Organocatalytic Kinetic Resolution of Sulfoximines

Article abstract of DOI:10.1021/jacs.6b00143

An efficient kinetic resolution of sulfoximines with enals was realized using chiral N-heterocyclic carbene (NHC) catalysts. The stereoselective amidation proceeds without additional acyl transfer agent. Both enantiomers of the sulfoximines can be obtaine

Full text of DOI:10.1021/jacs.6b00143

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Communication
Organocatalytic Kinetic Resolution of Sulfoximines
Shunxi Dong, Marcus Frings, Hanchao Cheng, Jian Wen, Duo Zhang, Gerhard Raabe, and Carsten Bolm
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.6b00143 • Publication Date (Web): 04 Feb 2016
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Journal of the American Chemical Society
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Organocatalytic Kinetic Resolution of Sulfoximines
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Shunxi Dong, Marcus Frings, Hanchao Cheng, Jian Wen, Duo Zhang, Gerhard Raabe and
Carsten Bolm*
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Institute of Organic Chemistry, RWTH Aachen University, Landoltweg 1, 52074 Aachen, Germany.
Supporting Information Placeholder
protection/deprotection sequences.9 For the preparation of
ABSTRACT: An efficient kinetic resolution of sulfoximines
with enals was realized using chiral N-heterocyclic carbene
(NHC) catalysts. The stereoselective amidation proceeds
other important compound classes, catalytic kinetic
resolution (KR) is often the method of choice.10 In this
context, we recently reported an iron-catalyzed imidative KR
without additional acyl transfer agent. Both enantiomers of
of racemic sulfoxides, leading to N-Ts protected sulfoximines
the sulfoximines can be obtained with excellent ee values (up
to 99% ee and –97% ee, respectively). Performing the
in enantiomerically enriched form.11 However, the low yield
(15%) of a product with high ee (94% ee) limited the utility of
catalysis on a gram scale allowed using the recovered sulfox-
this method. Although acylative KR reactions of amines have
imine (+)-1j in an asymmetric synthesis of FXa inhibitor F.
been well-established,10
a direct chemocatalytic KR of
sulfoximines has not been realized to date.12 Herein, we
describe the first process of such type using chiral NHCs as
catalysts leading to various sulfoximines with excellent ee
values for both enantiomers (up to 99% ee and –97% ee,
respectively).
Sulfoximines,1 the monoaza analogues of sulfones, have
been widely used in organic synthesis as reagents,2 chiral
auxiliaries,3 chiral ligands,4 and directing groups in C−H
activations.5 Moreover, sulfoximines have attracted attention
in agricultural science6 and medicinal chemistry1e
(compounds A-F; Figure 1). In most of these applications the
stereochemistry at sulfur proved important.
The slightly distorted tetrahedral arrangement at sulfur1a
presented a particular challenge for the KR of sulfoximines.
The initial results were disappointing. Well-established
chiral acyl transfer catalysts13 such as benzotetramizoles13a
and thiourea/DMAP combinatons13b only gave racemic S-
methyl-S-phenyl sulfoximine (1a). Inspired by Zhao’s work,14
we attempted the use of chiral NHCs.15 The common need of
an additive such as imidazole or 1-hydroxy-7-azabenzo-
triazole in NHC-catalyzed amide formations was foreseen as
potential difficulty.16 To our delight, however, even without
such additive,17 the reaction of sulfoximine (±)-1a with
cinnamaldehyde (2a) proceeded smoothly in the presence of
5 mol% of NHC catalyst 4, MnO2 (5 equiv), 4 Å MS, and DBU
(1 equiv), resulting in amide 3aa in 53% yield with 39% ee.
