SmI2-coupling reaction of chiral non-racemic α-bromo-α′-sulfinyl ketones with imines: synthesis of enantiomerically pure 2-methyl-3-amino-1-ol moieties

Article abstract of DOI:10.1016/j.tetasy.2009.11.020

Chiral non-racemic α-bromo-α′-sulfinyl ketones were shown to react with imines in the presence of SmI₂ to give the corresponding 1,3-aminoketo derivatives with good syn-diastereoselectivity. Further reduction of these adducts either with DIBAL-

Full text of DOI:10.1016/j.tetasy.2009.11.020

Tetrahedron: Asymmetry 20 (2009) 2780–2787
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
SmI2-coupling reaction of chiral non-racemic
-bromo-a0-sulfinyl ketones
a
with imines: synthesis of enantiomerically pure 2-methyl-3-amino-1-ol
moieties
*
Marie Barbarotto, Julie Geist, Sabine Choppin, Françoise Colobert
Laboratoire de Stéréochimie, UMR CNRS 7509, Université de Strasbourg (ECPM), 25 rue Becquerel, F-67087 Strasbourg cedex 2, France
a r t i c l e i n f o
a b s t r a c t
Chiral non-racemic a
-bromo-a0-sulfinyl ketones were shown to react with imines in the presence of SmI2
Article history:
Received 14 September 2009
Accepted 2 November 2009
Available online 6 January 2010
to give the corresponding 1,3-aminoketo derivatives with good syn-diastereoselectivity. Further reduc-
tion of these adducts either with DIBAL-H only or with DIBAL-H in the presence of Yb(OTf)3 afforded
syn- and anti-2-methyl-3-amino-1-ol moieties, respectively, in good yields and diastereoselectivities.
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
reoselective reduction8 of the corresponding b-keto sulfoxide 3, we
report a stereoselective access to the syn- and anti-stereotriad 4
One of the most important goals for the organic chemists over
the past few years has been the development of new stereoselec-
tive methods for the synthesis of enantiomerically pure complex
molecules with important biological properties. In this context,
the enantiopure structural units of b-aminoalcohols are a very
attractive fragment because of their presence in many compounds
with potential therapeutic properties1 and their use as catalysts
especially in the alkylation of aldehydes with dialkylzinc deriva-
and 5 (Scheme 1).
2. Results and discussion
The chiral non-racemic
a
-bromo-a0-t-butyl-sulfinyl ketone 1
was prepared as described in the procedure reported previously.7
We initiated our studies by considering different reaction temper-
atures and different solvents in the coupling reaction between 1
and p-chlorophenylaldimines 2a–c bearing N-protecting groups
such as N-phenyl,9 N-p-MeO phenyl (PMP),9 and N-sulfonyl-p-to-
lyl.10 The results are summarised in Table 1.
tives.2 In this family, b-alkyl-
c-aminoalcohol, an interesting stereo-
triad, is present in the nikkomycins that are nucleoside peptide
antibiotics with three contiguous stereocenters of a b-methyl
c
-amino secondary alcohol moiety.3
The best yield 72%, syn/anti selectivity 100/0 and syn-diastere-
oselectivity 85/15 were obtained in the coupling reaction between
1 and the p-chlorophenylaldimine 2c protected as N-sulfonyl-p-to-
lyl group using SmI2 in THF at ꢀ78 °C (Table 1, entry 7).
Samarium(II)iodide is known to be a polyvalent reducing agent
which has been applied to a multitude of important synthetic
reactions with generally high chemoselectivity and high levels of
stereochemical control.4
With N-phenyl and N-p-MeO phenyl-protected p-chlorophenyl-
aldimines 2a and 2b at ꢀ78 °C, the syn/anti selectivity is lower,
respectively, 70/30 and 75/25 with a syn-diastereoselectivity of
80/20 and 98/2 (Table 1, entries 1 and 2). Decreasing the temper-
ature to ꢀ100 °C did not increase the selectivity (Table 1, entry
3). With p-tolyl instead of t-butyl on the sulfoxide in the reaction
with N-p-MeO phenyl-protected p-chlorophenylaldimines 2b,
selectivity is higher but the yield decreased (Table 1, entry 4).
Using Lewis acids such as Sc(OTf)3 and Yb(OTf)3 did not im-
prove the yield or the diastereoselectivity (Table 1, entries 5 and 6).
Next, we applied our coupling reaction in THF at ꢀ78 °C in the
presence of SmI2 between 1 and various N-sulfonyl-p-tolyl-pro-
tected p-substituted (het)arylaldimines 2c–j (Table 2).
Its use for the preparation of enantiomerically pure unsymmet-
rical vicinal diamines by reductive cross-coupling of nitrones with
chiral N-tert-butanesulfinyl imines has been developed.5
In relation with a programme devoted to asymmetric synthesis
mediated by sulfoxides,6 we have recently described a highly
stereoselective Reformatsky-type reaction of chiral non-racemic
a
-bromo-a0-sulfinyl ketones with aldehydes in the presence of
SmI2.7
Herein we report the synthesis of syn- and anti-2-methyl-3-
amino-1-ol moieties. Using an SmI2-coupling reaction between
-bromo-a0-sulfinyl ketone 1 and various protected imines 2, as
a
well as the well established DIBAL-H or Lewis acid/DIBAL-H diaste-
As can be seen in entries 1–8, with the electron-deficient
p-substituted phenylaldimines such as p-chloro, p-bromo and
p-fluoro, we obtained the best selectivities and good yields (Table 2,
* Corresponding author. Tel.: +33 03 68852744; fax: +33 03 68852742.
E-mail address: francoise.colobert@unistra.fr (F. Colobert).
0957-4166/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2009.11.020

M. Barbarotto et al. / Tetrahedron: Asymmetry 20 (2009) 2780–2787
2781
O
O
S
R'
:
NH
OH
O
S
t-Bu
:
DIBAL-H
Br
R
THF, -78 ºC
t-Bu
1
R'
4
NH
O
O
S
SmI2
THF
+
:
R
t-Bu
3
R'
R'
H
NH
OH
O
N
DIBAL-H/Yb(OTf)3
THF, -78 ºC
:
S
R
R
t-Bu
5
2
Scheme 1. Synthesis of syn- and anti-2-methyl-3-amino-1-ol moieties.
Table 1
Asymmetric SmI2-coupling reactions with N-protected aldimines 2a–ca
R
N
NHR O
O
S
NHR O
O
S
O
O
S
:
SmI2
:
H
t-Bu
t-Bu
+
+
t-Bu
THF, T(ºC), 2h
Cl
Br
Cl
Cl
3a-c syn 2
3a-c syn 1
1
2a R = C
+ anti stereoisomers
6H5
2b R=p-CH3OC6H4
2c R= p-CH3C6H4SO2
Entry
aldimine
R
T(°C)
syn/antib
syn1/syn2b
anti1/anti2b
Yield 3a–cc (%)
1
2
3
4
5
6
7
2a
2b
2b
2b
2b
2b
2c
C6H5
ꢀ78
ꢀ78
ꢀ100
ꢀ78
ꢀ78
ꢀ78
ꢀ78
70/30
75/25
75/25
89/11
75 /25
79/21
100/0
80/20
98/2
98/2
2/98
98/2
2/98
85/15
80/20
90/10
90/10
50/50
85/15
85/15
—
57
65
53
p-CH3OC6H4
p-CH3OC6H4
p-CH3OC6H4
p-CH3OC6H4
p-CH3OC6H4
p-CH3C6H4SO2
30d
26e
40f
72
a
b
c
d
e
f
Reactions were performed with 0.80 mmol of compound 1.
