Catalytic Enantioselective Addition of Prochiral Radicals to Vinylpyridines

Article abstract of DOI:10.1021/jacs.9b00286

Pyridine, one of the most important azaarenes, is ubiquitous in functional molecules. The electronic properties of pyridine have been exploited to trigger asymmetric transformations of prochiral species as a direct approach for accessing chiral pyridine derivatives. However, the full potential of this synthetic strategy for the construction of enantioenriched ?-functionalized pyridines remains untapped. Here, we describe the first enantioselective addition of prochiral radicals to vinylpyridines under cooperative photoredox and asymmetric catalysis mediated by visible light. The enantioselective reductive couplings of vinylpyridines with aldehydes, ketones, and imines were achieved by employing a chiral Br?nsted acid to activate the reaction partners and provide stereocontrol via H-bonding interactions. Valuable chiral γ-secondary/tertiary hydroxyl- and amino-substituted pyridines were obtained in high yields with good to excellent enantioselectivities.

Full text of DOI:10.1021/jacs.9b00286

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Article
Catalytic Enantioselective Addition of Prochiral Radicals to Vinylpyridines
Kangning Cao, Siu Min Tan, Richmond Lee, Songwei Yang,
Hongshao Jia, Xiaowei Zhao, Baokun Qiao, and Zhiyong Jiang
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 13 Mar 2019
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Journal of the American Chemical Society
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Catalytic Enantioselective Addition of Prochiral Radicals to
Vinylpyridines
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Kangning Cao,†,‡,¶ Siu Min Tan,§,¶ Richmond Lee,§,¶ Songwei Yang,‡ Hongshao Jia,‡ Xiaowei Zhao,‡
Baokun Qiao,‡ and Zhiyong Jiang*,†,‡
†School of Chemistry and Chemical Engineering, Henan Normal University, Xinxiang, Henan, China 453007
‡Key Laboratory of Natural Medicine and Immuno-Engineering, Henan University, Kaifeng, Henan, China 475004
§Singapore University of Technology and Design, 8 Somapah Road, Singapore 487372
KEYWORDS. Asymmetric Photoredox Catalysis, Hydrogen-Bonding Catalysis, Prochiral Radicals, Reductive Coupling,
Vinylpyridines
ABSTRACT: Pyridine, one of the most important azaarenes, is ubiquitous in functional molecules. The electronic properties
of pyridine have been exploited to trigger asymmetric transformations of prochiral species as a direct approach for accessing
chiral pyridine derivatives. However, the full potential of this synthetic strategy for the construction of enantioenriched γ-
functionalized pyridines remains untapped. Here, we describe the first enantioselective addition of prochiral radicals to
vinylpyridines under cooperative photoredox and asymmetric catalysis mediated by visible light. The enantioselective
reductive couplings of vinylpyridines with aldehydes, ketones and imines were achieved by employing a chiral Brønsted acid
to activate the reaction partners and provide stereocontrol via H-bonding interactions. Valuable chiral γ-secondary/tertiary
hydroxyl- and amino-substituted pyridines were obtained in high yields with good to excellent enantioselectivities.
INTRODUCTION
Scheme 1. Development of an Enantioselective Radical
Addition Protocol to Access γ-Functionalized Pyridines
Pyridine is an important azaarene commonly found in
pharmaceuticals,1 agrochemicals,2 functional materials,3
ligands4 and natural products.5 The synthesis of pyridine-
containing chiral architectures has been the subject of
intense research in recent years.6-7 One widely accepted
protocol for the formation of such species is the
enantioselective functionalization of prochiral pyridines
triggered by the electron-deficient nature of the pyridine. In
addition to the advantage of being direct, this attractive
strategy is well-suited for various ground-up approaches,
allowing the construction of diverse stereocentres at the α-
and β-positions of pyridines.8-15 In particular, in 2015, Wang
and co-workers reported
a chiral secondary amine-
catalysed enantioselective conjugate addition of aldehydes
to 4-vinylpyridines, and this procedure generated γ-tertiary
carbon stereocentres for the first time (Scheme 1a).16 The
combinatorial use of a strong Brønsted acid to activate the
weakly electrophilic vinylpyridines and enamine catalysis
to provide a stereocontrolled environment for nucleophiles
was responsible for the high reactivity and
enantioselectivity. To improve the diversity of the suitable
prochiral nucleophiles, especially for challenging tertiary
variants
to
furnish
important
tetrasubstituted
stereocentres, the development of a more reactive protocol
with a practical stereocontrol strategy is of great interest.
