Efficient Synthesis of Sulfur-Stereogenic Sulfoximines via Ru(II)-Catalyzed Enantioselective C-H Functionalization Enabled by Chiral Carboxylic Acid

Article abstract of DOI:10.1021/jacs.1c03111

Ru(II)-catalyzed enantioselective C-H functionalization involving an enantiodetermining C-H cleavage step remains undeveloped. Here we describe a Ru(II)-catalyzed enantioselective C-H activation/annulation of sulfoximines with α-carbonyl sulfoxonium ylides using a novel class of chiral binaphthyl monocarboxylic acids as chiral ligands, which can be easily and modularly prepared from 1,1′-binaphthyl-2,2′-dicarboxylic acid. A broad range of sulfur-stereogenic sulfoximines were prepared in high yields with excellent enantioselectivities (up to 99% yield and 99% ee) via desymmetrization, kinetic resolution, and parallel kinetic resolution. Furthermore, the resolution products can be easily transformed to chiral sulfoxides and key intermediates for kinase inhibitors.

Full text of DOI:10.1021/jacs.1c03111

pubs.acs.org/JACS
Communication
Efficient Synthesis of Sulfur-Stereogenic Sulfoximines via Ru(II)-
Catalyzed Enantioselective C−H Functionalization Enabled by Chiral
Carboxylic Acid
Tao Zhou, Pu-Fan Qian, Jun-Yi Li, Yi-Bo Zhou, Hao-Chen Li, Hao-Yu Chen, and Bing-Feng Shi*
Cite This: J. Am. Chem. Soc. 2021, 143, 6810−6816
Read Online
sı
*
Metrics & More
Article Recommendations
Supporting Information
ACCESS
ABSTRACT: Ru(II)-catalyzed enantioselective C−H functionalization involving an enantiodetermining C−H cleavage step
remains undeveloped. Here we describe a Ru(II)-catalyzed enantioselective C−H activation/annulation of sulfoximines with α-
carbonyl sulfoxonium ylides using a novel class of chiral binaphthyl monocarboxylic acids as chiral ligands, which can be easily and
modularly prepared from 1,1′-binaphthyl-2,2′-dicarboxylic acid. A broad range of sulfur-stereogenic sulfoximines were prepared in
high yields with excellent enantioselectivities (up to 99% yield and 99% ee) via desymmetrization, kinetic resolution, and parallel
kinetic resolution. Furthermore, the resolution products can be easily transformed to chiral sulfoxides and key intermediates for
kinase inhibitors.
uthenium(II) catalysts have attracted much attention in
acids (MPAAs) as bidentate chiral ligands.21−23 Recently,
Rhigh-valent metal-catalyzed C−H activation because of asymmetric C−H functionalization involving an enantiodeter-
mining C−H cleavage step catalyzed by group 9 achiral
CpxMIII (M = Co,24−26 Rh,27−31 Ir32,33) and CCA-type ligands
have also been realized by Matsunaga, Yoshino, and us.34−36
Very recently, Ru(II)-catalyzed asymmetric C−H activation
reactions based on other approaches, such as enantioselective
C−H amination via an outer-sphere nitrene insertion37 or C−
H alkylation through an enantiodetermining proto-demetala-
tion,38 have also been achieved. However, Ru(II)-catalyzed
asymmetric C−H functionalization via an enantiodetermining
C−H cleavage step has not been reported to date.
Sulfoximines are important motifs in pharmaceutical and
agricultural chemicals39−41 as well as effective directing groups
for C−H functionalizations.42−52 Compared with sulfones and
sulfonamides, sulfoximines can provide strategic advantages
related to improved solubility properties or higher metabolic
stability. In particular, sulfoximines with stereogenic sulfur
atoms often show significant bioactivity, offering high potential
as active pharmaceutical ingredients.39−41 However, catalytic
asymmetric strategies for their efficient synthesis are rather
scarce and remain to be developed. Bolm and co-workers
developed several elegant methods, including the asymmetric
imination and oxidation of sulfides and kinetic resolutions of
sulfoximines, which have led to the reinforcement of this
area.53−56 More recently, the groups of Li and Cramer
independently reported the synthesis of sulfur-stereogenic
sulfoximines via a chiral CpxRh(III)-catalyzed asymmetric C−
their robustness, versatile reactivity, and unique selectivity, as
exemplified by Oi and Inoue, Ackermann, Bruneau and
Dixneuf, and many others during the past decade.1−6 Although
significant advances have been made, the enantioselective
version of Ru(II)-catalyzed C−H activation remains undevel-
oped.7−12 On the basis of the structure of the Ru(II)−arene
complexes, three possible strategies might be feasible to enable
Ru(II)-catalyzed asymmetric C−H activation (Scheme 1a).
