Synthesis of sterically controlled chiral β-amino alcohols and their application to the catalytic asymmetric sulfoxidation of sulfides

Article abstract of DOI:10.1016/j.tetasy.2005.07.035

Sterically hindered and enantiomerically pure β-amino alcohols 8a and 8b were prepared from the enantiomerically pure aziridine-2-carboxylic acid menthol ester 13. Vanadium complexes of the chiral Schiff-base ligands prepared from the β-amino alcohols catalyze an efficient enantioselective sulfoxidation of alkyl aryl sulfides, while enantioselectivities as high as 96% ee can be observed in the sulfoxidation of benzyl aryl sulfides.

Full text of DOI:10.1016/j.tetasy.2005.07.035

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 16 (2005) 3497–3501
Synthesis of sterically controlled chiral b-amino alcohols
and their application to the catalytic asymmetric
sulfoxidation of sulfides
Yong-Chul Jeong,a Yao Dong Huang,a Soojin Choib and Kwang-Hyun Ahna,*
aCollege of Environment and Applied Chemistry, Kyung Hee University, Yongin City 449-701, South Korea
bDaewoong Pharm Co., Ltd, San 84-1, Samgye-ri, Pogok-myun, Yongin City 449-814, South Korea
Received 21 July 2005; accepted 27 July 2005
Available online 9 September 2005
Abstract—Sterically hindered and enantiomerically pure b-amino alcohols 8a and 8b were prepared from the enantiomerically
pure aziridine-2-carboxylic acid menthol ester 13. Vanadium complexes of the chiral Schiff-base ligands prepared from the b-amino
alcohols catalyze an efficient enantioselective sulfoxidation of alkyl aryl sulfides, while enantioselectivities as high as 96% ee can be
observed in the sulfoxidation of benzyl aryl sulfides.
Ó 2005 Elsevier Ltd. All rights reserved.
1. Introduction
method for an enantiomerically pure amino alcohol,
such as 8, whose structural variation at the substituent
R1 may provide useful information on the enantio-
selectivity of the asymmetric sulfoxidation. Thus, we
herein report the efficient synthesis of bulky amino alco-
hols, 8a and 8b and their applications to the enantio-
selective sulfoxidation of sulfides via chiral Schiff-base
5. We also report the asymmetric sulfoxidation using
chiral indanol, 9.
Enantiomerically pure sulfoxides are of great value as
auxiliaries or intermediates in asymmetric synthesis.1
Recently, we have been interested in the asymmetric sul-
foxidation of sulfides to develop a methodology for the
synthesis of drugs containing a chiral sulfoxide moiety,
such as chiral lansoprazol or omeprazol. There are a
number of catalytic systems that enable us to perform
the asymmetric oxidation of sulfides to sulfoxides,
involving various transition metal complexes.2–4 In par-
ticular, the asymmetric sulfoxidation catalyzed by the
chiral vanadium complex derived from tricoordinated
2. Results and discussion
ligands, such as 1,3a
2
3b and 3,3c has received great atten-
To prepare amino alcohol 8, oxazoline derivative 11 was
synthesized and reacted with Grignard reagents accord-
ing to the literature procedure (Scheme 1).5a However,
we found that the oxazoline 11 was partially racemized
in the reaction with Grignard reagents. Thus, we devised
a new synthetic method for the amino alcohols accord-
ing to Scheme 2.
tion recently because of the facile syntheses of the
ligands from chiral amino alcohols and salicylaldehyde
derivatives in one step. We have reported that ligand
4a3d also catalyzes the enantioselective sulfoxidation of
sulfides efficiently.
In a continuing study with ligand 4, it was thought that
a bulky amino alcohol, which may give a steric effect lar-
ger than tert-butyl on R1 is necessary to improve the
enantioselectivity compared to the reaction with 4a.
Since a sterically hindered chiral amino alcohol is not
readily available, we decided to develop a synthetic
Our method used a readily available chiral aziridine 13,6
which has been applied in the synthesis of various chiral
intermediates, as a starting material.