Determined by 1H NMR analysis of the product.
Isolated yields after flash chromatography.
p-Tolyl group on the sulfoxide instead of a t-butyl group.
With Sc(OTf)3 (10 mol %).
With Yb(OTf)3 (10 mol %).
Table 2
SmI2-coupling reaction with various N-sulfonylp-tolyl-protected p-substituted (het)arylaldimines 2c–ja
SO2 p-Tol
O
O
S
SO2p-Tol
HN
O
O
S
N
SmI2
t-Bu
R
THF, -78 ºC, 2h
R
H
t-Bu
Br
1
2c-j
3c-j
Entry
2
R
syn/antib
syn1/syn2b
anti1/anti2b
Yield 3c–jc (%)
1
2
3
4
5
6
7
8
2c
2d
2e
2f
2g
2h
2i
p-ClC6H4
p-BrC6H4
p-FC6H4
100/0
100/0
100/0
100/0
79/21
100/0
72/28
55/45
85/15
85/15
89/11
90/10
72/28
80/20
80/20
100/0
—
—
—
—
70/30
—
100/0
100/0
72
68
50
40
53
C6H5
p-CH3OC6H4
Thiophène
p-NO2C6H4
p-CNC6H4
50
47d
50d
2j
a
b
c
Reactions were performed with 0.80 mmol of compound 1.
Determined by 1H NMR analysis of the product.
Isolated yields after flash chromatography.
d
Isolated yield of the corresponding alcohol.

2782
M. Barbarotto et al. / Tetrahedron: Asymmetry 20 (2009) 2780–2787
entries 1–3). In this family, compound 3d is very attractive because
of the presence of the bromine atom to perform metal-catalysed
cross-coupling reaction. With no substituent on the phenyl group,
the reactivity of the aldimine decreased (40% yield) but we noticed
the same selectivity (Table 2, entry 4).
With electron-rich p-substituted phenylaldimines such as-
p-methoxy 2g, the selectivity decreased dramatically (Table 2, entry
5). With a thiophene aldimine, the syn product was formed stereose-
lectively with modest yield (Table 2, entry 6). Surprisingly the strong
electron-deficient N-sulfonyl-p-tolyl-protected phenylaldimines
2i–j, respectively, para-substituted with a nitro and a cyano group
were hydrolysed to aldehyde in the reaction medium giving the cor-
responding alcohols (Table 2, entries 7 and 8).
In order to prepare the 1,3-amino-alcohol moieties we performed
the well-known diastereoselective reduction of b-ketosulfoxides8
either with DIBAL-H only or with DIBAL-H in the presence of
Yb(OTf)3. Starting from the adducts 3c and 3d, the syn- and anti-2-
methyl-3-amino-1-ol moieties 4c, 4d and 5d were obtained in good
yields and diastereoselectivities (Scheme 2).
Figure 1. Absolute stereochemistry and ORTEP of (2S,3R,4R)-4d. The protons are
To confirm the absolute configuration of the major stereoadduct
4d, after crystallisation, suitable crystals were obtained and the
structure (2S,3R,4R)-4d was determined by X-ray analysis (Fig. 1).
In order to obtain the enantiopure syn- and anti-2-methyl-3-
amino-1-ol derivatives, protection of the alcohol as an acetate al-
lowed an easier chromatographic separation to give the enantio-
omitted for more clarity.
TFAA/2,4,6-collidine pseudo-Pummerer conditions11 followed by
subsequent reduction with NaBH4 was performed to give the
corresponding alcohol 8 in 60% yield (Scheme 3) after flash
chromatography.
pure syn-2-methyl-3-amino-1-acetate moiety 6d ½a D20
¼ þ336 (c
ꢁ
3. Conclusion
0.6, acetone) as well as the enantiopure anti-2-methyl-3-amino-
1-acetate moiety 7d ½a D20
¼ þ205 (c 0.6, acetone) (Scheme 2).
ꢁ
In conclusion, we have developed an asymmetric SmI2-coupling
reaction between chiral
Finally to show the interest of the sulfinyl moiety inorganic syn-
a
-bromo-a0-sulfinyl ketones and various
thesis, treatment of the enantiopure compound 6d under classical
p -TolSO2
NH OAC
O
S
(R)
(R)
(S)
t-Bu
X
6d X=Br quantitative, d.e. > 98%
Ac2O, Pyr.
p-TolSO2
NH OH
(R)
O
S
DIBAL-H
(R)
(S)
t-Bu
THF, -78 ºC, 1h
X
p -TolSO2
NH
(R)
O
O
S
4c
4d
X=Cl 80%, d.e. > 80%
X=Br 95%, d.e. > 83%
(R)
t-Bu
p -TolSO2
NH OH
O
S
X
(R)
DIBAL-H/Yb(OTf)3
THF, -78 ºC, 1h
3c X=Cl
3d X=Br
(R)
(R)
t-Bu
X
5d
X=Br 95%, d.e.> 80%
Ac2O, Pyr.
p -TolSO2
NH OAc
O
S
(R)
(R)
(R)
t-Bu
X
7d X=Br quantitative, d.e.> 98%
Scheme 2. Diastereoselective reduction of the stereoadducts 3c and 3d.

M. Barbarotto et al. / Tetrahedron: Asymmetry 20 (2009) 2780–2787
2783
p -TolSO 2
1) 2,4,6-collidine
TFAA, CH3CN, 0 ºC
p -TolSO 2
NH OAC
O
S
NH OAC
OH
2) K2CO3
3) NaBH4
t-Bu
Br
Br
60%
6d
8
Scheme 3. Pummerer reaction of compound 6d.
N-sulfonyl-p-tolyl-protected p-substituted phenylaldimines with
satisfactory yields and selectivities. Subsequent diastereoselective
reduction led to enantiopure syn- and anti-2-methyl-3-amino-1-
alcohols in high yields and high diastereoselectivities.
1H NMR (300 MHz, CDCl3) d 8.45 (s, 1H, HC@N), 7.63 (A2B2, 4H,
CHAr, JAB = 8.4 Hz, = 117.6 Hz), 7.08 (A2B2, 4H, CHAr, JAB = 8.9 Hz,
D
m
Dm
= 89.6 Hz), 3.84 (s, 3H, OCH3); 13C NMR (75 MHz, CDCl3) d 158.5
(CAr), 156.7 (HC@N), 144.5, 136.9, 134.9, 129.7, 129.0, 122.2, 114.4
(CAr), 55.5 (OCH3).