The first one is to develop Ru(II) catalysts with precisely
designed chiral arene ligands (Strategy I). Although such a
strategy has been successfully applied to asymmetric C−H
functionalization catalyzed by group 9 CpxMIII(M = Co, Rh,
Ir) catalysts with tailor-made chiral Cpx ligands,13 unfortu-
nately, CpRu(II) complexes are inactive in C−H activation,
and the design of chiral arene ligands to replace p-cymene in
the most commonly used (p-cymene)Ru(II) is extremely
difficult and has never been achieved.1−6,14 The second
possible strategy (Strategy II) is the use of a chiral transient
directing group (cTDG),15−17 which was first developed by Yu
in Pd(II)-catalyzed asymmetric C−H activation17 and
elegantly applied to Ru(II)-catalyzed enantioselective intra-
molecular C−H activation/hydroarylation by Cui18 and
Wang19 in 2019. However, this strategy has been applied
only in Ru(II)-catalyzed C−H activation followed by an
enantiodetermining insertion (Scheme 1b). The last and most
appealing strategy would be the use of easily available external
chiral ligands. It is well-established that Ru(II)-catalyzed C−H
activation can be accelerated by carboxylate assistance.20
Therefore, one can argue that the use of chiral carboxylic
acids (CCAs) as external ligands may be able to induce an
enantiodetermining C−H bond cleavage. This concept was
first proved by Yu and co-workers in Pd(II)-catalyzed
enantioselective C−H activation using monoprotected amino
Received: March 23, 2021
Published: April 28, 2021
https://doi.org/10.1021/jacs.1c03111
J. Am. Chem. Soc. 2021, 143, 6810−6816
© 2021 American Chemical Society
6810

Journal of the American Chemical Society
pubs.acs.org/JACS
Communication
a
Scheme 1. Ru(II)-Catalyzed Enantioselective C−H
Activation
Table 1. Optimization of the Reaction Conditions
b
c
entry
ligand
solvent
yield (%)
ee (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
L1
L2
L3
L4
L5
L6
L7
L8
L8
L8
L8
L8
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
DCE
toluene
THF
MeOH
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
36
69
n.r.
71
79
54
92
79
82
25
20
31
84
67
81
63
72
−
4
15
55
35
94
94
81
16
13
96
94
97
98
98
95
91
91
−95
L9
L10
L11
L12
L13
L14
L15
L16
L17
d
H activation strategy.35,57,58 Although these contributions
elegantly demonstrated the power of asymmetric C−H
activation, extra steps were needed to prepare the chiral
Rh(III) cyclopentadienyl catalysts. In our continuous efforts to
develop readily available chiral ligands for asymmetric C−H
activation,59−62 we wondered whether a properly designed
CCA ligand would enable the Ru(II)-catalyzed asymmetric C−
H activation through Strategy III. The results of the
investigations are reported herein, and a novel class of chiral
binaphthyl monocarboxylic acids were designed for the Ru(II)-
catalyzed enantioselective C−H activation/annulation of
sulfoximines with α-carbonyl sulfoxonium ylides. A range of
chiral sulfoximines were prepared in high yields with excellent
enantioselectivities (up to 99% yield and 99% ee) via
desymmetrization, kinetic resolution (KR), and parallel kinetic
resolution (PKR) (Scheme 1c).
We initiated our investigation by optimizing the desymmet-
rization coupling of sulfoximine 1a and sulfoxonium ylide 2a
(Table 1). We realized that key to the success of this strategy is
the judicious choice of a CCA ligand that can create a rigid
chiral environment regardless of the monodentate nature due
to the lack of vacant coordination site. Therefore, we first
expected that a properly designed monodentate ligand with
sterically bulky substitutions could exert high stereoinduction
through steric repulsion. Two sterically bulky α-amino acids
(L1 and L2) were first examined (entries 1 and 2), and 3aa
was obtained in moderate yield and enantioselectivity, with the
sterically bulkier ligand (L2) being better (69% yield, 72% ee).
No product was observed when chiral phosphoric acid L3 was
evaluated (entry 3). We then investigated axially chiral CCAs
96
91
69
71
31
10
a
Reaction conditions: 1a (0.10 mmol), 2a (0.15 mmol), [(p-
cymene)RuCl2]2 (2.5 mol %), AgSbF6 (20 mol %), and ligand (10
b
mol %) in 2.0 mL of solvent. 1H NMR yields using 1,3,5-
c
trimethoxybenzene as an internal standard. Determined by chiral
HPLC. Isolated yield.
d
based on the binaphthyl backbone, a kind of privileged ligand
skeleton. While binaphthyl 2-monocarboxylic acid (L4) led to
almost racemic product (4% ee; entry 4), its 2′-naphthyl
analogue L5 with increased steric bulk gave slightly improved
enantioselectivity (15% ee; entry 5). Intriguingly, the use of
binaphthyl 2,2′-dicarboxylic acid (L6) and its monoester (L7)
resulted in significantly improved enantioselectivity (55% ee
with L6 and 35% ee with L7; entries 6 and 7). These intriguing
results suggested that the hydrogen-bonding interaction
between the 2′-carboxylic acid (L6) or ester (L7) of the
ligand and the NH group of sulfoximine 1a might play an
important role in the enantiodetermining step, rather than the
traditional steric interactions.63,64 We hypothesized that
replacement of the ester with the N,N-disubstituted amide (a
stronger hydrogen-bond acceptor than the ester) might led to
better stereocontrol. To our delight, an ester-to-amide
replacement (L7 → L8) resulted in dramatically increased
enantioselectivity (79% yield, 94% ee; entry 8). The yield
6811
https://doi.org/10.1021/jacs.1c03111
J. Am. Chem. Soc. 2021, 143, 6810−6816

Journal of the American Chemical Society
pubs.acs.org/JACS
Communication
increased slightly when DCE was used as the solvent (entry 9).
When THF or MeOH was used as the solvent, the
enantioselectivity was dramatically decreased (16% ee with
THF and 13% ee with MeOH; entries 11 and 12), which
might be due to the destruction of hydrogen bonding between
the ligand and the substrate. Although the detailed origin of
the enantioselectivity is unclear at this stage, a postulated
stereoinduction model involving a N−H···O hydrogen-
bonding interaction between the sulfoximine and the ligand
is proposed in Figure S1.