Aziridine (R,S)-13 was reacted with alkyl Grignard
reagent, RMgBr (R = ethyl, isobutyl), to give an
aziridine-2-alcohol derivative that was then treated with
methyl iodide and potassium hydride to produce 14. The
*
Corresponding author. E-mail: khahn@khu.ac.kr
0957-4166/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2005.07.035

3498
Y.-C. Jeong et al. / Tetrahedron: Asymmetry 16 (2005) 3497–3501
O
S
(S)
VO(acac)2/ligand
S
Ph
Me
Ph
Me
H2O2, CH2Cl2,
rt or 0 oC
R1
N
OH
OH
N
N
OH
N
OH
OH
O
O2N
OH
OH
Ph
OH
R2
O
4a, R1 = tBu, R2 = tBu
2
3
1
R1
R1
*
*
H2N
OH
N
OH
(R)-8a, R = C(Et)2OMe
(S)-8a, R = C(Et)2OMe
(R,R)-5a, R = C(Et)2OMe
(R,S)-5a, R = C(Et)2OMe
(R,S)-5b, R = C(iBu)2OMe
OH
O
(S)-8b, R = C(iBu)2OMe
O
O
O
or
OH
O
+
H2N
OH
N
OH
(R)-7
(S,R)-9
(R,S,R)-6
OH
O
O
ring opening of 14 by acetic acid gave 15, indicating that
the acetate nucleophile attacks the aziridine ring at the
less sterically hindered C(3) position to form 15.6a
Deacetylation of 15 by NaOH in refluxing ethanol–
water and debenzylation catalyzed by palladium carbon
in ethanol gave amino alcohols (S)-8a and (S)-8b.7 Ami-
no alcohol (R)-8a7 was also prepared from (R,R)-13
according to Scheme 2. Enantiomeric excesses of amino
alcohols 8a and 8b were determined by chiral HPLC
analysis of the oxazolines 12 prepared from the amino
alcohols and triethyl orthobenzoate, and found to be
more than 99% ee.
foxidation of thioanisole at 0 °C.9 The reaction pro-
duced (S)-methyl phenyl sulfoxide in 83% yield with
an enantioselectivity of 84% ee (Table 1, entry 2), which
is similar to the result obtained with (R,S)-4a (Table 1,
entry 1) reported previously.3d The enantioselectivity
obtained with (R,S)-5a, whose amino alcohol subunit
was an (S)-configuration was also 85% ee with (R)-
methyl phenyl sulfoxide as the major product. Unfortu-
nately, more sterically hindered (R,S)-5b gave an infe-
rior enantioselectivity (entry 4), indicating that a
proper steric effect at R1 of 5 is necessary to gain a high
enantioselectivity. Ligand (R,S,R)-6 showed a good
enantioselectivity of 82% ee (entry 5). However,
(S,S,R)-6 whose binaphthyl subunit is in an (S)-configu-
ration different from (R,S,R)-6 also gave the same (S)-
isomer of methyl phenyl sulfoxide as the major enantio-
mer, although with an inferior enantioselectivity (entry
6). The formation of the (S)-isomer of methyl phenyl
After the successful synthesis of enantiomerically pure
amino alcohols, 8, we tried to use these compounds in
the vanadium-catalyzed asymmetric sulfoxidation of sul-
fides. At first, the Schiff-base, (R,R)-5a8 prepared from
(R)-75b and (R)-8a was applied to the asymmetric sul-
MeO
R
R
O
R
OMe
R
O
1. EtMgBr, -78oC
2. KH, CH3I, THF
N
N
O
triethyl amine
C(OEt)3
H+
OEt
H2N
HO
H2N
OH
Ph
Ph
OEt
O
(R)-8a
R = ethyl
11
12
R = ethyl, 81% ee
10
Scheme 1.

Y.-C. Jeong et al. / Tetrahedron: Asymmetry 16 (2005) 3497–3501
3499
Ph
Ph
Ph
Me
AcOH/CH2Cl2
Reflux
1. RMgBr, THF
NH
Me
N
Me
N
R
OMe
2. KH, CH3I, THF
CO2menthol
AcO
R
R OMe
R
14a ; R = ethyl, 85%
15a ; R = ethyl, 65%
(R,S)-13
14b ; R = isobutyl, 85%
15b ; R = isobutyl, 75%
Ph
R
OMe
R
Me
HO
Pd/C
NH
EtOH
R
H2N
HO
NaOH
H2O, EtOH
R
OMe
16a ; R = ethyl, 88%
(S)-8a ; R = ethyl, 99%
16b ; R = isobutyl, 83%
(S)-8b ; R = isobutyl, 99%
Scheme 2.