4. Experimental
4.1. General
4.3. General procedure for the synthesis of sulfonamides:10
A mixture of aromatic aldehyde (10.82 mmol, 1 equiv) and p-
tolylsulfonamide (10.05 mmol, 1.1 equiv) was heated in toluene
(25 mL) with a Dean–Stark apparatus in the presence of activated
molecular sieve 5 Å and a catalytic amount of amberlyst 15 for
16 h. The mixture was cooled to room temperature without stir-
ring, filtered, washed with toluene (2 ꢂ 50 mL) and the filtrate
was concentrated under reduced pressure. The solid obtained
was then triturated in pentane.
THF was freshly distilled under an argon atmosphere on sodium
and benzophenone. Toluene was distilled under an argon atmo-
sphere on sodium. All other reagents and solvents were used as re-
ceived from commercial sources. All reactions were performed
under an argon atmosphere unless stated otherwise. 1H and 13C
NMR spectra were recorded in CDCl3 at room temperature on Bru-
ker 200, 300 or 400 MHz spectrometers. All chemical shifts (d) are
quoted in parts per million (ppm). 1H chemical shifts are refer-
enced to CDCl3 (d = 7.26). 13C chemical shifts are referenced to
CDCl3 (d = 77.0). Melting points were obtained on a Büchi 535
apparatus. IR spectra were recorded on a Perkin–Elmer Spectrum
One Spectrophotometer and only the most significant absorption
bands are given in cmꢀ1. HMRS were recorded by electrospray ion-
isation method obtained with a microTOF LC Bruker Daltonics
apparatus. Specific rotations were determined at room tempera-
ture in a Perkin–Elmer 241 polarimeter for sodium (k = 589 nm).
X-rays were recorded by a diffractometer Kappa CCD Oxford Cryo-
4.3.1. N-(4-Chlorobenzylidene)-4-methylbenzenesulfonamide 2c
White solid. Rf (cyclohexane/EtOAc 7:3) = 0.5. Mp = 175 °C.
Yield 98%. IR (neat)
m
1650, 1580, 1320, 1162; 1H NMR (300 MHz,
CDCl3) d 9.01 (s, 1H, HC@N), 7.92–7.87 (m, 4H, CHAr), 7.5–7.47
(m, 2H, CHAr), 7.38–7.36 (m, 2H, CHAr), 2.46 (s, 1H, CH3C6H4); 13C
NMR (75 MHz, CDCl3) d 168.9 (HC@N), 144.8, 141.4, 134.9, 132.4,
130.8, 129.9, 128.1, 126.5, (CAr), 21.678 (CH3C6H4).
4.3.2. N-(4-Bromobenzylidene)-4-methylbenzenesulfonamide 2d
White solid. Yield 98%. Rf (cyclohexane/EtOAc 7:3) = 0.46.
Mp = 190 °C. 1H NMR (300 MHz, CDCl3) d 8.90 (s, 1H, HC@N),
7.82–7.79 (m, 2H, CHAr), 7.72–7.70 (m, 2H, CHAr), 7.57–7.54 (m,
2H, CHAr), 7.29–7.22 (m, 2H, CHAr), 2.37 (s, 3H, CH3C6H4); 13C
NMR (75 MHz, CDCl3) d 168.8 (HC@N), 144.8, 143.6, 134.9, 132.4,
131.0, 129.9, 128.2, 126.5 (CAr), 21.7 (CH3C6H4).
system liquid N2 using monochromatic radiations Mo
0.71073 Å. Data of diffraction were corrected by absorption and
analysed with OPENMOLEN Package. Column chromatography was
Ka =
carried out on Silica Gel 60 (40–63 lm, Merck) or on unmetallated
silica gel.12 Thin layer chromatography (TLC) was carried out on
glass plates silica Gel 60 F254 or on aluminium plates Silica Gel
60 F254 purchased from Merck.
4.3.3. N-(4-Fluorobenzylidene)-4-methylbenzenesulfonamide 2e
White solid. Rf (cyclohexane/EtOAc 7:3) = 0.51. Mp = 111 °C.
Yield 98%. 1H NMR (CDCl3, 300 MHz) d 8.99 (s, 1H, HC@N), 7.98–
4.2. General procedure for the synthesis of N-protected
aldimines:9
7.92 (m, 2H, CHAr), 7.89 (d, 2H, CHAr, J = 8.4 Hz), 7.17 (t, 2H, CHAr
,
J = 8.7 Hz), 2.44 (s, 3H, CH3C6H4); 13C NMR (75 MHz, CDCl3) d
168.5 (HC@N), 144.7, 135.0, 133.8, 129.8, 128.1, 126.4, 116.8,
116.5 (CAr), 21.6 (CH3C6H4).
A solution of the amine (1 equiv) and aliphatic or aromatic alde-
hyde (1 equiv) in THF or dichloromethane with activated molecu-
lar sieve 5 Å was stirred for 14 h at room temperature. The
resulting mixture was filtered over Celite 545Ò and the solvent
was evaporated under reduced pressure. The aldimines will then
be used without any additional purification.
4.3.4. N-Benzylidene-4-methylbenzenesulfonamide 2f
White solid. Rf (cyclohexane/EtOAc 7:3) = 0.43. Mp = 105 °C.
Yield 90%. IR (neat)
m
1650, 1570, 1380, 1320, 1160; 1H NMR
(300 MHz, CDCl3) d 8.95 (s, 1H, HC@N), 7.86–7.80 (m, 4H, CHAr),
7.43–7.38 (m, 2H, CHAr), 7.28–7.25 (m, 2H, CHAr), 2.36 (s, 3H,
CH3C6H4); 13C NMR (75 MHz, CDCl3) d 170.17 (HC@N), 144.6,
136.4, 134.5, 132.4, 129.8, 129.8, 129.7, 129.2 (CAr), 21.7 (CH3C6H4).
4.2.1. N-(4-Chlorobenzylidene) aniline 2a
Yellow solid. Rf (cyclohexane/EtOAc 3:1) = 0.76. Yield 98%. IR
(neat)
m 3081–2875, 1622, 1586, 1565, 1486, 1403, 1168, 1087,
1074, 969, 827, 759; 1H NMR (300 MHz, CDCl3) d 8.43 (s, 1H,
HC@N), 7.84 (d, 2H, CHAr, J = 8.5 Hz), 7.47–7.44 (m, 2H, CHAr),
7.40–7.38 (m, 2H, CHAr), 7.27–7.25 (m, 1H, CHAr), 7.23–7.20 (m,
2H, CHAr); 13C NMR (75 MHz, CDCl3) d 158.8 (HC@N), 151.7,
137.4, 134.7, 129.9, 129.2, 129.1, 126.2, 120.8 (CAr).
4.3.5. N-(4-Methoxybenzylidene)-4-methylbenzenesufonamide
2 g
Beige solid. Rf (cyclohexane/EtOAc 7:3) = 0.55. Mp = 126 °C.