Radical-based transformations are well known to
proceed with high reactivity.17 In recent years, visible-light-
driven photoredox catalysis18-19 has been utilized as a
powerful and sustainable tool in radical chemistry to
accomplish various addition reactions of radical species to
vinylpyridines.20-27 In most cases, an extra catalyst to
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promote the transformation was not necessary, which is
but 3a was obtained in a 62% yield with only 11% ee (see
entry 100, Table S1 in the SI). When the 3-substitutent of
HE-1 was changed to an ethyl ester (HE-2) and to a methyl
Table 1. Optimization of the Reaction Conditionsa
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2
3
4
5
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7
8
consistent with the higher reactivity of these systems
compared to that of the ionic approach.20-24 In addition, the
groups of Melchiorre25 and Ngai26 revealed that both
organic and inorganic acid catalysts could readily activate
less reactive manifolds by interacting with the nitrogen
atom of the pyridine to reduce the energy of the LUMO at
the β-position of the alkene. Brønsted acid catalysis was
recently adopted by the Phipps group and by our group to
develop photoredox asymmetric Minisci-type additions
(Scheme 1a)28 and protonation29 strategies.30-35 While this
catalysis platform has been shown to generate tertiary
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yield
(%)b
93
ee
carbon stereocentres
α
to pyridines with high
entry variation from the standard conditions
(%)c
90
enantioselectivities,28,29,36 the corresponding conjugate
additions of α-amino radicals to alkenylpyridines to
generate β-tertiary stereocentres provided poor
enantioselectivities.25 This result is likely due to the longer
distance between the α-amino radical and the nitrogen-
coordinated chiral catalyst, which reduces the efficacy of
the enantiofacial induction. The formation of even more
distant γ-stereocentres through the analogous conjugate
addition of prochiral radicals to vinylpyridines is therefore
a formidable challenge.
1
None
2
C2 instead of C1
C3 instead of C1
HE-2 instead of HE-1
HE-3 instead of HE-1
iPr2NEt instead of HE-1
[Ru(bpy)3](PF6)2 instead of DPZ
[Ir(ppy)2(dtbbpy)]PF6 instead of DPZ
Eosin Y instead of DPZ
no 3 Å MS
88
15
3
72
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4
31
80
5
25
51
6d
7
N.R.
38
N.A.
66
Among the γ-functionalized pyridines, derivatives with a
secondary or tertiary alcohol or amine at the γ-position are
especially attractive owing to their varied and significant
biological activities (Scheme 1b).37-42 We envisioned that
the enantioselective addition of secondary/tertiary ketyl
and α-aminoalkyl radicals to vinylpyridines would provide
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78
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85
78
no C1
N.R.
N.R.
N.R.
N.R.
N.A.
N.A.
N.A.
N.A.
b
direct
access
to
γ-secondary/tertiary
Single-electron
alcohol-
transfer
functionalized
pyridines.
no DPZ
reductions of aldehydes, ketones and imines under
photoredox catalysis with tertiary amines as the sacrificial
electron/hydrogen donors have been reported to furnish
the corresponding radical species.26,27,32,43-47 As such, we
sought to perform the umpolung-type asymmetric
reductive coupling reactions of aldehydes, ketones and
imines with 2-vinylpyridines by exploring the viability of
chiral Brønsted acid catalysis (Scheme 1b).
no light
Air
aThe reaction was performed on a 0.05-mmol scale. Yields
were determined from the isolated compounds following chro-
matographic purification. Enantiomeric excesses were deter-
c
c
mined by HPLC analysis on a chiral stationary phase. t = 36%
h. bpy = 2,2’-bipyridine, dtbbpy = 4,4’-di-tert-butyl-2,2’-bipyri-
dine, ppy = 2-phenylpyridine. N.R. = no reaction. N. A. = not
available.
RESULTS AND DISCUSSION
(1) Reaction Optimization. We began our investigation by
selecting 2-vinylpyridine (1a) and benzaldehyde (2a) as
model substrates (Table 1). The initial study revealed that
the reaction proceeded well when using our developed
dicyanopyrazine-derived chromophore (DPZ) as the
photoredox catalyst with a catalytic amount of a phosphoric
acid instead of a Lewis acid (see entry 1, Table S1 in the SI).