Unreacted 1a was isolated in 44% yield with 45% ee (s = 4,
Table 1, entry 1). Encouraged by this result, the effects of
other NHCs were investigated.18 Triazolium 5a gave a better
result, providing the recovered sulfoximine with opposite
configuration (entry 2, –45% ee for 3aa and –62% ee for 1a, s
= 5). Then, different enals were used, and it was found that 2-
nitrocinnamaldehyde (2b) showed enhancements in both
reactivity and enantioselectivity (entry 3).18 A search for
alternative NHC catalysts led to chiral triazolium 6a
developed by Enders.19 Pleasingly, an s factor of 8 was
achieved with this (S)-3,3-dimethylbutan-2-amine-based
catalyst, albeit the reactivity was low. Subjecting a series of
structurally related N-substituted triazolium salts to the
model reaction18 showed that N-mesityl-substituted 6b20 did
not only lead to good ee values, but also to a high catalytic
activity (s = 10, Table 1, entry 5). Catalyst 6c bearing a bulkier
N-2,4,6-i-Pr3C6H2 substituent performed even better (s = 12,
Table 1, entry 6). Increasing the steric bulk further, for
example, by using tricyclohexyl- or tricyclopentyl-substituted
6d or 6e, respectively, gave no improvement (Table 1, entries
CF3
CH3
O
OH
CH3
N
N
CH3
O
O
S
HN
CH3
S
HN
OH
O
N
CN
H3C
NH2
F3C
N
LꢀMethionine (S)ꢀsulfoximine (B)
Sulfoxaflor (A)
S
NH
glutamine synthetase inhibitor
insecticide
O
BAY 1000394 (C)
panꢀCDK inhibitor
H3C
Cl
O
NH
S
CH3
H
N
O
N
CN
S
NH
O
CH3
H
O
O
H3C
RN
NH
Cl
S
O
HO
OH
O
R = C(O)CH2NEt2
VIOXX® analog (D)
Vitamine D analog (E)
Betrixaban analog (F)
COXꢀ2 inhibitor
CYP24 inhibitor
FXa inhibitor
Figure 1. Structures of selected bioactive sulfoximines
Although sulfoximines can be readily synthesized by
various methods, their preparation in enantioenriched form
is still challenging. Besides resolution,7 which is only
applicable to a small number of sulfoximines, the most
prominent strategies are stereospecific imidations of
optically
enantioenriched sulfimides.8d-f However, those approaches
are multi-step transformations with undesirable
active
sulfoxides8a-c and
oxidations
of
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Table 1. Optimization of the Reaction Conditionsa
Page 2 of 5
1
2
3
4
O
catalyst (5 mol%)
MnO2 (5 equiv)
DBU (1 equiv)
O
NH
R
O
O
NH
O
N
S
S
CH3
CH3
H
S
R
CH3
4 Å MS, THF
5
6
7
8
racꢀ1a
2a: R = H
2b: R = NO2
3aa: R = H
3ab: R = NO2
1a
O
H3C
tꢀBu
tꢀBu
tꢀBu
tꢀBu
N
N
O
N
O
R
H3C
N
N
R
N
N
H3C
H3C
N
6a:
6b:
6c:
6d:
6e:
6f:
R = Ph
R = Mes
N
9
BF4
tꢀBu
Mes
Bn
BF4
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
R = 2,4,6ꢀtriisopropylphenyl
R = 2,4,6ꢀtricyclohexylphenyl
R = 2,4,6ꢀtricyclopentylphenyl
R = 9ꢀphenanthrenyl
BF4
4
5a:
5b:
5c:
R = 2,4,6ꢀtrimethylphenyl (Mes)
R = 2,4,6ꢀtriisopropylphenyl
R = 9ꢀphenanthrenyl
O
7
entry
1d
2d
catalyst
4
T (oC)
–20
–20
–20
–20
–20
–20
–20
–20
–20
–20
–20
–45
–45
–60
–60
t (h)
48
48
24
48
48
48
48
48
48
48
72
yield of 3 (%)
53 (3aa)
58 (3aa)
42 (3ab)
30 (3ab)
45 (3ab)
54 (3ab)
57 (3ab)
50 (3ab)
54 (3ab)
51 (3ab)
51 (3ab)
38 (3ab)
59 (3ab)
53 (3ab)
56 (3ab)
ee of 3 (%)b
39
yield of 1a (%)