Yield 95%. IR (neat)
m
1655, 1576, 1324, 1162; 1H NMR (300 MHz,
CDCl3) d 8.95 (s, 1H, HC@N), 7.9–7.86 (m, 4H, CHAr), 7.35–7.32
(m, 2H, CHAr), 6.99–6.96 (m, 2H, CHAr), 3.89 (s, 3H, OCH3), 2.43
(s, 3H, CH3C6H4); 13C NMR (75 MHZ, CDCl3) d 169.3 (HC@N),
4.2.2. N-(4-Chlorobenzylidene)-4-methoxyaniline 2b
Grey solid. Rf (cyclohexane/EtOAc 3:1) = 0.7. Yield 99%. IR (neat)
m
2958–2852, 1619, 1574, 1504, 1300, 1243, 1092, 1029, 835, 821;

2784
M. Barbarotto et al. / Tetrahedron: Asymmetry 20 (2009) 2780–2787
165.3, 144.3, 135.7, 133.7, 129.7, 127.9, 125.4, 114.7 (CAr), 55.7
(OCH3), 21.6 (CH3C6H4).
4.4.2. [3R,4R,(S)R]-1-(tert-Butylsulfinyl)-4-(4-chlorophenyl)-4-
(4-methoxyphenylamino)-3-methylbutan-2-one 3b
The mixture was stirred for three hours at ꢀ78 °C. After flash
chromatography (cyclohexane/EtOAc 1:1), a mixture of four dia-
stereomers was isolated. Ratio syn/anti 75/25. Beige solid. Yield
65%. 1H NMR (major product) (300 MHz, CDCl3) d 7.28–7.25 (m,
4.3.6. 4-Methyl-N-(thiophen-2-
ylmethylene)benzenesulfonamide 2 h
Yellow solid. Rf (cyclohexane/EtOAc 7:3) = 0.57. Mp = 98 °C.
Yield 90%. 1H NMR (300 MHz, CDCl3) d 9.11 (s, 1H, HC@N), 7.87
(d, 2H, CHAr, J = 8.4 Hz), 7.77 (d, 2H, CHAr, J = 3.9 Hz), 7.33 (d, 2H,
CHAr, J = 7.8 Hz), 7.21 (t, 1H, CHAr, J = 4.35 Hz); 13C NMR (75 MHz,
CDCl3) d 162.5 (HC@N), 144.7, 142.2, 139.2, 138.6, 136.9, 130.1,
129.1, 128.3 (CAr), 21.9 (CH3C6H4).
4H, CHAr), 6.56 (A2B2, 4H, CHAr, JAB = 9.0 Hz and
D
m
= 44.7 Hz),
4.48 (d, 1H, CHNH, J = 9.4 Hz), 3.68 (s, 3H, OCH3), 3.47 (AB, 2H,
CH2S(O), JAB = 8.8 Hz and = 114.6 Hz), 3.26–3.20 (m, 1H,
D
m
CHCH3), 1.26 (s, 9H, t-Bu), 0.96 (d, 3H, CHCH3, J = 7.1 Hz).
4.4.3. [1R,2R,(S)R]-N-(4-(tert-Butylsulfinyl)-1-(4-chlorophenyl)-
2-methyl-3-oxobutyl)-4-methylbenzenesulfonamide 3c
4.3.7. N-(4-Nitrobenzylidene)-4-methylbenzenesulfonamide 2i
Yellow solid. Rf (cyclohexane/EtOAc 7:3) = 0.64. Mp = 205 °C.
The mixture was stirred for two hours at ꢀ78 °C. After chroma-
tography on unmetalled silica (EtOAc), a mixture of two diastereo-
mers was isolated. Ratio syn/anti 100/0, syn1/syn2 85/15. White
viscous foam. Yield 72%. Rf (EtOAc) = 0.5. 1H NMR (300 MHz, CDCl3)
(major product) d 7.35–7.33 (m, 2H, CHAr), 6.96–6.93 (m, 4H, CHAr),
6.85–6.82 (m, 2H, CHAr), 6.60 (d, 1H, CHNH, J = 9 Hz), 4.53 (dd, 1H,
CHNH, J = 9.3 Hz and 2.7 Hz), 3.68 (AB, 2H, CH2S(O)), JAB = 13.2 Hz
Yield 95%. IR (neat)
(300 MHz, CDCl3)
J = 9 Hz), 8.14 (d, 2H, CHAr, J = 9 Hz), 7.92 (d, 2H, CHAr, J = 9 Hz),
7.4 (d, 2H, CHAr J = 9 Hz), 2.46 (s, 3H, CH3C6H4); 13C NMR
m
1658, 1638, 1575, 1324, 1166; 1H NMR
d
9.12 (s, 1H, HC@N), 8.33 (d, 2H, CHAr
,
,
(75 MHz, CDCl3) d 167.5 (HC@N), 143.6, 140.1, 131.9, 130.0,
129.7, 128.4, 126.4, 124.3 (CAr), 21.7 (CH3C6H4).
and
Dm = 197 Hz), 3.41 (qt, 1H, CHCH3 J = 6.9 Hz), 2.23 (s, 3H,
CH3C6H4), 1.21 (s, 9H, t-Bu), 0.93 (d, 3H, CHCH3, J = 6.9 Hz); 13C
NMR (75 MHz, CDCl3) d 197.5 (C@O), 137.1, 133.1, 130.8, 129.0,
128.7, 128.4, 127.3, 126.5 (CAr), 65.9 (CH2S(O)), 56.3 (CHNH), 34.1
(C(CH3)3), 30.6 (CHCH3), 22.3 (C(CH3)3), 21.6 (CH3C6H4), 14.1
(CHCH3); HMRS (ESI+) calcd for C22H28Cl1N1Na1O4S2 (M+Na)
492.1046, found 492.1028.
4.3.8. N-(4-Cyanobenzylidene)-4-methylbenzenesulfonamide 2j
White solid. Mp = 170 °C. 1H NMR (300 MHz, CDCl3) d 8.97 (s,
1H, HC@N), 7.97–7.91 (m, 2H, CHAr), 7.83–7.69 (m, 4H, CHAr),
7.69–7.31 (m, 2H, CHAr), 2.37 (s, 3H, CH3C6H4); 13C NMR
(75 MHz, CDCl3) d 167.77 (HC@N), 145.3, 138.8, 135.9, 134.3,
132.8, 129.9, 128.4, 126.5 (CAr), 117.7 ((C6H4)CN), 21.7 (CH3C6H4).