The results prompted us to examine a range of chiral
phosphoric acids, tertiary amine reductants and reaction
parameters (see Table S1 in the SI). To our delight,
conducting the reaction in a mixture of CHCl3 and C6F5H as
the solvent (v/v = 4:1) at −50 °C for 60 h in the presence of
0.5 mol% DPZ, 8.0 mol% chiral SPINOL-based spirocyclic
chiral phosphoric acid (SPINOL-CPA) C1, 1.5 equiv. of
Hantzsch ester (HE) HE-1 and 35 mg of 3 Å molecular sieves
(MS) as an additive furnished chiral product 3a in 93% yield
and 90% ee (entry 1). The enantioselectivity was influenced
by the substituents at the 6,6’-positions of the SPINOL; for
instance, catalysts C2 and C3 afforded 3a in only 15% ee
and 35% ee, respectively (entries 2−3). The more
conveniently accessible (S)-BINOL-based TRIP-PA (C21)
was also tested under the optimized reaction conditions,
ketone (HE-3), the obtained yields and enantioselectivities
decreased (entries 4−5). The reduced yield stemmed from
the lower reaction rate and the unsatisfactory
chemoselectivity, as an unknown by-product was formed.
Furthermore, no reaction was observed when iPr2NEt was
used instead of HE-1 (entry 6). Other common photoredox
catalysts, such as [Ru(bpy)3](PF6)2, [Ir(ppy)2(dtbbpy)]PF6
and Eosin Y, were also examined (entries 7−9), but no
improvement in the enantioselectivity was observed, and
all isolated yields were lower. In these transformations,
unknown byproducts were detected. More importantly, it
was found that HE-1 was consumed to form the
corresponding pyridine in a faster manner than with DPZ as
the catalyst. In the absence of 3 Å MS, the ee of 3a fell to 78%
(entry 10). Finally, control experiments verified that CPA
C1, DPZ, visible light, and the oxygen-free environment are
essential to the success of the reaction (entries 11−14).
(2) Substrate Scope and Synthetic Applications.
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Table 2. Substrate scope with respect to the aldehydea
was increased to 25 °C , the desired product 3s was obtained
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5
6
in 78% yield after 36 h but with 0% ee. Finally, 3s was
generated in 92% yield and 81% ee when using 10 mol%
SPINOL-CPA C11 (see Table S1 in the SI for its structure)
and performing the reaction at −40 °C .
Table 3. Substrate scope with respect to ketonesa
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aThe reaction was performed on a 0.1-mmol scale. Yields
were determined from the isolated compounds following chro-
matographic purification. Enantiomeric excesses were deter-
mined by HPLC analysis on a chiral stationary phase. b2.0 equiv.
of HE-1 was used. cCHCl3 as the solvent. d10 mol% of C1, tolu-
ene as the solvent, T = −40 °C . e10 mol% of C11, 2.0 equiv. of
HE-1, toluene as the solvent, T = −40 °C , 60 h. Note: under
standard reaction conditions, no reaction was observed; when
T = 25 °C , yield = 78%, ee = 0%, 36 h.
aThe reaction was performed on a 0.1-mmol scale. The yields
were determined from the isolated compounds following chro-
matographic purification. Enantiomeric excesses were deter-
mined by HPLC analysis on a chiral stationary phase. b5.0-mmol
scale, t = 24 h, yield = 85%, ee = 94%. c3.0 equiv. of HE-1 was
used. d15 mol% of C1 was used and t = 36 h. eFor the newly
formed stereocentre, ee = 90%; when a racemic phosphoric
acid (diphenyl phosphate) was used, ee = 0% (i.e., dr = 1:1).