On the basis of the above rationalizations, various non-C2-
symmetric chiral monocarboxylic acids with N,N-disubstituted
amides were then evaluated. We found that both the yield and
enantioselectivity could be improved by increasing the
bulkiness of the substituents on the amides (L9−L15; entries
13−19), and 3aa was isolated in 96% yield with 98% ee when
L12 with a diisopropylcarbamoyl group was used (entry 16).
L16 and L17 derived from (S)-H8-BINOL and (S)-SPINOL
also gave 3aa with high enantioselectivity, albeit in significantly
lower yields (entries 20 and 21). Notably, this novel class of
chiral binaphthyl monocarboxylic acids could be easily and
modularly prepared from 1,1′-binaphthyl-2,2′-dicarboxylic acid
in a simple three-step sequence involving monoesterification/
amidation/hydrolysis (see the Supporting Information (SI) for
details).65
(Me or OMe) or halide substituent (F, Cl, or Br) at the para
position of the aryl ring were well-tolerated, affording the
desired chiral cyclic sulfoximines in high yields with excellent
enantioselectivities (3ab−af, 97−98% ee). Substrates with
substituents at the meta or ortho position also reacted
smoothly to give the corresponding products in high yields
and ee values (3ag−ai). α-2-Naphthoyl, α-2-furanyl, and α-2-
thienoyl sulfoxonium ylides also reacted well (3aj−al).
Moreover, α-fatty acyl sulfoxonium ylides were also compatible
with this transformation, giving the desired 3-alkyl-1,2-
benzothiazines in good yields and enantioselectivities (3an,
92%, 97 ee; 3ao, 87%, 97% ee).
We further evaluated the scope of sulfoximines (Table 3). A
wide range of sulfoximines bearing various electron-donating
a
Table 3. Scope of Sulfoximines
With the optimized conditions in hand, the scope of
sulfoxonium ylides was first examined (Table 2). α-Substituted
benzoyl sulfoxonium ylides bearing an electron-donating group
a
Table 2. Scope of Sulfoxonium Ylides
a
Reaction conditions: 1 (0.1 mmol), 2a (0.15 mmol), [(p-
cymene)RuCl2]2 (2.5 mol %), AgSbF6 (20 mol %), and L12 (10
mol %) in 2.0 mL of DCE at 35 °C for 12 h under N2 in a sealed
b
c
reaction tube. The reaction was run at 45 °C. 3ja: react at the less
hindered ortho position; 3ja’: react at the sterically hindered ortho
position.
groups (Me, OMe, or OCF3) or electron-withdrawing groups
(Cl, Br, Ac, or CF3) were coupled with sulfoxonium ylide 2a in
good to excellent yields and enantioselectivities (3ba−ha, 63−
97% yield, 96−98% ee). Sulfoximines with meta-Me and
-Acsubstituents selectively reacted at the less sterically bulky
ortho position (3ia and 3ka) while meta-Cl-substituted 1j gave
a mixture of 3ja and 3ja', with the reaction at the less hindered
C−H bond occurring predominantly (3ja, 75%; 3ja', 21%).
Interestingly, 3ja' was obtained with obviously lower
enantioselectivity than 3ja (3ja', 76% ee vs3ja, 96% ee),
probably due to the steric hindrance.Ortho-substituted
sulfoximines were also tolerated, leading to high enantiose-
lectivities (3la and 3ma). The absolute configuration of 3ca
was determined by X-ray diffraction analysis and extrapolated
to the other products.
Fortunately, Ru(II)-catalyzed kinetic resolution of racemic
sulfoximines rac-4 could also be achieved under slightly
modified conditions using L13 as a chiral ligand (Table 4).
Both electron-donating and -withdrawing groups on the aryls
were well-tolerated (4a−h), affording the cyclization products
(S)-5 and unreacted (R)-4 with moderate to excellent
a
Reaction conditions: 1a (0.1 mmol), 2 (0.15 mmol), [(p-
cymene)RuCl2]2 (2.5 mol %), AgSbF6 (20 mol %), and L12 (10
mol %) in 2.0 mL of DCE at 35 °C for 12 h under N2 in a sealed
reaction tube.
6812
https://doi.org/10.1021/jacs.1c03111
J. Am. Chem. Soc. 2021, 143, 6810−6816

Journal of the American Chemical Society
pubs.acs.org/JACS
Communication
a
Table 4. Kinetic Resolution of Racemic Sulfoximines
b
c
b
c
d
entry
rac-4
Ar
R
yield of (S)-5 (%)
ee of (S)-5 (%)
yield of (R)-4 (%)
ee of (R)-4 (%)
s
1
2
3
4
5
6
7
8
9
4a
4b
4c
4d
4e
4f
4g
4h
4i
Ph
Me
Me
Me
Me
Me
Me
Me
Me
Et
50
53
51
50
49
91
89
83
78
89
41
38
35
41
40
37
35
38
39
41
35
96
97
96
98
96
97
86
99
93
95
98
83
72
42
36
67
18
28
46
45
40
22
4-MeC6H4
4-MeOC6H4
4-BrC6H4
4-FC6H4
3-ClC6H4
3-AcC6H4
2-ClC6H4
Ph
e
e
29 (5f), 18 (5f′)
64 (5f), 65 (5f′)
46
52
53
50
49
82
80
86
83
67
10
11
4j
4k
Ph
Ph
cyclopropyl
Bn
a
Reaction conditions: 4 (0.2 mmol), 2a (0.15 mmol), [(p-cymene)RuCl2]2 (2 mol %), AgSbF6 (15 mol %), and L13 (7.5 mol %) in TCE/t-BuOH
b
c
d
= 0.5 mL/0.5 mL at 50 °C for 12 h under N2 in a sealed reaction tube. Isolated yields. Determined by chiral HPLC. Selectivity factor, given by s
e
= ln[(1 − C)(1 − ee4)]/ln[(1 − C)(1 + ee4)], where C = (ee4)/(ee4 + ee5). 5f was formed by reaction at the less sterically hindered ortho
position and 5f′ by reaction at the more hindered ortho position.
enantioselectivities. Interestingly, when m-Cl-substituted 4f
was subjected to the reaction, a mixture of 5f and 5f′ was
obtained, with the reaction at the less hindered C−H bond
occurring predominantly (29% for 5f and 18% for 5f′).