4.4.4. [1R,2R,(S)R]-N-(4-(tert-Butylsulfinyl)-1-(4-bromophe-
nyl)-2-methyl-3-oxobutyl)-4-methylbenzenesulfonamide 3d
The mixture was stirred for two hours at ꢀ78 °C. After flash
chromatography (EtOAc/cyclohexane 8:2), a mixture of two diaste-
reomers was isolated. Ratio syn/anti 100/0, syn1/syn2 85/15. White
viscous foam. Yield 68%. Rf (EtOAc/cyclohexane 80:20) = 0.3. 1H
NMR (300 MHz, CDCl3) (major product) d 7.35–7.32 (m, 2H, CHAr),
7.13–7.10 (m, 2H, CHAr), 6.96–6.94 (m, 2H, CHAr), 6.78–6.76 (m, 2H,
CHAr), 6.52 (d, 1H, CHNH, J = 9.6 Hz), 4.51 (dd, 1H, CHNH, J = 9.3 Hz
4.4. General procedure for the Reformatsky-type reaction
A solution of SmI2 was prepared by the addition of samarium(0)
powder (260 mg, 1.72 mmol, 2.2 equiv) to a solution of diiodo-
methane (125
blue solution was stirred at room temperature for two hours. The
mixture was cooled to ꢀ78 °C and a solution of -bromo-b-keto-
lL, 1.57 mmol, 2 equiv) in THF (16 mL). The deep
c
sulfoxide 1 (200 mg, 0.78 mmol, 1 equiv) in THF (3 mL) was added
by cannulation. Fifteen minutes later, a solution of the imine 2a–k
(1.3 equiv) in THF (3 mL) was added by cannulation. The mixture
was stirred at ꢀ78 °C for two or three hours. The mixture was
quenched with 15 mL of 0.1 M HCl solution, and 15 mL of saturated
NaCl aqueous solution was added to facilitate decantation. The two
layers were separated. The aqueous layer was extracted with ether
(40 mL) and dichloromethane (5 ꢂ 40 mL). The combined organic
extracts were washed with saturated Na2S2O3 aqueous solution
(50 mL) and brine (2 ꢂ 50 mL). The organic extracts were dried
on MgSO4, filtered and concentrated under reduced pressure. The
crude product was purified by flash chromatography.
and 5.7 Hz), 3.68 (AB, 2H, CH2S(O), JAB = 13.2 Hz and
Dm = 180 Hz),
3.41 (qd 1H, CHCH3, J = 2.7 Hz and 7.2 Hz), 2.25 (s, 3H, CH3C6H4),
1.24 (s, 9H, t-Bu), 0.90 (d, 3H, CHCH3, J = 6.9 Hz); 13C NMR
(75 MHz, CDCl3) d 204.0 (C@O), 142.2, 136.5, 135.1, 130.5, 129.0,
128.0, 126.0, 120.5 (CAr), 60.4 (CHNH), 58.0 (CH2S(O)), 38.1
(C(CH3)3), 30.6 (CHCH3), 22.8 (C(CH3)3), 21.4 (CH3C6H4), 14.4
(CHCH3); HMRS (ESI+) calcd for C22H28Br1Li1N1O4S2 (M+Li)
520.0803, found 520.0789.
4.4.5. [1R,2R,(S)R]-N-(4-(tert-Butylsulfinyl)-1-(4-fluorophenyl)-
2-methyl-3-oxobutyl)-4-methylbenzenesulfonamide 3e
4.4.1. [3R,4R,(S)R]-1-(tert-Butylsulfinyl)-4-(4-chlorophenyl)-3-
methyl-4-(phenylamino)butan-2-one 3a
The mixture was stirred for two hours at ꢀ78 °C. After flash
chromatography (cyclohexane/EtOAc/CH2Cl2 2:1:5) a mixture of
four diastereomers was isolated. Ratio syn/anti 70/30. Beige solid.
The mixture was stirred for two hours at ꢀ78 °C. After flash
chromatography (EtOAc/cyclohexane 1:1), a mixture of two diaste-
reomers was isolated. Ratio syn/anti 100/0, syn1/syn2 89/11. White
viscous foam. Yield 50%. Rf (EtOAc/cyclohexane 1:1) = 0.13. 1H
NMR (major product) (300 MHz, CDCl3) d 7.43 (d, 2H, CHAr
,
Yield 57%. Rf (cyclohexane/EtOAc/CH2Cl2 2:1:5) = 0.3. IR (neat)
m
J = 4.2 Hz), 7.03–6.95 (m, 4H, CHAr), 6.75 (t, 2H, CHAr, J = 8.7 Hz),
4.63 (dd, 1H, CHNH, J = 9.6 Hz and 6.9 Hz), 3.69 (AB, 2H, CH2S(O),
3322–3200, 2965–2929, 1710, 1603, 1492, 1369, 1246, 1085,
1030, 823, 752, 690; 1H NMR (300 MHz, CDCl3) d 7.31–7.26 (m,
JAB = 13.5 Hz and Dm = 192.7 Hz), 3.45 (qt, 1H, CHCH3, J = 6.9 Hz),
4H, CHAr), 7.05 (t, 2H, CHAr
,
J = 7.4 Hz), 6.61 (t, 1H, CHAr
,
2.29 (s, 3H,CH3C6H4), 1.27 (s, 9H, t-Bu), 1.02 (d, 3H, CHCH3,
J = 6.9 Hz); 13C NMR (75 MHz, CDCl3) d 205.2 (C@O), 163.6, 160.4,
143.0, 137.3, 132.9, 129.4, 129.3, 114.8 (CAr), 21.2 (CH3C6H4); 13C
NMR (75 MHz, CDCl3) d 204.2 (C@O), 163.6, 160.4, 143.0, 137.3,
132.9, 129.4, 129.3, 114.8 (CAr), 63.4 (CHNH), 60.9 (CH2S(O)), 58.2
(C(CH3)3), 56.6 (CHCH3), 26.3 (C(CH3)3), 21.9 (CH3C6H4), 17.0
(CHCH3); HMRS (ESI+) calcd for C22H28F1N1Na1O4S2 (M+Na)
476.1341, found 476.1332.
J = 7.3 Hz), 6.50 (d, 2H, CHAr, J = 7.6 Hz), 4.57 (d, 1H, CHNH,
J = 9.1 Hz), 3.42 (AB, 2H, CH2S(O), JAB = 11.5 Hz and = 129.4 Hz),
D
m
3.31 (qt, 1H, CHCH3, J = 7.1 Hz), 1.29 (s, 9H, t-Bu), 0.99 (d, 3H,
CHCH3, J = 7.1 Hz); 13C NMR (75 MHz, CDCl3) d 206.7 (C@O),
133.2, 129.0 (ꢂ6), 117.8 (CAr), 113.7 (CHNH), 57.5 (CH2S(O)), 55.0
(C(CH3)3), 53.5 (CHCH3), 22.7 (C(CH3)3), 14.7 (CHCH3); HMRS
(C21H27Cl1N1O2S1) calcd 392.1446, found 392.1437.