With the optimal reaction conditions in hand, we
examined the scope of this asymmetric reductive coupling
reaction with a wide range of aldehydes and vinylpyridines
for the synthesis of chiral pyridines bearing distinct γ-
secondary alcohols (Table 2). The reactions of 1a with
aromatic aldehydes containing electron-withdrawing or
electron-donating substituents on the aryl ring afforded 3a-
m in 56−90% yields with 87−95% ees. The good chemical
yields and excellent enantioselectivities achieved for
aldehydes with fused aromatic (3k) and heteroaromatic
(3l-m) ring substituents underscore the generality of this
catalytic system. Cinnamaldehyde, a representative α,β-
unsaturated aldehyde, was tested, and it provided 3n in
70% yield with 85% ee, and an alkene was introduced on
the stereogenic centre. Notably, the conditions were not
suitable for alkyl aldehydes (no reaction was observed),
likely because reducing them to the corresponding ketyl
radicals is quite difficult. In addition, no desired product
was observed when using photoredox catalysts with higher
We next attempted to generate an unprecedented and
challenging γ-tetrasubstituted stereocentre in a pyridine
derivative as a demonstration of the practicality and
generality of this radical addition reaction with ketones
(Table 3). Our preliminary study showed that the
transformation of 1a with acetophenone 4a under the
established conditions afforded desired product 5a in only
13% yield with 93% ee. This result prompted us to further
investigate the reaction parameters. Finally, 5a was
obtained in 89% yield and 94% ee when the reaction was
performed in CHCl3 at 5 °C under irradiation with two 3 W
blue LEDs. An array of ketones and 2-vinylpyridines were
subsequently examined, and products 5b-p were generated
in 40−85% yields and 86−94% ees. We were pleased to find
that when this reaction was conducted on a 5.0-mmol scale,
a similar yield and enantioselectivity were achieved (see
footnote b). 2-Fluoroacetophenone afforded corresponding
product 5l, containing an important C(sp3)−F bond, in 64%
yield with 91% ee. More importantly, this γ-tertiary
alcohol−pyridine-based molecular architecture was
successfully embedded in the complex natural product
oestrone (product 5p) via the direct use of an oestrone-
derived ketone as the substrate. In this reaction, the
excellent diastereoselectivity (19:1 dr) appeared to be due
to the chiral catalyst C1, as the racemic phosphoric acid
provided product 5p with 1:1 dr (see footnote e). These
results highlight the synthetic utility of this methodology.
Except for the reported 2-vinylpyridines (5n-o), other
previously tested derivatives and 4-vinylpyridine are not
3+
reduction potentials, such as fac-Ir(ppy)3 and fac-Ir(dF-
ppy)33+. 2-Vinylpyridines containing distinct substituents
on the pyridine ring were then examined. 2-Vinylpyridines
with 3-methyl, 3-fluoro, 4-methyl and 4-methoxy
substituents generated corresponding adducts 3o-r in 50 to
54% yields and 75 to 90% ees. However, no reaction was
observed for alkenes bearing electron-withdrawing groups,
e.g., bromo groups, at the 4-position or various substituents
at the 5- and 6-positions. No reaction was detected when 4-
vinylpyridine was subjected to the standard reaction
conditions (footnote e). When the reaction temperature
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suitable substrates since no reaction was observed. Scheme 2. Modifications of γ-Chiral Amine-Containing
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1
2
Pyridines.
Table 4. Substrate scope with respect to iminesa
3
4
5
6
7
8
9
We explored the application of this catalytic method to
alkenylpyridines by utilizing benzaldehyde (2a) as a
representative reaction partner (Scheme 3). 2-(1-
Phenylvinyl)pyridine (12), an α-branched vinylpyridine,29
was first examined under the reaction conditions depicted
in entry 1, Table 1, and no reaction was observed, indicating
that 12 is less reactive than 1a. When the amount of catalyst
C1 was increased to 15 mol%, the temperature was
increased to −5 °C, and 100 mg of 5 Å MS was used as an
additive, adduct 13 was obtained in 73% yield with 75%
(major diastereomer) and 68% ee (minor diastereomer)
and 2.5:1 dr after 60 h. (E)-2-Styrylpyridine (14),25 a β-
substituted alkenylpyridine, was then tested, and it
exhibited similarly poor reactivity. Moreover, no
enantioselectivity was found when the reaction was
conducted under standard conditions (entry 1, Table 1) but
at 25 °C . The reaction parameters were therefore further
investigated. As a result, desired product 15 was achieved
in 67% yield with 61% (major diastereomer) and 41% ee
(minor diastereomer) and 1.7:1 dr when SPINOL-CPA C6
(see Table S1 in the SI for its structure) was used as the
chiral catalyst. Notably, methyl acrylate was also tested, and
although it could be consumed within 48 h, the reaction was
messy, and no desired reductive coupling product was
observed.
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aThe reaction was performed on a 0.1-mmol scale. Yields
were determined from the isolated compounds following chro-
matographic purification. Enantiomeric excesses were deter-
mined by HPLC analysis on a chiral stationary phase. bT =
−40 °C , t = 45 h. c20 mol% of C33 (See Table S1 in the SI for its
structure), p-xylene as the solvent, T = 10 °C . dToluene as the
solvent, T = −25 °C .
Encouraged by the results achieved with aldehydes and
ketones, we tested imines as potential partners in the
reductive coupling reaction with vinylpyridines (Table 4).