Substituents such as ethyl, cyclopropyl, and benzyl on the
sulfoximines were also compatible with this resolution (4i−k).
The absolute configuration of (S)-5i was determined by X-ray
diffraction analysis and extrapolated to the other products.
To our delight, the more challenging parallel kinetic
resolution of sulfoximines bearing two different aromatic
groups was also compatible with this protocol (Scheme 2).66
Scheme 3. Synthetic Applications
Scheme 2. Parallel Kinetic Resolution of Racemic Diaryl
Sulfoximine rac-6
which are inhibitors of human cytochrome P450C24 (CYP24)
hydroxylase (Scheme 3b).69
Sulfoximine 6a with minimal electronic bias (R = Me) gave the
products 7a and 8a in the same yield with excellent ee values.
The yields of 7 and 8 were influenced when an electron-
withdrawing group (R = CF3, 6b) or electron-donating group
(R = OMe, 6c) was used, but the excellent enantioselectivities
were maintained.
The synthetic applications were then investigated to
illustrate the significance of this protocol. Chiral sulfoximines
(R)-4 could be easily reduced to the corresponding chiral
sulfoxides 9 in high yields without significant loss of
enantiopurity (Scheme 3a).67,68 Kinetic resolution of rac-4
using (R)-L13 as a chiral ligand led to the preparation of (S)-
4a and (S)-4e with 98% and 95% ee, respectively (see SI
section 2.6 for details). TBS protection gave 10a and 10e,
which were key precursors for the synthesis of 11a and 11e,
Several experiments were conducted to gain mechanistic
insights. H/D exchange studies in a mixture of D2O and DCE
were conducted. The reaction of sulfoximine 1b in the absence
of sulfoxonium ylide 2a revealed 24% D incorporation into
recovered 1b. When the reaction was conducted in the
presence of sulfoxonium ylide 2a, no deuterium incorporation
at the ortho position of the sulfoximine in either the recovered
1b or the product 3ba was observed. These results suggested
that although the C−H activation step was reversible in the
absence of ylide 2a, the subsequent coupling with the ylide was
significantly faster than the back reaction of C−H activation.
The kinetic isotope effect was also investigated in a parallel
experiment, giving a value of kH/kD = 1.5, indicating that C−H
bond cleavage might be the rate-limiting step in this reaction.
High-resolution mass spectrometry analysis suggested the
6813
https://doi.org/10.1021/jacs.1c03111
J. Am. Chem. Soc. 2021, 143, 6810−6816

Journal of the American Chemical Society
pubs.acs.org/JACS
Communication
Notes
formation of a five-membered ruthenacycle species in the
reaction of the Ru(II) catalyst and sulfoximine 1a (see the SI
for details).
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
In summary, we have reported the Ru(II)-catalyzed
enantioselective C−H activation/annulation of sulfoximines
with α-carbonyl sulfoxonium ylides enabled by a novel class of
chiral binaphthyl monocarboxylic acids. A wide range of chiral
sulfoximines were efficiently prepared in high yields with
excellent stereocontrol (up to 99% yield and 99% ee) via
desymmetrization, kinetic resolution, and parallel kinetic
resolution. The resolution products can be easily transformed
to chiral sulfoxides and key intermediates for kinase inhibitors.
We expect that this novel class of CCAs might stimulate the
development of other Ru(II)-catalyzed enantioselective C−H
functionalizations in the future. Further studies of the
mechanism and application of this new catalytic system are
in progress in our laboratory.
■
Financial support from the National Natural Science
Foundation of China (21925109, 21772170, and 21801223)
and Outstanding Young Talents of Zhejiang Province High-
Level Personnel of Special Support (ZJWR0108) is gratefully
acknowledged. This work is dedicated to the 100th anniversary
of chemistry at Nankai University.
REFERENCES
■
(1) Shan, C.; Zhu, L.; Qu, L.-B.; Bai, R.; Lan, Y. Mechanistic View of
Ru-Catalyzed C−H Bond Activation and Functionalization: Compu-
tational Advances. Chem. Soc. Rev. 2018, 47, 7552−7576.
(2) Nareddy, P.; Jordan, F.; Szostak, M. Recent Developments in
Ruthenium-Catalyzed C−H Arylation: Array of Mechanistic Mani-
folds. ACS Catal. 2017, 7, 5721−5745.
(3) Leitch, J. A.; Frost, C. G. Ruthenium-Catalysed σ-Activation for
Remote: Meta-Selective C−H Functionalisation. Chem. Soc. Rev.
2017, 46, 7145−7153.
ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/jacs.1c03111.
(4) Ackermann, L. Carboxylate-Assisted Ruthenium-Catalyzed
Alkyne Annulations by C−H/Het−H Bond Functionalizations. Acc.
Chem. Res. 2014, 47, 281−295.