M. Barbarotto et al. / Tetrahedron: Asymmetry 20 (2009) 2780–2787
2785
4.4.6. [1R,2R,(S)R]-N-(4-(tert-Butylsulinyl)-2-methyl-3-oxo-1-
phenylbutyl)-4-methylbenzenesulfonamide 3f
4.4.10. [3R,4R,(S)R]-1-(tert-Butylsulfinyl)-4-hydroxy-3-methyl-
4-(4-cyanophenyl)butan-2-one 3j
The mixture was stirred for two hours at ꢀ78 °C. After chroma-
tography on unmetalled silica (EtOAc) a mixture of two diastereo-
mers was isolated. Ratio syn/anti 100/0, syn1/syn2 90/10. Brown
oil. Yield 40%. Rf (EtOAc) = 0.4. 1H NMR (300 MHz, CDCl3) (major
product) d 7.72–7.49 (m, 2H, CHAr), 7.47–7.42 (m, 2H, CHAr),
6.39–6.18 (m, 5H, CHAr), 5.34 (d, 1H, HCNH, J = 10.1 Hz), 4.10 (AB,
The mixture was stirred for two hours at ꢀ78 °C. After flash
chromatography (EtOAc/cyclohexane 9:1) on unmetallated silica,
the major diastereomer was isolated. Yellow oil. Yield 50%. Rf
(EtOAc/cyclohexane 9:1) = 0.38. 1H NMR (300 MHz, CDCl3)
d
7.57–7.54 (m, 2H, CHAr), 7.43–7.41 (m, 2H, CHAr), 5.36 (d, 1H,
CHOH, J = 2.1 Hz), 3.58 (AB, 2H, CH2S(O)), JAB = 12.6 Hz and
2H, CH2S(O), JAB = 10.2 Hz and
D
m
= 86.7 Hz), 2.87–2.79 (m, 1H,
Dm = 155 Hz), 2.99 (qd, 1H, CHCH3, J = 7.2 Hz and 2.7 Hz), 1.21 (s,
CHCH3), 2.23 (s, 3H, CH3C6H4), 1.19 (s, 9H, t-Bu), 0.89 (d, 3H,
CHCH3, J = 7.0 Hz); 13C NMR (75 MHz, CDCl3) d 204.2 (C@O),
163.6, 160.4, 143.0, 137.3, 132.9, 129.4, 129.3, 114.8 (CAr), 63.4
(CHNH), 60.9 (CH2S(O)), 58.2 (C(CH3)3), 56.6 (CHCH3), 26.3
(C(CH3)3), 21.9 (CH3C6H4), 17.0 (CHCH3); HMRS (ESI+) calcd for
C22H28F1N1Na1O4S2 (M+Na) 476.1341, found 476.1332.
9H, t-Bu), 0.88 (d, 3H, CHCH3, J = 7.2 Hz); 13C NMR (300 MHz,
CDCl3) d 207.4 (C@O), 131.9, 131.7, 130.1, 129.9 (CAr), 118.0
(C6H4)CN), 49.7 (CH2S(O)), 46.1 (CHNH), 31.5 (C (CH3)3), 31.2
(CHCH3), 30.8 (C(CH3)3), 10.3 (CHCH3).
4.5. General procedure for the diastereoselective reduction
with DIBAL-H8
4.4.7. [1R,2R,(S)R]-N-(4-(tert-Butylsulfinyl)-1-(4-methoxyphe-
nyl)-2-methyl-3-oxobutyl)-4-methylbenzenesulfonamide 3g
The mixture was stirred for two hours at ꢀ78 °C. After flash
chromatography on unmetalled silica (EtOAc), a mixture of four
diastereomers was isolated. Ratio syn/anti 79/21, syn1/syn2 72/
28, anti1/anti2 70/30. White viscous foam. Yield 53%. Rf (EtOAc/
cyclohexane 90:10) = 0.5. 1H NMR (300 MHz, CDCl3) (major prod-
uct) d 7.39–7.36 (m, 2H, CHAr), 7.97–7.95 (m, 2H, CHAr), 6.82–
6.79 (m, 2H, CHAr), 6.57–6.52 (m, 2H, CHAr), 6.20 (d, 1H, HCNH,
J = 9 Hz), 4.47 (dd, 1H, CHNH, J = 6.9 Hz and 1.8 Hz), 3.64 (s, 3H,
A solution of DIBAL-H (1.0 M in toluene, 1.87 mmol, 2.4 equiv)
was added dropwise at ꢀ78 °C to a solution of b-ketosulfoxide
3c–d (0.778 mmol, 1 equiv) in THF (14 mL). The mixture was stir-
red for 1 hour at ꢀ78 °C. Then, the mixture was quenched with
methanol (2 mL). A saturated aqueous solution of disodium tar-
trate (20 mL) and ethyl acetate (20 mL) was added. The mixture
was vigorously stirred until the two layers were clearly separated.
The organic phase was collected and the aqueous layer was ex-
tracted with ethyl acetate (3 ꢂ 10 mL). The combined organic ex-
tracts were dried over Na2SO4, filtered and concentrated under
reduced pressure.
OCH3), 3.56 (AB, 2H, CH2S(O), JAB = 13.5 Hz and
Dm = 206 Hz), 3.37
(m, 1H, CHCH3), 2.22 (s, 3H, CH3C6H4), 1.21 (s, 9H, t-Bu), 0.93 (d,
3H, CHCH3, J = 6.9 Hz); 13C NMR (75 MHz, CDCl3) d 202.5 (C@O),
165.2, 143.3, 134.7, 133.7, 129.2, 126.9, 125.4, 113.7 (CAr), 58.3
((CH2)S(O)), 57.5 (CHNH), 55.9 (C(CH3)3), 55.1 (OCH3), 50.1
(CHCH3), 29.1 (C(CH3)3), 21.9 (CH3C6H4), 12.5 (CHCH3); HMRS
(ESI+) calcd for C23H31N1Na1O5S2 (M+Na) 488.1541, found
488.1512.
4.5.1. [1R,2R,3S,(S)R]-N-(1-(4-Chlorophenyl)-4-(tert-butylsul-
finyl)-3-hydroxy-2-methylbutyl)-4-methylsulfonamide 4c
White solid. Yield 80%. de >80%. Rf (EtOAc/cyclohexane
2:1) = 0.1. 1H NMR (300 MHz, CDCl3) d 7.41–7.38 (m, 2H, CHAr),
6.99–6.95 (m, 4H, CHAr), 6.84–6.82 (m, 2H, CHAr), 5.99 (s, 1H,
CHOH), 4.49–4.45 (m, 1H, CHNH), 4.14–4.12 (m, 1H, CHOH), 3.43
(q, 1H, CHCH3, J = 6 Hz), 2.28 (m, 2H, CH2S(O)), 2.26 (s, 3H,
CH3C6H4), 1.22 (s, 9H, t-Bu), 0.91 (d, 3H, CHCH3, J = 6.6 Hz); 13C
NMR (75 MHz, CDCl3) d 141.5, 139.5, 137.6, 131.4, 129.3, 128.5,
128.3, 120.3 (CAr), 69.2 (CHOH), 52.2 (CH2S(O)), 48.8 (CHNH),
41.2 (C(CH3)3), 35.2 (CHCH3), 29.3 (C(CH3)3), 21.3 (CH3C6H4), 14.1
(CHCH3).