The 2-vinylpyridines were tested first. For aldimines 6
containing 4-ethyoxyl-phenyl as the N-substituent, the
corresponding adducts 8a-c were obtained in 54−65%
yields with 81−89% ees when the transformations were
carried out in the presence of 0.5 mol% of DPZ, 20.0 mol%
of CPA C3 (See Table 1 for its structure), and 2.5 equiv. of
HE-2 in toluene at −50 °C . To access γ-tertiary amines from
ketimines 7, a higher temperature (−5 °C ) and two LEDs as
the energy source were necessary. Products 9a-k, bearing
aryl substituents with different electronic properties and
substitution patterns on the formed stereogenic centre,
were accessed in 50−76% yields with 80 to 99% ees.
Scheme 3. Coupling reactions of alkenylpyridines with
benzaldehyde 2a.
(3) Mechanistic Studies.
Notably, for 2-vinyl-3-methyl pyridine (9j),
a lower
temperature (−40 °C ) was required to achieve a sufficiently
high enantioselectivity. The reductive coupling did not
occur for other 2-vinylpyridines and alkyl-substituted
ketimines. 4-Vinylpyridine was also evaluated, and adducts
9l-m from the transformations with an aldimine and a
ketamine were produced with satisfactory results using the
modified reaction conditions. The transformations of these
products were then explored. As shown in Scheme 2, the
treatment of 9d with N,N’,N’’-trichloroisocyanuric acid
(TCAA) and H2SO4 cleaved the N-protecting group, i.e., the
4-ethyoxyl-phenyl moiety. The resulting free amine 10 was
subsequently converted to the N-Ts-protected product 11
in 65% yield over two steps and with 98% ee.
We next explored the mechanism of this umpolung-type
conjugate addition reaction. Stern−Volmer experiments
with an excitation wavelength of 448 nm showed no
measurable luminescence quenching of *DPZ (Et(S*/S•−) =
+0.91 V vs. SCE, Et(S*/S•+) = −1.17 V vs. SCE in CH3CN) by
red
HE-1 (E1/2 = +0.95 V vs. SCE in CH3CN), benzaldehyde
(2a) (E1/2red = −1.70 V vs. SCE in CH3CN) or 2-vinylpyridine
(1a) (E1/2red = −2.27 V vs. SCE in CH3CN) (in the absence and
presence of a Brønsted acid). The results are similar to
those reported by Ngai in the Lewis acid-catalysed
reductive couplings of aldehydes with 4-vinylpyridines.26
Indeed, their elegant work has included systematic
investigations on the mechanism. Nevertheless, since a
different chiral Brønsted acid catalysis32 was used in our
reaction system, control experiments and theoretical
studies via DFT calculations were carried out to explore the
mechanisms of the onset of the transformations, the
reduction process of carbonyls and the most stable
transition state of the CPA providing the stereocontrol.
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(entries 5 and 6). As depicted in entry 7, the transformation
Scheme 4. Control experiments.
1
2
3
4
5
6
7
8
under the standard reaction conditions furnished 3b in
75% yield with 90% ee. We also evaluated the
transformation using C1 and HE-3 with less steric
hindrance than HE-1 and in the absence of DPZ, and the
transformation still could not work (entry 8). The reaction
under the standard reaction conditions but irradiated by
visible light with emission wavelengths from 474 nm to 505
nm did not furnish 3b (entry 9). In addition, no
homocoupling products of 1a were observed, i.e., linear
hydrodimers and cyclobutane,49 which can exclude the
possibility of the reaction starting from the reduction of
vinylpyridines. All results suggest the high possibility of the
catalytic cycle beginning from the single-electron reduction
of the excited DPZ (*DPZ) with trace HE•, which is generated
from *HE and the carbonyl and imine compounds under
irradiation with visible light. Due to the low temperature,
the DPZ•− engaging in the SET reduction to provide more α-
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carbon
radical
species
becomes
indispensable.
Furthermore, CPA is crucial to promoting the
transformation. Of note, the ee value of 3a at different
reaction times with HE-2 or HE-3 as the reductant was
maintained in both transformations (see SI). As such, we
speculated that the achievement of diverse enantioselective
results when using distinct HEs is likely owing to the
different rates of yielding the corresponding pyridines,
which would affect the H-bonding induction of CPA to
substrates via a ternary transition state (vide infra).