Table 1. Asymmetric sulfoxidation of aryl sulfides with Schiff-bases 5 and 6
O
S
R
*
VO(acac)2 (1mol%), Ligand (1.5mol%)
S
R
H2O2 (1.1eq), CH2Cl2, 0oC
X
X
Entry
Sulfide
Schiff base
Yield (%)a
ee (%)b
Configc
1
2
3
4
5
6
7
8
C6H5–S–CH3
(R,S)-4a
(R,R)-5a
(R,S)-5a
(R,S)-5b
(R,S,R)-6
(S,S,R)-6
(R,R)-5a
(R,S)-5a
(R,R)-5a
(R,S)-5a
(R,R)-5a
(R,S)-5a
(R,R)-5a
(R,S)-5a
(R,R)-5a
(R,S)-5a
(R,R)-5a
(R,S)-5a
(R,R)-5a
(R,S)-5a
90
83
84
82
81
88
80
80
81
80
80
72
74
80
84
82
58
56
89
84
86
84
85
65
82
67
79
81
83
S
S
R
R
S
S
S
R
S
R
S
R
S
R
S
R
S
R
S
R
p-MeO–C6H5–S–CH3
p-Me–C6H5–S–CH3
p-Br–C6H5–S–CH3
p-NO2–C6H5–S–CH3
o-Br–C6H5–S–CH3
Phenyl vinyl sulfide
Benzyl phenyl sulfide
9
10
11
12
13
14
15
16
17
18
19
20
83
59d
66d
31e
55e
34
40
79
58
96f
96f
a Isolated yield.
b Determined by HPLC with a Dicel Chiralcel OD column.
c Absolute configuration of the major product was determined by comparison of its sign of specific rotation with the literature data.
1
d Determined by H NMR (CDCl3, 400 MHz) analysis using (R)-(+)-2,20-dihydroxy-1,10-binaphthyl as a shift reagent.
e Determined by 1H NMR (CDCl3, 400 MHz) analysis using (R)-(ꢀ)-2,2,2-trifluoro-1-(9-anthyl)ethanol as a shift reagent.
f Determined by HPLC with a Dicel Chiralcel OJ column.
sulfoxide from both (R,S,R)-6 and (S,S,R)-6 suggests
that the configuration of the sulfoxide is decided by
the configuration of R1 instead of the configuration of
the binaphthyl subunit.
groups (entries 7–10) were similar to the oxidation of
thioanisole (entries 2 and 3). However, thioanisoles,
which had electron withdrawing substituents gave their
sulfoxide with poor enantioselectivities (entries 11–14).
Additionally, (R,S)-5a showed better enantioselectivity
compared to (R,R)-5a in the sulfoxidation of thioanisoles
with electron withdrawing substituents. Sulfones that
were expected from oxidation of the corresponding sulf-
oxides were formed only to a minor extent (less than 3%).
Oxidations of aryl sulfides with various substituents were
also examined with ligand 5a (entries 7–16). Interest-
ingly, the enantioselectivities obtained in the oxidation
of thioanisole derivatives containing electron donating

3500
Y.-C. Jeong et al. / Tetrahedron: Asymmetry 16 (2005) 3497–3501
6. (a) Choi, S.-K.; Lee, J.-S.; Kim, J.-H.; Lee, W. G. J. Org.
Chem. 1997, 62, 743; (b) Hwang, G.-I.; Chung, J.-H.; Lee,
W. G. J. Org. Chem. 1996, 61, 6183.
We also examined the oxidation of benzyl phenyl sul-
fides with ligand 5a (entries 19 and 20). The reaction
proceeded with an excellent enantioselectivity producing
chiral benzyl phenyl sulfoxide in 96% ee (entries 19 and
20). These results being a little inferior compared to
the result obtained with 4a (99% ee),3d however, still
demonstrate the potential of our catalytic system.
