Diastereo- and Enantioselective Catalytic Radical Oxysulfonylation of Alkenes in β,γ-Unsaturated Ketoximes

Article abstract of DOI:10.1016/j.chempr.2020.03.024

The asymmetric radical-initiated difunctionalization of internal alkenes, which creates two vicinal stereocenters, has been a significant synthetic challenge despite the tremendous progress achieved for terminal alkenes. This is attributable to the common

Full text of DOI:10.1016/j.chempr.2020.03.024

Article
Diastereo- and Enantioselective Catalytic
Radical Oxysulfonylation of Alkenes in b,g-
Unsaturated Ketoximes
Xi-Tao Li, Ling Lv, Ting Wang, ...,
Xinhao Zhang, Gui-Juan Cheng,
Xin-Yuan Liu
chengguijuan@cuhk.edu.cn (G.-J.C.)
liuxy3@sustech.edu.cn (X.-Y.L.)
,
HIGHLIGHTS
Asymmetric radical
oxysulfonylation of both terminal
and internal alkenes,
Copper(I)-cinchona alkaloid-
derived sulfonamide ligand
catalyst,
A radical stereodiscrimination
process under Curtin-Hammett
kinetic control,
Chiral sulfones with great
potential for drug and
agrochemical discoveries
Liu and colleagues describe the first asymmetric radical oxysulfonylation of both
terminal and internal alkenes in b,g- unsaturated ketoximes using their developed
copper(I)-cinchona alkaloid-derived sulfonamide ligand catalyst. Experimental
and computational studies collectively suggest a CuII-CuI catalytic cycle involving
fast and reversible sulfonyl radical addition and subsequent rate- and stereo-
determining C–O bond formation, namely, a scenario under Curtin-Hammett
kinetic control. The method provides a robust platform for the synthesis of a
diverse array of valuable chiral sulfonyl-containing building blocks.
Li et al., Chem 6, 1–15
July 9, 2020 ª 2020 Elsevier Inc.
https://doi.org/10.1016/j.chempr.2020.03.024

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Article
Diastereo- and Enantioselective
Catalytic Radical Oxysulfonylation
of Alkenes in b,g-Unsaturated Ketoximes
Xi-Tao Li,1,6 Ling Lv,1,6 Ting Wang,2,6 Qiang-Shuai Gu,3 Guo-Xing Xu,1 Zhong-Liang Li,3 Liu Ye,3
1,7,
Xinhao Zhang,4,5 Gui-Juan Cheng,2, and Xin-Yuan Liu
*
*
SUMMARY
The Bigger Picture
Asymmetric catalysis with radical
species has become a practical
and robust tool for preparing
chiral molecules, important in
developing drugs, agrochemicals,
and materials. In radical addition
to alkene, however, the transient
nature of radicals can greatly
compromise the stereocontrol by
any chiral catalyst and thus,
catalytic asymmetric radical-
initiated difunctionalization of
internal alkenes has long
The asymmetric radical-initiated difunctionalization of internal alkenes, which
creates two vicinal stereocenters, has been a significant synthetic challenge
despite the tremendous progress achieved for terminal alkenes. This is attribut-
able to the common stepwise mechanism that involves an initial free radical
addition to the alkene in a nonstereoselective fashion. We report here the first
asymmetric radical 1,2-oxysulfonylation of both terminal and internal aryl al-
kenes in b,g-unsaturated ketoximes in the presence of copper(I)-cinchona alka-
loid-based sulfonamide catalyst. The experimental and computational mecha-
nistic studies collectively support
a
CuII-CuI mechanism featuring fast,
reversible addition of sulfonyl radicals to alkenes and subsequent rate- and
stereo-determining C–O bond formation, namely, a scenario under Curtin-
Hammett kinetic control. The method provides a robust platform for collective
synthesis of a diverse array of valuable chiral sulfonyl-containing building
blocks.
remained underdeveloped. Here,
we discovered a solution to this
conundrum by capitalizing on an
initial fast and reversible sulfonyl
radical addition process, which
renders the enantioselectivity in
this step inconsequential to the
overall stereoselectivity.