ee of 1a (%)b
sc
44
40
50
65
52
42
40
45
41
45
4
5a
–45
–68
72
–62
–50
32
5
5a
3
9
6a
6b
6c
4
8
5
70
57
10
12
11
6
67
81
6d
6e
6f
7
63
84
70
8
70
12
12
12
11
9
67
80
–70
–70
50
5b
5c
10
11
–70
–68
78
46
45
58
38
43
42
6c
12
13e
14e,f
15e
72
13
15
30
25
6c
72
64
94
91
6c
96
81
5b
96
–75
–95
a Unless otherwise noted, all reactions were carried out with the catalyst (5 mol%), 1a (31 mg, 0.20 mmol), 2b (21 mg, 0.12 mmol), DBU (30 ꢀL,
b
c
0.20 mmol), 4 Å MS (30 mg) and MnO2 (87 mg, 1.0 mmol) in THF (1 mL). Determined by CSP-HPLC analysis Selectivity factors (s),
calculated according to the following equation: s = ln[(1-C)*(1-ee1)]/ln[(1-C)*(1+ee1)], C= (ee1)/(ee1+ee3). d Use of 2a (19 ꢀL, 0.15 mmol) instead
of 2b. e 3,3',5,5'-tetra-tert-butyl-[1,1'-bi(cyclohexylidene)]-2,2',5,5'- tetraene-4,4'-dione (7, 49 mg, 0.12 mmol ) was used as the oxidant instead of
MnO2. f The absolute configuration of the major enantiomer 1a was (S) by comparing the specific rotation with the reported value.7b
7 and 8). Triazolium 6f bearing an N-9-phenanthrenyl
substituent performed equally well (s 12, entry 9),
with 5b or 6c as catalysts (Table 2). A broad range of
sulfoximines bearing different aryl substituents reacted
smoothly affording the desired amides 3ab and 3b–k with
moderate to high enantioselectivities (41−59% yield, 67−93%
ee for 6c, and 41–57% yield, –52 to –96% ee for 5b).
Unreacted 1a–k were recovered in yields of 38–55% with 65–
99% ee and in 40–53% yields with –65 to –97% ee (Table 2,
entries 1−22). Notably, substrates with 4-CF3, 4-SF5, and 2-
naphthyl substituents (1l–n) were also suitable (Table 2,
entries 23−28). 2-Pyridyl-substituted 1o gave low s factors
(Table 2, entries 29 and 30). Sulfoximines 1p and 1q with
cyclopropyl and benzyl substituents also underwent the KR
processes with s factors of 16−60 (Table 2, entries 31−34).
Product 3ab was readily hydrolyzed with aqueous HCl to
give 1a stereospecifically under retention of configuration.18
Finally, sulfondiimide 1r was reacted, giving product 3r with
58% ee (for 6c) and –75% ee (for 5b). In both cases, however,
unreacted 1r was recovered with low ee values (Table 2,
entries 35 and 36).
=
indicating a possible π-π stacking interaction between the
catalyst and the substrates. The same trend could be
deduced from the data obtained with triazoliums 5b (with an
N-2,4,6-i-Pr3C6H2 substituent) and 5c (bearing an N-9-
phenanthrenyl moiety) (Table 1, entries 10 and 11 vs entry 3).
With this promising lead, the reaction conditions were
systematically screened.18 Lowering the temperature from –
o
20 °C to –45 C led to a slight improvement of the s factor,
but at the expense of the reactivity (entry 12 vs entry 6).
When MnO2 was replaced by quinone 7 as the oxidant, both
the selectivity (s = 15) and the reactivity increased (entry 13).
o
Further, lowering the temperature to –60 C improved the s
value to 30 (Table 1, entry 14), and unreacted 1a was
recovered in 43% yield with 91% ee. Using 5b, the
enantiomer of sulfoximine 1a was formed in preference with
–95% ee (Table 1, entry 15).
