Efficient Kinetic Resolution of Sulfur-Stereogenic Sulfoximines by Exploiting CpXRhIII-Catalyzed C?H Functionalization

Article abstract of DOI:10.1002/anie.201904543

Chiral sulfoximines with stereogenic sulfur atoms are promising motifs in drug discovery. We report an efficient method to access chiral sulfoximines through a C?H functionalization based kinetic resolution. A rhodium(III) complex equipped with a chiral Cp^x ligand selectively participates in conjunction with phthaloyl phenylalanine in the C?H activation of just one of the two sulfoximine enantiomers. The intermediate reacts with various diazo compounds, providing access to chiral 1,2-benzothiazines with synthetically valuable substitution patterns. Both sulfoximines and 1,2-benzothiazines were obtained in high yields and excellent enantioselectivity, with s-values of up to 200. The utility of the method is illustrated by the synthesis of the key intermediates of two pharmacologically relevant kinase inhibitors.

Full text of DOI:10.1002/anie.201904543

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Accepted Article
Title: Efficient Kinetic Resolution of Sulfur-Stereogenic Sulfoximines
Exploiting CpXRh(III)-Catalyzed C-H Functionalization Marcus
Brauns and Nicolai Cramer
Authors: Marcus Brauns and Nicolai Cramer
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201904543
Angew. Chem. 10.1002/ange.201904543
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10.1002/anie.201904543
Angewandte Chemie International Edition
COMMUNICATION
Efficient Kinetic Resolution of Sulfur-Stereogenic Sulfoximines
Exploiting CpxRhIII-Catalyzed C-H Functionalization
Marcus Brauns and Nicolai Cramer[*]
Abstract: Chiral sulfoximines with stereogenic sulfur atoms are
promising motifs in drug discovery. We report an efficient method to
access chiral sulfoximines by a C-H functionalization-based kinetic
resolution. A rhodium(III) complex equipped with a chiral Cpx-ligand
selectively participates in conjunction with phthaloyl phenyl alanine
in the C-H activation of just one of the two sulfoximine enantiomers.
The intermediate reacts with various diazo compounds, providing
access to chiral 1,2-benzothiazines with synthetically valuable
substitution patterns. Both sulfoximines and 1,2-benzothiazines were
obtained in high yields and excellent enantioselectivities with
s-values of up to 200. The utility of the method is illustrated by the
synthesis of the key intermediates of two pharmacologically relevant
kinase inhibitors.
containing bioactive compounds have been disclosed and
entering clinical trials. For example, kinase inhibitors like
roniciclib,[6b] ceralasertib[3e] or Pfizer's PYK2 inhibitor[7] bear an
acyclic chiral sulfoximine moiety. Lilly's prazosine analog,[8] Gö
4962[9] and NSC 287474 are representative examples for cyclic
benzannulated sulfoximines.[10] The chirality of the sulfoximine
group has proven important, with each enantiomer of the
stereogenic sulfur atom having different properties.[11] For
instance, the (R)-configuration of the sulfur atom in ceralasertib
leads to a slightly higher bioactivity as well as enjoys a
significantly higher solubility compared to the corresponding (S)-
sulfur epimer.[6a] Although the situation for the synthesis of this
compound class has greatly improved,[3] the selective
preparation of chiral sulfoximines and corresponding motifs
remains challenging. While processes for selective imination and
oxidation,[12] as well as organo- and metal-catalyzed kinetic
resolutions[13] have been reported by Bolm et al., the number of
broadly useful tools for the synthesis of chiral sulfoximines
Already discovered in the late 1940s,[1] the sulfoximine functional
group had largely been undervalued and underutilized. More
recently, it has received a tremendous increase in attention,
especially in the last decade.[2] Improved access by new
synthetic methods reported by Bolm and others have reinforced
this trend.[3] Sulfoximines are a chemically robust functional
group, displaying configurationally stable S-stereogenicity.[2d, 4] In
medicinal chemistry, they often show significant bioactivity,
remains limited. Sulfoximines have emerged as suitable
15]
directing group for catalytic C-H functionalizations.[14,
Very
recently, we[16] and independently Li et al.[17] reported the
desymmetrization of prochiral sulfoximines via an
indicating
a
high potential as active pharmaceutical
Compared to sulfones and sulfonamides,
enantioselective C(sp2)-H bond functionalization[18] providing
access to broad range of cyclic benzannulated sulfoximines
(Scheme 1). However, the method has conceptual limitations
requiring two identical aryl groups in starting material, thus
precluding its application for the synthesis of acyclic aryl alkyl
substituted sulfoximines, like the one featured in roniciclib, for
instance.