INTRODUCTION
Transition-metal-catalyzed asymmetric difunctionalization of alkenes enables the
expedited construction of two vicinal carbon–carbon and/or carbon–heteroatom
chemical bonds and stereogenic centers from readily available alkene starting ma-
terials. Thus, it has been established as a powerful technique for the sustainable
preparation of chiral complex organic molecules.1–6 Recently, very impressive ad-
vances have been achieved in the development of Cu-catalyzed radical-initiated
asymmetric alkene difunctionalization. Such reactions usually involve the intermo-
lecular addition of free carbon- or heteroatom-centered radicals to alkenes fol-
lowed by asymmetric functionalization of the thus-generated alkyl radical interme-
diates with chiral metal species, a significant strategy pioneered by Fu, Reisman,
Buchwald, Liu, and others (Scheme 1A).7–19 In this aspect, Buchwald and Liu inde-
pendently reported the use of a copper-chiral bis(oxazoline) system to elegantly
realize a series of enantioselective alkene difunctionalization reactions.20–30 At
the same time, our group developed a copper-chiral anionic ligand system for
several types of asymmetric transformations.31–36 These methods, however, are
generally limited to terminal alkenes, while the use of internal olefins for concom-
itant generation of two vicinal stereocenters across the C=C double bonds has
proved very problematic. The difficulty lies on the stereocontrol in the first free
radical (R,) addition step and nonstereoselective formation of A and B has been
explicitly demonstrated in previous works (Scheme 1A, step 1).20,24,25 Thus, a
conceptually different strategy is urgently needed to achieve catalytic asymmetric
Accordingly, both high
enantioselectivity and high
diastereoselectivity have been
achieved in alkene
oxysulfonylation. We envision that
this strategy will elicit a surge of
research efforts on asymmetric
radical-initiated
difunctionalization of internal
alkenes, ultimately benefiting the
drug, agrochemical, and material
industries.
Chem 6, 1–15, July 9, 2020 ª 2020 Elsevier Inc.
1

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radical-initiated difunctionalization of internal alkenes with effective control of both
the diastereoselectivity and the enantioselectivity.
Sulfone moieties are prevalent in many biologically active molecules and pharma-
ceutical agents. Although great efforts have been devoted to establishing various
racemic radical 1,2-sulfonyl functionalization reactions of alkenes,37–46 the develop-
ment of corresponding catalytic asymmetric methods for access to chiral sulfones
has so far remained elusive.21,47,48 Our group has recently developed a copper-
cinchona alkaloid-based sulfonamide catalyst system for radical-initiated 1,2-oxytri-
fluoromethylation of alkenes under mild conditions.35 Thus, we wondered whether
such a copper catalyst system would meet the aforementioned challenges. The addi-
tion of sulfonyl radicals (RSO2,) to alkenes is known to be fast and reversible.49–53
Accordingly, we hypothesized that a scenario under Curtin-Hammett kinetic con-
trol54,55 might be achieved via a rapid equilibrium between the initial addition dia-
stereomers C and D (Scheme 1B). Subsequent rate-determining asymmetric func-
tionalization of these alkyl radicals might deliver the desirable product (e.g., PC)
with excellent control of both enantioselectivity and diastereoselectivity. The suc-
cessful implementation of this strategy will open a new door for precise stereocon-
trol on the challenging asymmetric radical-initiated difunctionalization of internal
alkenes.
The aryl and alkyl sulfone groups, thanks to their unique physicochemical properties,
are a kind of important pharmacophores in structure-based drug design and thus,
are of great importance in the development of drugs and agrochemicals.56–63 In
addition, enantiomerically enriched b-hydroxysulfone represents a privileged scaf-
fold found in many biologically relevant molecules, such as the anticancer drug bica-
lutamide and antifungal agents SSY726 and SCH42427.64–72 Nonetheless, their
asymmetric construction remains a significant challenge.73–79 Herein, we describe
our efforts toward the development of a general and efficient asymmetric radical
oxysulfonylation of both terminal and internal alkenes using a Cu(I)-cinchona alka-
loid-based sulfonamide catalyst. The reaction exhibits a broad scope across a range
of alkenes and diverse (hetero)aryl- and alkyl-substituted sulfonyl chlorides (Scheme
1C). Experimental and computational studies80 have been performed to suggest a
stereodiscrimination process under Curtin-Hammett kinetic control.