Having the optimized reaction conditions established, the
scope of the kinetic resolution of sulfoximines was studied
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Table 2. Substrate Scope for Kinetic Resolutions of Sulfoximines and a Sulfondiimide with Enal 2ba
1
2
3
4
5
6
7
8
catalyst (5 mol%)
oxidant 7 (0.6 equiv)
DBU (1 equiv)
O
NO2
O
X
NH
R2
X
NH
R2
X
N
S
S
+
H
+
R1
R1
S
R2
O2N
4 Å MS, THF, –60 °C
R1
2b
racꢀ1
3
1
entry
1
2c
R1
R2
X
t (h)
96
96
96
96
96
96
96
96
96
96
96
96
108
108
96
96
96
96
108
108
108
108
96
96
96
96
96
96
120
120
96
96
96
96
96
96
yield of 3 (%) ee of 3(%)b
yield of 1 (%) ee of 1 (%)b
s
C6H5
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
53 (3ab)
56 (3ab)
54 (3b)
57 (3b)
59 (3c)
56 (3c)
56 (3d)
54 (3d)
53 (3e)
56 (3e)
52 (3f)
54 (3f)
54 (3g)
53 (3g)
52 (3h)
54 (3h)
52 (3i)
57 (3i)
52 (3j)
55 (3j)
81
43 (1a)
42 (1a)
43 (1b)
40 (1b)
38 (1c)
42 (1c)
41 (1d)
42 (1d)
45 (1e)
40 (1e)
45 (1f)
43 (1f)
42 (1g)
42 (1g)
44 (1h)
43 (1h)
42 (1i)
41 (1i)
91
30
25
26
16
25
22
24
27
29
14
33
22
16
20
35
33
24
26
23
6
C6H5
–75
78
–95
92
9
3
4c
2-BrC6H4
2-BrC6H4
3-BrC6H4
3-BrC6H4
4-BrC6H4
4-BrC6H4
2-ClC6H4
2-ClC6H4
4-ClC6H4
4-ClC6H4
4-FC6H4
4-FC6H4
4-CH3C6H4
4-CH3C6H4
4-CH3OC6H4
4-CH3OC6H4
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
–67
67
–90
99
5
6c
–74
73
–93
96
7
8c
–77
80
–94
92
9
10c
–69
81
–85
94
11
12c
13
14c
–76
72
–90
85
–75
82
–88
94
15
16c
17
18c
–80
78
–95
89
–73
78
–97
87
19
4-CH3OC(O)C6H4
4-CH3OC(O)C6H4
4-NO2C6H4
4-NO2C6H4
4-CF3C6H4
4-CF3C6H4
4-SF5C6H4
4-SF5C6H4
2-naphthyl
2-naphthyl
2-pyridyl
2-pyridyl
C6H5
42 (1j)
42 (1j)
55 (1k)
53 (1k)
44 (1l)
47 (1l)
43 (1m)
41 (1m)
43 (1n)
44 (1n)
44 (1o)
44 (1o)
44 (1p)
44 (1p)
45 (1q)
40 (1q)
82 (1r)
80 (1r)
20c
21d
22c,d
23
24c
25
26c
27
28c
29
30c
31
32c
33
34c
35
36c
–52
93
–65
65
41 (3k)
41 (3k)
54 (3l)
52 (3l)
53 (3m)
56 (3m)
54 (3n)
54 (3n)
52 (3o)
54 (3o)
54 (3p)
54 (3p)
53 (3q)
56 (3q)
16 (3r)
18 (3r)
54
101
23
25
20
21
–96
76
–69
91
–80
75
–87
88
–73
79
–93
96
33
33
4
–80
43
–95
48
–53
84
–63
99
6
cyclopropyl
cyclopropyl
C6H5CH2
C6H5CH2
CH3
60
29
25
16
4
C6H5
–79
78
–93
90
C6H5
C6H5
–69
58
–90
11
C6H5
NC6H5
NC6H5
C6H5
CH3
–75
–17
8
a Unless otherwise noted, all reactions were carried out with 6c (5 mol%), 1 (0.20 mmol), 2b (21 mg, 0.12 mmol), DBU (30 ꢀL, 0.20 mmol), 4 Å
MS (30 mg) and oxidant 7 (49 mg, 0.12 mmol) in THF (1.o mL) at −60 oC. . b Determined by CSP-HPLC analysis. c Catalyst 5b was used instead
of 6c. d Use of 10 mol% of catalyst.