Accordingly, both CPA and PyH+ to perform the exothermic
proton-coupled electron transfer (PCET) in the reduction of
carbonyls, described by Knowles32 and Ngai26 respectively,
are plausible in our reaction systems.
In Ngai’s work, several experiments involving the pinacol
coupling of 2b were performed.26 We repeated these
transformations and evaluated the role of the phosphoric
acid catalyst (Scheme 4A). The pinacol coupling product 16
was obtained in 15% yield when 2b was reacted in the
presence of only HE-1 and irradiated by a 3 W blue LED
(entry 1, the emission wavelengths of the LED light are from
410 nm to 510 nm, see the SI). The addition of a catalytic
amount of DPZ could enhance the yield (entry 2, Scheme
4A). Furthermore, the use of phosphoric acid C34 as a
catalyst also provided a higher yield of 16 (entries 3 and 4,
Scheme 4A). Since excitation of HE-1 to *HE-1 is impossible
at λ > 445 nm, we tested the reaction with a laser line filter
(CWL = 488 ± 2 nm, FWHM = 10 ± 2 nm, the emission
wavelengths are from 474 nm to 505 nm, which can excite
DPZ to *DPZ, see SI). As expected, no reaction was observed
(entry 5, Scheme 4A). These results support the conclusions
of Ngai that photoactivated HE (*HE, Et(S*/S•−) = −2.28 V vs.
SCE)48 is necessary, the HE radical (HE•, E1/2red = −0.76 V vs.
SCE)26 should be generated, DPZ will engage in a SET
process to facilitate the reaction and phosphoric acid can
improve the transformation. The results of the additional
Stern-Volmer experiments using an excitation wavelength
of 415 nm could further manifest these suggestions (See SI).
Subsequently, control experiments for the reaction of 1a
with 2b were carried out (Scheme 4B). Under the standard
reaction conditions but without the catalysts DPZ and CPA
C1 and at 25 °C , the transformation was very sluggish and
provided adduct 3b in 5% yield after 48 h, and product 16
was not observed (entry 1). This chemoselectivity indicates
that conjugate addition was favoured over pinacol coupling
when the radical species derived from 2b encounters a
much higher concentration of 1a. The use of DPZ as a
catalyst can increase the yield to 60% in a shorter time
(entry 2). The presence of both DPZ and CPA C1 furnished
3b in 86% yield with 76% ee after only 1 h (entry 3).
Interestingly, the absence of DPZ presented similar results
(entry 4). When the temperature was decreased to −50 °C ,
no reaction was observed in the absence of either DPZ or C1
Figure 1. Density functional theory modelling of
reduced 2a radical addition to 1a with catalyst C1 and
the proposed mechanisms.
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The relationship between the ee of CPA C1 and the ee of
ACKNOWLEDGEMENTS
1
2
3
4
5
6
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8
product 5a was next evaluated, and a linear correlation was
determined (see SI). It could be concluded that only a single
molecule of the chiral phosphate is involved in the C−C
bond-forming step. We then calculated the transition state
(TS) energies for the radical conjugate addition of reduced
2a to 1a bound to C1 as the catalyst (see Figure 1A), and the
most stable TS, through a cooperative TSB forming R-3a as
the product, is consistent with the experimental results. As
predicted, catalyst C1 provides an enantio-discriminating
environment that favours the R-pathway over the S-
pathway and directs the C−C bond formation between
reduced 2a and 1a through H-bonding. From the above, two
plausible mechanisms with only a difference in the PCET
process are proposed, as depicted in Figure 1B.
Grants from the NSFC (21672052), Innovation Scientists and
Technicians Troop Construction Projects of Henan Province,
the Henan University of Science and Technology Innovation
Team Support Plan (14IRTSTHN006), and Henan University
and Singapore University of Technology and Design
(T1MOE1706 & IDG31800104) are gratefully acknowledged.
Computational resources from the National Supercomputing
Centre (Singapore) are also gratefully acknowledged. We also
appreciate Miss Xinyi Ye and Prof. Choon-Hong Tan (NTU) for
their generous help in the analysis of the HRMS data and Dr.
Yangyang Shen (Columbia University) for constructive
discussions.
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a
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ASSOCIATED CONTENT
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Supporting Information Available: [General information, opti-
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This material is available free of charge via the Internet at
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AUTHOR INFORMATION
Corresponding Author
*chmjzy@henu.edu.cn; jiangzhiyong@htu.edu.cn
Author Contributions
¶These authors contributed equally.
Notes
The authors declare no competing financial interests.
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