1Shenzhen Grubbs Institute and Department of
Chemistry, Guangdong Provincial Key Laboratory
of Catalysis, Southern University of Science and
Technology, Shenzhen 518055, China
RESULTS AND DISCUSSION
2Warshel Institute for Computational Biology,
School of Life and Health Sciences, The Chinese
University of Hong Kong, Shenzhen 518172,
China
Optimization Study
We began our investigation by reacting b,g-unsaturated ketoxime 1a with p-tolue-
nesulfonyl chloride (TsCl) 2a in the presence of CuOAc and different cinchona alka-
loid-based sulfonamide ligands (Table 1). In addition, Ag2CO3 was also added to
quench the in situ generated HCl. A series of quinine-, cinchonidine-, and cincho-
nine-derived sulfonamide ligands readily provided the desired sulfonyl-containing
isoxazoline 3aa in good yields with moderate enantioselectivity (entries 1–8), and
sulfonamide L1 performed the best in terms of both yield and enantioselectivity (en-
try 1, 82% yield, 76:24 er). Subsequent screening of different Cu salts (entries 10–13)
and solvents (entries 14–15) as well as an additive (entry 16) improved the er to 82:18
3Academy for Advanced Interdisciplinary Studies
and Department of Chemistry, Southern
University of Science and Technology, Shenzhen
518055, China
4Laboratory of Computational Chemistry and
Drug Design, Laboratory of Chemical Genomics,
Peking University Shenzhen Graduate School,
Shenzhen 518055, China
5Shenzhen Bay Laboratory, Shenzhen 518055,
China
˚
using Cu(OAc)2 in the presence of 4 A molecular sieves with CHCl3 as the solvent (en-
try 16). Lowering the reaction temperature to À10ꢀC obviously enhanced the enan-
tioselectivity (entry 17). Further increasing the amount of Ag2CO3 and adding proton
sponge slightly increased the er to 95:5, presumably by effectively and timely
quenching the in situ generated acid during the reaction (entry 18).
6These authors contributed equally
7Lead Contact
*Correspondence:
chengguijuan@cuhk.edu.cn (G.-J.C.),
liuxy3@sustech.edu.cn (X.-Y.L.)
https://doi.org/10.1016/j.chempr.2020.03.024
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Scheme 1. Asymmetric Radical-Initiated 1,2-Difunctionalization of Terminal and Internal Alkenes
Substrate Scope with Terminal Alkenes
With the optimal conditions being established, we next investigated the substrate
scope of the alkenyl ketoximes (Figure 1A). A variety of R1 groups containing elec-
t
tron-neutral (H), -donating (Me, Et, Bu, and OMe), or -withdrawing (F, Br, I, and
CF3) substituents at the para- or meta-positions of the phenyl ring were compatible
with the reaction, giving 3aa–3ka in 54%–85% yields with 93:7–96:4 er. In addition, a
bicyclic naphthalyl and a heterocyclic thiophenyl R1 groups were also tolerated to
deliver 3la and 3ma, respectively, in good yields and excellent stereoselectivities.
In regard to the R2 on the alkene moieties, a broad series of phenyl rings with com-
mon electron-donating or -withdrawing functional groups at different positions
(meta or para) were applicable to the reaction, affording 3na–3ta in 55%–95% yields
with 91:9–95:5 er. Heterocyclic furanyl- and thiophenyl-substituted alkenes could
also be employed in the reaction to give 3ua and 3va with good results, respectively.