To further evaluate the synthetic potential of the catalytic
system, the reaction was conducted on a gram scale, giving
(+)-1j in 43% yield with 90% ee. Sulfoximine 1j was selected
as target here because it represented a key fragment of
compound F, which as racemate revealed a strong human
FXa inhibitory activity (IC50= 2.1 nM) and anticoagulant
effects. Using recrystallized sulfoximine (+)-1j (with 95% ee)
prepared by the aforementioned kinetic resolution process
allowed for the first time the preparation of optically active
compound F (with a total yield of 50%; Scheme 1).21
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(5) For selected examples, see: (a) Rit, R. K.; Yadav, M. R.; Sahoo,
Scheme 1. Scale-up Experiment and Its Application
A. K. Org. Lett. 2012, 14, 3724. (b) Dong, W.; Wang, L.; Parthasarathy,
K.; Pan, F.; Bolm, C. Angew. Chem., Int. Ed. 2013, 52, 11573. (c) Cheng,
Y.; Bolm, C. Angew. Chem., Int. Ed. 2015, 54, 12349.
(6) Sparks, T. C.; Watson, G. B.; Loso, M. R.; Geng, C.; Babcock, J.
M.; Thomas, J. D. Pestic. Biochem. Physiol. 2013, 107, 1.
(7) Selected representative examples: (a) Mori, K.; Toda, F. Chem.
Lett. 1988, 17, 1997. (b) Brandt, J.; Gais, H.-J. Tetrahedron: Asymmetry
1997, 8, 909. (c) Gries, J.; Krüger, J. Synlett 2014, 25, 1831. (d)
Allenmark., S.; Bomgren, B. J. Chromatogr. A 1982, 252, 297.
(8) (a) Johnson, C. R.; Kirchhoff, R. A.; Corkins, H. G. J. Org. Chem.
1974, 39, 2458. (b) Bach, T.; Körber, C. Eur. J. Org. Chem. 1999, 1033.
(c) Okamura, H.; Bolm, C. Org. Lett. 2004, 6, 1305. (d) Cram, D. J.;
Day, J.; Rayner, D. R.; von Schriltz, D. M.; Duchamp, D. J.; Garwood,
D. C. J. Am. Chem. Soc. 1970, 92, 7369. (e) Collet, F.; Dodd, R. H.;
Dauban, P. Org. Lett. 2008, 10, 5473. (f) Wang, J.; Frings, M.; Bolm, C.
Angew. Chem., Int. Ed. 2013, 52, 8661.
(9) For an asymmetric deprotonation strategy starting from
prochiral sulfoximines, see: (a) McGrath, M. J.; Bolm, C. Beilstein J.
Org. Chem. 2007, 3, 33. (b) Pandey, A. G.; McGrath, M. J.; Mancheño,
O. G.; Bolm, C. Synthesis 2011, 3827.
(10) For selected reviews, see: (a) Vedejs, E.; Jure, M. Angew.
Chem., Int. Ed. 2005, 44, 3974. (b) Müller, C. E.; Schreiner, P. R.
Angew. Chem., Int. Ed. 2011, 50, 6012. (c) Pellissier, H. Adv. Synth.
Catal. 2011, 353, 1613. (d) Krasnov, V. P.; Gruzdev, D. A.; Levit, G. L.
Eur. J. Org. Chem. 2012, 1471.
(11) Wang, J.; Frings, M.; Bolm, C. Chem.–Eur. J. 2014, 20, 966.
(12) For a single example of an enzymatic kinetic resolution of a
sulfoximine derivative proceeding by ester hydrolysis and
subsequent decarboxylation, see: Kielbasinski, P. Pol. J. Chem. 1999,
73, 735.
(13) For selected examples, see: (a) Birman, V. B.; Jiang, H.; Li, X.;
Guo, L.; Uffman, E. W. J. Am. Chem. Soc. 2006, 128, 6536. (b) De, C.
K.; Klauber, E. G.; Seidel, D. J. Am. Chem. Soc. 2009, 131, 17060. (c)
Arai, S.; Bellemin-Laponnaz, S.; Fu, G. C. Angew. Chem., Int. Ed. 2001,
40, 234. (d) Fowler, B. S.; Mikochik, P. J.; Miller, S. J. J. Am. Chem. Soc.
2010, 132, 2870.