4.4.8. [1R,2R,(S)R]-N-(4-(tert-Butylsulfinyl)-2-methyl-3-oxo-1-
(thiophen-2-yl)butyl)-4-methylbenzenesulfonamide 3h
The mixture was stirred for two hours at ꢀ78 °C. After flash
chromatography (cyclohexane/EtOAc/CH2Cl2 5:4:1), a mixture of
two diastereomers was isolated. Ratio syn/anti 100/0, syn1/syn2
80/20. Yellow viscous oil. Yield 50%. Rf (cyclohexane/EtOAc/
CH2Cl2 5:4:1) = 0.23. 1H NMR (300 MHz, CDCl3) (major product)
d 7.56–7.53 (m, 2H, CHAr), 7.17–7.02 (m, 3H, CHAr), 6.74–6.69
(m, 2H CHAr), 6.28 (d, 1H, CHNH, J = 9.9 Hz), 4.87 (dd, 1H, CHNH,
J = 9.6 Hz and 6.6 Hz), 3.82 (AB, 2H, CH2S(O), JAB = 13.2 Hz and
4.5.2. [1R,2R,3S,(S)R]-N-(1-(4-Bromophenyl)-4-(tert-butylsul-
finyl)-3-hydroxy-2-methylbutyl)-4-methylsulfonamide 4d
White solid. Yield 95%. de >83%. Rf (EtOAc) = 0.4. 1H NMR
(300 MHz, CDCl3) d 8.052–8.024 (m, 2H, CHAr), 7.79–7.66 (m, 2H,
CHAr), 7.66–7.57 (m, 2H, CHAr), 7.47–7.43 (m, 2H, CHAr), 6.99 (d,
1H, CHNH, J = 8.7 Hz), 5.1 (dd, 1H, CHNH, J = 8.7 Hz and 4.8 Hz),
4.74–4.67 (m, 1H, CHOH), 3.51–3.24 (m, 2H, CH2S(O)), 2.43 (qt,
1H, CHCH3, J = 5.4 Hz), 2.25 (s, 3H, CH3C6H4), 1.84 (s, 9H, t-Bu),
1.54 (d, 3H, CHCH3, J = 8.7 Hz); 13C NMR (75 MHz, CDCl3) d 141.5,
139.5, 136.3, 131.4, 129.3, 128.5, 127.5, 126.7 (CAr), 69.8 (CHOH),
48.8 (CH2S(O)), 41.7 (CHNH), 34.2 (C(CH3)3), 30.4 (CHCH3), 22.8
(C(CH3)3), 21.2 (CH3C6H4), 14.1 (CHCH3) HMRS (ESI+) calcd for
C22H30Br1Li1N1O4S2 (M+Li) 522.0960, found 522.0955.
Dm = 89 Hz), 3.46 (m, 1H, CHCH3), 2.34 (s, 3H, CH3C6H4), 1.29 (s,
9H, t-Bu), 1.14 (d, 3H, CHCH3, J = 6.9 Hz); 13C NMR (75 MHz,
CDCl3) d 204.1 (C@O), 143.6, 140.1, 131.9, 130.0, 129.7, 128.4,
126.4, 124.3 (CAr), 60.1 (CHNH), 59.9 (CH2S(O)), 58.5 (C(CH3)3),
54.6 (CHCH3), 22.5 (C(CH3)3), 21.8 (CH3C6H4), 16.2 (CHCH3);
HMRS (ESI+) calcd for C20H27N1Na O4S3 464.0979 (M+Na), found
464.0991.
4.4.9. [3R,4R,(S)R]-1-(tert-Butylsulfinyl)-4-hydroxy-3-methyl-
4-(4-nitrophenyl)butan-2-one 3i
The mixture was stirred for two hours at ꢀ78 °C. After flash
chromatography (EtOAc/cyclohexane 8:2) on unmetallated silica
the major diastereomer was isolated. Brown solid. Yield 47%. Rf
(EtOAc/cyclohexane 8:2) = 0.4. 1H NMR (300 MHz, CDCl3) d 8.11–
8.07 (m, 2H, CHAr), 7.48–7.45 (m, 2H, CHAr), 5.39 (d, 1H, CHOH,
4.6. General procedure for the diastereoselective reduction
with DIBAL-H/Yb(OTf)38
A solution of b-ketosulfoxide 3d (0.194 mmol, 1 equiv) in THF
(4 mL) was added by cannulation to a solution of freshly flamed
Yb(OTf)3 (0.465 mmol, 2.4 equiv) in THF (3 mL) at 0 °C. The mix-
ture was stirred for 10 min at 0 °C, then cooled to ꢀ78 °C and stir-
red for 30 min. Then a solution of DIBAL-H (1.0 M in toluene,
0.776 mmol, 4 equiv) was added dropwise at ꢀ78 °C. The mixture
was stirred for 1 hour at ꢀ78 °C. Then, the mixture was quenched
J = 2.4 Hz), 3.61 (AB, 2H, CH2S(O)), JAB = 12.6 Hz and
Dm = 162 Hz),
3.0 (qd, 1H, CHCH3, J = 6.9 Hz and 2.7 Hz), 1.22 (s, 9H, t-Bu), 0.87
(d, 3H, CHCH3, J = 7.2 Hz); 13C NMR (300 MHz, CDCl3) d 203.4
(C@O), 128.6, 127.3, 126.8, 123.9 (CAr), 54.7 (CH2S(O)), 49.3
(CHNH), 34.9 (C(CH3)3), 30.7 (CHCH3), 22.7 (C(CH3)3), 9.9 (CHCH3).

2786
M. Barbarotto et al. / Tetrahedron: Asymmetry 20 (2009) 2780–2787
with methanol (2 mL). A saturated aqueous solution of disodium
tartrate (20 mL) and ethyl acetate (20 mL) was added. The mixture
was vigorously stirred until the two layers were clearly separated.
The organic phase was separated and the aqueous layer was ex-
tracted with ethyl acetate (3 ꢂ 10 mL). The combined organic ex-
tracts were dried over Na2SO4, filtered and concentrated under
reduced pressure.
CH3C6H4), 0.88 (d, 3H, CHCH3, J = 6.9 Hz); 13C NMR (75 MHz, CDCl3)
d 167.3 (C@O), 141.3, 135.2, 133.0, 130.7, 128.2, 128.0, 124.1, 120.6
(CAr), 71.9 (CHOAc), 56.6 (CHNH), 44.8 (CH2S(O)), 43.9 (CHCH3),
41.4 (C(CH3)3), 21.1 (C(CH3)3), 20.5 (CH3C6H4), 20.2 (OC@OCH3),
13.0 (CHCH3); HMRS (ESI+) calcd for C24H32Br1Li1N1O5S2 (M+Li)
564.1065, found 564.1064.