In the following study, we switched our attention to evaluate the scope of sulfonyl
chlorides. We were pleased to observe that a series of arylsulfonyl chlorides bearing
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Table 1. Optimization of Reaction Conditions for Terminal Alkenes
Entrya
1
[Cu]
Ligand
L1
L2
L3
L4
L5
L6
L7
L8
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
Solvent
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
EtOAc
CHCl3
CHCl3
CHCl3
CHCl3
Yield (%)b
82
Erc
CuOAc
CuOAc
CuOAc
CuOAc
CuOAc
CuOAc
CuOAc
CuOAc
ÀÀ
76:24
61:39
74:26
74:26
75:25
24:76
28:72
33:67
ÀÀ
2
77
3
78
4
79
5
73
6
79
7
80
8
68
9d
10
11
12
13
14
15
16e
17e,f
18e,f,g
0
CuBr
60
60:40
63:37
74:26
77:23
68:32
78:22
82:18
94:6
CuI
66
CuTc
82
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
78
76
80
80
81
79
95:5
aReaction conditions: 1a (0.05 mmol), 2a (0.055 mmol), [Cu] (0.005 mmol), ligand (0.0075 mmol), and Ag2CO3 (0.03 mmol) in solvent (1 mL) under argon.
bYield based on 1H NMR analysis of the crude product using CH2Br2 as an internal standard.
cDetermined by chiral HPLC analysis.
dNo copper.
e
˚
4 A molecular sieves (MS) (50 mg) were added.
fRun at À10ꢀC for 96 h.
gAg2CO3 (2.0 equiv), proton sponge (0.5 equiv), and CHCl3 (2 mL) were used.
substituents ranging from electron-rich (Et, tBu, OMe, and Ph) to electron-deficient
groups (Br, F, and CF3) and a polyarene naphthalene-derived sulfonyl chloride deliv-
ered the corresponding products 3ab–3ak in 53%–84% yields with 90:10–96:4 er.
The absolute configuration of 3aj has been determined to be S by X-ray structural
analysis (Figure S1). The heterocyclic thiophene-derived sulfonyl chloride also pro-
vided the product 3al in 75% yield with a 95:5 er. The substrate scope is not limited
to (hetero)aryl-substituted sulfonyl chlorides. For example, a series of acyclic alkyl
sulfonyl chlorides, including simple unfunctionalized linear and branched alkyl
4
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Figure 1. Substrate Scope and Transformation
(A) Substrate scope for asymmetric oxysulfonylation of terminal alkenes. Reactions were conducted on 0.2 mmol scale, isolated yields were given, and er
values were determined by HPLC analysis.
(B) Transformation of the oxysulfonylation product.
groups as well as a halogenated one, all worked well to give 3am–3ap with good re-
sults. In addition, different cyclic and O- or N-containing heterocyclic alkyl sulfonyl
chlorides were all well accommodated in this process to deliver 3aq–3at in 64%–
95% yield with 92:8–94:6 er. Notably, with this protocol, we were able to incorporate
a cyclopropane ring (3au and 3av), a versatile fragment frequently used in drug
development,81,82 into the chiral sulfonyl-containing isoxazolines. Nonetheless,
benzyl and allyl sulfonyl chlorides and o-toluenesulfonyl chloride were found to be
unsuitable for the reaction, possibly due to stability or steric issues associated
with the corresponding sulfonyl radicals, respectively. As for the utility of this meth-
odology, the isoxazoline unit in the products could be easily cleaved to afford amino
alcohols (Figure 1B). For example, treatment of 3aa under mild reductive conditions
afforded 4 in excellent yield. It features three important functional groups, including
amino, hydroxy, and sulfonyl moieties, and a conserved tertiary stereocenter, which
are prevalent in numerous drugs and bioactive molecules.
Investigation on Internal Alkenes
With regard to the challenging internal alkenes, we initially conducted time-course
experiments on internal alkenyl ketoximes (E)- and (Z)-5a using L7 (see Table 1 for
its structure) as the ligand under the otherwise standard conditions (Figure 2; Tables
S1 and S2). Obvious E-Z isomerization occurred as the reactions started, indicating
fast, reversible addition of sulfonyl radicals to alkenes as reported in literature.49–53
Most importantly, both (E)- and (Z)-5a afforded (5R,2’S)-6aa with the same absolute
configuration as the major product. The results strongly support the involvement of
the same rate- and stereo-determining C–O bond formation step for reactions on
both (E)- and (Z)-5a. And thus, the envisioned Curtin-Hammett kinetic control was
very likely operating under our reaction conditions.
