32; H, 9.94. C19H32O2S requires
C, 70.30; H, 9.99%); HPLC (COSMOSIL, hexane–iPrOH 94:6,
flow rate 1.0 mL minϪ1) tR 117.9 (SS,R) and 129.5 min (SS,S); Rf
0.15 (hexane–ethyl acetate 70:30); νmax(neat) 3500, 2980, 1660,
1500, 1280, 1060 cmϪ1; δH 1.25 [d, 18H, J 6.9, CH(CH3)2], 1.26
(d, 3H, J 6.9, CH3), 2.03 (dt, 2H, J 6.0, 6.9, CH2CH2CH), 2.68
(s, 1H, OH), 2.80–3.00 [m, 2H, CH(CH3)2 and SCH], 3.45–3.60
(m, 1H, SCH), 3.80–4.10 [m, 3H, CH(CH3)2 and CHOH], 7.04
(s, 1H, ArH), 7.08 (s, 1H, ArH); m/z (EI) 324 (Mϩ, 64%), 307
(80), 252 (60), 233 (98), 149 (100).
(S)-4-[(2,4,6-Triisopropylphenyl)sulfinyl]butan-2-one 9d. The
reaction was carried out as described above except using
PCC (72 mg, 0.336 mmol) and 8d (73 mg, 0.224 mmol). Usual
work-up gave the crude product, which was purified by column
chromatography (hexane–ethyl acetate 70:30) to afford 8d
(36 mg, 50%, 98% ee) (Found: C, 70.76; H, 9.38. C19H30O2S
requires C, 70.73; H, 9.40%); mp 104–105 ЊC; [α]D20 Ϫ97.6
(c 0.117, CHCl3); HPLC (CHIRALCEL OD-H, hexane–PriOH
95:5, flow rate 0.5 mL minϪ1) tR 14.4 (S) and 16.7 min (R); Rf
0.43 (hexane–ethyl acetate 50:50); νmax(neat) 2960, 2860, 1710,
1600, 1460, 1360, 1180, 1050, 1030 cmϪ1; δH 1.25 [d, 18H, J 6.9,
CH(CH3)2], 2.24 (s, 3H, COCH3), 2.90 [hep, 1H, J 6.9,
CH(CH3)2], 3.00–3.20 (m, 3H, COCH2 and SOCH), 3.40–3.60
(m, 1H, SOCH), 3.80–4.10 [br, 2H, CH(CH3)2], 7.08 (s, 2H,
ArH); δC 23.7, 24.2, 24.5, 24.6, 28.0, 30.0, 34.3, 37.6, 47.8,
123.1, 123.2, 133.9, 152.5, 205.3; m/z (EI) 322 (Mϩ, 2%), 255
(100), 149 (90).
(S)-1-[(2,4,6-Triisopropylphenyl)sulfinyl]pentan-3-ol 8e. The
reaction was carried out as described above except using 9e (30
mg, 0.089 mmol) and DIBAL (0.95 mol LϪ1 solution in hexane,
0.14 mL, 0.133 mmol). Usual work-up gave the crude product,
which was purified by column chromatography (hexane–ethyl
acetate 60:40) to afford 8e (28 mg, 92%). The (SS*,S*):
(SS*,R*) diastereomer ratio was determined to be 96:4 by
HPLC analysis (Found: C, 70.96; H, 10.12. C20H34O2S requires
C, 71.01; H, 10.05%); HPLC (COSMOSIL, hexane–iPrOH
94:6, flow rate 1.0 mL minϪ1) tR 42.9 (SS,R) and 45.4 min
(SS,S); Rf 0.39 (hexane–ethyl acetate 50:50); νmax(neat) 3480,
2970, 1660, 1250, 1080 cmϪ1; δH 0.98 (t, 3H, J 7.4, CH3), 1.25 [d,
18H, J 6.9, CH(CH3)2], 1.55 (dq, 2H, J 6.3, 7.4, CH2CH3), 1.95–
2.10 (m, 2H, CH2CH2CH), 2.50–2.70 (br, 1H, OH), 2.80–3.00
[m, 2H, CH(CH3)2 and SOCH], 3.45–3.60 (m, 1H, SOCH),
3.60–3.85 (m, 1H, CHOH), 3.80–4.10 [m, 2H, CH(CH3)2], 7.08
(s, 2H, ArH); m/z (EI) 338 (Mϩ, 60%), 321 (78), 252 (76), 233
(100), 149 (94).