5]
ingredients.[2c,
sulfoximines can provide strategic advantages related to
6]
improved solubility properties or higher metabolic stability.[5a,
Due to these benefits, an increasing number of sulfoximine-
Figure 1. Biologically active compounds with a stereogenic sulfoximine.
Scheme 1. Access to chiral sulfoximines by C-H functionalization technology.
[*]
Dr. M. Brauns, Prof. Dr. N. Cramer
Laboratory of Asymmetric Catalysis and Synthesis
EPFL SB ISIC LCSA, BCH 4305
1015 Lausanne (Switzerland)
E-mail: nicolai.cramer@epfl.ch
Homepage: https://lcsa.epfl.ch/cramer/
Supporting information for this article is given via a link at the
end of the document.
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10.1002/anie.201904543
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COMMUNICATION
We envisioned that a kinetic resolution based on a C-H
functionalization[19, 20] would allow to address this void. Herein,
we report an efficient kinetic resolution of differentially
substituted sulfoximines, enabling access to acyclic
enantioenriched aryl alkyl sulfoximines, as well as cyclic
benzothiazines. Our investigation of the kinetic resolution of
sulfoximines started with phenyl methyl sulfoximine (1a) and
diazoketoester 2a as model substrates (Table 1). Evaluation of a
small set of 3-substituted CpxRh(III)-complexes[21] in DCE
revealed Rh3 as promising lead, providing an s-value of 18
(91:9 er for 1a and 87.5:12.5 er for 3a, entry 3). While the
addition of achiral carboxylic acid significantly improved the
reaction rate, allowing lowering the reaction temperature to
40 °C and shortening the reaction time, it almost completely
levelled the selectivity (entries 5-8). Methanol as solvent partly
restored the selectivity (s=10 for pivalic acid and Rh4, entry 11).
It should be noted that the addition of A2 and A3 inverted the
selectivity (See SI for details).[17] Subsequently, we investigated
the potential synergistic effect of chiral carboxylic acids.[22] In this
respect, phthalimido-protected amino acids A5-A9[16, 23] showed
the best performance in conjunction with Rh4 (entries 12-16).
Achiral glycine-derived A5 resulted in an s-value of 28 (entry
12). Both phenylalanine and tert-leucine derived acids A6 and
A9 displayed an equally good performance with an s-value of 45
(entries 13, 16). Subsequently A6 was selected for its low cost
and availability. Notably, the enantioselectivity and efficiency
could be further increased by the reduction of the amount of acid
A6 to 10 mol% (entry 17). Now, the reaction reliably stalled at
50 % conversion, resulting in the formation of 1a in 99.5 er and
3a in 95:5 er translating to an s-value of 99. The dramatic
influence of the acid on the reaction performance becomes even
clearer when A6 was switched for its enantiomer ent-A6 (entry
18). The resolution process lost almost all performance, with the
s-value dropping sharply to 11, and benzothiazine 3a formed
with only 82:18 er.
6
7
8
9
Rh3 A2 (1.0)
Rh3 A3 (1.0)
Rh3 A4 (1.0)
Rh3 A2 (1.0)
DCE
42
38
60
42
50
37
56
53
52
53
53
52
55
39:61
45:55
71:29
39:61
82:I8
72:28
98:2
35:65
42:58
64:36
35:65
82:18
87:13
88:12
92:8
2
DCE
2
DCE
3
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
2
10 Rh3 A4 (1.0)
11 Rh4 A4 (1.0)
12 Rh4 A5 (1.0)
13 Rh4 A6 (1.0)
14 Rh4 A7 (1.0)
15 Rh4 A8 (1.0)
16 Rh4 A9 (1.0)
17 Rh4 A6 (0.1)
9
10
28
45
21
19
45
99
11
98:2
92:8
89:11
88:12
92:8
92:8
98:2
>99:1
90:10
95:5
18 Rh4 ent-A6 (0.1) MeOH
82:18
[a] 0.1 mmol rac-1, 0.06 mmol 2a, 3 mol% [Rh], 10 mol% A6, 0.3 M; [b]
determined by 1H-NMR; [c] determined by chiral HPLC; [d] calculated
according to: s = ln[(1-C) * (1-ee1a)] / ln[(1-C) * (1+ee1a)], C = (ee1a) /
(ee1a+ee3a); [e] with 12 mol% AgSbF6; [f] at 60 °C for 16 h.