This proof-of-principle result encouraged us to carry out further optimization of re-
action conditions with (E)-5a as the model substrate (Table 2). A screening of a series
of cinchona alkaloid-derived sulfonamide ligands (entries 1–8) revealed L8 (see Ta-
ble 1 for structures) as the optimal one. The corresponding product (5R,2’S)-6aa with
two vicinal stereocenters was obtained in good yield with good stereoselectivity (en-
tries 8 and 9). Interestingly, the use of a 1:1 mixture of (E)- and (Z)-5a as the substrate
gave similar results to that with one pure isomer (entry 10). In addition, the reaction
on internal alkenes also well tolerated a range of different substituents on the ketox-
ime, the alkene, and the sulfonyl moieties. The desired products 6ab, 6ac, and 6ba–
6ia were afforded in 57%–73% yields with good stereoselectivity (Scheme 2). The ab-
solute configuration of (5R,2’S)-6aa has been determined by X-ray crystallographic
analysis (Figure S2), and those of other products were assigned by analogy. Further-
more, cyclic internal alkenes were also viable substrates for the reaction. A series of
chiral spiro-heterocycles 6ja–6la with different skeletons (such as 5–5 and 5–6 spiro
rings) and functionalities (such as carbocycles and a N-containing heterocycle) were
efficiently constructed in good yields with excellent diastereoselectivities (> 20:1 dr)
and good enantioselectivities (up to 92:8 er) (Scheme 2). The absolute configuration
of 6ja has been determined by X-ray crystallographic analysis (Figure S3), and those
of other products were assigned by analogy.
6
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Figure 2. Time-Course Experiments
(A) Time-course experiments were conducted on (E)- and (Z)-5a using L7 (see Table 1 for its structure) as the ligand under the otherwise standard
conditions.
(B) Time-course experimental results on (E)-5a.
(C) Time-course experimental results on (Z)-5a.
Mechanistic Study
Control experiments were conducted to gain further insights into the reaction
mechanism. First, the addition of radical inhibitor 2,2,6,6-tetramethyl-1-piperi-
dinyl-oxy (TEMPO) significantly inhibited the desired reaction for the formation of
3aa (Scheme 3A). Thus, our reaction likely involves a radical mechanism. Interest-
ingly, the other product, 7, was formed in 41% yield, presumably via the generation
of an iminoxyl radical followed by 5-exo-trig cyclization and trap by TEMPO. Such a
mechanism has been consistently invoked for the formation of similar TEMPO-trap-
ped products from b,g-unsaturated ketoximes in literature.83,84 Notably, 7 is
racemic and thus, the presumed iminoxyl radical is likely not a common intermedi-
ate toward the formation of 3aa and 7. Radical clock probe 8 did not afford any
desired oxysulfonylation product under the standard conditions. Instead, it pro-
vided 9 in 10% yield, possibly via tandem radical addition, cyclopropane ring open-
ing, and hydroalkoxylation (Scheme 3B). All of these observations suggest that sul-
fonyl radicals are likely generated in situ, which upon further addition to alkenes
and subsequent C–O bond formation, give rise to the desired oxysulfonylation
products.
Computational Study
In order to gain more insight into the reaction mechanism, we resorted to theoretical
calculations. Two plausible reaction mechanisms, i.e., CuII-CuIII-CuI and CuII-CuI
mechanisms22,23,85–92 (paths A and B in Figure 3 and Figure S4) were proposed
based on the experimental observations and calculated with the density functional
theory (DFT) method. Both pathways start with the deprotonation of b,g-unsaturated
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Table 2. Optimization of Reaction Conditions for Internal Alkenes
Entrya
Ligand
L1
Yield (%)b
Drb
7:1
5:1
6:1
7:1
6:1
7:1
8:1
8:1
4:1
6:1
Erc
1
64
52
60
61
64
66
68
67
40
53
11:89
25:75
13:87
11:89
12:88
89:11
91:9
2
L2
3
L3
4
L4
5
L5
6
L6
7
L7
8
L8
93:7
9d
10e
L8
93:7
L8
93:7
aReaction conditions: (E)-5a (E/Z = 29:1) (0.1 mmol), 2a (0.11 mmol), Cu(OAc)2 (0.01 mmol), ligand
˚
(0.015 mmol) (see Table 1 for structures), Ag2CO3 (0.2 mmol), proton sponge (0.05 mmol), and 4 A MS
(100 mg) in CHCl3 (4 mL) under argon.