4.8. General procedure for the reductive Pummerer type
reaction:11
4.6.1. [1R,2R,3R,(S)R]-N-(1-(4-Bromophenyl)-4-(tert-butylsul-
finyl)-3-hydroxy-2-methylbutyl)-4-methylsulfonamide 5d
White solid. Yield 95%, d.e. > 80% Rf (EtOAc) = 0.4. 1H NMR
(300 MHz, CDCl3) d 7.44–7.34 (m, 2H, CHAr), 7.21–7.18 (m, 2H,
CHAr), 7.07–6.91 (m, 4H, CHAr), 6.81 (d, 1H, CHNH, J = 8.7 Hz),
4.53 (dd, 1H, CHNH, J = 8.7 Hz and 3 Hz), 3.98 (m, 1H, CHOH),
2.52 (m, 2H, CH2S(O)), 2.12 (m, 1H, CHCH3), 2.1 (s, 3H, CH3C6H4),
0.8 (d, 3H, CHCH3, J = 6.9 Hz); 13C NMR (75 MHz, CDCl3) d 142.9,
138.0, 136.3, 131.0, 129.9, 128.4, 127.5, 126.9 (CAr), 71.8 (CHOH),
45.8 (CH2S(O)), 43.7 (CHNH), 34.3 (C(CH3)3), 30.4 (CHCH3), 22.6
(C(CH3)3), 21.4 (CH3C6H4), 14.0 (CHCH3); HMRS (ESI+) calcd for
C22H30Br1Na1N1O4S2 (M+Na) 538.0697, found 538.0697.
2,4,6-Collidine (0.261 mmol, 3 equiv) was added dropwise at
0 °C to a solution of 6d (0.0870 mmol, 1 equiv) in acetonitrile
(1.5 mL). After 10 min, trifluoroacetic anhydride (0.435 mmol,
5 equiv) was added dropwise at 0 °C. The mixture was stirred for
20 min at 0 °C, then water (1 mL) and some K2CO3 were added in
order to reach a pH of 7. Ten minutes later, NaBH4 (0.870 mmol,
10 equiv) was added portionwise at 0 °C. The resulting suspension
was stirred for one hour at room temperature. The mixture was
slowly quenched with saturated NH4Cl aqueous solution (3 mL)
at 0 °C. The aqueous layer was extracted with ethyl acetate
(3 ꢂ 10 mL) and the combined organic extracts were washed with
1 M HCl solution (10 mL), saturated NaHCO3 aqueous solution
(10 mL) and brine (10 mL). The organic extracts were dried over
Na2SO4, filtered and concentrated under reduced pressure. The
crude product was purified by flash chromatography.
4.7. General procedure for the protection of the hydroxyl
group:13
Acetic anhydride (0.416 mmol, 1.1 equiv) was added dropwise
at room temperature to a solution of b-hydroxysulfoxide 4d, 5d
(0.39 mmol, 1 equiv) in pyridine (5.2 mL) and a small amount of
DMAP. The mixture was stirred for 12 h at room temperature.
The mixture was quenched with saturated NH4Cl aqueous solution
(5 mL), after which 1 M HCl solution (5 mL) was added to get rid of
the pyridine and 5 mL of ethyl acetate was added. The two layers
were separated and the aqueous layer was extracted with ethyl
acetate (3 ꢂ 10 mL) and dichloromethane (10 mL). The combined
organic extracts were dried over Na2SO4, filtered and concentrated
under reduced pressure.
4.8.1. [2S,3R,4R]-4-(4-Bromophenyl)-1-hydroxy-3-methyl-4-(4-
methylphenylsulfonamido)butan-2-yl acetate 8
After flash chromatography (EtOAc/cyclohexane 1:1), a colour-
less oil was obtained. Yield 60%. Rf (EtOAc/cyclohexane 1:1) = 0.4.
½
a 2D0
ꢁ
¼ þ115 (c 0.6, acetone). 1H NMR (300 MHz, CDCl3) d 7.50–
7.46 (m, 2H, CHAr), 7.26–7.19 (m, 2H, CHAr), 7.13–7.05 (m, 2H,
CHAr), 6.92–6.89 (m, 2H, CHAr), 5.58 (d, 1H, CHNH, J = 6 Hz), 4.40–
4.36 (m, 1H, CHNH), 4.11–3.93 (m, 2H, CH2OH), 3.64–3.59 (m,
1H, CHOAc), 2.38 (s, 3H, OC@OCH3), 2.05 (s, 3H, CH3C6H5), 1.82–
1.75 (m, 1H, CHCH3), 0.95 (d, 3H, CHCH3, J = 6.9 Hz); 13C NMR
(75 MHz, CDCl3) 171.2 (OC@OCH3), 143.5, 137.6, 136.9, 132.5,
131.3, 128.6, 127.3, 121.2 (CAr), 71.8 (CHOAc), 67.6 (CH2OH), 61.1
(CHNH), 41.3 (CHCH3), 21.5 (CH3C6H5), 20.8 (OC@OCH3), 12.5
(CHCH3); HMRS (ESI+) calcd for C20H24Br1Li1N1O5S1 (M+Li)
476.0719, found 476.0721.
4.7.1. [2S,3R,4R,(S)R]-4-(4-Bromophenyl)-1-(tert-butylsulfinyl)-
3-methyl-4-(4-methylphenylsulfonamido)butan-2-yl acetate 6d
The reaction was performed on a mixture of two diastereomers.
After flash chromatography (EtOAc/cyclohexane 8:2), the major
diastereomer was separated. Colourless oil. Yield 61%. de >98%. Rf
(EtOAc/cyclohexane 8:2) = 0.3. ½a D20
ꢁ
¼ þ336 (c 0.6, acetone). 1H
NMR (300 MHz, CDCl3) d 7.06 (A2B2, 4H, CHAr, JAB = 7.8 Hz and
Acknowledgements
Dm = 168 Hz), 7.04 (A2B2, 4H, JAB = 8.1 Hz and Dm = 46.8 Hz), 6.49
(d, 1H, CHNH, J = 9.6 Hz), 4.86 (dd, 1H, CHOAc, J = 6.6 Hz and
3 Hz), 4.282 (t, 1H, CHNH, J = 8.7 Hz), 2.81 (AB part of ABX, 2H,
Financial support for this work has been provided by CNRS and
University of Strasbourg. M. B. thanks the ministère de la recherche
for her fellowship.
CH2S(O), JAB = 13.2 Hz, JAX = 6.3 Hz, JBX = 7.2 Hz and
Dm = 70 Hz),
2.43–2.37 (m, 1H, CHCH3), 2.30 (s, 3H, OC=OCH3), 2.04 (s, 3H,
CH3C6H4), 1.22 (s, 9H, t-Bu), 1.14 (d, 3H, CHCH3, J = 6.9 Hz); 13C
NMR (75 MHz, CDCl3) d 169.3 (C@O), 142.3, 137.4, 137.0, 130.7,
128.4, 128.0, 126.2, 120.6 (CAr), 70.8 (CHOAc), 59.6 (CHNH), 47.8
(CH2S(O)), 41.9 (CHCH3), 41.2 (C(CH3)3), 22.1 (C(CH3)3), 20.7
(CH3C6H4), 20.3 (OC@OCH3), 14.0 (CHCH3); HMRS (ESI+) calcd for
C24H32Br1Li1N1O5S2 (M+Li) 564.1065, found 564.1069.
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