1
2
3
4
5
6
7
8
O
S
O
O
S
NH
NH
standard
conditions
CH3
CH3
O N
S
O
O
O2N
CH3
(with cat. 6c)
OCH3
O
OCH3
(+)ꢀ3j
(+)ꢀ1j
racꢀ1j
OCH3
O
S
CH3
43% (0.52 g)
90% ee
(5.6 mmol, 1.2 g)
54% (1.16 g)
74% ee
NCbz
c
a, b
(+)ꢀ1j
O
Cl
9
HN
O
Cl
0.39 g, 95% ee
(after recyst.)
8: R = CH3
9: R = H
OR
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
N
NH2
10
HN
Cl
HN
Cl
O
HN
O
N
O
N
d, e, f
CH3
CH3
HN
Cl
Cl
RN
S
CbzN
S
O
O
O
(+)ꢀF (0.52 g)
[α]D25 = +44.1 (c = 2.2, DMSO)
11
R = C(O)CH2N(C2H5)2
(a) ClCOOBn, py, CH2Cl2, 98%; (b) NaOH, THF/H2O (v/v, 1/1), 96%; (c) oxalyl chloride, CH2Cl2;
then 10, 94%; (d) H2SO4; (e) ClCH2C(O)Cl, TEA, THF; (f) HNEt2, KI, DMF, 56% over 3 steps.
In summary, catalytic resolutions of racemic sulfoximines
have been accomplished by chiral NHC-catalyzed enantio-
selective amidation reactions with enals. Both enantiomers
of various sulfoximines could be obtained with excellent ee
values. The utility of this strategy was demonstrated in the
asymmetric synthesis of human Factor Xa inhibitor F.
ASSOCIATED CONTENT
Supporting Information
Experimental details and analytical data. This material is
available free of charge via the Internet at http://pubs.acs.org.
(14) (a) Lu, S.; Poh, S. B.; Siau, W.-Y.; Zhao, Y. Angew. Chem., Int.
Ed. 2013, 52, 1731. (b) Lu, S.; Poh, S. B.; Zhao, Y. Angew. Chem., Int. Ed.
2014, 53, 11041.
AUTHOR INFORMATION
Corresponding Author
(15) For selected recent reviews, see: (a) Grossmann, A.; Enders, D.
Angew. Chem., Int. Ed. 2012, 51, 314. (b) Izquierdo, J.; Hutson, G. E.;
Cohen, D. T.; Scheidt, K. A. Angew. Chem., Int. Ed. 2012, 51, 11686. (c)
Ryan, S. J.; Candish, L.; Lupton, D. W. Chem. Soc. Rev. 2013, 42, 4906.
(d) Mahatthananchai, J.; Bode, J. W. Acc. Chem. Res. 2014, 47, 696. (e)
Hopkinson, M. N.; Richter, C.; Schedler, M.; Glorius, F. Nature 2014,
510, 485. (f) Flanigan, D. M.; Romanov-Michailidis, F.; White, N. A.;
Rovis, T. Chem. Rev. 2015, 115, 9307.
(16) (a) Bode, J. W.; Sohn, S. S. J. Am. Chem. Soc. 2007, 129, 13798.
(b) Vora, H. U.; Rovis, T. J. Am. Chem. Soc. 2007, 129, 13796. (c)
Mahatthananchai, J.; Zheng, P.; Bode, J. W. Angew. Chem., Int. Ed.
2011, 50, 1673. (d) Binanzer, M.; Hsieh, S.-Y.; Bode, J. W. J. Am. Chem.
Soc. 2011, 133, 19698.
E-mail: carsten.bolm@oc.rwth-aachen.de
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
S.D. acknowledges support by the Alexander von Humboldt
Foundation. H.C., J.W., and D.Z. are grateful to the China
Scholarship Council (CSC) for predoctoral stipends. We also
thank Peter Becker for helpful discussions.
REFERENCES
(17) We assume that this behavior is due to the low
nucleophilicity and basicity of the NH group of sulfoximine 1a (with
a pKa value of 24 in DMSO).