bYield and dr were based on 1H NMR analysis of the crude product using CH2Br2 as an internal standard.
cDetermined by chiral HPLC analysis.
d(Z)-5a (Z/E = 50:1) as the substrate.
e(E)-5a:(Z)-5a = 1:1.
ketoxime 1a by CuOAc-L1 complex, affording the Cu-L1-alkene intermediate (INT1).
t
Subsequently, the addition of sulfonyl radical to the alkene via triplet TSA1-S or
t
tTSB1-S generates the a-sulfonyl-alkyl radical (tINTA1-S or INTB1-S). This radical
may attach to the CuII center to form a CuIII complex, which undergoes further reduc-
tive elimination to deliver the oxysulfonylation product and the Cu-L1 catalyst (path
A). Alternatively, it may directly attack the oxygen atom on the CuII–O bond to afford
the product and Cu-L1 (path B). The attempts to locate the transition states of the
intramolecular addition of a-sulfonyl-alkyl radical to the CuII center or the O atom
were unsuccessful. Instead, the minimum energy crossing points (MECPs),93–96
MECP_A-S and MECP_B-S, which connect the triplet a-sulfonyl-alkyl radical and
singlet CuIII complex (sINTA2-S, path A) or CuI species (sINTB2-S, path B), respec-
tively, were located and calculated to be rate-determining. The latter (MECP_B-S)
has a lower electronic energy by 9.0 kcal/mol, which suggests that the CuII-CuI mech-
anism (path B) is likely more favorable.
Computational results suggested that the forward and backward reaction barriers
for the radical addition step are indeed very low (path B: 0.1 kcal/mol,
t
INT1/tTSB1-S; 4.1 kcal/mol, INTB1-S/tTSB1-S), which, in agreement with our
experimental observations, indicates a fast and reversible process. As a result,
the C–O bond formation step should determine the enantioselectivity, which we
analyzed next (Figure 4A). The located MECP_B-S (leading to S product) has a
lower electronic energy than MECP_B-R (leading to R product) by 4.3 kcal/mol,
which is consistent with the experimentally observed S-enantioselectivity with L1
ligand (see Table 1 for its structure). A favorable hydrogen bonding interaction be-
tween the ligand and the substrate was identified in MECP_B-S. Meanwhile, an un-
favorable electrostatic repulsion between oxygen atoms of the sulfonamide ligand
8
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Scheme 2. Substrate Scope for Asymmetric Oxysulfonylation of Internal Alkenes
Reactions were conducted on 0.2 mmol scale, isolated yields were given, and er values were determined by HPLC analysis.
aL6 (see Table 1 for its structure) used as the ligand.
bL8 (see Table 1 for its structure) used as the ligand.
cL1 (see Table 1 for its structure) used as the ligand at RT.
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Scheme 3. Mechanistic Study
and the sulfonyl radical was identified in MECP_B-R by the analysis of electrostatic
potential (ESP) surface (Figure 4B). Computational results suggest that the enantio-
selectivity of this oxysulfonylation reaction on terminal alkenes originates from the
hydrogen bonding interaction and electrostatic repulsion between the substrate
and the ligand.
Figure 3. Calculated Catalytic Cycles for the Copper-Catalyzed Asymmetric 1,2-Oxylsulfonylation of Terminal Alkenes
Calculations were done on 1a with PhSO2Cl as the radical precursor and L1 (see Table 1 for its structure) as the ligand, respectively. Relative free
energies (electronic energies) in kcal/mol are calculated with the DFT method in CHCl3 solvent. The superscripts s and t refer to the singlet and triplet
states, respectively.
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Figure 4. Stereoselectivity Analysis of Reactions on Terminal Alkenes
(A) 3D structures and relative electronic energies (kcal/mol) of MECP_B-S and MECP_B-R.
(B) The electrostatic potential surface of MECP_B-R.