7. Selected data 8a: (S)-form, [a]D = ꢀ16.8 (c 0.5, CHCl3);
1
(R)-form, [a]D = +17.8 (c 0.1, CHCl3); H NMR (CDCl3,
400 MHz) d 3.69 (dd, 1H, J1 = 10.4 Hz, J2 = 4.0 Hz), 3.48
(dd, 1H, J1 = 10.4 Hz, J2 = 8.4 Hz), 3.21 (s, 3H), 2.94 (dd,
1H, J1 = 8.4 Hz, J2 = 4.0 Hz) 2.45 (br s, 3H), 1.63–1.57 (m,
4H), 0.93–0.88 (m, 6H); 13C NMR (CDCl3, 100 MHz) d
79.57, 62.89, 57.04, 49.48, 25.26, 25.13, 8.39, 8.24; HRMS
(HFAB), m/z calcd for C8H20NO2 162.1494, found
162.1489.
3. Conclusion
Amino alcohol (S)-8b: [a]D = ꢀ10.0 (c 2.0, CHCl3); 1H
NMR (CDCl3, 300 MHz) d 3.71 (dd, 1H, J1 = 10.7 Hz,
J2 = 3.7 Hz), 3.45 (dd, 1H, J1 = 9.6 Hz, J2 = 8.7 Hz), 3.19
(s, 3H), 3.03 (dd, 1H, J1 = 8.5 Hz, J2 = 3.7 Hz), 3.21 (br s,
3H), 1.90–1.78 (m, 2H), 1.52–1.37 (m, 4H), 0.99–0.94 (m,
12H); 13C NMR (CDCl3, 75 MHz) d 80.64, 62.83, 58.16,
49.52, 41.78, 41.50, 224.94, 24.71, 24.51, 24.39, 23.87, 23.49;
HRMS (HFAB), m/z calcd for C12H27NO2 218.2120, found
218.2117.
In summary, we developed a new synthetic method for
sterically hindered chiral amino alcohol 8. The Schiff-
base ligand 5 derived from 8 showed a good enantio-
selectivity reaching 96% ee in the oxidation of sulfides.
Acknowledgement
8. Selected data (R,R)-5a: mp 92 °C; [a]D = ꢀ36.0 (c 0.5,
This work was supported by the Basic Research Pro-
gram of the Korean Science & Engineering Foundation
(R01-2003-000-10187-0).
1
CHCl3); H NMR (CDCl3, 400 MHz) d 8.62 (s, 1H), 8.01–
7.94 (m, 3H), 7.85–7.83 (m, 1H), 7.48–7.38 (m, 3H), 7.33–
7.26 (m, 3H), 7.12–7.09 (m, 1H), 4.15–4.07 (m, 1H), 3.72 (t,
1H, J = 9.6 Hz), 3.54 (dd, 1H, J1 = 9.3 Hz, J2 = 2.4 Hz),
3.25 (s, 3H), 2.26 (s, 1H), 1.74–1.47 (m, 4H), 0.91–0.81 (m,
6H), 0.76 (s, 9H); 13C NMR (CDCl3, 100 MHz): d 176.1,
166.4, 154.4, 146.9, 135.1, 133.8, 133.3, 131.7, 129.0, 128.4,
128.1, 127.1, 126.3, 126.1, 125.3, 125.0, 124.2, 123.4, 122.0,
120.3, 115.6, 80.0, 76.1, 63.1, 50.0, 38.6, 26.5, 26.0, 25.4,
8.55, 7.47. Anal. Calcd for C34H39NO5ÆH2O: C, 72.96; H,
7.38; N, 2.50. Found: C, 73.04; H, 7.01; N, 2.45.