Experimental procedures, spectral data for all new
compounds, and X-ray crystal structure data for 3ca
(CCDC 2057379) and 5i (CCDC 2057380) (PDF)
(5) Arockiam, P. B.; Bruneau, C.; Dixneuf, P. H. Ruthenium(II)-
Catalyzed C−H Bond Activation and Functionalization. Chem. Rev.
2012, 112, 5879−5918.
(6) Oi, S.; Fukita, S.; Hirata, N.; Watanuki, N.; Miyano, S.; Inoue, Y.
Ruthenium Complex-Catalyzed Direct Ortho Arylation and Alkeny-
lation of 2-Arylpyridines with Organic Halides. Org. Lett. 2001, 3,
2579−2581.
(7) Zheng, C.; You, S.-L. Recent development of direct asymmetric
functionalization of inert C−H bonds. RSC Adv. 2014, 4, 6173−6214.
(8) Newton, C. G.; Wang, S.- G.; Oliveira, C. C.; Cramer, N.
Catalytic Enantioselective Transformations Involving C−H Bond
Cleavage by Transition-Metal Complexes. Chem. Rev. 2017, 117,
8908−8976.
(9) Saint-Denis, T. G.; Zhu, R.-Y.; Chen, G.; Wu, Q.-F.; Yu, J.-Q.
Enantioselective C(sp3)−H bond activation by chiral transition metal
catalysts. Science 2018, 359, No. eaao4798.
Accession Codes
CCDC 2057379 and 2057380 contain the supplementary
crystallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
emailing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, U.K.; fax: +44 1223 336033.
AUTHOR INFORMATION
■
Corresponding Author
Bing-Feng Shi − Center of Chemistry for Frontier
Technologies, Department of Chemistry, Zhejiang University,
Hangzhou 310027, China; orcid.org/0000-0003-0375-
955X; Email: bfshi@zju.edu.cn
(10) Liao, G.; Zhou, T.; Yao, Q.-J.; Shi, B.-F. Recent advances in the
synthesis of axially chiral biaryls via transition metalcatalysed
asymmetric C−H functionalization. Chem. Commun. 2019, 55,
8514−8523.
(11) Yoshino, T.; Satake, S.; Matsunaga, S. Diverse Approaches for
Enantioselective C−H Functionalization Reactions Using Group 9
CpxMIII Catalysts. Chem. - Eur. J. 2020, 26, 7346−7357.
(12) Achar, T. K.; Maiti, S.; Jana, S.; Maiti, D. Transition Metal
Catalyzed Enantioselective C(sp2)−H Bond Functionalization. ACS
Catal. 2020, 10, 13748−13793.
Authors
Tao Zhou − Center of Chemistry for Frontier Technologies,
Department of Chemistry, Zhejiang University, Hangzhou
310027, China; orcid.org/0000-0001-7258-2845
Pu-Fan Qian − Center of Chemistry for Frontier Technologies,
Department of Chemistry, Zhejiang University, Hangzhou
310027, China
Jun-Yi Li − Center of Chemistry for Frontier Technologies,
Department of Chemistry, Zhejiang University, Hangzhou
310027, China
Yi-Bo Zhou − Center of Chemistry for Frontier Technologies,
Department of Chemistry, Zhejiang University, Hangzhou
310027, China
Hao-Chen Li − Center of Chemistry for Frontier Technologies,
Department of Chemistry, Zhejiang University, Hangzhou
310027, China
(13) Ye, B.; Cramer, N. Chiral Cyclopentadienyls: Enabling Ligands
for Asymmetric Rh(III)-Catalyzed C−H Functionalizations. Acc.
Chem. Res. 2015, 48, 1308−1318.
(14) Trost, B. M.; Frederiksen, M. U.; Rudd, M. T. Ruthenium-
Catalyzed Reactions - A Treasure Trove of Atom-Economic
Transformations. Angew. Chem., Int. Ed. 2005, 44, 6630−6666.
(15) Liao, G.; Zhang, T.; Lin, Z.-K.; Shi, B.-F. Transition Metal-
Catalyzed Enantioselective C−H Functionalization via Transient
Directing Group Strategies. Angew. Chem., Int. Ed. 2020, 59, 19773−
19786.
(16) Lapuh, M. I.; Mazeh, S.; Besset, T. Chiral Transient Directing
Groups in Transition-Metal-Catalyzed Enantioselective C−H Bond
Functionalization. ACS Catal. 2020, 10, 12898−12919.
(17) Zhang, F.-L.; Hong, K.; Li, T.-J.; Park, H.; Yu, J.-Q. Organic
Chemistry: Functionalization of C(sp3)−H Bonds Using a Transient
Directing Group. Science 2016, 351, 252−256.
Hao-Yu Chen − Center of Chemistry for Frontier
Technologies, Department of Chemistry, Zhejiang University,
Hangzhou 310027, China
Complete contact information is available at:
https://pubs.acs.org/10.1021/jacs.1c03111
(18) Li, Z.-Y.; Lakmal, H. H. C.; Qian, X.; Zhu, Z.; Donnadieu, B.;
McClain, S. J.; Xu, X.; Cui, X. Ruthenium-Catalyzed Enantioselective
6814
https://doi.org/10.1021/jacs.1c03111
J. Am. Chem. Soc. 2021, 143, 6810−6816

Journal of the American Chemical Society
pubs.acs.org/JACS
Communication
C−H Functionalization: A Practical Access to Optically Active
Indoline Derivatives. J. Am. Chem. Soc. 2019, 141, 15730−15736.