On the basis of the above experimental and computational studies, a working mech-
anism for the asymmetric radical oxysulfonylation reaction was tentatively proposed,
shown in Figure 5. The in situ formed bis-chelating CuI complex A with a strong
reducing capability first undergoes single-electron transfer with sulfonyl chloride
to afford CuII complex B and sulfonyl radical. Next, the CuII complex B reacts with
substrate 1 or 5 via deprotonation, leading to intermediated C. This intermediate
is then reversibly attacked by sulfonyl radical, giving rise to alkyl radical D. Its subse-
quent intramolecular radical substitution reaction delivers CuI-product complex E,
which finally dissociates to give product 3 or 6 and regenerate the CuI complex A.
The stoichiometric amounts of acid and chloride side products are scavenged by
Ag2CO3.
Figure 5. Mechanistic Proposal
Catalytic cycle for asymmetric radical 1,2-oxysulfonylation of both terminal and internal alkenes.
Chem 6, 1–15, July 9, 2020
11

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toximes, Chem (2020), https://doi.org/10.1016/j.chempr.2020.03.024
Conclusions
In summary, we have developed a general and efficient asymmetric radical oxysulfo-
nylation of alkenes in b,g-unsaturated ketoximes using copper(I)-cinchona alkaloid-
based sulfonamide complex as a strong single-electron-reducing catalyst. This
method exhibited a broad scope across a range of both terminal and internal alkenes
as well as diverse (hetero)aryl- or alkyl-substituted sulfonyl chlorides under very mild
conditions. Experimental and computational studies suggested a likely CuII-CuI cat-
alytic cycle with efficient stereodiscrimination under Curtin-Hammett kinetic control.
The sulfonyl-containing isoxazolines could undergo further transformations to pro-
vide valuable building blocks prevalent in numerous bioactive molecules. We antic-
ipate that the present strategy would open a new door for the precise control of di-
astereo- and enantioselectivities in the challenging asymmetric radical-initiated
difunctionalization of internal alkenes.
EXPERIMENTAL PROCEDURES
Full experimental procedures are provided in the Supplemental Information.
DATA AND CODE AVAILABILITY
The data for the X-ray crystallographic structures of 3aj, (5R,2’S)-6aa, and 6ja have
been deposited in the Cambridge Crystallographic Data Center under accession
numbers CCDC: 1957456, 1957457, and 1957458 and can be obtained free of
charge from www.ccdc.cam.ac.uk/getstructures.
SUPPLEMENTAL INFORMATION
Supplemental Information can be found online at https://doi.org/10.1016/j.chempr.
2020.03.024.
ACKNOWLEDGMENTS
This work is dedicated to the heroic city of Wuhan. Financial support from
the National Natural Science Foundation of China (nos. 21722203, 21831002,
21801120, 21803047, and 21933004), Shenzhen Special Funds (no.
JCYJ20170412152435366), Guangdong Provincial Key Laboratory of Catalysis
(No. 2020B121201002), Shenzhen Nobel Prize Scientists Laboratory Project (no.
C17783101), SUSTech Special Fund for the Construction of High-Level Universities
(no. G02216303), the China Postdoctoral Science Foundation (T.W., no.
2019M650147), Warshel Institute for Computational Biology funding (G.-J.C. and
T.W.) from Shenzhen City and Longgang District, and the Shenzhen San-Ming Proj-
ect (no. SZSM201809085) are greatly appreciated.
AUTHOR CONTRIBUTIONS
X.-T.L. performed the condition optimization, investigated the scope of the sub-
strates, and conducted the experimental mechanistic studies. L.L., G.-X.X., Z.-L.L.,
and L.Y. synthesized the alkene substrates and performed the application. T.W. per-
formed the computational study of the mechanism. Q.-S.G. participated in the
design and discussion of the mechanistic experiments. G.-J.C. and X.Z. directed
the computational study. X.-Y.L. directed the project and wrote the manuscript
with input from all authors. All authors analyzed the results and commented on
the manuscript.
12
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toximes, Chem (2020), https://doi.org/10.1016/j.chempr.2020.03.024
DECLARATION OF INTERESTS
The authors declare no competing interests.
Received: October 20, 2019
Revised: February 27, 2020
Accepted: March 30, 2020
Published: April 24, 2020
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