(S)-1-[(2,4,6-Triisopropylphenyl)sulfinyl]pentan-3-one 9e. The
reaction was carried out as described above except using
PCC (40 mg, 0.167 mmol) and 8e (38 mg, 0.111 mmol). Usual
work-up gave the crude product, which was purified by column
chromatography (hexane–Et2O 90:10) to afford 9e (17 mg,
45%, 98% ee); [α]D20 Ϫ100.4 (c 0.120, CHCl3); HPLC (CHIRAL-
PAC AD, hexane–iPrOH 95:5, flow rate 0.5 mL minϪ1) tR 20.9
(S) and 24.1 min (R) (Found: C, 71.38; H, 9.58. C20H32O2S
requires C, 71.45; H, 9.50%); Rf 0.27 (hexane–ethyl acetate
Preparation of the chiral homoallyl alcohol 13
1-Phenyl-3-[(2,4,6-triisopropylphenyl)sulfinyl]-4-(trimethyl-
silyl)butan-1-ol 12. To a THF (1.0 mL) solution of diisoprop-
ylamine (0.160 mL, 1.14 mmol) was added n-butyllithium
(1.52 mol LϪ1 solution in hexane; 0.72 mL, 0.109 mmol) at 0 ЊC
and the mixture was stirred for 10 min. The reaction mixture
was then cooled to Ϫ78 ЊC and a THF (1.0 mL) solution of 8c
(190 mg, 0.491 mmol) was added. After stirring of the mixture
for 30 min, a THF (1.0 mL) solution of (iodomethyl)trimethyl-
silane (1.10 mL, 0.741 mmol) was added and the mixture was
warmed to room temperature and stirred for 2 h. Usual work-
up gave the crude product, which was purified by column
chromatography (silica gel 12 g; hexane–ethyl acetate 70:30) to
give 12 (184 mg, 79%) (Found: C, 71.13; H, 9.38. C28H44O2SSi
70:30); νmax(neat) 2960, 1710, 1460, 1360, 1080, 970 cmϪ1
;
δH 1.10 (t, 3H, J 7.4, CH3), 1.25 [d, 18H, J 6.9, CH(CH3)2], 2.50
(q, 2H, J 7.4, CH2), 2.90 [hep, 1H, J 6.9, CH(CH3)2], 2.95–3.10
(m, 3H, COCH2 and SOCH), 3.45–3.60 (m, 1H, SOCH), 3.80–
4.10 [br, 2H, CH(CH3)2], 7.08 (s, 2H, ArH); m/z (EI) 336 (Mϩ,
0.2%), 252 (100), 233 (48), 149 (45).
Stereoselective reduction of chiral ꢀ-keto sulfoxides 9c–e with
DIBAL
(S)-1-Phenyl-3-[(2,4,6-triisopropylphenyl)sulfinyl]propan-1-ol
8c. To a solution of 9c (12.5 mg, 0.032 mmol) in THF (0.16 mL)
was added DIBAL (0.95 mol LϪ1 solution in hexane, 0.05 mL,
J. Chem. Soc., Perkin Trans. 1, 2000, 3143–3148
3147

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1983, 24, 503; G. Guanti, E. Narisano, F. Pero, L. Banfi and
C. Scolastico, J. Chem. Soc., Perkin Trans. 1, 1984, 189; T. Fujisawa,
A. Fujimura and Y. Ukaji, Chem. Lett., 1988, 1541.
requires C, 71.12; H, 9.36%); Rf 0.66 (hexane–ethyl acetate
50:50); νmax(neat) 3300, 2950, 1600, 1460, 1250, 1010, 840 cmϪ1
;
δH Ϫ0.09 [s, 9H, Si(CH)3], 0.35 (dd, 1H, J 1.9, 12.8, CHSi),
0.70 (d, 1H, J 12.8, CHSi), 1.10–1.40 [m, 18H, CH(CH3)2],
2.20–2.60 (m, 2H, CH2), 2.91 [hep, 1H, J 6.7, CH(CH3)2], 3.60–
3.90 [m, 2H, CH(CH3)2], 4.20–4.40 (m, 1H, SOCH), 4.85–5.00
(m, 1H, OCH), 5.75 (d, 1H, J 2.0, OH), 7.00–7.50 (m, 7H,
ArH); δC Ϫ0.9, 18.2, 22.6, 23.8, 25.7, 28.2, 29.6, 34.4, 45.4, 59.2,
73.6, 121.4, 125.0, 125.8, 127.2, 127.9, 128.4, 131.7, 145.3,
153.1.