(19) Li, G.; Liu, Q.; Vasamsetty, L.; Guo, W.; Wang, J.
Ruthenium(II)-Catalyzed Asymmetric Inert C−H Bond Activation
Assisted by a Chiral Transient Directing Group. Angew. Chem., Int. Ed.
2020, 59, 3475−3479.
(35) Sun, Y.; Cramer, N. Enantioselective synthesis of chiral-at-
sulfur 1,2-benzothiazines by CpxRhIII-catalyzed C−H functionaliza-
tion of sulfoximines. Angew. Chem., Int. Ed. 2018, 57, 15539−15543.
(36) Jang, Y.-S.; Dieckmann, M.; Cramer, N. Cooperative effects
between chiral Cpx-iridium(III) catalysts and chiral carboxylic acids in
enantioselective C−H amidations of phosphine oxides. Angew. Chem.,
Int. Ed. 2017, 56, 15088−15092.
(37) Miyazawa, T.; Suzuki, T.; Kumagai, Y.; Takizawa, K.; Kikuchi,
T.; Kato, S.; Onoda, A.; Hayashi, T.; Kamei, Y.; Kamiyama, F.; Anada,
M.; Kojima, M.; Yoshino, T.; Matsunaga, S. Chiral Paddle-wheel
Diruthenium Complexes for Asymmetric Catalysis. Nature Catal.
2020, 3, 851−858.
(38) Dhawa, U.; Connon, R.; Oliveira, J. C. A.; Steinbock, R.;
Ackermann, L. Enantioselective Ruthenium-Catalyzed C−H Alkyla-
tions by a Chiral Carboxylic Acid with Attractive Dispersive
Interactions. Org. Lett. 2021, 23, 2760.
(39) Wiezorek, S.; Lamers, P.; Bolm, C. Conversion and degradation
pathways of sulfoximines. Chem. Soc. Rev. 2019, 48, 5408−5423.
(40) Lucking, U. Neglected sulfur(VI) pharmacophores in drug
̈
(20) Ackermann, L. Carboxylate-Assisted Transition-Metal-Cata-
lyzed C−H Bond Functionalizations: Mechanism and Scope. Chem.
Rev. 2011, 111, 1315−1345.
(21) Shao, Q.; Wu, K.; Zhuang, Z.; Qian, S.; Yu, J.-Q. From
Pd(OAc)2 to Chiral Catalysts: The Discovery and Development of
Bifunctional Mono-N-Protected Amino Acid Ligands for Diverse C−
H Functionalization Reactions. Acc. Chem. Res. 2020, 53, 833−851.
(22) Engle, K. M.; Yu, J.-Q. Developing ligands for palladium(II)-
catalyzed C−H functionalization: intimate dialogue between ligand
and substrate. J. Org. Chem. 2013, 78, 8927−8955.
(23) Shi, B.-F.; Maugel, N.; Zhang, Y.-H.; Yu, J.-Q. PdII-Catalyzed
Enantioselective Activation of C(sp2)−H and C(sp3)−H Bonds Using
Monoprotected Amino Acids as Chiral Ligands. Angew. Chem., Int. Ed.
2008, 47, 4882−4886.
discovery: exploration of novel chemical space by the interplay of drug
design and method development. Org. Chem. Front. 2019, 6, 1319−
1324.
(24) Fukagawa, S.; Kato, Y.; Tanaka, R.; Kojima, M.; Yoshino, T.;
Matsunaga, S. Enantioselective C(sp3)−H Amidation of Thioamides
Catalyzed by a CobaltIII/Chiral Carboxylic Acid Hybrid System.
Angew. Chem., Int. Ed. 2019, 58, 1153−1157.
(25) Liu, Y.-H.; Li, P.-X.; Yao, Q.-J.; Zhang, Z.-Z.; Huang, D.-Y.; Le,
M. D.; Song, H.; Liu, L.; Shi, B.-F. Cp*Co(III)/MPAA-Catalyzed
Enantioselective Amidation of Ferrocenes Directed by Thioamides
under Mild Conditions. Org. Lett. 2019, 21, 1895−1899.
(26) Sekine, D.; Ikeda, K.; Fukagawa, S.; Kojima, M.; Yoshino, T.;
Matsunaga, S. Chiral 2-Aryl Ferrocene Carboxylic Acids for the
Catalytic Asymmetric C(sp3)−H Activation of Thioamides. Organo-
metallics 2019, 38, 3921−3926.
(27) Satake, S.; Kurihara, T.; Nishikawa, K.; Mochizuki, T.; Hatano,
M.; Ishihara, K.; Yoshino, T.; Matsunaga, S. Pentamethylcyclopenta-
dienyl Rhodium(III)-Chiral Disulfonate Hybrid Catalysis for
Enantioselective C−H Bond Functionalization. Nat. Catal. 2018, 1,
585−591.
(28) Lin, L.; Fukagawa, S.; Sekine, D.; Tomita, E.; Yoshino, T.;
Matsunaga, S. Chiral Carboxylic Acid Enabled Achiral Rhodium(III)-
Catalyzed Enantioselective C−H Functionalization. Angew. Chem., Int.
Ed. 2018, 57, 12048−12052.
(41) Lucking, U. Sulfoximines: A Neglected Opportunity in
̈
Medicinal Chemistry. Angew. Chem., Int. Ed. 2013, 52, 9399−9408.
(42) Rit, R. K.; Yadav, M. R.; Ghosh, K.; Sahoo, A. K. Reusable
directing groups [8-aminoquinoline, picolinamide, sulfoximine] in C
(sp3)−H bond activation: present and future. Tetrahedron 2015, 71,
4450−4459.