(1) For selected reviews, see: (a) Reggelin, M.; Zur, C. Synthesis
2000, 1. (b) Gais, H.-J. Heteroat. Chem. 2007, 18, 472. (c) Worch, C.;
Mayer, A. C.; Bolm, C. In Organosulfur Chemistry in Asymmetric
Synthesis (Eds.: Toru, T.; Bolm, C.), Wiley-VCH, Weinheim, 2008, p.
209. (d) Bizet, V.; Hendriks, C. M. M.; Bolm, C. Chem. Soc. Rev. 2015,
44, 3378. (e) Lücking, U. Angew. Chem., Int. Ed. 2013, 52, 9399.
(2) Johnson, C. R. Acc. Chem. Res. 1973, 6, 341.
(3) For selected examples, see: (a) Gais, H.-J.; Müller, H.; Bund, J.;
Scommoda, M.; Brandt, J.; Raabe, G. J. Am. Chem. Soc. 1995, 117, 2453.
(b) Harmata, M.; Hong, X. Org. Lett. 2007, 9, 2701. (c) Peraino, N. J.;
Wheeler, K. A.; Kerrigan, N. J. Org. Lett. 2015, 17, 1735.
(4) For reviews, see: (a) Harmata, M. Chemtracts 2003, 16, 660. (b)
Okamura, H.; Bolm, C. Chem. Lett. 2004, 33, 482. For selected
examples, see: (c) Bolm, C.; Simić, O. J. Am. Chem. Soc. 2001, 123,
3830. (d) Langner, M.; Bolm, C. Angew. Chem., Int. Ed. 2004, 43,
5984. (e) Frings, M.; Thomé, I.; Schiffers, I.; Pan, F.; Bolm, C. Chem. -
Eur. J. 2014, 20, 1691.
(18) For details, see the Supporting Information and the
Cambridge
Crystallographic
Data
Centre
via
www.ccdc.cam.ac.uk/data_request/cif where the data can be
obtained free of charge.
(19) (a) Teles, J. H.; Ebel, K.; Enders, D.; Breuer, K. Preparation of
optically active hydroxy ketones. Ger. Offen. DE19704273, Feb 5, 1997.
(b) Strand, R. S.; Solvang, T.; Sperger, C. A.; Fiksdahl, A. Tetrahedron:
Asymmetry 2012, 23, 838.
(20) CCDC 1438719 (6b) contains the supplementary
crystallographic data for this paper.
(21) Pandya, V.; Jain, M.; Chakrabarti, G.; Soni, H.; Parmar, B.;
Chaugule, B.; Patel, J.; Jarag, T.; Joshi, J.; Joshi, N.; Rath, A.; Unadkat,
V.; Sharma, B.; Ajani, H.; Kumar, J.; Sairam, K. V. V. M.; Patel, H.;
Patel, P. Eur. J. Med. Chem. 2012, 58, 136.
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An efficient kinetic resolution of sulfoximines with enals was realized using N-heterocyclic carbenes (NHC) as
catalysts. The stereoselective amidation does not require any additional acyl transfer agent and provides both
sulfoximine enantiomers with excellent ee values (up to 99% ee and –97% ee, respectively). The catalytic reaction
can be performed on a gram scale allowing an asymmetric synthesis of a known human Factor Xa inhibitor via a
suitably substituted NH-sulfoximine.
1
2
3
4
5
6
7
8
9
iꢀPr
O
6c (5 mol%)
H3
C
C
N
O
NH
R
O
S
N
N
iꢀPr
s factor up to 60
O
NH
R
N
S
H3
Ar
Ar
O2
N
R
S
iꢀPr
Ar
tꢀBu
(+)ꢀ1
up to 99% ee
BF4
(+)ꢀ3
oxidant (0.6 equiv),
DBU (1 equiv),
4 Å MS, THF, –60 °C
racꢀ1
6c
up to 93% ee
O
O
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
NO2
O
H3
C
C
N
N
iꢀPr
O
NH
R
H3
N
H
O
N
S
Bn
S
Ar
Ar
2b
O2
(–)ꢀ3
up to 96% ee
N
R
5b (5 mol%)
BF4
iꢀPr
(–)ꢀ1
up to 97% ee
iꢀPr
5b
s factor up to 101
5
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