Next, we investigated the scope for the kinetic resolution with
respect to the sulfoximine (Table 2). The developed catalytic
system proved to be robust for the selective conversion of
ortho-, meta- and para-substituted aryl sulfoximines (entries 1-
7). Both electron-donating (1b-1c) and electron-withdrawing
groups (1d-1f) on the arene were well tolerated. In all cases, the
resolution performed well and allowed for the isolation of both
the residual resolved sulfoximine 1 as well as benzothiazine 3 in
39-50 % yield with an enantiomeric ratio from 94:6 to 99.5:0.5
er. Remarkably, para-nitrophenyl methyl sulfoximine 1e[24] (entry
5) and 1-naphthyl methyl sulfoximine 1g (entry 7) were
particularly suited, resulting in s-values of >200 and 149,
respectively. Next, the tolerance for the different substituents R
was tested. Besides the methyl group (1a), benzyl-substitution
Table 1. Reaction optimization for the kinetic resolution of rac-1a.[a]
(1h) was smoothly resolved with
a comparable s-value.
Sterically demanding branched alkyls such as iPr (1h) or
cyclohexyl (1j) were tolerated and reacted well. However, their
respective s-values range from 38-42. Nevertheless, the yields
are very good and the obtained enantioselectivity never drop
below 93:7. In contrast, the valuable cyclopropyl substituent (1k
and 1l) behaved remarkably different resulting in excellent s-
values (entries 11 and 12). Synthetically attractive substrates
with heteroatom-containing saturated six-membered ring
substituents such as 4-tetrahydro-pyranyl (1m, entry 13) and N-
Boc-4-piperidinyl (1n, entry 14) reacted more selectively than
the parent cyclohexyl group. In particular, 1n was smoothly
resolved, with an s-value of 62, translating to the formation of 3n
in 49 % yield and 95:5 er and 46 % for unreacted starting
material 1n with 96:4 er.
Entry [Rh] A (Equiv.) Solvent % Conv.[b] er 1a[c] er 3a[c]
s-value[d]
1[e,f] Rh1 AgSbF6
2[e,f] Rh2 AgSbF6
DCE
DCE
DCE
DCE
DCE
38
42
52
46
45
67:33
77:23
91:9
78:22
88:12
88:12
82:18
72:28
5
13
18
8
3[f] Rh3
4[f] Rh4
-
-
77:23
68:32
5
Rh3 A1 (1.0)
4
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10.1002/anie.201904543
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COMMUNICATION
Table 2. Scope for the kinetic resolution of different racemic sulfoximines.[a]
Entry
1
rac-1x
1a
1b
1c
1d
1e
1f
R
Ar
% Conv.
52
% Yield 1x
er 1x
>99:1
93:7
% Yield 3x
er 3x
95:5
s-value
99
Me
Ph
45
39
47
46
47
41
42
46
42
45
41
46
48
47
2
Me
3-Me-C6H4
4-MeO-C6H4
4-Cl-C6H4
4-NO2-C6H4
2-Br-C6H4
1-naphthyl
Ph
49
94:6
43
3
Me
48
94.5:5.5 47
97:3
97
4
Me
50
95:5
98:2
94:6
99:1
97:3
93:7
49
47
48
42
49
43
96:4
74
5
Me
49
98.5:1.5
94.5:5.5
97:3
>200
50
6
Me
50
7
1g
1h
1i
Me
51
149
98
8
Bn
50
96.5:3.5
94:6
9
iPr
Ph
49
43
10
11
12
1j
Cy
Ph
50
93.5:6.5 45
93:7
38
1k
1l
cyclopropyl
cyclopropyl
Ph
52
>99:1
97:3
49
47
95:5
99
4-NO2-C6H4
49
98:2
175
13
14
1m
1n
Ph
Ph
50
51
40
46
95.5:4.5 49
95:5
95:5
60
62
96:4
49
[a] 0.3 mmol rac-1, 0.156 mmol 2a, 3 mol% Rh4, 10 mol% A6, 0.3 M in MeOH.
Subsequently, a range of diazo interceptors 2y were tested for
the kinetic resolution of rac-1a (Table 3). In addition to the
sterically demanding tert-butyl ester (3ab), a tosyl group (3ag)
was suitable as electron-withdrawing group R1. Substituents R2
High s-values were obtained, except for diazo compounds 3ac
and 3ad, which provided s-values between 48 and 52. This
clearly indicates that the diazo intermediate plays a non-
innocent role. Nevertheless, the method reliably provided
excellent yields and enantioselectivities throughout the complete
sulfoximine and diazo substrate spectrum.
could be varied as well to accommodate an aryl (3ac),[24]
a
heteroaryl (3ae) or a styryl group (3ae). Moreover, a methyl
(3ag) or cyclopropyl unit (3af) were well tolerated.
Table 3. Scope for the kinetic resolution of sulfoximine rac-1a with a variety of diazo compounds 3y.[a]
Entry
2y
2b
2c
2d
2e
2f
R1
R2
% Conv.