(43) Yadav, M. R.; Rit, R. K.; Shankar, M.; Sahoo, A. K. Reusable
and Removable Directing Groups for C(sp2)−H Bond Functionaliza-
tion of Arenes. Asian J. Org. Chem. 2015, 4, 846−864.
(44) Yadav, M. R.; Rit, R. K.; Sahoo, A. K. Sulfoximines: A Reusable
Directing Group for Chemo- and Regioselective ortho C−H
Oxidation of Arenes. Chem. - Eur. J. 2012, 18, 5541−5545.
(45) Dong, W.; Wang, L.; Parthasarathy, K.; Pan, F.; Bolm, C.
Rhodium-Catalyzed Oxidative Annulation of Sulfoximines and
Alkynes as an Approach to 1,2-Benzothiazines. Angew. Chem., Int.
Ed. 2013, 52, 11573−11576.
(46) Cheng, Y.; Bolm, C. Regioselective Syntheses of 1,2-
Benzothiazines by Rhodium-Catalyzed Annulation Reactions. Angew.
Chem., Int. Ed. 2015, 54, 12349−12352.
(29) Fukagawa, S.; Kojima, M.; Yoshino, T.; Matsunaga, S. Catalytic
Enantioselective Methylene C(sp3)−H Amidation of 8-Alkylquino-
lines Using a Cp*RhIII/Chiral Carboxylic Acid System. Angew. Chem.,
Int. Ed. 2019, 58, 18154−18158.
(30) Huang, L.-T.; Fukagawa, S.; Kojima, M.; Yoshino, T.;
Matsunaga, S. Rhodium(III)/Chiral Carboxylic Acid Catalyzed
Enantioselective C(sp3)−H Alkylation of 8-Ethylquinolines with
α,β-Unsaturated Carbonyl Compounds. Org. Lett. 2020, 22, 8256−
8260.
(31) Kato, Y.; Lin, L.; Kojima, M.; Yoshino, T.; Matsunaga, S.
Development of Pseudo-C2-symmetric Chiral Binaphthyl Mono-
carboxylic Acids for Enantioselective C(sp3)−H Functionalization
Reactions under Rh(III) Catalysis. ACS Catal. 2021, 11, 4271−4277.
(32) Liu, L.; Song, H.; Liu, Y.-H.; Wu, L.-S.; Shi, B.-F. Achiral
CpxIr(III)/chiral carboxylic acid catalyzed enantioselective C−H
amidation of ferrocenes under mild conditions. ACS Catal. 2020, 10,
7117−7122.
(33) Liu, W.; Yang, W.; Zhu, J.; Guo, Y.; Wang, N.; Ke, J.; Yu, P.;
He, C. Dual-ligand-enabled Ir(III)-catalyzed enantioselective C−H
amidation for the synthesis of chiral sulfoxides. ACS Catal. 2020, 10,
7207−7215.
(47) Chinnagolla, R. K.; Vijeta, A.; Jeganmohan, M. Ruthenium- and
palladium-catalyzed consecutive coupling and cyclization of aromatic
sulfoximines with phenylboronic acids: an efficient route to
dibenzothiazines. Chem. Commun. 2015, 51, 12992−12995.
(48) Ghosh, K.; Rit, R. K.; Ramesh, E.; Sahoo, A. K. Ruthenium-
Catalyzed Hydroarylation and One-Pot Twofold Unsymmetrical C−
H Functionalization of Arenes. Angew. Chem., Int. Ed. 2016, 55,
7821−7825.
(49) Jeon, W. H.; Son, J.-Y.; Kim, J. E.; Lee, P. H. Synthesis of 1,2-
Benzothiazines by a Rhodium-Catalyzed Domino C−H Activation/
Cyclization/Elimination Process from S-Aryl Sulfoximines and
Pyridotriazoles. Org. Lett. 2016, 18, 3498−3501.
(50) Xie, H.; Lan, J.; Gui, J.; Chen, F.; Jiang, H.; Zeng, W. Ru(II)-
Catalyzed Coupling-Cyclization of Sulfoximines with alpha-Carbonyl
Sulfoxonium Ylides as an Approach to 1,2-Benzothiazines. Adv. Synth.
Catal. 2018, 360, 3534−3543.
(51) Shankar, M.; Rit, R. K.; Sau, S.; Mukherjee, K.; Gandon, V.;
Sahoo, A. K. Double annulation of ortho- and peri-C−H bonds of
fused (hetero)arenes to unusual oxepino-pyridines. Chem. Sci. 2020,
11, 10770−10777.
(52) Ghosh, K.; Ghosh, A.; Mukherjee, K.; Rit, R. K.; Sahoo, A. K.
Sulfoximine-Assisted Unsymmetrical Twofold C−H Functionalizatio-
nof Arenes. J. Org. Chem. 2020, 85, 8618−8626.
(34) Wang, Q.; Zhang, W.-W.; Song, H.; Wang, J.; Zheng, C.; Gu,
Q.; You, S.-L. Rhodium-catalyzed atroposelective oxidative C−H/C−
H cross-coupling reaction of 1-aryl isoquinoline derivatives with
electron-rich heteroarenes. J. Am. Chem. Soc. 2020, 142, 15678−
15685.
(53) Wang, J.; Frings, M.; Bolm, C. Enantioselective Nitrene
Transfer to Sulfides Catalyzed by a Chiral Iron Complex. Angew.
Chem., Int. Ed. 2013, 52, 8661−8665.