4 For the reduction of γ-keto sulfoxides: (a) Y. Arai, A. Suzuki,
T. Masuda, Y. Masaki and M. Shiro, Chem. Pharm. Bull., 1996, 44,
1756; (b) G. Solladié, G. Hanquet and C. Rolland, Tetrahedron Lett.,
1997, 38, 5847; (c) G. Solladié, G. Hanquet, I. Izzo and R. Crumbie,
Tetrahedron Lett., 1999, 40, 3071; for the nucleophilic addition to
γ-keto sulfoxides: (d) L. D. Girodier and F. P. Rouessac, Tetrahedron:
Asymmetry, 1994, 5, 1203; (e) Y. Arai, T. Masuda, Y. Masaki and
T. Koizumi, Heterocycles, 1994, 38, 1751; ( f ) Y. Arai, A. Suzuki,
T. Masuda, Y. Masaki and M. Shiro, J. Chem. Soc., Perkin Trans. 1,
1995, 2913; (g) Y. Arai, T. Masuda and Y. Masaki, Synlett, 1997,
1459; for the 1,6-remote DIBAL reduction of ε-keto sulfoxides, see:
(h) C. Iwata, Y. Moritani, K. Sugiyama, M. Fujita and T. Imanishi,
Tetrahedron Lett., 1987, 28, 2255.
5 G. Solladié, F. Colobert and F. Somny, Tetrahedron Lett., 1999, 40,
1227.
6 T. Toru, Y. Watanabe, M. Tsusaka and Y. Ueno, J. Am. Chem. Soc.,
1993, 115, 10464; N. Mase, Y. Watanabe and T. Toru, J. Org. Chem.
1998, 63, 3899; Bull. Chem. Soc. Jpn., 1998, 71, 2957.
7 N. Mase, Y. Watanabe, Y. Ueno and T. Toru, J. Org. Chem., 1997,
62, 7794.
(S)-1-Phenylbut-3-en-1-ol 13. To a solution of 12 (152 mg,
0.321 mmol) in THF (1.0 mL) was added a THF solution of
TBAF (1.0 mol LϪ1; 0.64 mL, 0.64 mmol) at room temperature
and the mixture was stirred for 1 h. THF was then evaporated
off under reduced pressure and the residue was purified by
column chromatography (silica gel 5 g; hexane–CH2Cl2–Et2O
50:45:5) to afford 13 (43 mg, 91%) [α]D21 Ϫ44.8 (c 0.28, benzene)
{lit.,14 [α]D21 Ϫ48.7 (c 0.692, benzene)}.
8 S. Nakamura, H. Yasuda, Y. Watanabe and T. Toru, Tetrahedron
Lett., 2000, 41, 4157.
9 We have reported an efficient method for the preparation of
sulfinates: Y. Watanabe, N. Mase, M. Tateyama and T. Toru,
Tetrahedron: Asymmetry, 1999, 10, 737.
10 P. Pitchen and H. B. Kagan, Tetrahedron Lett., 1984, 25, 1049;
S. H. Zhao, O. Samuel and H. B. Kagan, Tetrahedron, 1987, 43,
5135.
Acknowledgements
This work was supported by a Grant-in Aid for Scientific
Research (no. 11650890) from the Ministry of Education,
Science, Sports and Culture of Japan and the Sasakawa
Scientific Research Grant from The Japan Science Society.
11 J. A. Dale, D. L. Dull and H. S. Mosher, J. Org. Chem., 1969, 34,
2543; J. A. Dale and S. H. Mosher, J. Am. Chem. Soc., 1973, 95,
512; B. M. Trost, J. L. Belletire, S. Godleski, P. G. McDougal,
J. M. Balkovek, J. J. Baldwin, M. E. Christy, G. S. Ponticello,
S. L. Varga and J. P. Springer, J. Org. Chem., 1986, 51, 2370.
12 Attempted thermal desulfinylation of 8c was unsuccessful even
under strong basic conditions using, e.g., DBU, due probably to the
bulkiness of the triisopropylphenyl group.
13 Easy transformation of a sulfinyl group to an olefin linkage has been
reported with the simultaneous elimination of the β-silyl group:
M. Ochiai, S. Tada, K. Sumi and E. Fujita, J. Chem. Soc., Chem.
Commun., 1982, 281; I. Fleming, J. Goldhill and D. A. Perry,
J. Chem. Soc., Perkin. Trans. 1, 1982, 1563; S. Kusuda, Y. Ueno and
T. Toru, Tetrahedron, 1994, 50, 1045; T. Toru, S. Nakamura,
H. Takemoto and Y. Ueno, Synlett, 1997, 449; S. Nakamura,
Y. Watanabe and T. Toru, J. Chem. Soc., Perkin Trans. 1, 1999, 3403;
J. Org. Chem., 2000, 65, 1758.
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