53
% yield 1a
er 1a
>99:1
>99:1
95:5
% yield 3ay
er 3ay
94:6
91:9
94:6
97:3
97:3
97:3
s-value
81
1
2
4
5
6
7
CO2tBu
CO2Et
CO2Et
CO2Et
CO2Et
Ts
Me
47
41
45
39
47
49
50
49
46
47
44
47
Ph
55
52
(E)-styryl
2-furyl
cyclopropyl
Me
51
48
50
97:3
115
100
106
49
95:5
2g
49
96:4
[a] 0.3 mmol rac-1a, 0.165 mmol 2y, 3 mol% Rh4, 10 mol% A6, 0.3 M in MeOH.
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10.1002/anie.201904543
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COMMUNICATION
To illustrate the relevance of our method, we performed the
resolution of rac-1e on a 4 mmol (800 mg) scale (Scheme 2).
Optically enriched (S)-1e and (R)-3e[24] were obtained in 47 %
yield with 98:2 er and 48 % yield and 99:1 er, respectively.
Sulfoximine (S)-1e was N-methylated and its nitro group was
subsequently hydrogenated catalytically. Obtained aniline 5 is a
key precursor for the synthesis of the proline-rich tyrosine kinase
2 (PYK2) inhibitor which may represent an anabolic therapy for
osteoporosis patients.[7] Resolution of cyclopropyl-containing
rac-1l provided access to (S)-1l in 49 % yield and 98:2 er. N-
acylation and reduction gave aniline 6 which is a direct precursor
for roniciclib.[6b]
critical importance of the carboxylic acid for the success of the
transformation.
Scheme 2. Application of the kinetic resolution for bioactive compounds.
Figure 2. Reaction kinetics of substrate 1a.
In conclusion, we developed an efficient kinetic resolution of
racemic sulfoximines based on a C-H functionalization. A
powerful synergistic Interplay of chiral trisubstituted Cpx ligand
RhIII-complex with a phthaloyl phenyl alanine enabled a strong
kinetic differentiation between the two enantiomers of
stereogenic sulfur atoms of the substrates. The kinetic resolution
proceeds with high yields and enantioselectivities for the product
as well as the remaining substrate, ensuring s-values of up to
>200. The transformation is tolerant to a range of differently
substituted sulfoximines and is shown to be compatible with a
selection of diazo interceptors. The utility of the transformation is
showcased by the formal synthesis of two kinase inhibitors.
Acknowledgements
This work is supported by the SNF (no 157741). We thank Dr. R.
Scopelliti and Dr. F. Fadaei Tirani for X-ray crystallographic
analysis of compounds 1e, 3e and 3ac.
Keywords: Asymmetric Catalysis • Chiral Cp Ligands • Kinetic
To gain insight into the reaction, we obtained sets of reaction
kinetics by 1H-NMR (Figure 2). The kinetics for both enantiomers
of 1a with one equivalent of diazoester 2a were separately
measured. Complete conversion for the fast reacting R-
enantiomer (red line) is reached at 6.5 hours. The conversion of
the slow reacting S-enantiomer (blue line) was very sluggish.
After 10 hours, more than 90 % of (S)-1a remained. This roughly
equals to a rate difference of 20, well matching to the observed
resolution selectivities. The reaction of rac-1a (black line) with a
full equivalent of 2a shows a significant decrease in reaction rate
after the 6.5 hour mark. This 50 % substrate conversion
corresponds to a complete consumption of the matching
enantiomer. Due to usage of one full equivalent of 2a it keeps
reacting with the mismatched enantiomer, resulting in a slow
increase in conversion. For the preparative kinetic resolutions,
reduction of the amount of 2 to 0.52 equivalents mitigated this
slow selectivity erosion over time avoiding the necessity for
exact timing of the reaction quench. For comparison, a reaction
of rac-1a in the absence of A6 (dotted grey line) is displayed.
Virtually no substrate is converted, once again evidencing the
Resolution • Sulfoximine • Rhodium
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Angewandte Chemie International Edition
COMMUNICATION
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[24] Absolute configurations were determined by X-ray crystallography of
3ac, 1e and 3e (CCDC 1908564, 1908565 and 1908566).
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10.1002/anie.201904543
Angewandte Chemie International Edition
COMMUNICATION
COMMUNICATION
Marcus Brauns, Nicolai Cramer*
Page No. – Page No.
Efficient Kinetic Resolution of Sulfur-
Stereogenic Sulfoximines Exploiting
CpxRhIII-Catalyzed C-H
Functionalization
Text for Table of Contents
An efficient method to access chiral sulfoximines by a C-H functionalization-
based kinetic resolution is disclosed. Together, phthaloyl phenyl alanine and a
CpxRhIII complex participate in the selective C-H activation of just one of the two
sulfoximine enantiomers and its reaction with diazo compounds to
benzothiazines. Excellent enantioselectivities with s-values of up to >200 are
obtained.
This article is protected by copyright. All rights reserved.