6815
https://doi.org/10.1021/jacs.1c03111
J. Am. Chem. Soc. 2021, 143, 6810−6816

Journal of the American Chemical Society
pubs.acs.org/JACS
Communication
(54) Legros, J.; Bolm, C. Iron-Catalyzed Asymmetric Sulfide
Oxidation with Aqueous Hydrogen Peroxide. Angew. Chem., Int. Ed.
2003, 42, 5487−5489.
(55) Dong, S.; Frings, M.; Cheng, H.; Wen, J.; Zhang, D.; Raabe, G.;
Bolm, C. Organocatalytic Kinetic Resolution of Sulfoximines. J. Am.
Chem. Soc. 2016, 138, 2166−2169.
(56) Wang, J.; Frings, M.; Bolm, C. Iron-Catalyzed Imidative Kinetic
Resolution of Racemic Sulfoxides. Chem. - Eur. J. 2014, 20, 966−969.
(57) Brauns, M.; Cramer, N. Efficient Kinetic Resolution of Sulfur-
Stereogenic Sulfoximines by Exploiting CpXRhIII-Catalyzed C−H
Functionalization. Angew. Chem., Int. Ed. 2019, 58, 8902−8906.
(58) Shen, B.; Wan, B.; Li, X. Enantiodivergent Desymmetrization in
the Rhodium(III)-Catalyzed Annulation of Sulfoximines with Diazo
Compounds. Angew. Chem., Int. Ed. 2018, 57, 15534−15538.
(59) Yan, S.-Y.; Han, Y.-Q.; Yao, Q.-J.; Nie, X.-L.; Liu, L.; Shi, B.-F.
Palladium (II)-Catalyzed Enantioselective Arylation of Unbiased
Methylene C(sp3)−H Bonds Enabled by a 2-Pyridinylisopropyl
Auxiliary and Chiral Phosphoric Acids. Angew. Chem., Int. Ed. 2018,
57, 9093−9097.
(60) Luo, J.; Zhang, T.; Wang, L.; Liao, G.; Yao, Q.-J.; Wu, Y.-J.;
Zhan, B.-B.; Lan, Y.; Lin, X.-F.; Shi, B.-F. Enantioselective Synthesis of
Biaryl Atropisomers via Pd-Catalyzed C−H Olefination using Chiral
Spiro Phosphoric Acid Ligands. Angew. Chem., Int. Ed. 2019, 58,
6708−6712.
(61) Han, Y.-Q.; Ding, Y.; Zhou, T.; Yan, S.-Y.; Song, H.; Shi, B.-F.
Pd(II)-Catalyzed Enantioselective Alkynylation of Unbiased Methyl-
ene C(sp3)−H Bonds Using 3,3′ -Fluorinated-BINOL as a Chiral
Ligand. J. Am. Chem. Soc. 2019, 141, 4558−4563.
(62) Jin, L.; Yao, Q.-J.; Xie, P.-P.; Li, Y.; Zhan, B.-B.; Han, Y.-Q.;
Hong, X.; Shi, B.-F. Atroposelective Synthesis of Axially Chiral
Styrenes via an Asymmetric C−H Functionalization Strategy. Chem.
2020, 6, 497−511.
(63) Fanourakis, A.; Docherty, P. J.; Chuentragool, P.; Phipps, R. J.
Recent Developments in Enantioselective Transition Metal Catalysis
Featuring Attractive Noncovalent Interactions between Ligand and
Substrate. ACS Catal. 2020, 10, 10672−10714.
(64) Zeng, W.; Chen, G.-Y.; Zhou, Y.-G.; Li, Y.-X. Hydrogen-
Bonding Directed Reversal of Enantioselectivity. J. Am. Chem. Soc.
2007, 129, 750−751.
(65) Furuta, T.; Nikaido, M.; Yamamoto, J.; Kuribayashi, T.;
Kawabata, T. Synthesis of Axially Chiral Amino Acid Derivatives via
the Selective Monoesterification of 1,1’-Biaryl-2,2’-dicarboxylic Acids.
Synthesis 2013, 45, 1312−1318.
(66) Zhu, Y.-C.; Li, Y.; Zhang, B.-C.; Zhang, F.-X.; Yang, Y.-N.;
Wang, X.-S. Palladium-Catalyzed Enantioselective C−H Olefination
of Diaryl Sulfoxides through Parallel Kinetic Resolution and
Desymmetrization. Angew. Chem., Int. Ed. 2018, 57, 5129−5133.
́
́
(67) Otocka, S.; Kwiatkowska, M.; Madalinska, L.; Kiełbasinski, P.
Chiral Organosulfur Ligands/Catalysts with a Stereogenic Sulfur
Atom: Applications in Asymmetric Synthesis. Chem. Rev. 2017, 117,
4147−4181.
(68) Trost, B. M.; Rao, M. Development of Chiral Sulfoxide
Ligands, for Asymmetric Catalysis. Angew. Chem., Int. Ed. 2015, 54,
5026−5043.
(69) Kahraman, M.; Sinishtaj, S.; Dolan, P. M.; Kensler, T. W.;
Peleg, S.; Saha, U.; Chuang, S. S.; Bernstein, G.; Korczak, B.; Posner,
G. H. Potent, Selective and Low-Calcemic Inhibitors of CYP24
Hydroxylase: 24-Sulfoximine Analogues of the Hormone 1α,25-
Dihydroxyvitamin D3. J. Med. Chem. 2004, 47, 6854−6863.
6816
https://doi.org/10.1021/jacs.1c03111
J. Am. Chem. Soc. 2021, 143, 6810−6816