Schiff-base (R,S)-5a: mp 98 °C; [a]D = +12.2 (c 0.5,
CHCl3); 1H NMR (CDCl3, 400 MHz) d 8.61 (s, 1H),
8.01–7.93 (m, 3H), 7.86–7.84 (m, 1H), 7.47–7.43 (m, 2H),
7.35–7.26 (m, 4H), 7.09–7.07 (m, 1H), 4.09 (d, 1H,
J = 8.4 Hz), 3.74 (t, 1H, J = 8.0 Hz), 3.52 (dd, 1H,
J1 = 7.8 Hz, J2 = 4.4 Hz), 3.26 (s, 3H), 2.13 (s, 1H), 1.73–
1.49 (m, 4H), 0.94–0.83 (m, 6H), 0.78 (s, 9H); 13C NMR
(CDCl3, 75 MHz) d 176.0, 166.4, 154.4, 147.1, 135.2, 133.9,
133.3, 131.7, 129.1, 128.4, 127.0, 126.5, 125.9, 125.3, 125.1,
124.2, 123.4, 122.0, 120.3, 115.7, 79.8, 76.5, 62.9, 50.0,
38.6, 26.5, 26.0, 25.4, 14.2, 8.5, 7.5. Anal. Calcd for
C34H39NO5ÆH2O: C, 72.96; H, 7.38; N, 2.50. Found: C,
73.12; H, 7.09; N, 2.49.
Schiff-base (R,S,R)-6: mp 126 °C; [a]D = +53.2 (c 0.5,
CHCl3); 1H NMR (CDCl3, 300 MHz) d 12.54 (s, 1H),
8.83 (s, 1H), 8.02–7.84 (m, 4H), 7.43–7.15 (m, 11H), 4.83 (d,
1H, J = 6.0 Hz), 4.68 (d, 1H, J = 6.0 Hz), 3.21 (dd, 1H,
J1 = 15.6 Hz, J2 = 6.0 Hz), 3.04 (dd, 1H, J1 = 15.6 Hz,
J2 = 6.0 Hz), 0.75 (s, 9H); 13C NMR (CDCl3, 75 MHz) d
176.39, 166.44, 154.21, 147.05, 140.71, 140.30, 135.30,
134.12, 133.32, 131.74, 129.17, 128.77, 128.61, 128.52,
128.20, 127.23, 127.03, 126.55, 125.87, 125.45, 125.40,
125.12, 125.04, 124.19, 123.62, 122.02, 120.42, 115.97,
75.68, 75.26, 39.47, 38.59, 26.41. Anal. Calcd for
C35H31NO4ÆH2O: C, 76.76; H, 6.07; N, 2.56. Found: C,
76.94; H, 6.09; N, 2.33.
Schiff-base (S,S,R)-6: mp 201 °C; [a]D = ꢀ25.6 (c 0.5,
CHCl3); 1H NMR (CDCl3, 300 MHz) d 12.54 (s, 1H),
8.85 (s, 1H), 8.03–7.85 (m, 4H), 7.47–7.11 (m, 11H), 4.86 (d,
1H, J = 6.0 Hz), 4.70 (d, 1H, J = 6.0 Hz), 3.22 (dd, 1H,
J1 = 15.6 Hz, J2 = 6.0 Hz), 3.03 (dd, 1H, J1 = 15.6 Hz,
J2 = 6.0 Hz), 0.72 (s, 9H); 13C NMR (CDCl3, 75 MHz) d
176.28, 166.59, 154.28, 147.06, 140.73, 140.35, 135.35,
134.16, 133.38, 131.76, 129.19, 128.75, 128.64, 128.56,
128.24, 127.65, 127.23, 126.53, 125.99, 125.51, 125.44,
125.22, 124.79, 124.05, 123.63, 122.08, 120.42, 115.95,
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Y.-C. Jeong et al. / Tetrahedron: Asymmetry 16 (2005) 3497–3501
3501
75.81, 75.29, 39.58, 38.57, 26.40. Anal. Calcd for
C35H31NO4: C, 79.37; H, 5.90; N, 2.64. Found: C, 79.23;
H 5.97; N, 2.64.
(1.0 mmol) and 30% H2O2 were added after 10 min stirring
at 0 °C. The mixture was stirred for 24 h at 0 °C and
quenched with satd Na2SO3 solution. The resulting solution
was extracted with CH2Cl2. The organic layer was briefly
dried over anhydrous MgSO4, filtered and concentrated
under reduced pressure. The crude product was purified by
flash column chromatography.
9. The general procedure used for the sulfoxidation reactions
is as follows: Vanadyl acetylacetonate (5.3 mg, 0.02 mmol)
and a ligand (0.03 mmol) were dissolved in CH2Cl2 (3 mL)
and then stirred for 10 min at room temperature. A sulfide